AU757789B2 - Method and reagents for the treatment of diseases or conditions related to molecules involved in angiogenic responses - Google Patents

Description

WO 99/50403 PCT/US99/06507 1

DESCRIPTION

Method And Reagents For The Treatment Of Diseases Or Conditions Related To Molecules Involved In Angiogenic Responses Background Of The Invention This invention relates to methods and reagents for the treatment of diseases or conditions relating to the levels of expression of angiogenic factors and receptors involved in the regulation of angiogenesis.

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

The formation of blood vessels in vertebrates can be described in two embyronic stages. During the first stage, known as vasculogenesis, yolk sac splanchnopleuric mesenchyme differentiates into vascular progenitor cells and then to blood island aggregates which are primitive blood cells surrounded by fused endothelial progenitors (angioblasts). These blood islands then fuse and go on to form a vascular plexus which supplies nutrients to the embryo (Merenmies et al., 1997, Gell Growth Development 8, 3-10). The next vascular developmental step is known as angiogenesis. From the vessels formed during vasculogenesis, new blood vessels sprout, elongate and develop into capillary loop formations of endothelial cells. It is a highly complex event involving local basement membrane disruption, endothelial cell proliferation, migration and microvessel morphogenesis (Rak et al., 1995, Anti-Cancer Drugs 6, 3-18). Organs such as the brain and kidney are vascularized through the angiogenic process (Dumont et al., 1995, Developmental Dynamics 203, 80-92).

WO 99/50403 PCT/US99/06507 2 Angiogenesis has been described to -occur through two mechanisms, vascular sprouting and intussusception.

Intussusception of pre-existing vessels occur after proliferation of endothelial cells producing a wide lumen.

Through the utilization of transcapillary pillars or posts of extracellular matrix, the lumen is split to form two vessels (Risau, 1997, Nature 386, 671-674). Sprouting angiogenesis also originates from pre-existing blood vessels and consists of new blood vessels sprouting, elongating and developing into capillary loop formations of endothelial cells. It is a highly complex event involving disruption of extracellular matrix, endothelial cell proliferation, chemotaxic migration and microvessel morphogenesis (Rak, supra). Many factors regulating positive and negative control of angiogenesis have been reported demonstrating the sophistication of this process.

An example of an angiogenic factor is Vascular Endothelial Growth Factor receptor (VEGFr) which has been shown to be specific to endothelial cells and is discussed in Pavco et al., Int. PCT Pub. No. WO 97/15662.

Unlike vasculogenesis, angiogenesis not only occurs in embyronic development, but can also occur throughout the lifespan of the organism during such events as wound healing, bone repair, inflammation, and female menstral cycles. Local delivery of oxygen and nutrients and the removal of waste requires a complex system of blood vessels which has the ability to adapt as the tissue requirements changes. Involvement of a large number of positive and negative factors in angiogenic regulation demonstrates the complexity of this process. When the balance between upregulating factors and downregulating factors is disrupted in favor of increased angiogenesis, disease states have been known to occur.

Many factors have been identified which contribute to increased angiogenesis including: WO 99/50403 PCT/US99/06507 3 1) ryl Hydrocarbon Nuclear Transporter (ARNT): ARNT (also known as HIF-13) forms heterodimers with several factors including HIF-a(Maxwell et al., 1997, Proc. Natl.

Acad. Sci. USA 94, 8104-8109). When HIF-a and ARNT complex together, they form a complex called HIF-1. HIF -1 is believed to be regulate genes involved in the response to oxygen deprivation. ARNT embryonic stem cells fail to induce VEGF expression in response to hypoxia. ARNT mice are not viable beyond embryonic day 10.5. Like VEGF knockout mice, these embryos show defective angiogenesis of the yolk sac (Maltepe et al., 1997, Nature 386, 403- 407).

Hepatoma cells containing an ARNT mutation that is functionally deficient in dimerizing with HIF-la shows greatly reduced VEGF expression in response to hypoxia compared to normal cells (Wood et al., 1996, J. Biol.

Chem. 271, 15117-15123). Tumor xenografts derived from these cells show reduced vascularity and approximately 2fold reduced tumor growth rates (Maxwell et al., 1997, supra).

2) Tie-2: Tie-2 (also known as Tek), is a tyrosine kinase protein receptor which consists of 1122 amino acids and is produced in endothelial (Merenmies et al., 1997, Cell Growth Differentiation 8, 3-10) as well as early hematopoeitic cells (Maisonpierree et al., 1993, Oncogene 8, 1631-1637). Tie-2 expression has been demonstrated in mice, rats and humans. The human gene is thought to be located on chromosome 9p21 (Dumont et al., 1994, Genes Development 8, 1897-1909). Tie-2 homozygous mutant endothelial cells were examined using anti-PECAM monoclonal antibody (Sato et al., 1997, Nature 376, 74). All of the homozygous mutants were dead within 10.5 days with obvious deformities in the head and heart present by day 9.5. In addition, large vessels were indistinguishable from small vessels and no capillary WO 99/50403 PCT/US99/06507 4 sprouts were seen in the brain. These observations suggested that Tie-2 plays an important role in angiogenesis rather than vasculogenesis. The earlier effects of Tie-2 mutant compared to the Tie-i mutant indicates separate roles for the two RTK's in angiogenesis.

Ligands to Tie-2 have been discovered and named angiopoietin 1 and 2 (angl and 2) (Davis, S. et al., 1993, Cell 87, 1161; Maisonpierre, P.C. et al.,1997, Science, 277, 55-60). Both factors consist of an NH2-terminal coiled-coil domain as well as a COOH-terminal fibrinogenlike domain. Angl binds to Tie-2/Tek but not Tie-i and stimulates angiogenesis through autophosphorylation. Ang2 is a 496 amino acid polypeptide whose human and mouse homologs are 85% identical. Autophosphorylation caused by Angl binding to the Tie-2 receptor can be blocked with the addition of Ang2. The Tie-2 receptor is unusual in that it utilizes both positive and negative control mechanisms.

3) Integrins: Integrins are a family of cell adhesion and migration mediating proteins that are comprised of at least 15 alpha and 8 beta subunits that are expressed as a number of different ap non-covalently bound heterodimers on cell surfaces (Varner, 1997, Regulation of Angiogenesis, ed I.D Goldberg E.M. Rosen, 361-390; Brooks, 1996, Eur J Cancer 14, 2423-2429). Each combination of integrin subunits is thought to have angiogenic capabilities, for example as 1 has been implicated in capillary tube formation Additionally, distinct integrins allow for the attachment to many different extracellular matrix (ECM) components including fibronectin, vitronectin, laminin and collagen (Stromblad Cheresh, 1996, Chemistry Biochemistry 3, 881-885).

Integrin production has been shown to be induced by a number a stimuli including intracellular pH increases, calcium concentration, inositol lipid synthesis, tyrosine WO 99/50403 PCT/US99/06507 phosphorylation of a focal contact associated tyrosine kinase, and activation of p34/cdc2 and cyclin A (Varner Cheresh, 1996, Curr Op in Cell Biol 8,724-730).

cvc3 a 160kDa protein is the most well characterized molecule of the integrin family and is believed to play a large role in angiogenesis (Varner, 1997, supra). oP3 binds the largest number of ECM components of all known heterodimers indicating any cell with these molecules on the cell surface could adhere to or migrate on almost any of the ECM components (Varner, 1997, supra). When vascular endothelial cells are in their quiescent state very little aIP3 is expressed, but is highly upregulated in several pathological conditions including neoplasms.

Antagonists to avP 3 can inhibit angiogenesis in the chick chorioallentoic membrane (CAM) model and in SCID mice and even reduce the tumor volume. When antibodies are administered for AvP 3 apoptosis is observed in the proliferating vascular vessels. This has led to suggestions that aCv3 provides a survival signal for vascular cells allowing for continued proliferation (Stromblad Cheresh, 1996, supra; Varner, 1997 supra).

Other angiogenic targets are included and their characteristics are defined in the following references, all of which are incorporated herein by reference in their entirety: Methionine Aminopeptidase: (Arfin et al., 1995, PNAS 92, 7714-7718 (Genbank Accession No. U29607) Sin, N. et.al., 1997, PNAS 94, 6099-6103; Griffith et al., 1997, Chem Biol. 461-471); Transcription factor Ets- 1: (Iwasaka, C. et al. 1996.J. Cell Physiol. 169, 522-531; Chen, Z. et al. ,1997, Cancer Res. 57, 2013-2019; Hultgardh-Nilsson A, et al., 1996, Circ Res. 78(4), 589- 595; Reddy et al., 1988, Oncogene Res. 3 239-246 (Genbank accession No. X14798)); Platelet-derived endothelial cell growth factor and its receptor (PD-ECGF PD-ECGFr): (Furukawa, T. et al., 1992, Nature 356, 668; WO 99/50403 WO 9950403PCTIUS99/06507 6 Moghaddam, A. et al., 1995, Proc. Natl. Acad. Sci.; Clark, R.A.F. et al. ,1996, Am J. Pathol. 148, 1407; Hoshina, et 1995, Int. J. Cancer 64, 79-82; Nakanishi, A. et al., 1992, J. Biol. Chem 267, 20311-20316; Finnis et al., unpublished (Genbank accession No. M63193); Transforming Growth factors (TGFs): (Schreiber et al., 1986, Science 232, 1250; Maione, T.E. and Sharpe, R.J.,11990, Trends Pharm. Sc, 11, 457-461; Noma et al., 1991,Growth Factors 4 247-255; Sukurai (unpublished) (Genbank accession No. AB009356);Transformning growth factor receptor: (Miyazono, K.,1996, Nippon Yakurigaku Zasshu 107, 133-140; Mahooti-Brooks. et al.,1996, J. Clin.

Invest. 97, 1436-1446; Lopez-Casillas et al., 1991, Cell 67 797-805; Lopez-Casillas et al., 1991, Cell 67 785-795 (Genbank Accession No. L07594); Angiogenin: (Fett et al., 1985, Biochemistryv 24, 5480-5486; Bicknell Vallee, 1988, PNAS 85, 5961-5965; Vallee Riordan,1988, Adv. Exp. Med. Biol 234, 41-53; Shapiro Vallee,1987, PNAS 84, 2238-2241; Shapiro et al.,1986, Biochemistryv 3527-3532; Olson et al., 1994, Cancer Res. 54, 4576-4579; Kurachi et al., 1985, Biochemistry 24, 5494-5499; Kurachi et al., 1985, Biochemistry 24 5494-5499(Genbank Accession No. M11567)); Tumor necrosis factor receptor: (Naismith et al. 1995, J. Inflamm 47, 1-7; Loetscher et al., 1990, Cell 61, 351-359; Himmier et al., 1990, DNA Cell Biol. 9, 705-715 (Genbank Accession No. M63121 M75861); Endothelial cell stimulating angiogenesis factor (ESAF): (Brown Weiss, 1988, Ann. Rheum. Dis. 47, 881- 885); Interleukin-8 (IL-8) (Elner et al., 1991, Am J. Pathol. 139, 977-988; Strieter et al.,1992, Am. J.

Pathol. 141, 1279-1284; Mukaida et al., 1989, J. Immunol.

143 1366-1371(Genbank Accession No. M28130)); Angiopoietin 1: (Davis, S. et al.,1996, Cell 87, 1161; Iwama, A. et al.,1993, Biochem Biophys. Res. Commun. 195, 301; Dumont, D.J. et al.,1995, Genes Dev 8, 1897; Sato, WO 99/50403 WO 9950403PCT/US99/06507 7 T.N. et al.,1995, Nature 376, 70; Suni, C. et al. 1996) Cell 87, 1171 (Genbank Accession No. U83508)) Angiopoietin 2 (Maisonpierre, et al.,1997, Science, 277, 55-60; Hanahan, 1997, Science 277, 48-50; Genbank Accession No.

AF004327 (unpublisheci));Insulin-like growth factor (IGF- 1) (Warren, R.S. et al.,1996, J. Biol. Chem. 271, 29483- 29488; Grant et.al., 1993,Diabetologia 36, 282-291; Nicosia et al., 1994,Am. J. Pathol. 145, 1023-1029; Steenbergh et al. Biochem. Biophys. Res. Cominun. 175, 507-514 (Genbank Accession: X57025) Insulin-like growth factor receptor (IGF-lr) (Ulirich et al., 1986, EMBO J.

2503-2512 (Genbank Accession No. X04434 M24599) B61: (Pandey, A. et al. 1995, Science 268, 567-569; Holzman et al., 1990, Mol. Cell. Biol. 10, 5830-5838 (Genbank Accession No. M57730 M37476); B61 receptor (Eck) (Pandey, A. et al. 1995, Science 268, 567-569; Lindberg Hunter, 1990, Mol. Cell. Biol. 10 6316-6324 (Genbank Accession No. M59371 M36395) Protein kinase C: (Morris et al., 1988, Cell Physiol. 23, C318-C322; Qikawa, T. et al., 1992, J. Antibiot. 45, 1155-1160; Finkenzeller. et al., 1992, Cancer Res. 52, 4821-4823; Kubo et al., 1987, FEBS Lett. 223 138-142 (Genbank Accession No. X06318 M27545); SH2 domain (Guo, D. et al., 1995, J. Biol.

Chem 270, 6729-6733) a. Phospholipase c-g:(Guo, D. at al., 1995, Biol.

Chem 270, 6729-6733; Rhee, S.G. et al. (1992) Biol.

Chemn 267, 12393-12396; Burgess et al., 1990, Mol. Cell.

Biol. 10, 4770-4777 (Genbank Accession No. M34667)) b. Phosphatidylinositol 3 kinase (P1-3) (Downs, C.P.

et al.,1991, Cell Signalling 3, 501-513; Genbank accession No. Z29090; Genbank accession No. Z46973) c. Ras GTPase activating protein (GAP) (Trahey, M.

et al.,1987, Science 238, 542-545; Guo, D. et al., 1995, Biol. Chemn 270, 6729-6733; Trahey et al., 1988, Science 242, 1697-1700 (Genbank accession No. M23612)) 8 d. Oncogene adaptor protein Nck: (Park Rhee, 1992, Mol. Cell. Biol. 12,5816- 5823; Johnson, 1990, Nucleic Acids Res. 18 1048 (Genbank accession No. X17576)); Granulocyte Colony-Stimulating Factor: (Devlin et al., 1987, J. Leukoc. Biol. 41,302-306 (Genbank accession No. M17706)); Hepatocyte growth factor: (Miyazawa et al., 1991, Eur. J. Biochem. 197 15-22 (Genbank accession No. X57574); Proliferin: (Groskopf et al., 1997, Endocrinology 138 2835-2840; Jackson D, et al., 1994, Science. 266 (5190), 1581-1584; Volpert et al., 1996, Endocrinology 137 3871-3876); Placental growth factor: (Kodama et al., 1997, Eur J Gynaecol Oncol.; 18 508510 Ziche et al., 1997, Lab Invest. 76 517-531; Relf et al., 1997, Cancer Res. 57 963-969 Genbank accession No. Y09268) Summary Of The Invention S. The invention features the use of enzymatic nucleic acid molecules and methods for their use to down regulate or inhibit the expression of angiogenic factors. Specifically, the enzymatic nucleic acids of the present invention are used as a treatment for indications relating to angiogenesis including but not limited to cancer, age related macular degeneration (ARMD), diabetic retinopathy, inflammation, arthritis, psoriasis and the like.

Thus, herein disclosed are nucleic acid molecules that cleave RNAs encoding angiogenic selected from a group comprising: Tie-2, integrin subunit P3, integrin subunit 20 ca6, and aryl hydrocarbon nuclear transporter (ARNT).

According to an embodiment of the invention, there is provided an enzymatic nucleic acid molecule with RNA cleaving activity, wherein said enzymatic nucleic acid molecule specifically cleaves RNA encoded by an aryl hydrocarbon nuclear transporter (ARNT) gene.

By "inhibit" it is meant that the activity of the cleaved RNA is reduced below that observed in the absence of the nucleic acid. In one embodiment, inhibition with ribozymes preferably is below that level observed in the presence of an enzymatically inactive RNA molecule that is WO 99/50403 PCT/US99/06507 9 able to bind to the same site on the mRNA, but is unable to cleave that RNA.

By "angiogenic factors" is meant a peptide molecule which is involved in a process or pathway necessary for the formation of novel blood vessels.

In another preferred embodiment, the invention features the use of enzymatic nucleic acids that cleave the RNAs encoded by angiogenic factors selected from a group comprising: Methionine Aminopeptidase; Ets-1 Transcription factor; integrins; platelet derived endothelial cell growth factor (PD-ECGF); PD-ECGF receptor; Transforming Growth factors (TGFs); Transforming growth factor receptor; Angiogenin; Endothelial cell stimulating angiogenesis factor (ESAF); Interleukin-8 (IL- Angiopoietin 1 and 2; TIE-1; insulin-like growth factor (IGF-1); insulin-like growth factor receptor (IGF- Ir); B61; B61 receptor (Eck); Protein kinase C; an SH2 domain Phospholipase c-g, Phosphatidylinositol 3 kinase Ras GTPase activating protein (GAP); Oncogene adaptor protein Nck; Granulocyte Colony- Stimulating Factor; Hepatocyte growth factor; Proliferin; and Placental growth factor.

By "enzymatic nucleic acid" it is meant a nucleic acid molecule capable of catalyzing reactions including, but not limited to, site-specific cleavage and/or ligation of other nucleic acid molecules, cleavage of peptide and amide bonds, and trans-splicing. Such a molecule with endonuclease activity may have complementarity in a substrate binding region to a specified gene target, and also has an enzymatic activity that specifically cleaves RNA or DNA in that target. That is, the nucleic acid molecule with endonuclease activity is able to intramolecularly or intermolecularly cleave RNA or DNA and thereby inactivate a target RNA or DNA molecule. This complementarity functions to allow sufficient WO 99/50403 PCT/US99/06507 hybridization of the enzymatic RNA molecule to the target RNA or DNA to allow the cleavage to occur. 100% complementarity is preferred, but complementarity as low as 50-75% may also be useful in this invention. The nucleic acids may be modified at the base, sugar, and/or phosphate groups. The term enzymatic nucleic acid is used interchangeably with phrases such as ribozymes, catalytic RNA, enzymatic RNA, catalytic DNA, 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 meant to be limiting 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 nucleic acid regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart a nucleic acid cleaving activity to the molecule (Cech et al., U.S. Patent No. 4,987,071; Cech et al., 1988, JAMA).

By "enzymatic portion" or "catalytic domain" is meant that portion/region of the ribozyme essential for cleavage of a nucleic acid substrate (for example see Figure 1).

By "substrate binding arm" or "substrate binding domain" is meant that portion/region of a ribozyme which is complementary to able to base-pair with) a portion of its substrate. Generally, such complementarity is 100%, but can be less if desired. For example, as few as 10 bases out of 14 may be base-paired. Such arms are shown generally in Figure 1. That is, these arms contain sequences within a ribozyme which are intended to bring ribozyme and target RNA together through complementary WO 99/50403 PCT/US99/06507 11 base-pairing interactions. The ribozyme of the invention may have binding arms that are contiguous or noncontiguous and may be of varying lengths. The length of the binding arm(s) are preferably greater than or equal to four nucleotides; specifically 12-100 nucleotides; more specifically 14-24 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; five and five nucleotides, six and six nucleotides or seven and seven nucleotides long) or asymmetrical the binding arms are of different length; 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 DNAzyme is meant, an enzymatic nucleic acid molecule lacking a 2'-OH group.

In one of the preferred embodiments, the enzymatic nucleic acid molecule is formed in a hammerhead or hairpin motif, but may also be formed in the motif of a hepatitis 6 virus, group I intron, group II' intron or RNase P RNA (in association with an RNA guide sequence), Neurospora VS RNA or DNAzymes. Examples of such hammerhead motifs are described by Dreyfus, supra, Rossi et al., 1992, AIDS Research and Human Retroviruses 8, 183; of hairpin motifs 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; of the hepatitis d virus motif is described by Perrotta and Been, 1992 Biochemistry 31, 16; of the RNaseP motif 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; Neurospora VS RNA ribozyme motif is described by Collins (Saville and Collins, 1990 Cell 61, WO 99/50403 PCT/US99/06507 12 685-696; 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); 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; of the Group I intron by Cech et al., U.S.

Patent 4,987,071 and of DNAzymes by Usman et al., 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. These specific motifs 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 gene RNA regions, and that it have nucleotide sequences within or surrounding that substrate binding site which impart an RNA cleaving activity to the molecule (Cech et al., U.S.

Patent No. 4,987,071).

By "equivalent" RNA to Tie-2, integrin subunit P3, integrin subunit a6, or ARNT is meant to include those naturally occurring RNA molecules having homology (partial or complete) to Tie-2, integrin subunit P3, integrin subunit a6, or ARNT or encoding for proteins with similar function as Tie-2, integrin subunit 33, integrin subunit a6, or ARNT in various animals, including human, rodent, primate, rabbit and pig. The equivalent RNA sequence also includes in addition to the coding region, regions such as 5'-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.

13 By "complementarity" is meant a nucleic acid molecule that can form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types (for example, Hoogsteen type) of base-paired interactions.

Also herein disclosed is a method for producing a class of enzymatic cleaving agents which exhibit a high degree of specificity for the RNA of a desired target. The enzymatic nucleic acid molecule may be targeted to a highly conserved sequence region of target RNAs encoding Tie-2, integrin subunit P3, integrin subunit cx6, or ARNT proteins such that specific treatment of a disease or condition can be provided with either one or several enzymatic nucleic acids. Such enzymatic nucleic acid molecules can be delivered exogenously to specific cells as required. Alternatively, the ribozymes can be expressed from DNA/RNA vectors that are delivered to specific cells.

Thus, according to another embodiment of the invention, there is provided an expression vector comprising a nucleic acid sequence encoding at least one enzymatic nucleic acid molecule of the invention in a manner which allows expression of that 15 enzymatic nucleic acid molecule.

:i According to another embodiment of the invention, there is provided a method for modulating expression of ARNT gene in a mammalian cell comprising the step of administering to said cell an enzymatic nucleic acid molecule of the invention.

According to another embodiment of the invention, there is provided a method for modulating expression of ARNT gene in a mammalian cell comprising the step of administering to said cell an expression vector comprising a nucleic acid sequence encoding an enzymatic nucleic acid molecule of the invention.

According to another embodiment of the invention, there is provided a method of cleaving an ARNT RNA molecule comprising the step of, contacting an enzymatic 25 nucleic acid molecule of the invention with said ARNT RNA molecule under conditions suitable for the cleavage of said ARNT RNA molecule.

o Mammalian cells, typically human cells, including an enzymatic nucleic acid molecule of the invention, or an expression vector comprising a nucleic acid sequence S. encoding an enzymatic nucleic acid molecule of the invention, are also provided.

By "highly conserved sequence region" is meant a nucleotide sequence of one or more regions in a nucleic acid molecule does not vary significantly from one generation to the other or from one biological system to the other.

Such ribozymes are useful for the prevention of the diseases and conditions including cancer, diabetic retinopathy, macular degeneration, neovascular glaucoma, myopic degeneration, arthritis, psoriasis, verruca vulgaris, angiofibroma of tuberous sclerosis, pot-wine stains, Sturge Weber syndrome, Kippel-Trenaunay-Weber syndrome, Osler-Weber-Rendu syndrome and any other diseases or conditions that are related to the Slevels of Tie-2, integrin subunit 33, integrin subunit ac6, or ARNT activity in a cell or f 1 1, 14 Thus, according to another embodiment of the invention, there is provided a pharmaceutical composition comprising an enzymatic nucleic acid molecule of the invention. There is also provided a pharmaceutical composition comprising an expression vector of the invention.

According to another embodiment of the invention, there is provided a method for treatment of cancer, diabetic retinopathy, age related macular degeneration (ARMD), inflammation, or arthritis comprising the step of administering to a patient an enzymatic nucleic acid molecule of the invention, or a pharmaceutical composition comprising said enzymatic nucleic acid molecule. According to a related aspect, there is provided the use of an enzymatic nucleic acid molecule of the invention for the manufacture of a medicament for treating cancer, diabetic retinopathy, age related macular degeneration (ARMD), inflammation, or arthritis in a patient.

According to another embodiment of the invention, there is provided a method for treatment of cancer, comprising the step of administering to a patient an expression vector 15 of the invention, or a pharmaceutical composition comprising said expression vector.

:i According to a related aspect, there is provided the use of an expression vector of the .invention for the manufacture of a medicament for treatment of cancer in a patient.

According to another embodiment of the invention, there is provided a method for treatment of diabetic retinopathy, age related macular degeneration (ARMD), inflammation, or arthritis comprising the step of administering to a patient an expression vector of the invention, or a pharmaceutical composition comprising said expression vector. According to a related aspect, there is provided the use of an expression vector of the invention for the manufacture of a medicament for treating diabetic retinopathy, age related macular degeneration (ARMD), inflammation, or arthritis in a patient.

25 According to another embodiment of the invention, there is provided a method of treatment of a patient having a condition associated with an elevated level of aryl o hydrocarbon nuclear transporter (ARNT), comprising administering to said patient an enzymatic nucleic acid molecule of the invention, or a pharmaceutical composition S• comprising said enzymatic nucleic acid molecule. According to a related aspect, there is provided the use of an enzymatic nucleic acid molecule of the invention for the manufacture of a medicament for treating a patient having a condition associated with an elevated level of aryl hydrocarbon nuclear transporter (ARNT).

According to another embodiment of the invention, there is provided a method of treatment of a patient having a condition associated with an elevated level of aryl hydrocarbon nuclear transporter (ARNT), comprising administering to said patient an expression vector of the invention, or a pharmaceutical composition comprising said expression vector. According to a related aspect, there is provided the use of an A 1T expression vector of the invention for the manufacture of a medicament for treating a A524183speci patient having a condition associated with an elevated level of aryl hydrocarbon nuclear transporter (ARNT).

According to another embodiment of the invention, there is provided a method of treatment of a patient having a condition associated with the level of aryl hydrocarbon nuclear transporter (ARNT), comprising the steps of: contacting cells of said patient with an enzymatic nucleic acid molecule of the invention; and administering to said patient one or more additional drugs. According to a related aspect, there is provided the use of an enzymatic nucleic acid molecule of the invention for the manufacture of a medicament for treating a patient having a condition associated with the level of aryl hydrocarbon nuclear transporter (ARNT).

According to another embodiment of the invention, there is provided a method of treatment of a patient having a condition associated with the level of aryl hydrocarbon nuclear transporter (ARNT), comprising the steps of: contacting cells of said patient with an expression vector of the invention; and administering to said patient one or 15 more additional drugs. According to a related aspect, there is provided the use of an expression vector of the invention for the manufacture of a medicament for treating a patient having a condition associated with the level of aryl hydrocarbon nuclear transporter (ARNT).

By "related" is meant that the inhibition of Tie-2, integrin subunit p3, integrin subunit a6, and/or ARNT RNAs and thus reduction in the level respective protein activity will relieve to some extent the symptoms of the disease or condition.

The ribozymes may have binding arms which are complementary to the target sequences in Tables III-X. Examples of such ribozymes are also shown in Tables III-X.

Tables III and IV display target sequences and ribozymes for ARNT, Tables V and VI 25 display target sequences and ribozymes for Tie-2, tables VII and VIII display target sequences and ribozymes for integrin subunit alpha 6, and tables IX and X display target sequences and ribozymes for integrin subunit beta 3. Examples of such ribozymes consist essentially of sequences defined in these Tables.

By "consists essentially of' is meant that the active ribozyme contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind mRNA such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage.

Thus, herein disclosed are ribozymes that inhibit gene expression and/or cell proliferation. These chemically or enzymatically synthesized RNA molecules contain substrate binding domains that bind to accessible regions of their target mRNAs. The RNA molecules also contain domains that catalyze the cleavage of RNA. The RNA molecules are preferably ribozymes of the hammerhead or hairpin motif. Alternatively,

T

e ribozymes are DNAzymes. Upon binding, the 183spcci ribozymes cleave the target mRNAs, preventing translation and protein accumulation. In the absence of the expression of the target gene, cell proliferation is inhibited.

Chemically synthesized RNA molecules also include RNA molecules assembled together from various fragments of RNA using a chemical or an enzymatic ligation method.

As disclosed herein, ribozymes may be added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through injection, infusion pump or stent, with or without their incorporation in biopolymers. The ribozyme may be administered to the site of Tie-2, integrin subunit 33, integrin subunit a6, or ARNT expression tumor cells, endothelial cells) in an appropriate liposomal vehicle.

Thus, according to another embodiment of the invention, there is provided a method for treatment of cancer comprising the steps of: a) isolating cells from a patient; b) administering to said cells an enzymatic nucleic acid molecule of the invention; and c) 15 introducing said cells back into said patient.

According to another embodiment of the invention, there is provided a method for treatment of cancer comprising the steps of: a) isolating cells from a patient; b) administering to said cells an expression vector of the invention; and c) introducing said cells back into said patient.

As also disclosed herein, ribozymes that cleave target molecules and inhibit Tie-2, integrin subunit P3, integrin subunit a6, or ARNT activity are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors are preferably DNA plasmids or viral vectors. Ribozyme expressing viral vectors could be S* constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or S 25 alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes. Such vectors might be repeatedly administered as necessary. Once expressed, the ribozymes cleave the target RNA. Delivery of ribozyme expressing vectors could be systemic, such as by intravenous or intramuscular 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 and Stinchcomb, 1996, TIG., 12, 510). In another aspect of the invention, ribozymes that cleave WO 99/50403 PCTIUS99/06507 16 target molecules and inhibit cell proliferation are expressed from transcription units inserted into DNA, RNA, or viral vectors. Preferably, the recombinant vectors capable of expressing the ribozymes are locally delivered as described above, and transiently persist in smooth muscle cells. However, other mammalian cell vectors that direct the expression of RNA may be used for this purpose.

By "patient" is meant an organism which is a donor or recipient of explanted cells or the cells themselves.

"Patient" also refers to an organism to which enzymatic nucleic acid molecules can be administered. Preferably, a patient is a mammal or mammalian cells. More preferably, a patient is a human or human cells.

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

These ribozymes, 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 Tie-2, integrin subunit P3, integrin subunit a6, or ARNT, the patient may be treated, or other appropriate cells may be treated, as is evident to those skilled in the art.

In a further embodiment, the described ribozymes can be used in combination with other known treatments to treat conditions or diseases discussed above. For example, the described ribozymes could be used in combination with one or more known therapeutic agents to treat cancer.

In preferred embodiments, the ribozymes have binding arms which are complementary to the sequences in the tables, shown as Seq. I.D. Nos. 394-786, 849-910, 1612- 2312, 2381-2448, 3588-4726, 4821-4914, 5702-6488, and 6569-6648. Examples of such ribozymes are shown as Seq.

I.D. Nos.1-393, 787-848, 911-1611, 2313-2380, 2449-3587, WO 99/50403 PCT/US99/06507 17 4727-4820. 4915-5701, and 6489-6568. Other sequences may be present which do not interfere with such cleavage.

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

Description Of The Preferred Embodiments The drawings will first briefly be described.

Figure 1 shows the secondary structure model for seven different classes of enzymatic nucleic acid molecules. Arrow indicates the site of cleavage. indicate the target sequence. Lines interspersed with dots are meant to indicate tertiary interactions. is meant to indicate base-paired interaction. Group I Intron: P1-P9.0 represent various stem-loop structures (Cech et al., 1994, Nature Struc. Bio., 1, 273). RNase P (M1RNA): EGS represents external guide sequence (Forster et al., 1990, Science, 249, 783; Pace et al., 1990, J.

Biol. Chem., 265, 3587). Group II Intron: 5'SS means splice site; 3'SS means 3'-splice site; IBS means intron binding site; EBS means exon binding site (Pyle et al., 1994, Biochemistry, 33, 2716). VS RNA: I-VI are meant to indicate six stem-loop structures; shaded regions are meant to indicate tertiary interaction (Collins, International PCT Publication No. WO 96/19577). HDV Ribozyme: :I-IV are meant to indicate four stem-loop structures (Been et al., US Patent No. 5,625,047).

Hammerhead Ribozyme: :I-III are meant to indicate three stem-loop structures; stems I-III can be of any length and may be symmetrical or asymmetrical (Usman et al., 1996, Curr. Op. Struct. Bio., 1, 527). Hairpin Ribozyme: Helix 1, 4 and 5 can be of any length; Helix 2 is between 3 and 8 base-pairs long; Y is a pyrimidine; Helix 2 (H2) is provided with a least 4 base pairs n is 1, 2, 3 or 4) and helix 5 can be optionally provided of length 2 or WO 99/50403 PCT/US99/06507 18 more bases (preferably 3 20 bases, m is from 1 or more). Helix 2 and helix 5 may be covalently linked by one or more bases r is 1 base). Helix 1, 4 or may also be extended by 2 or more base pairs 4 20 base pairs) to stabilize the ribozyme structure, and preferably is a protein binding site. In each instance, each N and N' independently is any normal or modified base and each dash represents a potential base-pairing interaction. These nucleotides may be modified at the sugar, base or phosphate. Complete base-pairing is not required in the helices, but is preferred. Helix 1 and 4 can be of any size o and p is each independently from 0 to any number, 20) as long as some basepairing is maintained. Essential bases are shown as specific bases in the structure, but those in the art will recognize that one or more may be modified chemically (abasic, base, sugar and/or phosphate modifications) or replaced with another base without significant effect.

Helix 4 can be formed from two separate molecules, i.e., without a connecting loop. The connecting loop when present may be a ribonucleotide with or without modifications to its base, sugar or phosphate. is 2 bases. The connecting loop can also be replaced with a non-nucleotide linker molecule. H refers to bases A, U, or C. Y refers to pyrimidine bases. refers to a covalent bond. (Burke et al., 1996, Nucleic Acids Mol.

Biol., 10, 129; Chowrira et al., US Patent No. 5,631,359).

Figure 2 is a diagrammatic representation of a hammerhead ribozyme targeted against Tie-2 at position 1037.

Enzymatic Nucleic Acid Molecules Seven basic varieties of naturally-occurring enzymatic RNAs are known presently. In addition, several in vitro selection (evolution) strategies (Orgel, 1979, WO 99/50403 PCT/US99/06507 19 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 phosphodiester bonds in trans (and thus can cleave other RNA molecules) under physiological conditions. Table I summarizes some of the characteristics of some of these ribozymes. In general, enzymatic nucleic acids act by first binding to a target RNA. Such binding occurs through the target binding portion of an enzymatic nucleic acid which is held in close proximity to an enzymatic portion of the molecule that acts to cleave the target RNA. Thus, the enzymatic nucleic acid first recognizes and then binds a target RNA through complementary base-pairing, and once bound to the correct site, acts enzymatically to cut the target RNA.

Strategic cleavage of such a target RNA will destroy its ability to direct synthesis of an encoded protein. After an enzymatic nucleic acid has bound and cleaved its RNA target, it is released from that RNA to search for another target and can repeatedly bind and cleave new targets.

The enzymatic nature of a ribozyme is advantageous over other technologies, since the concentration of ribozyme necessary to affect a therapeutic treatment is lower. This advantage reflects the ability of the WO 99/50403 PCT/US99/06507 ribozyme to act enzymatically. Thus, a single ribozyme molecule is able to cleave many molecules of target RNA.

In addition, the ribozyme is a highly specific inhibitor, with the specificity of inhibition depending not only on the base-pairing mechanism of binding to the target RNA, but also on the mechanism of target RNA cleavage. Single mismatches, or base-substitutions, near the site of cleavage can be chosen to completely eliminate catalytic activity of a ribozyme.

Nucleic acid molecules having an endonuclease enzymatic activity are able to repeatedly cleave other separate RNA molecules in a nucleotide base sequencespecific manner. Such enzymatic nucleic acid molecules can be targeted to virtually any RNA transcript, and efficient cleavage achieved 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 ribozymes show promise as therapeutic agents for human disease (Usman McSwiggen, 1995 Ann. Rep. Med. Chem. 285-294; Christoffersen and Marr, 1995 J. Med. Chem. 38, 2023-2037). Ribozymes can be designed to cleave specific RNA targets within the background of cellular RNA. Such a cleavage event renders the RNA non-functional and abrogates protein expression from that RNA. In this manner, synthesis of a protein associated with a disease state can be selectively inhibited.

Ribozymes that cleave the specified sites in Tie-2, integrin subunit p3, integrin subunit a6, and aryl hydrocarbon nuclear transporter (ARNT) mRNAs represent a novel therapeutic approach to treat cancer, macular WO 99/50403 PCT/US99/06507 21 degeneration, diabetic retinopathy, inflammation, psoriasis and other diseases. Applicant indicates that ribozymes are able to inhibit the activity of Tie-2; integrin subunit 03; integrin subunit a6; and aryl hydrocarbon nuclear transporter (ARNT) and that the catalytic activity of the ribozymes is required for their inhibitory effect. Those of ordinary skill in the art will find that it is clear from the examples described that other ribozymes that cleave Tie-2, integrin subunit p3, integrin subunit a6, and aryl hydrocarbon nuclear transporter (ARNT) mRNAs may be readily designed and are within the scope of the invention.

Target sites Targets for useful ribozymes 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.

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. Ribozymes to such targets are designed as described in those applications and synthesized to be tested in vitro and in vivo, as also described. Such ribozymes can also be optimized and delivered as described therein.

The sequence of human Tie-2, integrin subunit P3, integrin subunit a6, and aryl hydrocarbon nuclear transporter (ARNT) mRNAs were screened for optimal ribozyme target sites using a computer folding algorithm.

Hammerhead or hairpin ribozyme cleavage sites were identified. These sites are shown in Tables III-X (All sequences are 5' to 3' in the tables) The nucleotide base position is noted in the Tables as that site to be cleaved by the designated type of ribozyme. The nucleotide base WO 99/50403 PCT/US99/06507 22 position is noted in the tables as that site to be cleaved by the designated type of ribozyme.

Hammerhead or hairpin ribozymes were designed that could bind and were individually analyzed by computer folding (Jaeger et al., 1989 Proc. Natl. Acad. Sci. USA, 86, 7706) to assess whether the ribozyme sequences fold into the appropriate secondary structure. Those ribozymes with unfavorable intramolecular interactions between the binding arms and the catalytic core are eliminated from consideration. Varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA. Ribozymes of the hammerhead or hairpin motif were designed to anneal to various sites in the mRNA message. The binding arms are complementary to the target site sequences described above.

Ribozyme Synthesis 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 antisense oligonucleotides, hammerhead or the hairpin ribozymes) are used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of the mRNA structure. However, these nucleic acid molecules can also 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; Sullenger 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- WO 99/50403 PCT/US99/06507 23 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). 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 ribozyme (Draper et al., PCT W093/23569, and Sullivan et al., PCT W094/02595, both hereby incorporated in their totality by reference herein; 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).

The ribozymes were chemically synthesized. The method of synthesis used follows the procedure for normal RNA synthesis 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 and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the end, and phosphoramidites at the 3'-end. In a nonlimiting example, small scale synthesis were conducted on a 394 Applied Biosystems, Inc. synthesizer using a modified 2.5 pmol scale protocol with a 5 min coupling step for alkylsilyl protected nucleotides and 2.5 min coupling step for 2'-O-methylated nucleotides. Table II outlines the amounts, and the contact times, of the reagents used in the synthesis cycle. A 6.5-fold excess (163 pL of 0.1 M 16.3 umol) of phosphoramidite and a 24fold excess of S-ethyl tetrazole (238 pL of 0.25 M 59.5 pmol) relative to polymer-bound 5'-hydroxyl was used in each coupling cycle. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, were 97.5-99%. Other oligonucleotide synthesis reagents for the WO 99/50403 PCT/US99/06507 24 394 Applied Biosystems, Inc. synthesizer :detritylation solution was 2% TCA in methylene chloride (ABI); capping was performed with 16% N-methyl imidazole in THF (ABI) and acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution was 16.9 mM 12, 49 mM pyridine, 9% water in THF (Millipore). B J Synthesis Grade acetonitrile was used directly from the reagent bottle. S- Ethyl tetrazole solution (0.25 M in acetonitrile) was made up from the solid obtained from American International Chemical, Inc.

Deprotection of the RNA was performed as follows. The polymer-bound oligoribonucleotide, trityl-off, was transferred from the synthesis column to a 4mL glass screw top vial and suspended in a solution of methylamine (MA) at 65 oC for 10 min. After cooling to -20 oC, the supernatant was removed from the polymer support. The support was washed three times with 1.0 mL of EtOH:MeCN:H 2 0/3:1:1, vortexed and the supernatant was then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, were dried to a white powder.

The base-deprotected oligoribonucleotide was resuspended in anhydrous TEA*HF/NMP solution (250 uL of a solution of 1.5mL N-methylpyrrolidinone, 750 pL TEA and 1.0 mL TEA*3HF to provide a 1.4M HF concentration) and heated to 65 0 C for 1.5 h. The resulting, fully deprotected, oligomer was quenched with 50 mM TEAB (9 mL) prior to anion exchange desalting.

For anion exchange desalting of the deprotected oligomer, the TEAB solution was loaded onto a Qiagen 500® anion exchange cartridge (Qiagen Inc.) that was prewashed with 50 mM TEAB (10 mL). After washing the loaded cartridge with 50 mM TEAB (10 mL), the RNA was eluted with 2 M TEAB (10 mL) and dried down to a white powder.

WO 99/50403 PCT/US99/06507 Inactive hammerhead ribozymes were synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel, K. et al., 1992, Nucleic Acids Res., 3252).

The average stepwise coupling yields were >98% (Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684).

Hairpin ribozymes are synthesized in two parts and annealed to reconstruct the active ribozyme (Chowrira and Burke, 1992 Nucleic Acids Res., 20, 2835-2840). Ribozymes are also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol. 180, 51).

Ribozymes are modified to enhance stability and/or enhance catalytic activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'flouro, 2'-O-methyl, 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 6, 14090).

Ribozymes were purified by gel electrophoresis using general methods or are purified by high pressure liquid chromatography (HPLC; See Stinchcomb et al., International PCT Publication No. WO 95/23225, the totality of which is hereby incorporated herein by reference) and are resuspended in water.

The sequences of the ribozymes that are chemically synthesized, useful in this study, are shown in Tables III-X. Those in the art will recognize that these sequences are representative only of many more such sequences where the enzymatic portion of the ribozyme (all but the binding arms) is altered to affect activity. For example, stem-loop II sequence of hammerhead ribozymes can be altered (substitution, deletion, and/or insertion) to contain any sequences provided a minimum of two basepaired stem structure can form. Similarly, stem-loop IV WO 99/50403 PCT/US99/06507 26 sequence of hairpin ribozymes, can be altered (substitution, deletion, and/or insertion) to contain any sequence, provided a minimum of two base-paired stem structure can form. Preferably, no more than 200 bases are inserted at these locations. The sequences listed in Tables III-X may be formed of ribonucleotides or other nucleotides or non-nucleotides. Such ribozymes (which have enzymatic activity) are equivalent to the ribozymes described specifically in the Tables.

Optimizing Ribozyme Activity Catalytic activity of the ribozymes described in the instant invention can be optimized as described by Draper et al., supra. The details will not be repeated here, but include altering the length of the ribozyme binding arms, or chemically synthesizing ribozymes with modifications (base, sugar and/or phosphate) that prevent their degradation by serum ribonucleases and/or enhance their enzymatic activity (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 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; and Burgin et al., supra; all of these describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of enzymatic RNA molecules). Modifications which enhance their efficacy in cells, and removal of bases from stem loop structures to shorten RNA 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 WO 99/50403 PCT/US99/06507 27 introduced into enzymatic nucleic acid molecules without significantly effecting catalysis and with significant enhancement in their nuclease stability and efficacy.

Ribozymes are modified to enhance stability and/or enhance catalytic activity by modification with nuclease resistant groups, for example, 2'-amino, 2'-C-allyl, 2'-flouro, 2'- O-methyl, 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 35, 14090). Sugar modification of enzymatic 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; 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 catalysts of the instant invention.

Nucleic acid catalysts having chemical modifications which maintain or enhance enzymatic 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. As exemplified herein such ribozymes are useful in a cell and/or in vivo even if activity over all is reduced 10 fold (Burgin et al., 1996, Biochemistry, WO 99/50403 PCT/US99/06507 28 14090). Such ribozymes herein are said to "maintain" the enzymatic activity on all RNA ribozyme.

Therapeutic ribozymes delivered exogenously must optimally be 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, ribozymes must be resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of RNA (Wincott et al., 1995 Nucleic Acids Res.

23, 2677; incorporated by reference herein) have expanded the ability to modify ribozymes by introducing nucleotide modifications to enhance their nuclease stability as described above.

By "nucleotide" as used herein is as 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 sugar moiety. Nucleotide 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; all hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art and has recently been summarized by Limbach et al., 1994, Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of base modifications that can be introduced into enzymatic nucleic acids without significantly effecting their catalytic activity include, inosine, purine, WO 99/50403 PCTIUS99/06507 29 pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2, 4, 6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines methylcytidine), 5-alkyluridines ribothymidine), halouridine 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines 6-methyluridine) and others (Burgin et al., 1996, Biochemistry, 35, 14090). 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 may be used within the catalytic core of the enzyme and/or in the substrate-binding regions.

By "unmodified nucleoside" is meant one of the bases adenine, cytosine, guanine, uracil joined to the 1' carbon of b-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.

Various modifications to ribozyme structure can be made to enhance the utility of ribozymes. Such modifications will enhance shelf-life, half-life in vitro, stability, and ease of introduction of such ribozymes to the target site, to enhance penetration of cellular membranes, and confer the ability to recognize and bind to targeted cells.

Administration of Ribozymes Sullivan et al., PCT WO 94/02595, describes the general methods for delivery of enzymatic RNA molecules Ribozymes may 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. For some WO 99/50403 PCT/US99/06507 indications, ribozymes may be directly delivered ex vivo to cells or tissues with or without the aforementioned vehicles. Alternatively, the RNA/vehicle combination is locally delivered by direct injection or by use of a catheter, infusion pump or stent. Other routes of delivery include, but are not limited to, intravascular, intramuscular, subcutaneous or joint injection, aerosol inhalation, oral (tablet or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery. More detailed descriptions of ribozyme delivery and administration are provided in Sullivan et al., supra and Draper et al., PCT W93/23569 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 negatively charged 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 may 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 like.

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

WO 99/50403 PCT/US99/06507 31 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 to reach 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 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 may provide enhanced delivery of the drug to target cells by taking advantage of the WO 99/50403 PCT/US99/06507 32 specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as the cancer cells.

The invention also features the use of the a composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). These formulations offer an 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; Ishiwataet al., Chem.

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 these 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 WO 99/50403 PCT/US99/06507 33 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 may be provided. Id. at 1449. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition, antioxidants and suspending agents may be used.

Id.

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.

Alternatively, the enzymatic 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, 5531-4; Ojwang et al., 1992 Proc. Natl. Acad. Sci.

USA 89, 10802-6; Chen et al., 1992 Nucleic Acids Res., WO 99/50403 PCT/US99/06507 34 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, 45; all of the references are hereby incorporated in their totality 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 ribozyme (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 the references are hereby incorporated in their totality by reference herein).

In another aspect of the invention, enzymatic nucleic acid molecules that cleave target molecules are 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 could be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. Preferably, the recombinant vectors capable of expressing the ribozymes are delivered as described above, and persist in target cells. Alternatively, viral vectors may be used that provide for transient expression of ribozymes. Such vectors might be repeatedly administered as necessary.

Once expressed, the ribozymes cleave the target RNA. The active ribozyme contains an enzymatic center or core equivalent to those in the examples, and binding arms able to bind target nucleic acid molecules such that cleavage at the target site occurs. Other sequences may be present which do not interfere with such cleavage. Delivery of ribozyme expressing vectors could be systemic, such as by WO 99/50403 PCT/US99/06507 intravenous or intramuscular 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).

In one aspect the invention features, an expression vector comprising nucleic acid sequence encoding at least one of the nucleic acid catalyst of the instant invention is disclosed. The nucleic acid sequence encoding the nucleic acid catalyst of the instant invention is operable linked in a manner which allows expression of that nucleic acid molecule.

In another aspect the invention features, the expression vector comprises: a transcription initiation region eukaryotic pol I, II or III initiation region); b) a transcription termination region eukaryotic pol I, II or III termination region); c) a gene encoding at least one of the nucleic acid catalyst of the instant invention; and wherein said gene 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 may optionally include an open reading frame (ORF) for a protein operably linked on the 5' side or the 3'-side of the gene encoding the nucleic acid catalyst of the invention; and/or an intron (intervening sequences).

Transcription of the ribozyme sequences are driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA WO 99/50403 PCT/US99/06507 36 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. U S 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). Several investigators have demonstrated that ribozymes expressed from such promoters can function in mammalian cells Kashani-Sabet et al., 1992 Antisense Res. Dev., 2, 3-15; 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. U S A, 90, 6340-4; L'Huillier et al., 1992 EMBO J. 11, 4411-8; Lisziewicz et al., 1993 Proc. Natl. Acad. Sci. U. S. 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 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 adenoassociated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).

WO 99/50403 PCT/US99/06507 37 In yet another aspect the invention features an expression vector comprising nucleic acid sequence encoding at least one of the catalytic nucleic acid molecule 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 gene encoding at least one said nucleic acid molecule; and wherein said gene 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 preferred embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; d) a gene encoding at least one said nucleic acid molecule, wherein said gene is operably linked to the 3'-end of said open reading frame; and wherein said gene 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 gene encoding at least one said nucleic acid molecule; and wherein said gene 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 gene encoding at least one said nucleic acid molecule, wherein said gene is operably linked to the 3'-end of said open reading frame; and wherein said gene is operably linked to said initiation WO 99/50403 PCT/US99/06507 38 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.

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

The following examples demonstrate the selection of ribozymes that cleave Tie-2, integrin subunit b3, integrin subunit a6, and aryl hydrocarbon nuclear transporter (ARNT). The methods described herein represent a scheme by which ribozymes may be derived that cleave other RNA targets required for angiogenesis. Also provided is a description of how such ribozymes may be delivered to cells. The examples demonstrate that upon delivery, the ribozymes inhibit cell proliferation in culture and modulate gene expression in vivo. Moreover, significantly reduced inhibition is observed if mutated ribozymes that are catalytically inactive are applied to the cells.

Thus, inhibition requires the catalytic activity of the ribozymes.

Example 1: Identification of Potential Ribozyme Cleavage Sites in TIE-2 The sequence of human Tie-2 was screened for accessible sites using a computer folding algorithm.

Regions of the mRNA that did not form secondary folding structures and contained potential hammerhead and/or hairpin ribozyme cleavage sites were identified. The sequences of these cleavage sites are shown in tables V-

VI.

WO 99/50403 PCT/US99/06507 39 Example 2: Selection of Ribozyme Cleavage Sites in Human TIE-2 RNA To test whether the sites predicted by the computerbased RNA folding algorithm corresponded to accessible sites in Tie-2 RNA, 20 hammerhead sites were selected for analysis. Ribozyme target sites were chosen by analyzing genomic sequences of Tie-2 (Ziegler et al., 1993, Oncogene 8 663-670 (Genbank sequence HUMTEKRPTK accession number: M69238) and prioritizing the sites on the basis of folding. Hammerhead ribozymes were designed that could bind each target (see Figure 1) and were 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 ribozyme sequences fold into the appropriate secondary structure. Those ribozymes with unfavorable intramolecular interactions between the binding arms and the catalytic core were eliminated from consideration. As noted below, varying binding arm lengths can be chosen to optimize activity. Generally, at least 5 bases on each arm are able to bind to, or otherwise interact with, the target RNA. An example of a ribozyme targeted to Tie-2 is shown in figure 2.

Example 3: Chemical Synthesis and Purification of Ribozymes for Efficient Cleavage of TIE-2 RNA Ribozymes of the hammerhead or hairpin motif were designed to anneal to various sites in the RNA message.

The binding arms are complementary to the target site sequences described above. The ribozymes were chemically synthesized. The method of synthesis used followed the procedure for normal RNA synthesis 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., supra, and made use of common nucleic acid protecting WO 99/50403 PCT/US99/06507 and coupling groups, such as dimethoxytrityl at the end, and phosphoramidites at the 3'-end. The average stepwise coupling yields were >98%.

Inactive ribozymes were synthesized by substituting a U for G5 and a U for A14 (numbering from Hertel et al., 1992 Nucleic Acids Res., 20, 3252). Hairpin ribozymes were synthesized in two parts and annealed to reconstruct the active ribozyme (Chowrira and Burke, 1992 Nucleic Acids Res., 20, 2835-2840). Ribozymes were also synthesized from DNA templates using bacteriophage T7 RNA polymerase (Milligan and Uhlenbeck, 1989, Methods Enzymol.

180, 51). Ribozymes were modified 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).

Ribozymes were purified by gel electrophoresis using general methods or were purified by high pressure liquid chromatography (HPLC; See Wincott et al., supra; the totality of which is hereby incorporated herein by reference) and were resuspended in water. The sequences of the chemically synthesized ribozymes used in this study are shown below in Table V-VI.

Example 4: Ribozyme Cleavage of TIE-2 RNA Target in vitro Ribozymes targeted to the human Tie-2 RNA are designed and synthesized as described above. These ribozymes can be tested for cleavage activity in vitro, for example using the following procedure. The target sequences and the nucleotide location within the Tie-2 mRNA are given in Table V.

Cleavage Reactions: Full-length or partially fulllength, internally-labeled target RNA for ribozyme cleavage assay is prepared by in vitro transcription in the presence of [a- 3 2 p] CTP, passed over a G 50 Sephadex column by spin chromatography and used as substrate RNA WO 99/50403 PCT/US99/06507 41 without further purification. Alternately, substrates are 32 P-end labeled using T4 polynucleotide kinase enzyme.

Assays are performed by pre-warming a 2X concentration of purified ribozyme in ribozyme cleavage buffer (50 mM Tris- HC1, pH 7.5 at 37 0 C, 10 mM MgCl2) and the cleavage reaction was initiated by adding the 2X ribozyme 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, 0 assays are carried out for 1 hour at 37 C using a final concentration of either 40 nM or 1 mM ribozyme, i.e., ribozyme 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 ribozyme 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.

Use of Ribozymes Targeting TIE-2 The rate of tumor growth is believed to be a function of blood supplied and therefore a function of angiogenesis (Rak, Supra; Blood Zetter, 1990, Biochimica et Biophysica Acta 1032, 89-118). Elevated levels of a number of these angiogenic factors including Tie-2; integrin subunit p3; integrin subunit a6; and aryl hydrocarbon nuclear transporter have been reported in a number of cancers. Thus, inhibition of expression of these angiogenic factors (for example using ribozymes) would potentially reduce that rate of growth of these tumors. The use of ribozymes would be desirable over such therapies as chemotherapeutics since, chemotherapeutic compounds such as doxorubicin because of its highly WO 99/50403 PCT/US99/06507 42 specific inhibition and reduction of the likelihood for side effects. Ribozymes, with their catalytic activity and increased site specificity (see above), are likely to represent a potent and safe therapeutic molecule for the treatment of cancer. Tumor angiogenesis and other indications are discussed below.

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 of rhabdomyosarcoma, glioblastoma multiforme cells in nude mice. Similarly, expression of a dominant negative mutated form of the flt-1 VEGF receptor inhibits vascularization induced by human glioblastoma cells in nude mice (Millauer et al., 1994, Nature 367, 576).

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 WO 99/50403 PCT/US99/06507 43 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).

Intradermal 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 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.

WO 99/50403 PCT/US99/06507 44 Animal Models There are several animal models in which the antiangiogenesis effect of nucleic acids of the present invention, such as ribozymes, directed against ARNT RNAs 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 angiogenic compound is inserted into a pocket surgically created in the cornea. Angiogenesis is monitored 3 to 5 days later. Ribozymes directed against ARNT, Tie-2 or integrin subunit RNAs 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).

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, vessels grow into the Matrigel over a period of 3 to 5 days and angiogenesis can be assessed.

Again, ribozymes directed against ARNT, Tie-2 or integrin subunit RNAs would be delivered in the Matrigel.

Several animal models exist for screening of antiangiogenic 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; Ormerod et al., 1990 Am. J. Pathol. 137: 1243-1252) or intracorneal growth factor implant (Grant et al., 1993 Diabetologia 36: 282-291; Pandey et al. 1995 supra; WO 99/50403 PCT/US99/06507 Zieche et al., 1992 Lab. Invest. 67: 711-715), vessel 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 hypoxiainduced neovascularization in the mouse retina (Pierce et al., 1995 Proc. Natl. Acad. Sci. USA. 92: 905-909).

The cornea 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, thermal or alkalai burn, endotoxin). The corneal model would utilize the intrastromal corneal implantation of a Teflon pellet soaked in a angiogenic compound-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 nontissue 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 WO 99/50403 PCT/US99/06507 46 temperature, the Matrigel or Millipore® filter disk forms a solid implant. An angiogenic compound would be embedded in the Matrigel or Millipore® filter disk which would be used to recruit vessels within the matrix of the Matrigel or Millipore® filter disk that 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, may be less problematic 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 will target only VEGFr RNA. In other words, the involvement of other nonspecific 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 RNA ribozymes produce their effects. In addition, the models will allow for testing the specificity of the anti-VEGFr RNA ribozymes by using either a- or bFGF as a pro-angiogenic factor. Vessel recruitment using FGF should not be affected in either model by anti-VEGFr RNA 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 correltations with WO 99/50403 PCT/US99/06507 47 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 there is a correlation between VEGF and angiogenesis in these models.

Other model systems to study tumor angiogenesis is reviewed by Folkman, 1985 Adv. Cancer. Res.. 43, 175.

Use of murine models For a typical systemic study involving 10 mice (20 g each) per dose group, 5 doses 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 may 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.

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 10: tumor cells from metastatically aggressive tumor cell lines (Lewis lung lines 3LL or D122, LLc-LN7; B-16-BL6 melanoma) in C57BL/6J mice.

WO 99/50403 PCT/US99/06507 48 Alternatively, the Lewis lung model can be produced by the surgical implantation of tumor spheres (approximately 0.8 mm in diameter). Metastasis also may be modeled by injecting the tumor cells directly 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 would 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) Delivery of ribozymes and ribozyme formulations in the Lewis lung model Several ribozyme formulations, including cationic lipid complexes which may be useful for inflammatory diseases DIMRIE/DOPE, etc.) and RES evading WO 99/50403 PCT/US99/06507 49 liposomes which may be used to enhance vascular exposure of the ribozymes, are of interest in cancer models due to their presumed biodistribution to the lung. Thus, liposome formulations can be used for delivering ribozymes to sites of pathology linked to an angiogenic response.

Diagnostic uses Ribozymes of this invention may be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of Tie-2; integrin subunit P3; integrin subunit a6; and/or aryl hydrocarbon nuclear transporter RNA in a cell. The close relationship between ribozyme 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 ribozymes described in this invention, one may 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 ribozymes may 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 may be defined as important mediators of the disease. These experiments will lead to better treatment of the disease progression by affording the possibility of combinational therapies multiple ribozymes targeted to different genes, ribozymes coupled with known small molecule inhibitors, or intermittent treatment with combinations of ribozymes and/or other chemical or biological molecules). Other in vitro uses of ribozymes of this invention are well known in the art, and include detection of the presence of RNAs associated with Tie-2; integrin subunit p3; integrin subunit a6; and/or aryl hydrocarbon nuclear transporter related condition. Such WO 99/50403 PCT/US99/06507 RNA is detected by determining the presence of a cleavage product after treatment with a ribozyme using standard methodology.

In a specific example, ribozymes which can cleave only wild-type or mutant forms of the target RNA are used for the assay. The first ribozyme is used to identify wild-type RNA present in the sample and the second ribozyme will be used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA will be cleaved by both ribozymes to demonstrate the relative ribozyme efficiencies in the reactions and the absence of cleavage of the "non-targeted" RNA species. The cleavage products from the synthetic substrates will also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus each analysis will require two ribozymes, two substrates and one unknown sample which will be combined into six reactions. The presence of cleavage products will be 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 Tie-2; integrin subunit P3; integrin subunit a6; ARNT) 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 will be correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.

WO 99/50403 PCT/US99/06507 51 Additional Uses Potential usefulness of sequence-specific enzymatic nucleic acid molecules of the instant invention might 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, the pattern of restriction fragments could be used to establish sequence relationships between two related RNAs, and large RNAs could be specifically cleaved to fragments of a size more useful for study. The ability to engineer sequence specificity of the ribozyme is ideal for cleavage of RNAs of unknown sequence.

Other embodiments are within the following claims.

WO 99/50403 PCT/US99/06507 52 TABLE I Characteristics of naturally occurring ribozymes Group I Introns S Size: -150 to >1000 nucleotides.

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

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

Reaction mechanism: attack by the 3'-OH of guanosine to generate cleavage products with 3'-OH and guanosine.

Additional protein cofactors required in some cases to help folding and maintainance of the active structure.

Over 300 known members of this class. Found as an intervening sequence in Tetrahymena thermophila rRNA, fungal mitochondria, chloroplasts, phage T4, blue-green algae, and others.

Major structural features largely established through phylogenetic comparisons, mutagenesis, and biochemical studies 2 Complete kinetic framework established for one ribozyme 3 4 6 1 Michel, Francois; Westhof, Eric. Slippery substrates. Nat.

Struct. Biol. (1994), 5-7.

2 Lisacek, Frederique; Diaz, Yolande; Michel, Francois. Automatic identification of group I intron cores in genomic DNA sequences. J.

Mol. Biol. (1994), 235(4), 1206-17.

3 Herschlag, Daniel; Cech, Thomas Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 1. Kinetic description of the WO 99/50403 PCT/US99/06507 53 Studies of ribozyme folding and substrate docking underway 9 reaction of an RNA substrate complementary to the active site.

Biochemistry (1990), 29(44), 10159-71.

i Herschlag, Daniel; Cech, Thomas Catalysis of RNA cleavage by the Tetrahymena thermophila ribozyme. 2. Kinetic description of the reaction of an RNA substrate that forms a mismatch at the active site.

Biochemistry (1990), 29(44), 10172-80.

Knitt, Deborah Herschlag, Daniel. pH Dependencies of the Tetrahymena Ribozyme Reveal an Unconventional Origin of an Apparent pKa. Biochemistry (1996), 35(5), 1560-70.

6 Bevilacqua, Philip Sugimoto, Naoki; Turner, Douglas A mechanistic framework for the second step of splicing catalyzed by the Tetrahymena ribozyme. Biochemistry (1996), 35(2), 648-58.

2 Li, Yi; Bevilacqua, Philip Mathews, David; Turner, Douglas Thermodynamic and activation parameters for binding of a pyrenelabeled substrate by the Tetrahymena ribozyme: docking is not diffusion-controlled and is driven by a favorable entropy change.

Biochemistry (1995), 34(44), 14394-9.

2 Banerjee, Aloke Raj; Turner, Douglas The time dependence of chemical modification reveals slow steps in the folding of a group I ribozyme. Biochemistry (1995), 34(19), 6504-12.

2 Zarrinkar, Patrick Williamson, James The P9.1-P9.2 peripheral extension helps guide folding of the Tetrahymena ribozyme.

Nucleic Acids Res. (1996), 24(5), 854-8.

WO 99/50403 PCT/US99/06507 54 Chemical modification investigation of important residues well established [0,11].

S The small (4-6 nt) binding site may make this ribozyme too non-specific for targeted RNA cleavage, however, the Tetrahymena group I intron has been used to repair a "defective" P-galactosidase message by the ligation of new P-galactosidase sequences onto the defective message [12.

RNAse P RNA (Ml RNA) Size: -290 to 400 nucleotides.

RNA portion of a ubiquitous ribonucleoprotein enzyme.

Cleaves tRNA precursors to form mature tRNA [13] S Reaction mechanism: possible attack by M2+-OH to generate cleavage products with 3'-OH and Strobel, Scott Cech, Thomas Minor groove recognition of the conserved G.cntdot.U pair at the Tetrahymena ribozyme reaction site. Science (Washington, D. (1995), 267(5198), 675-9.

11 Strobel, Scott Cech, Thomas Exocyclic Amine of the Conserved G.cntdot.U Pair at the Cleavage Site of the Tetrahymena Ribozyme Contributes to 5'-Splice Site Selection and Transition State Stabilization. Biochemistry (1996), 35(4), 1201-11.

12 Sullenger, Bruce Cech, Thomas Ribozyme-mediated repair of defective mRNA by targeted trans-splicing. Nature (London) (1994), 371(6498), 619-22.

i3 Robertson, Altman, Smith, J.D. J. Biol. Chem., 247, 5243-5251 (1972).

WO 99/50403 PCT/US99/06507 RNAse P is found throughout the prokaryotes and eukaryotes. The RNA subunit has been sequenced from bacteria, yeast, rodents, and primates.

S Recruitment of endogenous RNAse P for therapeutic applications is possible through hybridization of an External Guide Sequence (EGS) to the target RNA Important phosphate and 2' OH contacts recently identified 16 1 i] Group II Introns Size: >1000 nucleotides.

Trans cleavage of target RNAs recently demonstrated [18,19] 1 4 Forster, Anthony Altman, Sidney. External guide sequences for an RNA enzyme. Science (Washington, D. 1883-) (1990), 249(4970), 783-6.

Yuan, Hwang, E. Altman, S. Targeted cleavage of mRNA by human RNase P. Proc. Natl. Acad. Sci. USA (1992) 89, 8006-10.

16 Harris, Michael Pace, Norman Identification of phosphates involved in catalysis by the ribozyme RNase P RNA. RNA (1995), 210-18.

1 7 Pan, Tao; Loria, Andrew; Zhong, Kun. Probing of tertiary interactions in RNA: 2'-hydroxyl-base contacts between the RNase P RNA and pre-tRNA. Proc. Natl. Acad. Sci. U. S. A. (1995), 92(26), 12510- 14.

S Pyle, Anna Marie; Green, Justin Building a Kinetic Framework for Group II Intron Ribozyme Activity: Quantitation of Interdomain Binding and Reaction Rate. Biochemistry (1994), 33(9), 2716-25.

WO 99/50403 PCT/US99/06507 56 Sequence requirements not fully determined.

Reaction mechanism: 2'-OH of an internal adenosine generates cleavage products with 3'-OH and a "lariat" RNA containing a and a branch point.

Only natural ribozyme with demonstrated participation in DNA cleavage 20 2 1 in addition to RNA cleavage and ligation.

Major structural features largely established through phylogenetic comparisons 2 Important 2' OH contacts beginning to be identified [23] 19 Michels, William J. Jr.; Pyle, Anna Marie. Conversion of a Group II Intron into a New Multiple-Turnover Ribozyme that Selectively Cleaves Oligonucleotides: Elucidation of Reaction Mechanism and Structure/Function Relationships. Biochemistry (1995), 34(9), 2965-77.

Zimmerly, Steven; Guo, Huatao; Eskes, Robert; Yang, Jian; Perlman, Philip Lambowitz, Alan A group II intron RNA is a catalytic component of a DNA endonuclease involved in intron mobility.

Cell (Cambridge, Mass.) (1995), 83(4), 529-38.

21 Griffin, Edmund Jr.; Qin, Zhifeng; Michels, Williams J., Jr.; Pyle, Anna Marie. Group II intron ribozymes that cleave DNA and RNA linkages with similar efficiency, and lack contacts with substrate 2'-hydroxyl groups. Chem. Biol. (1995), 2(11), 761-70.

22 Michel, Francois; Ferat, Jean Luc. Structure and activities of group II introns. Annu. Rev. Biochem. (1995), 64, 435-61.

23 Abramovitz, Dana Friedman, Richard Pyle, Anna Marie.

Catalytic role of 2'-hydroxyl groups within a group II intron active site. Science (Washington, D. (1996), 271(5254), 1410-13.

WO 99/50403 PCT/US99/06507 57 Kinetic framework under development [2 4 Neurospora VS RNA Size: -144 nucleotides.

Trans cleavage of hairpin target RNAs recently demonstrated 5 Sequence requirements not fully determined.

Reaction mechanism: attack by 2'-OH 5' to the scissile bond to generate cleavage products with cyclic phosphate and 5'-OH ends.

Binding sites and structural requirements not fully determined.

Only 1 known member of this class. Found in Neurospora VS RNA.

Hammerhead Ribozyme (see text for references) Size: ~13 to 40 nucleotides.

Requires the target sequence UH immediately of the cleavage site.

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

Reaction mechanism: attack by 2'-OH 5' to the scissile bond to generate cleavage products with cyclic phosphate and 5'-OH ends.

2 4 Daniels, Danette Michels, William Jr.; Pyle, Anna Marie.

Two competing pathways for self-splicing by group II introns: a quantitative analysis of in vitro reaction rates and products. J. Mol.

Biol. (1996), 256(1), 31-49.

Guo, Hans C. Collins, Richard Efficient trans-cleavage of a stem-loop RNA substrate by a ribozyme derived from Neurospora VS RNA. EMBO J. (1995), 14(2), 368-76.

WO 99/50403 PCT/US99/06507 58 14 known members of this class. Found in a number of plant pathogens (virusoids) that use RNA as the infectious agent.

Essential structural features largely defined, including 2 crystal structures [26,2 Minimal ligation activity demonstrated (for engineering through in vitro selection) 8 Complete kinetic framework established for two or more ribozymes [29].

Chemical modification investigation of important residues well established 3 Hairpin Ribozyme Size: ~50 nucleotides.

26 Scott, Finch, Aaron,K. The crystal structure of an all RNA hammerhead ribozyme:Aproposed mechanism for RNA catalytic cleavage. Cell, (1995), 81, 991-1002.

27 McKay, Structure and function of the hammerhead ribozyme: an unfinished story. RNA, (1996), 2, 395-403.

28 Long, Uhlenbeck, Hertel, K. Ligation with hammerhead ribozymes. US Patent No. 5,633,133.

29 Hertel, Herschlag, Uhlenbeck, O. A kinetic and thermodynamic framework for the hammerhead ribozyme reaction.

Biochemistry, (1994) 33, 3374-3385.Beigelman, et al., Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708.

Beigelman, et al., Chemical modifications of hammerhead ribozymes. J. Biol. Chem., (1995) 270, 25702-25708.

WO 99/50403 PCT/US99/06507 59 S Requires the target sequence GUC immediately 3' of the cleavage site.

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

Reaction mechanism: attack by 2'-OH 5' to the scissile bond to generate cleavage products with cyclic phosphate and 5'-OH ends.

3 known members 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.

Essential structural features largely defined 31 32 33 34 S Hampel, Arnold; Tritz, Richard; Hicks, Margaret; Cruz, Phillip.

'Hairpin' catalytic RNA model: evidence for helixes and sequence requirement for substrate RNA. Nucleic Acids Res. (1990), 18(2), 299- 304.

22 Chowrira, Bharat Berzal-Herranz, Alfredo; Burke, John M..

Novel guanosine requirement for catalysis by the hairpin ribozyme.

Nature (London) (1991), 354(6351), 320-2.

3 3 Berzal-Herranz, Alfredo; Joseph, Simpson; Chowrira, Bharat M.; Butcher, Samuel Burke, John Essential nucleotide sequences and secondary structure elements of the hairpin ribozyme. EMBO J. (1993), 12(6), 2567-73.

34 Joseph, Simpson; Berzal-Herranz, Alfredo; Chowrira, Bharat M.; Butcher, Samuel Substrate selection rules for the hairpin ribozyme determined by in vitro selection, mutation, and analysis of mismatched substrates. Genes Dev. (1993), 130-8.

