AU2002344237B2 - Nucleic Acid Based Modulation of Female Reproductive Diseases and Conditions - Google Patents

Description

NUCLEIC ACID BASED MODULATION OF FEMALE REPRODUCTIVE DISEASES AND CONDITIONS Technical Field of the Invention This invention relates to methods and reagents for the treatment of diseases or s conditions relating to the levels of expression of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor(s). Specifically, the instant invention features nucleic-acid based molecules and methods that modulate the expression of vascular endothelial growth factor and/or vascular endothelial growth factor receptors, such as VEGFR1 and/or VEGFR2, that are useful in preventing, treating, o0 controlling and/or diagnosing disorders and conditions related to angiogenesis, including but not limited to cancer, tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, proliferative diabetic retinopathy, hypoxia-induced angiogenesis, rheumatoid arthritis, psoriasis, wound healing, endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.

Background of the Invention The following is a discussion of relevant art, none of which is admitted to be prior art to the present invention.

[R:\LIBFF]83553spec.doc:gcc WO 02/096927 PCT/US02/17674 2 VEGF, also referred to as vascular permeability factor (VPF) and vasculotropin, is a potent and highly specific mitogen of vascular endothelial cells (for a review see Ferrara, 1993 Trends Cardiovas, Med. 3, 244; Neufeld et al., 1994, Prog. Growth Factor Res. 5, 89).

VEGF-induced neovascularization is implicated in various pathological conditions such as tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, proliferative diabetic retinopathy, hypoxia-induced angiogenesis, rheumatoid arthritis, psoriasis, wound healing and others.

VEGF, an endothelial cell-specific mitogen, is a 34-45 kDa glycoprotein with a wide range of activities that include promotion of angiogenesis, enhancement of vascularpermeability and others. VEGF belongs to the platelet-derived growth factor (PDGF) family of growth factors with approximately 18% homology with the A and B chain of PDGF at the amino acid level. Additionally, VEGF contains the eight conserved cysteine residues common to all growth factors belonging to the PDGF family (Neufeld et al., supra). VEGF protein is believed to exist predominantly as disulfide-linked homodimers; monomers of VEGF have been shown to be inactive (Plouet et al., 1989 EMBO J. 8, 3801).

VEGF exerts its influence on vascular endothelial cells by binding to specific highaffinity cell surface receptors. Covalent cross-linking experiments with 1 25 I-labeled VEGF protein have led to the identification of three high molecular weight complexes of 225, 195 and 175 kDa presumed to be VEGF and VEGF receptor complexes (Vaisman et al., 1990 J.

Biol. Chem. 265, 19461). Based on these studies VEGF-specific receptors of 180, 150 and 130 kDa molecular mass were predicted. In endothelial cells, receptors of 150 and 130 kDa have been identified. The VEGF receptors belong to the superfamily of receptor tyrosine kinases (RTKs) characterized by a conserved cytoplasmic catalytic kinase domain and a hydrophilic kinase sequence. The extracellular domains of the VEGF receptors consist of seven immunoglobulin-like domains that are thought to be involved in VEGF binding functions.

The two most abundant and high-affinity receptors of VEGF are fit-1 (VEGFR1) (finslike tyrosine kinase) cloned by Shibuya et al., 1990 Oncogene 5, 519 and KDR (VEGFR2) (kinase-insert-domain-containing receptor) cloned by Terman et al., 1991 Oncogene 6, 1677.

The murine homolog of KDR, cloned by Mathcws et al., 1991, Proc. Natl. Acad. Sci., USA, 88, 9026, shares 85% amino acid homology with KDR and is termed as flk-1 (fetal liver kinase-1). The high-affinity binding of VEGF to its receptors is modulated by cell surfaceassociated heparin and heparin-like molecules (Gitay-Goren et al., 1992 J. Biol. Chem. 267, 6093).

WO 02/096927 PCT/US02/17674 3 VEGF expression has been associated with several pathological states such as tumor angiogenesis, several forms of blindness, rheumatoid arthritis, psoriasis and others. In addition, a number of studies have demonstrated that VEGF is both necessary and sufficient for neovascularization. Takashita et al., 1995 J Clin. Invest. 93, 662, demonstrated that a single injection of VEGF augmented collateral vessel development in a rabbit model of ischemia. VEGF also can induce neovascularization when injected into the cornea.

Expression of the VEGF gene in CHO cells is sufficient to confer tumorigenic potential to the cells. Kim et al., supra and Millauer et al., supra used monoclonal antibodies against VEGF or a dominant negative form of VEGFR2 receptor to inhibit tumor-induced neovascularization.

During development, VEGF and its receptors are associated with regions of new vascular growth (Millauer et al., 1993 Cell 72, 835; Shalaby et al., 1993 J. Clin. Invest. 91, 2235). Furthermore, transgenic mice lacking either of the VEGF receptors are defective in blood vessel formation and these mice do not survive; VEGFR2 appears to be required for differentiation of endothelial cells, while VEGFR1 appears to be required at later stages of vessel formation (Shalaby et al., 1995 Nature 376, 62; Fung et al., 1995 Nature 376, 66).

Thus, these receptors apparently need to be present to properly signal endothelial cells or their precursors to respond to vascularization-promoting stimuli.

Increasing evidence suggests that the VEGF family may also be involved with both the etiology and maintenance of peritoneal endometriosis. Peritoneal endometriosis is a significant debilitating gynecological problem of widespread prevalence. It is now generally accepted that the pathogenesis of peritoneal endometriosis involves the implantation of exfoliated endometrium. Maintenance of exfoliated endometrial tissue is dependent upon the generation and maintenance of an extensive blood supply both within and surrounding the ectopic tissue.

Endometriosis is a disease affecting an estimated 77 million women and teenagers worldwide. Endometriosis is a leading cause of infertility, chronic pelvic pain and hysterectomy. Endometriosis can be characterized when endometrial tissue (the tissue inside the uterus which builds up and is shed each month during menses) is found outside the uterus, in other areas of the body. The endometrial tissue can respond to hormonal commands each month and break down and bleed. However, unlike the endometrium, these tissue deposits have no way of leaving the body. The result is internal bleeding, degeneration of blood and tissue shed from the growths, inflammation of the surrounding areas, expression of irritating enzymes and formation of scar tissue. In addition, depending on the location of the growths, WO 02/096927 PCT/US02/17674 4 interference with the bowel, bladder, intestines and other areas of the pelvic cavity can occur.

Endometrial tissue has even been found lodged in the skin and at other extrapelvic locations like the arm, leg and even brain.

Currently, the presence of Endometriosis can only be confirmed through surgery such as laparoscopy, but can be suspected based on symptoms, physical findings and diagnostic tests. Endometriosis can be treated in many different ways, both surgically and medically.

Most commonly, surgery will be performed during which the disease will be excised, ablated, fulgarated, cauterized or otherwise removed, and adhesions will also be freed. Surgeries include but are not limited to laparoscopy; laparotomy; presacral and uterosacral and various levels of hysterectomies, where some or all of the reproductive organs are removed. Often, this method will only relieve the symptoms associated with growths on the reproductive organs, not the bowels or kidneys and related areas where Endometriosis can be present.

There are several drugs used to treat Endometriosis that are utilized either alone or in combination with surgery. These include contraceptives, GnRH agonists, and/or synthetic hormones. GnRH agonists are commonly used on women in all stages of the disease and may sometimes have serious side affects. GnRH (gonadotropin releasing hormone) analogues are classified into 2 groups: agonists and antagonists. Agonists are commonly used in the treatment of Endometriosis by suppressing the manufacture of follicle stimulating hormone (FSH) and luteinizing hormone common hormones required in ovulation. When they are not secreted, the body will go into "pseudo-menopause," stalling the growth of more implants. However, these are again only stop-gap measures that can be utilized only for short term intervals. Once the body returns to it's normal state, the Endometriosis will again begin to implant itself.

Angiogenesis is likely to be involved in the pathogenesis of endometriosis. According to the transplantation theory, when the exfoliated endometrium is attached to the peritoneal layer, the establishment of a new blood supply is essential for the survival of the endometrial implant and development of endometriosis (Donnez et al., 1998, Hum. Reprod., 13, 1686- 1690). Endometrial growth and repair after menstruation are associated with profound angiogenesis. Abnormalities in these processes result in excessive or unpredictable bleeding patterns and are common in many women. It is therefore important to understand which factors regulate normal endometrial angiogenesis. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that plays an important role in normal and pathological angiogenesis (Fasciani et al., 2000, Mol. Hum. Reprod., 6, 50-54; Sharkey et al., 2000, J. Clin. Endocrinol. Metab., 85, 402-409). Sources of this factor include the eutopic WO 02/096927 PCT/US02/17674 endometrium, ectopic endometriotic tissue and peritoneal fluid macrophages. Important to its etiology is the correct peritoneal environment in which the exfoliated endometrium is seeded and implants. Established ectopic tissue is then dependent on the peritoneal environment for its survival, an environment that supports angiogenesis. The increasing knowledge of the involvement of the VEGF family in endometriotic angiogenesis raises the possibility of novel approaches to its medical management, with particular focus on the anti-angiogenic control of the action of VEGF (McLaren, 2001, Hum. Reprod. Update, 6, 45-55).

Pavco et al., Intemational PCT Publication No. WO 97/15662, describes methods and reagents for treating diseases or conditions related to levels of vascular endothelial growth factor receptor.

Robinson, International PCT Publication No. WO 95/04142, describes the use of certain antisense oligonucleotides targeted against VEGF RNA to inhibit VEGF expression.

Jellinek et al., 1994 Biochemistry 33, 10450 describe the use of specific VEGF-specific high-affinity RNA aptamers to inhibit the binding of VEGF to its receptors.

Rockwell and Goldstein, International PCT Publication No. WO 95/21868, describe the use of certain anti-VEGF receptor monoclonal antibodies to neutralize the effect of VEGF on endothelial cells.

Pappa, International PCT Publication No. WO 01/32920, describes inhibitors, including certain ribozyme and antisense nucleic acid molecules, of specific genes, including cathepsin D, AEBP-1, stromelysin-3, cystatin B, protease inhibitor 1, sFRP4, gelsolin, IGFBP-3, dual specificity phosphatase 1, PAEP, Ig gamma chain, ferritin, complement component 3, proalpha-1 type II collagen, proline 4-hydroxylase, alpha-2 type I collagen, claudin-4, melanoma adhesion protein, procollagen C-endopeptidase enhancer, nascent-polypeptide-associated complex alpha polypeptide, elongation factor 1 alpha (EF-l-alpha), vitamin D3 hydroxylase, CSRP-1, steroidogenic acute regulatory protein, apolipoprotein E, transcobalamin II, prosaposin, early growth response 1 (EGRI), ribosomal protein S6, adenosine deaminase RNA-specific protein, RAD21, guanine nucleotide binding protein beta polypeptide 2-like 1 (RACK1) and podocalyxin genes which are all differentially expressed in tissues within individual patients with endometriosis.

Labarbera et al., International PCT Publication No. WO 00/73416, describes specific antisense nucleic acid molecules targeting follicle-stimulating hormone receptor.

00 6 Storella et al., International PCT Publication No. WO 99/63116, describes modulators of Prothymosin gene products for treating endometriosis, including certain Sribozymes and antisense nucleic acid molecules.

Summary of the Invention 5 This invention features nucleic acid-based molecules, for example, enzymatic Cc nucleic acid molecules, allozymes, antisense nucleic acids, 2-5A antisense chimeras, triplex forming oligonucleotides, decoy RNA, dsRNA, siRNA, aptamers, and antisense Cc nucleic acids containing nucleic acid cleaving chemical groups, and methods to modulate Svascular endothelial growth factor (VEGF) and/or vascular endothelial growth factor C 10 receptor (VEGFr) gene expression. Non-limiting examples of genes that encode vascular endothelial growth factor receptors of the invention include VEGFR1, VEGFR2 or combinations thereof. In particular, the instant invention features nucleic acid-based molecules and methods that modulate the expression of vascular endothelial growth factor and/or vascular endothelial growth factor receptors, such as VEGFR1 and/or VEGFR2, Is that are useful in preventing, treating, controlling, and/or diagnosing angiogenesis related diseases and conditions, including but not limited to tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and female reproductive disorders and conditions, including but not limited to endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.

According to a first embodiment of the invention, there is provided a compound having Formula II: (SEQ 10 NO: 5978) aaagccGaaAagacaaB-3' wherein each a is a 2'O-methyl adenosine nucleotide, each g is a 2'0 methyl guanosine nucleotide, each c is a 2'O-methyl cytidine nucleotide, each u is a 2'O-methyl uridine nucleotide, each A is an adenosine, each G is a guanosine, each individually represents a phosphorothioate internucleotide linkage, U is a 2'-deoxy-2'-C-allyl uridine, and B is an inverted deoxyabasic moiety.

According to a second embodiment of the invention, there is provided a method of administering to a cell the compound in accordance with the first embodiment of the present invention comprising contacting said cell with the compound under conditions suitable for said administration.

1402527-1:acc 6a In one embodiment, the invention features one or more nucleic acid-based molecules and methods that independently or in combination modulate the expression of gene(s) encoding vascular endothelial growth factor receptors. Specifically, the present invention features nucleic acid molecules that modulate the expression of VEGF (for example Genbank Accession No. NM_003376), VEGFR1 receptor (for example Genbank Accession No. NM_002019), and VEGFR2 receptor (for example Genbank Accession No. NM_002253) that are useful in preventing, treating, controlling, and/or diagnosing tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and female reproductive disorders and conditions, including but not limited to 1402527-1:CC WO 02/096927 PCT/US02/17674 7 endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and menopausal dysfunction.

In one embodiment, the present invention features a compound having Formula I: (SEQ ID NO: 5977) 5' gsasgsnsugcUGAuGagg ccgaaa ggccGaaAgucugB 3' wherein each a is 2'-O-methyl adenosine nucleotide, each g is a 2'-O-methyl guanosine nucleotide, each c is a 2'-O-methyl cytidine nucleotide, each u is a 2'-O-methyl uridine nucleotide, each A is adenosine, each G is guanosine, each s individually represents a phosphorothioate intemuclectide linkage, U is 2'-deoxy-2'-C-allyl uridine, and B is an inverted deoxyabasic moiety. This compound is also referred to as ANGIOZYME

T

ribozyme.

In another embodiment, the present invention features a compound having Formula II: (SEQ ID NO: 5978).

asau ucU GAu Gag gcg aaa gec Gaa Aag aca aB-3' wherein each a is 2'-O-methyl adenosine nucleotide, each g is a 2'-O-methyl guanosine nucleotide, each c is a 2'-O-methyl cytidine nucleotide, each u is a 2'-O-methyl uridine nucleotide, each A is adenosine, each G is guanosine, each s individually represents a phosphorothioate internucleotide linkage, U is 2'-deoxy-2'-C-allyl uridine, and B is an inverted deoxyabasic moiety.

In one embodiment, the invention features a composition comprising a nucleic acid molecule of the invention in a pharmaceutically acceptable carrier. In another embodiment, the invention features a composition comprising a compound of Formula I andior Formula II in a pharmaceutically acceptable carrier or diluent.

In one embodiment, the invention features a method of administering to a cell, for example a mammalian cell, including a human cell, a nucleic acid molecule of the invention comprising contacting the cell with the nucleic acid molecule under conditions suitable for administration, for example in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome. In another embodiment, the invention features a method of administering to a cell, for example a mammalian cell, including a human cell, a compound of Formula I and/or Formula IIcomprising contacting the cell with the compound under WO 02/096927 PCT/US02/17674 8 conditions suitable for administration, for example in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.

In one embodiment, the present invention features a mammalian cell comprising a nucleic acid molecule of the invention, wherein the mammalian cell is, for example, a human cell. In another embodiment, the present invention also features a mammalian cell comprising the compound of Formula I and/or Formula II, wherein the mammalian cell is, for example, a human cell.

In one embodiment, the invention features a method of inhibiting angiogenesis, for example tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, or endometrial neovascularization, in a subject comprising contacting the subject with a nucleic acid molecule of the invention, under conditions suitable for the inlibiion. In another embodiment, the invention features a method of inhibiting angiogenesis, for example tumor angiogenesis, or ocular indications such as diabetic retinopathy, or age related macular degeneration, or endometrial neovascularization, in a subject, comprising contacting the subject with a compound of Formula I and/or Formula II, under conditions suitable for the inhibition.

In another embodiment, the invention features a method of treatment of a subjecthaving an ocular condition associated with the increased level of a VEGF receptor, for example diabetic retinopathy, or age related macular degeneration, comprising contacting cells of the subjectwith a nucleic acid molecule, such as an enzymatic nucleic acid molecule targeted against a VEGF receptor RNA, molecule according to Formula I and/or II, under conditions suitable for the treatment.

In another embodiment, the invention features a method of treatment of a subjecthaving a condition associated with an increased level of VEGR and/or a VEGF receptor, for example tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, ocular diseases or ocular indications such as diabetic retinopathy, or age related macular degeneration, rhuematoid arthritis, psoriasis endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction, comprising contacting cells of the subject with a nucleic acid molecule of the invention, such as a compound of Formula I and/or Formula I, under conditions suitable for the treatment.

In yet another embodiment, the inventive method of treatment further comprises the use of one or more drug therapies under conditions suitable for the treatment. Non-limiting WO 02/096927 PCT/US02/17674 9 examples of other drug therapies that can be used in combination with nucleic acid molecules of the invention include to 5-fluoro uridine, Leucovorin, Irinotecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, or Carboplatin, GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including but not limited to Dcpo-Provera or Provera (medroxyprogesterone acetate), or any other estrogen/progesterone contraceptive.

In one embodiment, the invention features a method of administering to a mammal, for example a human, a nucleic acid molecule of the invention comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome. In another embodiment, the invention features a method of administering to a mammal, for example a human, a compound of Formula I and/or Formula II comprising contacting the mammal with the compound under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.

In one embodiment, the invention features a nucleic acid molecule which down regulates expression of a vascular endothelial growth factor (VEGF) and/or vascular endothelial growth factor receptor (VEGFr) gene, for example, wherein the VEGFr gene comprises VEGFR1 or VEGFR2 and any combination thereof.

In one embodiment, a nucleic acid molecule of the invention, such as an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups, is adapted to treat, control and/or diagnose tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, ocular diseases or ocular indications, such as diabetic retinopathy, or age related macular degeneration, rhuematoid arthritis, psoriasis endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction.

Such nucleic acid molecules are also useful for the prevention of the diseases and conditions including diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, verruca vulgaris, angiofibroma of tuberous sclerosis, port-wine stains, Sturge Wcber syndrome, Kippel-Trenaunay-Weber syndrome, Osler-Weber-Rendu syndrome WO 02/096927 PCT/US02/17674 and other diseases or conditions that are related to the levels of VEGFR1 or VEGFR2 in a cell or tissue.

In another embodiment, the invention features a composition in a pharmaceutically acceptable carrier or diluent, comprising the nucleic acid molecule of the instant invention.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention is adapted for birth control.

In one embodiment, an enzymatic nucleic acid molecule of the invention is in a hammerhead, Inozyme, Zinzyme, DNAzyme, Amberzyme, or G-cleaver configuration.

In one embodiment, an enzymatic nucleic acid molecule of the invention comprises between 8 and 100 bases complementary to RNA of VEGFR1 and/or VEGFR2 gene. In another embodiment, an enzymatic nucleic acid molecule of the invention comprises between 14 and 24 bases complementary to RNA of VEGFR1 and/or VEGFR2 gene.

In one embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein one strand of the RNA is complementary to RNA of a VEGFR1 and/or VEGFR2 gene. In another embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein one strand of the RNA comprises a portion of a sequence of RNA having a VEGFR1 and/or VEGFR2 sequence. In yet another embodiment, a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a non-nucleotide linker. Alternately, a siRNA molecule of the invention comprises a double stranded RNA wherein both strands of RNA are connected by a nucleotide linker, such as a loop or stem loop structure.

In one embodiment, a single strand component of a siRNA molecule of the invention is from about 14 to about 50 nucleotides in length. In another embodiment, a single strand component of a siRNA molecule of the invention is about 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 nucleotides in length. In yet another embodiment, a single strand component of a siRNA molecule of the invention is about 23 nucleotides in length. In one embodiment, a siRNA molecule of the invention is from about 28 to about 56 nucleotides in length. In another embodiment, a siRNA molecule of the invention is about 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, or 52 nucleotides in length. In yet another embodiment, a siRNA molecule of the invention is about 46 nucleotides in length.

WO 02/096927 PCT/US02/17674 11 In one embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention is chemically synthesized.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention comprises at least one 2'-sugar modification.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acids containing nucleic acid cleaving chemical groups of the invention comprises at least one nucleic acid base modification.

In another embodiment, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention comprises at least one phosphate backbone modification.

In one embodiment, the invention features a mammalian cell, for example a human cell, comprising a nucleic acid molecule of the invention.

In another embodiment, the invention features a method of reducing VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 expression or activity in a cell comprising contacting the cell with a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr, under conditions suitable for the reduction.

In another embodiment, a method of treatment of a subject having a condition associated with the level of VEGF and/or VEGFr, such as VEGFRI and/or VEGFR2 is featured, wherein the method further comprises the use of one or more drug therapies under conditions suitable for the treatment.

In one embodiment, the invention features a method for treatment of a subject having tumor angiogenesis, tumor angiogenesis, cancers including but not limited to tumor and cancer types shown under Diagnosis in Table III, ocular diseases or ocular indications such as diabetic retinopathy, or age related macular degeneration, rhuematoid arthritis, psoriasis and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular WO 02/096927 PCT/US02/17674 12 menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction, comprising administering to the subject a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr under conditions suitable for the treatment.

In another embodiment, the invention features a method for birth control in a subject comprising administering to the subject a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr under conditions suitable for the treatment.

In another embodiment, the invention features a method of cleaving RNA encoded by a VEGF, VEGFR1 and/or VEGFR2 gene comprising contacting an enzymatic nucleic acid molecule of the invention having endonuclease activity with RNA encoded by a VEGFR1 and/or VEGFR2 gene under conditions suitable for the cleavage, for example, wherein the cleavage is carried out in the presence of a divalent cation, such as Mg 2 In one embodiment, a nucleic acid molecule of the invention comprises a cap structure, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap structure is at the 5'-end, or 3'-end, or both the 5'-end and the 3'-end of the enzymatic nucleic acid molecule.

In another embodiment, a nucleic acid molecule of the invention comprises a cap structure, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative, wherein the cap structure is at the 5'-end, or 3'-end, or both the 5'-end and the 3'-end of the antisense nucleic acid molecule.

In one embodiment, the invention features an expression vector comprising a nucleic acid sequence encoding at least one nucleic acid molecule of the invention such that the vector allows expression of the nucleic acid molecule.

In another embodiment, the invention features a mammalian cell, for example, a human cellcomprising an expression vector of the invention.

In yet another embodiment, an expression vector of the invention further comprises a sequence for a nucleic acid molecule complementary to RNA encoded by a VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 gene.

WO 02/096927 PCT/US02/17674 13 In one embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more nucleic acid molecules of the invention, which can be the same or different.

In another embodiment, the invention features a method for treatment or control of tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction, comprising administering to a subject a nucleic acid molecule of the invention that modulates the expression and/or activity of VEGF and/or VEGFr, such as an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention, under conditions suitable for the treatment, including administering to the subject one or more other therapies, for example, 5-fluoro uridine, Leucovorin, Irinotecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, or Carboplatin.GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including but not limited to Depo-Provera or Provera (medroxyprogesterone acetate), or any other estrogen/progesterone contraceptive.

In one embodiment, the method of treatment features a nucleic acid molecule of the invention, such as an enzymatic nucleic acid or antisense nucleic acid molecule, that comprises at least five ribose residues, at least ten 2'-O-methyl modifications, and a end modification, such as a inverted abasic moiety. In another embodiment, a nucleic acid molecule of the invention further comprises phosphorothioate linkages on at least three of the terminal nucleotides.

In another embodiment, the invention features a method of administering to a mammal, for example a human, an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention, comprising contacting the mammal with the nucleic acid molecule under conditions suitable for the administration, for example, in the presence of a delivery reagent such as a lipid, cationic lipid, phospholipid, or liposome.

WO 02/096927 PCT/US02/17674 14 In yet another embodiment, the invention features a method of administering to a mammal an enzymatic nucleic acid molecule, antisense nucleic acid molecule, 2-5A antisense chimera, triplex forming oligonucleotide, decoy RNA, dsRNA, siRNA, aptamer, or antisense nucleic acid containing nucleic acid cleaving chemical groups of the invention in conjunction with other therapies, comprising contacting the mammal, for example a human, with the nucleic acid molecule and the other therapy under conditions suitable for the administration.

In another embodiment, other therapies contemplated by the instant invention that can be used in conjunction with the nucleic acid molecules of the instant invention include, but are not limited to, 5-fluoro uridine, Leucovorin, Irinotecan (CAMPTOSAR® or CPT-11 or Camptothecin-11 or Campto), Paclitaxel, or Carboplatin, GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including but not limited to Depo-Provera or Provera (medroxyprogesterone acetate), or other estrogen/progesterone contraceptive.

In one embodiment, the invention features the use of an enzymatic nucleic acid molecule, to down-regulate the expression of VEGFR1 and/or VEGFR2 genes in the treatment or control of tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), or menopausal dysfunction. Such enzymatic nucleic acid molecule can be in the hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and/or DNAzyme motif.

In another embodiment, the invention features the use of an enzymatic nucleic acid moleculeto down-regulate the expression of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 genes, as a method of birth control. Such enzymatic nucleic acid molecule can be in the hammerhead, NCH, G-cleaver, Amberzyme, Zinzyme, and/or DNAzyme motif. In one embodiment, the nucleic acid molecules of the invention have complementarity to the substrate.sequences in Tables V and VI. Examples of enzymatic nucleic acid molecules of the invention are shown in Tables V and VI. Examples of such enzymatic nucleic acid molecules consist essentially of sequences defined in these Tables.

By "inhibit", "down-regulate", or "reduce", it is meant that the expression of the gene, or level of nucleic acids or equivalent nucleic acids encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, such as VEGFR1, VEGFR2 WO 02/096927 PCT/US02/17674 and/or flk-1, is reduced below that observed in the absence of the nucleic acid molecules of the invention. In one embodiment, inhibition, down-regulation or reduction with enzymatic nucleic acid molecule preferably is below that level observed in the presence of an enzymatically inactive or attenuated molecule that is able to bind to the same site on the target nucleic acid, but is unable to cleave that nucleic acid. In another embodiment, inhibition, down-regulation, or reduction with antisense oligonucleotides is preferably below that level observed in the presence of, for example, an oligonucleotide with scrambled sequence or with mismatches. In another embodiment, inhibition, down-regulation, or reduction of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 with the nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.

By "up-regulate" is meant that the expression of a gene, or level of nucleic acids or equivalent nucleic acids encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, such as VEGFR1 and/or VEGFR2, is greater than that observed in the absence of the nucleic acid molecules of the invention. For example, the expression of a gene, such as VEGF and/or VEGFr, such as VEGFRI and/or VEGFR2 gene, can be increased in order to treat, prevent, ameliorate, or modulate a pathological condition caused or exacerbated by an absence or low level of gene expression.

By "modulate" is meant that the expression of a gene, or level of nucleic acids or equivalent nucleic acids encoding one or more proteins or protein subunits, or activity of one or more proteins protein subunit(s) is up-regulated or down-regulated, such that the expression, level, or activity is greater than or less than that observed in the absence of the nucleic acid molecules of the invention.

By "enzymatic nucleic acid molecule" it is meant a nucleic acid molecule which has complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity which is active to specifically cleave a target nucleic acid. That is, the enzymatic nucleic acid molecule is able to intermolecularly cleave a nucleic acid and thereby inactivate a target nucleic acid molecule. These complementary regions allow sufficient hybridization of the enzymatic nucleic acid molecule to the target nucleic acid and thus permit cleavage. One hundred percent complementarity is preferred, but complementarity as low as 50-75% can also be useful in this invention (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al., 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). The nucleic acids can be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such WO 02/096927 PCT/US02/17674 16 as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, aptazyme or aptamer-binding ribozyme, regulatable ribozyme, catalytic oligonucleotides, nucleozyme, DNAzyme, RNA enzyme, endoribonuclease, endonuclease, minizyme, leadzyme, oligozyme or DNA enzyme.

All of these terminologies describe nucleic acid molecules with enzymatic activity. The specific enzymatic nucleic acid molecules described in the instant application are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it has a specific substrate binding site which is complementary to one or more of the target nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving and/or ligation activity to the molecule (Cech et al., U.S. Patent No. 4,987,071; Cech et al., 1988, 260 JAMA 3030).

Several varieties of naturally-occurring enzymatic nucleic acids are known presently.

Each can catalyze the hydrolysis of nucleic acid phosphodiester bonds in trans (and thus can cleave other nucleic acid molecules) under physiological conditions. Table I summarizes some of the characteristics of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target nucleic acid. Such binding occurs through the target binding portion of a enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target nucleic acid. Thus, the enzymatic nucleic acid first recognizes and then binds a target nucleic acid through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target nucleic acid. Strategic cleavage of such a target nucleic acid will destroy its ability to direct synthesis of an encoded protein.

After an enzymatic nucleic acid has bound and cleaved its nucleic acid target, it is released from that nucleic acid to search for another target and can repeatedly bind and cleave new targets. Thus, a single ribozyme molecule is able to cleave many molecules of target nucleic acid. In addition, the ribozyme is a highly specific inhibitor of gene expression, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target nucleic acid, but also on the mechanism of target nucleic acid cleavage. Single mismatches, or base-substitutions, near the site of cleavage can completely eliminate catalytic activity of a ribozyme.

In one embodiment of the inventions described herein, an enzymatic nucleic acid molecule of the invention is formed in a hammerhead or hairpin motif, but can also be formed in the motif of a hepatitis delta virus, group I intron, group II intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA, DNAzymes, NCH cleaving motifs, or G-cleavers. Examples of such hammerhead motifs are described by Dreyfus, supra, Rossi et al., 1992, AIDS Research and Human Retroviruses 8, 183; of hairpin motifs WO 02/096927 PCT/US02/17674 17 by Hampel et al., EP0360257, Hampel and Tritz, 1989 Biochemistry 28, 4929, Feldstein et al., 1989, Gene 82, 53, Haseloff and Gerlach, 1989, Gene, 82, 43, and Hampel et al., 1990 Nucleic Acids Res. 18, 299; Chowrira McSwiggen, US. Patent No. 5,631,359; an examples of a hepatitis delta virus motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; examples of RNase P motifs are described by Guerrier-Takada et al., 1983 Cell 35, 849; Forster and Altman, 1990, Science 249, 783; Li and Altman, 1996, Nucleic Acids Res. 24, 835; examples of Neurospora VS RNA ribozyme motifs are described by Collins (Saville and Collins, 1990 Cell 61, 685-696; Saville and Collins, 1991 Proc. Natl. Acad. Sci. USA 88, 8826-8830; Collins and Olive, 1993 Biochemistry 32, 2795-2799; Guo and Collins, 1995, EMBO. J. 14, 363); examples of Group II introns are described by Griffin et al., 1995, Chem.

Biol. 2, 761; Michels and Pyle, 1995, Biochemistry 34, 2965; Pyle et al., International PCT Publication No. WO 96/22689; an example of a Group I intron is described by.Cech et al., U.S. Patent 4,987,071; and examples of DNAzymes are described by Usman et a., International PCT Publication No. WO 95/11304; Chartrand et al., 1995, NAR 23, 4092; Breaker et al., 1995, Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262, and Beigelman et al., International PCT publication No. WO 99/55857. NCH cleaving motifs are described in Ludwig Sproat, International PCT Publication No. WO 98/58058; and G-cleavers are described in Kore et al., 1998, Nucleic Acids Research 26, 4116-4120 and Eckstein et al., International PCT Publication No. WO 99/16871. Additional motifs such as the Aptazyme (Breaker et al., WO 98/43993), Amberzyme (Beigelman et al., U.S. Serial No. 09/301,511) and Zinzyme (Figure 7) (Beigelman et al., U.S. Serial No. 09/918,728), all included by reference herein including drawings, can also be used in the present invention. These specific motifs or configurations are not limiting in the invention and those skilled in the art will recognize that all that is important in an enzymatic nucleic acid molecule of this invention is that it have a specific substrate binding site which is complementary to one or more of the target gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a RNA cleaving activity to the molecule (Cech et al., U.S.

Patent No. 4,987,071).

By "nucleic acid molecule" as used herein is meant a molecule having nucleotides. The nucleic acid can be single, double, or multiple stranded and can comprise modified or unmodified nucleotides or non-nucleotides or various mixtures and combinations thereof.

By "enzymatic portion" or "catalytic domain" is meant that portion/region of a enzymatic nucleic acid molecule essential for cleavage of a nucleic acid substrate (for example see Figure 6).

WO 02/096927 PCT/US02/17674 18 By "substrate binding arm" or "substrate binding domain" is meant that portion/region of a enzymatic nucleic acid which is able to interact, for example via complementarity able to base-pair with), with a portion of its substrate. Preferably, such complementarity is 100%, but can be less if desired. For example, as few as 10 bases out of 14 can be base-paired (see for example Werner and Uhlenbeck, 1995, Nucleic Acids Research, 23, 2092-2096; Hammann et al., 1999, Antisense and Nucleic Acid Drug Dev., 9, 25-31). Examples of such arms are shown generally in Figures 6-8. That is, these arms contain sequences within a enzymatic nucleic acid which are intended to bring enzymatic nucleic acid and target nucleic acid together through complementary base-pairing interactions. An enzymatic nucleic acid of the invention can have binding arms that are contiguous or non-contiguous and can be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to four nucleotides and of sufficient length to stably interact with the target nucleic acid; preferably 12-100 nucleotides; more preferably 14-24 nucleotides long (see for example Wemer and Uhlenbeck, supra; Hamman et al., supra; Hampel et al., EP0360257; Berzal-Herranz et a., 1993, EMBO J, 12, 2567-73) or between 8 and 14 nucleotides long. If two binding arms are chosen, the design is such that the length of the binding arms are symmetrical each of the binding arms is of the same length; four and four, five and five nucleotides, or six and six nucleotides, or seven and seven nucleotides long) or asymmetrical the binding arms are of different length; three and five, six and three nucleotides; three and six nucleotides long; four and five nucleotides long; four and six nucleotides long; four and seven nucleotides long; and the like).

By "Inozyme" or "NCH" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as NCH Rz in Figure 6 and in Ludwig et al., International PCT Publication No. WO 98/58058 and US Patent Application Serial No.

08/878,640. Inozymes possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NCH/, where N is a nucleotide, C is cytidine and H is adenosine, uridine or cytidine, and represents the cleavage site. H is used interchangeably with X. Inozymes can also possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NCN/, where N is a nucleotide, C is cytidine, and represents the cleavage site. in Figure 6 represents an Inosine nucleotide, preferably a ribo-Inosine or xylo-Inosine nucleoside.

By "G-cleaver" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described as G-cleaver Rz in Figure 6 and in Eckstein et al., US 6,127,173. G-cleavers possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NYN/, where N is a nucleotide, Y is uridine or cytidine and WO 02/096927 PCT/US02/17674 19 represents the cleavage site. G-cleavers can be chemically modified as is generally shown in Figure 6.

By "amberzyme" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in Beigelman et al., International PCT publication No. WO 99/55857 and US Patent Application Serial No. 09/476,387.

Amberzymes possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet NG/N, where N is a nucleotide, G is guanosine, and represents the cleavage site. Amberzymes can be chemically modified to increase nuclease stability through substitutions using modified nucleotides. In addition, differing nucleoside and/or nonnucleoside linkers can be used to substitute the 5'-gaaa-3' loops shown in the figure.

Amberzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide group within its own nucleic acid sequence for activity.

By "zinzyme" motif or configuration is meant, an enzymatic nucleic acid molecule comprising a motif as is generally described in Figure 7 and in Beigelman et al., International PCT publication No. WO 99/55857 and US Patent Application Serial No. 09/918,728.

Zinzymes possess endonuclease activity to cleave nucleic acid substrates having a cleavage triplet including but not limited to YG/Y, where Y is uridine or cytidine, and G is guanosine and represents the cleavage site. Zinzymes can be chemically modified to increase nuclease stability through substitutions as are generally shown in Figure 7, including substituting 2'-O-methyl guanosine nucleotides for guanosine nucleotides. In addition, differing nucleotide and/or non-nucleotide linkers can be used to substitute the 5'-gaaa-2' loop shown in the figure. Zinzymes represent a non-limiting example of an enzymatic nucleic acid molecule that does not require a ribonucleotide group within its own nucleic acid sequence for activity.

By 'DNAzyme' is meant, an enzymatic nucleic acid molecule that does not require the presence of a 2'-OH group within its own nucleic acid sequence for activity. In particular embodiments the enzymatic nucleic acid molecule can have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2'-OH groups. DNAzymes can be synthesized chemically or expressed endogenously in vivo, by means of a single stranded DNA vector or equivalent thereof. An example of a DNAzyme is shown in Figure 8 and is generally reviewed in Usman et al., US patent No., 6,159,714; Chartrand et aL, 1995, NAR 23, 4092; Breaker et al, 1995, Chem. Bio. 2, 655; Santoro et al., 1997, PNAS 94, 4262; Breaker, 1999, Nature Biotechnology, 17, 422-423; and WO 02/096927 PCT/US02/17674 Santoro et. al., 2000, J Am. Chem. Soc., 122, 2433-39. The "10-23" DNAzyme motif is one particular type of DNAzyme that was evolved using in vitro selection, see Santoro et al., supra and as generally described in Joyce et al., US 5,807,718. Additional DNAzyme motifs can be selected for using techniques similar to those described in these references, and hence, are within the scope of the present invention.

By "sufficient length" is meant a nucleic acid molecule of the invention is long enough to provide the intended function under the expected condition. For example, a nucleic acid molecule of the invention needs to be of "sufficient length" to provide stable interaction with a target nucleic acid molecule under the expected binding conditions and environment. In another non-limiting example, for the binding arms of an enzymatic nucleic acid, "sufficient length" means that the binding arm sequence is long enough to provide stable binding to a target site under the expected reaction conditions and environment. The binding arms are not so long as to prevent useful turnover of the nucleic acid molecule.

By "stably interact" is meant interaction of an oligonucleotides with target nucleic acid by forming hydrogen bonds with complementary nucleotides in the target under physiological conditions) that is sufficient to the intended purpose cleavage of target nucleic acid by an enzyme).

By "equivalent" RNA to VEGF, VEGFR1 and/or VEGFR2 is meant to include nucleic acid molecules having homology (partial or complete) to a nucleic acid encoding VEGF, VEGFR1 and/or VEGFR2 proteins or encoding proteins with similar function as VEGF, VEGFR1 and/or VEGFR2 proteins in various organisms, including human, rodent, primate, rabbit, pig, protozoans, fungi, plants, and other microorganisms and parasites. The equivalent nucleic acid sequence also includes, in addition to the coding region, regions such as untranslated region, 3'-untranslated region, introns, intron-exon junction and the like.

By "homology" is meant the nucleotide sequence of two or more nucleic acid molecules is partially or completely identical.

By "antisense nucleic acid", it is meant a non-enzymatic nucleic acid molecule that binds to target nucleic acid by means of RNA-RNA or RNA-DNA or RNA-PNA (protein nucleic acid; Egholm et al., 1993 Nature 365, 566) interactions and alters the activity of the target nucleic acid (for a review, see Stein and Cheng, 1993 Science 261, 1004 and Woolf et al., US patent No. 5,849,902). Typically, antisense molecules are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule WO 02/096927 PCT/US02/17674 21 forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, an antisense molecule can be complementary to two (or even more) noncontiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both. For a review of current antisense strategies, see Schmajuk et al., 1999, J. Biol. Chem., 274, 21783-21789, Delihas et al., 1997, Nature, 15, 751-753, Stein et al., 1997, Antisense N. A. Drug Dev., 7, 151, Crooke, 2000, Methods Enzymol., 313, 3-45; Crooke, 1998, Biotech. Genet. Eng. Rev., 121-157, Crooke, 1997, Ad. Pharmacol., 40, 1-49. In addition, antisense DNA can be used to target nucleic acid by means of DNA-RNA interactions, thereby activating RNase H, which digests the target nucleic acid in the duplex. The antisense oligonucleotides can comprise one or more RNAse H activating region, which is capable of activating RNAse H cleavage of a target nucleic acid. Antisense DNA can be synthesized chemically or expressed via the use of a single stranded DNA expression vector or equivalent thereof By "RNase H activating region" is meant a region (generally greater than or equal to 4- 25 nucleotides in length, preferably from 5-11 nucleotides in length) of a nucleic acid molecule capable of binding to a target nucleic acid to form a non-covalent complex that is recognized by cellular RNase H enzyme (see for example Arrow et al., US 5,849,902; Arrow et al., US 5,989,912). The RNase H enzyme binds to a nucleic acid molecule-target nucleic acid complex and cleaves the target nucleic acid sequence. The RNase H activating region comprises, for example, phosphodiester, phosphorothioate (preferably at least four of the nucleotides are phosphorothiote substitutions; more specifically, 4-11 of the nucleotides are phosphorothiote substitutions); phosphorodithioate, 5'-thiophosphate, or methylphosphonate backbone chemistry or a combination thereof In addition to one or more backbone chemistries described above, the RNase H activating region can also comprise a variety of sugar chemistries. For example, the RNase H activating region can comprise deoxyribose, arabino, fluoroarabino or a combination thereof, nucleotide sugar chemistry. Those skilled in the art will recognize that the foregoing are non-limiting examples and that any combination of phosphate, sugar and base chemistry of a nucleic acid that supports the activity of RNase H enzyme is within the scope of the definition of the RNase H activating region and the instant invention.

By "2-5A antisense chimera" is meant an antisense oligonucleotide containing a phosphorylated 2'-5'-linked adenylate residue. These chimeras bind to target nucleic acid in a sequence-specific manner and activate a cellular 2-SA-dependent ribonuclease which, in turn, cleaves the target nucleic acid (Torrence et al., 1993 Proc. Natl. Acad. Sci. USA 90, 1300; WO 02/096927 PCT/US02/17674 22 Silverman et al., 2000, Methods Enzymol., 313, 522-533; Player and Torrence, 1998, Pharmacol. Ther., 78, 55-113).

By "triplex forming oligonucleotides" is meant an oligonucleotide that can bind to a double-stranded polynucleotide, such as DNA, in a sequence-specific manner to form a triplestrand helix. Formation of such triple helix structure has been shown to inhibit transcription of the targeted gene (Duval-Valentin et al., 1992 Proc. Natl. Acad. Sei. USA 89, 504; Fox, 2000, Curr. Med. Chem., 7, 17-37; Praseuth et. al., 2000, Biochim. Biophys. Acta, 1489, 181- 206).

By "gene" it is meant a nucleic acid that encodes an RNA, for example, nucleic acid sequences including but not limited to structural genes encoding a polypeptide.

The term "complementarity" as used herein refers to the ability of a nucleic acid to form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. In reference to nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its target or complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, enzymatic nucleic acid cleavage, antisense or triple helix inhibition. Determination of binding free energies for nucleic acid molecules is well known in the art (see, Turner et al., 1987, CSH Symp.

Quant. Biol. LII pp.123-133; Frier et al., 1986, Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987, J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule which can form hydrogen bonds Watson-Crick base pairing) with a second nucleic acid sequence 5, 6, 7, 8, 9, 10 out of 10 being 50%, 60%, 70%, 80%, 90%, and 100% complementary). "Perfectly complementary" means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.

By "RNA" is meant a molecule comprising at least one ribonucleotide residue. By "ribonucleotide" or is meant a nucleotide with a hydroxyl group at the 2' position of a (-D-ribo-furanose moiety.

By "nucleic acid decoy molecule", or "decoy" as used herein is meant a nucleic acid molecule that mimics the natural binding domain for a ligand. The decoy therefore competes with the natural binding target for the binding of a specific ligand. For example, it has been shown that over-expression of HIV trans-activation response (TAR) RNA can act as a WO 02/096927 PCT/US02/17674 23 "decoy" and efficiently binds HIV tat protein, thereby preventing it from binding to TAR sequences encoded in the HIV RNA (Sullenger et al., 1990, Cell, 63, 601-608).

By "aptamer" or "nucleic acid aptamer" as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has sequence that is distinct from sequence recognized by the target molecule in its natural setting.

Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid. The target molecule can be any molecule of interest. For example, the aptamer can be used to bind to a ligand binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein.

Similarly, the nucleic acid molecules of the instant invention can bind to VEGFR1 or VEGFR2 receptors to block activity of the receptor. This is a non-limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art, see for example Gold et al., US 5,475,096 and 5,270,163; Gold et al., 1995, Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000, J. Biotechnol., 74, 5; Sun, 2000, Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000, J Biotechnol., 74, 27; Hermann and Patel, 2000, Science, 287, 820; and Jayasena, 1999, Clinical Chemistry, 45, 1628.

The term "double stranded RNA" or "dsRNA" as used herein refers to a double stranded RNA molecule capable of RNA interference "RNAi", including short interfering RNA "siRNA" see for example Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411, 494-498; and Kreutzer et al., International PCT Publication No. WO 00/44895; Zernicka-Goetz et al., International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al., International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps- Depaillette, International PCT Publication No. WO 99/07409; and Li et al., International PCT Publication No. WO 00/44914.

By "nucleic acid sensor molecule" or "allozyme" as used herein is meant a nucleic acid molecule comprising an enzymatic domain and a sensor domain, where the enzymatic nucleic acid domain's ability to catalyze a chemical reaction is dependent on the interaction with a target signaling molecule, such as a nucleic acid, polynucleotide, oligonucleotide, peptide, polypeptide, or protein, for example VEGF, VEGFR1 and/or VEGFR2. The introduction of chemical modifications, additional functional groups, and/or linkers, to the nucleic acid sensor molecule can provide enhanced catalytic activity of the nucleic acid sensor molecule, increased binding affinity of the sensor domain to a target nucleic acid, and/or improved nuclease/chemical stability of the nucleic acid sensor molecule, and are WO 02/096927 PCT/US02/17674 24 hence within the scope of the present invention (see for example Usman et al., US Patent Application No. 09/877,526, George et al., US Patent Nos. 5,834,186 and 5,741,679, Shih et al., US Patent No. 5,589,332, Nathan et al, US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al., International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al., US Patent Application Serial No. 09/205,520).

By "sensor component" or "sensor domain" of the nucleic acid sensor molecule as used herein is meant, a nucleic acid sequence RNA or DNA or analogs thereof) which interacts with a target signaling molecule, for example a nucleic acid sequence in one or more regions of a target nucleic acid molecule or more than one target nucleic acid molecule, and which interaction causes the enzymatic nucleic acid component of the nucleic acid sensor molecule to either catalyze a reaction or stop catalyzing a reaction. In the presence of target signaling molecule of the invention, such as VEGF, VEGFR1 and/or VEGFR2, the ability of the sensor component, for example, to modulate the catalytic activity of the nucleic acid sensor molecule, is inhibited or diminished. The sensor component can comprise recognition properties relating to chemical or physical signals capable of modulating the nucleic acid sensor molecule via chemical or physical changes to the structure of the nucleic acid sensor molecule. The sensor component can be derived from a naturally occurring nucleic acid binding sequence, for example, RNAs that bind to other nucleic acid sequences in vivo.

Alternately, the sensor component can be derived from a nucleic acid molecule (aptamer) which is evolved to bind to a nucleic acid sequence within a target nucleic acid molecule (see for example Gold et al., US 5,475,096 and 5,270,163). The sensor component can be covalently linked to the nucleic acid sensor molecule, or can be non-covalently associated. A person skilled in the art will recognize that all that is required is that the sensor component is able to selectively inhibit the activity of the nucleic acid sensor molecule to catalyze a reaction.

By "target molecule" or "target signaling molecule" is meant a molecule capable of interacting with a nucleic acid sensor molecule, specifically a sensor domain of a nucleic acid sensor molecule, in a manner that causes the nucleic acid sensor molecule to be active or inactive. The interaction of the signaling agent with a nucleic acid sensor molecule can result in modification of the enzymatic nucleic acid component of the nucleic acid sensor molecule via chemical, physical, topological, or conformational changes to the structure of the molecule, such that the activity of the enzymatic nucleic acid component of the nucleic acid sensor molecule is modulated, for example is activated or deactivated. Signaling agents can comprise target signaling molecules such as macromolecules, ligands, small molecules, WO 02/096927 PCT/US02/17674 metals and ions, nucleic acid molecules including but not limited to RNA and DNA or analogs thereof, proteins, peptides, antibodies, polysaccharides, lipids, sugars, microbial or cellular metabolites, pharmaceuticals, and organic and inorganic molecules in a purified or unpurified form, for example VEGF, VEGFR1 and/or VEGFR2.

The term "triplex forming oligonucleotides" as used herein refers to an oligonucleotide that can bind to a double-stranded DNA in a sequence-specific manner to form a triple-strand helix. Formation of such a triple helix structure has been shown to inhibit transcription of a targeted gene (Duval-Valentin et al., 1992 Proc. Natl. Acad. Sci. USA 89, 504; Fox, 2000, Curr. Med. Chem., 7, 17-37; Praseuth et. al., 2000, Biochim. Biophys. Acta, 1489, 181-206).

The nucleic acid molecules that modulate the expression of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 specific nucleic acids, represent a novel therapeutic approach to treat or control a variety of angiogenesis related disorders and conditions, including but not limited to tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), and/or menopausal dysfunction. The nucleic acid molecules that modulate the expression of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 specific nucleic acids also represent a novel approach to control ovulation or embryonic implantation and therefore provide a novel means of birth control.

In one embodiment of the present invention, a nucleic acid molecule of the instant invention can be between 12 and 100 nucleotides in length. An exemplary enzymatic nucleic acid molecule of the invention is shown as Formula I and/or Formula II. For example, enzymatic nucleic acid molecules of the invention are preferably between 15 and nucleotides in length, more preferably between 25 and 40 nucleotides in length, 34, 36, or 38 nucleotides in length (for example see Jarvis et al., 1996, J. Biol. Chem., 271, 29107- 29112). Exemplary DNAzymes of the invention are preferably between 15 and 40 nucleotides in length, more preferably between 25 and 35 nucleotides in length, 29, 30, 31, or 32 nucleotides in length (see for example Santoro et al., 1998, Biochemistry, 37, 13330-13342; Chartrand et al., 1995, Nucleic Acids Research, 23, 4092-4096). Exemplary antisense molecules of the invention are preferably between 15 and 75 nucleotides in length, more preferably between 20 and 35 nucleotides in length, 25, 26, 27, or 28 nucleotides in length (see for example Woolf et al., 1992, PNAS., 89, 7305-7309; Milner et al., 1997, Nature Biotechnology, 15, 537-541). Exemplary triplex forming oligonucleotide molecules of the invention are preferably between 10 and 40 nucleotides in length, more preferably WO 02/096927 PCT/US02/17674 26 between 12 and 25 nucleotides in length, 18, 19, 20, or 21 nucleotides in length (see for example Maher et al., 1990, Biochemistry, 29, 8820-8826; Strobel and Dervan, 1990, Science, 249, 73-75). Those skilled in the art will recognize that all that is required is that the nucleic acid molecule be of length and conformation sufficient and suitable for the nucleic acid molecule to catalyze a reaction contemplated herein. The length of the nucleic acid molecules of the instant invention are not limiting within the general limits stated.

In a preferred embodiment, a nucleic acid molecule that modulates, for example, down-regulates, VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 replication or expression comprises between 8 and 100 bases complementary to a nucleic acid molecule of VEGFR1 and/or VEGFR2. More preferably, a nucleic acid molecule that modulates VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 replication or expression comprises between 14 and 24 bases complementary to a nucleic acid molecule of VEGFR1 and/or VEGFR2.

The invention provides a method for producing a class of nucleic acid-based gene modulating agents which exhibit a high degree of specificity for the nucleic acid of a desired target. For example, a nucleic acid molecule of the invention is preferably targeted to a highly conserved sequence region of target nucleic acids encoding VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 (specifically VEGF, VEGFR1 and/or VEGFR2 genes) such that specific treatment of a disease or condition can be provided with either one or several nucleic acid molecules of the invention. Such nucleic acid molecules can be delivered exogenously to specific tissue or cellular targets as required. Alternatively, the nucleic acid molecules can be expressed from DNA and/or RNA vectors that are delivered to specific cells.

As used in herein "cell" is used in its usual biological sense, and does not refer to an entire multicellular organism. The cell can, for example, be in vitro, in cell culture, or present in a multicellular organism, including,, birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell may be prokaryotic bacterial cell) or eukaryotic mammalian or plant cell).

By "VEGFR1 and/or VEGFR2 proteins" is meant, protein receptor or a mutant protein derivative thereof, having vascular endothelial growth factor receptor activity, for example, having the ability to bind vascular endothelial growth factor and/or having tyrosine kinase activity.

WO 02/096927 PCT/US02/17674 27 By "highly conserved sequence region" is meant, a nucleotide sequence of one or more regions in a target gene does not vary significantly from one generation to the other or from one biological system to the other.

"Angiogenesis" refers to formation of new blood vessels which is an essential process in reproduction, development and wound repair. "Tumor angiogenesis" refers to the induction of the growth of blood vessels from surrounding tissue into a solid tumor. Tumor growth and tumor metastasis are dependent on angiogenesis (for a review see Folkman, 1985 supra; Folkman 1990 J Natl. Cancer Inst., 82, 4; Folkman and Shing, 1992 J. Biol. Chem.

267, 10931).

Angiogenesis plays an important role in other diseases such as arthritis wherein new blood vessels have been shown to invade the joints and degrade cartilage (Folkman and Shing, supra).

"Retinopathy" refers to inflammation of the retina and/or degenerative condition of the retina which may lead to occlusion of the retina and eventual blindness. In "diabetic retinopathy" angiogenesis causes the capillaries in the retina to invade the vitreous resulting in bleeding and blindness which is also seen in neonatal retinopathy (for a review see Folkman, 1985 supra; Folkman 1990 supra; Folkman and Shing, 1992 supra).

Nucleic acid-based inhibitors of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2, expression are useful for the prevention, treatment, and/or control of angiogenesis related disorders and conditions, including but not limited to, tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, and other diseases or conditions that are related to or will respond to the levels of VEGF, VEGFR1 and/or VEGFR2 in a cell or tissue, alone or in combination with other therapies. The reduction of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 expression (specifically VEGF, VEGFRI and/or VEGFR2 gene RNA levels) and thus reduction in the level of the respective protein relieves, to some degree, the symptoms of the disease or condition. Nucleic acid-based inhibitors of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 expression are also useful as birth control agents, for example by inhibition of ovulation or embryonic uterine implantation.

WO 02/096927 PCT/US02/17674 28 The nucleic acid molecules of the invention can be added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection or infusion pump, with or without their incorporation in biopolymers. In preferred embodiments, the nucleic acid inhibitors comprise sequences, which are complementary to polynucleotides, for example DNA and RNA, having VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 sequence.

Triplex molecules of the invention can be provided targeted to DNA target regions, and containing the DNA equivalent of a target sequence or a sequence complementary to the specified target (substrate) sequence. Antisense molecules typically are complementary to a target sequence along a single contiguous sequence of the antisense molecule. However, in certain embodiments, an antisense molecule can bind to substrate such that the substrate molecule forms a loop, and/or an antisense molecule can bind such that the antisense molecule forms a loop. Thus, the antisense molecule can be complementary to two (or even more) non-contiguous substrate sequences or two (or even more) non-contiguous sequence portions of an antisense molecule can be complementary to a target sequence or both.

By "consists essentially of' is meant that the active nucleic acid molecule of the invention, for example, an enzymatic nucleic acid molecule, contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind nucleic acid such that cleavage at the target site occurs. Other sequences can be present which do not interfere with such cleavage. Thus, a core region can, for example, include one or more loop, stem-loop structure, or linker which does not prevent enzymatic activity. Thus, a particular region of a nucleic acid molecule of the invention can be such a loop, stem-loop, nucleotide linker, and/or non-nucleotide linker and can be represented generally as sequence Thus, a core region may, for example, include one or more loop or stem-loop structures which do not prevent enzymatic activity. For example, a core sequence for a hammerhead enzymatic nucleic acid can comprise a conserved sequence, such as 5'-CUGAUGAG-3' and 3' connected by where X is 5'-GCCGUUAGGC-3' (SEQ ID NO 5979), or any other Stem II region known in the art, or a nucleotide and/or non-nucleotide linker. Similarly, for other nucleic acid molecules of the instant invention, such as Inozyme, G-cleaver, amberzyme, zinzyme, DNAzyme, antisense, 2-5A antisense, triplex forming nucleic acid, aptamers, decoy nucleic acids, dsRNA or siRNA, other sequences or non-nucleotide linkers can be present that do not interfere with the function of the nucleic acid molecule.

WO 02/096927 PCT/US02/17674 29 Sequence X can be a linker of 2 nucleotides in length, preferably 3, 4, 5, 6, 7, 8, 9, 20, 26, 30, where the nucleotides can preferably be internally base-paired to form a stem of preferably 2 base pairs. Alternatively or in addition, sequence X can be a non-nucleotide linker. In yet another embodiment, the nucleotide linker X can be a nucleic acid aptamer, such as an ATP aptamer, HIV Rev aptamer (RRE), HIV Tat aptamer (TAR) and others (for a review see Gold et al., 1995, Annu. Rev. Biochem., 64, 763; and Szostak Ellington, 1993, in The RNA World, ed. Gesteland and Atkins, pp. 511, CSH Laboratory Press). A nucleic acid aptamer includes a nucleic acid sequence capable of interacting with a ligand. The ligand can be any natural or a synthetic molecule, including but not limited to a resin, metabolites, nucleosides, nucleotides, drugs, toxins, transition state analogs, peptides, lipids, proteins, amino acids, nucleic acid molecules, hormones, carbohydrates, receptors, cells, viruses, bacteria and others.

In yet another embodiment, the non-nucleotide linker X is as defined herein. The tenn "non-nucleotide" as used herein include either abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, or polyhydrocarbon compounds. Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 18:6353 and Nucleic Acids Res. 1987, 15:3113; Cload and Schepartz, J Am. Chem. Soc. 1991, 113:6324; Richardson and Schepartz, J Am. Chem. Soc. 1991, 113:5109; Ma et al., Nucleic Acids Res.

1993, 21:2585 and Biochemistry 1993, 32:1751; Durand et al., Nucleic Acids Res. 1990, 18:6353; McCurdy et al., Nucleosides Nucleotides 1991, 10:287; Jschke et al., Tetrahedron Lett. 1993, 34:301; Ono et al., Biochemistiy 1991, 30:9914; Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 113:4000, all hereby incorporated by reference herein.

A "non-nucleotide" further means any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine. Thus, in one embodiment, the invention features an enzymatic nucleic acid molecule having one or more non-nucleotide moieties, and having enzymatic activity to cleave an RNA or DNA molecule.

In another aspect of the invention, nucleic acid molecules that interact with target nucleic acid molecules and down-regulate VEGF and/or VEGFr, such as VEGFR1 and/or WO 02/096927 PCT/US02/17674 VEGFR2 (specifically VEGF, VEGFR1 and/or VEGFR2 gene) activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Enzymatic nucleic acid molecule or antisense expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. The recombinant vectors capable of expressing the enzymatic nucleic acid molecules or antisense are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of enzymatic nucleic acid molecules or antisense. Such vectors can be repeatedly administered as necessary. Once expressed, the enzymatic nucleic acid molecules or antisense bind to the target nucleic acid and down-regulate its function or expression.

Delivery of enzymatic nucleic acid molecule or antisense expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells explanted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector.

By "vectors" is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.

By "subject" or "patient" is meant an organism, which is a donor or recipient of explanted cells, or the cells themselves. "Subject" or "Patient" also refers to an organism to which the nucleic acid molecules of the invention can be administered. Preferably, a subject or patient is a mammal or mammalian cells. More preferably, a subject or patient is a human or human cells.

By "enhanced enzymatic activity" is meant to include activity measured in cells and/or in vivo where the activity is a reflection of both the catalytic activity and the stability of the nucleic acid molecules of the invention. In this invention, the product of these properties can be increased in vivo compared to an all RNA enzymatic nucleic acid or all DNA enzyme. In some cases, the activity or stability of the nucleic acid molecule can be decreased less than ten-fold), but the overall activity of the nucleic acid molecule is enhanced, in vivo.

The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other drugs, can be used to treat diseases or conditions discussed above.

For example, to treat a disease or condition associated with the levels of VEGFR1 and/or VEGFR2, the patient can be treated, or other appropriate cells can be treated, as is evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.

WO 02/096927 PCT/US02/17674 31 In a further embodiment, the described molecules of the invention can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described molecules can be used in combination with one or more known therapeutic agents to treat angiogenesis related disorders and conditions, including but not limited to tumor angiogenesis, cancers such as breast cancer, lung cancer, colorectal cancer, renal cancer, pancreatic cancer, or melanoma, or ocular indications such as diabetic retinopathy, or age related macular degeneration, and/or endometriosis, birth control, endometrial tumors, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, endometrial carcinoma, and/or other diseases or conditions which respond to the modulation of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 expression.

Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.

Brief Description of the Drawings Figure 1 shows a secondary structure model of ANGIOZYMETM ribozyme bound to its RNA target.

Figure 2 shows a time course of inhibition of primary tumor growth following systemic administration of ANGIOZYMETM in the LLC mouse model.

Figure 3 shows inhibition of primary tumor growth following systemic administration of ANGIOZYMETM according to a certain dosing regimen in the LLC mouse model.

Figure 4 shows a dose-dependent inhibition of tumor metastases following systemic administration of ANGIOZYMETM in a mouse colorectal model.

Figure 5 is a graph showing the plasma concentration profile of ANGIOZYMETM after a single subcutaneous (SC) dose of 10, 30, 100 or 300 mg/m 2 Figure 6 shows examples of chemically stabilized ribozyme motifs. HH Rz, represents hammerhead ribozyme motif (Usman et al., 1996, Curr. Op. Struct. Bio., 1, 527); NCH Rz represents the NCH ribozyme motif (Ludwig et al,, International PCT Publication No. WO 98/58058 and US Patent Application Serial No. 08/878,640); G-Cleaver, represents Gcleaver ribozyme motif (Kore et al., 1998, Nucleic Acids Research 26, 4116-4120, Eckstein et WO 02/096927 PCT/US02/17674 32 al., US 6,127,173). N or n, represent independently a nucleotide which can be same or different and have complementarity to each other; rI, represents ribo-Inosine nucleotide; arrow indicates the site of cleavage within the target. Position 4 of the HH Rz and the NCH Rz is shown as having 2'-C-allyl modification, but those skilled in the art will recognize that this position can be modified with other modifications well known in the art, so long as such modifications do not significantly inhibit the activity of the ribozyme.

Figure 7 shows an example of a Zinzyme A ribozyme motif that is chemically stabilized (see for example Beigelman et al., International PCT publication No. WO 99/55857 and US Patent Application Serial No. 09/918,728).

Figure 8 shows an example of a DNAzyme motif described by Santoro et al., 1997, PNAS, 94, 4262 and Joyce et al., US 5,807,718 Figure 9 shows data demonstrating the inhibition of soluble VEGFR1 in a clinical study using ANGIOZYME (SEQ ID NO: 5977).

Figure 10 shows an generalized outline for the mouse model of proliferative retinopathy showing the points of ribozyme administration.

Figure 11 shows a graph demonstrating the efficacy of a VEGF-receptor-targeted enzymatic nucleic acid molecule in a mouse model of proliferative retinopathy.

Detailed Description of the Invention Nucleic Acid Molecules and Mechanism of Action Enzymatic Nucleic Acid: Several varieties of naturally-occurring enzymatic nucleic acids are presently known. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, Proc. R. Soc. London, B 205, 435) have been used to evolve new nucleic acid catalysts capable of catalyzing cleavage and ligation of phosphodiester linkages (Joyce, 1989, Gene, 82, 83-87; Beaudry et al., 1992, Science 257, 635-641; Joyce, 1992, Scientific American 267, 90-97; Breaker et al., 1994, TIBTECH 12, 268; Bartel et al.,1993, Science 261:1411-1418; Szostak, 1993, TIBS 17, 89-93; Kumar et al., 1995, FASEB 9, 1183; Breaker, 1996, Curr.

Op. Biotech., 7, 442; Santoro et al., 1997, Proc. Natl. Acad. Sci., 94, 4262; Tang et al., 1997, RNA 3, 914; Nakamaye Eckstein, 1994, supra; Long Uhlenbeck, 1994, supra; Ishizaka et al., 1995, supra; Vaish et al., 1997, Biochemistry 36, 6495; all of these are incorporated by reference herein). Each can catalyze a series of reactions including the hydrolysis of WO 02/096927 PCT/US02/17674 33 phosphodiester bonds in trans (and thus can cleave other nucleic acid molecules) under physiological conditions.

The enzymatic nature of an enzymatic nucleic acid molecule has significant advantages, one advantage being that the concentration of enzymatic nucleic acid molecule necessary to affect a therapeutic treatment is lower. This advantage reflects the ability of the enzymatic nucleic acid molecule to act enzymatically. Thus, a single enzymatic nucleic acid molecule is able to cleave many molecules of target nucleic acid. In addition, the enzymatic nucleic acid molecule is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target nucleic acid, but also on the mechanism of target nucleic acid cleavage. Single mismatches, or basesubstitutions, near the site of cleavage can be chosen to completely eliminate catalytic activity of a enzymatic nucleic acid molecule.

Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate nucleic acid molecules in a nucleotide base sequence-specific manner. With the proper design, such enzymatic nucleic acid molecules can be targeted to RNA transcripts, and achieve efficient cleavage in vitro (Zaug et al., 324,.Nature 429 1986; Uhlenbeck, 1987 Nature 328, 596; Kim et al., 84 Proc. Natl. Acad. Sci. USA 8788, 1987; Dreyfus, 1988, Einstein Quart. J. Bio. Med., 6, 92; Haseloff and Gerlach, 334 Nature 585, 1988; Cech, 260 JAMA 3030, 1988; and Jefferies et al., 17 Nucleic Acids Research 1371, 1989; Santoro et al., 1997 supra).

Because of their sequence specificity, trans-cleaving enzymatic nucleic acid molecules can be used as therapeutic agents for human disease (Usman McSwiggen, 1995 Ann. Rep.

Med. Chem. 30, 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037).

Enzymatic nucleic acid molecules can be designed to cleave specific nucleic acid targets within the background of cellular nucleic acid. Such a cleavage event renders the nucleic acid non-functional and abrogates protein expression from that nucleic acid. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited (Warashina et al., 1999, Chemistry and Biology, 6, 237-250).

Enzymatic nucleic acid molecules of the invention that are allosterically regulated ("allozymes") can be used to down-regulate VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2, expression. These allosteric enzymatic nucleic acids or allozymes (see for example Usman et al., US Patent Application No. 09/877,526, George et al., US Patent Nos.

5,834,186 and 5,741,679, Shih et al., US Patent No. 5,589,332, Nathan et al., US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker WO 02/096927 PCT/US02/17674 34 et al., International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al., US Patent Application Serial No. 09/205,520) are designed to respond to a signaling agent, for example, mutant VEGFR1 and/or VEGFR2 protein, wild-type VEGFR1 and/or VEGFR2 protein, mutant VEGFR1 and/or VEGFR2 RNA, wild-type VEGFR1 and/or VEGFR2 RNA, other proteins and/or RNAs involved in VEGF signal transduction, compounds, metals, polymers, molecules and/or drugs that are targeted to VEGFR1 and/or VEGFR2 expression, which in turn modulates the activity of the enzymatic nucleic acid molecule. In response to interaction with a predetermined signaling agent, the activity of the allosteric enzymatic nucleic acid is activated or inhibited such that the expression of a particular target is selectively down-regulated. The target can comprise wild-type VEGFR1 and/or VEGFR2, mutant VEGFR1 and/or VEGFR2, and/or a predetermined component of the VEGF signal transduction pathway. In a specific example, allosteric enzymatic nucleic acid molecules that are activated by interaction with a RNA encoding VEGF protein are used as therapeutic agents in vivo. The presence of RNA encoding the VEGF protein activates the allosteric enzymatic nucleic acid molecule that subsequently cleaves the RNA encoding a VEGFR1 and/or VEGFR2 protein resulting in the inhibition of VEGFR1 and/or VEGFR2 protein expression.

In another non-limiting example, an allozyme can be activated by a VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 protein, peptide, or mutant polypeptide that causes the allozyme to inhibit the expression of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 genes, by, for example, cleaving RNA encoded by VEGF, VEGFR1 and/or VEGFR2 gene. In this non-limiting example, the allozyme acts as a decoy to inhibit the function of VEGF, VEGFR1 and/or VEGFR2 and also inhibit the expression of VEGF, VEGFR1 and/or VEGFR2 once activated by the VEGF, VEGFR1 and/or VEGFR2 protein.

Antisense: Antisense molecules can be modified or unmodified RNA, DNA, or mixed polymer oligonucleotides and primarily function by specifically binding to matching sequences resulting in inhibition of peptide synthesis (Wu-Pong, Nov 1994, BioPharm, 33). The antisense oligonucleotide binds to target RNA by Watson Crick base-pairing and blocks gene expression by preventing ribosomal translation of the bound sequences either by steric blocking or by activating RNase H enzyme. Antisense molecules can also alter protein synthesis by interfering with RNA processing or transport from the nucleus into the cytoplasm (Mukhopadhyay Roth, 1996, Crit. Rev. in Oncogenesis 7, 151-190).

In addition, binding of single stranded DNA to RNA can result in nuclease degradation of the heteroduplex (Wu-Pong, supra; Crooke, supra). To date, the only backbone modified WO 02/096927 PCT/US02/17674 DNA chemistry which act as substrates for RNase H are phosphorothioates, phosphorodithioates, and borontrifluoridates. Recently it has been reported that 2'-arabino and 2'-fluoro arabino- containing oligos can also activate RNase H activity.

A number of antisense molecules have been described that utilize novel configurations of chemically modified nucleotides, secondary structure, and/or RNase H substrate domains (Woolf et al, International PCT Publication No. WO 98/13526; Thompson et al., International PCT Publication No. WO 99/54459; Hartmann et al., USSN 60/101,174 which was filed on September 21, 1998) all of these are incorporated by reference herein in their entirety.

In addition, antisense deoxyoligoribonucleotidcs can be used to target RNA by means of DNA-RNA interactions, thereby activating RNase H, which digests the target RNA in the duplex. Antisense DNA can be expressed via the use of a single stranded DNA intracellular expression vector or equivalents and variations thereof.

Triplex Forming Oligonucleotides (TFO): Single stranded DNA can be designed to bind to genomic DNA in a sequence specific manner. TFOs are comprised ofpyrimidine-rich oligonucleotides which bind DNA helices through Hoogsteen Base-pairing (Wu-Pong, supra). The resulting triple helix composed of the DNA sense, DNA antisense, and TFO disrupts RNA synthesis by RNA polymerase. The TFO mechanism can result in gene expression or cell death since binding can be irreversible (Mukhopadhyay Roth, supra).

2-5A Antisense Chimera: The 2-5A system is an interferon mediated mechanism for RNA degradation found in higher vertebrates (Mitra et al., 1996, Proc Nat Acad Sci USA 93, 6780-6785). Two types of enzymes, 2-5A synthetase and RNase L, are required for RNA cleavage. The 2-5A synthetases require double stranded RNA to form oligoadenylates 2-5A then acts as an allosteric effector for utilizing RNase L which has the ability to cleave single stranded RNA. The ability to form 2-5A structures with double stranded RNA makes this system particularly useful for inhibition of viral replication.

oligoadenylate structures can be covalently linked to antisense molecules to form chimeric oligonucleotides capable of RNA cleavage (Torrence, supra). These molecules putatively bind and activate a 2-5A dependent RNase, the oligonucleotide/enzyme complex then binds to a target RNA molecule which can then be cleaved by the RNase enzyme.

WO 02/096927 PCT/US02/17674 36 RNAi: Double-stranded RNAs can suppress expression of homologous genes through an evolutionarily conserved process named RNA interference (RNAi) or post-transcriptional gene silencing (PTGS). One mechanism underlying silencing is the degradation of target mRNAs by an RNP complex, which contains short interfering RNAs (siRNAs) as guides to substrate selection. Short interfering RNAs are typically 21 to 23 nucleotides in length. A bidentate nuclease called Dicer has been implicated as the protein responsible for siRNA production. For example, a double-stranded RNA (dsRNA) matching a gene sequence is synthesized in vitro and introduced into a cell. The dsRNA feeds into a biological pathway and is broken into short pieces of short interfering (si) RNAs. With the help of cellular enzymes such as Dicer, the siRNA triggers the degradation of the messenger RNA that matches its sequence (see for example Tuschl et al., International PCT Publication No. WO 01/75164; Bass, 2001, Nature, 411, 428-429; Elbashir et al., 2001, Nature, 411,494-498; and Kreutzer et al., International PCT Publication No. WO 00/44895).