WO 99/50403 PCT/US99/06507 Ligation activity (in addition to cleavage activity) makes ribozyme amenable to engineering through in vitro selection Complete kinetic framework established for one ribozyme [36] Chemical modification investigation of important residues begun [3,38] Hepatitis Delta Virus (HDV) Ribozyme Size: -60 nucleotides.

Trans cleavage of target RNAs demonstrated [39].

Berzal-Herranz, Alfredo; Joseph, Simpson; Burke, John In vitro selection of active hairpin ribozymes by sequential RNAcatalyzed cleavage and ligation reactions. Genes Dev. (1992), 6(1), 129-34.

6 Hegg, Lisa Fedor, Martha Kinetics and Thermodynamics of Intermolecular Catalysis by Hairpin Ribozymes. Biochemistry (1995), 34(48), 15813-28.

37 Grasby, Jane Mersmann, Karin; Singh, Mohinder; Gait, Michael Purine Functional Groups in Essential Residues of the Hairpin Ribozyme Required for Catalytic Cleavage of RNA. Biochemistry (1995), 34(12), 4068-76.

3 e Schmidt, Sabine; Beigelman, Leonid; Karpeisky, Alexander; Usman, Nassim; Sorensen, Ulrik Gait, Michael Base and sugar requirements for RNA cleavage of essential nucleoside residues in internal loop B of the hairpin ribozyme: implications for secondary structure. Nucleic Acids Res. (1996), 24(4), 573-81.

39 Perrotta, Anne Been, Michael Cleavage of oligoribonucleotides by a ribozyme derived from the hepatitis .delta.

virus RNA sequence. Biochemistry (1992), 31(1), 16-21.

WO 99/50403 PCT/US99/06507 61 S Binding sites and structural requirements not fully determined, although no sequences 5' of cleavage site are required. Folded ribozyme contains a pseudoknot structure 4 0 Reaction mechanism: attack by 2'-OH 5' to the scissile bond to generate cleavage products with cyclic phosphate and 5'-OH ends.

Only 2 known members of this class. Found in human HDV.

Circular form of HDV is active and shows increased nuclease stability [41] Perrotta, Anne Been, Michael A pseudoknot-like structure required for efficient self-cleavage of hepatitis delta virus RNA.

Nature (London) (1991), 350(6317), 434-6.

4 Puttaraju, Perrotta, Anne Been, Michael A circular trans-acting hepatitis delta virus ribozyme. Nucleic Acids Res.

(1993), 21(18), 4253-8.

WO 99/50403 WO 9950403PCT/US99/06507 62 Table 11: 2.5 pmol RNA Synthesis Cycle Reagent Phosphoramidites S-Ethyl Tetrazole Acetic Anhydride N-Methyl Imidazole

TCA

Iodine Acetonitrile Equivalents 6.5 23.8 100 186 83.2 8.0

NA

Amount 163 IlL 238 lIL 233 .1L 233 pL 1.73 mL 1.18 mL 6.67 mL Time* 5 sec 5 sec 21 sec 45 sec

NA

Wait time does not include contact time during delivery.

WO 99/50403 WO 9950403PCTIUS99/06507 63 TABLE III: HAMMERHEAD RIBOZYME AND SITE SEQUENCES FOR ARNT Posi- Seq. Seq. I. D.

tion RZ I. D. No. Substrate No.

AGUGGGAG CUGAUGAG X CGAA 1 UGGCGGCUC 394 _____AGCCGCCA

CUCGCACU

13 CCCAGUGG CUGAUGAG X CGAA 2 CGGCUCCUC 395 AGGAGCCG

CCACUGGG

49 UGGCCGCA CUGAUGAG X CGAA 3 GGUGGCAUC 396 AUGCCACC

UGCGGCCA

69 GUUGGCAG CUGAUGAG X CGAA 4 CGGCGACUA 397 AGUCGCCG

CUGCCAAC

91 GUACAUCU CUGAUGAG X CGAA 5 AAUGACAUC 398 AUGUCAUU

AGAUGUAC

98 AGUGAUGG CUGAUGAG X CGAA 6 UCAGAUGUA 399 ACAUCUGA

CCAUCACU

103 GACCCAGU CUGAUGAG X CGAA 7 UGUACCAUC 400 AUGGUACA

ACUGGGUC

111 AAUGGCUG CUGAUGAG X CGAA 8 CACUGGGUC 401 ACCCAGUG

CAGCCAUU

119 CCAGAGGC CUGAUGAG X CGAA 9 CCAGCCAUU 402 AUGGCUGG

GCCUCUGG

124 AGUUUCCA CUGAUGAG X CGAA 10 CAUUGCCUC 403 ____AGGCAAUG

UGGAAACU

133 CAGGUCCA CUGAtJGAG X CGAA 11 UGGAAACUC 404 ____AGUUUCCA

UGGACCUG

146 CCACCUUG CUGAUGAG X CGAA 12 CCUGGAAUU 405 AUUCCAGG

CAAGGUGG

147 UCCACCUU CUGAUGAG X CGAA 13 CUGGAAUUC 406 ____AAUUCCAG

AAGGUGGA

164 CUCUGGAC CUGAUGAG X CGAA 14 GGAGCCAUU 407 ____AUGGCUCC

GUCCAGAG

167 GCCCUCUG CUGAUGAG X CGAA 15 GCCAUUGUC 408 ____ACAAUGGC

CAGAGGGC

WO 99/50403 WO 9950403PCT[US99/06507 30 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

177 CCGCUUAA CUGAUGAG X CGAA 16 AGAGGGCUA 409 AGCCCUCU UUAAGCGG 179 CGCCGCUU CUGAUGAG X CGAA 17 AGGGCUAUU 410 AUAGCCCU AAGCGGCG 180 ICGCCGCU CUGAUGAG X CGAA 18 GGGCUAUUA 411 AAUAGCCC AGCGGCGA_____ 201 AUCAUCAA CUGAUGAG X CGAA 19 GGCUGGAUU 412 AUCCAGCC UUGAUGAU 202 CAUCAUCA CUGAUGAG X CGAA 20 GCUGGAUUU 413 AAUCCAGC UGAUGAUG_____ 203 UCAUCAUC CUGAUGAG X CGAA 21 CUGGAUUUU 414 AAAUCCAG IGAUGAUGA_____ 228 CAAAAAUU CUGAUGAG X CGAA 22 GGAACAGUA 415 ACUGUUCC AAUUUUUG 232 ACCUCAAA CUGAUGAG X CGAA 23 CAGUAAAUU 416 AUUUACUG UUUGAGGU 233 CACCUCAA CUGAUGAG X CGAA 24 AGUAAAUUU 417 AAUUUACU UUGAGGUG 234 ACACCUCA CUGAUGAG X CGAA 25 GUAAAUUUU 418 AAAUUUAC UGAGGUGU 235 CACACCUC CUGAUGAG X CGAA 26 UAAAUUUUU 419 AAAAUUUA GAGGUGUG 252 AGACAUCU CUGAUGAG X CGAA 27 AUGAUGAUC 420 AUCAUCAU AGAUGUCU 259 UAUCGUUA CUGAtJGAG X CGAA 28 UCAGAUGUC 421 ACAUCUGA _____UAACGAUA 261 CUUAUCGU CUGAUGAG X CGAA 29 AGAUGUCUA 422 IAGACAUCU _____ACGAUAAG 267 CCGCUCCU CUGAUGAG X CGAA 30 CUAACGAUA 423 AUCGUUAG AGGAGCGG 277 ACCUGGCA CUGAUGAG X CGAA 31 GGAGCGGUU 424 ACCGCUCC UGCCAGGU WO 99/50403 WO 9950403PCT/US99/06507 Posi- Seq. Seq. T.D.

tion RZ I.D. No. Substrate No.

278 GACCUGGO CUGAUGAG X CGAA 32 GAGCGG(JUU 425 AACCGCUC GCCAGGUC 286 CAUCAUCC CUGAUGAG X CGAA 33 UGCCAGGUC 426 ACCUGGCA GGAUGAUG 304 UAUCCGCA CUGAUGAG X CGAA 34 GCAGAGCUC 427 AGCUCUGC UGCGGAUA 312 UCUCUCUU CUGAUGAG X CGAA 35 CUGCGGAUA 428 AUCCGCAG AAGAGAGA 323 UCCCUGGC CUGAUGAG X CGAA 36 GAGAGACUU 429 AGUCUCUC GCCAGGGA 336 UUCACUGU CUGAUGAG X CGAA 37 GGGAAAAUC 430 AUUUUCCC ACAGUGAA 347 CGCCGUUC CEJGAUGAG X CGAA 38 AGUGAAAUU 431 AUUUCACU GAACGGCG 379 CUGUGAUG CUGAUGAG X CGAA 39 GACAGCCUA 432 AGGCUGUC CAUCACAG 383 AGUUCUGU CUGAUGAG X CGAA 40 GCCUACAUC 433 AUGUAGGC ACAGAACU 394 CCAUAUCU CUGAUGAG X CGAA 41 AGAACUGUC 434 ACAGUUCU AGAUAUGG 399 GGGUACCA CUGAUGAG X CGAA 42 tJGUCAGAUA 435 AUCUGACA 404 CAGGUGGG CUGAUGAG X CGAA 43 GAUAUGGUA 436 ACCAUAUC 414 CAGGGCAC CUGAUGAG X CGAA 44 CCACCUGUA 437 ACAGGUGG GUGCCCUG 426 UGGUUUUC CUGAUGAG X CGAA 45 CCCUGGCUC 438 AGCCAGGG _____GAAAACCA 443 AAGAUGGU CUGAUGAG X CGAA 46 GACAAGCUA 439 AGCUUGUC ACCAUCUU 449 AUGCGUAA CUGAUGAG X CGAA 47 CUAACCAUC 440 1 AUGGUUAG

IUUACGCAU

WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

451 CCAUGCGU CUGAUGAG X CGAA 48 AACCAUCUU 441 AGAUGGUU _____ACGCAUGG 452 GCCAUGCG CUGAUGAG X CGAA 49 ACCAUCUUA 442 AAGAUGGU CGCAUGGC 464 AUGUGAGA CUGAUGAG X CGAA 50 AUGGCAGUU 443 ACUGCCAU UCUCACAU 465 CAUGUGAG CUGAUGAG X CGAA 51 UGGCAGUUU 444 AACUGCCA CUCACAUG 466 UCAUGUGA CUGAUGAG X CGAA 52 GGCAGUUUC 445 AAACUGCC UCACAUGA 468 CUUCAUGU CUGAUGAG X CGAA 53 CAGUUUCUC 446 AGAAACUG _____ACAUGAAG 478 CCCGCAAG CUGAUGAG X CGAA 54 CAUGAAGUC 447 ACUUCAUG fCUUGCGGG 481 UUCCCCGC CUGAUGAG X CGAA 55 GAAGUJCCUU 448 AGGACUUC GCGGGGAA 502 CAUCAGUG CUGAUGAG X CGAA 56 CAACACAUC 449 AUGUGUUG CACUGAUG 514 GCUUAUAG CUGAUGAG X CGAA 57 UGAUGGCUC 450 AGCCAUCA CUAUAAGC_____ 517 ACGGCUUA CUGAUGAG X CGAA 58 tJGGCUCCUA 4,51 AGGAGCCA UAAGCCGU_____ 519 AGACGGCU CUGAUGAG X CGAA 59 GCUCCUAUA 452 AUAGGAGC AGCCGUCU_____ 526 UGAGGAAA CUGAUGAG X CGAA 60 UAAGCCGUC 453 ACGGCUUA IUUUCCUCA 528 AGUGAGGA CUGAUGAG X CGAA 61 AGCCGUCUU 454 ____AGACGGCU UCCUCACU_____ 529 CAGUGAGG CUGAUGAG X CGAA 62 GCCGUCUUU 455 AAGACGGC ICCUCACUG 530 UCAGUGAG CUGAUGAG X CGAA 63 CCGUCUUUC 456 AAAGACGG

CUCACUGA

WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I. D. No. Substrate No.

533 UGAUCAGU CUGAUGAG X CGAA 64 UCUUtJCCUC 457 AGGAAAGA

ACUGAUCA

540 CAGUUCCU CUGAUGAG X CGAA 65 UCACUGAUC 458 AUCAGUGA

AGGAACUG

555 CAAGAUCA CUGAUGAG X CGAA 66 UGAAACAUU 459 AUGUUUCA

UGAUCUUG

556 CCAAGAUC CUGAUGAG X CGAA 67 GAAACAUUU 460 AAUGUUUC IGAUCUUGG 560 GCCUCCAA CUGAUGAG X CGAA 68 CAUUUGAUC 461 AUCAAAUG UUGGAGGC 562 CUGCCUCC CUGAUGAG X CGAA 69 UUUGAUCUU 462 AGAUCAAA

GGAGGCAG

580 UAAACAGA CUGAUGAG X CGAA 70 AGAUGGCUU 463 AGCCAUCU UCUGUUUA 581 AUAAACAG CUGAUGAG X CGAA 71 GAUGGCUUU 464 AAGCCAUC CUGUUUAU 582 AAUAAACA CUGAUGAG X CGAA 72 AUGGCUUUC 465 AAAGCCAU UGUUUAUU 586 AGACAAUA CUGAUGAG X CGAA 73 CUUUCUGUU 466 ____ACAGAAAG UAUUGUCU 587 GAGACAAU CUGAUGAG X CGAA 74 UUUCUGUUU 467 ____AACAGAAA

AUUGUCUC

588 UGAGACAA CUGAUGAG X CGAA 75 UUCUGUUUA 468 AAACAGAA UUGUCUCA 590 CAUGAGAC CUGAUGAG X CGAA 76 CUGUUUAUU 469 AUAAACAG GUCUCAUG 593 UCACAUGA CUGAUGAG X CGAA 77 UUUAUUGUC 470 ACAAUAAA UCAUGUGA 595 UCUCACAU CUGAUGAG X CGAA 78 UAUUGUCUC 471 ____AGACAAUA AUGUGAGA 619 CAGACACA CUGAUGAG X CGAA 79 GGUGGUGUA 472 ____ACACCACC UGUGUCUG WO 99/50403 WO 9950403PCT[US99/06507 Posi- Seq. Seq. I. D.

tion RZ I. D. No. Substrate No.

625 CGGAGUCA CtJGAUGAG X CGAA 80 GUAUGUGUC 473 ,ACACAUAC

UGACUCCG

631 GAGUCACG CUGAUGAG X CGAA 81 GUCUGACUC 474 AGUCAGAC CGUGACUC 639 CAAAACAG CUGAUGAG X CGAA 82 CCGUGACUC 475 IAGUCACGG CUGUUUUG 644 UGGUUCAA CUGAUGAG X CGAA 83 ACUCCUGUU 476 ACAGGAGU UUGAACCA 645 CUGGUUCA CUGAUGAG X CGAA 84 CUCCUGUUU 477 AACAGGAG UGAACCAG 646 GCUGGUUC CUGAUGAG X CGAA 85 UCCUGUUUU 478 AAACAGGA GAACCAGC 661 ACCAUUCA CUGAUGAG X CGAA 86 GCCACAGUC 479 ACUGUGGC IUGAAUGGU 670 UGCUGCCA CUGAUGAG X CGAA 87 UGAAUGGUU 480 ACCAUUCA _____UGGCAGCA 671 GUGCUGCC CUGAUGAG X CGAA 88 GAAUGGUUU 481 AACCAUUC GGCAGCAC 683 UGAUCAUA CUGAUGAG X CGAA 89 AGCACACUC 482 AGUGUGCU UAUGAUCA 685 CCUGAUCA CUGAUGAG X CGAA 90 CACACUCUA 483 ____AGAGUGUG IUGAUCAGG 690 GUGCACCU CUGAUGAG X CGAA 91 UCUAUGAUC 484 ____AUCAUAGA AGGUGCAC 714 ACGAAGUU CUGAUGAG X CGAA 92 AUGUGGAUA 485 ____AUCCACAU AACUUCGU 719 UGCUCACG CUGAUGAG X CGAA 93 GAUAAACUU 486 ____AGUUUAUC CGUGAGCA 720 CUGCUCAC CUGAUGAG X CGAA 94 AUAAACUUC 487 ____AAGUUUAU GUGAGCAG 731 GAAGUGGA CUGAUGAG X CGAA 95 GAGCAGCUU 488 ____AGCUGCUC UCCACUUC WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I. D. No. Substrate No.

732 UGAAGUGG CUGAUGAG X CGAA 96 AGCAGCUUU 489 IAAGCUGCUJ CCACUUCA 733 CUGAAGUG CUGAUGAG X CGAA 97 GCAGCUUUC 490 AAAGCUGC CACUUCAG 738 AUUUUCUG CUGAUGAG X CGAA 98 UUUCCACUU 491 AGUGGAAA CAGAAAAU 739 CAUUUUCU CUGAUGAG X CGAA 99 (JUCCACUUC 492 AAGUGGAA AGAAAAUG 762 AUCCAGGA CUGAUGAG X CGAA 100 CAGGGCGUA 493 ACGCCCUG _____UCCUGGAU 764 AGAUCCAG CUGAUGAG X CGAA 101 GGGCGUAUC 494 AUACGCCC CUGGAUCU 771 AGUCUUUA CUGAUGAG X CGAA 102 UCCUGGAUC 495 AUCCAGGA UAAAGACU 773 CCAGUCUU CUGAUGAG X CGAA 103 CUGGAUCUA 496 AGAUCCAG AAGACUGG 801 AGACUGCU CUGAUGAG X CGAA 104 AGGAAGGUC 497 ACCUUCCU AGCAGUCU 808 UCAUGGAA CUGAUGAG X CGAA 105 UCAGCAGUC 498 ACUGCUGA UUCCAUGA 810 UCUCAUGG CUGAUGAG X CGAA 106 AGOAGUCUD 499 AGACUGCU CCAUGAGA 811 UUCUCAUG CUGAUGAG X CGAA 107 GCAGUCUUC 500 ____AAGACUGC fCAUGAGAA 825 UGAGCCCA CUGAUGAG X CGAA 108 GAAUGUGUA 501 ACACAUUC UGGGCUCA 832 AUCUCCUU CUGAUGAG X CGAA 109 UAUGGGCUC 502 AGCCCAUA _____AAGGAGAU 841 AAAUAAAC CUGAUGAG X CGAA 110 AAGGAGAUC 503 AUCUCCUU _____GUUUAUUU 844 GGCAAAUA CUGAUGAG X CGAA 111 GAGAUCGUU 504 ACGAUCUC _____UAUUUGCC I WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I. D.

tion RZ I.0D. No. Substrate No.

845 CGGCAAAU CUGAUGAG X CGAA 112 AGAUCGUUU 505 AACGAUCU AUUUGCCG 846 UCGGCAAA CUGAUGAG X CGAA 113 GAUCGUUUA 506 AAACGAUC UUUGCCGA 848 AUUCGGCA CUGAUGAG X CGAA 114 UCGUUUAUU 507 AUAAACGA UGCCGAAU 849 CAUUCGGC CUGAUGAG X CGAA 115 CGUUUAUUU 508 AAUAAACG GCCGAAUG 870 CACAGAGC CUGAUGAG X CGAA 116 GUGGCAGUA 509 ACUGCCAC IGCUCUGUG 874 GGUCCACA CUGAUGAG X CGAA 117 CAGUAGCUC 510 AGCUACUG UGUGGACC 887 UUCACAGA CUGAUGAG X CGAA 118 GACCCAGUU 511 ACUGGGUC UCUGUGAA 888 AUUCACAG CUGAUGAG X CGAA 119 ACCCAGUUU 512 AACUGGGU CUGUGAAU 889 UAUUCACA CUGAUGAG X CGAA 120 CCCAGUUUC 513 AAACUGGG UGUGAAUA 897 GCUCAGCC CUGAUGAG X CGAA 121 CUGUGAAUA 514 AUUCACAG GGCUGAGC 907 UCCUCACA CUGAUGAG X CGAA 122 GCUGAGCUU 515 AGCUCAGC UGUGAGGA 908 UUCCUCAC CUGAUGAG X CGAA 123 CUGAGCUUU 516 AAGCUCAG GUGAGGAA 935 ACAGAGCC CUGAUGAG X CGAA 124 AAUGGACUU 517 AGUCCAUU GGCUCUGU 940 CCUUUACA CUGAUGAG X CGAA 125 ACUUGGCUC 518 AGCCAAGU _____UGUAAAGG 944 CCAUCCUU CUGAUGAG X CGAA 126 GGCUCUGUA 519 ACAGAGCC AAGGAUGG 960 CACGAAGU CUGAUGAG X CGAA 127 GGGAACCUC 520 1 AGGUUCCC ACUUCGUG WO 99/50403 WO 9950403PCT/US99/06507 Posi- Seq. Seq. I. D.

tion RZ T.D. No. Substrate No.

964 CCACCACG CUGAUGAG X CGAA 128 ACCUCACUU 521 AGUGAGGU CGUGGUGG 965 ACCACCAC CUGAUGAG X CGAA 129 CCUCACUUC 522 AAGUGAGG IGUGGUGGU 974 GUGCAGUG CUGAUGAG X CGAA 130 GUGGUGGUC 523 ACCACCAC CACUGCAC 988 CCUUGAUG CUGAUGAG X CGAA 131 CACAGGCUA 524 AGCCUGUG CAUCAAGG 992 CAGGCCUU CUGAUGAG X CGAA 132 GGCUACAUC 525 AUGUAGCC AAGGCCUG 1016 GGGAGGGA CUGAUGAG X CGAA 133 GCAGGUGUU 526 ACACCUGC UCCCUCCC 1017 UGGGAGGG CUGAUGAG X CGAA 134 CAGGUGUUU 527 AACACCUG CCCUCCCA 1018 CUGGGAGG CUGAUGAG X CGAA 135 AGGUGUUUC 528 AAACACCU _____CCUCCCAG 1022 UCAUCUGO CUGAUGAG X CGAA 136 GUUUCCCUC 529 AGGGAAAC ICCAGAUGA 1060 CUAGGCAA CUGAUGAG X CGAA 137 AAGCAAGUU 530 ACUUGCUU UUGCCUAG 1061 ACUAGGCA CUGAUGAG X CGAA 138 AGCAAGUUU 531 AACUUGCU UGCCUAGU 1062 CACUAGGC CUGAUGAG X CGAA 139 GCAAGUUUU 532 AAACUUGC GCCUAGUG 1067 AUGGCCAC CUGAUGAG X CGAA 140 UUUUGCCUA 533 AGGCAAAA GUGGCCAU 1076 AAUCUGCC CUGAUGAG X CGAA 141 GUGGCCAUU 534 AUGGCCAC GGCAGAUU 1084 UUACCUGC CUGAUGAG X CGAA 142 UGGCAGAUU 535 AUCUGCCA GCAGGUAA 1091 GAACUAGU CUGAUGAG X CGAA 143 UUGCAGGUA 536 ACCUGCAA IACUAGUUC I WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

1095 GGGAGAAC CUGAUGAG X CGAA 144 AGGUAACUA 537 AGUUACCU _____GUUCUCCC 1098 GUUGGGAG CUGAUGAG X CGAA 145 UAACUAGUU 538 ACUAGUUA _____CUCCCAAC 1099 AGUUGGGA CUGAUGAG X CGAA 146 AACUAGUUC 539 AACUAGUU _____UCCCAACU 1101 ACAGUUGG CUGAUGAG X CGAA 147 CUAGUUCUC 540 AGAACUAG _____CCAACUGU 1110 CAUGUCUG CUGAUGAG X CGAA 148 CCAACUGUA 541 ACAGUUGG _____CAGACAUG 1122 ACAAACAU CUGAUGAG X CGAA 149 ACAUGAGUA 542 ACUCAUGU AUGUUUGU 1127 GGUUGACA CUGAUGAG X CGAA 150 AGUAAUGUU 543 ACAUUACU UGUCAACC 1128 UGGUUGAC CUGAUGAG X CGAA 151 GUAAUGUUU 544 AACAUUAC GUCAACCA 1131 UGUUGGUU CUGAUGAG X CGAA 152 AUGUUUGUC 545 ACAAACAU AACCAACA 1144 GGGAGAUG CUGAUGAG X CGAA 153 AACAGAGUU 546 ACUCUGUU _____CAUCUCCC 1145 CGGGAGAU CUGAUGAG X CGAA 154 ACAGAGUUC 547 AACUCUGU ______AUCUCCCG 1148 UGUCGGGA CUGAUGAG X CGAA 155 GAGUUCAUC 548 ____AUGAACUC UCCCGACA 1150 UGUGUCGG CUGAUGAG X CGAA 156 GUUCAUCUC 549 AGAUGAAC CCGACACA 1163 AUACCCUC CUGAUGAG X CGAA 157 CACAACAUU 550 ____AUGUUGUG GAGGGUAU 1170 AGUGAAGA CUGAUGAG X CGAA 158 UUGAGGGUA 551 ACCCUCAA UCUUCACU 1172 AAAGUGAA CUGAUGAG X CGAA 159 GAGGGUAUC 552 AUACCCUC IUUCACUUU WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I No. Substrate No.

1174 CAAAAGUG CUGAUGAG X CGAA 160 GGGUAUCUU 553 AGAUACCC ICACUUUUG 1175 ACAAAAGU CUGAUGAG X CGAA 161 GGUAUCUUC 554 ____AAGAUACC ACUUUUGU 1179 AUCCACAA CUGAUGAG X CGAA 162 UCUUCACUU 555 AGUGAAGA UUGUGGAU 1180 GAUCCACA CUGAUGAG X CGAA 163 CUUCACUUU 556 AAGUGAAG UGUGGAUC 1181 UGAUCCAC CUGAUGAG X CGAA 164 UUCACUUUU 557 AAAGUGAA GUGGAUCA 1188 ACAGCGGU CUGAUGAG X CGAA 165 DUGUGGAUC 558 ____AUCCACAA ACCGCUGU 1203 GCCAACAG CUGAUGAG X CGAA 166 GUGUGGCUA 559 AGCCACAC CUGUUGGC 1208 UGGUAGOC CUGAUGAG X CGAA 167 GCUACUGUU 560 ACAGUAGC GGCUACCA 1213 GUGGCUGG CUGAUGAG X CGAA 168 UGUUGGCUA 561 AGCCAACA fCCAGCCAC 1229 UUUCCUAA CUGAUGAG X CGAA 169 CAGGAACUC 562 AGUUCCUG UUAGGAAA 1231 UCUUUCCU CUGAUGAG X CGAA 170 GGAACUCUU 563 ____AGAGUUCC AGGAAAGA 1232 UUCUUUCC CUGAUGAG X CGAA 171 GAACUCUUA 564 AAGAGUUC GGAAAGAA 1242 UUCUACAA CUGAUGAG X CGAA 172 GAAAGAAUA 565 AUUCUUUC UUGUAGAA_____ 1244 AAUUCUAC CUGAUGAG X CGAA 173 AAGAAUAUU 566 AUAUUCUU GUAGAAUU 1247 CAGAAUUC CUGAUGAG X CGAA 174 AAUAUUGUA 567 ACAAUAUU IGAAUUCUG 1252 GAUGACAG CUGAUGAG X CGAA 175 UGUAGAAUU 568 AUUCUACA

CUGUCAUC

WO 99/50403 WO 9950403PCT/US99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

1253 GGAUGACA CUGAUGAG X CGAA 176 GUAGAAUUC 569 AAUUCUAC UGUCAUCC 1257 UUCAGGAU CUGAUGAG X CGAA 177 AAUUCUGUC 570 ACAGAAUU 1260 GUCUUCAG CUGAUGAG X CGAA 178 UCUGUCAUC 571 AUGACAGA CUGAAGAC 1277 UCUCUUAG CUGAUGAG X CGAA 179 CAGCAGCUU 572 ACCUGCUG C UAAGAGA 1278 GUCUCUUA CUGAUGAG X CGAA 180 AGCAGCUUC 573 AAGCUGCU UAAGAGAC 1280 CUGUCUCU CUGAUGAG X CGAA 181 CAGCUUCUA 574 AGAAGCUG IAGAGACAG_____ 1291 CCUGUUGG CUGAUGAG X CGAA 182 AGACAGCUU 575 AGCUGUCU CCAACAGG 1292 ACCUGUUG CUGAUGAG X CGAA 183 GACAGCUUC 576 AAGCUGUC CAACAGGU 1301 AAUUUCAC CUGAUGAG X CGAA 184 CAACAGGUA 577 IACCUGUUG GUGAAAUU 1309 GGCCUUUU CUGAUGAG X CGAA 185 AGUGAAAUU 578 AUUUCACU _____AAAAGGCC 1310 UGGCCUUU CUGAUGAG X CGAA 186 GUGAAAUUA 579 AAUUUCAC _____AAAGGCCA 1327 ACAUGACA CUGAUGAG X CGAA 187 AGUGCUGUC 580 ACAGCACU UGUCAUGU 1331 CGGAACAU CUGAUGAG X CGAA 188 CUGUCUGUC 581 ACAGACAG _____AUGUUCCG 1336 GGAACCGG CUGAUGAG X CGAA 189 UGUCAUGUU 582 ACAUGACA CCGGUUCC 1337 CGGAACCG CUGAUGAG X CGAA 190 GUCAUGUUC 583 AACAUGAC CGGUUCCG 1342 UAGACCGG CUGAUGAG X CGAA 191 GUUCCGGUU 584 ACCGGAAC CCGGUCUA WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I. D. No. Substrate No.

1343 UUAGACCG CUGAIJGAG X CGAA 192 tJUCCGGIJUC 585 AACCGGAA CGGUCrJAA 1348 GGUUCUUA CUGAUGAG X CGAA 193 GUUCCGGUC 586 ACCGGAAC UAAGAACC 1350 UUGGUUCU CUGAUGAG X CGAA 194 UCCGGUCUA 587 AGACCGGA AGAACCAA 1367 CUCAUCCA CUGAUGAG X CGAA 195 GAAUGGCUC 588 AGCCAUUC UGGAUGAG 1384 AAGUAAAG CUGAUGAG X CGAA 196 AACCAGCUC 589 AGCUGGUU CUUUACUU 1387 GGAAAGUA CUGAUGAG X CGAA 197 CAGCUCCUU 590 AGGAGCUG UACUUUCC 1388 UGGAAAGU CUGAUGAG X CGAA 198 AGCUCCUUU 591 AAGGAGCU ACUUUCCA 1389 CUGGAAAG CUGAUGAG X CGAA 199 GCUCCUUUA 592 AAAGGAGC CUUUCCAG 1392 GUUCUGGA CUGAUGAG X CGAA 200 CCUUUACUU 593 AGUAAAGG UCCAGAAC 1393 GGUUCUGG CUGAUGAG X CGAA 201 CUUUACUUU 594 ____AAGUAAAG CCAGAACC 1394 GGGUUCUG CUGAUGAG X CGAA 202 UUUACUUUC 595 ____AAAGUAAA CAGAACCC 1404 AUCUGAGU CUGAUGAG X CGAA 203 AGAACCCUU 596 AGGGUUCU ACUCAGAU 1405 CAUCUGAG CUGAUGAG X CGAA 204 GAACCCUUA 597 ____AAGGGUUC _____CUCAGAUG 1408 UUUCAUCU CUGAUGAG X CGAA 205 CCCUUACUC 598 ____AGUAAGGG IAGAUGAAA_____ 1418 AUGUACUC CUGAUGAG X CGAA 206 GAUGAAAUU 599 ____AUUUCAUC GAGUACAU 1423 AGAUGAUG CUGAUGAG X CGAA 207 AAUUGAGUA 600 IACUCAAUU CAUCAUCUI WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I. D. No. Substrate No.

1427 GEJACAGAU CUGAUGAG X CGAA 208 GAGUACAUC 601 AUGUACUC AEJCUGUAC 1430 UUGGUACA CUGAUGAG X CGAA 209 UACAUCAUC 602 AUGAUGUA UGUACCAA 1434 GGUGUUGG CUGAUGAG X CGAA 210 UCAUCUGUA 603 ACAGAUGA CCAACACC 1456 CUUGGCUA CUGAUGAG X CGAA 211 GAAGAACUC 604 AGUUCUUC UAGCCAAG 1458 UUCUUGGC CUGAUGAG X CGAA 212 AGAACUCUA 605 AGAGUUCU GCCAAGAA 1476 OGAGAGUG CUGAUGAG X CGAA 213 CACGGCCUA 606 AGGCCGUG CACUCUCC 1481 GUGUUGGA CUGAUGAG X CGAA 214 CCUACACUC 607 AGUGUAGG UCCAACAC 1483 UUGUGUUG CUGAUGAG X CGAA 215 UACACUCUC 608 AGAGUGUA ICAACACAA 1493 GGCCUCUG CUGAUGAG X CGAA 216 AACACAAUC 609 AUUGUGUU CAGAGGCC 1508 GUGGGACC CUGAUGAG X CGAA 217 CCACAACUA 610 AGUUGUGG GGUCCCAC 1512 AGCUGUGG CUGAUGAG X CGAA 218 AACUAGGUC 611 ACCUAGUU ICCACAGCU 1521 GGGUAAAU CUGAUGAG X CGAA 219 CCACAGCUA 612 AGCUGUGG AUUUACCC 1524 CAGGGGUA CUGAUGAG X CGAA 220 CAGCUAAUU 613 AUUAGCUG _____UACCCCUG 1525 CCAGGGGU CUGAUGAG X CGAA 221 AGCUAAUUU 614 AAUUAGCU

____ACCCCUGG

1526 UCCAGGGG CUGAUGAG X CGAA 222 GCUAAUUUA 615 AAAUUAGC CCCCUGGA 1543 GCUGUCCU CUGAUGAG X CGAA 223 GAUGGGCUC 616 AGCCCAUC AGGACAGC WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tiori RZ I. D. No. Substrate No.

1585 CCAUGUCC CUGAUGAC X CGAA 224 AACAGAAUU 617 AEJUCUGUU GGACAUGG 1595 CUUCCUGG CUGAUGAG X CGAA 225 GACAUGGUA 618 ACCAUGtJC CCAGGAAG 1621 AAUGAUUG CUGAUGAG X CGAA 226 GGCCAGCUA 619 AGCUGGCC CAAUCAUU 1626 CUGGGAAU CUGAUGAG X CGAA 227 GCUACAAUC 620 AUUGUAGC AUIJCCCAG 1629 CACCUGGG CUGAUGAG X CGAA 228 ACAAUCAUU 621 AUGAUUGU CCCAGGUG 1630 CCACCUGG CUGAUGAG X CGAA 229 CAAUCAUUC 622 AAUGAUUG 1640 ACAGGCUG CUGAUGAG X CGAA 230 CAGGUGGUU 623 ACCACCUG CAGCCUGU_____ 1641 CACAGGCU CUGAUGAG X CGAA 231 AGGUGGUUC 624 AACCACCU IAGCCUGUG 1682 GACUUCUC CUGAUGAG X CGAA 232 AAGCCCCUU 625 IAGGGGCUU GAGAAGUC 1690 AACCAUCU CUGAUGAG X CGAA 233 UGAGAAGUC 626 ACUUCUCA IAGAUGGUU 1698 GGCAAAUA CUGAUGAG X CGAA 234 CAGAUGGUU 627 ACCAUCUG UAUUUGCC 1699 GGGCAAAU CUGAUGAG X CGAA 235 AGAUGGUUU 628 AACCAUCU AUUUGCCC 1700 UGGGCAAA CUGAUGAG X CGAA 236 GAUGGUUUA 629 AAACCAUC _____UUUGCCCA 1702 CCUGGGCA CUGAUGAG X CGAA 237 UGGUUUAUU 630 AUAAACCA UGCCCAGG 1703 UCCUGGGC CUGAUGAG X CGAA 238 GGUUUAUUU 631 IAAUAAACC _____GCCCAGGA 1713 UGGAUCUC CUGAUGAG X CGAA 239 CCCAGGAUA 632 AUCCUGGG GAGAUCCA WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

1719 AAAUCUUG CUGAUGAG X CGAA 240 AUAGAGAUC 633 AUCUCUAU CAAGAUUU 1726 (UUCUGAA CUGAUGAG X CGAA 241 UCCAAGAUU 634 IAUCUUGGA UUCAGAAA_____ 1727 AUUUCUGA CUGAUGAG X CGAA 242 CCAAGAUUU 635 AAUCUUGG UCAGAAAU_____ 1728 GAUUUCUG CUGAUGAG X CGAA 243 CAAGAUUUU 636 AAAUCUU)G CAGAAAUC 1729 AGAUUUCU CUGAUGAG X CGAA 244 AAGAUUUUC 637 AAAAUCUU AGAAAUCU 1736 UUGUGAUA CUGAUJGAG X CGAA 245 tJCAGAAAUC 638 AUUUCUGA UAUCACAA_____ 1738 UGUUGUGA CUGAUGAG X CGAA 246 AGAAAUCUA 639 AGAUUUCU 1740 GAUGUUGU CUGAUGAG X CGAA 247 AAAUCUAUC 640 AUAGAUUU ACAACAUC 1748 UCCGCAUU CUGAUGAG X CGAA 248 CACAACAUC 641 AUGUUGUG AAUGCGGA 1758 UUUACUCU CUGAUGAG X CGAA 249 AUGCGGAUC 642 AUCCGCAU _____AGAGUAAA 1764 GAUGCCUU CUGAUGAG X CGAA 250 AUCAGAGUA 643 ACUCUGAU AAGGCAUC 1772 CUGGAGGA CUGAUGAG X CGAA 251 AAAGGCAUC 644 AUGCCUUU UCCUCCAG 1774 UGGUGGAG CUGAUGAG X CGAA 252 AGGCAUCUC 645 AGAUGCCU CUCCAGCA 1777 CAGUGCUG CUGAUGAG X CGAA 253 CAUCUCCUC 646 ____AGGAGAUG CAGGACUG 1787 GUGGCAGG CUGAUGAG X CGAA 254 AGCACUGUC 647 _____ACAGUGCU CCUGCCAC 1805 UGGGAGAA CUGAUGAG X CGAA 255 CAACAGCUA 648 AGCUGUUG IUUCUCCCA WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

1807 CCUGGGAG CUGAUGAG X CGAA 256 ACAGCUAUU 649 AUAGCUGU CUCCCAGG 1808 CCCUGGGA CUGAUGAG X CGAA 257 CAGCUAUUC 650 AAUAGCUG UCCCAGGG 1810 UGCCCUGG CUGAUGAG X CGAA 258 GCUAUUCUC 651 AGAAUAGC CCAGGGCA 1825 UAGGAGGG CUGAUGAG X CGAA 259 CAACACAUU 652 AUGUGUUG CCCUCCUA 1826 GUAGGA:GG CUGAUGAG X CGAA 260 AACACAUUC 653 AAUGUGUU CCUCCUAC 1830 GGGGGUAG CUGAUGAG X CGAA 261 CAUUCCCUC 654 AGGGAAUG CIJACCCCC 1833 CCGGGGGG CUGAUGAG X CGAA 262 UCCCUCCUA 655 AGGAGGGA CCCCCCGG 1854 AUUCCUGA CUGAUGAG X CGAA 263 CAGAGAAUU 656 AUUCUCUG UCAGGAAU 1855 UAUUCCUG CUGAUGAG X CGAA 264 AGAGAAUUU 657 AAUUCUCU CAGGAAUA 1856 CUAUUCCU CUGAUGAG X CGAA 265 GAGAAUUUC 658 AAAUUCUC _____AGGAAUAG 1863 UAGGCCAC CUGAUGAG X CGAA 266 UCAGGAAUA 659 AUUCCUGA _____GUGGCCUA 1871 GGAGGGGC CUGAUGAG X CGAA 267 AGUGGCCUA 660 AGGCCACU 1878 GGUUACAG CUGAUGAG X CGAA 268 UAGCCCCUC 661 AGGGGCUA CUGUAACC_____ 1883 ACAAUGGU CUGAUGAG X CGAA 269 CCUCCUGUA 662 ACAGGAGG IACCAUUGU_____ 1889 GGCUGGAC CUGAUGAG X CGAA 270 GUAACCAUU 663 AUGGUUAC 1892 GAUGGCUG CUGAUGAG X CGAA 271 ACCAUUGUC 664 IACAAUGGU

ICAGCCAUC

WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

1900 CAGAAGCU CUGAUGAG X CGAA 272 CCAGCCAUC 665 AUGGCUGG IAGCUUCUG 1905 UCCUGCAG CUGAUGAG X CGAA 273 CAUCAGCUU 666 AGCUGAUG CUGCAGGA 1906 GUCCUGCA CUGAUGAG X CGAA 274 AUCAGCUUC 667 AAGCUGAU UGCAGGAC 1921 UCUGGGCC CUGAUGAG X CGAA 275 ACAGAUGUU 668 ACAUCUGJ GGCCCAGA 1931 UGGCGGGA CUGAUGAG X CGAA 276 GCCCAGAUU 669 AUCUGGGC UCCCGCCA 1932 GUGGCGGG CUGAUGAG X CGAA 277 CCCAGAUUU 670 AAUCUGGG CCCGCCAC 1933 AGUGGCGG CUGAUGAG X CGAA 278 CCAGAUUUC 671 AAAUCUGG CCGCCACU 1942 UGGGGUUG CUGAUGAG X CGAA 279 CCGCCACUC 672 AGUGGCGG CAACCCCA 1971 AGGGGUCC CUGAUGAG X CGAA 280 CCCCAACUU 673 AGUUGGGG GGACCCCU 1980 GCGGGUAG CUGAUGAG X CGAA 281 GGACCCCUA 674 AGGGGUCC CUACCCGC 1983 UGAGCGGG CUGAUGAG X CGAA 282 CCCCUACUA 675 AGUAGGGG CCCGCUCA 1990 AAAAGCCU CUGAUGAG X CGAA 283 UACCCGCUC 676 AGCGGGUA AGGCUUUU 1996 GGGCAGAA CUGAUGAG X CGAA 284 CUCAGGCUU 677 AGCCUGAG UUCUGCCC 1997 UGGGCAGA CUGAUGAG X CGAA 285 UCAGGCUUU 678 AAGCCUGA _____UCUGCCCA 1998 CUGGGCAG CUGAUGAG X CGAA 286 CAGGCUUUU 679 AAAGCCUG C UGCCCAG 1999 GCUGGGCA CUGAUGAG X CGAA 287 AGGCUUUUC 680 IAAAAGCCU IUGCCCAGC WO 99/50403 WO 9950403PCT[US99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

202.6 AGCCUGGC CUGAUGAG X CGAA 288 AGGUGGCUA 681 AGCCACCU CCCAGGCU 2025 CUUAGCAG CUGAUGAG X CGAA 289 CCCAGGCUA 682 AGCCUGGG CUGCUAAG 2031 ACGAGUCU CUGAUGAG X CGAA 290 CUACUGCUA 683 IAGCAGUAG

AGACUCGU

2037 GGAAGUAC CUGAUGAG X CGAA 291 CUAAGACUC 684 AGUCUUAG GUACUUCC 2040 CUGGGAAG CUGAUGAG X CGAA 292 AGACUCGUA 685 ACGAGUCU CUUCCCAG 2043 AAACUGGG CUGAUGAG X CGAA 293 CUCGUACUU 686 AGUACGAG CCCAGUUU 2044 CAAACUGG CUGAUGAG X CGAA 294 UCGUACUUC 687 IAAGUACGA

CCAGUUUG

2050 CCACACCA CUGAUGAG X CGAA 295 UUCCCAGUU 688 ACUGGGAA UGGUGUGG 2051 CCCACACC CUGAUGAG X CGAA 296 UCCCAGUUU 689 AACUGGGA GGUGUGGG 2065 GAGUCUGA CUGAUGAG X CGAA 297 GGGCAGCUU 690 AGCUGCCC IUCAGACUC 2066 GGAGUCUG CUGAUGAG X CGAA 298 GGCAGCUUU 691 AAGCUGCC CAGACUCC 2067 UGGAGUCU CUGAUGAG X CGAA 299 GCAGCUUUC 692 AAAGCUGC AGACUCCA 2073 GGAGGAUG CUGAUGAG X CGAA 300 UUCAGACUC 693 AGUCUGAA CAUCCUCC 2077 UGAAGGAG CUGAUGAG X CGAA 301 GACUCCAUC 694 AUGGAGUC____ CEJCCUUCA 2080 AGCUGAAG CUGAUGAG X CGAA 302 UCCAUCCUC 695 AGGAUGGA CUUCAGCU 2083 UGGAGCUG CUGAUGAG X CGAA 303 AUCCUCCUU 696 1 AGGAGGAU

CAGCUCCA

WO 99/50403 WO 9950403PCT/US99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

2084 AUGGAGCU CUGAUGAG X CGAA 304 UCCUCCUUC 697 AAGGAGGA AGCUCCAU 2089 GGGACAJG CUGAUGAG X CGAA 305 CUUCAGCUC 698 AGCUGAAG CAUGUCCC 2095 CAGGGAGG CUGAUGAG X CGAA 306 CUCCAUGUC 699 ACAUGGAG ICCUCCCUG 2099 GCACCAGG CUGAUGAG X CGAA 307 AUGUCCCUC 700 AGGGACAU CCUGGUGC 2119 CACCAGGC CUGAUGAG X CGAA 308 AACUGCAUC 701 AUGCAGUU GCCUGGUG 2137 GACUAGGG CUGAUGAG X CGAA 309 UGCUGCCUA 702 AGGCAGCA CCCUAGUC 2142 GGUGAGAC CUGAEJGAG X CGAA 310 CCUACCCUA 703 AGGGUAGG GUCEJCACC 2145 AUUGGUGA CUGAUGAG X CGAA 311 ACCCUAGUC 704 ACUAGGGU UCACCAAU 2147 CGAUUGGU CUGAUGAG X CGAA 312 CCUAGUCUC 705 AGACUAGG ACCAAUCG 2154 AGAUCCAC CUGAUGAG X CGAA 313 UCACCAAUJC 706 _____AUUGGUGA GUGGAUCU 2161 CAAAGUUA CUGAUGAG X CGAA 314 UCGUGGAUC 707 ____AUCCACGA EJAACUUUG 2163 AGCAAAGU CUGAUGAG X CGAA 315 GUGGAUCUA 708 AGAUCCAC ACUUUGCU 2167 CAGGAGCA CUGAUGAG X CGAA 316 AUCUAACUU 709 AGUUAGAU UGCUCCUG 2168 UCAGGAGC CUGAUGAG X CGAA 317 UCUAACUUU 710 AAGUUAGA GCUCCUGA 2172 AGUCUCAG CUGAUGAG X CGAA 318 ACUUUGCUC 711 AGCAAAGU CUGAGACU 2200 GUGUCUGG CUGAUGAG X CGAA 319 AGGACAAUU 712 _____AUUGUCCU CCAGACAC WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ I.D. No. Substrate No.

2201 CGUGUCUG CUGAUGAG X CGAA 320 GGACAAUUC 713 AAUUGUCC CAGACACG 2231 UGUGGCCA CUGAUGAG X CGAA 321 GUGGGUGUC 714 ACACCCAC UGGCCACA 2259 ACGAUGAU CUGAUGAG X CGAA 322 AGCAGCCUC 715 AGGCUGCU IAUCAUCGU 2262 UGAACGAU CUGAUGAG X CGAA 323 AGCCUCAUC 7 16G AUGAGGCU AUCGUUCA 2265 ACUUGAAC CUGAUGAG X CGAA 324 CUCAUCAUC 717 AUGAUGAG GUUCAAGU 2268 AGAACUUG CUGAUGAG X CGAA 325 AUCAUCGUU 718 ACGAUGAU CAAGUUCU 2269 UAGAACUU CUGAUGAG X CGAA 326 UCAUCGUUC 719 AACGAUGA AAGUUCUA 2274 CUCACUAG CUGAUGAG X CGAA 327 GUUCAAGUU 720 ACUUGAAC CUAGUGAG 2275 GCUCACUA CUGAUGAG X CGAA 328 UUCAAGUUC 721 AACUUGAA UAGUGAGC 2277 UUGCUCAC CUGAUGAG X CGAA 329 CAAGUUCUA 722 AGAACUUG GUGAGCAA 2291 GGUUGUUG CUGAtJGAG X CGAA 330 CAACAUGUU 723 ACAUGUUG CAACAACC 2292 CGGUUGUU CUGAUGAG X CGAA 331 AACAUGUUC 724 AACAUGUU AACAACCG 2330 UCCUGGAA CUGAUGAG X CGAA 332 CCUGAGGUC 725 ACCUCAGG EJUCCAGGA 2332 UCUCCUGG CUGAUGAG X CGAA 333 UGAGGUCUU 726 AGACCUCA CCAGGAGA 2333 AUCUCCUG CUGAUGAG X CGAA 334 GAGGUCUUC 727 AAGACCUC CAGGAGAU_____ 2347 CCAGCAUG CUGAUGAG X CGAA 335 GAUGCUGUC 728 ACAGCAUC

CAUGCUGG

WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

tion RZ 1.D. No. Substrate No.

2361 GUUGCUCU CUGAUGAG X CGAA 336 tJGGGAGAUC 729 AtJCUCCCA AGAGCAAC 2374 CAUUGUUG CUGAUGAG X CGAA 337 CAACAGCJA 730 AGCUGUUG CAACAAUG 2389 GAUCAGGG CUGAUGAG X CGAA 338 UGAAGAAUU 731 AUUCUUCA CCCUGAUC 2390 AGAUCAGG CUGAUGAG X CGAA 339 GAAGAAUUC 732 AAUUCUUC CCUGAUCU 2397 CAUAGUUA CUGAUGAG X CGAA 340 UCOCUGAUC 733 AUCAGGGA OAACUAUG 2399 AACAUAGU CUGAUGAG X CGAA 341 CCUGAUCUA 734 AGAUCAGG ACUAUGUU 2403 GGGAAACA CUGAUGAG X CGAA 342 AUCUAACUA 735 AGUUAGAU IUGUUUCCC 2407 AGGGGGGA CUGAUGAG X CGAA 343 AACUAUGUU 736 ACAUAGUU UCCCCCCU 2408 AAGGGGGG CUGAUGAG X CGAA 344 ACUAUGUUU 737 AACAUAGU CCCCCCUU 2409 AAAGGGGG CUGAUGAG X CGAA 345 CUAUGUUUC 738 AAACAUAG CCCCCUUU 2416 AUUCUGAA CUGAUGAG X CGAA 346 UCCCCCCUU 739 AGGGGGGA UUCAGAAU_____ 2417 UAUUCUGA CUGAUGAG X CGAA 347 CCCCCCUUU 740 AAGGGGGG UCAGAAUA_____ 2418 CUAUUCUG CUGAUGAG X CGAA 348 CCCCCUUUU 741 AAAGGGG fCAGAAUAG 2419 UCUAUUCU CUGAUGAG X CGAA 349 CCCCUUUUC 742 AAAAGGGG 2425 AAUAGUUC CUGAUGAG X CGAA 350 UUCAGAAUA 743 AUUCUGAA GAACUAUU 2431 CACCCCAA CUGAUGAG X CGAA 351 AUAGAACUA 744 IAGUUCUAU UUGGGGUG WO 99/50403 WO 9950403PCT[US99/06507 Posi- Seq. Seq. TAD.

tion RZ I.D. No. Substrate No.

2433 CUCACCCC CUGAUGAG X CGAA 352 AGAACUAJU 745 AUAGUUCU GGGGUGAG 2445 CCACCCCU CUGAUGAG X CGAA 353 GUGAGGAUA 746 AUCCUCAC AGGGGUGG 2466 CAAACAGU CUGAUGAG X CGAA 354 GAAAAAAUC 747 AUUUUUUC ACUGUOUG 2472 UAAAAACA CUGAUGAG X CGAA 355 AUCACUGUU 748 ____ACAGUGAU UGUUUUUA 2473 UUAAAAAC CUGAUGAG X CGAA 356 UCACUGUJU 749 AACAGUGA GUUUUUAA 2476 UUUUUAAA CUGAUGAG X CGAA 357 CUGUUUGJU 750 ACAAACAG UUUPAAAAA 2477 CUUUUUAA CUGAUGAG X CGAA 358 UGUUUGUUU 751 AACAAACA UUAAAAAG 2478 GCUUUUUA CUGAUGAG X CGAA 359 GUUUGUUUU 752 AAACAAAC UAAAAAGC 2479 UGCUUUUU CUGAUGAG X CGAA 360 UUUGUUUUU 753 AAAACAAA AAAAAGCA 2480 UUGCUUUU CUGAUGAG X CGAA 361 UUGUUUUUA 754 AAAAACAA AAAAGCAA 2491 UACAGAAA CUGAUGAG X CGAA 362 AAGCAAAUC 755 AUUUGCUU UUUCUGUA 2493 UUUACAGA CUGAUGAG X CGAA 363 GCAAAUCUU 756 AGAUUUGC UCUGUAAA 2494 GUUUACAG CUGAUGAG X CGAA 364 CAAAUCUUU 757 AAGAUUUG CUGUAAAC 2495 UGUUUACA CUGAUGAG X CGAA 365 AAAUCUUUC 758 AAAGAUUU

UGUAAACA

2499 AUUCUGUU CUGAUGAG X CGAA 366 CUUUCUGUA 759 ACAGAAAG AACAGAAU 2508 GGAACUUU CUGAUGAG X CGAA 367 AACAGAAUA 760 1 AUUCUGUU

IAAAGUUCC

WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. Seq. I.D.

*tion RZ I.AD. No. Substrate No.

2514 GGGAGAGG CUGAUGAG X CGAA 368 AUAAAAGUU 761 ACUUUUAU CCUCUCCC 52515 AGGGAGAG CUGAUGAG X CGAA 369 UAAAAGUUC 762 AACUUUUA CUCUCCCU 2518 GGAAGGGA CUGAUGAG X CGAA 370 AAGUUCCUC 763 AGGAACUU UCCCUUCC 2520 AGGGAAGG CUGAUGAG X CGAA 371 GtJUCCUCUC 764 ____AGAGGAAC -CCUUCCCU 2524 GGGAAGGG CUGAUGAG X CGAA 372 CUCUCCCUU 765 AGGGAGAG CCCUUCCC 2525 AGGGAAGG CUGAUGAG X CGAA 373 UCUCCCUUC 766 AAGGGAGA CCUUCCCU 2529 GGUGAGGG CUGAUGAG X CGAA 374 CCUUCCCUU 767 AGGGAAGG ICCCUCACC 2530 GGGUGAGG CUGAUGAG X CGAA 375 CUUCCCUUC 768 AAGGGAAG CCUCACCC 2534 UCAGGGGU CUGAUGAG X CGAA 376 CCUUCCCUC 769 AGGGAAGG ACCCCUGA 2548 AAAGGGGG CUGAUGAG X CGAA 377 UGACAUGUA 770 ACAUGUCA CCCCCUUU 2555 AGAAGGGA CUGAUGAG X CGAA 378 UACCCCCUU 771 AGGGGGUA _____UCCCUUCU 2556 CAGAAGGG CUGAUGAG X CGAA 379 ACCCCCUUU 772 AAGGGGGU CCCUUCUG 2557 CCAGAAGG CUGAUGAG X CGAA 380 CCCCCUUUC 773 AAAGGGGG CCUUCUGG 2561 ACAGCCAG CUGAUGAG X CGAA 381 CUUUCCCUU 774 AGGGAAAG

CTJGGCUGU

2562 AACAGCCA CUGAUGAG X CGAA 382 UUUCCCUUC 775 AAGGGAAA _____UGGCUGUU 2570 AGCAGGGG CUGAUGAG X CGAA 383 CUGGCUGUU 776 1ACAGCCAG

ICCCCUGCU

WO 99/50403 WO 9950403PCT[US99/06507 Posi- Seq. Seq. I.D.

tion RZ L.D. No. Substrate No.

2571 GAGCAGGG CUGAUGAG X CGAA 384 UGGCUGUUC 777 AACAGCCA CCCUGCUC 2579 AGGCAACA CUGAUGAG X CGAA 385 CCCCUGCUC 778 AGCAGGGG UGUUGCCU_____ 2583 UAGGAGGC CUGAUGAG X CGAA 386 UGCUCUGUU 779 ACAGAGCA GCCUCCUA 2588 UACCUUAG CUGAUGAG X CGAA 387 UGUUGCCUC 780 AGGCAACA CUAAGGUA 2591 UGUUACCU CUGAUGAG X CGAA 388 UGCCUCCUA 781 AGGAGGCA AGGUAACA 2596 AUAAAUGU CUGAUGAG X CGAA 389 CCUAAGGUA 782 ACCUUAGG IACAUUUAU 2601 UUUUUAUA CUGAUGAG X CGAA 390 GGUAACAUU 783 AUGUUACC UAUAAAAA 2602 UUUUUUAU CUGAUGAG X CGAA 391 GUAACAUUU 784 AAUGUUAC AUAAAAAA 2603 UUUUUUUA CUGAUGAG X CGAA 392 UAACAUUUA 785 AAAUGUUA IUAAAAAAA 2605 UUUUUUUU CUGAUGAG X CGAA 393 ACAUUUAUA 786 AUAAAUGU AAAAAAAA I WO 99/50403 WO 9950403PCT/US99/06507 88 TABLE IV: HAIRPIN RIBOZYME SEQUENCES AND TARGET SITES FOR ARNT Posi- Seq. 1.D. Seq.

tion RZ No. Substrate 1.0. No.

6 GGGAGG AGAA GCCA ACCAGAGAAACA 787 UJGGCG GCU CCUCCC 849 X GUACAUUACCUGGUA 92 UGGUAC AGAA GAUG ACCAGAGAAACA 788 CAUCA GAU GUACCA 850 IX GUACAUUACCUGGUA 253 UUAGAC AGAA GAUC ACCAGAGAAACA 789 GAUCA GAU GUCUAA 851 X GUACAUUACCUGGUA 274 CUGGCA AGAA GCUC ACCAGAGAAACA 790 GAGCG GUU UGCCAG 852 X GUACAUUACCUGGUA 287 CUCAUC AGAA GACC ACCAGAGAAACA 791 GGUCG GAU GAUGAG 853 IX GUACAUUACCUGGUA 374 GAUGUA AGAA GUCA ACCAGAGAAACA 792 UGACA GCC UACAUC 854 X GUACAUUACCUGGUA 411 GGGCAC AGAA GGUG ACCAGAGAAACA 793 CACCU GUA GUGCCC 855 X GUACAUUACCUGGUA 461 GUGAGA AGAA GCCA ACCAGAGAAACA 794 UGGCA GUU UCUCAC 856 X GUACAUUACCUGGUA 506 GGAGCC AGAA GUGG ACCAGAGAAACA 795 CCACU GAU GGCUCC 857 IX GUACAUUACCUGGUA 523 AGGAAA AGAA GCUU ACCAGAGAAACA 796 AAGCC GUC UUUCCU 858 X GUACAUUACCUGGUA 536 UUCCUG AGAA GUGA ACCAGAGAAACA 797 UCACU GAU CAGGAA 859 X GUACAUUACCUGGUA 572 AAGCC AGAA GCUG ACCAGAGAAACA 798 CAGCA GAU GGCUUU 860 X GUACAUUACCUGGUA 583 ACAAUA AGAA GAAA ACCAGAGAAACA 799 UUtJCU GUU UAUUGU 861 X GUACAUUACCUGGUA 626 CACGGA AGAA GACA ACCAGAGAAACA 800 UGUCU GAC UCCGUG 862 X GUACAUUACCUGGUA 641 GUUCAA AGAA GGAG ACCAGAGAAACA 801 CUCCU GUU UUGAAC 863 IX GUACAUUACCUGGUA WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. I.D. Seq.

tion RZ No. Substrate I.D. No.

658 CAUUCA AGAA GUGG ACCAGAGAAACA 802 CCACA CUC UGAAUG 864 X GUACAUUACCUGGUA 701 CACAUC AGAA GGGU ACCAGACAAACA 803 ACOCA GAU GAUGUG 865 X GUACAIJUACCUGGUA 727 GUGGAA AGAA GCUC ACCAGAGAAACA 804 GAGCA CCU UUCCAC 866 X GUACAUUACCUGGUA 805 AUGGAA AGAA GCUG ACCAGAGAAACA 805 CAGCA GUC UUCCAU 867 X GUACAUUACCUGGUA 867 CAGAGC AGAA GCCA ACCAGAGAAACA 806 UGGCA GUA GCUCUG 868 X GUACAUUACCUGGUA 884 CACAGA AGAA GGGU ACCAGAGAAACA 807 ACOCA GUU UCUGUG 869 X GUACAUUACCUGGUA 918 UCCUGO AGAA GUUtC ACCAGAGAAACA 808 GAACA GAU GCAGGA 870 X GUACAUUACCUGGUA 1025 GUCAUC AGAA GGGA ACCAGAGAAACA 809 UCOCA GAU GAUGAC 871 X GUACAUUACCUGGUA 1080 CCUGCA AGAA GCCA ACCAGAGAAACA 810 UGGCA GAU UGCAGG 872 X GUACAUUACCUGGUA 1107 UGUCUG AGAA GUUG ACCAGAGAAACA 811 CAACU GUA CAGACA 873 X GUACAUUACCUGGUA 1191 COACAC AGAA GUGA ACCAGAGAAACA 812 UCACC GCU GUGUGG 874 X GUACAUUACCUGGUA 1205 GUAGOC AGAA GUAG ACCAGAGAAACA 813 CUACU GUU GGCUAC 875 X GUACAUUACCUGGUA 1273 CUUAGA AGAA GCUG ACCAGAGAAACA 814 CAGCA GCU UCUAAG 876 X GUACAUUACCUGGUA 1287 GUUGGA AGAA GUCU ACCAGAGAAACA 815 AGACA GCU UCCAAC 877 X GUACAUUACCUGGUA 1324 AUGACA AGAA GCAC ACCAGAGAAACA 816 GUGCU GUC UGUCAU 878 X GUACAUUACCUGGUA 1339 GACCGG AGAA GGAA ACCAGAGAAACA 817 UUCCG GUU COGGUC 879 X GUACAUUACCUGGUAII WO 99/50403 WO 9950403PCTIUS99/06507 Posi- Seq. I. D. Seq.

tion RZ No. Substrate I.D. No.

1345 UUCUUA AGAA GGAA ACCAGAGAAACA 818 LJUCCG GUC UAAGAA 880 IX GUAGAUUACCUGGUA 1380 UAAAGG AGAA GGUU ACCAGAGAAACA 819 ACCA GCU CCUUUA 881 X GUACAtJUACCUGGUA 1409 AUUUC AGAA GAGU ACCAGAGAAACA 820 ACUCA GAU GAAAEJU 882 IX GUACAUUACCUGGUA 1431 UGUOG AGAA GAUG ACCAGAGAAACA 821 CAUCU GUA CCAACA 883 X GUACAUUACCUGGUA 1471 AGUGUA AGAA GUGG ACCAGAGAAACA 822 CCACG GCC UACAGU 884 IX GUACAUUACCUGGUA 1549 GGUGCC AGAA GUCC ACCAGAGAAACA 823 GGACA GCU GGCACC 885 X GUACAUUACCUGGUA 1642 GUCACA AGAA GAAC ACCAGAGAAACA 824 GUUCA GCC UGUGAC 886 X GUACAUUACCUGGUA 1691 UAAACC AGAA GACU ACCAGAGAAACA 825 AGUCA GAU GGUUUA 887 X GUACAUUACCUGGUA 1754 ACUCUG AGAA GCAU ACCAGAGAAACA 826 AUGCG GAU CAGAGU 888 X GUACAUUACCUGGUA 1784 GGCAGG AGAA GUGC ACCAGAGAAACA 827 GCACU GUC CCUGCC 889 X GUACAUUACCUGGUA 1840 UCUGCC AGAA GGGG ACCAGAGAAACA 828 CCCCG GCC GGCAGA 890 IX GUACAUUACCUGGUA 1901 UGCAGA AGAA GAUG ACCAGAGAAACA 829 CAUCA GCU UCUGGA 891 X GUACAUUACCUGGUA 1915 GCCAAC AGAA GUCC ACCAGAGAAACA 830 GGACA GAU GUUGGC 892 X GUACAUUACCUGGUA 1927 CGGGAA AGAA GGGC ACCAGAGAAACA 831 GCCCA GAU UUCCCG 893 IX GUACAUUACCUGGUA 1986 AGCCUG AGAA GGUA ACCAGAGAAACA 832 UACCC GCU CAGGCU 894 X GUACAUUACCUGGUA 2000 CUGCUG AGAA GAAA ACCAGAGAAACA 833 UUUCU GCC CAGCAG 895 IX GUACAUUACCUGGUA WO 99/50403 WO 9950403PCTIUS99/06507 Posit ion Seq. I. D.

Seq.

I. D. No.

896 Substrate L I 2047 ACACCA AGAA GGGA ACCAGAGAAACA X GUACAUUACCUGGUA UCCCA GUU UGGUGU 2061 UCUGAA AGAA GCCC ACCAGAGAAACA 835 GGGCA GCU UUCAGA 897 X GUACAEJUACCUGGUA 2068 GAUGGA AGAA GAAA ACCAGAGAAACA 836 UUUCA GAC UCCAUC 898 X GUACAUUACCUGGUA 2085 ACAUGG AGAA GAAG ACCAGAGAAACA 837 CUUCA GCU CCAUGU 899 X GUACAUUACCUGGUA 2129 GUAGGC AGAA GCAC ACCAGAGAAACA 838 GUGCU GCU GCCUAC 900 X GUACAUUACCUGGUA 2132 AGGGUA AGAA GCAG ACCAGAGAAACA 839 CUGCU GCC UACCCU 901

GUACAUUACCUGGUA

2185 CCUGCA AGAA GUCC ACCACAGAAACA 840 GGACA GAC UGCAGG 902

GUACAUUACCUGGUA

2254 UGAUGA AGAA GCUJG ACCAGAGAAACA 841 CAGCA GCC UCAUCA 903

GUACAUUACCUGGUA

2320 ACCUCA AGAA GGCC ACCAGAGAAACA 842 GGCCA GCC UGAGGU 904

GUACAUUACCUGGUA

2344 AGCAUG AGAA GCAU ACCAGAGAAACA 843 AUGCU GUC CAUGCU 905

GUACAUUACCUGGUA

2393 AGUUAG AGAA GGGA ACCAGAGAAACA 844 UCCCU GAU CUAACU 906

GUACAUUACC.GGUA

2469 AACA AGAA GUGA ACCAGAGAAACA 845 fCACU GUU UGUUUU 907 X GUACAUUACCUGGUA 2567 CAGGGG AGAA GCCA ACCAGAGAAACA 846 UGGCU GUU CCCCUG 908 X GUACAUUACCUGGUA 2575 CAACAG AGAA GGGG ACCAGAGAAACA 847 CCCCU GCU CUGUUG 909 GUACAUUACCUGGUA 2580 GGAGGC AGAA GAGC ACCAGAGAAACA 848 GCUCU GUU GCCUCC 910 X GUACAUUACCUGGUAI WO 99/50403 WO 9950403PCT[US99/06507 92 TABLE V: HAMMERHEAD RIBOZYMES AND TARGET SITES FOR TIE Seq. I. D. Seq. I.0D.

Position RZ No. Substrate No.

13 CAAGAAGG GUGAUGAG 911 UGUGCUGUU 1612 X CGAA ACAGCACA CCUUCUUG 14 GCAAGAAG CUGAUGAG 912 GUGCUGUUC 1613 X CGAA AACAGCAC CUUCUUGC 17 GAGGCAAG CUGAUGAG 913 CUGUUCCUU 1614 X CGAA AGGAACAG CUUGCCUC 18 AGAGGCAA CUGAUGAG 914 UGUUCCUUC 1615 X CGAA AAGGAACA UUGCCUCU UUAGAGGC CUGAUGAG 915 UUCCUUCUU 1616 X CGAA AGAAGGAA GCCUCUAA ACAAGUUA CUGAUGAG 916 UCUUGCCUC 1617 X CGAA AGGCAAGA UAACUUGU 27 UUACAAGU CUGAUGAG 917 UUGCCUCUA 1618 CGAA AGAGGCAA ACUUGUAA 31 UUGUUUAC CUGAUGAG 918 CUCUAACUU 1619 X CGAA AGUUAGAG GUAAACAA 34 GUCUUGUU CUGAUGAG 919 UAACUUGUA 1620 X CGAA ACAAGUUA AACAAGAC CGUCCUAG CUGAUGAG 920 CAAGACGUA 1621 X CGAA ACGUCUUG CUAGGACG 48 CAUCGUCC CUGAUGAG 921 GACGUACUA 1622 X CGAA AGUACGUC GGACGAUG 59 CUUUCCAU CUGAUGAG 922 ACGAUGCUA 1623 X CGAA AGCAUCGU AUGGAAAG 69 CGGUUUGU CUGAUGAG 923 UGGAAAGUC 1624 X CGAA ACUUUCCA ACAAACCG 84 CUUUCAAA CUGAUGAG 924 CGCUGGGUU 1625 X CGAA ACCCAGCG UUUGAAAG CCUUUCAA CUGAUGAG 925 GCUGGGUUU 1626 X CGAA AACCCAGC UUGAAAGG WO 99/50403 WO 9950403PCTIUS99/06507 Seq. I.D. Seq. I. D.

Position RZ No. Substrate No.

86 UCCUUUCA CUGAUGAG 926 CUGGGUUUU 1627 X CGAA AAACCCAG UGAAAGGA 87 AUCCtJUUC CUGAUGAG 927 UGGGUUUUU 1628 X CGAA AAAACCCA GAAAGGAU 96 GUCCCAAG CUGAUGAG 928 GAAAGGAUC 1629 X CGAA AUCCUUUC CUUGGGAC 99 GAGGUCCC CUGAUGAG 929 AGGAUCCUU 1630 X CGAA AGGAUCCU GGGACCUC 107 AUGUGCAU CUGAUGAG 930 UGGGACCUC 1631 X CGAA AGGUCCCA AUGCACAU 116 UUUCCACA CUGAUGAG 931 AUGCACAUU 1632 X CGAA AUGUGCAU EGUGGAAA 117 GUUUCCAC CUGAUGAG 932 UGCACAUUU 1633 X CGAA AAUGUGCA GUGGAAAC 139 CUUCCCCA CUGAUGAG 933 GGAGAGAUU 1634 CGAA AUCUCUCC UGGGGAAG 140 GCUUCCCC CUGAUGAG 934 GAGAGAUUU 1635 X CGAA AAUCUCUC GGGGAAGC 156 UGGCUAAA CUGAUGAG 935 CAUGGACUC 1636 X CGAA AGUCCAUG [UUAGCCA 158 GCUGGCUA CUGAUGAG 936 UGGACUCUU 1637 X CGAA AGAGUCCA UAGCCAGC 159 AGCUGGCU CUGAUGAG 937 GGACUCUUU 1638 X CGAA AAGAGUCC AGCCAGCU 160 AAGCUGGC CUGAUGAG 938 GACUCUUUA 1639 X CGAA AAAGAGUC GCCAGCUU 168 AGAGAACU CUGAUGAG 939 AGCCAGCUU 1640 X CGAA AGCUGGCU AGUUCUCU 169 CAGAGAAC CUGAUGAG 940 GCCAGCUUA 1641 X CGAA AAGCUGGC GUUCUCUG 172 CCACAGAG CUGAUGAG 941 AGCUUAGUU 1642 X CGAA ACUAAGCU CUCUGUGG WO 99/50403 WO 9950403PCTIUS99/06507 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

173 UCCACAGA CUGAUGAG 942 GCUUAGUUC 1643 CGAA AACUAAGC EJCUGUGGA 175 ACUCCACA CUGAUGAG 943 UUAGUUCUC 1644 X CGAA AGAACUAA UGUGGAGU 184 AGCAAGCU CUGAUGAG 944 UGUGGAGUC 1645 X CGAA ACUCCACA AGCULJGCU 189 AAAGGAGC CUGAUGAG 945 AGUCAGCUU 1646 X CGAA AGCUGACU GCUCCUUU 193 CCAGAAAG CUGAUGAG 946 AGCUUGCUC 1647 X CGAA AGCAAGCU CUUUCUGG 196 GUUCCAGA CUGAUGAG 947 UUGCUCCUU 1648 X CGAA AGGAGCAA UCUGGAAC 197 AGUUCCAG CUGAUGAG 948 UGCUCCUUU 1649 X CGAA AAGGAGCA CUGGAACU 198 CAGUUCCA CUGAUGAG 949 GCUCCUUUC 1650 X CGAA AAAGGAGC UGGAACUG 225 UCAAGAUC CUGAUGAG 950 CAUGGACUU 1651 X CGAA AGUCCAUG GAUCUUGA 229 UUGAUCAA CUGAUGAG 951 GACUUGAUC 1652 X CGAA AUCAAGUC UUGAUCAA 231 AAUUGAUC CUGAUGAG 952 CUUGAUCUU 1653 X CGAA AGAUCAAG GAUCAAUU 235 AGGGAAUU CUGAUGAG 953 AUCUUGAUC 1654 X CGAA AUCAAGAU AAUUCCCU 239 AGGUAGGG CUGAUGAG 954 UGAUCAAUU 1655 X CGAA AUUGAUCA CCCUACCU 240 GAGGUAGG CUGAUGAG 955 GAUCAAUUC 1656 X CGAA AAUUGAUC CCUACCUC 244 ACAAGAGG CUGAUGAG 956 AAUUCCCUA 1657 X CGAA AGGGAAUU CCUCUUGU 248 AGAUACAA CUGAUGAG 957 CCCUACCUC 1658 X CGAA AGGUAGGG IUUGUAUCU WO 99/50403 WO 9950403PCT/US99/06507 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

250 UCAGAUAC CUGAUGAG 958 CUACCUCUU 1659 X CGAA AGAGGUAG GUAUCUGA 253 GCAUCAGA CUGAUGAG 959 CCUCUUGUA 1660 X CGAA ACAAGAGG UCUGAUGC 255 CAGCAUCA CUGAUGAG 960 UCUUGUAUC 1661 X CGAA AUACAAGA UGAUCCUG 270 AGGUGAGA CUGAUGAG 961 UGAAACAUC 1662 X CGAA AUGUUUCA UCUCACCU 272 GCAGGUGA CUGAUGAG 962 AAACAUCUC 1663 X CGAA AGAUGUUU UCACCUGC 274 AUGCAGGU CUGAUGAG 963 ACAUCUCUC 1664 X CGAA AGAGAUGU ACCUGCAU 283 CCAGAGGC CUGAUGAG 964 ACCUGCAUU 1665 X CGAA AUGCAGGU GCCUCUGG 288 GCCACCCA CUGAUGAG 965 CAUUGCCUC 1666 X CGAA AGGCAAUG ______UGGGUGGC 313 CCUAUGGU CUGAUGAG 966 GAGCCCAUC 1667 X CGAA AUGGGCUC ACCAUAGG 319 UCCCUUCC CUGAUGAG 967 AUCACCAUA 1668 X CGAA AUGGUGAU GGAAGGGA 330 AGGCUUCA CUGAUGAG 968 AAGGGACUU 1669 X CGAA AGUCCCUU UGPJAGCCU______ 331 AAGGCUUC CUGAUGAG 969 AGGGACUUU 1670 X CGAA AAGUCCCU GAAGCCUU 339 GGUUCAUU CUGAUGAG 970 UGAAGCCUU 1671 X CGAA AGGCUUCA AAUGAACC 340 UGGUUCAU CUGAUGAG 971 GAAGCCUUA 1672 X CGAA AAGGCUUC AUGAACCA 359 UUCCAGCG CUGAUGAG 972 ACCAGGAUC 1673 X CGAA AUCCUGGU CGCUGGAA 370 UCUUGAGU CUGAUGAG 973 CUGGAAGUU 1674 fX CGAA ACUUCCAG ACUCAAGAI WO 99/50403 WO 9950403PCT/US99/06507 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

371 AUCUUGAG CUGAUGAG 974 UGGAAGUUA 1675 X CGAA AACUUCCA CUCAAGAU 374 CACAUCUU CUGAUGAG 975 AAGUUACUC 1676 X CGAA AGUAACUU AAGAUGUG 398 AACUUUUU CUGAUGAG 976 AAUGGGCUA 1677 X CGAA AGCCCAUU AU'AAGUU 406 UUCCAAAC CUGAUGAG 977 AAAAAAGUU 1678 X CGAA ACUUUUUU GUUUGGAA 409 CUCUUCCA CUGAUGAG 978 AAAGUUGUU 1679 X CGAA ACAACUUU UGGAAGAG 410 UCUCUUCC CUGAUGAG 979 AAGUUGUUU 1680 X CGAA AACAACUU GGAAGAGA 428 GAUCUUAC CUGAUGAG 980 AAAAGGCUA 1681 X CGAA AGCCUUUU GUAAGAUC 431 AUEJGAUCU CUGAUGAG 981 AGGCUAGUA 1682 X CGAA ACUAGCCU AGAUCAAJ 436 GCACCAUU CUGAUGAG 982 AGtJAAGAJC 1683 X CGAA AUCUUACU AAtJGGUGC 446 ACAGAAAU CUGAUGAG 983 AUGGUGCUU 1684 X CGAA AGCACCAU AEJUUCUGU 447 CACAGAAA CUGAUGAG 984 UGGUGCUUA 1685 X CGAA AAGCACCA UUUCUGUG 449 UUCACAGA CUGAUGAG 985 GUGCUUAUU 1686 CGAA AUAAGCAC UCUGUGAA 450 CUUCACAG CUGAUGAG 986 UGCUUAUUU 1687 X CGAA AAUAAGCA CUGUGAAG 451 CCUUCACA CUGAUGAG 987 GCUUAUUUC 1688 X CGAA AAAUAAGC UGUGAAGG 466 UCUCCUCG CUGAUGAG 988 GGGCGAGUU 1689 X CGAA ACUCGCCC CGAGGAGA 467 CUCUCCUC CUGAUGAG 989 GGCGAGUUC 1690 IX CGAA AACUCGCC GAGGAGAG WO 99/50403 WO 9950403PCTIUS99/06507 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

481 CGUAUCCU CUGAUGAG 990 GAGGCPAAUC 1691 X CGAA AUUGCCUC AGGAUACG 487 AUGGUUCG CUGAUGAG 991 AUCAGGAUA 1692 X CGAA AUCCUGAU CGAACCAU 506 AGCUUGUU CUGAUGAG 992 AGAUGCGUC 1693 X CGAA ACGCAUCU AACAAGCU 515 UAGGAAGG CUGAUGAG 993 AACAAGCUU 1694 X CGAA AGCUUGUU CCUUCCUA 516 GUAGGAAG CUGAUGAG 994 ACAAGCUUC 1695 X CGAA AAGCUUGU CUUCCUAC 519 CUGGUAGG CUGAUGAG 995 AGCUUCCUU 1696 X CGAA AGGAAGCU CCUACCAG 520 GCUGGUAG CUGAUGAG 996 GCUUCCUUC 1697 X CGAA AAGGAAGC CUACCAGC 523 GUAGCUGG CUGAUGAG 997 UCCUUCCUA 1698 X CGAA AGGAAGGA CCAGCUAC 530 AGUUAAAG CUGAUGAG 998 UACCAGCUA 1699 X CGAA AGCUGGUA CEJUUAACU 533 CAUAGUUA CUGAUGAG 999 CAGCUACUU 1700 X CGAA AGUAGGUG UAACUAUG 534 UCAUAGUU CUGAUGAG 1000 AGCUACUUU 1701 X CGAA AAGUAGCU AACUAUGA 535 GUCAUAGU CUGAUGAG 1001 GCUACUUUA 1702 X CGAA AAAGUAGC ACUAUGAC 539 CACAGUCA CUGAUGAG 1002 CUUUAACUA 1703 X CGAA AGUUAAAG UGACUGUG 560 GUUCACGU CUGAUGAG 1003 AGGGAGAUA 1704 X CGAA AUCUCCCU ACGUGAAC 571 UUGAAAGA CUGAUGAG 1004 GUGAACAUA 1705 X CGAA AUGUUCAC UCUUUCAA 573 UUUUGAAA CUGAUGAG 1005 GAACAUAUC 1706 IX CGAA AUAUGUUC IUUUCAAA WO 99/50403 WO 9950403PCT/US99/06507 Seq. 1. D. Seq. I.D.

Position RZ No. Substrate No.

575 CUUUUUGA CUGAUGAG 1006 ACAUAUCUU 1707 X CGAA AGAUAUGU UCAAAAAG 576 CCUUUUUG CUGAUGAG 1007 CAUAUCUUU 1708 X CGAA AAGAUAUG CAAAAAGG 577 ACCUUUUU CUGAUGAG 1008 AUAUCUUUC 1709 X CGAA AAAGAUAU AAAAAGGU 586 UUAAUCAA CUGAUGAG 1009 AAAAAGGUA 1710 X CGAA ACCUUUUU UUGAUUAA 588 CUUUAAUC CUGAUGAG 1010 AAAGGUAUU 1711 X CGAA AUACCUUU GAUUAAAG 592 UCUUCUUU CUGAUGAG 1011 GUAUUGAUU 1712 X CGAA AUCAAUAC AAAGAAGA 593 UUCUUCUU CUGAUGAG 1012 UAUUGAUUA 1713 X CGAA AAUCAAUA AAGAAGAA 613 UUUUUGUA CUGAUGAG 1013 GCAGUGAUU 1714 X CGAA AUCACUGC UACAAAAA 614 AUUUUUGU CUGAUGAG 1014 CAGUGAUUU 1715 X CGAA AAUCACUG ACAAAAAU 615 CAUUUUUG CUGAUGAG 1015 AGUGAUUUA 1716 X CGAA AAAUCACU CAAAAAUG 626 GAUGAAGG CUGAUGAG 1016 AAAAUGGUU 1717 X CGAA ACCAUUUU CCUUCAUC 627 GGAUGAAG CUGAUGAG 1017 AAAUGGUUC 1718 CGAA AACCAUUU CUUCAUCC 630 AAUGGAUG CUGAUGAG 1018 UGGUUCCUU 1719 X CGAA AGGAACCA CAUCCAUU 631 GAAUGGAU CUGAUGAG 1019 GGUUCCUUC 1720 X CGAA AAGGAACC AUCCAUUC 634 ACUGAAJG CUGAUGAG 1020 UCCUUCAUC 1721 X CGAA AUGAAGGA CAUUCAGU 638 GGGCACUG CUGAUGAG 1021 UCAUCCAUU 1722 X CGAA AUGGAUGA CAGUGCCC WO 99/50403 WO 9950403PCT/US99/06507 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

639 GGGGCACU CUGAUGAG 1022 CAUCCAUUC 172 X CGAA AAUGGAUG

AGUGCCCC

658 AUAEJCAGG CEJGAUGAG 1023 CAUGAAGUA 1724 X CGAA ACUUCAUG CCUGAUAU 665 UUCUAGAA CUGAUGAG 1024 UACCUGAUA 1725 X CGAA AUCAGGUA UEJCUAGAA 667 ACUUCUAG CUGAUGAG 1025 CCUGAUAUU 1726 X CGAA AUAUCAGG CUAGAAGU 668 UACUUCUA CUGAUGAG 1026 CtJGAUAUUC 1727 X CGAA AAUAUCAG UAGAAGUA 670 UGUACUUC CUGAUGAG 1027 GAUAUUCUA 1728 X CGAA AGAAUAUC GAAGUACA 676 GGCAGGUG CUGAUGAG 1028 CUAGAAGUA 1729 X CGAA ACUUCUAG CACCUGCC______ 686 CUGAGCAU CUGAUGAG 1029 ACCUGCCUC 1730 X CGAA AGGCAGGU AUGCUCAG 692 CUGGGGCU CUGAUGAG 1030 CUCAUGCUC 1731 X CGAA AGCAUGAG AGCCCCAG 714 UGGCCGAG CUGAUGAG 1031 UGGAGUGUA 1732 X CGAA ACACUCCA CUCGGCCA 717 ACCUGGOC CUGAUGAG 1032 AGUGUACUC 1733 X CGAA AGUACACU GGCCAGGU 726 CUCCUAUA CUGAUGAG 1033 GGCCAGGUA 1734 X CGAA ACCUGGCC UAUAGGAG 728 UCCUCCUA CUGAUGAG 1034 CCAGGUAUA 1735 X CGAA AUACCUGG UAGGAGGA 730 UUUCCUCC CUGAUGAG 1035 AGGUAUAUA 1736 X CGAA AUAUACCU GGAGGAAA 742 GAGGUGAA CUGAUGAG 1036 GGAAACCUC 1737 X CGAA AGGUUUCC UUCACCUC 744 CCGAGGUG CUGAUGAG 1037 AAACCUCUU 1738 X CGAA AGAGGUUU ICACCUCGG WO 99/50403 WO 9950403PCT/US99/06507 100 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

745 GCCGAGGU CUGAUGAG 1038 AACCUCUUC 1739 X CGAA AAGAGGUU ACCUCGGC 750 UGAAGGCC CUGAUGAG 1039 CUUCACCUC 1740 X CGAA AGGUGAAG GGCCUUCA 756 GCCUGGUG CUGAUGAG 1040 CUCGGCCUU 1741 X CGAA AGGCCGAG CACCAGGC 757 AGCCUGGU CUGAUGAG 1041 UCGGCCUUC 1742 X CGAA AAGGCCGA ACCAGGCU 769 CUCCGGAC CUGAUGAG 1042 AGGCUGAUA 1743 X CGAA AUCAGCCU GUCCGGAG 772 CAUCUCCG CUGAUGAG 1043 CUGAUAGUC 1744 X CGAA ACUAUCAG CGGAGAUG 815 AGUACAGA CUGAUGAG 1044 GCAACCAUC 1745 X CGAA AUGGUUGC UCUGUACU 817 GCAGUACA CUGAUGAG 1045 AACCAUCUC 1746 X CGAA AGAUGGUU UGUACUGC 821 ACAAGCAG CUGAUGAG 1046 AUCUCUGUA 1747 X CGAA ACAGAGAU CUGCUUGU 827 GUUCAUAC CUGAUGAG 1047 GUACUGCUU 1748 X CGAA AGCAGUAC GUAUGAAC 830 AUUGUUCA CUGAUGAG 1048 CUGCUUGUA 1749 X CGAA ACAAGCAG UGAACAAU 844 UCAUGGCA CUGAUGAG 1049 AAUGGUGUC 1750 CGAA ACACCAUU ______UGCCAUGA 857 UUCUCCAG CUGAUGAG 1050 AUGAAGAUA 1751 X CGAA AUCUUCAU CUGGAGAA 871 GGAGGGCA CUGAUGAG 1051 GAAUGCAUU 1752 X CGAA AUGCAUUC UGCCCUCC 872 AGGAGGGC CUGAUGAG 1052 AAUGCAUUU 1753 X CGAA AAUGCAUU GCCCUCCU 878 AAACCCAG CUGAUGAG 1053 UUUGCCCUC 1754 X CGAA AGGGCAAA

CUGGGUUU

WO 99/50403 WO 9950403PCTIUS99/06507 101 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

885 UUCCCAUA CUGAUGAG 1054 UCCUGGGUU 1755 X CGAA ACCCAGGA UAUGGGAA 886 CUUCCCAU CUGAUGAG 1055 CCUGGGUUU 1756 X CGAA AACCCAGG AUJGGGAAG 887 CCUUCCCA CUGAUGAG 1056 CUGGGUEJUA 1757 X CGAA AAACCCAG UGGGAAGG 911 CAGUUCAC CUGAUGAG 1057 AGAAGGCUU 1758 X CGAA AGCCUUCU GUGAACUG 927 UUCUGCCA CUGAUGAG 1058 GCACACGUU 1759 X CGAA ACGUGUGC UGGCAGAA 928 GUUCUGCC CUGAUGAG 1059 CACACGUUU 1760 X CGAA AACGUGUG GGCAGAAC 938 UUCUUUAC CUGAUGAG 1060 GCAGAACUU 1761 X CGAA AGUUCUGC GUAAAGAA 941 CCuuUCUU CUGAUGAG 1061 GAACUUGUA 1762 X CGAA ACAAGUUC AAGAAAGG 975 ACACAUAA CUGAUGAG 1062 AUGCAAGUC 1763 X CGAA ACUUGCAU UUAUGUGU 977 GAACACAU CUGAUGAG 1063 GCAAGUCUU 1764 X CGAA AGACUUGC AUGUGUUC 978 AGAACACA CUGAUGAG 1064 CAAGUJCUUA 1765 X CGAA AAGACUUG UGUGUUCU 984 GGAGACAG CUGAUGAG 1065 UUAUGUGUU 1766 CGAA ACACAUAA 985 GGGAGACA CUGAUGAG 1066 UAUGUGUUC 1767 X CGAA AACACAUA UGUCUCCC 989 GUCAGGGA CUGAUGAG 1067 UGUUCUGUC 1768 X CGAA ACAGAACA UCCCUGAC 991 GGGUCAGG CUGAUGAG 1068 UUCUGUCUC 1769 X CGAA AGACAGAA CCUGACCC 1002 AACACCCA CUGAUGAG 1069 UGACCCCUA 1770 X CGAA AGGGGUCA UGGGUGUU WO 99/50403 WO 9950403PCTIUS99/06507 102 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1010 GGCACAGG GUGAUGAG 1070 AUGGGUGUU 1771 X CGAA ACACCCAU CCUGUGCC 1011 UGGCACAG CUGAUGAG 1071 UGGGUGUUC 1772 X CGAA AACACCCA CUGUGCCA 1034 GCACUGGA CUGAUGAG 1072 GGAAGGGUC 1773 X CGAA ACCCUUCC tJGCAGUGC 1064 CCCGUAAA CUGAUGAG 1073 ACCCUGGUU 1774 X CGAA ACCAGGGU UUUACGGG 1065 GCCCGUAA CUGAUGAG 1074 CCCUGGUUU 1775 X CGAA AACCAGGG UUACGGGC 1066 GGCCCGUA CUGAUGAG 1075 CCUGGUUUU 1776 X CGAA AAACCAGG UACGGGCC 1067 UGGCCCGU CUGAUGAG 1076 CUGGUUUUU 1777 X CGAA AAAACCAG ACGGGCCA 1068 CUGGCCCG CUGAUGAG 1077 IJGGUUUUUA 1778 X CGAA AAAAACCA CGGGCCAG 1079 AAGCUUAC CUGAUGAG 1078 GGCCAGAUU 1779 X CGAA AUCUGGCC GUAAGCUU 1082 CCUAAGCU CUGAUGAG 1079 CAGAUUGUA 1780 X CGAA ACAAUCUG AGCUUAGG 1087 CUGCACCU CUGAEJGAG 1080 UGUAAGCUU 1781 CGAA AGCUUACA AGGUGGAG 1088 GCUGCACC CUGAUGAG 1081 GUAAGCUUA 1782 X CGAA AAGCUUAC GUCG 1121 UUGGAAGC CUGAUGAG 1082 UGUGUGAUC 1783 X CGAA AUCACACA GUCA 1125 AUCCUUGG CUGAUGAG 1083 UGAUCGCUU 1784 X CGAA AGCGAUCA CAGA 1126 CAUCCUUG CUGAUGAG 1084 GAUCGCUUC 1785 X CGAA AAGCGAUC CAAGGAUG 1136 AGAGCAGA CUGAUGAG 1085 AAGGAUGUC 1786 X CGAA ACAUCCUU I UCUGCUCUI WO 99/50403 WO 9950403PCTIUS99/06507 103 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1138 GGAGAGCA CUGAtJGAG 1086 GGAUGUCUC 1787 X CGAA AGACAUCC UGCUCUCC 1143 AUCCUGGA CUGAUGAG 1087 UCUCUGCUC 1788 X CGAA AGCAGAGA UCCAGGAU 1145 CCAUCCUG CUGAUGAG 1088 UCUGCUCUC 1789 X CGAA AGAGCAGA CAGGAUGG 1162 UCACACUG CUGAUGAG 1089 CAGGGGCUC 1790 X CGAA AGCCCCUG CAGUGUGA 1183 AUCCUCGG CUGAUGAG 1090 GAAGGCAUA 1791 X CGAA AUGCCUUC CCGAGGAU 1204 AAAUCCAC CUGAUGAG 1091 CCAAAGAUA 1792 X CGAA AUCUUUGG GUGGAUUU 1211 AUCUGGCA CUGAUGAG 1092 UAGUGGAUU 1793 X CGAA AUCCACUA UGCCAGAU 1212 GAUCUGGC CUGAUGAG 1093 AGUGGAUJU 1794 X CGAA AAUCCACU GCCAGAUC 1220 UUCUAUAU CUGAUGAG 1094 UGCCAGAUC 1795 X CGAA AUCUGGCA AUAUAGAA 1223 UACUUCUA CUGAUGAG 1095 CAGAUCAUA 1796 X CGAA AUGAUCUG UAGAAGUA 1225 UUUACUUC CUGAUGAG 1096 GAUCAUAUA 1797 CGAA AUAUGAUC GAAGUAAA 1231 CCACUGUU CUGAUGAG 1097 AUAGAAGUA 1798 CGAA ACUUCUAU AACAGUGG 1241 AUUAAAUU CUGAUGAG 1098 ACAGUGGUA 1799 X CGAA ACCACUGU AAUUUAAU 1245 UGGGAUUA CUGAUGAG 1099 UGGUAAAUU 1800 X CGAA AUUUACCA UAAUCCCA 1246 AUGGGAUU CUGAUGAG 1100 GGUAAAUUU 1801 X CGAA AAUUUACC AAUCCCAU 1247 AAUGGGAU CUGAUGAG 1101 GUAAAUUUA 1802 IX CGAA AAAUUUAC AUCCCAUU WO 99/50403 WO 9950403PCT[US99/06507 104 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1250 GCAAAUGG CUGAUGAG 1102 AAUUUAAUC 1803 X CGAA AUUAAAUU CCAUUUGC 1255 GCUUUGCA CUGAUGAG 1103 AAUCCCAUU 1804 X CGAA AUGGGAUU UGCAAAGC 1256 AGCUUUGC CUGAUGAG 1104 AUCCCAUUU 1805 X CGAA AAUGGGAU GCAAAGCU 1265 CCAGCCAG CUGAUGAG 1105 GCAAAGCUU 1806 X CGAA AGCUUUGC CUGGCUGG 1266 GCCAGCCA CUGAUGAG 1106 CAAAGCUUC 1807 X CGAA AAGCUUUG UGGCUGGC 1279 UUAGUAGG CUGAUGAG 1107 UGGCCGCUA 1808 X CGAA AGCGGCCA CCUACUAA 1283 UUCAUUAG CUGAUGAG 1108 CGCUACCUA 1809 X CGAA AGGUAGCG CUAAUGAA 1286 UUCUUCAU CUGAUGAG 1109 UACCUACUA 1810 X CGAA AGUAGGUA AUGAAGAA 1327 UUUGGAUG CUGAUGAG 1110 ACAGUGCUC 1811 X CGAA AGCACUGU CAUCCAAA 1331 GUCUUUUG CUGAUGAG 1111 UGCUCCAUC 1812 X CGAA AUGGAGCA CAAAAGAC 1341 UAUGGUUA CUGAUGAG 1112 AAAAGACUU 1813 X CGAA AGUCUUUU UAACCAUA 1342 GUAUGGUU CUGAUGAG 1113 AAAGACUUU 1814 X CGAA AAGUCUUU AACCAUAC 1343 CGUAUGGU CUGAUGAG 1114 AAGACUUUA 1815 X CGAA AAAGUCUU ACCAUACG 1349 AUGAUCCG CUGAUGAG 1115 UUAACCAUA 1816 X CGAA AUGGUUAA CGGAUCAU 1355 UGAGAAAU CUGAUGAG 1116 AUACGGAUC 1817 X CGAA AUCCGUAU AUUUCUCA 1358 UACUGAGA CUGAUGAG 1117 CGGAUCAUU 1818 X CGAA AUGAUCCG UCUCAGUA WO 99/50403 WO 9950403PCT/US99/06507 105 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1359 CIJACUGAG CUGAUGAG 1118 GGAUCAUUU 1819 X CGAA AAUGAUCC CUCAGUAG 1360 GCUACUGA CUGAUGAG 1119 GAUCAUUUC 1820 X CGAA AAAUGAUC UCAGUAGC 1362 UGGCUACU CUGAUGAG 1120 UCAUUUCUC 1821 X CGAA AGAAAUGA AGUAGCCA 1366 AAUAUGGC CUGAUGAG 1121 UUCUCAGUA 1822 X CGAA ACUGAGAA GCCAUAUU 1372 AUGGUJGAA CUGAUGAG 1122 GUAGCCAUA 1823 X CGAA AUGGCUAC UUCACCAU 1374 GGAUGGUG CUGAUGAG 1123 AGCCAUAUU 1824 X CGAA AUAUGGCU CACCAUCC 1375 UGGAUGGU CUGAUGAG 1124 GCCAUAUUC 1825 X CGAA AAUAUGGC ACCAUCCA 1381 AtJCCGGUG CUGAUGAG 1125 UUCACCAUC 1826 X CGAA AUGGUGAA CACCGGAU 1390 GGGGGGAG CUGAUGAG 1126 CACCGGAUC 1827 X CGAA AUCCGGUG CUCCCCCC 1393 UCAGGGGG CUGAUGAG 1127 CGGAUCCUC 1828 X CGAA AGGAUCCG CCCCCUGA______ 1404 AAACUCCU CUGAUGAG 1128 CCCUGACUC 1829 X CGAA AGUCAGGG AGGAGUUU 1411 CAGACCCA CUGAUGAG 1129 UCAGGAGUU 1830 X CGAA ACUCCUGA UGGGUCUG 1412 GCAGACCC CUGAUGAG 1130 CAGGAGUUU 1831 X CGAA AACUCCUG GGGUCUGC______ 1417 ACACUGCA CUGAUGAG 1131 GUUUGGGUC 1832 X CGAA ACCCAAAC UGCAGUGU 1458 AAAUGUUG CUGAUGAG 1132 AAAGCCCUU 1833 X CGAA AGGGCUUU ______CAACAUUU 1459 GAAAUGUU CUGAUGAG 1133 AAGCCCUUC 1834 X CGAA AAGGGCUU

AACAUUUC

WO 99/50403 WO 9950403PCTIUS99/06507 106 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1465 UUAACAGA CUGAUGAG 1134 UUCAACAUU 1835 X CGAA AUGUUGAA UCLTGUUAA 1466 UUUAACAG CUGAUGAG 1135 UCAACAUUU 1836 X CGAA AAUGUUGA CUGUUAAA 1467 CtJUUAACA CUGAUGAG 1136 CAACAUUUC 1837 X CGAA AAAUGUUG UGUUAAAG 1471 AGAACUUU CUGAtJGAG 1137 AUUUCUGUU 1838 X CGAA ACAGAAAU AAAGUUCU 1472 AAGAACUU CUGAUGAG 1138 UUUCUGUUA 1839 X CGAA AACAGAAA AAGUUCUU 1477 UUUGGAAG CUGAUGAG 1139 GUUAAAGUU 1840 X CGAA ACUUUAAC CUUCCAAA 1478 CUUUGGAA CUGAUGAG 1140 UUAAAGUUC 1841 X CGAA AACUUUAA UUCCAAAG 1480 GGCUUUGG CUGAUGAG 1141 AAAGUUCUU 1842 X CGAA AGAACUUU CCAAAGCC 1481 GGGCUUUG CUGAUGAG 1142 AAGUUCUUC 1843 X CGAA AAGAACUU CAAAGCCC 1510 CCAGUGUC CUGAUGAG 1143 AACGUGAUU 1844 X CGAA AUCACGUU GACACUGG 1523 AGCAAAGU CUGAUGAG 1144 CUGGACAUA 1845 X CGAA AUGUCCAG ACUUUGCU 1527 UGACAGCA CUGAUGAG 1145 ACAUAACUU 1846 X CGAA AGUUAUGU UGCUGUCA 1528 AUGACAGC CUGAUGAG 1146 CAUAACUUU 1847 X CGAA AAGUUAUG GCUGUCAU 1534 AUGUUGAU CUGAUGAG 1147 UUUGCUGUC 1848 X CGAA ACAGCAAA AUCAACAU 1537 CUGAUGUU CUGAUGAG 1148 GCUGUCAUC 1849 X CGAA AUGACAGC AACAUCAG 1543 UCAGAGCU CUGAUGAG 1149 AUCAACAUC 1850 X CGAA AUGUUGAU AGCUCUGA WO 99/50403 WO 9950403PCTIUS99/06507 107 Seq. I. D. Seq. 1. D.

Position RZ No. Substrate No.

1548 AAGGCUCA CUGAUGAG 1150 CAUCAGCUC 1851 X CGAA AGCUGAUG UGAGCCUU 1556 CCCAAAGU CUGAUGAG 1151 CUGAGCCUU 1852 X CGAA AGGCUCAG ACUUUGGG 1557 CCCCAAAG CUGAUGAG 1152 UGAGCCUUA 1853 X CGAA AAGGCUCA CUUUGGGG 1560 CAUCCCCA CUGAUGAG 1153 GCCUUACUU 1854 X CGAA AGUAAGGC UGGGGAUG 1561 CCAUCCCC CUGAUGAG 1154 CCUUACUUU 1855 X CGAA AAGUAAGG GGGGAUGG 1576 UUGGAUUU CUGAUGAG 1155 GGACCAAUC 1856 X CGAA AUUGGUCC AAAUCCAA 1581 GCUUCUUG CUGAUGAG 1156 AAUCAAAUC 1857 X CGAA AUUUGAUU CAAGAAGC 1591 UUGUAUAG CUGAUGAG 1157 AAGAAGCUU 1858 X CGAA AGCUUCUU CUAUACAA 1592 UUUGUAUA CUGAUGAG 1158 AGAAGCUUC 1859 X CGAA AAGCUUCU UAUACAAA 1594 GGUUUGUA CUGAUGAG 1159 AAGCUUCUA 1860 X CGAA AGAAGCUU UACAAACC 1596 CGGGUUUG CUGAUGAG 1160 GCUUCUAUA 1861 CGAA AUAGAAGC CAAACCCG 1606 UAGUGAUU CUGAUGAG 1161 AAACCCGUU 1862 CGAA ACGGGUUU AAUCACUA 1607 AUAGUGAU CUGAUGAG 1162 AACCCGUUA 1863 CGAA AACGGGUU AUCACUAU 1610 CUCAUAGU CUGAUGAG 1163 CCGUUAAUC 1864 CGAA AUUAACGG ACUAUGAG 1614 AAGCCUCA CUGAUGAG 1164 UAAUCACUA 1865 X CGAA AGUGAUUA UGAGGCUU 1622 AUGUUGCC CUGAUGAG 1165 AUGAGGCUU 1866 X CGAA AGCCUCAU GGCAACAU WO 99/50403 WO 9950403PCTIUS99/06507 108 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1631 CACUUGAA GUGAUGAG 1166 GGCAACAJA 1867 CGAA AUGUUGCC UUCAAGUG 1633 GUCACOUG CUGAUGAG 1167 CAACAUAUU 1868 X CGAA AUAUGUUG CAAGUGAC 1634 UGUCACUU CUGAUGAG 1168 AACAUAUUC 1869 X CGAA AAUAUGUU AAGtJGACA 1651 AGUGUAAC CEGAUGAG 1169 AAUGAGAUU 1870 X CGAA AUCUCAUU GUUACACU 1654 UUGAGUGU CUGAUGAG 1170 GAGAUUGUU 1871 X CGAA ACAAUCUC ACACUCAA 1655 GUUGAGUG CUGAUGAG 1171 AGAUUGUUA 1872 X CGAA AACAAUCU CACUJCAAC 1660 AAAUAGUU CUGAUGAG 1172 GUUACACUC 1873 X CGAA AGUGUAAC AACUAUUU 1665 GUUCCAAA CUGAUGAG 1173 ACUCAACUA 1874 X CGAA AGUUGAGU UUUGGAAC 1667 AGGUUCCA CUGAUGAG 1174 UCAACUAUU 1875 X CGAA AUAGUUGA UGGAACCU 1668 GAGGUUCC CUGAUGAG 1175 CAACUAUUU 1876 X CGAA AAUAGUUG GGAACCUC 1676 UUCUGUCC CUGAUGAG 1176 UGGAACCUC 1877 X CGAA AGGUUCCA GGACAGAA 1686 AGAGUUCA CUGAUGAG 1177 GACAGAAUA 1878 X CGAA AUUCUGUC UGAACUCU 1693 UGCACACA CUGAUGAG 1178 UAUGAACUC 1879 CGAA AGUUCAUA UGUGUGCA 1708 CCACGACG CUGAUGAG 1179 CAACUGGUC 1880 X CGAA ACCAGUUG CGUCGUGG 1712 CUCUCCAC CUGAUGAG 1180 UGGUCCGUC 1881 X CGAA ACGGACCA GUGGAGAG 1736 AGGUCCAG CUGAUGAG 1181 AAGGGCAUC 1882 IX CGAA AUGCCCUU

CUGGACCU

WO 99/50403 WO 9950403PCTIUS99/06507 109 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1755 CUGUUGUG CUGAEJGAG 1182 GAGACGCUU 1883 X CGAA AGCGJCEC CACAACAG 1756 GCUGUUGU CUGAEJGAG 1183 AGACGCUUC 1884 X CGAA AAGCGtJCU ACAACAGC 1766 UCCGAUAG CUGAUGAG 1184 CAACAGCUU 1885 X CGAA AGCUGUUG CUAUCGGA 1767 GUCCGAUA CUGAUGAG 1185 AACAGCUUC 1886 X CGAA AAGCUGUU UAUCGGAC 1769 GAGUCCGA CUGAUGAG 1186 CAGCUUCUA 1887 X CGAA AGAAGCUG UCGGACUC 1771 GGGAGUCC CUGAUGAG 1187 GCUUCUAUC 1888 X CGAA AUAGAAGC GGACUCCC 1777 GGAGGAGG CUGAUGAG 1188 AUCGGACUC 1889 X CGAA AGUCCGAU CCUCCUCC 1781 UCUUGGAG CUGAUGAG 1189 GACUCCCUC 1890 X CGAA AGGGAGUC CUCCAAGA 1784 ACCUCUUG CUGAUGAG 1190 UCCCUCCUC 1891 X CGAA AGGAGGGA CAAGAGGU 1793 GAGAUUUA CUGAUGAG 1191 CAAGAGGUC 1892 X CGAA ACCUCUUG UAAAUCUC 1795 AGGAGAUU CUGAUGAG 1192 AGAGGUCUA 1893 X CGAA AGACCUCU AAUCUCCU 1799 AGGCAGGA CUGAUGAG 1193 GUCUAAAUC 1894 X CGAA AUUUAGAC UCCUGCCU 1801 UUAGGCAG CUGAUGAG 1194 CUAAAUCUC 1895 X CGAA AGAUUUAG CUGCCUAA 1808 CUGACUUU CUGAUGAG 1195 UCCUGCCUA 1896 X CGAA AGGCAGGA AAAGUCAG 1814 AGUGGUCU CUGAUGAG 1196 CUAAAAGUC 1897 X CGAA ACUUUUAG AGACCACU 1823 CAAAUUUA CUGAUGAG 1197 AGACCACUC 1898 X CGAA AGUGGUCU UAAAUUUG WO 99/50403 WO 9950403PCTIUS99/06507 110 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1825 GUCAAAUU CUGAUGAG 1198 ACCACUCUA 1899 X CGAA AGAGUGGU AAUUEJGAC 1829 CCAGGUCA CUGAUGAG 1199 CUCUAAAUU 1900 X CGAA AUUUAGAG UGACCUGG 1830 GCCAGGUC CUGAUGAG 1200 UCUAAAUUU 1901 X CGAA AAUUUAGA GACCUGGC 1846 CUUGGAAA CUGAUGAG 1201 CAACCAAUA 1902 X CGAA AUUGGUUG UUUCCAAG 1848 AGCUUGGA CUGAUGAG 1202 ACCAAUAUU 1903 X CGAA AUAUUGGU UCCAAGCU 1849 GAGCUUGG CUGAUGAG 1203 CCAAUAUUU 1904 X CGAA AAUAUUGG CCAAGCUC 1850 CGAGCUUG CUGAUGAG 1204 CAAUAUUUC 1905 X CGAA AAAUAUUG CAAGCUCG 1857 CAUCUUCC CUGAUGAG 1205 UCCAAGCUC 1906 X CGAA AGCUUGGA GGAAGAUG 1869 CAACAUAA CUGAUGAG 1206 AGAUGACUU 1907 X CGAA AGUCAUCU UUAUGUUG 1870 UCAACAUA CUGAUGAG 1207 GAUGACUUU 1908 X CGAA AAGUCAUC UAUGUUGA 1871 UUCAACAU CUGAUGAG 1208 AUGACUUUU 1909 X CGAA AAAGUCAU AUGUUGAA 1872 CUUCAACA CUGAUGAG 1209 UGACUUUUA 1910 X CGAA AAAAGUCA UGUUGAAG 1876 UCCACUUC CUGAUGAG 1210 UUUUAUGUU 1911 X CGAA ACAUAAAA GAAGUGGA 1893 UUUGCACA CUGAUGAG 1211 GAGAAGGUC 1912 X CGAA ACCUUCUC UGUGCAAA 1910 AUUCUGCU CUGAUGAG 1212 AAAGUGAUC 1913 X CGAA AUCACUUU AGCAGAAU 1919 AACUUUAA CUGAUGAG 1213 AGCAGAAUA 1914 X CGAA AUUCUGCU UUAAAGUU WO 99/50403 WO 9950403PCTIUS99/06507 ill Seq. T.D. Seq. I.D.

Position RZ No. Substrate No.

1921 GGAACUUU CUGAUGAG 1214 CAGAAUAUU 1915 X CGAA AUAUUCUG AAAGUUCC 1922 UGGAACUU CUGAUGAG 1215 AGAAUAUUA 1916 X CGAA AAUAUUCU AAGUUCCA 1927 UUGCCUGG CUGAUGAG 1216 AUUAAAGUU 1917 X CGAA ACUUUAAU CCAGGCAA 1928 GUUGCCUG CUGAUGAG 1217 UUAAAGUUC 1918 X CGAA AACUUUAA CAGGCAAC 1938 CCGAAGUC CUGAUGAG 1218 AGGCAACUU 1919 X CGAA AGUUGCCU GACUUCGG 1943 UAGCACCG CUGAUGAG 1219 ACUUGACUU 1920 X CGAA AGUCAAGU CGGUGCUA 1944 GUAGCACC CUGAUGAG 1220 CUUGACUUC 1921 X CGAA AAGUCAAG GGUGCUAC 1951 UUGUUAAG CUGAUGAG 1221 UCGGUGCUA 1922 X CGAA AGCACCGA CUUAACAA 1954 AAGUUGUU CUGAUGAG 1222 GUGCUACUU 1923 X CGAA AGUAGGAC AACAACUU 1955 UAAGUUGU CUGAUGAG 1223 UGCUACUUA 1924 X CGAA AAGUAGCA ACAACUUA 1962 UGGGAUGU CUGAUGAG 1224 UAACAACUU 1925 CGAA AGUUGUUA ACAUCCCA 1963 CUGGGAUG CUGAUGAG 1225 AACAACUUA 1926 CGAA AAGUUGUU CAUCCCAG 1967 CUCCCUGG CUGAUGAG 1226 ACUUACAUC 1927 CGAA AUGUAAGU CCAGGGAG 1980 GGACCACG CUGAUGAG 1227 GGAGCAGUA 1928 X CGAA ACUGCUCC CGUGGUCC 1987 CUAGCUCG CUGAUGAG 1228 UACGUGGUC 1929 X CGAA ACCACGUA CGAGCUAG 1994 GUUGACUC CUGAUGAG 1229 UCCGAGCUA 1930 X CGAA AGCUCGGA I GAGUCAAC WO 99/50403 WO 9950403PCTIUS99/06507 112 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1999 UUGGUGUUJ CUGAUGAG 1230 GCUAGAGUC 1931 X CGAA ACU.CUAGC AACACCAA 2033 AGCAGUGA CUGAUGAG 1231 GUGAAGAUC 1932 X CGAA AUCUUCAC UCACUGCU 2035 CAAGCAGU CEJGAUGAG 1232 GAAGAUCUC 1933 X CGAA AGAUCOUC ACUGCUUG 2042 AAGGGUCC CUGAUGAG 1233 UCACUGCUU 1934 X CGAA AGCAGUGA GGACCCUU 2050 AUGUCACU CUGAUGAG 1234 UGGACCCUU 1935 X CGAA AGGGUCCA AGUGACAU 2051 AAUGUCAC CUGAUGAG 1235 GGACCCUUA 1936 X CGAA AAGGGUCC GUGACAUU 2059 GGAGGAAG CUGAUGAG 1236 AGUGACAUU 1937 X CGAA AUGUCACU CUUCCUCC 2060 AGGAGGAA CUGAUGAG 1237 GUGACAUUC 1938 X CGAA AAUGUCAC UUCCUCCU______ 2062 UGAGGAGG CUGAUGAG 1238 GACAUUCUU 1939 X CGAA AGAAUGUC CCUCCUCA 2063 UUGAGGAG CUGAUGAG 1239 ACAUUCUUC 1940 X CGAA AAGAAUGU CUCCUCAA 2066 UGGUUGAG CUGAUGAG 1240 UUCUUCCUC 1941 X CGAA AGGAAGAA CUCAACCA 2069 UUCUGGUU CUGAUGAG 1241 UUCCUCCUC 1942 X CGAA AGGAGGAA AACCAGAA 2083 GAAAUCUU CUGAUGAG 1242 GAAAACAUC 1943 X CGAA AUGUUUUC AAGAUUUC 2089 AUGUUGGA CUGAUGAG 1243 AUCAAGAUU 1944 X CGAA AUCUUGAU UCCAACAU 2090 AAUGUUGG CUGAUGAG 1244 UCAAGAUUU 1945 X CGAA AAUCUUGA CCAACAUU 2091 UAAUGUUG CUGAUGAG 1245 CAAGAUUUC 1946 X CGAA AAAUCUUG ICAACAUUAI WO 99/50403 WO 9950403PCTIUS99/06507 113 Seq. 1.0. Seq. 1.D.

Position RZ No. Substrate No.

2098 GAGLJGUGU CUGAUGAG 1246 UCCAACAUU 1947 X CGAA AUGUUGGA ACACACUC 2099 GGAGUGUG CUGAUGAG 1247 CCAACAUUA 1948 X CGAA AAUGUUGG CACACUCC 2106 CAGCCGAG CUGAUGAG 1248 UACACACUC 1949 X CGAA AGUGUGUA CUCGGCUG 2109 UCACAGCC CUGAUGAG 1249 ACACUCCUC 1950 X CGAA AGGAGUGU GGCUGUGA 2119 GUCCAAGA CUGAUGAG 1250 GCUGUGAUU 1951 X CGAA AUCACAGC UCUUGGAC 2120 UGUCCAAG CUGAUGAG 1251 CUGUGAUUU 1952 X CGAA AAUCACAG CUUGGACA 2121 UUGUCCAA CUGAUGAG 1252 UGUGAUUUC 1953 X CGAA AAAUCACA UUGGACAA 2123 UAUUGUCC CUGAUGAG 1253 UGAUUUCUU 1954 X CGAA AGAAAUCA GGACAAUA 2131 CCAUCCAA CUGAUGAG 1254 UGGACAAUA 1955 X CGAA AUUGUCCA UUGGAUGG 2133 AGCCAUCC CUGAUGAG 1255 GACAAUAUU 1956 X CGAA AUAUUGUC GGAUGGCU 2142 AAAUAGAA CUGAUGAG 1256 GGAUGGCUA 1957 X CGAA AGCCAUCC UUCUAUUU 2144 AGAAAUAG CUGAUGAG 1257 AUGGCUAUU 1958 X CGAA AUAGCCAU CUAUUUCU 2145 AAGAAAUA CUGAUGAG 1258 UGGCUAUUC 1959 X CGAA AAUAGCCA UAUUUCUU 2147 AGAAGAAA CUGAUGAG 1259 GCUAUUCUA 1960 X CGAA AGAAUAGC UUUCUUCU 2149 AUAGAAGA CUGAUGAG 1260 UAUUCUAUU 1961 X CGAA AUAGAAUA UCUUCUAU 2150 AAUAGAAG CUGAUGAG 1261 AUUCUAUUU 1962 X CGAA AAUAGAAU CUUCUAUUI WO 99/50403 WO 9950403PCTIUS99/06507 114 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2151 UAAUJAGAA CUGAUGAC 1262 UUCUAUUUC 1963 X CGAA AAAUAGAA UUCUAUtJA 2153 AGUAAUAG CUGAUGAG 1263 CUAUJUCtJU 1964 X CGAA AGAAAUAG CUAUUACU 2154 UAGtJAAUA CUGAUGAG 1264 UAUUUCUUC 1965 X CGAA AAGAAAUA UAUUACUA 2156 GAUAGUAA CUGAUGAG 1265 UUUCUUCUA 1966 X CGAA AGAAGAA.A UUACUAUC 2158 CGGAUAGU CUGAUGAG 1266 UCUUCUAUU 1967 X CGAA AUAGAAGA ACUAUCCG 2159 ACGGAUAG CUGAUGAG 1267 CUUCUAUUA 1968 X CGAA AAUAGAAG CUAUCCGU 2162 GUAACGGA CUGAUGAG 1268 CUAUUACUA 1969 X CGAA AGUAAUAG UCCGUUAC 2164 UUGUAACG CUGAUGAG 1269 AUUACUAUC 1970 X CGAA AUAGUAAU CGUUACAA 2168 AACCUUGU CUGAUGAG 1270 CUAUCCGUU 1971 X CGAA ACGGAUAG ACAAGGUU 2169 GAACCUUG CUGAUGAG 1271. UAUCCGUUA 1972 X CGAA AACGGAUA CAAGGUUC 2176 UUGCCUUG CUGAUGAG 1272 UACAAGGUU 1973 X CGAA ACCUUGUA CAAGGCAA 2177 CUUGCCUU CUGAUGAG 1273 ACAAGGUUC 1974 X CGAA AACCUUGU AAGGCAAG 2203 UUCACAUC CUGAUGAG 1274 CAGCACGUU 1975 X CGAA ACGUGCUG GAUGUGAA 2215 GCAUUCUU CUGAUGAG 1275 GUGAAGAUA 1976 X CGAA AUCUUCAC AAGAAUGC 2230 UACUGAAU CUGAUGAG 1276 GCCACCAUC 1977 CGAA AUGGUGGC AUUCAGUA 2233 UGAUACUG CUGAUGAG 1277 ACCAUCAUU 1978 X CGAA AUGAUGGU

CAGUAUCA

WO 99/50403 WO 9950403PCTIUS99/06507 115 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2234 CUGAUACU CUGAUGAG 1278 CCAUCAJUC 1979 X CGAA AAUGAUGG AGUAUCAG 2238 UGAGCUGA CUGAUGAG 1279 CAUUCAGUA 1980 X CGAA ACUGAAUG UCAGCUCA 2240 CUUGAGCU CUGAUGAG 1280 UUCAGUAUC 1981 X CGAA AUACUGAA AGCUCAAG 2245 AGGCCCUU CUGAUGAG 1281 UAUCAGCUC 1982 X CGAA AGCUGAUA AAGGGCCU 2254 UCAGGCUC CUGAUGAG 1282 AAGGGCCUA 1983 X CGAA AGGCCCUU GAGCCUGA 2271 CCACCUGG CUGAUGAG 1283 AACAGCAtJA 1984 X CGAA AUGCUGUU CCAGGUGG 2284 UCUGCAAA CUGAUGAG 1284 GUGGACAUU 1985 X CGAA AUGUCCAC UUUGCAGA 2285 CUCUGCAA CUGAUGAG 1285 UGGACAUUU 1986 X CGAA AAUGUCCA UUGCAGAG 2286 UCUCUGCA CUGAUGAG 1286 GGACAUUUU 1987 X CGAA AAAUGUCC UGCAGAGA 2287 UUCUCUGC CUGAUGAG 1287 GACAUUUUU 1988 X CGAA AAAAUGUC GCAGAGAA 2302 CUUGACCC CUGAUGAG 1288 AACAACAUA 1989 X CGAA AUGUUGUU GGGUCAAG______ 2307 GGUUGCUU CUGAUGAG 1289 CAUAGGGUC 1990 X CGAA ACCCUAUG AAGCAACC 2322 CAUGAGAA CUGAUGAG 1290 CCCAGCCUU 1991 X CGAA AGGCUGGG UUCUCAUG 2323 UCAUGAGA CUGAUGAG 1291 CCAGCCUUU 1992 X CGAA AAGGCUGG UCUCAUGA 2324 UUCAUGAG CUGAUGAG 1292 CAGCCUUUU 1993 X CGAA AAAGGCUG CUCAUGAA 2325 GUUCAUGA CUGAUGAG 1293 AGCCUUUUC 1994 ,X CGAA AAAAGGCU UCAUGAAC WO 99/50403 WO 9950403PCTIUS99/06507 116 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2327 CAGtJUCAU CUGAUGAG 1294 CCUUUUCUC 1995 X CGAA AGAAAAGG AUGAACUG 2344 GAUEJCUGG CUGAUGAG 1295 GUGACCCUC 1996 X CGAA AGGGUCAC CCAGAAUC 2352 GUGCUUGA CUGAUGAG 1296 CCCAGAAUC 1997 X CGAA AUUCUGGG UCAAGCAC 2354 UGGUGCUU CUGAUGAG 1297 CAGAAUCUC 1998 X CGAA AGAUUCUG AAGCACCA 2371 CCCCCUCC CUGAUGAG 1298 GCGGACCUC 1999 X CGAA AGGUCCGC GGAGGGGG 2392 AUGGCUAU CUGAUGAG 1299 AUGCtJGCUU 2000 X CGAA AGCAGCAU AUAGCCAU 2393 GAUGGCUA CUGAUGAG 1300 UGCUGCUUA 2001 X CGAA AAGCAGCA UAGCCAUC 2395 AGGAUGGC CUGAUGAG 1301 CUGCUUAUA 2002 X CGAA AUAAGCAG GCCAUCCU 2401 GAGCCAAG CUGAUGAG 1302 AUAGCCAUC 2003 X CGAA AUGGCUAU CUUGGCUC 2404 GCAGAGCC CUGAUGAG 1303 GCCAUCCUU 2004 X CGAA AGGAUGGC GGCUCUGC 2409 UUCCAGCA CUGAUGAG 1304 CCUUGGCUC 2005 X CGAA AGCCAAGG UGCUGGAA 2439 GAAAGGCC CUGAUGAG 1305 UGUGCUGUU 2006 X CGAA ACAGCACA GGCCUUUC 2445 UGAUCAGA CUGAUGAG 1306 GUUGGCCUU 2007 X CGAA AGGCCAAC UCUGAUCA 2446 AUGAUCAG CUGAUGAG 1307 UUGGCCUUU 2008 CGAA AAGGCCAA CUGAUCAU 2447 UAUGAUCA CUGAUGAG 1308 UGGCCUUUC 2009 CGAA AAAGGCCA UGAUCAUA 2452 UGCAAUAU CUGAUGAG 1309 UUUCUGAUC 2010 X CGAA AUCAGAAA IAUAUUGCA WO 99/50403 WO 9950403PCTIUS99/06507 117 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2455 AAUUGCAA CUGAUGAG 1310 CUGAUCAUA 2011 X CGAA AUGAUCAG UUGCAAUU 2457 UCAAUUGC CUGAUGAG 1311 GAUCAUAUU 2012 X CGAA AUAUGAUC GCAAUUGA 2463 CCCUCUUC CUGAUGAG 1312 AUUGCAAUU 2013 X CGAA AUUGCAAU GAAGAGGG 2502 CGUUUUGG CUGAUGAG 1313 CCAAGCCUU 2014 X CGAA AGGCUUGG CCAAAACG 2503 ACGUUUUG CUGAUGAG 1314 CAAGCCUUC 2015 X CGAA AAGGCUUG CAAAACGU 2535 CUGAGUUG CUGAUGAG 1315 UGUGCAGUU 2016 X CGAA ACUGCACA CAACUCAG 2536 CCUGAGUU CUGAUGAG 1316 GUGCAGUUC 2017 X CGAA AACUGCAC AACUCAGG 2541 GAGUCCCU CUGAUGAG 1317 GUUCAACUC 2018 X CGAA AGUUGAAC AGGGACUC 2549 UAGGGCCA CUGAUGAG 1318 CAGGGACUC 2019 X CGAA AGUCCCUG UGGCCCUA 2557 UUCCUGUU CUGAUGAG 1319 CUGGCCCUA 2020 X CGAA AGGGCCAG AACAGGAA 2569 UUGUUUUU CUGAUGAG 1320 AGGAAGGUC 2021 X CGAA ACCUUCCU AAAAACAA 2585 AAUUGUAG CUGAUGAG 1321 ACOCAGAUC 2022 X CGAA AUCUGGGU CUACAAUU 2588 AUAAAUUG CUGAUGAG 1322 CAGAUCCUA 2023 X CGAA AGGAUCUG CAAUUUAU 2593 ACUGGAUA CUGAUGAG 1323 CCUACAAUU 2024 X CGAA AUUGUAGG UAUCCAGU 2594 CACUGGAU CUGAUGAG 1324 CUACAAUUU 2025 X CGAA AAUUGUAG AUCCAGUG 2595 GCACUGGA CUGAUGAG 1325 UACAAUUUA 2026 X CGAA AAAUUGUA UCCAGUGC WO 99/50403 WO 9950403PCT[US99/06507 118 Seq. 1.0. Seq. I.D.

Position RZ No. Substrate No.

2597 AAGCACUG CUGAUGAG 1326 CAAUUUAUC 2027 X CGAA AUAJ\UUG CAGUGCUU 2605 UUCCAGUC CUGAUGAG 1327 CCAGUGCUU 2028 X CGAA AGCAGUGG GACUGGAA 2620 UGAAAUUU CUGAUGAG 1328 AAUGACAUC 2029 X CGAA AUGUCAUU AAAUUUCA 2625 CAUCUUGA CUGAUGAG 1329 CAUCAAAUU 2030 X CGAA AUUUGAUG UCAAGAUG 2626 ACAUCUUG CUGAUGAG 1330 AUCAAAUUU 2031 X CGAA AAUUUGAU CAAGAUGU 2627 CACAUCUU CUGAUGAG 1331 UCAAAUUUC 2032 X CGAA AAAUUUGA AAGAUGUG 2638 CCCUCCCC CUGAUGAG 1332 GAUGUGAUU 2033 X CGAA AUCACAUC GGGGAGGG 2651 UUGGCCAA CUGAUGAG 1333 AGGGCAAUU 2034 X CGAA AUUGCCCU UUGGCCAA 2652 CUUGGCCA CUGAUGAG 1334 GGGCAAUUU 2035 X CGAA AAUUGCCC UGGCCAAG 2653 ACUUGGCC CUGAUGAG 1335 GGCAAUUUU 2036 X CGAA AAAUUGCC GGCCAAGU 2662 GCCUUAAG CUGAUGAG 1336 GGCCAAGUU 2037 CGAA ACUUGGCC CUUAAGGC 2663 CGCCUUAA CUGAUGAG 1337 GCCAAGUUC 2038 X CGAA AACUUGGC UUAAGGCG 2665 CGCGCCUU CUGAUGAG 1338 CAAGUUCUU 2039 X CGAA AGAACUUG AAGGCGCG 2666 GCGCGCCU CUGAUGAG 1339 AAGUUCUUA 2040 X CGAA AAGAACUU AGGCGCGC 2677 UCCUUCUU CUGAUGAG 1340 GCGCGCAUC 2041 X CGAA AUGCGCGC AAGAAGGA 2691 CCAUCCGU CUGAUGAG 1341 GGAUGGGUU 2042 X CGAA ACCCAUCC ACGGAUGG WO 99/50403 WO 9950403PCTIUS99/06507 119 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2692 UCCAUCCG CUGAEJGAG 1342 GAUGGGUUA 2043 X CGAA AACCCAUC CGGAEJGGA 2710 AUUCUUIJU CUGAUGAG 1343 GCUGCCAUC 2044 X CGAA AUGGCAGC AAAAGAAU 2727 UGGAGGCA CUGAUGAG 1344 GAAAGAAUA 2045 X CGAA AUUCUUUC UGCCUCCA 2733 CAUCUUUG CUGAUGAG 1345 AUAUGCCUC 2046 X CGAA AGGCAUAU CAAAGAUG 2744 GUCCCUGU CUGAUGAG 1346 AAGAUGAUC 2047 X CGAA AUCAUCUU ACAGGGAC 2754 CUCCUGGA CUGAUGAG 1347 CAGGGACUU 2048 X CGAA AGUCCCUG UGCAGGAG 2755 UCUCCUGC CUGAUGAG 1348 AGGGACUUU 2049 X CGAA AAGUCCCU GCAGGAGA 2773 UUACAAAG CUGAUGAG 1349 CUGGAAGUU 2050 X CGAA ACUUCCAG CUUUGUAA 2774 UUUACAAA CUGAUGAG 1350 UGGAAGUUC 2051 X CGAA AACUUCCA UUUGUAAA 2776 AGUUUACA CUGAUGAG 1351 GAAGUUCUU 2052 X CGAA AGAACUUC UGUAAACU 2777 AAGUUUAC CUGAUGAG 1352 AAGUUCUUU 2053 X CGAA AAGAACUU GUAAACUU 2780 UCCAAGUU CUGAUGAG 1353 UUCUUUGUA 2054 X CGAA ACAAAGAA AACUUGGA 2785 UGGUGUCC CUGAUGAG 1354 UGUAAACUU 2055 X CGAA AGUUUACA GGACACCA 2795 GAUGUUUG CUGAUGAG 1355 GACACCAUC 2056 X CGAA AUGGUGUC CAAACAUC 2803 AGAUUGAU CUGAUGAG 13.56 CCAAACAUC 2057 CGAA AUGUUUGG AUCAAUCU 2806 AAGAGAUU CUGAUGAG 1357 AACAUCAUC 2058 CGAA AUGAUGUU ______AAUCUCUU WO 99/50403 WO 9950403PCTJUS99/06507 120 Seq. I. D. Seq. I.D.

Position RZ No. Substrate No.

2810 UCCUAAGA CUGAUGAG 1358 UCAUCAAUC 2059 X CGAA AIJUGAUGA UCUUAGGA 2812 GCUCCUAA CUGAUGAG 1359 AUCAAUCUC 2060 X CGAA AGAUUGAU UUAGGAGC 2814 AUGCUCCU CUGAUGAG 1360 CAAUCUCUU 2061 X CGAA AGAGAUUG AGGAGCAU 2815 CAUGCUCC CUGAUGAG 1361 AAUCUCUUA 2062 X CGAA AAGAGAUU GGAGCAUG 2831 GUAGCCUC CUGAUGAG 1362 GUGAACAUC 2063 X CGAA AUGUUCAC GAGGCUAC 2838 GGUACAAG CUGAUGAG 1363 UCGAGGCUA 2064 X CGAA AGCCUCGA CUUGUACC 2841 CCAGGUAC CUGAUGAG 1364 AGGCUACUU 2065 X CGAA AGUAGCCU GUACCUGG 2844 UGGCCAGG CUGAUGAG 1365 CUACUUGUA 2066 X CGAA ACAAGUAG CCUGGCCA 2854 GCGUACUC CUGAUGAG 1366 CUGGCCAUU 2067 X CGAA AUGGCCAG GAGUACGC 2859 GGGGCGCG CUGAUGAG 1367 CAUUGAGUA 2068 X CGAA ACUCAAUG CGCGCCCC 2878 AAGUCCAG CUGAUGAG 1368 GGAAACCUU 2069 X CGAA AGGUUUCC CUGGACUU______ 2879 GAAGUCCA CUGAUGAG 1369 GAAACCUUC 2070 X CGAA AAGGUUUC UGGACUUC 2886 UGCGAAGG CUGAUGAG 1370 UCUGGACUU 2071 X CGAA AGUCCAGA CCUUCGCA 2887 UUGCGAAG CUGAUGAG 1371 CUGGACUUC 2072 X CGAA AAGUCCAG CUUCGCAA 2890 CUCUUGCG CUGAUGAG 1372 GACUUCCUU 2073 X CGAA AGGAAGUC CGCAAGAG 2891 GCUCUUGC CUGAUGAG 1373 ACUUCCUUC 2074 X CGAA AAGGAAGU GCAAGAGC WO 99/50403 WO 9950403PCTIUS99/06507 121 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2925 CAAUGGCA CUGAUGAG 1374 CCCAGCAUU 2075 X CGAA AUGCUGGG UGCCAUUG 2926 GCAAUGGC CUGAUGAG 1375 CCAGCAUUU 2076 X CGAA AAUGCUGG GCCAUUGC 2932 CUAUUGGC CUGAUGAG 1376 UUUGCCAUU 2077 X CGAA AUGGCAAA GCCAAUAG 2939 CGCGGUGC CUGAUGAG 1377 UUGCCAAUA 2078 X CGAA AUUGGCAA GCACCGCG 2949 ACAGUGUG CUGAUGAG 1378 CACCGCGUC 2079 X CGAA ACGCGGUG CACACUGU 2958 GCUGGGAG CUGAUGAG 1379 CACACUGUC 2080 X CGAA ACAGUGUG CUCCCAGC 2961 GCUGCUGG CUGAUGAG 1380 ACUGUCCUC 2081 X CGAA AGGACAGU CCAGCAGC 2971 AAGUGAAG CUGAUGAG 1381 CAGCAGCUC 2082 X CGAA AGCUGCUG CUUCACUU 2974 GCGAAGUG CUGAUGAG 1382 CAGGUCCUD 2083 X CGAA AGGAGCUG CACUUCGC 2975 AGCGAAGU CUGAUGAG 1383 AGCUCCUUC 2084 X CGAA AAGGAGCU ACUUCGCU 2979 CGGCAGCG CUGAUGAG 1384 CCUUCACUU 2085 X CGAA AGUGAAGG CGCUGCCG 2980 UCGGCAGC CUGAUGAG 1385 CUUCACUUC 2086 X CGAA AAGUGAAG GCUGCCGA 3009 GGCUCAAG CUGAUGAG 1386 CAUGGACUA 2087 X CGAA AGUCCAUG CUUGAGCC 3012 UUUGGCUC CUGAUGAG 1387 GGACUACUU 2088 X CGAA AGUAGUCC GAGCCAAA 3027 UGUGGAUA CUGAUGAG 1388 AAAACAGUU 2089 X CGAA ACUGUUUU UAUCCACA 3028 CUGUGGAU CUGAUGAG 1389 AAACAGUUU 2090 X CGAA AACUGUUU IAUCCACAG WO 99/50403 WO 9950403PCT/US99/06507 122 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

3029 CCUGUGGA CUGAUGAC 1390 AACAGUUUA 2091 X CGAA AAACUGUU UCCACAGG 3031 UCCCUGUG CUGAUGAG 1391 CAGUUUAUC 2092 X CGAA AUAAACUG CACAGGGA 3041 GGCAGCCA CUGAUGAG 1392 ACAGGGAUC 2093 X CGAA AUCCCUGU UGGCUGCC 3058 CCAACUAA CEJGAUGAG 1393 AGAAACAUU 2094 X CGAA AUGUUUCU UUAGUUGG 3059 ACCAACUA CUGAUGAG 1394 GAAACAUUU) 2095 X CGAA AAUGUUUC UAGUUGGU 3060 CACCAACU CUGAUGAG 1395 AAACAUUUU 2096 X CGAA AAAUGUUU AGUUGGUG 3061 UCACCAAC CUGAUGAG 1396 AACAUUUUA 2097 X CGAA AAAAUGUU GUUGGUGA 3064 UUUUCACC CUGAUGAG 1397 AUUUUAGUU 2098 X CGAA ACUAAAAU GGUGAAAA 3075 UUGCCACA CUGAUGAG 1398 UGAAAACUA 2099 X CGAA AGUUUUCA UGUGGCAA 3088 AAAUCUGC CUGAUGAG 1399 GCAAAAAUA 2100 X CGAA AUUUUUGC GCAGAUUU 3095 CAAUCCAA CUGAUGAG 1400 UAGCAGAUU 2101 X CGAA AUCUGCUA UUGGAUUG 3096 ACAAUCCA CEJGAUGAG 1401 AGCAGAUUU 2102 X CGAA AAUJCUGCU UGGAUUGU 3097 GACAAUCC CUGAUGAG 1402 GCAGAUUUU 2103 X CGAA AAAUCUGC GGAUUGUC 3102 CUCGGGAC CUGAUGAG 1403 UUUUGGAUU 2104 X CGAA AUCCAAAA GUCCCGAG 3105 GACCUCGG CUGAUGAG 1404 UGGAUUGUC 2105 X CGAA ACAAUCCA CCGAGGUC 3113 CACCUCUU CUGAUGAG 1405 CCCGAGGUC 2106 X CGAA ACCUCGGG AAGAGGUG WO 99/50403 WO 9950403PCT/US99/06507 123 Seq. T.D. Seq. I.D.

Position RZ No. Substrate No.

3123 UUUUCACG CUGAtJGAG 1406 AGAGGUGUA 2107 X CGAA ACACCUCU CGEJGAAAA 3148 CGCACEJGG CUGAUCAG 1407 GGAAGGCUC 2108 X CGAA AGCCUUCC CCAGUGCG 3169 AGUGACUC CUGAUGAG 1408 AUGGCCAUC 2109 X CGAA AUGGCCAU GAGUCACU 3174 AAUUCAGU CUGAUGAG 1409 CAUCGAGUC 2110 X CGAA ACUCGAUG ACUGAAUU 3182 CACACUGU CUGAUGAG 1410 CACUGAAUU 2111 X CGAA AUUCAGUG ACAGUGUG 3183 ACACACUG CUGAUGAG 1411 ACUGAAUUA 2112 X CGAA AAUUCAGU CAGUGUGU 3192 UGGUUGUG CUGAUGAG 1412 CAGUGUGUA 2113 X CGAA ACACACUG CACAACCA 3211 UAGGACCA CUGAUGAG 1413 AGUGAUGUA 2114 X CGAA ACAUCACU UGGUCCUA 3216 CACCAUAG CUGAUGAG 1414 UGUAUGGUC 2115 X CGAA ACCAUACA CUAUGGUG 3219 ACACACCA CUGAUGAG 1415 AUGGtICCUA 2116 X CGAA AGGACCAU UGGUGUGU 3228 CCCAUAGU CUGAUGAG 1416 UGGUGUGUU 2117 X CGAA ACACACCA ACUAUGGG 3229 UCCCAUAG CUGAUGAG 1417 GGUGUGUUA 2118 X CGAA AACACACC CUAUGGGA 3232 AUCUCCCA CUGAUGAG 1418 GUGUtJACUA 2119 X CGAA AGUAACAC UGGGAGAU 3241 AAGCUAAC CUGAUGAG 1419 UGGGAGAUU 2120 X CGAA AUCUCCCA GUUAGCUU 3244 CCUAAGCU CUGAUGAG 1420 GAGAUUGUU 2121 X CGAA ACAAUCUC AGCEJUAGG 3245 UCCUAAGC CUGAUGAG 1421 AGAUUGUUA 2122 X CGAA AACAAUCU

GCUEJAGGA

WO 99/50403 WO 9950403PCTIUS99/06507 124 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3249 UGCCEJCCU CUGAUGAG 1422 UGUUAGCUU 2123 X CGAA AGCUAACA AGGAGGCA 3250 GUGCCUCC CUGAUGAG 1423 GUUAGCUUA 2124 X CGAA AAGCIJAAC GGAGGCAC 3264 UCCCGCAG CUGAUGAG 1424 CACACCCUA 2125 X CGAA AGGGUGUG CUGCGGGA 3278 UUCUGCAC CUGAUGAG 1425 GGAUGACUU 2126 X CGAA AGUCAUCC GUGCAGAA 3289 UUCUCGUA CUGAUGAG 1426 GCAGAACUC 2127 X CGAA AGUUCUGC UACGAGAA 3291 GCUUCUCG CUGAUGAG 1427 AGAACUCUA 2128 X CGAA AGAGUUCU CGAGAAGC 3312 CCAGUCEJG CUGAUGAG 1428 CCAGGGCUA 2129 X CGAA AGCCCUGG CAGACUGG 3351 UUAGAUCA CUGAUGAG 1429 UGAGGUGUA 2130 X CGAA ACACCUCA UGAUCUAA 3356 UCUCAUUA CUGAUGAG 1430 UGUAUGAUC 2131 X CGAA AUCAUACA UAAUGAGA 3358 UGUCUCAU CUGAUGAG 1431 UAUGAUCUA 2132 X CGAA AGAUCAUA AUGAGACA 3386 CCUCUCAU CUGAUGAG 1432 AGAAGCCUU 2133 CGAA AGGCUUCU AUGAGAGG 3387 GCCUCUCA CUGAUGAG 1433 GAAGCCUUA 2134 X CGAA AAGGCUUC UGAGAGGC 3399 GGGCAAAU CUGAUGAG 1434 GAGGCCAUC 2135 X CGAA AUGGCCUC AUUUGCCC 3402 UCUGGGCA CUGAUGAG 1435 GCCAUCAUU 2136 X CGAA AUGAUGGC UGCCCAGA 3403 AUCUGGGC CUGAUGAG 1436 CCAUCAUUU 2137 X CGAA AAUGAUGG GCCCAGAU 3412 GACACCAA CUGAUGAG 1437 GCCCAGAUA 2138 X CGAA AUCUGGGC I UUGGUGUCI WO 99/50403 WO 9950403PCT/US99/06507 125 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3414 AGGACACC CUGAUGAG 1438 CCAGAUAUU 2139 X CGAA AUAUCUGG GGUGtJCCU 3420 UGUUUAAG CUGAUGAG 1439 AUUGGUGUC 2140 X CGAA ACACCAAU CUUAAACA 3423 UUCUCUUU CUGAUGAG 1440 GGUGUCCUU 2141 X CGAA AGGACACC AAACAGAA 3424 AUUCUGUU CEJGAUGAG 1441 GUGUCCUUA 2142 X CGAA AAGGACAC AACAGAAU 3435 GCUCCUCU CUGAUGAG 1442 CAGAAUGUU 2143 X CGAA ACAUUCUG AGAGGAGC 3436 CGCUCCUC CUGAUGAG 1443 AGAAUGUUA 2144 X CGAA AACAUUCU GAGGAGCG 3453 UAUUCACG CUGAUGAG 1444 AAAGACCUA 2145 X CGAA AGGUCUUU CGUGAAUA 3461 AAGCGU.GG CUGAUGAG 1445 ACGUGAAUA 2146 X CGAA AUUCACGU CCACGCUU 3469 UUCUCAUA CUGAUGAG 1446 ACCACGCUU 2147 X CGAA AGCGUGGU UAUGAGAA 3470 CUUCUCAU CUGAUGAG 1447 CCACGCUUU 2148 X CGAA AAGCGUGG AUGAGAAG 3471 ACUUCUCA CUGAUGAG 1448 CACGCUUUA 2149 X CGAA AAAGCGUG UGAGAAGU 3480 CAUAAGUA CUGAUGAG 1449 UGAGAAGUU 2150 X CGAA ACUUCUCA UACUEJAUG 3481 GCAUAAGU CUGAUGAG 1450 GAGAAGUUU 2151 X CGAA AACUUCUC ACUUAUGC 3482 UGCAUAAG CUGAUGAG 1451 AGAAGUUUA 2152 X CGAA AAACUUCU CUUAUGCA 3485 UCCUGCAU CUGAUGAG 1452 AGUUUACUU 2153 X CGAA AGUAAACU AUGCAGGA______ 3486 UUCCUGCA CUGAUGAG 1453 GUUUACUUA 2154 X CGAA AAGUAAAC UGCAGGAA WO 99/50403 WO 9950403PCTIUS99/06507 126 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3496 GAACAGUC CUGAUGAG 1454 GCAGGAAUU 2155 X CGAA AUUCCUGC GACUGUUC 3503 UUCAGCAG CUGAUGAG 1455 UUGACUGUU 2156 X CGAA ACAGUCAA CUGCUGAA 3504 CUUCAGCA CUGAUGAG 1456 UGACUGUUC 2157 X CGAA AACAGUCA UGCUGAAG 3522 EUCUGUCC CUGAUGAG 1457 AGCGGCCUA 2158 X CGAA AGGCCGCU GGACAGAA 3534 GGUAUACA CUGAUGAG 1458 CAGAACAUC 2159 X CGAA AUGUUCUG UGUAUACC 3538 AGAGGGUA CUGAUGAG 1459 ACAUCUGUA 2160 X CGAA ACAGAUGU UACCCUCU 3540 ACAGAGGG CUGAUGAG 1460 AUCUGUAUA 2161 X CGAA AUACAGAU CCCUCUGU 3545 GGGAAACA CUGAUGAG 1461 UAUACCCUC 2162 X CGAA AGGGUAUA tJGUUEUCCC 3549 GAAAGGGA CUGAUGAG 1462 CCCUCUGUU 2163 X CGAA ACAGAGGG UCCCUUUC 3550 UGAAAGGG CUGAUGAG 1463 CCUCUGUUU 2164 X CGAA AACAGAGG CCCUUUCA 3551 GUGAAAGG CUGAUGAG 1464 CUCUGUUUC 2165 X CGAA AAACAGAG CCUtJUCAC 3555 GCCAGUGA CUGAUGAG 1465 GUUUCCCUU 2166 X CGAA AGGGAAAC UCACUGGC 3556 UGCCAGUG CUGAUGAG 1466 UUUCCCUUU 2167 X CGAA AAGGGAAA CACEJGGCA 3557 AUGCCAGU CUGAUGAG 1467 UUCCCUUUC 2168 X CGAA AAAGGGAA ACUGGCAU_____ 3576 CAGUUGUC CUGAUGAG 1468 GAGACCCUU 2169 X CGAA AGGGUCUC GACAACUG 3601 CUUUGGCA CUGAUGAG 1469 ACAUGCCUC 2170 X CGAA AGGCAUGU IUGCCAAAG WO 99/50403 WO 9950403PCTIUS99/06507 127 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3618 CACEJUAUA CUGAUGAG 1470 GAUGUGAUA 2171 X CGAA AUCACAUC UAUAAGUG 3620 UACACUUA CUGAUGAG 1471 UGUGAUAUA 2172 X CGAA AUAUCACA UAAGUGUA 3622 UGUACACU CUGAUGAG 1472 UGAUAUAUA 2173 X CGAA AUAUAUCA AGUGUACA 3628 CACAUAUG CUGAUGAG 1473 AUAAGUGUA 2174 X CGAA ACACUUAU CAUAUGUG 3632 CCAGCACA CUGAUGAG 1474 GUGUACAUA 2175 X CGAA AUGUACAC UGUGCUGG 3644 CUUGUUAG CUGAUGAG 1475 GCUGGAAUU 2176 X CGAA AUUCCAGC CUAACAAG 3645 ACUUGUUA CUGAUGAG 1476 CUGGAAUUC 2177 X CGAA AAUUCCAG UAACAAGU 3647 UGACUUGU CUGAUGAG 1477 GGAAUUCUA 2178 X CGAA AGAAUUCC ACAAGUCA 3654 UAACCUAU CUGAUGAG 1478 UAACAAGUC 2179 X CGAA ACUUGUUA AUAGGUUA 3657 UAUUAACC CUGAUGAG 1479 CAAGUCAUA 2180 X CGAA AUGACUUG GGUUAAUA______ 3661 UAAAUAUU CUGAUGAG 1480 UCAUAGGUU 2181 X CGAA ACCUAUGA AAUAUUUA 3662 UUAAAUAU CUGAUGAG 1481 CAUAGGUUA 2182 X CGAA AACCUAUG AUAUUUAA 3665 GUCUUAAA CUGAUGAG 1482 AGGUUAAUA 2183 X CGAA AUUAACCU UUUAAGAC 3667 GUGUCUUA CUGAUGAG 1483 GUUAAUAUU 2184 X CGAA AUAUUAAC UAAGACAC 3668 AGUGUCUU CUGAUGAG 1484 UUAAUAUUU 2185 X CGAA AAUAUUAA AAGACACU 3669 CAGUGUCU CUGAUGAG 1485 UAAUAUUUA 2186 X CGAA AAAUAUUA AGACACUG WO 99/50403 WO 9950403PCTIUS99/06507 128 Seq. 1.D. Seq. I.D.