Taret sites Targets for useful nucleic acid molecules of the invention, such as enzymatic nucleic acid molecules, dsRNA, and antisense nucleic acids can be determined as disclosed in Draper et al., WO 93/23569; Sullivan et al., WO 93/23057; Thompson et al., WO 94/02595; Draper et al., WO 95/04818; McSwiggen et al., US Patent No. 5,525,468, and hereby incorporated by reference herein in totality. Other examples include the following PCT applications, which concern inactivation of expression of disease-related genes: WO 95/23225, WO 95/13380, WO 94/02595, incorporated by reference herein. Rather than repeat the guidance provided in those documents here, below are provided specific examples of such methods, not limiting to those in the art. Enzymatic nucleic acid molecules and antisense to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described. The sequences of human VEGF, VEGFR1 and/or VEGFR2 RNAs are screened for optimal nucleic acid target sites using a computer-folding algorithm.

Potential nucleic acid binding/cleavage sites are identified. While human sequences can be screened and nucleic acid molecules thereafter designed, as discussed in Stinchcomb et al., WO 95/23225, mouse targeted enzymatic nucleic acid molecules can be useful to test efficacy of action of the nucleic acid molecule prior to testing in humans.

Nucleic acid molecule binding/cleavage sites are identified, for example enzymatic nucleic acid, antisense, and dsRNA mediated binding sites are chosen. For enzymatic nucleic acid molecules of the invention, the nucleic acid molecules are individually analyzed by computer folding (Jaeger et al., 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether WO 02/096927 PCT/US02/17674 37 the sequences fold into the appropriate secondary structure. Those nucleic acid molecules with unfavorable intramolecular interactions such as between the binding arms and the catalytic core can be eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity.

Nucleic acids, such as antisense, RNAi, and/or enzymatic nucleic acid molecule binding/cleavage sites are identified and are designed to anneal to various sites in the nucleic acid target. The binding arms of enzymatic nucleic acid molecules of the invention are complementary to the target site sequences described above. Antisense and RNAi sequences are designed to have partial or complete complementarity to the nucleic acid target. The nucleic acid molecules can be chemically synthesized. The method of synthesis used follows the procedure for normal DNA/RNA synthesis as described below and in Usman et al., 1987 J. Am. Chem. Soc., 109, 7845; Scaringe et al, 1990 Nucleic Acids Res., 18, 5433; and Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684; Caruthers et al., 1992, Methods in Enzymology 211,3-19.

Synthesis of Nucleic acid Molecules Synthesis of nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs ("small refers to nucleic acid motifs less than about 100 nucleotides in length, preferably less than about 80 nucleotides in length, and more preferably less than about 50 nucleotides in length; antisense oligonucleotides, enzymatic nucleic acids, aptamers, allozymes, decoys, siRNA etc.) are preferably used for exogenous delivery.

The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of RNA structure. Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.

DNA Oligonucleotides are synthesized using protocols known in the art as described in Caruthers et al., 1992, Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997, Methods Mol. Bio., 74, 59, Brennan et al, 1998, Biotechnol Bioeng., 61, 33-45, and Brennan, US patent No. 6,001,311. All of these references are incorporated herein by reference. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 pmol scale protocol with a 2.5 min coupling step for 2'-O-methylated nucleotides and a 45 sec coupling step for 2'-deoxy nucleotides. Table II WO 02/096927 PCT/US02/17674 38 outlines the amounts and the contact times of the reagents used in the synthesis cycle.

Alternatively, syntheses at the 0.2 jumol scale can be performed on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 gL of 0.11 M 6.6 jtmol) of 2'-O-methyl phosphoramidite and a 105-fold excess of S-ethyl tetrazole (60 IL of 0.25 M 15 tmol) can be used in each coupling cycle of 2'-O-methyl residues relative to polymer-bound hydroxyl. A 22-fold excess (40 gL of 0.11 M 4.4 imol) of deoxy phosphoramidite and a excess of S-ethyl tetrazole (40 pL of 0.25 M 10 tmol) can be used in each coupling cycle of deoxy residues relative to polymer-bound 5'-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and acetic anhydride/10% 2,6-1utidine in THF (ABI); and oxidation solution is 16.9 mM 12, 49 mM pyridine, 9% water in THF (PERSEPTIVE

M

Burdick Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc.

Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2- Benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.

Deprotection of the DNA polynucleotides is performed as follows: the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 aC for 10 min. After cooling to -20 oC, the supernatant is removed from the polymer support. The support is washed three times with mL of EtOH:MeCN:H20/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder.

The method of synthesis used for RNA oligonucleotides including certain nucleic acid molecules of the invention follows the procedure as described in Usman et al., 1987, J Am.

Chem. Soc., 109, 7845; Scaringe et al., 1990, Nucleic Acids Res., 18, 5433; and Wincott et al., 1995, Nucleic Acids Res. 23, 2677-2684 Wincott et al., 1997, Methods Mol Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 umol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a min coupling step for 2'-O-methylated nucleotides. Table II outlines the amounts and the WO 02/096927 PCT/US02/17674 39 contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 pmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, CA) with minimal modification to the cycle. A 33-fold excess (60 L of 0.11 M 6.6 tmol) of 2'-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 ptL of 0.25 M 15 gmol) can be used in each coupling cycle of 2'-O-methyl residues relative to polymer-bound 5'-hydroxyl. A 66-fold excess (120 PL of 0.11 M 13.2 pmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 iL of 0.25 M 30 imol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5'-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include; detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM I2, 49 mM pyridine, 9% water in THF (PERSEPTIVE

TM

Burdick Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-Benzodithiol-3-one 1,1dioxide0.05 M in acetonitrile) is used.

Deprotection of the RNA is performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65 OC for min. After cooling to -20 oC, the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H20/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder. The base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 iL of a solution of 1.5 mL Nmethylpyrrolidinone, 750 pL TEA and 1 mL TEA*3HF to provide a 1.4 M HF concentration) and heated to 65 After 1.5 h, the oligomer is quenched with 1.5 M NH 4

HCO

3 Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO: 1/1 (0.8 mL) at 65 "C for 15 min. The vial is brought to r.t. TEA-3HF (0.1 mL) is added and the vial is heated at 65 °C for 15 min. The sample is cooled at -20 °C and then quenched with 1.5 M NH 4

HCO

3 WO 02/096927 PCT/US02/17674 For purification of the trityl-on oligomers, the quenched NH4HC0 3 solution is loaded onto a C-18 containing cartridge that had been prcwashed with acetonitrile followed by mM TEAA. After washing the loaded cartridge with water, the RNA is detritylated with TFA for 13 min. The cartridge is then washed again with water, salt exchanged with 1 M NaC1 and washed with water again. The oligonucleotide is then eluted with acetonitrile.

Inactive hammerhead ribozymes or binding attenuated control (BAC) oligonucleotides) are synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. et al., 1992, Nucleic Acids Res., 20, 3252). Similarly, one or more nucleotide substitutions can be introduced in other enzymatic nucleic acid molecules to inactivate the molecule and such molecules can serve as a negative control.

The average stepwise coupling yields are typically >98% (Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96 well format, all that is important is the ratio of chemicals used in the reaction.

Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example by ligation (Moore et aL, 1992, Science 256, 9923; Draper et al., International PCT publication No. WO 93/23569; Shabarova et al., 1991, Nucleic Acids Research 19, 4247; Bellon et al., 1997, Nucleosides Nucleotides, 16, 951; Bellon et al., 1997, Bioconjugate Chem. 8, 204).

Preferably, the nucleic acid molecules of the present invention are modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2'-amino, 2'- C-allyl, 2'-flouro, 2'-O-methyl, 2'-H (for a review see Usman and Cedergren, 1992, TIBS 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163). Ribozymes are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., Supra, the totality of which is hereby incorporated herein by reference) and are re-suspended in water.

Optimizing Activity of the nucleic acid molecule of the invention.

Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases can increase their potency (see Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991, Science 253, 314; Usman and Cedergren, 1992, Trends WO 02/096927 PCT/US02/17674 41 in Biochem. Sci. 17, 334; Usman et al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, US Patent No. 5,334,711; Gold et al., US 6,300,074; and Burgin et al., supra; all of which are incorporated by reference herein). Modifications which enhance their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired. (All these publications are hereby incorporated by reference herein).

There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'-O-methyl, 2'-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992, TIBS. 17, 34; Usman et al., 1994, Nucleic Acids Symp. Ser. 31, 163; Burgin et al., 1996, Biochemistry, 14090). Sugar modification of nucleic acid molecules have been extensively described in the art (see Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al.

Nature, 1990, 344, 565-568; Pieken et al. Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci. 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, US Patent No. 5,334,711 and Beigelman et al., 1995, J Biol. Chem., 270, 25702; Beigelman et al., International PCT publication No. WO 97/26270; Beigelman et al., US Patent No. 5,716,824; Usman et al., US patent No.

5,627,053; Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., USSN 60/082,404 which was filed on April 20, 1998; Karpeisky et al., 1998, Tetrahedron Lett., 39, 1131; Earnshaw and Gait, 1998, Biopolymers (Nucleic acid Sciences), 48, 39-55; Verma and Eckstein, 1998, Annu. Rev. Biochem., 67, 99-134; and Burlina et al., 1997, Bioorg. Med. Chem., 5, 1999-2010; all of the references are hereby incorporated in their totality by reference herein). Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into ribozymes without inhibiting catalysis, and are incorporated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the nucleic acid molecules of the instant invention.

While chemical modification of oligonucleotide intemucleotide linkages with phosphorothioate, phosphorothioate, and/or 5'-methylphosphonate linkages improves stability, too many of these modifications can cause some toxicity. Therefore when designing nucleic acid molecules the amount of these internucleotide linkages should be minimized.

WO 02/096927 PCT/US02/17674 42 The reduction in the concentration of these linkages should lower toxicity resulting in increased efficacy and higher specificity of these molecules.

Nucleic acid molecules having chemical modifications that maintain or enhance activity are provided. Such nucleic acid is also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity may not be significantly lowered.

Therapeutic nucleic acid molecules delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Clearly, nucleic acid molecules must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA and DNA (Wincott et al., 1995 Nucleic Acids Res. 23, 2677; Caruthers et al., 1992, Methods in Enzymology 211,3-19 (incorporated by reference herein) have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.

In one embodiment, nucleic acid molecules of the invention include one or more Gclamp nucleotides. A G-clamp nucleotide is a modified cytosine analog wherein the modifications confer the ability to hydrogen bond both Watson-Crick and Hoogsteen faces of a complementary guanine within a duplex, see for example Lin and Matteucci, 1998, J. Am.

Chem. Soc., 120, 8531-8532. A single G-clamp analog substitution within an oligonucleotide can result in substantially enhanced helical thermal stability and mismatch discrimination when hybridized to complementary oligonucleotides. The inclusion of such nucleotides in nucleic acid molecules of the invention results in both enhanced affinity and specificity to nucleic acid targets. In another embodiment, nucleic acid molecules of the invention include one or more LNA "locked nucleic acid" nucleotides such as a 4'-C mythylene bicyclo nucleotide (see for example Wengel et al, International PCT Publication No. WO 00/66604 and WO 99/14226).

In another embodiment, the invention features conjugates and/or complexes of nucleic acid molecules targeting VEGF receptors such as VEGFR1 and/or VEGFR2. Such conjugates and/or complexes can be used to facilitate delivery of molecules into a biological system, such as cells. The conjugates and complexes provided by the instant invention can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention. The present invention encompasses the design and synthesis of novel conjugates and complexes for the delivery of molecules, including but not limited to small WO 02/096927 PCT/US02/17674 43 molecules, lipids, phospholipids, nucleosides, nucleotides, nucleic acids, antibodies, toxins, negatively charged polymers and other polymers, for example proteins, peptides, hormones, carbohydrates, polyethylene glycols, or polyamines, across cellular membranes. In general, the transporters described are designed to be used either individually or as part of a multicomponent system, with or without degradable linkers. These compounds are expected to improve delivery and/or localization of nucleic acid molecules of the invention into a number of cell types originating from different tissues, in the presence or absence of serum (see Sullenger and Cech, US 5,854,038), Conjugates of the molecules described herein can be attached to biologically active molecules via linkers that are biodegradable, such as biodegradable nucleic acid linker molecules.

The term "biodegradable nucleic acid linker molecule" as used herein, refers to a nucleic acid molecule that is designed as a biodegradable linker to connect one molecule to another molecule, for example, a biologically active molecule. The stability of the biodegradable nucleic acid linker molecule can be modulated by using various combinations of ribonucleotides, deoxyribonucleotides, and chemically modified nucleotides, for example, 2'-O-methyl, 2'-fluoro, 2'-amino, 2'-O-amino, 2'-C-allyl, 2'-O-allyl, and other 2'-modified or base modified nucleotides. The biodegradable nucleic acid linker molecule can be a dimer, trimer, tetramer or longer nucleic acid molecule, for example, an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphorus based linkage, for example, a phosphoramidate or phosphodiester linkage. The biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications.

The term "biodegradable" as used herein, refers to degradation in a biological system, for example enzymatic degradation or chemical degradation.

The term "biologically active molecule" as used herein, refers to compounds or molecules that are capable of eliciting or modifying a biological response in a system. Nonlimiting examples of biologically active molecules contemplated by the instant invention include therapeutically active molecules such as antibodies, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, siRNA, dsRNA, allozymes, aptamers, decoys and analogs thereof. Biologically active molecules of the invention also include molecules capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active WO 02/096927 PCT/US02/17674 44 molecules, for example, lipids and polymers such as polyamines, polyamides, polyethylene glycol and other polyethers.

The term "phospholipid" as used herein, refers to a hydrophobic molecule comprising at least one phosphorus group. For example, a phospholipid can comprise a phosphorus containing group and saturated or unsaturated alkyl group, optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups.

Therapeutic nucleic acid molecules enzymatic nucleic acid molecules and antisense nucleic acid molecules) delivered exogenously are optimally stable within cells until translation of the target RNA has been inhibited long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. These nucleic acid molecules should be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.

In another embodiment, nucleic acid catalysts having chemical modifications that maintain or enhance enzymatic activity are provided. Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acid. Thus, in a cell and/or in vivo the activity of the nucleic acid may not be significantly lowered. As exemplified herein such enzymatic nucleic acids are useful in a cell and/or in vivo even if activity over all is reduced fold (Burgin et al., 1996, Biochemistry, 35, 14090). Such enzymatic nucleic acids herein are said to "maintain" the enzymatic activity of an all RNA ribozyme or all DNA DNAzyme.

In another aspect the nucleic acid molecules comprise a 5' and/or a cap structure.

By "cap structure" is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see for example Wincott et al., WO 97/26270, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and can help in delivery and/or localization within a cell. The cap can be present at the 5'-terminus (5'-cap) or at the 3'-terminus (3'-cap) or can be present on both terminus. In non-limiting examples, the 5'-cap includes inverted abasic residue (moiety), 4',5'-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4'-thio nucleotide, carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alphanucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic WO 02/096927 PCT/US02/17674 dihydroxypcntyl nucleotide, 3'-3'-inverted nucleotide moiety; 3'-3'-inverted abasic moiety; 3'- 2'-inverted nucleotide moiety; 3'-2'-inverted abasic moiety; 1,4-butanediol phosphate; 3'phosphoramidate; hexylphosphate; aminohexyl phosphate; 3'-phosphate; 3'-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety (for more details see Wincott et al., International PCT publication No. WO 97/26270, incorporated by reference herein).

In another embodiment the 3'-cap includes, for example 4',5'-methylene nucleotide; 1- (beta-D-erythrofuranosyl) nucleotide; 4'-thio nucleotide, carbocyclic nucleotide; alkyl phosphate; 1,3-diamino-2-propyl phosphate, 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3',4'-seco nucleotide; 3,4-dihydroxybutyl nucleotide; nucleotide, 5'-5'-inverted nucleotide moiety; 5'-5'-inverted abasic moiety; 5'-phosphorothioate; 1,4-butanediol phosphate; 5'-amino; bridging and/or non-bridging 5'-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5'-mercapto moieties (for more details see Beaucage and Iyer, 1993, Tetrahedron 49, 1925; incorporated by reference herein).

By the term "non-nucleotide" is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine.

An "alkyl" group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups. Preferably, the alkyl group has 1 to 12 carbons.

More preferably it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons.

The alkyl group can be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, NO2 or N(CH3) 2 amino, or SH. The term also includes alkenyl groups which are unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12 carbons. More preferably it is a lower alkenyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkenyl group can be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, NO 2 halogen, N(CH 3 amino, or SH. The term "alkyl" also includes alkynyl groups which have an unsaturated hydrocarbon group containing at least WO 02/096927 PCT/US02/17674 46 one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups.

Preferably, the alkynyl group has 1 to 12 carbons. More preferably it is a lower alkynyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkynyl group can be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, NO 2 or N(CH 3 2 amino or SH.

Such alkyl groups can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. An "aryl" group refers to an aromatic group which has at least one ring having a conjugated p electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which can be optionally substituted. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkcnyl, alkynyl, and amino groups. An "alkylaryl" group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An "amide" refers to an where R is either alkyl, aryl, alkylaryl or hydrogen. An "ester" refers to an where R is either alkyl, aryl, alkylaryl or hydrogen.

By "nucleotide" is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a phosphorylated sugar. Nucleotides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1' position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; Uhlman Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of chemically modified and other natural nucleic acid bases that can be introduced into nucleic acids include, for example, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines WO 02/096927 WO 02/96927PCT/US02/17674 47 5-alkyluridines ribothyrnidine), 5-halouridine or 6-azapyrimidines or 6-alkylpyrimidines 6-methyluridine), propyne, quesosine, 2thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, (carboxyhydroxymethyl)uridine, 5 '-carboxymethylamninomethyl-2-thiouridine, carboxymethylaminomethyluridine, beta-D-galactosylqueosine, 1 -methyladenosine, 1Imethylinosine, 2,2-dimothylguano sine, 3-methylcytidine, 2-methyladenosine, 2methylguanosine, N6-methyladenosine, 7-methylguanosine, 5-methoxyaminomethyl-2thiouridine, 5-n-ethylanainomethyluridine, 5-methylcarbonylmethyluridine, methyloxyuridine, 5-methlyl-2-thiouridine, 2-methylthio-N6-isoperitenyladenosine, beta-Dmannosylqueosine, uridine-5-Dxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al., 1996, Biochemistry, 35, 14090; U~hlman Peyman, supra). By "modified bases" in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.

By "nucleoside" is meant a heterocyclic nitrogenous base in N-glycosidic linkage with a sugar. Nucleosides are recognized in the art to include natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1'position of a nucleoside sugar moiety. Nueceosides generally comprise a base and sugar group. The nucleosides can be unmodified or modified at the sugar, and/or base moiety, (also referred to interchangeably as nucleoside analogs, modified nucleosides, non-natural nucleosides, nonstandard nucleosides and other; see for example, Usman and McSwiggen, supra; Eckstein et al., [nternational PCT Publication No. WO 92/07065; Usman et International PCT Publication No. WO 93/15187; Uhhnan Peyman, supra all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al, 1994, Nucleic Acids Res. 22, 2183. Some of the nonlimiting examples of chemically modified and othe:r natural nucleic acid bases that can be introduced into nucleic acids include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthiyl, amninophenyl, 5-alkylcytidines 5-methylcytidine), 5-alkylin-idines ribothymidine), 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines 6methyluridine), propyne, quesosine, 2-thiouridine, 4-thiouridine, wybutosine, wybutoxosine, 4-acetylcytidine, 5-(carboxyhydroxymethyl)uridine, 5 '-carboxymethylamninomethyl-2thiouridine, 5-carboxyinethylaminomethyluridine, beta-IJ-galactosylqueosine, 1 methyladenosine, 1 -methylinosi-ne, 2,2-dimethylguana sine, 3-methylcytidine, 2methyladenosine, 2-nriethylguanosine, N6-methyladenosine, 7-methylguano sine, WO 02/096927 PCT/US02/17674 48 methoxyaminomethyl-2-thiouridine, 5-methylaminomethyluridine, methylcarbonylmethyluridine, 5-methyloxyuridine, 5-methyl-2-thiouridine, 2-methylthio-N6isopentenyladenosine, beta-D-mannosylqueosine, uridine-5-oxyacetic acid, 2-thiocytidine, threonine derivatives and others (Burgin et al., 1996, Biochemistry, 35, 14090; Uhlman Peyman, supra). By "modified bases" in this aspect is meant nucleoside bases other than adenine, guanine, cytosine and uracil at 1' position or their equivalents; such bases can be used at any position, for example, within the catalytic core of an enzymatic nucleic acid molecule and/or in the substrate-binding regions of the nucleic acid molecule.

In one embodiment, the invention features modified enzymatic nucleic acid molecules with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, morpholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of oligonucleotide backbone modifications see Hunziker and Leumann, 1995, Nucleic AcidAnalogues: Synthesis and Properties, in Modern Synthetic Methods, VCH, 331-417, and Mesmaeker et al., 1994, Novel Backbone Replacements for Oligonucleotides, in Carbohydrate Modifications in Antisense Research, ACS, 24-39. These references are hereby incorporated by reference herein.

By "abasic" is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1' position, for example a 3',3'-linked or 5',5'-linked deoxyabasic ribose derivative (for more details see Wincott et al., International PCT publication No. WO 97/26270).

By "unmodified nucleoside" is meant one of the bases adenine, cytosine, guanine, thymine, uracil joined to the 1' carbon of p-D-ribo-furanose.

By "modified nucleoside" is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate.

In connection with 2'-modified nucleotides as described for the present invention, by "amino" is meant 2'-NH 2 or NH 2 which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al., U.S. Patent 5,672,695 and Matulic-Adamic et al., WO 98/28317, respectively, which are both incorporated by reference in their entireties.

Various modifications to nucleic acid antisense and ribozyme) structure can be made to enhance the utility of these molecules. For example, such modifications can enhance WO 02/096927 PCT/US02/17674 49 shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, including, enhancing penetration of cellular membranes and conferring the ability to recognize and bind to targeted cells.

Use of the nucleic acid-based molecules of the invention can lead to better treatment of the disease progression by affording the possibility of combination therapies multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs) and/or other chemical or biological molecules). The treatment of patients with nucleic acid molecules can also include combinations of different types of nucleic acid molecules. Therapies can be devised which include a mixture of enzymatic nucleic acid molecules (including different enzymatic nucleic acid molecule motifs), allozymes, antisense, dsRNA, aptamers, and/or 2-5A chimera molecules to one or more targets to alleviate symptoms of a disease.

Administration of Nucleic Acid Molecules Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992, Trends Cell Bio., 2, 139; and Delivery Strategies for Antisense Oligonucleotide Therapeutics, ed. Akhtar, 1995 which are both incorporated herein by reference. Sullivan et al., PCT WO 94/02595, further describes the general methods for delivery of enzymatic RNA molecules.

These protocols can be utilized for the delivery of virtually any nucleic acid molecule.

Nucleic acid molecules can be administered to cells by a variety of methods known to those familiar to the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as hydrogels, cyclodextrins, biodegradable nanocapsules, and bioadhesive microspheres. Alternatively, the nucleic acid/vehicle combination is locally delivered by direct injection or by use of an infusion pump. Other routes of delivery include, but are not limited to oral (tablet or pill form) and/or intrathecal delivery (Gold, 1997, Neuroscience, 76, 1153-1158). Other approaches include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. For a comprehensive review on drug delivery strategies including CNS delivery, see Ho et al., 1999, Curr. Opin. Mol. Ther., 1, 336-343 and Jain, Drug Delivery Systems: Technologies and Commercial Opportunities, Decision Resources, 1998 and Groothuis et al., 1997, J. NeuroVirol., 3, 387-400. More detailed descriptions of nucleic acid delivery and administration are provided in Sullivan et al., supra, Draper et al., PCT WO 02/096927 PCT/US02/17674 W093/23569, Beigelman et al., PCT W099/05094, and Klimuk et al., PCT W099/04819 all of which have been incorporated by reference herein.

The molecules of the instant invention can be used as pharmaceutical agents.

Pharmaceutical agents prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state in a patient.

The polynucleotides of the invention can be administered RNA, DNA or protein) and introduced into a patient by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration; suppositories for rectal administration; sterile solutions; suspensions for injectable administration; and the other compositions known in the art.

The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.

A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, systemic administration, into a cell or patient, preferably a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell a cell to which the negatively charged polymer is desired to be delivered to). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms which prevent the composition or formulation from exerting its effect.

By "systemic administration" is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body.

Administration routes which lead to systemic absorption include, without limitations: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes expose the desired negatively charged polymers, nucleic acids, to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can WO 02/096927 PCT/US02/17674 51 potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation which can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cells implicated in endometriosis, birth control, endometrial tumors, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, and endometrial carcinoma.

By pharmaceutically acceptable formulation is meant, a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: PEG conjugated nucleic acids, phospholipid conjugated nucleic acids, nucleic acids containing lipophilic moieties, phosphorothioates, P-glycoprotein inhibitors (such as Pluronic P85) which can enhance entry of drugs into various tissues, for example the CNS (Jolliet- Riant and Tillement, 1999, Fundam. Clin. Pharmacol., 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after implantation (Emerich, DF et al, 1999, Cell Transplant, 8, 47-58) Alkermes, Inc. Cambridge, MA; and loaded nanoparticles, such as those made of polybutyleyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms (Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). Other non-limiting examples of delivery strategies, including CNS delivery of the nucleic acid molecules of the instant invention include material described in Boado et al., 1998, J. Pharm. Sci., 87, 1308-1315; Tyler et al., 1999, FEBS Lett., 421, 280-284; Pardridge et al., 1995, PNAS USA., 92, 5592- 5596; Boado, 1995, Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada et al., 1998, Nucleic Acids Res., 26, 4910-4916; and Tyler et al,, 1999, PNAS USA., 96, 7053-7058. All these references are hereby incorporated herein by reference.

The invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). Nucleic acid molecules of the invention can also comprise covalently attached PEG molecules of various molecular weights. These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem.

WO 02/096927 PCT/US02/17674 52 Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995, Biochim. Biophys. Acta, 1238, 86-90). The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al., J. Biol. Chem.

1995, 42, 24864-24870; Choi et al., International PCT Publication No. WO 96/10391; Ansell et al., International PCT Publication No. WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392; all of which are incorporated by reference herein). Longcirculating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen. All of these references are incorporated by reference herein.

The present invention also includes compositions prepared for storage or administration which include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. Gennaro edit. 1985) hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of phydroxybenzoic acid. In addition, antioxidants and suspending agents can be used.

A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors which those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer.

The nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular intravenous), intramuscular, or intrathecal injection or WO 02/096927 PCT/US02/17674 53 infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier. One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.

Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters WO 02/096927 PCT/US02/17674 54 derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl phydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, clive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these.

Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.

Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension.

This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and WO 02/096927 PCT/USO2/17674 isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation ofinjectables.

The nucleic acid molecules of the invention can also be administered in the form of suppositories, for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

Nucleic acid molecules of the invention can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.

It is understood that the specific dose level for any particular patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

For administration to non-human animals, the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.

The nucleic acid molecules of the present invention can also be administered to a patient in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.

WO 02/096927 PCT/US02/17674 56 Alternatively, certain of the nucleic acid molecules of the instant invention can be expressed within cells from eukaryotic promoters Izant and Weintraub, 1985, Science, 229, 345; McGarry and Lindquist, 1986, Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et al., 1991, Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al., 1992, Antisense Res.

Dev., 2, 3-15; Dropulic et al., 1992, J. Virol., 66, 1432-41; Weerasinghe et al., 1991, J.

Virol., 65, 5531-4; Ojwang et al., 1992, Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990 Science, 247, 1222-1225; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Good et al., 1997, Gene Therapy, 4, all of these references are hereby incorporated in their totalities by reference herein). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992, Nucleic Acids Symp.

Ser., 27, 15-6; Taira et al., 1991, Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993, Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994, J. Biol. Chem., 269, 25856; all of these references are hereby incorporated in their totalities by reference herein). Gene therapy approaches specific to the CNS are described by Blesch et al., 2000, Drug News Perspect., 13, 269-280; Peterson et al., 2000, Cent. Nerv. Syst. Dis., 485-508; Peel and Klein, 2000, J.

Neurosci. Methods, 98, 95-104; Hagihara et al., 2000, Gene Ther., 7, 759-763; and Herrlinger et al., 2000, Methods Mol. Med., 35,287-312. AAV-mediated delivery of nucleic acid to cells of the nervous system is further described by Kaplitt et al., US 6,180,613.

In another aspect of the invention, RNA molecules of the present invention are preferably expressed from transcription units (see for example Couture et al., 1996, TIG., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the nucleic acid molecules are delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the nucleic acid molecule binds to the target mRNA. Delivery of nucleic acid molecule expressing vectors can be systemic, such as by intravenous or intra-muscular administration, by administration to target cells ex-planted from the patient followed by reintroduction into the patient, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al., 1996, TIG., 12, 510).

WO 02/096927 PCT/US02/17674 57 In one aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the nucleic acid molecules of the instant invention. The nucleic acid sequence encoding the nucleic acid molecule of the instant invention is operably linked in a manner which allows expression of that nucleic acid molecule.

In another aspect the invention features an expression vector comprising: a) a transcription initiation region eukaryotic pol I, nI or Im initiation region); b) a transcription termination region eukaryotic pol I, I or I1 termination region); c) a nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5' side or the 3'-side of the sequence encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

Transcription of the nucleic acid molecule sequences are driven from a promoter for eukaryotic RNA polymerase I (pol RNA polymerase II (pol 11), or RNA polymerase II (pol III). Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990, Proc. Natl. Acad. Sci. US A, 87, 6743-7; Gao and Huang 1993, Nucleic Acids Res.., 21, 2867-72; Lieber et al., 1993, Methods Enzymol., 217, 47-66; Zhou et al., 1990, Mol. Cell. Biol., 10, 4529-37). All of these references are incorporated by reference herein. Several investigators have demonstrated that nucleic acid molecules, such as ribozymes expressed from such promoters can function in mammalian cells Kashani-Sabet et al., 1992, Antisense Res. Dev., 2, 3- Ojwang et al., 1992, Proc. Natl. Acad. Sci. U S A, 89, 10802-6; Chen et al., 1992, Nucleic Acids Res., 20, 4581-9; Yu et al., 1993, Proc. Natl. Acad. Sci. USA, 90, 6340-4; L'Huillier et al., 1992, EMBO J, 11, 4411-8; Lisziewicz et al., 1993, Proc. Natl. Acad. Sci.

U. S. A, 90, 8000-4; Thompson et al., 1995, Nucleic Acids Res., 23, 2259; Sullenger Cech, 1993, Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as ribozymes in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994, Nucleic Acid Res., 22, 2830; Noonberg et al., US Patent No. 5,624,803; Good et al., 1997, Gene Ther., 4, 45; Beigelman et al., International PCT Publication No. WO WO 02/096927 PCT/US02/17674 58 96/18736; all of these publications are incorporated by reference herein. The above ribozyme transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).

In another aspect the invention features an expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid molecules of the invention, in a manner which allows expression of that nucleic acid molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; c) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

In another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule. In yet another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) a nucleic acid sequence encoding at least one said nucleic acid molecule; and wherein said sequence is operably linked to said initiation region, said intron and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; e) a nucleic acid sequence encoding at least one said nucleic acid molecule, wherein said sequence is operably linked to the 3'-end of said open reading frame; and wherein said sequence is operably linked to said initiation region, said intron, said open reading frame and said termination region, in a manner which allows expression and/or delivery of said nucleic acid molecule.

Flt-1 (VEGFR1), KDR (VEGFR2) and/or flk-1 are attractive nucleic acid-based therapeutic targets by several criteria. The interaction between VEGF and VEGF-R is wellestablished. Efficacy can be tested in well-defined and predictive animal models. Finally, the disease conditions are serious and current therapies are inadequate. Whereas protein-based WO 02/096927 PCT/US02/17674 59 therapies are designed to affect VEGF activity, nucleic acid-based therapy based on the molecules and methods described herein provides a direct and elegant approach to directly modulate fit-1, KDR and/or flk-1 expression.

Because VEGFR1 and VEGFR2 mRNAs are highly homologous in certain regions, some nucleic acid target sites are also homologous. In this case, a single nucleic acid molecule of the invention can target both VEGFR1 and VEGFR2 mRNAs. At partially homologous sites, a single nucleic acid molecule can sometimes be designed to accommodate a site on both mRNAs by including G/U base pairing. For example, if there is a G present in a enzymatic nucleic acid target site in VEGFR1 mRNA at the same position there is an A in the VEGFR2 enzymatic nucleic acid target site, the enzymatic nucleic acid can be synthesized with a U at the complementary position and it will bind both to sites. The advantage of one enzymatic nucleic acid that targets both VEGFR1 and VEGFR2 mRNAs is clear, especially in cases where both VEGF receptors may contribute to the progression of angiogenesis in the disease state.

Examples The following are non-limiting examples showing the selection, isolation, synthesis and activity of exemplary nucleic acids of the instant invention.

The following examples demonstrate the selection and design of antisense, aptamer, dsRNA, allozyme, hammerhead, DNAzyme, NCH, Amberzyme, Zinzyme, or G-Cleaver ribozyme molecules and binding/cleavage sites within VEGF, VEGFR1 and/or VEGFR2

RNA.

Example 1: Enzymatic nucleic acid-mediated inhibition of angiogenesis in vivo The study described below was performed to assess the anti-angiogenic activity of hammerhead ribozymes targeted against fit-1 4229 site (SED ID NO: 5977) in the rat cornea model of VEGF induced angiogenesis (see above). These ribozymes have either active or inactive catalytic core and either bind and cleave or just bind to VEGF-R mRNA of the fit-1 subtype. The active ribozymes, that are able to bind and cleave the target RNA, have been shown to inhibit (1 25 I-labeled) VEGF binding in cultured endothelial cells and produce a dose-dependent decrease in VEGF induced endothelial cell proliferation in these cells. The catalytically inactive forms of these ribozymes, which can only bind to the RNA but cannot catalyze RNA cleavage, failed to inhibit VEGF binding and failed to decrease VEGF induced endothelial cell proliferation. The ribozymes and VEGF were co-delivered using the filter WO 02/096927 PCT/US02/17674 disk method: Nitrocellulose filter disks (Millipore®) of 0.057 diameter were immersed in appropriate solutions and were surgically implanted in rat cornea as described by Pandey et al., supra. This delivery method has been shown to deliver rhodamine-labeled free ribozyme to scleral cells and, in all likelihood cells of the pericorneal vascular plexus. Since the active ribozymes show cell culture efficacy and can be delivered to the target site using the disk method, it is essential that these ribozymes be assessed for in vivo anti-angiogenic activity.

The stimulus for angiogenesis in this study was the treatment of the filter disk with uM VEGF which is implanted within the cornea's stroma. This dose yields reproducible neovascularization stemming from the pericomeal vascular plexus growing toward the disk in a dose-response study 5 days following implant. Filter disks treated only with the vehicle for VEGF show no angiogenic response. The ribozymes were co-adminstered with VEGF on a disk in two different ribozyme concentrations. One concern with the simultaneous administration is that the ribozymes will not be able to inhibit angiogenesis since VEGF receptors can be stimulated. However, we have observed that in low VEGF doses, the neovascular response reverts to normal suggesting that the VEGF stimulus is essential for maintaining the angiogenic response. Blocking the production of VEGF receptors using simultaneous administration of anti-VEGF-R mRNA ribozymes could attenuate the normal neovascularization induced by the filter disk treated with VEGF.

Materials and Methods: 1. Stock hammerhead ribozyme solutions: a. fit-1 4229 (786 tM)- Active b. fit-1 4229 (736 gM)- Inactive 2. Experimantal solutions/groups: Group 1 Solution 1 Control VEGF solution: 30 uM in 82mM Tris base Group 2 Solution 2 fit-1 4229 (1 gg/pL) in 30 jiM VEGF/82 mM Tris base Group 3 Solution 3 fit-1 4229 (10 pg/pL) in 30 gM VEGF/82 mM Tris base Group 4 Solution 4 No VEGF, fit-1 4229 (10 jgg/pL) in 82 mM Tris base Group 5 Solution 5 No VEGF, No ribozyme in 82 mM Tris base WO 02/096927 PCT/US02/17674 61 eyes per group, 5 animals (Since they have similar molecular weights, the molar concentrations should be essentially similar).

Each solution (VEGF and RIBOZYMES) were prepared as a 2X solution for 1:1 mixing for final concentrations above, with the exception of solution 1 in which VEGF was 2X and diluted with ribozyme diluent (sterile water).

3. VEGF Solutions The 2X VEGF solution (60 pM) was prepared from a stock of 0.82 jtg/gL in 50 mM Tris base. 200 iL of VEGF stock was concentrated by speed vac to a final volume of 60.8 pL, for a final concentration of 2.7 pAg/L or 60 pM. Six 10 gL aliquots was prepared for daily mixing. 2X solutions for VEGF and Ribozyme was stored at 4 0 C until the day of the surgery.

Solutions were mixed for each day of surgery. Original 2X solutions was prepared on the day before the first day of the surgery.

4. Surgical Solutions: Anesthesia: stock ketamine hydrochloride 100 mg/mL stock xylazine hydrochloride 20 mg/mL stock acepromazine 10 mg/mL Final anesthesia solution: 50 mg/mL ketamine, 10 mg/mL xylazine, and 0.5 mg/mL acepromazine 5% povidone iodine for opthalmic surgical wash 2% lidocaine (sterile) for opthalmic administration (2 drops per eye) sterile 0.9% NaC1 for opthalmic irrigation Surgical Methods: Standard surgical procedure as described in Pandey et al., supra. Filter disks were incubated in 1 gL of each solution for approximately 30 minutes prior to implantation.

6. Experimental Protocol: WO 02/096927 PCT/US02/17674 62 The animal cornea were treated with the treatment groups as described above. Animals were allowed to recover for 5 days after treatment with daily observation (scoring 0 On the fifth day animals were euthanized and digital images of each eye was obtained for quantitaion using Image Pro Plus. Quantitated neovascular surface area were analyzed by ANOVA followed by two post-hoc tests including Dunnets and Tukey-Kramer tests for significance at the 95% confidence level. Dunnets provide information on the significance between the differences within the means of treatments vs. controls while Tukey-Kramer provide information on the significance of differences within the means of each group.

The flt-1 4229 (SEQ ID NO: 5977) active hammerhead ribozyme at both concentrations was effective at inhibiting angiogenesis while the inactive ribozyme did not show any significant reduction in angiogenesis. A statistically signifiant reduction in neovascular surface area was observed only with active ribozymes. This result clearly shows that the ribozymes are capable of significantly inhibiting angiogenesis in vivo. Specifically, given ribozyme mechanism of action, the observed inhibition is by the binding and cleavage of target RNA by ribozymes.

Example 2: Bioactivitv of anti-angio genesis ribozymes targeting flt-1 and kdr RNA MATERIALS AND METHODS Ribozymes Hammerhead ribozymes and controls designed to have attenuated activity (attenuated controls) were synthesized and purified as previously described above. The attenuated ribozyme controls maintain the binding arm sequence of the parent ribozyme and thus are still capable of binding to the mRNA target. However, they have two nucleotide changes in the core sequence that substantially reduce their ability to carry out the cleavage reaction. Ribozymes were designed to target Fit-1 orKDR mRNA sites conserved in human, mouse, and rat. In general, ribozymes with binding arms of seven nucleotides were designed and tested. If, however, only six nucleotides surrounding the cleavage site were conserved in all three species, six nucleotide binding arms were used. Data are presented herein for 2'-NH 2 uridine modified ribozymes in cell proliferation studies and for 2'-C-allyl uridine modified ribozymes in RNAse protection, in vitro cleavage and corneal studies.

In vitro ribozyme cleavage assays: In vitro RNA cleavage rates on a 15 nucleotide synthetic RNA substrate were measured as previously described above.

Cell culture: Human dermal microvascular endothelial cells (HMVEC-d, Clonetics Corp.) were maintained at 37 0 C in flasks or plates coated with 1.5% porcine skin gelatin (300 WO 02/096927 PCT/US02/17674 63 bloom, Sigma) in Growth medium (Clonetics Corp.) supplemented with 10-20% fetal bovine serum (FBS, Hyclone). Cells were grown to confluency and used up to the seventh passage.

Stimulation medium consisted of 50% Sigma 99 media and 50% RPMI 1640 with Lglutamine and additional supplementation with 10 yg/mL Insulin-Transferrin-Selenium (Gibco BRL) and 10% FBS. Cell growth was stimulated by incubation in Stimulation medium supplemented with 20 ng/mL of either VEGF 1 65 or bFGF. VEGF 1 65 (165 amino acids) was selected for cell culture and animal studies because it is the predominant form of the four native fonrs of VEGF generated by alternative mRNA splicing. Cell culture assays were carried out in triplicate.

Ribozyme and ribozyme/LIPOFECTAMINETM formulations: Cell culture: Ribozymes or attenuated controls (50-200 nM) were formulated for cell culture studies and used immediately. Formulations were carried out with LIPOFECTAMINETM (Gibco BRL) at a 3:1 lipid to phosphate charge ratio in serum-free medium (OPTI-MEM

T

M, Gibco BRL) by mixing for 20 minutes at room temperature. For example, a 3:1 lipid to phosphate charge ratio was established by complexing 200 nM ribozyme with 10.8 g~g/ L LIPOFECTAMINETM (13.5 ItM DOSPA).

In vivo: For corneal studies, lyophilized ribozyme or attenuated controls were resuspended in sterile water at a final stock concentration of 170 tg/ttL (highest dose). Lower doses (1.7-50 tg/itL) were prepared by serial dilution in sterile water.

Proliferation assay: HMVEC-d were seeded (5 x 103 cells/well) in 48-well plates (Costar) and incubated 24-30 hours in Growth medium at 37°C. After removal of the Growth medium, cells were treated with 50-200 nM LIPOFECTAMINETM complexes of ribozyme or attenuated controls for 2 hours in OPTI-MEM

T

M. The ribozyme/control-containing medium was removed and the cells were washed extensively in IX PBS. The medium was then replaced with Stimulation medium or Stimulation medium supplemented with 20 ng/mL

VEGF

1 65 or bFGF. After 48 hours, the cell number was determined using a CoulterT M cell counter. Data are presented as cell number per well following 48 hours of VEGF stimulation.

RNAse protection assay: HMVEC-d were seeded (2 x 10 5 cells/well) in 6-well plates (Costar) and allowed to grow 32-36 hours in Growth medium at 37°C. Cells were treated with

LIPOFECTAMINE

T complexes containing 200 nM ribozyme or attenuated control for 2 h as described under "Proliferation Assay" and then incubated in Growth medium containing ng/mL VEGF 165 for 24 hours. Cells were harvested and an RNAse protection assay was carried out using the Ambion Direct Protect kit and protocol with the exception that 50 mM WO 02/096927 PCT/US02/17674 64 EDTA was added to the lysis buffer to eliminate the possibility of ribozyme cleavage during sample preparation. Antisense RNA probes targeting portions of Flt-1 and KDR were prepared by transcription in the presence of 32 P]-UTP. Samples were analyzed on polyacrylamide gels and the level of protected RNA fragments was quantified using a Molecular Dynamics Phosphorlmager. The levels of Fit-1 and KDR were normalized to the level of cyclophilin (human cyclophilin probe template, Ambion) in each sample. The coefficient of variation for cyclophilin levels was 11% [265940 cpm 29386 for all conditions tested here in the presence of either active ribozymes or attenuated controls).

Thus, cyclophilin is useful as an internal standard in these studies.

Rat corneal pocket assay of VEGF-induced angiogenesis: Animal guidelines and anesthesia. Animal housing and experimentation adhered to standards outlined in the 1996 Guide for the Care and Use of Laboratory Animals (National Research Council). Male Sprague Dawley rats (250-300 g) were anesthetized with ketamine mg/kg), xylazine (10 mg/kg), and acepromazine (0.5 mg/kg) administered intramuscularly The level of anesthesia was monitored every 2-3 min by applying hind limb paw pressure and examining for limb withdrawal. Atropine (0.4 mg/kg, im) was also administered to prevent potential corneal reflex-induced bradycardia.

Preparation of VEGF soaked disk. For corneal implantation, 0.57 mm diameter nitrocellulose disks, prepared from 0.45 tm pore diameter nitrocellulose filter membranes (Millipore Corporation), were soaked for 30 min in 1 tL of 30 j[M VEGF 65 in 82 mM Tris-HC1 (pH 6.9) in covered petri dishes on ice.

Corneal surgery. The rat corneal model used in this study was a modified from Koch et al. Supra and Pandey et al., supra. Briefly, corneas were irrigated with 0.5% povidone iodine solution followed by normal saline and two drops of 2% lidocaine. Under a dissecting microscope (Leica MZ-6), a stromal pocket was created and a presoaked filter disk (see above) was inserted into the pocket such that its edge was 1 mm from the corneal limbus.

Intraconjunctival injection of test solutions. Immediately after disk insertion, the tip of a 40-50 tpm OD injector (constructed in our laboratory) was inserted within the conjunctival tissue 1 mm away from the edge of the corneal limbus that was directly adjacent to the VEGF-soaked filter disk. Six hundred nanoliters of test solution (ribozyme, attenuated control or sterile water vehicle) were dispensed at a rate of 1.2 gL/min using a syringe pump (Kd Scientific). The injector was then removed, serially rinsed in 70% ethanol and sterile water and immersed in sterile water between each injection. Once the test solution was injected, WO 02/096927 PCT/US02/17674 closure of the eyelid was maintained using microaneurism clips until the animal began to recover gross motor activity. Following treatment, animals were warmed on a heating pad at 37 0

C.

Animal treatment groups/experimental protocol. Ribozymes targeting Fit-1 site 4229 (SEQ ID NO: 5977) and KDR mRNA site 726 (SEQ ID NO: 5978) were tested in the corneal model along with their attenuated controls. Five treatment groups were assigned to examine the effects of five doses of each test substance over a dose range of 1-100 gg on VEGFstimulated angiogenesis. Negative (30 gM VEGF soaked filter disk and intraconjunctival injection of 600 nL sterile water) and no stimulus (Tris-soaked filter disk and intraconjunctival injection of sterile water) control groups were also included. Each group consisted of five animals (10 eyes) receiving the same treatment.

Quantitation of angiogenic response. Five days after disk implantation, animals were euthanized following im administration of 0.4 mg/kg atropine and corneas were digitally imaged. The neovascular surface area (NSA, expressed in pixels) was measured postmortem from blood-filled corneal vessels using computerized morphometry (Image Pro Plus, Media Cybernetics, v2.0). The individual mean NSA was determined in triplicate from three regions of identical size in the area of maximal neovascularization between the filter disk and the limbus. The number of pixels corresponding to the blood-filled corneal vessels in these regions was summated to produce an index of NSA. A group mean NSA was then calculated.

Data from each treatment group were normalized to VEGF/ribozyme vehicle-treated control NSA and finally expressed as percent inhibition of VEGF-induced angiogenesis.

Statistics. After determining the normality of treatment group means, group mean percent inhibition of VEGF-induced angiogenesis was subjected to a one-way analysis of variance. This was followed by two post-hoc tests for significance including Dunnett's (comparison to VEGF control) and Tukey-Kramer (all other group mean comparisons) at alpha= 0.05. Statistical analyses were performed using JMP v.3.1.6 (SAS Institute).

RESULTS

Ribozyme-mediated reduction of VEGF-induced cell proliferation: Ribozyme cleavage of Fit-1 or KDR mRNA should result in a decrease in the density of cell surface VEGF receptors. This decrease should limit VEGF binding and consequently interfere with the mitogenic signaling induced by VEGF. To determine if cell proliferation was impacted by anti-Flt-i and/or anti-KDR ribozyme treatment, proliferation assays using cultured human microvascular cells were carried out. Ribozymes included in the proliferation assays were WO 02/096927 PCT/US02/17674 66 initially chosen by their ability to decrease the level of VEGF binding to treated cells. In these initial studies, ribozymes targeting 20 sites in the coding region of each mRNA were screened. The most effective ribozymes against two sites in each target, Flt-1 sites 1358 and 4229 and KDR sites 726 and 3950, were included in the proliferation assays reported here. In addition, attenuated analogs of each ribozyme were used as controls. These attenuated controls are still capable of binding to the mRNA target since the binding arm sequence is maintained. However, these controls have two nucleotide changes in the core sequence that substantially reduce their ability to carry out the cleavage reaction.

The active ribozymes tested decreased the relative proliferation of HMVEC-d after VEGF stimulation, an effect that increased with ribozyme concentration. This concentration dependency was not observed following treatment with the attenuated controls designed for these sites. In fact, little or no change in cell growth was noted following treatment with the attenuated controls, even though these controls can still bind to the specific target sequences.

At 200 nM, there was a distinct "window" between the anti-proliferative effects of each ribozyme and its attenuated control; a trend also observed at lower doses. This window of inhibition of proliferation (56-77% based on total cells/well) reflects the contribution of ribozyme-mediated activity. In comparison, no effect of anti-Fit-i or anti-KDR ribozymes was noted on bFGF-stimulated cell proliferation. Moreover, an irrelevant, but active, ribozyme whose binding sequence is not found in either Fit-1 or KDR mRNA had no effect in this assay. These data are consistent with the basic ribozyme mechanism in which binding and cleavage are necessary components. Although the relative surface distribution of Fit-1 and KDR receptors in this cell type is not known, the antiproliferative effects of these ribozymes indicate that, at least in cell culture, both receptors are functionally coupled to proliferation.

Specific reduction of Fit-1 or KDR mRNA by ribozyme treatment: To confirm that anti-Fit-1 and anti-KDR ribozymes reduce their respective mRNA targets, cellular levels of Fit-1 or KDR were quantified using an RNAse protection assay with specific Flt-i or KDR probes. For each target, one ribozyme/attenuated control pair was chosen for continued study.

Exposure of HMVEC-d to active ribozyme targeting Flt-i site 4229 decreased Fit-1 mRNA, but not KDR mRNA. Likewise, treatment with the active ribozyme targeting KDR site 726 decreased KDR, but not Fit-1 niRNA. Both ribozymes decreased the level of their respective target RNA by greater than 50%. The degree of reduction associated with the corresponding attenuated controls was not greater than 13%.

In vitro activity of anti-Fit and anti-KDR ribozymes.

WO 02/096927 PCT/US02/17674 67 To confirm further the necessity of an active ribozyme core, in vitro cleavage activities were determined for the Fit-i site 4229 ribozyme and the KDR site 726 ribozyme as well as their paired attenuated controls. The first order rate constants calculated from the time-course of short substrate cleavage for the anti-Fit-i ribozyme and its attenuated control were 0.081 0.0007 min"' and 0.001 6 x 10 5 minf 1 respectively. For the anti-KDR ribozyme and its paired control, the first order rate constants were 0.434 0.024 min' 1 and 0.002 1 x min', respectively. Although the attenuated controls retain a very slight level of cleavage activity under these optimized conditions, the decrease in in vitro cleavage activity between each active ribozyme and its paired attenuated control is about two orders of magnitude.

Thus, an active core is essential for cleavage activity in vitro and is also necessary for ribozyme activity in cell culture.

Ribozyme-mediated reduction of VEGF-induced angiogenesis in vivo. To assess whether ribozymes targeting VEGF receptor mRNA could impact the complex process of angiogenesis, prototypic anti-Fit-I and KDR ribozymes that were identified in cell culture studies were screened in a rat corneal pocket assay of VEGF-induced angiogenesis. In this assay, corneas implanted with VEGF-containing filter disks exhibited a robust neovascular response in the corneal region between the disk and the corneal limbus (from which the new vessels emerge). Disks containing a vehicle solution elicited no angiogenic response. In separate studies, intraconjunctival injections of sterile water vehicle did not affect the magnitude of the VEGF-induced angiogenic response. In addition, ribozyme injections alone did not induce angiogenesis.

The dose-related effects of anti-Flt-1 or KDR ribozymes on the VEGF-induced angiogenic response were then examined. The antiangiogenic effect of the anti-Flt-1 (site 4229) and KDR (site 726) ribozymes and their attenuated controls over a dose range from 1 to 100 [ig, respectively was determined. For both ribozymes, the maximal antiangiogenic response (48 and 36% for anti-Flt-I and KDR ribozymes, respectively) was observed at a dose of 10 tg.

The anti-Fit-i ribozyme produced a significantly greater antiangiogenic response than its attenuated control at 3 and 10 ig Its attenuated control exhibited a small but significant antiangiogenic response at doses above 10 tg compared to vehicle treated VEGF controls At its maximum, this response was not significantly greater than that observed with the lowest dose of active anti-Flt-I ribozyme. The anti-KDR ribozyme significantly inhibited angiogenesis from 3 to 30 tg The anti-KDR attenuated control had no significant effect at any dose tested.

WO 02/096927 PCT/US02/17674 68 Example 3. In vivo inhibition of tumor growth and metastases by VEGF-R ribozvmes.

A. Lewis Lung Carcinoma Mouse Model: Ribozymes were chemically synthesized as described above. The sequence of ANGIOZYME T M bound to its target RNA is shown in Figure 1.

The tumors in this study were derived from a cell line (LLC-HM) which gives rise to reproducible numbers of spontaneous lung metastases when propagated in vivo. The LLC- HM line was obtained from Dr. Michael O'Reilly, Harvard University. Tumor neovascularization in Lewis lung carcinoma has been shown to be VEGF-dependent. Tumors from mice bearing LLC-HM (selected for the highly metastatic phenotype by serial propagation) were harvested 20 days post-inoculation. A tumor brei suspension was prepared from these tumors according to standard protocols. On day 0 of the study, 0.5 x 106 viable LLC-HM tumor cells were injected subcutaneously (sc) into the dorsum or flank of previously untreated mice (100 gL injectate). Tumors were allowed to grow for a period of 3 days prior to initiating continuous intravenous administration of saline or

ANGIOZYME

T M via Alzet mini-pumps. One set of animals was dosed from days 3 to 17, inclusive. Tumor length and width measurements and volumes were calculated according to the formula: Volume 0.5(length)(width) 2 At post-inoculation day 25, animals were euthanized and lungs harvested. The number of lung macrometastatic nodules was counted.

It should be noted that metastatic foci were quantified 8 days after the cessation of dosing.

Ribozyme solutions were prepared to deliver to another set of animals 100, 10, 3, or 1 mg/kg/day of ANGIOZYMETM via Alzet mini-pumps. A total of 10 animals per dose or saline control group were surgically implanted on the left flank with osmotic mini-pumps prefilled with the respective test solution three days following tumor inoculation. Pumps were attached to indwelling jugular vein catheters.

Figure 2 shows the antitumor effects of ANGIOZYME

T

M. There is a statistically significant inhibition (p 0.05) of primary LLC-HM tumor growth in tumors grown in the flank regions compared to saline control. ANGIOZYMETM significantly reduced (p 0.05) the number of lung metastatic foci in animals inoculated either in the flank regions. Figure 3 illustrates the dose-dependent anti-metastatic effect of ANGIOZYMETM compared to saline control.

B. Mouse Colorectal Cancer Model. KM12L4a-16 is a human colorectal cancer cell line. On day 0 of the study, 0.5 x 106 KM12L4a-16 cells were implanted into the spleen of nude mice. Three days after tumor inoculation, Alzet minipumps were implanted and continuous subcutaneous delivery of either saline or 12, 36 or 100 mg/kg/ day of WO 02/096927 PCT/US02/17674 ANGIOZYMETM was initiated. On day 5, the spleens containing the primary tumors were removed. On day 18, the Alzet minipumps were replaced with fresh pumps so that delivery of saline or ANGIOZYMETM was continuous over a 28 day period from day 3 to day 32.

Animals were euthanized on day 41 and the liver tumor burden was evaluated.

Following treatment with 100 mg/kg/day of ANGIOZYMETM, there was a significant reduction in the incidence and median number of liver metastasis (Figure In salinetreated animals, the median number of metastases was 101. However, at the high dose of ANGIOZYMET (100 mg/kg/day), the median number of metastases was zero.

Example 4: Effect of ANGIOZYMETM alone or in combination with chemotherapeutic agents in the mouse Lewis Lung Carcinoma Model.

Methods Tumor inoculations. Male C57/BL6 mice, age 6 to 8 weeks, were inoculated subcutaneously in the flank with 5 x 105 LLC-HM cells from brei preparations made from tumors grown in mice.

Ribozymes and controls. RPI.4610, also known as ANGIOZYME T (SEQ ID NO: 5977), is an anti-Flt-i ribozyme that targets site 4229 in the human Flt-1 receptor mRNA (EMBL accession no. X51602). The controls tested include RPI.13141, an attenuated version of RPI.4610 in which four nucleotides in the catalytic core are changed so that the cleavage activity is dramatically decreased. RPI.13141, however, maintains the base composition and binding arms of RPI.4610 and so is still capable of binding to the target site. The second control (RPI.13030) also has changes to the catalytic core (three) to inhibit cleavage activity, but in addition the sequence of the binding arms has been scrambled so that it can no longer bind to the target sequence. One nucleotide in the arm of RPI.13030 is also changed to maintain the same base composition as RPI.4610.

Ribozyme administrations. Ribozymes and controls were resuspended in normal saline. Administration was initiated seven days following tumor inoculation. Animals either received a daily subcutaneous injection (30 mg/kg test substance) from day 7 to day 20 or were instrumented with an Alzet osmotic minipump (12 gL/day flow rate) containing a solution of ribozyme or control. Subcutaneous infusion pumps delivered the test substances (30 mg/kg/day) from day 7 to 20 (14-day pumps, 420 mg/kg total test substance) or days 7-34 (28-day pumps, 840 mg/kg total test substance). Where indicated, chemotherapeutic agents were given in combination with ribozyme treatment. Cyclophosphamide was given by intraperitoneal administration on days 7, 9 and 11 (125 mg/kg). Gemcitabine was given by WO 02/096927 PCT/US02/17674 intraperitoneal administration on days 8, 11 and 14 (125 mg/kg). Untreated, uninstrumented animals were used as comparison. Five animals were included in each group.

Results The antiangiogenic ribozyme, ANGIOZYMETM, was tested in a model of Lewis lung carcinoma alone and in combination with two chemotherapeutic agents. Previously (see above), 30 mg/kg/day ANGIOZYMETM alone was determined to inhibit both primary tumor growth and lung metastases in a highly metastatic variant of Lewis lung (continuous 14-day iv deliveryvia Alzet minipump, manuscript in preparation).

In this study, 30 mg/kg/day ANGIOZYIE T M delivered either as a daily subcutaneous bolus injection or as a continuous infusion from an Alzet minipump resulted in a delay in tumor growth. On average, tumor growth to 500 mm 3 was delayed by ~7 days in animals being treated with ANGIOZYMETM compared to an untreated group. Growth of tumors in animals being treated with either of two attenuated controls was delayed by only 2 days.

ANGIOZYME

T M delivered by subcutaneous bolus was also tested in combination with either Gemcytabine or cyclophosphamide. Tumor growth delay increased by about 3 days in the presence of combination therapy with ANGIOZYMETM and Gemcytabine over the effects of either treatment alone. The combination of ANGIOZYMETM and cyclophosphamide did not increase tumor growth delay over that of cyclophosphamide alone, however, suboptimal doses of cyclophosphamide were not included in this study. Neither of the attenuated controls increased the effect of the chemotherapeutic agents.

The effect of ANGIOZYME T M on metastases to the lung was also determined in the presence and absence of additional chemotherapeutic treatment. Macrometastases to the lungs were counted in two animals in each treatment group on day 20. In the presence of ANGIOZYMETM, with or without a chemotherapeutic agent, the lung metastases were reduced to zero. Treatment with either Gemcytabine or cyclophosphamide alone (mean number of metastases 4.5 and 4, respectively) were not as effective as ANGIOZYMETM alone or when used in combination with ANGIOZYMETM. Neither of the attenuated controls increased the effect of the chemotherapeutic agents.

The effect on metastases to the lung was also determined following continuous treatment with ANGIOZYMETM. At day 20, an average of -8 macrometastases were noted in the treatment groups which had been instrumented with Alzet minipumps (either 14- or 28day pumps). This is a decrease in metastases of ~50% from the untreated group. Since WO 02/096927 PCT/US02/17674 71 ANGIOZYMETM delivered by a daily subcutaneous bolus resulted in zero metastases (Fig.4) in the two animals counted, it is possible that the additional burden of being instrumented with the minipump contributes to a slightly decreased response to ANGIOZYMETM.

Example 5: Identification of Potential Target Sites in Human VEGFR1 and/or VEGFR2 RNA The sequence of human VEGFR1 and/or VEGFR2 genes are screened for accessible sites using a computer-folding algorithm. Regions of the RNA that do not form secondary folding structures and contain potential enzymatic nucleic acid molecule and/or antisense binding/cleavage sites are identified. An exemplary sequence of an enzymatic nucleic acid molecule of the invention is shown in Formula I and/or Formula II (SEQ ID Nos: 5977 and 5978, respectively). Other nucleic acid molecules and targets contemplated by the invention are described in Pavoy et al., US Patent Application No. 09/870,161, incorporated by reference herein in its entirety. Similarly, other nucleic acid molecules of the invention, including antisense, aptamers, dsRNA, siRNA, and/or 2,5-A chimeras, can be designed to modulate the expression of the nucleic acid targets described in Pavco et al., US Patent Application No. 09/870,161.

Example 6: Selection of Enzymatic Nucleic Acid Cleavage Sites in Human VEGFR1 and/or VEGFR2 RNA Enzymatic nucleic acid molecule target sites are chosen by analyzing sequences of human VEGFR1 receptor (for example Genbank Accession No. NM_002019), and VEGFR2 receptor (for example Genbank Accession No. NM_002253) genes and prioritizing the sites on the basis of folding. Enzymatic nucleic acid molecules are designed that can bind each target and are individually analyzed by computer folding (Christoffersen et al., 1994 J. Mol.

Struc. Theochem, 311, 273; Jaeger et al., 1989, Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the enzymatic nucleic acid molecule sequences fold into the appropriate secondary structure. Those enzymatic nucleic acid molecules with unfavorable intramolecular interactions between the binding arms and the catalytic core can be eliminated from consideration. As discussed herein, varying binding arm lengths can be chosen to optimize activity. Generally, at least 4 bases on each arm are able to bind to, or otherwise interact with, the target RNA.

Example 7: Chemical Synthesis and Purification of Ribozvmes and Antisense for Efficient Cleavage and/or blocking of VEGFR1 and/or VEGFR2 RNA WO 02/096927 PCT/US02/17674 72 Enzymatic nucleic acid molecules and antisense constructs are designed to anneal to various sites in the RNA message. The binding arms of the enzymatic nucleic acid molecules are complementary to the target site sequences described above, while the antisense constructs are fully complementary to the target site sequences described above. RNAi molecules (dsRNA) likewise have one strand of RNA or a portion of RNA complementarity to the target site sequence or a portion of the target site sequence. For example, complementarity within the double-strand RNAi structure is formed from two separate individual RNA strands or from self-complementary areas of a topologically closed, individual RNA strand which can be optionally circular. The nucleic acid molecules were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis as described above and in Usman et al., (1987 J. Am. Chem. Soc., 109, 7845), Scaringe et al., (1990 Nucleic Acids Res., 18, 5433) and Wincott et al., supra, and made use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5'-end, and phosphoramidites at the 3'-end. The average stepwise coupling yields were typically >98%.

Nucleic acid molecules are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51). Nucleic acid molecules of the invention are purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Wincott et al., supra; the totality of which is hereby incorporated herein by reference) and are resuspended in water.

Examples of sequences of chemically synthesized enzymatic nucleic acid molecules are shown in Formula I (SEQ ID NO: 5977), Formula II (SEQ ID NO: 5978) and in Pavco et al., US Patent Application No. 09/870,161.

Example 8: Enzymatic Nucleic Acid Molecule Cleavage of VEGFRI and/or VEGFR2 RNA Target in vitro Enzymatic nucleic acid molecules targeted to the human VEGFR1 and/or VEGFR2 RNA are designed and synthesized as described above. These enzymatic nucleic acid molecules can be tested for cleavage activity in vitro, for example, using the following procedure. The target sequences and the nucleotide location within the VEGFR1 and/or VEGFR2 RNA are described in Pavco et al., US Patent Application No. 09/870,161.

Cleavage Reactions: Full-length or partially full-length, internally-labeled target RNA for enzymatic nucleic acid molecule cleavage assay is prepared by in vitro transcription in the presence of [a- 32 p] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA without further purification. Alternately, substrates are 5'- 32 P-end WO 02/096927 PCT/US02/17674 73 labeled using T4 polynucleotide kinase enzyme. Assays are performed by pre-warming a 2X concentration of purified enzymatic nucleic acid molecule in enzymatic nucleic acid molecule cleavage buffer (50 mM Tris-HC1, pH 7.5 at 37 0 C, 10 mM MgCI 2 and the cleavage reaction was initiated by adding the 2X enzymatic nucleic acid molecule mix to an equal volume of substrate RNA (maximum of 1-5 nM) that was also pre-warmed in cleavage buffer. As an initial screen, assays are carried out for 1 hour at 37°C using a final concentration of either nM or 1 mM enzymatic nucleic acid molecule, enzymatic nucleic acid molecule excess.

The reaction is quenched by the addition of an equal volume of 95% formamide, 20 mM EDTA, 0.05% bromophenol blue and 0.05% xylene cyanol after which the sample is heated to 95"C for 2 minutes, quick chilled and loaded onto a denaturing polyacrylamide gel.

Substrate RNA and the specific RNA cleavage products generated by enzymatic nucleic acid molecule cleavage are visualized on an autoradiograph of the gel. The percentage of cleavage is determined by Phosphor Imager® quantitation of bands representing the intact substrate and the cleavage products.

Example 9: Phase I/I Study of Repetitive Dosing of ANGIOZYMETM Targeting the VEGFR1 (FLT-1) Receptor of VEGF A ribozyme therapeutic agent ANGIOZYMETM (SEQ ID NO: 5977), was assessed by daily subcutaneous administration in a phase I/II trial for 31 patients with refractory solid tumors.

Demographic information relating to patients enrolled in the study are shown in Table III.

The primary study endpoint was to determine the safety and maximum tolerated dose of ANGIOZYMETM. Secondary endpoints assessed ANGIOZYME T M pharmacokinetics and clinical response. Patients were treated at the following doses: 3 patients received doses of mg/m 2 /day, 4 patients received 30 mg/m 2 /day, 20 patients received 100 mg/m 2 /day, and 4 patients received 300 mg/m 2 /day. All but one patient were dosed for a minimum of 29 consecutive days with 24-hour pharmacokinetic analyses on Day 1 and 29. Clinical response was assessed monthly. Results The data from 20 patients indicated that ANGIOZYMETM was well tolerated, with no systemic adverse events. Figure 5 shows the plasma concentration profile of ANGIOZYMETM after a single subcutaneous dose of 10, 100, or 300 mg/m 2 The pharmacokinetic parameters of ANGIOZYME T M after subcutaneous bolus administration are outlined in Table IV. An MTD (maximum tolerated dose) could not be established. One patient in the 300 mg/m 2 /d group experienced a grade 3 injection site reaction. Patients in the other groups experienced intermittent grade 1 and grade 2 injection site reactions with erythema and induration. No systemic or laboratory toxicities were observed. Pharmacokinetic analyses demonstrated dose-dependent plasma concentrations with good bioavailability tl/2 209-384 min, and no accumulation after repeated WO 02/096927 PCT/US02/17674 74 doses. To date, 17/28 of evaluable patients have had stable disease for periods of one to six months and two patients (nasopharyngeal squamous cell carcinoma and melanoma) had minor clinical responses. The patient with nasopharyngeal carcinoma demonstrated central tumor necrosis as indicated by MRI. The longest period of treatment thus far has been 8 months for two patients at 100 mg/m 2 /d (breast, peritoneal mesothelioma).

Example 10: Down-regulation of VEGFR1 gene expression to treat gynecologic neovascularization dependent conditions One patient in the Phase I/Il trial described in Example 19 was menstruating prior to enrollment in the ANGIOZYMETM monotherapy trial. After 1-2 months on trial, the patient's menstrual cycles ceased. The patient remained on trial for approximately 11 months and did not menstruate. The patient then went off the trial for about 4 months and the menstrual cycles resumed. Re-enrollment in the ANGIOZYMETM trial resulted in the patient's menstrual cycle stopping again. This clinical observation suggests that ANGIOZYMETM is interfering with the patient's menstrual cycle, perhaps by inhibiting neovascularization of uterine tissue. This data also suggests that ANGIOZYMETM has a direct effect on the endometrial tissue or an effect on LHIFSH stimulation. These results suggest the treatment or control, using ANGIOZYMETM (SEQ ID NO: 5977) and/or other nucleic acid molecules of the instant invention, of various clinical targets and/or processes associated with female reproduction and gynecologic neovascularization, such as endometriosis, birth control, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, endometrial carcinoma or other condition associated with the expression of VEGFR1 and/or VEGFR2 VEGF receptors.

Example 11: Down-regulation of VEGFR1 in clinical setting Twenty-seven of the patients enrolled in the Phase ViII trial described in Example 19 had day 1 (baseline) and day 43 (six-week) serum samples assayed for VEGFR1 biomarker.

VEGFR1 levels were statistically different after six weeks of ANGIOZYME treatment (Figure Although statistical testing involving all 27 patients showed statistical support for effects, not all patients presented with elevated levels of VEGF-R1. Since the effects of ANGIOZYME on VEGF-R1 may only be demonstrated when sufficient levels are present at baseline, a cutoff of 100 pg/mL was chosen and changes in this VEGF-R1 were re-analyzed.

Ten of the 27 patients presented with baseline VEGF-R1 levels in excess of 100 pg/mL. For this subgroup VEGF-R1 levels were lower by 3-fold, p<.001. After six weeks of treatment the average (geometric mean) of VEGF-RI decreased for this subgroup from 419 pg/ml to WO 02/096927 PCT/US02/17674 1 3 2pg/ml, p<.001. These results show that treatment with ANGIOZYME results in a statistically significant reduction in VEGFR1 expression.

Example 22: In vivo inhibition of neovascularization in an ocular animal model by VEGF-R ribozymes.

Summary of the Mouse Model: A mouse model of proliferative retinopathy (Aiello et al., 1995, Proc. Natl. Acad. Sci. USA 92: 10457-10461; Robinson et al., 1996, Proc. Natl.

Acad. Sci. USA 93: 4851-4856; Pierce et al., 1996, Archives of Ophthalmology 114: 1219- 1228) in which neovascularization of the mouse retina is induced by exposure of 7-day old mice to 75% oxygen followed by a return to normal room air. The initial period in high oxygen causes an obliteration of developing blood vessels in the retina. Exposure to room air five days later is perceived as hypoxia by the now underperfused retina. The result is an immediate upregulation of VEGF mRNA and VEGF protein (between 6-12 hours) followed by an extensive retinal neovascularization that peaks in -5 days. Although this model is more representative of retinopathy of prematurity than diabetic retinopathy, it is an accepted small animal model in which to study neovascular pathophysiology of the retina. In fact, intravitreal injection of certain antisense DNA constructs targeting VEGF mRNA have been found to be antiangiogenic in this model, as were soluble VEGF receptor chimeric proteins designed to bind VEGF in the vitreous humor (Aiello et al., 1995, Proc. Natl. Acad. Sci. USA 92: 10457-10461; Robinson et al., 1996, Proc. Natl. Acad. Sci. USA 93: 4851-4856; Pierce et al., 1996, Archives of Ophthalmology 114: 1219-1228).

Summary of experiment: The effect of an anti-KDR/Flk-1 ribozyme on the peak level of neovascularization was tested in the mouse model described above. As shown in Figure P7 mice were removed from the hyperoxic chamber and the mice received two intraocular injections (P12 and P13) in the right eye of 10 gg RPI.4731, the anti- KDR/Flk-1 ribozyme.

The left eye of each mouse was treated as a control and received intraocular injections of saline. Five days after being exposed to room air, neovascular nuclei in the retina of both eyes were counted. Data are presented in Figure 11. There was a significant decrease in retinal neovascularization compared to the control, saline-injected eyes.

RPI.4731 sequence and chemical composition: 5'-usasCs asau ucU GAu Gag gcg aaa gcc Gaa Aag aca aB-3' (SEQ ID NO: 5978) where: uppercase G, A ribonucleotides lowercase 2'-OMe U 2'-C-allyl uridine WO 02/096927 PCT/US02/17674 76 B inverted abasic nucleotide S phosphorothioate internucleotide linkage Indications 1) Tumor angiogenesis: Angiogenesis has been shown to be necessary for tumors to grow into pathological size (Folkman, 1971, PNAS 76, 5217-5221; Wellstein Czubayko, 1996, Breast Cancer Res and Treatment 38, 109-119). In addition, it allows tumor cells to travel through the circulatory system during metastasis. Increased levels of gene expression of a number of angiogenic factors such as vascular endothelial growth factor (VEGF) have been reported in vascularized and edema-associated brain tumors (Berkman et al., 1993 J.