Position RZ No. Substrate No.

3684 AUCACUUA CUGAUGAG 1486 UGAAAAAUC 2187 X CGAA AUUUUUCA UAAGUGAU 3686 AUAUCACU CUGAUGAG 1487 AAAAAUCUA 2188 X CGAA AGAUUUUU AGUGAUAU 3693 CUGAUUUA CUGAUGAG 1488 UAAGUGAUA 2189 X CGAA AUCACUUA UAAAUCAG 3695 AUCUGAUU CUGAUGAG 1489 AGUGAUAUA 2190 X CGAA AUAUCACU AAUCAGAU 3699 AAGAAUCU CUGAUGAG 1490 AUAUAAAUC 2191 X CGAA AUUUAUAU AGAEJUCUU 3704 GAGAGAAG CUGAUGAG 1491 AAUCAGAUU 2192 X CGAA AUCUGAUU CUUCUCUC 3705 AGAGAGAA CUGAUGAG 1492 AUCAGAUUC 2193 X CGAA AAUCUGAU UUCUCUCrj 3707 UGAGAGAG CUGAUGAG 1493 CAGAUUCUU 2194 X CGAA AGAAUCUG CUCUCUCA 3708 AUGAGAGA CUGAUGAG 1494 AGAUtJCUUC 2195 X CGAA AAGAAUCU UCUCUCAU 3710 AAAUGAGA CUGAUGAG 1495 AUUCUUCUC 2196 X CGAA AGAAGAAU UCUCAUUU 3712 UAAAAUGA CUGAUGAG 1496 UCUUCUCUC 2197 X CGAA AGAGAAGA UCAUUUUA 3714 GAUAAAAU CUGAUGAG 1497 UUCUCUCUC 2198 X CGAA AGAGAGAA AUUUUAUC 3717 AGGGAUAA CUGAUGAG 1498 UCUCUCAUU 2199 X CGAA AUGAGAGA UUAUCCCU 3718 GAGGGAUA CUGAUGAG 1499 CUCUCAUUU 2200 X CGAA AAUGAGAG UAUCCCUC 3719 UGAGGGAU CUGAUGAG 1500 UCUCAUUUU 2201 X CGAA AAAUGAGA AUCCCUCA 3720 GUGAGGGA CUGAUGAG 1501 CUCAUUUUA 2202 X CGAA AAAAUGAG IUCCCUCAC WO 99/50403 WO 9950403PCTIUS99/06507 129 Seq. 1.D. Seq. I.D.

Position RZ No. Substrate No.

3722 AGGUGAGG CUGAUGAG 1502 CAUUEJUAUC 2203 X CGAA AUAAAAUG CCUCACCU 3726 CUACAGGU CUGAUGAG 1503 UUAUCCCUC 2204 X CGAA AGGGAUAA ACCUGUAG 3733 UGGCAUGC CUGAUGAG 1504 UCACCUGUA 2205 X CGAA ACAGGUGA GCAUGCCA 3744 UGAAACGG CUGAUGAG 1505 AUGCCAGUC 2206 X CGAA ACUGGCAU CCGUUUCA 3749 CUAAAUGA CUGAUGAG 1506 AGUCCCGUU 2207 X CGAA ACGGGACU UCAUUUAG 3750 ACUAAAUG CUGAUGAG 1507 GUCCCGUUU 2208 X CGAA AACGGGAC CAUUUAGU 3751 GACUAAAU CUGAUGAG 1508 UCCCGUUUC 2209 X CGAA AAACGGGA AUUUAGUC 3754 CAUGACUA CUGAUGAG 1509 CGUUUCAUU 2210 X CGAA AUGAAACG 3755 ACAUGACU CUGAUGAG 1510 GUUUCAUUU 2211 X CGAA AAUGAAAC AGUCAUGU 3756 CACAUGAC CUGAUGAG 1511 UUUCAUUUA 2212 X CGAA AAAUGAAA GUCAUGUG 3759 GGUCACAU CUGAUGAG 1512 CAUUUAGUC 2213 X CGAA ACUAAAUG AUGUGACC 3771 ACAAGACA CUGAUGAG 1513 UGACCACUC 2214 X CGAA AGUGGUCA UGUCUUGU 3775 AAACACAA CUGAUGAG 1514 CACUCUGUC 2215 X CGAA ACAGAGUG UUGUGUUU 3777 GGAAACAC CUGAUGAG 1515 CUCUGUCUU 2216 X CGAA AGACAGAG GUGUUUCC 3782 GOUGUGGA CUGAUGAG 1516 UCUUGUGUU 2217 X CGAA ACACAAGA UCCACAGC______ 3783 GGCUGUGG CUGAUGAG 151-7 CUUGUGUUU 2218 IX CGAA AACACAAG ICCACAGCCI WO 99/50403 WO 9950403PCTIUS99/06507 130 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3784 AGGCUGUG CUGAUGAG 1518 UUGUGUUUC 2219 X CGAA AAACACAA CACAGCCU 3799 CUGGACUG CUGAUGAG 1519 CUGCAAGUU 2220 X CGAA ACUUGCAG CAGUCCAG 3800 CCUGGACU CUGAUGAG 1520 UGCAAGUUC 2221 X CGAA AACUUGCA AGUCCAGG 3804 GCAUCCUG CUGAtJGAG 1521 AG(JUCAGUC 2222 X CGAA ACUGAACU CAGGAUGC 3814 UUAGAUGU CUGAUGAG 1522 AGGAUGCUA 2223 X CGAA AGCAUCCU ACAUCUAA 3819 UAUUUUUA CUGAUGAG 1523 GCUAACAUC 2224 X CGAA AUGUUAGC UAAAAAUA 3821 UCUAUUUU CUGAUGAG 1524 UAACAUCUA 2225 X CGAA AGAUGUUA AAAAUAGA 3827 UUUAAGUC CUGAUGAG 1525 CUAAAAAUA 2226 X CGAA AUUUUUAG GACUUAAA 3832 UGAGAUUU CUGAUGAG 1526 AAUAGACUU 2227 X CGAA AGUCUAUU AAAUCUCA 3833 AUGAGAUU CUGAUGAG 1527 AUAGACUUA 2228 X CGAA AAGUCUAU AAUCUCAU 3837 AGCAAUGA CUGAUGAG 1528 ACUUAAAUC 2229 X CGAA AUUUAAGU UCAUUGCU 3839 UAAGCAAU CUGAUGAG 1529 UUAAAUCUC 2230 X CGAA AGAUUUAA AUUGCUUA 3842 UUGUAAGC CUGAUGAG 1530 AAUCUCAUU 2231 X CGAA AUGAGAUU GCUUACAA 3846 AGGCUUGU CUGAUGAG 1531 UCAUUGCUU 2232 X CGAA AGCAAUGA ACAAGCCU 3847 UAGGCUUG CUGAUGAG 1532 CAUUGCUUA 2233 X CGAA AAGCAAUG CAAGCCUA 3855 AAGAUUCU CUGAUGAG 1533 ACAAGCCUA 2234 X CGAA AGGCUUGU IAGAAUCUU WO 99/50403 WO 9950403PCTIUS99/06507 131 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

3861 UCUCUI4AA CUGAUGAG 1534 CUAAGAAUC 2235 X CGAA AUUCUUAG UUUAGAGA 3863 CUUCUCUA CUGAUGAG 1535 AAGAAUCUU 2236 X CGAA AGAUUCUU UAGAGAAG 3864 ACUUCUCU CUGAUGAG 1536 AGAAUCUUU 2237 X CGAA AAGAUUCU AGAGAAGJ 3865 UACUUCUC CUGAUGAG 1537 GAAUCUUUA 2238 X CGAA AAAGAUUC GAGAAGUA 3873 CUUAUGUA CUGAUGAG 1538 AGAGAAGUA 2239 X CGAA ACUUCUCU UACAUAAG 3875 AACUUAUG CUGAUGAG 1539 AGAAGUJAUA 2240 X CGAA AUACUUCU CAUAAGUU 3879 CCUAAACU CUGAUGAG 1540 GUAUACAUA 2241 X CGAA AUGUAUAC AGUUUAGG 3883 UUAUCCUA CUGAUGAG 1541 ACAUAAGUU 2242 X CGAA ACUUAUGU UAGGAUAA 3884 UUUAUCCU CUGAUGAG 1542 CAUAAGUUU 2243 X CGAA AACUUAUG AGGAUAAA 3885 UUUUAUCC CUGAUGAG 1543 AUAAGUUUA 2244 X CGAA AAACUUAU GGAUAAAA 3890 CAUUAUUU CUGAUGAG 1544 UUUAGGAUA 2245 X CGAA AUCCUAAA AAAUAAUG 3895 AAUCCCAU CUGAUGAG 1545 GAUAAAAUA 2246 X CGAA AUUUUAUC AUGGGAUU 3903 GAAAAGAA CUGAUGAG 1546 AAUGGGAUU 2247 X CGAA AUCCCAUU UUCUUUUC 3904 AGAAAAGA CUGAUGAG 1547 AUGGGAUUU 2248 X CGAA AAUCCCAU UCUUUUCU 3905 AAGAAAAG CUGAUGAG 1548 UGGGAUUUU 2249 X CGAA AAAUCCCA CUUUUCUU 3906 AAAGAAAA CUGAUGAG 1549 GGGAUUUUC 2250 X CGAA AAAAUCCC lUUUUCUUUI WO 99/50403 WO 9950403PCTIUS99/06507 132 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3908 GAAAAGAA CUGAUGAG 1550 GAUUEJUCUU 2251 X CGAA AGAAAAUC UUCUUUUC 3909 AGAAAAGA CUGAUGAG 1551 AUUUUCUUU 2252 X CGAA AAGAPAAU tJCUUUUCU 3910 GAGAAAAG CUGAUGAG 1552 UUUUCUJUU 2253 X CGAA AAAGAAAA CUUUUCUC 3911 AGAGAAAA CUGAUGAG 1553 UUUCUUU~C 2254 X CGAA AAAAGAAA UUUUCUCU 3913 CCAGAGAA CUGAUGAG 1554 UCUUTJUCUU 2255 X CGAA AGAAAAGA UUCUCUGG 3914 ACCAGAGA CUGAUGAG 1555 CUUUUCUUU 2256 X CGAA AAGAAAAG UCUCUGGU 3915 UACCAGAG CUGAUGAG 1556 tJUUUCUUUU 2257 X CGAA AAAGAAAA CUCUGGUA 3916 UUACCAGA CUGAUGAG 1557 UUUCUUUUC 2258 X CGAA AAAAGAAA UCUGGUAA 3918 UAUUACCA CUGAUGAG 1558 UCUUUUCUC 2259 X CGAA AGAAAAGA UGGUAAUA 3923 GUCAAUAU CUGAUGAG 1559 UCUCUGGUA 2260 X CGAA ACCAGAGA AUAUUGAC 3926 CAAGUCAA CUGAUGAG 1560 CUGGUJAAUA 2261 X CGAA AUUACCAG UUGACUUG 3928 UACAAGUC CUGAUGAG 1561 GGUAAUAUU 2262 X CGAA AUAUUACC GACUUGUA 3933 AAAUAUAC CUGAUGAG 1562 UAUUGACUU 2263 X CGAA AGUCAAUA GUAUAUUU 3936 UUAAAAUA CUGAUGAG 1563 UGACUUGUA 2264 X CGAA ACAAGUCA UAUUUUAA 3938 UCUUAAAA CUGAUGAG 1564 ACUUGUAUA 2265 X CGAA AUACAAGU UUUUAAGA 3940 UUUCUUAA CUGAUGAG 1565 UUGUAUAUU 2266 X CGAA AUAUACAA UUAAGAAA WO 99/50403 WO 9950403PCT[US99/06507 133 Seq.I.D.Seq. I.D.

Position RZ No. Substrate No.

3941 AUUUCUUA CUGAtJGAG 1566 UGUAUAUUU 2267 X CGAA AAUAUACA UAAA 3942 UAUUUCtJU CUGAUGAG 1567 GUAUAUUUU 2268 X CGAA AAAUJAUAC AAGAAAUA 3943 UUAUUUCU CUGAUGAG 1568 UAUAUUUUA 2269 X CGAA AAAAUAUA AGAAAUAA 3950 CUUUCUGU CUGAUGAG 1569 UAAGAAAUA 2270 X CGAA AUUUCUUA ACAGAAAG 3971 GUCUCCCA CUGAUGAG 1570 GGUGACAUU 2271 X CGAA AUGUCACC UGGGAGAC 3972 UGUCUCCC CUGAUGAG 1571 GUGACAUUU 2272 X CGAA AAUGUCAC GGGAGACA 3989 AAUAUAUA CUGAUGAG 1572 UGUGACAUU 2273 X CGAA AUGUCACA UAUAUAUU 3990 CAAUAUAU CUGAUGAG 1573 GUGACAUUU 2274 X CGAA AAUGUCAC AUAUAUUG 3991 UCAAUAUA CUGAUGAG 1574 UGACAUUUA 2275 X CGAA AAAUGUCA UAUAUUGA 3993 AUUCAAUA CUGAUGAG 1575 ACAUUUAUA 2276 X CGAA AUAAAUGU UAUUGAAU 3995 UAAUUCAA CUGAUGAG 1576 AUUUAUAUA 2277 X CGAA AUAUAAAU UUGAAUUA 3997 AUUAAUUC CUGAUGAG 1577 UUAUAUAUU 2278 X CGAA AUAUAUAA GAAUUAAU 4002 GGGAUAUU CUGAUGAG 1578 UAUUGAAUU 2279 X CGAA AUUCAAUA AAUAUCCC 4003 AGGGAUAU CUGAUGAG 1579 AUUGAAUUA 2280 X CGAA AAUUCAAU AUAUCCCU 4006 UGUAGGGA CUGAUGAG 1580 GAAUUAAUA 2281 X CGAA AUUAAUUC UCCCUACA 4008 CAUGUAGG CUGAUGAG 1581 AUUAAUAUC 2282 X CGAA AUAUUAAU CCUACAUG WO 99/50403 WO 9950403PCTIUS99/06507 134 Seq. I. D. Seq. 1. D.

Position RZ No. Substrate No.

4012 AAUACAUG CUGAUGAG 1582 AUAUCCCUA 2283 X CGAA AGGGAUAU CAUGUAUU 4018 AEJGUGCAA CUGAUGAG 1583 CUACAUGUA 2284 X CGAA ACAUGUAG UUGCACAU 4020 CAAUGUGC CUGAUGAG 1584 ACAUGUAUU 2285 X CGAA AUACAUGU GCACAUUG 4027 CUUUUUAC CUGAUGAG 1585 UUGCACAUU 2286 X CGAA AUGUGCAA GUAAAAAG 4030 AAACUUUU CUGAUGAG 1586 CACAUUGUA 2287 X CGAA ACAAUGUG AAAAGUUU 4037 AAAACUAA CUGAUGAG 1587 UAAAAAGUU 2288 X CGAA ACUUUUUA UUAGUUUU 4038 CAAAACUA CUGAUGAG 1588 AAAAAGUUU 2289 X CGAA AACUUUUU UAGUUUUG 4039 UCAAAACU CUGAUGAG 1589 AAAAGUUUU 2290 X CGAA AAACUUUU AGUUUUGA 4040 AUCAAAAC CUGAUGAG 1590 AAAGUUUUA 2291 X CGAA AAAACUUU GUUUUGAU 4043 CUCAUCAA CUGAUGAG 1591 GUUUUAGUU 2292 X CGAA ACUAAAAC UUGAUGAG 4044 ACUCAUCA CUGAUGAG 1592 UUUUAGUUU 2293 X CGAA AACUAAAA UGAUGAGU 4045 AACUCAUC CUGAUGAG 1593 UUUAGUUUU 2294 X CGAA AAACUAAA ______GAUGAGUU 4053 AAACUCAC CUGAUGAG 1594 UGAUGAGUU 2295 X CGAA ACUCAUCA GUGAGUUU 4060 ACAAGGUA CUGAUGAG 1595 UUGUGAGUU 2296 X CGAA ACUCACAA UACCUUGU 4061 UACAAGGU CUGAUGAG 1596 UGUGAGUUU 2297 X CGAA AACUCACA ACCUUGUA 4062 AUACAAGG CUGAUGAG 1597 GUGAGUUUA 2298 X CGAA AAACUCAC ICCUUGUAU WO 99/50403 WO 9950403PCTIUS99/06507 135 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

4066 CAGtJAUAC CUGAUGAG 1598 GUUUACCUU 2299 X CGAA AGGUAAAC GEJAUACUG 4069 CUACAGUA CUGAUGAG 1599 UACCUUGJA 2300 X CGAA ACAAGGUA UACUGUAG 4071 GCCUACAG CUGAUGAG 1600 CCUUGUAUA 2301 X CGAA AUACAAGG CUGUAGGC 4076 AGUGUGCC CUGAUGAG 1601 UAUACUGUA 2302 X CGAA ACAGUAUA GGCACACU 4085 UCAGUGCA CUGAUGAG 1602 GGCACACUU 2303 X CGAA AGUGUGCC UGCACUGA 4086 AUCAGUGC CUGAUGAG 1603 GCACACUUU 2304 X CGAA AAGUGUGC GCACUGAU 4095 UCAUGAUA CUGAUGAG 1604 GCACUGAUA 2305 X CGAA AUCAGUGC UAUCAUGA 4097 ACUCAUGA CUGAUGAG 1605 ACUGAUAUA 2306 X CGAA AUAUCAGU UCAUGAGU 4099 UCACUCAU CUGAUGAG 1606 UGAUAUAUC 2307 X CGAA AUAUAUCA AUGAGUGA 4110 AAGACAUU CUGAUGAG 1607 GAGUGAAUA 2308 X CGAA AUUCACUC AAUGUCUU 4116 GUAGGCAA CUGAUGAG 1608 AUAAAUGUC 2309 CGAA ACAUUUAU UUGCCUAC 4118 GAGUAGGC CUGAUGAG 1609 AAAUGUCUU 2310 CGAA AGACAUUU GCCUACUC 4123 UUUUUGAG CUGAUGAG 1610 UCUUGCCUA 2311 X CGAA AGGCAAGA CUCAAAAA 4126 UUUUUUUU CUGAUGAG 1611 UGCCUACUC 2312 X CGAA AGUAGGCA AAAAAAAA WO 99/50403 WO 9950403PCTIUS99/06507 136 TABLE VI: HAIRPIN RiZOZYMES AND TRARGET SITES FOR TIE-2 Seq. Seq. 1.D.

Position RZ 1.D. No. Substrate No.

AGAAGG AGAA GCAC ACCAGAGAAACA 2313 GUGCU GUU 2381 X GUACAUtJACCUGGUA CCUUCU 76 AAACCC AGAA GUUU ACCAGAGAAACA 2314 AAACC GCU 2382 X GUACAUUACCUGGUA _____GGGUUU 164 GAACUA AGAA GGCU ACCAGAGAAACA 2315 AGCCA GCU 2383 X GUACAL]UACCUGGUA U.AGUUC 185 GGAGCA AGAA GACU ACCAGAGAAACA 2316 AGEJCA GCU 2384 X GUACAUUACCUGGUA LGCUCC 256 UUCAGC AGAA GAUA ACCAGAGAAACA 2317 EAUCU GAU 2385 IX GUACAUUACCUGGUA

GCEJGA\

360 ACUUCC ACAA GAUC ACCAGAGAAACA 2318 GAUCC GCU 2386 X GUACAtJUACCUGGUA GGAAGU 681 GCAUGA AGAA GGUG ACCAGAGAAACA 2319 CACCU GCC 2387 X GUACAUUACCUGGUA UCAUGC 693 UCCUGG AGAA GAGC ACCAGAGAAACA 2320 GCUCA GCC 2388 X GUACAUUACCUGGUA CCAGGA 751 GGUGAA AGAA GAGG ACCAGAGAAACA 2321 CCUCG GCC 2389 X GUACAUUACCUGGUA UEJCACC 818 AAGCAG AGAA GAGA ACCAGAGAAACA 2322 [CUCU GEJA 2390 X GUACAUUACCUGGUA CUGCUU 823 CAUACA AGAA GUAC ACCAGAGAAACA 2323 GUACU GCU 2391 X GUACAUUACCUGGUA UGEJAUG 986 CAGGGA AGAA GAAC ACCAGAGAAACA 2324 GUUCU GUC 2392 X GUACAUUACCUGGUA UCCCUG 994 AUAGGG AGAA GGGA ACCAGAGAAACA 2325 UCCCU GAC 2393 X GUACAUUACCUGGUA CCCUAU 1075 CEJUACA AGAA GGCC ACCAGAGAAACA 2326 GGCCA GAU 2394 X GUACAUUACCUGGUA UGUAAG 1094 UGUUGC AGAA GCAC ACCAGAGAAACA 2327 GUGCA GCU 2395 X GUACAUUACCUGGUA lGCAACA WO 99/50403 WO 9950403PCT[US99/06507 137 Seq. Seq. I.D.

Position RZ No. Substrate No.

1139 CUGGAG AGAA GAGA ACCAGAGAAACA 2328 UCUCU GCU 2396 X GUACAUUACCUGGUA _____CUCCAG 1216 UAUAUG AGAA GGCA ACCAGAGAAACA 2329 tGCCA GAU 2397 X GUACAUUACCUGGJA _____CAIJAUA 1312 UGUCCC AGAA GGCU ACCAGAGAAACA 2330 AGCCG GAU 2398 X GUACAUrJACCUGGUA GGGACA 1351 GAAAUG AGAA GUAU ACCAGAGAAACA 2331 AUACG GAU 2399 X GUACAUUACCUGGUA CAUUUC 1363 UAUGGC AGAA GAGA ACCAGAGAAACA 2332 UCUCA GUA 2400 X GUACAUUACCUGGUA GCCAUA 1386 GGGAGG AGAA GGUG ACCAGAGAAACA 2333 CACCG GAU 2401 X GUACAUUACCUGGUA CCUCCC 1399 UCCUGA AGAA GGGG ACCAGAGAAACA 2334 CCCCU GAC 2402 X GUACAUUACCUGGUA UCAGGA 1544 GCUCAG AGAA GAUG ACCAGAGAAACA 2335 CAUCA GCU 2403 X GUACAUUACCUGGUA _____CUGAGC 1709 CUCCAC AGAA GACC ACCAGAGAAACA 2336 GGUCC GUC 2404 X GUACAUUACCUGGUA GUGGAG 1762 GAUAGA AGAA GUUG ACCAGAGAAACA 2337 CAACA GCU 2405 X GUACAUUACCUGGJA UCUAUC 1772 GAGGGA AGAA GAUA ACCAGAGAAACA 2338 UAUCG GAG 2406 X GUACAUUACCUGGUA _____UCCCUC 1803 CUUUUA AGAA GGAG ACCAGAGAAACA 2339 CUCCU GCC 2407 GUACAUUACCUGGUA UAAAAG 1815 AGAGUG AGAA GACU ACCAGAGAAACA 2340 AGUCA GAG 2408 X GUACAUUACCUGGUA

CACUCU

1977 ACCACG AGAA GCUC ACCAGAGAAACA 2341 GAGCA GUA 2409 X GUACAUUACCUGGUA CGUGGU 2038 GGUCCA AGAA GUGA ACCAGAGAAACA 2342 UCACU GCU 2410 X GUACAUUACCUGGUA UGGACC 2110 AAUCAC AGAA GAGG ACCAGAGAAACA 2343 CCUCG GCU 2411 X GUACAUUACCUGGUA IGUGAUU WO 99/50403 WO 9950403PCT[US99/06507 138 Seq. Seq. I.D.

Position RZ I.D. No. Substrate No.

2235 ACCUGA AGAA GAAU ACCAGAGAAACA 2344 AUUCA GUA 2412 X GUACAUUACCUGGUA UCAGCU 2241 CCCUUG AGAA GAUA ACCAGAGAAACA 2345 UAUCA GCU 2413 X GUACAUUACCUGGUA CAAGGG 2317 AGAAAA AGAA GGGU ACCAGAGAAACA 2346 ACCCA GCC 2414 X GUACAUUACCJGGEJA UUtJUCU 2365 UCCGAG AGAA GCUG ACCAGAGAAACA 2347 CAGCG GAG 2415 X GUACAUUACCUGGUA CUCGGA 2388 GCUAUA AGAA GCAU ACCAGAGAAACA 2348 AUGCU GCU 2416 X GUACAUUACCUGGUA UAUAGC 2410 CAUUCC AGAA GAGC ACCAGAGAAACA 2349 GCUCU GCU 2417 X GUACAUUACCUGGUA GGAAUG 2423 CAGUCA AGAA GGUC ACCAGAGAAACA 2350 GACCU GCC 2418 X GUACAUUACCUGGUA UGACUG 2427 AGCACA AGAA GGCA ACCAGAGAAACA 2351 UGCCU GAG 2419 X GUACAUUACCUGGUA _____UGUGCU 2436 AAGGCC AGAA GCAC ACCAGAGAAACA 2352 GUGCU GUU 2420 X GUACAUUACCUGGUA GGCCUU 2448 AAUAUG AGAA GAAA ACCAGAGAAACA 2353 UUUCU GAU 2421 X GUACAUUACCUGGUA CAUAUU 2524 CUGGAC AGAA GGUU ACCAGAGAAACA 2354 AACCA GCU 2422 X GUACAUUACCUGGUA GUGCAG 2532 GAGUUG AGAA GCAC ACCAGAGAAACA 2355 GUGCA GUU 2423 X GUACAtJUACCUGGUA CAACUC 2581 UGUAGG AGAA GGGU ACCAGAGAAACA 2356 ACCCA GAU 2424 X GUACAUUACCUGGUA CCUACA 2694 GCAUCC AGAA GUAA ACCAGAGAAACA 2357 UUACG GAU 2425 X GUACAUUACCUGGUA GGAUGC 2914 UGCUGG AGAA GUCU ACCAGAGAAACA 2358 AGACG GAG 2426 X GUACAUUACCUGGUA CCAGCA 2955 UGGGAG AGAA GUGU ACCAGAGAAACA 2359 ACACU GUC 2427 X GUACAUUACCUGGUA I ICUCCCA WO 99/50403 WO 9950403PCTIUS99/06507 139 Seq. Seq. I.D.

Position RZ I No. Substrate No.

2967 UGAAGG AGAA GCUG ACCAGAGAAACA 2360 CAGCA GCU 2428 X GUACAUUACCEJGGUA CCUUCA 2983 CACGUC AGAA GCGA ACCAGAGAAACA 2361 UCGCU GCC 2429 X GUACAEJUACCUGGUA GACGtJG 2986 GGCCAC AGAA GCAG ACCAGAGAAACA 2362 CUGCC GAC 2430 X GUACAUUACCUGGUA GUGGCC 3024 EGGAUA AGAA GUUU ACCAGAGAAACA 2363 AAACA GUU 2431 X GUACAUUACCUGGUA UALJCCA 3091 UCCAAA AGAA GCUA ACCAGAGAAACA 2364 UAGCA GAU 2432 X GUACAUUACCUGGJA UUUGGA 3300 CCCUGG AGAA GCUU ACCAGAGAAACA 2365 AAGCU GCC 2433 X GUACAUUACCUGGUA CCAGGG 3314 UCUCCA AGAA GUAG ACCAGAGAAACA 2366 CUACA GAC 2434 X GUACAtJUACCUGGUA UGGAGA 3500 CAGCAG AGAA GUCA ACCAGAGAAACA 2367 UGACU GUU 2435 X GUACAUUACCUGGUA CUGCUG 3505 UUCUUC AGAA GAAC ACCAGAGAAACA 2368 GUUCU GCU 2436 X GUACAUUACCUGGUA GAAGAA 3517 GUCCUA AGAA GCUU ACCAGAGAAACA 2369 AAGCG GCC 2437 X GUACAUUACCUGGUA UAGGAC 3535 AGGGUA AGAA GAUG ACCAGAGAAACA 2370 CAUCU GUA 2438 X GUACAUUACCUGGUA _____UACCCU 3546 AAGGGA AGAA GAGG ACCAGAGAAACA 2371 CCUCU GUD 2439 X GUACAUUACCUGGUA ucccuu 3583 UUUCUC AGAA GUUG ACCAGAGAAACA 2372 CAACU GCU 2440 X GUACAUUACCUGGUA GAGAAA 3700 AGAAGA AGAA GAUU ACCAGAGAAACA 2373 AAUCA GAU 2441 X GUACAUUACCUGGUA _____UCUUCU 3730 GCAUGC AGAA GGUG ACCAGAGAAACA 2374 CACCU GUA 2442 X GUACAUUACCUGGUA _____GCAUGC 3741 AAACGG AGAA GGCA ACCAGAGAAACA 2375 UGCCA GUC 2443 X GUACAUUACCUGGUA CCGUUU WO 99/50403 WO 9950403PCT/US99/06507 140 Seq. Seq. I.D.

Position RZ I.D. No. Substrate No.

3746 AAAUGA AGAA GGAC ACCAGAGAAACA 2376 GUCCC GUU 2444 X GLACAUUACCUGGUA UCAUUU 3772 ACACAA AGAA GAGU ACCAGAGAAACA 2377 ACUCU GUC 2445 X GUACAUUACCUGGUA UUGtJGU 3788 CUUGCA AGAA GUGG ACCAGAGAAACA 2378 CCACA GCC 2446 X GUACAUUACCUGGUA UGCAAG 3801 AUCCUG AGAA GAAC ACCAGAGAAACA 2379 GUUCA GUC 2447 X GUACAUUACCUGGUA CAGGAU 4073 UGUGCC AGAA GEJAU ACCAGAGAAACA 2380 AUACU GUA 2448 X GUACAUUACCUGGUA GGCACA WO 99/50403 WO 9950403PCTIUS99/06507 141 TABLE VII: HAMMERHEAD RIBOZYME AND TARGET SITE SEQUENCES FOR INTEGRIN ALPHA 6 SUBUNIT Seq. I.D. Seq. 1.D.

Position RZ No. Substrate No.

11 ACCCCCGG CUGAUGAG X 2449 GCGACCGUC 3588 CGAA ACGGUCGC CCGGGGGU 63 GCUGCUGC CUGAUGAG X 2450 GCUGCGGUA 3589 ACCGCAGC GCAGCAGC______ 82 CUGGGtJCC CUGAUGAG X 2451 GGCAGCCUC 3590 CGAA AGGCUGCC IGGACCCAG 119 GGAGCGGG CUGAUGAG X 2452 CUGCAGGUC 3591 CGAA ACCUGCAG CCCGCUCC 126 GGGGAGGG CUGAUGAG X 2453 UCCCCGCUC 3592 CGAA AGCGGGGA CCCUCCCC 131 CGCACGGG CUGAUGAG X 2454 GCUCCCCUC 3593 CGAA AGGGGAGC CCCGUGCG______ 141 CAUGGGCG CUGAUGAG X 2455 CCGUGCGUC 3594 CGAA ACGCACGG CGCCCAUG 172 GGUAGAGC CUGAUGAG X 2456 GCUGUGCUU 3595 CGAA AGCACAGC GCUCUACC 176 GACAGGUA CUGAUGAG X 2457 UGCUUGCUC 3596 AGCAAGCA UACCUGUC 178 CCGACAGG CUGAUGAG X 2458 CUUGCUCUA 3597 CGAA AGAGCAAG CCUGUCGG 184 GCCCCGCC CUGAUGAG X 2459 CUACCUGUC 3598 ACAGGUAG GGCGGGGC 194 CGGGACAG CUGAUGAG X 2460 GCGGGGCUC 3599 AGCCCCGC CUGUCCCG 199 CGAGCCGG CUGAUGAG X 2461 GCUCCUGUC 3600 CGAA ACAGGAGC CCGGCUCG 206 GCUGCGCC CUGAUGAG X 2462 UCCCGGCUC 3601 CGAA AGCCGGGA GGCGCAGC 217 CCAAGUUG CUGAUGAG X 2463 CGCAGCCUU 3602 fCGAA AGGCUGCG CAACUUGG WO 99/50403 WO 9950403PCTIUS99/06507 142 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

218 UCCAAGUU CUGAUGAG X 2464 GCAGCCUUC 3603 CGAA AAGGCUGC AACUUGGA 223 GAGUGUCC CUGAUGAG X 2465 CUUCAACUU 3604 CGAA AGUUGAAG GGACACUC 231 GUCGUCCC CUGAUGAG X 2466 UGGACACUC 3605 CGAA AGUGUCCA GGGAGGAC 248 UAUUUCCG CUGAUGAG X 2467 AACGUGAUC 3606 CGAA AUCACGUU CGGAAAUA 256 GGUCUCCA CUGAUGAG X 2468 CCGGAAAUA 3607 CGAA AUUUCCGG UGGAGACC 275 AAGCCGAA CUGAUGAG X 2469 GGGAGCCUC 3608 AGGCUCCC UUCGGCUU 277 AGAAGCCG CUGAUGAG X 2470 GAGCCUCUU 3609 CGAA AGAGGCUC CGGCUUCU 278 GAGAAGCC CUGAUGAG X 2471. AGCCUCUUC 3610 CGAA AAGAGGCU GGCUUCUC 283 CCAGCGAG CUGAUGAG X 2472 CUUCGGCUU 3611 CGAA AGCCGAAG -CUCGCUGG______ 284 GCCAGCGA CUGAUGAG X 2473 UUCGGCUUC 3612 AAGCCGAA UCGCUGGC 286 UGGCCAGC CUGAUGAG X 2474 CGGCUUCUC 3613 AGAAGCCG GCUGGCCA______ 331 CCACGAGC CUGAUGAG X 2475 GCGGCUGUU 3614 ACAGCCGC IGCUCGUGG______ 335 GCCCCCAC CUGAUGAG X 2476 CUGUUGCUC 3615 CGAA AGCAACAG GUGGGGGC______ 362 UGCAGUGG CUGAUGAG X 2477 GAAGCGCUU 3616 CGAA AGCGCUUC CCACUGCA______ 363 CUGCAGUG CUGAUGAG X 2478 AAGCGCUUC 3617 CGAA AAGCGCUU CACUGCAG 397 CGCAGCUG CUGAUGAG X 2479 AGGGCUGUA 3618 CGAA ACAGCCCU

CAGCUGCG______

WO 99/50403 WO 9950403PCTIUS99/06507 143 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

410 CGGGCGGU CUGAUGAG X 2480 UGCGACAUC 3619 CGAA AUGUCGCA ACCGCCCG 437 UCAAACUC CUGAUGAG X 2481 ACGCGGAUC 3620 CGAA AUCCGCGU GAGUUUGA 442 CGUUAUCA CUGAUGAG X 2482 GAUCGAGUU 3621 CGAA ACUCGAUC UGAUAACG 443 UCGUUAUC CUGAUGAG X 2483 AUCGAGUUU 3622 CGAA AACUCGAU GAUAACGA 447 AGCAUCGU CUGAUGAG X 2484 AGUUUGAUA 3623 CGAA AUCAAACU ACGAUGCU 466 UGCUUUCU CUGAUGAG X 2485 CCCCACGUC 3624 CGAA ACGUGGGG AGAAAGCA 483 CAUCCACU CUGAUGAG X 2486 AGGAAGAUC 3625 CGAA AUCUUCCU AGUGGAUG 497 UGGACGGU CUGAUGAG X 2487 AUGGGGGUC 3626 CGAA ACCCCCAU ACCGUCCA 503 UGGCUCUG CUGAUGAG X 2488 GUCACCGUC 3627 CGAA ACGGUGAC CAGAGCCA 516 GCCCCCUG CUGAUGAG X 2489 GCCAAGGUC 3628 CGAA ACCUUGGC ICAGGGGGC 530 CAUGUCAC CUGAUGAG X 2490 GGCAAGGUC 3629 CGAA ACCUUGCC GUGACAUG 543 AUAUCGGU CUGAUGAG X 2491 CAUGUGCUC 3630 CGAA AGCACAUG ACCGAUAU 550 UUUUUUCA CUGAUGAG X 2492 UCACCGAUA 3631 CGAA AUCGGUGA UGAAAAAA 569 UUCGUAUU CUGAUGAG X 2493 CAGCAUGUU 3632 ACAUGCUG AAUACGAA 570 CUUCGUAU CUGAUGAG X 2494 AGCAUGUUA 3633 CGAA AACAUGCU _____AUACGAAG 573 CUGCUUCG CUGAUGAG X 2495 AUGUUAAUA 3634 ICGAA AUUAACAU CGAAGCAG WO 99/50403 WO 9950403PCT/US99/06507 144 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

586 UGtJGUCGG CUGAUGAG X 2496 GCAGGAAUC 3635 CGAA AUUCCUGC CG(AGACA 596 CGCCCAAA CUGAUGAG X 2497 CGAGACAUC 3636 CGAA AUGUCUCG UUUGGGCG______ 598 ACCGCCCA CUGAUGAG X 2498 AGACAUCUU 3637 CGAA AGAUGUCU UGGGCGGU______ 599 CACCGCCC CUGAUGAG X 2499 GACAUCUUU 3638 CGAA AAGAUGUC _____GGGCGGUG 609 CAGGACAU CUGAUGAG X 2500 GGCGGUGUU 3639 CGAA ACACCGCC AUGUCCUG 34 610 UCAGGACA CUGAUGAG X 2501 GCGGUGUUA 34 CGAA AACACCGC UGUCCUGA 614 UGACUCAG CUGAUGAG X 2502 UGUUAUGUC 3641 CGAA ACAUAACA CUGAGUCA 621 GAGAUUCU CUGAUGAG X 2503 UCCUGAGJC 3642 CGAA ACUCAGGA AGAAUCUC 627 AAuCCUGA CUGAUGAG X 2504 GUCAGAAUC 3643 CGAA AUUCUGAC UCAGGAUU 629 UCAAUCCU CUGAUGAG X 2505 CAGAAUCUC 3644 CGAA AGAUUCUG AGGAUUGA______ 635 UCGUCUUC CUGAUGAG X 2506 CUCAGGAUU 3645 CGAA AUCCUGAG GAAGACGA______ 645 CCCAUCCA CUGAUGAG X 2507 AAGACGAUA 3646 CGAA AUCGUCUU UGGAUGGG______ 660 AAAGCUCC CUGAUGAG X 2508 GGGGAGAUU 3647 CGAA AUCUCCCC GGAGCUUU 667 CAUCACAA CUGAUGAG X 2509 UUGGAGCUU 3648 CGAA AGCUCCAA UUGUGAUG 668 CCAUCACA CUGAUGAG X 2510 UGGAGCUUU 3649 CGAA AAGCUCCA UGUGAUGG 669 CCCAUCAC CUGAUGAG X 2511 GGAGCUUUU 3650 CGAA AAAGCUCC GUGAUGGG WO 99/50403 WO 9950403PCT/US99/06507 145 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

682 GGCCUJCUC CUGAUGAG X 2512 EGGGCGAUU 3651 CGAA AUCGCCCA GAGAGGCC 700 AAGAGCCA CUGAUGAG X 2513 UGAGAAAUU 3652 CGAA AUUUCUCA UGGCUCUU 701 CAAGAGCC CUGAUGAG X 2514 GAGAAAUUU 3653 CGAA AAUUUCUC GGCUCUUG 706 GCUGGCAA CUGAUGAG X 2515 AUUUGGCUC 3654 CGAA AGCCAAAU UUGCCAGC______ 708 UUGCUGGC CUGAUGAG X 2516 UUGGCUCUU 3655 CGAA AGAGCCAA GCCAGCAA 722 GUAGCUGC CUGAUGAG X 2517 CAAGGUGUA 3656 CGAA ACACCUUG GCAGCUAC 729 AGUAAAAG CUGAUGAG X 2518 UAGCAGCUA 3657 CGAA AGCUGCUA CUUUUACU 732 UUUAGUAA CUGAUGAG X 2519 CAGCUACUU 3658 CGAA AGUAGGUG UUACUAAA 733 CUUUAGUA CUGAUGAG X 2520 AGCUACUUU 3659 CGAA AAGUAGCU _____UACUAAAG 734 UCUUUAGU CUGAUGAG X 2521 GCUACUUUU 3660 AAAGUAGC _____ACUAAAGA 735 GUCUUUAG CUGAUGAG X 2522 CUACUUUUA 3661 AAAAGUAG CUAAAGAC______ 738 AAAGUCUU CUGAUGAG X 2523 CUUUUACUA 3662 AGUAAAAG AAGACUUU______ 745 UGUAAUGA CUGAUGAG X 2524 UAAAGACUU 3663 CGAA AGUCUUUA UCAUUACA______ 746 AUGUAAUG CUGAUGAG X 2525 AAAGACUUU 3664 CGAA AAGUCUUU CAUUACAU______ 747 AAUGUAAU CUGAUGAG X 2526 A.AGACUUUC 3665 CGAA AAAGUCUU AUUACAUU 750 UACAAUGU CUGAUGAG X 2527 ACUUUCAUU 3666 CGAA AUGAAAGU ACAUUGUA WO 99/50403 WO 9950403PCTIUS99/06507 146 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

751 AUACAAUG CUGAEJGAG X 2528 CUUUCAUUA 3667 CGAA AAUGAAAG CAUUGUAU 755 CCAAAUAC CUGAUGAG X 2529 CAUUACAUU 3668 CGAA AUGEJAAUG GUAUUUGG 758 GCUCCAAA CUGAUGAG X 2530 UACAUUGUA 3669 CGAA ACAAUGUA UUUGGAGC 760 GGGCUCCA CUGAUGAG X 2531 CAUUGUAUU 3670 CGAA AUACAAUG UGGAGCCC 761 GGGGCUCC CUGAUGAG X 2532 AUUGUAUUU 3671 CGAA AAUACAAU GGAGCCCC 774 GUUAUAAG CUGAUGAG X 2533 CCCCGGGUA 3672 CGAA ACCCGGGG CUUAUAAC______ 777 CCAGUUAU CUGAUGAG X 2534 CGGGUACUU 3673 CGAA AGUACCCG AUAACUGG______ 778 UCCAGUUA CUGAUGAG X 2535 GGGUACUUA 3674 CGAA AAGUACCC UA.ACUGGA 780 UUUCCAGU CUGAUGAG X 2536 GUACUUAUA 3675 CGAA AUAAGUAC ACUGGAAA 794 ACACGAAC CUGAUGAG X 2537 AAAGGGAUU 3676 CGAA AUCCCUUU GUUCGUGU 797 UCUACACG CUGAUGAG X 2538 GGGAUUGUU 3677 CGAA ACAAUCCC ICGUGUAGA 798 CUCUACAC CUGAUGAG X 2539 GGAUUGUUC 3678 CGAA AACAAUCC GUGUAGAG______ 803 UUUUGCUC CUGAUGAG X 2540 GUUCGUGUA 3679 CGAA ACACGAAC GAGCAAAA 816 AAAAGUGU CUGAUGAG X 2541 AAAAGAAUA 3680 CGAA AUUCUUUU ACACUUUU 822 GUCAAAAA CUGAUGAG X 2542 AUAACACJU 3681 CGAA AGUGUUAU UUUUUGAC 823 UGUCAAAA CUGAUGAG X 2543 UAACACUUU 3682 CGAA AAGUGUUA UUUUGACA______

L

WO 99/50403 WO 9950403PCTIUS99/06507 147 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

824 AUGtJCAAA CUGAUGAG X 2544 AACACUUUU 3683 CGAA AAAGUGUU UUUGACAU 825 CAUGUCAA CUGAUGAG X 2545 ACACUUUUU 3684 CGAA AAAAGUGU UUGACAUG 826 UCAUGUCA CUGAUGAG X 2546 CACUUUUUU 3685 CGAA AAAAAGUG UGACAUGA 827 UUCAUGUC CUGAUGAG X 2547 ACUUUUUUU 3686 CGAA AAAAAAGU 839 UCUUCAAA CUGAUGAG X 2548 AUGAACAUC 3687 CGAA AUGUUCAU UUUGAAGA 841 CAUCUUCA CUGAUGAG X 2549 GAACAUCUU 3688 CGAA AGAUGUUC UGAAGAUG 842 CCAUCUUC CUGAUGAG X 2550 AACAUCUUU 3689 CGAA AAGAUGUU GAAGAUGG 855 AACUUCAU CUGAUGAG X 2551 AUGGGCCUU 3690 CGAA AGGCCCAU AUGAAGUU 856 CAACUUCA CUGAUGAG X 2552 UGGGCCUUA 3691 CGAA AAGGCCCA ______UGAAGUUG 863 UCUCCACC CUGAUGAG X 2553 UAUGAAGUU 3692 CGAA ACUUCAUA GGUGGAGA 891 AGGAACGA CUGAUGAG X 2554 AUGAAAGUC 3693 CGAA ACUUUCAU IUCGUUCCU 893 ACAGGAAC CUGAUGAG X 2555 GAAAGUCUC 3694 CGAA AGACUUUC GUUCCUGU 896 GGAACAGG CUGAUGAG X 2556 AGUCUCGUU 3 695 CGAA ACGAGACU

CCUGUUCC

897 AGGAACAG CUGAUGAG X 2557 GUCUCGUUC 3696 CGAA AACGAGAC

CUGUUCCU______

902 UUAGCAGG CUGAUGAG X 2558 GUUCCUGUU 3697 CGAA ACAGGAAC CCUGCUAA 903 GUUAGCAG CUGAUGAG X 2559 UUCCUGUUC 3698 CGAA AACAGGAA CUGCUAAC WO 99/50403 WO 9950403PCT/US99/06507 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

909 GUAACUGU CUGAUGAG X 2560 UUCCUGCUA 3699 AGCAGGAA ACAGUUAC 915 ACCUAAGU CUGAUGAG X 2561 CUAACAGUU 3700 ACUGUUAG ACUUAGGU 916 AACCUAAG CUGAUGAG X 2562 UAACAGUUA 3701 AACUGUUA ______CUUAGGUU 919 AAAAACCU CUGAUGAG X 2563 CAGUUACUU 3702 AGUAACUG _____AGGUUUUU 920 GAAAAACC CUGAUGAG X 2564 AGUUACUUA 3703 CGAA AAGUAACU GGUUUUUC 924 CAAAGAAA CUGAUGAG X 2565 ACUUAGGUU 3704 CGAA ACCUJAAGU UUUCUUUG 925 CCAAAGAA CUGAUGAG X 2566 CUUAGGUUU 3705 CGAA AACCUAAG UUCUUUGG 926 UCCAAAGA CUGAUGAG X 2567 UUAGGUUUU 3706 CGAA AAACCUAA UJCUUUGGA 927 GUCCAAAG CUGAUGAG X 2568 UAGGUUUUU 3707 CGAA AAAACCUA CUUUGGAC 928 AGUCCAAA CUGAUGAG X 2569 AGGUUUUUC 3708 CGAA AAAAACCU UUUGGACU 930 UGAGUCCA CUGAUGAG X 2570 GUUUUUCUU 3709 AGAAAAAC _____UGGACUCA 931 CUGAGUCC CUGAUGAG X 2571 uuuuucuuu 3710 AAGAA.AA GGACUCAG______ 937 CUUUCCCU CUGAUGAG X 2572 UUUGGACUC 3711 CGAA AGUCCAAA AGGGAAAG 948 AGAAACAA CUGAUGAG X 2573 GGAAAGGUA 3712 CGAA ACCUUUCC

IUUGUUUCU

950 UUAGAAAC CUGAUGAG X 2574 AAAGGUAUU 3713 AUACCUUU GEUUCUAA______ 953 UCUUUAGA CUGAUGAG X 2575 GGUAUUGUU 3714 CGAA ACAAUACC UCUAAAGA WO 99/50403 WO 9950403PCTIUS99/06507 149 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

954 AUCUUEJAG CUGAUGAG X 2576 GUAUUGUUU 3715 CGAA AACAAUAC CUAAAGAU 955 CAUCUUUA CUGAUGAG X 2577 UAUIJGUUUC 3716 CGAA AAACAAUA UAAAGAUG 957 CUCAUCUU CUGAUGAG X 2578 UUGLJUUCUA 3717 CGAA AGAAACAA AAGAUGAG 968 ACAAAAGU CUGAUGAG X 2579 GAUGAGAUC 3718 CGAA AUCUCAUC ACUUUUGU 972 AGAUACAA CUGAUGAG X 2580 AGAIJCACUU 3719 CGAA AGUGAUCU UUGUAUCU 973 CAGAUACA CUGAUGAG X 2581 GAUCACUUU 3720 CGAA AAGUGAUC _____UGUAUCUG 974 CCAGAUAC CUGAUGAG X 2582 AUCACUUUU 3721 CGAA AAAGUGAU GUAUCUGG 977 GCACCAGA CUGAUGAG X 2583 ACUUUUGUA 3722 CGAA ACAAAAGU _____UCUGGUGC 979 GAGCACCA CUGAUGAG X 2584 UUUUGUAUC 3723 AUACAAAA UGGUGCUC 987 GGCUCUGG CUGAUGAG X 2585 CUGGUGCUC 3724 CGAA AGCACCAG CCAGAGCC 999 UCCACUGU CUGAUGAG X 2586 GAGCCAAUC 3725 CGAA AUUGGCUC ACAGUGGA 1016 UUCAGCAA CUGAUGAG X 2587 GCCGUGGUU 3726 CGAA ACCACGGC UUGCUGAA 1017 CUUCAGCA CUGAUGAG X 2588 CCGUGGUUU 3727 CGAA AACCACGG UGCUGAAG 1018 UCUUCAGC CUGAUGAG X 2589 CGUGGUUUU 3728 CGAA AAACCACG GCUGAAGA______ 1039 GAUGUGCA CUGAUGAG X 2590 CAUGAAGUC 3729 CGAA ACUUCAUG UGCACAUC 1047 AGGGAGGA CUGAUGAG X 2591 CUGCACAUC 3730 CGAA AUGUGCAG uccucccu WO 99/50403 WO 9950403PCT/US99/06507 150 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1049 UGAGGGAG CUGAUGAG X 2592 GCACAUCUC 3731 CGAA AGAUGUGC CEJCCCUGA 1052 UGCUCAGG CUGAUGAG X 2593 CAUCUCCUC 3732 CGAA AGGAGAUG CCUGAGCA 1064 CCAUCGAA CUGAUGAG X 2594 GAGCACAUA 3733 CGAA AUGUGCUC ______UUCGAUGG 1066 CUCCAUCG CUGAUGAG X 2595 GCACAUAUU 3734 CGAA AUAUGUGC CGAUGGAG_____ 1067 UCUCCAUC CUGAUGAG X 2596 CACAUAUUC 3735 AAUAUGUG GAUGGAGA 1080 AGAGGCCA CUGAUGAG X 2597 GAGAAGGUC 3736 CGAA ACCUUCUC UGGCCUCU 1087 CAAAUGAA CUGAUGAG X 2598 UCUGGCCUC 3737 CGAA AGGCCAGA UUCAUUUG 1089 GCCAAAUG CUGAUGAG X 2599 UGGCCUCUU 3738 CGAA AGAGGCCA _____CAUUUGGC 1090 AGCCAAAU CUGAUGAG X 2600 GGCCUCUUC 3739 CGAA AAGAGGCC AUUUGGCU 1093 CAUAGCCA CUGAUGAG X 2601 CUCUUCAUU 3740 CGAA AUGAAGAG UGGCUAUG 1094 UCAUAGCC CUGAUGAG X 2602 UCUUCAUUU 3741 CGAA AAUGAAGA _____GGCUAUGA 1099 CCACAUCA CUGAUGAG X 2603 AUUUGGCUA 3742 CGAA AGCCAAAU _____UGAUGUGG 1121 UCCUUGUU CUGAUGAG X 2604 GUGGACCUC 3743 CGAA AGGUCCAC AACAAGGA 1143 AAUAACUA CUGAUGAG X 2605 GGCAAGAUA 3744 AUCUUGCC

UAGUUAUU

1145 CCAAUAAC CUGAUGAG X 2606 CAAGAUAUA 3745 CGAA AUAUCUUG GUUAUUGG 1148 GCUCCAAU CUGAUGAG X 2607 GAUAUAGUU 3746 CGAA ACUAUAUC IAUUGGAGC WO 99/50403 WO 9950403PCT/US99/06507 151 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1149 GGCUCCAA CUGAUGAG X 2608 AUAUAGUUA 3747 CGAA AACUAUAU UUGGAGCC 1151 GGGGCUCC CUGAUGAG X 2609 AUAGUUAUU 3748 CGAA AUAACUAU GGAGCCCC 1165 UAUCAAAA CUGAUGAG X 2610 CCCACAGUA 3749 CGAA ACUGUGGG UUUUGAUA 1167 UCUAUCAA CUGAUGAG X 2611 CACAGUAUU 3750 CGAA AUACUGUG UUGAUAGA 1168 CUCUAUCA CUGAUGAG X 2612 ACAGUAUUU 3751 CGAA AAUACUGU UGAEJAGAG 1169 UCUCtJAUC CUGAUGAG X 2613 CAGUAUUUU 3752 CGAA AAAUACUG GAUAGAGA 1173 UCCAUCUC CUGAUGAG X 2614 AUUUUGAUA 3753 CGAA AUCAAAAU GAGAUGGA 1187 GCACCUCC CUGAUGAG X 2615 GGAGAAGUU 3754 CGAA ACUUCUCC GGAGGUGC 1201 UGUAGACA CUGAUGAG X 2616 UGCAGUGUA 3755 CGAA ACACUGCA UGUCUACA 1205 UUCAUGUA CUGAUGAG X 2617 GUGUAUGUC 3756 ACAUACAC UACAUGAA 1207 GGUUCAUG CUGAUGAG X 2618 GUAUGUCUA 3757 AGACAUAC CAUGAACC 1233 CUUCACAU CUGAUGAG X 2619 GAUGGAAUA 3758 AUUCCAUC AEJGUGAAG 1247 UUAAGACG CUGAUGAG X 2620 AAGCCAAUU 3759 CGAA AUUGGCUU CGUCUUAA 1248 AUUAAGAC CUGAUGAG X 2621 AGCCAAUUC 3760 CGAA AAUUGGCU IGUCUUAAU 1251 UCCAUUAA CUGAUGAG X 2622 CAAUUCGUJC 3761 CGAA ACGAAUUG UUAAUGGA 1253 GUUCCAUU CUGAUGAG X 2623 AUUCGUCUU 3762 AGACGAAU IAAUGGAAC WO 99/50403 WO 9950403PCTJUS99/06507 152 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1254 GGUUCCAU CUGAUGAG X 2624 UUCGUCUUA 3763 CGAA AAGACGAA AUGGAACC 1269 AAACAUAG CUGAUGAG X 2625 CCAAAGAUU 3764 CGAA AUCUUUGG CUAUGUUU 1270 CAAACAUA CUGAUGAG X 2626 CAAAGAUUC 3765 CGAA AAUCUUUG UAUGUUUG 1272 GCCAAACA CUGAUGAG X 2627 AAGAUUCUA 3766 CGAA AGAAUCUU UGUUUGGC 1276 CAAUGCCA CUGAUGAG X 2628 UUCUAUGUU 3767 CGAA ACAUAGAA UGGCAUUG 1277 GCAAUGCC CUGAUGAG X 2629 UCUAUGUUJ 3768 CGAA AACAUAGA GGCAUUGC 1283 UUUACUGC CLIGAUGAG X 2630 UIJUGGCAUU 3769 CGAA AUGCCAAA GCAGUAAA 1289 AUAUUUUU CUGAUGAG X 2631 AUUGCAGUA 3770 CGAA ACUGCAAU AAAAAUAU 1296 AUCUCCAA CUGAUGAG X 2632 UAAAAAAUJA 3771 CGAA AUUUUUUA UUGGAGAU 1298 AUAUCUCC CUGAUGAG X 2633 AAAAAUAUU 3772 CGAA AUAUUUUU GGAGAUAU______ 1305 UUGAUUAA CUGAUGAG X 2634 UUGGAGAUA 3773 AUCUCCAA UUAAUJCAA 1307 UCUUGAUU CUGAUGAG X 2635 GGAGAUAUU 3774 AUAUCUCC AAUCAAGA 1308 AUCUUGAU CUGAUGAG X 2636 GAGAUAUUA 3775 AAUAUCUC AUCAAGAU 1311 GCCAUCUU CUGAUGAG X 2637 AUAUUAAUC 3776 CGAA AUJUAAUAU AAGAUGGC 1321 UAUCUGGG CUGAUGAG X 2638 AGAUGGCUA 3777 CGAA AGCCAUCU CCCAGAUA I 1329 AACUGCAA CUGAUGAG X 2639 ACCCAGAUA 3778 CGAA AUCUGGGU UUGCAGUU WO 99/50403 WO 9950403PCTIUS99/06507 153 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1331 CCAACUGC CUGAUGAG X 2640 CCAGAUAUU 3779 CGAA AUAUCUGG GCAGUUGG 1337 GGAGCUCC CUGAUGAG X 2641 AUUGCAGUU 3780 CGAA ACUGCAAU GGAGCUCC 1344 AUCAUACG CUGAUGAG X 2642 UUGGAGCUC 3781 CGAA AGCUCCAA CGUAUGAU 1348 AGUCAUCA CUGAUGAG X 2643 AGCUCCGUA 3782 CGAA ACGGAGCU UGAUGACU 1357 CCUUUCCC CUGAUGAG X 2644 UGAUGACUU 3783 CGAA AGUCAUCA IGGGAAAGG 1367 UAGAUAAA CUGAUGAG X 2645 GGAAAGGUU 3784 CGAA ACCUUUCC UUUAUCUA______ 1368 AUAGAUAA CUGAUGAG X 2646 GAAAGGUUU 3785 CGAA AACCUUUC IUUAUCUAU 1369 GAUAGAUA CUGAUGAG X 2647 AAAGGUUUU 3786 CGAA AAACCUUU UAUCUAUC 1370 UGAUAGAU CUGAUGAG X 2648 AAGGUUUUU 3787 CGAA AAAACCUU AUCUAUCA 1371 AUGAUAGA CUGAUGAG X 2649 AGGUUUUUA 3788 CGAA AAAAACCU UCUAUCAU 1373 CCAUGAUA CUGAUGAG X 2650 GUUUUUAUC 3789 CGAA AUAAAAAC UAUCAUGG______ 1375 AUCCAUGA CUGAUGAG X 2651 UUUUAUCUA 3790 CGAA AGAUAAAA UCAUGGAU 1377 AGAUCCAU CUGAUGAG X 2652 UUAUCUAUC 3791 CGAA AUAGAUAA AUGGAUCU 1384 CAUUUGCA CUGAUGAG X 2653 UCAUGGAUC 3792 AUCCAUGA UGCAAAUG 1397 UUGGUAUU CUGAUGAG X 2654 AAUGGAAUA 3793 CGAA AUUCCAUU AAUACCAA 1401 UGGUUUGG CUGAUGAG X 2655 GAAUAAAUA 3794 CGAA AUUUAUUC CCAAACCA WO 99/50403 WO 9950403PCT/US99/06507 1~54 Seq. 1. D. Seq. I. D.

Position RZ No. Substrate No.