Clini. Invest. 91, 153). A more direct demostration of the role of VEGF in tumor angiogenesis was demonstrated by Jim Kim et al., 1993 Nature 362,841 wherein, monoclonal antibodies against VEGF were successfully used to inhibit the growth ofrhabdomyosarcoma, glioblastoma multiforme cells in nude mice. Similarly, expression of a dominant negative mutated form of the fit-1 VEGF receptor inhibits vascularization induced by human glioblastoma cells in nude mice (Millauer et al., 1994, Nature 367, 576). Specific tumor/cancer types that can be targeted using the nucleic acid molecules of the invention include but are not limited to the tumor/cancer types described under Diagnosis in Table III.

2) Ocular diseases: Neovascularization has been shown to cause or exacerbate ocular diseases including but not limited to, macular degeneration, neovascular glaucoma, diabetic retinopathy, myopic degeneration, and trachoma (Norrby, 1997, APMIS 105, 417-437). Aiello et al., 1994 New Engl. J. Med. 331, 1480, showed that the ocular fluid, of a majority of patients suffering from diabetic retinopathy and other retinal disorders, contains a high concentration of VEGF. Miller et al., 1994 Am. J. Pathol. 145, 574, reported elevated levels of VEGF mRNA in patients suffering from retinal ischemia. These observations support a direct role for VEGF in ocular diseases. Other factors including those that stimulate VEGF synthesis may also contribute to these indications.

3) Dermatological Disorders: Many indications have been identified which may by angiogenesis dependent including but not limited to psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot-wine stains, Sturge Weber syndrome, Kippel-Trenaunay-Weber syndrome, and Osler-Weber-Rendu syndrome (Norrby, supra). Intradennal injection of the angiogenic factor b-FGF demonstrated angiogenesis in nude mice (Weckbecker et al., 1992, Angiogenesis: Key principles-Science-Technology-Medicine, ed R. Steiner) Detmar et al., 1994 J. Exp. Med. 180, 1141 reported that VEGF and its receptors were over-expressed in WO 02/096927 PCT/US02/17674 77 psoriatic skin and psoriatic dermal microvessels, suggesting that VEGF plays a significant role in psoriasis.

4) Rheumatoid arthritis: Immunohistochemistry and in situ hybridization studies on tissues from the joints of patients suffering from rheumatoid arthritis show an increased level of VEGF and its receptors (Fava et al., 1994 J Exp. Med. 180, 341). Additionally, Koch et al., 1994 J. Immunol. 152, 4149, found that VEGF-specific antibodies were able to significantly reduce the mitogenic activity of synovial tissues from patients suffering from rheumatoid arthritis. These observations support a direct role for VEGF in rheumatoid arthritis. Other angiogenic factors including those of the present invention may also be involved in arthritis.

Endometriosis: Various studies indicate that VEGF is directly implicated in endometriosis. In one study, VEGF concentrations measured by ELISA in peritoneal fluid were found to be significantly higher in women with endometriosis than in women without endometriosis (24.1 15 ng/ml vs 13.3 7.2 ng/ml in normals). In patients with endometriosis, higher concentrations of VEGF were detected in the proliferative phase of the menstrual cycle (33 13 ng/ml) compared to the secretory phase (10.7 5 ng/ml). The cyclic variation was not noted in fluid from normal patients (McLaren et al., 1996, Human Reprod.

11, 220-223). In another study, women with moderate to severe endometriosis had significantly higher concentrations of peritoneal fluid VEGF than women without endometriosis. There was a positive correlation between the severity of endometriosis and the concentration of VEGF in peritoneal fluid. In human endometrial biopsies, VEGF expression increased relative to the early proliferative phase approximately and 3.6-fold in midproliferative, late proliferative, and secretory endometrium (Shifren et al., 1996, J. Clin.

Endocrinol. Metab. 81, 3112-3118).

In a third study, VEGF-positive staining of human ectopic endometrium was shown to be localized to macrophages (double immunofluorescent staining with CD14 marker).

Peritoneal fluid macrophages demonstrated VEGF staining in women with and without endometriosis. However, increased activation of macrophages (acid phosphatatse activity) was demonstrated in fluid from women with endometriosis compared with controls.

Peritoneal fluid macrophage conditioned media from patients with endometriosis resulted in significantly increased cell proliferation thymidine incorporation) in HUVEC cells compared to controls. The percentage of peritoneal fluid macrophages with VEGFR2 mRNA was higher during the secretory phase, and significantly higher in fluid from women with endometriosis (80 15%) compared with controls (32 Flt-mRNA was detected in WO 02/096927 PCT/US02/17674 78 peritoneal fluid macrophages from women with and without endometriosis, but there was no difference between the groups or any evidence of cyclic dependence (McLaren et al., 1996, J.

Clin. Invest. 98, 482-489).

In the early proliferative phase of the menstrual cycle, VEGF has been found to be expressed in secretory columnar epithelium (estrogen-responsive) lining both the oviducts and the uterus in female mice. During the secretory phase, VEGF expression was shown to have shifted to the underlying stroma composing the functional endometrium. In addition to examining the endometrium, neovascularization of ovarian follicles and the corpus luteum, as well as angiogenesis in embryonic implantation sites have been analyzed. For these processes, VEGF was expressed in spatial and temporal proximity to forming vasculature (Shweiki et al., 1993, J. Cin. Invest. 91, 2235-2243).

The present body of knowledge in VEGFR1 and/or VEGFR2 research indicates the need for methods to assay VEGFR1 and/or VEGFR2 activity and for compounds that can regulate VEGFR1 and/or VEGFR2 expression for research, diagnostic, and therapeutic use.

As described herein, the nucleic acid molecules of the present invention can be used in assays to diagnose disease state related of VEGF, VEGFRI and/or VEGFR2 levels. In addition, the nucleic acid molecules can be used to treat disease state related to VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 levels.

Particular processes, diseases, or conditions that can be associated with VEGFR1 and/or VEGFR2 levels include, but are not limited to, gynecologic neovascularization, such as endometriosis, endometrial carcinoma, gynecologic bleeding disorders, irregular menstrual cycles, ovulation, premenstrual syndrome (PMS), menopausal dysfunction, other diseases and conditions discussed herein, and other diseases or conditions that are related to or respond to the levels of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2, in a cell or tissue, alone or in combination with other therapies The use of GnRH (gonadotropin releasing hormone) agonists, Lupron Depot (Leuprolide Acetate), Synarel (naferalin acetate), Zolodex (goserelin acetate), Suprefact (buserelin acetate), Danazol, or oral contraceptives including, but not limited to, Depo-Provera or Provera (medroxyprogesterone acetate), or any other estrogen/progesterone contraceptive, are all non-limiting examples of compounds and methods that can be combined with or used in conjunction with the nucleic acid molecules of the instant invention. Various chemotherapies can be readily combined with nucleic acid molecules of the invention for the treatment of endometrial carcinoma. Common chemotherapies that can be combined with nucleic acid molecules of the instant invention include various combinations of cytotoxic drugs to kill the WO 02/096927 PCT/US02/17674 79 cancer cells. These drugs include but are not limited to paclitaxel (Taxol), docetaxel, cisplatin, methotrexate, cyclophosphamide, doxorubin, fluorouracil carboplatin, edatrexate, gemcitabine, vinorelbine etc. Those skilled in the art will recognize that other drug compounds and therapies can be readily combined with the nucleic acid molecules of the instant invention and are hence within the scope of the instant invention.

Animal Models There are several animal models in which the anti-angiogenesis effect of nucleic acids of the present invention, such as ribozymes, directed against VEGF-R mRNAs can be tested.

Typically, a corneal model has been used to study angiogenesis in rat and rabbit since recruitment of vessels can easily be followed in this normally avascular tissue (Pandey et al., 1995 Science 268: 567-569). In these models, a small Teflon or Hydron disk pretreated with an angiogenesis factor bFGF or VEGF) is inserted into a pocket surgically created in the cornea. Angiogenesis is monitored 3 to 5 days later. Ribozymes directed against VEGF-R mRNAs would be delivered in the disk as well, or dropwise to the eye over the time course of the experiment. In another eye model, hypoxia has been shown to cause both increased expression of VEGF and neovascularization in the retina (Pierce et al., 1995 Proc. Natl.

Acad. Sci. USA. 92: 905-909; Shweiki et al., 1992 J Clin. Invest. 91: 2235-2243).

In human glioblastomas, it has been shown that VEGF is at least partially responsible for tumor angiogenesis (Plate et al., 1992 Nature 359, 845). Animal models have been developed in which glioblastoma cells are implanted subcutaneously into nude mice and the progress of tumor growth and angiogenesism is studied (Kim et al., 1993 supra; Millauer et al., 1994 supra).

Another animal model that addresses neovascularization involves Matrigel, an extract of basement membrane that becomes a solid gel when injected subcutaneously (Passaniti et al., 1992 Lab. Invest. 67: 519-528). When the Matrigel is supplemented with angiogenesis factors such as VEGF, vessels grow into the Matrigel over a period of 3 to 5 days and angiogenesis can be assessed. Ribozymes directed against VEGF-R mRNAs can be delivered in the Matrigel to assess anti-angiogesis effect.

Several animal models exist for screening of anti-angiogenic agents. These include corneal vessel formation following corneal injury (Burger et al., 1985 Cornea 4: 35-41; Lepri, et al., 1994 J. Ocular Pharmacol. 10: 273-280; Onnerod et al., 1990 Am. J. Pathol.

137: 1243-1252) or intracomeal growth factor implant (Grant et al., 1993 Diabetologia 36: 282-291; Pandey et al 1995 supra; Zieche et al., 1992 Lab. Invest. 67: 711-715), vessel WO 02/096927 PCT/US02/17674 growth into Matrigel matrix containing growth factors (Passaniti et al., 1992 supra), female reproductive organ neovascularization following hormonal manipulation (Shweiki et al., 1993 Clin. Invest. 91: 2235-2243), several models involving inhibition of tumor growth in highly vascularized solid tumors (O'Reilly et al., 1994 Cell 79: 315-328; Senger et al., 1993 Cancer and Metas. Rev. 12: 303-324; Takahasi et al., 1994 Cancer Res. 54: 4233-4237; Kim et al., 1993 supra), and transient hypoxia-induced neovascularization in the mouse retina (Pierce et al., 1995 Proc Natl. Acad. Sci. USA. 92: 905-909).

The corea model, described in Pandey et al. supra, is the most common and well characterized anti-angiogenic agent efficacy screening model. This model involves an avascular tissue into which vessels are recruited by a stimulating agent (growth factor, thermnnal or alkalai bum, endotoxin). The corneal model utilizes the intrastromal corneal implantation of a Teflon pellet soaked in a VEGF-Hydron solution to recruit blood vessels toward the pellet which can be quantitated using standard microscopic and image analysis techniques. To evaluate their anti-angiogenic efficacy, ribozymes are applied topically to the eye or bound within Hydron on the Teflon pellet itself. This avascular cornea as well as the Matrigel (see below) provide for low background assays. While the corneal model has been performed extensively in the rabbit, studies in the rat have also been conducted.

The mouse model (Passaniti et al., supra) is a non-tissue model which utilizes Matrigel, an extract of basement membrane (Kleinman et al., 1986) or Millipore® filter disk, which can be impregnated with growth factors and anti-angiogenic agents in a liquid form prior to injection. Upon subcutaneous administration at body temperature, the Matrigel or Millipore® filter disk forms a solid implant. VEGF embedded in the Matrigel or Millipore® filter disk would be used to recruit vessels within the matrix of the Matrigel or Millipore® filter disk which can be processed histologically for endothelial cell specific vWF (factor VIII antigen) immunohistochemistry, Trichrome-Masson stain, or hemoglobin content. Like the cornea, the Matrigel or Millipore® filter disk are avascular; however, it is not tissue. In the Matrigel or Millipore® filter disk model, ribozymes are administered within the matrix of the Matrigel or Millipore® filter disk to test their anti-angiogenic efficacy. Thus, delivery issues in this model, as with delivery of ribozymes by Hydron- coated Teflon pellets in the rat cornea model, are minimized due to the homogeneous presence of the ribozyme within the respective matrix.

These models offer a distinct advantage over several other angiogenic models listed previously. The ability to use VEGF as a pro-angiogenic stimulus in both models is highly desirable since ribozymes target only VEGFr mRNA. In other words, the involvement of WO 02/096927 PCT/US02/17674 81 other non-specific types of stimuli in the cornea and Matrigel models is not advantageous from the standpoint of understanding the pharmacologic mechanism by which the anti- VEGFr mRNA ribozymes produce their effects. In addition, the models allow for testing the specificity of the anti-VEGFr mRNA ribozymes by using either aFGF or bFGF as a proangiogenic factor. Vessel recruitment using FGF should not be affected in either model by anti-VEGFr mRNA ribozymes. Other models of angiogenesis, including vessel formation in the female reproductive system using hormonal manipulation (Shweiki et al., 1993 supra); a variety of vascular solid tumor models which involve indirect correlations with angiogenesis (O'Reilly et al., 1994 supra; Senger et al., 1993 supra; Takahasi et al., 1994 supra; Kim et al., 1993 supra); and retinal neovascularization following transient hypoxia (Pierce et al., 1995 supra), were not selected for efficacy screening due to their non-specific nature, although they can be useful models due to a demonstrated correlation between VEGF and angiogenesis.

Other model systems to study tumor angiogenesis is reviewed by Folkman, 1985 Adv.

Cancer. Res.. 43, 175.

Use ofmurine models For a typical systemic study involving 10 mice (20 g each) per dose group, 5 doses (1, 3, 10, 30 and 100 mg/kg daily over 14 days continuous administration), approximately 400 mg of ribozyme, formulated in saline would be used. A similar study in young adult rats (200 g) would require over 4 g. Parallel pharmacokinetic studies involve the use of similar quantities of ribozymes further justifying the use of murine models.

Ribozymes and Lewis lung carcinoma and B-16 melanoma murine models Identifying a common animal model for systemic efficacy testing of ribozymes is an efficient way of screening ribozymes for systemic efficacy.

The Lewis lung carcinoma and B-16 murine melanoma models are well accepted models of primary and metastatic cancer and are used for initial screening of anti-cancer agents. These murine models are not dependent upon the use of immunodeficient mice, are relatively inexpensive, and minimize housing concerns. Both the Lewis lung and B-16 melanoma models involve subcutaneous implantation of approximately 106 tumor cells from metastatically aggressive tumor cell lines (Lewis lung lines 3LL or D122, LLc-LN7; B-16- BL6 melanoma) in C57BL/6J mice. Alternatively, the Lewis lung model can be produced by the surgical implantation of tumor spheres (approximately 0.8 mm in diameter). Metastasis WO 02/096927 PCT/US02/17674 82 also can be modeled by injecting the tumor cells directly intraveneously. In the Lewis lung model, microscopic metastases can be observed approximately 14 days following implantation with quantifiable macroscopic metastatic tumors developing within 21-25 days.

The B-16 melanoma exhibits a similar time course with tumor neovascularization beginning 4 days following implantation. Since both primary and metastatic tumors exist in these models after 21-25 days in the same animal, multiple measurements can be taken as indices of efficacy. Primary tumor volume and growth latency as well as the number of micro- and macroscopic metastatic lung foci or number of animals exhibiting metastases can be quantitated. The percent increase in lifespan can also be measured. Thus, these models provide suitable primary efficacy assays for screening systemically administered ribozymes/ribozyme formulations.

In the Lewis lung and B-16 melanoma models, systemic pharmacotherapy with a wide variety of agents usually begins 1-7 days following tumor implantation/inoculation with either continuous or multiple administration regimens. Concurrent pharmacokinetic studies can be performed to determine whether sufficient tissue levels of ribozymes can be achieved for pharmacodynamic effect to be expected. Furthermore, primary tumors and secondary lung metastases can be removed and subjected to a variety of in vitro studies target RNA reduction).

Flt-1, KDR and/or flk-1 protein levels can be measured clinically or experimentally by FACS analysis. Flt-1, KDR and/or flk-1 encoded mRNA levels can be assessed by Northern analysis, RNase-protection, primer extension analysis and/or quantitative RT-PCR.

Ribozymes that block flt-1, KDR and/or flk-1 protein encoding mRNAs and therefore result in decreased levels of flt-1, KDR and/or flk-1 activity by more than 20% in vitro can be identified.

Ribozymes and/or genes encoding them are delivered by either free delivery, liposome delivery, cationic lipid delivery, adeno-associated virus vector delivery, adenovirus vector delivery, retrovirus vector delivery or plasmid vector delivery in these animal model experiments (see above).

Subjects can be treated by locally administering nucleic acids targeted against VEGF-R by direct injection. Routes of administration include, but are not limited to, intravascular, intramuscular, subcutaneous, intraarticular, aerosol inhalation, oral (tablet, capsule or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery.

WO 02/096927 PCT/US02/17674 83 Surgically induced models of endometriosis have been developed in rats, mice, and rabbits. Non-human primates demonstrate spontaneous endometriosis, but surgical induction can also be used. In addition to the surgical technique, cycle monitoring can be performed by daily vaginal cytology in primates. For all of the surgically induced models of endometriosis, the following general procedure is used. An initial laparotomy is performed to implant tissue from a donor animal. A portion of one uterine horn (or one complete horn in the case of mice) is removed. The endometrium of this piece of uterus is separated from the myometrium and cut into small segments (4-10 rmn2). Segments (approximately 3) are sutured to various locations within the abdominal cavity (peritoneum, intestinal mesentery vessels, uterus, broad ligament). Cummings and Metcalf (1996) attached whole segments of mouse uterus without separating the endometrium from the myometrium. Implants are allowed to grow for 3-6 weeks. A second laparotomy is sometimes performed to verify development of endometriosis-like foci (vascularization and cysts filled with clear fluid). This second laparotomy was done in the studies by Quereda et al., (1996) and Stoeckemann et al., (1995).

After 3-6 weeks post-surgery and/or following visualization of endometriosis, drug treatment is initiated and continued for a prescribed period of time. At the termination of these studies, animals are euthanized. Endpoints include, but are not limited to, changes in the surface area of the implants and tissue mass of the ectopic endometrial implants (see for example Brogniez et al., 1995, Human Reprod. 10, 927-931; Cummings et al., 1996, Tox. Appl.

Pharm. 138, 131-139; Cummings and Metcalf, 1996, Proc. Soc. Exp. Biol. Med. 212, 332- 337; D'Hooghe et al., 1996, Fertility and Sterility. 66, 809-813; Quereda et al., 1996, Eur. J.

Obstet. Gynecol. Rep. Biol. 67, 35-40; and Stoeckemann et al., 1995, Human Reprod. 3264-3271).

Combination therapies Gemcytabine and cyclophosphamide are non-limiting examples of chemotherapeutic agents that can be combined with or used in conjunction with the nucleic acid molecules (e.g.

ribozymes and antisense molecules) of the instant invention. Those skilled in the art will recognize that other anti-angiogenic and/or anti-cancer compounds and therapies can be similarly be readily combined with the nucleic acid molecules of the instant invention (e.g.

ribozymes and antisense molecules) and are hence within the scope of the instant invention.

Such compounds and therapies are well known in the art (see for example Cancer: Principles WO 02/096927 PCT/US02/17674 84 and Pranctice of Oncology, Volumes 1 and 2, eds Devita, Hellman, and Rosenberg, J.B. Lippincott Company, Philadelphia, USA; incorporated herein by reference) and include, without limitations, folates, antifolates, pyrimidine analogs, fluoropyrimidines, purine analogs, adenosine analogs, topoisomerase I inhibitors, anthrapyrazoles, retinoids, antibiotics, anthacyclins, platinum analogs, alkylating agents, nitrosoureas, plant derived compounds such as vinca alkaloids, epipodophyllotoxins, tyrosine kinase inhibitors, taxols, radiation therapy, surgery, nutritional supplements, gene therapy, radiotherapy, for example 3D-CRT, immunotoxin therapy, for example ricin, and monoclonal antibodies. Specific examples of chemotherapeutic compounds than can be combined with or used in conjuction with the nucleic acid molecules of the invention include but are not limited to Paclitaxel; Docetaxel; Methotrexate; Doxorubin; Edatrexate; Vinorelbine; Tomaxifen; Leucovorin; fluoro uridine Irinotecan (CAMPTOSAR) or CPT-11 or Camptothecin-11 or Campto); Cisplatin; Carboplatin; Amsacrine; Cytarabine; Bleomycin; Mitomycin C; Dactinomycin; Mithramycin; Hexamethylmelamine; Dacarbazine; L-asperginase; Nitrogen mustard; Melphalan, Chlorambucil; Busulfan; Ifosfamide; 4-hydroperoxycyclophosphamide, Thiotepa; Tamoxifen, Herceptin; IMC C225; ABX-EGF: and combinations thereof.

Diagnostic uses The nucleic acid molecules of this invention enzymatic nucleic acid molecules) can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of VEGF and/or VEGFr, such as VEGFR1 and/or VEGFR2 RNA in a cell. The close relationship between enzymatic nucleic acid molecule activity and the structure of the target RNA allows the detection of mutations in any region of the molecule which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple enzymatic nucleic acid molecules described in this invention, one can map nucleotide changes which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with enzymatic nucleic acid molecules can be used to inhibit gene expression and define the role (essentially) of specified gene products in the progression of disease. In this manner, other genetic targets can be defined as important mediators of the disease. These experiments can lead to better treatment of the disease progression by affording the possibility of combinational therapies multiple enzymatic nucleic acid molecules targeted to different genes, enzymatic nucleic acid molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations of enzymatic nucleic acid molecules and/or other chemical or biological molecules). Other in WO 02/096927 PCT/US02/17674 vitro uses of enzymatic nucleic acid molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with VEGF, VEGFR1 and/or VEGFR2-related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an enzymatic nucleic acid molecule using standard methodology.

In a specific example, enzymatic nucleic acid molecules which cleave only wild-type or mutant forms of the target RNA are used for the assay. The first enzymatic nucleic acid molecule is used to identify wild-type RNA present in the sample and the second enzymatic nucleic acid molecule is used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both enzymatic nucleic acid molecules to demonstrate the relative enzymatic nucleic acid molecule efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis requires two enzymatic nucleic acid molecules, two substrates and one unknown sample which is combined into six reactions. The presence of cleavage products is determined using an RNAse protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype VEGFR1 and/or VEGFR2) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels will be adequate and will decrease the cost of the initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively. The use of enzymatic nucleic acid molecules in diagnostic applications contemplated by the instant invention is described, for example, in Usman et al., US Patent Application No. 09/877,526, George et al., US Patent Nos. 5,834,186 and 5,741,679, Shih et al., US Patent No. 5,589,332, Nathan et al., US Patent No 5,871,914, Nathan and Ellington, International PCT publication No. WO 00/24931, Breaker et al., International PCT Publication Nos. WO 00/26226 and 98/27104, and Sullenger et al., US Patent Application Serial No. 09/205,520.

Additional Uses Uses of sequence-specific enzymatic nucleic acid molecules of the instant invention can have many of the same applications for the study of RNA that DNA restriction endonucleases have for the study of DNA (Nathans et al., 1975 Ann. Rev. Biochem. 44:273). For example, WO 02/096927 PCT/US02/17674 86 the pattern of restriction fragments can be used to establish sequence relationships between two related RNAs, and large RNAs can be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the enzymatic nucleic acid molecule is ideal for cleavage of RNAs of unknown sequence. Applicant has described the use of nucleic acid molecules to down-regulate gene expression of target genes in bacterial, microbial, fungal, viral, and eukaryotic systems including plant, or mammalian cells.

All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.

One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims.

The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of' and "consisting of' may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.

WO 02/096927 PCT/US02/17674 In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.

Other embodiments are within the following claims.

WO 02/096927 PCT/US02/17674 88 TABLE I Characteristics of Ribozymes Group I Introns Size: -200 to >1000 nucleotides.

Requires a U in the target sequence immediately 5' of the cleavage site.

Binds 4-6 nucleotides at 5' side of cleavage site.

Over 75 known members of this class. Found in Tetrahymena thermophila rRNA, fungal mitochondria, chloroplasts, phage T4, blue-green algae, and others.

RNAseP RNA (M1 RNA) Size: -290 to 400 nucleotides.

RNA portion of a ribonucleoprotein enzyme. Cleaves tRNA precursors to form mature tRNA.

Roughly 10 known members of this group all are bacterial in origin.

Hammerhead Ribozyme Size: -13 to 40 nucleotides.

Requires the target sequence UH immediately 5' of the cleavage site.

Binds a variable number of nucleotides on both sides of the cleavage site.

14 known members of this class. Found in a number of plant pathogens (virusoids) that use RNA as the infectious agent (Figure 1 and 2) Hairpin Ribozyme Size: -50 nucleotides.

Requires the target sequence GUC immediately 3' of the cleavage site.

Binds 4-6 nucleotides at 5' side of the cleavage site and a variable number to the 3' side of the cleavage site.

Only 3 known member of this class. Found in three plant pathogen (satellite RNAs of the tobacco ringspot virus, arabis mosaic virus and chicory yellow mottle virus) which uses RNA as the infectious agent (Figure 3).

Hepatitis Delta Virus (HDV) Ribozyme Size: 50 60 nucleotides (at present).

Sequence requirements not fully determined.

Binding sites and structural requirements not fully determined, although no sequences 5' of cleavage site are required.

Only 1 known member of this class. Found in human HDV (Figure 4).

Neurospora VS RNA Ribozyme WO 02/096927 PCT/US02/17674 89 Size: -144 nucleotides (at present) Cleavage of target RNAs recently demonstrated.

Sequence requirements not fully determined.

Binding sites and structural requirements not fully determined. Only 1 known member of this class. Found in Neurospora VS RNA (Figure Table II: A. 2.5 pmol Synthesis Cycle ABI 394 Instrument Reagent Equivalents Amount Wait Time* DNA Wait Time* 2'- 0-methyl Wait Time*

RNA

Phosphoramidites S-Ethyl Tetrazole Acetic Anhydride N-Methyl Imidazole

TCA

Iodine Beaucage Acetonitrile 6.5 23.8 100 186 176 11.2 12.9

NA

163 jiL 238 pL 233 pL 233 pL 2.3 mL 1.7 mL 645 pL 6.67 mL 45 sec 45 sec 5 sec 5 sec 21 sec 45 sec 100 sec

NA

2.5 min 2.5 min 5 sec 5 sec 21 sec 45 sec 300 sec

NA

7.5 min 7.5 min 5 sec 5 sec 21 sec 45 sec 300 sec:

NA

B. 0.2 pmol Synthesis Cycle ABI 394 Instrument Reagent Equivalents Amount Wait Time* DNA Wait Time* 2'- 0-methyl Phosphoramidites S-Ethyl Tetrazole Acetic Anhydride N-Methyl Imidazole

TCA

Iodine 15 38.7 655 1245 700 20.6 31 iJL 31 pL 124 pL 124 piL 732 pL 244 pl- 45 sec 45 sec 5 sec 5 sec 10 sec 15 sec 233 sec 233 min 5 sec 5 sec 10 sec, 15 sec Wait Time

RNA

465 sec 465 sec 5 sec 5 sec 10 sec 15 sec Beaucage Acetonifrile 232 pL 100 sec 2.64 mL NA 300 sec

NA

300 sec

NA

C. 0.2 pmol Synthesis Cycle 96 well Instrument Reagent Equivalents DNA/2'-O-mothyl/Ribo Phosphoramidites S-Ethyl Tetrazole Acetic Anhydride N-Methyl Imidazole

TCA

Iodine Beaucage Acetonitrile 22f33/66 70[105/210 265/265/265 502/502/502 238/475/475 6.8/6.8/6.8 34151/51

NA

Amount DNAI2'-O-methyl/Ribo 40/60/120 liL 40/60/120 pL 50/50/50 pl- 50/50/50 pL 250/5001500 pl- 80/80/80 pL 80/120/120 115011150/1150 il- Wait Time* Wait Time* 2'-O- DNA methyl Wait Time Ribo 60 sec 60 sec 10 sec 10 sec 15 sec 30 sec 100 sec

NA

180 sec 180 min 10 sec 10 sec 15 sec 30 sec 200 sec

NA

36Osec 360 sec 10 sec 10 sec 15 see 30 sec 200 sec

NA

Wait time does not include contact time during delivery.

WO 02/096927 PCT/US02/17674 Table III: Patient Demographics Dose cohort (mg/mr) Pt# Age Sex Diagnosis Doses 1001 49 F NSCLimug 29 1002 65 F liposarcoma 120 1003 49 M nasopharyngeal CA 109 1004 35 M non-small cell lung 1 1005 45 F melanoma (ocular) 113 1006 57 M colon 199 1007 39 F epitheliod hemangioendothelioma 198 100 1008 52 M adrenal CA 57 100 1009 44 F breast 100 1010 62 F renal 134 300 1011 24 F melanoma 31 300 1012 57 M renal cell 178 300 1013 53 M nasopharyngeal SCCA 29 300 1014 64 F peritoneal mesothelioma 324 100 1015 65 M melanoma 140 100 1016 77 F breast 265 100 1017 F melanoma 100 1018 26 F melanoma 7 100 1019 69 F endometrial sarcoma 500 100 1020 65 M carcinoid 124 100 1021 59 M gallbladder adeno carcinoma 34 100 1022 43 M colorectal 8 100 1023 78 F breast 100 1024 40 F parotid adenocarcinoma 285 100 1025 52 F breast 71 100 1026 39 F breast 34 100 1027 55 F breast 36 100 1028 52 M melanoma 29 100 1029 38 M pancreatic 36 100 1030 83 M melanoma 41 100 1031 50 M medullary thyroid 108 One patient taken off study due to progressive disease. Allowed to resume ANGIOZYME on a compassionate basis.

As of September 1, 2001, all patients were off study. (Although one patient resumed treatment per above note) Table IV Pharmacokinetic parameters of ANGIOZYMIE after bolus subcutaneous administration.