1418 CCCUUGAG CUGAUGAG X 2656 ACACAGGUU 3795 CGAA ACCUGUGU CUCAAGGG 1419 ACCCUUGA CUGAUGAG X 2657 CACAGGUUC 3796 CGAA AACCUGUG UCAAGGGU 1421 AUACCCUU CUGAUGAG X 2658 CAGGUUCUC 3797 CGAA AGAACCUG AAGGGUAU 1428 AGGUGAUA CUGAUGAG X 2659 UCAAGGGUA 3798 CGAA ACCCUUGA UAUCACCU 1430 UAAGGUGA CUGAUGAG X 2660 AAGGGUAUA 3799 CGAA AUACCCUU UCACCUUA 1432 AAUAAGGU CUGAUGAG X 2661 GGGUAUAUC 3800 CGAA AUAUACCC ACCUUAUU 1437 UCCAAAAU CtJGAUGAG X 2662 UAUCACCUU 3801 CGAA AGGUGAUA AUUUUGGA 1438 AUCCAAAA CUGAUGAG X 2663 AUCACCUUA 3802 CGAA AAGGUGAU UUUUGGAU 1440 AUAUCCAA CUGAUGAG X 2664 CACCUUAUU 3803 CGAA AUAAGGUG UUGGAUAU 1441 AAUAUCCA CUGAUGAG X 2665 ACCUUAUUU 3804 CGAA AAUJAAGGU UGGAUAUU 1442 GAAUAUCC CUGAUGAG X 2666 CCUUAUUUU 3805 CGAA AAAUAAGG GGAUAUUC 1447 CAAUUGAA CUGAUGAG X 2667 UUUUGGAUA 3806 CGAA AUCCAAAA UUCAAUUG 1449 AGCAAUUG CUGAUGAG X 2668 UUGGAUAUU 3807 CGAA AUAUCCAA CAAUUGCU 1450 CAGCAAUU CUGAUGAG X 2669 UGGAUAUUC 3808 CGAA AAUAUCCA AAUUGCUG 1454 UUUCCAGC CUGAUGAG X 2670 UAUUCAAUU 3809 CGAA AUUGAAUA GCUGGAAA 1472 UUUCGAUC CUGAUGAG X 2671 AUGGACCUU 3810 ICGAA AGGUCCAU IGAUCGAAA I WO 99/50403 WO 9950403PCTIUS99/06507 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1476 GGAAUUUC CUGAUGAG X 2672 ACCUUGAUC 3811 CGAA AUCAAGGU GAAAUUCC 1482 AGGGUAGG CUGAUGAG X 2673 AUCGAAAUU 3812 AUUUCGAU CCUACCCU______ 1483 CAGGGUAG CUGAUGAG X 2674 UCGAAAUUC 3813 CGAA AAUUUCGA CUACCCUG 1486 CAUCAGGG CUGAUGAG X 2675 AAAUUCCUA 3814 CGAA AGGAAUUU CCCUGAUG 1496 CCAACAGC CUGAUGAG X 2676 CCUGAUGUU 3815 CGAA ACAUCAGG GCUGUUGG 1502 AGGGAACC CUGAUGAG X 2677 GUUGCUGUU 3816 CGAA ACAGCAAC GGUUCCCU______ 1506 UGAGAGGG CUGAUGAG X 2678 CUGUUGGUU 3817 CGAA ACCAACAG CCCUCUCA______ 1507 CUGAGAGG CUGAUGAG X 2679 UGUUGGUUC 3818 CGAA AACCAACA CCUCUCAG______ 1511 GAAUCUGA CUGAUGAG X 2680 GGUUCCCUC 3819 CGAA AGGGAACC UCAGAUUC______ 1513 CUGAAUCU CUGAUGAG X 2681 UUCCCUCUC 3820 CGAA AGAGGGAA AGAUUCAG 1518 AGUUACUG CUGAUGAG X 2682 UCUCAGAUU 3821 CGAA AUCUGAGA CAGUAACU 1519 UAGUUACU CUGAUGAG X 2683 CUCAGAUUC 3822 CGAA AAUCUGAG AGUAACUA 1523 AAAAUAGU CUGAUGAG X 2684 GAUUCAGUA 3823 CGAA ACUGAAUC ACUAUUUU______ 1527 UCUGAAAA CUGAUGAG X 2685 CAGUAACUA 3824 CGAA AGUUACUG UUUUCAGA 1529 GAUCUGAA CUGAUGAG X 2686 GUAACUAUU 3825 AUAGUUAC UUCAGAUC 1530 GGAUCUGA CUGAUGAG X 2687 UAACUAUUU 3826 AAUAGUUA UCAGAUCC WO 99/50403 WO 9950403PCT[US99/06507 156 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1531 GGGAUCUG CUGAUGAG X 2688 AACUAUJUU 3827 CGAA AAAUAGUU CAGAUCCC 1532 CGGGAUCU CUGAUGAG X 2689 ACUAUUUUC 3828 CGAA AAAAUAGU AGAUCCCG 1537 CAGGCCGG CUGAUGAG X 2690 UUUCAGAUC 3829 CGAA AUCUGAAA CCGGCCUG______ 1550 UGAAUAUU CUGAUGAG X 2691 CCUGUGAUU 3830 CGAA AUCACAGG AAUAUUCA 1551 CUGAAUAU CUGAUGAG X 2692 CUGUGAUUA 3831 CGAA AAUCACAG AEJAUUCAG 1554 UUUCUGAA CUGAUGAG X 2693 UGAU)UAAUA 3832 CGAA AUUAAUCA UUCAGAAA 1556 GUUUUCUG CUGAUGAG X 2694 AtJUAAUAUU 3833 CGAA AUAUUAAU CAGAAAAC 1557 GGUUUUCU CUGAUGAG X 2695 UUAAUAUUC 3834 CGAA AAUAUUAA AGAAAACC 1568 GUUACUGU CUGAUGAG X 2696 AAAACCAUC 3835 CGAA AUGGUUUU ACAGUAAC 1574 UUAGGAGU CUGAUGAG X 2697 AUCACAGUA 3836 CGAA ACUGUGAU _____ACUCCUAA 1578 UCUGUUAG CUGAUGAG X 2698 CAGUAACUC 3837 CGAA AGUUACUG CtJAACAGA 1581 AAUUCUGU CUGAUGAG X 2699 UAACUCCUA 3838 CGAA AGGAGUUA 1589 CGGAGGUC CUGAUGAG X 2700 AACAGAAUU 3839 CGAA AUUCUGUU GCUC 1595 UUCUGGCG CUGAUGAG X 2701 AUUGACCUC 3840 CGAA AGGUCAAU CCAA 1623 UAUCCCAC CUGAUGAG X 2702 GGGCGCCUA 3841 CGAA AGGCGCCC GUGGGAUA 1631 UGGAGGCA CUGAUGAG X 2703 AGUGGGAUA 3842 CGAA AUCCCACU UGCCUCCA______ WO 99/50403 WO 9950403PCT/US99/06507 157 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1637 UUAACCUG CUGAUGAG X 2704 AUAUGCCUC 3843 CGAA AGGCAUAU 1CAGGUUAA 1643 CAGGAUUU CUGAUGAG X 2705 CUCCAGGUU 3844 CGAA ACCUGGAG AAAUCCUG 1644 ACAGGAUU CUGAUGAG X 2706 UCCAGGUUA 3845 CGAA AACCUGGA AAUCCUGU 1648 CAAAACAG CUGAUGAG X 2707 GGUUAAAUC 3846 CGAA AUUUAACC CUGUUUUG 1653 AUAUUCAA CUGAUGAG X 2708 AAUCCUGUU 3847 CGAA ACAGGAUU IUUGAAUAU 1654 UAUAUUCA CUGAUGAG X 2709 AUCCUGUUU 3848 AACAGGAU UGAAUAUA 1655 GUAUAUUC CUGAUGAG X 2710 UCCUGUUUU 3849 CGAA AAACAGGA IGAAUAUAC 1660 UAGCAGUA CUGAUGAG X 2711 UUUUGAAUA 3850 CGAA AUUCAAAA UACUGCUA 1662 GUUAGCAG CUGAUGAG X 2712 UUGAAUAUA 3851 CGAA AUAUUCAA CUGCUAAC 1668 AGCGGGGU CUGAUGAG X 2713 AUACUGCUA 3852 CGAA AGCAGUAU ACCCCGCU 1680 AGGAUUAU CUGAUGAG X 2714 CCGCUGGUU 3853 CGAA ACCAGCGG AUAAUCCU 1681 AAGGAUUA CUGAUGAG X 2715 CGCUGGUUA 3854 AACCAGCG UAAUCCUU 1683 UGAAGGAU CUGAUGAG X 2716 CUGGUUAUA 3855 CGAA AUAACCAG AIJCCUUCA 1686 UAUUGAAG CUGAUGAG X 2717 GUUAUAAUC 3856 CGAA AUUAUAAC CUUCAAUA 1689 UGAUAUUG CUGAUGAG X 2718 AUAAUCCUU 3 857 AGGAUUAU CAAUAUCA 1690 UUGAUAUU CUGAUGAG X 2719 UAAUCCUUC 3858 AAGGAUUA AAUAUCAA WO 99/50403 WO 9950403PCTIUS99/06507 158 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1694 ACAAUUGA CUGALJGAG X 2720 CCUUCAAUA 3859 CGAA AUEJGAAGG UCAAUUGU 1696 CCACAAUU CUGALJGAG X 2721 UtJCAAUAUC 3860 CGAA AUAUUGAA AAUUGUGG 1700 GUGCCCAC CUGAUGAG X 2722 AUAUCAAUU 3861 CGAA AUUGAUAU GUGGGCAC 1712 UCAGCUUC CUGAUGAG X 2723 GGCACACUU 3862 CGAA AGUGUGCC GAAGCUGA 1738 AUAGCCCA CUGAUGAG X 2724 AAGAAAAUC 3863 CGAA AUUUUCUU UGGGCUAU 1745 CUUGAGGA CUGAUGAG X 2725 UCUGGGCUA 3864 CGAA AGCCCAGA UJCCUCAAG 1747 CUCUUGAG CUGAUGAG X 2726 UGGGCUAUC 3865 CGAA AUAGCCCA CUCAAGAG 1750 GAACUCUU CUGAUGAG X 2727 GCUAUCCUC 3866 CGAA AGGAUAGC AAGAGUUC 1757 CGAAACUG CUGAUGAG X 2728 UCAAGAGUU 3867 CGAA ACUCUUGA CAGUUUCG 1758 UCGAAACU CUGAUGAG X 2729 CAAGAGUUC 3868 CGAA AACUCUUG AGUUUCGA 1762 GGUUUCGA CUGAUGAG X 2730 AGUUCAGUU 3869 ACUGAACU UCGAAACC______ 1763 UGGUUUCG CUGAUGAG X 2731 GUUCAGUUU 3870 AACUGAAC CGAAACCA______ 1764 UUGGUUUC CUGAUGAG X 2732 UUCAGUUUC 3871 CGAA AAACUGAA GAAACCAA______ 1776 GGGCUCAG CUGAUGAG X 2733 ACCAAGGUU 3872 ACCUUGGU CUGAGCCC______ 1777 UGGGCUCA CUGAUGAG X 2734 CCAAGGUUC 3873 CGAA ACCUUGG UGAGCCCA 1789 CUUGAGUA CUGAUGAG X 2-735 GCCCAAAUA 3874 AUUUGGGC UACUCAAG WO 99/50403 WO 9950403PCTIUS99/06507 159 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1791 UUCUUGAG CUGAUGAG X 2736 CCAAAUAUA 3875 AUAEJUUGG CUCAAGAA 1794 EAGUUCUU CUGAUGAG X 2737 AAUAUACUC 3876 AGUJAUAUU IAAGAACUA 1802 UUCAGAGU CUGAUGAG X 2738 CAAGAACUA 3877 CGAA AGUUCUUG ACUCUGAA 1806 CCUCUUCA CUGAUGAG X 2739 AACUJAACUC 3878 CGAA AGUUAGUU UGAAGAGG 1853 UUAUCCUG CUGAUGAG X 2740 CUGUGGCUA 3879 CGAA AGCCACAG CAGGAUAA 1860 UCUGAUAU CUGAUGAG X 2741 UACAGGAUA 3880 CGAA AUCCUGUA AUAUCAGA 1863 AUCUCUGA CUGAUGAG X 2742 AGGAUAAUA 3881 CGAA AUUAUCCU UCAGAGAU 1865 UUAUCUCU CUGAUGAG X 2743 GAUAAUAUC 3882 CGAA AUAUUAUC AGAGAUAA 1872 ACGCAGUU CUGAUGAG X 2744 UCAGAGAUA 3883 CGAA AUCUCUGA AACUGCGU 1881 GGGAAUGG CUGAUGAG X 2745 AACUGCGUC 3884 CGAA ACGCAGUU CCAUUCCC 1886 GUUAUGGG CUGAUGAG X 2746 CGUCCCAUJ 3885 CGAA AUGGGACG CCCAUAAC 1887 AGUUAUGG CUGAUGAG X 2747 GUCCCAUUC 3886 AAUGGGAC CCAUAACU 1892 GAGGCAGU CUGAUGAG X 2748 AUUCCCAUA 3887 AUGGGAAU ACUGCCUC 1900 UCUCCACU CUGAUGAG X 2749 AACUGCCUC 3888 CGAA AGGCAGUU AGUGGAGA 1910 GGCUCUUG CUGAUGAG X 2750 GUGGAGAUC 3889 AUCUCCAC CAAGAGCC 1924 GCCUACGA CUGAUGAG X 2751 GCCAAGCUC 3890 AGCUUGGC UCGUAGGC WO 99/50403 WO 9950403PCTIUS99/06507 160 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

1926 UCGCCUAC CUGAUGAG X 2752 CAAGCUCUC 3891 CGAA AGAGCUUG GUAGGCGA 1929 CACUCGCC CUGAUGAG X 2753 GCUCUCGUA 3892 CGAA ACGAGAGC GGCGAGUG 1941 UGGAAGUG CUJGAUGAG X 2754 GAGUGAAUU 3893 CGAA AUUCACUC CACUUCCA 1942 CUGGAAGU CUGAUGAG X 2755 AGUGAAUUC 3894 CGAA AAUUCACU IACUUCCAG 1946 ACUUCUGG CUGAUGAG X 2756 AAUUCACUU 3895 CGAA AGUGAAUU CCAGAAGU 1947 AACUUCUG CUGAUGAG X 2757 AUUCACUUC 3896 CGAA AAGUGAAU CAGAAGUU 1955 AUUGGAAG CUGAUGAG X 2758 CCAGAAGUU 3897 CGAA ACUUCUGG CUUCCAAU______ 1956 AAUUGGAA CUGAUGAG X 2759 CAGAAGUUC 3898 CGAA AACUUCUG IUUCCAAUU 1958 AGAAUUGG CUGAUGAG X 2760 GAAGUUCUU 3899 CGAA AGAACUUC CCAAUUCU 1959 CAGAAUUG CUGAUGAG X 2761 AAGUUCUUC 3900 AAGAACUU 1964 GAAUUCAG CUGAUGAG X 2762 CUUCCAAUU 3901 CGAA AUUGGAAG 1965 UGAAUUCA CUGAUGAG X 2763 UtJCCAAUUC 3902 CGAA AAUUGGAA _____UGAAUUCA 1971 UUCAUCUG CUGAUGAG X 2764 UUCUGAAUU 3903 CGAA AUUCAGAA CAGAUGAA 1972 GUUCAUCU CUGAUGAG X 2765 UCUGAAUUC 3904 CGAA AAUUCAGA AGAUGAAC 1992 AUCAAUAU CUGAUGAG X 2766 AGACAGCUC 3905 CGAA AGCUGUCU AUAUUGAU 1995 AACAUCAA CUGAUGAG X 2767 CAGCUCAUA 3906 CGAA AUGAGCUG UtJGAUGUU WO 99/50403 WO 9950403PCTIUS99/06507 3 0 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

1997 UGAACAUC CUGAUGAG X 2768 GCUCAUAUU 3907 CGAA AUAUGAGC GAUGUUCA 2003 AAGAAGUG CUGAUGAG X 2769 AUUGAUGUU 3908 CGAA ACAUCAAU -CACUUCUU 2004 tJAAGAAGU CUGAUGAG X 2770 UUGAUGUUC 3909 CGAA AACAUCAA ACUUCUUA 2008 CUUUUAAG CUGAUGAG X 2771 UGUUCACUU 3910 CGAA AGUGAACA CEJUAAAAG 2009 UCUUUUAA CUGAUGAG X 2772 GUUCACUUC 3911 CGAA AAGUGAAC UUAAAAGA 2011 CCUCUUUU CUGAUGAG X 2773 UCACUUCUU 3912 CGAA AGAAGUGA AAAAGAGG 2012 CCCUCUUU CUGAUGAG X 2774 CACUUCUUA 3913 AAGAAGUG AAAGAGGG 2039 CUGUUACA CUGAUGAG X 2775 GACAAUGUA 3914 ACAUUGUC UGUAACAG 2043 GUUGCUGU CUGAUGAG X 2776 AUGUAUGUA 3915 ACAUACAU ACAGCAAC 2054 UCUAGUUU CUGAUGAG X 2777 AGCAACCUU 3916 AGGUUGCU AAACUAGA 2055 UUCUAGUU CUGAUGAG X 2778 GCAACCUUA 3917 AAGGUUGC AACUJAGAA 2060 tJUAUAUUC CUGAUGAG X 2779 CUUAAACUA 3918 AGUUUAAG GAAUAUAA 2065 AAAAUUUA CUGAUGAG X 2780 ACUAGAAJA 3919 CGAA AUUCUAGU UAAAUUUU 2067 GCAAAAUU CUGAUGAG X 2781 UAGAAUAUA 3920 CGAA AUAUUCUA AAUUUUGC 2071 GGGUGCAA CUGAUGAG X 2782 AUAUAAAUU 3921 AUUUAUAU UUGCACCC 2072 CGGGUGCA CUGAUGAG X 2783 UAUAAAUUU 3922 AAUUUAUA UGCACCCG WO 99150403 WO 9950403PCTIUS99/06507 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

2073 UCGGGUGC CUGAUGAG X 2784 AUAAAUUUU 3923 CGAA AAAUUUAU GCACCCGA 2091 UUUGEJCUU CUGAUGAG X 2785 AAGGAAAUC 3924 CGAA AUUUCCUU AAGACAAA 2101 AAUAAGAA CUGAUGAG X 2786 AGACAAAUU 3925 CGAA AUUUGUCU UUCUUAUU 2102 AAAUAAGA CUGAUGAG X 2787 GACAAAUUU 3926 AAUUUGUC IUCUUAUUU 2103 UAAAUAAG CUGAUGAG X 2788 ACAAAUUUU 3927 CGAA AAAUUUGU CUUAUUUA 2104 GUAAAUAA CUGAUGAG X 2789 CAAAUUUUC 3928 CGAA AAAAUUUG- UUAUUUAC 2106 UGGUAAAU CUGAUGAG X 2790 AAUUUUCUU 3929 CGAA AGAAAAUU AUUUACCA 2107 UUGGUAAA CUGAUGAG X 2791 AUUUUCUUA 3930 CGAA AAGAAAAU UUUACCAA 2109 AAUUGGUA CUGAUGAG X 2792 UUUCUUAUU 3931 AUAAGAAA UACCAAUU 2110 GAAUUGGU CUGAUGAG X 2793 UUCUUAUUU 3932 C-GAA AAUAAGAA ACCAAUUC 2111 UGAAUUGG CUGAUGAG X 2794 UCUUAUUUA 3933 CGAA AAAUAAGA CCAAUUCA 2117 CCUUUUUG CUGAUGAG X 2795 UUACCAAUU 3934 CGAA AUUGGUAA ICAAAAAGG 2118 ACCUUUUU CUGAUGAG X 2796 UACCAAUUC 3935 CGAA AAUUGGUA AAAAAGGU 2129 AGUUCUGG CUGAUGAG X 2797 AAAGGUGUA 3936 ACACCUUU CCAGAACU 2138 UUUAGAAC CUGAUGAG X 2798 CCAGAACUA 3937 CGAA AGUUCUGG GUUCUAAA 2141 UCUUUUAG CUGAUGAG X 2799 GAACUAGUU 3938 -CGAA ACUAGUUC CUAAAAGA WO 99/50403 WO 9950403PCTIUS99/06507 163 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

2142 AUCIJUUUA CUGAUGAG X 2800 AACUAGUUC 3939 CGAA AACUAGUU UAAAAGAU 2144 UGAUCUJUU CUGAUGAG X 2801 CUAGUUCUA 3940 CGAA AGAACUAG AAAGAUCA 2151 AUCCUUCU CUGAUGAG X 2802 UAAAAGAUC 3941 CGAA AUCUUUUA AGAAGGAU 2160 UAAAGCAA CUGAUGAG X 2803 AGAAGGAUA 3942 CGAA AUCCUUCU UUGCUUUA 2162 UCUAAAGC CUGAUGAG X 2804 AAGGAUAUU 3943 CGAA AUAUCCUU GCUUUAGA 2166 UAUUUCUA CUGAUGAG X 2805 AUAUUGCUU 3944 CGAA AGCAAUAU UAGAAAUA 2167 UUAUUUCU CUGAUGAG X 2806 UAUUGCUUU 3945 CGAA AAGCAAUA IAGAAAUAA 2168 GUUAUUUC CUGAUGAG X 2807 AUUGCUUUA 3946 CGAA AAAGCAAU GAAAUAAC 2174 GUCACUGU CUGAUGAG X 2808 UUAGAAAUA 3947 CGAA AUUUCUAA ACAGUGAC 2193 UGGGUUGG CUGAUGAG X 2809 ACAGCCCUU 3948 AGGGCUGU CCAACCCA 2194 UUGGGUUG CUGAUGAG X 2810 CAGCCCUUC 3949 AAGGGCUG CAACCCAA 2208 UUUUGUGG CUGAUGAG X 2811 CAAGGAAUC 3950 AUUCCUUG CCACAAAA 2241 AAUCAGUU CUGAUGAG X 2812 AUGAGGCUA 3951 AGCCUCAU AACUGAUU 2249 AACGUUGC CUGAUGAG X 2813 AAACUGAUU 3952 AUCAGUUU GCAACGUU 2257 UGUCUGGA CUGAUGAG X 2814 UGCAACGUU 3953 ACGUUGCA UCCAGACA 2258 GUGUCUGG CUGAUGAG X 2815 GCAACGUUU 3954 AACGUUGC CCAGACAC WO 99/50403 WO 9950403PCTIUS99/06507 164 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

2259 AGUGUCUG CUGAUGAG X 2816 CAACGUUUC 3955 AAACGUUG CAGACACU 2268 AUAGGUUA CUGAUGAG X 2817 CAGACACUU 3956 CGAA AGUGUCUG UAACCUAU 2269 AAUAGGUU CUGAUGAG X 2818 AGACACUUU 3957 CGAA AAGUGUCU AACCUAUU 2270 GAAUAGGU CUGAUGAG X 2819 GACACUUUA 3958 CGAA AAAGUGUC ACCUAUUC 2275 AUGCAGAA CUGAUGAG X 2820 UUUAACCUA 3959 CGAA AGGUUAAA UUCUGCAU 2277 AUAUGCAG CUGAUGAG X 2821 UAACCUAUU 3960 CGAA AUAGGUUA CUGCAUAU 2278 UAUAUGCA CUGAUGAG X 2822 AACCUAUUC 3961 CGAA AAUAGGUU UGCAUAUA 2284 GUUCUCUA CUGAUGAG X 2823 UUCUGCAUA 3962 AUGCAGAA UAGAGAAC 2286 CAGUUCUC CUGAUGAG X 2824 CUGCAUAUA 3963 CGAA AUAUGCAG GAGAACUG 2301 CUCAGGGA CUGAUGAG X 2825 UGAGGGCUU 3964 CGAA AGCCCUCA UCCCUGAG 2302 UCUCAGGG CUGAUGAG X 2826 GAGGGCUUU 3965 CGAA AAGCCCUC CCCUGAGA 2303 UUCUCAGG CUGAUGAG X 2827 AGGGCUUUC 3966 AAAGCCCU CCUGAGAA 2317 CACAACUC CUGAUGAG X 2828 GAAACAGUU 3967 ACUGUUUC GAGUUGUG 2322 GGCAACAC CUGAUGAG X 2829 AGUUGAGUU 3968 ACUCAACU GUGUUGCC 2327 UGGUUGGC CUGAUGAG X 2830 AGUUGUGUU 3969 ACACAACU GCCAACCA 2344 CAGCUUGC CUGAUGAG X 2831 GAAUGGCUC 3970 AGCCAUUC -GCAAGCUG WO 99/50403 WO 9950403PCTIUS99/06507 165 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

2363 GGAUUUCC CUGAUGAG X 2832 UGUGAGGUC 3971 CGAA AGCUCACA GGAAAUCC 2370 UUUAAAAG CUGAUGAG X 2833 UCGGAAAUC 3972 CGAA AUUUCCGA CUUUUAAA 2373 UCUUUUAA CUGAUGAG X 2834 GAAAUCCUU 3973 CGAA AGGAUUUC UUAAAAGA 2374 UUCUUUUA CUGAUGAG X 2835 AAAUCCUUU 3974 CGAA AAGGAUUU UAAAAGAA 2375 UUUCUUUU CUGAUGAG X 2836 AAUCCUUUU 3975 AAAGGAUU AAAAGAAA 2376 AUUUCUUU CUGAUGAG X 2837 AUCCUUUUA 3976 AAAAGGAU AAAGAAAU 2385 GACAUUUG CLJGAUGAG X 2838 AAAGAAAUU 3977 AUUUCUUU CAAAUGUC 2386 UGACAUUU CUGAUGAG X 2839 AAGAAAUUC 3978 CGAA AAUUUCUU AAAUGUCA 2393 UAAAAAGU CUGAUGAG X 2840 UCAAAUGUC 3979 CGAA ACAUUUGA ACUUUUUA 2397 CAAAUAAA CUGAUGAG X 2841 AUGUCACUU 3980 CGAA AGUGACAU UUUAUUUG 2398 CCAAAtJAA CUGAUGAG X 2842 UGUCACUUU 3981 CGAA AAGUGACA UUAUUUGG 2399 ACCAAAUA CUGAUGAG X 2843 GUCACUUUU 3982 AAAGUGAC _____UAUUUGGU 2400 AACCAAAJ CUGAEJGAG X 2844 UCACUUUUU 3983 CGAA AAAAGUGA AUUUGGUU 2401 AAACCAAA CUGAUGAG X 2845 CACUUUUUA 3984 CGAA AAAAAGUG UUUGGUUU 2403 UAAAACCA CUGAUGAG X 2846 CUUUUUAUU 3985 CGAA AUAAAAAG UGGUUUUA 2404 UUAAAACC CUGAUGAG X 2847 UUUUUAUUU 3986 AAUAAAAA GGUUUUAA WO 99/50403 WO 9950403PCT/US99/06507 166 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2408 GLJACUUAA CUGAUGAG X 2848 UAUUUGGUU 3987 ACCAAAUA UUAAGUAC 2409 UGUACtJUA CUGAUGAG X 2849 AUUUGGUUU 3988 CGAA AACCAAAU

UAAGUACA

2410 UUGUACUU CUGAUGAG X 2850 UUUGGUUUU 3989 CGA1A AAACCAAA

AAGUACAA

2411 GUUGUACU CUGAUGAG X 2851 UUGGUUUUA 3990 CGAA AAAACCAA

AGUACAAC

2415 UUCAGUUG CUGAUGAG X 2852 UUUUAAGUA 3991 CGAA ACUUAAAA

CAACUGAA

2426 UCAAAGGU CUGAUGAG X 2853 ACUGAAGUC 3992 ACUUCAGU

ACCUUUGA

2431 GGGUGUCA CUGAUGAG X 2854 AGUCACCUU 3993 AGGUGACU UGACACCC 2432 GGGGUGUC CUGAUGAG X 2855 GUCACCUUU 3994 AAGGUGAC GACACCCC 2443 UAUCCAGA CUGAUGAG X 2856 CACCCCAUA 3995 AUGGGGUG UCUGGAUA 2445 AAUAUCCA CUGAUGAG X 2857 CCCCAUAUC 3996 CGAA AUAUGGGG

UGGAUAUU

2451 CAGAUUAA CUGAUGAG X 2858 AUCUGGAUA 3997 CGAA AUCCAGAU UUAAUCUG 2453 UUCAGAUU CUGAUGAG X 2859 CUGGAUAUU 3998 CGAA AUAUCCAG

AAUCUGAA

2454 CUUCAGAU CUGAUGAG X 2860 UGGAUAUUA 3999 AAUAUCCA AUCUGAAG 2457 UAACUUCA CUGAUGAG X 2861 AUAUUAAUC 4000 AUUAAUAU UGAAGUUA 2464 UUGUUUCU CUGAUGAG X 2862 UCUGAAGUU 4001 ACUUCAGA AGAAACAA 2465 GUUGUUUC CUGAUGAG X 2863 CUGAAGUUA 4002 CGAA AACUUCAG fGAAACAAC WO 99/50403 WO 9950403PCT[US99/06507 167 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2481 AUUAUCtJU CUGAtJGAG X 2864 CAAGCAAJC 4003 CGAA AUUGCUUG AAGAUAAU 2487 AGCCAAAU CUGAUGAG X 2865 AUCAAGAUA 4004 AUCEJUGAU AUUUGGCU 2490 UGGAGCCA CUGAUGAG X 2866 AAGAUAAUU 4005 CGAA AUUAUCUU UGGCUCCA 2491 UUGGAGCC CUGAUGAG X 2867 AGAUAAUUU 4006 CGAA AAUUAUCtJ GGCUCCAA 2496 UGUAAUUG CUGAUGAG X 2868 AUUUGGCUC 4007 AGCCAAAU CAAUUACA 2501 LIUAGCUGU CUGAUGAG X 2869 GCEJCCAAUU 4008 CGAA AUUGGAGC ACAGCUAA 2502 UUUAGCUG CUGAEJGAG X 2870 CUCCAAUUA 4009 CGAA AAUUGGAG CAGCUAAA 2508 UUUUGCUU CUGAUGAG X 2871 UUACAGCUA 4010 CGAA AGCUGUAA AAGCAAAA 2522 AGUUCAAU CUGAUGAG X 2872 AAAGUGGUU 4011 CGAA ACCACUUU AUUGAACU 2523 CAGUUCAA CUGAUGAG X 2873 AAGUGGUUA 4012 CGAA AACCACUU UUGAACUG 2525 AGCAGUUC CUGAUGAG X 2874 GUGGUUAUU 4013 CGAA AUAACCAC GAACUGCU 2534 ACCGAUAA CUGAUGAG X 2875 GAACUGCUU 4014 CGAA AGCAGUUC UUAUCGGU 2535 GACCGAUA CUGAUGAG X 2876 AACUGCUUU 4015 CGAA AAGCAGUU UAUCGGUC 2536 AGACCGAU CUGAUGAG X 2877 ACUGCUUUU 4016 CGAA AAAGCAGU AUCGGUCU 2537 GAGACCGA CUGAUGAG X 2878 CUGCUUUUA 4017 CGAA AAAAGCAG UCGGUCUC______ 2539 CCGAGACC CUGAUGAG X 2879 GCUUUUAUC 4018 CGAA AUAAAAGC ______GGUCUCGG WO 99/50403 WO 9950403PCTIUS99/06507 168 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

2543 ACUCCCGA CEJGAEJGAG X 2880 UUAUCGGUC 4019 CGAA ACCGAUAA UCGGGAGU 2545 CAACUCCC CUCAUGAG X 2881 AUCGGUCUC 4020 CGAA AGACCGAU GGGAGUUG______ 2552 GGUUUAGC CUGAUGAG X 2882 UCGGGAGUU 4021 ACUCCCGA GCUAAACC 2556 GGAAGGUU CUGAUGAG X 2883 GAGUUGCUA 4022 CGAA AGCAACUC AACCUUCC 2562 CACCUGGO CUGAUGAG X 2884 CUAAACCUU 4023 AGGUUUAG CCCAGGUG 2563 ACACCUGG CUGAUGAG X 2885 UAAACCUUC 4024 CGAA AAGGUUUA CCAGGUGU 2572 CUCCAAAA CUGAUGAG X 2886 CCAGGUGUA 4025 ACACCUGG UUEJUGGAG 2574 ACCUCCAA CUGAUGAG X 2887 AGGUGUAUU 4026 CGAA AUACACCU UUGGAGGU 2575 UACCUCCA CUGAUGAG X 2888 GGUGUAUUU 4027 CGAA AAUACACC IUGGAGGUA 2576 GUACCUCC CUGAUGAG X 2889 GUGUAUUUU 4028 CGAA AAAUACAC GGAGGUAC 2583 AACAACUG CUGAUGAG X 2890 UUGGAGGUA 4029 ACCUCCAA ICAGUUGUU 2588 UCGCCAAC CUGAUGAG X 2891 GGUACAGUU 4030 CGAA ACUGUACC GUEJGGCGA 2591 UGCUCGCC CUGAUGAG X 2892 ACAGUUGUU 4031 CGAA ACAACUGU GGCGAGCA 2604 AGAUUUCA CUGAUGAG X 2893 AGCAAGCUA 4032 CGAA AGCUUGCU UGAAAUCU 2611 CAUCUUCA CUGAUGAG X 2894 UAUGAAAUC 4033 CGAA AUUUCAUA UGAAGAUG 2631 CUCUAUUA CUGAUGAG X 2895 UGGGAAGUU 4034 CGAA ACUUCCCA UAAUAGAG WO 99/50403 WO 9950403PCTIUS99/06507 169 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2632 ACUCUAUU CUGAUGAG X 2896 GGGAAGUUU 4035 CGAA AACUUCCC AAtJAGAGU 2633 UACUCUAU CUGAUGAG X 2897 GGAAGUUUA 4036 AAACUUCC AUAGAGUA 2636 UCAUACUC CUGAUGAG X 2898 AGUUUAAUA 4037 CGAA AUUAAACU GAGUAUGA 2641 UGAAUUCA CUGAUGAG X 2899 AAUAGAGUA 4038 CGAA ACUCUAUU UGAAUUCA 2647 UUACCCUG CUGAUGAG X 2900 GUAUGAAUU 4039 CGAA AUUCAUAC CAGGGUAA 2648 AUUACCCU CUGAUGAG X 2901 UAEJGAAUUC 4040 CGAA AAUUCAUA AGGGUAAU 2654 AAGUUUAU CUGAUGAG X 2902 UUCAGGGUA 4041 CGAA ACCCUGAA AUAAACUU 2657 CCUAAGUU CUGAtJGAG X 2903 AGGGUAAUA 4042 CGAA AUUACCCU IAACUUAGG 2662 GUUUACCU CUGAUGAG X 2904 AAtJAAACUU 4043 AGUUUAUU AGGUAAAC 2663 GGUUUACC CUGAUGAG X 2905 AUAAACUUA 4044 CGAA AAGUUUAU GGUAAACC 2667 AAGAGGUU CUGAUGAG X 2906 ACEJUAGGUA 4045 CGAA ACCUAAGU AACCUCUU 2673 GUUUGUAA CUGAUGAG X 2907 GUAAACCUC 4046 CGAA AGGUUUAC UUACAAAC 2675 AGGUUUGU CUGAUGAG X 2908 AAACCUCUU 4047 CGAA AGAGGUUU ACAAACCU 2676 GAGGUUUG CUGAUGAG X 2909 AACCUCUUA 4048 AAGAGGUU CAAACCUC 2684 GCUGUGCC CUGAUGAG X 2910 ACAAACCOC 4049 AGGUUUGU GGCACAGC 2698 GAAUGUUC CUGAUGAG X 2911 AGCAACCUU 4050 AGGUUGCU I GAACAUUC I WO 99/50403 WO 9950403PCTIUS99/06507 170 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2705 GGCCACUG CUGAUGAG X 2912 UUGAACAUU 4051 CGAA AUGUUCAA CAGUGGCC 2706 UGGCCACU CUGAUGAG X 2913 LGAACAUUC 4052 CGAA AAUGUUCA AGUGGCCA 2723 CCAUUGCU CUGAUGAG X 2914 AAAGAAAUU 4053 CGAA AUUUCUUU AGCAAUGG 2724 CCCAUUGC CUGAUGAG X 2915 AAGAAAUUA 4054 CGAA AAUUUCUU GCAAUGGG 2740 AAUAAAGC CUGAUGAG X 2916 GAAAUGGUU 4055 CGAA ACCAUUUC IGCUUUAUU 2744 ACCAAAUA CUGAUGAG X 2917 UGGUUGCUU 4056 CGAA AGCAACCA UAUUUGGU 2745 CACCAAAU CUGAUGAG X 2918 GGUUGCUUU 4057 CGAA AAGCAACC AUUUGGUG 2746 UCACCAAA CUGAUGAG X 2919 GUUGCUUUA 4058 CGAA AAAGCAAC _____UUUGGUGA 2748 UUUCACCA CUGAUGAG X 2920 UGCUUUAUU 4059 CGAA AUAAAGCA UGGUGAAA 2749 CUUUCACC CUGAUGAG X 2921 GCUUUAUUU 4060 CGAA AAUAAAGC GGUGAAAG 2759 UUGGAUUC CUGAUGAG X 2922 GUGAAAGUA 4061 CGAA ACUUUCAC _____GAAUCCAA 2764 AUCCUUUG CUGAUGAG X 2923 AGUAGAAUC 4062 CGAA AUUCUACU CAAAGGAU 2773 CCUUUUCC CUGAUGAG X 2924 CAAAGGAUU 4063 CGAA AUCCUUUG IGGAAAAGG 2783 UCACAAGU CUGAUGAG X 2925 GAAAAGGUA 4064 CGAA ACCUUUUC _____ACUUGUGA 2787 UGGCUCAC CUGAUGAG X 2926 AGGUAACUU 4065 CGAA AGUUACCU IGUGAGCCA 2807 AGGGAGUU CUGAUGAG X 2927 AAGGAGAUA 4066 CGAA AUCUCCUU AACUCCCU I WO 99/50403 WO 9950403PCTIUS99/06507 171 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

2812 GGUUCAGG CUGAUGAG X 2928 GAUAAACUC 4067 CGAA AGUUUAUC CCIJGAACC 2822 GACUCCGU CUGAUGAG X 2929 CUGAACCUA 4068 CGAA AGGUUCAG ACGGAGUC 2830 AGUUGUGA CUGAUGAG X 2930 AACGGAGUC 4069 CGAA ACEJCCGUU UCACAACU 2832 UGAGUUGU CUGAUGAG X 2931 CGGAGUCUC 4070 CGAA AGACUCCG ACAACUCA 2839 UCUUUCUU CUGAUGAG X 2932 UCACAACUC 4071 CGAA AGUUGUGA AAGAAAGA 2858 UUUUCAGU CUGAUGAG X 2933 CGGGAAAUU 4072 CGAA AUUUCCCG ACUGAAAA 2859 UUUUUCAG CUGAUGAG X 2934 GGGAAAUUA 4073 CGAA AAUUUCCC CUGAAAAA 2873 UUAUCAUC CUGAUGAG X 2935 AAACAGAUA 4074 CGAA AUCUGUUU GAUGAUAA 2880 UUUUCUGU CUGAUGAG X 2936 UAGAUGAUA 4075 CGAA AUCAUCUA ACAGAAAA 2890 AUAAAGAA CUGAUGAG X 2937 CAGAAAAUU 4076 AUUUUCUG UUCUUUAU 2891 AAUAAAGA CUGAUGAG X 2938 AGAAAAUUU 4077 CGAA AAUUUUCU UCUUUAUU 2892 AAAUAAAG CUGAUGAG X 2939 GAAAAUUUU 4078 CGAA AAAUUUUC CUUUAUUU______ 2893 CAAAUAAA CUGAUGAG X 2940 AAAAUUUUC 4079 CGAA AAAAUJUUU IUUUAUUUG______ 2895 AGCAAAUA CUGAUGAG X 2941 AAUUUUCUU 4080 CGAA AGAAAAUU 2896 CAGCAAAU CUGAUGAG X 2942 AUUUUCUUU 4081 CGAA AAGAAAAUJ AUUUGCUG 2897 UCAGCAAA CUGAUGAG X 2943 UUUUCUUUA 4082 CGAA AAAGAAAA UUUGCUGA WO 99/50403 WO 9950403PCTIUS99/06507 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

2899 UUtJCAGCA CUGAUGAG X 2944 UUCUUUAUU 4083 AUAAAGAA IUGCUGAAA 2900 CUUUCAGC CUGAUGAG X 2945 UCUUUAUUU 4084 CGAA AAUAAAGA GCUGAAAG 2914 GAGUCUGG CUGAUGAG X 2946 AAGAAAAUA 4085 CGAA AUUUUCUU CCAGACUC 2922 ACAGUUAA CUGAUGAG X 2947 ACCAGACUC 4086 CGAA AGUCUGGU UUAACUGU 2924 CUACAGUU CUGAUGAG X 2948 CAGACUCUU 4087 AGAGUCUG AACUGUAG 2925 GCUACAGU CUGAUGAG X 2949 AGACUCUUA 4088 AAGAGUCU ACUGUAGC 2931 GUUCACGC CUGAUGAG X 2950 UUAACUGUA 4089 ACAGU.UAA GCGUGAAC 2957 GGGCAUCU CUGAUGAG X 2951 GUGAACAUC 4090 CGAA AUGUUCAC AGAUGCCC 2992 AAAUAAGA CUGAUGAG X 2952 CAAGGCGUC 4091 ACGCCUUG UCUUAUUU 2994 CAAAAUAA CUGAUGAG X 2953 AGGCGUCUC 4092 CGAA AGACGCCU UUAUUUUG 2996 CGCAAAAU CUGAUGAG X 2954 GCGUCUCUU 4093 AGAGACGC _____AUUUUGCG 2997 GCGCAAAA CUGAUGAG X 2955 CGUCUCUUA 4094 CGAA AAGAGACG _____UUUUGCGC 2999 GAGCGCAA CUGAUGAG X 2956 UCUCUUAUU 4095 CGAA AUJAAGAGA _____UIJGCGCUC 3000 CGAGCGCA CUGAUGAG X 2957 CUCUUAUUU 4096 CGAA AAUAAGAG UGCGCUCG 3001 UCGAGCGC CUGAUGAG X 2958 UCUUAUUUU 4097 CGAA AAAUAAGA GCGCUCGA 3007 AUAACCUC CUGAUGAG X 2959 UUUGCGCUC 4098 CGAA AGCGCAAA lGAGGUUAU WO 99/50403 WO 9950403PCTIUS99/06507 173 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

3013 UGtJUCCAU CUGAUGAG X 2960 CUCGAGGUU 4099 CGAA ACCUCGAG AUGGAACA 3014 CUGUUCCA CUGAUGAG X 2961 UCGAGGUUA 4100 CGAA AACCUCGA UGGAACAG 3028 CCUCUAGA CUGAUGAG X 2962 CAGCACAUU 4101 CGAA AUGUGGUG UCUAGAGG 3029 UCCUCUAG CUGAUGAG X 2963 AGCACAUUU 4102 CGAA AAUGUGCU CUAGAGGA 3030 UUCCUCUA CUGAUGAG X 2964 GCACAUUUC 4103 CGAA AAAUGUGC UAGAGGAA 3032 UAUUCCUC CUGAUGAG X 2965 ACAUUUCUA 4104 CGAA AGAAAUGU IGAGGAAUA 3040 GUUUGGAA CUGAUGAG X 2966 AGAGGAAUA 4105 CGAA AUUCCUCU UUCCAAAC 3042 CAGUUUGG CUGAUGAG X 2967 AGGAAUAUU 4106 CGAA AUAUUCCU ICCAAACUG 3043 UCAGUUUG CUGAUGAG X 2968 GGAAUAUUC 4107 CGAA AAUAUUCC CAAACUGA 3055 UGUCCAAG CUGAUGAG X 2969 ACtJGAACUA 4108 CGAA AGUUCAGU CUUGGACA 3058 GAAUGUCC CUGAUGAG X 2970 GAACUACUU 4109 CGAA AGUAGUUC IGGACAUUC 3065 CGCAUGAG CUGAUGAG X 2971 UUGGACAUU 4110 CGAA AUGUCCAA 3066 UCGCAUGA CUGAUGAG X 2972 UGGACAUUC 4111 CGAA AAUGUCCA UCAUGCGA 3068 GCUCGCAU CUGAUGAG X 2973 GACAUUCUC 4112 AGAAUGUC _____AUGCGAGC 3079 CAUCAAUG CUGAUGAG X 2974 GCGAGCCUU 4113 AGGCUCGC _____CAUUGAUG 3080 ACAUCAAU CUGAUGAG X 2975 CGAGCCUUC 4114 CGAA AAGGCUCG IAUUGAUGU I WO 99/50403 WO 9950403PCTIUS99/06507 174 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3083 GUCACAUC CUGAUGAG X 2976 GCCUUCAUU 4115 CGAA AUGAAGGC GAUGUGAC 3108 CAGCCUGA CUGAUGAG X 2977 CCGAAAAUA 4116 CGAA AUUUUCGG UCAGGCUG 3110 GGCAGCCU CUGAUGAG X 2978 GAAAAUAUC 4117 CGAA AUAUUUUC AGGCUGCC 3132 UCGAACCU CUGAUGAG X 2979 CAGGCACUC 4118 CGAA AGUOCCUG AGGUUCGA 3137 GUCACUCG CUGAUGAG X 2980 ACUCAGGUU 4119 CGAA ACCUGAGU CGAGUGAC 3138 AGUCACUC CUGAUGAG X 2981 CUCAGGUUC 4120 CGAA AACCUGAG GAGUGACU 3151 UUGAGGGA CUGAUGAG X 2982 GACUGUGUU 4121 CGAA ACACAGUC UCCCUCAA 3152 UUUGAGGG CUGAUGAG X 2983 ACUGUGUUU 4122 AACACAGU CCCUCAAA 3153 CUUUGAGG CUGAUGAG X 2984 CUGUGUUUC 4123 CGAA AAACACAG CCUCAAAG 3157 CAGUCUUU CUGAUGAG X 2985 GUUUCCCUC 4124 AGGGAAAC AAAGACUG 3167 UACUGAGC CUGAUGAG X 2986 AAGACUGUA 4125 ACAGUCUU GCUCAGUA 3171 CGAAUACU CUGAUGAG X 2987 CUGUAGCUC 4126 AGCUACAG AGUAUUCG______ 3175 CUCCCGAA CUGAUGAG X 2988 AGCUCAGUA 4127 ACUGAGCU UUCGGGAG 3177 UACUCCCG CUGAUGAG X 2989 CUCAGUAUU 4128 AUACUGAG CGGGAGUA 3178 GUACUCCC CUGAUGAG X 2990 UCAGUAUUC 4129 CGAA AAUACUGA GGGAGUAC 3185 CACCAAGG CUGAUGAG X 2991 UCGGGAGUA 4130 fCGAA ACUCCCGA CCUUGGUG WO 99/50403 WO 9950403PCTIUS99/06507 175 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

3189 GAUCCACC CUGAUGAG X 2992 GAGUACCUU 4131 CGAA AGGUACUC GGUGGAUC 3197 ACUAGGAU CUGAUGAG X 2993 UGGUGGAUC 4132 CGAA AUCCACCA AUCCUAGU 3200 GCCACUAG CUGAUGAG X 2994 UGGAUCAUC 4133 CGAA AUGAUCCA CUAGUGGC 3203 AUAGCCAC CUGAUGAG X 2995 AUCAUCCUA 4134 CGAA AGGAUGAU GUGGCUAU 3210 AGCGAGAA CUGAUGAG X 2996 UAGUGGCUA 4135 CGAA AGCCACUA UUCUCGCU 3212 CCAGCGAG CUGAUGAG X 2997 GUGGCUAUU 4136 CGAA AUAGCCAC CUCGCUGG 3213 CCCAGCGA CUGAUGAG X 2998 UGGCUAUUC 4137 CGAA AAUAGCCA UCGCUGGG 3215 AUCCCAGC CUGAUGAG X 2999 GCUAUUCUC 4138 CGAA AGAAUAGC GCUGGGAU 3224 AGCAUCAA CUGAUGAG X 3000 GCUGGGAUC 4139 CGAA AUCCCAGC IUUGAUGCU 3226 CAAGCAUC CUGAUGAG X 3001 UGGGAUCUU 4140 CGAA AGAUCCCA GAUGCUUG 3233 AAUAAAGC CUGAUGAG X 3002 UUGAUGCJU 4141 CGAA AGCAUCAA GCUUUAUU 3237 CACUAAUA CUGAUGAG X 3003 UGCUUGCUU 4142 CGAA AGCAAGCA 3238 ACACUAAU CUGAUGAG X 3004 GCUUGCUUU 4143 CGAA AAGCAAGC AUGG 3239 AACACUAA CUGAUGAG X 3005 CUUGCUUUA 4144 CGAA AAAGCAAG UAUU 3241 UAAACACU CUGAUGAG X 3006 UGCUUUAUU 4145 CGAA AUAAAGCA AGUGUUUA 3242 AUAAACAC CUGAUGAG X 3007 GCUUUAUUA 4146 ICGAA AAUAAAGC IGUGUUUAU WO 99/50403 WO 9950403PCTIUS99/06507 176 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

3247 AUAGJAtA CUGAUGAG X 3008 AUUAGUGUU 4147 CGAA ACACUAAU UAUACUAU 3248 CAUAGUAU CUGAUGAG X 3009 UUAGUGUUU 4146 CGAA AACACUAA AUACUAUG 3249 CCAUAGUA CUGAUGAG X 3010 UAGUGUUUA 4149 CGAA AAACACUA UACUAUGG 3251 UUCCAUAG CUGAUGAG X 3011 GUGUUUAUA 4150 CGAA AUAAACAC _____CUAUGGAA 3254 CACUUCCA CUGAUGAG X 3012 UUUAUACUA 4151 CGAA AGUAUAAA UGGAAGUG 3267 CUUGAAGA CUGAUGAG X 3013 AGUGUGGUU 4152 CGAA ACCACACU UCUUCAAG 3268 UCUUGAAG CUGAUGAG X 3014 GUGUGGUUU 4153 CGAA AACCACAC CUUCAAGA 3269 CUCUUGAA CUGAUGAG X 3015 UGUGGUUUC 4154 CGAA AAACCACA UUCAAGAG 3271 UUCUCUUG CUGAUGAG X 3016 UGGUUUCUU 4155 CGAA AGAAACCA CAAGAGAA 3272 UUUCUCUU CUGAEJGAG X 3017 GGUUUCUUC 4156 AAGAAACC AAGAGAAA 3282 AUCUUUCU CUGAUGAG X 3018 AGAGAAAUA 4157 CGAA AUUUCUCU AGAAAGAU 3291 AUCAUAAU CUGAUGAG X 3019 AGAAAGAUC 4158 CGAA AUCUUUCU AUUAUGAU______ 3294 GGCAUCAU CUGAUGAG X 3020 AAGAUCAUU 4159 AUGAUCUU AUGAUGCC 3295 UGGCAUCA CUGAUGAG X 3021 AGAUCAUUA 4160 CGAA AAUGAUCU UGAUGCCA 3307 CCUUGUGA CUGAUGAG X 3022 UGCCACAUA 4161 CGAA AUGUGGCA UCACAAGG 3309 AGCCUUGU CUGAUGAG X 3023 CCACAUAUC 4162 ICGAA AUAUGUGG

ACAAGGCU

WO 99/50403 WO 9950403PCTIUS99/06507 177 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

3323 UGAGCAUG CUGAUGAG X 3024 GCUGAGAUC 4163 CGAA AUCUCAGC CAUGCUCA 3330 AGAUGGCU CUGAUGAG X 3025 UCCAUGGUC 4164 CGAA AGCAUGGA AGCCAUCU 3337 CUUUAUCA CUGAUGAG X 3026 UCAGCCAUC 4165 CGAA AUGGCUGA UGAUAAAG 3342 CCUCUCUU CUGAUGAG X 3027 CAUCUGAUA 4166 CGAA AUCAGAUG AAGAGAGG 3353 UCAGAAGU CUGAUGAG X 3028 GAGAGGCUU 4167 CGAA AGCCUCUC ACUUCUGA 3354 AUCAGAAG CUGAUGAG X 3029 AGAGGCUUA 4168 CGAA AAGCCUCU ICUtJCUGAU 3357 UGGAUCAG CUGAUGAG X 3030 GGCUUACUU 4169 CGAA AGUAAGCC CUGAUGCA 3358 AUGCAUCA CUGAUGAG X 3031 GCUUACUUC 4170 CGAA AAGUAAGC UGAUGCAU 3367 AUCAAUAC CUGAUGAG X 3032 UGAUGCAUA 4171 CGAA AUGCAUCA GUAUUGAU 3370 UAGAUCAA CUGAUGAG X 3033 UGCAUAGUA 4172 CGAA ACUAUGCA UUGAUCUA 3372 AGUAGAUC CUGAUGAG X 3034 CAtJAGUAUU 4173 CGAA AUACUAUG GAtJCUACU 3376 CAGAAGUA CUGAUGAG X 3035 GUAUUGAUC 4174 CGAA AUCAAUAC UACUUCUG 3378 UACAGAAG CUGAUGAG X 3036 AUUGAUCUA 4175 CGAA AGAUCAAU CUUCUGUA 3381 AAUUACAG CUGAUGAG X 3037 GAUCUACUU 4176 AGUAGAUC CUGUAAUU______ 3382 CAAUUACA CUGAUGAG X 3038 AUCUACUUC 4177 CGAA AAGUAGAU UGUAAUUG 3386 CACACAAU CUGAUGAG X 3039 ACUUCUGUA 4178 CGAA ACAGAAGU AUUGUGUG WO 99/50403 WO 9950403PCTIUS99/06507 178 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3389 AUCCACAC CUGAUGAG X 3040 UCUGUAAUU 4179 CGAA AUUACAGA GUGUGGAU 3398 GUUUAAAG CtJGAUGAG X 3041 GUGUGGAUU 4180 CGAA AUCCACAC CUUUAAAC 3399 CGUUUAAA CUGAUGAG X 3042 UGUGGAUUC 4181 CGAA AAUCCACA UUUAAACG 3401 AGCGUUUA CUGAUGAG X 3043 UGGAUUCUU 4182 CGAA AGAAUCCA UAAACGCU 3402 GAGCGUUU CUGAUGAG X 3044 GGAUUCUUU 4183 CGAA AAGAAUCC AAACGCUC 3403 AGAGCGUU CUGAUGAG X 3045 GAUUCUrJUA 4184 CGAA AAAGAAUC AACGCUCU 3410 CGUACCUA CUGAUGAG X 3046 UAAACGCUC 4185 CGAA AGCGUUUA UAGGUACG 3412 AUCGUACC CUGAUGAG X 3047 AACGCUCUA 4186 AGAGCGUU GGUACGAU 3416 UGUCAUCG CUGAUGAG X 3048 CUCUAGGUA 4187 CGAA ACCUAGAG CGAUGACA 3429 UAUCGGGG CUGAUGAG X 3049 GACAGUGUU 4188 CGAA ACACUGUC CCCCGAUA 3430 GUAUCGGG CUGAUGAG X 3050 ACAGUGUUC 4189 AACACUGU CCCGAUAC 3437 CAGCAUGG CUGAUGAG X 3051 UCCCCGAUA 4190 AUCGGGGA CCAUGCUG 3447 CGGAUCCU CUGAUGAG X 3052 CAUGCUGUA 4191 ACAGCAUG AGGAUCCG 3453 UCUUUCCG CUGAUGAG X 3053 GUAAGGAUC 4192 AUCCUUAC CGGAAAGA 3474 UCAUCUUU CUGAUGAG X 3054 CGAGAGAUC 4193 AUCUCUCG AAAGAUGA 3488 UAUCAAUA CUGAUGAG X 3055 UGAAAAGUA 4194 CGAA ACUUUUCA ______UAUUGAUA WO 99/50403 WO 9950403PCTIUS99/06507 179 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3490 GUUAUCAA CUGAUGAG X 3056 AAAAGEJAUA 4195 CGAA AUACUUUU UUGAUAAC 3492 AGGUUAUC CUGAUGAG X 3057 AAGUAUAUU 4196 CGAA AUAUACUU GAUAACCU 3496 UUCAAGGJ CUGAUGAG X 3058 ALJAUUGAUA 4197 CGAA AUCAAUAU ACCUUGAA 3501 UUUUUUUC CUGAUGAG X 3059 GAUAACCUU 4198 CGAA AGGUUAUC GAAAAAAA 3519 CACUUUGU CUGAUGAG X 3060 CAGUGGAUC 4199 CGAA AUCCACUG ACAAAGUG 3545 GCUAUGAG CUGAUGAG X 3061 UGAAAGCUA 4200 CGAA AGCUUUCA CtJCAUAGC 3548 CCCGCUAU CUGAUGAG X 3062 AAGCUACUC 4201 AGUAGCUU AUAGCGGG 3551 GCCCCCGC CUGAUGAG X 3063 CUACUCAUA 4202 AUGAGUAG GCGGGGGC 3562 UUUUUUUU CUGAUGAG X 3064 GGGGGCCUA 4203 AGGCCCCC AAAAAAAA 3577 GUACUGUG CUGAUGAG X 3065 AAAAAGCUU 4204 CGAA AGCUUUUU CACAGUAC 3578 GGUACUGU CUGAUGAG X 3066 AAAAGCUUC 4205 CGAA AAGCUUUU ACAGUACC 3584 AGUUUGGG CUGAUGAG X 3067 UUCACAGUA 4206 ACUGUGAA CCCAAACU 3596 GUUGGAAA CUGAUGAG X 3068 AAACUGCUU 4207 AGCAGUUU UUUCCAAC 3597 AGUUGGAA CUGAUGAG X 3069 AACUGCUUU 4208 CGAA AAGCAGUU _____UUCCAACU 3598 GAGUUGGA CUGAUGAG X 3070 ACUGCUUUU 4209 AAAGCAGU _____UCCAACUC 3599 UGAGUUGG CUGAUGAG X 3071 CUGCUUUUU 4210 CGAA AAAAGCAG ICCAACUCA WO 99/50403 WO 9950403PCTIUS99/06507 180 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3600 CUGAGUUG CUGAUGAG X 3072 UGCJ(JLUUC 4211 CGAA AAAAAGCA CAACUCAG 3606 GAAUUUCU CUGAUGAG X 3073 UUCCAACUC 4212 CGAA AGUUGGAA AGAAAUUC 3613 CCAAAUUG CUGAUGAG X 3074 UCAGAAAUU 4213 CGAA AUUUCUGA CAAUEJUGG 3614 UCCAAAUU CUGAUGAG X 3075 CAGAAAUUC 4214 CGAA AAUUUCUG AAUUUGGA 3618 UAAAUCCA CUGAUGAG X 3076 AAUUCAAUU 4215 CGAA AUUGAAUU UGGAUUUA 3619 UUAAAUCC CUGAUGAG X 3077 AUUCAAUUU 4216 CGAA AAUUGAAU GGAUUUAA 3624 GGCUUUUA CUGAUGAG X 3078 AUtJUGGAUU 4217 CGAA AUCCAAAU UAAAAGCC 3625 AGGCUUUU CUGAUGAG X 3079 UUUGGAUUU 4218 CGAA AAUJCCAAA AAAAGCCU 3626 CAGGCUUU CUGAUGAG X 3080 UUGGAUUUA 4219 CGAA AAAUCCAA AAAGCCUG 3637 CAGGGAUU CUGAUGAG X 3081 AGCCUGCUC 4220 CGAA AGCAGGCU AAUCCCUG 3641 UCCUCAGG CUGAUGAG X 3082 UGCUCAAUC 4221 CGAA AUUGAGCA CCUGAGGA 3655 CACUCUGA CUGAUGAG X 3083 GGACUGAUU 4222 CGAA AUCAGUCC UCAGAGUG 3656 UCACUCUG CUGAUGAG X 3084 GACUGAUUU 4223 CGAA AAUCAGUC CAGAGUGA 3657 GUCACUCU CUGAUGAG X 3085 ACUGAUUUC 4224 CGAA AAAUCAGU

AGAGUGAC

3667 ACUGUGUG CUGAUGAG X 3086 GAGUGACUA 4225 CGAA AGUCACUC CACACAGU 3676 UAGGUUCG CUGAUGAG X 3087 CACACAGUA 4226 CGAA ACUGUGUG CGAACCUA I WO 99/50403 WO 9950403PCTIUS99/06507 181 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3684 UAAAACUG CUGAUGAG X 3088 ACGAACCUA 4227 CGAA AGGUUCGU CAGUUUUA 3689 ACAGUUAA CUGAUGAG X 3089 CCUACAGUU 4228 CGAA ACUGUAGG UUAACUGU 3690 CACAGUUA CUGAUGAG X 3090 CUACAGUUU 4229 CGAA AACUGUAG UAACUGUG 3691 CCACAGUU CUGAUGAG X 3091 UACAGUUUU 4230 CGAA AAACUGUA AACUGUGG 3692 UCCACAGU CUGAUGAG X 3092 ACAGUUUUA 4231 CGAA AAAACUGU ACUGUGGA 3702 CGUAACAA CUGAUGAG X 3093 CUGUGGAUA 4232 CGAA AUCCACAG UUGUUACG 3704 UACGUAAC CUGAUGAG X 3094 GUGGAUAUU 4233 CGAA AUAUCCAC GUUACGUA 3707 GGCUACGU CUGAUGAG X 3095 GAUAUUGUU 4234 CGAA ACAAUAUC ACGUAGCC 3708 AGGCUACG CUGAUGAG X 3096 AUAUUGUUA 4235 CGAA AACAAUAU CGUAGCCU 3712 CCUUAGGC CUGAUGAG X 3097 UGUUACGUA 4236 CGAA ACGUAACA GCCUAAGG 3717 AGGAGCCU CUGAUGAG X 3098 CGUAGCCUA 4237 CGAA AGGCUACG AGGCUCCU 3723 CAAAACAG CUGAUGAG X 3099 CUAAGGCUC 4238 CGAA AGCCUUAG CUGUUUUG______ 3728 CUGUGCAA CUGAUGAG X 3100 GCUCCUGUU 4239 CGAA ACAGGAGC UUGCACAG 3729 GCUGUGCA CUGAUGAG X 3101 CUCCUGUUU 4240 CGAA AACAGGAG UGCACAGC 3730 GGCUGUGC CUGAUGAG X 3102 UCCUGUUUU 4241 CGAA AAACAGGA GCACAGCC 3743 CAGUUUUA CUGAUGAG X 3103 AGCCAAAUU 4242 CGAA AUUUGGCU UAAAACUG WO 99/50403 WO 9950403PCTIUS99/06507 182 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

3744 ACAGUUUU CUGAUGAG X 3104 GCCAAAUJU 4243 AAUUUGGC AAAACUGU 3745 AACAGUUU CUGAUGAG X 3105 CCAAAUUUA 4244 CGAA AAAUUUGG AAACUGUU______ 3753 UCCAUUCC CUGAUGAG X 3106 AAAACUGUU 4245 CGAA ACAGUUUU GGAAUGGA 3763 UAAAGAAA CUGAUGAG X 3107 GAAUGGAUU 4246 CGAA AUCCAUUC UUUCUUUA 3764 UUAAAGAA CUGAUGAG X 3108 AAUGGAUUU 4247 CGAA AAUCCAUU UUCUUUAA 3765 GUUAAAGA CUGAUGAG X 3109 AUGGAUUUU 4248 CGAA AAAUCCAU UCUUUAAC 3766 AGUUAAAG CUGAUGAG X 3110 UGGAUUUUU 4249 CGAA AAAAUCCA CUUUAACU 3767 CAGUUAAA CUGAUGAG X 3111 GGAUUUUUC 4250 CGAA AAAAAUCC UtJUAACUG 3769 GGCAGUUA CUGAUGAG X 3112 AUUUUUCUU 4251 CGAA AGAAAAAU UAACUGCC 3770 CGGCAGUU CUGAUGAG X 3113 UUUUUCUUU 4252 CGAA AAGAAAAA AACUGCCG 3771 ACGGCAGU CUGAUGAG X 3114 UUUUCUUUA 4253 CGAA AAAGAAAA ACUGCCGU 3780 AGUUAAAU CUGAUGAG X 3115 ACUGCCGUA 4254 CGAA ACGGCAGU AUUUAACU 3783 GAAAGUUA CUGAUGAG X 3116 GCCGUAAUU 4255 CGAA AUUACGGC UAACUUUC 3784 AGAAAGUU CUGAUGAG X 3117 CCGUAAUUU 4256 CGAA AAUUACGG AACUUUCU 3785 CAGAAAGU CUGAUGAG X 3118 CGUAAUUUA 4257 CGAA AAAUUACG ACUUUCUG 3789 AACCCAGA CUGAUGAG X 3119 AUUUAACUU 4258 CGAA AGUUAAAU UCUGGGUU I WO 99/50403 WO 9950403PCTIUS99/06507 183 Seq. I. D.

Seq. I. D.

Position Substrate 3790 CAACCCAG CUGAUGAG X 3120 UUUAACUUU 4259 CGAA AAGUEJAAA CUGGGDUG 3791 GCAACCCA CUGAUGAG X 3121 UUAACUUUC 4260 CGAA AAAGUUAA jUGGGUUGC 3797 ACAAAGGC CUGAUGAG X 3122 UUCUGGGUU 4261 CGAA ACCCAGAA GCCUUUGU 3802 CAAAAACA CUGAUGAG X 3123 GGUUGCCUU 4262 CGAA AGGCAACC UGUUUUUG 3803 CCAAAAAC CUGAUGAG X 3124 GUUGCCUUU 4263 CGAA AAGGCAAC GUUUUUGG 3806 ACGCCAAA CUGAUGAG X 3125 GCCUUUGUU 4264 CGAA ACAAAGGC UUUGGCGU 3807 CACGCCAA CUGAUGAG X 3126 CCUUUGUUU 4265 AACAAAGG UUGGCGUG 3808 CCACGCCA CUGAUGAG X 3127 CUUUGUUUU 4266 AAACAAAG UGGCGUGG 3809 GCCACGCC CUGAUGAG X 3128 UUUGUUUUU 4267 AAAACAAA GGCGUGGC 3823 CAUGAUGU CUGAUGAG X 3129 GGCUGACUU 4268 CGAA AGUCAGCC ACAUCAUG 3824 ACAUGAUG CUGAUGAG X 3130 GCUGACUUA 4269 AAGUCAGC CAUCAUGU 3828 CAACACAU CUGAUGAG X 3131 ACUUACAUC 4270 AUGUAAGU AUJGUGUUG 3835 CCUUCCCC CUGAUGAG X 3132 UCAUGUGUU 4271 CGAA ACACAUGA GGAG 3855 CUGAGUGC CUGAUGAG X 3133 UGCCCAGUU 4272 CGAA ACUGGGCA GAUA 3861 UGUCACCU CUGAUGAG X 3134 GUUGCACUC 4273 CGAA AGUGCAAC -AGGUGACA 3871 AUCUGGAG CUGAUGAG X 3135 GGUGACAUC 4274 fCGAA AUGUCACC CUCCAGAU WO 99/50403 WO 9950403PCT/US99/06507 184 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3874 ACUAUCUG CUGAUGAG X 3136 GACAUCCUC 4275 CGAA AGGAUGUC CAGAUAGU 3880 AGCUACAC CUGAUGAG X 3137 CUCCAGAUA 4276 CGAA AUCUGGAG GUGUAGCU 3885 UCCUCAGC CUGAUGAG X 3138 GAUAGUGUA 4277 CGAA ACACUAUC GCUGAGGA 3901 GGUGAGUG CUGAUGAG X 3139 AGGCACCUA 4278 CGAA AGGUGCCU CACUCACC 3906 GUGCAGGU CUGAUGAG X 3140 CCUACACUC 4279 CGAA AGUGUAGG ACCUGCAC 3916 CACUCUGU CUGAUGAG X 3141 CCUGCACUA 4280 AGUGCAGG ACAGAGUG 3930 GAGGUUAG CUGAUGAG X 3142 GUGGCCGUC 4281 ACGGCCAC CUAACCUC 3933 CCCGAGGU CUGAUGAG X 3143 GCCGUCCUA 4282 AGGACGGC ACCUCGGG 3938 GCAGGCCC CUGAUGAG X 3144 CCtJAACCUC 4283 CGAA AGGUUAGG GGGCCUGC 3958 ACGUGAUG CUGAUGAG X 3145 GCAGACGUC 4284 ACGUCUGC CAUCACGU 3962 GCUAACGU CUGAUGAG X 3146 AGGUCCAUC 4285 CGAA AUGGACGU ACGUUAGC______ 3967 GGACAGCU CUGAUGAG X 3147 CAUCACGUU 4286 CGAA ACGUGAUG AGCUGUCC 3968 GGGACAGC CUGAUGAG X 3148 AUJCACGUUA 4287 CGAA AACGUGAU GCUGUCCC______ 3974 UGAUGUGG CUGAUGAG X 3149 UUAGCUGUC 4288 ACAGCUAA 3981 AGUCUUGU CUGAUGAG X 3150 UCCCACAUC 4289 CGAA AUGUGGGA ACAAGACU 3990 CAAUGGCA CUGAUGAG X 3151 ACAAGACUA 4290 CGAA AGUCUUGU UGCCAUUG WO 99/50403 WO 9950403PCTIUS99/06507 185 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

3997 ACUACCCC CUGAUGAG X 3152 UAUGCCAUU 4291 AUGGCAUA GGGGUAGU 4003 AACACAAC CUGAUGAG X 3153 AUUGGGGUA 4292 CGAA ACCCCAAU GUUGUGUU 4006 UGAAACAC CUGAUGAG X 3154 GGGGUAGUU 4293 CGAA ACUACCCC GUGEJUUCA 4011 UCCGUUGA CUGAUGAG X 3155 AGUUGUGUU 4294 CGAA ACACAACU UCAACGGA 4012 UUCCGUUG CUGAUGAG X 3156 GUUGUGUUU 4295 CGAA AACACAAC CAACGGAA 4013 EUUCCGUU CUGAUGAG X 3157 UUGUGUUUC 4296 CGAA AAACACAA IAACGGAAA 4029 UAGUUUAA CUGAUGAG X 3158 AGUGCUGUC 4297 CGAA ACAGCACU UUAAACUA 4031 UUUAGUUU CUGAUGAG X 3159 UGCUGUCUU 4298 CGAA AGACAGCA AAACUAAA 4032 AUUUAGUU CUGAUGAG X 3160 GCUGUCUUA 4299 CGAA AAGACAGC AACUAAAU 4037 UGCACAUU CUGALJGAG X 3161 CUUAAACUA 4300 CGAA AGUUUAAG AAUGUGCA 4048 UCACCUUC CUGAUGAG X 3162 UGUGCAAUA 4301 CGAA AUUGCACA GAAGGUGA 4060 AGGAUGGC CUGAUGAG X 3163 GGUGAUGUU 4302 CGAA ACAUCACC IGCCAUCCU 4066 GACGGUAG CUGAUGAG X 3164 GUUGCCAUC 4303 CGAA AUGGCAAC CUACCGUC 4069 AAAGACGG CUGAUGAG X 3165 GCCAUCCUA 4304 CGAA AGGAUGGC ICCGUCUUU 4074 CAGGAAAA CUGAUGAG X 3166 CCUACCGUC 4305 CGAA ACGGUAGG UUUUCCUG 4076 AACAGGAA CUGAUGAG X 3167 UACCGUCUU 4306 CGAA AGACGGUA UUCCUGUU

I

WO 99/50403 WO 9950403PCTIUS99/06507 186 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4077 AAACAGGA CUGAUGAG X 3168 ACCGUCUUU 4307 CGAA AAGACGGU UCCUGUUJ 4078 GAAACAGG CUGAUGAG X 3169 CCGUCUUUU 4308 CGAA AAAGACGG CCUGUUUC______ 4079 GGAAACAG CUGAUGAG X 3170 CGEJCUUUUC 4309 CGAA AAAAGACG CUGUUUCC 4084 AGCUAGGA CUGAUGAG X 3171 UUUCCUGUU 4310 CGAA ACAGGAAA UCCUAGCU 4085 CAGCUAGG CUGAUGAG X 3172 UUCCUGUUU 4311 CGAA AACAGGAA CCUAGCUG 4086 ACAGCUAG CUGAUGAG X 3173 UCCUGUUUC 4312 CGAA AAACAGGA CUAGCUGU 4089 CACACAGC CUGAUGAG X 3174 UGUUUCCUA 4313 CGAA AGGAAACA GCUGUGUG 4101 UGAGCAGG CUGAUGAG X 3175 GUGUGAAUA 4314 CGAA AUUCACAC CCUGCUCA 4108 UUUGACGU CUGAUGAG X 3176 UACCUGCUC 4315 CGAA AGCAGGUA ACGUCAAA 4113 AUGCAUUU CUGAUGAG X 3177 GCUCACGUC 4316 CGAA ACGUGAGC _____AAAUGCAU 4122 GAAACUUG CUGAUGAG X 3178 AAAUGCAUA 4317 CGAA AUGCAUUU CAAGUUUC 4128 GAGAAUGA CUGAUGAG X 3179 AUACAAGUU 4318 CGAA ACUUGUAU UCAUUCUC 4129 GGAGAAUG CUGAUGAG X 3180 UACAAGUUU 4319 AACUUGUA CAUUCUCC 4130 GGGAGAAU CUGAUGAG X 3181 ACAAGUUUC 4320 CGAA AAACUUGU

AUUCUCCC

4133 AAAGGGAG CUGAUGAG X 3182 AGUUUCAUU 4321 CGAA AUGAAACU CUCCCUUU 4134 GAAAGGGA CUGAUGAG X 3183 GUUUCAUUC 4322 CGAA AAUGAAAC UCCCUUUC WO 99/50403 WO 9950403PCT/US99/06507 187 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

4136 GUGAAAGG CUGAUGAG X 3184 UUCAUUCUC 4323 CGAA AGAAUGAA CCUUUCAC 4140 EUUAGUGA CUGAUGAG X 3185 UUCUCCCUU 4324 CGAA AGGGAGAA UCACUAAA 4141 UUUUAGUG CUGAUGAG X 3186 UCUCCCUUU 4325 CGAA AAGGGAGA CACUAAAA 4142 UUUUUAGU CUGAUGAG X 3187 CUCCCUUUC 4326 CGAA AAAGGGAG ACUAAAAA 4146 UGUGUUUU CUGAUGAG X 3188 CUUUCACUA 4327 CGAA AGUGAAAG AAAACACA 4170 UAGCAUUC CUGAUGAG X 3189 AACAGACJU 4328 CGAA AGUCUGUU GAAUGCUA 4178 AGUAUAAC CUGAUGAG X 3190 UGAAUGCUA 4329 CGAA AGCAUUCA GUUAUACU 4181 AUAAGUAU CUGAUGAG X 3191 AUGCUAGUU 4330 CGAA ACUAGCAU AUACUUAU 4182 AAUAAGUA CUGAUGAG X 3192 UGCUAGUUA 4331 CGAA AACUAGCA UACUUAUU 4184 CAAAUAAG CUGAUGAG X 3193 CUAGUUAUA 4332 CGAA AUAACUAG CUUAUUUG 4187 AUACAAAU CUGAUGAG X 3194 GUUAUACUU 4333 CGAA AGUAUAAC AUUUGUAU______ 4188 UAUACAAA CUGAUGAG X 3195 UUAUACUUA 4334 CGAA AAGUAUAA UUUGUAUA______ 4190 CAUAUACA CUGAUGAG X 3196 AUACUUAUU 4335 CGAA AUAAGUAU UGUAUAUG______ 4191 CCAUAUAC CUGAUGAG X 3197 UACUUAUUU 4336 CGAA AAUAAGUA GUAUAUGG 4194 AUACCAUA CUGAUGAG X 3198 UUAUUUGUA 4337 CGAA ACAAAUAA UAUGGUAU 4196 AAAUACCA CUGAUGAG X 3199 AUUUGUAUA 4338 CGAA AUACAAAU UGGUAUUU WO 99/50403 WO 9950403PCTIUS99/06507 188 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4201 AAAAUAAA CUGAUGAG X 3200 UAUAUGGUA 4339 CGAA ACCAUAUA UUUAUUUU 4203 AAAAAAUA CUGAUGAG X 3201 UAUGGUAUU 4340 CGAA AUACCAUA UAUUUUUU 4204 GAAAAAAU CUGAUGAG X 3202 AUGGUAUUU 4341 CGAA AAUACCAU AtJUUUUUC 4205 AGAAAAAA CUGAUGAG X 3203 UGGUAUUUA 4342 CGAA AAAUACCA UUUuucu 4207 AAAGAAAA CUGAUGAG X 3204 GUAUUUAUU 4343 CGAA AUAAAUAC UUUucuuu 4208 AAAAGAAA CUGAUGAG X 3205 UAUUUAUUU 4344 CGAA AAUAAAUA UUUCUUUU 4209 GAAAAGAA CUGAUGAG X 3206 AUUUAUUUU 4345 CGAA AAAUAAAU UUCUUUUC 4210 AGAAAAGA CUGAUGAG X 3207 UUUAUUUUU 4346 AAAAUAAA UCUUUUCU 4211 AAGAAAAG CUGAUGAG X 3208 UUAUUUUUU 4347 CGAA AAAAAUAA CUUUUCUU 4212 AAAGAAAA CUGAUGAG X 3209 UAUUUUUUC 4348 CGAA AAAAAAUA UUUUCUUU______ 4214 GUAAAGAA CUGAUGAG X 3210 UUUUUUCUU 4349 CGAA AGAAAAAA UUCUUUAC 4215 UGUAAAGA CUGAUGAG X 3211 uuuuucuuu 4350 CGAA AAGAAAAA UCUtJUACA 4216 UUGUAAAG CUGAUGAG X 3212 UUUUCuuuu 4351 CGAA AAAGAAAA CUUUACAA 4217 UUUGUAAA CUGAUGAG X 3213 UUUCUUUUC 4352 CGAA AAAAGAAA UUUACAAA 4219 GGUUUGUA CUGAUGAG X 3214 UCUUUUCUU 4353 CGAA AGAAAAGA UACAAACC 4220 UGGUUUGU CUGAUGAG X 3215 CUUUUCUUU 4354 CGAA AAGAAAAG ACAAACCA WO 99/50403 WO 9950403PCT[US99/06507 189 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4221 AUGGUUUG CUGAIJGAG X 3216 UUUUCUUUA 4355 CGAA AAAGAAAA CAAACCAU 4230 AAUAACAA CUGAUGAG X 3217 CAAACCAEJU 4356 CGAA AUGGUUUG UUGUUAUU 4231. CAAUAACA CUGAUGAG X 3218 AAACCAUUU 4357 CGAA AAUGGUUU UGUUAUUG 4232 UCAAUAAC CUGAUGAG X 3219 AACCAUUUU 4358 CGAA AAAUGGUU GUUAUUGA 4235 UAGUCAAU CUGAUGAG X 3220 CAUUUUGUU 4359 CGAA ACAAAAUG AUUGACUA 4236 UUAGUCAA CUGAUGAG X 3221 AUUUUGUUA 4360 AACAAAAU _____UUGACUAA 4238 UGUUAGUC CUGAUGAG X 3222 UUUGUUAUU 4361 CGAA AUAACAAA GACUAACA 4243 UGGCCUGU CUGAUGAG X 3223 UAUUGACUA 4362 CGAA AGUCAAUA ACAGGCCA 4258 AAACUGGA CUGAUGAG X 3224 CAAAGAGUC 4363 CGAA ACUCUUUG UCCAGUUU 4260 GUAAACUG CUGAUGAG X 3225 AAGAGUCUC 4364 AGACUCUU CAGUUUAC 4265 GAAGGGUA CUGAUGAG X 3226 UCUCCAGUU 4365 CGAA ACUGGAGA UACCCUUC 4266 UGAAGGGU CUGAUGAG X 3227 CUCCAGUUU 4366 CGAA AACUGGAG ACCCUUCA 4267 CUGAAGGG CUGAUGAG X 3228 UCCAGUUUA 4367 CGAA AAACUGGA CCCUUCAG 4272 CCAACCUG CUGAUGAG X 3229 UUUACCCUU 4368 CGAA AGGGUAAA CAGGUUGG 4273 ACCAACCU CUGAUGAG X 3230 UUACCCUUC 4369 AAGGGUAA 4278 AUUAAACC CUGAUGAG X 3231 CUUCAGGUU 4370 CGAA ACCUGAAG GGUUUAAU WO 99/50403 WO 9950403PCTIUS99/06507 190 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4282 AUUGAUJUA CUGAUGAG X 3232 AGGUUGGUU 4371 CGAA ACCAACCU IUAAUCAAU 4283 GAUUGAUU CUGAUGAG X 3233 GGUUGGUUU 4372 CGAA AACCAACG AAUCAAUC 4284 UGAUUGAU CUGAUGAG X 3234 GUUGGUUUA 4373 CGAA AAACCAAC AUCAAUCA 4287 UUCUGAUU CUGAUGAG X 3235 GGUUUAAUC 4374 AUUAJAACC AAUCAGAA 4291 CUAAUUCU CUGAUGAG X 3236 UAAUCAAUC 4375 CGAA AUUGAUUA AGAAUUAG 4297 CUAAUUCU CUGAUGAG X 3237 AUCAGAAUU 4376 CGAA AUUCUGAU AGAAUUAG 4298 UCUAAUUC CUGAUGAG X 3238 UCAGAAUUA 4377 AAUUCUGA GAAUUAGA 4303 CAUGCUCU CUGAUGAG X 3239 AUUAGAAUU 4378 CGAA AUUCUAAU AGAGGAUG 4304 CCAUGCUC CUGAUGAG X 3240 UUAGAAUUA 4379 CGAA AAUUCUAA GAGCAUGG 4319 AUAGUGAU CUGAUGAG X 3241 GGGAGGGUC 4380 CGAA ACCCUCCC AUCACUAU 4322 GUCAUAGU CUGAUGAG X 3242 AGGGUCAUC 4381 CGAA AUGACCCU ACUAUGAC______ 4326 DUAGGUCA CUGAUGAG X 3243 UCAUCACUA 4382 CGAA AGUGAUGA IUGACCUAA 4333 AAAUAAUU CUGAUGAG X 3244 UAUGACCUA 4383 AGGUCAUA AAUUAUUU 4337 CAGUAAAU CUGAUGAG X 3245 ACCUAAAUU 4384 CGAA AUUUAGGU IAUUUACUG 4338 GCAGUAAA CUGAUGAG X 3246 CCUAAAUUA 4385 AAUUUAGG UUUACUGC 4340 UUGCAGUA CUGAUGAG X 3247 EJAAAUUAUU 4386 CGAA AUAAUUUA

IUACUGCAAI

WO 99/50403 WO 9950403PCT/US99/06507 191 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4341 UUUGCAGU CUGAUGAG X 3248 AAAUUAUUU 4387 CGAA AAUAAUUU ACUGCAAA 4342 UUUUGCAG CUGAUGAG X 3249 AAUUAUUUA 4388 CGAA AAAUAAUU CUGCAAAA 4358 UUUAUAAA CUGAUGAG X 3250 AAGAAAAUC 4389 CGAA AUUUUCUU UUUAUAAA 4360 CAUUUAUA CUGAUGAG X 3251 GAAAAUCUU 4390 CGAA AGAUUUUC UAUAAAUG 4361 ACAUUUAU CUGAUGAG X 3252 AAAAUCUUU 4391.