nwjni 2 1 30 JngW/n 100 nw/ni 2 1 300 nw/rn Mean SD IMean SD [Mean SD [Mean SD jDay 1 Cma (ug/niL) ALTCt (ug*hr/mL) AUCinf (ug*hr/mL) t(112) (hr) CL/F (L/hrin 2 0.43 2.60 4.40 3.62 2.24 0.07 1.43 0.06 0.79 0.08 0.62 0.28 6.04 2.70 7.99 1.66 7.32 6.94 3.73 0.92 3.17 0.69 34.14 2.28 37.51 1.91 4.58 0.02 2.96 0.61 8.91 2.93 89.87 21.68 101.57 13.47 9.26 6.20 2.99 0.43 'a 9 Cmax (ug/mL) 0.35 0.19 1.17 0.53 3.23 0.35 8.93 6.71 AIJCt (ug*Ilr/mL) 2.11 1.31 7.29 1.16 31.87 1.91 119.42 65.84 AUCinf (ug*hr/InL) 3.38 1.31 8.54 2.46 33.61 2.16 132.73 67.82 t(1!2) (hir) 4.49 1.60 3.26 1.01 4.66 0.35 7.24 0.70 CL/F (L/hr/mi) 2.49 1.48 ,3.69 0.94 13.21 0.56 ,2.72 1.40 WO 02/096927 PCT/US02/17674 94 Table V: Human FLT DNAzyme and Substrate Sequence Pos Substrate Seq ID DNAzyme Seq ID No No 17 UCCUCUCG G CUCCUCCC 1 GGGAGGAG GGCTAGCTACAACGA CGAGAGGA 1703 28 CCUCCCCG G CAGCGGCG 2 CGCCGCTG GOCTAGCTACAACCA CGCGGAGG 1704 31 CCCCGGCA 0 CGGCGGCGA 3 CGCCGCCG GOCTFAGCTACAACCA TGCCGGGG 1705 34 CGGCAGCG G CGGCGGCU 4 JAGCC43CCG GGCTAGCTACAACGA CGCTGCCG 1705 37 CAGCGGCG G CGGCUCOG 5 ICCGAGCCG GtGCTAGCTACAACC3A CGCCGCTG 1707 CGGCGGCG G CIJCGGAGC 6 GCTCCGAG GGCTAGCTACAACG3A CGCCGCCG 1708 47 GGCUCGGA G CGGc3CUCC '7 GGAGCCCG GGCrAGCTACAACGA TCCGAGCC 1709 51 CGGAGCGG G CTJCCCGG 8 CCCCOGAG GGCTAGCTACAACGA CCGCTCCG 1710 59 GCUCCGGG G CUCGGGUG 9 CACCCGA34 GGCTAGC'VACAACGA CCCGGAGC 1711 GG3CUCGG G U0GCAGCG-G 10 CCGCTGCA GGCTAGCTACAACGA CCGAGCCC 1712 67 GCUCGGGU G CAGCGG3CC 11 GGCCGCTG3 GGCTAGCTACAACGA ACCCGAGC 1713 CGGGTJGCA G CGGCCAGC 12 GCTGCCCG GGCTAGCTACAACGA TGCACCCG 1714 73 GIJGCAGCG G CCAGCGGG 13 CCCGCTGG GOCTAGCTACAACGA CGCTGCAC 1715 '77 AGCGGCCA G CGGOCCUG 14 CAGGCCCG GGCTAGCTACAACGA TGGCCGCT 1716 81 GCCAGCGG G CCUGGCGG 15 CCGCCAGG GGCTAGCTACAACGA CCGCTGGC 1717 86 CGG3GCCUG3 G CGGCGA-G 15 CCTCGCCG GGCTAGCTACAACGA CAGGCCCG 1718 89 GCCUGGCG G CGAGGALU 17 AATCCTCG GGCTAGCTACAACGA CGCCAGGC 1719 CGI3CGAGG A UTJACCCC-G 18 CCG2GGTAA GOCTAGCTACAACGA CCTCGCCG 1720 98 CGAGGAUU A CCCGGGGA 19 TCCCCGGG GGCTAGCTACAACGA AATCCTCG 1721 108 CCGGGGAA G UGGIJUGUC 20 GACAACCA GGCTAGCTACAACGA TTCCCCGG 1722 111 GGGAAGUG G UtJGUCUCC 21 IGGAGACAA GGCTAOCTACAACGA CACTTCCC 1723 114 AAGUGCGUU G UCLICCUOG 22 CCAGGAGA COCTAGCTACAACGA AACCACTT 1724 122 GUCUCCTJG G CIJGGAGCC 23 GGCTCCAG GGCTAGCTACAACGA CAGGAGAC 1725 128 UGGCUC-GA G CCGCGAGA 24 TCTCGCGG GGCTAGCTACAACGA TCCAGCCA 1726 131 CLIGGAGCC G CGAGACGG 25 CCGTCTCG GGCTAGCTACAACGA GGCTCCAG 1727 136 GCCGCG-AG A CGGGCGCU 26 AGCGCCCG GGCTAGCTACAACGA CTCGCGGC 1728 140 CGAGACGG G CGCUCAGG 27 CCTGAGCG GGCTAGCTACAACGA CCGTCTCG 1729 142 AGACGGGC GI CUCAGGIC 28 GCCCTGAG GGCTAGCTACAACGA GCCCGTCT 1730 149 CGCUCAGG GI CGCGGGGC 29 GCCCCGCG GGCTAGCTACAACGA CCTGACGCG 1731 151 CUCAGGGC GI CGGGGCCG 30 CGGCCCCG GGCTAGCTACAACGA GCCCTIAG 1732 156 GGCGCGGG LI CCLIGCLIGC 31 GCCLICCGG GGCI'AGCTACAACGA CCCGCG-CC 1733 160 CGGGLICCG GI CGGCGGCG 32 CGCCGCCG GGCTAGCTACAACGA CGLICCCCG 1734 163 GGCCGGCG GI CGGCGAAC 33 GTTCGCCG GGCI'AGCTACAACGA CGCCICCC 1735 166 COLICGGLC GI CGAACGAG 34 CTCGTTCI GGCTALICTACAACGA CLICCGCCG 1736 170 GGCGGCGA A CLIAGAGGA 35 TCCTCTCG GGCTAGCTACAACGA TCGCC-CC 1737 178 ACIAIAGG A CGGLACUCU 36 ALIAGTCCG GLICTAGCTACAACLIA CCTCTCIT 1738 182 GAILAGG A CUCULIGCG 37 CLICCAGAG LGCTAGCTACAACGA CCLITCCTC 1739 188 GLIACUCUG GI CGLICCGGG 38 CCCLIGCCG LGCTAGCTACAACGA CAGAITCC 1740 191 CUCUGLGCG G CCGGUG 39 CLIACCCGI GGCTAGCTACAACGA CGCCA-AG 1741 196 GCGGCCGG GI UCGUUJLGC 40 GCCAACGA GGCTAGCTACAACGA CCGGCCGC 1742 199 GCCGGGUIIC LI UUGGLCCGG 41 ccLGCCAA rGcTAGcTACAAcGA GACCCCGC 1743 203 GGIJCGUUG G CCGGGGGA 42 ITCCCCCGG GGCTAGCTACAACGA CAACLIACC 1744 212 CCGGGGGA G CGCGGGCA 43 ITGCCCGCG GGCTAGCTACAACGA TCCCCCGG 1745 214 GGGGGAGC LI CGLIGCACC 44 IGLTGCCCG GGCTAGCTACAACGA GCTCCCCC 1746 218 GAGCGCGG LI CACCGGGC 45 IGCCCGGTG GGCTAGCTACAACGA CCLICLCTC 1747 220 GCGCLIGGC A CCOGICLIA 46 TCGCCCLIG GGLCTAGCTACAACLIA LICCCLICLC 1748 225 GGCACCGG G CGAGCAGG 47 CCTGCTCG GLICTAGCTACAACGA CCGGTGCC 1749 229 CCLILILCGA LI CAGGLCCGC 48 LICGLICCTG LIGCTAGCTACAACGA TCGCCCGG 1750 WO 02/096927 PCT/US02/17674 233 GCGAGCAG G CCGCGUCG 49 CGACGCGG GGCTAGCTACAACGA CTGCTCGC 1751 236 AGCAGGCC G CGIJCGCGC 50 GCGCGACG GGCTAGCTACAACGA GGCCTGCT 1752 238 CAGGCCGC G UCGCGCUC 51 GAGCGCGA GGCTAGCTACAACGA GCGGCCTG 1753 241 GCCGCGUC G CGCt3CACC 52 GGTGAGCG GGCTAGCTACAACGA GACGCGGC 1754 243 CGCGUCGC G CUCACCAU 53 ATGO3TQAG COCTAOCTACAACGA GCGACGCG 1755 247 UCGCGCUC A CCAtJGGUC 54 GACCATGG GGCTAGCTACAACGA GAGCGCGA 1756 250 CGCUCACC A UGGUCAGC 55 GCTGACCA GGCTAGCTACAACGA GGTGAGCG 1757 253 UCACCAUG G UCAGCUAC 56 GTAGCTGA GGCTAGCTACAACGA CATGGTGA 1758 257 CAUGGUCA G CUACTJGGG 57 CCCAGTAG GGCTAGCTACAACGA TGACCATG 1759 260 GGUCAGCU A CUGGGACA 58 TGTCCCAG GGCTAGCTACAACGA AGCTGACC 1760 266 CUACUGGG A CACCGGGG 59 CCCCGGTG GGCTAGCTACAACGA CCCAGTAG 1761 268 ACUGGGAC A CCGGGGUC 60 GACCCCGG GGCTAGCTACAACGA GTCCCAGT 17S2 274 ACACCOOG a UCCUGCUG 61 CAGCAGC-A GOCTAGCTACAACGA CCCGGTGT 1763 279 GGGGUCCY G CUGUGCGC 62 GCGCACA.G GGCTAGCTACAACGA AGGACCCC 1754 282 GL3CCUGCU G UGCGCGCU 63 AGCOCCICA GGCTAGCTACAACGA AGCAGGAC 1765 284 CCUGCUGUJ G CGCGCUGC 64 GCAGCGCG GGCTAGCTACAACGA ACAGCAGG 1766 286 UGCUGUGC G CGCUGCUC 65 GAGCAGCG GGCTAGCTACAACGA GCACAGCA 1767 288 CtJGUGCGC G CUGCUCAG 66 CTGAGCAG GGCTAGCTACAACGA GCGCACAG 1768 291 UGCGCGCUJ G CUCAGCJG 67 CAGCTGAG GGCTAGCTACAACGA AGCGCGCA 1759 296 c3CtGCUCA G CtJGUCUGC 68 GCAGACAG GGCTAGCTACAACGA TGAGCAGC 1770 299 GCUCAGCU G UCUGCUUTC 69 IGAAGCAGA GGCTAGCTACAACGA AGCTGAGC 1771 303 AGCUGUCU G CTJUCIJCAC 70 GTGAGAAG GGCTAGCTACAACGA AGACAGCT 1772 310 UCIUCUC A CACGAUCU 71 AGATCCTG CCCTAGCTACAACGA GAGAAGCA 1773 315 CUCACAGG A UCUAGULJC 72 GAACTAGA GGCTAGCTACAACGA CCTGTGAG 1774 320 AGGAUCUA G LiUCAGGUU 73 AACCTGAAL GGCTAGCTACAACGA TAGATOCT 1775 326 UAGIJUCAG G UUJCAAAAU 74 ATTTTGAA GGCTAGCTACAACGA CTGAACTA 1776 333 GGUUCAPA A UtJAAAAGA 75 TCTTTTAA GGCTAGCTACAACGA TTTGAACC 1777 341 AUTJAAAAG A UCCUGAAC 76 GTTCAGGA GGCTAGCTACAACGA CTTTTAAT 1778 348 GAUCCUCA A CUCGAGUJU 77 AAACTCAG GGCTAGCTACAACGA TCAGGATC 1779 353 UGAACUGA G U=tAAAAG 78 CTTTTAAA GGCTAGCTACAACGA TCAGTTCA 1780 362 UUTJAAAAG G CACCCAGC 79 GCTCGGTC GGCTAGCTACAACGA CTTTTAAA 1781 364 UAAAAGGC A CCCAGCAC 80 GTGCTGGG GGCTAGCTACAACGA GCCTTTTA 1782 369 GGCACCCA G CACAUCAU 81 ATGATGTG GCTACCTACAACGA TGCCTGCC 1783 371 CACCCAGC A CAUCAUGC 82 GCATGATG GGCTAGCTACAACGA GCTGGGTG 1784 373 CCCAGCAC A UCAUGCAA 83 TTGCATGA GGCTAGCTACAACCA GTGCTGGG 1785 376 ACCACAUC A UGCAAGCA 84 TGCTTGCA GGCTAGCTACAACGA GATGTGCT 1786 378 CACAUCAU G CAAGCAGG 85 CCTGCTTG GGCTAGCTACAACGA ATGATGTG 1787 382 UCAUGCAA G CAGGCCAG 86 CTGGCCTC GGCTAGCTACAACGA TTGCACCGA 1788 386 GCALAGCAG G CCAGACAC 87 GTGTCTGG GGCTAGCTACAALCGA CTGCTTGC 1789 391 CAGGCCAG A CACUGCAU 88 ATGCAGTG GGCTAGCTACAACGA CTGGCCTG 1790 393 CUCCACAC A CUGCAUCU 89 ACATGCAC GGCTAGCTACAACGA GTCTGGCC 1791 396 CAGACACU G CAUCUCCA 90 TGGAGATG GGCTAGCTACAACGA AGTGTCTG 1792 398 GACACUGC A UCUCCAAU 91 ATTGGAGA GGCTAGCTACAACGA GCAGTGTC 1793 405 CAEJCUCCA A UCAGGGG 92 CCCCTGCA GGCTAGCTACAACGA TGGAGATO 1794 407 UCUCCAAJ G CAGCGGGG 93 CCCCCCTC GGCTAGCTACAACCA ATTGGAGA 1795 418 GGCCGAA C CAGCCCAU 94 ATGGGCTG GGCTAGCTACAACGA TTCCCCCC 1796 4 21 GGGAAGCA G CCCAUAAA 95 TTTATcGG GGCTAGCTACAACGA TGCTTCCC 1797 425 AGCAGCCC A UAAAIJGGU 96 ACCATTTA GGCTAGCTACAACGA GGGCTGCT 1798 429 GCCCAUAA A UGGUCULTU 97 AAAGACCA CCCTAGCTACAACGA TTATCCCC 1799 432 CAUAAAUG C UCUUUJCC 98 GGCAAAGA GGCTAGCTACAACGA CATTTATG 1800 438 UGCUCUUTU G CCUCAAALU 99 ATTTCAGG GOCTAGCTACAACGA AAAGACCA 1801l 445 UGCCUGAA A UGGUGAGU 100 ACTCACCA GGCTAGCTACAACGA TTCAGGCA 1.802 WO 02/096927 PCT/US02/17674 448 CUGAAAUG G UGAGUAAG 101 CTTACTCA GGCTAGCTACAACGA CATTTCAG 1803 452 AAUGGt33A G UAAGGAAA 1D2 TTTCCTTA GGCTAGCTACAACGA TCACCATT 1804 461 UAAGGAAA G CGAAAGGC 103 GCCTTTCG GGCTAGCTACAACGA TTTCCTFTA 1BCS 468 AGCGAAAG G CUGAGCAJ 104 ATGCTCAG GGCTAGCTACAACGA CTTTCGCT 1806 473 AAGGCUGA G CAUAACUA 105 TAGTTATG GGCTAGCTACAACGA TCAGCCTT 18C7 475 GGCtJGAGC A tJAAC(JAAA 106 TTTAGTTA GGCTAGCTACAACGA GCPCAGCC 1808 478 UJGAGCAUA A CUAA.AUCT 107 AGATTTAG GGCTAGCTACAACGA TATGCPCA 18C9 483 AUAACUAA A UCUGCCUG 108 CAGGCAGA G3GCTAGCTACAACGA TTAGTTAT 1810 487 CUAAAUCJ G CCUGUGGA 109 TCCACAGG GGCTAGCTACAACGA AGATTTAG 1811 491 AIJCUGCCU G UGGAAGAA 110 TTCTTCCA GGCTAGCTACAACCA AGGCAGAT 1812 500 tGGAAGAA A UGGCAAAC Ill GTTTGCCA GGCTAGCTACAACGA TTCTTCCA 1813 503 AAGAAAUG G CAAACAAU 112 ATTGTTTG GGCTAGCTACAACOA CATTTCTT 1814_ 507 AAIJCGCAA A CAAUUtCUC 113 CACAATTG CGCTACCTACAACGA TTOCCATT 1815 510 GGCAAACA A UIJCUGCAG 114 CTGCAGAA GGCTAGCTACAACGA TGTTTGCC 1816 515 ACAAUUCU G CAGUACUCt 115 AAGTACTG GGCTAh9CTACAACGA AGAATTGT 1817 518 AUtYCtGCA G UACUUUAA 116 TTAAAGTA GGCTAc3CTACAACGA TGCAGAAT 1818 520 UCUGCAGI A CUUtUAACC 117 GGTTAAAG GGCTAGCTACAACGA ACTGCAGA 1819 526 GUACUUIA A CCIJGAAC 118 GTTCAAGG GGCTAGCTACAACGA TAAAGTAC 1820 533 AACCUUGA A CACAGCUC 119 GAGCTGTG GGCTAGCTACAACGA TCAAGGTT 1821 535 CCUUGAAC A CAGCUCAA 120 TTGAGCTG GOCTAGCTACAACGA GTTCAAGG 1822 538 UGAACACA G CUCAAGCA 121 ITGCTTGAG GGCTAGCTACAACGA TGTGTTCA 1.823 544 CAGCUCAA G CAAACCAC 122 GTGGTTTG GGCTAGCTACAACGA TTGAGCT9 1824 548 UCAAGCAA A CCACACJG 123 CA9TGTGG GOCTAGCTACAACGA TTOCTTGA 1825 551 AGCAAACC A CACUGGCU 124 AGCCAGTG GGCTAGCTACAACGA GGTTTGCT 1826 553 CAAACCAC A CUGGCUUC -12 5 GAAGCCAG GGCTAGCTACAACGA GTGGTTTG 1827 557 CCACACUG 9 CUtJCUACA 126 TGTAGAAG GGCTAGCTACAACGA CAGTGTGG 1828 563 UGGCtYUCU A CAGCUGCA 127 TGCAGCTG GGCTAGCTACAACGA AGAAGCCA 1829 568 CUUCUACA G CUGCAAAU 128 ATTTGCAG GgCTAGCTACAACGA TGTAGAAG 1830 569 CUACAGCU G CAAAUAJC 129 GATATTTG GGCTAGCTACAACGA AGCTGTAG 1831 573 AGCUGCAk A UAUCUAGC 130 GCTAGATA GGCTAGCTACAACGA TTGCAGCT 1832 575 CUGCAAAU A UCUACCUG 131 CAGCTAGA G3CTAGCTACAACGA ATTTGCAG 1833 580 AAUAUCUA G CUGUACCU 132 AGGTACAG GGCTAGCTACAACGA TAGATATT 1834 583 AUCUAGCJ G UACCUACU 133 AGTAGGTA GCTAOCTACAACGA AGCTAGAT 1835 585 CUAGCUGU A CCUACUJC 134 GAAGTAGG GGCTAGCTACAACGA ACAGCTAG 1836 589 CUGUACCU A CUUCAAAG 135 CTTTGAAG GGCTAGCTACAACGA AGGTACAG 1837 607 AGAAGGAA A CAGAAUCU 136 AGATTCTG GGCTAGCTACAACGA TTCCTTCT 1838 612 GAAACAGA A UCUGCAAU 137 ATTGCAGA GGCTAGCTACAACGA TCTGTTTC 1839 618 CAGAAUCU G CAAUCUAJ 138 ATAGATTG GGCTA9CTACAACGA AGATTCTO 1840 619 AAUCUGCA A UCUAUAUA 139 TATATAGA GGCTAGCTACAACGA TGCAGATT 1841 623 UGCAAUC U A UAUAUUIA 140 TAAATATA GGCTAGCTACAACGA AGATTGCA 1842 625 CAAUCUAU A UAUUUAUU 141 AATAA4TA GGCTAGCTACAACGA ATAGATTG 1843 627 AUCUAUAU A UTYUAUJUAG 142 CTAATAAA GGCTAGCTACAACGA ATATAGAT 1844 631 AUAUAUUU A UUAGUGAU 143 ATCACTAA GOCTAGCTACAACGA AAATATAT 1845 635 AUUUATUJA G UGAUACAG 144 CTGTATCA GGCTAGCTACAACGA TAATAAAT 1846 638 UAUUAGUG A TJACAGGUA 145 TACCTGTA GGCTAGCTACAACGA CACTAATA 1847 640 UJUAGUGAI A CAGGUAGA 146 TCTACCTG GGCTAGCTACAACGA ATCACTA. 1848 644 UGAUACAG G TJAGACCUU 147 AAGGTCTA GGCTAGCTACAACGA CTGTATCA 1849 648 ACAGGUAG A CCUUUCGU 148 ACGAAAGG GGCTAGCTACAACGA CTACCTGT 1850 655 GACCUOUC G UAGAGAUG 149 CATCTCTA GGCTAGCTACAACGA 9AAAGGTC 1851 661 UCGUAGAG A UGUACAGU 150 ACTGTACA GGCTAGCTACAACGA CTCTACGA 1852 663 GUAGAGAU G TJACAGUGA 151 TCACTTA GGCTAGCTACAACGA ATCTCTACI 1853 665 AGAGAUGU A CAGUGAAA 152 TTTCACTG GGCTAGCTACAACGA ACATCTCT118 WO 02/096927 PCT/US02/17674 668 GAUGUACA G UGAAAUCC 153 IGGATTTCA GGCTAGCTACAACGA TG3TACATC 1855 673 ACAGtTGAA A UCCCCGAA 2.54 ITTCGGGGA GGCTAG.CTACAACGA TTCACTGT 1856 682 UCCCCGAA A UUAUACAC 15S IGTOTATAA GGCTAGCTACAACGA TTCGGG-2A 1857 68S CCGAAAUJ A UACACAUG 156 CATGTGTA GGCTAGCTACAACOA AATTTCGG 1858 697 GAAAJTAU A CACAUGAC 157 GTCATGTG GGCTAQCTACAACCA ATAATTTC 1859 689 AAUUAUAC A CAUGACUG 158 CAGTCATG GGC FAGCTACAACGA GTATAATT 1860 691 UUAUACAC A UGACUGAA 159 TTCAGTCA GGCTAGCTACAACGA GTGTATAA 1861 694 UACACAUG A CtJGAAGGA 160 TCCTTCAG GGCTAGCTACAACOA CATGTGTA 1862 708 GGAAGGGA G CUCGTJCAU 161 ATGACGAG GGCTAGCTACAACGA TCCCTTCC 1863 712 GGGAGCJC G UCAUTJCCC 162 GGGAATGA GGCTAGCTACALACGA GAGCTC!CC 1864 715 AGCUCGUC A IJUCCCUGC 163 GCAGGGAA GGCTAGCTACAACGA GACGAGCT 1865 722 CAUUCCCU G CCGGGUUA 164 TAACCCGG GGCTAGCTACAACGA AGGGAATG 1866 727 CCUGCCGG G UUtACGUCA 165 T2GACGTAA GGCTAC3CTACAACCA CCOCCAGG 1267 730 GCCGOGUU A CGUCACCU 166 AGGTGACG3 GGCTAGCTACAACOA AACCCGGC 1868 732 CGGGUUIAC G UCACCUAA 167 PTAGGTGA GGCTAGCTACAACGA GTAACCCG 1869 735 GTUACGUC A CCUAACAU 168 ATGTTAGG GGCTAGCTACAACGA GACGTAAC 1870 740 GUCACCUA A CAUCACIG 169 CAGTGATG GGCTAGCTACAACGA TAGGTGAC 1871 742 CACCt3AAC A UCACUG1J 170 AACAGTGAk GGCTAGCTACAACGA GTTAGGTG 1872 745 CUAACAUC A CUGUtJACU 171 AGTAACA37 GGCTAGCTACAACGA GATGTTAG 1873 748 ACAUCACU G UEJACUUUA 172 TAAAGTAA GGCTAGCTACAACGA AGTGATGT 1874 751 UCACUGLTU A CUEJUAAAA 1V73 TTTTAAAG GGCrAGCTACAACGA AACAGTGA 1875 752 UTUAAAAAA G IJUUCCACU 174 AGTGGAAA GGCTAGCTACAACGA TTTTTTAA 1875 768 AAGUUUtCC A CUTJGACAC 175 GTGTCAAG- GGCTAGCTACAACGA GGAAACTT 1877 773 UCCACJEG A CACUUJGA 176 TCr.AAGTG GGCTAGCTACAACGA CAAGTGGA 1878 775 CACUJC-AC A CUIJUGAUC 17 7 GATCAAAG GGCTAGCTACAACGA GTCAAGTG 1879 781 ACACUUUG A UCCCtJGAU 178 IATCAGGGA GGCTAGCTACAACGA CAAAGTGT 1880 788 GAUCCCUG A UGGAAAAC 179 GTTTTCCA GGCTAGCTACAACGA CAGGGATC 1881 795 GAUGGAAA A CGCAUAAU 180 ATTATGCG GGCTAGCTACAACGA TTTCCATC 1882 797 UGGAAAAC G CAUAAUCU 181 AGATTATG GGCTAGCTACAACGA GTTTTCCA 1883 799 GAAAACGC A UAAUCUGG 182 CCAGATTA GGCTAGCTACAACGA GCGTVTTC 1884 802 AACGCAUA A UCUrGMGC 183 GTCCCAGA GGCTAGCTACAACGA TATGCOATT 1885 809 AAUC2UGGG A CAGUAGAA 184 TTCTACTG GGCTAGCTACAACGA CCCAGATT 1885 812 CUGGGACA G UAGAAAGG 185 CCTTTCTA GGCTAGCTACAACGA TGTCCCAG 1887 821 UAGAAAGG G CUUCAUCA 186 TGATGAAG GGCTAGCTACALACGA CCTTTCTA 1888 826 AGGGCtUUTC A UCAUAUCA 187 TGATATGA GGCTAGCTACAACGA GAAGCCCT 1889 829 GCtJUCAUC A UAUCAAAU 188 ATTTGATA GGCTAGCTACAACGA GATGAAGC 1890- 831 UUCAUCAU A UCAA-AUGC 189 GCATTTGA GGCTAGCTACAACGA ATGATGAA 1891 836 CAtTAUCAA A UGCAACGU 190 JACGTTGCA GGCTAGCTACAACGA TTGATATG 1892 838 UAUCAAAU G CAACGUAC 191 jGTACGTTG GGCTAGCTACAACGA ATTTGATA 1893 841 CAAAUGCA A CGUACAAA 192 TTTGTACG GGCTAGCTACAACGA TGCATTTG 1894 843 AAUGCAAC G UACAAAGA 193 TCTTTGTA GGCTAGCTACAACGA GTTGCATT 1895 845 UGCAACGU A CAAAGAAA 194 TTTCTTTG GGCTAGCTACAACGA ACGTTG3CA 1896 853 ACAAAGAA A UAGGGCUU 195 AAGCCCTA GGCTAGCTACAACGA TTCTTTGT 1897 858 GAAAUAGG G CUEJOUCAC 196 GTCAGAAG GGCTAGCTACAACGA CCTATTTC 1898 865 GGCUEJCUG A CCUGUGAA 197 TTCACAGG GGCTAGCTACAACGA CAGAAGCC 1899 869 UCUGACCU G UGAAGCAA 198 TTGCTTCA GCCTAGCTACAACGA AGGTCAGA 1900 874 CCUGUGAA G CAACAGUC 199 GACTGTTG GGCTAGCTACAACGA TTCACAGG 1901 877 GUGAAGCA A CAGUCAAU 200 ATTGACTG GGCTAGCTACAACGA TGCTTCAC 1902 880 AAGCAACA G UCAAUGGG 201 CCCATTGA GGCTAGCTACAACGA TGTTGCTT 1903 884 AACAGUCA A UGGGCAUU 202 AATGCCCA GGCTAGCTACAACGA TGACTGTT 1904 888 GUCAAUGG G CAUUGUA 203 ITACAAATG GGCTAGCTACAACGA CCATTGAC 1905 8.90 CAAUGGGC A UUUGUAUA 204 TATACAAA GGCTAGCTACAACGA GCC TGJ 1906 WO 02/096927 PCT/US02/17674 8.94 1GGGCALE G UAUAAGPAC 205 GTCWTATA GGCTAGCTACAACGA AAATGCCO 1907 896 GCAUUJ2U A UAAGACAXA 206 TTGTCWTA GGCTAGCTACAACrGA ACAAATGC 1908 901 TJGUAUAAG A CAAACUAU 207 ATAGTTTG GGCPAGCTACAACGA CTTATACA 1909 905 UAAGACAA A CUAJCICA 208 TGAGATAG GGCTAOCTACAACGA TTGTCTTA 1910 908 t3ACAAACTI A UCUCACAC 209 GTQTGAGA GGCTAGCTACAACGA AGTTPGTC 1911 913 ACUAUCJC A CACAUCGA 210 TCGATGTG GGCTAGCTACAACGA GAGATAGTI 1912 915 UAUCUCAC A CAUCGACA 211 TGTCGATG GGCTAGCTACAACGA GTGAGATA 1913 917 UCUCACAC A UCGACAAA 212 TTTGTCGA GGCTAGCT.ACAACGA GTGTGAGA 1914 921 ACACAUCG A CAAACCAA 213 TTGGTTTG GGCTAGCTACAACGA CGATGTGT 1915 925 AUCcAACAA A CCA1AUACA 214 Trn7ATTGG GGCPAGCTACAACGA TTGTCGAT 1916 929 ACAAACCA A UACAALTCA 215 JTGATTGTA GGCTAGCTACAACGA TGGTTTGT 1917 931 AAACCAAU A CAAUCAJA 216 ITATGATTG GGCTAGCTACAAC3A ATTGGTTT 1918 934 CCAZ\UACA A UCAUAG3AU 217 IATCTATGA% GGCTAGCTACAACCA TGTATTCC 1919 937 AUACAAJC A UAGAUGUC 218 JGACATCTA GGCTAGCTACAACGA GATTGTAT 1920 941 AAUCAUAG A UGUCCA-AA 219 TTTGGACA GGCTAGCTACAACGA CTATGATT 1921 943 UCAUAGAU G UCCAAAJA 220 TATTTGGA GGCTAGCTACAACGA ATCTATGA 1922 949 AUGUCCAA A UAAGCACA 221 TGTGCTTA GGCTAGCTACAACGA TTGGACAT 1923 953 CCAAAUAA G CACACCAC 222 GTGGTGTG GGCTAGCTACAACGA TTATTTGG 1924 955 AAAUAAGC A CACCACGC 223 GCGTGGTG GGCTAGCTACAACGA GCTTATTT 1925 957 AUAAGCAC A CCACGCCC 224 GGGCGTGG GGCTAGCTACAACGA GTGCTTAT 1926 960 AGCACACC A CGCCCAGU 225 ACTGGGCG GGCTAGCTACAACGA GGTGI'GCT 1927 962 CACACCAC G CCCAGI3CA 226 TGACTGGG GGCTAGCTACAACGA GTGGTGTG 1928 967 CACGCCCA G EJCAAAIJUA 227 TAATTTGA c2GCTAeCTACAACGA TGGCCCTG 1929 972 CCAGUCAA A tJUACUEJAG 228 CTAAGTAA GGCTAGCTACAACGA TTGACTGG 1930 975 GUCAAXJU A CUJEAGAC-G 229 CCTCTAAG GGCTAGCTACAACGA AATTTGAC 1931 983 ACUEJACAG G CCAUACUC 220 IGAOTATGG GGCTAGCTACAACGA CTCTAAGT 1932 986 TJAGAGGCC A UACUCUUG 231 CAAGAGTA GGCTAGCTACAACGA GGCCTCTA 1933 988 G3AGGCCAU A CJCTJUGUC 232 GACAAGAG2 GGCTAGCTACAACGA ATGGCCTC 1934 994 AUACUCTJ G UCCUCAAJ 233 ATTGAGGA GGC'FAGCTACAACGA AAGAGTAT 1935 1001 UGUCCUCA A UEJGUACUG 234 CAGTACAA GGCTAGCTACAACGA TGAGGACA 1936 1004 CCUCAAUJ G HACUGCLA 235 TAGCAGTA GGCTAGCTACAACGA AATTGAJ30 1937 1006 UCAAUUGJ A CUGCUACC 236 GGTAGCAG GGCTAGCTACAACGA ACAATT3A 1938 1009 AULTGUACU G CUACCACU 237 AGTGGTAG GGCTAGCTACAACOA AGTACAAT 1929 1012 GUACUGCU A CCACUCCC 238 GGGAGTGG GGCTAGCTACAACGA AGCAGTAC 1940 1015 CUGCUACC A CUCCCUUG 239 CAAGGGAG GGCTAGCTACAkACCA GGTAGCAG 1941 102S UCCCUJQA A CACGAGAG 240 CTCTCGTG GGCTAGCTACAACGA TCAAGG"3A 1942 1027 CCUUGAAC A CGAGAGUU 241 AACTCTCG GGCTAGCTACAACGA GTTCAA3G 1943 1033 ACACGAGA G UUCAZAAUG 242 CATTTGAA GGCTAGCTACAACGA TCTCGT3T 1944 1039 GAGUUCAA A UGACCLJGG 243 CCAGGTCA GGCTAGCTACALACGA TTGAACTC 1945 1042 UJUCAAAUJG A CCUGGAGU 244 ACTCCAGG GGCTAGCTACAACGA CATTTGAA 1946 1049 GACCUGnA G EJUACCCUG 245 CAGGGTAA GGCTAGCTACAACGA TICAGGIC 1947 1052 CUGGAGUU A OCCUGAUG 246 CATCAGGG GGCTAGCTACAACGA AACTCCAG 1948 1058 UEJACCCUG A UGAAAAAA 247 TTTTTTCA GGCTAGCTACAACGA CAGGGTAA 1949 1067 UGAAAAAA A UAAGAGAG 248 CTCTCTTA GGCTAGCTACAACGA TTTTTTCA 1950 1075 AUAAGAGA G CUUCCGUA 249 TACGGAAG GGCTAGCTAC4ACGA TCTCTTAT 1951 1081 GAGCUUCC G UAALGGCGA 250 TCGCCTTA GGCTAGCTACAkACGA GGAAGCTC 1952 1086 UCCGUAAkG G CGACGAAU 251 ATTCGTCG GGCTAGCTACAACGA CTTACGGA 1953 1089 GUAAGGCG A CGAAUUGA 252 TCAATTCG GGCTAGCTACAACGA CGCCTTAC 1954 1093 GGCGACGA A ULUGACCAA 253 TTG3GTCAA GGCTAGCTACAACGA TCGTCGCC 1955 1097 ACGAAUUG A CCAAAGCA 254 TGCTTTGG GGCTAGCTACAACGA CALATTCGT 1956 1103 UGACCAAA G CAAUUCCC 255 GGGAATTG GGCTAGCTACAACGA TTTGGTCA 1957 1106 CCAAAGCA A UUCCCAUG 256 CATGGGAA GGCTAGCTACAACGA TGCTTTGG 1 1958 WO 02/096927 PCT/US02/17674 1112 CAAUUCCC A UGCCAACA 257 TGTTGGCA GGCTAGCTACAACGA GGGAATTG 1959 1114 AIUhCCCAU G CCAACAIJA 258 TATGT'TGG CGCTAGCTACAACCA ATOGGAAT 1960 1118 CCAUGCCA A CAUAUUTCU 259 AGAATATG GGCTAGCTACAACGA TGGCAT3G 196.- 1120 AUGCCAAC A tTAUEJCUAC 260 GTAGAATA GGCTAGCTACAACGA GTTGGCAT 1962 1122 GCCAACAU A Ut3CUACAG 261 CTGTAGAA GGCTAGCTACAACGA ATGTTG3C 1963 1127 CAUALUCU A CAGUGUUC 262 GAACACTG GGCTAGCTACAACGA AGAATATG 1964 1130 ATJUCIIACA G3 UGUEJCUtJA 263 TAAGAACA GGCTAGCTACAACGA TGTAG3AAT 1965 1132 UCUACAGtJ G LUTUACU 264 AGTAAGAA GGCTAGCTACAACGA ACTGTAGA 1966 1138 GUGU1JCUEJ A CUAUUGAC 265 GTCAATAG GGCTAGCTACAACGA AAGAACAC 1967 1141 UU1CUACtI A UEJGACAAA 266 TTTGTCAA GGCTAGCTACAACCA AGTAAGAA 1968 1145 UACUAUUG A CAAAAUGC 267 GCATTTTG GGCTAGCTACAACGA CAATAGTA 1969 1150 ULTCACAAA A IJCCAGAAC 268 GTTCTGCA GGCTAGCTACAACGA TTTGTCAA 1970 1152 GACAAAAU G CAGAACAA 269 TTGTTCTG GGCTAGCTACAACGA ATTTTGTC 197:- 1157 A1XUGCAGA A CAAAGACA 270 TGTCTTTG GGCTAGCTACAACGA TCTGCATT 1972 1163 GAACAAAG A CAAAGc3AC 271 GTCCTTTG GGCTAGCTACAACGA CTTTGTTC 1973 1170 GACAAAGG A CULUAUAC 272 IGTATAAAG GGCTAGCTACAACGA CCTTTGTC 1974 1175 AGGACUUU A UACUUGUC 273 JGACAAGTA GGCTAGCTACAACGA AAAGTCCT 1975 1177 G3ACU{3UAU A CUUGtJCGU 274 IACGACAA3 GGCTAGCTACAACGA ATAAAGTC 1976 1181 UIJAUACLTU G UCGUGUAA 275 ITTACACGA GGCTAGCTACAACGA AAGTATAA 1977 1184 UACUTJGUC G UGUAAOOA 276 TCCTT'ACA GGCTAGCTACAACGA GACAAGTA 1978 1186 CIJEGICGU G UAAGGAGU 277 ACTCCTTA GGCTAGCTACAACGA ACGACAAG 1979 1193 UGUAAGGA G UGGACCAU 278 ATGGTCCA GGCTAGCTACAACGA TCCTTACA 1980 1197 AGQAGUGG A CCAUCAUU 279 AATGATGG GGCTAGCTACAACGA CCACTC--T 1981 1200 AGtJGGACC A UCAUJCAA 280 TTGAATGA GGCTAGCTACAACGA GGTCCACT 1982 1203 GGACCAUC A UUCAAAUC 281 GATTTGAA GGCTAGCTACAACGA GATGGT"cC 1983 1209 UCAUTJCAA A UCtJGUOAA 282 TTAACAGA GGCTAGCTACAACGA TTGAATGA 1984 1213 UCAAAUCU G UEJAACACC 283 GGTGTTAA GGCTAGCTACAACGA AGATTTGA 1985 1217 AUCUGU(JA A CACCUCAG 284 CTGAGGTG QGCTAGCTACAACGA TAACAGAT 1986 1219 CUGUEJATC A CCUCAGUG 285 CACTGAGG GGCTAGCTACAACGA GTTAACAG 1987 1225 ACACCUCA G UGCAUAUA 286 TATATGCA GGCTAGCTACAACGA TGAGGT3T 1988 1227 ACCUCAGU G CAEJAUAUA 287 TAFATATG GGCTAGCTACAACGA ACTGAGGT 1989 1229 CUCAGUGC A UAEJAUAUG 288 CATATATA GGCTAGCTACAACGA GCACTGAG 1990 1231 CAGtTOCAU A UAtJAUGAU 289 ATCATATA GGCTAGCTACAACGA ATGCACTG 1991 1233 GUGCAUAU A UAUGAUAA 290 TTATCATA GGCTAGCTACAACGA ATATGC-AC 1992 1235 GCAUAUAU A UGAUAAAG 291 CTTTATCA GGCTAGCTACAACGA ATATATGC 1993 1238 OAUATJAUG A UAAAGCAU 292 ATGCTTTA GGCTAGCTACAAC4A CATATATA 1994 1243 AUGAUAAA G CAUCAUC 293 GATGAATG GGCTAGCTACAACGA TTTATCAT 1995 1245 GAUAAACC A ULJCAtTCAC 294 GTGATGAA 3GCTAGCTACAACGA GCTTTATC 1996 1249 AAGCAUUC A UCACUGUG 295 CACAGTGA GGCTAGCTACAACGA GAATGCTT 1997 1252 CAUUCAUC A CUGUGAAA 296 TTTCACAG GGCTAGCTACAACGA GATGAATG 1998 1255 UCAUCACU G UGAAACAU 297 ATGTTTCA GOCTAOCTACAACGA AGTGATGA 1999 1260 ACUGUGAA A CAEJCGAAA 298 TTTCGATG GGCTAGCTACAACGA TTCACAGT 2000 1262 UOUGAAAC A UCGAAAAC 299 GTTTTCGA GOCTAGCTACAACGA GTTTCACA 2001 1269 CAUCGAAA A CAGCAGGU 300 ACCTGCTG GGCTAGCTACAACGA TTTCGATG 2002 1272 CGAAAACA G CAGGUGCIJ 301 AGCACCTG GGCTAGCTACAACGA TGTTTTCG 2003 1276 AACAGCAG G UGCUUGAA 302 TTCAAGCA GGCTAGCTACAXCGA CTGCTGTT 2004 1278 CAGCAGGU G CUEJGAAAC 303 GTTTCAAG GGCTAGCTACAACGA ACCTGCTG 2005 1285 UGCUEJGAA A CCGTJAGCUJ 304 AGCTACGG GGCTAGCTACAACGA TTCAAGCA 2006 1288 UIJGAAACC G IJAGCUGGC 305 GCCAGCTA GGCTAGCTACAACGA GGTTTCAA 2007 1291 AAACCGUA G CUGGCAAG 306 CTTGCCAG GGCTAGCTACAACGA TACGGTTT 2008 1295 CGUAGCUG G CAAG-CGGU 307 ACCGCTTG GGCTAGCTACAACGA CAGCTACC 2009 1299 GCUGGCAA G CGGUCUEJA L308 TAAGACCG GGCTAGCTACAACGA TTGCCAGCI 2010 WO 02/096927 PCT/US02/17674 1302 GGCAAGCG G UCUUACCG 309 CGGTAAGA GGCTAGCTACAACGA CGCTTGCC 2011 1307 GCGGUCUUJ A CCGGCTJCIU 310 AGAGCCGG GGCTAGCTACAACGA AAGACCGC 2012 1211 UCUEJACCG G CtJCUCUJAI 311 ATAGAGAG GGCTAGCTACAACGA CGGTAAGA 2013 1318 GGCUCUCU A UGAAAGUG 312 CACTTTCA GGCTAGCTACAACGA AGAGAGCC 2014 1324 CUAUGAAA G IJGAAGGCA 313 TGCCTTCA GGCTAGCTACAACGA TTTCATAG 2015 1330 AAGUGAAG G CAUUEJCCC 314 GGGAAATG GGCTAGCTACAACGA CTFTCACTPT 201G 1332 GUG3AAGGC A UU1JCCCUC 315 GAGGQAAA GGCTAGCTACAACGA GCCTTCAC 2017 1341 UUEJCCCUC G CCGGAA3U 316 ACTTCCGC- GGCTAGCTACAACGA GAGGGAAA 2018 1348 CGCCGGAA G UEJGUAUGG 317 CCATACAA GGCTAGCTACAACGA TTCCG3GCG 2019 1351 CGGAAGUJ G tAUGGUUA 318 TAACCATA GGCTAGCTACAACGA AACTTCCG 2020 1353 GAAGUUGU A UGGtJUAAA 319 TTTAACCA GGCTAGCTACAACGA ACAACTTC 2021 1356 GUTJGTJAIG G UUAAAAGA 320 TCTTTTAA GGCTAGCTACAACGA CATACAAC 2022 1364 GUUTAAAAG A U~cGIJ1AC 321 GTAACCCA GGCTAGCTACAACGA CTTTTAAC 2023 1368 AAAGAUGG G UUACCUGC 322 GCAGGTAA GGCTAGCTACAACGA CCATCTCT 2024 1371 GATJGGGUJ A CCUGCGAC 323 GTCGCAGG GGCTAGCTACA-ACGA AACCCATC 2025 1375 GGTUJACCU G CGACtJGAG 324 CTCACTCC GCCTAGCTACAACCA AGGTAACC 202G 1378 UACCUGCG A CtYGAGAAA 325 TTTCTCAG GGCTAGCTACAACGA CGCAGGTA 2027 1386 ACUGAGAA A TCUGCUCG 326 CGAGCAGA GGCTAGCTACAACGA TTCTCAGT 2028 1390 AGAAAUCU G CUCGCUAU 327 ATAGCOGAC GGCTAGCTACAACGA AGATTTCT 2029 1394 AUCUGCUC G CUAUUUGA 328 TCAAATAG GGCTAGCTACAACGA GAGCAGAT 2030 1397 UGCUCGCU A UUEJGACUC 329 GAGTCAAA GGCTAGCTACAACGA AGCGAGCA 2031 1402 GCUAUtUG A CUCGUGGC 330 GCCACGAC GGCTAGCTACAACGA CAAALTAGC 2032 1406 UIJUGACUC G UGGCUACT 331 AGTAGCCA GGCTAGCTACAACGA GAGTCAAA 2033 1409 GACUCGUG G CUACUCGU 332 ACGAGTAG GGCTAGCTACAACGA CACGAGTC 2034 1412 UCGUGGCU A CUCGUIJAA 333 TTAACGAG GGCTAGCTACAACGA AGCCACGA 2035 1416 GGCUACUC G UJEAAUUAIJ 3:34 ATAATTAA GG.CTAGCTACAACGA GAGTAGCC 2036 1420 ACUCGUUA A tJUAUCAAG 335 CTTGATAA GGCTAGCTACAACGA TAACGAGT 2037 1423 CGUUAALUJ A UCAAGGAC 336 GTCCTTCA GGCTAGCTACAACGA AATTAACG 2038 1430 UAUCAAGG A CGUAACUG 337 CACTTACC COCTAOCTACAACGA CCTTGATA 2039 1432 UCAAGGAC G UAACUGAA 338 TTCAGTTA GGCTAGCTACAACGA GTCCTTGA 2040 1435 AGGACGUA A CUGAAGAG 339 CTCTTCAG GGCTAGCTACAACGA TACGTCCT 2041 1445 UGAAGAGG A UGCAGGGA 340 TCCCTGCA GGCTAGCTACAACGA CCTCTTCA 2042 1447 AAGAGGAU G CAGGGAAU 341 ATTCCCTG GGCTAGCTACAACGA ATCCTCTT 2043 1454 UGCAGGGA A tUAUACAA 342 TTGTATAA GCCTAGCTACAACGA TCCCTCCA 2044 1457 AGGGAAUETJ A (ACAAUCU 343 AGATTGTA GGCTAGCTACAACGA AATTCCCT 2045 1459 GGAAUTJAU A CAAUCUTUG 344 CAAGATTG GGCTAGCTACAACGA ATAATTCC 2046 1462 AUEJAUACA A UCUUGCUG 345 CAGCAAGA GGCTAGCTACAACGA TGTATAAT 2047 1467 ACAAUCUU G CtJGAGCAU 346 ATGCTCAG GGCTAGCTACALACGA AAGATTGT 2048 1472 CU1JCCUGA G CAUAAAAC 347 CTTTTATC CCCTAGCTACAACGA TCAGCAAG 2049 1474 UGCtJGAGC A UAAAACAG 348 CTGTTTTA GGCTAGCTACAACGA GCTCAGCA 2050 1479 AGCAUAAA A CAGUCAAA 349 TTTGACTG GGCTAGCTACAACGA TTTATGCT 2051 1482 AUAAAACA G UCAAAUGU 350 ACATTTGA GGCTAGCTACAACGA TGTTTTAT 2052 1487 ACAGUCAA A UGUGUUUA 351 TAAACACA GGCTAGCTACAACGA TTGACTGT 2053 1489 AGUCAAAU G UGUUUJAA 3S2 TTTAAACA CCCTAGCTACAACGA ATTTCACT 2054 1491 tTCAAAUGU G UJEIEAAAA 353 TTTTTAA' GGCTAGCTACAACGA ACATTTGA 2055 1499 GULJUAAIAA A CCUCACJG 354 CAGTGAGG GGCTAGCTACAACGA 'ITTTAAAC 2056 1504 AAAACCtJC A CUGCCACU 355 AGT1GGCAG CCCTAGCTACAACGA GACGTTTT 2057 1507 ACCUCACU G CCACUCUA 356 TAGAGTGG GOCTAGCTACAACGA AGTGACGT 2058 1510 UCACUGCC A CUCUAAUU 357 AATTAGAG CCCTAGCTACAACGA GGCAGTGA 2059 1516 CCACUCUA A UUGUCAAU 358 ATTGACAA GGCTAGCTACAACGA TAGAGTGG 2060 1519 CUCUAATJU G UCAZAUGUG 359 CACATTGA GGCTAGCTACAACGA AATTAGAG 2061 F15231 AAUUGUCA A UGUGAAAC 13650 IGTTTCACA GGCTAGCTACAACCA TGACAATT 2062 WO 02/096927 PCT/US02/17674 1525 UUGUCAAU G UGAAACCC 361 G3GGTTTCA GGCTAGCTACAACGA ATTGACAA 2063 1530 AAUGUGAA A CCCCAGAU 362 IATCTGGGG GGCTAGCTACAACGA TTCACATT 2064 1537 AACCCCAG A UOUACGAA 363 TTCGTAAA GGCTAGCTACAACGA CTGGGGTT 2065 1541 CCAGAUUU A CGAAAAGG 364 CCTTTTCG GGCTAGCTACAACGA AAATCTGG 2066 1549 ACGAAAAG G CCOGUTCA 365 TGACACGG GGCTAG3CTACAACGA CTTTTCGT 2067 1552 AAAAGGCC G UGUCAUCG 366 CGATGACA GGCTAGCTACAACGA GGCCTTTT 2068 1554 AAGGCCGU G UCALTCGUU 367 AACGATGA GGCTAGCTACAACGA ACGGCCTT 2069 1557 GCCGOC-UC A UCGUUCC 368 2GGAAACGA GGCTAGCTACAACGA GACACGGC 2070 1560 GUGUCAUC G UCCCAGA 369 TCTGGAAA GGCTAGCTACAACGA GATGACAC 2071 1568 GTUTCCAG A CCCGGCUC 370 9AGCCGGG GGCTAGCTACAACGA CTGCGAAA-C 2072 1573 CAGACCCG G CUCUCUAC 371 GTAGAGAG GGCTAGCTACAACGA CGGGTCTG 2073 1580 GGCUCUCJ A CCCACUGG 372 CCAGTGGG GGCPAGCTACAACGA AGAGAGCC 2074 1584 CUCUACCO A CUCCOCAC1 373 CTCCCCAC CCCTAOCTACAACGA GGGTAGAG 2075 .1589 CCCACUGG G CAGCAGAC 374 GTCTGCTG GGCTAGCTACAACGA CCAGTGGG 2076 1592 ACUGGGCA G CAGACAALA 375 TTTGTCTG GGCTAGCTACAACGA TGCCCAGT 2077 1596 GGCAGCAG A CAPAAUCCU 376 AGGATTTIG GGCTAGCTACAACGA CTGCTGCC 2078 1600 GCAGACAA A UCCUGACU 377 AGTCAGGA GGCTAGCTACAACGA TTGTCTGC 2079 1606 AAAUCCUG A CUtJGUACC 378 GGTACAAG GGCTAGCTACAACOA CAGGATTT 2080 1610 CCUGACUU G UACCGCAU 379 ATGCGGTA GGCTAGCTACAACGA AAGTCAGG 2081 1612 TJGACUtJGU A CCGCAUAU 380 ATATGCGG GGCTAGCTACAACGA ACAAGTCA 2082 1615 CUEJGUACC G CAUAUGGU 381 ACCATATG GGCTAGCTACAACGA GGTACAAG 2083 1617 UGUACCGC A UATJGGUAU 382 ATACCATA GGCTAGCTACAACGA GCGGTACA 2084 1619 TJACCGCAU A UGGUAUCC 383 GGATACCA GGCTAGCTACAACGA ATGCGGTA 2085 1622 CGCAUAUG G UATJCCCUC 384 GAGGGATA GGCTAGCTACAAC3A CATATGCG 2086 1624 CAUAUGGU A UCCCUCAA 385 TTGAGGGA GGCTAGCTACAACGA ACCATATG 2087 1632 AUCCCUCA A CCUACAAU 38G ATTGTAGG GGCTAGCTACAACGA TGAGGGAT 2088 1636 CUCAACCU A CAAUCAAG 387 CTTGATTG GGCTAGCTACAACGA AGGTTGAG 2089 1639 AACCUACA A UCAAGUGG 388 CCACTTGA GG.CTAGCTACAACGA TGTAGGTP 2090 1644 ACAAUCAA G UGGUUCUG 389 CAGAACCA GGCTAGCTACAACGA TTGATTGT 2091 1647 AUCAAGUG G UUCUGGCA 390 'GCCAGAA GGCTAGCTACAACGA CAC'ITGAT 2092 1653 UGGLUJCUG G CACCCCUG 391 CAGGGGTG- GGCTAGCTACAACGA CAGAACCA 2093 1655 GUEJCTGGC A CCCCUGUA 392 TACAGGGG GGCTAGCTACAACGA GCCAGAAC 2094 1681 GCACCCCU G UAACCAUA 393 TATGGTTA GGCTAGCTACAACCA AGGGGTGC 2095 1664 CCCCI3GUA A CCAUAAUC 394 GATTATGG GGCTAGCTACAACGA TACAGGGG 2096 1667 CUGUAACC A UAAUCAUU 395 IAATGATTA GGCTAGCTACAACGA GGTTACAG 20-97 1670 UAACC-AUA A UCAUUCCG 396 CGGAATGA GGCTAGCTACAACGA TATGGTTA 2098 1673 CCAUAAUC A UTJCCGAAG 397 CTTCGGAA GGCTAGCTACAACGA GATTATGG 2099 1681 AUEJCCGA A G CAAGGUGU 398 ACACCTTG GGCTAGCTAC.AACGA TTCGGAAT 2100 16865 GAAGCAAG G UGUGACU 399 AAGTCACA GGCTAGCTACAALCGA CTTGCTTC 2101 1688 AGCAAGGU G UGACUEIGU 400 AAAAGTCA GGCTAGCTACAACGA ACCTTGCT 2102 1691 AAGGUc2UG A CTEUGUU 401 AACAAAAG GrGCTAGCTACAACGA CACACCTT 2103 1697 UGACUUUU G UtJCCAAUA 402 TATTGGAA GGCTAGCTACAACGA AAAAGTCA 2104 1703 UTUGUEJCCA A UAAUGAAG 403 CTTCATTA GGCTAGCTACAACGA TGGAACAA 2105 170G UEJCCAAIJA A tJGAAGAGU 404 ACTCTTCA GGCTAGCTACAACGA TATTGGAA 2105 1713 AAUGAAGA G UCCUEJUAU 405 ATAAAGGA GGCTAGCTACAACGA TCTTCATT 2107 1720 AGUCCUJU A UCCUCCAU 406 ATCCAGGA GGCTAGCTACAACGA AAAGGACT 2108 1727 UAUCCUGG A UGCUGACA 407 TGTCAGCA GGCTAGCTACAACGA CCAGGATA 2109 1729 UCCUGGAU G CUGACAGC 408 GCTGTCAG GGCTAGCTACAACGA ATCCAGGA 2110 1733 GGAUGCUG A CAGCAACA 409 TGTTGCTGz GGCTAGCTACAACGA CAGCATCC 2111 1736 UGCUGACA G CAACAUGG 4-10D CCATGTTG GGCTAGCTACAACGA TGTCAGCA 2112 1739 UGACAGCA A CAUGGGAA 411 TTCCCAT9 GGCTAGCTACAACGA TGCTGTCAj 211.3 1741 1 ACAGCAAC A UGGGAAAC GTTTCCCA GGCTAGCTACAACGA GTTGCTGTj 21.14 WO 02/096927 PCT/US02/17674 1748 CAUGGGAA A CAGAAUUG 413 CAATTCTG GGCTAGCTACAACGA TTCCCATG 2115 1753 GAAACAGA A tJIGAGAGC 414 GCTCTCAA GGCTAGCTACAACGA TCTGTTTC 2116 1760 AAEJUGAGA G CAUCACJC 415 GAGTGATG GGCPAGCTACAACGA TCTCAATT 2117 1762 tJUGAGAGC A UCACUCAG 416 CTGAGTGA GGCTAGCTACAACGA GCTCTCAA 2118 1765 AGAGCAUC A CUCAGCGC 417 GCGCTGAG GGCTAGCTACAACGA GATGCTCT 2119 1770 AUCACUCA G CGCAUGGC 418 GCCATGCG GGCTAGCTACAACGA TGAGTGAT 2120 1772 CACUCAGC G CAUGGCAA 419 TTGCCATG GGCTAc3CTACAACGA GCTGAGTG 2121 1774 CUCAGCGC A UGGCAAUA 420 TATTGCCA GGCTAGCTACAACGA GCGCTGAG 2122 1777 AGCGCAUG G CAAUAAUA 421 TATTATTG GGCTAGCTACAACGA CATGCGCT 2123 17)8 0 GCAUGGCA A UAAUAGAA 422 TTCTATTA GGCPAGCTACAZACGA TGCCATG;C 2124 1783 UGGCAAUA A tAGAAGGA 423 TCCTTCTA GGCPAGCTACAACGA TATTGCCA 2125 1796 AGGAAAGA A UAAGAUGG 424 CCATCTTA GGCTAGCTACAACOA TCTTTCCT 2126 1001 AGAAUAAG A UGGCUAGC 425 GCTAGCCA GGCTAGCTACAACGA CTTATTCT 2127 1804 AUAAGAJG G CUAGCACC 426 GGTGCTAG GGCTAGCTACAACGA CATCTTAT 2128 1808 GAUGGCUA G CACCLTUGG 427 CCAAGGTG GGCTAGCTACkACGA TAGCCATC 2129 1810 UGGCIJAGC A CCUUGGUU 428 AACCAAGG GGCTAGCTACAACGA GCTAGCCA 2130 1816 GCACCUUG G UUGUGGCU 429 AGCCACAA CGCTAGCTACAACGA CAAGGTGC 2131 1819 CCIJUGGUEJ G UGGCUGAC 430 GTCAGCCA GGCTAOCTACAACGA AACCAAGG 2132 1822 UGGLTUGUG G CUGACIJCU 431 AGAGTCAG GGCTAGCTACAACG. CACAACCA 2133 1826 UGTJGGCUG A CUCUAGAA 432 TTCTAGAG GO~CTAGCTACAACGA CAGCCACA 2134 1834 ACUCUAGA A tJUUCUGGA 433 TCCAGAALA GGCTAGCTACAACGA TCTAGAGT 213 1843 UUUCUGGA A UCUACAUU 434 AATGTAGA GGCTAOCTACAACGA TCCAGAAA 2136 1847 UGGAAUCU A CAUU(UGCA 435 TGCAAATG GGCTAGCTACAACGA AGATTCCA 2137 1849 GAAUCUAC A UUUGCAUA 436 TATGCAAA GGCTAGCTACALACGA GTAGATTC 2138 1853 CUACAUJU G CAUAGCUU 437 AAGCTATG GGCTAGCTACAACGA AAATGTAG 2139 1855 ACAtUUGC A UAGCUJCC 438 GGAAGCTA GGCTAGCTAC.ACGA GCAAATST 2140 1858 L1UUGCAtJA G CUCCAAU 439 ATTGGAAG GGCTAGCTACAACGA TATGCAAA 2141 1865 AGCLUCCA A UAAAGJUG 440 CAACTTTA GOCTAGCTAC-AACGA TGGAAGCT 2142 1870 CCAAUAAA G UUGGGACU 441 AGTCCCAA GGCTAGCTACAACGA TTTA1"1G:G 2143 1876 AAGUUGGG A CUGUGGGA 442 TCCCACAG GGCTAGCTACAACGA CCCAACTT 2144 1879 UUGGGACU G tGGGAAGA 443 TCTTCCCA GGCTAGCTACAACGA AGTCCCAA 2145 1889 GGGAAGAA A CAUAAGCJ 444 AGCTTATG GGCTAGCTACAACGA TTCTTCCC 2146 1891 GAAGAAAC A UAAGCLTU 445 AAAGCTTA GGCTAGCTACAACGA GTTTCTTC 2147 1895 ?AAACAUAA G CUUUUAUA 446 TATAAAAG GGCTAGCTAC.AACGA TTATGTTT 2148 1901 AAGCUUJEU A UAUCACAG 447 CTGTGATA GGCTAGCTAC.ACGA AAAAGCTT 2149 1903 GCUULTUAU A UCACAGAG 448 ATCTGTGA GGCPAGCTACAACGA ATAAALAGC 2150 1506 UUUAUAUC A CAGAUGUG 449 CACATCTG GGCTAGCTACAACGA GATATAAA 2151 1910 UAUCACAG A IUGUGCCAA 450 TTGGCACA GGCTAGCTACAACGA CTGTGATA 2152 1912 UCACAGAU G UGCCAAAU 451 ATTTGGCA GGCTAGCTAC-aACGA ATCTGTGA 2153 1914 ACAGAUGU G CCAAAUGG 452 CCATTTGG GGC UAGCTACAACGA ACATCTGT 2154 1919 UGUGCCAA A UGGUUJTC 453 GAAACCCA GOC'FAGCTACAACGA TTGGCACA 2155 1923 CCAAAUJGG G tJEUCAUGU 454 ACATGAAA GGCTAGCTACAACGA CCATTTGG 2156 1928 UGOGULJUC A UGUUAALCU 455 AGTTAACA GOCTAGCTAC-AACGA GAAACCCA 2157 19530 GGUUEJCAU G UUAACUUG 456 CAAGTTAA GGCTAGCTACAZ'ACGA ATGAAA-,C 2158 1934 UCAUGUJA A CUUGGAAA 457 TTTCUAAG GGCTAGCTACAACGA TAAGATGA 2159 1945 UGGAAAAA A UGCCGACG 458 CGTCGGCA GGCPAGCTACAACGA TTTTTCCA 2160 1547 GAAAAAAU G CCGACGGA 459 TCCGTCGG GGCTAGCTACA4ACGA ATTTTTTC 2161 1551 AAAUGCCG A CGGAAGGA 460 TCCTTCCG GGCPAGCTACAACGA CGGCATTT 2162 1964 AGGAGAGG A CCUGAAAC 461 GTTTCAGG GGCTAGCTACAkACGA CCTCTCCT 2163 1971 GACCUGAA A CtJGUCUUG 462 CAAGACAG GGCTAGCTACAACGA TTCAGGTC 2164 1974 CUGAAACU G UCUEJOCAC 463 GTGCAAGA GGCTFAGCTACAACGA AGTTTCAG 21G5 1979 ACUGUCUU G CACAGUEJA7464 TAACTGTG GGCPAGCTACAACGA AA GACAGT1 2166 WO 02/096927 PCT/US02/17674 -1981 UGUCUJGC A CAGUTUAAC 465 GTTAACTG GGCTAGCTACAACGA GCAAGACA 2167 1984 1CUUGCACA G TJUAACAAG 466 CTTGTTAA GGCTAGCTACAACOA TGTGCAAG 2168 1988 CACAGIJUA A CAAGUCU 467 AGAACTTG GGCTAGCTACAACGA TAACTGTG 2169 1992 GtJUAACAA G UUCUJEAUA 468 TATAAGAA GGCTAGCTACAACGA TTGTTAAC 2170 1998 AAQUJCUI A UACAGAGGA 469 TCTCTGTA GGCTAGCTACAACGA AAGAACTT 2171 2000 GIJECtUAU A CAGAGACG 470 CGTCTCTG GGCTAGCTACAACGA A FAAGAAC 217d2 2006 AUACAGAG A CGUJACtJU 471 AAGTAACG GGCTAGCTACAACGA CTCTGTAT 217 3 2008 ACAGAGAC G UEJACLTU2-G 472 CCAAGTAA GGCTAGCTACAACGA GTCTCTGT 2174 2011 GAGACGJU A CUTJGGAUJ 473 A ATCCAAG GGCTAGCTACAACGA AACGTCTC 2175 2017 JUACUUGG A DUUlLACUG 474 CAGTA1AAA GGCTAGCTACAACGA CCAAGTAA 2176 2022 UGGAUUU A CUGCGGAC 475 GTCCGCAG GGCTAGCTACAACGA AAAATCCA 2177 2025 AUUUJUACJ G CGGACAGU 476 ACTGTCCG GGCTAGCTACAACGA AGTAAAAT 2178 2029 UACUGCGG A CAGUUAAU 477 ATTAACTC GGCTAGCTACAACGA CCGCAGTA 2179 2032 UGCGGACA G DUJAAIJAAC 478 GTTATTAA GcCTAGCTACAACGA TGTCCGCA 2180 2036 GACAGUTA A UAACAGAA 479 TPTCTGTTA GGCTAGCTACAACGA TAACTGTC 2181 2039 AGUtJAAUA A CAGAACAA 480 TTGTTCTG GGCTAGCTACAACGA TATTAACT 2182 2044 AtJAACAGA A CAAUGCAC 481 GTGCATTG GGCTAGCTACAACGA TCTGTTAT 2183 2047 ACAGAACA A UGCACUAC 482 GTAGTGCA GGCTAGCTACAACGA TGTTCTGT 2184 2049 AGAACAAU G CACUACAG 483 CTGTAGTG GGCTAGCTACAACCA ATTGTTCT 2185 2051 AACAAUGC A CIJACAGTJA 484 TACTGTAG GGCTAGCTACAACCA GCATTGTT 2186 2054 AAUGCACT A CAGUAUUJA 485 TAATACTG GGCTAGCTACAACGA AGTGCATT 2187 2057 GCACUACA G UAULJAGCA 486 TGCTAATA GGCTAGCTACAACGA TGTAGTG3C 2188 2059 ACUACAGU A U{JAGCAAG 487 CTTGCTAA GGCTAGCTACAACGA ACTGTAGT 2189 2063 CAGUAUJA G CAAGCAAA 488 TTTGCTTG GGCTAGCTACAACGA TAATACTG 2190 2067 AUJEAGCAA G CAAAAAAU 489 ATTTTTTG GGCTAGCTACAACGA TTGCTAAT 2191 2074 AGCAAAAA A UGGCCAUC 490 GATGGCCA GGCTAGCTACAACGA TTTTTGCT 2192 2D77 AAAAAAUG G CCAUCACU 491 AGTGATGG GGCTAGCTACA1CGA CATTT7TTT 2193 2080 AAAUGGCC A UCACTJAAG 492 CTTAGTGA GGCTAGCTACA4CGA GGCCA!2TT 2194 2083 UGGCCAUC A CUAAGGAG 493 CTCCTTPG GGCTAGCXACAACGA GATGGCCA 2195 2091 ACLTAAGGA G CACUCCAU 494 ATGGAGTG GGCTACCTACAACGA TCCTTAGT 2196 2093 UAAGGAGC A CUCCAUCA 495 TGATGGAG GGCTAGCTACAACGA GCTCCTTA 2197 2098 AGCACUCC A UCACUCUU 496 AAGAGT-A GGCTACCTACAACGA GGAGTGCT 2198 2101 ACUCCAUC A CUCUUAAU 497 ATTAAGAG CGCTAGCTACAACGA GATGGAGT 2199 2108 CACUCUJA A UCUUACCA 498 TGGTAAGA GGCTAGCTACAACGA TAAGAGTG 2200 2113 UtJAAUCtJU A CCAUCAUG 499 CATGATGG GGCTAGCTACAACGA AAGATTAA 2201 2116 AUCUTJACC A UCAUGAAU 500 ATTCATGA GGCTAGCTACAACGA GGTAAGAT 2202 2119 ULTACCAUC A UGAAUGUU 501 JAACATTCA GGCTAGCTACAACGA GATGGTAA 2203 2123 CAUCAUGA A UGUUJUCCC 502 GGGAAACA nGCTAGCTACAAC3A TCATGATG 2204 2125 UCAUGAAU G UUEJCCCUG 503 CAGGGAAA GGCTAGCTACAACGA ATTCATGA 2205 2133 GLTUCCCU G CAAGAUUC 504 GAATCTTG GGCTAGCTACAACGA AGGGAAAC 2206 2138 CCUGCAAG A UJ1CAGGCA 505 TGCCTGAA GGCTAGCTACAACGA CTTGCAGG 2207 2144 AGAUEJCAG G CACCUAUG 506 CATAGGTG GGCTAGCTACAACGA CTGAATCT 2208 2146 AUUCAGGC A CCUAUGCC 507 GGCATAGG GGCTAGCTACAACGA GCCTGAAT 2209 2150 AGGCACCU A UGCCUGCA 508 TGCAGGCA GGCTAGCTACAACGA AGGTGCCT 2210 2152 GCACCUAU G COUGCAGA 509 TCTGCAGG GGCTAGCTACAACGA ATAGGTGC 2211 2156 CUAUGCCU 0 CACAGCCA S50 TGGCTCTG GGCTAGCTACAACGA AGGCATAG 2212 21G1 CCUGCA.GA G CCAGGAAU 511 ATTCCTGG GGCTAGCTACAACGA TCTGCAGG 2213 2168 AGCCAGGA A UGUAUACA 512 TGTATACA GGCTAGCTACAACGA TCCTGGCT 2214 2170 CCAGGAAU G UAUACACA 513 TGTGTATA GGCTAGCTACAACGA ATTCCTGG 2215 2172 AGGAAUGU A UACACAGC 514 CCTGTGTA GGCTAGCTACAACGA ACATTCCT 2216 2174 GAAUGUAU A CACAGG s15 CCCCTGTG GGCTAGCTACAACGA ATACAITO 2217 2.176 1AUGUAUAC A CAGGCGAA 516 TTCCCCTG GGCTAGCTACAACGA GTATACAT 221B WO 02/096927 PCT/US02/17674 2188 GGGAAGAA A LCCUCCAG 517 CTGGAGGA GGCTAGCTACAACGA 1'TCTTCCC 2219 2206 AGAAAGAA A IUUACAAUC 518 GATTGTAA GGCTAGCTACAACGA TTCTTTCT 2220 2209 AAGAAAUJ A CAAUCAGA 519 TCTGATTG GGCrLAGCTACAACGA AATTrCTT 2221 2212 AAAUUACA A LTCAGAGAJ 520 ATCTCTGA GGCTAGCTACAACGA TGTAATTT 2222 2219 AAUCAGAG A UCAGGAJAG 521 CTTCCTGA GGCTAGCTACAACGA CTCTGATT 2223 2227 AUCAGGAA G CACCAUPC 522 GTATGGTG GGCTAGCTACAACGA TTCCTGAT 2224 2229 CAGGAAGC A CCAUACCU 523 AGGTATGG GGCTAGCTACAACGA GCTTCCTG 2225 2232 GAAGCACC A UACCUCCU 524 AGGAGGTA GGCTAGCTACAACGA GGTGCTTC 2226 2234 AGCACCAU A CCUCCIJGC 525 GCAGGAG73 GGCTAGCTACAACGA ATGGTGCT 2227 2241 UACCIJCCU G CGAAACCU 526 AGGTTTCG GGCPAcACTACAACGA AGGAGGTA 2228 2246 CCTJGCGAA A CCtTCAGtJG 527 CACTGAGG GGCTAGCTACAACGA TTCGCAGG 2229 2252 AAACCUCA G UGAUCACA 528 TGTGATCA GGCTAG.CTACAACGA TGAGGTTT 2230 2255 CCUCAGtJG A UCACACAC 529 CTGTCTGA GCCTAOCTACAACGA CACTGACG 2231 2258 CAGUGAUC A CACAGUGG 530 CCACTGTG GGCPAGCTACAACGA GATCACTG 2232 2260 GUGAUCAC A CAGTJGGCC 531 GGCCACTS GGCTAGCTACAACGA GTGATCAC 2233 2263 AUCACACA G UGGCCAUTC 532 GATGGCCA GGCTAGCTACAACGA TGTGTGAT 2234 2266 ACACAGUG G CCAUCAGC 533 GCTGATGG GGCTAGCTACAACGA CACTGTGT 2235 2249 CAGITCGCC A tJCAGCAGU S34 ACTGCTGA GGCTAGCTACAACGA GGCCACTG 2236 2273 GGCCAUJCA G CAGUUCCA 535 TG3GAACTG GGCTAGCTACAACGA TGATGGCC 2237 2276 CAUCAGCA G UUCCACCA 536 TGGTGGAA GGCTAGCTACAACGA TGCTGATG 2238 2281 GCAGUUCC A CCACUUJTA 537 TAAAGTG3 GGCTAGCTACAACGA GGAACTGC 2239 2284 GUUCCACC A CUUUAGAC 538 IGTCTAAAG CCCTAGCTACAACGA GGTGGAAC 2240 2291 CACUJUAG A CUCUCAUC 539 CATGACASGGCCTAGCTACAACGA CTAAAGTG 2241 2294 ULUAGACU G ECAUGCUA 540 TAGCATGA GGCFAGCTACAACGA AGTCTAAA 2242 2297 AGACUGUC A UGCUAAUG 541 CATTAGCA GGCTAGCTACAACGA GACAGTCT 2243 2299 ACUGUCAUGC CUAAUGGU 542 ACCATPAG GGCTAGCTACAACGA ATGACAGT 2244 2303 UCAUGCUA A UGGUGUCC 543 GGACACCA GGCTAGCTACAACGA TAGCATGA 2245 2306 UGCUAAUG G UGUCCCCG 544 ICGGGGACA GGCTAGCTACAACGA CATTAGCA 2244 2308 CUAAUGGU G UCCCCGAG 545 CTCGGA GGCTAGCTACAACGA ACCATTAG 2247 2316 GUCCCCGA G CCUCAGAU 546 ATCTGAGG GGCTAGCTACAACGA TCGGGGAC 2248 2323 AGCCUCAG A UCACUUCG 547 CCAAGTGA GGCTACCTACAACGA CTCAGCCT 224.9 2326 CUCAGAUC A CUUGGUJE 548 AAACCAAG GGCTAGCTACAACGA CATCTGAG 2250 2331 AUCACUUG G UUEJAAAAA S49 TTTTTAAA GGCTACCTACAACGA CAAGTCAT 2251 2339 GUUUAAAA A CAACCACA 550 TGTGGTTG GGCTAGCTACAACGA TTTTAAAC 2252 2342 UAAAAACA A CCACAAAA 551 TTTTGTGG GGCTAGCTACAACGA 3GTTTTTA 2253 2345 AAACAACC A CAAAAUAC 552 GTATTTTG GGCTAGCTACAACGA CGTTGTTT 2254 2350 ACCACAAA A UACAACAA 553 TTGTTGTA GGCTAGCTACAACGA TTTGTGGT 2255 2352 CACAAAAU A CAACAAGA 554 TCTTGTTG GGCTAGCTACA-AC!GA ATTTTGTG 2256 2355 AAAAUACA A CAAGAGCC 555 GGCTCTTG GGCTAGCTACAACGA TGTATTTT 2257 2361 CAACAA G CCLTGGAAU 556 ATTCCAGG GGCTAGCTACAACGA TCTTGTTG 2258 2368 ACCCUGGA A UUAUUUJUA S57 TAAAATAA CGCTACCTACAACGA TCCAGGCT 2259 2371 CUGGAAUU A UUUUAGGA 558 TCCTAAAA GGCTAGCTACAACGA AATTCCAG 2260 2379 AUOUUAGG A CCAGGAAG 559 CTTCCTGG GGCTAGCTACAACGA CCTAAAAT 2261 2387 ACCAGGAA G CAGCACGC 560 GCGTGCTG GGCTAGCTACAACGA TTCCTGGT 2262 2390 AGGAAGCA G CACGCUGU 561 ACAGCGTG GGCTAGCTACAACGA TGCTTCCT 2263 2392 GAAGCAGC A CGCUGUUU 562 AAACAGCG GGCTAGCTACAACGA GCTGCTTC 2264 2394 AGCAGCAC G CUGUUUAU 563 ATAAACAG GGCTAGCTACAACGA GTGCTGCT 2265 2397 AGCACGCU G UUUAUUCGA 564 TCAATAAA GGCTAGCTACAACGA AGCGTGCT 2266 2401 CGCUGUEJ A tUCAAAGA 565 TCTTTCAA CGCTAGCTACAACGA AAACAGCG 2267 2410 UEJGAAAGA C UCACAGAA 566 TTCTGTGA GGCTAGCTACAACGA TCTTTCAA 2268 2413 AAArAgUC A CAGAAGAG 567 CTCTTCTG GGCTAGCTACAACGA GACTCTTT 2269 2423 AGAAGAGG A UGAAGGUG 568 CACCTTCA GGCTAGCTACAACGA CCTCTWCT 2270 WO 02/096927 PCT/US02/17674 2429 GGAUGAAG G UGUCUTJC 569 GATAGACA GGCTAGCTACA.ACGA CTTCATCC 2271 2431 AUGAAGGU G UCtJAUCAC 570 GTGATAGA GGCTAGCTACAACGA ACCTTCAT 2272 2435 AGGUc3UCU A UCACtJGCA 571 TGCAGTGA GGCTAGCTACAACGA AGACACCT 2273 2438 UGUCUAUC A CUGCAAAG 572 CTTTGCAG GGCTAGCTACAACGA GATAGACA 2274 2441 CUAUCACU G CAAAGCCA 573 TGGCTTTG GOCTAGCTACAACGA AGTGATAG 2275 2446 ACUGCAAA G CCACCAAC 574 GTTGGTGG GGCTAGCTACAACGA TTTGCAGT 2276 2449 GCAAAGCC A CCAACCAG 575 CTGGTTGG GGCTAGCTACAACGA GGCTTTGC 2277 2453 AGCCACJCA A CCAGAA-G 576 CCTTCTGG GGCTAGCTACAACGA TGGTGOCT 2278 2462 CCAGAI4GG G CUCIJGtGG 577 CCACAGAG GGCTAGCTACAACGA CCTTCTGG 2279 2467 AGGGCUCU G UGGAAAGU 578 ACTTTCCA GGCTAGCTACAACCGA AGAGCCCT 22810 2474 UGUGGAAA G UEJCAGCAY 579 ATGCTGAA GGCTAGCTACAACGA TTTCCACA 2281 2479 AAAGUUCA G CAUACCCC 580 GAGGTATS GGCTAGCTACAACGA TGAACTTT 2282 2401 AGUtJCAGC A UACCIJCAC 521 OTtOACOTA CGCTAGCTACAACGA GCTGAACT 2283 2483 UUCAGCAU A CCUCACtJG 582 CAGTGAGG GGCTAGCTACAACGA ATGCTGAA 2284 2488 CAUACCUC A CUGtJUCAAL 583 TTGAACASS GGCTAGCTACAACGA GAGOTATG 2285 2491 ACCUCACJ G UtJCAAGGA 584 TCCTTGAA GGCTAGCTACAACGA AGTGAGGT 2285 2500 UUCAAGGA A CCtJCGGAC 585 GTCCGAGG GGCTAGCTACAACGA TCCTTGAA 2287 2507 AACCUCGG A CAAGUCUA 586 TAGACTTG GGCTAGCTACAACGA CCGAGGTT 2288 2511 UCGGACAA G UCUAA1JCU 587 AGATTAGA GGCTAGCTACALACGA TTGTCCGA 2289 2516 CAAGUCUA A UCUGGAGC 588 GCTCCAGA GGCTAGCTACAACGA TAGACTTG 2290 2523 AA{JCIGGA G CUGAUCAC 589 GTGATCAG GGCTAGCTACAACGA TCCAGATT 2291 2527 UGGAGCTJG A UCACUCUA 590 TAGAGTGA GGCTAGCTACAACGA CAGCTCCA 2292 2530 AGCUGAUC A CUCUAACA 591 TGTTAGAG GGCTAGCTACAACGA GATCAGCT 2293 2536 UCACUCUA A CAUGCACC 552 GGTGCATG GGCTAGCTACAACGA TAGAGTGA 2294 2538 ACUCUAAC A UGCACCUG 593 CAGGTGCA GGCTAGCTACAACGA GTTAGA.GT 2295 2540 UCUAACAU G CACCUGUG 594 CACAGGTG, GGCTAGCTACAACGA ATGTTAGA 2296 2542 UAACAUGC A CCUGUGUG 595 CACACAGG GGCTAGCTACAACGA GCATGTTA 2297 2546 AUGCACCU 9 UGUGGCUG 596 CAGCCACA GGCTAGCTACAACGA AGGTGCAT 2298 2548 GCACCUGU G UGGCUGCG 597 CGCAGCCA GGCTAGCTACAALCGA ACAGGTGC 2299 2551 CCUGUG-UG G CUGCGACU 598 AGTCGCAG GGCTAGCTACAACGA CACACAGG 2300 2554 GUGUCGCU G CGACUCUC 599 GAGAGTCG GGCTAGCTACAACGA AGCCACAC 2301 2557 UGGCUGCG A CUCUCUUC G00 GAAGAGAG GGCTAGCTACAACGA CGCAGCCA 2302 2569 CUCUTJCUG 9 CUCCUAUJ 601 AATAGGAG GGCTAGCTACAACGA CAGAAGAG 2303 2574 UGGCUCCU A UUAACCCU 602 AGGGTTAA GGCTAGCTACAACGA AGGAGCCA 2304 2578 UCCUAUTUA A CCCUCCUU 603 AAGGAGGG GGCTAGCTACAACGA TAATAGGA 2305 2587 CCCUCCUJ A UCCGAAAA 604 TTTTCGGA GGCTAGCTACAACGA AAGGAGGG 2306 2596 UCCGAAAA A UGAAAAGG 605 CCTTTTCA GGCTAGCTACAACGA TTTTCGGA 2307 2604 AUGAAAAG G UCUUCEJUC 606 cAAGAAGA GGCTAGCTACAACGA CTTTTCAT 2308 2617 CUUCUGAA A UAAAGACU 607 AGTCTTTA GGCTAGCTACAACGA TTCAGAAG 2309 2623 AAAUAAAG A CUGACUAC 608 GTAGTCAG GGCTAGCTACAACGA CTTTATTT 2310 2627 AAAGACUG A CUACCUAU 609 ATAGGTAG G.GCTAGCTACAACGA CAGTCTTT 2311 26530 GACUGACU A CCUAUCAA 510 TTGATAGG GGCTAGCTACAACGA AGTCAGTC 2312 2634 GACUACCU A UCAAUUAU 611 ATAATTGA GGCTAGCTACAACGA AGGTAGTC 2313 2638 ACCUAUCA A UrJAUAAUG 612 CATTATAA GGCTAGCTACAACGA TGATAGGT 2314 2641 UAUCAAUUE A UAAUGGAC 613 GTCCATTA GGCTAGCTACAACGA AATTGATA 2315 2644 CAAUUAUA A UGGACCCA 614 TGGGTCCA GGCTAGCTACAACGA TATAATTG 2316 2648 UAUAAUGG A CCCAGAUG 515 CATCTGGG GGCTAGCTACAACGA CCATTATA 2317 2654 GGACCCAG A UGAALGUUC 616 GAACTTCA GGCTAGCTACAACGA CTGGGTCC 2318 2659 CAGAUGAA G UUCCUUUTG 617 CAAAGGAA GGCTAGCTACAACGA TTCATCTG 2319 2559 UCCUTJUGG A UGAGCAGU 518 ACTGCTCA GGCTAGCTACAACGA CCAAAGGA 2320 2673 ULIGGAUGA G CAGUGUGA 619 TCACACTU GGCTAGCTACAACGA TCATCCAA 2321 F2675 GAUGAGCA G UGUGAGCG 620 CGCTCACA GGCTAGCTACAACGA TGCTCATC 2322 WO 02/096927 PCT/US02/17674 2678 {GAGCAGU G UGAGCGGC 621 GCCGCTCA GGCTAGCTACAAC3A ACTGCTCA 2323 2682 CAGUGUGA G CGGCUC"CC 622 GGGAGCCG GGCTAGCTA-CAACGA TCACACTG 2324 2685 UGtJGAGCG 0 CUCCCtJUA 623 TAAGGGAG GGCTAG-CTACAACGA CGC2TCACA 2325 2693 GCIJCCCUJE A UGAUGCCA G24 TGGCATCA GGCTAGCTACAACGA AAGGGAGC 2326 2696 CCCUUAUQ A UGCCAGCA 625 TGCTGGCA GGCTAGCTACAACGA CATAAGGG 2327 2698 CULUAUGAU G CCAGCAAG 626 CTTGCTGG GGCTAG3CTACAACGA ATCATAAG 2328 2702 UGAUGCCA G CAAGIJGGG 627 CCCACTTG GGCTAGCTACAACGA TGGCATCA 2329 2706 GCCAGCAA G UGCACUU 628 AACTCCCA GGCTAGCTACAACGA TTGCTGGC 2330 2712 AAGUGGGA G UTTJGCCCG 629 CGGGCAAA GGCTAGCTACAACGA TCCCACTT 2331 2716 GGGACGtJ G CCCGGGAG 630 CTCCCGCG GCCTAGCTACAACGA AAACTCCC 2332 2727 CGGGAGAG A CTJTJAAACTJ 631 AGTTTAAG GGCTAGCTACAACGA CTCTCCCG 2333 2733 AGACUUAA A CUGGGCAA 632 TTGCCCAG GGCTAGCTACAACGA TTAAGTCT 2334 2738 UAAACIJGG G CAAAtJCAC 633 GTCATTTG CCTAOCTACAACGA CCAGTTTA 2335 2742 CUGGGCAA A UCACOIJGG 634 CCAAGTGA GGCTAGCTACAACGA TTGCCCAG 2336 2745 GGCAAAUC A CUUGGAAG 635 CTTCCAAG GGCTAGCTACAACGA GATTTGCC 2337 2758 GAAGAGGG G CIUtJUGGA 636 TCCAAAAG GGCTAGCTACAACGA CCCTCTTC 2338 2770 UUGGAAAA G TJGGUUCAA 637 TTGAACCA GGCTAGCTACAACGA TTTTCCAA 2339 2773 GAAAAGUG G UTUCAAGCA 638 TPCCTTGAA GGCTACCTACAACGA CACTTTTC 2340 2779 UGGU(JCAA G CAUCAGCA 639 TGCTGATG GGCTAGCTACAACGA TTGAACCA 2341 2781 CIJUCAAGC A UCAGCAUJ 640 AATGCTGA GGCTAGCTACAACGA GCTTCAAC 2342 2785 AAGCAUCA G CAUUTJGGC 641 GCCAAALTG GGCTAGCTACAACGA TGATGCTT 2343 2787 GCAUCAGC A UIJUGGCA3 642 ATGCCAAA GGCTAOCTACAACGA GCTCATGC 2344 2792 AGCATTJ G CAUUAAGA 643 TCTTAATG GGCTAGCTACAACCA C.AAATGCT 2345 2794 CA(JUUGGC A UUAAGAAA 644 TTTCTTAA GGCTAOCTACAACGA GCCAAATG 2346 2802 AUtJAAGAA A UCACCUAC 645 GTAGGTGA GGCTAGCTACAACGA TTCTTAAT 2347 2805 AAGAAAUC A CCUACGUG 646 CACGTA-G GGCTACCTACAACGA CATTTCTT 2348 2809 AAUCACCU A CGUGCCGG 647 CCGGCACG GGCTAGCTACAACGA AGGTVGATT 2349 2811 UCACCUAC G UGCCGGAC 648 OTCCGGCA GGCTAGCTACAACGA GTAGGTGA 2350 25.13 ACCUACGU G CCGGACUG 649 CAGTCCGG GGCTAGCTACAACGA ACGTAGGT 2351 2818 CCTJGCCGG A CUGUGGCU 650 AGCCACAG GGCTAGCTACAACGA CCGCCACG 2352 2B21 GCCGGACI G UGGCUGUC 651 CACAGCCA CCCTAGCTACAACGA AGTCCGGC 2353 2824 GGACUGUG G CUGUGAAA 652 TTTCACAG GGCTAGCTACAACGA CACAGUCC 2354 2327 CUGUGGCJ G UGAAAAUG 653 CATTTTCA GGCTAGCTACAACGA AGCCACAG 2355 2B33 CUGUGAAA A UGCUGAAA 654 TTTCAGCA GGCTAGCTACAACGA TTTCACAG 2356 2335 GUGAAAAJ G CUCAAAGA 655 TCTTTCAG GGCTAGCTACAACGA ATPTTCAC 2357 2B48 AAGAGCC 0 CCACCGCC 656 GGCCGTVGO GGCTAGCTACAACGA CCCCTCTT 2358 2851 ACGc3GGCC A CGGCCAGC 657 GCTGGCCG GGCTAGCTACAACGA GGCCCCCT 2359 2854 GGGCCACG G CCAGCGAG 658 CTCGCTGG GGCTAG4CTACAACGA CGTGGCCC 2360 2858 CACGGCCA G CGAGUACA 659 TGTACTCG GGCTAGCTACAACGA TGGCCGTG 2361 2862 GCCAGCGA G UACAAAGC 680 GCTTTGTA GGCTAGCTACAACGA TCGCTGGC 2362 2364 CAGCGAG4U A CAAALC{C 661 GAGCTTTG GGCTAGCTACAACGA ACTCCCTC 2363 2869 AGUACAAA G CUCUGAUC 662 CATCAGAG GGCTAGCTACAACGA TTTGTACT 2364 2875 AAGCUCUG A UGACUGAG 663 CTCAGTCA CGCTAGCTACAACCA CAGACCTT 2365 2878 CUCUCAUC A CUGACCUA 664 TAGCTCAG GGCTAGCTACAACGA CATCAGAG 2366 2383 AUGACUGA G CUAAAAAU 665 ATTTTTAG GGCTAGCTACAACCA TCAGTCAT 2367 2890 AGCUAAAA A UCUUGACC 666 GGTCAAGA GGCTAGCTACAACGA TTTTAGCT 2368 2896 AAAUCUUG A CCCACAUU 667 AATGTGGG GGCTAGCTACAACGA CAAGATTT 2369 2900 CUUGACCC A CAUUGGCC 658 GGCCAATG GGCTAGCTACAACGA GGGTCAAG 2370 2902 UGACCCAC A U(JGGCCAC 669 GTGGCCAA GGCTAGCTACAACGA GTGGGTCA 2371 2906 CCACAUJG C CCACCAUC 670 GATGGTGG GGCTAGCTACAACGA CAATGTGG 2372 2909 CAIUCCCC A CCAUCtJGA 671 TCAGATGAC GGCTAGCTACAACGA GCCCAATG 2373 29121 UGGCCACC A UCUGAACG 672 JCGTTCAGA GGCTAGCTACAACGA GGTGGCCA 2374 WO 02/096927 PCT/US02/17674 2918 CCAUCUGA A CGUGGUUA 673 TAACCACG GGCTAGCTACAACGA TCAGATGG 2375 2920 AUCUGAAC G UGGUUAAC 674 GTTAACCA GGCTAGCTACAACGA GTTCAGAT 2376 2923 tJGAACGUG G UUAACCUG 675 CAGGT9'AA GGCTAGCTACAACGA CACGTTCA 2377 2527 CGUGGUUA A CCUGCUGG 676 CCAGCAGG GGCTAGCTACAACGA TAACCACG 2378 2931 GUUAACCJ G CUGGGAGC 677 GCTCCCAG GGCTAOCTACAACGA AGc3TTAAC 2379 25938 UGCtJGGGA G CCUGCACC 578 GGTGCAGG GGCTAGCTACAACGA TCCCAGCA 2380 2942 GGGAGCCU G CACCAAGC 679 GCTTGGTG GGCTAGCTACAACGA AGGCTCCC 2381 2944 GAGCCUGC A CCAAc3CAA 680 TTGCTTGG3 GGCTAGCTACAACGA GCAGGCTC 2382 2949 UGCACCAA G CAAGGAGG 681 CCTCCTTG GGCTAGCTACAACGA TTGGTGCA 2383 2958 CAAGGAGG G CCUCUGAU 6812 ATCAG~AGG GOCTAGCTACA-ACG3A CCTCCTTG 2384 2965 GGCCUCTG A UGGUGAUU 683 AATCACCA GGCTAGCTACAACGA C-AGAGGCC 2385 2968 CUCUGAUG G UGAUUGUU 684 AACAATCA GGCTAGCTACAACGA CATCAGAG 2386 2971 UGAUGUG A UIJGUUGAA 685 TTCAAC2AA GGCTAGCTACAkACGA CACCATCA 2387 2974 UGGUGAUU G UJEGAAUAC 686 GTATTCAA GGCTAGCTACAACGA -ATCACCA 2383 2979 AULJGUIJGA A UACUGCAA 627 TTGCAGTA GOCTAGCTACAACGA TCAACAAT 2389 2981 UGUtJGAAU A CUGCAAAU 688 ATTTGCAG GOCTAGCTACAACGA ATTCAACA 239D 2984 UGAAUACU G CAAAUAUG 689 CATATTTG GGCTAGCTACAACGA AGTATTCA 2391 2988 UACUGCAA A UAUGGAAA 690 TTTCCATA GGCTAGCTACAACGA TTGCAGTA 2392 2990 CUGCAAAU A UGGAAAUC 591 GATTTCCA GGCTAGCTACAACGA ATTTGCAG 2393 2996 AUAUGGAA A UCUCUCCA 692 TGGAGAGA GGCTAGCTACAACGA TTCCATAT 2394 3005 UCUCUCCA A CUACCUCA 693 JTGAGGTAG GGCTAGCTACAACGA TGGAGAGA 2395 3008 CUCCAACU A CCUCAA-A 694 TCTTGAGG GGCTAGCTACAACGA AGTTGGAG 23 96 3017 CCUCAAGA G CAAACGUG 695 CACGTTTG GG3CTAGCTACAACGA TCTTGAGG 2397 3021 AAGAGCAA A CGUGACLTU 696 AAGTCACS GGCTAGCTACAACGA TTGCTCTT 2398 3023 GAGCAAAC G UGACUJAU 697 ATAAGTCA GGCTAGCTACAACGA GTTTGCTC 2399 3026 CAAACC-UG A CIJUAUULTU 698 AAAATAAG GGCTAGCTACAACGA CACGTTTG 2400 3030 CGUGACU A UUEUUUTCU 699 AGAAAALAA GGCTAGCTACAACGA AAGTCACG 2401 3041 UEJUUCLTCA A CAAGGAUG 700 CATCCTTG GGCTAGCTACAACGA TGAGAAAA 2402 3047 CAACAAGG A UGCAGCAC 701 GTGCTGCA GGCTAGCTACAACGA CCTTGTTG 2403 3049 ACALAGGAU G CAGCACUA 702 TAGTGCTG GGCTAGCTACAACGA ATCCTTGT 2404 3052 AGGAUGCA 0 CACUACAC 703 GTGTAGTG GGCT'AUCTACAACGA TGCATCCT 2405 3054 GAUGCAGC A CUACACAU 704 ATGTGTAG GGCTAGCTACAACGA GCTGCATC 2406 3057 GCAGCACU A CACAUGGA 705 ITCCATGTG GGCTAGCTACAACGA AGTGCTGC 2407 3059 AGCACUAC A CAUGGAGC 706 jGCTCCATG GGCTAGCTACAACGA GTAGTGCT 2408 3061 CACUACAC A UGGAGCCU 707 AGGCTCC-A GGCTAGCTACAACGA GTGTAGTG 2409 3066 CACAUGGA G CCUAAGAA 708 TTCTTAGG GGCTAGCTACAACGA TCCATGTG 2410 3082 AAGAAAAA A UGGAGCCA 709 TGGCTCCA GGCTAGCTACAACGA TTTTTCTT 2411 3087 AAAAUGGA G CCAGGCCU 71-0 AGGCCTGG GGCTAGCTACAACGA TCCATTTT 2412 3092 GGAGCCAG G CCUGGAAC 711 GTTCCAGG GGCTAGCTACAACGA CTGGCTCC 2413 3099 GGCCUGA A CAAGGCAA 712 TTGCCTTG GGCTAGCTACAACGA TCCAGGCC 2414 3104 GGAACAAG G CAAGAAAC 713 GTTTCTTG GGCTAOCTACAACGA CTTGTTCC 2415 3111 GGCAAGAA A CCAAGACU 714 IAGTCTTGG GGCTAGCTACAACGA TTCTTGCC 2416 3117 AAACCAAG A CUAGAUAG 715 JCTATCTAG GGCTAGCTACAACGA CTTGGTTT 2417 3122 AAGACUAG A UAGCGUCA 71G TGACGCTA GGCTAGCTACAACGA CTAGTCTT 2418 3125 ACUAGAUA G CGUCACCA 717 TGTGACG GGCTAGCTACAACGA TATCTAGT 2419 3127 UAGAUAGC G UCACCAUC 718 GCTGGTGA GGCTAGCTACAACGA GCTATCTA 2420 3130 AUAGCGUC A CCAGCAGC 719 GCTGCTGG GGCTAGCTACAACGA GACGCTAT 2421 3134 CGUCACCA G CAGCGAAA 720 TTTCGCTG GGCTAGCTACAACGA TGGTGACG 2422 3137 CACCAGCA G CGAALAGCU 721 JAGCTTTCG GGCTAGCTACAACGA TGCTGGTG 2423 3143 CAGCGAAA U CUUEUGCGA 722 TCGCAAAG UGCTAGCTACAACGA TTTCGCTG 2424 3148 AAAGCUUJ U CGAGCUCC 723 GGAUCTCO GGCTAGCTACAACGA AAAGCTTT 2425 312 CUTJUGCGA G CUCCGGCU 724 IAGCCGGAG GGCTAGCTACAACGA TCGCAAAGI 2426 WO 02/096927 PCT/US02/17674 3158 GAGCUCCG G CtUtUtCAGG 725 CCTGAAAG GGCTAGCTACAACGA CGGAGCTC 2427 3170 UCAGGAAG A LJAAAAGUC 726 GACTTTTA GGCPAGCTACAACGA CTTCCTGA 2428 3176 AGAUAAAA G UCUGAGUG 727 CACTCAGA GGCTAGCTACAACGA TTTTATCT 2429 3182 -AAGUCUGA G UGAUGUUG 728 CAACATCA GGCTAGCTACAACGA TCAGACTFT 2430 3185 UCUGAGJG A UGUTJGAGG 729 CCTCAACA GGCTAGCTACAACCA CACTCAGA 2431 3187 UGAc3UGAU G UUGAGGAA 730 TTCCTCAA Gc2CTAGCTACAZACGA ATCACTCA 2432 3203 AGAGGAGG A UUCUGACG 731 CGTCAGAA GGCTAGCTACAACGA CCTCCTCT 2433 3209 GGAUUCUG A CGGTJUUCU 732 AGAAACCG GGCI'AGCTACAACGA CAGAATCC 2434 3212 UIJCUGACG G UtiUCUACA 733 TGTAGAAA GGCTAGCTACAACGA CGTCAGAA 2435 3218 CGGTJUUCU A CAAGGAGC 734 GCTCCTTG GGCTAG4CTACAACGA AGAAACCG 2436 3225 UACAAGGA G CCCAUCAC 735 GTGATGGG GGCTAGCTACAACGA TCCTTGTA 2437 3229 AGGAGCCC A UCACUAUG 736 CATAGTGA GGCTAGCTACAACGA GGGCTC-T 2438 3232 AGCCCAUC A CtYAUCC?.A 737 TTCCATAG OCCTAGCTACAACGA CATCGGCT 2439 3235 CCAUCACU A UGGAAt3AU 738 ATCTTCCA GGCTAGCTACAACGA AGTGATC3G 2440 3242 UAUGt3AAG A UCUGAUUTU 739 AAATCAGA GGCTFAGCTACAACGA CTTCCATA 2441 3247 AAGAUCUG A UUUCUUAC 740 GTAAGAAA GGCTAGCTACAACGA CAGATCTT 2442 3254 GAUUUCUU A CAGUEJTUC 741 GAAAACTG GGCTAt3CTACAACGA AAGAAATC 2443 3257 UEICIUtACA G UUUJICAAG 742 CTTGAAAA GGCTAGCTACAACGA TGTAAGAA 2444 3265 GUUUUCA G UGGCCAGA 743 TCTt3GCCA GGCTAGCTACAACGA TTGAAALAC 2445 3268 UUCAAGUG G CCAGAGGC 744 GCCTCTGG GGCTAGCTACAACGA CACTTGAA 2446 3275 GGCCAGAG G CAUGGAGU 745 ACTCCATG GGCTAGCTACAACGA CTCTGGCC 2447 3277 CCAGAGGC A UGGAGUUC 746 GAACTCCA GOCTAGCTACAACGA GCCTCTGG 2448 3222 GGAUGGA G UTJCCUGUC 747 GACAGGAA GOCTAGCTACAACGA TCCATGCC 2449 3288 GAGUUCCU G tJCUUCCAG 748 CTGGAAGA GGCTAGCTACAACGA AGGAACTC 2450 3300 UCCAGAAA G IGCAUUCA 749 TGAATGCA GGCTAGCTACAACGA TTTCTGG3A 2451 3302 CAGAAAGU G CAUIJCAUC 750 GATGAATG GGCTAGCTACAACGA ACTTTCTG 2452 3304 GAAAGUJGC A UTCJCAUCGG 751 CCGATGAA GGC FAGCTACAACGA GCACTTTC 2453 3308 GUGCAUUC A tJCGGGACC 752 GGTCCCGA GtCTAGCTACAACGA GAATGCAC 2454 3314 UCAUCGGG A CCUGGCAG 753 CTGCCAGG GGCTAGCTACAACGA CCCGATGA 2455 3319 GGGACCUG G CAGCGAGA 754 TCTCGCTG GGCTAGCTACAACGA CAGGTCCC 2456 3322 ACCUGUCA G CGAGAAAC 7-55 GTTTCTCG COCTIXGCTACAACGA TGCCAGGT 2457 3329 AGCGAGAA A CAUUCULU 756 AAGAATG GGCTAGCTACAACGA TTCTCGCT 2458 3231 COAGAAAC A UUECIUUUA 7S7 TAAAAGAA, GGCTAGCTACAACGA GTTTCTCG 2459 3339 AUEJCUUUU A UCUGAGAA 758 TTCTCAGA GGCTAGCTACAACGA AAAAGAAT 2460 3347 AUCUGAGA A CAACGUGG 759 CCACGTTG GGCTAGCTACAACGA TCTCAGAT 2461 3350 UGAGAACA A CGUGGUGA 760 TCACCACG GGCTAGCTACAACGA TGPTCTCA 2462 3352 AGAACAAC G UGGUGAAG 761 CTTCACCAk GGCTAGCTACAACGA GTTGTTCT 2463 3355 ACAACGUG G UGAAGAUU 762 AATCTTCA GGCTAGCTACAACGA CACGTTGT 2464 3361 UGGUGAAG A UUUGUGAU 763 ATCACAAA GGCTAGCTACALACGA CTTCACCA 2465 3365 GAAGAUUTU G IJGAUUUTJG 764 CAAAATCA GGCTAGCTACAACGA AAATCTTC 2466 3368 GAUUtrGUG A UULTEJGGCC 765 GGCCAAAA GGCTAGCTACAACGA CACAA.ATC 2467 3374 tJGAUUTJUG G CCUUGCCC 766 GGGCAAGG GGCTAGCTACAACGA CAAJAtTCA 2468 3379 UUGGCCUU G CCCGGGAU 767 ATCCCGGG GGCTAGCTACAACGA AAGGCCAA 2469 3386 UGCCCGGG A UAUUUtAUA 768 TATAAATA GGCTAGCTACAACGA CCCGGGCA 2470 3388 CCCGGC-AU A UUUAUAAG 769 CTTATAAA GGCTAGCTACAACGA ATCCCGG 2471 3392 GGAUAUUJ A UAAGAACC 770 GGTTCTTA GGCTAGCTACAACGA AAATATCC 2472 3398 UUAUAAGA A CCCCGAUU 771 AATCGGG3 GGCTAGCTACAACGA TCTTATAA 2473 3404 GAACCCCG A UUAUGUGA 772 TCACATAA GGCTAGCTACAACGA CGGGGTTC 2474 3407 CCCCGAUJ A UGUGAGAA 773 TTCTCACA GGCTAGCTACAACGA AATCGOGG 2475 340.9 CCGAUUAUJ G UGAGAAAA 774 TTTTCTCA GGCTAGCTACAACGA ATAATCGG 2475 3422 AAALAGGAG A UACUJCGAC 7-75 GiTCGAGTA GrCTAGCTAcAAcrA CTCCTTTT 2477 3424 AAGGAGAU A CUCGACUU 776 AAGTCGAG GGCTAGCTACAACGA ATCTCCTT 2478 WO 02/096927 PCT/US02/17674 3429 GAtfACUCG A CIJUCCUCU 777 AGAGGAAG GGCTAGCTACAACGA Cc3AcTATC 2479 3441 CCTJCUGAA A UGGAUGGC 778 GCCATCCA GGCTAGCTACAACGA TTCAGAGG 2480 3445 UGAAAJGG A UGGCUCCC 779 GGGAGCCA GGCTAOCTACAACGA CCATTTCA 2481 3448 AATJGGAUG G CUCCCGAA 760 TTCGGGAG GGCTAGCTACAACGA CATCCATT 2482 345G GCUCCCGA A UCTJAtCUU 781 AAGATA-A GGCTAG3CTACAACGA TCcGaGAGC 2483 3460 CCGAAUCU A UCUJEUGAC 782 GTCAAAGA GGCTAGCTACAACGA AGATTCGG 2484 3467 UAUCIJUUG A CAAAAUCU 763 AGATTTTG GGCTAGCTACAACGA CAAAGATA 2485 3472 UUGACAAA A UCUACAGC 784 GCTGTAGA GGCTAGCTACAACGA TTTGTCAA 2486 3476 CAAAAUCU A CAGCACCA 765 TGGTGCTG GGCTAGCTACAACGA AGATTTTG 2487 3479 AAUCIJACA G CACCAAGA 7B6 TCTTGG3TG GGCTAGCTACAACCGA TGTAGATT 2488 3481 UCUACAGC A CCAAGAGC 787 GCTCTTGG GGCTAGCTACAACGA GCTGTAGA 2489 3488 CACCAAGA G CGACGUGU 788 ACACGTCG GGCTAG3CTACAACGA TCTTGGTG 2490 3491 CAAGAGCG A CGUGUGGU 769 ACCACACG GOCTACICTACAXC(3A CGCTCTTG 2491 3493 AGAGCGAC G UGUGGUCU 790 AGACCACA GGCTAGCTACAACGA GTCGCTCT 2452 3495 AGCGACGU G UGGUCIEA 791 TAAGACCA GGCTA(3CTACAACGA ACGTCGCT 2493 3498 GACGUGUG G TJCUUACGG 792 CCGTAAGA GGCTAGCTACAACGA CACACG'C 2494 3503 GUGGUCUJ A CGGAGUAU 793 ATACTCCG GGCTAGCTACAACGA AAGACCAC 2495 3508 CUtJACGGA G UAUEJGCUG 794 CAGCAAIA GGCTAGCTACAACGA TCCGTAAG 2496 3510 UACGGAGU A UTJGCUGUG 795 CACAGCAA GGCTAGCTACAACGA ACTCCGTA 2497 3513 GGAGUAUU G CUGUGGGA 796 TCCCACAG GGCTAGCTACAACGA AATACTCC 2498 3516 GUAUUGCU G UGGGAAAU 797 IATTTCCCA GGCTAGCTACAACGA AGCAATAC 2499 3523 UGUGGGAA A UCUUCUCC 798 GGAGAAGA GGCTAGCTACAACGA TTCCCACA 2500 3836 CUCCtJUAG G U3GT3TJCUC 799 GAGACCCA GGCTAOCTACAACGA CTAAGGAG 2501 3540 UUAGGUGG G UCUCCAUA 800 TATGGAGA GGCTAGCTACAACGA CCACCTAA 2502 3546 GGGUCUCC A UACCCAGG 801 CCTGGGTA GGCTAGCTACAACGA GGAGACCC 2503 3548 GUCUCCAU A OCCAGGAG 802 CTCCTGGG GGCTAGCTACAACGA ATGGAGAC 2504 3556 ACCCAGGA G UACAAAUG 803 ICATTTGTA GGCTAGCTACAACGA TCCTGGGT 2505 3558 CCAGGAGU A CAAAEJGGA 804 ITCCATTTG GGCTAGCTACAACGA ACTCCTGG 2506 3562 GAGUACAA A TGGAUGAG 805 CTCATCCA GGCTAGCTACAACGA TTGTACTC 2507 3566 ACAAAUGG A UGAGGACU 806 AGTCCTCA GGCTAGCTACAACGA CCATTTGT 2508 3572 GGAUGAGG A CUTJUEGCA 807 TGCAAAAG GGCTAGCTACAACGA CCTCATCC 2509 3578 GGACIJUUU G CAGUCGCC 808 GGCGACTG GGCTAGCTACAACGA AAAAGTCC 2510 3581 CULJUUUGCA G UCGCCUGA 809 TCAGGCGA GGCTAGCTACAACGA TGCAAALAG 2511 3584 TJTGCAGLJC G CCUGAGGG 810 CCCTCAGG GGCTAGCTACAACGA GACTGCAA 2512 3596 GAGGGAAG G CAUGAGGA 811 TCCTCATG GGCTAGCTACAACGA CTTCCCTC 2513 3598 GGGAAGGC A UGAGGAUG 812 CATCCTCA GGCTAGCTACAACGA GCCTTCCC 2514 3604 GCAUGAGG A UGAGAGCU 813 AGCTCTCA Gc3CTAGCTACAACGA CCTCATGC 2515 3610 GGAUGAGA G CUCCUGAG 814 CTCAGGAG GGCTAGCTACAACGA TCTCATCC 2516 3618 GCUCCUGA G UACUCUAC 815 GTAGAGTA GGCTAGCTACAACGA TCAGGAGC 2517 3620 UCCUGAGU A CUCUACUC 816 GAGTAGAG GGCTAGCTACAACGA ACTCAGGA 2518 3625 AG{TACUCU A CUCCUGAA 817 TTCAGGAG GOCTAGCTACAACGA AGAGTACT 2519 3634 CIJCCUGAA A UCUAUCAG 818 CTGATAGA GGCTAGCTACAACGA TTCAGGAG 2520 3638 UGAAAUCU A UCAGAUCA 819 TGATCTGA GGCTAGCTACAACGA AGATTTCA 2521 3643 UCUAEYCAG A UCAUGCUG 820 CAGCATEJA GGCTAGCTACAACGA CTGATAGA 2522 364G AUCAGAUC A UCCUGGAC 821 GTCCAGCA GGCTAGCTACAACGA GATCTGAT 2523 3648 CAGAUCAU G CUGGACUG 822 CAGTCCAG GGCTAGCTACAACGA ATGATCTG 2524 3653 CAUGCUGG A CUGCUGGC 823 GCCAGCAG GGCTAGCTACAACGA CCAGCATG 2525 3656 GCUGGACU G CUGGCACA 824 TGTGCCAG GGCTAGCTACAACGA AGTCCAGC 2526 3660 GACUGCUG G CACAGAGA 825 TCTCTGTG GGCTAGCTACAACGA CAGCAGTC 2527 3662 CUGCUGGC A CAGAGACC 826 GGTCTCTG GGCTAGCTACAACGA GCCAGCAG 2528 3668 GCACAGAG A CCCAAAAG 827 CTTTTGGG GGCTAGCTACAACGA CTCTGTGC 2529 3681- AAAGAAAG G CCAAGAUU 828 AATCTTGG GGCTAGCTACAACGA CTTTCTTTj 2530 WO 02/096927 PCT/US02/17674 3687 AGGCCAAG A IUUGCAGA 829 TCTGCAAA GGCTAGCTACAACGA CTTGGCCT 2531 3691 CAAGAUtJ G CAGAACIJU 830 AAGTTCTG3 GGCTAGCTACAACGA PJAATCTTG 2532 3696 TUCEJCAGA A CtUtGUGGA B31 TCCACAA3 GGCTAGCTACAACGA TCTGCAAA 2533 3700 CAGAACUU G IGGAAAAA 832 TTTTTCCA GGCTAGCTACAACGA AAc3TTCTG 2534 3708 GUUGAAAA A CtJAGGIJGA 833 TCACCTAG3 Ct3CTAGCTACAACCA TTTTCCAC 2S35 3713 AAAACUAG G UGAUtJUGC 834 GCAAATCA GGCTAGCTACAACGA CTAGTTTT 2536 3716 ACUAGGUG A UUUTGCUEJC 835 GAAGCAAA GGCTAGCTACAACGA CACCX'AGT 2537 3720 GGUGAUUY G CUUCAAGC 836 GCTTGAAG GGCTAGCTACAACGA AAATCACC 2838 3727 UGCtTUCAAL G CAAAUGUA 837 TACATTTG GGCTAGCTACAACGA TTGAAGCA 2839 3731 UCAAGCAA A UGUACALAC 838 GTTGTACA GGCTAGCTACAACCA TTGCTTGA 2840 3733 AAGCAAAU G UACAACAG 839 CTGTTGTA GGCTAGCTACAACGA ATTTGCTT 2541 3'735 GCAAAUGU A CAACAGGA 840 TCCTGTTG GGCTAGCTACAACGA ACATTTGC 2542 3732 AAUGUACA A CAGGALTGG 841 CCATCCTG GGCTAGCTACAACGA TGTACATT 25413 3743 ACAACAGG A UGGUAAAG 842 CTTTACCA GGCTAGCTACAACGA CCTGTTGT 2544 37146 ACAGGAUG G UAAAGACU 843 AGTCTTTA GGCTAGCTACAACGA CATCCTGT 2545 3 752 UGGUAAAG A CUACAUCC 844 GGATGTAG GGCTAGCTACAACGA CTTTACCA 2545 3755 UAAAGACU A CAUCCCAA 845 TTGGGATG GGCTAGCTACAACGA AGTCTTTA 2547 3757 AAGACTJAC A UCCCAAUC 846 GATTGGGA GGCTAGCTACAACGA GTAGTCTT 2548 3763 ACAUCCCA A UCAAUGCC B47 GGCATTGA GGCTAGCTACAACGA TGGGATGT 2549 37)67 CCCAAUCA A UGCCAUAC 848 GTATGGCA GGCTAGCTACAACGA TGATTGGG 2550 3769 CAAUCAAU G CCAUACUG 849 CAGTATGG GGCTAGCTACAACGA ATTGATTG 2551 3772 UCAATGCC A UACUGACA 850 TGTCAGTA GGCTAGCTACAACGA GGCATIGA 2552 3774 AAUGCCAU A CUGACAGG 251 CCTGTCAO GGCTAGCTACAACGA ATGGCATT 2553 3778 CCAUACUG A CAGGAAAU 852 ATTTCCTG GGCTAGCTACAACGA CAGTATGG 2554 3785 GACAGGAA A UAGUGGGU 853 ACCCACTA GGCTAGCTACAACGA TTCCTGTC 2555 3788 AGGAAAUA G UGGGULTUA 854 TAAACCCA GGCTAGCTACAACGA TATTTCCT 2556 3792 AAUAGUGG G tUUACAUA 855 ITATGTAAA GGCTAGCTACAACGA CCACTATT 2557 3796 GUGGGUU A CAUACIJCA 856 TGAGTATG GGCTAGCTACAACGA AAACCCAC 2558 3798 GGGULUAC A UACIJCAAC 887 GTTGAGTA GGCTAGCTACAACGA GTAAACCC 2559 3800 GUIJTACAU A CUCAACUC 858 GAGTTGAG GGCTAGCTACAACGA ATGTAAAC 2560 3805 CAUACUCA A CUCCUGCC 859 GGCAGGAG GGCTAGCTACAACGA TGAGTATG 2561 3811 CAACUCCU G CCUUCUCU 860 AGAGAAGG GGCTAGCTACAACGA AGGAGTTG 2562 3824 CUCUGAGG A CUEICIUCA 861 TGAAGAAG GGCTAGCTACAACGA CCTCAGAG 2563 3839 CAAGGAAA G tAUUUCA.G 862 CTGAALTA GGCTAGCTACAACGA TTTCCTTG 2564 3841 AGGAAAGU A tJUTCAGCU 863 AGCTGAAA GGCTAGCTACAACGA ACTTTCCT 2565 3847 GUAUULCA G CtTCCGAPAG 864 CTTCGGAG GGCTAGCTACAACCA TGAAATAC 2566 3855 GCUCCGAA G UUTJAAUUC 865 GAATTAZAA GGCTAGCTACAACGA 3TTCGGAGC 2557 3860 GAAGUUEJA A UUCAGGAA 866 ITTCCTGAA GGCTAGCTACAACGA TAAACTTC 2568 38G9 UtICAGGAA G CUCUGAUG 867 CATCAGAG GGCTAGCTACAACGA TTCCTGAA 2569 3875 AAGCUCUG A UGAUGUCA 868 TGACATCA GGCTAGCTACAACGA CAGAGCTT 2570 3878 CUCUGAUG A UGUCAGAU 869 ATCTGACA GGCTAGCTACAACGA CATCAGAG 3571 3880 C{JGAtJGAU G UCAGAUAJ 870 ATATCTGA GGCTAGCTACAACGA ATCATCAG 2572 3885 GAUGUCAG A UAUGUAAA 871 TTTACATA GGCTAGCTACAACGA CTGACATC 2573 3887 UGUCAGAU A UGUAA.AUG 872 CATTTACA GGCTAGCTACAACGA ATCTGACA 2574 3889 UCAGAUAU G UAAAUGCU 873 AGCATTTA CGCTAGCTACAACGA ATATCTGA 2575 3893 AUAUJGUAA A UGCUUJECA 874 TGAAAGCA GGCTAGCTACAACGA TTACATAT 2576 3895 AUGUAAAU G CULTUCAAG 875 CTTGAAAG GGCTAGCTACAACGA ATTTACAT 2577 3903 GCTJEJECAA G UUCAUGAG 876 CTCATGAA GGCTAGCTACAACGA TTGAAAGC 2578 3907 UCAAGUUC A UGAGCCUG 877 CAGGCWCA GGCTAGCTACAACGA GAACTTGA 2579 3911 GUETCAUGA G CCUGGAAA 878 TTTCCAGG GGCTAGCTACAACGA TCATGAAC 2580 3922 UGGAAAGA A UCAAAACC 879 GGTTTTGA GGCTAGCTACAACGA TCTTTCCA 2581 3928 GAAUCAAA A CCUUTJGAA 880 TTCAAJAUG GGCTAGCTACAACGA TTTGATTC 2582 WO 02/096927 PCT/US02/17674 3939 UUUGAAGA A CUUUJUACC 881 GGTAAA4G GGCTAGCTACAACGA TCTTCAAA 2583 3945 GAACUUUU A CCGAAUGC 882 OCATTCGG GGCTAGCTACAACGA AAAAGTTC 2584 3950 UUTJACCGA A UGCCACCU 883 AGGTGGCA GGCTAGCTACAACGA TCGGTAAA 2585 3952 UACCGAAU G CCACCUCC 884 GGAGGTGG GGCTAGCTACAACGA ATTCGGTA 2586 3955 CGAAUGCC A CCUCCAUG 885 O!AT'GAGG GGCTAGCTACAACGA GGCATTCG 2587 3961 CCACCUCC A UGUUtJGAU 886 ATCAAACA GGCTAGCTACAACGA GGAGGTGG 2588 3963 ACCUCCAUJ G UULS3AUGA 887 TCATCAAA GGCTAGCTACAACGA ATGGAGGT 2589 3968 CAUGUUG A UGACUJACC 888 GGTAGTCA GGCTAGCTACAACGA CAALACATG 2590 3971 GUUUGAUG A CUACCAGG 889 CCTGGTAG cGCTAGCTACAACGA CATC1AAAC 2591 3974 UGAUGACJ A CCAGGGCG 890 CGCCCTGG GGCTAGCTACAACGA AGTCATCA 2S92 3980 CUACCAGG G CGACAGCA 891 TGCTGTCG GGCTAGCTACAACGA CCTGGTAG 2593 3983 CCAGGGCG A CAGCAGCA 892 TGCTGCTG GGCTAOCTACAACGA CGCCCTGG 2S94 390G GOCOACA 0 CAGCACUC 893 GAGTCCTG CCTAGCTACAACGA PGTCGCCC 2595 3989 CGACAGCA G CACtYCUGU 894 ACAGAGTG GGCTAGCTACAACGA TGCTGTCG 259G 3991 ACAGCAGC A CUCUGUUG 895 CAACAGAG GGCTAGCTACAACGA GCTGCTGT 2597 3996 AGCACUCU G UrJGGCC1JC 896 GAGGCCAA GGCTAGCTACAACGA AGAGTGCT 2598 4000 CUCUGUJG G CCUCUCCC 897 GGGAGAGG GGCTAGCTACAACGA CAACAGAG 2599 4009 CCIJCUCCC A UGCUGAAG 898 CTTCAGCA GGCTAGCTACAACGA GGGAGAGG 2600 4011 UCUCCCAU G CUGAAGCG 899 CGCTTCAG GGCTAG3CTACAACGA ATGGGAGA 2601 4017 AUGCUGAA G CGCUUCAC 900 GTGAAGCG GGCTAGCTACAACGA TTCAGCAT 2602 4019 GCUGAAGC G CUJUCACCU 901 AGGTGAAG GGCTAGCTACAACGA GCTTCAGC 2603 4024 AGCGCUUC A CCUGGACJ 902 AGTCCAGG GGCTAGCTACAACGA GAAGCGCT 2604 4020 UCACCUGG A CUGACAGC 903 GCTGTCAG GGCTAGCTACAACGA CCAGGTGA 2605 4034 CUGGACUG A CAGCAAAC 904 GTTTGCTG GGCTAGCTACAACGA CAGTCCAG 2606 4037 GACUGACA G CAAACCCA 905 TGGGTTTG GGCTAGCTACAACGA TGTCAGTC 2607 4041 GACAGCAA A CCCAAGGC 906 GCCTTGGG GGCTAGCTACAACGA TTGCTGTC 2608 4048 AACCCAAG G CCUCGCUC 907 GAGCGAGG GGCTAGCTACAACGA CTTGGGTT 2609 4053 AAGGCCUC G CUCAAGAU 908 ATCTTGAG GGCTAGCTACAACGA GAGGCCTT 2610 4060 CGCUCAALG A UULGACUIJG 909 CAAGTCAA GGCTAGCTACAACGA CTTGAGCG 2611 4064 CAAGAUUG A CUUtGAGAG 910 CTCTCAAG GGCTAGCTACAACGA CAATCTTG 2612 4072 ACUUGAGA G UAACCAGU 911 ACTGGTTA GGCTAOCTACAACGA TCTCAAGT 2613 4075 UGAGAGUA A CCAGUAAA 912 TTTACTGG GGCTAGCTACAACGA TACTCTCA 2614 4079 AGLTAACCA G UAAAAGUA 913 TACTTTTA CGCTAOCTACAACCA TGTTACT 2615 4085 CAGUAAAA G UAAGGAGU 914 ACTCCTTA GGCTAGCTACAACGA TTTTACTG 2516 4092 ACUAAGGA G UCGGGGCU 915 AGCCCCGA GGCTAGCTACAACGA TCCTTACT 2617 4098 GAGUCGGG G CUGUCUGA 916 TCAGACAG GGCTAGCTACAACGA CCCGACTC 2618 4101 UCGGGGCU G UCUGAUGU 917 ACATCAGA GGCTAGCTACAACGA AGCCCCGA 2619 4106 GCUGUCUG A UGUCAGCA 918 TGCTGACA GGCTAGCTACAACGA CAGACAGC 2620 4108 UGUCUGA G UCAGCAGG 919 CCTGCTGA GGCTAGCTACAACGA ATCAGACA 2621 4112 UGAUGUCA G CAGGCCCA 920 TGGGCCTG GGCTAGCTACAACGA TGACATCA 2622 4116 GUCAGCAG G CCCAGUUJU 921 IAAACTGGG GcTAGC-TACAACGA CTGCTGAC 2623 4121 CAGGCCCA G UTJUCUGCC 922 GGCAGAAA GGCTAGCTACAACGA TGGGCCTG 2624 4127 CAGULUUCU G CCAUUCCA 923 TGGAATGG GGCTAGCTACAACGA AGAAACTG 2625 4130 UUTJCUGCC A UUCCAGOG 924 AGCTGGAA GGCTAGCTACAACGA GGCAGAAA 2526 4136 CCAUUCCA G CUGUGGGC 925 GCCCACAG GGCTAGCTACAACGA TGGAATGG 2627 4139 UEJCCAGCU G UGGGCACG 926 CGTGCCCA GGCTAGCTACAACGA AGCTGGAA 2628 4143 AGCUGUGG G CACGUCAG 927 CWGACGTG GGCTAGCTACAACGA CCACAGCT 2629 4145 CUGUGGGC A CGUCAGCG 928 CGCTGACG GGCTAGCTACAACGA GCCCACAC 2630 4147 GUGGGCAC G UCAGCGAA 929 TTCCCTGA GGCTAGCTACAACGA GTGCCCAC 2631 4151 GCACGUCA G CGAACGCA_ 930 TGCCTTCG GGCTAGCTACAACGA TGACG7GC 2632 4167 CAGCGAAG G CAAGCGCA 931 TGCGCTTG GGCTAGCTACAACGA CTTCGCTG I2633 4161 GAAGGCAA G CGCAGGJU 9 32 IAACCTGCG GGCTAGCTACAACGA TTGCCTTCj 2634 WO 02/096927 PCT/US02/17674 -4163 AGGCAAGC G CAGGUtICA 933 TGAACCTG GGCTAGCTACAACGA GCTTGCCT 2635 4167 AAGCGCAQ G UUCACCJA 934 TAGGTGAA GGCTAGCTACAACGA CTGCGCTT 2636 4171 GCAGGUJC A CCUACGAC 935 GTCGTAGG GGCTAGCTACAACGA GAACCTGC 2G37 41'75 GUUECACCU A CGACCACG 936 CGTGGTCG GGCTAGCTACAACGA AGGTGAAC 2638 4178 CACCUACG A CCACGCUG 937 CAGCGTGG GGCTAGCTACAACGA CGTAGGTG 2639 4181 CUACGACC A CGCtJGAGC 938 GCTCAGCG GGCTAGCTACAACGA GGTCGTAG 2640 4183 ACGACCAC G CUGAGCUG 939 CAGCTCAG GGCTAGCTACAACGA GTGGTCGT 2641 4188 CACGCUGA G CTJGGAAAG 940 CTTTCCAG GGCTAGCTACAACGA TCAGCGTG 2642 4201 AAAGGAAA A UCGCGUGC 941 GCACGCGA GGCTAGCTACAACGA TTTCCTTT 2643 4204 GGAAAAUC G CGTJGCUGC 942 GCAGCACG GGCTAGCTACAACGA GATTTTCC 2644 4206 AAAAUCGC G UGCtJGCUC 943 GAGCAGCA GGCTAGCTACAACGA GCGATTTT 2645 4208 AAUCGCGU G CUCCUCCC 944 GGGAGCAG GGCTAGCTACAACGA ACGCGATT 2646 4211 CGCGUGCU G CUCCCCGC 945 COGOAC GGCTAOCTACAACGA ACCACCOG 2647 42.18 UGCUCCCC G CCCCCAGA 946 TCTGGGGG GGCTAGCTACAACGA GGGGAGCA 2648 4226 GCCCCCAG A CUACAACU 947 AGTTGTAG GGCTAOCTACAACGA CTCGGGCCC 2649 4229 CCCAGACU A CAACUCGG 948 CCGAGTTG GGCTAGCTACAACGA AGTCTGGG 2650 4232 AGACUACA A CUCGGUGG 949 CCACCGAG GGCTAGCTACAACGA TGTAGTCT 2651 4237 ACAACUCC G UGGUCCUG 980 CAGGACCA GGCTACCTACAACGA CCAGTTGT 2652 4240 ACUCGGUG G UCCUGJAC 951 GTACAGGA GGCTAGCTACAACGA CACCGAGT 2653 424S GtJGGUCCU G UACUCCAC 952 GTGGAGTA GGCTAGCTACAACGA ACCACCAC 2654 4247 GGUCCUGU A CUCCACCC 953 GGGTGGAG GGCTAGCTACAACGA ACAGGACC 2655 4252 UGtJACUCC A CCCCACCC 954 GGCTGGGG GGCTAGCTACAACGA CGAGTACA 2656 4257 UCCACCCC A CCCAUCUA 955 TAGATGCC GGCTACCTACAACCA GOGTOGA 2657 4261 CCCCACCC A UCUAGAGU 956 ACTCTAGA GGCTAGCTACAACGA GG3GTGGG 2658 4268 CALTOUAGA G UCEJGACAC 957 GTGTCAAA GGCTAGCTACAACGA TCTAGATG 2659 4273 AGAGUJTG A CACGAAGC 958 G3CTTCGTG CGCTAGCTACAACGA CAAACTCT 2660 4275 ACUEUCAC A CGAAGCCJ 959 AGGCTTCC GGCTAGCTACAACGA GTCAAACT 2661 4280 GACACGAA G CCUUAUU 960 AAATAACG CCCTAGCTACAALCGA TTCGTGTC 2662 4285 GAAGCCUU A UTtCUAGA 961 TCTAGAAA GGCTAGCTACAACGA AAGGCTTC 2663 4295 UEJCtAGAA G CACAUGUG 962 CACATGTG GGCTAGCTACAACGA TTCTAGAA 2664 4297 CUAGAAGC A CAUGUGUA 963 TACACATG GGCTAGCTACAACGA GCTTCTAG 2665 4299 ACAAGCAC A UGU3CtAUU 964 AATACACA GGCTAGCTACAACGA GTGCTPCT 2666 4301 AACCACAU C UGUAUUUTA 965 TAAATACA CCCTAGCTACAACC2A ATCTCCTT 2667 4303 GCACAUGU G UAEJUUAUA 966 TATAAATA GGCTAGCTACAACCA ACATGTGC 2668 4305 ACAUGEJGU A ULTUAUACC 967 CGTATAAA GGCTAGCTACAACGA ACACATGT 2669 4309 GUGUAUJU A UACCCCCA 968 TGGGGGTA GGCTAGCTACAACGA AAATACAC 2670 4311 GUAUUJAJ A CCCCCA3C 969 CCTGGGGG GGCTAGCTACAACGA ATAAATAC 2671 4322 CCCAGGAAL A CUJAGCUUJ 970 AAACCTAC GGCTACCTACAACGA TTCCTGCG 2672 4326 GCAAACUA G CUtUUUGCC 971 GGCAAAAG GGCTAGCTACAACGA TAGTTTCC 2673 4332 UAGCUUJE G CCAGUAUJ 972 AATACTGG GGCTAGCTACAACGA AAAAGCTA 2674 4336 UEUTJOCCA a UAUEJAUGC 973 GCATAATA GGCTAGCTACAACGA TCCCAAAA 2675 4338 UUGCCAGU A UUAUGCAY 974 ATGCATAA GGCTAGCTACAACGA ACTGGCAA 2676 4341 CCAGUAJU A UGCAUAJA 975 TATATGCA CCCTAGCTACAACCA AATACTGG 2677 4343 AGUAEJVAU G CAtTALTAUA 976 TATATAUIG GGCTAGCTACAACGA ATAATACT 2678 4345 UAUUAUGC A UAEJAUAAG 977 CTTATATA GGCTAGCTACAACGA GCATAATA 2679 4347 UTJAUGCATJ A UAUAAGTUU 978 I'ACTTAC-A GGCTAGCTACAACGA ATGCATAA 2680 4349 AUGCAUAU A UAAGUJTJA 979 TAAACTTA GGCTAGCTACAACGA ATATGCAT 2681 4353 AUAUAUAA a UTJUACACC 980 GGTGTAALA GGCTAGCTACAACGA TTATATAT 2682 4357 AUAAUUU A CACCUUUIA 981 TAAAGGCCC GGCTAGCTACAACGA AAACTTAT 2683 4359 AACUUIAC A CCUUUAJC 982 GATAAAC GGCTAGCTACAACCA GTAAACTT 2684 4365 ACACCEJUU A UCUEJUCCA 983 TGCAAACA CCCTACCTACA\CGA AAACCTGTI 2685 4373 AUCLTUUCC A UGGGAGCC 1984 IGGCTCCCA GGCTAGCTACACGA GGAAAGATJ 2686 WO 02/096927 PCT/US02/17674 4379 CCAUGGGA G CCAGCUGC 985 GCAGCTGG GGCTrAGCTACAACGA TCCCATGG 2687 4383 GGGAGCCA G CIJGCUUtJ 986 AAAAGCAG GGCTAGCTACAACGA TGGCTCCC 2688 4386 AGCCAGCU G CUUUUUGU 967 ACAAAAAG GOCTAGCTACAACGA AGC0TQGCT 2689 4393 UGCUEJEJO G 'UGAUUUUJ 988 AAAAATCA GGC'CAGCTACAACGA AAAAAGCA 2690 4396 UUUEJEGTG A UUUULTJUJA 969 TAAAAAAA SOCTAGCTACAACCA CACAAAAA 2691 4405 UTUUtUUJA A UAGTGCUJ 990 AAGCACTA GGCTAcGCTACAACGA TAAAAAAA 2692 4408 UUEJAAUJA G UGCUOUUJ 991 AAAAAGCA GGCTAGCTACAACGA TATTAAAA 2693 4410 UEJAAUAGU G CUUUTUtJ 992 AAAAAAG GGCTAGCTACAACGA ACTATTAA 2694 4424 UUUTtJ A CUAACAAG 993 CTTGTTAG GGCTAGCTACAACGA CAAAAAAA 2695 4428 UEUhGACtJA A CAAGAAUG 994 CATTCTTS GGCTAGCTACAACG4A TAGTCAAA 2696 4434 UAACAAGA A UGUAACYC 995 GAGTTACA GGCTAGCTACAACGA TCTTGITA 2697 4436 ACAAGAAU G UAACUCCA 996 TGGAGTTA GGCTAGCTACAACGA ATTCTTGT 2698 4439 AGAAUGtJA A CUCCAGAU 997 ATCTGOAG GGCTAGCTACAACGA TACATTCT 2699 4446 AACUCCAG A UAGAGAAA 998 TTTCTCTA GGCTAGCTAC2AACGA CTGGAGTT 2700 4454 AUAGAGAA A UAGUGACA 999 TGTCACTA GGCTAGCTACAACGA TTCTCIAT 2701 4457 GAGAAAUA G UGACAAGU 1000 ACTTGTCA GGCTAGCTACAACGA TAT3TTCTC 2702 4460 AAAUAGUG A CAAGUGAA 1001 TTCACTTG GGCTAGCTACAACGA CACTATTT 2703 4464 AGtTGACAA G UGAAGAAC 1002 GTTCTTCA GGCTAGCTACAACGA TTGTCACT 2704 4471 AGUGAAGA A CACtYACUG 1003 CAGTAGTG GGCTAGCTACAACGA TCTTCACT 2705 4473 Th3AAGAAC A CUACT33CU 1004 AGCAGTAG GGCTAGCTACAACGA GTTCTICA 2706 4476 AGAACACU A CLTGCUAAA 1005 TTTAGCAG GGCTAGCTACAACGA AGTGTTCT 2707 4479 ACACUACU G CUAAAUCC 1006 GGATTTAG GGCTAGCTACAACGA AGTAGTGT 2708 4484 ACUGCUAA A UCCUCAUG 1007 CATGAGG3A GGCTAGCTACAACGA TTAGCAGT 2709 4490 AAAUJCCUC A UGUUACTC 1008 GAGTAACA GGCTAGCTACAACGA GAGGATTT 2710 4492 AUCCUCAU G UUACUCAG 1009 CTGAGTAA GGCTAGCTACAACGA ATGAGGAT 2711 4495 CUCAUGUJ A CUCAGUGU 1010 ACACTGAG GGCTAGCTACAACGA AACAT-AG 2712 4500 GUJUACTJCA G UGLTUAGAG 1011 CTCTAACA GGCTAGCTACAACGA TGAGTAAC 2713 4502 TJACUCAc3U G3 UrAGAG3AA 1012 TTC PCTAA GGCTAGCTACAACGA ACTGAGTA 2714 4511 UtJAGAGAA A UCCUUCCU 1013 AGGAAGGA GGCTAGCTACAACGA TTCTCTAA 2715 4522 CUTJCCUAA A CCCAAUGA 1014 TCATTGGG GGCTAGCTACAACGA TTAGGAAG 2716 4527 UAAACCCA A UGACUUCC 1015 GGAAGTCA GGCTAGCTACAACGA TGGGTTTA 2717 4530 ACCCAAUG A CUUCCCUG 1016 CAGGGAAG GGCTAGCTACAACGA CATTG-GT 2718 4538 ACUEJCCCU G CUCCAACC 1017 GGTTG3GAG GOCcTAOCTACAACGA AGGGAACT 2719 4544 CUGOUCCA A CCCCCGCC 1018 GGCGGGGG GGCTAGCTACAACGA TGGAGCAG 2720 4580 CAACCCCC G CCACCUCA 1019 TGAGGTGG GGCTAGCTACAACGA GGGGGTTG 2721 4553 CCCCCGCC A CCUCAGGG 1020 CCCTGAGG GGCTAGCTACAACGA GGCGGGGG 2722 4561 ACCUCAGG G CACGCAGG 1021 CCTGCGTG GGCTAG3CTACAACGA CCTGA-GT 2723 45G3 CUCAGGGC A CGCAGGAC 1022 IGTCCTGCG GGCTAGCTACAACGA GCCCTGAG 2724 4565 CAGGGCAC G CAGGACCA 1023 ITGGTCCTG GGcTAGcTAcAAcGA GTGCCCTG 27259 4570 CACGCAGG A CCAGUUUG 1024 ICAAACTGG GGCTAGCTACAACGA CCTGCGTG 2726 4574 CAGGACCA G ULTIJGAUUG 1025 CAATCAAAL GGCTAGCTACAACGA TGGTCCTG 2727 4579 CCAGTUUUG A UUGAGGAG 1026 CTCCTCAA GGCTAGCTACAACGA CAAACIGG 2728 4587 AUUGAGGA G CUGCACUG 1027 CAGTGCAG GGCTAGCTACAACGA TCCTCAAT 2729 4590 GAGGAGCU G CACUGAUC 1028 GATCAGTG GGCTAGCTACAACGA AGCTCCTC 2730 4592 GGAGCUGC A CUGAUCAC 1029 GTGATCAG GGCTAGCTACAACGA GCAGCTCC 2731 4596 CUGCACUG A UCACCCAA 1030 TTGOGTGA GGCTAGCTACAACGA CAGTGCAG 2732 4599 CACUGAUC A CCCAAUGC 1031 GCATTGGG GGCTAGCTACAACGA GATCAGTG 2733 4604 AUCACCCA A UGCAUCAC 10o32 GTGAT GCA GGCTAGCTACAACGA TGGGTGAT 2734 4606 CACCCAAU G CAUCACGU 10T33 ACGTGATG GGCTAGCTACAACGA ATTGGGTG 2735 4 608 CCCAAUGC A UCACGUAC 1034 GTACGTGA GGCTAGCTACAACGA GCAT1'GGG 2736 4611 AAUGCAUC A CGUACCCC 1035 IGGGGTACG GGCTAGCTACAACGA GATGCATT 2737 4613 UCCAUCAC G UACCCCAC 11036 _.GTGGGGTA GGCTAGCTACAACGA GTGATGCA 2738 WO 02/096927 PCT/US02/17674 4615 CAUCACGU A CCCCACIJG 1037 CAGTGGGG GGCTAGCTACAACGA ACGTGATG 2739 4620 CGUACCCC A CUGGGCCA 1038 TGGCCCAG GGCI'AGCTACAACGA GGGGTACG 2740 4625 CCCACUGG G CCAGCCCU 1039 AGGGCTGG GGCTAGCTACAACGA CCAGTGGG 2741 4629 CUGGGCCA G CCCUGCAG 1040 CTGCAGGG cGCTAGCTACAACGA TGGCCCAG 2742 4634 CCAGCCCU