CGAA AAGAUUUU AUAAAUJGU 4362 UACAUUUA CUGAUGAG X 3253 AAAUCUUUA 4392 CGAA AAAGAUUU UAAAUGUA 4364 GGUACAUU CUGAUGAG X 3254 AUCUUUAUA 4393 CGAA AUAAAGAU AAUGUACC 4370 CUCUCUGG CUGAUGAG X 3255 AUAAAUGUA 4394 ACAUUUAU CCAGAGAG 4382 AUUAAAAC CUGAUGAG X 3256 GAGAGAGUU 4395 CGAA ACUCUCUC GUUUUAAU 4385 GUUAUUAA CUGAUGAG X 3257 AGAGUUGUU 4396 CGAA ACAACUCU _____UUAAUAAC 4386 AGUUAUUA CUGAUGAG X 3258 GAGUUGUUU 4397 CGAA AACAACUC _____UAAUAACU 4387 AAGUUAUU CUGAUGAG X 3259 AGUUGUUUU 4398 AAACAACU AAUAACUU 4388 UAAGUUAU CUGAUGAG X 3260 GUUGUUUUA 4399 CGAA AAAACAAC AUAACUUA 4391 AGAUAAGU CUGAUGAG X 3261 GUUUUAAUA 4400 CGAA AUUAAAAC ACUUAUCU 4395 UUAUAGAU CUGAUGAG X 3262 UAAUAACUU 4401 CGAA AGUUAUUA AUCUAUAA 4396 UUUAUAGA CUGAUGAG X 3263 AAUAACUUA 4402 fCGAA AAGUUAUU

UCUAUAAA

WO 99/50403 WO 9950403PCTIUS99/06507 192 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4398 AGUUtJAUA CUGAUGAG X 3264 UAACUUAUC 4403 CGAA AUAAGUUA IUAUAAACU 4400 AUAGUUUA CUGAUGAG X 3265 ACUUAUCUA 4404 AGAUAAGU UAAACUAU 4402 UUAUAGUU CUGAUGAG X 3266 UUAUCUAUA 4405 CGAA AUAGAUAA IAACUAUAA 4407 AGAGGUUA CUGAUGAG X 3267 UAUAAACUA 4406 CGAA AGUUUAUA UAACCUCU 4409 GGAGAGGU CUGAUGAG X 3268 UAAACUAUA 4407 CGAA AUAGUUUA ACCUCUCC 4414 AUGAAGGA CUGAUGAG X 3269 UAUAACCUC 4408 AGGUUAUA UCCUUCAU 4416 UCAUGAAG CUGAUGAG X 3270 UAACCUCUC 4409 CGAA AGAGGUUA ICUUCAUGA 4419 CUGUCAUG CUGAUGAG X 3271 CCUCUCCUU 4410 CGAA AGGAGAGG CAUGACAG 4420 GCUGUCAU CUGAUGAG X 3272 CUCUCCUUC 4411 CGAA AAGGAGAG AUGACAGC 4431 GUGGGGUG CUGAUGAG X 3273 GACAGCCUC 4412 AGGOUGUC CACCCCAC 4452 AUUUCUUA CUGAUGAG X 3274 CAAAAGGUU 4413 ACCUUUUG UAAGAAMU______ 4453 UAUUUCUU CUGAUGAG X 3275 AAAAGGUUU 4414 AACCUUUU AAGAAAUA 4454 CUAUUUCU CUGAUGAG X 3276 AAAGGUUUA 4415 AAACCUUU AGAAAUAG 4461 UAUAAUUC CUGAUGAG X 3277 UAAGAAAUA 4416 CGAA AUUUCUUA GAAUUAUA 4466 ACAGUUAU CUGAUGAG X 3278 AAUAGAAUU 4417 AUUCUAUU AUAACUGU______ 4467 UACAGUUA CUGAUGAG X 3279 AUAGAAUUJA 4418 AAUUCUAU IUAACUGUA WO 99/50403 WO 9950403PCT/US99/06507 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

4469 UUUACAGU CUGAUGAG X 3280 AGAAUUAUA 4419 AUAAUUCU ACUGUAAA 4475 AACAUCUU CUGAUGAG X 3281 AUAACUGUA 4420 CGAA ACAGUUAU AAGAUGUU 4483 CUGAAAUA CUGAUGAG X 3282 AAAGAUGUU 4421 CGAA ACAUCUUU UAUUUCAG 4484 CCUGAAAU CUGAUGAG X 3283 AAGAUGUUU 4422 CGAA AACAUCUU AUUUCAGG 4485 GCCUGAAA CUGAUGAG X 3284 AGAUGtJUUA 4423 CGAA AAACAUCU IUUUCAGGC 4487 AUGCCUGA CUGAUGAG X 3285 AEJGUUUAUU 4424 CGAA AUAAACAU UCAGGCAU 4488 AAUGCCUG CUGAUGAG X 3286 UGUUUAUUU 4425 CGAA AAUAAACA CAGGCAUU 4489 CAAUGCCU CUGAUGAG X 3287 GUUUAUUUC 4426 CGAA AAAUAAAC AGGCAUUG 4496 AAAUAUCC CUGAUGAG X 3288 UCAGGCAUU 4427 CGAA AUGCCUGA GGAUAUUU 4501 GUAAAAAA CUGAUGAG X 3289 CAUUGGAUA 4428 AUCCAAUG IUUUUUUAC 4503 AAGUAAAA CUGAUGAG X 3290 UUGGAUAUU 4429 AUAUCCAA ULJUUACUU 4504 AAAGUAAA CUGAUGAG X 3291 UGGAUAUUU 4430 AAUAUCCA UUUACUUU 4505 UAAAGUAA CUGAUGAG X 3292 GGAUAUUUU 4431 AAAUAUCC UUACUUUA 4506 CUAAAGUA CUGAUGAG X 3293 GAUAUUUUU 4432 CGAA AAAAUAUC UACUUUAG 4507 UCUAAAGU CUGAUGAG X 3294 AUAUUUUUU 4433 CGAA AAAAAUAU ACUUUAGA 4508 UUCUAAAG CUGAUGAG X 3295 UAUUUUUUA 4434 AAAAAAUA CUUUJAGAA I WO 99/50403 WO 9950403PCTIUS99/06507 194 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

4511 GGCUUCUA CUGAUGAG X 3296 UUUUUACUU 4435 AGUAAAAA UAGAAGCC 4512 AGGCUUCU CUGAUGAG X 3297 UUUUACUUU 4436 AAGUAAAA _____AGAAGCCU 4513 CAGGCUUC CUGAUGAG X 3298 UUUACUUUA 4437 AAAGUAAA _____GAAGCCUJG 4525 AGAAACAU CUGAUGAG X 3299 GCCUGCAUA 4438 AUGCAGGC _____AUGUUUCU 4530 AAUCCAGA CUGAUGAG X 3300 CAUAAUGUU 4439 CGAA ACAUUAUG UCUGGAUU 4531 AAAUCCAG CUGAUGAG X 3301 AUAAUGUUJU 4440 CGAA AACAUUAU CUGGAUUU 4532 UAAAUCCA CUGAUGAG X 3302 UAAUGUUUC 4441 AAACAUUA IUGGAUUUA 4538 AGUAUGUA CUGAUGAG X 3303 UUCUGGAUU 4442 AUCCAGAA UACAUACU 4539 CAGtJAUGU CUGAUGAG X 3304 UCUGGAUUU 4443 AAUCCAGA ACAUACUG 4540 ACAGUAUG CUGAUGAG X 3305 CUGGAUUUA 4444 AAAUCCAG CAUACUGU 4544 UGUUACAG CUGAUGAG X 3306 AUUUACAUA 4445 AUGUAAAU CUGUAACA 4549 CUGAAUGU CUGAUGAG X 3307 CAUACUGUA 4446 ACAGUAUG ACAUUCAG______ 4554 AAUUCCUG CUGAUGAG X 3308 UGUAACAUU 4447 CGAA AUGUUACA CAGGAAUU 4555 GAAUUCCU CUGAUGAG X 3309 GUAACAUUC 4448 AAUGUUAC AGGAAUUC 4562 UCUCCAAG CUGAUGAG X 3310 UCAGGAAUU 4449 CGAA AUUCCUGA CUUGGAGA 4563 UUCUCCAA CUGAUGAG X 3311 CAGGAAUUC 4450 ICGAA AAUUCCUG UUGGAGAA WO 99/50403 WO 9950403PCTIUS99/06507 195 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4565 UCUUCUCC CIJGAIJGAG X 3312 GGAAUUCUU 4451 CGAA AGAAUUCC GGAGAAGA 4579 AGUGAAUA CUGAUGAG X 3313 AGAUGGGUU 4452 CGAA ACCCAUCU UAUUCACU 4580 GAGUGAAU CUGAUGAG X 3314 GAUGGGUUU 4453 CGAA AACCCAUC IAUUCACUG 4581 UCAGUGAA CUGAUGAG X 3315 AUGGGUUUA 4454 CGAA AAACCCAU UUCACUGA 4583 GUUCAGUG CUGAUGAG X 3316 GGGUUUAUU 4455 CGAA AUAAACCC CACUGAAC 4584 AGUUCAGU CUGAUGAG X 3317 GGUUUAUUC 4456 CGAA AAUAAACC ACUGAACU 4593 CCGCACUA CUGAUGAG X 3318 ACUGAACUC 4457 CGAA AGUUCAGU UAGUGCGG 4595 AACCGCAC CUGAUGAG X 3319 UGAACUCUA 4458 CGAA AGAGUUCA GUGCGGUU 4603 AGUGAGUA CUGAUGAG X 3320 AGUGCGGUU 4459 CGAA ACCGCACU UACUCACU 4604 CAGUGAGU CUGAUGAG X 3321 GUGCGGUUU 4460 AACCGCAC ACUCACUG 4605 GCAGUGAG CUGAUGAG X 3322 UGCGGUUUA 4461 CGAA AAACCGCA CUCACUGC 4608 GCAGCAGU CUGAUGAG X 3323 GGUUUACUC 4462 CGAA AGUAAACC IACUGCUGC 4621 AUAUACAG CUGAUGAG X 3324 CUGCAAAUA 4463 CGAA AUUUGCAG CUGUAUAU 4626 CCUGAAUA CUGAUGAG X 3325 AAUACUGUA 4464 CGAA ACAGUAUU IUAUUCAGG 4628 GUCCUGAA CUGAUGAG X 3326 UACUGUAUA 4465 CGAA AUACAGUA UUCAGGAC 4630 AAGUCCUG CUGAUGAG X 3327 CUGUAUAUU 4466 CGAA AUAUACAG I CAGGACUU WO 99/50403 WO 9950403PCT/US99/06507 196 Seq. 1.13. Seq. 1.13.

Position RZ No. Substrate No.

4631 CAAGUCCU CUGAUGAG X 3328 UGUAUAUUC 4467 CGAA AAUAUACA IAGGACUUG 4638 UUUCUUIJC CUGAUGAG X 3329 UCAGGACUU 4468 CGAA AGUCCUGA GAAAGAAA 4659 UAGUUCCA CUGAUGAG X 3330 GAAUGCCUA 4469 CGAA AGGCAUUC IUGGAACUA 4667 GGAUCCAC CUGAUGAG X 3331 AUGGAACUA 4470 CGAA AGUUCCAU GUGGAUCC 4674 UCAGUUUG CUGAUGAG X 3332 UAGUGGAUC 4471 CGAA AUCCACUA CAAACUGA 4684 UUAUACUG CUGAUGAG X 3333 AAACUGAUC 4472 CGAA AUCAGUUU CAGUAUAA 4689 UAGUCUUA CUGAUGAG X 3334 GAUCCAGUA 4473 CGAA ACUGGAUC UAAGACUA 4691 AGUAGUCU CUGAUGAG X 3335 UCCAGUAUA 4474 CGAA AUACUGGA AGACUACU 4697 AGAUUCAG CUGAUGAG X 3336 AUAAGACUA 4475 AGUCUUAU CUGAAUCU 4704 UGGUAGCA CUGAUGAG X 3337 UACUGAAUC 4476 AUUCAGUA UGCUACCA 4709 UGUUUUGG CUGAUGAG X 3338 AAUCUGCUA 4477 AGCAGAUU CCAAAACA 4720 CACUGAUU CUGAUGAG X 3339 AAAACAGUU 4478 CGAA ACUGUUUU AAUCAGUG 4721 UCACUGAU CUGAUGAG X 3340 AAACAGUUA 4479 CGAA AACUGUUU AUCAGUGA 4724 GACUCACU CUGAUGAG X 3341 CAGUUAAUC 4480 CGAA AUUAACUG AGUGAGUC 4732 GAACACUC CUGAUGAG X 3342 CAGUGAGUC 4481 CGAA ACUCACUG GAGUGUUC 4739 AAAAAUAG CUGAUGAG X 3343 UCGAGUGUU 4482 CGAA ACACUCGA CUAUUUUU WO 99/50403 WO 9950403PCT/US99/06507 197 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4740 AAAAAAtJA CUGAUGAG X 3344 CGAGUGUUC 4483 CGAA AACACUCG UAUJLUUUU 4742 ACAAAAAA CUGAUGAG X 3345 AGUGUUCUA 4484 CGAA AGAACACU UUUUEJUGU 4744 AAACAAAA CUGAtJGAG X 3346 UGUUCUAUU 4485 CGAA AUAGAACA UUUUGUUU 4745 AAAACAAA CUGAUGAG X 3347 GUUCUAUUU 4486 CGAA AAUAGAAC UUUGUUUU 4746 CAAAACAA CUGAUGAG X 3348 UUCUAUUUU 4487 CGAA AAAUAGAA UUGUUUUG 4747 ACAAAACA CUGAUGAG X 3349 UCUAUUUUU 4488 CGAA AAAAUAGA UGUUUUGU 4748 AACAAAAC CUGAUGAG X 3350 CUAUUUUUU 4489 CGAA AAAAAUAG GUUUUGUU 4751 GGAAACAA CUGAUGAG X 3351 UUUUUUGUU 4490 CGAA ACAAAAAA UUGUUUCC 4752 AGGAAACA CUGAUGAG X 3352 UUUUUGUUU 4491 CGAA AACAAAAA UGUUUCCU 4753 GAGGAAAC CUGAUGAG X 3353 UUUUGUUUU 4492 CGAA AAACAAAA GUUUCCUC 4756 GGGGAGGA CUGAUGAG X 3354 UGUUUUGUU 4493 ACAAAACA UCCUCCCC 4757 AGGGGAGG CUGAUGAG X 3355 GUUUUGUUU 4494 CGAA AACAAAAC CCEJCCCCU 4758 UAGGGGAG CUGAUGAG X 3356 UUUUGUUUC 4495 AAACAAAA CUCCCCUA 4761 AGAUAGGG CUGAUGAG X 3357 UGUUUCCUC 4496 AGGAAACA CCCUAUCU 4766 AAUACAGA CUGAUGAG X 3358 CCUCCCCUA 4497 CGAA AGGGGAGG UCUGUAUU 4768 GGAAUACA CUGAUGAG X 3359 UCCCCUAUC 4498 CGAA AUAGGGGA UGUAUUCC WO 99/50403 WO 9950403PCT/US99/06507 198 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4772 EUUGGGAA GUGAUGAG X 3360 CUAUCUGUA 4499 ACAGAUAG UUCCCAAA 4774 UUUUUGGG CUGAUGAG X 3361 AUCUGUAUU 4500 AUACAGAU CCCAAAAA 4775 AUUUUUGG CUGAUGAG X 3362 UCUGUAUUC 4501 CGAA AAUACAGA CCAAAAAU 4784 CCCAAAGU CUGAUGAG X 3363 CCAAAAAUU 4502 CGAA AUUUUUGG ACUUUGGG 4785 CCCCAAAG CUGAUGAG X 3364 CAAAAAUUA 4503 CGAA AAUUUUUG CUUUGGGG 4788 UAGCCCCA CUGAUGAG X 3365 AAAUUACUU 4504 AGUAAUUU UGGGGCUA 4789 UUAGCCCC CUGAUGAG X 3366 AAUUACUUU 4505 CGAA AAGUAAUU GGGGCUAA 4796 UGUUAAAU CUGAUGAG X 3367 UUGGGGCUA 4506 CGAA AGCCCCAA AUUUAACA 4799 UCUUGUUA CUGAUGAG X 3368 GGGCUAAUU 4507 CGAA AUUAGCCC UAACAAGA 4800 UUCUUGUU CUGAUGAG X 3369 GGCUAAUUU 4508 CGAA AAUUAGCC AACAAGAA 4801 GUUCUUGU CUGAUGAG X 3370 GCUAAUUUA 4509 GAA AAAUUAGC ACAAGAAC 4811 ACAAUUUA CUGAUGAG X 3371 CAAGAACUU 4510 CGAA AGUUCUUG UAAAUUGU 4812 CACAAUUU CUGAUGAG X 3372 AAGAACUUU 4511 CGAA AAGUUCUU AAAUUGUG 4813 ACACAAUU CUGAUGAG X 3373 AGAACUUUA 4512 CGAA AAAGUUCU AAUUGUGU 4817 UAAAACAC CUGAUGAG X 3374 CUUUAAAUU 4513 CGAA AUUUAAAG GUGUUUUA 4822 ACAAUUAA CUGAUGAG X 3375 AAUUGUGUU 4514 CGAA ACACAAUU IUUAAUUGU WO 99/50403 WO 9950403PCTIUJS99/06507 199 is Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

4823 UACAAUUA CUGAUGAG X 3376 AUUGUGJUU 4515 CGAA AACACAAU UAAUUGUA 4824 UUACAAUU CUGAUGAG X 3377 UUGUGtJUUU 4516 CGAA AAACACAA AAUUGUAA______ 4825 UUUACAAU CUGAUGAG X 3378 UGUGUUUUA 4517 CGAA AAAACACA AUUGUAAA 4828 AUUUUUAC CUGAUGAG X 3379 GUUUUAAUU 4518 CGAA AUUAAAAC GUAAAAAU 4831 GCCAUUUU CUGAUGAG X 3380 UUAAUUGUA 4519 CGAA ACAAUUAA AAAAUGGC 4852 AGAGUAAU CUGAUGAG X 3381 GGUGGAAUU 4520 CGAA AUUCCACC AUUACUCU 4853 UAGAGUAA CUGAUGAG X 3382 GUGGAAUUA 4521 CGAA AAUUCCAC UUACUCUA 4855 UAUAGAGU CUGAUGAG X 3383 GGAAUUAUU 4522 CGAA AUAAUUCC ACUCUAUA 4856 GtJAUAGAG CUGAUGAG X 3384 GAAUUAUUA 4523 CGAA AAUAAUUC CUCUAUAC 4859 AAUGUAUA CUGAUGAG X 3385 UUAUUACUC 4524 CGAA AGUAAUAA UAUACAUU 4861 UGAAUGUA CUGAUGAG X 3386 AUUACUCUA 4525 CGAA AGAGUAAU UACAUUCA 4863 GUUGAAUG CUGAUGAG X 3387 UACUCUAUA 4526 CGAA AUAGAGUA CAUUCAAC______ 4867 CUCUGUUG CUGAUGAG X 3388 CUAUACAUU 4527 CGAA AUGUAUAG CAACAGAG 4868 UCUCUGUU CUGAUGAG X 3389 UAUACAUUC 4528 CGAA AAUGUAUA _____AACAGAGA 4883 UUCAUAUC CUGAUGAG X 3390 GACUGAAUA 4529 CGAA AUUCAGUC GAUAUGAA 4887 AGCUUUCA CUGAUGAG X 3391 GAAUAGAUA 4530 ICGAA AUCUAUUC ______UGAAAGCU WO 99/50403 WO 9950403PCTIUS99/06507 200 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4899 tUAAAAAA CUGAUGAG X 3392 AAGCUGAUU 4531 CGAA AUCAGCUU UUtJUUUAA 4900 AUUAAAAA CUGAUGAG X 3393 AGCUGAUUU 4532 CGAA AAUCAGCU UUUUUAAU 4901 AAUUAAAA CUGAUGAG X 3394 GCtJGAUUUU 4533 CGAA AAAUCAGC UUtJUAAUU 4902 UAAUUAA.A CUGAUGAG X 3395 CUGAUUUUU 4534 CGAA AAAAUCAG UUUAAUUA 4903 GUAAUUAA CUGAUGAG X 3396 UGAUUUUUU 4535 CGAA AAAAAUCA UUAAUUAC 4904 GGUAAUUA CUGAUGAG X 3397 GAUUUUUUU 4536 CGAA AAAAAAUC _____UAAUUACC 4905 UGGUAAUU CUGAUGAG X 3398 AUUUUUUUU 4537 AAAAAAAU _____AAUUACCA 4906 AUGGUAAU CUGAUGAG X 3399 UUEUUUUUA 4538 CGAA AAAAAAAA AUEJACCAU 4909 AGCAUGGU CUGAUGAG X 3400 UUUUUAAUU 4539 CGAA AUUAAAAA ACCAUGCU 4910 AAGCAUGG CUGAUGAG X 3401 UUUUAAUUA 4540 CGAA AAUUAAA.A CCAUGCUU 4918 ACAUUGUG CUGAUGAG X 3402 ACCAUGCUU 4541 CGAA AGCAUGGU CACAAUGU 4919 AACAUUGU CUGAUGAG X 3403 CCAUGCUUC 4542 CGAA AAGCAUGG _____ACAAUGUU 4927 UAUAACUU CUGAUGAG X 3404 CACAAUGUU 4543 CGAA ACAUDGUG AAGUUAUA 4928 AUAUAACU CUGAUGAG X 3405 ACAAUGUUA 4544 CGAA AACAUUGU AGtJUAUAU 4932 CCCCAUAU CUGAUGAG X 3406 UGUJUAAGUU 4545 CGAA ACUUAACA _____AUAUGGGG 4933 UCCCCAUA CUGAUGAG X 3407 GUUAAGUUA 4546 CGAA AAcuuAAc UAtJGGGGA WO 99/50403 WO 9950403PCT[US99/06507 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

4935 GCUCCCCA CUGAUGAG X 3408 UAAGUUAUA 4547 AUAACrJUA UGGGGAGC 4961 AAACAAAU CUGAUGAG X 3409 CAGGEJGCUA 4548 CGAA AGGACCUG AUUUGUUU 4964 CCAAAACA CUGAUGAG X 3410 GUGCUAAUU 4549 CGAA AUUAGCAC UGUUUUGG 4965 UCCAAAAC CUGAUGAG X 3411 UGCUAAUUU 4550 CGAA AAUUAGCA GUUUUGGA 4968 AUAUCCAA CUGAUGAG X 3412 UAAUUUGUU 4551 CGAA ACAAAUUA UUGGAUAU 4969 UAUAUCCA CUGAUGAG X 3413 AAUUUGUUU 4552 CGAA AACAAAUU UGGAUAUA 4970 CUAUAUCC CUGAUGAG X 3414 AUUUGUUUU 4553 CGAA AAACAAAU GGAUAUAG 4975 UUAUACUA CUGAUGAG X 3415 UUUUGGAUA 4554 CGAA AUCCAAAA UAGUAUAA 4977 GCUUAUAC CUGAUGAG X 3416 UUGGAUAUA 4555 CGAA AUAUCCAA GUAUAAGC 4980 ACUGCEJUA CUGAUGAG X 3417 GAUAUAGUA 4556 CGAA ACUAUAUC UAAGCAGU 4982 ACACUGCU CUGAUGAG X 3418 UAUAGUAUA 4557 CGAA AUACUAUA AGCAGUGU 4991 AAAACACA CUGAUGAG X 3419 AGGAGUGUC 4558 ACACUGCU UGUGUUUU 4997 UCUUUCAA CUGAUGAG X 3420 GUCUGUGUU 4559 CGAA ACACAGAC UUGAAAGA 4998 UUCUUUCA CUGAUGAG X 3421 UCUGUGUUU 4560 CGAA AACACAGA UGAAAGAA 4999 AUUCUUUC CUGAUGAG X 3422 CUGUGUUUU 4561 CGAA AAACACAG GAAAGAAU 5008 CUGUGUUC CUGAUGAG X 3423 GAAAGAAUA 4562 CGAA AUUCUUUC IGAACACAG I WO 99/50403 WO 9950403PCTIUS99/06507 202 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

5018 GOACUACA CUGAUGAG X 3424 AACACAGUU 4563 CGAA ACUGUGUU UGUAGUGC 5019 GGCACUAC CUGAUGAG X 3425 ACACAGUUU 4564 CGAA AACUGUGU GUAGUGCC 5022 AGUGGCAC CUGAUGAG X 3426 CAGUUUGUA 4565 CGAA ACAAACUG GUGCCACU 5033 CCCAAAAC CUGAUGAG X 3427 GCCACUGUU 4566 CGAA ACAGUGGC GUUUUGGG 5036 CCCCCCAA CUGAUGAG X 3428 ACUGUUGUU 4567 CGAA ACAACAGU UUGGGGGG 5037 CCCCCCCA CUGAUGAG X 3429 CUGUUGUUU 4568 CGAA AACAACAG UGGGGGGG 5038 CCCCCCCC CUGAUGAG X 3430 UGUUGUUUU 4569 CGAA AAACAACA GGGGGGGG______ 5049 AAGAAAAA CUGAUGAG X 3431 GGGGGGCUU 4570 CGAA AGCCCCCC UUUUUCUU______ 5050 AAAGAAAA CUGAUGAG X 3432 GGGGGCUUU 4571 CGAA AAGCCCCC UUUUCUUU 5051 AAAAGAAA CUGAUGAG X 3433 GGGGCUUUU 4572 AAAGCCCC UUUCUUUU______ 5052 AAAAAGAA CUGAUGAG X 3434 GGGCUUUUU 4573 AAAAGCCC UUCUUUUU______ 5053 GAAAAAGA CUGAUGAG X 3435 GGCUUUUUU 4574 AAAAAGCC UCUUUUUC 5054 GGAAAAAG CUGAUGAG X 3436 GCUUUUUUU 4575 CGAA AAAAAAGC CUUUUUCC______ 5055 CGGAAAAA CUGAUGAG X 3437 CUUUUUUUC 4576 CGAA AAAAAAAG UUUUUCCG______ 5057 UCCGGAAA CUGAUGAG X 3438 UUUUUUCUU 4577 CGAA AGAAAAAA UUUCCGGA 5058 UUCCGGAA CUGAUGAG X 3439 UUUUUCUUU 4578 CGAA AAGAAAAA UUCCGGAA WO 99/50403 WO 9950403PCT/US99/06507 203 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

5059 UUUCCGGA CUGAUGAG X 3440 UUUUCUUUU 4579 CGAA AAAGAAAA UCCGGAAA 5060 UUUUCCGG CEJGAUGAG X 3441 UUUCUUUUU 4580 CGAA AAAAGAAA CCGGAAAA 5061 AUUUUCCG CUGAUGAG X 3442 UUCtJUUUUC 4581 CGAA AAAAAGAA ICGGAAAAU 5070 GGUUUAAG CUGAUGAG X 3443 CGGAAAAUC 4582 CGAA AUUUUCCG CtJUAAACC 5073 UAAGGUUU CUGAUGAG X 3444 AAAAUCCUJU 4583 CGAA AGGAUUUU IAAACCUUA 5074 UUAAGGUU CUGAUGAG X 3445 AAAUCCUUA 4584 CGAA AAGGAUUU AACCUUAA 5080 AGUAUCUU CUGAUGAG X 3446 UUAAACCUU 4585 CGAA AGGUUUAA IAAGAUACU 5081 UACUAUCU CUGAUGAG X 3447 UAAACCUUA 4586 CGAA AAGGUUUA AGAUACUA 5086 GUCCUUAG CUGAUGAG X 3448 CUUAAGAUA 4587 CGAA AUCUUAAG CUAAGGAC 5089 AACGUCCU CUGAUGAG X 3449 AAGAUACUA 4588 CGAA AGUAUCUU AGGACGUU 5097 ACCAAAAC CUGAUGAG X 3450 AAGGACGUU 4589 CGAA ACGUCCUU GUUUUGGU 5100 ACAACCAA CUGAUGAG X 3451 GACGUUGUU 4590 CGAA ACAACGUC UUGGUUGU______ 5101 UACAACCA CUGAUGAG X 3452 ACGUUGUUU 4591 CGAA AACAACGU UGGUUGUA 5102 GUACAACC CUGAUGAG X 3453 CGUUGUUUU 4592 CGAA AAACAACG GGUUGUAC______ 5106 CCAAGUAC CUGAUGAG X 3454 GUUUUGGUU 4593 CGAA ACCAAAAC GUACUUGG 5109 AUUCCAAG CUGAUGAG X 3455 UUGGUUGUA 4594 ,CGAA ACAACCAA

CUUGGAAU

WO 99/50403 WO 9950403PCT/US99/06507 204 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

5112 AGAAUUCC CUGAUGAG X 3456 GUUGUACUU 4595 CGAA AGUACAAC GGAAUUCU 5118 UGACUAAG CUGAUGAG X 3457 CUUGGAAtJU 4596 CGAA AUUCCAAG CUUAGUCA 5119 GUGACUAA CUGAUGAG X 3458 UUGGAAUUC 4597 AAUUCCAA UUAGUCAC 5121 UUGUGACU CUGAUGAG X 3459 GGAAUUCUU 4598 CGAA AGAAUUCC AGUCACAA 5122 UUUGUGAC CUGAUGAG X 3460 GAAUUCUUA 4599 CGAA AAGAAUUC GUCACAAA 5125 UAUUUUGU CUGAUGAG X 3461 UUCUUAGUC 4600 ACUAAGAA ACAAAAUA 5133 ACAAAAUA CUGAUGAG X 3462 CACAAAAUA 4601 CGAA AUUUUGUG UAUUUUGU 5135 AAACAAAA CUGAUGAG X 3463 CAAAAUAUA 4602 CGAA AUAUUUUG UUUUGUUU 5137 GUAAACAA CUGAUGAG X 3464 AAAUAUAUU 4603 CGAA AUAUAUUU UUGUUUAC 5138 UGUAAACA CUGAUGAG X 3465 AAUAUAUUU 4604 AAUAUAUU UGHUUACA 5139 UUGUAAAC CUGAUGAG X 3466 AUAUAUUUU 4605 CGAA AAAUAUAU _____GUUUACAA 5142 UUUUUGUA CUGAUGAG X 3467 UAUUUUGUU 4606 CGAA ACAAAAUA _____UACAAAAA 5143 AUUUUUGU CUGAUGAG X 3468 AUUUUGUUU 4607 CGAA AACAAAAU ACAAAAAU 5144 AAUUUUUG CUGAUGAG X 3469 UUUUGUUUA 4608 AAACAAAA _____CAAAAAUU 5152 UUUACAGA CUGAUGAG X 3470 ACAAAAAUU 4609 CGAA AUUUUUGU _____UCUGUAAA 5153 UUUUACAG CUGAUGAG X 3471 CAAAAAUUU 4610 ICGAA AAUUUUUG ______CUGUAAAA I WO 99/50403 WO 9950403PCTIUS99/06507 205 Seq. I.0D. Seq. I. D.

Position RZ No. Substrate No.

5154 GUUUUACA CUGAUGAG X 3472 AAAAAUUUC 4611 AAAUUUUU UGUAAAAC 5158 ACCUGUUU CUGAUGAG X 3473 AUUUCUGUA 4612 CGAA ACAGAAAU AAACAGGU 5167 ACUGUUAU CUGAUGAG X 3474 AAACAGGUU 4613 CGAA ACCUGUUU AUAACAGU______ 5168 CACUGUUA CUGAUGAG X 3475 AACAGGUUA 4614 CGAA AACCUGUU UAACAGUG______ 5170 AACACUGU CUGAUGAG X 3476 CAGGUUAUA 4615 CGAA AUAACCUG ACAGUGUU 5178 AGACUUUA CUGAUGAG X 3477 AACAGUGUU 4616 CGAA ACACUGUU UAAAGUCU______ 5179 GAGACUUU CUGAUGAG X 3478 ACAGUGUUU 4617 CGAA AACACUGU AAAGUCUC______ 5180 UGAGACUU CUGAUGAG X 3479 CAGUGUUUA 4618 CGAA AAACACUG AAGUCUCA______ 5185 GAAACUGA CUGAUGAG X 3480 UUUAAAGUC 4619 CGAA ACUUUAAA UCAGUUUC 5187 AAGAAACU CUGAUGAG X 3481 UAAAGUCUC 4620 CGAA AGACUUUA 5191 AAGCAAGA CUGAUGAG X 3482 GUCUCAGUU 4621 CGAA ACUGAGAC UCUUGCUU 5192 CAAGCAAG CUGAUGAG X 3483 UCUCAGUUU 4622 CGAA AACUGAGA CUUGCUUG 5193 CCAAGCAA CUGAUGAG X 3484 CUCAGUUUC 4623 CGAA AAACUGAG UUGCUUGG______ 5195 CCCCAAGC CUGAUGAG X 3485 CAGUUUCUU 4624 CGAA AGAAACUG ______GCUUGGGG 5199 AGUUCCCC CUGAUGAG X 3486 UUCUUGCUU 4625 CGAA AGCAAGAA GGGGAACU 5208 AGGGACAC CUGAUGAG X 3487 GGGGAACUU 4626 CGAA AGUUCCCC GUGUCCCU WO 99/50403 WO 9950403PCTIUS99/06507 206 Seq. I.D. Seq. I. D.

Position RZ No. Substrate No.

5213 ACAUUAGG CUGAEJGAG X 3488 ACUUGEJGUC 4627 CGAA ACACAAGU CCUAAUGU 5217 UAACACAU CUGAUGAG X 3489 GUGUCCCUA 4628 CGAA AGGGACAC IAUGUGUUA 5224 AGCAAUCU CUGAUGAG X 3490 UAAUGUGUU 4629 CGAA ACACAUUA AGAUUGCU 5225 UAGCAAUC CUGAUGAG X 3491 AAUGUGUUA 4630 CGAA AACACAUU GAUUGCUA 5229 AAUCUAGC CUGAUGAG X 3492 UGUUAGAUU 4631 CGAA AUCUAACA GCUAGAUU 5233 UAGCAAUC CUGAUGAG X 3493 AGAUUGCUA 4632 CGAA AGCAAUCU GAUUGCUA 5237 UCCUUAGC CUGAUGAG X 3494 UGCUAGAUU 4633 CGAA AUCUAGCA IGCUAAGGA 5241 CAGCUCCU CUGAUGAG X 3495 AGAUUGCUA 4634 CGAA AGCAAUCU AGGAGCUG 5252 CUGUCAAG CUGAUGAG X 3496 GAGCUGAUA 4635 CGAA AUCAGCUC CUUGACAG 5255 AAACUGUC CUGAUGAG X 3497 CUGAUACUU 4636 CGAA AGUAUCAG GACAGUUU 5262 GUCUAAAA CUGAUGAG X 3498 UUGACAGUU 4637 CGAA ACUGUCAA _____UUUUAGAC 5263 GGUCUAAA CUGAUGAG X 3499 UGACAGUUU 4638 CGAA AACUGUCA UUUAGACC 5264 AGGUCUAA CUGAUGAG X 3500 GACAGUUUU 4639 CGAA AAACUGUC UUAGACCU 5265 CAGGUCUA CUGAUGAG X 3501 ACAGUUUUU 4640 CGAA AAAACUGU UAGACCUG______ 5266 ACAGGUCU CUGAUGAG X 3502 CAGUUUUUU 4641 CGAA AAAAACUG AGACCUGU 5267 CACAGGUC CUGAUGAG X 3503 AGUUUUUUA 4642 CGAA AAAAAACU IGACCUGUG

I

WO 99/50403 WO 9950403PCT/US99/06507 207 Seq. I.D. Seq. I. D.

Position RZ No. Substrate No.

5277 UUUUUAGU CUGAUGAG X 3504 ACCUGUGUU 4643 CGAA ACACAGGU ACUAAAAA 5278 UUUUUUAG CUGAUGAG X 3505 CCUGUGUUA 4644 CGAA AACACAGG CUAAAAAA 5281 CUUUUUUU CUGAUGAG X 3506 GUGUUACUA 4645 CGAA AGUAACAC AAAAAAAG 5298 CCUUUUCC CUGAUGAG X 3507 AUGAAUGUC 4646 CGAA ACAUUCAU GGAAAAGG 5311 ACCCUCCC CUGAUGAG X 3508 AAGGGUGUU 4647 CGAA ACACCCUU GGGAGGGU 5323 UCUUUGUU CUGAUGAG X 3509 AGGGUGGUC 4648 ACCACCCU 5343 AACACCAU CUGAUGAG X 3510 AAAGAUGUU 4649 CGAA ACAUCUUU AUGGUGUU 5344 AAACACCA CUGAUGAG X 3511 AAGAUGUUA 4650 CGAA AACAUCUU UGGUGUUU 5351 UAAGUCUA CUGAUGAG X 3512 UAUGGUGUU 4651 CGAA ACACCAUA UAGACUUA 5352 AUAAGUCU CUGAUGAG X 3513 AUGGUGUUU 4652 CGAA AACACCAU AGACUUAU 5353 CAUAAGUC CUGAUGAG X 3514 UGGUGUUUA 4653 AAACACCA GACUUAUG 5358 ACAACCAU CUGAUGAG X 3515 UUUAGACUU 4654 AGUCUAAA AUGGUUGU 5359 AACAACCA CUGAUGAG X 3516 UUAGACUUA 4655 CGAA AAGUCUAA UGGUUGUU 5364 UUUUUAAC CUGAUGAG X 3517 CUUAUGGUU 4656 ACCAUAAG GUUAAAAA 5367 ACAUUUUU CUGAUGAG X 3518 AUGGUUGUU 4657 CGAA ACAACCAU IAAAAAUGU______ 5368 GACAUUUU CUGAUGAG X 3519 UGGUUGUUA 4658 CGAA AACAACCA

AAAAUGUC

WO 99/50403 WO 9950403PCT/US99/06507 208 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

5376 CUUGAGAU CUGAUGAG X 3520 AAAAAUGUC 4659 CGAA ACAUUUUU AUCUCAAG 5379 UGACUUGA CUGAUGAG X 3521 AAUGUCAUC 4660 CGAA AUGACAUU UCAAGUCA 5381 CUUGACUU CUGAUGAG X 3522 UGUCAUCUC 4661 CGAA AGAUGACA AAGUCAAG 5386 AGUGACUU CUGAUGAG X 3523 ECUCAAGUC 4662 CGAA ACUUGAGA AAGUCACU 5391 AGACCAGU CUGAUGAG X 3524 AGUCAAGUC 4663 CGAA ACUUGACU ACUGGUCU 5398 UGCAAACA CUGAUGAG X 3525 UCACUGGUC 4664 CGAA ACCAGUGA UGUUEJGCA 5402 CAAAUGCA CUGAUGAG X 3526 UGGUCUGUU 4665 CGAA ACAGACCA tGCAUUUG 5403 UCAAAUGC CUGAUGAG X 3527 GGUCUGUUU 4666 CGAA AACAGACC GCAUUUGA 5408 AUGUAUCA CUGAUGAG X 3528 GUUUGCAUU 4667 CGAA AUGCAAAC UGAUACAU 5409 AAUGUAUC CUGAUGAG X 3529 UtJUGCAUUU 4668 CGAA AAUGCAAA GAUACAUU 5413 CAAAAAUG CUGAUGAG X 3530 CAUUUGAUA 4669 AUCAAAUG CAUUUUUG______ 5417 AGUACAAA CUGAUGAG X 3531 UGAUACAUU 4670 AUGUAUCA UUUGUACU______ 5418 UAGUACAA CUGAUGAG X 3532 GAUACAUUU 4671 CGAA AAUGUAUC UUGUACUA______ 5419 UUAGUACA CUGAUGAG X 3533 AUACAUUUU 4672 CGAA AAAUGUAU UGUACUAA 5420 GUUAGUAC CUGAUGAG X 3534 UACAUUUUU 4673 CGAA AAAAUGUA GUACUAAC 5423 CUAGUUAG CUGAUGAG X 3535 AUUUUUGUA 4674 fCGAA ACAAAAAU

CUAACUAG

WO 99/50403 WO 9950403PCT/US99/06507 209 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No.

5426 AUGCUAGU CUGAUGAG X 3536 EJUUGUACUA 4675 CGAA AGUACAAA ACUAGCAU 5430 UACAAUGC CUGAUGAG X 3537 UACUAACUA 4676 CGAA AGUUAGUA GCAUUGUA 5435 AAUUUUAC CUGAUGAG X 3538 ACUAGCAUU 4677 CGAA AUGCUAGU GUAAAAUU 5438 AAUAAUUU CUGAUGAG X 3539 AGCAUUGUA 4678 CGAA ACAAUGCU AAAUUAUU 5443 CAUGAAAU CUGAUGAG X 3540 UGUAAAAUU 4679 CGAA AUUUUACA AUUUCAUG 5444 UCAUGAAA CUGAUGAG X 3541 GUAAAAUUA 4680 CGAA AAUUUUAC EJUUCAUGA 5446 AAUCAUGA CUGAUGAG X 3542 AAAAUUAUU 4681 CGAA AUAAUUUU ______UCAUGAUU 5447 UAAUCAUG CUGAUGAG X 3543 AAAUUAUUU 4682 CGAA AAUAAUUU CAUGAUUA 5448 CUAAUCAU CUGAUGAG X 3544 AAUUAUUUC 4683 CGAA AAAUAAUU AUGAUUAG 5454 UAAUUUCU CUGAUGAG X 3545 UUCAUGAUU 4684 CGAA AUCAUGAA AGAAAUUA 5455 GUAAUUUC CUGAUGAG X 3546 UCAUGAUUA 4685 CGAA AAUCAUGA GAAAUUAC 5461 CCACAGGU CUGAUGAG X 3547 UUAGAAAUU 4686 AUtJUCUAA _____ACCUGUGG 5462 UCCACAGG CUGAUGAG X 3548 UAGAAAUUA 4687 CGAA AAUUUCUA CCUGUGGA______ 5472 UAUACAAA CUGAUGAG X 3549 CUGUGGAUA 4688 CGAA AUCCACAG IUUUGUAUA 5474 UUUAUACA CUGAUGAG X 3550 GUGGAUAUU 4689 CGAA AUAUCCAC UGUAUAAA 5475 UUUUAUAC CUGAUGAG X 3551 UGGAUAUUU 4690 CGAA A.AUAUCCA IGUAUAAAA WO 99/50403 WO 9950403PCT[US99/06507 210 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

5478 CACUUUUA CUGAUGAG X 3552 AUAUUEJGUA 4691 CGAA ACAAAUAU UAAAAGtJG 5480 CACACtJUU CEJGAUGAG X 3553 AUUUGUAUA 4692 CGAA AUACAAAU AAAGUGUG 5493 AAAAAAIJU CUGAUGAG X 3554 UGUGAAAUA 4693 CGAA AUUUCACA AAUUUUUU 5497 UIJAUAAAA CUGAUGAG X 3555 AAAUAAAUU 4694 CGAA AUUUAUUU UUUUAUAA 5498 UUUAUAAA CUGAUGAG X 3556 AAUAAAUUU 4695 CGAA AAUUUAUU UUUAUAAA 5499 UUEJUAUAA CUGAUGAG X 3557 AUAAAUUUU 4696 CGAA AAAUUUAU UUAUAAAA 5500 CUUUUAUA CUGAUGAG X 3558 UAAAUUUUU 4697 CGAA AAAAUUUA UAUAAAAG 5501 ACUUUUAU CUGAUGAG X 3559 AAAUUUUUU 4698 CGAA AAAAAUUU -AUAAAAGU______ 5502 CACUUUUA CUGAUGAG X 3560 AAUUUUUUA 4699 CGAA AAAAAAUU UAAAAGUG______ 5504 AACACUUU CUGAUGAG X 3561 UUUUUUAUA 4700 CGAA AUAAAAAA AAAGUGUU______ 5512 AAACAAUG CUGAUGAG X 3562 AAAAGUGUU 4701 CGAA ACACUUUU CAUUGUUU______ 5513 GAAACAAU CUGAUGAG X 3563 AAAGUGUUC 4702 CGAA AACACUUU AUUGUUUC______ 5516 UACGAAAC CUGAUGAG X 3564 GUGUUCAUU 4703 CGAA AUGAACAC GUUUCGUA______ 5519 UGUUACGA CUGAUGAG X 3565 UUCAUUGUU 4704 CGAA ACAAUGAA 5520 GUGUUACG CUGAUGAG X 3566 UCAUUGUUU 4705 CGAA AACAAUGA CGUAACAC 5521 UGUGUUAC CUGAUGAG X 3567 CAUUGUUUC 4706 CGAA AAACAAUG I GUAACACA WO 99/50403 WO 9950403PCTIUS99/06507 Seq. I.D. Seq. I. D.

Position RZ No. Substrate No.

5524 UGCEJGUGU CUGAIJGAG X 3568 UGUUUCGtJA 4707 CGAA ACGAAACA IACACAGCA 55534 ACAUAUAC CUGAUGAG X 3569 CACAGCAUU 4708 CGAA AUGCUGUG GUAUAUGU 5537 UUCACAUA CUGAUGAG X 3570 AGCAUUGUA 4709 CGAA ACAAUGCU UAUGUGAA 5539 GCUUCACA CUGAUGAG X 3571 CAUUGUAUA 4710 AUACAAUG UGUGAAGC 5553 UAAUUUUA CUGAUGAG X 3572 AGCAAACUC 4711 CGAA AGUUUGCU UAAAAUUA 5555 UAUAAUUU CUGAUGAG X 3573 CAAACUCUA 4712 CGAA AGAGUUUG AAAUUAUA 5560 UCAUUUAU CUGAUGAG X 3574 UCUAAAAUU 4713 CGAA AUUUUAGA AUAAAUGA 5561 GUCAUUUA CUGAUGAG X 3575 CUAAAAUUA 4714 CGAA AAUUUUAG UAAAUGAC 5563 UUGUCAUU CUGAUGAG X 3576 AAAAUUAUA 4715 CGAA AUAAUUUU AAUGACAA 5579 AAAUAGAU CUGAUGAG X 3577 ACCUGAAUU 4716 CGAA AUUCAGGU AUCUAUUU 5580 GAAAUAGA CUGAUGAG X 3578 CCUGAAUUJA 4717 CGAA AAJJUCAGG UCUAUUUC 5582 AUGAAAUA CUGAUGAG X 3579 UGAAUUAUC 4718 CGAA AUAAUUJCA UAUUUCAU 5584 UGAUGAAA CUGAUGAG X 3580 AAUUAUCUA 4719 CGAA AGAUAAUU UUUCAUCA 5586 UUUGAUGA CUGAUGAG X 3581 UUAUCUAUU 4720 CGAA AUAGAUAA

UCAUCAAA

5587 UUUUGAUG CUGAUGAG X 3582 UAUCUAUUU 4721 CGAA AAUAGAUA CAUCAAAA I 5588 UUUUUGAU CUGAUGAG X 3583 AUCUAUUUC 4722 CGAA AAAUAGAU L!l AUCAAAAA WO 99/50403 WO 9950403PCTIUS99/06507 212 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No.

5591 UUUUtUUUU CUGAUGAG X 3584 UAUUUCAUC 4723 CGAA AUGAAAUA AAAAAAAA 5614 UGCCCAUA CUGAUGAG X 3585 AAAAAACUU 4724 CGAA AGUUUUUU UAUGGGCA 5615 GUGCCCAU CUGAUGAG X 3586 AAAAACUUU 4725 CGAA AAGUUUUU IAUGGGCAC 5616 UGUGCCCA CUGAUGAG X 3587 AAAACUUUA 4726 CGAA AAAGUUUU

UGGGCACA

WO 99/50403 WO 9950403PCTIUS99/06507 213 TABLE VIII: HAIRPIN RIBOZYME AND TARGET SEQUENCES FOR INTEGRIN ALPHA 6 SUBUNIT Seq. I.D. Seq. I.D.

Position RZ No. Substrate No 8 CCCCGG AGAA GUCG 4727 CGACC GUC 4821 ACCAGAGAAACA X CCGGGG

GUACAUUACCUGGUA

UGCUGC AGAA GCAG 4728 CUGCG GUA 4822 ACCAGAGAAACA X GCAGCA

GUACAUUACCUGGUA________

77 GUCCGA AGAA GCCG 4729 CGCCA GCC 4823 ACCAGAGAAACA X UCGGAC

GUACAUUACCUGGUA

83 GGCUGG AGAA GAGG 4730 CCUCG GAG 4824 ACCAGAGAAACA X CCAGCC GUACAUUACCUGGUA 89 GCUCCG AGAA GGGU 4731 ACCCA GCC 4825 ACCAGAGAAACA X CGGAGC

GUACAUUACCUGGUA_____

106 UGCAGC AGAA GCCC 4732 GGGCG GCC 4826 ACCAGAGAAACA X GCUGCA

_______GUACAUUACCUGGUA________

109 ACCUGC AGAA GCCG 4733 CGGCC GCU 4827 ACCAGAGAAACA X GCAGGU GUACAUUACCUGGUA 122 GAGGGG AGAA GGGA 4734 UCCCC GCU 4828 ACCAGAGAAACA X CCCCUC GUACAUUACCUGGUA 142 GCCAUG AGAA GACG 4735 CGUCC GCC 4829 ACCAGAGAAACA X CAUGGC

_______GUACAUUACCUGGUA

152 CCCGGC AGAA GCCA 4736 UGGCC GCC 4830 ACCAGAGAAACA X GCCGGG IGUACAUUACCUGGUA WO 99/50403 WO 9950403PCT/US99/06507 214 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No 155 CUGCCC AGAA GCGG 4737 CCGCC GCC 4831 ACCAGAGAAACA X GGGCAG

GUACAUUACCUGGJA_____

163 AAGCAC AGAA GCCC 4738 GGGCA GCU 4832 ACCAGAGAAACA X GUGCUU

GUACAUUACCUGGUA________

181 CCCGCC AGAA GGJA 4739 EJACCU GUC 4833 ACCAGAGAAACA X GGCGGG

GUACAUUACCUGGUA________

196 AGCCGG AGAA GGAG 4740 CUCCU GUC 4834 ACCAGAGAAACA X CCGGCU

GUACAUUACCUGGUA________

202 GCGCCG AGAA GGGA 4741 UCCCG GCU 4835 ACCAGAGAAACA X CGGCGC GUACAUUACCUGGUA 212 GUUGAA AGAA GCGC 4742 GCGCA GCC 4836 ACCAGAGAAACA X UUCAAC GUACAUUACCUGGUA 279 GCGAGA AGAA GAAG 4743 CUUCG GCU 4837 ACCAGAGAAACA X UCUCGC GUACAUUACCUGGJA 310 UCCUOG AGAA GCAG 4744 CUGCA GCC 4838 ACCAGAGAAACA X CGAGGA IGUACAUUACCUGGUA 325 AGCAAC AGAA GCUU 4745 AAGCG GCU 4839 ACCAGAGAAACA X GUUGCU

GUACAUUACCUGGUA

328 ACGAGC AGAA GCCG 4746 CGGCU GUU 4840 ACCAGAGAAACA X GCUCGU

GUACAUUACCUGGUA___________

WO 99/50403 WO 9950403PCT!US99/06507 215 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No 394 CAGCUG AGAA GCCC 4747 GGGCU GUA 4841 ACCAGAGAAACA X CAGCUG

GUACAUUACCUGGUA

399 UGUCGC AGAA GUAC 4748 GUACA GCU 4842 ACCAGAGAAACA X GCGACA

GUACAUUACCUGGUA

413 CCCCCG AGAA GUGA 4749 UCACC GCC 4843 ACCAGAGAAACA X CGGGGG

GUACAUUACCUGGUA

433 AACUCG AGAA GCGU 4750 ACGCG GAU 4844 ACCAGAGAAACA X CGAGUU

GUACAUUACCUGGUA

455 CGUGGG AGAA GCAU 4751 AUGCU GAC 4845 ACCAGAGAAACA X CCCACG

GUACAUUACCUGGUA

500 GCUCUG AGAA GUGA 4752 UCACC GUC 4846 ACCAGAGAAACA X CAGAGC

________GUACAUUACCUGGUA

899 AGCAGG AGAA GGAA 4753 UUCCU GUU 4847 ACCAGAGAAACA X CCUGCU

_______GUACAUUACCUGGUA

1162 UCAAAA AGAA GUGG 4754 CCACA GUA 4848 ACCAGAGAAACA X UUUUGA

________GUACAUUACCUGGUA

1224 UAUUCC AGAA GCCU 4755 AGGCA GALJ 4849 ACCAGAGAAACA X GGAAUA GUACAUUACCUGGUA 1334 AGCUCC AGAA GCAA 4756 UUGCA GUU 4850 ACCAGAGAAACA X GGAGCU I GUACAUUACCUGGUA______________ WO 99/50403 WO 9950403PCTIUS99/06507 21.6 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No 1345 UCAUCA AGAA GAGC 4757 GCUCC GUA 4851 ACCAGAGAAACA X UGAUGA

IGUACAUUACCUGGUA

1490 AGCAAC AGAA GGGU 4758 ACCCU GAU 4852 ACCAGAGAAACA X GUUGCU

GUACAUUACCUGGUA

1499 GGAACC AGAA GCAA 4759 UUGCU GUUl 4853 ACCAGAGAAACA X GGUUCC

GUACAUUACCUGGUA

1514 UACUGA AGAA GAGA 4760 UCUCA GAU 4854 ACCAGAGAAACA X UCAGUA fGUACAUUACCUGGUA 1533 GCCGGG AGAA GAAA 4761 UUUCA GAUl 4855 ACCAGAGAAACA X CCCGGC

GUACAUUACCUGGUA

1540 AUCACA AGAA GGGA 4762 UCCCG GCC 4856 ACCAGAGAAACA X UGUGAU

________GUACAUUACCUGGUA

1650 AUUCAA AGAA GGAU 4763 AUCCU GUUl 4857 ACCAGAGAAACA X UUGAAU

GUACAUUACCUGGUA

1673 AUAACC AGAA GGGU 4764 ACCCC GCU 4858 ACCAGAGAAACA X GGUUAU

GUACAUUACCUGGUA

1759 UUUCCA AGAA GAAC 4765 GUUCA GUU 4859 ACCAGAGAAACA X UCGAAA

GUACAUUACCUGGUA

1895 CACUGA AGAA GUUA 4766 UAACU GCC 4860 ACCAGAGAAACA X UCAGUG

________GUACAUUACCUGGUA

WO 99/50403 WO 9950403PCTIUS99/06507 217 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No 1973 GGGUUC AGAA GAAU 4767 AUUCA GAU 4861 ACCAGAGAAACA X GAACCC GUACAUtJACCUGGUA 1988 AAUAUG AGAA GUCU 4768 AGACA GCU 4862 ACCAGAGAAACA X CAUAUU

GUACAUUACCUGGUA

2187 IGGAAG AGAA GUUU 4769 AAACA GCC 4863 ACCAGAGAAACA X CUUCCA

GUACAUUACCUGGUA

2245 GUUGCA AGAA GUUIJ 4770 AAACU GAU 4864 ACCAGAGAAACA X UGCAAC

GUACAUUACCUGGUA

2314 CAACUC AGAA GUUU 4771 AAACA GTJU 4865 ACCAGAGAAACA X GAGUUG

GUACAUUACCUGGUA

2351 CUCACA AGAA GCUU 4772 AAGCU GAC 4866 ACCAGAGAAACA X UGUGAG

GUACAUUACCUGGUA

2530 GAtJAAA AGAA GUUC 4773 GAACU GCU 4867 ACCAGAGAAACA X UUUAUC

GUACAUUACCUGGUA_____________

2540 UCCCGA AGAA GAUA 4774 UAUCG GUC 4868 ACCAGAGAAACA X UCGGGA ________GUACAUUACCUGGUA 2585 GCCAAC AGAA GUAC 4775 GUACA GUU 4869 ACCAGAGAAACA X GUUGGC

GUACAUUACCUGGUA_____

2917 UUAAGA AGAA GGUA 4776 UACCA GAC 4870 ACCAGAGAAACA X UCUUAA I GUACAUUACCUGGUA WO 99/50403 WO 9950403PCTIUS99/06507 218 Seq. 1.D. Seq. I.D.

Position RZ No. Substrate No 2928 UCACGC AGAA GUtJA 4777 UAACU GUA 4871 ACCAGAGAAACA X GCGLJGA GUACAEJUACCtJGGUA 2958 GCGGGC AGAA GAUG 4778 CAUCA GAU 4872 ACCAGAGAAACA X GCCCGC

GUACAUUACCUGGUA

2965 CCCCGC AGAA GGCA 4779 UGCCC GCU 4873 ACCAGAGAAACA X GCGGGG

GUACAUUACCUGGUA

3092 GGCAGC AGAA GUCA 4780 UGACU GCU 4874 ACCAGAGAAACA X GCUGCC

GUACAUUACCUGGUA

3095 UUCGGC AGAA GCAG 4781 CUGCU GCU 4875 ACCAGAGAAACA, X GCCGAA

,GUACAUUACCUGGUA

3098 AUUUC AGAA GCAG 4782 CUGCU GCC 4876 ACCAGAGAAACA X GAAAAU

GUACAUUACCUGGUA

3164 CUGAGC AGAA GUCU 4783 AGACU GUA 4877 ACCAGAGAAACA X GCUCAG

GUACAUUACCUGGUA

3172 CCCGAA AGAA GAGC 4784 GCUCA GUA 4878 ACCAGAGAAACA X UUCGGG

GUACAUUACCUGGUA

3359 CUAUGC AGAA GAAG 4785 CUUCU GAO 4879 ACCAGAGAAACA X GCAUAG

GUACAUUACCUGGUA

3581 UUUGGG AGAA GOCA 4786 OCACA GUA 4880 ACCAGAGAAACA X CCCAAA _______GUACAUOACCUGGUA WO 99/50403 WO 9950403PCTIUS99/06507 219 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No 3592 GGAAAA AGAA GUUU 4787 AAACU GCU 4881 ACCAGAGAAACA X UUUUCC

GUACAUUACCUGGUA

3633 GGAEJUG AGAA GGCU 4788 AGCCU GCU 4882 ACCAGAGAAACA X CAAUCC GUACAUUACCUGGUA 3651 UCUGAA AGAA GUCC 4789 GGACU GAU 4883 ACCAGAGAAACA X UUCAGA

GUACAUUACCUGGUA______________

3673 GGUUCG AGAA GUGU 4790 ACACA GUA 4884 ACCAGAGAAACA X CGAACC 3686 AGUUAA AGAA GUAG 4791 CUACA GUU 4885 ACCAGAGAAACA X EJUAACU 3725 GUGCAA AGAA GGAG 4792 CUCCU GUU 4886 ACCAGAGAAACA X UUGGAC 3750 CAUUCC AGAA GUUU 4793 AAACU GUU 4887 ACCAGAGAAACA X GGAAUG GUACAUUACCUGGUA 3774 AAUUAC AGAA GUUA 4794 UAACU GCC 4888 ACCAGAGAAACA X GUAAUU 3818 AUGUAA AGAA GCCA 4795 UGGCU GAG 4889 ACCAGAGAAACA X UUACAU GUACAUUACCUGGUA 3847 CAACUG AGAA GGCC 4796 GGCCU GCC 4890 ACCAGAGAAACA X CAGUUG GUACAUUACCUGGUA WO 99/50403 WO 9950403PCTIUS99/06507 220 Seq. I. D. Seq. I.0D.

Position RZ No. Substrate No 3852 GAGUGC AGAA GGGC 4 797 GCCCA GUU 4891 ACCAGAGAAACA X GCACEJC

IGUACAUUACCUGGUA

3927 GGUUAG AGAA GCCA 4798 tJGGCC G(JC 4892 ACCAGAGAAACA X CUAACC

GUACAUUACCUGGUA

3944 CUGCGC AGAA GGCC 4799 GGCCU GCU 4893 ACCAGAGAAACA X GCGCAG

,GUACAUUACCUGGUA

3952 AUGGAC AGAA GCGC 4800 GCGCA GAC 4894 ACCAGAGAAACA X GUCCAU _______GEACAUUACCUGGUA 3971 AUGUGG AGAA GCUA 4801 UAGCU GUC 4895 ACCAGAGAAACA X CCACAU

GUACAUUACCUGGUA________

4026 GUUUAA AGAA GCAC 4802 GUGCU GUC 4896 ACCAGAGAAACA X UUAAAC GUACAUUACCUGGUA 4071 GGAAAA AGAA GUAG 4803 CtJACC GUC 4897 ACCAGAGAAACA X UUUUCC

GUACAUUACCUGGUA_____________

4081 CUAGGA AGAA GGAA 4804 UUCCU GUU 4898 ACCAGAGAAACA X UCCUAG

GUACAUUACCUGGUA______________

4104 GACGUG AGAA GGUA 4805 UACCU GCU 4899 ACCAGAGAAACA X CACGUC GUACAUUACCUGGUA 4165 AUUCAA AGAA GUUG 4806 CAACA GAC 4900 ACCAGAGAAACA X UUGAAUJ

GUACAUUACCUGGUA_____________

WO 99/50403 WO 9950403PCT/US99/06507 221 Seq. I. D. Seq. I. D.

Position RZ No. Substrate No 4262 AGGGUA AGAA GGAG 4807 CUCCA GUU 4901 ACCAGAGAAACA X UACCCU

GUACAUUACCUGGUA

4426 GGUGGA AGAA GUCA 4808 UGACA GCC 4902 ACCAGAGAAACA X UCCACC

GUACAUUACCUGGUA______________

4600 UGAGUA AGAA GCAC 4809 GUGCG GUU 4903 ACCAGAGAAACA X UACUCA

GUACAUUACCUGGUA

4611 AUUUGC AGAA GUGA 4810 UCACU GCU 4904 ACCAGAGAAACA X GCAAAU

GUACAUUACCUGGUA

4623 UGAAUA AGAA GUAU 4811 AUACU GtJA 4905 ACCAGAGAAACA X UAUUCA GUACAUUACCUGGUA 4680 UACUGG AGAA GUU~U 4812 AAACU GAU 4906 ACCAGAGAAACA X CCAGUA GUACAUUACCUGGUA 4686 GUCUUA AGAA GGAU 4813 AUCCA GUA 4907 ACCAGAGAAACA *X UAAGAC

GUACAUUACCUGGUA_____

4769 UGGGAA AGAA GAUA 4814 EJAUCU GUA 4908 ACCAGAGAAACA X UUCCCA

GUACAUUACCUGGUA_____

4895 AAAAAA AGAA GCUU 4815 AAGCU GAU 4909 ACCAGAGAAACA X UUUUUU GUACAUUACCUGGUA 5015 ACUACA AGAA GUGU 4816 ACACA GUU 4910 ACCAGAGAAACA X UGUAGU GUACAUUACCUGGUA WO 99/50403 WO 9950403PCTIUS99/06507 222 Seq. I.D. Seq. I.D.

Position RZ No. Substrate No 5030 CAAAAC AGAA GUGG 4817 CCACU GUEJ 4911 ACCAGAGAAACA X GUUUUG

IGUACAUUACCUGGUA

5188 GCAAGA AGAA GAGA 4818 UCUCA GUU 4912 ACCAGAGAAACA X UCUUGC

GUACAUUACCUGGUA

5259 CUAAAA AGAA GUCA 4819 UGACA GUU 4913 ACCAGAGAAACA X UUUUAG

GUACAUUACCUGGUA

5399 AAUGCA AGAA GACC 4820 GGUCU GUU 4914 ACCAGAGAAACA X UGCAUU

______GUACAUUACCUGGUA

WO 99/50403 WO 9950403PCTIUS99/06507 223 TABLE IX: HAMMERHEAD RIBOZYME AND TARGET SEQUENCES FOR INTEGRIN SUBUNIT BETA 3 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

17 GAGGGCAA CUCAUGAG X CGAA 4915 GAUGUGGUC 5702 ACCACAUC UUGCCCUC 19 UUGAGGGC CUGAUGAG X CGAA 4916 UGUGGUCUU 5703 AGACCACA ______GCCCUCAA UACCUGUU CUGAUGAG X CGAA 4917 CUUGCCCUC 5704 AGGGCAAG AACAGGUA 33 AGACUACC CUGAUGAG X CGAA 4918 CAACAGGUA 5705 ACCUGUUG GGUAGUCU 37 CGGUAGAC CUGAUGAG X CGAA 4919 AGGUAGGUA 5706 ACCUACCU GUCUACCG UUCCGGUA CUGAUGAG X CGAA 4920 UAGGUAGUC 5707 ACUACCUA UACCGGAA 42 UUUUCCGG CUGAUGAG X CGAA 4921 GGUAGUCUA 5708 AGACUACC CCGGAAAA______ 58 UCUUGCCU CUGAUGAG X CGAA 4922 ACCAAACUA 5709 AGUUUGGU AGGCAAGA 74 UAUUCACU CUGAUGAG X CGAA 4923 AAAAAAAUU 5710 AUUUUU[UU AGUGAAUA UUAUUCAC CUGAUGAG X CGAA 4924 AAAAAAUUA 5711 AAUUUU[UU GUGAAUAA 82 UCCUUU[AU CUGAUGAG X CGAA 4925 UAGUGAAUA 5712 AUUCACUA AUAAAGGA______ CAGUCCUU CUGAUGAG X CGAA 4926 UGAAUAAUA 5713 AUUAUUCA AAGGACUG 101 CUUCUCUG CUGAUGAG X CGAA 4927 GAACCGGUU 5714 ACCGGUUC CAGAGAAG______ 102 CCUUCUCU CUGAUGAG X CGAA 4928 AACCGGUUC 5715 AACCGGUU AGAGAAGG 114 AUCUGCUG CUGAUGAG X CGAA 4929 GAAGGCAUU 5716 AUGCCUUC CAGCAGAU WO 99/50403 WO 9950403PCTIUS99/06507 224 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

115 CAUCUGCU CUGAUGAG X CGAA 4930 AAGGCAUUC 5717 AAUGCCUU AGCAGAUG 125 GACUGGCA CUGAUGAG X CGAA 4931 GCAGAUGUU 5718 ACAUCUGC ______UGCCAGUC 126 UGACUGGC CUGAUGAG X CGAA 4932 CAGAUGUUU 5719 AACAUCUG GCCAGUCA 133 AUUCAUUU CUGAUGAG X CGAA 4933 UUGCCAGUC 5720 ACUGGCAA AAAUGAAU 142 CACACUUU CUGAUGAG X CGAA 4934 AAAUGAAUU 5721 AUUCAUUU AAAGUGUJG 143 UCACACUU CUGAUGAG X CGAA 4935 AAUGAAUUA 5722 AAUUCAUU AAGUGUGA 164 ACUACCUC CUGAUGAG X CGAA 4936 AUGAAACUC 5723 AGUUUCAU GAGGUAGU 170 UCACCCAC CUGAUGAG X CGAA 4937 CUCGAGGUA 5724 _____ACCUCGAG GUGGGUGA 185 AUUCUUGG CUGAUGAG X CGAA 4938 GAAUGUGUC 5725 ACACAUC CCAAGAAU 194 UUUCGCUG CUGAUGAG X CGAA 4939 CCAAGAAUC 5726 AUUCUUGG CAGCGAAA 209 UCCUGGGA CUGAUGAG X CGAA 4940 AACAGGGUC 5727 ACCCUGUU (CCCAGGA 211 CCUCCUGG CUGAUGAG X CGAA 4941 CAGGGUCUC 5728 AGACCCUG CCAGGAGG 235 CCUCUCCG CUGAUGAG X CGAA 4942 GGAAGGGUC 5729 ACCCUUCC CGGAGAGG 255 AAGGCCAG CUGAUGAG X CGAA 4943 CACAGGCUC 5730 AGCCUGUG CUGGCCUU 263 UGCUUAGA CUGAUGAG X CGAA 4944 CCUGGCCUU 5731 _____AGGCCAGG ______UCUAAGCA 264 GUGCUUAG CUGAUGAG X CGAA 4945 CUGGCCUUU 5732 AAGGCCAG CUAAGCAC WO 99/50403 WO 9950403PCT/US99/06507 225 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

265 UGUGCUUA CUGAUGAG X CGAA 4946 LGGCCUUUC 5733 AAAGGCCA ______UAAGCACA 267 GGEJGUGCU CUGAUGAG X CGAA 4947 GCCUUUCUA 5734 AGAAAGGC AGCACACC 287 GGGUCCGC CUGAUGAG X CGAA 4948 UGCCCAGUC 5735 ACUGGGCA GCGGACCC 337 CCCACGAG CUGAUGAG X CGAA 4949 AGGCGGGUC 5736 ACCCGCCU CUCGUGGG 340 UCGCCCAC CUGAUGAG X CGAA 4950 CGGGUCCUC 5737 AGGACCCG GUGGGCGA 378 UGGGAAAC CUGAUGAG X CGAA 4951 GGAGCAAUA 5738 AUUGCUCC GUUUCCCA 381 CGGUGGGA CUGAUGAG X CGAA 4952 GCAAUAGUU 5739 ACUAUUGC UCCCACCG 382 GCGGUGGG CUGAUGAG X CGAA 4953 CAAUAGUUU 5740 AACUAUUG ______CCCACCGC 383 AGCGGUGG CUGAUGAG X CGAA 4954 AAUAGUUUC 5741 AAACUAUU CCACCGCU 392 CUGAGAGG CUGAUGAG X CGAA 4955 CCACCGCUC 5742 _____AGCGGUGG 396 GCGCCUGA CUGAUGAG X CGAA 4956 CGCUCCCUC 5743 AGGGAGCG UCAGGCGC 398 CUGCGCCU CUGAUGAG X CGAA 4957 CUCCCUCUC 5744 AGAGGGAG AGGCGCAG 410 CUUCUCUA CUGAUGAG X CGAA 4958 CGCAGGGUC 5745 ACCCUGCG UAGAGAAG______ 412 CGCUUCUC CUGAUGAG X CGAA 4959 CAGGGUCUA 5746 AGACCCUG GAGAAGCG______ 430 CUUCUCUA CUGAUGAG X CGAA 4960 GAGGGGAUC 5747 AUCCCCUC UJAGAGAAG______ 432 GGCUUCUC CUGAUGAG X CGAA 4961 GGGGAUCUA 5748 AGAUCCCC IGAGAAGCCI WO 99/50403 WO 9950403PCTIUS99/06507 226 Posi- Seq. I.D. Seq. I. D.

tion RZ No. Sub strate No.