G CAGCCCAA 1041 TTGGGCTG GGCTAGCTACAACGA AGGGCTGG 2743 4637 GCCCUGCA G CCCARAAC 1042 GTTTTGGG GGCTAGCTACAACGA TGCAGGGC 2744 4644 AGCCCAAA A CCCAGGGC 1043 GCCCTGGG GGCTAGCTACAACGA TTTGGGCT 2745 4651 AACCCAGG G CAACAAGC 1044 GCTTGTTG GGCTAO3CTACAACGA CCTG38GTT 2746 4654 CCAGGGCA A CAAGCCCG 1045 CGGGCTTG GGCTAGCTACA1ACGA TGCCCTGG 2747 4658 GGCAACAA 9 CCCGUUTAG 1046 CTAACGGG GcCTAGCTACAACGA TTGTTGCC 2748 4662 ACAAGCCC G UUIAGCCCC 1047 GGGGC'rAA GGCTAGCTACAACGA GGGCTTGT 2749 4666 GCCCGUUA G CCCCAGGG 1048 CCCTGGGG GGCTAGCTACAACGA TAACGGGC 2750 4676 CCCACGGG A UCACUGGC 1049 c3CCAG'rGA COCTAGCTACAACGA CCCCTGGG 2751 4679 Ac3GGGAUC A CUGGCUGG 1050 CCAGCCAG GGCTAGCTACAACGA GATCCCC7 2752 4683 GAtTCACUG G CUGGCCUG3 1051 CAGGCCAG GGCTAGCTACAACG3A CAGTGATC 2753 4687 ACUGGCTG G CCUGAGCA 1052 TGCTCAGG GGCTAGCTACAACGA CAGCCAGT 2754 46593 UGGCCTJGA G CAACAUCJ 1053 AGATGTTG GGCTAGCTACAACGA TCAGGCCA 2755 4696 CCUGAGCA A CAUCUCGG 1054 CCGAGATG GGCTAGCTACAACGA TGCTCAGG 2756 4698 UGAGCAAC A UCUJCGGGA 1055 TCCCGAGA GGCTAGCTACAACGA GTTGCTCA 2757 4707 UCUCGGA G UCCUCUAG 1056 CTAGAGGAA r2CTAGCTACAACGA TCCCGAGA 2758 4715 GUCCUCUA G CAGGCCUA 1057 ITAGGCCTG GGCTAGCTACAACGA TAGAGGAC 2759 4719 UCUACCAG G CCUAAGAC 1058 GTCTTAGG GGCTAGCTACAXCGA CTGCTAGA 2760 4726 GGCCUAAC A CAUGUJGAG 1059 CTCACATG GGCTAGCTACAACGA CTTAGGCC 2761 4728 CCUAAGAC A UGUGAGGA 1060 TCCTCACA GGCTAGCTACAACGA GTCTTAGG 2762 4730 UAAGACAU G UGAGGAGG 1061 CCTCC'FCA GGCTAGCTACAACGA ATGTCTTA 2763 4752 GAAAAAAA G CAAAAAGC 1062 GCTTTTTG GGCTAGCTACAACGA TTTTTTTC 2764 4759 AGCAAAAA G CAAGGGAG 1063 ICTCCCTTG GGCTAGCTACAACGA TTTTTGCT 2765 4777 AAAGAGAA A CCGGGAGA 1064 TCTCCCGG GGCTAGCTACAACOA TTCTCTTT 2766 4788 GGGAGAAG G CAUGAGAA 1065 TTCTCATG GGCTAGCTACAACGA CTTCTCCC 2767 4790 GAGAAGGC A UGAGAAAG 1066 CTTTCTCA GGCTAGCTACAACGA GCCTTCTC 2768 4800 GAGAAAGA A UEJUGAGAC 1067 GTCTCAAA GGCTAGCTACAACGA TPCTTTCTC 2769 4807 AAUUUGAG A CGCACCAU 1068 ATGGTGCG GGCTAGCTACAACGA CTCAAALTT 2770 4809 UUUGAGAC G CACCAtIGU 1069 ACATOGTG GGCTAGCTACAACGA GTCTCAAA 2771 4811 UGAGACGC A CCAUGUGG 1070 CCACATGG GGCTAGCTACAACGA GCGTCTCA 2772 4814 GACGCACC A UGUGGGCA 1071 TGCCCACA GGCTAGCTACAACGA GGTGCGTC 2773 4816 CGCACCAU G UGGGCACG 1072 CGTGCCCA GGCTAGCTACAACGA ATGGTGCG 2774 4820 CCAUGIJGG G CACGGAGG 1073 CCTCCGTG GGCTAGCTACAACGA CCACATGG 2775 4822 AUGUGGGC A CGGAGGGG 1074 CCCCTCCG GCTAC;CTACALACGA GCCCACAT 2776 4832 GGAGGGGG A CGGGGCUC 1075 GAGCCCCG GGCTAGCTACAACGA CCCCCTCC 2777 4837 GGGACGGG G CUCAGCAA 1076 TTGCTGAG GGCTAGCTACAACGA CCCGTCCC 2778 4842 GGGGCUCA G CAAUGCCA 1077 TGGCATTG GGCTAGCTACAACGA TGAGCCCC 2779 4845 GCUCAGCA A UGCCAUTh 1078 AAATGGCA GGCTAGCTACAACGA TGCTGAGC 2780 4847 UCAGCAAU G CCAUUUCA 1079 TGAAATC-G GGCTAOCTACAACGA ATTGCTGA 2781 4850 GCAAUGCC A UEJtCAGUG 1080 CACTGAAA GGCTAGCTACAACGA GGCATTGC 2782 48S6 CCAUUUCA G UGGCUUECC 1081 GGAAGCCA GGCTAGCTACAACGA TGAAATGG 2783 4859 tJUUCAGIJG G CUUCCCAG 1082 CTGGGAAG GGCTAGCTACAACGA CACTGAAA 2784 4867 GCUUCCCA G CUCUGACC 1083 GGTCAGAG GGCTAGCTACAACGA TGGGAAGC 2785 4873 CAGCUCUG A CCCUtJCUA 1084 TAGAAGGG GGCTAGCTACAACGA CAGAGCTG 2786 4881 ACCCtJUCU A CAUUUGAG 1085 CTCAAATG GGCTAGCTACAACGA AGAAGGGT 2787 4883 CCUEJCUAC A TJEGAGGG 1086 CCCTCAAA G3GCTAGCTACAACGA GTAGAAGG 2788 4891 AUUUGAGG G CCCAGCCA 1087 TGGCTGGG GGCTAGCTACAACGA CCTCAAAT 2789 4896 AGGGCCCA G CCAGGAGC 1088 GCTCCTGG GGCTAGCTACAACGA TGGGCCCT 2790 WO 02/096927 PCT/US02/17674 4903 AGCCAGGA G CAGAIJGGA 1089 TCCATCTG GGCTAGCTACAACGA TCCTGGCT 2791 4907 AGGAGCAG A UGGACAGC 1090 GCTGTCCA GGCTAGCTACAACGA CTGCTCCT 2792 4911 GCAGAUGG A CAGCGAYG 1091 CATCGCTG GGCTAGCTACAACGA CCATCTOC 2793 4914 GATJGGACA G CGAUGAGG 1092 CCTCATCG GGCTAGCTACAACGA TGTCCATC 27.94 4917 GGACAGCG A IGAGGGGA 1093 TCCCCTCA GGCTAGCTACAACGA CGCTGTCC 2795 4925 AUGAGGGG A CAUUtJICt 1094 JAGAAAATG GGCTAGCTACAACGA CCCCTCAT 2796 4927 GAGGOQAC A U=JTCUGG 1095 ICCAGAAAA GGCTAGCTACAACGA GTCCCCTC 2797 4936 ULUUJCIJGG A IUCUGGGA 1096 ITCCCAGAA GGCTAGCTACAACGA CCAGAAAA 2798 4946 UCUGGGAG G CAAGAAAA 1097 ITTTTCTTG GGCTAGCTACAACGA CTCCCAGA 2799 4557 AGAAAAGG A CAAAUAUC 10 98 IGATATTTG GGCTAGCTACAA~rA CCTTTTCT 2800 4S61 AAGGACAA A LAUCUUUU 1099 AAAAGATA GGCTAGCTACAACGA TTGTCCTT 2801 4963 GGACAAAU A tJCUUUEUUU 1100 AAAAAAGA GGCTAGCTACAACGA ATTTGTCC 2802 4975 UUUT3UGGA A CUAAAGCA 1101 PGCTTTAC CGCTAGCTACAACGA TCCAAAAA 2803 4981 GAACUAAA G CAAAUUIU 1102 AAAATTTG GGCTAGCTACALACGA TTTAGTTC 2804 4988 UAALAGCAA A UUUUAGAC 1103 GTCTAAAAL GGCTAGCTACAkACGA TTGCTTTA 2805 4992 AAUUUTUAG A CCUTJACC 1104 GGTAAAGG GGCTAGCTACAACGA CTAAAATT 28606E 4998 AGACCtJUU A CCUAUGGA 1105 TCCATAGG GGCTAGCTACAACGA AAAGGTCT 2807 5002 CUEJCACCU A UGGAAGUG 1106 CAC PTCCA GGCTAGCTACAACGA AGGTAAAG 280B 5008 CUAUGGAA G UGGTJEJCUA 1107 TAGAACCA GGCTAGCTACAACGA TTCCATAG 2809 5011 UGGAAGJG G TJUCUAUGU 1108 ACATAGAA GGCTAGCTACAACGA CACTTCCA 2810 5016 GUGGUUtCU A UGUCCATU 1109 AATGGACA GGCTAGCTACAACGA AGAACCAC 2811 5018 GGtAYCUAU G UCCAUIJCU 1110 AGAATGGA GGCTAGCTACAACGA ATAGAACC 2812 5022 CUAUGUCC A UTJCUCALtJ 1111 AATGAGAA GGCTAGCTACAACGA GCACATAG 2813 5028 CCAUEJCUC A UTJCGUG3GC 1112 GCCACGA-A GGCTAGCTACAACGA GAGAATGG 2814 5032 UCUCAUTC G UGGCAUGU 1113 ACATGCCA GGCTAGCTACAACGA GAATGAGA 2815 5035 CATJUCGUG G CAUGUUUU 1114 AAAACATS GOCTAGCTACAACGA CACGAATC 2816 50371 UEJCGUGGC A UGUTTUTGA 1115 TCAAAACA GGCTAGCTACAACGA GCCACGAA 2817 5039 CGUGGCAU G LUUUGAU 1116 AATCAAAA GGCVAGCTACAACGA ATGCCACG 2818 5045 AUGUUUUG A UUTLJGUAGC 1117 GCTACAAA GGCTAGCTACAACGA CAAAACAT 2819 5049 ULUGJAUUU G UAGCACUG 1118 CAGTGCTA GGCTAGCTACAACGA AAkATCAAA 2820 5052 GAUUUGUA G CACUGACO 1119 CCTCAGTG GGCTAGCTACAACGA TACAAATC 2821 5054 UUUGUAGC A CUGACCCU 1120 ACCCTCAC GGCTAGCTACAACGA GCTACAAA 2822 5061 CACUGACCG G UCCCACTJC 1121 OAGTGCCA GCCTACCTACAACGA CCTCAGTG 2823 5084 UGAGGGUG G CACUCAAC 1122 GTTGAGTG GGCTAGCTACAACGA CACCCTCA 2824 5066 AGGGUGGC A CUCAACTJC 1123 GAGTTGAG CCCTAGCTACAACGA GCCACCCT 2825 5071 GGCACUCA A CUCUGAGC 1124 GCTCAGAG GGCTAGCTACAACGA TGAGTCCC 2826 5078 AACUCTJCA G CCCAUACU 1125 AGTATGGG GGCTAGCTACAACGA TCAGAGTT 2827 5082 CUJGAGCCC A UACIJUTG 1128 CAAAAGTA GGCTAGCTACAACGA GGGCTCAG 2828 5084 GAGCCCAU A CUUITUGGC 1127 GCCAAAAG GGCTAGCTACAACGA ATGGGCTC 2829 5091 UACUUUJC G CUCCUCXJA 1128 TAGAGGAG GGCTAGCTACAACGA CAAAAGTA 2830 5100 CUCCUCUA G UAAGAUGC 1129 GCATCTTA GGCTAGCTACAACGA TAGAGGAG 2831 5105 CUAGtJAAC A UGCACUGA 1130 TCAGTGCA GGCTAGCTACAACGA CTTACTAG 2832 5107 AGUAAGAJ G CACUGAAA 1131 TTTCAGTG CGCTAGCTACAACGA ATCTTACT 2833 5109 UAAGAUGC A CUGAAAAC 1132 GTTTTCP.G GGCTAGCTACAACGA GCATCTTA 2834 5116 CACUGAAA A CUUAGCCA 1133 TGGCTAAG GGCTAGCTACAACGA TTTCAGTG 2835 5121 AAAACUUA C CCAGAGIJT 1134 IAACTCTGG GGCTAGCTACAACCA TAALGTTTT 2836 5127 UAGCCAGA G UUJAGGULJG 1135 ICAACCTAA GGCTAGCTACAACGA TCTGGCTA 2837 5132 AGAGutIAG C uIJCucucc 1136 GGAGACAA GGCTAGCTAcAACGA CTAACTCT 2838 5135 GULJAGGUU G UCUCCAGG 1137 CCTCCAGA GGCTAGCTACAACGA AACCTAAC 2839 5143 GUCUCCAG G CCAUGAUG 1138 CATCATGG GGCTAGCTACAACCA CTCGAGAC 284 0 5146 UCCACCCC A UGAUGGCC 1139 GGCCATCA GGCTAGCTACAACGA GGCCTGGA 2841 5149 AGGOCAUG A UGGCCUUA 1140 TAAGGCCA GGCTAGCTACAACGA CATGGCCT 2842 WO 02/096927 PCT/US02/17674 5152 CCAUGAUG G CCUUACAC 12.41 GTGTAAGG GGCTAGCTACAACGA CATCATGG 2843 5157 ALTGGCCUO A CACUGAAA 1142 ITTCAGTG GGCTAGCTACAACGA AAGGCCAT 2844 5159 GGCCIJUAC A CUGAAAAU 1143 ATTTTCAG GGCTAGCTACAACGA GTAAGGCC 2845 5166 CACUGAAA A UGUCACAU 1144 ATGTGACA GGCTAGCTACAACGA TTTCAGTG 2846 5168 CUGAAAAU G UCACAUUC 1145 GAATGTGA GGCTAGCTACAACGA ATTTTCAG 2847 5171 AAAAUGUC A CAUUCtJAU 1146 ATAGAATG GGCTAGCTACAACGA GACATTTT 2848 5173 AAUGUCAC A UIJCtYA=t 1147 AAATAGAA GGCTAGCTACAACGA GTGACATT 2849 5178 CACAUJCU A UUTUhGGGJ 1148 ACCCAAAA GGCTAGCTACAACGA AGAATGTG 2850 5185 UAUUJT~GG G UALTUAAUA 1149 TATTAA2A GGCTAGCTACAACGA CCAAAATA 2851 5187 UtJEJTGGGU A t.TEAAUAUA 1150 TATATTAA GGCTAGCTACAACGA ACCCAAAA 2852 5191 GGGUAEJUA A UAUAUAGU 1151 ACTATATA GGCTAGCTACAACGA TAATACCC 2853 5193 GUAU.AATJ A tJAUAGUCC 1152 GGACTATA GGCTAGCTACAACGA ATTAATAC 2854 S195 AUUAAUAU A UAc3UCCAG 1153 CTGCACTA COCTAOCTACAACOA ATATTAAT 2855 5198 AAUAUAUA G UCCAGACA 1154 TGTCTGGA GGCTAGCTACAACGA TATATATT 2856 5204 UAGUCCAG A CACUEJAAC 1165 GTTAAGTG GGCTAGCTACAACGA CTGGACTA 28S7 5206 GUCCAGAC A CUTJAACUC 1156 GAGTTALAG GGCTAGCTACAACGA GTCTGGAC 2858 5211 GACACUEA A CUCAAUUU 1157 AAATTGAG GGCTAGCTACAACGA TAAGTGTC 2859 5216 TUAACIJCA A UU1CUUGG 1158 CCAAGAAA GGCTAGCTACAACGA TGAGTTAA 2860 5224 ATUCUEJG G UAUEJAUUEC 1159 GAATAALTA GGCTAGCTACAACGA CAAGAAALT 2861 5226 UUCUUGGIJ A UJAUUCUG 1160 CAGAATAA GGCTAGCTACAACGA ACCAAGAA 2862 5229 UEJGGUAUEJ A UEJCUGTJU 1161 AAACAGAA GGCTAGCTACAACGA AATACCAA 2863 5234 AUJUUCU G UUUtJGCAC 1162 GTGCAAAA GGCTAGCTACAACGA AG-AATAAT 2864 5239 UCUGEUUTJ G CACAGUEJA 1163 TAACTGTG GGCTAGCTACAACGA AAALACAGA 2865 5241 UGUUUGC A CAGUJUAGU 1164 ACTAACTG GGCTAGCTACAACGA GCAAAACA 2866 5244 UTUJGCACA G UEJAGUUGU 1165 ACAACTAA GGCTAGCTACAACGA TGTGCAAA 2867 5248 CACAGUEJA G U(JGUGAAA 1166 ITTTCACAA GGCTAGCTACAACGA TAACTGTG 2868 5251 AGUUAGUU G UGAAAGAA 1167 ITTCTTTCA GGCTAGCTACAACGA ALACTAACT 2869 5261 GAAAGAAA G CUGAGAAG 1168 C TTCTCAG GGCTAGCTACAACGA TTTCTTTC 2870 5271 IJGAGAAGA A UGAAAAUJG 1169 CATTT2TCA GGCTAGCTACAACGA TCTTCTCA 2871 5277 GAAUGAAA A UGCAGUCC 1170 GGACTGCA GGCTAGCTACAACGA TTTCATTC 2872 5279 AUGAU G CAGUCCUG 1171 CAGGACTG GGCTAGCTACAACGA ATTTTCAT 2873 5282 AAAAUGCA G UCCUGAGG 1172 CCTCAGGA GGCTAGCTACAACGA TOCATTTT 2874 5294 UGAGGAGA G UUEJTCUCC 1173 GGAGAAAA GGCTAOCTACAACGA TCTCCTCA 2875 5303 UUUUCUCC A UAUCAAAA 1174 TTTTGATA GGCTAGCTACAACGA GGAGAAAA 2876 5305 UEJCUCCAU A UCAAAACG 1175 CGPTTTGA GGCTAGCTACAACGA ATGGAGAA 2877 5311 AUAUJCAAA A CGAGGGCU 1176 AGCCCTCG GGCTAGCTACAACGA TTTGATAT 2878 5317 AAACGAGG G CUGAUGGA 1177 TCCATCAG GGCTAGCTACAACGA CCTCGTTT 2879 5321 GAGGOCUG A UGGAGGAA 1178 TTCCTCCA GGCTAGCTACAALCGA CAGCCCTC 2880 5334 GGAAAAAG G UCAAUAAG 1179 CTTATTC-A GGCTAGCTACAACGA CTTTTTCC 2881 5338 AAAGGUCA A UAAGGUCA 180 TGACCTTA GGCTAGCTACAACGA TGACCTTT 2882 S343 UCAAUAAG G UCAAGGGA 1181 TCCCTTGA GGCTAGCTACAACGA CTTATTGA 2883 5354 AAGGGAAG A CCCCGUCU 1182 AGACGGGG GGCTAGCTACAACGA CTTCCCTT 2884 53S9 AAGACCCC G UCUCUAUA 1183 ITATAGA-A GGCTAGCTACAACGA GGGGTCTT 2885 5365 CCGUCUCU A UACCAACC 1184 GGTTGGTA GGCTAGCTACAACGIA AGAGACGG 2886 5367 GUCUCUAU A CCAACCAA 1185 TTGGTTGG GGCTAGCTACAACGA ATAGAGAC 2887 S371 CUAUJACA A CCAAACCA 1186 TGGTTTG-G GGCTAGCTACAACGA TGGTATAG 2888 5376 CCAACCAA A CCAAUUCA 1187 TGAATTGG GGCTAGCTACAACGA TTGGTTGG 2889 5380 CCAAACCA A UEJCACCAA 1188 TTGGTGAA GGCTAGCTACAACGA TGGTTTGG 2890 5384 ACCAAUUJC A CCAACACA 1189 TGTGTPC-G GGCTAGCTACAACGA GAATTGGT 2891 5388 AEJUCACCA A CACAGEJUG 1190 CAACTGTG GGCTAGCTACAACGA TGGTGAAT 2892 5390 UCACCAALC A CAGTJUGGG 1191 CCCAACTG GGCTAGCTACAACGA GTTGGTGA 2893 5393 1CCAACACA G UUGGGACC :1192 GGTCCC.-A GGCTAGCTACAALCGA TGTGTTGG 2894 WO 02/096927 PCT/US02/17674 5399 CAGUUtGGG A CCCAAAAC 1193 GTTTTGGG GGCTAGCTACAACGA CCCAACTG 2895 5406; GACCCAAA A CACAGGAA 1194 TTCCTGTG GGCTAGCTACAACGA TTTGGGTC 2896 S408 CCCAAAAC A CAGGAAGU 1195 ACTTCCTG GCCTAGCTACAACGA GTTTTGGG 28D7 5415 CACAGGAA G UCAGUCAC 1196 GTGACTGA GOCTAGCTACAACGA TTCCTGTG 2893 5419 GGAAGUCA G LTCACG=JE 1197 AAACOTGA GOCTAGCTACAACGA TGACTTCC 2899 5422 AGUCAGUC A CGIUUCCU 1198 AGGAAACG GGCTAGCTACAACGA GACTGACT 2900 5424 UCAGUCAC G UUEJCCtJUU 1199 AAAGGAAA GGCTAGCTACAACGA GTGACTGA 2901 5435 UCCUUUC A UOTJAAUJGG 1200 CCATTAAA GGCTAGCTACAACGA GAAAA-GA 2902 5440 UUCAUJUA A UGGGGAUU 1201 AATCCCCA GGCTAGCTACAACGA TAAATGAA 2903 5446 UAAUGGGG A UEJCCACUA 1202 TAGTGGAA GGCTAGCTACAALCGA CCCCATTA 2904 5451 GGGATUCC A CUAUCUCA 1203 TGAGATAG GGCTAGCTACAACGA GGAATCCC 2905 5454 AUtJCCACU A UCUCACAC 1204 GTGTGAGA GGCTAGCTACAACGA AGTGGAAT 2906 5459 ACUAtJCUC A CACUAAUC 1205 GATTAGTC GGCTAGCTACAACGA GAGATAOT 2907 5461 tJAUCUCAC A CUAAUCUG 1206 CAGATTAG GGCTAGCTACAACGA GTGAGATA 2908 5465 UCACACUA A UCUGAAAG 1207 CTTTCAGA GGCTAGCTACAALCGA TAGTGTGA 2909 5475 CUGAAAGG A UGUGGAAG 1208 CTTCCACA GGCTAGCTACAACGA CCTTTCAG 2910 5477 GAAAGCAU G UGGAAGAG 1209 CTCTTCCA GGCTAGCTACAACGA ATCCTTTC 2911 5485 GUGGAAGA G CAUTJAGCU 1210 AGCTAALTG GGCTAGCTACAACGA TCTTCCAC 2912 5487 GGAAGAGC A TJEAGCUGG 1211 CCAGCTAA GGCTAGCTACALACGA GCTCTTCC 2913 5491 GAGCAUTA G CTJGGCGCA 1212 TGCGCCAG GGCTAGCTACAACGA TAATGCTC 2914 5495 AU*UAGCUG G CGCAUAUU 1213 IAATATGCG GGCTAGCTACAACGA CAGCTAAT 2915 5497 UAGCUGGC G CAUAUUAA 1214 TTAATATG GGCTAGCTACAACGA GCCAGCTA 2916 5499 GCUGGCGC A UAUtJAAGC 1215 GCTTAATA GGCTAGCTACAACGA GCGCCAGC 2917 5501 UGGCGCAU A UtJAAGCAC 1216 GTGCTTAA GGCTAGCTACAACGA ATGCGCCA 2918 5506 CAUAUUJAA G CACUUTUAA 1217 TTAAAGTG GGCTAGCTACAACGA TTAATATG 2915 5508 UAUUAAGC A CUUUAAGC 1218 GCTTAAAG GGCTAGCTACAACGA GCTTAATA 2920 5515 CACUUUAA G CUCCUUGA 1219 TCAAGGAG GGCTAGCTACAACGA TTAAAGTG 2921 5524 CUCCJEGA G UAAAAAGG 1220 CCTTTTTA GGCTAGCTACAACGA TCAAGGAG 2922 5532 GUAAAAAG G UGGUAUGU 1221 ACATACCA GGCTAGCTACAACGA CTTTTTAC 2923 5535 AA8AGUG G UAUGUAAU 1222 ATTACATA GGCTAGCTACAACGA CACCTTTT 2924 5537 AAGGUGGU A UGUAAUUJ 1223 AAATTACA UU0CTAGCTACAACGA ACCACCTk 2925 5539 GGUGGUAU G UAAUUUAU 1224 ATAAATTA GGCTAGCTACAACGA ATACCACC 2926 5542 GGUAUGUA A UTUUUCA 1225 TGCA PAAA GUC-TAGCTACAACGA TACATACC 2927 5546 UGUAALEJ A UGCAAGGU 1226 ACCTTGCA GGCTAGCTACAACGA AAATTACA 2928 5548 UAAUJUUAU G CAAGGUAU 1227 ATACCTTG GGCTAGCTACAACOA ATAAATTA 2929 5553 UAUGCAAG G UAUUUCUC 1228 GAGAAATA GGCTAGCTACAACGA CTTGCATA 2930 5555 UGCAAGGU A UUUCUCCA 1229 TGGAGAAA GGCTAGCTACAACGA ACCTTGCA 2931 5564 U[UUCCA G 'UUGGGACU 1230 AGTCCCAA GGCTAGCTACAACGA TGGAGAAA 2932 5570 CAGUJUGGG A CUCAGGAU 1231 ATCC VUAG GGCTAGCTACAACGA CCCAACTG 2933 5577 GACTJCAGG A UAUUAGUJ 1232 AACTAATA GGCTAGCTACAACGA CCTGAGTC 2934 5579 CUCAUGAU A UUAGUUAA 1233 TTAACTAA UUGCTAGCTACAACGA ATCCTGAG 2935 5583 GGATUAUUA G UUAAUGAG 1234 CTCATTAA GGCTAGCTACAALCGA PAATATCC 2936 5587 AUUAGUUA A UGAGCCAU 1235 ATGUCTCA GGCTAGCTACAACGA TAACTAAT 2937 5591 GUTUAAUGA G CCAUCACU 1236 AGTGAT-G GGCTAOCTACAACGA TCATTAAC 2938 5594 AAUGAGCC A UCACUAGA 1237 TCTAGTGA GGCTAUCTACAACGA GGCTCATT 2.939 5597 GAUCCAUC A CUAGAAGA 1238 TCTTCTAG UUCTAGCTACAACGA GATGGCTC 2940 5809 GAAGAAAA G CCCAUUUU 1239 AAAATGGG GGCTAGCTACAACGA TTTTCTTC 2941 5613 AAAAGCCC A UUUUCAAC 1240 GTTGAAAA GGCTAGCTACAACGA GGGCTTTT 2942 5620 CAUUUU~CA A CUGCJTIU 1241 CAAAGCAG GGCTAGCTACAACGA TGAAAATG 2943 5623 ULJUCAACU G CUTJUGAAA 1242 TTTCAAAG GGCTAUCTACAACGA AGTTGAAAL 2944 5631 GCUGA A CLTtUCCU, 1T243 CAGGCAAG GGCTAGCTACAACGA TTCAAAGCI 2945 5635 UGAAACUU G CCUGGGGU 1244 ACCCCAGG GGCTAGCTACAACGA AAGTTTCA 1 2946 WO 02/096927 PCT/US02/17674 5642 UGCCUGGG G UCUGAGCA 1245 TGCTCAGA GGCTAGCTACAACGA CCCAGGCA 2947 5648 CGGUCUGA G CAUGAIJSG 1246 CCATCATG GGCTAGCTACAACGA TCAGACCC 2948 5650 GUCUGAGC A UGAUGGGA 1247 TCCCATCA GGCrFAGCTACAACGA GCTCAGAC 2949 5653 UGAGCAUG A UGGGAAUA 1248 TATTCCCA GGCTAGCTACAACGA CATGCTCA 2950 5659 UGAUGGGA A UAGGGAGA 1249 TCTCCCT-k GOCTAGCTACAACGA TCCCATCA 2951 5667 AUAGGGAG A CAGGGIJAG 1250 CTACCCTG GGCTAGCTACAACGA CTCCCTAT 2952 5672 GAGACAGG G IAGGAAAG 1251 CTTTCCTAk GGCTAGCTACAACGA CCTGTCTC 2953 5682 AGGAAAGG G CGCCUACU 1252 AGTAGGCG GGCTAGCTACAACGA CCTTTCCT 2954 5684 GAAAGC3GC G CCUACIJCU 1253 AGAGTAG34 GcCTAGCTACAACGA GCCCTTTC 2955 5688 GGGCGCCU A CUCUUCAG 1254 CTGAAGAC4 G3CTAGCTACAACGA AG9GCCC 2956 5698 IJCUIJCAGG G IJCtAAAGA 1255 TCTTTAGA GGCTAGCTACAACGA CCTGAAGA 2957 5706 GUCUAAAG A UCAAGUGG 1256 CCACTTGA GGCTAGCTACAACGA CTTTAGAC 2958 5711 AACAUCAA 0 tCGOCCUU 1257 AAGGCCCA GGCTAGCTACAACGA TTGATCTT 2959 5715 TJCAAGUGG G CCUUGGAU 1258 ATCCAAG2 GGCTAGCTACAACGA CCACTTGA 2960 5722 GGCCIJUGG A UCGCUAAG 1259 CTTAGCGA GCCTAGCTACAACOA CCAAGGCC 29G1 5725 CUUTGGAUC G CUAAGCIYG 1260 ICAGCTTAZ GGCTAGCTACAACGA GATCCAAG 2962 5730 AUCGCUAA G CUGCTCU 1261 AGAGGOAG GGCTAGCTACAACGA TTAGCGAT 2963 5734 CTAAGCUG G CUCITGUtJU 1262 AAACAGAG GGCTAGCTACAACGA CAGCTTAG 2964 5739 CTJGGCUCU G IUTJGAUGC 1263 GCATCA\A GGCTAGCTACAACGA AGAGCCAG 2965 5744 UCUGJLUhT A UGCUAJEJI 1264_ AAATAGCA GGCTAGCTACAACGA CAAACAGA 2966 5746 IJGUUUJGAU G CTJAUUEJAU 1265 ATAAATAG GGCTAGCTACAACGA ATCAAACA 2967 5749 UUJGAUGCU A UU3UAUGCA 1266 ITGCATAAA GGCTAGCTACAACGA AGCATCAA 2968 5753 TJCCUAUU A UGCAAGUU 1267 AACTTGCA GGCTAGCTACAACGA AAATAGCA 2969 5755 CUAUUJUAU G CAAGUUAG 1268 CTAACTTG GGCTAGCTACALACGA ATAAATAG 2970 5759 UtJAUGCAA G UTUAGGGUC 1269 GACCCTAA GCCTAGCTACAACGA TTGCATAA 2971 5765 AAGUUTAGG G UCUAUGUA 1270 TACATAGA GGCTAGCTACAACGA CCTAACTP 2972 5769 UAGGGUCU A UGUAUUEYA 1271 TAAATACA GGCTAGCTACAACGA AGACCCTA 2973 5771 GGGUCUAU G UAUUUAGG 1272 CCTAAATA GGCTAGCTACAACGA ATAGACCC 2974 5773 GUCUATJCU A UUAGGAU 1273 ATCCTAAA GGCTAGCTACAACGA ACATAGAC 2975 5780 UAUUIJAGG A UGCGCCUA 1274 TAGGCGCA GGCTAGCTACAACGA CCTAAATA 2976 5782 ULJUAGCAU G CGCCUACU 1275 AGTAGGCG GOCTAGCTACALACGA ATCCTAAA 2977 5784 UAGGAUGC G CCUACUCU 1276 AGAGTAGG GGCTAGCTACAACGA GCATCCTA 2978 S788 AUGCCCU A CUCUITCAG 1277 CTGAAGAG GGCTAGCTACAACGA A0GCGCAT 2979 5798 (JCUECAGG G UCUAAAGA 1278 TCTTTAGA GGCTAGCTACAACGA CCTGAAGA 2980 5806 GUCUAAAG A UCAAGUGG 1279 CCACTTCA GGCTACCTACAACCA CTTTAGAC 2981 5811 AAGAUCAA G UGGGCCU3 1280 AAGGCCCA GGCTAGCTACAACGA TTGATCTT 2982 5815 TJCAAGUGG G CCUJXGGAU 1281 ATCC GGCTAGCTACAACGA CCACTTGA 2963 5822 GGCCtJUGG A UCGCIJAAG 1282 CTTAGCGA GGCTAGCTACAACGA CCAAGGCC 2984 5325 CUTICCAUC G CUAAGCUG 1283 CAGCTTAG GGCTAGCTACAACGA GATCCALAG 2985 5830 AUCGCUAA G CUGGCUCU 1284 AGAGCCAG GGCTAGCTACAACGA TTAGCGAT 2986 5834 CUAAGCUG G CUJCUULT 1285 AAACAGAG C.GCTAC ACAACGA CACCTTAG 2987 5839 CUGGCUCU G UUUGAUGC 1286 GCATCAAA GGCTAGCTACAACGA AGAGCCAG 2988 5844 UCUGUUJC A UGCUAUUJ 1287 AAATAGCA GGCTACCTACAACGA CAAACAGA 2989 5846 UGUUUGAU G CUAUUIJAU 1288 ATAAATAG GGCTAGCTACAACGA ATCAAACA 2990 5849 UUGAUCCU A UUUtAUGCA 1289 TGCATAAA GCCTACCTACAACGA AGCATCAA 2991 5853 UGCUAUrUU A UGCAAGUJ 1290 AACTTGCA GGCTAGCTACALACGA AAALTAGCA 2992 5855 CUAULUAU G CAAGUEJAG 1291 CTAACTTG GGCTAGCTACAACGA ATAAATAG 2993 5859 UUAUGCAA G UIJAGGGUC 1292 GACCCTAA GGCTAGCTACAACGA TTGCATAA 2994 5865 AAGUUAGG C UCUAUGUA 1293 TACATAGA GGCTAGCTAC2AACGA CCTAACTT 2995 5869 UAGGGUCU A UGUATJUUA 1294 TAAATACA GGCTAGCTACAACGA AGACCCTAJ 2996 5871 CCCUCUAU C UAUUUAGG 1295 CCTAAATA GGCTAGCTACAACGA ATAGACCC 12997 5873 IGUCUAUGJ A UUUAGGAU 1296 ATCCTAAA GGCTAGCTACAACGA ACATAGACI 2998 WO 02/096927 PCT/US02/17674 5880 TJAUUUJAGG A UGUCUGCA 1297 TGCAGACA GGCTAGCTACAACGA CCTAAATA 2999 5882 UUUAGGAU G UCtJQCACC 1298 GGTGCAGA GGCTAGCTACAACG3A ATCCTAAA 3000 5885 GGAUGUCU G CACCUUCJ 1299 AGAAGGTG GGCTAGCTACAACGA AGACATCC 3001 5888 ATJGUCUGC A CCIJECTJGC 1300 GCAGAAGG GGCTAGCTACAACGA GCAGACAT 3002 S899 CACCUTlCU G CAGCCAGU 1301 ACTGGCTC GGCTAGCTACAACGA AGAAGGTG 3003 5898 CUEJCUGCA G CCAGUCAG 1302 CTGACTGG GGC'PAGCTACAACGA TGCAGAAG 3004 5S02 UGCAGCCA G UCAGAAGC 1303 GCTTCTGA GGCTAGCTACAACGA TGGCTGCA 3005 5909 AGUCAGAA G CUGGAGAG 1304 CTCTCCAG GGCTPAGCTACAACGA TTCTGAC' 3006 5918 CUGGAGAG G CAACAGUG 1305 CACTGTTG GGCTAGCTACAACGA CTCTCCAG 3007 5921 GAGAGGCA A CAGUGGAU 1306 ATCCACTG GGCTAGCTACAACGA TGCCTCTC 3006 5-924 AGGCAACA G UGGAUIJGC 1307 GCAATCCA GGCTAGCTACAACGA TGTTGCCT 3009 5928 AACAGUGG A IJUGCUJGCU 1308 AGCAGCAAk GGCTAGCTACAACGA CCACTGTT 3010 5931 AGUGGAUJ G CUGCUEJCU 1309 AGAAGCAG GOCTAGCTACAACGA AATCCACT 3011 5934 GGAUEJGCU G CTJUCUUGG 1310 CCAAGAAG GGCTAGCTACAACGA AGCAATCC 3012 5951 GGAGAAGA G UAUGCUTJC 1311 GAAGCATA GGCTAGCTACAACGA TCTTCTCC 3013 5953 AGAAGAGIJ A UGCUUCCIJ 1312 AGGAAGCA CCCTAGCTACAACGA ACTCTTCT 3014 5955 AAGAGUAU G CUtJCCUTJU 1313 AAAGGAAG GOCTAGCTACAACGA ATACTCTT 3015 5965 UEJCCLUIJ A tICCAUGUA 1314 TACATGGA GGCTAGCTACALACGA AAAAGGAAL 3019 5969 IYIJUAUCC A UGUAAUUEJ 1315 AAATTACA GGCTAGCTACAACGA GGATAAAA 3017 5971 LT13AUCCAU G UAAULTUAA 1316 TTAAATTA GGCTAGCTACAACGA ATGGATAA 3018 S974 UCCAIJCUA A UUmAACUG 1317 CAGTTAAA GGCTACCTACAACGA TACATGGA 3019 5979 GUAATEJIA A CUGTJAGAA 1318 TTCTACA3 GGCTAGCTACAACGA TAAATTAC 3020 5982 AUETAACU G UAGAACCU 1319 AGGTTCTA GGCTAGCTACAACGA AGTTAAAT 3021 5987 ACUGUAGA A CCUGAGCU 1320 AGCTCAGG GGCTAGCTACAACGA TCYFACAGT 3022 5993 CAACCUGA G CUCUAAC-U 1321 ACTTAGAG GGCTAGCTACP.ACGA TCAGGTTC 3023 6000 ACCUCUAA G UAACCGAA 1222 TTCCCTTA GGCTAGCTACAACGA TTAGAGCT 3024 6003 UCUAA-UA A CCGAAGAA 1323 TTCTTCGG GGCTAGCTACAACGA TACTTAGA 3025 6011 ACCGAA.GA A UGUAUGCC 1324 GGCATACA GGCTAGCTACAACGA TC VTCGCT 3026 6013 CGAAGAAU G UAUGCCUC 1325 GAGGCATA GGCPAGCTACAACGA ATTCTTCG 3027 6015 AAGAAUGU A UGCCUCUG 1326 CAGAGGCA GGCTAGCTACAACGA ACATTCT' 3028 6017 CAAUGUAU G CCUCUGUU 1327 AACAGAGG GGCTAGCTACAACGA ATACATTC 3029 6023 AUGCCUCU G UCTCUIJAUG 1328 CATAAGAA GGCTAGCTACAACGA AGACAGCAT 3030 6029 CUGUEJCUUJ A UGUGCCAC 1329 GTGGCACA GGCTAGCTACAACGA AAGAACAG 3031 6031 GUUCUUAJ G UGCCACAU 1330 ATGTGGCA GGCTAGCTACAACGA ATAAGAAC 3032 6033 UCUUJAUGJ G CCACAUCC 1331 GGATGTGG GGCTAGCTACAACGA ACATAAGA 3033 6036 tJAIGUCCC A CAUCCUUGI 1332 CAAGGATG GGCTAGCTACAACGA GGCACATA 3034 6038 UGUGCCAC A UCCUUGUU 1333 AACAAGGA GGCTAGCTACAACGA GTGGCACA 3035 6044 ACAUCCUU G UUIJAAACG 1334 CCTTTAAA GGCTAGCTACAACGA AAGGATGP 3036 6052 GU1TUAAAG G CUCUCUGU 1335 ACAGAGAG GGCTAGCTACAACGA CTTTAAAC 3037 6059 GGCUCUCU G UAUGAAGA 1336 TCTTCATA GGCTAGCTACAACGA AGAGAGCC 3038 6061 CIICUCUGtI A UGAAGAGA 1337 TCTCTTCA GGCTAGCTACAACGA ACACACAG 3039 6069 AUGAAGAG A UCGGACCG 1338 CGGTCCCA GGCTAGCTACAACGA CTCTTCAT 3040 6074 GAGAUGGG A CCGUCAUC 1339 GATGACGG GGCTAGCTACAACGA CCCATCTC 3041 6077 AUGCGACC G UCAUCAGC 1340 GCTGATGA GCCTAGCTACAACGA CGTCCCAT 3042 6080 GGACCGUC A UCAGCACA 1341 TGTGCTGA GGCTAGCTACAACGA GACGGTCC 3043 6084 CGUCAUCA G CACAUUCC 1342 GGAATGTG GGCTAGCTACAALCGA TGATGACG 3044 6086 UCAUCAGC A CAUUCCCU 1343 ACGGAATG GGCI'AGCTACAACGA CCTGATGA 3045 6088 AUCAGCAC A UUCCCUAG 1344 CTAGAA CGCTAGCTACAACGA GTGCTGAT 3046 6096 AUUCCCUA G UGAGCCUA 1345 TAGOCTCA GGCTAGCTACAACCA TAGGGAAT 3047 6100 CCUAGUGA G CCUACUGG 1346 CCAGTAGG GGCTAGCTACAACGA TCACTAGG 3048 6104 GUGAGCCU A CUGGCUCC 1347 GGAGCCAG GGCTAGCTACAACGA AGGCTCAC 3049 6108 GCCUACUG G CUCCUGOC 1348 IGCCAGGAG GGCrAGCTACAACGA CAGTAGGC 3050 WO 02/096927 PCT/US02/17674 6115 GGCUCCUG G CAGCGGCU 1349 AGCCGCTG GGCTAGCTACAACGA CAGGAGCC 3051 6118 UCCUGGCA G CGGCUUUU 1350 AAAAGCCG GGCTAc3CTACAACGA Tc3CCAGGA 3052 G121 UGGCAGCG G CLT(tJEGCG 1361 CACAAAAG GGCTAGCTACAACGA CGCTG.CCA 3063 6127 CGGCUUJU G UGGAAGAC 13652 GTCTTCCA GGCTAGCTACAACGA AAAAGCCG 3054 6134 UGLTCGAAG A CUCACUAG 1353 CTAGTGAG GGCTAGCTACAACGA CTTCCACA 3055 6138 GAAGACUC A CUAGCCAG 1354 CTGGCTAG GGCTAGCTACAACGA GAGTCTTC 3056 6142 ACtTCACtTA G CCAGAAGA 1356 TCTTCTGG GGCTAGCTACAACGA TAGTGAGT 3057 6156 AGAGAGGA G UGGGACAG 1356 CTGTCCCA GGCTAGCTACAACGA TCCTCTCT 3058 6161 GGAGUGGG A CAGUCCUC 1357 GAGGACTG GGCTAGCTACAACGA CCCACTCC 3059 6164 GUGGGACA 9 UCCTCICC 1358 GGAGAGGA GGCTAGCTACAACGA TGTCCCAC 30630 6173 UCCUCUCC A CCAAGAUC 1359 GATCTTGG GGCTAGCTACAACGA GGAGAGGA 3061 6179 CCACCAAG A UCUAAAUC 1360 GATTTAGA GGCTAGCTACAACGA CTTGGTGG 3062 6185 AGAUCUA\ A UCCAAACA 1261 TGTTTGGA GGCTAGCTACAACGA TTAGATCT 3063 6191 AAAUCCAA A CAAAAGCA 1362 TGCTTTTG GGCTAGCTACAACGA TTGGATTT 3064 6197 AAACAAAA G CAGGCLJAG 1363 CTAGCCTG GGCTAGCTACAACGA TTTTGTTT 3065 6201 AAAAGCAG G CIJAGAGCC 1364 GGCTCTAG GGCTAGCTACAACGA CTGCTTTT 3066 6207 AGGCUAGA G CCAGAAGA 1365 TCTTCTGG GGCTAGCTACAACGA TCTAGCCT 3067 6220 AAGAGAGG A CAAAUCUJ 1366 AAGATTTG GGCTAGCTACAACGA CCTCTCTT 3068 6224 GAGGACAA A UCUUJGUJ 1367 AACAAAGA GGCTAGCTACAACGA TTGTCCTC 3069 6230 AAAUCUUU G UUGTJUCCU 1368 AGGAACAA GGCTAGCTACAACGA AAAGATTT 3070 6233 UCUUUGTU G UUCCUCUJ 1369 AAGAGGAA GGCTAGCTACAACGA AACAAAGA 3071 6246 UCTJUCUUTU A CACATJACG 1370 CGTATGTG GGCTAGCTACAACGA AAAGAAGA 3072 6248 UEJCUUTJAC A CAUACGCA 1371 TGCGTATG GGCTAGCTACAACGA GTAAAGAA 3073 6250 CTUUACAC A UACGCAAA 1372 TTTGCGTA GGCTAGCTACAACGA GTGTAAAG 3074 6252 UUACACAU A CGCAAACC 1373 GGTTTGCG GGCTAGCTACAACGA ATGTGTAA 3075 6254 ACACAUAC G CAAACCAC 1374 STGOTTTG GGCTAGCTACAACGA GTATGYTGT 3076 6258 AUACGCAA A CCACCUGJ 1375 ACAGGTGG GGCTAGCTACAACGA TTGCG'TAT 3077 6261 CGCAAACC A CCUGUGAC 1376 GTCACA3G GGCTAGCTACAACGA GGTTTGCG 3078 6265 AACCACCJ G UGACAGCU 1377 AGCTGTCA GGCTAGCTACAACGA AGGTGGTT 3079 6268 CACCUGUG A CAGCUGGC 1378 GCCAGCTG GGCTAGCTACAACGA CACAGGTG 3080 6271 CUGUGACA G CUGGCAAU 1379 ATTGCCAG GGCTAGCTACAACGA TGTUACAG 3081 6275 GACAGCJG G CAATUUJA 1380 TAAA.ATTG GGCTAGCTACAACGA CAGCTGTC 3082 6278 AGCUGGCA A UUUTJAUAA 1381 TTATAAAA GGCTAGCTACAACGA TGCCAGCT 3083 6283 GCAAUUUT A UAAAUCAG 1382 CTGATI'TA GGCTAGCTACAACGA AAAATTGC 3084 6287 UUOTJAIAA A UCAGGUAA 1383 TTACCI'GA GGCTAGCTACAACGA TTATAAAA 3086 6292 UAAAUCAG G UAACUGGA 1384 TCCAGTTA GGCTAGCTACAACGA CTGATTTA 3086 6295 AUCAGGUA A CUGGAAGG 1385 CCTTCCPAG GGCTAGCTACAACGA TACCTGAT 3087 6306 GGAAGGAG G UUAAACUC 1386 GAGTTTAAL GGCTAGCTACAACGA CTCCTTCC 3088 6311 GAGGUUAA A CUCAGAAA 1387 TTTCTGAG GGCTAGCTACAACGA TTAACCTC 3089 6327 AAALAGAALG A CCtJCAGUC 1388 GACTGAGG GGCTAGCTACAACGA CTTCTTTT 3090 6333 AGACCUCA G UCAATUCU 1389 AGAATTC-A GGCTAGCTACAACGA TGAGGTCT 3091 65337 CUCAGUCA A UTYCUCUAC 1390 GTAGAGAA GGCTAGCTACAACGA TGACTGAG 3092 6344 AAUUCUCU A CIJUUUUUU 1391 AAAAAAG GGCTAGCTACAACGA AGACAATT 3093 6366 UEUUCCAA A UCAGAUAA 1392 TTATCTGA GGCTAGCTACAACGA TTGGAAAA 3094 6371 CAAAUCAG A UAAUAGCC 1393 GGCTATTA GGCTAGCTACAACGA CTGATTTG 305 6374 AUCAGAUA A UAGCCCAG 1394 CTGGGCTA UGCTAGCTACAACGA TATCTGAT 3096 6377 AGAUAAUA G CCCAGCAA 1395 TTGCTGGG GGCTAGCTACAACGA TATTATCT 30-97 6382 AUAGCCCA G CAAAUAGU 1396 ACTATTTG GGCTAGCTACAACGA TGGGCTAT 3098 6386 CCCAGCAA A UAGUGAUA 1397 TATCACTA GGCTAGCTACAACGA TTGCTGUG 3099 6389 AGCAAAUA U UGAUAACA 1398 TGTTATCA GGCTAGCTACAACGA TATTTGCT 3100 6:392 AAAUAGUG A UAACAAAU 1399 -ATTTUTTA GGCTAGCTACAACGA 6395 UAGUGAUA A CAAAUAAA 1400 TTATGGCTAGCTACAACGA TATCACTAI 3102 WO 02/096927 PCT/US02/17674 63D9 GAUAA;CALA A TAAAACCU 1401 AGGTTTTA GGCTAGCTACAACGA TTGTThAPC 3103 64D4 CAAAIJAAA A CCtJUAGCU 1402 AGCTAAGG GGCTAGCTACAACGA TTTATTTG 3104 6410 AA.ACCUUA G CUGUTJCAU 1403 ATGAACAG GGCTAGCTACAACGA TAAGGTTT 3105 6413 CCUUAGCU G3 UEJCAUGUC 1404 GACATGAA GGCTAGCTACAACGA AGCTAAGG 3106 6417 AGCUJQTUC A UGUCtAJGA 1405 TCAAGACA GGCTAGCTACAACGA GAACAGCT 3107 6419 CTJGIUCAU G UCUUGAUJ 1406 AATCALAGA GGCTAGCTACAACGA ATGAACAG 3108 6425 AUTGUCU7UG A UUTUCAAUA 1407 TATTGAAA GGCTAGCTACAACGA CAAGACAT 3109 6431 UGAU~nJCA A UAAUJAAJ 1408 ATTAATTA GGCTAGCTACAACGA TGAAATCA 3110 6434 UJUUCAAUA A UUtAAUEJCL 1409 AGAATTAA GGCTAGCTACAACGA TATTGAAA 3111 6438 AAUAAUtJA A Ut3CUJEAAU 1410 ATTAAGAA GGCTAGCTACALACGA TA-ATTATT 3112 6445 AAUUCUrJA A I5CALUAAG 1411 CTTAATGA GGCTAGCTACAACGA TAAGAALTT 3113 6448 UCUJEAAUC A ULJAAGAGA 1412 TCTCTTAA GGCTAGCTACAACGA GATTAAGA 3114 6456 AUUAAGAG A CCAUAAUA 1413 TATTATGG GGCTAGCTACAACGA CTCTTAAT 3115 6459 AAGAGACC A UAAUAAATJ 1414 JATTTATTA GGCTAGCTACAACGA GGTCTCTT 3116 6462 AGACCAUA A TJAAAUACTJ 1415 AGTATTTA GGCTAGCTACAACGA TATGGTCT 3117 6466 CAUAAUAA A UACUCCUUL 1416 AAGGAGTA GGCTAGCTACAACGA TTATTATG 3118 6468 UAAUA.AAU A CtJCCUUMT 1417 AAAAGGAG GGCTAGCTACAACGA ATTTATTA 3119 6487 AGAGAAAA G CAAAACCA 1418 TGGTTTTG GGCPAOCTACAACGA TTTTCTCT 3120 6492 AAAGCAAA A CCAUIJAGA 1419 TCTAATGG GGCTAGCTACAACQA TTTGCTTT 3121 6495 GCAAAACC A UEJAGAAUU 1420 AATTCTAA GGCTAGCNAC~aACGA GGTTTTGC 3122 6501 CCAUJ1AGA A UUGUUACU 1421 AG3TAACAA GGCTAGCTACAkACGA TCTAALTGG 3123 6504 UUEAGAAUEY G tJEACUCAG 1422 CTGAGTAA GGCTAGCTACAACGA AATTCTAA 3124 6507 GAAUUGUJ A CUCAGOUC 1423 GAGCTGAG3 GGCTAGCTACAACGA AACAATTC 3125 6S12 GUtJACUCA G CUCCUUCA 1424 TGAAGGAG GGCTAGCTACAACGA TGAGTAAC 3126 6522 UCCUUCAA A CUCAGGUU 1425 AACCTGAG GOCTAGCTACAACGA TTGAAGGA 3127 6928 AAACUCAG G UUUJGUAGC 1426 GCTACAAA GGCTAGCTACAACGA CTGAGTTT 3128 6532 UCAGGUUU G UAGCAUAC 1427 GTATGCTA GGCTAGCTACAACGA AAACCTGA 3129 6535 GGUUUGUA G CAUACAUG 1428 CATGTAT 4 GGCTAGCTACAACGA TACAAACC 3130 6537 tJEJEGLAGC A UACAUGAG. 1429 CTCATGTA GGCTAGCTACAACCA GCTACAAA 3131 6539 UGUAGCAJ A CAUGAGUC 1430 GACTCATG GGCTAGCTACAACGA ATGCTACA 3132 6541 UAGCAUAC A UGAGUCCA 1431 TGGACTCA GGCTAGCTACAACGA GTATGCTA 3133 6545 AUACAUGA G UCCAUCCA 1432 TGGATGGA GGCTAGCTACAACGA TCATGTAT 3134 6549 AUGAGUCC A UCCAUCAG 1433 CTGATGGA GGCTAGCTACAACGA GGACTCAT 3135 6553 GUCCAUCC A UCAGUCAA 1434 TTGACTGA GGCTAGCTACAACGA GGATUC-AC 3136 6557 AUCCAUCA G UCAAAGAA 1.435 TTCTTTGA GGCTAGCTACAACGA TGATGGAT 3137 6565 GUCAAAGA A UGGLUCCA 1436 TGGAACCA GGCTAGCTACAACGA TCTTTGAC 3138 6568 AAAGAAUG G UtJCCAUCU 1437 AGATGGAA GGCTAGCTACAACGA CATTCTTT 3139 6573 AUGGUUCC A UCUGGAGU 1438 ACTCCAGA GGCTAGCTACAACGA GGAACCAT 3140 6580 CAUCUGGA G UCUtJAAUG 1439 CATTAAGA GGCTAGCTACAACGA TCCAGATG 3141 6586 GAGUCUUA A UGUAGAAA 1440 TTTCTACA GGCTAGCTACAACGA TAAGACTC 3142 6588 GUCUUJAAU G UAGAAAGA 1441 TCTTTCTA GGCTAGCTACAACGA ATTAAGAC 3143 6600 AAAGAAAA A tYGGAGACU 1442 AGTCTCCA GGCTAGCTACAACGA TTTTCTTT 3144 6606 AAAIJGGAG A CUEJGUAAU 1443 ATTACAAG GGCTAGCTACAACGA CTCCATT7 3145 6610 GGAGACUT G UAAUAAUG 1444 CATTATTA GGCTAGCTACAACGA AAGTCTCC 3146 6613 GACUUGUA A UAAUGAGC 1445 OCTCATTA GGCTAGCTACAACGA IACAAGTC 3147 6616 UTJGUAAUA A UGAGCUAG 1446 CTAGCTCA GGCTAGCTACAACGA TATTACAA 3148 6620 AAUAAUGA G CUAGUEJAC 1447 GTAACTAG GGCTAGCTACAACGA TCATTATT 3149 6624 AUGAGCUA G UEJACPAAG 1448 CTTTGTAA GGCTAGCTACAACGA TAGCTCAT 3150 6627 AGCUAGUU A CAAAGUGC 1449 GCACTTTG GGCTAGCTACAACGA AACTAGCT 3151 6632 GUUrACAAA G UGCUUGUU 1450 AACAAGCA GGCTAGCTACAACGA TTTGTAAC 3152 6634 UACAAAGU G CUtTGUtJCA 1451 TGAACAAG GGCTAGCTACAACGA ACTTTGTA 3153 6638 AAGUGCUU G UUCAUEJAA 1452 TTAAT9AA GGCTAGCTACAACGA AI4GCACTT 31S4 WO 02/096927 PCT/US02/17674 66412 GCIUGUUC A UUAAAAUA 1453 TATTTTAA GGCTAGCTACAACGA GAACAAGC 3155 6648 UCAUEJAAA A TJAGCACTJG 1454 CAGTGCTA GGCTAGCTACAACGA TTTAATGA 3156 6651 UUTAAAAUA G CACUGAAA 1455 TTTCAGTG GGCTAGCTACAACGA TATTTTAA 3157 6653 AAAAUAGC A CUGAAAAU 1456 ATTTTCAG GGCTAGCTACAACGA GCTATTTT 3158 G660 CACUGAAA A UTJGAAACA 1457 TGTTTCAA GGCTAGCTACAACGA TTTCAGTG 3159 6666 AAALUJGAA A CAtYGAATJ 1458 AATTCATG GGCTAGCTACAACGA TTCAATTT 3160 6668 AUOJGAAAC A UGAAUUAA 1459 TTAATTCA GGCTAGCTACAACGA GTTTCAAT 3161 6672 AAACAUGA A UEJAACUGA 1460 TCAGTTAA GGCTAGCTACAACGA TCATGTTT 3162 6676 AUGAAUTJA A CUGAUAAJ3 1461 ATTATCAG GGCTAGCTACAACGA TAATTCAT 3163 6680 AUJLAACTJG A UAAUAUIlJC 1462 GAATATTA CGrTArCTACAACGA CAGTTAAT 3164 6683 AACUGATJA A UAUUICCA. 1463 TTGGAATA GGCTAGCTACAACGA TATCAGTT 3165 6685 CUGAUAAU A UEJCCAAUC 1464 GATTGGAA GGCTAGCTACAACGA ATTATCAG 3166 6691 AUAUEJCCA A UCAU(UJCC 1465 CCAAATGA GGCTAGCTACAACGA TCCAATAT 3167 6694 UTJCCAATJC A UUIUGCCAU 1466 ATGGCAAA CGCTAGCTACAACGA GATTGGAA 3168 6698 AAUCAYJU G CCAULJ{1AJ 1467 ATAAATGG GGCTAGCTACAACCA AAATGATT 3169 6701 CAUUEJGCC A UtUUAUGAC 1468 GTOATAAA GGCTAGCTACAACGA GGCAAATG 3170 6705 UGCCATYJU A LJGACAAAA 1469 TTTTGTCA GGCTAGCTACAACGA AAATGGCA 3171 6708 CAUUEJAUG A CAAAAAUG 1470 CATTTTTG GGCTAGCTACAACGA CATAAATG 3172 6714 UJGACAAAA A IJGGUEJGGC 1471 GCCAACCA GGCTAGCTACAACGA TTTTGTCA 3173 6717 CAAAAAUG G UUGGCACU 1472 AGTGCCAA GGCTAGCTACAACGA CATTTTTG 3174 6721 AAUGGUJG G CACUAACA 1473 TGTTAGTG GGCTAGCTACAACGA CAACCATT 3175 6723 UGGTJUGGC A CUAACAAA 1474 ITTTGTTAG GGCTAGCTACAACGA GCCAACCA 3176 6727 UGGCACUA A CAAAGAAC 1475 GTTCTTTG CGCTAGCTACAACGA TEATGCCA 3177 6734 AACAAAG3A A CGAGCACU 1476 AGTGCTCG GGCTAGCTACAACGA TCTTTGTT 3178 6738 AAGAACOA 0 CACUUCCU 1477 AGGAACTG GGCTAGCTACAACGA TCGTTCTT 3179 6740 C3AACGA3C A CUtJCCULU 1478 AAAGGAAG GGCTAGCTACAACGA GCTCGTTC 3180 6753 CUUUJCAGA G UIJUCUGA13 1479 CTCAGAAA GGCTAGCTACAACGA TCTGAAAG 3181 6762 UEJUCUGAG A UAAUGUAC 1480 GTACATTA GGCTAGCTACAACGA CTCAGAAA 3182 6765 CUGAGAUA A LTGUACGUG 1481 CACGTACA GGCTAGCTACAACGA TATCTCAG 3183 6767 GAGAUAAU G UACGUGGA 1482 TCCACGTA GGCTAGCTACAACGA ATTATCTC 3184 6769 GAUAAUGU A CGUGCAAC 1483 GTTCCACG GGCTAGCTACAACGA ACATTATC 3185 6771 UAAUGUAC G UGGAACAG 1484 CTGTTCCA GGCPAGCTACAACGA GTACATTA 3186 6776 UACGUCCA A CAGUCUG3 1485 CCAGACTG CCCTAGCTACAACGA TCCACGTA 3187 6779 GUGGAACA G LTCUGGGUG 1486 CACCCAGA GGCTAGCTACAACGA TGTTCCAC 3188 6785 CAGUCUGG G IJGGAAUGG 1487 CCATTCCA GGCT'AGCTACAACGA CCAGACTG 3189 G790 UGGGUG3CA A LTGGGCUG 1488 CAGCCCCA GGCCTAGCTACAACGA TCCACCCA 3190 6795 GGAAUGGG G CUGAAACC 1489 GGTTTCAG GGCTAGCTACAACGA CCCATTCC 3191 6801 GGGCUGAA A CCAUGUGC 1490 GCACATGG GGCTAGCTACAACGA TTCAGCCC 3192 6804 CtJGAAACC A LGUGCAAG 1491 CTTGCACA GGCTAGCTACAACGA GGTTTCAG 3193 6806 GAAACCAU G LTCCAAGUC :14-92 GACTTGCA GGCTAOCTACAACGA ATGGTTTC 3194 6808 AACCAUGU G CAAGUCUG 1493 CAGACTTG CCCTAGCTACAACGA ACATGGTT 3195 6812 AUGtJGCAA G IJCUGUGUC 14 94 IGACACAGA GGCTAGCTACAACGA TTGCACAT 3.196 6816 GCAAGTJCU G TJGUCUUGJ 1495 JACAAGACA GGCTAGCTACAACGA AGACTTGC 319 7 6818 AAGUCtJCU G tJCO1JGTCA 14.96 JTGACAAGA GCTACTACAACGA ACAGACTT 3198 6823 UGUGUCUU G C AGUCCA 1497 ITGGACTGA GGCTAGCTACAACGA AAGACACA 3199 6827 UCUUCUCA G LCCAAGAA 1498 TTCTTCGA GC'ACCTACAACOA TGACAAGA 3200 6836 UCCAAGAA G UGACACCG 1499 CGrTGTCA GGCTAGCTACAACGA TTCTTGGA 3201 G839 AAGAAGJG A CACCGAGA 1500 TCTCGGTG GGCTAGCTACAACGA CACTTCTT 3202 6841 GAAGUGAC A CCGAGAJC 1501 CATCTCGG GGCTAGCTACAACGA GTCACTrC 3203 6847 ACACCGAG A UGUEJAAUU 1502 AATTAACA GGCTAGCTACAACGA CTCCGTGT 3204 6849 ACCGAGAU G tJUAAUUUU 1.503 AAAATTAA GGCTAGCTACAACGA ATCTCGGT 1 320.5 6853 AGAUGUUA A UUCTUAGGG CCCTAAAA GGCTAGCTACAACGA TAACATCTJ 3206 WO 02/096927 WO 02/96927PCT/US02/17674 6862 tUtUtJAGGG A CCCGUGCC 1505 GGCACGGG GGCTAGCTACAACGA CCCTAAAA 3207 6866 AGGGACCC G UGCCUUGU 1506 ACAAGGCA GGCTAGCTACAACGA GGGTCCCT 320B 6868 GGACCCGT G CCUUGUTJ 1507 AAACAAGG r.GCTAGCTACAACGA ACGGGTCC 3209 6873 CGTJGCCUJ G UEJTCCUAG 1508 CTAGGAAA GGCTAGCTACAACGA AAGGCACG 321D 6881 GUUTUCCUA G CCCACAAG 1509 CTTGTGGG GGCTAGCTACAACGA TAGGAAAC 3211 6885 CCUAGCCC A CAAGAALUG 1510 CATTCTTG GGCTAGCTACAACGA GGGCTAGG 3212 691 CCACAAGA A UGCAAACA 1511 TGTTTGCA GGCTAGCTACAACCA TCTTGTGG 3213 6893 ACAAGAAU 03 CAAACAUC 1512 GATGTTTG GGCTAGCTACAACGA ATTCTTGT 3214 6897 GAAUGCAA A CAUCAAAC 1513 GTTTGATG GGCTAGCTACAACGA TTGCATIC 3215 6899 AUGCAAAC A UCAAACAG 1514 CTGTTTGA GGCPAGCTACAACGA GTTTGCAT 3216 6904 AACAUOAA A CAGAJACJ 1515 AGTATCTG GGCTAGCTACAACGA TTGATGTT 3217 6908 UCAAACAG A TJACUCGCU 1516 AG0CGAGTCA GGCTAGCTAC9.ACGA CTGTTTGA 3218 f;6910 AAACACA A C!UC!GCTIAG 1517 CTAGCGAG GGCTAGCTACAAC2A ATCTGTTT 3219 6914 AGAUACUC G CTJAGCCLTC 1518 GAGGCTAG GGCTAGCTACAACGA GAGTATCT 3220 6918 ACUCGCUA G CCUCAUUJ 1519 AAATGAG7G GGCTAGCTACAACGA TAGCGAGT 3221 6923 CUAGCCUC A UIJIAAAL1JU 1520 AATTTAAX GGCTAGCTACAACCA GAGOCTAG 3222 6929 tJCAULJUAA A UtIGAUUAA 1521 TTAATCAA GGCTAGCTACAACGA TTAAATGA 3223 6933 UUAAAJUG A UUAAAGGA 1522 PCCTTTAA GGCTAGCTACAACGA CAATTTAA 3224 6945 AAGGAGGA G UGCAUCUUT 1523 AAGATGCA GGCTAGCTACAACGA TCCTCCTT 3225 6947 GGAGGAGU G CAUCUUCG 1524 CA?.AGATG GGCTAGCTACAACGA ACTCCTCC 3226 6949 AGGAGt3GC A UCUUEJGGC 1525 GCCAAAGA GGCTAGCTACAACGA GCACTCCT 3227 6955 CAUCUtJUG G CCGACAGT 1526 JACTGTCGG GGCTAGCTACAACGA CAAAGATG 322B 6960 UUtJGGCCG A CAGUGGJG 1527 JCACCACTG GGCTAGCTACAACOA CGGCCAAA 3229 6963 GGCCGACA G UGGUGUAA 1528 TTACACCA GGCTAGCTACAACGA TGTCGGCC 3230 6966 CGACAGUG G UGUAACUG 1529 CAGTTACA GGCTAGCTACAACQA CACTGTCG 3231 6968 ACAGUGGU G UAACUGUG 1530 CACAGTTA CCTAGCTACAACGA ACCACTGT 3232 6971 GUGGUGUA A CU.GUGUGU 1531 ACACACAG GGCTAGCTACAACGA TACACCAC 3233 6974 GUGUAACU G UGUGUGUG 1532 CACACACA GGCTAGCTACAACGA AGTTACAC 3234 6976 GUAACUGU G UGUGtJGUG 1.533 ICACACACA GGCTAGCTACAACGA ACAGTTAC 3235 6978 AACtJGUGU G UGUGTJGUG 1534 CACACAC-A GGCTAGCTACAACGA ACACAGTT 3236 6980 CUGUGUGU G UGUGUGUG 1535 CACACACA GGCTAGCTACAACGA ACACACAG 3237 6982 GUGUGUGU G UGUGUGUG 1536 CACACACA GGCTAGCTACAACGA ACACACAC 323B 6984 GUGUGUGU G UGUGUGUG 1637 CACACACA GGCTAGCTACAACGA ACACACAC 3233 6986 GUGUGUGU G UGUGUGUG 1538 CACACACA GGCTAGCTACAACGA ACACACAC 3240 6988 GIJGUGUGU G UGUGUGUG 1539 CACACACA GGCTAGCTACAACGA ACACACAC 3241 6990 GUGUGDGU G UGUGUGUG 1540 CACACACA GGCTAGCTACAACGA ACACACAC 3242 6992 GUGUGUGU G UGUGUGUG 1541 CACACACA GGCTAGCTACAACGA ACACACAC 3243 6994 GUGUGUGU G UGUGUGUG 1542 CACACACA GGCTAGCTACAACGA ACACACAC 3244 6996 GUGUJGUGU G UGUGUGUG 1543 CACACACA GGCTAGCTACAACGA ACACACAC 3245 6998 GUGUGUGU G UGUGUGUG 1544 CACACACA GGCTAGCTACAACGA ACACACAC 3246 7000 GUGUGUGU G UGUGUGUG 1545 CACACACA GGCTAGCTACAACGA ACACACAC 3247 7002 GUGUGTJGU G UGUGUGUG 1546 CACACACA GGCTAGCTACAACGA ACACACAC 3248 7004 GUGUGUGU G IJGUGUGTJG 1547 CACACACA GGCTAGCTACAACGA ACACACAC 3249 7 CO 6 GUGUGUGU G UGUGUGUG 1548 CACACACA GOCTAGCTACAACGA ACACACAC 3250 7TC08 GUGtJGUGU G UGUGUGGG 1549 CCCACACA GGCTAGCTACAACGA ACACACAC 3251 7010 GUGUGU3GU G UGUGGGUG 1560 CACCCACA GGCTAOCTACAACOA ACACACAC 3252 701C32 GUGUGUGU G UGGOUGIUG 1551. CACACCCA GGCTAGCTACAACGA ACACACAC 3253 7016 E GUGtJGUGG G UGUGGGUG 15 52 CACCCACA GGCPAGCTACAACGA CCACACAC 3254 7022 70i24 GUGUGGGU G UGGGUGU3A 1553 TACACCCA GGCTAGCTACAACGA ACCCACACI 3255 GGGUGUGG G UGUAUGUG 1 1554 CACATACA GGCTAGCTACAACGA CCACACCCJ 3256 GUGUGGGU G UAUGUGUG 1 1555 CACACATA GGCTAGCTACAACGA ACCCACAC GUGGGUGU A UGUGUGUU 1556 AACACACA GGCTAGCTACM~CGA

ACACCCAC

TAGCTACAACGA ACALC LkC

E

3257 358 WO 02/096927 PCT/US02/17674 7028 GCGIGUAU G UGUGUUJU 1557 AAAACACA GGCTAGCTACAACGA ATACACCC 3259 7030 CtJGUAUGU G UGUEJUUGU 1558 ACAAAACA GGCTAGCTACAACGA ACATACAC 3260 7032 GUAUGUGJ G UUUJGTGC 1559 GCACAAAA GGCTAGCTACAACGA ACACATAC 3261 7037 UGUGUUUU G tJGCAUAAC 1560 GTTATGCA GGCTAGCTACAACGA AAAACACA 3262 7039 UGUUUtJO4 G CAUAACUA 1561 TAGTTATG GGCTAGCTACAACGA ACAAAACA 3263 7041 UUUUTGUGC A UAACUAUJ 1562 AATAGTTA GGCTAGCTACAACGA GCACAAAA 3264 7044 UGUGCAUA A CUAUUUAA 1563 TTAAATAG GGCT'AGCTACAACGA TATGCACA 3265 7047 GCAUAACU A UUEAAG3SA 1564 TCCTTAAA GGCTAGCTACAACGA AGTTAT3C 3266 7057 UtJAAGGAA A CUGGAAUJ 1565 AATTCCAG GGCTAGCTACAACGA TTCCTTAA 3267 7063 AAACUGGA A LUUEAAAG 1566 CTTTAAAA GGCTAGCTACAACGA TCCAGTTT 3268 7071 AUUUUAAA G tJUACULJUU 1567 AAAAGTAA GGCTAGCTACAACGA TTTAAAAT 3269 7074 UTJAAAGUY A CUUUTUAUJA 1568 TATAAAAG GGCTAGCTACAACGA AACTTTAA 3270 7080 UUACUUUUt A UACAAACC 1569 GGTTTGTA GGCTAGCTACAACGA AAAAGTAA 3271 7082 ACUUUAU A CAAACCAA 1570 TTGGTTTG GGCTAGCTACAACGA ATAAAAGT 3272 7086 TJUAUACAA A CCAAGAAU 1571 ATTCTTGG GGCTAGCTACAACGA TTGTATAA 3273 7093 AACCAAGA A UAUAUGCJ 1572 AGCATATA GGCTAGCTACAACGA TCTTGGTT 3274 7095 CCAAGAAU A UAUGCTJAC 1573 GTAGCATA GGCTAGCTACAACGA ATTCTTGG 3275 7097 AAGAALUAU A UGCUACAG 1574 CTGTAGCA GGCTAGCTACAACC3A ATATTCTT 3276 7099 GAAUAJAU G CTJACAGAU 1575 ATCTGTAG GGCTAGCTACAACGA ATATATTC 3277 7102 UAUAUGCU A CAGAUAUIA 1576 TATATCTG GGCTAGCTACAACOA AGCATATA 3278 7106 UGCUACAG A LAUAAGAC 1577 GTCTTATA GGCTAGCTACAACGA CTGTAGCA 3279 7108 CU.ACAGAU A UAAGACAG 1578 CTGTCTTA GGCTAGCTACAACGA ATCTGTAG 3280 7113 GAUAUAAG A CAGACAUG 1579 CATGTCTG GGCTAGCTACAACGA CTTATATC 3281 7117 UAAGACAG A CAtTGGUUU 1580 AAACCATG GGCTAG3CTACAACGA CTGTCTTA 3282 7119 AGACAGAC A UGGUUGG 1581 CCAAACCA GGCTAGCTACAACGA GTCTGTCT 3283 7122 CAGACAUG G UU(JGGtYCC 1582 GGACCAAA GGCTAGCTACAACGA CATGTCTG 3284 7127 AUGGUUUG G UCCUAUAU 1583 ATATAGGA GGCTAGCTACAkACGA CAAACCAT 3285 7132 UUGGUCCU A UAUUCUA 1S84 TAGAAATA GGCTAGCTACAACGA AGGACCAA 3286 7134 GGUCCUAU A UUUCUAGU 1585 ACTAGAAA GGCTAGCTACAACGA ATAGGACC 3287 7141 UAUUUCA G UCAUGAUG 1586 CATCATGA GGCTAGCTACAACGA TAGAAATA 3288 7144 UUCUAGUC A UGAUGAAU 1587 JATTCATCA GGCTAGCTACAkACGA GACTAGAA 3289 7147 UAGUCAJG A tJGAAUGUA 1588 TACATTCA GGCTAGCTACAACGA CATGACTA 3290 7151 CAUGAUSA A UGUAUTJ 1589 AAAATACA GGCTAGCTACAACGA TCATCATG 3291 7153 UGAUGAAU G UAUUEJGU 1590 ACAAAATA GGCTAGCTACAACGA ATTCATCA 3292 7155 AUGAAUGU A LUUJGUAU 1591 ATACAAAA GGCTAGCTACAACGA ACATTCAT 3293 7160 UGUAUUUTU G UAUACCAU 1592 ATGGTATA GGCTAGCTACAACGA AAAATACA 3294 7162 UAUUUUGU A UACCAUCU 1593 AGATGGTA GGCTAGCTACAACGA ACAAAATA 3295 7164 UUUTUGUAU A CCAUCUJC 1594 GAAGATGG4 rGCTAGCTACAiACGA ATACA1AAA 3296 7167 UGUAUACC A UCUUCAUA 1595 TATGAAGA GGCTAGCTACAACGA GGTATACA 3297 7173 C--CAUCUUC A UAUAAUAU 1596 ATATTATA GGCTAGCTACAACGA GAAGATGG 3298 7175 AUCUUCAU A UAAUAUAC 1597 GTATATTA GGCTAGCTACAACGA ATGAAGAT 3299 7178 UUCAUAUA A UAUACUUA 1598 TAAGTATA GGCTAGCTAC.UCGA TATATGAA 3300 7180 CAUAUAAU A UACUUAAA 1599 TTTAAGTA GGCTA CTACAACGA ATTATATG 3301 7182 UAUAAUTAU A CUUAAAAA 1600 TTTTTAAG GGCPAGCTACAACGA ATATTATA 3302 7190 ACUUAAAA A UAUGUCUC 1601 AAGAALATA GGCTAGCTACAACGA TTTTAAGT 3303 7192 UTUAAAAAU A UUUCUUAA 1602 TTAAGAAA GGCTAGCTACAACGA ATTTTTAA 3304 7200 AUUEJCUUA A UUGGGAUUJ 1603 AATCCCAA GGCTAGCTACAACGA TAAGAAAT 3305 7206 UAAUUGGG A UUUGUAAU 16!04 ATTACAAA GGCTAGCTACAACGA CCCAATTA 3306 7210 UGGGAULTU G UAAUCGUA 1605 TACGATTA GGCTAGCTACAACGA AAATCCCA 3307 7213 GAUUITGUA A UCGUACCA 1606 TGGTACGA GGCTAGCTACAACGA TACAAATC 3308 7216 UTUGUAAUC G UACCAACU 1607 AGTTGGTA GGCTAGCTACAACGA GATTACAA 3309 7218 GUAAUCGU A CCAACUUA 1608 TAAGTTGG GGCTAGCTACAACGA ACGATTAC 3310 WO 02/096927 PCT/US02/17674 7222 IUCGUACCA A CUUAAUUG 1609 CAATTAAG GGCTAGCTACAACGA TGGTACGAI 3311 7227 CCAACUJA A tJUGAUAAA 1610 TTTATC2AA GGCTAGCTACAACGA TAAGTTGG 3312 7231 C~rAJEJ A UAAACUUG 1611 CAAGTTTA c33CTAGETACAACGA CAATTAAG 3-313 7235 AUtTGAU3AA A CU(TJGGCPAA 1612 TTGCCAAG GGCTAGCTAC-AACGA TTATCAAT 3314 7240 IAAACUUG G CAACUGCU 1613 AGCAGTTG GGCTAGCTACAACGA CAAGTTTA 3315 7243 ACUEJGGCA A CUGCUUtUt 1614 AAAAGCAG GGCTAGCTACAACGA TGCCAAGT 3315 7246 UGGCAACU G CUUTJUAIUG 1615 CATAA.AAG GGCTAGCTACAACGA AGTTGCCA 3317 72S2 CUGCUUUU A UGUUCUGU 1616 ACAGAACA GGCTAGCTACAACGA AAAAGCAG 331B 7254 CtUUUAJ G UUCUGUCU 1617 AGACAGA GGCTAGCTACAACGA ATAAAAGC 3319 7259 UAUGUJCU G UCUCCUJC 1618 GAAGGAGA GGCTAGCTACAACGA AGAACATA 3320 7269 CUCCUJCC A UAAAUUEJU 1619 JAAAATTTA GGCTAGCTACAACGA GGAAGGAG 3321 7273 UUtCCAUAA A UUUUEJCAA 1620 TTGAAAAA GGCTAGCTACAACGA TTATGGAA 3322 7283 UIJJTCAAA A UAC!IAAUJT 1621 AATTAGTA GGCTAGCTACAACrGA TTTGAAAA 3323 7285 UTUCAAAAU A CUAAUUCA 1622 TGAATTAG GGCTAGCTACAACGA ATTTTGAA 3324 7289 AAAUACUA A ITJCAACAA 1623 TTGTTGAA GGCTAGCTACAACGA TAGTATTT 3325 7294 CtAAUUCA A CAAAGAAA 1624 TTTCTTTG GGCTAGCTACAACZA TGAATTAG 3326 7305 AAGAAAAA G CUCUUIJ 1625 JAAAAGAC. GQCTAGCTACAACGA TTTTTCTT 3327 7323 UUCCUAAA A UAAACLTCA 1626 ITGAGTTTA GcICTAGCTACAACGA TTTAGGAA 3328 7327 UAAAAUAA A CtJCAAAUU 1627 AATTTGAG GGCTAGCTACAACGA TTATTTTA 3329 7333 AAACUCAA A tUUAUCCU 1628 AGGATAAA GGCTAGCTACAAC3A TTGAGTTT 3330 7337 UCAAAUUJ A UCCDIYGUU 1629 AACAAGGA GG3CTAGCTACAACGA AAALTTTGA 3331 7343 TJUAUCCUU G UUEJAGAGC 1630 GCTCTAAA GGCTAGCTACAACGA AAGGATAA 3332 7350 UGUfJUAGA G CAGAGAAA 1631 TTTCTCTG GGCTAGCTACAACGA TCTAAACA 3333 7360 AGAGAAAA A UTJAAGAAA 1632 ITTTCTTAA GGCTAGCTACAACGA TTTTCTCT 3334 7370 UAAGAAAA A CLITJEGAAA 1633 ITTTCAAAG GGCTAGCTACAACCA TTTTCTTA 3335 7378 ACUTJ1GAA A TIGGUCIJCA 1634 ITGAGACCA GGCrvAGCTACAACGA TTCAAA-3T 3336 7381 LTUGA-AAG G UCUCAAAA 1635 ITTTTGAGA GGCTAGCTACAACGA CATTTCAA 3337 7391 CUCAAAAA A UUtGCUAAA 1636 TTTAGCAA GGCTAGCTACAACGA TTTTTGAG 3338 7394 AA7AAAALU C CUAAADAU 1637 ATATTTAG GGCPAG3CTACAACGA AATTTTTT 3339 7399 AUUEGCUAA A UAUJUUCA 1638 TGAAAATA GGCTAGCTACAACGA TTAGCAAT 3340 7401 UGCUAAAU A UUTJECAAU 1639 ATTGAAAA GGCTAGCTACAACGA ATTTAc3CA 3341 7408 UAUULTUUCA A UGGAAAAC 1.640 GTTTTCCA GGCTAGCTACAACGA TGAAAATA 3342 7415 AAUGGAAA A CUAAAUGU 1641 JACATTTAG GGCTAGCTACAACGA TTTCCATT 3343 7420 AAAACUPAA A UT3CUAGUU 1642 JAACTALACA GGCTAGCTACAACGA TTAGITTTT 3344 7422 AACUAAAU G TJUAGULUJA 1643 TAAACTAA GGCTAGCTAC.AACGA ATTTAGTT 3345 7426 AAAUGIYJA G UUTUAGCUG 1644 CAGCTAAA GGCTACCTACAACGA TAACATTT 3346 7431 UUAGUUYJA G CUGAUU1GU 1645 ACAATCAG GGCTAGCTACAACGA TAAACTAA 3347 7435 UUUAGCUG A UtJGUAUGG 1646 CCATACAA GGCTAGCTACAkACGA CAGCTAAA 3348 7438 ACUtGA7U G UAUCCOGU 1647 ACCCCATA GGCTAGCTACAACGA AATCAGCT 3349 7440 CEJGAUUGU A UCGGGUUU 1648 AAACCCCA cGCTAGCTACAACGA ACAATCAG 3350 7445 UGLTAUGGG G TJUUUCGAA 1649 TTCGAAAA GCTAGCTAC!AACGA CCCATACA 3351 7453 GUEUUCGA A CCUUUtCAC 1650 GTGAAAGG GGCTAGCTACAACGA TCGAAAAC 3352 7450 AACCIUUC A CUUUUTG 1651 ACAAAAAG GGCTAGCTACAACGA GAAAGGTT 3353 7457 CACTE=t G UEUCIJUUU 1652 AAAACAAA GGCTACCTACAACGA AAAAAGTG 3354 7471 UUEJUGTUE G ULJUUACCJ 1653 JAGGTAAAA GGCTAGCTACAACGA AAACAAAA 3355 7476 TUTJULJU A CCUAUUJC 1654 GAAATAGG GGCTAGCTACAACCA AAAACAAA 3356 74B0 UIJUUACCTJ A UTJUCACAA 1655 TTGTGAAA GGCTAGCTACAACGA AGGTAAAA 3357 CCUALTUC A CAACUGJC 1656 CACAGTTG CGCTAGCTACAACGA GAAATAGG 3358 7438 ALUTJCACA A CUGUGUAA 1657 TTACACAG GGCTAGCTACAACGA TGTGAAAT 3359 7491 UCACAACU G UGtTAAAITJ 1658 AATTTACA GGCTAGCTACAACGA AGTTGTGA 3360 7493 ACAACUGU G UAAAUUGC 1659 IGCAATTTA GGCTAGCTACAACGA ACAGTTrGT 3361 7497 CU~tGGAA A UUJCCCAAJ 1660o ATTGGCAA GGCTAGCTACAACGA TTACACAG 3362 WO 02/096927 PCT/US02/17674 7500 1UGIJAU G CCAAUAAU 1661 AT EATTGG GGCTAGCTACAACGA AATTTACA 3363 7504 AATJUGCCA A UAAUUJCCU 1662 AGGAATTA GI3CTAGCTACAACGA TGGCAATT 3364 7507 UGCCAAJA A UTJCCUGUC 1663 GACAGGAA GGCTAc3CTACAACGA TATTGGCA 3365 17513 UAAUUCCU G UCCAUGAA 1664 TTCATGGA GGCTAGCTACAACGA AGGAATTA 3366 7517 UCCUGUCC A UGAAAAUG 1655 CATTTTCA GGCTAGCTACZAACGA GGACAG"3A 2367 7523 CCAUGAAA A UGC2AAtJU 1666 AATTTGCA GGCTAGCTACAACGA TTTCATOG 3368 7525 AUGAAAAU G CAAAUUAU 1667 ATAATTTG GOCTAGCTACAACGA ATTTTCAT 3369 7529 AAAUGCAA A LTUtAtCCAG 1658 CTGGATAA GGCTAGCTACAACGA TTGCATTT 3370 7532 UGCAAAJU A UCCAGUGU 166.9 ACACTGGA GGCTAc3CTACAACGA AATTTGCA 3371 7537 AUIJAECCA G UGUAGAUA 1670 TATCTACA GGCTAGCTACAACGA TGGATAAT 3372 75939 UAUCCAGU G t5AGAUATJA 1671 TATATCTA GGCTAGCTACAACGA ACTGGATA 3373 7543 CAGUGUAG A tJAUAUEJG 1672 CAAATATA GGCTAGCTACAACGA CTACACTG 3374 754S GUGLTAGAU A UAUUtJGAC 1673 GTCAAATA GOCTAGCTACAACGA ATCTACAC 3375 7547 GUAGAUAU A UUUGACCA 1674 TGGTCAAA GGCTAGCTACAACGA ATATCTAC 3376 7552 UAUAUUTUG A CCAUCACC 1675 GGTGATGG GGCTAGCTACAACGA CAAATATA 3377 7555 AUEJUGACC A UCACCCA 16 76 ITAGGOTGA GGCCTAGCTACAACGA GGTCAAAT 3378 7558 UGACCAJC A CCCUAUGG 1677 JCCATAGGG GGCTAGCTACAACGA GATGGTCA 3379 7563 AUCACCCU A IJGGAUAUJ 1678 AATATCCA GGCTAGCTACAALCGA AGGGTGAT 3380 7567 CCCUAUGG A UAUUGGCU 1679 AGCCAATA GGCTAGCTAC7AACGA CCATAGGG 3381 7569 CUAUGGAU A IJUGGCUAG 1680 CTAGCCAA GGCTAGCTACAACGA ATCCATAG 3382 7573 GGAUAUUG G CUAGL=U 1681 AATAACTAG GGCTAGCTACAALCGA CAATATCC 3383 7577 AUIJGGCUA G UUUUGCCU 1682 AGGCAAAA GGCTAG4CTACAACGA TAGCCAAT 3384 7582 CtJAGJUEUtJ G CCUUUAUJ 1683 AATAAAGG GGCTAGCTACAACGA AAAACTAG 338S 7588 UUGCCUUUL A UUAAGCAA 1684 TTGCTTAA GGCTAGCTACAACGA AAAGGCAA 3386 7593 UUEJAUtJAA G CAAAUJCA 1685 TGAATTTG GGCTAGCTACAACGA TTAATAAA 3387 7S97 UUAAGCAA A UUCAUUUC 1686 GAAATGAA GGCTAGCTACAACGA TTGCTTAA 3388 7601 GCAAAUUC A UUCAGCC 1687 GGCTGAAA GGCTAGCTACAACGA GALATTTGC 3389 7607 UCAUUTUCA G CCTJGAAUG 1688 CATTCAGG GGCTAGCTACAACGA TGAAATGA 3390 7613 CAGCCUSA A UGUCUc3CC 1689 GGCAGACA GGCTAGCTACAACGA TCAGGCTG 3391 7615 GCCUGAAY G UCUGCCUA 1690 TAGGCAGA GGCTAGCTACAACGA ATTCAG3C 3392 7619 GAAUGUCY G CCUAUAUA 1691 TATATAGG GGCTAGCTACAACGA AGACATTC 3393 7623 GUCUGCCU A tJAUAUUECU 16592 AGAATATA GGCTAGCTACAACGA AGGCAGAC 3394 7625 CUGCCUAT A UAUTJCUCU 1693 AGAGAATA GGCTAGCTACAACGA ATAGGCAG 3395 7627 GCCUAUAJ A UUCUCEJGC 1694 GCAGAGAA GGCYFAGCTACAACGA ATATAG3C 3396 7634 UJAUtJCUCU G CUCUUUGU 1695 ACAAAGAG GGCTAGCTACAACGA AGAGAATA 3397 7641 UGCUCUUU G UAUEJCUCC 1696 GGAGAATA GGCTAGCTACAACGA AAAGAGCA 3398 7643 CtYCUUUGU A UUCUCCUJ 1697 AAGGAGAA GGCTAGCTACAACGA ACAAAGAG 3399 7655 UCCUUIJCA A CCCGUUAA 1G6 TTAACGGG GGCTAGCTACAACGA TCAAAG3A 3400 7659 UUGAACCC G tJUAAAACA 1699 TGTTTTAA GGCTAGCTACAACGA GGGTTCAA 3401 7665 CCGUTJAAA A CAtICCUGU 1700 ACAGGATG GGCTAGCTACAACGA TTTAALCGG 3402 7667 GUUAAAAC A UCCU.G1LGG 1701 CCACAGGA GGCTAGCTAC!AACGA GTTTPAAC 3403 7672 AACAUCCU G UJGGCACUJC 1702 GAGTGCCA GGCTAGCTACAACGA AGGATGTT 3404 Input Sequence HSFLT. Cut Site R/Y Arm Length 8. Core Sequence GGCTAGCTACAACGA HSIFLT (Human fit mRNA for receptor-related tyrosine kinase.; Acc# X5 1602; 7680 bp) WO 02/096927 PCT/US02/17674 127 Table VI: Human KDR DNAzyme and Substrate sequence Fos Substrate Seq ID DNAzyme Seq ID No No 14 GTJCCCGGG A CCCCGGGA 3405 TCCCGGGG GGCTAGCTACAACGA CCCGGGAC 4691 CCGGGAGA G CGGJCAGU 3406 ACTGACCG GGCrAGCTACAACGA TCTCCCGG 4692 28 GGAGAGCG G TJCAGUGUG 3407 CACACTGA GGCTAGCTACAACGA CGCTCTCC 46.93 32 AGCGGUCA G IJGUG1JGGU 3408 ACCACACA GGCTAGCTACAACGA TGACCGCT 4694 34 CGGUCAGU G TJGUGGUCG 3409 CGACCACA GGCTAGCPACAACGA ACTGACCG 4695 36 GUCAGIJGU G TJGGUCGCU 3410 AGCGACCA GGCTAGCTACAACGA ACACTGAC 4696 39 AGUGUGcUG G UCGCUGCG 3411 CGCAGCGA GG CTAGCTACAACGA CACACACT 4697 42 GUGUJGGUC G CUGCGUU3 3412 AAACGCAG GGCTAGCTACAACGA GACCACAC 4698 UGGUCGCU G CGUUIJCCU 3413 AGGAAACG GGCTAGCrACAACGA AGCGACCA 4699 47 GUCGCLTGC G UEJUCCUCU 3414 AGAGGAAA OCCTAOCTACAACGA GCAGCGAC 4700 56 LTUUCCIJCU G CCtJGCGCC 3415 GGCGCAGG GGCTAGCTACAACGA AGAGGAAA 4701 CUCUGCCU G CGCCGGGC 3416 GCCCGGCG GCTAGCTACAACGA AGGCAGAG 4702 62 CUGCCUGC G CCGGGCAU 3417 ATGCCCGG GGCTAGCTACAACGA GCAGGCAG 4703 67 UGCGCCGG G CAUCACUJ 3418 AAGTGATG GGCTAGCTACAACGA CCGGCGCA 4704 69 CGCCGGGC A UCACUUGC 3419 GCAALGTGA GGLTAOCTACAACCA GCCCGGCG 4705 72__CGGGCAUC A CTJUGCGCG 3420 CGCGCAAG GG2TAGCTACAACGA GATGCCCG 4706 )AUCACUJ G CGCGCCGC 3421 GCGGCGCG GGETAGCTACAACGA AAGTGATG 4707 78 UCACUTGC G CGCCGCAG 3422 CTGCGGCG GGCTAGCTACAACGA GCAAGTGA 4708 ACUUGCGC G CCGCAGAA 3423 TTCTGCGG GGCTAGCTACAACGA GCGCAACT 4709 83 UGCCCC G CAGAAAGU 3424 ACTTTCTG GGCTAOCTACAACCA GGCCCGCA 4710 CGCAGAAA G tJCCGUCtJC 3425 CAGACGGA GGCTAGCTACAACGA TTTCTGCG 4711 94 GAAAGUCC G tJCUGGCAG 3426 CTGCCAGA GGCTAGCTACAACGA GGACTTTC 4712 99 UCCGUCUC G CAGCCUGG 3427 CCAGGCTG GGCTAGCTACAACGA CAGACGGA 4713 102 GUCUGGCA G CCUGGAUA 3428 TATCCAGG GGCTAGCTACAACGA TGCCAGAC 4714 108 CAGCCtYCG A IJAUCCUCU 3429 AGACCATA GTAGCTACAACGA CCAGGCTG 4715 110 GCCUGGAU A UCCUCUCC 3430 GGAGAGGA GGCTAGCTACAACGA ATCCAGGC 4716 120 CCTJCUCCU A CCGGCACC 3431 CCTGCCGG GGCTAGCTACAACGA AGGACAGG 4717 124 UCCUACCG G CACCCCCA 3432 TGCCCGTG CCCTAGCTACAACGA CGGTAGGA 4718 126 CUACCGGC A CCCGCAGA 3433 TCTGCCCG GGCTAGCTACAACCA CCCTAG 4719 130 CGGCACCC G CAGACGCC 3434 CGTCCTC GGCTAOCTACAACCA GCCTCCC 4720 134 ACCCCCAG A CGCCCCUG 3435 CAGGGCG GGCTAGCTACAACGA CTGCGGGT 4721 136 CCGCAGAC C CCCCUGCA 3436 TGCAGGGG GGCTAGCTACAACGA GTCTGCGG 4722 142 ACGCCCCU G CAGCCGCC 3437 GGCGGCTG GGCTAGCTACAACCA AGGGGCGT 4723 145 CCCCUGCA G CCGCCGGU 3438 ACCGGCGG GGCTAGCTACAACGA TGCAGGGG 4724 148 CUGCAGCC G CCGGUCGG 3439 CCGACCGG GGCTAGCTACAACGA GgCTGCAG 472S 152 ACC CCG G UCGGCGCC 3440 GGCGCCGA GGCTAGCTACAACGA CC-GCGGCT 4726 156 GCCGGUCG G CGCCCGGG 3441 CCCGGGCG GGCTAGCTACAACGA CGACCGGC 4727 158 CGGUCGGC G CCCGGGCU 3442 ACCCCCCG GCCTAGCTACAACCA CCCACCG 4728 164 GCGCCCGG G CUCCCUAG 3443 CTAGGGAG GGCTAGCTACAACGA CCGGGCGC 4729 172 GCUCCCUA G CCCUGUGC 3444 GCACAGCG GGCTAGCTACAACGA TAGGACC 4730 177 CUAGCCCU G TJGCGCUCA 3445 TGAGCGCA GGCTAGCTACAACGA AGGGCTAG 4731 179 ACCCCUCU G CGCUCAAC 3446 GTTGAGCG GGCTAGCTACAACGA ACAGCGCT 4732 181 CCCUGUGC G CUCAACUG 3447 CACTTGAG GGCTAGCTACAACGA GCACAGGG 4733 186 UGCGCUCA A CUGUCCUG 3448 CAGGACAG GGCTAGCTACAACGA TGAGCGCA 4734 189 GCUCAACU G TJCCUGCGC 3449 GCGCAGGA GGCTAGCTACAACGA AGTTGA3C 4735 1.94 ACUGUCCU G CGCUGCGG 3450 CCGCAGCG GGCTAGCTACAACGA AGGACAGT 4736 196 UGUCCUGC G CtJCCGGGG 3451 CCCCGCAG GGCTAGCTACAACGA GCAGCACA 4737 199 CCUCCU G CGGGGUGC 3452 GCACCCCG GGCTAGCTACAACGA ACCCACC 4738 204 GCUGOGGG G UGCCGCGA 3453 TCGCGGCA GGCTAGCTACAACGA CCCGCAGC 4739 WO 02/096927 PCT[US02/17674 206 UGCGGGGU G3 CCGCGAGJ 3454 ACTC3C(G Gc3CTA(CTACAACGA ACCCCGCA 4740 209 GGGGUG(CC G3 C(3A(3UCC 345S (3GAACTC3 GG(CTA(CTACAAC(3A GG(CACCCC 4741 213 UGCCGCGA G3 IJLCCACCU 3456 AGGTGGAA GGCTAGCTACAACGA TCGC(3GCA 4742 218 C33AGUEJCC A CCUCC(3CG 34S7 C(3CG(3AGG G(3CTAGCTACAAC3A GG(AACTC(3 4743 224 CCACCIJCC G C(3CCUCCU 3458 AGGA(3GCG G(3CTAGCTACAACGA G(3AGGTGG( 4744 226 ACCUCC3C G3 CCUCCUC 3459 GAAGG(A(3G GG(CTA(CTACAAC(3A GCG3A(GT 4745 240 DJUCUCIJAG A CAGG(CGCU 3460 A(C(CCCTG GO(CTAGCTACAAC(3A CTIAGA(3AA 4746 244 CUAGACAG G C(3CUGGGA 3461 TCCCA(3CG GG(CTAGCTACAACGA CTGTCTA3 4747 246 AGACA3(C G CUGGGAGA 3462 TCTCCCA3 GG(CTAGCTACAAC(3A (3CCT(3TCT 4748 259 (3AcAAAGA A CCG(3CUCC 3463 GG(AGCCG(3 GG(CTAGCTACAACGA TCTTTCS'C 4749 263 AA(3AACCG G3 CUCCCGAG 3464 CTCGG(3AG (3GCTAGCI'ACAAC(3A C(3GTTCTT 4750 271 (3CICCC(3A G3 UUCJ(GGC 3465 GCCCAGAA GGCTAGCTACAAC3A TCG(3GA(3C 4751 278 AGU1CUGG G CAUUUC3C 3466 GC(3AAATG GG(CTAGCTACAACGA CCAGAACT 4752 280 UJUCUGG(GC A UUJUC(3CCC 3467 GG(3CGAAA (3GCTAGCTACAACGA GCCCAGAA 4753 285 GG(CAUUJC (3 CCCGGcCUC 3468 GAGCCGGG( GG(CTA(CTACAAC(3A GAAALT(CC 4754 290 TJUCGCCC3 (3 CUCGAGGU 3469 ACCTCGAG GG(CTAGCTACAACGA C(GGC(3AAL 4755 297 GG(CUC(3A( G3 U(3CA(2rAJ 3470 ATCCTGCA GG(CTAGCTACAACGA CTCGA(3CC 4756 299 2UC(3A(GU G3 CAG(3AUGC 3471 GCATCCTG GGCTAGCrACAACGA ACCTCGAG 4757 304 GG(U(3CA(3G A U(3CAGA(3C 3472 GCTCT(3CA GGCTAGCTACAACGA CCTGCACC 4758 306 TJGCAG3(AU G CA(3A(CAA 3473 TTGCTCTG GGCTAGCTACAACGA ATCCT(3CA 4759 311 (3AUGCA(3A G CAAGGU3C 3474 GCACCTTG G(3CTAGCTACAACG3A TCT(3CATC 4760 316 AGA(3CAA3 G U(3CU(CUG 347S CA(3CA(3CA GG(CTA(CTACAAC(3A CTT(3CTCT 4761 318 AGCAAGGU G3 CUGCUGGC 3476 GCCAGCAG GGCTAGCTACAACGA ACCTTGCT 4762 321 AAGGUGCU G3 CUGGCCGUT 3477 ACG(3CCAG G(3CTAGCTACAACGA AGCACCTT 4763 325 U(3CU(3CTG G3 CC(3UC(3CC 3478 GG(C(3ACG(3 GG(CTAGCTACAAC(3A CACCACCA 4764 328 IJGCUGG(CC G UC(3CCCU3 3479 CAGGG(C(3A GG(CTAGCTACAAC(3A (3GCCAGCA 4765 331 UGGCC(3UC (3 CCCU3IJ(G 3480 CCACAG(3( (3(CTACTACAAC(3A (3ACGG(CCA 4766 336 (UCGCCCU G3 UGGOUCUG 3481 CAGAGCCA GGCTAGCTACAACGA A(3GGC(3AC 4767 339 (3CCC(UUG G CUCUGCGJ 3482 AC(3CAGAG GG(CTA(CTACAACGA CACAGG(3C 4768 344 (3UGG(CUC(J G CGU(3GAGA 3483 TCTCCAC3 GGCTAGCTACAACGA AGA(3CCAC 4769 34G (3GCUCUGcC G UGGA(3ACC 3484 GG(TCTCCA GGCTAGCTACAAC3A GCAGA(3CC 4770 352 (CGUGGAG A CCCGGGCC 3485 G(3CCCGGG GGCTAGCTACAACGA CTCCAC3C 4771 358 AGACCC3G G CC(3CCUCU 3486 A(3AGGC(3G GGCTAGCTACAAC3A CCGGGTCT 4772 361 CCC(GGGCC (3 CCUCJGUG 3487 CACAGAGG GG(CTAGCTACAACGA GGCCCGGG 4773 367 CCGCCUCJ G U(3(3(UTUG 3488 CAAACCCA GG(CTA(CTACA-AC(3A AGAGGCGG 4774 371 CUCUGUG3 G UGGUGCCIA 3489 TAGGCAAA GGCTAGCTACAACGA CCACAGAG 4775 375 GU(GGUUU G3 CCUAc3UGU 3490 ACACTAGG GGCTAGCTACAACGA AAACCCAC 4776 38D UTUGCCUA G UGUIJUCUC 3491 (3AGAAACA GGCTAGCTACAAC3A TAGG(CAAA 4777 382 UGCCUAGU G UUUCUCUU 3492 AAGAGAAA (GCTAGCTACAACGA ACTAGG(CA 4778 392 UUCUCULG A UCU(3CCCA 3493 TGGGCAGA GG(CTA(CTACAAC(3A CAA(3A(AA 4779 396 CUEJGAUCU G3 CCCAGG3CU 3494 A(3CCTGGG GGCTAGCPACAACGA AGATCAAG 4780 402 CUGCCCAG G CUCA3CAU 3495 ATJCTGA3 GG(CTA(3CTACAAC(3A CT3(3(CA3 4781 407 CAGGCUCA G3 CAUACAAA 3496 TTT3'AT(3 GO(CTA(CTACAAC(3A TGAGCCT3 4782 409 GGCUCAGC A UACAAA.A 3497 TTTTTGTA GG(CTA(CTACAAC(3A (3CTGAGCC 4783 411 CUCAGCAU A CAAAAA3A 3498 TCTTTTT3 GG(CTA(CTACAAC(3A AT(3CT(3AG 4784 419 ACAAAAAG A CAUACUUA 3499 TAAPGTAT3 (GCTA(CTACAACGA CTTTTT(3T 4785 421 AJAAAA(3AC A UACUJACA 3500 TGTAAGTA GG(CTA(CTACAAC(3A (3TCTTTTT 4786 423 AAA(3ACAU A CUtJACAAU 3501 ATTGTAA3 (GCTA(3CTACAAC(3A ATGTCTTT 4787 427 ACAUACUU A CAAUJAA3 3502 CTTAATT3 GGCTA(3CTACAACGA AAGTAT3T 4788 430 UACUUACA A UUIAAGGCU 3503 AGCCTTAA (3GCTA(3CTACAAC(3A TGTAAGTA 4789 436 CAAUUAAG G3 CUAAUACA 3504 TGTATTA3 GGCTAGCTACAAC3A CTTAATTG 4790 440 UAAGGCUA A UACAACUC 3505 (3AcTTGTA G(3CTAGCTACAACGA TAGCCTTA 4791 442 AGGCUAAU A CAACUCUU 3SO6 AAGAGTTG GGCTAGCTACAACGA ATTAGCCTI 4792 WO 02/096927 PCT/US02/17674 445 CUAAUACA A CUCtJUCAA 3507 TTGAAGAG GGCTAGCTACAACGA TGTATTAG 4793 454 CtJCUUECAA A UIJACUUGC 3508 CCAAGTAA GGCTAGCTACAACGA TTGAAGAG 4794 457 UEJCAAAUU A CUUGCAGG 3509 CCTGCAAG GGCTAGCTACAACGA AATTTGAA 4795 461 AAUUACUTJ G CAGGGGAC 3510 GTCCCCTG GGCTAGCTACAACGA AAGTAATT 4796 468 UGCAGGG3 A CAGAGGGA 3511 TCCCTCTG GGCTAGCTACAACGA CCCCTGCA 4797 476 ACAGAGGG A CUUGGACU 3512 AGTCCAAG GGCTAGCTACAACGA CCCTCTGT 4798 482 GGACUTJGG A CUGGCUUT 3513 AAAGCCAG GGCTAGCTACAAC3A CCAAGTCC 4799 486 UUGGACUG G CUUTUGGCC 3514 GGCCAAAG GGCTAGCTACAACGA CAGTCCAA 4800 492 UGGCUUUG G9 CCCAAUAA 3515 TTATTGGG GGCTAGCTACAACCA CAAA£9CCA 4801 497 UUGGCCCA A UAAUCAGA 3516 TCTGATTA GGCTAGCTACAACGA TGGGCCAA 4802 500 GCCCAAUA A UCAGAGUG 3517 CACTCTGA GGCTAGCTACAACCA TATTGGGC 4803 506 UAAUCAGA G9 Uc3GCAGUG 3518 CACTGCCA QGCTAGCTACAACGA TOTGATTA 4804 509 tYCAGAGUG G CAGUGAGC 3519 GCTCACTG GGCTA3CTACAACGA CACTCTGA 4805 512 GAGUGGCA G UGAGCAAA 3520 TTTGCTCA GGCTAGCTACAACGA TGCCACTC 4806 516 GGCAGLTGA G CAAAGGGY 3521 ACCCTTTG GGCTAGCPACAACGA TCACT£9CC 4807 523 AGCAAAGG £9 UGGAGGUG 3522 CACCTCCA GGCTAGCTACAACGA CCTTTGCT 4808 529 GGGUGA G9 UGACU3A 3523 CTCAGTCA GGCTAGCTACAACGA CTCCACCC 4809 532 UGGAGGUG A CUGAGUGC 3524 GCACTCAG GGCTAGCTACAACGA CACCTCCA 4810 537 GUGACTJGA G TJGCAGCGA 3525 TCGCTGCA GGCTAGCTACAACGA TCAGTCAC 4811 539 GACUGAGU G3 CAGCGAUG 352G CATCGCTG GGCTAGCTACAACGA ACTCAGTC 4812 542 tTGAGUGCA G CGAUGGCC 3527 GGCCATCG GGCTAGCTACAACGA TGCACTCA 4813 545 GUGCAGCG A UGGCCUCU 3528 AGAGGCCA GGCTAGCTACALACGA CGCTGCAC 4814 548 CAGCGAUG G CCUCUUCU 3529 AGAAGAGG GGCTAGCTACAACGA CATCGCTG 4815 557 CCUCU£JCU G UAAGACAC 3530 GTGTCTTA GGCTAGCTACAACGA AGAAGAGG 4816 562 LTCUGUAAG A CACUCACA 3531 TGIGAGTG GGCTAGCTACAACGA CTTACAGA 4817 564 UGUAAGAC A CUCACAAUJ 3532 ATTGTGAG GGCTAGCTACAACGA GTCTTACA 4818 568 AGACACUC A CAAUUCCA 3533 TGGAATTG GGCTAGCFACAAC3A GAGTGTCT 4819 571 CACUCACA A UUCCAAAA 3534 TTTTGGAA GGCTAGCTACA.ACGA TGTGAGTG 4820 580 UUCCAAAA G9 UGAUCGGA 3535 3TCCGATCA GGCTAGCTACAACGA TTTTGGAA 4821 583 CAAAAGUG A UCGGAAU 3536 ATTTCCGA GGCTAGCTACAACGA CACTJTTTG 4822 590 GAUCGGAA A UGACACUG 3537 CAGTGTCA GGCTAGCTACAACGA TTCCGATC 4823 S93 CGGAAAUJG A CACUGGAG 3538 CTCCAGTG GGCTAGCTACAACGA CATTTCCG 4824 GAAAUGAC A CUCCAGCC 3539 GGCTCCAG GGCTAGCTACAACGA GTCATTTC 4825 601 ACACUGGA G9 CCUACAAG 3540 CTTGTAGG GGCTAGCTACAACGA TCCAGTGT 4826 605 UGGAGCCU A CAAGUGCU 3541 AGCACTTG GGCTAGCTACAACGA AGGCTCCA 4827 609 GCCUACAA G UGCUUCUA 3542 WAGAAGCA GGCTAGCTACAACGA TTGTAGGC 4828 611 CUACAAGU G CUUCUACC 3543 GGTAGAAG GGCTAGCTACAACGA ACTTGTAG 4829 617 SU£9CUJUM A CCG£9GAALA 3544 TTTCCCGG GGCTAGCTACAACGA AGAAGCAC 4830 625 ACCGGGAA A CUGACUUG 3545 CAAGTCAG GGCTAGCTACAACGA TTCCCGGT 4831 629 GGAAACUG A CUUGGCCU 3546 AGGCCAAG GGCTA£9CTACAACG3A CAGTTTCC 4832 634 CUGACUUG G CCUCGGUC 3547 GACCGAGG GGCTAGCTACAACGA CAAGTCAG 4833 640 UGGCCUC9 £9 UCAUJUUAU 3548 ATAAATGA GOCTA£9CTACAACGA CGAGGCCA 4834 643 CCUCGGUJC A ULUAUGUC 3549 GACATAAA OGCTAGCTACAACGA GACCGAGG 4835 647 GGUCAUJEJ A UGUCUAUG 3550 CATAGACA GGCTAGCTACAACGA AAATGACC 4836 649 UCAUtJUAU G UCUAUGUJ 3551 AACATAGA GGCTA£3CTACAACGA ATAAATGA 4837 653 UUAUGUCU A UGUUJCAAG 3552 CTTGAACA GGCTAGCTACAACGA AGACATAA 4838 655 AUGUCUAU G UUCAAGAU 3553 ATCTTGAA GGCTAGCTACAACGA ATAGACAT 4839 662 tYGUEYCAA£9 A UUACA£9AU 3554 ATCTGTAA G£9CTA£CTACAACGA CTTGAACA 4840 665 UCAAGAUU A CAGAUCUC 3555 GAGATCTG GGCTAGCTACAACGA AATCTTGA 4841 669 GAUEJACAG A UCUCCAUU 3556 AATGGAGA GGCTAGCTACAACGA CTGTAATC 4842 675 AGAUCITCC A UUUAUUGC 3557 £9CAATAAA GGCTAGCTACAACGA GGAGATCT 4843 679 CUCCAIJUU A UUGCUUCU 3558 AGAAGCAA GGCTAGCTACAACGA AAATGGAG 4844 682 ICAUUAUU £9 CULJC!UGUI 3559 AACA9AAC GGCTAGCTACAACGA AATAAATGj 4845 WO 02/096927 PCT/US02/17674 688 IUUGCUJECU G UUAGUGAC 3560 GTCACTAA GGCTAGCTACAACGA AGAAGCAA 4846 6.92 tRJCUCUJEA G UGACOAAC 3561 GTTCGTCA COCTAGICTACAACCA TAACACAA 4847 695 tJGUUAGUG A CCAACAUG 3562 CATGTTGG GGCTAGCTACAACGA CACTAACA 4848 G99 AGUGACCA A CAUGGAGO 3563 ACTCCATG GGCTAGCTACAACGAk TGGTCACT 4849 701 UGACCAAC A UGGAGUCG 3564 CGACTCCA GGCTAGCTACAACGAk GTTGGTCA 4850 706 AACAUGGA G UCGUGUAC 3565 GTACACGA GG'TAGCTACAACGAk TCCAWGTT 4851 709 AUGGAGUC G UGUACAJT 3566 AATGTACA GGCTAGCTACAACGA GAC'FCCAT 4852 711 GGAGUCGU G UACAUJAC 3567 GTAATGTA GGCTAGCTACAACG.0 ACGACTCC 4853 713 AGUCGTJGU A CAUTACTJG 3568 CAGTAATG GGC VAGCTACAACGA ACACCACT 4854 715 {JCGUGTJAC A UEJACUGAG 3569 CTCAGTAA GGCTAGCTACAACGAk GTACACGA 4855 718 UGUACAUJ A CUGAGAAC 3570 GTTCTCAG GGCTAGCTACAACGAk AATGTACA 4856 725 UACIYGAGA A CAAAAACA 3671 TGTTTTTG GGCTAGCTACAACGA TCTCAGTA 4857 731 GAACAAAA A CAAAACUG 3572 CAGTTTTG GGCTAGCTACAACGAk TTTTGTTC 4858 73G AAAAC.AAA A CIJGUGGUG 3573 CACCACAG GGCTAGCTACAACGA TTTGTTTT 4859 739 ACAAAACU G UGGUGAUU 3574 AALTCACCA GGCTAGCTACAACGAk AGTTTTGT 4860 742 AAACUGUG G UGAUUCCA 3575 TGGAATCA GGCTAGCTACAACGA CACAGTTT 4861 745 CIJOUGGUG A ITUCCAUGU 3576 ACATGGAA GGCTAGCTACAAC-A, CACCACAG 4862 750 GUGAUUCC A UGUCTJCGG 3577 CCGAGACA GGCTAGCTACAACGA GGAATCAC 4863 752 GAULTCCAU G UCUCGGGU 3578 ACCCGAGA GGCTAGCTACAACGA ATGGAATC 4864 759 tGUCUCGG G UCCAUJtJC 3579 GAAATCGA GGCTAGCTACAACGA CCGAGACA 4865 763 UCGGGUCC A ULUCAAAU 3580 ATTTGAAA GCCTAGCTACAACGA GGACCCGA 4866 770 CAUUUCAA A UCUCAACG 3581 CGTTGAGA GCCTAOCTACAACGAk TTGAAATG 4867 776 AAAUCIJCA A CGUGTJCAC 3582 GTGACACG GGCTAGCTACAACGAk TGAGATTT 4868 778 AUCIJCAAC G UGUCACUU 3583 AAGTGACA GGCTAGCTACAACGAk GTTGAGAT 4869 780 CUCAACGU G UCACUUUtG 3584 CAAAGTGA GGCTAGCTACAACGAk ACGTTGAG 4870 783 AACGUGUC A CUUUGUGC 3585 GCACAAAG GGCTAGCTACAACGAz GACACGTT 4871 788 GUCACUTE G UGCAAGAU 3586 ATCTTGCA GGCTAGCTACAACGAk AAAGTGAC 4872 790 CACUUJTGU G CAAGAUAC 3587 GTATCTTG GGCTAGCTACAACGAk ACAA.AGTG 4873 795 IGUGCAAG A UACCCAGA 3588 TCTGGGTA GGCTAGCTACAACGAz CTTGCACA 4874 797 UG-CAAGAU A CCCAGAAA 3589 TTTCTGGG GGCTACCTACAACCA ATCTTGCA 4875 810 GAAAAGAG A ULUGULJCC 3590 GGAACAAA GGCTAGCTACAACGA CTCTTTTC 4876 814 AGAGAUUU G UtJCCUGAU 3591 ATCAGGAA GGCTAGCTACAACCA AAATCTCT 4877 821 UGUEJCCUG A UCGUAACA 3592 TGTTACCA GGCTAGCTACAACGA CAGGAACA 4878 824 UCCUGAUG G UAACAGAA 3593 TTCTGTTA GGCTAGCTACAACGAk CATCAGGA 4879 827 UGAUGGUA A CAGAAUUJ 3594 AAATTCTG GGCTAGCTACAACGA TACCATCA 4880 832 GUAACAGA A UUUCCUGG 3595 CCAGGAAA GGCTAGCTACAACGA TCTGTTAC 4881 842 UEJCCUGGG A CAGCAAGA 3596 TCTTGCTG GGCTAGCTACAACGA CCCAGGAA 4882 845 CtJCGGACA G CAACAAGG 3597 CCTTCTTG GGCTAGCTACAACGAk TGTCCCAG 4883 854 CAAGAALGG G CUTJTACUA 3598 TAGTAAAG GGCTAGCTACAACG-A CCTTCTTG 4884 859 AGGUCUUU A CUAUEJCCC 3599 GGGAALTAC GCTAGCTACAACGA4 AAAGCCCT 4885 862 GCULJUACU A UEJCCCAGC 3600 GCTGGGAA GGCTAGCTACAACGA AGTAAAGC 4886 869 UAUUTCCCA G CUACAUGA 3601 TCATGTAC GGCTAGCTACAACGA TGGGAATA 4887 272 UCCCAGCU A CAUCAUCA 3602 TGATCATC COCTAGCT'ACAACGCA AOUTCCA 488 874 CCAGCUAC A UGAUCAGC 3603 GCTGATCA GGCTAGCTACAACGA GTAGCTGG 4889 877 GCUACAUG A UCAGCUAU 3604 ATAGCTGA GCTAGCTACAACGA CATGTAGC 4890 881 CAUGAUCA G CUAUGCJC 3605 CAGCATAG GGZ-TAGCTACAACG.A TGATCATG 4891 884 GAUCAGCU A UGCUGGCA 3606 TGCCACCA GGCTAGCTACAACGAk AGCTGATC 4892 886 UCACLAU G CUGGCAUG 3607 CATGCCAG GGCTAOCTACAAXCCA ATAGCTGA 4893 890 CfJAUGCUG G CAUGGUCU 3608 AGACCAT'G GGCTAGC2TACAACUAq CAGCATAG 4894 892 AUGCUGGC A UGGUCJIJC 3609 GAAGACCA GGCTAGCTACAACGA GCCAGCAT 4896 895 CUGGCAUG G UCUUCUGU 3610 ACAGA GCTAGCTACAACGA7' CATGCCAG 4896 902 GGUCUYCU G UGAAGCAA 3611 TTGCTTCA GGCTAGCTACAACGA AGAAGACC 4897 907 UCtICUCAA G CAAAAAUU 3612 AATTTTTG CGCTACCTACAACGA TTCACAGA 4898 WO 02/096927 PCT[US02/17674 913 JAAGCAAAA A UEJAAUGAU 3 613 ATCATTAA CGCTAGCTACAACGA TTTTGCTT 4899 917 AAAAAITUA A UGAtJGAAA 3614 TTTCATCA CGCTAGCTACAACGA TAATTTTT 4900 920 AAUtJAAUG A tJGAAAGLTU 3615 AACTTTCA GGCTAGCTACAACGA CATTAATT 4901 926 UGAUGAAA G tJJACCAGTJ 3616 ACTGGTAA GGCTAGCTACAACGA TTTCATCA 4902 929 UGAAAGUJ A CCAGUCUA 3617 TAGACTGG CGCTAGCTACAACGA AACTTTCA 4903 933 AGLJUACCA G UCUAUJAU 3618 ATAATAGA CGCTAGCTACAACGA TGGTAACT 4904 937 ACCAGUCU A UUtAtGUAC 3619 GTACATAA GGCTAGCTACAACGA AGACTGGT 490S 940 AGUCtJAUUJ A UGUACAJA 3620 TATGTACA CGCTAGCTACAACGA AATAGACT 4906 942 UCUAUUAU G UACAUAGU 3621 ACTATGTA CGCTACCTACAACGA ATAATAGA 4907 944 UAUJEAUc4U A CAUAGUTUG 3622 CAACTATG GGCTAGCTACAACGA ACATAATA 4908 946 UUAUGUAC A UAGtJUGUC 3623 GACAACTA GGCTAGCTACAACGA GTACATAA 4909 949 UGUACAUA G UCUCGUJ 3624 AACACAA CGCTAGCTACAACGA TATGTACA 4910 952 ACAUAGU3I G UCGUUGUA 3625 TACAACGA GGCTAGCTACAACGA AACTATGT 4911 955 UAGUUGUC G UEJGUAGGG 3626 CCCTACAA GGCTAGCTACAACGA GACAACTA 4912 958 TJEGUCGUU G UAGGGUAU 3627 ATACCCTA GGCTAGCTACAACGA AACGACAA 4913 963 GLTUGUAGG G IJAUAGGAU 3628 ATCCTATA GGCTAGCTACAACGA CCTACAAC 4914 965 UGUAGGGU A UAGGAUUUE 3629 AAATCCTA GGCTAc3CTACAACGA ACCCTACA 4915 970 GGUAUAGG A UUUAUGAU 3630 ATCATAAA GGCTAGCTACAACGA CCTATACC 4916 974 UAGGAUJ A UGAIJGUGG 3631 CCACATCA GGCTAGCTACAACGA AAATCCTA 4917 9 77 C;AUUUAUG A UGUGGUJC 3632 GAACCACA GGCTAGCTACAACGA CATAAATC 4918 979 UUAUGAU G UGGUUCUG 3633 CAGAACCA GGCTAGCTACAACGA ATCATAAA 4919 982 AUGAUGG G UEYCUGAGU 3634 ACTCAGAA GGCTAGCTACAACGA CACATCAT 4920 989 GGIJUCTJGA G UCCGtICUC 3635 GAGACGGA GGCTAGCTACAACGA TCAGAACC 4921 993 CUGAGUCC G UCUCAUGG 3636 CCATGAGA GG3CTAGCTAC'AACGA GGACTCAG 4922 998 UCCGUCUC A UGGAAUUG 3637 CAATTCCA GGCTAGCTACAACGA GAGACOGA 4923 1003 CUCAUGGA A U1JGAACUA 3638 TAGTTCAA GGCTAGCTACAACGA TCCATGAG 4924 1008 GGAAUJGA A CUAEJCUGU 3639 ACAGATAG GG3CTAGCTACAACGA TCAATTCC 4925 1011 AUIJGAACU A UCUGUJOG 3640 CCAACAGA GGCTAGCTACAACGA AGTTCAAT 4926 1015 AACUAUCU G UEJGGAGAA 3641 TTCTCCAA CGCTAGCTACAACGA AGATAGIT 4927 1026 GGAGAAAA 0 CUEJGUCUU 3642 AALGACAAG GGCTAGCTACAACGA TTTTCTCC 4928 1030 AAAAGCUJ G UCUJEAAAU 3643 ATTTAAGA GGCTAGCTACAACGA AAGCTTTT 4929 1037 UGUCUUAA A UUJGTACAG 3644 CTGTACAA GGCTAGCTACAACGA TTAAGACA 4930 1040 CULJAAAUJ G UACAGCAA 3645 TTGCTGTA GGCTAGCTACAACGA AATTTAAG 4931 1l042 UAAAUJGU A CAGCAAGA 3646 TCTTGCTG GGCTAGCTACAACGA ACAATTTA 4932 1045 AUUGUACA G CAAGAACU 3647 AGTTCTTG GGCTAGCTACAACGA TGTACAAT 4933 1051 CAGCAAGA A CUGAACUA 3648 TAGTTCAG GGCTAGCTACAACGA TCTTG7CTG 4934 1056 AGAACUGA A CUAAAUGU 3649 ACATTTAG GGCTAGCTACAACGA TCAGTTCT 4935 1061 UGAACUAA A UGUGGGGA 3650 TCCCCACA GGCTACCTACAACGA TTAGTTCA 4936 1063 AACUAAAU G UGGGGAUU 3651 AATCCCCA GGCTAGCTACAACGA ATTTAGTT 4937 1069 AUGUGGGG A TJUGACUTJC 3652 GAAGTCAA GGCTAGCTACAACGA CCCCACAT 4938 1073 GGGGAUJG A CU(JCAACU 3653 AGTTGAAG GGCTAGCTACAACGA CAATCCCC 4939 1079 UGACUTCA A CUGGGAAU 3654 ATTCCCAG GGCTAGCTACAACGA TGAAGTCA 4940 1086 AACUGGGA A UACCCUTJC 3655 GAAGGGTA GGCTAGCTACAACGA TCCCAGTT 4941 1088 CUGGGAAU A CCCtJUCUJ 3656 AAGAAGGG GGCTAGCTACAACGA ATTCCCAG 4942 1101 UCUUCGAA G CAUCAGCA 36S7 TGCTUATG GOCTAGCTACAACGA TTCGAAGA 4943 1103 UUCGAAGC A UCAGCAUA 3658 TATGCTGA GGCTAGCTACAACGA GCTTCGAA 4944 1107 AAGCAUCA G CAUAAGAA 3659 TTCTTATG GGCTAGCTACAACGA TGATGCTT 4945 1109 GCAEJCAGC A UAAGAAAC 3660 GTTTCTTA GGCTAGCTACAACGA GCTGATGC 4946 1116 CAUAAGAA A CUEJGUAAA 3661 TTTACAAG GGCTAGCTACAACGA TTCTTATG 4947 1120 AGAAACUUt G UAAACCGA 3662 TCGGTTTA GGCTAGCTACAACGA AAGTTTCT 4948 1124 ACUUGUAA A CCGAGACC 3663 GGTCTCGG GGCTAGCTACAACGA TTACAAGT 4949 1130 AAACCGAG A CCUAAAAA 366 TTAGGCAGTACAACGA CTCGGTTT 4950 1138 ACCUAAAA A CCCAGUCU 3665 AGACTGGG GGCTAGCTACAACGA TTTTAGGT 4951 WO 02/096927 WO 02/96927PCT/US02/17674 1143]AAA-ACCCA G UCUGGGAG 3666 CTCCCAGA GGCTAGCTACAACGA TGGGTTTT 4952 1151 GUCUGGG\ G UGAGAUGA 3667 TCATCTCA GGCTAGCTACAACGA TCCCAGAC 4953 1156 GGAGUGAG A UGAAGAAA 3668 TTTCTTCA GGCTAGCTACAACGA CTCACTCC 4954 1164 AUGAAGAA A UUUUUGAG 3669 CTCAAAAA GGCTAGCTACAACGA TTCTTCAT 4955 1172 AIAJUUUGA G CACCUUAA 3670 TTAAGGTG GGCTAGCTACAACOA TCAAAAAT 4956 1174 UUUtUGAGC A CCUUtAACTJ 3671 AGTTAAGG GGCTAGCTACAACGA GCTCAAAA 4957 1180 GCACCtJUA A CIJAUAGAJ 3672 ATCTATAG GGCTAGCTACAACGA TAAGGTGC 4958 1183 CCtTAACU A UAGAUGGU 3673 ACCATCTA GGCTAGCTACAACGA AGTTAAGG 4959 1187 AACUAUAG A UGGUGUAA 3674 TTACACCA GGCTAGCTACAACGA CTATAGTT 4960 1190 UAUAGAUG G UGUAACCC 3675 GGGTTACA GGCTAGCTACAACGA CATCTATA 4961 1192 tTAGAUGGJ G UAACCCGG 3676 CCGGGTTA GGCTAGCTACAACGA ACCATOTA 4962 119S AUGGUGUA A CCCOOAQUJ 3677 ACTCCGGG GGCTAGCTACAACGA TACACCAT 4963 1202 AACCCGGA G UGACCAAG 3678 CTTGc3TCA GGCTAGCTACAACGA TCCGCGTT 4964 1205 CCGGAGUG A CCAAGGAT 3679 ATCCTTGG GGCTAGCTACAACGA CACTCCGG 4965 1212 GACCAAGG A LUUGUACAC 3680 GTGTACAA GGCTAGCTACAACGA CCTTGGTC 4966 1215 CAAGGAUJ G UACACCUG 3681 CAGGTGTA GGCTAGCTACAACGA AATCCTTG 4967 1217 AGGAUUGU A CACCUGUG 3682 CACAGGTG GGCTAGCTACAACGA ACAATCCT 4968 1219 GAUUGUAC A CCUGUGCA 3683 TGCACAGG GGCTAGCTACAACGA GTACAATC 4969 1223 GUACACCU G UGCAGCAU 3684 ATGCTGCA GGCTAGCTACAACGA AGGTGTAC 4970 1225 ACACCUGJ G CAGCAUCC 3685 GGATGCTG GGCTAGCTACAACGA ACAGGTGT 4971 1228 CCEJGUGCA G CAIJCCAGU 3685 ACTGGATG GGCTAGCTACAACGA TGCACAGG 4972 1230 UGUGCAGC A UCCAGUGG 3687 CCACTGGA GGCTAGCTACAACGA GCTGCACA 4973 1235 AGCAUCCA G UGGGCUGA 3688 TCAGCCCA GGCTAGCTACAACGA TGGATGCT 4974 1239 UCCAGTJGG a CUGAUGAC 3689 GTCATCAG GGCTAGCTACAACGA CCACTGGA 4975 1243 GUGGGcuG A UGACCAAG 3690 CTTGGTCA GGCTAGCTACAACGA CAGCCCAC 4976 1246 GGCUGAUG A CCAAGAAG 3691 CTTCTTG3 GGCTAGCTACAACGA CATCAGCC 4977 1256 CAAGAAGA A CAGCACAU 3692 ATGTGCTG GGCTAGCTACAACGA TCTTCTTG 4978 1259 GAAGAACA G CACAUUTG 3693 CAAATGTG GGCTAc3CTACAACGA TGTTCTTC 4979 1261 AGAACAGC A CAUUJGIC 3694 GACAALATG GGCTAGCTACAACGA GCTGTTCT 4980 1263 AACAGC-AC A UUGUCAG 369S C-TGACAAA GGnCTAG3CTACAACGA GTGCTGTT 4981 1267 GCACAUUJ G UCAGGGUC 3696 GACCCTGA GGCTAGCTACAACGA AAATGTGC 4982 1273 UUGUCAGG G UCCAUGAA 3697 TTCATGGA GGCTAGCTACAACGA CCTGACAA 4983 1277 CAG2GGUCC A UGAAAAAC 3698 GTTTTTCA GGCTAGCTACAACGA GGACCCTG 4984 1284 CAtJGAAAA A CCUUUUGU 3699 ACAAAAGG GGCTAGCTACAACGA TTTTCATG 4985 1291 AACCUUUU a UTJGCUUUU 3700 AAAAGCAA GGCTAGCTACAALCGA A-ALAAGGTT 4986 1294 CUUUUGUUT G CUUJEJGGA 3701 TCCAAAAG GGCTAGCTACAACGA AACAAAAG 4987 1304 UUUUGGAA G UGGCAUGG 3702 CCATGCCA GGCTAGCTACAACGA TTCCAAAA 4988 1207 UGGAAGUG G CAUGGAAU 3703 ATTCCATG GGCTAGCTACAACGA CACTTCCA 4989 1309 GAAGUGGC A UGGAAUCU 3704 AGATTCCA GGCTAGCTACAACGA GCCACTTC 4990 1314 GGCAUGGA A ucucuGGu 3705 ACCAGAGA GGCTAGCTACAACGA TCCATGCC 4991 1321 AAUCUCUG a UGGAAG3CC 3706 GGCTTCCA GGCTAGCTACAACGA CAGAGATT 4992 1327 UGGUGGAA a CCACGGUG 3707 CACCGTGG GGCTAGCTACAACGA TTCCACCA 4993 1330 UGGAAGCC A cGGUaaaa 3708 CCCCACCG GGCTAGCTACAACGA GGCTTCCA 4994 1233 AAGCCACG G UGGGGGAG 3709 CTCCCCCA GGCTAGCTACAACGA CGTGGCTT 4995 1241 GU3GGGGA G CGUGUCAG 3710 CTGACACG GGCTAGCTACAACGA TCCCCCAC 4996 1343 GCOGGAGC C UGUCACAA 3711 TTCTGACA 3GCTAGCTACAACGA GCTCCCCC 4997 1345 GGGAGCGU G UCAGAAUC 3712 GATTCTGA GGCTAGCTACAACGA ACGCTCCC 4998 1251 GUGUCAGA A UCCCUGCG 3713 CGCAGGGA- GGCTAGCTACAALCGA TCTGACAC 1999 1357 GAAUCCCU G CGAAGUAC 3714 GTACTTCG GCTAGCTACAACGA AGGGATTC 5000 1362 CCUGCGAA a UACCUUGG 3715 CCAAGGTA GGCTAGCTACALACGA TTCGCAGG 5001 1364 UGCGAAGU A CCUUGGJU 3716 AACCAAGG GGCTAGCTACAACGA ACTTCGCA 5002 1370 GUACCUJTG G UUACCCAC 3717 GTGGGTAA GGCTAGCTACAACGA CAAGGTAC 5003 1373 CCUUaaUU A CCCACCCC 3 718 OGGGGTGGG GGCTAGCTACAACGA AACCAAGG 5004 WO 02/096927 PCT/US02/17674 1377 1GGUUACCC A CCCCCAGA 3719 TCTGGGGG GGCTAGCTACAACGA GGGTAACC 5005 1387 CCCCAGAA A UAAAAUGG 3720 CCATTFTTA GGCTAGCTACAACGA TTCTGGGG 5006 1392 GAAAUAAA A UGGUAUAA 3721 TTATACCA GGCTAGCTACAACGA TTTATTTC 5007 13 95 AUAAAAUG G UAUAAAAA 3722 TTTTTATA GGCTAGCTACAACGA CATTTTAT 5008 1397 AAAAUGGU A UAAAAAJG 3723 CATTTTTA GGCTAGCTACAACGA ACCATTTT 5009 1403 GUAUAAAA A UGGAAUAC 3724 GTATTCCA GGCTAGCTACAACGA TTTTATAC 5010 1408 AAAAUGGA A UACCCCUU 3725 AGGGTA GGCTAGCTACAACGA TCCATTTT 5011 1410 AAUGGAAU A CCCCUUGA 3726 TCAAGG2GG GGCTAGCTACAACG4 ATTCCATT 5012 1419 CCCCUUTGA G~ tCCAAUCA 3727 TGATTGGA GGCTAGCTACAACGA TCAAGGGG 5013 1424 IJOAGUCCA A UCACACAA 3728 TTGTGTGA GGCTAGCTACAACGA TGGACTCA 5014 1il4 27 GUCCAAUC A CACAAUJA 3729 TAATTGTG GGCTAGCTACAACGA GAT'rGGAC 5015 [1429 CCAAUCAC A CAAOJUAAA 3730 TTTAATTG GGCTAGCTACAACGA GTGATTGG 5016 1I432 AUCACACA A UtJAAAGCG 3731 CGCTTTAA GGCTAGCTACAACGA TGTGTGAT 5017 1438 CAAUEJAAA G CCGGGCAU 3732 ATGCCCCG GGCTAGCTACAACGA TTTA.ATTG 5018 1443 AAAGCGGG G CAUGUACU 3733 AGTACATG GGCTAGCTACAACGA CCCGCTTT 5019 1445 AGCGGGGC A UGtTACUGA 3734 TCAGTACA GGCTAGCTACAACGA GCCCCGCT 5020 91447 CGGGGCAU G UACUGACG 3735 CGTCAGTA GGCTAGCTACAACGA ATCCCCG 5021 1449 GGGCAUGU A CUGACGAU 3736 ATCGTCAG GGCTAGCTACAACGA ACATGCCC 5022 1453 AUGUACUG A CGAU!JAUG 3737 CATAATCG GGCTAGCTACAACGA CAGTACAT 5023 1456 UACUGACG A UtJAUGGAA 3738 TTCCATAA GGCTAGCTACAACGA CGTCAGTA 5024 1459 UGACGAUjU A TJGGAAGUG 373,9 CACTT'CCA GGCTAGCTACAACGA AATCCTCA 5025 1465 TJAUGGAA G UGAGUGALA 3740 TTCACTCA GGCTAGCTACAACGA TTCCATAA S026 14G9 GGAAGUCA G UGAAAGAG 3741 CTCTTTCA GGCTAGCTACAACGA TCACTTCC 5027 1478 UCAAAGAG A CACAGGAA 3742 TTCCTGTG GGCTAGCTACAACGA CTCTTTCA 5028 1480 AAAGAGAC A CAGGAAALU 3743 ATTTCCTG GGCTAGCTACAACGA GTCTCTTT 5029 1.487 CACAGGAA A UEJACACUG 3744 CAGTGTAA GGCTAGCTACAACGA TTCCTGTG3 5030 1490 AGGAAAUU A CACJGIJCA 3745 TGACAGTG GGCTAGCTACAACGA AATTTCCT 5031 1492 GAAAUJAC A CUGtJCAUC 3746 GATGACAG GCcTAGCrACAACGA GTAATTTC 5032 1495 AUUACACU G UCAUCCUJ 3747 AACCATGA GGCTAGCTACAACGA AGTGTAAT 5033 1498 ACACUGUC A UCCIT1ACC 3748 GCTAAGGA CGCTAGCTACAACGA GACAGTGT 5034 1504 UCAUCCUJ A CCAAUCCC 3749 GGGATTGG GC2TAGCTACAACGA AAGGATGA 5035 1508 CCUIJACCA A UCCCAUJU 3750 AAATGGGA GGCTACCTACAACGA TCGTAACC 5036 1513 CCAAUCCC A UUJECAAAC 3751 CTTTGAAA CCTAGCTACAACGA GGGATTGG 5037 1527 AAGGAGAA G CAGAGCCA 3752 TGCCTCTG GGCTAGCTACAACGA TTCTCCTT 5038 1532 GAAGCAGA C CCAUGUGG 3753 CCACATGG GGCTAGCTACAACGA TCTGCTTC 5039 1535 GCAGAOCC A UCUGGUCU 3754 AGACCACA GGCTAGCTACAACGA GGCTCTGC 5040 1537 AGAGCCAU G UGGUCUCU 3755 AGAGACCA GGCTAGCTACAACGA ATGGCTCT 5041 1540 GCCAUGUG G UCUCUCUG 3756 CAGACAGA GGCTAGCTACAACGA CACATGGC 5042 1549 UCUCUCUG G UEJGUGUAU 3757 ATACACAA GGCTAGCTACAACGA CAGAGAGA 5043 1552 CUCUGGUU G UGUAUGUC 3758 GACATACA GGCTAGC CACAACGA AACCAGAG 8044 1554 CUGGUtJGU G UAUGUCCC 3759 GGGACATA GGCTAGCTACAACGA ACAACCAG 5045 1556 GGUEJGUGU A UGUCCCAC 3760 GTGGGACA GGCTAGCTACAACGA ACACAACC 5046 1888 LUGUGUAU G UCCCACCC 3761. CCCTCCCA CCTACCTACAACGA ATACACAA 5047 1563 UAUGUCCC A COCCAGAD 3762 ATCTGGGG GGCTAGCTACAACGA GGGACATA 5048 1570 CACCCCAG A TUCCGUGAG 3763 CTCACCAA GGCTAGCTACAACGA CTGGGGTG 5049 1574 CCACAUUG G UCACAAAU 3704 ATTTCTCA GGCTAGCTACAACGA CAATCTGG 5050 1581 GGUGAGAA A IJCUCUAAU 3765 ATTAGAGA GGCTAGCTACAACGA TTCTCACC 5051 1588 AAUCUCUA A UCUCUCCU 3766 AGGAGAGA GGCTAGCTACAACGA TAGAGATT 5052 1597 UCUCUCCU G UGGAUUCC 3767 GGAATCCA GGCTAGCTACAACGA AGGAG2AGA 5053 1601 UCCUGUCG A UUCCUACCI 3768 GGTAGGAA GGCTAGCTACAACGA CCACAGGA 8084 1607 GGAUUCCU A CCAGUACG 3769 CGTACTGG GGCTAGCTACAACGA AGGAATCC 5055 1611 UCCUACCA G UACGGCACI 377 .0 GTGCCGTA CGCTAGCTACAACGA TGGTACCA 5056 1613 CUACCAGU A CGGCACCA 3771 TGGTGCCG GGCTAGCTACAACGA ACTGGTAG 5057 WO 02/096927 PCT/US02/17674 16161ICCAGUACG G CACCACUCI 3772 -I UAGTGGTG GGCTAGCTACAACGA CGTACTGG 1 508 1618 AGUACGGC A CCACUCAJA 3773 TT'3AGTGG GGCTAGCTACAACGA G3CCGTACT 5059 1.521 ACGGCACC A CUCAAACG 3774 CGTTTGAG Gc3CTAGC'FACAACGA GGTGCCGT 5060 1627 CCACUCAA A CGCUGACA 3775 TGTCAGCG GGCTAGCTACAACGA TTGAGTGG 5061 1G29 ACUCAAAC G CUGACAUG 3776 CATGTCAG GGCTAOCTACAACG3A GTTTGAGT 5062 1633 AAACGCUG A CAUGUACG 3777 CGTACATG GGCTAGCTACAACG3A CAGCGTTT 5063 1635 ACGCUGAC A UGIJACGGU 3778 ACCGTACA GGCTAGCTACAACGA GTCAGCGT 5064 1637 GCUGACAT G UACGGUCU 3779 AGACCGTA GGCTAGCTACAACGA ATGTCAGC 5065 1639 UGACAUGY A CGGUCUAU 3780 ATAGACCG r3GCTAGCTACAACGA ACATGTCA 5066 1642 CAUGUACG. G UCUAUGCC 3781 GGATAGA GGCTAGCTACAACGA CGTACATG 5067 1646 UACGGUCU A UGCCAUEJC 3782 GAATGGCA GGCTAGCTACAACGA AGACCGTA 5068 1648 CGGUCUAU G CCAUUCCU 3783 AGGAATGG GCCTAOCTACAACGA ATAGACCG 5069 1651 UCUAUGCC A UtJCCUCCC 3784 GGGAGGAA GGCTAGCTACAAC3A GGCATAGA 5070 1662 CCUCCCCC G CAUCACAU 3785 ATGTGATG GGCTAGCTACAACGA GGGGGAGG 5071 1664 UCCCCCCC A UCACAUCC 3786 GGATGTGA GGCTAGCTACAACGA GCGGGGGA 5072 1667 CCCGCAUC A CAUCCACU 3787 AGTGGATG GGCTAGCTACAACGA GATGCGGG 5073 16691CGCAUCAC A UCCACUGG 3788 CCAGTGGA GGCTAGCTACAACGA GTGATGCG S074 1673 TJCACAUCC A CUGGUAUU 3789 AATACCAG GGCTAGCTACAACGA GGATGTGA 5075 1677 AUCCACUG G UAUGGCA 3790 TGCCAATA GGCTAG3CTACAACGA CAGTGGAT 5076- 1679 CCACUGGU A UIJGGCAGU 3791 ACTGCCAA GGCTAGCTACAACGA ACCAGTGG 5077 1683 UGGUAtTUG G CAGtJUGGA 3792 TCCAACTG GGCTAGCTACAACGA CAATACCA 5078 1686 UAUEJGGCA G IJUGGAGGA 3793 TCCTCCAA GGCTAGCTACAACGA TOCCAATA 5079 1698 GAGGAAGA G UGCGCCAA 3794 TTGGCGCA GGCTAGCTACAACCA TCTTCCTC 5080 1700 GGAAGAGU G CGCCAACG 3795 CGTTGGCG GGCTAGCTACAACGA ACTCTTCC 5081 1702 AACAGUGC G CCAACGAG 3796 CTCGTTGG GGCTAGC'FACAACGA GCACTCTT 5082 1706 GUGCGCCA A CGAGCCCA 3797 TGGGCTCG GGCTAGCTACAACGA TGGCGCAC 5083 1710 GCCAACGA G CCCAGCCA 3798 TGGCTGGG GGCTAGCTACAACGA TCGTTGGC 5084 1715 CGAGCCCA G CCAAGCUG 3799 CAGCTTGG GGCTAGCTACAACGA TGGGCTCG 5085 1720 CCAGCCAA G CUGUCUCA 3800 TGAGACAG GGCTAGCTACAACGA TTGGCTGG 5086 1723 GCCAAGCU G UCUCAGUG 3801. CACTc4AGA GGCTAGCTACAACGA AGCTTGGC 5087 1729 CUGUCUCA G UGACAAAC 3802 GTTTGTCA GGCTAGCTACAACGA TGAGACAG 5088 1732 IJCUCAGUG A CAAACCCA 3803 TGGGTTTG GGCTAGCTACAACGA CACTGAGA 5089 17361AGUGACAA A CCCAUACC 3804 CGTATCGG CGCTAGCTACAACGA TTGTCACT 5090 1740 ACAAACCC A UACCCUUG 3805 CAAGGGTA GGCTAGCTACAACGA GGGTTTGT 5091 1742 AAACCCAU A CCCUUCUC 3806 CACAAGGG GOCTAGCTACAACGA ATGGGTTT 5092 1740 AUACCCUTJ G UGA7AGAAU 3807 ATTCTTCA GGCTAGCTACAACGA AAGGGTAT 5093 1755 UGUGAAGA A UGGAGAAG 3808 CTTCTCCA GGCTAGCTACAACGA TCTTCACA 5094 1763 AUGGAGAA G UGUGGAGG 3809 CCTCCACA GGCTACCTACAACCA TTCTCCAT 5095 1765 GGAGAAGU G UGGAGGAC 3810 GTCCTCCA GGCTAGCTACAACGA ACTTCTCC 5096 1772 UGtJGGAGG A CUUCCAGG 3811 CCTGGAAG GGCTAGCTACAACGA CCTCCACA 5097 1787 GGGAGGAA A UAAA.AJEG 3812 CAATTTTA GGCTAGCTACAACGA TTCCTCCC 5098 1792 GAAAUAAA A UUGAAGtJU 3813 AACTTCAA CCCTAGCTACAACGA TTTATTTC 5099 1798 AAAUEJGAA G TJUAAUAAA 3814 TTTATTAA GGCTACCTACAACGA TTCAATTT 5100 1802 UGAAGUUA A UAAAAAUC 3815 GATTTTTA GGCTAGCTACAACGA TAACTTCA 5101 1808 UAAUAA7AA A UCAAUUUEG 386 CAAATTGA GGCTAGCTACAACGA TTTTATTA 5102 1812 AAAAAEJCA A ULUCCUCU 3017 AGAGCAAA GGCTAGCTACAACGA TGATTTTT 5103 1816 AUCAAUUU G CUCUAAUU 3818 AATTAGAG GGCTAGCTACAACGA AAAFTGAT 5104 1822 LGCUCUA A UUGAAGGA 3819 TCCTO'CAA GGCTAGCTACAACGA TAGAGCAA 5105 1835 AGGAAAAA A CAAAACtJG 3820 CAGTTTTG GGC'fAGCTACAACGfl TTITTTCCT 5106 14 0 AAAACAAA A CUGUAAGU 3821 ACTTACAG GGCTAGCTACAACGA TTTGTTTT 5107 18 43 ACAAAACU G UAAGUACC 3822 GGTACTTA GGCTAGCTACAACGA AGTTTTGT 5108 1847 AACUGUAA G UACCCUEJG 3823 CAAGGGTA GGCTAGCTACAACGA TTACAGTT 5109 1L8 49 CUGUAAGU A CCCJUGUU 3824 JAACAAGGG GCCTAGCTACAACGA ACTTACAG 5110 WO 02/096927 PCT[US02/17674 1855 GtJACCCIJU G UtTAUCCAA 3825 TTGOATAA GGCTAGCTACAACGA AAGGGTAC 5111 1858 CCCUUGUUT A UCCAAGCG 3826 CGCTPGGA GGCTAGCTACAACGA AACAAGGG 5112 1864 UUATJCCAA G CGGCAAAU 3827 ATTTGCCG GGC2TAGCTACAACGA TTGGATAA 5113 1867 tTCCAAGCG G CAAAUJGUG 3828 CACATTTG GOCTAGCTACAACGA COCTTGGA 5114 1871 AGCG3GCAA A UGUGUCAG 3829 CTGACACA GGCTAGCTACAACGA TTGCCGCT 5115 1873 CGGCAAAU G UGUCAGCU 3830 AGCTGACA GGCTAGCTACAACGA ATTTGCCG 5116 1875 GCAAAUGU G tYCACCULJU 3831 AA2NGCTGA GGCTAGCTACAACCA ACATT'PGC 5117 1879 AUGUGUCA G CUUUGUAC 3832 GTACAAAG GGCTAGCTACAACCA TGACACAT 5118 1884 UCAGCUJT G UACAAAJG 3833 CATTTGTA GGCTAGCTACAACOA AAAGC'PGA 5119 1886 AGCUEJUGU A CAAAUGUG 3834 CACATTTG GGCTAGCTACAACGA ACAAAGCT 5120 1890 UUGUACAA A UGUGAAGC 3835 GCTTCACA GGCTAGCTACAACGA TTGTACAA 5121 1892 GUACAAAU G tJGAAGCGG 3836 CCGCTTCA GGCTAGCTACAACGA ATTTGTAC 5122 18.97 AAUGUGAA G CGGUCAAC 3837 GTTGACCG GGCTAGCTACAACGA TTCACATT 5123 1900 GUGAAGCG G UCAACAAA 3838 TTTGTTGA GGCTAGCTACAACGA CGCTTCAC 5124 1904 AGCGGUCA A CAAAGUCG 3839 CGACTTTG GGCTAGCTACAACGA TGACCGCT 5125 1909 UCAACAAA G UCGGGAGA 3840 TCTCCCGA GGCTAGCTACAAC3A TTTGTTGA 5126 1927 GAGAGAGG G UGAUCUCC 3841 GGAGATCA GGCTAGCTACAACGA CCTCTCTC 5127 1930 AGAGGGUG A UCUCCO1JC 3842 GAAGGAGA GGCTAGCTACAACGA CACCCUICT 5128 1940 CUCCUJCC A CGUGACCA 3843 TGGTCACG CGCTAGCTACAACGA GGAAGGAG 5129 1942 CCUTJCCAC G UGACCAGG 3844 CCTGGTCA CGCTAGCTACAACGA GTGGAAGG 5130 1945 UCCACGUG A CCAGGGGU 3845 ACCCCTGG GGCTAGCTACAACGA CACGTGGA 5131 1952 GACCAGGG G UCCUGAAA 3846 TTTCAGGA GGCTAGCTACAACGA CCCTrOGTC 5132 1960 GUCCUGAA A UUACUUhJG 3847 CAAZAGTAA GGCTAGCTACAACGA TTCAGGAC 5133 963 CtGAAAUUT A CUUUGCAA 3848 TTGCAAAG GGCTAGCTACAACGA AATTTCAG 5134 1958 AULJACUUU G CAACCIJGA 3849 TCAGGTTG CGCTAGCTACAACGA AAAGTAAT 5135 1971 ACUU1JUGCA A CCJGACAU 3850 ATGTCAGG GGCTAGCTACAACGA TGCAAAGT 5136 196- ACU A CAUGCAGC 3851 GCTOCATO GGCTAGCTACAACGA CAGGTTGC 5137 71978 AACUGAC A UGCACCOC 3852 GCTGCA G3GCTAGCTACAACGA GTCAGGTT 5138 198 CCUGACAU G CAGCCCAC 3853 GTGGGCTG GGCTAGCTACAACGA ATGTCAGG 5139 1±98,3 GACAIJOCA G CCCACTJ0A 3854 TCAGTGGG GGCTAGCTACAACGA TGCATGTC 5140 1987 UG3CAGCCC A CUGAGCAG 3855 CTGCTCAG GGCTAGCTACAACGA GGGCTGCA 5141 1992 CCCACUGA G CAGGAGAG 3856 CTCTCCTG GGCTAGCTACAACGA TCAGTGGG4 5142 2000 GCAGGAGA G CGUGUCUU 3857 AAGACACG GGCTAGCTACAACGA TCTCCTGC 5143 2002 AGGAGAGC G LJGUCUtJTG 3858 CAAAGACA GGCTAGCTACAACGA GCTCTCCT 5144 2004 GAGAGCGU G UCUUJUGUG 3859 CACAAAGA GGCTAGCT-ACAACGA ACGCTCTC S145 2010 GUGTJCUULU G UGGIJOCAC 3860 GTGCACCA GGCTAGC1ACAACGA AAAGACAC 5146 2013 UCtUUUGUG G UGCACIJGC 3861 GCAGTGCA GGCTAGCTACAACGA CACAAAGA 5147 2015 UUUJGUGGU G CACUCCAG 3862 CTGCAGTG GGCTAGCTACAACGA ACCACAAA 5148 2017 UGtJGGUGC A CUGCAGAC 3863 GTCTGCAG GGCTAGCTACAACGA GCACCACA 5149 2020 GGUGCACU G CAGACAGA 3864 TCTOTCTG GGCTAGCTACAACGA A0TGCACC 5150 2024 CACUGCAG A CAGAUCUA 3865 TAGATCTG GGCTAGCTACAACGA CTGCAGTG 5151 2028 GCAGACAG A IJCUACGUU 3866 AACOTAGA GGCTAGCTACAACGA CTGTCTGC 5152 2032 ACAGAUCU A CGUUGAG 3867 CTCAAACG CGCTAOCTACAACGA AGATCTGT 5153 2034 AGAUCtJAC G UUTUGAGAA 3868 TTCTCAALA GCTAGCTACAACCA GTAGATCT 5154 2042 GUUEJGAGA A CCUCACAU 3859 ATGTOAGG GGCTAGCTACAACGA TCTCAAAC 5155 2047 AGAACCUC A CAUGGUAC 3870 GTACCATG GGCTAGCTACAACGA GAGGTTCT 5156 2049 AACCUCAC A UGGUACAA 3871 TTGTACCA GGCTAGCTACAACGA GTGAGGTT 5157 2052 CUCACAUG 0 UACAAGCU 3872 A0CTTGTA GGCTAGCTACAACGA CATGTGAG 5158 20541 CACAUGGJ A CAAGCLUG 3873 CAAGCTTG GGCTAGCTACAACGA ACCATGTG 5159 2 05 8 UGGUACAA 0 CUUGGCCC 3874 GGGCCAAG GGCTAGCTACAACGA TTGTACCA 5150 2063 CAAGCUTG G CCCACAGC 3875 GCTGTGGG GGCTAGCTACAACGA CAAGCTTG 5161 2067 CUUGGCCC A CAGCCLTCU~ 3876 2070IGGCCCACA G CCUCUGCCj 3877 AL GGCTO GGCTAGCTACAACGA GGGCCAAG I~GGCAGAGG G-CTAGCTACAACGA TGTGGGCC 5162 WO 02/096927 PCT[US02/17674 2076 CAGCCUCU G CCAAtJCCA 3878 TGG2ATTGG GGCTAGCTACAACGA AGAGGCTG 5164 2080 CUCUGCCA A UCCAUGUG 3879 CACATGGA GGCTAGCTACAACGA TGGCAGAG 51G5 2084 GCCAAtJCC A UGUGGGAG 3880 CTCCCACA GGCTAGCTACAACGA GGATTGGC 5166 2086 CAAUCCAU G UGGGAGAG 3881 CTCTCCCA GGCTAGCTACAACGA ATGGATTG S167 2094 GUGGGAGA G IJTGCCCAC 3882 GTGGGCAA GGCTAGCTACAACGA TCTCCCAC 5168 2097 GGAGAGULJ G CCCACACC 3883 GGTGTGGG GGCTAGCTACAACGA AACTCTCC 5169 2101 AGr.UGCCC A CACCtJGUU 3884 AACAGGTG GGCTAGCTACAACGA GCGCAACT 5170 2103 UUGCCCAC A CCUGUUUG 3885 CAAACAGG GGCTAGCTACAACGA GTGGGCAA 5171 2107 CCACACCU G tUGCAAG 3886 CTTGCAAA CGCTAGCTACAACCGA AGGTGTGG 5172 2111 ACCUGUUUT G CAAGAACU 3887 AGTTCTTG GGCTAGCTACAACGA AAACAGGT 5173 2117 UEJGCAAGA A CUUGGAUA 3888 TATCCAAG GGCTAGCTACAACGA TCTTGCAA 5174 2123 GAACUT5GG A UACUCUU 3889 AAAGAGTA GGCTAGCTACAACGA CCAAGTTC 5175 2125 ACtJUGGAU A CUCUUTJGG 3890 CCAAAGAG GGCTAGCTACAACGA ATCCAAGT 5176 2136 CUEJUGGAA A UrJGAAUGC 3891 GCATTCAA GGCTAGCTACAACGA TTCCAALAG 5177 2141 GAAAUUGA A UGC-ACCA 3892 TGGTGGCA GGCTAGC:ACAACGA TCAATTTC 5178 2143 AAUtJGAAU G CCACCAUG 3893 CATGGTGG GGCTAGCTACAACGA ATTCAATT 5179 2146 UGAAUJGCC A CCAUGUJC 3894 GAACATGG GGCTAGCTACAACGA GGCATTCA 5180 2149 AUGCCACC A UGUUCUCU 3895 AGAGAACA GGCTAGCTACAACGA GGTGGCAT 5181 2151 GCCACCAU G UUCUCUAA 3896 TTAGAGAA GGCTAGCTACAACGA ATGGTGGC 5182 2159 GMUCUCIJA A UAGCACAA 3897 TTGTGCTA GGCTAGCTACAACGA TAGAGAAC 5183 2162 CUCUAATJA G CACAAAUG 3898 CATTTGTG GGCTAGCTACAACGA TATTAGAG 5184 2164 CUAAUAGC A CAAAUGAC 3899 GTCATTTG GGCTAGCTACAACGA OCTATTAG S185 2168 UAGCACAA A UGACAUUU 3900 AAATGTCA GGCTAGCTACAACGA TTGTGCTA 5186 2171 CACAAAUG A C-AUUUJGA 3901 TCAAAATG GGCTAGCTACAACGA CATTTGTG 5187 2173 CAAAUGAC A UUUEJGAUC 3902 GATCAAAA GGCTAGCTACAACCA STCATTG 5180 2179 ACAUUUUtG A IJCAUGGAG 3903 CTCCATGA GGCTAOCTACAACGA CAAAATGT 5189 2182 UEJOEJGAUC A UGGAGCUU 3904 AAGCTCCA GGCTAGCTACAACGA SATCAAAA 5190 2187 AUCAUGGA G CtJUAAGAA 3905 TTCTTAAG GGCTAGCTACAACGA TCCATGAT 5191 2195 GCUUAAGA A UGCAUCCJ 3906 AGGATGCA GGCTAGCTACAACGA TCTTAAGC 5192 2197 UIJAAGAAU G CAUCCUJG 3907 CAAGGATG GGCTAGCTACAACGA ATTCTTAA 5193 2199 AAGAAUGC A UCCUJGCA 3908 TGCAAGGA GGCTAGCTACAACGA CATTCTT 5.194 2205 GCAUCCJI G CAGGACCA 3905 TGGTCCTG GGCTAGCTACAACrA -AAMGGATGC 5195 2210 CUJUGCAGG A CCAAGGAG 3910 CTCCTTGG GGCTAGCTACAACGA CCTGCAAG 5196 2219 CCAAGGAG A CUAUGtXCU 3911 AGACATAG GGCTAGCTACAACGA CTCCTTGG 5197 2222 AGGAGACU A UGUCtJGCC 3912 GGCAGACA GGCTAGCTACAACGA AGTCTCCT 5198 2224 GAGACtTAU G UCUGCCUU 3913 AAGGCAGA GGCTAGCTACAACAA -ATAGTCTC 5199 2228 CUAUGUCU G CCUUJGCUC 3914 GAGCAAGG GGCTAGCTACAACGA AGACATAG 5200 2233 UCUGCCUU G CUCAAGAC 3915 GTCTTGAG GGCTAGCTACAACGA AAGGCAGA 5201 2240 UGCUCAAG A CAGGAAGA 3916 TCTTCCTG GGCTAGCTACAACGA CTTGAGCA 5202 2248 ACAGGAAG A CCAAGAAA 3917 TTTCTTUG GUCTAGCTACAACGA CTTCCTGT 5203 2259 AAGAAAAG A CAUUGCGU 3918 ACGCAATG GGCTAGCTACAACGA CTTTTCTT 5204 22G1 GAAAAGAC A UUGCC-UGG 3919 CCACGCAA GGCTAGCTACAACGA GTCTTTTC 5205 2264 A.AGACAUU G CGUGGUCA 3920 TGACCACG GOCTAGCTACAAC3A AATGTCTT 5206 2266 GACAUUGC G UGGUCAGG 3921 CCTGACCA GOCTAGCTACAACGA GCAATGTC 5207 2269 AIJUGCGUG G UCAGGCAG 3922 CTGCCTGA GGCTAGCTACAACGA CACGCAAT 5208 2274 GUGGUCAG G CAGCUCAC 3923 GTGAGCTG GOCTAGCTACAACGA CTGACCAC 5209 2277 GUCAGGCA 0 CUCACAGU 3924 ACTUTUAG GGCTAGCTACAACGA TCTGAC 5210 2281 GGCACUCLC A CAGIJCCUA 3925 TAGGACTG GGCTAGCTACAACGA GAGCTGCC 5211 2284 AUCTJCACA G UCCTJAGAG 3926 CTCTAGGA GGCTAGCTACAACGA TGTGAGCT 5212 2292 GUCCUAGA G CGUGUGGC 3927 GCCACACG GGCTAGCTACAACGA TCTAGGAC 5213 2294 CCUAGAGC G UGUG~C3ACI 3928 GTGCCACA GrGCTAGCTACAACGA GCTCTAGG 5214 2296 UAGAGCGU G UGGCACCCI 3.929 12299 29AGCGUGUG G CACCCACGI 3930 GGGTGCCA GGCTAGCTACAACGA ACGCTCTAI 5215 CGTGGGTG GGCTAGCTACAACGA CACACGCTI 5216 WO 02/096927 PCT/US02/17674 2301 CGUGUGGC A CCCACGAU 3931 ATCGTGGG GGCTAGCTACAACGA GCCACACG 5217 2305 UGGCACCC A CGAUCACA 3932 TGTGATCG GGCTAGCTACAACGA 'GGTGCCA 5218 2308 CACCCACG A UCACAGGA 3933 TCCTGTGA GGCTAGCTACAACGA CGTGGGTG 5219 2311 CCACGAUC A CAGGAAAC 3934 GTTTCCTG GGCTAGC'FACAACGA GATCGTGG 5220 2318 CACAGGAA A CCUCGAGA 3935 TCTCCAGG GGCTAGCTACAACGA TTCCTGTG 5221 2327 CCUGGAGA A UCAGACGA 3936 TCGTCTGA GGCTAGCTACAACGA TCTCCAGG 5222 2332 AGAAUCAG A CGACAAGU 3937 ACTTGTCG GGCTrAGCTACAACGA CTGATTCT 5223 2335 AUCAGACG A CAAGUAUU 3938 AATACTTG GGCTAGCTACAACGA CGTCTGAT 5224 2339 GACGACAA G UAUEJGGGG 3939 CCCCAATA GGCTAGCTACAACGA TTGTCGTC 5225 2341 CGACAAGJ A UIJGGGGAA 3940 TTCCCCAA GGCTAGCTACAACGA ACTTGTCG 5226 2351 TJGGGGAAA G CAUCGAAG 3941 CTTCGATG GGCTAGCTACAACGA TTTCCCCA 5227 2353 GrGGAAAGC A UCGAAGOUC 3942 GACTPCGA GGCTAGCTACAAC3A GCTTTCCC 5228 2359 GCAUCGAA G UCUCAUGC 39413 GCATGAGA GGCTAGCTACAACGA TTCGATGC 5229 2364 GAAGUCUC A UGCACGGC 3944 GCCGTGCA GGCTAGCTACAACG2A GAGACTTC 5230 2366 AGUCUCAU G CACGGCAU 3945 ATGCCGTG GGCTAGCTACAACGA ATGAGACT 5231 2368 UCUCAUGC A CGGCAUCU 3946 AGATGCCG GGCTAGCTACAACGA GCATGAGA 5232 2371 CAUGCACG G CAUCUGGG 3947 CCCAGATG GGCTAGCTACAACGA CGTGCATG 5233 2373 UGCACGGC A UCUGGGAA 3948 TTCCCAGA GGCTAGCTACAACGA GCCGTGCA 5234 2381 AUCUGGGA A UCCCCCUC 3949 GAGGGGGA GGCTAGCTACAACGA TCCCAGAT 5235 2391 CCCCCUCC A CAGAUCAU 3950 ATGAPCTG GGCTAGCTACAACGA GGAGGGGG 5236 2395 CUCCACAG A UCAUGUJGG 3951 CCACATGA GGCTAGCTAC2AACGA CTGTGGAG 5237 2398 CACAGAUC A UGUGGUU 3952 AAACCACA GGCTAGCTACAACGA GATCTGTG 5238 2400 CAGAUCAU G UGGUUTUAA 3953 TTAAACCA GGCTAGCTACAACGA ATGATCTG 5239 2403 AUCAUGt2G G UUTUAAAGA 3954 TCTTTAAIA GGCTAGCTACAACGA CACATGAT 5240 2411 GUIJUAAAS A UAAUGAGA 3955 TCTCATTA GGCTAGCTACAACGA CTTTAAAC 5241 2414 UAAAGAUA A UGAGACCC 3956 GGGTCTCA GGCTAGCTACAACGA TATCTTTA 5242 2419 AUAAUGAG A CCCUUGUA 3957 TACAAGGG GGCTAGCTACAACGA CTCATTAT 5243 2425 AGACCCUU G UAGAAGAC 3958 GTCTTCTA GGCTAGCTACAACGA AAGGGTCT 5244 2432 UGUAGAALG A CUCAGGCA 3959 TGCCTGAG GGCTAGCTACAACGA CTTCTACA 5245 2438 AGACUCAG G CAUUGUAU 3960 ATACAATG GGCTAC4CTACAACGA CTGAGTCT 5246 2440 ACUCAGGC A UUGUAUUG 3961 CAATACAA GGCTAGCTACAAkCGA GCCTGAGT 5247 2443 CAGGCAUU G UAUUGAAG 3962 CTTCAATA GGCTAGCTACAACGA AATOCCTG 5248 2445 GGCAUCG A UUGAAGGA 3963 TCCTTCAA GGCTAGCTACAACGA ACAATGCC 5249 2453 AUUGAAGG A UGGGAACC 3964 GGTTCCCA GGCTAGCTACAACGA CCTTCAAT 5250 2459 GGAUGGGA A CCGGAACC 39G5 GGTTCCGG GGCTAGCTACAACGA TCCCATCC 5251 2465 GAACCGGA A CCUCACUA 3966 TAGTGAGG GGCTAGCTACAACGA TCCGGTTC 5252 2470 GGAACCUC A CUAUCCGC 3967 GCGGATAG GGCTAGCTACAACGA GAGGTTCC 5253 2473 ACCUCACJ A UCCGCAGA 3968 TCTGCGGA GGCTAGCTACAACGA AGTGAGGT 5254 2477 CACUAUCC G CAGAGUGA 3959 TCACTCTG GGCTAGCTACAACGA GGATAGTG 5255 2482 UCCGCAGA G UGAGGAALG 3970 CTTCCTCA GGCTAGCTACAACGA TCTGCGGA 5256 2495 GAAGGAGG A CGAAGGCC 3971 GGCCTTCG GGCTAGCPACAACGA CCTCCTTC 5257 2501 GGACGAAG G CCUCUACA 3972 TGTAGAGG GGCTAGCTACAACGA CTTCGTCC 5258 2507 AGGCCUCU A CACCIJGCC 3973 GGCAGGTG GGCTAGCTIACAACGA AGAUCCT S259 2509 GCCUCUAC A CCUGCCAG 3974 CTGGCAGG GGCTAGCTACAACGA GTAGAGGC 5260 2513 CUACACOG G CCAGGCAU 3975 ATGCCTGG GGCTAGCTACAACGA AGGTGTAG 5261 2518 CCUGCCAG 0 CAUGCACU 3976 ACTGCATG GGCTAGCTACAACGA CTGGCAGG 5262 2520 UCCAGGC A UGCAGUGU 3977 ACACTGCA GGCTAGCTACAACGA GCCTGGCA 5263 2522 CCAGGCAU G CAGUGUUC 3978 GAACACTG GGCTAGCTACAACGA ATGCCTGG 5264 2525 GG3CAUGCA G UGUUCUUG 3979 CAAGAACA GGCTAGCTACAACGA TGCATGCC 5265 2527 CAUGCAGU G UUtGC3 39 80 GCCAALGAA GGCTAGCTACAACGA ACTGCATG 5266 2534 UGUICOTG G CUGUGCALA 3981 ITTGCACAG GGCTAGCTACAACCA CAAGAACAJ 5267 2537 [UCUUGGCU G UGCAAAAG 2539 [UTGGCUGU G CA2AAALG 3982 CTTTTGCA GGCTAGCTACAACGA AGCCAAGA j5268 CACTTTTG GOCTAGCTACAACGA ACAGCCAA j5269 WO 02/096927 PCT[US02/17674 2545 GUGCAA~ G UGGAGGCA 3984 TGCCTCCA Gt3CTAGCTACAACGA, TTTTGCAC 5270 2551 AGUGGAG G CAUUUTJUC 3985 GAAAAATG GGCTAGCTACAACGA CTCCACTT S271 r2-553 GUGGAGGC A UUUERJCAU 3986 ATGAAAAA GGCTAGCTACAACGA GCCTCCAC 5272 2560 CAtUIJOUC A UAAUAGAA 3987 __TTCTATTA GGCTAGCTACAACGA GAAAAATG 5273 25-63 UUUEJCAUA A UAGAAGGU 3988 ACCTTCTA GGCTAGCTACAACGA TATGAAAA 5274 2570 AAUAGAAG G TJGCCCAGG 3989 CCTGGOCA GGCTAGCTACAACGA CTTCTATT 5275 2572 UAGAAGGUJ G CCCAGGAA 3990 TTCCTOGG tGCTAGCTACAACGA ACCTTCTA 5276 2584 AGGAAAAG A CGAACUUJG 3991 CAAGTTCG GGCTAGCTACAACGA CTTTTCCT 5277 2588 AAAGACGA A CUEJGGAAA 3992 TTTCCAAG GGCTAGCTACAACGA TCGTCTTT 5278 2596 ACUUGGAA A UCAUJAIU 3993 AATAATGA G3GCTAGCTACAACGA TTCCAAGT 5279 2599 UGGAAAUC A UUJAUUCUA 3994 TAGAATAA GGCTAGCTACAACGA GATTTCCA 5280 2602 AAAUCAUU A UIJCUAGUA 3995 TACTAGAA GGCTAGCTACAACGA AATGATTT 5281 2608 UJTAUUCUA G UAGGCACG 3996 CGTGCCTA GGCTAGCTACAACGA TAGAATAA 5282 2612 UCtJAGUAG G CACGGCGG 3997 CCGCCGTG GGCTAGCTACAACGA CTACTAGA 5283 2614 UAGtYAGGC A CGGCGGXG 3998 CACCGCCG GGCTAGCTACAACGA GCCTACTA 5284 2617 UAGGCACG G CGGJGATJU 3999 AATCACCG GGCTAGCTACAACGA CGTGCCTA 5285 2620 GCACGGCG G UGAUTJGCC 4000 GG3CAATCA GCTAGCTACAACGA CGCCGTGC 5286 2623 CGGCGGUG A TYJGCCAUG 4001 CATGGCAA GGCTAGCTACAACGA CACCGCCG 5287 2626 CGGUGAULJ G CCAUGUJC 4002 GALACATGG GGCTAGCTACAACGA AATCACCG 5288 2629 UGAUJTJCC A UGTJUCULC 4003 GAAGAACA GGCTAGCTACAACGA GGCAATCA 5289 2631 ATJGCCAJ G UUCEUUCUG 4004 CAGAAGAA GGCTAGCTACAACGA ATGGCAAT 5290 2640 UUCIJUCUG G CUACLUCU 4005 AGAAGTAG GGCTAGCTACAALCGA CAGAAc3AA 5291 2643 UTJCUGGCTJ A CUtJCCUGU 4006 ACAAGAAG GGCTAGCTACAACGA AGCCAGAA 5292 2650 UACTUCUUJ G UCAUCAUC 4007 GATGATGA GGCTAGCTACAACGA AAGAAGTA 5293 2653 UUCIJUGUC A UCAUCCTJA 4008 TAGGATGA GGCTAGCTACA&CCA GACAAGAA 5294 2656 UUGUCAUC A UCCUACGG 4009 CCGTAGGA GGCTAGCTACAACGA GATGACAA 5295 2661 AUCAUCCJ A CGGACCGU 4010 ACGGTCCG CGCTAGCTACAALCOA ACGATOAT 5296 2665 UCCUACGG A CCGUUAAG 4011 CTTAACGG C-GCTAGCTACAACGA CCGTAGGA 5297 2668 UACGGACC G UUAAGCGG 4012 CCGCTTAA GGCTAGCTACAACGA GGTCCGTA 5298 2673 ACCUJA G CGGGCCAA 4013 TTGGCCCG GGCTAGCTACAACGA TTAACGGT 5299 2677 UUAAGCCG G CCAAUGGA 4014 TCCATTGG GGcCTAGCTACAACGA CCGCTI'AA 5300 2681 GCGGGCCA A UGGAGGGG 4015 CCCCTCCA GGCTAGCTACAACGA TGCCCCC 5301.