461 GGGCCGCG CUGAUGAG X CGAA 4962 GCGCGAGUC 5749 ACUCGCGC

CGCGGCCC

477 UGGGACGC CUGAUGAG X CGAA 4963 CGCCCCGUU 5750 ACGGGGCG GCGUCCCA 482 GUGGGUGG CUGAUGAG X CGAA 4964 CGUUGCGUC 5751 ____ACGCAACG

CCACCCAC

496 GGGGAGGG CUGAUGAG X CGAA 4965 CACCGCGUC 5752 ACGCGGUG

CCCUCCCC_

501 GGGGAGGG CUGAUGAG X CGAA 4966 CGUCCCCUC 5753 AGGGGACG CCCUCCCC 506 CGGGAGGG CUGAUGAG X CGAA 4967 CCUCCCCUC 5754 AGGGGAGG

CCCUCCCG

511 CGCAGCGG CUGAUGAG X CGAA 4968 CCUCCCCUC 5755 AGGGGAGG CCGCUGCG 614 GUCGCCCA CUGAUGAG X CGAA 4969 CGGCCGCUC 5756 AGCGGCCG

UGGGCGAC

653 CCUACGCC CUGAUGAG X CGAA 4970 GCGGGCGUU 5757 _____ACGCCCGC

GGCGUAGG

659 UCACCUCC CUGAUGAG X CGAA 4971 GUUGGCGUA 5758 _____ACGCCAAC

GGAGGUGA

676 CCGAGCCG CUGAUGAG X CGAA 4972 GUGAGGCUC 5759 _____AGCCUCAC

CGGCUCGG

682 ACGCUGCC CUGAUGAG X CGAA 4973 CUCCGGCUC 5760 _____AGCCGGAG GGCAGCGU 691 GCAGCUGC CUGAUGAG X CGAA 4974 GGCAGCGUC 5761 ACGCUGCC

GCAGCUGC______

708 GGGGCGCA CUGAUGAG X CGAA 4975 CCCAGGAUC 5762 _____AUCCUGGG

UGCGCCCC

720 CGCAACUU CUGAUGAG X CGAA 4976 GCCCCGGUC 5763 ACCGGGGC

AAGUUGCG

725 AAGUCCGC CUGAUGAG X CGAA 4977 GGUCAAGUU 5764 ACUUGACC GCGGACUU WO 99/50403 WO 9950403PCTIUS99/06507 227 Pos i- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

733 CCGGCUCC CUGAUGAG X CGAA 4978 UGCGGACUU 5765 AGUCCGCA GGAGCCGG 760 GACGNGCG CUGAUGAG X CGAA 4979 GGACUGGUC 5766 _____ACCAGUCC CGCNCGUC 768 CCCACGCA CUGAUGAG X CGAA 4980 CCGCNCGUC 5767 ACGNGCGG ______UGCGUGGG 780 GACACGNG CUGAUGAG X CGAA 4981 GUGGGAAUN 5768 AUUCCCAC CNCGUGUC 788 CCAGCCAG CUGAUGAG X CGAA 4982 NCNCGUGUC 5769 ACACGNGN CUGGCUGG 803 CCGGNUCC CUGAUGAG X CGAA 4983 GGCNCGGUC 5770 ACCGNGCC ______GGANCCGG 825 GGGCCAGG CUGAUGAG X CGAA 4984 GGGNACCUU 5771 AGGUNCCC CCUGGCCC 826 CGGGCCAG CUGAUGAG X CGAA 4985 GGNACCUUC 5772 AAGGUNCC CUGGCCCG 877 UCUCGGAG CUGAUGAG X CGAA 4986 GAGCGGGUC 5773 _____ACCCGCUC CUCCGAGA 880 GCGUCUCG CUGAUGAG X CGAA 4987 CGGGUCCUC 5774 _____AGGACCCG ______CGAGACGC 898 GCCUGGCU CUGAUGAG X CGAA 4988 GAAGCCAUC 5775 _____AUGGCUUC AGCCAGGC 916 CGGCCGGG CUGAUGAG X CGAA 4989 GANNNCCUU 5776 _____AGGNNNUC CCCGGCCG 917 GCGGCCGG CUGAUGAG X CGAA 4990 ANNNCCUUC 5777 _____AAGGNNNU CCGGCCGC 954 GGCUCAGA CUGAUGAG X CGAA 4991 GGGCGCAUC 5778 AUGCGCCC ______UCUGAGCC 956 GGGGCUCA CUGAUGAG X CGAA 4992 GCGCAUCUC 5779 _____AGAUGCGC UGAGCCCC 970 CCCCGGGU CUGAUGAG X CGAA 4993 CCCGCGCUC 5780 AGCGCGGG IACCCGGGG WO 99/50403 WO 9950403PCT/US99/06507 228 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

989 NCACCCGC CUGAUGAG X CGAA 4994 GCGCGCGUC 5781 ACGCGCGC GCGGGUGN 999 CCGACCAG CUGAUGAG X CGAA 4995 CGGGEJGNUC 5782 ANCACCCG CUGGUCGG 1005 CUUGGNCC CUGAUGAG X CGAA 4996 NUCCUGGUC 5783 ACCAGGAN GGNCCAAG 1048 ACCCCCGG CUGAUGAG X CGAA 4997 GUGGGGCUU 5784 AGCCCCAC CCGGGGGU 1049 AACCCCCG CUGAUGAG X CGAA 4998 UGGGGCUUC 5785 AAGCCCCA CGGGGGUU 1057 GCGGGAAC CUGAUGAG X CGAA 4999 CCGGGGGUU 5786 ACCCCCGG GUUCCCGC 1060 GGGGCGGG CUGAUGAG X CGAA 5000 GGGGUUGUU 5787 ACAACCCC CCCGCCCC 1061 AGGGGCGG CUGAUGAG X CGAA 5001 GGGUUGUUC 5788 AACAACCC CCGCCCCU 1070 CCUCUGCC CUGAUGAG X CGAA 5002 CCGCCCCUU 5789 AGGGGCGG

GGCAGAGG

1089 CAGGAAGU CUGAUGAG X CGAA 5003 UGCCCUGUA 5790 _____ACAGGGCA ACUUCCUG 1093 CACCCAGG CUGAUGAG X CGAA 5004 CUGUAACUU 5791 ____AGUUACAG CCUGGGUG 1094 UCACCCAG CUGAUGAG X CGAA 5005 UGUAACUUC 5792 _____AAGUUACA CUGGGUGA 1123 GAAAUGUA CUGAUGAG X CGAA 5006 GCGCGGGUU 5793 ACCCGCGC UACAUUUC 1124 GGAAAUGU CUGAUGAG X CGAA 5007 CGCGGGUUU 5794

ACAUUUCC_

1125 GGGAAAUG CUGAUGAG X CGAA 5008 GCGGGUUUA 5795 AAACCCGC

CAUUUCCCI

1129 UGUGGGGA CUGAUGAG X CGAA 5009 GEJUUACAUU 5796 AUGUAAAC UCCCCACA WO 99/50403 WO 9950403PCTIUS99/06507 229 Posi- Seq. I.D. Seq. I. D.

tion RZ No. Substrate No.

1130 AUGUGGGG CUGAUGAG X CGAA 5010 UUUACAUUU 5797 AAUGUAAA CCCCACAU 1131 AAUGUGGG CUGAUGAG X CGAA 5011 UUACAEJUUC 5798 AAAUGUAA CCCACAUU 1139 AAAUUGGA CUGAUGAG X CGAA 5012 CCCCACAUU 5799 AUGUGGGG ______UCCAAUUUJ 1140 GAAAUUGG CUGAUGAG X CGAA 5013 CCCACAUUU 5800 ____AAUGUGGG _____CCAAUUUC 1141 AGAAAUUG CUGAUGAG X CGAA 5014 CCACAUUUC 5801 AAAUGUGG CAAUUUCU 1146 ACAGGAGA CUGAUGAG X CGAA 5015 UUUCCAAUU 5802 AUUGGAAA ______UCUCCUGU 1147 AACAGGAG CUGAUGAG X CGAA 5016 UUCCAAUUU 5803 AAUUGGAA CUCCUGUU 1148 UAACAGGA CUGAUGAG X CGAA 5017 UCCAAUUUC 5804 AAAUUGGA UCCUGUUA 1150 CGUAACAG CUGAUGAG X CGAA 5018 CAAUUUCUC 5805 AGAAAUUG CUGUUACG 1155 GAAAGCGU CUGAUGAG X CGAA 5019 UCUCCUGUU 5806 ACAGGAGA ACGCUUUC 1156 AGAAAGCG CUGAUGAG X CGAA 5020 CUCCUGUUA 5807 AACAGGAG CGCUUUCU 1161 UCUGGAGA CUGAUGAG X CGAA 5021 GUUACGCUU 5808 AGCGUAAC UCUCCAGA 1162 UUCUGGAG CUGAUGAG X CGAA 5022 UUACGCUUU 5809 AAGCGUAA CUCCAGAA 1163 CUUCUGGA CUGAUGAG X CGAA 5023 UACGCUUUC 5810 AAAGCGUA

UCCAGAAG

1165 ACCUUCUG CUGAUGAG X CGAA 5024 CGCUUUCUC 5811 AGAAAGCG CAGAAGGU 1174 AA.AGAAAA CUGAUGAG X CGAA 5025 CAGAAGGUU 5812 IACCUUCUG

UUUUCUUU

WO 99/50403 WO 9950403PCT[US99/06507 230 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

1175 GAAAGAAA CUGAUGAG X CGAA 5026 AGAAGGUUU 5813 AACCUUCU UUUCUUUC 1176 GGAAAGAA CUGAUGAG X CGAA 5027 GAAGGUUUU 5814 AAACCUUC UUCUUUCC 1177 AGGAAAGA CUGAUGAG X CGAA 5028 AAGGUUUUU 5815 AAAACCUU _______ICUUUCCU 1178 AAGGAAAG CUGAUGAG X CGAA 5029 AGGUUUUUU 5816 AAAAACCU CUUUCCUU 1179 AAAGGAA.A CUGAUGAG X CGAA 5030 GGUUUUUUC 5817 AAAAAACC UUUCCUUU 1181 AAAAAGGA CUGAUGAG X CGAA 5031 EJUUUUUCUU 5818 AGAAAAAA ______ECCUUUUU 1182 AAAAAAGG CUGAUGAG X CGAA 5032 EJUUUUCUUU 5819 AAGAAAAA CCUUUUUU 1183 GAAAAAAG CUGAUGAG X CGAA 5033 UUUUCUUUC 5820 AAAGAAAA CtJUUUUUC 1186 AAAGAAAA CUGAUGAG X CGAA 5034 UCUUUCCUU 5821 AGGAAAGA EJUUUCUUU 1187 GAAAGAAA CUGAUGAG X CGAA 5035 CUUUCCUUU 5822 AAGGAAAG UGUCUGUC 1188 AGAAAGAA CUGAUGAG X CGAA 5036 UUUCCUUUU 5823 AAAGGAAA UUCUUUCU 1189 AAGAAAGA CUGAUGAG X CGAA 5037 UUCCUUUUU 5824 AAAAGGAA UCUGUCUG 1190 AAAGAAAG CUGAUGAG X CGAA 5038 UCCUUUUUU 5825 AAAAAGGA

CUUUCUUU

1191 GAAAGAAA CUGAUGAG X CGAA 5039 CCUUUUUUC 5826 AAAAAAGG UUUCUUUC 1193 AAGAAAGA CUGAUGAG X CGAA 5040 UUUUUUCUU 5827 AGAAAAAA UCUUUCUU 1194 AAAGAAAG CUGAUGAG X CGAA 5041 UUUUUCUUU 5828 AAGAAAAA cUUUCUUU WO 99/50403 WO 9950403PCTIUS99/06507 231 Posi- Seq. I.D. Seq. I.D.

tion- RZ No. Substrate No.

1195 GAAAGAAA CUGAUGAG X CGAA 5042 EJUUUCUUUC 5829 AAAGAAAA UJUUCUUUC 1197 AAGAAAGA CUGAUGAG X CGAA 5043 UUCUUUCUU 5830 AGAAAGAA UCUUUCUU 1198 AAAGAAAG CUGAUGAG X CGAA 5044 UCUUUCUUU 5831 AAGAAAGA CUUUCUUU 1199 AAAAGAAA CUGAUGAG X CGAA 5045 CUUUCUUUC 5832 AAAGAAAG UUUCUUUU 1201 AAAAAAGA CUGAUGAG X CGAA 5046 UUCUUUCUU 5833 AGAAAGAA UCUUUUUU 1202 AAAAAAAG CUGAUGAG X CGAA 5047 UCUUUCUUU 5834 AAGAAAGA CUUUUUUU 1203 UAAAAAAA CUGAUGAG X CGAA 5048 CUUUCUUUC 5835 AAAGAAAG tJUUUUUUA 1205 GGUAAAAA CUGAUGAG X CGAA 5049 UUCUUUCUU 5836 AGAAAGAA UUUUUACC 1206 AGGUAAAA CUGAUGAG X CGAA 5050 UCUUUCUUU 5837 AAGAAAGA UUUUACCU 1207 AAGGUAAA CUGAUGAG X CGAA 5051 CUUUCUUUU 5838 AAAGAAAG UUUACCUU 1208 GAAGGUAA CUGAUGAG X CGAA 5052 UUUCUUUUU 5839 _____AAAAGAAA UUACCUUC 1209 UGAAGGUA CUGAUGAG X CGAA 5053 UUCUUUUUU 5840 AAAAAGAA UACCUUCA 1210 UUGAAGGU CUGAUGAG X CGAA 5054 UCUUUUUUU 5841 AAAAAAGA ______ACCUUCAA 1211 GUUGAAGG CUGAUGAG X CGAA 5055 CUUUUUUUA 5842 AAAAAAAG 1215 GUAUGUUG CUGAUGAG X CGAA 5056 UUUUACCUU 5843 AGGUAAAA CAACAUAC 1216 AGUAUGUU CUGAUGAG X CGAA 5057 UUUACCUUC 5844 AAGGUAAA

AACAUACU

WO 99/50403 WO 9950403PCTIUJS99/06507 232 Posi- Seq. I.D. Seq. 1.D.

tion RZ No. Substrate No.

1222 CGCAGGAC CUGAUGAG X CGAA 5058 UUCAACAUA 5845 AUGtJUGAA CUCCUGCG 1225 CCCCGCAG CUGAUGAG X CGAA 5059 AACAUACUC 5846 AGUAUGUU ______CUGCGGGG 1235 UCCAAAAC CUGAUGAG X CGAA 5060 UGCGGGGUU 5847 ACCCCGCA GUUUUGGA 1238 UGCUCCAA CUGAUGAG X CGAA 5061 GGGGUUGUU 5848 ACAACCCC ______UUGGAGCA 1239 CUGCUCCA CUGAUGAG X CGAA 5062 GGGUUGUUU 5849 AACAACCC UGGAGCAG 1240 CCUGCUCC CUGAUGAG X CGAA 5063 GGUUGUUUU 5850 AAACAACC GGAGCAGG 1257 AGGAGGCA CUGAUGAG X CGAA 5064 AUGAGGCUU 5851 AGCCUCAU UGCCUCCU 1258 GAGGAGGC CUGAUGAG X CGAA 5065 UGAGGCUUU 5852 AAGCCUCA GCCUCCUC 1263 CACUGGAG CUGAUGAG X CGAA 5066 CUUUGCCUC 5853 AGGCAAAG CUCCAGUG 1266 GGACACUG CUGAUGAG X CGAA 5067 UGCCUCCUC 5854 AGGAGGCA CAGUGUCC 1273 CACCUGGG CUGAUGAG X CGAA 5068 UCCAGUGUC 5855 _____ACACUGGA CCCAGGUG 1294 UGGGAGCA CUGAUGAG X CGAA 5069 CGGUGCCUC 5856 AGGCACCG UGCUCCCA 1299 UGCCCUGG CUGAUGAG X CGAA 5070 CCUCUGCUC 5857 AGCAGAGG ______CCAGGGCA 1327 ACACUAGA CUGAUGAG X CGAA 5071 CGAAAAAUC 5858 _____AUUUUUCG UCUAGUGU 1329 AUACACUA CUGAUGAG X CGAA 5072 AAAAAUCUC 5859 AGAUUUUU UAGUGUAU 1331 GAAUACAC CUGAUGAG X CGAA 5073 AAAUCUCUA 5860 IAGAGAUUU

GUGUAUUC

WO 99/50403 WO 9950403PCT[US99/06507 233 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

1336 UCCCCGAA CUGAUGAG X CGAA 5074 UCUAGUGUA 5861 ACACUAGA UUCGGGGA 2.338 GUUCCCCG CUGAUGAG X CGAA 5075 UAGUGUAUU 5862 AUACACUA CGGGGAAC 1339 GGUUCCCC CUGAUGAG X CGAA 5076 AGUGUAUUC 5863 AAUACACU GGGGAACC 1359 GCCCAAGG CUGAUGAG X CGAA 5077 AAAAGGCUC 5864 AGCCUUUU CCUUGGGC 1363 ACCGGCCC CUGAUGAG X CGAA 5078 GGCUCCCUU 5865 AGGGAGCC GGGCCGGU 1377 AAGCCAAG CUGAUGAG X CGAA 5079 GGUGGGAUC 5866 AUCCCACC CUUGGCUU 1380 ACAAAGCC CUGAUGAG X CGAA 5080 GGGAUCCUU 5867 AGGAUCCC GGCUUUGU 1385 CAGAGACA CUGAUGAG X CGAA 5081 CCUUGGCUU 5868 AGCCAAGG UGUCUCUG 1386 CCAGAGAC CUGAUGAG X CGAA 5082 CUUGGCUUU 5869 AACAG GUCUCUGG 1389 CAGCCAGA CUGAUGAG X CGAA 5083 GGCUUUGUC 5870 ACAAAGCC UCUGGCUG 1391 AGCAGCCA CUGAUGAG X CGAA 5084 CUUUGUCUC 5871 AGACAAAG UGGCUGCU 1411 UGACGGCU CUGAUGAG X CGAA 5085 CACACCGUC 5872 ACGGUGUG AGCCGUCA 1418 AUUGCCCU CUGAUGAG X CGAA 5086 UCAGCCGUC 5873 ACGGCUGA AGGGCAAU 1427 CGAAUGCC CUGAUGAG X CGAA 5087 AGGGCAAUU 5874 AUUGCCCU GGCAUUCG 1433 AGAGGCCG CUGAUGAG X CGAA 5088 AUUGGCAUU 5875 AUGCCAAU ______CGGCCUCU 1434 AAGAGGCC CUGAUGAG X CGAA 5089 UUGGCAUUC 5876 AAUGCCAA GGCCUCUU WO 99/50403 WO 9950403PCTIUS99/06507 234 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

1440 GUACCAAA CUGAUGAG X CGAA 5090 UUCGGCCUC 5877 AGGCCGAA UUUGGUAC 1442 CAGUACCA CUGAUGAG X CGAA 5091 CGGCCUCUU 5878 AGAGGCCG UGGUACtJG 1443 CCAGUACC CUGAUGAG X CGAA 5092 GGCCUCUUU 5879 AAGAGGCC GGUACUGG 1447 GUCCCCAG CUGAUGAG X CGAA 5093 UCUUUGGUA 5880 ACCAAAGA CUGGGGAC 1491 CGGGCAGC CUGAUGAG X CGAA 5094 CCCGGGGUU 5881 ACCCCGGG GCUGCCCG 1504 UCAGAGAG CUGAUGAG X CGAA 5095 CCCGUGGUC 5882 ACCACGGG CUCUCUGA 1507 GACUCAGA CUGAUGAG X CGAA 5096 GUGGUCCUC 5883 AGGACCAC UCUGAGUC 1509 AGGACUCA CUGAUGAG X CGAA 5097 GGUCCUCUC 5884 _____AGAGGACC UGAGUCCU 1515 UCACCAAG CUGAUGAG X CGAA 5098 CUCUGAGUC 5885 ACUCAGAG CUUGGUGA 1518 AAAUCACC CUGAUGAG X CGAA 5099 UGAGUCCUU 5886 _____AGGACUCA GGUGAUUU 1525 CCAGGCAA CUGAUGAG X CGAA 5100 UUGGUGAUU 5887 _____AUCACCAA UUGCCUGG 1526 CCCAGGCA CUGAUGAG X CGAA 5101 UGGUGAUUU 5888 _____AAUCACCA UGCCUGGG 1527 GCCCAGGC CUGAUGAG X CGAA 5102 GGUGAUUUU 5889 _____AAAUJCACC GCCUGGGC 1554 CAGACCAG CUGAUGAG X CGAA 5103 CCCUGGCUC 5890 _____AGCCAGGG ______CUGGUCUG 1560 CCCCAGCA CUGAUGAG X CGAA 5104 CUCCUGGUC 5891 ACCAGGAG UGCUGGGG 1575 CUGAGGCA CUGAUGAG X CGAA 5105 GGCCGCCUC 5892 IAGGCGGCC UGCCUCAG WO 99/50403 WO 9950403PCTIUS99/06507 235 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

1581 CAUCCUCU CUGAUGAG X CGAA 5106 CUCUGCCUC 5893 AGGCAGAG AGAGGAUG 1606 AAAAUACU CUGAUGAG X CGAA 5107 GUGCAUGUA 5894 ACAUGCAC AGUAUUUU 1610 AUUAAAAA CUGAUGAG X CGAA 5108 AUGUAAGUA 5895 ACUUACAU UUUUUAAU 1612 UUAUUAAA CUGAUGAG X CGAA 5109 GUAAGUAUU 5896 AUACUUAC UUUAAUAA 1613 UUUAUUAA CUGAUGAG X CGAA 5110 UAAGUAUUU 5897 AAUACUUA UUAAUAAA 1614 UUUUAUUA CUGAUGAG X CGAA 5111 AAGUAUUUU 5898 AAAUACUU UAAUAAAA 1615 UUUUUAtJU CUGAUGAG X CGAA 5112 AGUAUUUUU 5899 AAAAUACU AAUAAAAA 1616 GUUUUUAU CUGAUGAG X CGAA 5113 GUAUUUUUA 5900 AAAAAUAC _____AUAAAAAC 1619 ACAGUUUU CUGAUGAG X CGAA 5114 UUUUUAAUA 5901 AUUAAAAA AAAACUGU 1628 ACGAGUAC CUGAUGAG X CGAA 5115 AAAACUGUA 5902 ACAGUUUU ______GUACUCGU 1631 UUUACGAG CUGAUGAG X CGAA 5116 ACUGUAGUA 5903 ACUACAGU CUCGUAAA 1634 UGUUUUAC CUGAUGAG X CGAA 5117 GUAGUACUC 5904 AGUACUAC GUAAAACA 1637 GAUUGUUU CUGAUGAG X CGAA 5118 GUACUCGUA 5905 ACGAGUAC AAACAAUC 1645 AGGGUGUA CUGAUGAG X CGAA 5119 AAAACAAUC 5906 AUUGUUUU ______UACACCCU 1647 GCAGGGUG CUGAUGAG X CGAA 5120 AACAAUCUA 5907 AGAUUGUU ______CACCCUGC 1665 AAAUAACA CUGAUGAG X CGAA 5121 GAAGGGAUU 5908 AUCCCUUC IUGUUAUUUI WO 99/50403 WO 9950403PCT/US99/06507 236 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

1666 AAAAUAAC CUGAUCAG X CGAA 5122 AAGGGAUUU 5909 AAUCCCUU GUUAUUUU 1669 AAUAAAAU CUGAUGAG X CGAA 5123 GGAUUUGUU 5910 ACAAAUCC AUUUUAUU 1670 AAAUAAAA CUGAUGAG X CGAA 5124 GAUUUGUUA 5911 AACAAAUC UUUUAUUU 1672 UAAAAUAA CUGAtJGAG X CGAA 5125 UUUGUUAUU 5912 AUAACAAA UUAEJUUUA 1673 AUAAAAUA CUGAUGAG X CGAA 5126 UUGUUAUUU 5913 AAUAACAA UAUUUUAU 1674 AAUAAAAU CUGAUGAG X CGAA 5127 UGUUAUUUU 5914 AAAUAACA AUUUUAUU 1675 UAAUAAAA CUGAUGAG X CGAA 5128 GUUAUUUUA 5915 AAAAUAAC UUUUAUUA 1677 AAUAAUAA CUGAUGAG X CGAA 5129 UAUUUUAUU 5916 AUAAAAUJA UUAUUAUU 1678 AAAUAAUA CUGAUGAG X CGAA 5130 AUUUUAUUU 5917 AAUAAAAU UAUUAUUU 1679 UAAAUAAU CUGAUGAG X CGAA 5131 UUUUAUUUU 5918 AAAUAAAA AUUAUUUA 1680 AUAAAUAA CUGAUGAG X CGAA 5132 UUUAUUUUA 5919 AAAAUAAA UUAUUUAU 1682 AAAUAAAU CUGAUGAG X CGAA 5133 UAUUUUAUU 5920 AUAAAAUA AUUUAUUU 1683 UAAAUAAA CUGAUGAG X CGAA 5134 AUUUUAUUA 5921 AAUAA-AAU UUUAUUUA 1685 AAUAAAUA CUGAUGAG X CGAA 5135 UUUAUUAUU 5922 AUAAUAAA UAUUUAUU______ 1686 AAAUAAAU CUGAUGAG X CGAA 5136 UUAUUAUUU 5923 _____AAUAAUAA AUUUAUUU 1687 UAAAUAAA CUGAUGAG X CGAA 5137 UAUUAUUUA 5924 AAAUAAUA UUUAUUUA WO 99/50403 WO 9950403PCT/US99/06507 237 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

1689 AAUAAAUA GUGAUGAG X CGAA 5138 EJUAUUUAUU 5925 AUAAAUAA UAUUUAUU 1690 AAAUAAAU CUGAUGAG X CGAA 5139 UAUUUAUUU 5926 AAUAAAUA AUUUAUUU 1691 UAAAUAAA CUGAUGAG X CGAA 5140 AUUUAUUUA 5927 AAAUAAAU EJUUAUUUA 1693 AAUAAAUA CUGAUGAG X CGAA 5141 UUAUUUAUU 5928 AUAAAUAA UAUUUAUU 1694 AAAUAAAU CUGAUGAG X CGAA 5142 UAUUUAUUU 5929 AAUAAAUA AUUUAUUU 1695 UAAAUAAA CUGAUGAG X CGAA 5143 AUUUAUUUA 5930 AAAUAAAU UUUAUUUA 1697 AAUAAAUA CUGAUGAG X CGAA 5144 UUAUUUAUU 5931 ,AUAAAUAA UAUUUAUU 1698 AAAUAAAU CUGAUGAG X CGAA 5145 UAUUUAUUU 5932 AAUAAAUA AUUUAUUU 1699 AAAAUAAA CUGAUGAG X CGAA 5146 AUUUAUUUA 5933 AAAUAAAU UUUAUUUU 1701 CAAAAAUA CUGAUGAG X CGAA 5147 UUAUUUAUU 5934 AUAAAUAA UAUUUUUG 1702 UCAAAAAU CUGAUGAG X CGAA 5148 UAUUUAUUU 5935 ,AAUAAAUA AUUUUUGA 1703 CUCAAAAA CUGAUGAG X CGAA 5149 AUUUAUUUA 5936 A12.AUAAAU ______UUUUUGAG 1705 GUCUCAAA CUGAUGAG X CGAA 5150 UUAUUUAUU 5937 AUAAAUAA UUUGAGAC 1706 CGUCUCAA CUGAUGAG X CGAA 5151 UAUUUAUUU 5938 AAUAAAUA UUGAGACG 1707 CCGUCUCA CUGAUGAG X CGAA 5152 AUUUAUUUU 5939 AAAUAAAU ______UGAGACGG 1708 UCCGUCUC CUGAUGAG X CGAA 5153 UUUAUUUUU 5940 AAAAUAAA I GAGACGGA WO 99/50403 WO 9950403PCT/US99/06507 238 Posi- Seq. I Seq. I. D.

tion RZ No. Substrate No.

1719 CAGAGCAA CUGAUGAG X CGAA 5154 GACGGAGUC 5941 ACUCCGUC UUGCUCUG______ 1721 GACAGAGC CUGAUGAG X CGAA 5155 CGGAGUCUU 5942 IAGACEJCCG GCIJCUGUC 1725 GGGCGACA CUGAUGAG X CGAA 5156 GUCUUGCUC 5943 AGCAAGAC UGUCGCCC 1729 GCCUGGGC CUGAUGAG X CGAA 5157 UGCUCUGUC 5944 ACAGAGCA GCCCAGGC 1756 GAGCCGAG CUGAUGAG X CGAA 5158 UGGUGGGUU 5945 ACCCACCA CUCGGCUC 1757 UGAGCCGA CUGAUGAG X CGAA 5159 GGUGGGUUC 5946 AACCCACC UCGGCUCA______ 1759 AGUGAGCC CUGAUGAG X CGAA 5160 UGGGUUCUC 5947 AGAACCCA 1764 GUUGCAGU CUGAUGAG X CGAA 5161 UCUCGGCUC 5948 AGCCGAGA ACUGCAAC______ 1774 GGAGGCAG CUGAUGAG X CGAA 5162 CUGCAACUU 5949 AGUUGCAG CUGCCUCC______ 1775 AGGAGGCA CUGAUGAG X CGAA 5163 UGCAACUUC 5950 AAGUUGCA UGCCUCCU______ 1781 AAACCCAG CUGAUGAG X CGAA 5164 UUCUGCCUC 5951 AGGCAGAA CUGGGUUU______ 1788 AUCGCUUA CUGAUGAG X CGAA 5165 UCCUGGGUU 5952 ACCCAGGA UAAGCGAU 1789 AAUCGCUU CUGAUGAG X CGAA 5166 CCUGGGUUU 5953 AACCCAGG AAGCGAUU______ 1790 GAAUCGCU CUGAUGAG X CGAA 5167 CUGGGUUUA 5954 AAACCCAG AGCGAUUC 1797 GCCAGAAG CUGAUGAG X CGAA 5168 UAAGCGAUU 5955 AUCGCUUA CUUCUGGC 1798 AGCCAGAA CUGAUGAG X CGAA 5169 AAGCGAUUC 5956 AAUCGCUU

IUUCUGGCU______

WO 99/50403 WO 9950403PCT/US99/06507 239 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

1800 EGAGCCAG CUGAUGAG X CGAA 5170 GCGAUUCUU 5957 AGAAUCGC CUGGCUCA 1801 CUGAGCCA CUGAUGAG X CGAA 5171 CGAUUCUUC 5958 AAGAAUCG UGGCUCAG 1807 GGGAGGCU CUGAUGAG X CGAA 5172 UUCUGGCUC 5959 AGCCAGAA AGCCUCCC 1813 CUACUCGG CUGAUGAG X CGAA 5173 CUCAGCCUC 5960 AGGCUGAG CCGAGUAG 1820 AUCCCAGC CUGAUGAG X CGAA 5174 UCCCGAGUA 5961 ACUCGGGA GCUGGGAU 1829 GCGCCUGU CUGAUGAG X CGAA 5175 GCUGGGAUU 5962 ____AUCCCAGC ACAGGCGC 1830 GGCGCCUG CUGAUGAG X CGAA 5176 CUGGGAUUA 5963 ____AAUCCCAG CAGGCGCC 1856 ACAAAAAU CUGAUGAG X CGAA 5177 GGCCGGCUA 5964 AGCCGGCC AUUUUUGU 1859 AAUACAAA CUGAUGAG X CGAA 5178 CGGCUAAUU 5965 IAUUAGCCG UUUGUAUU 1860 AAAUACAA CUGAUGAG X CGAA 5179 GGCUAAUUU 5966 ____AAUUAGCC UUGUJAUUU 1861 AAAAUACA CUGAUGAG X CGAA 5180 GCUJAAUUUU 5967 IAAAUUAGC ______UGUAUUUU 1862 AAAAAUAC CUGAUGAG X CGAA 5181 CUAAUUUUU 5968 AAAAUUAG GUAUUUUU 1865 ACUAAAAA CUGAUGAG X CGAA 5182 AUUUUUGUA 5969 ACAAAAAU UUUUUAGU 1867 CUACUAAA CUGAUGAG X CGAA 5183 UUUUGUAUU 5970 AUACAAAA UUUAGUAG 1868 UCUACUAA CUGAUGAG X CGAA 5184 UUUGUAUUU 5971 AAUACAAA UUAGUAGA 1869 CUCUACUA CUGAUGAG X CGAA 5185 UUGUAUUUU 5972 AAAUACAA IUAGUAGAG WO 99/50403 WO 9950403PCTIUS99/06507 240 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

1870 UCUCUACU CUGAUGAG X CGAA 5186 UGUAUUUUU 5973 AAAAUACA AGUAGAGA 1871 GUCUCUAC CUGAUGAG X CGAA 5187 GUAUUUUUA 5974 AAAAAUAC GUAGAGAC 1874 CGCGUCUC CUGAUGAG X CGAA 5188 UUUUUAGUA 5975 ACUAAAAA GAGACGCG 1885 CAUGGUGA CUGAUGAG X CGAA 5189 GACGCGGUU 5976 ACCGCGUC UCACCAUG 1886 ACAUGGUG CUGAUGAG X CGAA 5190 ACGCGGUUU 5977 AACCGCGU CACCAUGU 1887 AACAUGGU CUGAUGAG X CGAA 5191 CGCGGUUUC 5978 AAACCGCG ACCAUGUU 1895 GCCUGGCC CUGAUGAG X CGAA 5192 CACCAUGUU 5979 ACAUGGUG GGCCAGGC 1908 GAGGUCCA CUGAUGAG X CGAA 5193 AGGCUGGUC 5980 ACCAGCCU UGGAGCUC 1916 GAGGCCAG CUGAUGAG X CGAA 5194 CUGGAGCUC 5981 AGCUCCAG CUGGCCUC 1924 GAUCACUU CUGAUGAG X CGAA 5195 CCUGGCCUC 5982 AGGCCAGG AAGUGAUC 1932 GGUGGGCG CUGAUGAG X CGAA 5196 CAAGUGAUC 5983 AUCACUUG CGCCCACC 1942 GGGAGGCU CUGAUGAG X CGAA 5197 GCCCACCUC 5984 AGGUGGGC AGCCUCCC 1948 CACUUUGG CUGAUGAG X CGAA 5198 CUCAGCCUC 5985 AGGCUGAG ______CCAAAGUG 1965 CACGCCUG CUGAUGAG X CGAA 5199 CUGGGAAUA 5986 IAUUCCCAG

CAGGCGUG

1996 UUAAAAUA CUGAUGAG X CGAA 5200 GCCAGGAUU 5987 _____AUCCUGGC UAUUUUAA 1997 UUUAAAAU CUGAUGAG X CGAA 5201 CCAGGAUUU 5988 AAUCCUGG I AUUUUAAA WO 99/50403 WO 9950403PCTIUS99/06507 241 Posi- Seq. 1. D. Seq. I. D.

tion RZ No. Substrate No.

1998 UUEJUAAAA CUGAUGAG X CGAA 5202 CAGGAUUUA 5989 AAAUCCUG UUUUAAAA 2000 C(JUUUUAA CUGAUGAG X CGAA 5203 GGAUUUAUU 5990 AUAAAUCC UUAAAAAG 2001 CCUUUUUA CUGAUGAG X CGAA 5204 GAUUUAUUU 5991 AAUAAAUC UAAAAAGG 2002 CCCUUUUU CUGAUGAG X CGAA 5205 AUUUAUUUU 5992 _____AAAUAAAU AAAAAGGG 2003 UCCCUUUU CUGAUGAG X CGAA 5206 UUUAUUUUA 5993 AAAAUAAA AAAAGGGA 2016 UAUCAACA CUGAUGAG X CGAA 5207 GGGAAGAUU 5994 _____AUCUUCCC UGUUGAUA 2017 UUAUCAAC CUGAUGAG X CGAA 5208 GGAAGAUUU 5995 AAUCUUCC GUUGAUAA 2020 AAUUUAUC CUGAUGAG X CGAA 5209 AGAUUUGUU 5996 _____ACAAAUCU GAUAAAUU 2024 AGUGAAUU CUGAUGAG X CGAA 5210 UUGUUGAUA 5997 AUCAACAA AAUUCACU 2028 UUGAAGUG CUGAUGAG X CGAA 5211 UGAUAAAUU 5998 _____AUUUAUCA CACUUCAA 2029 UUUGAAGU CUGAUGAG X CGAA 5212 GAUAAAUUC 5999 _____AAUUUAUC ______ACUUCAAA 2033 UAUCUUUG CUGAUGAG X CGAA 5213 AAUUCACUU 6000 IAGUGAAUU CAAAGAUA 2034 UUAUCUUU CUGAUGAG X CGAA 5214 AEJUCACUUC 6001 AAGUGAAU AAAGAUAA 2041 GAAUAGUU CUGAUGAG X CGAA 5215 UCAAAGAUA 6002 AUCUUUGA ______AACUAUUC 2046 UUUUCGAA CUGAUGAG X CGAA 5216 GAUAAACUA 6003 AGUUUAUC UUCGAAAA 2048 UAUUUUCG CUGAUGAG X CGAA 5217 UAAACUAUU 6004 AUAGUUUA CGAAAAUA WO 99/50403 WO 9950403PCTIUS99/06507 242 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

2049 GUAUUUUC CUGAUGAG X CGAA 5218 AAACUAUUC 6005 AAUAGUUU GAAAAUAC 2056 CACUAAAG CUGAUGAG X CGAA 5219 UCGAAAAUA 6006 AUUUUCGA CUUUAGUG 2059 AAUCACUA CUGAUGAG X CGAA 5220 AAAAUACUU 6007 AGUAUUUU UAGUGAUU 2060 GAAUCACU CUGAUGAG X CGAA 5221 AAAUACUUU 6008 AAGUAUUU AGUGAUUC 2061 GGAAUCAC CUGAUGAG X CGAA 5222 AAUACUUUA 6009 AAAGUAUU GUGAUUCC 2067 UUGACGGG CUGAUGAG X CGAA 5223 UUAGUGAUU 6010 AUCACUAA CCCGUCAA 2068 CUUGACGG CUGAUGAG X CGAA 5224 UAGUGAUUC 6011 IAAUCACUA

CCGUCAAG

2073 AGAGUCUU CUGAUGAG X CGAA 5225 AUUCCCGUC 6012 ACGGGAAU AAGACUCU 2080 ACACAGAA CUGAUGAG X CGAA 5226 UCAAGACUC 6013 AGUCUUGA UUCUGUGU 2082 AUACACAG CUGAUGAG X CGAA 5227 AAGACUCUU 6014 AGAGUCUU CUGUGUAU 2083 CAUACACA CUGAUGAG X CGAA 5228 AGACUCUUC 6015 AAGAGUCU UGUGUAUG 2089 UCUAUACA CUGAUGAG X CGAA 5229 UUCUGUGUA 6016 ACACAGAA UGUAUAGA 2093 UACGUCUA CUGAUGAG X CGAA 5230 GUGUAUGUA 6017 ACAUACAC UAGACGUA 2095 UAUACGUC CUGAUGAG X CGAA 5231 GUAUGUAUA 6018 _____AUACAUAC GACGUAUA 2101 AUGAGUUA CUGAUGAG X CGAA 5232 AUAGACGUA 6019 _____ACGUCUAU UAACUCAU 2103 GAAUGAGU CUGAUGAG X CGAA 5233 AGACGUAUA 6020 IAUACGUCU

ACUCAUUC

WO 99/50403 WO 9950403PCTIUS99/06507 243 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

2107 UCCAGAAU CUGAUGAG X CGAA 5234 GUAUAACJC 6021 AGtJUAUAC AUtJCtGGA 2110 CUGUCCAG CUGAUGAG X CGAA 5235 tJAACUCAUU 6022 AUGAGUUA CUGGACAG 2111 CCUGUCCA CUGAUGAG X CGAA 5236 AACUCAUUC 6023 AAUGAGUU UGGACAGG 2128 AAAAAAGA CUGAUGAG X CGAA 5237 GCAAGGAUA 6024 AUCCUUGC UCUUUUUU 2130 CAAAAAAA CUGAUGAG X CGAA 5238 AAGGAUAUC 6025 AUAUCCUU UUUUUUUG 2132 AACAAAAA CUGAUGAG X CGAA 5239 GGAUAUCUU 6026 AGAUAUCC UUUUUGUU 2133 AAACAAAA CUGAUGAG X CGAA 5240 GAUAUCUUU 6027 AAGAUAUC UUUUGUUU 2134 CAAACAAA CUGAUGAG X CGAA 5241 AUAUCUUUU 6028 IAAAGAUAU

UUUGUUUG

2135 ACAAACAA CUGAUGAG X CGAA 5242 UAUCUUUUU 6029 AAAAGAUA UUGUUUGU 2136 AACAAACA CUGAUGAG X CGAA 5243 AUCUUUUUU 6030 IAAAAAGAU UGUUUGUU 2137 AAACAAAC CUGAUGAG X CGAA 5244 UCUUUUUUU 6031 AAAAAAGA GUUUGUUU 2140 AACAAACA CUGAUGAG X CGAA 5245 UUUUUUGUU 6032 ACAAAAAA UGUUUGUU 2141 AAACAAAC CUGAUGAG X CGAA 5246 UUUUUGUUU 6033 AACAAAAA GUUUGUUU 2144 AACAAACA CUGAUGAG X CGAA 5247 UUGUUUGUU 6034 ACAAACAA

UUUU

2145 AAACAAAC CUGAUGAG X CGAA 5248 UGUUUGUUU 6035 AACAAACA GUUUGUUU 2148 UCAAAACA CUGAUGAG X CGAA 5249 UUGUUUGUU 6036 ACAAACAA UGUUUUGA WO 99/50403 WO 9950403PCT/US99/06507 244 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

2149 CLJCAAAAC CUGAUGAG X CGAA 5250 UGUUUGtJUU 6037 AACAAACA GUUUUGAG 2152 CAUCUCAA CUGAUGAG X CGAA 5251 UUGEJUUGUU 6038 ACAAACAA ______UUGAGAUG 2153 CCAUCUCA CUGAUGAG X CGAA 5252 UGUUUGUUU 6039 AACAAACA UGAGAUGG 2154 UCCAUCUC CUGAUGAG X CGAA 5253 GUUUGUUUU 6040 AAACAAAC ______GAGAUGGA 2165 GACAGCGA CUGAUGAG X CGAA 5254 GAUGGACUC 6041 AGUCCAUC UCGCUGUC 2167 GCGACAGC CUGAUGAG X CGAA 5255 UGGACUCUC 6042 AGAGUCCA GCUGUCGC 2173 AGCCUGGC CUGAUGAG X CGAA 5256 CUCGCUGUC 6043 ACAGCGAG ______GCCAGGCU 2182 CUGCACUC CUGAUGAG X CGAA 5257 GCCAGGCUA 6044 AGCCUGGC GAGUGCAG 2200 UGAGCUGA CUGAUGAG X CGAA 5258 GGCGCGAUU 6045 AUCGCGCC UCAGCUCA 2201 GUGAGCUG CUGAUGAG X CGAA 5259 GCGCGAUUU 6046 _____AAUCGCGC ______CAGCUCAC 2202 AGUGAGCU CUGAUGAG X CGAA 5260 CGCGAUUUC 6047 AAAUCGCG AGCUCACU 2207 GUUGCAGU CUGAUGAG X CGAA 5261 UUUCAGCUC 6048 _____AGCUGAAA ACUGCAAC 2218 GGGAAGCG CUGAUGAG X CGAA 5262 UGCAACCUC 6049 _____AGGUUGCA CGCUUCCC 2223 AACCCGGG CUGAUGAG X CGAA 5263 CCUCCGCUU 6050 _____AGCGGAGG CCCGGGUU 2224 GAACCCGG CUGAUGAG X CGAA 5264 CUCCGCUUC 6051 _____AAGCGGAG CCGGGUUC 2231 AUCGCUUG CUGAUGAG X CGAA 5265 UCCCGGGUU 6052 IACCCGGGA CAAGCGAU WO 99/50403 WO 9959403PCTIUS99/06507 245 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

2232 AAUCGCUU CUGAUGAG X CGAA 5266 CCCGGGUUC 6053 AACCCGGG AAGCGAUU 2240 GGCAGGAG CUGAUGAG X CGAA 5267 CAAGCGAUU 6054 AUCGCUUG CUCCUGCC 2241 AGGCAGGA CUGAUGAG X CGAA 5268 AAGCGAUUC 6055 AAUCGCUU UCCUGCCU 2243 UGAGGCAG CUGAUGAG X CGAA 5269 GCGAUUCUC 6056 AGAAUCGC CUGCCUCA 2250 GGGAGGCU CUGAUGAG X CGAA 5270 UCCUGCCUC 6057 AGGCAGGA AGCCUCCC 2256 CUACUCGG CUGAUGAG X CGAA 5271 CUCAGCCUC 6058 AGGCUGAG CCGAGUAG 2263 AUCCCAGC CUGAUGAG X CGAA 5272 UCCCGAGUA 6059 ACUCGGGA GCUGGGAU 2272 GUGCCUGU CUGAUGAG X CGAA 5273 GCUGGGAUU 6060 AUCCCAGC ACAGGCAC 2273 CGUGCCUG CUGAUGAG X CGAA 5274 CUGGGAUUA 6061 AAUCCCAG CAGGCACG 2296 AAAAUUAG CUGAUGAG X CGAA 5275 CACGCCCUA 6062 _____AGGGCGUG CUAAUUUU 2299 UCAAAAAU CUGAUGAG X CGAA 5276 GCCCUACUA 6063 _____AGUAGGGC ______AUUUUUGA 2302 AAAUCAAA CUGAUGAG X CGAA 5277 CUACUAAUU 6064 _____AUUAGUAG ______UUUGAUUU 2303 AAAAUCAA CUGAUGAG X CGAA 5278 UACUAAUUU 6065 AAUUAGUA UUGAUUUU 2304 AAAAAUCA CUGAUGAG X CGAA 5279 ACUAAUUUU 6066 AAAUUAGU UGAUUUUU 2305 UAAAAAUC CUGAUGAG X CGAA 5280 CUAAUUUUU 6067 AAAAUUAG GAUUUUUA 2309 CUACUAAA CUGAUGAG X CGAA 5281 UUUUUGAUU 6068 AUCAAAAA UUUAGUAG WO 99/50403 WO 9950403PCT/US99/06507 246 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

2310 UCUACUAA CtJGAUGAG X CGAA 5282 UUtJUGAUUU 6069 IAAUCAAAA ______UUAGUAGA 2311 CUCUACUA CUGAUGAG X CGAA 5283 UUUGAUUUU 6070 AAAUCAAA UAGtJAGAG 2312 UCUCUACU CUGAUGAG X CGAA 5284 UUGAUUUUU 6071

AGUAGAGA

2313 GUCUCUAC CUGAUGAG X CGAA 5285 UGAUUUUUA 6072 AAAAAUCA GUAGAGAC 2316 CCCGUCUC CUGAUGAG X CGAA 5286 UUUUUAGUA 6073 ACUAAAAA GAGACGGG 2327 CAUGGGGA CUGAUGAG X CGAA 5287 GACGGGAUU 6074 _____AUCCCGUC ______UCCCCAUG 2328 ACAUGGGG CUGAUGAG X CGAA 5288 ACGGGAUUU 6075 _____AAUCCCGU ______CCCCAUGU 2329 AACAUGGG CUGAUGAG X CGAA 5289 CGGGAUUUC 6076 AAAUCCCG CCCAUGUU 2337 UCCUGGCC CUGAUGAG X CGAA 5290 CCCCAUGUU 6077 ACAUGGGG GGCCAGGA 2350 GAGAUCGA CUGAUGAG X CGAA 5291 AGGAUGAUC 6078 _____AUCAUCCU ______UGGAUCUC 2352 AAGAGAUC CUGAUGAG X CGAA 5292 GAUGAUCUC 6079 AGAUCAUC GAUCUCUU 2356 GGUCAAGA CUGAUGAG X CGAA 5293 AUCUCGAUC 6080 AUCGAGAU ______UCUUGACC 2358 GGGGUCAA CUGAUGAG X CGAA 5294 CUCGAUCUC 6081 AGAUCGAG UUGACCCC 2360 ACGGGGUC CUGAUGAG X CGAA 5295 CGAUCUCUU 6082 AGAGAUCG ______GACCCCGU 2372 GGCAGGCU CUGAUGAG X CGAA 5296 CCCGUGAUC 6083 AUCACGGG IAGCCUGCC 2382 GGGAGGCC CUGAUGAG X CGAA 5297 GCCUGCCUU 6084 AGGCAGGC GGCCUCCC WO 99/50403 WO 9950403PCTIUS99/06507 247 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

2388 CACUUUGG CUGAUGAG X CGAA 5298 CUUGGCCUC 6085 AGGCCAAG ______CCAAAGUG 2404 ACGCCUGU CtJGAUGAG X CGAA 5299 GCUGGGAUU 6086 AEJGCCAGC ______ACAGGCGU 2405 CACGCCtJG CUGAUGAG X CGAA 5300 CUGGGAUUA 6087 AAUCCCAG 2437 CUUCAAGA CUGAUGAG X CGAA 5301 CCAAGGGUA 6088 ACCCUUGG_____ UCUUGAAG______ 2439 UCCUUCAA CUGAUGAG X CGAA 5302 AAGGGUAUC 6089 AUACCCUU UUGAAGGA 2441 CCUCCUUC CUGAUGAG X CGAA 5303 GGGUAUCUU 6090 IAGAUACCC GAAGGAGG 2453 UCAACUGU CUGAUGAG X CGAA 5304 GGAGGGAUU 6091 AUCCCUCC ACAGUUGA 2454 AUCAACUG CUGAUGAG X CGAA 5305 GAGGGAUUA 6092 AAUCCCUC CAGUUGAU 2459 UACAUAUC CUGAUGAG X CGAA 5306 AUUACAGUU 6093 ACUGUAAU GAUAUGUA 2463 CCUCUACA CUGAUGAG X CGAA 5307 CAGUUGAUA 6094 AUCAACUG UGUAGAGG 2467 UAUUCCUC CUGAUGAG X CGAA 5308 UGAUAUGUA 6095 ACAUAUCA _____GAGGAAUA 2475 CACUGCAA CUGAUGAG X CGAA 5309 AGAGGAAUA 6096 AUUCCUCU UUGCAGUG 2477 ACCACUGC CUGAUGAG X CGAA 5310 AGGAAUAUU 6097 AUAUUCCU ______GCAGUGGU 2486 GCAGCAAU CUGAUGAG X CGAA 5311 GCAGUGGUU 6098 ACCACUGC ______AUUGCUGC 2487 UGCAGCAA CUGAUGAG X CGAA 5312 CAGUGGUUA 6099 AACCACUG ______UUGCUGCA 2489 AAUGCAGC CUGAUGAG X CGAA 5313 GUGGUUAUU 6100 AUAACCAC GCUGCAUU WO 99/50403 WO 9950403PCT[US99/06507 248 Posi- Seq. 1.D. Seq. I.D.

tion RZ No. Substrate No.

2497 ACAHAGGA CUGAUGAG X CGAA 5314 tJGCUGCAUU 6101 AUGCAGCA UCCUAUGU 2498 CACAUAGG CUGAUGAG X CGAA 5315 GCUGCAUUU 6102 AAUGCAGC CCEJAUGUG 2499 UCACAUAG CUGAUGAG X GGAA 5316 CUGCAUUUC 6103 AAAUGCAG CUAUGUGA 2502 CAGUCACA CUGAUGAG X CGAA 5317 CAUUUCCUA 6104 AGGAAAUG UGUGACUG 2516 AUCUGUUU CUGAUGAG X CGAA 5318 CUGGGACUA 6105 AGUCCCAG AAACAGAU 2525 UAUCAGCU CUGAUGAG X CGAA 5319 AAACAGAUC 6106 AUCUGUUU AGCUGAUA 2533 GCUAACAC CtJGAUGAG X CGAA 5320 CAGCUGAUA 6107 AUCAGCUG GUGUUAGC 2538 UGCACGCU CUGAUGAG X CGAA 5321 GAUAGUGUU 6108 ACACUAUC AGCGUGCA 2539 CUGCACGC CUGAUGAG X CGAA 5322 AUAGUGUUA 6109 AACACUAU GCGUGCAG 2556 AGUCAUCA CUGAUGAG X CGAA 5323 UGAGCAGUC 6110 ACUGCUCA UGAUGACU 2565 CUGUGUCA CUGAUGAG X CGAA 5324 UGAUGACUA 6111 AGUCAUCA -UGACACAG 2578 GAGAUUCU CUGAUGAG X CGAA 5325 ACAGAAAUA 6112 AUUUCUGU AGAAUCUC 2584 AUGCUGGA CUGAUGAG X CGAA 5326 AUAAGAAUC 6113 AUUCUUAU UCCAGCAU 2586 GAAUGCUG CUGAUGAG X CGAA 5327 AAGAAUCUC 6114 AGAUUCUU CAGCAUUC 2593 CAGGGCAG CUGAUGAG X CGAA 5328 UCCAGCAUU 6115 AUGCUGGA CUGCCCUG 2594 CCAGGGCA CUGAUGAG X CGAA 5329 CCAGCAUUC 6116 AAUGCUGG

UGCCCUGG

WO 99/50403 WO 9950403PCTIUS99/06507 249 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

2617 !CUGACCC CUGAUGAG X CGAA 5330 UGGAGCCUU 6117 ,AGGCUCCA GGGUCAGA 2622 CAGCAUJCU CUGAUGAG X CGAA 5331 CCUUGGGUC 6118 ACCCAAGG AGAUGCUG 2637 GGCAUCAA CUGAUGAG X CGAA 5332 UGCUGGCUA 6119 AGCCAGCA UUGAUGCC 2639 CCGGCAUC CUGAUGAG X CGAA 5333 CUGGCUAUU 6120 AUAGCCAG GAUGCCGG 2660 CCCUGGUG CUGAUGAG X CGAA 5334 GGAGAAAUC 6121 AUUUCUCC CACCAGGG 2674 UUUUUACU CUGAUGAG X CGAA 5335 GGGCAACUC 6122 AGUUGCCC AGUAAAAA 2678 UUAUUUUU CUGAUGAG X CGAA 5336 AACUCAGUA 6123 ACUGAGUU AAAAAUAA 2685 UAUUUAUU CUGAUGAG X CGAA 5337 UAAAAAAUA 6124 AUUUUUUA AAUAAAUA 2689 UAUUUAUU CUGAUGAG X CGAA 5338 AAAUAAAUA 6125 AUUUAUUU AAUAAAUA 2693 UAUUUAUU CUGAUGAG X CGAA 5339 AAAUAAAUA 6126 AUUUAUUU AAUAAAUA 2697 UAUUUAUU CUGAUGAG X CGAA 5340 AAAUAAAUA 6127 _____AUUUAUUU AAUAAAUA 2701 UAUUUAUU CUGAUGAG X CGAA 5341 AAAUAAAUA 6128 AUUUAUUUGUAXCGA54 AAUAAAUA 62 2709 UAAUUAUU CUGAUGAG X CGAA 5343 AAAUAAAUA 6130 2713 UUUUUAAU CUGAUGAG X CGAA 5344 AAAUAAAUA 6131 AUUUAUUU AUUAAAAA 2716 CUUUUUUU CUGAUGAG X CGAA 5345 UAAAUAAUU 6132 _____AUUAUUUA LAATAAAAAG WO 99/50403 WO 9950403PCTIUS99/06507 250 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

2717 CCUUUUUU CLJGAUGAG X CGAA 5346 AAAUAAUUA 6133 AAUUAUUU ______AAAAAAGG 2728 GACAAGGA CUGAtJGAG X CGAA 5347 AAAAGGGUA 6134 ACCCUUUU ______UCCUUGUC 2730 AGGACAAG CUGAUGAG X CGAA 5348 AAGGGUAUC 6135 AUACCCUU ______CEJUGUCCU 2733 GACAGGAC CUGAUGAG X CGAA 5349 GGUAUCCUU 6136 AGGAUACC ______GUCCUGUC 2736 CUGGACAG CUGAUGAG X CGAA 5350 AUCCUUGUC 6137 ACAAGGAU CUGUCCAG 2741 UCAUCCUG CUGAUGAG X CGAA 5351 UGUCCUGUC 6138 ACAGGACA CAGGAUGA 2756 AUGGAAGC CUGAUGAG X CGAA 5352 GAGAUGCUU 6139 AGCAUCUC ______GCUUCCAU 2760 GUGCAUGG CUGAUGAG X CGAA 5353 UGCUUGCUU 6140 AGCAAGCA CCAUGCAC 2761 AGUGCAUG CUGAUGAG X CGAA 5354 GCUUGCUUC 6141 AAGCAAGC CAUGCACU 2770 AUUGUCGU CUGAUGAG X CGAA 5355 CAUGCACUU 6142 AGUGCAUG ACGACAAU 2771 AAUUGUCG CUGAUGAG X CGAA 5356 AUGCACUUA 6143 AAGUGCAU CGACAAUU 2779 ACAGCAAA CUGAUGAG X CGAA 5357 ACGACAAUU 6144 AUUGUCGU UUUGCUGU______ 2780 GACAGCAA CUGAUGAG X CGAA 5358 CGACAAUUU 6145 AAUUGUCG UUGCUGUC 2781 UGACAGCA CUGAUGAG X CGAA 5359 GACAAUUUU 6146 AAAUUGUC UGCUGUCA 2782 AUGACAGC CUGAUGAG X CGAA 5360 ACAAUUUUU 6147 AAAAUUGU GCUGUCAU 2788 UUUUUAAU CUGAUGAG X CGAA 5361 UUUGCUGUC 6148 ACAGCAAA IAUUAAAAA WO 99/50403 WO 9950403PCTIUS99/06507 251 Posi- Seq. I.D. Seq. I.ID.

tion RZ No. Substrate No.

2791 AAUUUUUU CUGAUGAG X CGAA 5362 GCUGUCAUU 6149 AUGACAGC AAAAAAUU 2792 AAAUUUUU CUGAUGAG X CGAA 5363 CUGUCAUUA 6150 AAUGACAG AAAAAUUU______ 2799 AAUGUGAA CUGAUGAG X CGAA 5364 fUAAAAAAUU 6151 AUUUUUUA UUCACAUU 2800 GAAUGUGA CUGAUGAG X CGAA 5365 AAAAAAUUU 6152 AAUUUUUU UCACAUUC 2801 UGAAUGUG CUGAUGAG X CGAA 5366 AAAAAUUUU 6153 AAAUUUUU CACAUUCA 2802 GUGAAUGU CUGAUGAG X CGAA 5367 AAAAUUUUC 6154 AAAAUUUU ______ACAUUCAC 2807 AGACUGUG CUGAUGAG X CGAA 5368 UUUCACAUU 6155 AUGUGAAA 2808 AAGACUGU CUGAUGAG X CGAA 5369 tJUCACAUUC 6156 AAUGUGAA ______ACAGUCUU 2814 AUUUAGAA CUGAUGAG X CGAA 5370 UUCACAGUC 6157 ACUGUGAA ,UUCUAAAU 2816 GAAUUUAG CUGAUGAG X CGAA 5371 CACAGUCUU 6158 AGACUGUG CUAAAUUC 2817 UGAAUUUA CUGAUGAG X CGAA 5372 ACAGUCUUC 6159 AAGACUGU

UAAAUUCA______

2819 AGUGAAUU CUGAUGAG X CGAA 5373 AGUCUUCUA 6160 AGAAGACU AAUUCACU 2823 CCAAAGUG CUGAUGAG X CGAA 5374 UUCUAAAUU 6161 AUUUAGAA CACUUUGG 2824 UCCAAAGJ CUGAUGAG X CGAA 5375 UCUAAAUUC 6162 AAUUUAGA ACUUUGGA 2828 ACACUCCA CUGAUGAG X CGAA 5376 AAUUCACUU 6163 AGUGAAUU UGGAGUGU 2829 UACACUCC CUGAUGAG X CGAA 5377 AUUCACUUU 6164 AAGUGAAU

GGAGUGUA

WO 99/50403 WO 9950403PCTfUS99/06507 252 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

2837 GAAUCCAA CUGAUGAG X CGAA 5378 UGGAGUGHA 6165 ACACUCCA

UUGGAUUC

2839 UGGAAUCC CUGAUGAG X CGAA 5379 GAGUGUAUU 6166 AUACACUC GGAUUCCA 2844 UGCAGUGG CUGAUGAG X CGAA 5380 UAUUGGAUU 6167 AUCCAAUA CCACEJGCA 2845 AUGCAGUG CUGAUGAG X CGAA 5381 AUUGGAUUC 6168 AAUCCAAU ______CACUGCAU 2854 CGUAUGUC CUGAUGAG X CGAA 5382 CACUGCAUU 6169 AUGCAGUG GACAUACG 2860 AACUUACG CUGAUGAG X CGAA 5383 AUUGACAUA 6170 AUGUCAAU CGUAAGUU 2864 UGCAAACU CUGAUGAG X CGAA 5384 ACAUACGUA 6171 ACGUAUGU AGUUUGCA 2868 UUAAUGCA CUGAUGAG X CGAA 5385 ACGUAAGUU 6172 ACUUACGU tJGCAUUAA 2869 UUUAAUGC CUGAUGAG X CGAA 5386 CGUAAGUUU 6173 AACUUACG GCAUUAAA 2874 GAUCUUUU CUGAUGAG X CGAA 5387 GUUUGCAUU 6174 AUGCAAAC ______AAAAGAUJC 2875 GGAUCUUU CUGAUGAG X CGAA 5388 UUUGCAUUA 6175 AAUGCAAA ______AAAGAUCC 2882 UCUUAAAG CUGAUGAG X CGAA 5389 UAAAAGAUC 6176 AUCUUUUA ______CUUUAAGA 2885 AUAUCUUA CUGAUGAG X CGAA 5390 AAGAUCCUU 6177 AGGAUCUU UAAGAUAU 2886 GAUAUCUU CUGAUGAG X CGAA 5391 AGAUCCUUU 6178 AAGGAUCU AAGAUAUC 2887 AGAUAUCU CUGAUGAG X CGAA 5392 GAUCCUUUA 6179 AAAGGAUC AGAUAUCU 2892 UGACCAGA CUGAUGAG X CGAA 5393 UUUAAGAUA 6180 AUCUUAAA UCUGGUCA WO 99/50403 WO 9950403PCT/US99/06507 253 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

2894 CCUGACCA CUGAUGAG X CGAA 5394 UAAGAUAUC 6181 AUAUCUUA ______UGGUCAGG 2899 CCGUGCCU CUGAUGAG X CGAA 5395 UAUCUGGUC 6182 _____ACCAGAUA 2913 ACAGGCGU CUGAUGAG X CGAA 5396 CGGUGGCUC 6183 AGCCACCG 2922 GCUGGGAU CUGAUGAG X CGAA 5397 ACGCCUGUA 6184 ____ACAGGCGU ______AUCCCAGC 2925 AGUGCUGG CUGAUGAG X CGAA 5398 CCUGUAAUC 6185 AUUACAGG CCAGCACU 2934 ACUUCCCA CUGAUGAG X CGAA 5399 CCAGCACUU 6186 AGUGCUGG UGGGAAGU 2935 CACUUCCC CUGAUGAG X CGAA 5400 CAGCACUUU 6187 AAGUGCUG GGGAAGUG 2949 AAUCCUUC CUGAUGAG X CGAA 5401 GUGGAGGUA 6188 ACCUCCAC GAAGGAUU 2957 GCUCAAGC CUGAUGAG X CGAA 5402 AGAAGGAUU 6189 AUCCUUCU GCUUGAGC 2961 CUGGGCUC CUGAUGAG X CGAA 5403 GGAUUGCUU 6190 _____AGCAAUCC GAGCCCAG 2974 UGGUCUCG CUGAUGAG X CGAA 5404 CCAGGAGUU 6191 _____ACUCCUGG CGAGACCA______ 2975 CUGGUCUC CUGAUGAG X CGAA 5405 CAGGAGUUC 6192 IAACUCCUG 2986 UGUUGCCC CUGAUGAG X CGAA 5406 GACCAGCUU 6193 AGCUGGUC 2996 GGUCUCAC CUGAUGAG X CGAA 5407 GGCAACAUA 6194 3006 GUAGAGAU CUGAUGAG X CGAA 5408 UGAGACCUA 6195 AGGUCUCA 3009 UUAGUAGA CUGAUGAG X CGAA 5409 GACCUAAUC 6196 AUUAGGUC IUCUACUAA WO 99/50403 WO 9950403PCTIUS99/06507 254 Posi- Seq. I.0D. Seq. tion RZ No. Substrate No.

3011 UUUUAGUA CUGAUGAG X CGAA 5410 CCUAAUCUC 6197 AGAUUAGG UACUAAAA 3013 AUUUUUAG CUGAUGAG X CGAA 5411 UAAUCUCUA 6198 IAGAGAUUA CUAAAAAU 3016 UUAAUUUU CUGAUGAG X CGAA 5412 UCUCUACUA 6199 AGUAGAGA AAAAUUAA 3022 UUUUUUUU CUGAUGAG X CGAA 5413 CUAAAAAUU 6200 IAUUUUUAG AAAAAAAA 3023 UUUUUUUU CUGAUGAG X CGAA 5414 UAAAAAUUA 6201 AAUUUUUA AAAAAAAA 3033 CGCCUAAG CUGAUGAG X CGAA 5415 AAAAAAAUC 6202 AEJUUUUUU CUUAGGCG 3036 GAUCGCCU CUGAUGAG X CGAA 5416 AAAAUCCUU 6203 AGGAUUUU ______AGGCGAUC 3037 AGAUCGCC CUGAUGAG X CGAA 5417 AAAUCCUUA 6204 AAGGAUUU GGCGAUCU 3044 UGUGAACA CUGAUGAG X CGAA 5418 UAGGCGAUC 6205 AUCGCCUA UGUUCACA 3048 AAUCUGUG CUGAUGAG X CGAA 5419 CGAUCUGUU 6206 ACAGAUCG CACAGAUU 3049 UAAUCUGU CUGAUGAG X CGAA 5420 GAUCUGUUC 6207 AACAGAUC ______ACAGAUUA 3056 ACAAGAUU CUGAUGAG X CGAA 5421 UCACAGAUU 6208 _____AUCUGUGA AAUCUUGU 3057 CACAAGAU CUGAUGAG X CGAA 5422 CACAGAUUA 6209 AAUCUGUG ______AUCUUGUG 3060 AAUCACAA CUGAUGAG X CGAA 5423 AGAUUAAUC 6210 _____AUUAAUCU ______UUGUGAUU 3062 CCAAUCAC CUGAUGAG X CGAA 5424 AUUAAUCUU 6211 _____AGAUUAAU GUGAUUGG 3068 AUCGCCCC CUGAUGAG X CGAA 5425 CUUGUGAUU 6212 AUCACAAG IGGGGCGAU WO 99/50403 WO 9950403PCT/US99/06507 255 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

3077 ACUUtCUGG CUGAUGAG X CGAA 5426 GGGGCGAUU 6213 AUCGCCCC CCAGAAGU 3078 CACEJUCUG CUGAUGAG X CGAA 5427 GGGCGAUUC 6214 AAUCGCCC CAGAAGUG 3096 CUCAGCAC CUGAUGAG X CGAA 5428 UGAUGGGUU 6215 ACCCAUCA ______GUGCUGAG 3107 UGUGGGGC CUGAUGAG X CGAA 5429 GCUGAGCUA 6216 AGCUCAGC GCCCCACA 3118 CUCAGAGA CUGAUGAG X CGAA 5430 CCCACACUC 6217 AGUGUGGG UCUCUGAG 3120 UUCUCAGA CUGAUGAG X CGAA 5431 CACACUCUC 6218 AGAGUGUG UCUGAGAA 3122 GCUUCUCA CUGAUGAG X CGAA 5432 CACUCUCUC 6219 AGAGAGUG ______UGAGAAGC 3136 CACUACUG CUGAUGAG X CGAA 5433 AGCAGUGUA 6220 ACACUGCU ______CAGUAGUG 3141 UUAAACAC CUGAUGAG X CGAA 5434 UGUACAGUA 6221 ACUGUACA GUGUUUAA 3146 UGCCCUUA CUGAUGAG X CGAA 5435 AGUAGUGUU 6222 ACACUACU ______UAAGGGCA 3147 CUGCCCUU CUGAUGAG X CGAA 5436 GUAGUGUUU 6223 AACACUAC ______AAGGGCAG 3148 CCUGCCCU CUGAUGAG X CGAA 5437 UAGUGUUUA 6224 _____AAACACUA 3161 UGACUUUA CUGAUGAG X CGAA 5438 CAGGGGCUC 6225 _____AGCCCCUG UAAAGUCA 3163 UCUGACUU CUGAUGAG X CGAA 5439 GGGGCUCUA 6226 _____AGAGCCCC ______AAGUCAGA 3168 GGAAGUCU CUGAUGAG X CGAA 5440 UCUAAAGUC 6227 ,ACUUUAGA ______AGACUUCC 3174 UACUCUGG CUGAUGAG X CGAA 5441 GUCAGACUU 6228 AGUCUGAC CCAGAGUA WO 99/50403 WO 9950403PCTIUS99/06507 256 Posi- Seq. I.D. Seq. I. D.

tion RZ No. Substrate No.