2691 Cc3Ac3CGA A CUGA-AGAC 4016 GTCTTCAG C-CCTAGCTACAACGA TCCCCTCC 5302 2698 AACUGAAG A CAGGCUAC 4017 GTAGCCTG GGCTAGCTACAACGA CTTC-ACTT 5303 2702 GAAGACAG G CUACtJUGU 4018 ACAAGTAG GGCTAGCTACAALCGA CTGTCTTC 5304 2705 GACAGGCU A CLTJXGUCCA 4019 TGGACAAG GGCTAGCTACAACGA AGCCTGTiC 5305 2709 GGCUACUU G UCCAUCGU 4020 ACGATGGA GGCTAGCTACAACGA AAGTAGCC 5306 2713 ACLJUGUCC A UCGUCAUG 4 021 CATG3ACGA GGCTAGCTACAACCA GGACAAGT 5307 2716 UGUCCAUC G UCAUGGAU 4022 ATCCATGA GGCTAGCTACAACGA GATGGACA 5308 2719 CCAUCGUC A UGGAUCCA 4023 TGGATCCA GGCTAOCTACAACOA GACGATGG 5309 2723 CGUCALICC A UCCAGAUG 4024 CATCTGGA GGCTAGCTACAACOA 'OCATGACG 5310 2729 GGAUCCAG A UGAACUCC 4025 GGAGTTCA CGCTAGCTACAACCA CTGGATCC 5311 2733 CCACAUGA A CUCCCAUU 4026 AATCCCAG CGCTAC3CTACAACCA TCATCTGG 5312 273.9 GAACUCCC A UEJGGAUGA 4027 TCATCCAA CGCTAGCTACAACGA GGGAGTTC 5313 2744 CCCAUUCC A UGAACAUh 4028 AATGTTCA CCCTAGCTACAACCA CCAATGGG 5314 2748 UTJCCAUGA A CAUEJGUGA 4029 TCACAATG GGCTAGCTACAACCA TCATCCAA 5315 2750 GGAUGAAC A UUGUCLAAC 4030 CTTCACAA GGCTAGCTACAACGA CTTCATCC 5316 2753 UGAACAUU G UGAACCAC 4031 GTCGTTCA GGCTACACAACGA AATGTTCA 5317 2757 CAUtJGUGA A CGACUJGCC 4032 GGCAGTCG CG3CTAGCTACAACGA TCACAATG 5318 2760 UGUGAACG A CUGCCUUA 4033 TAAGGCAG GGCTAGCTACAACGA CGTTCACA 5319 2763 ICAACG3ACU G CCUtJAUGA~ 4034 TCATAAGG GGCTAGCTACAACGA AGTCGTTC 2771 [CGCUU A UGCAGCCA 4036 TGCTCA GGCTAGCTACAALCGA AAGAC 2768 [ACEJCtU A UGCAGCA 4035 [TGGCTCA CGCTACCTACAACGA AAGGCAGT 5320 5321 5322 WO 02/096927 PCT/US02/17674 2773_ CUTJAUGAU G CCAGCAAA 4037 TTTGCTGG GGCTAGCTACAACGA ATCATAAG 5323 2777 UGAUGCCA G CAAAUGGG 4038 CCCATTTG GGCTAGCTACAA2GA TGGCATCA 5324 2781 GCCAGCAA A UGGGAAJU 4039 AATTCCCA GGCTAGCTACAACGA TTGCTGGC 5325 2787 AAAUGGGA A tUUCCCCAG 4040 CTGGGGAA GGCTAGCTACAACGA TCCCATTT 5326 2798 CCCCAGAG A CCGGCt3GA 4041 TCAGCCGOCGCCTAGCTACAACCA CTCTCCCG 5327 2802 AGAGACCG G CTJGAAGCU 4042 AGCTTCAG GGCTAGCTACAACGA CGGTCTCT 5328 2808 CGGCUGAA G CUAGGT3AA 4043 TTACCTAG GGCTAGCTACAACGA TTCAGCCG 5329 2813 GAAGCUAG G tJAAGCCUC 4044 GAGGCTTA GGCTAGCWACAACGA CTAGCTTC 5330 2817 CUAGGUAA G CCUCUJGG 4045 CCAAGAGG GGCTAGCTACAACGA TTACCTAG 5331 2825 GCCUCUUG G CCGUGGUG 4046 CACCACGG GGCTAGCTACAACGA CAAGAGGC 5332 2828 UCIJUGGCC G UGGUGCCU 4047 AGGCACCA GGCTAGCTACAACGA GGCCAAGA 5333 2831 UGCC8U G UGCCIUUGJ 4048 CAAAGCCCA GGCTAGCTACAACGA CACGGCCA 5334 2833 GCCGUGGU G CCUUEJGGC 4049 GCCAAAGG GGCTAGCTACAACGA ACCACGGC 5335 2840 UGCCUUUG G CCAAGUGA 4050 TCACTTGG GGCTAGCTACAACGA CAAACGCA 5336 2845 UUGGCCAA G tJGAUUGAA 4051 TTCAATCA GGCTAGCTACAACGA TTGGCCAA 5337 2848 GCCAAGUG A UUJGAAGCA 4052 TGCTTCAA GGCTAGCTACAACGJA CACTTGGC 5338 2854 IJCAUIJGAA G CAGAUGCC 4053 GGCATCTG GGCTAGCTACAACGA TTCAATCA 5339 285B UGAAGCAG A UGCCUUUTG 4054 CAAAGGCA GGCTAGCTACAACG-A CTGCTTCA 5340 2860 AAGCAGAU G CCUUUGGA 4055 TCCAAAGG GGCTAGCTACAACGAZ ATCTGCTT 5341 2869 CCUUEJGGA A UEJ2ACAAG 4056 CTTCTCAA GGCTAGCTACAACGAk TCCAAAGG 5342 2873 IJGGAAUUG A CAAGACAG 405'! CTGTCTTG' GGCTAGCfACAACGA CAA-TTCCA 5343 2878 UU~GACAAG A CAGCAACU 4058 AGTTGCTG GGCTAGCTACAACGA CTTGTCAA 5344 2681 ACAAGACA G CAACUUGC 4059 GCAAGTTG GGCTAGCTPACAACGA TGTCTTGT 5345 2884 AGACACCA A CUUGCAGG 4060 CCTCCAAC GGCTACCTACAACGA TGCTGTCT 5346 2889 AGCAACUtJ G CAGGACAG 4061 CTGTCCTC GCCTACCTACAACCA AACTTCT 5347 2E93 CUUGCAGG A CAGUAGCA 4062 TGCTACTG GGCTAGCPACAACGA CCTGCAAC 5348 2896 GCAGGACA G UAGCAGJC 4063 GACTGCTA GGCTAGCTACAACGA TGTCCTGC 5349 2899 GGACAGUA G CAGUCAAA 4064 TTTGACTG GGCTAGCTACAACGA TACPGTCC 5350 2902 CAGGCA G UCAAAAJG 4065 CATTTTGA GGCTAGCTACAACGA TGCTACTG 5351 2908 CAGCA~AA A TJCUAAA 4066 TTTrAACA GGCTACACAACGA TTTGACTG 5352 2910 GUCAAAAU G UUGJAAAGA 4067 TCTTTCAA GGCTAGCTACAACGA ATTTTGAC 5353 2923 AAGAAGGA G CAACACAC 4088 GTGTGTTG GGCTAGCTACAACGA TCCTTCTT 5354 2928 AAGGAGCA A CACACAGU 4089 ACTGTGTG GCCTAGCTrACAACCA TOCTCCTT 5355 2928 GGAGCAAC A CACAGUGA 4070 TCACTGTG GGCTAGCTACAACGA GTTGCTCC 5358 2930 ACCAACAC A CAGUCACC 4071 GCTCACTG GGCTAGCTACAACGA GTCTCCT 5357 2933 AACACACA G UGAGCAJC 4072 GATGCTCA CGCTACCTACAACGA TCGTGTT 5358 2937 CACAGUGA G CAUCGAGC 4073 GCTCGATG GGCTAGCTACAACGA TCACTGTG 5359 2939 CAGUGAGC A UCGAGCUC 4074 GAGCTCGA GGCTAGCTACAACGA GCTCACTG 5360 2944 ACCAUGGA G CUCUCAUG 4075 CATGAGAG GGCTAGCTACAACGA TCGATGCT 5361 2950 GACCUCUC A UGUCUGAA 4078 TTCAGACA GGCTAGCTACAACGA GAGAGCTC 5382 2952 GCUCtJCAU G UCUGAACU 4077 AGTTCAGA GGCTAGCTACAACGA ATGAGAGC 5363 2958 AUGUCUCA A CUCAAGAU 4078 ATCTTCAG GGCTALGCTACAACGA TCAGACAT 5384 2988 AACUCAAG A UCCUCAUJ 4079 AATGAGGA GGCTAGCTACAACGA CTTGAGTT 5385 2971 AGAUCCUC A UEJCAUAUJ 4080 A8.TATGAA GGCTAGCTACAACGA GAGGATCT 5388 2975 CCUCAUUC A UAUUGGUC 4081 GACCAATA GGCTAGCTACAACGA GAATGACG 5387 2977 UCAEAJCAU A IUtJCUCAC 4082 GTGACCAA GGCT-AGCTACAACCA ATGAATGA 538 2981 UCAUAUUG G UCACCAUC 4083 GATGGTGA GGCTAGCTACAACGA CAATATGA 5389 2984 UAUTJGGUC A CCAUCUCA 4084 TGAGATGG GGCTAGCTACAACGA GACCAATA 5370 2957 UGGUCACC A UCUCAAUG 4085 CATTGAGA GGCTAGCTACAACGA GGTGACCA 5371 2993 CCAUCUCA A UGUGGUCA 4088 TGACCACA GGCTAGCTACAACGA TGAGATGG 5372 2995 AUCUCAAU C UGCUOAAC 4087 CTTGACCA GGCTAGCTACAACCA ATTGAGAT 5372 2998JUCAAUGUG G UCAACCUU 4088 AACGTTGA GGCTAGCTACAACGA CACATTGA 5:374 3002JUGUGOUCA A CCUUCUAG 4089 CTAGAAGG GCCTAGCTACAACGA TGACCACA 5275 WO 02/096927 PCT[US02/17674 302 CCUUTCUAG G UGCCUGUA 4090 TACAGGCA GGCTAGCTACAACGA CTAGAAGG 5376 3013 tJOCUACGU G CCUGTJACC 4091 GG3TACAGG GOCTAGCTACAACGA ACCTAGAA 5377 3017 AGGUGCCU G UACCPAGC 4092 GCTIT3GTA GGCTAGCTACAACGA Ac3GCACCT 5378 3019 GUGCCUGU A CCAAGCCA 4093 TGGCTTGG GGCTAGCTACAACGA ACAGGCAC 5379 3024 UGUACCAA G CCAGGAGG 4094 CCTCCTGG GGCTAGCTACAACGA TTGGTACA 5380 3033 CCAGGAGG G CCACUJCAU 4 0 95 ATGAGTGG GGCTAGCTACAACGA CCTCCTGG 5381 3036 GGAGGGCC A CUCAUGGU 4096 ACCATGAG GG.CTAGCTACAACGA '2GCCCTCC 5382 3040 GGCCACUC A UGGIGAUJ 4097 AATCACCA GGCTAGCTACAACGA GAGTGGCC 5383 3043 CACUCAUG 9 UGAUUGUG 4098 CACAATCA GOCTAGCTACAACGA CATGAGTG 5384 3046 UCAUGGUG A UtJGUGGAA 4099 TTCCACAA GGCTAGCTACAACGA CACCATGA 5385 3049 UGGUGAUUG UGGAAUJC 4100 GAATTCCA GOCTAGCTACAACGA AATCACCA 538G 3054 AUUGUGGA A UTJCUCCAA 4101 TTGCAGAA GGCTAGCTACAACGA TCCACAAT S387 3059 GGAAUUCU G CAAAUTJG 4102 CAAATTTG GGCTAGCTACAACGA AGAATTCC 5388 3063 TJUCUGCAA A tJIIEGGAAA 41D3 TTTCCAAA GOCTAGCTACAACGA TTGCAGAA 5389 3071 AUUEJGGAA A CCUGUCCA 4104 TGGACAGG GOCTAGCTACAACGA TTCCAAAT 5390 3075 GGAAACCU G UCCACUUA 4105 TAAGTGGA GGCTAGCTACAACGA AGGTTTCC 5391 3079 ACCUGUCC A CUUACCUG 4106 CAGGTAAG GGCTAGCTACAACGA GGACAGOT 5392 3083 GUCCACUU A CCUGAGGA 4107 TCCTCAGG GGCTAGCTACAACGA AAGTGGAC 5393 3092 CCUGAGGA G CAAGAGAA 4108 TTCTCTTG GOCTAGCTACAACGA TCCTCAGG 5394 3101 CAAGAGAA A UGAAUWtG 4109 CAAAkTTCA GSCTAGCTACAACGA TTCTCTTG 5395 3105 AGAAAJGA A UTJUGUCCC 4110 GGGJACAAA GGCTAGCTACAACGA TCATTTCT 539G 3109 AUGAAUUU G UCCCCUAC 4111 GTAGGGGA GrCTAGCTACAACGA AAATTCAT 5397 3116 tJGUCCCCU A CAAGACCA 4112 TGGTCTTG GGCTAGCTACAACGA AGGGGACA 5398 3121 CCUACAAG A CCAALAGGG 4113 CCCTTTGG GOCTAGCTACAACGA CTTGTAGG 8399 3130 CCAAAGGG G CACGJAUUJC 4114 GAATCGTG GOCTAGCTACAACGA CCCTTTGG 5400 3132 AAAGGGGC A CGAUCUCCG 4115 CGGALATCG GGCTAGCTACAACGA GCCCCTTT 5401 3135 GGGGCACG A UUCCGUCA 4116 TGACGGAA G3CTAGCTACAACGA CGTGCCCC 5402 3140 ACGAUUCC G UCAAGGGA 4117 TCCCTTGA GOCTAGCTACAACGA GGAATCGT 5403 3152 AGGGAAAG A CUACGUUG 4118 CAACGTAG GOCTAGCTACAACGA CTTTCCCT 5404 3155 GAAACACU A CGUUGGAG 4119 CTCCAACG G3CTAGCTACAACGA AGTCTTTC 5405 3157 AAGACUAC G UUGGAGCA 4120 TGCTCCAA G3CTAGCTACAACGA GTAGTCTT 5406 3163 ACGUUGGA G CAAUCCCU 4121 AGGGATTG G3CTAGCTACAACGA TCCAACGT 5407 31GG UUGGAGCA A UCCCT3GUG 4122 CACAGGGA GGCTAGCTACAACGA TGCTCCAA 5408 3172 CAAUCCCU G UGGATJCUG 4123 CAGATCCA GOCTAGCTACAACGA AGGGATTG 5409 31.76 CCCUGUGG A UCUGAAAC 4124 GTTTCAGA GG.CTAGCTACAACGA CCACAGGG 5410 3183 GAUCUGAA A CGGCGCUU 42.25 AAGCGCCG GGCTAGCTACAACGA TTCAGATC 5411 3186 CUGAAACG G CGCTTGGA 4126 TCCAAGCG G3CTAGCTACAACGA CGTTTCAG 5412 32.88 GAAACGGC G CUUGGACA 4127 TGTCCAAG GOCTAGCTACAACGA GCCGTTTC 5413 3194 GCGCUUC3G A CAGCAUCA 4128 TGATGCTG GGCTAGCTACAACGA CCAAGCGC 5414 3197 CUtIGGACA G CAUCACCA 4129 TGGTGATG GTCTAGCTACAACGA TGTCCAAG 5415 3199 UGGACAGC A UCACCAGJ 4130 ACTGGTGA GGCTAGCTACAACGA GCTGTCCA 5416 3202 ACAGCAUC A CCAGUAGC 4132. GCTACTGG G3CTAGCTACAACGA GATGCTGT 5417 3206 CATJCACCA G UAGCCAGA 4133 TCTGGCTA GOCTAGCTACAACGA TOSTOATS 5418 3209 CACCAGUA G CCAGAGCU 4133 AGCTCTGG GO2CTAGCTACAACGA TACTGGTG 5419 3215 UAGCCAGA G CUCAGCCA 4134 TGGCTGAG GOCTAGCTACAACGA TCTGGCTA 5420 3220 AGASCUCA G CCAGCUCU 4135 AGAGCTGG GG.CTAGCTACAACGA TGAGCTCT 5421 3224 CUCAGCCA G CUCUSGAU 4136 ATCCAGAS GCTAGCTACAACGA TGGCTGAG 5422 3231 AGCUCUGG A UUUGUGSA 4137 TCCACAAA GGCTAGCTACAACGA CCAGAGCT 5423 3235 CUGGAUUU G UGGASSAG 4138 CTCCTCCA GGCTAGCTACAACSA AAATCCAG 5424 3246 GAGGAGAA G UCCCUCAG 4139 CTGAGGGA GGCTAGCTACAACGA TTCTCCTC 5425 3254 CUCCCUCA G UGAUGUAG 4140 CTACATCA GGCTAGCTACAACGA TGAGGGAC 5426 3257 COUCAGUG A UGUAGAAG 4141 CTTCTACA GGCTAGCTACAACGA CACTGAGG 5427 3259 CCAGUGAU G UAGAA3AA 4142 TTCTTCTA GGCTAGCTACAACGA ATCACTGAI 5428 WO 02/096927 PCT[US02/17674 3274 AAGAGGAA G CUCCUGAA 4143 TTCAGGAG GGCTAGCTACAACGA TTCCTCTT 5429 3284 UCCIJGAAG A UCUGUAJA 4144 TATACAGA GGCTAGCTACAACGA CTTCAGGA 5430 3288 GAAGAUCU G UAUAAGGA 4145 TCCTTATA GGCTAGCTACAACGA AG3ATCTTC 5431 3290 AGAUCUGJ A UAAGGACU 4146 AGTCCTTA GGCTAGCTACAACGA ACAGATCT 5432 3296 GLTATAAGG A CLUJCCUGA 4147 TCAGGAAG GGCTAGCTACAACGA CCTTATAC 5433 3304 ACLOUCCUG A CCULTGGAG 4148 CTCCAAGG GGCTAGCTACAACGA CAGGAAGT 5434 3312 ACCUEJGGA G CAUCUCAU 4149 ATGAGATG GGCTAGCTACAACGA TCCAAGOT 5435 3314 CUUGGAGC A UCUCAUCU 4150 AGATGAGA GGCTAGCTACAACGA GCTCCAAG 5436 3319 AGCAUCUC A UCUGUUAC 4151 GTAACAGA GGCTAGCTACAACCA GAGATGCT 5437 3323 UCUCAUCJ G UUACAGC 4152 AGCTGTAA GGCTAGCTACAACGA AGATGAGA 5438 3326 CAUCUGUJ A CAGCUUCC 4153 GG0AAGCTG GGCTAGCTACAACGA AACAGATG 5439 3329 CUGUIJACA 0 CITECCAAG 4154 C T3GAAG GGCTAGCTACAACGA TGTAACAG 5440 3337 GCUUCCAA G UGGCUAAG 4155 CTTAGCCA GGCTAGCTACAACGA TTGGAAGC 5441 3340 UCCAAGUG G CUAAGGGC 4156 GCCCTTAG GGCTAGCTACAACGA CACTTGGA 5442 3347 GGCtTAAGG G CAUGGAGU 4157 ACTCCATG GGCTAGCTACAACGA CCTTAGCC 5443 3349 CUAAGGGC A UGGAGUJC 4158 GAACTCCA GGCTAGCTACAACGA GCCCTTAG 5444 3354 GGCAUGGA G UTJCUUIGGC 4159 GCCPAGAA GGCTAGCTACAACGA TCCATGCC 5445 3361 AGIJUCCUG G CAUCGCGA 4160 TCGCGATG GGCTAGCTACAACGA CAAGAACT 5446 3363 UIJCUUGGC A UCGCGAAA 4151 TTTCGCGA GGCTAGCTACAACGA GCCAAGAA 5447 3366 UUGGCAUC G CGAAGG 4162 CACTTTCG GGCTArGCTACAACGA GATGCCAA 5448 3372 UCGCGAAA G UGUAUJCCA 4163 TGGATACA GGCTAGCTACAACGA TTTCGCGA 5449 3374 GCGAAAGU G UAUCCACA 4164 TGTGGATA GGCTAGCTACAACGA ACTTTCGC 5450 3376 GAAAGUGU A IJCCACAGG 4166 CCTGTGGA GGCTAGCTACAACGA ACACTTTC 5451 3380 GUGtTAUCC A CAGGGACC 4166 GGTCCCTG GGCTAGCTACAACGA GGATACAC 5452 3386 CCACAGGG A CCUCCCGG 41657 CCGCCAGG GGCTAGCTACAACGA CCCTGTCC 5453 3391 GGGACCUG G CGGCACGA 4168 TCGTGCCG GGCTAGCTACAACGA CAGGTCCC 5454 3394 ACCUGGCG G CACGAAAU 4169 ATTTCGTG GGCTAGCTACAACGA CCCCACCT 5455 3396 CUGGCGGC A CGAAAUAU 4170 ATATTTCG GGCTAGCTACAACGA GCCGCCAG 5456 3401 GGCACGAA A UAUCCUCU 4171 AGAGGATA GGCTAGCTACAACGA TTCGTGCC 5457 3403 CACGAAAU A UCCUCUUA 4172 TA-AGAGGA GGCTAGCTACAACGA ATTTCGTG 5458 3411 AUCCJCUJ A UCGGAGAA 4173 TTCTCCGA GGCTAGCTACAACGA AAGAGGAT 5459 3422 GGAGAAGA A CGUGGUUA 4174 TAACCACG GGCTAGCTACAACGA TCTTCTCC 5460 3424 AGAACAAC G UC3GOIAAA 4175 TTTAACCA GGCTAGCTACAACGA GTTCTTCT 5461 3427 AGAACGUG G UtJAAAAUC 4176 GATTTTAA GGCTAGCTACAACGA CACGTTCT 5462 3433 UGGtJUAAA A UCtJGUGAC 4177 GTCACAGA GGCTAGCTACAACGA TTTAACCA 5463 3437 UAAAAUCU G UGACULUJG 4178 CAAAGTCA GGCTAGCTACAACGA AGATTTTA 54654 3440 AAUCtJGUG A CUUtJGGCU 4179 AGCCAAAG GGCTAGCTACAACGA CACAGATT 5465 3446 UGACUUUG G CUUGGCCC 4180 GGGCCAAG CCTAGCTACAACGA CAAACTCA 5466 3451 UEJGGCUJUG G CCCGGGAU 4181 ATCCCGGG GGCTAGCTACAACGA CAAGCCAA 5467 3458 GGCCCGGG A UAUUAUA 4182 TATAAATA GGCTAGCTACAACGA CCCGGGCC S468 3460 CCCGC3GAJ A TUUAUAAA 4183 TTTATAAA GGCTAGCTACAACGA ATCCCGGG 5469 3464 GGAUAUUU A UAAAGAUC 4184 GATCTTTA GGCTAGCTACAACGA AAATATCC 5470 3 47 0 UIJAUAAAG A UCCAGAUtJ 4185 AATCTGGA GOCTAGCTACAACGA CTTTATAA 5471 3476 AGAUCCAG A UUAIJGUCA 4186 TGACATAA GGCTAGCTACAACGA CTGGATCT 5472 3479 UCCAGALTU A UGUCAGAZ- 4187 TTCTGACA G'CCTAGCTACAACGA AATCTGGA 5473 3481 CAGAUUAU G UCAGAAAA 4188 TTTTCTGA GGCTAGCTACAACGA ATAATCTG 5474 3494 AAAAGGAG A TJGCUCGCC 4189 GGCGAGCA GOCTAGCTACAACGA CTCCTTTT 5475 3495 AAGGAGAU 0 CUCGCCUC 4190 GAGCCGAC CCTAGCTACAACGA ATCTCCTT 5476 3 5 00 AGAUGCUC G CCUCCCU{J 4191 AAGGGAGG GGCTAGCTACAACCA GAGCATCT 5477 3513 CCUUtUGAA A UGGAU3GC 4192 GCCATCCA GGCTAGCTACAACGA TTCAAAGG 5478 3517 UGAAAUCG A IJGGCCCCA 4193 TGGGGCCA GOCTAGCTACAACGA CCATTTCA 5479 3520 AGGAUG G CCCCAGAA 4194 TTCCGGGG GGCTAGCTACAACGA CATCCATT 5480 3529 CCCCAGAA A CAAUTTJtJ 4195 1AAAAATTG GGCTAGCTACAACGA :TCTGGGG 5481 WO 02/096927 PCT/US02/17674 3532 CAGAAACA A UUUTJUGAC 419G GTCAAAAA GGCTAGCTACAACGA TGTTTCTG 5482 3539 AAUULTJUG A CAGAGUGU 4197 ACACTCTG~ GGCTAGCTACAACGA CAAAAATT 5483 3544 UUIGACAGA G UGIJACACA 4198 TGTGTACA GGCTAGCTACAACGA TCTGTCAA 5484 3546 GACAGAGU G UACACAAU 4199 ATTGTGTA GGCTAGCTACAACGA ACTCTGTC 5485 3548 CAGAGUGU A CACAAUCC 4200 GGATTGTG GGCTAGCTACAACGA ACACTCTG 5486 3550 GAGUGEJAC A CAAXJCCAG 4201 CTGGAITG GGCTAGCTACAACGA GTACACTC 5487 3553 UGIJACACA A UCCAGAGU 4202 ACTCTGGA GGCTAGCTACAACGA TGTGTACA 5488 3540 AAUCCAGA G UGACGUCU 4203 AGACGTCA GGCTAGCTACAACGA TCTGGATT 5489 3563 CCAGAGLTG A CGTJCUGGU 4204 ACCAGACG GGCTAGCTACAACGA CACTCTGO 5490 3565 AGAGUGAC G UCIJGGUCtY 4205 AGACCAGA GGCTAGCTACAACGA GTCACTCT 5491 3570 GACGUCUG G UCUEJUUGG 4206 CCAAAAGA GGCTAGCTACAACGA CAGACGTC 5492 3578 GUCUfJG G UGUUUJGC 4207 GCAAAACA GGCTAGCTACAACGA CAAAAGAC 5493 3580 CUEUTJGGU G TJUUTGCUG 4208 CAGCAAAA GGCTAGCTACAACGA ACCAAAAG 5494 358S SGU~GI1hU G CUUGJGGA 4209 TCCCACAG GGCTAGCTACAACGA AAAACACC 5495 3588 UUUUGCU G UGGGAAAU 4210 ATTTCCCA GGCTAGCTACAACGA AGCAAAAC 5496 3595 UGUGGGAA A UAUUULJCC 4211 GGAAAATA GGCTAGCTACAACGA TTCCCACA 5497 3597 UGGGAAAU A UUUUCCUY 4212 AAGGAAAA GGCTAGCTACAACGA ATTTCCCA 5498 3608 IJUCCUUAG G UGCUUCUC 4213 GAGAZXGCA GGCTAGCTACAACGA CTAAGGAA 5499 3610 CCUUAGGU G CUUCUCCA 4214 TGGAGAAG GGCTAUCTACAACGA ACCTAAGG 5500 3618 GCUtJCUCC A UAUCCIYGG 4215 CCAGGATA GGCTAGCTACAACGA GGAGAAGC 5501 3620 LTUCUCCAU A UCCTJGGGG 4216 CCCCAGGA GGCTAGCTACAACGA ATGGAGAA 550_2 3628 AUCCUGGG G UAAAGAUU 4217 AATCTTTA GGCTAGCTACAACGA CCCAGGAT 5503 3634 GGGUAAAG A UUGAUGAA 4218 TTCATCAA GGCTAGCTACAACGA CTTTACCC 5504 3 63 8 AAAGAUJG A UGAAGAAU 4219 ATTCTTCA GGCTAGCTACAACGA CAATCTTT 5505 3645 GAUGAAGA A MUG~3UAG 4220 CTACAAAA GGCTAGCTACAACGA TCTTCATC 5506 3650 AGAAUTJU G UAGGCGAU 4221 ATCGCCTA GGCTAGCTACAACGA AAAATTCT 5507 3654 UUUUAG G CGAUUGAA 4222 TTCAATCG GGCTAGCTACAACGA CTACAAAA 5508 3657 LTGUAGGCG A UUGAAAGA 4223 TCTTTCAA GGCTAGCTACAACGA CGCCTACA 5509) 3670 AAGAAGUA A CUAGAAUG 4224 CATTCTAG GCCTAGCTACAACGA TCCTTCTT 5510 36 CAACUACA A UGACUCCC 4225 GGCCCTCA OCCTAUCTACAACGA TCTAGTTC 5511 3682 GAAUGAGG G CCCCUGAU 4226 ATCAGGGG GGCTAGCTACAACGA CCTCATTC 5512 3689 GGCCCCUG A UUAUACUA 4227 TAGTATAA GGCTAGCTACAACGA CAGGGGCC 5513 3592 CCCUGAUJ A UACUACAC 4228 GTGTAGTA GGCTAGCTACAACGA AATCAGGG 5514 3594 CUGAUtJAU A CUACACCA 4229 TGGTGTAG GGCTAGCTACAACGA ATAATCAG 5515 3597 ATJTAUACU A CACCAGAA 4230 TTCTGGTG GGCTAGCTACAACGA A9TATAAT 5514 3599 UAUACUAC A CCAGAAAJ 4231 ATTTCTGG GGCTAGCTACAACGA GTAGTATA 5517 3706 CACCAGAA A UGLIACCAG 4232 CTGGTACA GGCTAGCTACAACGA TTCTGGTG 5518 3708 CCAGAAAU G UACCAGAC 4233 GTCTGGTA GGCTAGCTACAACGA ATTTCTGG 5519 3710 AGAAAUGU A CCAGACCA 4234 TGGTCTGG GGCTAGCTACAACGA ACATTTCT 5520 3715 UGUACCAG A CCAUGCUG 4235 CAGCATUG GUCTAGCTACAACGA CTUU'rACA 5521 3718 ACCAGACC A UGCUGGAC 4236 GTCCAGCA GGCTAGCTACAACGA GCTGG 5522 3720 CAGACCAU G CUGGACUG 4237 CAGTCCAG GGCTAGCTACAACGA ATGGTCTG 5523 3725 CAUGCUGG A CUGGUGGC 4238 GCCAGCAG GGCTAGCTACAACGA CCAGCATG 5524 3728 GCUGGACU G CUGGCACG 4239 CUTGCCAG GGCTAGCTACAACGA AGTCCAGC 5525 3732 GACUGCUG G CACGGGGA 4340 TCCCCGTG UUCTAGCTACAACGA CAGCAGTC 5526 3734 CUGCUGGC A CGGGGAGC 4241 GCTCCCCG GGCTAGCTACAACGA GCCAGCAG 5527 3741 CACGGA G CCCAGUCA 4242 TGACTGGG GGCTAGCTACAACGA TCCCCGTG 5528 3746 GGAUCCCA G UCAGAGAC 4243 GTCTCTGA GGCTAGCTACAACGA TGGGCTCC 5529 3753 AGUCAGAG A CCCACGUUT 4244 AACGTGGG GGCTAGCTACAACGA CTCTGACT 5530 3757 AGAGACCC A CUUUUCA 4246 TGAAAACG CCT'AGCTACAACGA GGGTCTCT 5531 3759 AGACCCAC G UUEJUCAGA 4246 TCTGAAAA GGCTAGCTACAACGA GTGGGTCT 5532 3768 UUUUCAGA GU tUGGUGGA 4247 TCCACCAA GGCTAGCTACAACGA TCTGAAAA 5533 37721CAGAGUUG G UGGAACAU 4248 -ATGTTCCA GGCTAGCTACAACGA CAACTCTG 5534 WO 02/096927 PCT[US02/17674 3777 UUGGLTGGA A CAUUtJGGG 4249 CCCAAATG GGCTAGCTACAACGA TCCACCAA 5535 3779 GGUGGAAC A UTJGGGAA 42S0 TTCCCAAA GGCTAGCTACAACGA GTTCCACC 5536 3788 UEJTGGGAA A UCTJCUUGC 4251 GCAAGAG3A GGCTAGCTACAACGA TTCCCAPA 5537 3795 AAUCUCUTU G CAAGCUAA 4252 TTAGCTTG GGCTAGCTACAACGA AAGAGATT 5538 3799 UCUtJGCAA G CUAAUGCJ 4253 AGCATTAG GGCTAGCTACAACGA TTI3CAAGA 5539 3803 GCAAGCUA A UGCIJCAGC 4254 GCTGAGCA GGCTAGCTACAACGA TAGCTTGC 5S40 3805 AAGCUAAU G CUCAGCAG3 4255 CTGCTGAG GOCTAGCTACAACGA ATTAGCTT 5541 3810 AAUGCUCA G CAGGAUGG 4256 CCATCCTG GGCTAGCTACAACGA TGAGCATT 5542 3815 IJCAGCAGG A UCGCAAAG 4257 CTTTGCCA GGCTAGCTACAACCA CCTGCTGA 5543 3818 GCAGGAJG G CAAAG3ACU 4258 AGTCTTTG GGCTAGCTACAACGA CATCCTGC 5544 3824 UGGCAAAG A CTJACAUJG 4259 CAATGTAG GGCTAGCTACAACGA CTTTGCCA 5545 3827 CAAACACU A CAUUGUUC 4260 GAACAATG GGCTAGCTACAACGA AOTCTTTG 554G 3829 AAGACUJAC A UUtGUUCUJ 4261 AAGAACAA GGCTAGCTACAACGA GTAGTCIT 5547 3832 ACUACAUU G UEJCUUCCG 42G2 CGGAAGAA GGCTAGCTACAACGA ALATGTAGT 5548 3841 TULCUUtCCG A UAUCAGAG 4263 CTCTGATA GGCTAGCTACAACGA CGGAAGAA 5549 3843 CUEJCCGAU A UCAGAGAC 4264 GTCTCTGA GGCTAGCTACAACGA ATCGGAAG 5550 3850 UJAUCAGAG A CLT(JtGAGC 4265 GCTCAAAkG GOCTAGCTACAACGA CTCTrATA 5551 3857 GACUUtYGA G CAtYGGAAG 4256 CTTCCATG GGCTAGCTACAACGA TCAAAGTC 5552 3859 CUEJUGAGC A UGGAAGAG 4267 CTCTTCCA GGCTAGCTACAACGA GCTCAALAG 5553 3869 GGAAGAGG A UTICUGGAC 4268 GTCCAGAA GGCTAGCTACAACGA CCTCTTCC 5554 3876 GAUUtCUGG A CUCLTCUCU 4269 AGAGAGAG GGCTAGCTACAACGA CCAGAATC 5555 3885 CUCUCTCI G CCUACCUC 4270 GAGGTAGG GGCTAGCTACAACGA AGAGAGAG 5556 3889 CUCUGCCU A CCUCACCU 4271 AGGTGAGG GGCTAGCTACAACGA AGGCAGAG 5557 3894 CCTJACCLTC A CCUGUJUC 4272 GAAACAGG GGCTAGCTACAACGA GAGGTAGG 5558 3898 CCUCACCU G3 UUUCCUGU 4273 ACASGAAA GGCTAGCTACAACGA AGGTGAGG 5559 3905 UGDUEJCCU G UAUGGAGG 4274 CCTCCATA GGCTAGCTACAACGA AGGAAACA 5560 3907 UUUCCUGU A UGGAGGAG 4275 CTCCTCCA GGCTAGCTACAACCA ACAGGAAAL 5561 3922 AGGAGGAA G UAUGUGAC 4276 GTCACATA GGCTAGCTACAACGA TTCCTCCT 5562 3924 GAGGAAGU A UGUGACCC 4277 GGGTCACA GGCTAGCTACAACGA AkCTTCCTC 5563 3926 GGAAGUAU G3 UGACCCCA 4278 TGGIGGTCA GGCTAGCTACAACGA ATACTTCC 5564 3929 AGTJAUGUG A CCCCAAAU 4279 ATTTGGGG GGCTAGCTACAACGA CACATACT 5565 3936 GACCCCAA A UEJCCAUTJA 4280 TAATGGAA GGCTAGCTACAACGA TTGGGGTC 5566 3941 CAAAU1JCC A UTJAUGACA 4281 TGTCATAA GGCTAGCTACAACGA GGAATTTG 5567 3944 AUtJCCAUU A UGACAACA 4282 TGTTGTCA GGCTAGCTACAACGA AATGGAAT 5568 3947 CCAIJGAUG A CAACACAG 4283 CTGTGTTG GGCTAGCTACAACGA CATAATGG 5S69 3950 UUAUGACA A CACAGCAG 4284 CTGCTGTG GGCTAGCTACAACGA TGTCATAA 5570 3952 AUGACAAC A CAGCAGGA 4285 TCCTGCTG GGCTAGCTACAACGA GTTGTCAT 5571 3955 ACAACACA G CAGGAAUC 4286 GATTCCTG GGCTAGCTACAACGA TGTGTTGT 5572 3961 CAGCAGGA A UCAGUCAG 4287 CTGACTGA GGCTAGCTACAACGA TCCTGCTG 5573 3965 A(3GAAUCA G3 UCAGHAUC 4288 GAAPACTGA GGCTAGCTACAACGA TGATTCCT S574 3969 AUCAGUCA G UAUCUGCA 4289 TGCAGATA GGCTAGCTACAACGA TGACTGAT 5575 3971 CAGUCAGU A UCUGCAGA 4290 TCTSCAGA GGCTAGCTACAACGA ACTGACTG 5576 3975 CAGLTATCU G CAGAACAG 4291 CTGTTCTG GGCTAGCTACAAC3A AGATACTG 5577 3980 UCUGCAGA A CAGTJAAGC 4292 GCTTACTG GGCTAGCTACAACGA TCTGCAGA 5578 3983 GCAGAACA G3 UAAGCGAA 4293 TTC2CTTA (GCTAGCTACAAC3A TGTTCTGC 5579 3987 AACAGUAA G3 CGAAAGAG 4294 CTCTTTCG GGCTAGCTACAACGA TTACTGTT 5580 3995 GCGAAAGA G3 CCGGCCUG 4295 CAGGCCGG GGCTAGCTACAACGA TCTTTCGC 5581 3999 AAGAGCCOG CCUGUGAG 4296 CTCACAGG (GCTAGCTACAACGA CGGCTCTT 5582 4003 GCCGGCCU G UGAGUGUA 4297 TACJACTCA GGCTAGCTACAACGA AGGCCGGC 5583 4007 GCCUGUGA G3 UGUAAAAA 4298 TTTTTACA GGCTAGCTACAACGA TCACAGGC 5584 4009 CUOUGAGU G3 UAAAAACA 4299 TGTTTTTA GGCTAGCTACAACGA ACTCACAG 5585 40151GUGUAAAA A CAULUGAA 4300 TTCAkAATG GGCTAGCTACAACGA TTTTACAC 5586 40171GUAAAAAC A UUUGAAGA 4:301 TCTTCAAA GGCTAGCTACAACGA GTTTTTAC 5587 WO 02/096927 PCT/US02/17674 4025 AUUJEGAAG A TJAUCCCGU 4302 ACGGGATA GGCTAc3CTACAAC3A CTTCAAAT 5588 4027 UUGAAGAU A UCCC3UA 4303 TAACGGGA GGCTAGCTACAACG3A ATCTTCA.A 5589 4032 GAUAUCCC G UUAGAAGA 4304 TCTTCTAA GGCTAGCTACAACGA GGGATATC 5590 4041 TJUAGAAGA A CCAGAAGU 4305 ACTTCTGG GGCTAGCTACAACGA TCTTCTAA 5591 4048 AACCACAA 0 UAAA0IJA 4306 TACTTTTA GOCTAGCTACAACCA TTCTGGTT 5592 4054 AAGUAAAA G UAAUCCCA 4307 TCCGATTA GGCTAGCTACAACGA TTTTACTT 5593 4057 UAAAAGUA A UCCCAGAU 4308 ATCTGGGA GGCTAGCTACAACGA TACTTTTA 5594 4064 AAUCCCAG A UGACAACC 4309 GGTTGTCA GGCTAGCTACAACGA CTGGGATT 5595 4067 CCCAGATG A CAACCAGA 4310 TCTGGTTG GGCTAGCTACAACGA CATCTGGG 5596 4070 AGAUGACA A CCAGACGG 4311 CCOTCTOG GOCTAGCTACAACGA TGTCATCT 5597 4075 ACAACCAG A CGGACAGU 4312 ACTGTCCG GGCTAGCTACAACGA CTGGTTGT 5598 4079 CCAGACGG A CAGUGCUA 4313 TACCACTG GGCTAGCTACAACGA CCGTCTGG 5599 4082 GACGGACA G UGGUAJGG 4314 CCATACCA GGCTAGCTACAACGA TGTCCGTC 5600 4085 GGACAGIJG G UATJGGUUC 4315 GAACCATA GOCTAGCTACAACC-A CACTGTCC 5601 4087 ACAOUGGU A UG0JJUCUU 4316 AAG3AACCA GGCTAGCTACAACCA ACCACTGT 5602 4090 GUGGUAUG G UEJCUEJGCC 4317 GGCAAGAA GGCTAGCTACAACGA CATACCAC 5603 4096 UGGUCUU G CCUCAGAA 4318 TTCTGAGG GGCTAGCTACAACCGA AAGAACCA 5604 4107 UCAGAAGA G CtJGAAAAC 4319 GTTTTCAG GGCTAGCTACAACC-A TCTTCTGA 5605 4114 AGCTJGAAA A CUEJUGGAA 4320 TTCCAAAG GGCTAGCTACAACGA TTTCAGCT 5606 4124 UUCCGAAC A CAGAACCA 4321 TGGTTCTG GGCTAGCTACAACCGA CTTCCAAA 5607 4129 AAGACAGA A CCAAAIJUA 4322 TAATTTGG GGCTAGCTACAACGA TCTGTCTT 59608 4134 AGAACCAA A UUAUCUCC 4323 GGAGATAA GGCTAGCTACAACC-A TTGGTTCT 5609 4137 ACCAAAUU A UCUCCAUC 4324 GATGG1AGA GGCTAGCTACAACCA AATTTCGT 5610 4143 UUAUCUCC A UCUUtJUGG 4325 CCAAAAGA GGCTAGCTACAACCGA CGAGATAA 5611 4151I AUCUULUC 0 UGGAAUGG 4326 CCATTCCA GGCTAOCTACAACGA CAAAACAT 5612 4156 UCCOTJGGA A UGGUGOCC 4327 GGGCACCA GGCTAGCTACAACC-A TCCACCAA 5613 4159 GUGGAAUG G UGCCCAGC 4328 GCTGGGCA GGCTAGCTACAACGA CATTCCAC 5614 4161 GGAAUGGU G CCCAGCAA 4329 TTGCTGGG GGCTAGCTACAACC-A ACCATTCC 5615 4166 GGUGCCCA G CAAAAGCA 4330 TGCT-TTTG GGCTAGCTACAACGA TGGGCACC 5616 4172 CAGCAAAA G CAGGGAGJ 4331 ACTCCCTG GGCTAGCTACAACC-A TTTTGCTG 5517 4179 AGCAGGGA G UCUGtYGCC 4332 GCCACAGA GGCTAGCTACAACG3A TCCCTGCT 5618 4183 GGGAGUCU G UGGCAUCU 4333 AGATGCCA GGCTAGCTACAACG-A AGACTCCC 5619 4185 AGUCUGUG G CAUCUGAA 4334 TTCAGATG GGCTAGCTACAACGA CACAO.ACT 5620 4188 UCUGUGGC A UCUGAAGG 4335 CCTTCAGA GGCTAGCTACAACG-A GCCACAGA 5621 4195 AUCUGAAG G CUCAAACC 433G GGTTTGAG GGCTAGCTACAACGA CTTCAG3AT 5622 4202 AGGCUCAA A CCAGACAA 4337 TTGTCTGG GGCTAGCTACAACCGA TTGAGCCT 5623 4207 CAAACCAG A CAAGCGGC 4338 GCCGCTTG GC-CTAGCTACAACGA CTGGTTTG 5624 4211 CCAGACAA G CGGCUACC 4339 GGTAGCCG GGCTAGCTACAACC-A TTGTCTGG52 4214 GACAAGCG G CUACCAGU 4340 ACTGGTAG GGCTAGCTACAACGA CGCTTGTC 5626 4217 AAGCGGCU A CCAGUCCG 4341 CGGACTGG GGCTAGCTACAACC-A AGCCGCTT 5627 4221 GGCUACCA G UCCGGAUA 4342 TATCCGGA GGCTACCTACAACGA TGGTAGCC 5628 4227 CAGUCCGG A UAUCACUC 4343 GAGTGATA GGCTAGCTACAACC-A CCGGACTG52 4229 GTJCCGGAU A UCACUCCG 4344 CGCAGTGA GGcTACCTACAACGA ATCCGGAC 5630 4232 CGGAUAUC A CUCCGAUG 4345 CATCGGAG GGCTAGCTACAACG-A GATATCCG 5631 4238 UCACUCCG A UGACACAG 4346 CTGTGTCA CCCTAGCTACAACGA CGGAGTGA 5632 42411 CUCCGAUG A CACAGACA 4347 TCTCTGTGOCGCTAOCTACAACCA CATCCGAG 5633 4243 CCGAUGAC A CAGACACC 4348 GGTGTCTG GGCTAGCTACAACGA GTCATCGG 5634 4247 UGACACAG A CACCACCG 4349 CGGTGGTG CGCTAGCTACAACC-A CTGTGTCA 5635 4249 ACACAGAC A CCACCGUG 4350 CACGGTGG GGCTAGCTACAACC-A GTCTGTGT 5636 4252 CAGACACC A CCGUGUAC 4351 GTACACGG GC-CTAGCTACAACGA GGTGTCTG 5637 4255 ACACCACC C UGUACUCC 4352 GCAGTACA GGCTAGCTACAAC-A GGTGGTGT 5538 4257 ACCACCGU G UACIJCCAGI 4353 CTGGAGTA GGCTAGCTACAACGA ACGGTGGT 5639 425.91CACCGUGU A CUCCAGUGF4354 CACTGGAG GGCTAGCTACAACGA ACACGGTG 5540 WO 02/096927 PCT/US02/17674 4265 GUACLXCCA G UGAGGAAG 4355 CTTCCTCA GGCTAGCTACAACGA TGGAGTAC 5641 4273 GUGAGGAA G CAGAACUJ 4356 AAGTTCTG GGCTAGCTACAACCGA TTCCTCAC 5642 4278 GAAGCAGA A CUUUTUAAA 4357 TTTAAAAG GGCTAGCTACAACGA TCTc3CTTC 5643 4287 CUUUJEAAA G CUGAUAGA 4358 TCTATCAG GGCTAGCTACAACGA TTTAAAAG 5644 4291 UAAAGCUG A UAGAGAUJ 4359 AATCTCTA cGCTAGCTACAACCGA CAGCTTTA 5645 4297 UGAUAGAG A UUGGAGUG 4360 CACTCCAA GGCTAGCTACAACGA CTCTATCA 5646 4303 AGAUtJGGA G IJGCAAACC 4361 OGTTTGCA GGCTAGCTACAACG-A TCCAATCT 5647 4305 AUL2RGAGU G CAAACCG3G 4362 CCGGTTTG GGCTAGCTACAACGA ACTCCAAT 5648 4309 GAGUGCAA A CCGGUAGC 4363 GCTACCGG GGCTAGCTACAACGA TTGCACTC 5649 4313 GCAAACCG G UAGCACAG 4364 CTGTGCTA GGCTAGCTACAACGA CGGTTTGC 5650 4316 AACCGGUA G CACAGCCC 4365 GGGCTGTG GGCTAGCTACAACGA TACCGGTT 5651 4318 CCGQTJACC A CAGCCCAG 4366 CTGGGCTG CC AGCTACAACCA GCTACCG3Q 5652 4321 GUAGCACA G CCCAGAUUt 4367 AATCTGGG GGCTAGCTACAACGA TGTGCTAC 5653 4327 CAGCCCAG A UUCUCCAG 4368 CTGGAGAA GGCTAGCTACAACGA CTGGGCTG 5654 4335 AUEJCUCCA G CCUc3ACUC 4369 GAGTCAGG GcCTAGCTACAACGA TGGAGAAT 5655 4340 CCAGCCUG A CLTCGGGGA 4370 TCCCCGAG GGCTAGCTACAACGA CAGGCTGG 5656 4348 ACUCO30t A CCA CACUG 43'71 CArGhTGG GCTAGCTACAACC;A CC!CCGAGT 5657 4351 CGGGGACC A CACUGAG3C 4372 GCTCAGTG GGCTAGCTACAACG3A GGTCCCCG 5658 4353 GGGACCAC A CUGAGCUC 4373 GAGCTCAG GGCTAGCTACAACGA GTGGTCCC 5659 4358 CACACUGA G CUCUCCUC 4374 GAGGAGAG GC3CTAGCTACAACGA TCAGTGTG 5660 4369 CUCCUCCU G UUUAA1AAG 4375 CTTTTAAA GGCTAGCTACAACGA AGGAGGAG 5661 438.1 AAAAGGAA G CAUCCACA 4376 TGTGGATG GGCTAGCTACAACGA TTCCTTTT 5662 4383 AAGGAAGC A UCCACACC 4377 GGTGTGGA GGCTAGCTACAACGA GCTTCCTT 5663 4387 AAGCAUCC A CACCCCAA 4378 TTGGGGTG GGCTAGCTACAACGA GGATGCTT 5664 4389 GCAUCCAC A CCCCAACU 4379 AGTTGGGG GGCTAGCTACAACGA GTGGATGC 5665 4395 ACACCCCA A CUCCCGGA 4380 TCCGGGAG GGCTAGCTACAACGA TGG3GGTGT 5666 4403 ACLTCCCGG A CAUCACAU 4381 ATGTGATG GGCTAGCTACAACGA CCGGGAGT 5667 4405 UCCCGGAC A UCACAUGA 4382 TCATGTGA GGCTAGCTACAACGA GTCCGGGA 5668 4408 CGGACAUC A CAUAGAG 4383 CTCTCATG GGCTAGCTACAACGA GATGTCCG 5669 4410 GACAUCAC A UGAGAGGU 4384 ACCTCTCA GGCTAGCTACAACGA GTGATGTC 5670 4417 CAUGAGAG G UCUGCUCA 4385 TGAGCAGA GGCTAGCTACAACGA CTCTCATG 5671 4421 AGAGGUCU G CUCAGATJJ 4386 AATCTGAG GGCTAGCTACAACGA AGACCTCT 5672 4427 CUGCUCAG A UUUtJGAAG 4387 CTTCAAAA GOCTAGCTACAACOA CTGACCAG 5673 4435 AUUtJUGAA G UGUJGUJC 4388 GAACAACA GGCTAGCTACAACGA TTCAAAAT 5674 4437 UUGAAGU G UUGUtICUJ 4389 AAGAACAA GGCTAGCTACAACGA ACTTCAAA 5675 4440 GAAGUGUU G UIYCtUUCC 4390 GGAAAGAA GGCTAGCTACAACGA AACACTTC 5676 4449 UUCU3JUCC A CCAGCAGG 4391 CCTGCTGG GGCTAGCTACAACGA GGAAAGAA 5677 4453 UTTCCACCA G CAGGAAGU 4392 ACTTCCTG GOCTAGCTACAACGA TOGTGGAA 5678 4460 AGCAGGAA G UAGCCGCA 4393 TGCGGCTA GGCTAGCTACAACGA TTCC TGCT 5679 4463 AGGAAGUA G CCGCAUUU 4394 AAATGCGG GGCTAGCTACAACGA TACTTCCT 5680 4466 AAGIJAGCC G CAUEJUGAU 4395 ATCAAATG GGCTAGCTACA.ACGA GGCTACTT 5681 4468 GUAGCCGC A TUEJGAUtJU 4396 AAATCAAA GGCTAGCTACAACGA GCGGCTAC 5 682 4473 CGCAUUUG A UUUEJCAUTJ 4397 AATGAAAA GGCTAGCTACAACGA CAAATGCG 5693 4479 UGAUUUJUC A UULUCGACA 4398 TGTCGAAA GGCTAGCTACAACGA GAAAATCA 5684 4485 UCALT~tUCG A CAACAGAA 4399 TTCTGTTG GGCTAGCTACAACGA CGAAATGA 5685 4488 LUUTCGACA A CAGAAAAA 4400 TTTTTCTG GGCTAGCTACAACGA Tc3TCGAAA 5686 4499 GAAAAAGG A CCIYCGGAC 4401 GTCCGAGG GGCTAGCTACAACGA CCTTTTTC 5687 4506 GACCUCGG A CUGCAGGG 4402 CCCTGCAG GGCTAGCTACAACGA CCGAGOTC S688 450-9 CUCCGACU G CAGGGAGC 4403 GCTCCCTG GGCTAGCTACAACGA AGTCCGAG 5689 4516 UGCAGGGA G CCAGUCUU 4404 AAGACTGG GGCTAGCTACAACGA TCCCTGCA 5690 4520 GGGAGCCA G UCUTJCUAG 4405 CTAGAAGA GGCTAGCTACAACGA TGGCTCCC 5691 4529 UCUtJCUAG G CAUAUCCU 4406 AGGATATG GGCTAGCTACAACGA CTAGAAGA 5692 4-031 tTUCUAGGC A UAUCCUGG 4407 CCAGCATA GCAGCTACAACGA GCCTACAA 5693 WO 02/096927 PCT/US02/17674 45S3 3 CUAGGCAU A UCCUGGAA 4408 TTCCAGGA GGCTAGCTACAACGA ATGCCTAG 56594 4545 UGGAAGAG G CtJUGtJGAC 4409 GTCACAAG GGCTAGCTACAACGA CT'CTTCCA 5695 4549 AGAGGCUJ G UGACCCAA 4410 TTGGGTCA GGCTAGCTACAACGA AIXGCCTCT 5696 4552 GGCUJGTG A CCCAAGAA 4411 TTCTTGGG GGCTAGCTACAACGA CACAAGCC 5G97 4560 ACCCAAGA A UGIJGUCUG 4412 CAGACACA GGCTAGCTACAACGA TCTTGGGT 5698B 4562 CCAAGAAU G TJGtICEGUG 4413 CACAGACA GGCTAGCTACAACGA ATTCTTGG 5699 4564 AAGAAUGU G UCUGUtJC 4414 GACACAGA GGCTAGCTACAACGA ACATTCTT 5700 4568 AUGUGJCT G UGUCUJCU 4415 AGAAGACA GGCTAGCTACAACGA AGACACAT 5701 4570 GTJGUCIJGU G LCUUCUCC 4416 GGAGAAGA GGCTAGCTACAACGA ACAGACAC 5702 4581 UUCUCCCA G UGt]1GACC 4417 GGTCAACA GGCTAGCTACAACGA TGGGAGAA 5703 4583 CUCCCAGU G UUGACCJG 4418 CAGGTCAA GGCTAGCTACAACGA ACTGGGAG 5704 4587 CAGUGUJG A CCUGAUCC 4419 GGATCAGG GGCTAOCTACAACGA CAACACTG 5705 4592 UtJGACCUG A UCCUCUJU 4420 AAAGAGGA GGCTAGCTACAACGA CAGGTCAA 5706 4605 CUUUTYUUC A UUCAUUUA 4421 TAAATGAA GGCTAGCTACAACGA GAAAAAAG 5707 4609 UEJCAUUC A UUAAAAA 4422 TTTTTAAA GGCTAGCTACAACGA GAATGAA.A 5708 4618 U(AAAAA G CAUtJAUCA 4423 TGATAATG GGCTAGCTACAACGA TTTTTAALA 5709 4620 UAAPAAGC A UtJAUCAUG 4424 CATGATAA GGCTAGCTACAACGA GCTTTTTA 5710 4623 AALAGCAUJ A UCAUGCCC 4425 GGGCATGA GGCTAGCTACAACGA AATGCTTT 5711 4626 GCAJIJAUC A UGCCCCJG 4426 CAGGGGCA GGCTAGCTACAACGA GATAATGC 5712 4 62 8 AUUA-UCAU G CCCCtJGCU 4427 AGCAGGGG GGCTAGCTACAACGA ATGATAAT 5713 4634 AUGCCCCU G CUGCGGGU 4428 ACCCGCAG GGCTAGCTACAACGA AGGGGCAT 5714 4637 CCCCUGCU G CGGC.UCUC 4429 GAGACCCG GGCTAGCTACAACGA AGCAGGGG 5715 4641 UGCUGCGG G UCtYCACCA 4430 TGGTGAGA GGCTAGCTACAACGA CCGCAGCA 5716 4646 CGGGUCUC A CCAUJGGGJ 4431 ACCCATGG GGCTAGCTACAACGA GAGACCCG 5717 4649 GtYCUCACC A UGGGUUUA 4432 TAALACCCA GCTAGCTACAACGA GGTGAGAC 5718 4653 CACCAtJCG G tUUAGAAC 4433 GTTCTAAA GGCTAGCTACAACGA CCATGGTG 5719 4660 GGUEJEJAGA A CAAAGAGC 4434 GCTCTTTG GGCTAGCTACAACGA TCTAAACC 5720 4 66 7 AACAALAGA G CUtJCAAGC 4435 GCTTGAAG CG3CTAGCTACAACGA TCTTFGTT 5721 4674 AGCUUCAA G CAAUGGCC 4436 GGCCATTG GGCTAGCTACAACGA TTGAAGCT 5722 4677 UTJCAAGCA A UGGCCCCA 4437 TGGGGCCA GGCTAGCTACAACGA TGCTTGAA 5723 4660 AAGCAAUG G CCCCALTCC 4438 GGATGGGG GGCTAGCTACAACGA CATTGCTT 5724 4685 AUGCCCC A UCCUCAAA 4439 TTPGACCA GGCTAGCTACAACGA GGGGCCAT 5725 4697 UCAAAGAA C UACCAGUA 4440 TACTOCTA GCTAGCTACAACGA TTCTTTGA 5726 4700 AAGAAGUA 0 CAGUACCI 4441 AGGTACTG GGCTAGCTACAACGA TACTTCTT 5727 4703 AAGUAGCA G UACCUGGG 4442 CCCAGGTA GGCPAGCTACAACCA TGCPACTT 5728 4705 GIJAGCAGU A CCUCGGGA 4443 TCCCCAGG GC-CTAGCTACAACGA ACTGCTAC 5729 4714 CCUGGGGA G CUGACACU 4444 AGTGTCAG GGCTAGCTACAACGA TCCCCAGG 5730 4718 GGGAGCUG A CACUCCUC 444S CAGAACTG CC-CTAGCTACAACGA CAGCTCCC 6731 4720 GACLTAC A CUTTCUGUA 4445 TACAGAAG GGCTAGCTACAACGA GTCAGCTC53 4726 ACACUEJCU G UAAAACJA 4447 TAGTTTTA GC-CTAGCTACAACCA AGAAGTGT 5733 4731 UCIJCUAAA A CtAGAAGA 4448 TCTTCTAG GGCTAGCTACAACGA TTTACAGA 5734 4739 ACUAGAAG A UAAACCAG 4449 CTGOTTTA GGCTAGCTACAACGA CTTCTAGT 5735 4743 GAAGAUAA A CCAGGCAA 4450 TTGCCTGG GGCTAOCTACAACGA TTATCTTC 5736 4748 UAAACCAG G CAACGUAA 4451 TTACGTTG GGCTAGCTACAACGA CTCGTTTA 5737 4751 ACCAGGCA A CCIJAAGUG 452 CACTTACG GGCTAGCTACALACGA TGCCTGGT 5738 4753 CAGGCAAC G UAAGUGUJ 4453 AACACTTA GGCTAGCTACAACGA GP'I'CCCTG3 5739 4757 CAACGUAA G UGIJUCGAG 4454 CTCGAACA GGCTAGCTACAACGA TTACGTTG 5740 4759 ACGUAAGU G UEJCGAC.GU 445S ACCTCGAA GGCTAGCTACAACGA ACTTACGT 5741 4766 UGGUCGAG G tJCUUGAAG 4456 CTTCAACA GGCTAGCTACAACGA CTCGAACA 5742 4768 UUCGAGGU G UUGAAGAU 4457 ATCTTCAA GGCTAGCTACAACGA ACCTCGAA 5743 4775 UGUUGAAG A UGGGAAGG 4458 CCTTCCCA GGCTAgCTACAACGA CTTCAACA 5744 4784 UGGGAAGG A UUUCGCAG(3 4459 CCTGCAAA GGCTAGCTACAACGA CCTTCCCA 5745 4788 AAGGAUUUJ G CAGCC4460 1CAGCCCTG GGCTAGCTACAACCA AAATCCTTj 5746 WO 02/096927 PCT/US02/17674 4793 UUUGCAGG G CIJGAGUCU 4461 AGACTCAG GGCTAGCTACAACGA CCTGCAAA 5747 4 7998 AGGGCUGA G UCTJAUCCA 4462 TGGATAGA GfCTAGCTACAACGA TCAGCCCT 5748 4 8 02 CUGAGUCT A UCCA-AGAG 4463 CTCTTGGA GGCTAGCTACAACGA AGACTCAG 5749 4811. UCCAAGAG G CULUGJUUUT 4464 AAACAAAG GGCTAGCTACAACGA CTCTTGGA 57S0 4816 GAG3GCUUI G UUEJAGGAC 4465 GTCCTAAA GGCTAGCTACAACGA AAAGCCTC 5751 4823 JUGUUUtAGG A CGUGGGUC 4466 GACCCACG GGCTAGCTACAACGA CCTAAACA 5752 4 82 5 UUUAGGAC G UGUCCC 4467 GGGACCCA CoCTAGCTACAACGA GTCCTAAA 5753 4829 GGACGUGG G TJCCCAAGC 4468 GCTTGGGA GGCTAGCTACAACGA CCACGTCC 5754 4836 GGUCCCAA G CCAAGCCU 4469 AGGCTTGG GGCTAGCTACAACGA TTGGGACC 5755 4841 CAAGCCAA G CCUEJAAGU 4470 ACTTAAGG GGCTAGCTACAACGA TTGGCTTG 5756 4848 AGCCUtJAA G UGTJGGAAU 4471 ATTCCACA GGCTAGCTACAACGA TTAAGGCT 5757 4850 CCUTAAGU G UGGAALUUC 4472 GAATTCCA GGCTAGCTACAACGA ACTTAAGG 5758 4855 AGUGUGGA A UJICGAUU 4473 AATCCGAA GGCTAGCTACAACGA TCCACACT 5759 4861 GAAUtJCGG A UUGAUAGA 4474 TCTATCAA GGCTAGCTACAACGA CCGAATTC 5760 4865 UCGGAU3C A UAGAAAGG 4475 CCTTTCTA GGCTAGCTACAACGA CAATCCGA 5761 4877 AAAGGAAG A CUAACGUtJJ 4476 AACGTTAC3 GGCTAGCTACAACGA CTTCCTTT 5762 4881 GAAGACtJA A CGUEJACCU 4477 AGGTAACG GGCTAGCTACAACGA TAGTCTTC 57653 4 683 AGACUAAC G TJUACCUEJG 4478 CAAGGTAA GGCTAGCTACAACGA GTTAGTCT 5764 4 8 86 CUAACGUJ A CCUEJCCUU 4479 AAGCAAGG GGCTAGCTACAACGA AACGTTAG 5765 4891 GUUACCUU G CUTMJCCAG 4480 CTCCAAAG GGCTAGCTACAACGA AAGGTAAC 5766 4901 IJUUGGAGA G UACUGGAG 4481 CTCCAGTA GGCTAGCrTACAACGA TCTCCAAA 5767 4903 UGGAGAGU A CUGGAGCC 4482 GGCTCCAG GGCTAGCTACAACGA ACTCTCCA 5768 498.9 GUACIJCCA G CCUGCAAA 4483 TTTGCAGG GGCTAGCTACAACGA TCCAGTAC 5769 4913 LTGGAGCCU G CAAAtJGCA 4484 TGCATTTG GGCTAGCTACAACGA AGGCTCCA 5770 4917 GCCLGCAA A UGCAUEJCU 4485 ACAATGCA GGCTAGCTACAACGA TTGCAGGC 5771 4919 CUGCAAAU G CAUEJGUGU 4486 ACACAATG GGCTAGCTACAACGA ATTTGCAG 5772 4921 GCAAAUGC A UUGUGUUU 4487 AAACACAA GGCTAGCTACAACGA GCATTTGC 5773 4.924 AAUCCAUU G UGIUJGCU 4488 AGCAAACA GGCTAGCTACAACGA AATCCATT 5774 4926 UGCAEJGU G ULUGCUCU 4489 AGAGCAAA GGCTAGCTACAACGA ACAATGCA 5775 4 930D UEJCCUUEJ G CUCUGGUG 4490 CACCAGAG GG4CTAGCTACAAC4A AALACACAX 5776 4936 UUGCUCUG G UGGAGGUG 4491 CACCTCCA GGCTAGCTACAALCGA CAGAGCAA 5777 4942 UGGtJGGAG G UGGGCAUG 4492 CATGCCCA GGCTAGCTACAACGA CTCCACCA 5778 4946 GCAGGUGG G CAUC0GGU 4493 ACCCCATC GCCTAOCTACAACCA CCACCTCC 5779 4948 AGGLTGGGC A UGGGGUCU 4494 AGACCCCA GGCTAGCTACAALCGA GCCCACCT 5780 4953 CCCAUGCG G UCtTUUCU 4495 AGAACAGA CCCTACCTACAACGA CCCATGCC 5701 4957 UGGGGUCU G UtJCTGAAA 4496 TTTCACAA GGCTAGCTACAACGA AGACCCCA 5782 4965 GUUCUGAA A UGUAALAGG 4497 CCTTTACA GGCTAGCTACAACGA TTCAGAAC 5783 4-967 UCUGAAAU G UAAAGGGU 4498 ACCCTTTA GGCTAGCTACAACGA ATTTCACA 5784 4974 UGUAAAGG G LTUCAGACG 4499 CGTCTGAA GGCTAGCTACAACGA CCTTTACA 5785 4980 GGGIThCAG A CGGGGUULT 4500 AAACCCCG GGCTAGCTACAACGA CTGAACCC 5786 4985 CAGACGGG G =UCUGGU 4501 ACCAGAAA GGCTAGCTACAACGA CCCGTCTG 5787 4992 GGLUtCUG G UULUAGAA 4 50 2 TTCTAAAA GGCTAGCTACAACGA CAGAA.ACC 5788 0802 UTUUACAAG C UUJCCCUGU 4503 ACACGCAA GGCTAGCTACAACGA CTTCTAAA 5789 5005 AGAAGGUJ C CGUGUtJCU 4504 AGAACACG GGCTAGCTACAACGA AACCTTCT 5790 5087 AAGGULJGC C UGUCCUTO 4505 GAAGAACA GGCTAGCTACAACGA GCAACCTT 5791 S089 GGLEJOCGU C UUCUUCGA 4506 TCGAAGAA GGCTAGCTACAACGA ACCCAACC 5792 5018 UUECUUCGA C UUGGGCUA 4507 TAGCCCAA GGCTAGCTACAACGA TCGAAGAA 5793 5823 CGAGUTJCC C CUAAAGUA 4508 TACTTTAG GGCTAGCTACAACGA CCAACTCG 5794 5029 GGGCUAAA G UAGAGUTC 450.9 GAACTCTA GGCTAGCTACAACGA TTTAGCCC 5795 5834 AAAGUAGA G UUCGUUGU 4510 ACAACGAA GGCTAGCTACAACGA TCTACTTT 5796 03 8 UAGAGUUC G UEJGUGCUG 4511 CAGCACAA GGCTAGCTACAACGA CAACTCTA 5797 5041 AGUUCGUU G UGCUGUUJ 4512 AAACAGCA GGCTAGCTACAACGA AACGAACT 5798 5043 TJTJCGUEJGU G CUGUUYCU 4513 AGAAACAG GGCTAGCTACAACGA ACAACGAA S799 WO 02/096927 PCT/US02/17674 5045 GTJUGUGCU G UJUCLGAC 4514 GTCAGAAA GGCI'AGCTACAACGA AGCACAAC 5800 5053 UGULTUCUG A CUCCTJAAU 4515 ATTAGGAG GC-CTAGCTACAACGA CAGAALACA 5802.

5060 GACUCCUA A UGAGAGUJ 4516 AACTCTCA GGCTAGCTACAACGA TAGGAGTC 5802 5066 UAAUGAGA G UUCCUUCC 4517 GGAAGGAA GCCTAGCTACAACCA TCTCATTA 5803 5077 OCUEJOCAG A CCGUXJAGC 4510 GCTAACGG GGCTAGCTACAACGA CTGGAAGG 5004 5080 UCCAGACO G UEJAGCUGJ 4519 ACAGCTAA GGCTAGCTACAACGA GGTCTGGA 5805 5084 GACCGUUtA G CUGUCUCC 4520 GGAGACAG GGCTAGCTACAACGA TAACGGTC 5806 5087 CGUUAGCU G UCUCCUUG 4521 CAAGGAGA GC-CTAGCTACAACGA AGCTAACG 5807 5095 GUCIJCCUJ G CCAAGCCC 4522 GGGCTTGG GGCTAGCTACAACGA AAGGAGAC 5808 5100 CUTJGCCAA, G CCCCAGGA 4523 TCCTGGGG GGCTAGCTACALACCA TTGGCAALG 5809 5114 GGAALGAAA A UGAUCCAG 4524 CTGCATCA GCCTAGCTACAACGA TTTCTTCC 5810 5117 AGAAAAUG A UGCAGCUC 4525 GAOCTGCA GGCTAgCTACAACGA CATTTTCT 5811 5119 AA\AAUGAU G CAGCTJCUG 4526 CAGAGCTG GGCTAGCTACAACGA ATCATTTT 5812 5122 AUGAUGCA G CUCUGGCU 4527 AGCCAGAG CGCTAGCTACAACGA TGCATCAT 5813 5120 CAGCUCUG G CUCCUUGJ 4528 ACAAGGAG GGCTAGCTACAACGA CAGAGCTG 5814 5135 GGCUCCUU G UCUCCCAG 4529 CTGC3GAGA EGCTAGCTACAACGA AAGGAGCC 5815 5144 IYCUCCCAG G CUGAUCCU 4530 AGGATCAG GGCTAGCTACAACGA CTGGGAGA 5815 5148 CCAt3GCUG A UCCUUUAU 4531 ATAAAGGA GGCTAGCTACAACGA CAGCCTGG 5817 5155 GAUCCEJUU A UUCAGAAU 4532 ATTCTGAA GC-CTAGCTACAACGA AALAGGATC 5818 5162 UAUEJCAGA A UACCACAA 4533 TTGTGGTA GGCTAGCTACAACGA TCTGAATA 5819 5164 UUCAGAAU A CCACAAAG 4534 CT'I'UTGG GGCTAC4CTACAACGA ATTCTGAA 5820 5167 AG2AUACC A CAAAGAAA 4S35 TTTCTTTG GGCTAGCTACAACGA GGTATTCT 5821 5178 AAGAAAGG A CATJUCAGC 4536 GCTGAATG GGCPAGCTACAACGA CCTTTCTT 5822 5180 GAAAGGAC A tJUCAGCUC 4537 GAGCTGAA GGCTAGCTACAACGA GTCCTTTC 5823 5185 GACAUEJCA G CUCAAGGC 4538 GCCTTGAG GGCTAGCTACALACGA TGAATGTC 5824 5192 AGCUCAAG G CUCCCUGC 4539 GCAGGGAG GGCTAGCTACAACGA CTTGAGCT 5825 5199 GGCUCCCU G CCGUGUUG 4540 CAACACGG GGCTAGCTACAACGA AGGGAGCC 5826 5202 UCCCUGCC G UGUEJGAAG 4541 CTTCAACA GGCTAGCTACAACGA GGCAGGGA 5827 5204 CCUGCCGU G UUGAAGAG 4542 CTCTTCAA GGCTAGCTACALACGA ACGGCAGG 5828 5212 GUUGAAGA G UTECUGACU 4543 AGTCAGAAL GCCTAGCTACAACGA TCTTCAAC 5829 5215 GAGEJUCUG A CUGCACAA 4544 TTGTGCAG GGCTAGCTACAACGA CAGAZ4CTC 5830 5221 UUCUGACU G CACAAACC 4545 GGTTTGTG GGCTAGCTACAACGA AGTCAGAA 5831 5223 CUGAkCUGC A CAAACCAG 4546 CTGGTTTG GCCTAOCTACAACCA GCACTCAG 5832 5227 CUGCACAA A CCAGCUUC 4547 GAAGCTGG GGCTAGCTACALACGA TTGTGCAG 5833 5231 ACAAACCA G CULJCUGGU 4548 ACCAGAAG GGCTAGCTACAACGA TGGTTTGT 5834 5238 AGCUUCIJG G UJTJCUUCU 4549 AGAAGAAA EGCTAGCTACAACGA CAGAAGCT 5835 5250 CUUCUGGA A UGAAUACC 4550 GGT'ATTCA GGCTAGCTACAACGA TCCAGAAG 5835 5254 UGGAAUGA A HUACCCUCA 4551 TGAGGGTA GGCTAGCTACAACGA TCATTCCA 5837 5256 GAAUCAAU A CCCUCAUA 4552 TATGAGGG GGCTAGCTACAACGA ATTCATTC 5838 5262 AUACCCUC A EJAUCUGUC 4553 GACAGATA GGCTAGCTACAACGA GAGGGTAT 5839 5264 ACCCUCAU A UCUGUCCJ 4554 AGGACAGA GGCTAGCTACAACGA ATGAGGGT 5840 5268 UCAUAUCU G UCCUGAUG 4555 CATCAGGA GGCTAGCTACAACGA AGATATGA 5841 5274 CUGUCCUG A UTGUGAUAU 4556 ATATCACA GGCTAGCTACAACGA CAGGACAG 5842 5275 GUCCUGAU G UGAUAUGU 4557 ACATATCA GGCTAGCTACAACGA ATCAGGAC 5843 5279 CUGAUGUG A UAIJOUCUG 4558 CAGACATA GGCTAGCTACAACGA CACATCAG 5844 5281 CAUGUGAU A UCLICUGAG 4559 CTCAGACA GGCTAOCTACAACGA ATCACATC 5845 5283 UGUGAUAU G UCUGAGAC 4550 GTCTCAGA GGCTAGCTACAACGA ATATCACA 5846 5290 UGUCUGAG A CUGAAUGC 4561 GCATTCAG GGCTAGCTACAACGA CTCAGACA 5847 5295 GAGACUGA A UGCGGGAG 45652 CTCCCGCA GGCTAGCTACAACGA TCAGTCTC 5848 5297 GACUGAAU G CGGGAGGU 4563 ACCTCCCG GC-CTAGCTACAACGA ATTCAGTC 5849 5204 UGCGGGAG G TUCAAUGU 4564 ACATTGAA GGCTAGCTACA-ACGA CTCCCGCA 5850 5309 GAGGUUCA A UGTUGAAGC 4565 GCTTCACA GGCTAGCTACAACGA TGAACCTC 5851 5311 GGUEJCAAU G UGAAGCUGI 4565 CAGCTTCA GC-CTAGCTACAACGA ATTGAACC 5852 WO 02/096927 PCT/US02/17674 53 16 AAUJGUGAA G CUGUGUGU 4 56 7 ACACACAG GGCTAGCTACAACGA TTCACATT 5853 5319 GUGAAGC3 G UGIJGUGGU 4568 ACCACACA GGCTAOCTACAACGA AGCTTCAC 5854 5321 GAAGCUGU G UGUJGGUGU 4569 ACACCACA GGCTAGCTACAACGA ACAGCTTC 5855 5323 AGCUGUGU G UGGUGUCA 4570 TGACACCA GGCTAGCTACAACGA ACACAGCT 5856 532G UGUGUGUG G UGUCAAAG 4571 CTTTGACA GGCTAGCTACAACGA CACACACA 5857 5328JUGUGUGGU G UCAAAGUO 4572 AACTTTGA GGCTAGCTACAACGA ACCACACA 5858 5334 GUGIJCAAA G TJTJICAGGA 4573 TCCTGAAA GGCTAGCTACAACGA TTTGACAC 5859 5346 CAGGAAGG A UULTUACCC 4574 GGGTAAAA GGCTAGCTACAACGA CCTTCCTG 5860 5351 AGGAUUUJ A CCCUULEJG 4575 CAAPAAGGG GGCTAGCTACAACGA AAAATCCT 5861 5359 ACCCUUJU G UTJCUtCCC 4576 GGAAGAA GCCTAGCTACAACGA AAAAGGGT 5862 5371 UtJCCCCCU G UCCCCAAC 4577 GTTGGGGA GGCTAGCTACAACGA AGGGGGAA 5863 5378 UGUCCCCA A CCCACUCU 4578 AGAGTGGG QGCTAGCTACAACCA TGGGGACA 5864 5382 CCCAACCC A CUCUCACC 4579 GGTGAGAG GGCTAGCTACAACGA GGGTTGGG 5865 5388 CCACtTCUC A CCCCGCAA 4580 TTGCGGGG GGCTAGCTACAACGA GAGAGTGG 5866 5393 CUCACCCC G CAACCCAU 4581 ATGGGTTCO CCCTAGCTACAACGA GGGGTGAG 5867 5396 ACCCCGCA A CCCAUCAG 4582 CTGATGGG GGCTAGCTACAACGA TGCGGGGT 5868 5400 CGCAACCC A UCAUAUUE 4583 AATACTGA GCCTAGCTACAACrA GGGTTCG 5869 5404 ACCCAUCA G UAIJUUUAG 4584 CTAAAATA GC-CTAGCTACAACGA TGATGGGT 5870 5406 CCAIJCAGU A UUUUTAGUUT 4585 AACTAAAA GGCTAGCTACAACGA ACTGATGG 5871 5412 GUAU]TJEA G UEJAUUUGG 4586 CCAAATAA GGCTAGCTACAACGA TAAAATAC 5872 541S UUUAGUU A UUIJGGCCU 4587 AGGCCAAA GCGCTAGCTACAACGA AACTAAAA 5873 5420 GUEJAIUUG G CCUCUACU 4588 AGTAGACG GGCTACCTACAACCA CAAATAAC 5874 5426 UGGCCUCJ A CUCCAGUA 4589 TACTGGAG GGCTAGCTACAACGA AGAGGCCA 5875 5432 CtJACUCCA G UAAACCUG 4590 CAGGTTTA GC-CTAGCTACAACGA TGGAGTAG 5876 5436 UCCAGUAA A CCUGAUE3C 4591 CAATCAGG GCTCAGCTACAACGA TTACTGGA 5877 5441 UAAACCUG A TJEJCGUUU 4592 -AAACCCAA GGCTAGCTACAACGA CAGGTTTA 5578 5446 CUGAUtJGG G3 UUUGUUCA 4593 TGAACAAA GGCTAGCTACAACGA CCAATCAG 5879 5450 UtJGGGtYUU G UUCACUCU 4594 AGAGTGAA GGCTAGCTACAACGA AAACCCALA 5880 5454 GUUUGUUC A CUCUCUGA 4595 TCAGAGAG GGCTAGCTACAACGA GAACAAAC 5881 5463 CUCUCUGA A UGAIJAUI 4596 AATIU\TCA SGCTAGCTACAACGA TCAGAGAG 5882 5466 UCUGAAUG A UUAtJUAGC 4597 GCTAATAA GGCTAGCTACAACGA CATTCAGA 5883 5469 GAAUGAUU A UEJAGCCAG 4598 CTGGCTAA GGCTAGCTACAACGA AA'TCATTC 5884 5473 GAUEJAUUA G CCACACUU 4599 AAGTCTC CC-CTAGCTACAACCA TAATAATC 5885 5478 UtJAGCCAG A CU'JCAAAA 4600 TTPTGAAG GCCTAGCTACAACGA CTGGCTAA 5886 5486 ACUUCAAA A UEJAUULUA 4601 TAAAATAA GGCTAGCTACAACGA TTTGAAGT 5887 5489 UCAAAAUU A UUIJUAUAG 4602 CTATAAAA GGCTAGCTACAACGA AATTT3TGA 5888 5494 AUIJAUUUU A UAGCCCAA 4803 TTGGGCTA GGCTAGCTACAACGA AA2AATAAT 5889 5497 AUUUUAUA G CCCAAAUU 4604 AATTTGGG GCCTAGCTACAACCA PATAAAAT 5890 5503 UAGCCCAAL A UEJAUAACA 4805 TGTTATAA GGCTAGCTACAACGA TTGGGCTA 5891 5506 CCCAAAUI A UAACAUCU 4606 AGATGTTA GGCTAGCTACAACGA AALTTTCQC 5892 5509 AAALTUAUA A CAUCUAUU 4607 AATAGATG GGCTAGCTACAACGA TATAATTT 5893 5531 AtJUAUAAC A UCIJAUTJGU 4608 ACAATAGA GGCTAGCTACAACGA CTTATAAT 5894 5515 UAACAUCU A UTJGUAUTJA 4609 TAATACAA GGCTAGCTACAACGA AGATGTTA 5895 5518 CAUCUAUU G UAUUAUUJ 4610 AAATAATA GGCTAGCTACAACGA AATAGATG 5896 5520 UCUAUUGU A UUAUUUAG 4611 CTAAATAA GGCTAGCTACAACGA ACAATAGA 5897 5523 AUEJGUAUU A UUUAGACU 4612 AGTCTAAA GGCTAGCTACAACGA AATACAAT 5898 5529 UCAUUUAG A CUIJUUAAC 4613 GTTAAAAG GGCTAGCTACAACGA CTAAATAA 5899 5536 GACUIUCA A CAUAUAGA 4614 TCTATATG GGCTAGCTACAACGA TAAALAGTC 5900 5538 CU=UAAC A UAUAGAGC 4815 GCTCTATA GGCTAGCTACAACGA GTTAAAAG 5901 5540 =UAACAU A UAGAGCUA 4616 TAGCTCTA GGCTAGCTACAACGA ATGTTAAA 5902 5545 CAUATJAGA G CUAUUTUCU 4617 ACAAATAG GGCTAGCTACAACCA TCTATATG 5903 5548 AIJAGAGCU A UUUCUACU 4618 AGTAGAAA GGCTAGCTAC1AACGA AGCTCTAT 5904 5554 CUAUUTJCU A CUGAUUUTU 4619 AAAATCAG GCTAGCTACAACGA ;AGAAALTAG WO 02/096927 PCT/US02/17674 55581UUCUACUG A UUUUTUGCC 4620 GGCAAAAA GGCTAGCTACAACGA CAGTAGAA 5906 5564 JGAUUJJE G CCCUtGUJ 4621 AACAAGGG COCTAGCTACAACGA AAAAATCA 5907 5570 UULGCCCUJE G UEJCUGUCC 4622 GGACAGAA CGCCTAGCTACAACGA AAGGGCAA 5908 5575 CUUGUUCU G tJCCUUUU 4623 AAAAGGA GGCTAGCTACAACGA AGAACAAG 5909 5597 AAAAGAAA A UGUGUUUJ 4624 AAAACACA GGCTAGCTACAACGA TTTCTTTT 5910 5599 AAGAAAAU G UGLUUUtT 4625 AAAAAACA GGCTAGCTACAACGA ATTTTCTT 5911 5601 GAA1AAUGU G UUTJUGU 4626 ACAAAAAA GGCTAGCTACAACGA ACATTTTC 5912 5608 UGUJ1UUIU G UTJTGGUAC 4627 GTACCAAA GGCTAGCTACAACGA AAAAAACA 5913 5613 UUJUGUUUG G UACCATAG 4628 CTATGGTA GGCTAGCTACAACGA CAALACAAA 5914 5615 UGtJUUGGU A CCAUAGUG 4629 CACTATG3 GGCTAGCTACAACGA ACCAAACA 5915 5618 UUGGUACC A UACUGUGA 4630 TCACACTA GGCTAGCTACAACGA GGTACCAA 5916 5621 GUACCAUA G UGUGAAAU 4631 ATTTCACA GGCTAGCTACAACGA TATOCTAC S917 5623 ACCAUAGU G UCAAAUGC 4632 GCATTTCA GGCTACCTACAACGA ACTATGGT 5918 5G6 AGUCTJGAA A UCUtGGGA 4633 TCCCAGCA GGCTAGCTACAACGA TTCACACT 5919 5630 UCUGAAAU G CUJCGGAAC 4634 GTTCCCAG GGCTACCTACAACGA ATTTCACA 5920 5637 IJGCUGGGA A CAAUGACU 4635 AGTCATTG GGCTAGCTACAACGA TCCCAGCA 5921 5640 UGAACA A TCACUAUA 4636 TATAGTCA GGCTAGCTACAACGA TGTTCCCA S922 5643 GAACAAUG A CUAUAAGA 4637 TCTTATAG GGCTAGCTACAACGA CATTGTTC 5923 5646 CAAUGACU A UAAGACAU 4638 ATGTCTTA GGCTAGCTACAACGA AGTCATTG 5924 56S1 ACUAU7AC A CAUGCUAU 4639 ATAGCATG GGCTAGCTACAACGA CTTATAGT 5925 5653 UAUAAGAC A UGCUAUGG 4640 CCATAGCA GGCTAGCTACAACGA GTCTTATA 5926 5655 UAAGACAU G CUAUCCCA 4641 TOCCATAG CCCTACCTACAACCA ATCTCTTA 5927 5658 GACAUGCJ A LTCGCACAU 4642 ATGTGCCA CGCTAGCTACAACGA AGCATGTC 5928 5661 AUCCUAUG G CACAUAUA 4643 TATATGTG GGCTAGCTACAACGA CATAGCAT 5929 5663 GCUAUGGC A CAUAUAUJ 4644 AATATATG GGCTAGCTACAACGA GCCATAGC 5930 5665 UAIJCCCAC A UAUAUUUA 4645 TAAATATA GGCTAGCTACAACGA GTGCCATA 5931 5667 UGGCACAU A UAtUEJUAUA 4646 TATAAATA GGCTAGCTACAACGA ATGTGCCA 5932 5669 GCACAUAU A UUIEATTAGU 4647 ACTATAAA GGCTAGCTACAACGA ATATGTGC 5933 5673 AflAUAUTJU A UAGUCUGU 4648 ACAGACTA GGCTAGCTACAACGA AAATATAT 5934 5676 UAUEJTJAUA G IJCUGUEJUA 4649 TA3ACAGA GGCTAGCTACAACGA TATAAATA 5935 5680 UAUAGUCLJ G UULJAUGUA 4650 -TACATAAA GGCTAGCTACAACGA AGACTATA 5936 5684 GCUGUUU~~t A tJCUAGAAA 4651 TTTCTACA GCCTAGCTACAACGA AAACAGAC 5937 5686 CUCUUUAJ C IJACAAACA 4652 TGTTTCTA GGCTAGCTACAACGA ATAAACAG 5938 5692 AUGLTAGAA A CAAAUGUA 4653 TACATTTG GGCTAGCTACAACGA TTCTACAT 5939 S696 AGAAACAA A UGUAAUAJ 4654 ATATTACA GGCTAGCTACAACG3A TTGTTTCT 5940 5698 AAACAAAJ G UAAUAUAU 4655 ATATATTA GGCTAGCTACAACG3A ATTTGTTT 5941 5701 CAAAUGUA A UAUAUUAA 4656 TTAATATA GGCTAGCTACAACGA TACATTTG 5942 5703 AAUGUAAU A UALJUAAAG 4657 CTTTAATA GGCTAGCTACAACGA ATTACATT 5943 5705 UGUAAUAU A UTUAAAGCC 4658 GGCTTTAA GGCTAGCTACAACGA ATATTACA 5944 5711 AUAUEJAAA G CCUJAUAU 4659 ATATAAGG CGCTAGCTACAACGA TTTAATAT 5945 5716 AAAGCCUJ A UAUAUAAU 4660 ATTATATA GGCTAGCTACAACGA AAGGCTTT 5946 5718 ACCCUUAJ A UAUAAUGA 4661 TCATTATA CCCTAGCTACAACGA ATAACGCT 5947 5720 CCUUAUAJ A UAAUGAAC 4662 GTTCATTA CCCTAGCTACAACGA ATATAAGC 5948 5723 UAUAUAUA A UGAACUJU 4663 AAAGTTCA GGCTAGCTACAACGA TATATATA 5949 5727 UAUAAUGA A CUTJUGUAC 4664 GTACAAAG GGCTAGCTACAACGA TCATTATA 5950 5732 UGAACUtJL G UACUAUUTC 4665 GALATAGTA GGCTAGCTACAACG4A AAAGTTCA 5951 5734 AACULTUGU A CUAUIJCAC 4666 GTGAATAG GGCTAGCTACAACGA ACAAAGTT 5952 5737 UUUGUACU A tJUCACAUJ 4667 AATGTGAA GGCTAGCTACAACGA ACTACAAX 5953 5741 UACUAUUC A CAtL=GU 4668 ACAAAATG GGCTAGCTACAACGA GAATAGTA 5954 5743 CUAUUTCAC A UTJTUtJUAU 4669 ATACAAAA GG3CTAGCTACAACGA GTGAATAG 5955 5748 CACAUJTJ G UALUCAGUA 4670 TACTGATA GGCTAGCTACAACGA AAAATGTG 5956 5750 CAUUUUGJ A UCAGJATU 4671 AATACTGA CGCTACCTACAACGA ACAAAATC 5957 .5754 UUGUAUCA G UAUJUAUGU 4672 JACATAATA GCCTAOCTACAALCGA TGATACAA 5958 WO 02/096927 WO 02/96927PCT/US02/17674 S756 GIJAUCAGU A UJEAUGUAG 4673 CTACATAA GGCTAGCTACAACGA ACTGATAC 5959 75S9 UCAGUAULT A UGUAGCAJ 4674 ATGCTACA CGC'DAOCTACAACOA AATACTGA 59G0 5761 AGUAULJAU G UAGCAUAA 4675 TTATGCTA GGCTAGCTACAACGA ATAATACT 5961 5764 AUEJAUGUA G CAUAACAA 4676 TTGTTATG GGCTAGCTACAACG4A TACATAAT 5962 5766 UAEJGUAGC A UAACAAAG 4677 CTTTGTTA GGCTAGCTACAACGA GCTACATA 5963 5769 GUAGCAUA A CAAAGGUC 4678 GACCTTTG GGCTAGCTACAACGA TATGCTAC 5964 5775 UAACAAAQ G UCAUAAUG 4679 CATTATGA GGCTAGCTACAACGA CTTTGTTrA 5965 5778 CAAAGG3UC A UAAUGCTI 4680 AAGCATTA GGCTAGCTACAACGA GACCTTTG 5966 5781 AGGEJCAUA A UGCULUJCA 4681 TGAAAGCA GGCTAGCTACJ4ACGA TAWGACCT 5967 5783 GUCAUAAU G CUUtJCAGC 4682 GCTGAAAG GGCTAGCTACAACGA ATTATGAC 5968 5790 IJGCUUEJCA G CAAUtJGAU 4683 ATCAATTG GGCTAGCTACAACGA TGAAAGCA 5969 5793 U1JUCACCA A UEJGAUGUC 4684 GACATCAA GGCTAGCTACAACGA TGCTGAAA 5970 5797 AGCAAEJUG A UGUCAUJEJ 4685 AAATGACA GGCDAGCTACAACGA CAATTGCT 5971 5799 CAAUEJGAU G UJCAUUUJA 4686 TAAAATGA GGCTAGCTACAACGA ATCAATTG 5972 5802 UTUGAUSUC A UEJT.UATTA 4687 TAATAAAA GGCTAGCTACAACGA GACATCAA 5973 8 07 GUCAUU A TJUAAAGAA 4688 TTCTTTAA GGCTAGCTACAACGA AAAATGAC 5974 5815 AUULAAAc4A A CAUEJGAAA 4689 TTTCAATG GGCTAGCTACAACGA TCTTTAAT 5975 5817 UAAAGAAC A UUGAAAAA 4690 TTTTCAA GGCTAGCTACAACGA GTT~CTTTA 5976 Input Sequence =AF035 121. Cut Site PY Arm Length 8. Core Sequence GGCTAGCTACAACGA AF035121 (Homo sapiens KDR/flk-1 protein miRNA, complete eds.; Acc# AF03512 1; 5830 bp)

Claims (10)

1. 2. The compound of claim 1, substantially as hereinbefore described with 0o reference to any one of the examples.
2. 3. A composition comprising the compound of claim 1 or 2 and a pharmaceutically acceptable carrier or diluent.
3. 4. A method of administering to a cell the compound of claim 1 or 2 comprising contacting said cell with the compound under conditions suitable for said administration.
4. 5. The method of claim 4, wherein said cell is a mammalian cell.
5. 6. The method of claim 4, wherein said cell is a human cell.
6. 7. The method of claim 4, wherein said administration is in the presence of a delivery reagent.
7. 8. The method of claim 7, wherein said delivery reagent is a lipid.
8. 9. The method of claim 8, wherein said lipid is a cationic lipid. The method of claim 8, wherein said lipid is a phospholipid.
9. 11. The method of claim 7, wherein said delivery reagent is a liposome. Dated 15 September, 2008 Sirna Therapeutics, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON
10. 1402527-.:cc