3175 UUtACUCUG CUGAUGAG X CGAA 5442 UCAGACUUC 6229 AAGUCUGA CAGAGUAA 3182 GGGGGUAU CUGAUGAG X CGAA 5443 UCCAGAGUA 6230 ACUCUGGA AUACCCCC 3185 GGGGGGGG CUGAUGAG X CGAA 5444 AGAGUAAUA 6231 AUUACUCU CCCCCCCC 3203 UGAUUUGU CUGAUGAG X CGAA 5445 CCCAACCUC 6232 AGGUUGGG ACAAAUCA 3210 UAGAAACU CUGAUGAG X CGAA 5446 UCACAAAUC 6233 AUUUGUGA AGUUUCUA 3214 AUAGUAGA CUGAUGAG X CGAA 5447 A.AAUCAGUU 6234 ACUGAUUU UCUACUAU 3215 UAUAGUAG CUGAUGAG X CGAA 5448 AAUCAGUUU 6235 AACUGAUU CUACUAUA 3216 AUAUAGUA CUGAUGAG X CGAA 5449 AUCAGUUUC 6236 AAACUGAU UACUAUAU 3218 AAAUAUAG CUGAUGAG X CGAA 5450 CAGUUUCUA 6237 AGAAACUG CUAUAUUU 3221 UAUAAAUA CUGAUGAG X CGAA 5451 UUUCUACUA 6238 AGUAGAAA UAUUUAUA 3223 GAUAUAAA CUGAUGAG X CGAA 5452 UCUACUAUA 6239 AUAGUAGA UUUAUAUC 3225 CAGAUAUA CUGAUGAG X CGAA 5453 UACUAUAUU 6240 ____AUAUAGUA UAUAUCUG 3226 GCAGAUAU CUGAUGAG X CGAA 5454 ACUAUAUUU 6241 AAUAUAGU AUAUCUGC 3227 GGCAGAUA CUGAUGAG X CGAA 5455 CUAUAUUUA 6242 AAAUAUAG UAUCUGCC______ 3229 AUGGCAGA CUGAUGAG X CGAA 5456 AUAUUUAUA 6243 AUAAAUAU UCUGCCAU______ 3231 GGAUGGCA CUGAUGAG X CGAA 5457 AUUUAUAUC 6244 ,AUAUAAAU

UGCCAUCC

WO 99/50403 WO 9950403PCTIUS99/06507 257 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

3238 AACACUGG CUGALJGAG X CGAA 5458 UCUGCCAUC 6245 ,AUGGCAGA CCAGUGUU 3246 CIJACCACC CUGAUGAG X CGAA 5459 CCCAGUGUU 6246 _____ACACUGGG GGrJGGUAG 3253 GAAGACCC CUGAUGAG X CGAA 5460 UUGGUGGUA 6247 _____ACCACCAA ______GGGUCUUC 3258 GAUCUGAA CUGAUGAG X CGAA 5461 GGUACGGUC 6248 ACCCUACC UUCAGAUC 3260 GGGAUCUG CUGAUGAG X CGAA 5462 UAGGGUCUU 6249 IAGACCCUA CAGAUCCC 3261 AGGGAUCU CUGAUGAG X CGAA 5463 AGGGUCUUC 6250 AAGACCCU ______AGAUCCCU 3266 UCCCCAGG CUGAUGAG X CGAA 5464 CUUCAGAUC 6251 AUCUGAAG CCUGGGGA 3296 AACUCUCC CUGAUGAG X CGAA 5465 AUGAGAGUA 6252 IACUCUCAU ______GGAGAGUU 3304 CCCAACAC CUGAUGAG X CGAA 5466 AGGAGAGUU 6253 _____ACUCUCOD GUGUUGGG 3309 GGAGUCCC CUGAUGAG X CGAA 5467 AGUUGUGUU 6254 ____ACACAACU GGGACUCC 3316 AACACUUG CUGAUGAG X CGAA 5468 UUGGGACUC 6255 AGUCCCAA CAAGUGUU 3324 GCCCCUUC CUGAUGAG X CGAA 5469 CCAAGUGUU 6256 ACACUUGG GAAGGGGC 3362 UCUGGGAC CUGAUGAG X CGAA 5470 AGAGAGGUU 6257 ACCUCUCU GUCCCAGA 3365 UACUCUGG CUGAUGAG X CGAA 5471 GAGGUUGUC 6258 _____ACAACCUC CCAGAGUA 3373 GACUCCGC CUGAUGAG X CGAA 5472 CCCAGAGUA 6259 _____ACUCUGGG GCGGAGUC 3381 CCAAAGCA CUGAUGAG X CGAA 5473 AGCGGAGUC 6260 _____ACUCCGCU UGCUUUGG WO 99/50403 WO 9950403PCTIUS99/06507 258 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

3386 UCtJCCCCA CUGAUGAG X CGAA 5474 AGUCUGCUU 6261 AGCAGACU ______UGGGGAGA 3387 UUCUCCCC CUGAUGAG X CGAA 5475 GUCUGCUUU 6262 AAGCAGAC ______GGGGAGAA 3403 CCUCAGUC CUGAUGAG X CGAA 5476 AGAGAGAUU 6263 AUCUCUCU GACUGAGG 3414 CUUGAUGC CUGAUGAG X CGAA 5477 CUGAGGAUA 6264 AUCCUCAG GCAUCAAG 3419 AAAAACUU CUGAUGAG X CGAA 5478 GAUAGCAUC 6265 AUGCUAUC AAGUUUUU 3424 AAAUAAAA CUGAUGAG X CGAA 5479 CAUCAAGUU 6266 ACUUGAUG tJUUUAUUU 3425 AAAAUAAA CUGAUGAG X CGAA -5480 AUCAAGUUU 6267 AACUUGAU UUUAUUUU 3426 UAAAAUAA CUGAUGAG X CGAA 5481 UCAAGUUUU 6268 AAACUUGA EJUAUUUUA 3427 AUAAAAUA CUGAUGAG X CGAA 5482 CAAGUUUUU 6269 AAAACUUG UAUUUUAU 3428 CAUAAAAU CUGAUGAG X CGAA 5483 AAGUUUUUU 6270 AAAAACUU AUUUUAUG 3429 ACAUAAAA CUGAUGAG X CGAA 5484 AGUUUUUUA 6271 AAAAAACU UUUUAUGU 3431 GUACAUAA CUGAUGAG X CGAA 5485 UUUUUUAUU 6272 AUAAAAAA EJUAUGUAC 3432 UGUACAUA CUGAUGAG X CGAA 5486 UUUUUAUUU 6273 AAUAAAAA UAUGUACA 3433 UUGUACAU CUGAUGAG X CGAA 5487 UUUUAUUUU 6274 AAAUAAAA AUGUACAA 3434 UUUGUACA CUGAUGAG X CGAA 5488 EJUUAUUUUA 6275 AAAAUAAA UGUACAAA 3438 CAUCUUUG CUGAUGAG X CGAA 5489 tJUUUAUGUA 6276 _____ACAUAAAA _____CAAAGAUG WO 99/50403 WO 9950403PCT[US99/06507 259 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

3449 GCEJAAAAA CUGAUGAG X CGAA 5490 AAGAUGAUC 6277 fAUCAUCUU EJUUUUAGC 3451 AAGCUAAA CUJGAUGAG X CGAA 5491 GAUGAUCUU 6278 AGAUCAUC UUUAGCUU 3452 GAAGCUAA CUGAUGAG X CGAA 5492 AUGAUCUUU 6279 AAGAUCAU UUAGCUUC 3453 UGAAGCUA CUGAUGAG X CGAA 5493 UGAUCUUUU 6280 AAAGAUCA UAGCUUCA 3454 GUGAAGCU CUGAUGAG X CGAA 5494 GAUCUUUUU 6281 AAAAGAUC AGCUUCAC 3455 GGUGAAGC CUGAUGAG X CGAA 5495 AUCUUUUUA 6282 AAAAAGAU GCUUCACC 3459 CCUGGGUG CUGAUGAG X CGAA 5496 UUUUAGCUU 6283 AGCUAAAA CACCCAGG 3460 UCCUGGGU CUGAUGAG X CGAA 5497 UUUAGCUUC 6284 AAGCUAAA ACCCAGGA 3472 AAAACCCA CUGAUGAG X CGAA 5498 CAGGAAGUA 6285 ACUUCCUG UGGGUUUU 3478 AGACACAA CUGAUGAG X CGAA 5499 GUAUGGGUU 6286 ACCCAUAC UUGUGUCU 3479 AAGACACA CUGAUGAG X CGAA 5500 UAUGGGUUU 6287 AACCCAUA UGUGUCUU 3480 GAAGACAC CUGAUGAG X CGAA 5501 AUGGGUUUU 6288 AAACCCAU GUGUCUUC 3485 ACGAGGAA CUGAUGAG X CGAA 5502 UUUUGUGUC 6289 ACACAAAA UUCCUCGU______ 3487 ACACGAGG CUGAUGAG X CGAA 5503 UUGUGUCUU 6290 AGACACAA CCUCGUGU 3488 AACACGAG CUGAUGAG X CGAA 5504 UGUGUCUUC 6291 AAGACACA CUCGUGUU 3491 CUAAACAC CUGAUGAG X CGAA 5505 GUCUUCCUC 6292 AGGAAGAC ______GUGUUUAG WO 99/50403 WO 9950403PCT/US99/06507 260 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

3496 AAAACCUA CUGAUCAG X CGAA 5506 CCUCGUGUU 6293 ACACGAGG

UAGGUUUU

3497 AAAAACCU CUGAUGAG X CGAA 5507 CUCGUGUUU 6294 AACACGAG AGGUUUUU 3498 UAAAAACC CUGAUGAG X CGAA 5508 UCGUGUUUA 6295 AAACACGA

GGUUUUUA

3502 AGAAUAAA CUGAUGAG X CGAA 5509 GUUUAGGUU 6296 ACCUAAAC UUUAUUCU 3503 CAGAAUAA CUGAUGAG X CGAA 5510 UUUAGGUJU 6297 AACCUAAA

UUAUUCUG

3504 UCAGAAUA CUGAUGAG X CGAA 5511 UUAGGUUUU 6298 AAACCUAA UAUUCUGA 3505 GUCAGAAU CUGAUGAG X CGAA 5512 UAGGUUUUU 6299 AAAACCUA AUUCUGAC 3506 GGUCAGAA CUGAUGAG X CGAA 5513 AGGLJUUUUA 6300 AAAAACCU ______UUCUGACC 3508 UAGGUCAG CUGAUGAG X CGAA 5514 GUUUUUAUU 6301 AUAAAAAC

CUGACCUA

3509 UUAGGUCA CUGAUGAG X CGAA 5515 UUUUUAUUC 6302 AAUAAAAA UGACCUAA 3516 GACCUAAU CUGAUGAG X CGAA 5516 UCUGACCUA 6303 AGGUCAGA ______AUUAGGUC 3519 UUAGACCU CUGAUGAG X CGAA 5517 GACCUAAUU 6304 AUUAGGUC ______AGGUCUAA 3520 CUUAGACC CUGAUGAG X CGAA 5518 ACCUAAUUA 6305 AAUUAGGU GGUCUAAG 3524 UCAGCUUA CUGAUGAG X CGAA 5519 AAUUAGGUC 6306 ACCUAAUU

UAAGCUGA

3526 CCUCAGCU CUGAUGAG X CGAA 5520 UUAGGUCUA 630? AGACCUAA AGCUGAGG 3539 AGAGAAAU CUGAUGAG X CGAA 5521 GAGGUGCUU 6308 _____ACCACCUC AUUUCUCU WO 99/50403 WO 9950403PCT/US99/06507 261 Posi- Seq. I.D. Seq. T.D.

tion RZ No. Substrate No.

3540 AAGAGAAA CUGAUGAG X CGAA 5522 AGGUGCUUA 6309 AAGCACCU UUUCUCUU 3542 AGAAGAGA CUGAUGAG X CGAA 5523 GUGCUUAUU 6310 IAUAAGCAC ucucuucu 3543 CAGAAGAG CUGAUGAG X CGAA 5524 UGCUUAUUU 6311 AAUAAGCA CtJCUUCUG 3544 CCAGAAGA CUGAUGAG X CGAA 5525 GCUUAUUUC 6312 AAAUAAGC UCUUCUGG 3546 CUCCAGAA CUGAUGAG X CGAA 5526 UUAUUUCUC 6313 AGAAAUAA EJUCUGGAG 3548 AACUCCAG CUGAUGAG X CGAA 5527 AUUUCUCUU 6314 AGAGAAAU CUGGAGUU 3549 AAACUCCA CUGAUGAG X CGAA 5528 UUUCUCUUC 6315 AAGAGAAA ______UGGAGUUU 3556 AGGAUAUA CUGAUGAG X CGAA 5529 UCUGGAGUU 6316 ACUCCAGA UAUAUCCU 3557 UAGGAUAU CUGAUGAG X CGAA 5530 CUGGAGUUU 6317 AACUCCAG AUAUCCUA 3558 CUAGGAUA CUGAUGAG X CGAA 5531 UGGAGUUUA 6318 AAACUCCA UAUCCUAG 3560 UUCUAGGA CUGAUGAG X CGAA 5532 GAGUUUAUA 6319 AUAAACUC UCCUAGAA 3562 GCUUCUAG CUGAUGAG X CGAA 5533 GUUUAUAUC 6320 AUAUAAAC CUAGAAGC 3565 AGAGCUUC CUGAUGAG X CGAA 5534 UAUAUCCrJA 6321 IAGGAUAUA GAAGCUCU 3572 CGAUUGGA CUGAUGAG X CGAA 5535 UAGAAGCUC 6322

UCCAAUCG

3574 UUCGAUUG CUGAUGAG X CGAA 5536 GAAGCUJCUC 6323 _____AGAGCUUC CAAUCGAA______ 3579 AGGGCUUC CUGAUGAG X CGAA 5537 UCUCCAAUC 6324 AUUGGAGA GAAGCCCU WO 99/50403 WO 9950403PCTIUS99/06507 262 Posi- Seq. I.D. Seq. I. D.

tion RZ No. Substrate No.

3588 UACCUGCA CUGAUGAG X CGAA 5538 GAAGCCCUC 6325 _____AGGGCUUC UGCAGGUA 3596 CCUGAGGA CUGAUGAG X CGAA 5539 CUGCAGGUA 6326 _____ACCUGCAG UCCUCAGG 3598 GACCUGAG CUGAUGAG X CGAA 5540 GCAGGUAUC 6327 _____AUACCUGC CUCAGGUC 3601 CAGGACCU CUGAUGAG X CGAA 5541 GGUAUCCUC 6328 AGGAUACC AGGUCCUG 3606 UUCUCCAG CUGAUGAG X CGAA 5542 CCUCAGGUC 6329 ACCUGAGG CUGGAGAA 3631 AAGCCAAC CUGAUGAG X CGAA 5543 GGAAGGCUU 6330 _____AGCCUUCC GUUGGCUU 3634 CCGAAGCC CUGAUGAG X CGAA 5544 AGGCUUGUU 6331 _____ACAAGCCU GGCUUCGG 3639 CCUUUCCG CUGAUGAG X CGAA 5545 UGTJUGGCUU 6332 AGCCAACA ______CGGAAAGG 3640 CCCUUUCC CUGAUGAG X CGAA 5546 GUUGGCUUC 6333 AAGCCAAC GGAAAGGG 3655 UUAAACCA CUGAUGAG X CGAA 5547 GGAGGGCUA 6334 AGCCCUCC ______UGGUUUAA 3660 UGGCUUUA CUGAUGAG X CGAA 5548 GCUAUGGUU 6335 ACCAUAGC ______UAAAGCCA 3661 CUGGCUUU CUGAUGAG X CGAA 5549 CUAUGGUUU 6336 _____AACCAUAG ______AAAGCCAG 3662 ACUGGCUU CUGAUGAG X CGAA 5550 UAUGGUUUA 6337 AAACCAUA AAGCCAGU 3671 CCACAUCU CUGAUGAG X CGAA 5551 AAGCCAGUA 6338 _____ACUGGCUU AGAUGUOG 3682 AAGAAUCA CUGAUGAG X CGAA 5552 AUGUGGGUU 6339 ACCCACAU UGAUUCUU 3683 CAAGAAUC CUGAUGAG X CGAA 5553 UGUGGGUUU 6340 IAACCCACA GAUUCUUG WO 99/50403 WO 9950403PCTIUS99/06507 263 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

3687 AAGUCAAG CUGAUGAG X CGAA 5554 GGUUUGAUU 6341 IAUCAAACC

CUUGACUU

3688 AAAGUCAA CUGAUGAG X CGAA 5555 GUUUGAUUC 6342 AAUCAAAC UUGACUUU 3690 ACAAAGUC CUGAUGAG X CGAA 5556 UUGAUUCUU 6343 AGAAUCAA ______GACUUUGU 3695 AGGAGACA CUGAUGAG X CGAA 5557 UCUUGACUU 6344 AGUCAAGA UGUCUCCU 3696 CAGGAGAC CUGAUGAG X CGAA 5558 CUUGACUUU 6345 AAGUCAAG GUCUCCUG 3699 CUACAGGA CUGAUGAG X CGAA 5559 GACUUUGUC 6346 ACAAAGUC UCCUGUAG 3701 GCCUACAG CUGAUGAG X CGAA 5560 CUUUGUCUC 6347 AGACAAAG CUGUAGGC 3706 ACACAGCC CUGAUGAG X CGAA 5561 UCUCCUGUA 6348 _____ACAGGAGA

GGCUGUGU

3720 ACUUAUUU CUGAUGAG X CGAA 5562 UGUGGCCUU 6349 AGGCCACA AAAUAAGU 3721 AACUUAUU CUGAUGAG X CGAA 5563 GUGGCCUUA 6350 ____AAGGCCAC AAUAAGUU 3725 AGGUAACU CUGAUGAG X CGAA 5564 CCUUAAAUA 6351 _____AUUUAAGG AGUUACCU______ 3729 GAUUAGGU CUGAUGAG X CGAA 5565 AAAUAAGUU 6352 ____ACUUAUUU ACCUAAUC______ 3730 AGAUUAGG CUGAUGAG X CGAA 5566 AAUAAGUUA 6353 _____AACUUAUU CCUAAUCU______ 3734 CAAGAGAU CUGAUGAG X CGAA 5567 AGUUACCUA 6354 _____AGGUAACU AUCUCUUG______ 3737 ACUCAAGA CUGAUGAG X CGAA 5568 UACCUAAUC 6355 AUUAGGUA UCUUGAGU 3739 GGACUCAA CUGAUGAG X CGAA 5569 CCtJAAUCUC 6356 AGAUUAGG IUUGAGUCC WO 99/50403 WO 9950403PCT[US99/06507 264 Posi- Seq. T.D. Seq. I. D.

tion RZ No. Substrate No.

3741 GAGGACUC CUJGAUGAG X CGAA 5570 EJAAUCUCLJU 6357 AGAGAUUA GAGEJCCUC 3746 AAACEJGAG CUGAUGAG X CGAA 5571 UCUUGAGUC 6358 ACUCAAGA CUCAGUUU 3749 AGGAAACU CUGAUGAG X CGAA 5572 UGAGUCCUC 6359 AGGACUCA AGUUUCCU 3753 AAUGAGGA CUGAUGAG X CGAA 5573 UCCUCAGUU 6360 ACUGAGGA UCCUCAUU 3754 AAAUGAGG CUGAUGAG X CGAA 5574 CCUCAGUUU 6361 fAACUGAGG CCUCA.UUU 3755 CAAAUGAG CUGAUGAG X CGAA 5575 CUCAGUUUC 6362 AAACUGAG CUCAUUUG 3758 UUACAAAU CUGAUGAG X CGAA 5576 AGUUUCCUC 6363 AGGAAACU AUUUGUAA 3761 GCCUUACA CUGAUGAG X CGAA 5577 UUCCUCAUU 6364 AUGAGGAA UGUAAGGC 3762 UGCCUUAC CUGAUGAG X CGAA 5578 UCCUCAUUU 6365 AAUGAGGA GUAAGGCA 3765 CUCUGCCU CUGAUGAG X CGAA 5579 UCAUUUGUA 6366 ACAAAUGA AGGCAGAG 3786 CAUAAUCA CUGAUGAG X CGAA 5580 CAAUGCCUA 6367 AGGCAUUG UGAUUAUG 3791 AUCAGCAU CUGAUGAG X CGAA 5581 CCUAUGAUU 6368 AUCAUAGG ______AUGCUGAU 3792 AAUCAGCA CUGAUGAG X CGAA 5582 CUAUGAUUA 6369 AAUCAUAG UGCUGAUU 3800 UUUCAUUU CUGAUGAG X CGAA 5583 AUGCUGAUU 6370 AUCAGCAU AAAUGAAA 3801 GUUUCAUU CUGAUGAG X CGAA 5584 UGCUGAUUA 6371 AAUCAGCA AAUGAAAC 3823 UAAACACU CUGAUGAG X CGAA 5585 CACAAAAUA 6372 _____AUUUUGUG IAGUGUUUA WO 99/50403 WO 9950403PCT/US99/06507 265 Pos i- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

3829 AUUCAUtJA CEJGAL]GAG X CGAA 5586 AUAAGtJGUU 6373 ACACEJUAU UAAUGAAU 3830 CAUUCAUU CUGAUGAG X CGAA 5587 UAAGUGUUU 6374 AACACUUA AAUGAAUG 3831 UCAUUCAU CUGAUGAG X CGAA 5588 AAGUGUUUA 6375 AAACACUU AUGAAUGA 3845 GACAAUAG CUGAUGAG X CGAA 5589 UGACAACUA 6376 AGUUGUCA CUAUUGUC 3848 AAUGACAA CUGAUGAG X CGAA 5590 CAACUACUA 6377 IAGUAGUUG

UUGUCAUU

3850 AUAAUGAC CUGAUGAG X CGAA 5591 ACUACUAUU 6378 AUAGUAGU GUCAUUAU 3853 AGAAUAAU CUGAUGAG X CGAA 5592 ACUAUUGUC 6379 ACAAUAGU AUUAUUCU 3856 GGAAGAAU CUGAUGAG X CGAA 5593 AUUGUCAUU 6380 AUGACAAU AUUCUUCC 3857 AGGAAGAA CUGAUGAG X CGAA 5594 UUGUCAUUA 6381 AAUGACAA UUCUUCCU 3859 AL]AGGAAG CUGAUGAG X CGAA 5595 GUCAUUAUU 6382 IAUAAUGAC CUUCCUAU 3860 GAUAGGAA CUGAUGAG X CGAA 5596 UCAUUAUUC 6383 AAUAAUGA ______UUCCUAUC 3862 UGGAUAGG CUGAUGAG X CGAA 5597 AUUAUUCUU 6384 AGAAUAAU ______CCUAUCCA 3863 AUGGAUAG CUGAUGAG X CGAA 5598 UUAUUCUUC 6385 AAGAAUAA CUAUCCAU 3866 AGCAUGGA CUGAUGAG X CGAA 5599 UUCUUCCUA 6386 AGGAAGAA 3868 AUAGCAUG CUGAUGAG X CGAA 5600 CUUCCUAUC 6387 IAUAGGAAG CAUGCUAU 3875 AUGGCAGA CUGAUGAG X CGAA 5601 UCCAUGCUA 6388 AGCAUGGA ______UCUGCCAU WO 99/50403 WO 9950403PCT/US99/06507 266 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

3877 ACAUGGCA CUGAUGAG X CGAA 5602 CAUGCUAUC 6389 AUAGCAUG UGCCAUGU 3886 GCCUCCAA CUGAUGAG X CGAA 5603 UGCCAUGUA 6390 ACAUGGCA UUGGAGGC 3888 UUGCCUCC CUGAUGAG X CGAA 5604 CCAUGUAUU 6391 AUACAUGG GGAGGCAA 3904 GAAGUAGU CUGAUGAG X CGAA 5605 AAAGCUGUU 6392 ACAGCUUU ACUACUUC 3905 UGAAGUAG CUGAUGAG X CGAA 5606 AAGCUGUUA 6393 AACAGCUU CUACUUCA 3908 GCAUGAAG CUGAUGAG X CGAA 5607 CUGUUACUA 6394 AGUAACAG CUUCAUGC 3911 UAUGCAUG CUGAUGAG X CGAA 5608 UUACUACUU 6395 IAGUAGUAA CAUGCAUA 3912 AUAUGCAU CUGAUGAG X CGAA 5609 UACUACUUC 6396 AAGUAGUA AUGCAUAU 3919 AUAGCGCA CUGAUGAG X CGAA 5610 UCAUGCAUA 6397 AUGCAUGA UGCGCUAU 3926 AGCCUGCA CIJGAUGAG X CGAA 5611 UAUGCGCUA 6398 AGCGCAUA UGCAGGCU 3935 CAUUCUGG CUGAUGAG X CGAA 5612 UGCAGGCUU 6399 AGCCUGCA CCAGAAUG 3936 UCAUUCUG CUGAUGAG X CGAA 5613 GCAGGCUUC 6400 AAGCCUGC CAGAAUGA 3957 GGGAAAGG CUGAUGAG X CGAA 5614 GAUGGGGUC 6401 ACCCCAUC CCUUUCCC 3961 GUGGGGGA CUGAUGAG X CGAA 5615 GGGUCCCUU 6402 AGGGACCC UCCCCCAC______ 3962 UGUGGGGG CUGAUGAG X CGAA 5616 GGUCCCUUU 6403 AAGGGACC CCCCCACA______ 3963 AUGUGGGG CUGAUGAG X CGAA 5617 GUCCCUUUC 6404 AAAGGGAC

CCCCACAUI

WO 99/50403 WO 9950403PCTIUS99/06507 267 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

3972 CUCUCACA CtJGAUGAG X CGAA 5618 CCCCACAUA 6405 AUGUGGGG UGUGAGAG 3986 AUAAGAGG CUGAUGAG X CGAA 5619 GAGGGGGUC 6406 ACCCCCUC CCUCUUAU 3990 UGAAAUAA CUGAUGAG X CGAA 5620 GGGUCCCUC 6407 AGGGACCC UUAUUUCA 3992 GUUGAAAU CUGAUGAG X CGAA 5621 GUCCCUCUU 6408 AGAGGGAC AUUUCAAC 3993 AGUUGAAA CUGAUGAG X CGAA 5622 UCCCUCUUA 6409 AAGAGGGA UUUCAACU 3995 CGAGUUGA CUGAUGAG X CGAA 5623 CCUCUUAUU 6410 _____AUAAGAGG UCAACUCG 3996 ACGAGUUG CUGAUGAG X CGAA 5624 CUCUUAUUU 6411 AAUAAGAG CAACUCGU 3997 AACGAGUU CUGAUGAG X CGAA 5625 UCUUAUUUC 6412 _____AAAUAAGA ______AACUCGUU 4002 UGAGGAAC CUGAUGAG X CGAA 5626 UUUCAACUC 6413 _____AGUUGAAA ______GUUCCUCA 4005 CAAUGAGG CUGAUGAG X CGAA 5627 CAACUCGUU 6414 _____ACGAGUUG CCUCAUUG 4006 GCAAUGAG CUGAUGAG X CGAA 5628 AACUCGUUC 6415 _____AACGAGUU ______CUCAUUGC 4009 CCAGCAAU CUGAUGAG X CGAA 5629 UCGUUCCUC 6416 _____AGGAACGA AUUGCUGG 4012 AAACCAGC CUGAUGAG X CGAA 5630 UUCCUCAUU 6417 AUGAGGAA ______GCUGGUUU 4019 AUAUGCCA CUGAUGAG X CGAA 5631 UUGCUGGUU 6418 _____ACCAGCAA UGGCAUAU 4020 GAUAUGCC CUGAUGAG X CGAA 5632 UGCUGGUUU 6419 _____AACCAGCA GGCAUAUC 4026 AGCUGAGA CUGAUGAG X CGAA 5633 UUUGGCAUA 6420 AUGCCAAA IUCUCAGCU WO 99/50403 WO 9950403PCT/US99/06507 268 Posi- Seq. I.D. Seq. I.D.

tion RZ No. Substrate No.

4028 GUAGCtJGA CUGAUGAG X CGAA 5634 UGGCAUAUC 6421 AUAUGCCA UCAGCUAC 4030 GAGUAGCU CUGAUGAG X CGAA 5635 GCAUAUCUC 6422 AGAUAUGC AGCUACUC 4035 GGUUAGAG CUGAUGAG X CGAA 5636 UCUCAGCUA 6423 AGCUGAGA ______CUCUAACC 4038 CCGGGUUA CUGAUGAG X CGAA 5637 CAGCUACUC 6424 AGUAGCUG ______UAACCCGG 4040 UGCCGGGU CUGAUGAG X CGAA 5638 GCUACUCUA 6425 AGAGUAGC ACCCGGCA 4054 CUUCUGUG CUGAUGAG X CGAA 5639 GCAAGAAUC 6426 AUUCUUGC CACAGAAG 4084 AAAUGUAU CUGAUGAG X CGAA 5640 AAAAGGCUU 6427 AGCCUUUU AUACAUUU 4085 CAAAUGUA CUGAUGAG X CGAA 5641 AAAGGCUUA 6428 AAGCCUUU UACAUUUG 4087 AGCAAAUG CUGAUGAG X CGAA 5642 AGGCUUAUA 6429 AUAAGCCU CAUUUGCU 4091 GUAAAGCA CUGAUGAG X CGAA 5643 UUAUACAUU 6430 AUGUAUAA UGGULTUAC 4092 GGUAAAGC CUGAUGAG X CGAA 5644 UAUACAUUU 6431 AAUGUAUA GCUUUACC 4096 UAUGGGUA CUGAUGAG X CGAA 5645 CAUUUGCUU 6432 AGCAAAUG UACCCAUA 4097 UUAUGGGU CUGAUGAG X CGAA 5646 AUUUGCUUU 6433 AAGCAAAU ACCCAUAA 4098 CUUAUGGG CUGAUGAG X CGAA 5647 UUUGCUUUA 6434 AAAGCAAA CCCAUAAG 4104 GGUUUUCU CUGAUGAG X CGAA 5648 UUACCCAUA 6435 AUGGGUAA AGAAAACC 4114 CAGGGCUU CUGAUGAG X CGAA 5649 GAAAACCUC 6436 AGGUUUUC AAGCCCUG WO 99/50403 WO 9950403PCT[US99/06507 269 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

4124 UUUUCAGA CUGAtJGAG X CGAA 5650 AGCCCUGUA 6437 ACAGGGCU

UCUGAAAA

4126 UUUUUUCA CUGAUGAG X CGAA 5651 CCCUGUAUC 6438 AUACAGGG

UGAAAAAA

4144 GAUCCUUU CUGAUGAG X CGAA 5652 AGGAAGAUA 6439 _____AUCUUCCU

AAAGGAUC

4152 GUCUUAUA CUGAUGAG X CGAA 5653 AAAAGGAUC 6440 _____AUCCUUUU

-UAUAAGAC

4154 AAGUCUUA CUGAUGAG X CGAA 5654 AAGGAUCUA 6441 _____AGAUCCUU

UAAGACUU

4156 UGAAGUCU CUGAUGAG X CGAA 5655 GGAUCUAUA 6442 AUAGAUCC

AGACUUCA

4162 GGAACUUG CUGAUGAG X CGAA 5656 AUAAGACUU 6443 AGUCUUAU

CAAGUUCC

4163 UGGAACUU CUGAUGAG X CGAA 5657 UAAGACUUC 6444 AAGUJCUUA

AAGUUCCA

4168 UCUCAUGG CUGAUGAG X CGAA 5658 CUUCAAGUU 6445 ACUUGAAG

CCAUGAGA

4169 UUCUCAUG CUGAUGAG X CGAA 5659 UUCAAGUUC 6446 AACUUGAA CAUGAGAA 4189 ACAAAAUA CUGAUGAG X CGAA 5660 GGACAUGUC 6447 ACAUGUCC

UAUUUUGU

4191 GAACAAAA CUGAUGAG X CGAA 5661 ACAUGUCUA 6448 _____AGACAUGU

UUUUGUUC

4193 UUGAACAA CUGAUGAG X CGAA 5662 AUGUCUAUU 6449 _____AUAGACAU

UUGUUCAA

4194 AUUGAACA CUGAUGAG X CGAA 5663 UGUCUAUUU 6450 AAUAGACA

UGUUCAAU

4195 UAUUGAAC CUGAUGAG X CGAA 5664 GUCUAUUUU 6451 _____AAAUAGAC

GUUCAAUA

4198 GAGUAUUG CUGAUGAG X CGAA 5665 UAUUUUGUU 6452 _____ACAAAAUA

CAAUACUC

WO 99/50403 WO 9950403PCTIUS99/06507 270 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

4199 AGAGEJAUU CUGAUGAG X CGAA 5666 AUUUUGUUC 6453 AACAAAAU

AAUACUCU

4203 GCAUAGAG CUGAUGAG X CGAA 5667 UGUUCAAUA 6454 AUUGAACA

CUCUAUGC

4206 UGGGCAUA CUGAUGAG X CGAA 5668 UCAAUJACUC 6455 AGUAUUGA

UAUGCCCA

4208 AGUGGGCA CUGAUGAG X CGAA 5669 AAUACUCUA 6456 AGAGUAUU

UGCCCACU

4228 UUGCUGCC CUGAUGAG X CGAA 5670 UGGCACAUA 6457 AUGUGCCA

GGCAGCAA

4244 UCCACAGA CUGAUGAG X CGAA 5671 AAACAAAUA 6458 AUUUGUUU

UCUGUGGA

4246 AUUCCACA CUGAUGAG X CGAA 5672 ACAAAUAUC 6459 AUAUUUGU

UGUGGAAU

4258 CCUUUACA CUGAUGAG X CGAA 5673 GGAAUGCUA 6460 AGCAUUCC

UGUAAAGG

4262 GAUGCCUU CUGAUGAG X CGAA 5674 EJGCUAUGUA 6461 _____ACAUAGCA

______AAGGCAUC

4270 CAUCUAUA CUGAUGAG X CGAA 5675 AAAGGCAUC 6462 _____AUGCCUUU

UAUAGAUG

4272 AUCAUCUA CUGAUGAG X CGAA 5676 AGGCAUCUA 6463 _____AGAUGCCU

UAGAUGAU

4274 ACAUCAUC CUGAUGAG X CGAA 5677 GCAUCUAUA 6464 _____AUAGAUGC

GAUGAUGU

4287 CUUAAAGG CUGAUGAG X CGAA 5678 AUGUGCCUC 6465 fAGGCACAU CCUUUAAG 4291 GUUUCUUA CUGAUGAG X CGAA 5679 GCCUCCCUU 6466 AGGGAGGC

UAAGAAAC

4292 GGUUUCUU CUGAUGAG X CGAA 5680 CCUcccuuu 6467 AAGGGAGG

AAGAAACC

4293 GGGUUUCU CUGAUGAG X CGAA 5681 CUCCCUUUA 6468 AAAGGGAG

AGAAACCC

WO 99/50403 WO 9950403PCT/US99/06507 271 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

4305 UAUUCAAA CUGAUGAG X CGAA 5682 AACCCAAUA 6469 AUUGGGUU

UUUGAAUA

4307 AAUAUUCA CUGAUGAG X CGAA 5683 CCCAAUAUU 6470 AUAUUGGG UGAAUAUU 4308 AAAUAUUC CUGAUGAG X CGAA 5684 CCAAUAUUU 6471 AAUAUUGG GAAUAUUU 4313 AGUGCAAA CUGAUGAG X CGAA 5685 AUUUGAAUA 6472 AUUCAAAU UUUGCACU 4315 UGAGUGCA CUGAUGAG X CGAA 5686 UUGAAUAUU 6473 AUAUUCAA UGCACUCA 4316 AUGAGUGC CUGAUGAG X CGAA 5687 UGAAUAUUU 6474 AAUAUUCA GCACUCAU 4322 GUAUGAAU CUGAUGAG X CGAA 5688 UUUGCACUC 6475 AGUGCAAA AUUCAUAC 4325 CUUGUAUG CUGAUGAG X CGAA 5689 GCACUCAUU 6476 AUGAGUGC CAUACAAG 4326 UCUUGUAU CUGAUGAG X CGAA 5690 CACUCAUUC 6477 AAUGAGUG AUACAAGA 4329 GGAUCUUG CUGAUGAG X CGAA 5691 UCAUUCAUA 6478 _____AUGAAUGA CAAGAUCC 4336 CACUUGAG CUGAUGAG X CGAA 5692 UACAAGAUC 6479 _____AUCUUGUA C UCAAGUG 4339 GAGCACUU CUGAUGAG X CGAA 5693 AAGAUCCUC 6480 _____AGGAUCUU AAGUGCUC______ 4347 UCCAAACG CUGAUGAG X CGAA 5694 CAAGUGCUC 6481 AGCACUUG

CGUUUGGA

4351 AUUAUCCA CUGAUGAG X CGAA 5695 UGCUCCGUU 6482 ACGGAGCA UGGAUAAU 4352 GAUUAUCC CUGAUGAG X CGAA 5696 GCUCCGUUU 6483 AACGGAGC GGAUAAUC 4357 CUCCAGAU CUGAUGAG X CGAA 5697 GUUUGGAUA 6484 AUCCAAAC IAUCUGGAG WO 99/50403 WO 9950403PCTIUS99/06507 272 Posi- Seq. I. D. Seq. I. D.

tion RZ No. Substrate No.

4360 ACCCUCCA CUGAUGAG X CGAA 5698 UGGAUAAUC 6485 AUUAUCCA

UGGAGGGU

4369 UGUUUtJCA CUGAUGAG X CGAA 5699 UGGAGGGUA 6486 ACCCUCCA UGAAAACA 4379 AUCUUGGC CUGAUGAG X CGAA 5700 GAAAACAUA 6487 AUGUUUUC GCCAAGAU 4388 GAAUUCAU CUGAUGAG X CGAA 5701 GCCAAGAUC 6488 AUCUUGGC fAUGAAUUC WO 99/50403 WO 9950403PCT[US99/06507 273 TABLE X: HAIRPIN RiBOZYME AND TARGET SEQUENCES FOR INTEGRIN SUBUNIT BETA 3 Seq. Seq.

Position RZ 1.0. No. Substrate I.D. No.

98 UCUCUG AGAA GGUU ACCAGAGAAACA 6489 ACCG GUU 6569 XGUACAUUACCUGGUA CAGAGA 119 GCAAAC AGAA GCUG ACCAGAGAAACA 6490 CAGCA GAU 6570 XGUACAUUACCUGGUA GUUUGC 284 GUCCGC AGAA GGGC ACCAGAGAAACA 6491 GCCCA GUC 6571 XGUACAUUACCUGGUA _____GCGGAC 290 CCGGGG AGAA GCGA ACCAGAGAA.ACA 6492 UCGCG GAO 6572 XGUACAUUACCUGGUA CCCCGG 313 CGGGUC AGAA GCGC ACCAGAGAAACA 6493 GCGCU GAO 6573 XGUACAUUACCUGGUA GACCCG 322 CCUGCC AGAA GGGU ACCAGAGAAACA 6494 ACCCG GCU 6574 XGUACAUUACCUGGUA GGCAGG 388 AGAGGG AGAA GUGG ACCAGAGAAACA 6495 CCACC GCU 6575 XGUACAUUACCUGGUA CCCUCU 465 GGGGCG AGAA GCGG ACCAGAGAAACA 6496 CCGCG GCC 6576 XGUACAUUACCUGGUA CGCCCC 469 CAACGG AGAA GGCC ACCAGAGAAACA 6497 GGCCC GCC 6577 X_ GUACAUUACCUGGUA CCGUUG 474 GGACGC AGAA GGGC ACCAGAGAAACA 6498 GCCCC GUU 6578 X_ GUACAUUACCUGGUA _____GOGUC 513 UUCCGC AGAA GGAG ACCAGAGAAACA 6499 CUCCC GCU 6579 XGUACAUUACCUGGUA GCGGAA 527 GCCCGC AGAA GCUU ACCAGAGAAACA 6500 ACG GCC 6580 XGUACAUUACCUGGUA GCGGGC 578 CAUCUC AGAA GCCU ACCAGAGAAACA 6501 AGGCG GAO 6581 XGUACAUUACCUGGUA GAGAUG 595 GGCCGC AGAA GCGO ACCAGAGAA.ACA 6502 GCGCG GCC 6582 XGUACAUUACCUGGUA GOGGC 601 GGCCGG AGAA GCGG ACCAGAGAAJ\CA 6503 CCGOG GCC 6583 FGUACAUUACCUGGUA CCGGCC WO 99/50403 WO 9950403PCT/US99/06507 274 Seq. Seq.

Position RZ I.D. No. Substrate I.D. No.

607 CAGAGC AGAA GGGG ACCAGAGAAACA 6504 CCOG GCC 6584 X_ GUACAUUACCUGGUA GOEJOUG 610 GCCCAG AGAA GCCG ACCAGAGAAACA 6505 CGGCC GCU 6585 X_ GUACAUUACCUGGUA CUGGGC 678 CUGCCG AGAA GGAG ACCAGAGAAACA 6506 CUCCG GCU 6586 X_ GUACAUUACCUGGUA

CGGCAG

694 UGGGOC AGAA GCGA ACCAGAGAAACA 6507 UCGCA GCU 6587 X_ GUACAUUACCUGGJA GCCCCA 697 UCCUGG AGAA GCUG ACCAGAGAAACA 6508 CAGCU GCC 6588 X_ GUACAUUACCUGGUA CCAGGA 728 CUCCAA AGAA GCAA ACCAGAGAAACA 6509 EJUGCG GAC 6589 X_ GUACAUUACCUGGUA EJUGGAG 800 GGUCC AGAA GGC ACCAGAGAAACA X 6510 GCNCG GUC 6590 ________GUACAUUACCUGGJA

GGANC

920 CGCGGC AGAA GGGA ACCAGAGAAACA 6511 UCCCG GCC 6591 XGUACAUUACCUGGUA GCCGCG 923 CGCCGC AGAA GCCG ACCAGAGAAACA 6512 CGGCC GCC 6592 XGUACAUUACCUGGUA GCGGCG 1006 UCCEJUG AGAA GACC ACCAGAGAAACA 6513 GGUCG GNC 6593 XGUACAUUACCUGGUA CAAGGA 1020 UUCCUG AGAA GUCG ACCAGAGAAACA 6514 CGACU GCC 6594 X_ GUACAUUACCUGGUA CAGGAA 1063 CCAAGG AGAA GGAA ACCAGAGAAACA 6515 UUCCC GCC 6595 X_ GUACAUUACCUGGUA ICCUUGG 1295 CCUGGG AGAA GAGG ACCAGAGAAACA 6516 CCUCU GCU 6596 X_ GUACAUUACCUGGUA CCAGG 1307 UGCAGG AGAA GCCC ACCAGAGAAACA 6517 GGGCA GAO 6597 X_ GUACAUUACCUGGUA ICCUGCA 1396 GUGCGC AGA\ GCCA ACCAGAGAAACA 6518 UGGCU GCU 6598 X_ GUACAUUACCUGGUA GCGCAC 1412 CCUGAC AGAA GACG ACCAGAGAAACA 6519 CGUCA GCC 6599 GUACAUUACCUGGUA

IGUCAGGI

WO 99/50403 WO 9950403PCT/US99/06507 275 Seq. Seq.

Position RZ I No. Substrate I.D. No.

1435 CAAAGA AGAA GAAU ACCAGAGAAACA 6520 AUUCG GCC 6600 X_ GUACAUUACCUGGUA UCUUJUG 1481 ACCCCG AGAA GUGC ACCAGAGAAACA 6521 GCACA GCC 6601 XGUACAUtJACCUGGUA CGGGGU 1494 ACCACG AGAA GCAA ACCAGACAAACA 6522 UUGCU GCC 6602 XGUACAUEJACCUGGUA CGUGGU 1561 GGCCCC AGAA GACC ACCAGAGAAACA 6523 GGUCU GCU 6603 XGUACAUUACCUGGUA GGGGCC 1570 GGCAGA AGAA GCCC ACCAGAGAAACA 6524 GGGCC GCC 6604 XGUACAUUACCUGGUA UCUGCC 1576 CUCEJGA AGAA GAGG ACCAGAGAAACA 6525 CCUCU GCC 6605 XGUACAUUACCUGGUA UCAGAG 1625 GAGUAC AGAA GUUU ACCAGAGAAACA 6526 AACu GUA 6606 XGUACAUUACCUGGUA GEJACUC 1726 CUGGGC AGAA GAGC ACCAGAGAAACA 6527 GCUCU GUC 6607 X_ GUACAUUACCEJGGUA IGCCCAG 1760 GCAGUG AGAA GAGA ACCAGAGAALACA 6528 UCUCG GCU 6608 X_ GUACAUUACCUGGUA CACUGC 1776 CCAGGA AGAA GAAG ACCAGAGAAACA 6529 CUUCU GCC 6609 X_ GUACAUUACCUGGUA IUCCUGG 1808 UCGGGA AGAA GAGC ACCAGAGAAACA 6530 GCUCA GCC 6610 X_ GUACADUACCUGGJA UCCCGA 1848 UUAGCC AGAA GUGG ACCAGAGAAACA 6531 CCACG GCC 6611 X GUACAUUACCUGGJA GGCUAA 1882 UGGUGA AGAA GCGU ACCAGAGAAACA 6532 ACGCG GUU 6612 X_ GUACAUUACCUGGUA UCACCA 1933 GAGGUG AGAA GAUC ACCAGAGAAACA 6533 GAUCC GCC 6613 X_ GUACAUUACCUGGUA CACCUC 1943 UUGGGA AGAA GAGG ACCAGAGAAACA 6534 CCUCA GCC 6614 X_ GUACAUUACCUGGUA UJCCCAA 2170 CCUGGC AGAA GCGA ACCAGAGAAACA 6535 UCGCU GUC 6615 GUACAUUACCUGGUA I GCCAGGI WO 99/50403 WO 9950403PCT/US99/06507 276 Seq. Seq.

Position RZ I. D. No. Substrate I.D. No.

2203 GCAGUG AGAA GAAA ACCAGAGAAACA 6536 UtJUCA GCU 6616 X_ GUACAUUACCUGGUA _____CACUGC 2219 CCGGGA AGAA GAGG ACCAGAGAAACA 6537 CCUCG GCU 6617 X_ GUACAUUACCUGGUA CCCGG 2245 GGCrJGA AGAA GGAG ACCAGAGAAACA 6538 CUCCU GCC 6618 X_ GIJACAULACCUGGUA _____UCAGCC 2251 UCGGGA AGAA GAGG ACCAGAGAAACA 6539 CCUCA GCC 6619 XGUACAUUACCUGGUA IUCCCGA 2373 AGGCA AGAA GAUC ACCAGAGAAACA 6540 GAUCA GCC 6620 XGUACAUUACCUGGUA UGCCUU 2377 GGCCAA AGAA GGCU ACCAGAGAAACA 6541 AGCCU GCC 6621 X_ GUACAUUACCUGGUA _____UUGGCC 2456 CAUAUC AGAA GUAA ACCAGAGAAACA 6542 UUACA GUU 6622 XGUACAUUACCUGGJA GAUAUG 2521 CAGCUG AGAA GUUU ACCAGAGAAACA 6543 AACA GAU 6623 XGUACAUUACCUGGUA CAGCUG 2526 ACEAUC AGAA GAUC ACCAGAGAAACA 6544 GAUCA GCU 6624 XGUACAUUACCUGGUA GAUAGU 2553 UCAUCA AGAA GCUC ACCAGAGAAACA 6545 GAGCA GUC 6625 X_ GUACAUUACCUGGUA _____UGAUGA 2557 AUAGUC AGAA GACU ACCAGAGAAACA 6546 AGUCU GAU 6626 X_ GUACAUUACCUGGJA GACUAU 2595 UCCCAG AGAA GAAU ACCAGAGAAACA 6547 AUUCU GCC 6627 XGUACAUUACCUGGUA _____CUGGGA 2623 AGCAGC AGAA GACC ACCAGAGAAACA 6548 GGUCA GAU 6628 X_ GUACAUUACCUGGUA _____GCUGCU 2629 AUAGCC AGAA GCAU ACCAGAGAAACA 6549 AJGCU GCU 6629 X_ GUACAUUACCUGGUA _____GGCUAU 2738 AUCCUG AGAA GGAC ACCAGAGAAACA 6550 GUCCU GUC 6630 X_ GUACAUDACCUGGJA CAGGAU 2811 UUAGAA AGAA GUGA ACCAGAGAAACA 6551 UCACA GUC 6631 kGUACAUUACCUGGUA IUUCUAA WO 99/50403 WO 9950403PCTIUS99/06507 277 Seq. Seq.

Position RZ I.D. No. Substrate I.D. No.

2982 UGCCCA AGAA GGUC ACCAGAGAAACA 6552 GACCA GCU 6632 XGUACAUUACCUGGUA UGGGCA 3045 UCUGUG AGAA GAUC ACCAGAGAAACA 6553 GAUCU GUU 6633 XGUACAUUACCUGGUA CACAGA 3052 AGAUUA AGAA GUGA ACCAGAGAAACA 6554 UCACA GAU 6634 XGUACAUUACCUGGUA UAAUCU 3138 AACAC AGAA GUAC ACCAGAGAAACA 6555 GUACA GUA 6635 XGUACAUUACCUGGUA GUGUUU 3169 CUGGAA AGAA GACU ACCAGAGAAACA 6556 AGUCA GAC 6636 XGUACAUUACCUGGUA UUCCAG 3211 AGUAGA AGAA GAUU ACCAGAGAAACA 6557 AUCA GUU 6637 XGUACAUUACCUGGUA UCUACU 3262 CCAGGG AGAA GAAG ACCAGAGAAACA 6558 CUUCA GAU 6638 XGUACAUUACCUGGUA CCCUGG 3278 CCCACC AGAA GCUU ACCAGAGAAACA 6559 SACA GAU 6639 XGUACAUUACCJGGUA GGUGGG 3382 CCCCAA AGAA GACU ACCAGAGAAACA 6560 AGUCU GCU 6640 XGUACAULJACCUGGUA UU.GGGG 3510 AUUAG AGAA GAAU ACCAGAGAAACA 6561 AUUCU GAG 6641 XGUACAUUACCUGGUA CUAAUU 3703 ACAGCC AGAA GGAG ACCAGAGAAACA 6562 CUCCU GUA 6642 XGUACAUUACCUGGUA _____GGCUGU 3750 UGAGGA AGAA GAGG ACCAGAGAAACA 6563 CCUCA GUU 6643 XGUACAUUACCEJGGUA UCCUCA 3796 CAUUUA AGAA GCAU ACCAGAGAAACA 6564 AUGCU GAU 6644 X_ GUACAUUACCUGGUA UAAAUG 3948 GACCCC AGAA GUUU ACCAGAGAAACA 6565 AACu GAU 6645 X_ GUACAUUACCUGGUA _____GGGGUC 4121 UUCAGA AGAA GGGC ACCAGAGAAACA 6566 GCCCU GUA 6646 X_ GUACAUUACCUGGUA _____UCUGAA 4216 GUGCCA AGAA GUGG ACCAGAGAAACA 6567 CCACU GCC 6647 IGUACAUUACCUGGUA UGGCAC WO 99/50403 PCT/US99/06507 278 Seq. Seq.

Position RZ I.D. No. Substrate I.D. No.

4348 UAUCCA AGAA GAGC ACCAGAGAAACA 6568 GCUCC GUU 6648 kGUACAUUACCUGGUA IUGGAUA EDITORIAL NOTE 33647/99 SEQUENCE LISTING PAGES 1 TO 13 ARE PART OF THE DESCRIPTION AND ARE FOLLOWED BY CLAIM PAGES NUMBERED 279 TO 283.

WO 99/50403 PCT/US99/06507 SEQUENCE LISTING <110> Wycoff, Keith L.

Jaiswal, Sudhir K.

<120> METHODS AND COMPOSITIONS FOR PRODUCTION OF MULTIMERIC PROTEINS IN TRANSGENIC PLANTS <130> 415142000100 <140> Unassigned <141> Herewith <160> 8 <170> FastSEQ for Windows Version <210> 1 <211> 721 <212> DNA <213> Homo sapiens <220> <221> CDS <222> <400> 1 ggatctaacc atg gga tct aaa cct ttt ttg tct ctt ctt tca ttg tca Met Gly Ser Lys Pro Phe Leu Ser Leu Leu Ser Leu Ser ttg ctt Leu Leu ttg ttt aca tct Leu Phe Thr Ser agt ttg gca gac Ser Leu Ala Asp att Ile gtg atg acc cag Val Met Thr Gin cca gca atc atg Pro Ala Ile Met gca tct cca ggg Ala Ser Pro Gly aag gtc acc ata Lys Val Thr Ile acc Thr tgc agt gcc age Cys Ser Ala Ser agt gta agt tac atg cac tgg ttc cag Ser Val Ser Tyr Met His Trp Phe Gin cag aag Gin Lys 193 cca ggc act Pro Gly Thr tct gga gtc Ser Gly Val tct Ser ccc aaa ctc tgg Pro Lys Leu Trp tat agc aca tcc Tyr Ser Thr Ser aac ctg gct Asn Leu Ala acc tct tac Thr Ser Tyr 241 289 cct got cgc ttc Pro Ala Arg Phe agt Ser 85 ggc agt gga tct Gly Ser Gly Ser ggg Gly tct ctc aca atc agc cga atg gag gct gaa gat gct gcc act tat tac Ser Leu Thr Ile Ser Arg Met Glu Ala Glu Asp Ala Ala Thr Tyr Tyr 337 WO 99/50403 WO 9950403PCTIUS99/06507 tgc Cys 110 cat caa agg act His Gin Arg Thr agc Ser 115 tac cca tac aca Tyr Pro Tyr Thr ttc Phe 120 gga ggg ggg acc Gly Gly Gly Thr 385 ctt gag atc aaa Leu Giu Ile Lys act gtg gct gca Thr Vai Ala Ala tct gtc ttc atc Ser Val Phe Ile ttc ccg Phe Pro 140 433 cca tct gat Pro Ser Asp ctg aat aac Leu Asn Asn 160 gag Glu 145 cag ttg aaa tct Gin Leu Lys Ser gga Gly 150 act gcc tct gtt Thr Ala Ser Val gtg tgc ctg Val Cys Leu 155 aag gtg gat Lys Val Asp 481 529 ttc tat ccc aga Phe Tyr Pro Arg gag Glu 165 gcc aaa gta cag Ala Lys Val Gin tgg Trp 170 aac gcc Asn Ala 175 ctc caa tcg ggt Leu Gin Ser Gly aac Asn 180 tcc cag gag agt Ser Gin Glu Ser aca gag cag gac Thr Giu Gin Asp agc Ser 190 aag gac agc acc Lys Asp Ser Thr tac Tyr 195 agc ctc agc agc Ser Leu Ser Ser acc Thr 200 ctg acg ctg agc Leu Thr Leu Ser gca gac tac gag Ala Asp Tyr Glu cac aaa gtc tac His Lys Val Tyr tgc gaa gtc acc Cys Giu Val Thr cat cag His Gin 220 673 ggc ctg agc Gly Leu Ser t cg Ser 225 ccc gtc aca eag Pro Val Thr Lys agc Ser 230 ttc aac agg gga.

Phe Asn Arg Gly gag tgt Giu Cys 235 <210> <211> <212> <213> 2 236

PRT

Homo sapiens <400> 2 Met Gly Ser Lys Pro Phe Leu Ser Leu Ser Leu Ser Leu Thr Ser Thr Ser Leu Ala Asp Ile 25 Met Ser Ala Ser Pro Gly Glu Lys Leu Leu Met Thr Gin Ile Ser Ser Val Thr Ile 40 Thr Lys Ser Pro Ala Cys Ser Ala Pro Gly Thr Ser Ser Val Ser Tyr Met His Trp Phe 55 Pro Lys Leu Trp Leu Tyr Ser Thr Ser Ala Arg Phe Ser Gly Ser Gly Ser Gly Gin Asn Thr Gin Leu Ala Ser Gly Ser Tyr Ser WO 99/50403 WO 9950403PCTIUS99/06507 Ile Ser Arg Arg Thr Ser 115 Lys Arg Thr Met 100 Tyr Glu Ala Glu Asp Ala Thr Tyr Tyr Pro Tyr Thr Phe 120 Ser Gly Gly Thr Lys 125 Pro Cys His Gin 110 Leu Giu Ile Pro Ser Asp Val Ala Ala Val Phe Ile 130 Giu Gin Phe 140 Cys Leu Lys Ser Gly 150 Ala Ala Ser Val Leu Leu Asn As n 160 Tyr Pro Arg Lys Val Gin T rp 170 Thr Val Asp Asn Ala Leu 175 Gin Ser Gly Ser Thr Tyr 195 Giu Lys His As n 180 Ser Gin Giu Ser Giu Gin Asp Leu Ser Ser Thr 200 Cys Thr Leu Ser Lys 205 Gin Ser Lys Asp 190 Ala Asp Tyr Giy Leu Ser Lys Val Tyr Glu Vai Thr 210 Ser Pro 225 His 220 Cys Val Thr Lys Ser 230 Asn Arg Gly <210> 3 <211> 1476 <212> DNA <213> <220> <221> <222> Homno sapiens

CDS

(24) (1472) <400> 3 ggatctatcg attcccgggt acc atg gga tct aaa cct ttt ttg tct ctt ctt Met Giy Ser Lys Pro Phe Leu Ser Leu Leu tca ttg tca. ttg Ser Leu Ser Leu ttg ttt aca tct Leu Phe Thr Ser agt ttg gca ggg Ser Leu Ala Gly gtc cag Vai Gin ctt cag cag Leu Gin Gin ata tcc tgc Ile Ser Cys gga cct gac ctg Gly Pro Asp Leu gt g Val aaa cct ggg gcc Lys Pro Gly Ala tca gtq aag Ser Val Lys aac ata cac Asri Ile His aag gct tct gga Lys Ala Ser Gly tac Tyr 50 aca ttc act gac Thr Phe Thr Asp tac Tyr 149 197 245 tgg gtg Trp Val aag cag agc cgt Lys Gin Ser Arg aag agc ctt gag Lys Ser Leu Giu att gga tat att Ile Gly Tyr Ile tat Tyr cct tac aat qgt Pro Tyr Asn Gly aat As n 80 act tac tac aac Thr Tyr Tyr Asn cag Gin 85 aag ttc aag aac Lys Phe Lys Asn aag Lys 293 gcc aca ttg act gta gac aat tcc tcc acc tca gcc tac atg gag ctc34 341 WO 99/50403 PCT/US99/06507 Ala Thr Leu Thr Va1 Asp Asn Ser Ser Thr 100 Ser Ala Tyr Met Glu Leu 105 cgc ago ctg Arg Ser Leu ttt gac tao Phe Asp Tyr 125 aca Thr 110 tot gag gao tct Ser Glu Asp Ser gca Ala 115 gto tat tao tgt Val Tyr Tyr Cys gca aco tao Ala Thr Tyr 120 toa goa too Ser Ala Ser 389 437 tgg ggo caa ggo Trp Gly Gin Gly ac Thr 130 act otc aoa gtg Thr Leu Thr Val ago Ser 135 ccg aoo Pro Thr 140 ago cc aag gto Ser Pro Lys Val tto Phe 145 ccg otg ago otc Pro Leu Ser Leu gao Asp 150 ago aoo cc caa Ser Thr Pro Gin 485 533 ggg aao gtg gto Gly Asn Val Val gt0 Va1 160 gca tgo ctg gto Ala Cys Leu Val ggo tto tto ccc Gly Phe Phe Pro gag cca otc agt Glu Pro Leu Ser ac tgg ago gaa Thr Trp Ser Glu ago Ser 180 gga oag aao gtg Gly Gin Asn Val ac goo Thr Ala 185 aga aao tto Arg Asn Phe ago ago cag Ser Ser Gin 205 oca Pro 190 cct ago cag gat Pro Ser Gin Asp goo Ala 195 too ggg gac ctg Ser Gly Asp Leu tao aoo acg Tyr Thr Thr 200 ggo aag too Gly Lys Ser 629 677 Otg aoo ctg ccg Leu Thr Leu Pro goo Ala 210 aca oag tgc cca Thr Gin Cys Pro gao Asp 215 gtg aca Val Thr 220 tgo cac gtg aag Cys His Val Lys cac His 225 tao aog aat too Tyr Thr Asn Ser ago Ser 230 oag gat gtg act Gin Asp Val Thr gtg Val 235 cc tgo oga gtt Pro Cys Arg Val

CCC

Pro 240 cca cct cc cca Pro Pro Pro Pro tgo cac cc oga Cys His Pro Arg tcg otg cac oga Ser Leu His Arg goo otc gag gao Ala Leu Glu Asp otg Leu 260 otc tta ggt toa Leu Leu Gly Ser gaa gcg Glu Ala 265 aac otc acg Asn Leu Thr tto aoo tgg Phe Thr Trp 285 tgo Cys 270 aca otg aoo ggo Thr Leu Thr Gly ctg Leu 275 aga gat goo tct Arg Asp Ala Ser ggt goo aoo Gly Ala Thr 280 gga cca cct Gly Pro Pro 869 917 acg cc toa agt Thr Pro Ser Ser ggg Gly 290 aag ago got gtt Lys Ser Ala Val oaa Gin 295 gag ogt Glu Arg 300 gac otc tgt ggo Asp Leu Cys Gly tgo Cys 305 tao ago gtg too Tyr Ser Val Ser aga Arg 310 gta ott cct ggo Val Leu Pro Gly 965 WO 99/50403 WO 9950403PCT/US99/06507 tgt Cys 315 gcc cag cca tgg Ala Gin Pro Trp cat ggg gag acc His Gly Glu Thr acc tgc act gct Thr Cys Thr Ala gcc Al a 330 1013 cac ccc gag ttg His Pro Glu Leu aag Lys 335 acc cca cta acc Thr Pro Leu Thr gcc Ala 340 aac atc aca aaa Asn Ile Thr Lys tcc gga Ser Gly 345 1061 aac aca ttc Asn Thr The ctg gcc ctg Leu Ala Leu 365 ccc gag gtc cac Pro Giu Val His ctq Leu 355 ctg ccg ccg ccg Leu Pro Pro Pro tcg gag gag Ser Glu Glu 360 cgt ggc ttc Arg Gly Phe 1109 1157 aac gag ctg gtg Asn Giu Leu Val ctg acg tgc ctg Leu Thr Cys Leu agc ccc Ser Pro 380 aag gat gtg ctg Lys Asp Val Leu gt t Val 385 cgc tgg ctg cag Arg Trp Leu Gin ggg Gly 390 tca cag gag ctg Ser Gln Giu Leu ccc Pro 395 cgc gag aag tac Arg Glu Lys Tyr act tgg gca tcc Thr Trp Ala Ser cag gag ccc agc Gin Glu Pro Ser cag Gin 410 1205 1253 1301 ggc acc acc acc Gly Thr Thr Thr tat Tyr 415 gct gtg acc agc Ala Val Thr Ser ata Ile 420 ctg cgc gtg gca Leu Arg Val Ala gcc gag Ala Glu 425 gac tgg aag Asp Trp Lys ctg ccg ctg Leu Pro Leu 445 ggg gag acc ttc Gly Glu Thr Phe tgc atg gtg ggc Cys Met Val Gly cac gag gcc His Glu Ala 440 gcg ggt aaa Ala Gly Lys 1349 1397 gcc ttc aca cag Ala Phe Thr Gin aag Lys 450 acc atc gac cgc Thr Ile Asp Arg ccc acc Pro Thr 460 cat atc aat gtg His Ile Asn Val gtt gtc atg gcg Val Val Met Ala gcg gac ggc acc Ala Asp Gly Thr 1445 tac aga tct gaa Tyr Arg Ser Giu aag Lys 480 gat gaa ctt taga Asp Glu Leu 1476 <210> 4 <211> 483 <212> PRT <213> Homo sapiens <400> 4 Met Gly Ser Lys Pro Phe Leu Ser Leu Leu Ser Leu Ser Leu Leu Leu 1 5 10 WO 99/50403 PCT/US99/06507 Phe Thr Ser Thr Ser Leu Ala Gly Val Gin Leu Gin Gin Ser Gly Pro 25 Asp Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser 40 Gly Tyr Thr Phe Thr Asp Tyr Asn Ile His Trp Val Lys Gin Ser Arg 55 Gly Lys Ser Leu Glu Trp Ile Gly Tyr Ile Tyr Pro Tyr Asn Gly Asn 70 75 Thr Tyr Tyr Asn Gin Lys Phe Lys Asn Lys Ala Thr Leu Thr Val Asp 90 Asn Ser Ser Thr Ser Ala Tyr Met Glu Leu Arg Ser Leu Thr Ser Glu 100 105 110 Asp Ser Ala Val Tyr Tyr Cys Ala Thr Tyr Phe Asp Tyr Trp Gly Gin 115 120 125 Gly Thr Thr Leu Thr Val Ser Ser Ala Ser Pro Thr Ser Pro Lys Val 130 135 140 Phe Pro Leu Ser Leu Asp Ser Thr Pro Gin Asp Gly Asn Val Val Val 145 150 155 160 Ala Cys Leu Val Gin Gly Phe Phe Pro Gin Glu Pro Leu Ser Val Thr 165 170 175 Trp Ser Glu Ser Gly Gin Asn Val Thr Ala Arg Asn Phe Pro Pro Ser 180 185 190 Gin Asp Ala Ser Gly Asp Leu Tyr Thr Thr Ser Ser Gin Leu Thr Leu 195 200 205 Pro Ala Thr Gin Cys Pro Asp Gly Lys Ser Val Thr Cys His Val Lys 210 215 220 His Tyr Thr Asn Ser Ser Gin Asp Val Thr Val Pro Cys Arg Val Pro 225 230 235 240 Pro Pro Pro Pro Cys Cys His Pro Arg Leu Ser Leu His Arg Pro Ala 245 250 255 Leu Glu Asp Leu Leu Leu Gly Ser Glu Ala Asn Leu Thr Cys Thr Leu 260 265 270 Thr Gly Leu Arg Asp Ala Ser Gly Ala Thr Phe Thr Trp Thr Pro Ser 275 280 285 Ser Gly Lys Ser Ala Val Gin Gly Pro Pro Glu Arg Asp Leu Cys Gly 290 295 300 Cys Tyr Ser Val Ser Arg Val Leu Pro Gly Cys Ala Gin Pro Trp Asn 305 310 315 320 His Gly Glu Thr Phe Thr Cys Thr Ala Ala His Pro Glu Leu Lys Thr 325 330 335 Pro Leu Thr Ala A:n Ile Thr Lys Ser Gly Asn Thr Phe Arg Pro Glu 340 345 350 Val His Leu Leu Pro Pro Pro Ser Glu Glu Leu Ala Leu Asn Glu Leu 355 360 365 Val Thr Leu Thr Cys Leu Ala Arg Gly Phe Ser Pro Lys Asp Val Leu 370 375 380 Val Arg Trp Leu Gin Gly Ser Gin Glu Leu Pro Arg Glu Lys Tyr Leu 385 390 395 400 Thr Trp Ala Ser Arg Gin Glu Pro Ser Gin Gly Thr Thr Thr Tyr Ala 405 410 415 Val Thr Ser Ile Leu Arg Val Ala Ala Glu Asp Trp Lys Lys Gly Glu 420 425 430 Thr Phe Ser Cys Met Val Gly His Glu Ala Leu Pro Leu Ala Phe Thr 435 440 445 6 WO 99/50403 PCT/US99/06507 Gin Lys Thr 450 Ser Val Val 465 Asp Giu Leu <210> <211> <212> <213> Ile Asp Arg Leu Ala Gly Lys Pro Thr His Ile Asn Val 455 460 Met Ala Glu Ala Asp Gly Thr Cys Tyr Arg Ser Glu Lys 470 475 480 504

DNA

Homo sapiens <220> <221> <222>

CDS

(25) (501) <400> aggatctatc gattcccggg tacc atg gag aac cat ttg ctt ttc tgg gga Met Glu Asn His Leu Leu Phe Trp Gly gtc Val ctg gcg gtt ttt Leu Ala Val Phe aag gct gtt cat Lys Ala Val His gtg Val aaa gcc caa gaa Lys Ala Gin Glu gaa agg att gtt Glu Arg Ile Val ctt Leu gtt gac aac aaa Val Asp Asn Lys tgt Cys 35 aag tgt gcc cgg Lys Cys Ala Arg att act Ile Thr tcc agg atc Ser Arg Ile aga aac atc Arg Asn Ile atc Ile cgt tct tcc gaa Arg Ser Ser Glu Oct aat gag gac Pro Asn Giu Asp att gtg gag Ile Val Glu aat atc tct Asn Ile Ser cga att att gtt Arg Ile Ile Val cct Pro 65 ctg aac aac agg Leu Asn Asn Arg gag Glu gat ccc Asp Pro acc tca cca ttg Thr Ser Pro Leu aga Arg 80 acc aga ttt gtg Thr Arg Phe Val tao Tyr cat ttg tot gao His Leu Ser Asp ctc Leu tgt aaa aaa tgt Cys Lys Lys Cys oct aca gaa gtg Pro Thr Giu Val otg gat aat cag Leu Asp Asn Gin ata Ile 105 gtt act got aco Val Thr Ala Thr oag Gin 110 ago aat atc tgt Ser Asn Ile Cys gat Asp 115 gaa gao agt got Glu Asp Ser Ala aca gag Thr Glu 120 aco tgc tao Thr Cys Tyr act Thr 125 tat gao aga aac Tyr Asp Arg Asn aag Lys 130 tgc tao aoa got gtg gtc cca Cys Tyr Thr Ala Val Val Pro otc gta tat ggt ggt gag aco aaa atg gtg gaa aca gc tta aco cca WO 99/50403 WO 9950403PCTIUS99/06507 Leu Val Tyr 140 gat gcc tgc Asp Ala Cys 155 Gly Gly Glu Thr Lys Met Val Giu Thr Ala Leu Thr Pro 145 150 tat cct gac tga Tyr Pro Asp 6 159

PRT

Homo sapiens <210> (211> <212> <213> Met Ala As n Giu Pro Thr Thr Ile Asn Lys 145 <400> 6 Giu Asn H: Val His V, Lys Cys L, Asp Pro A: Leu Asn Ak Arg Phe V, Giu Val G.

Cys Asp G' 115 Lys Cys T, 130 Met Val G' Le u Lys Cys Giu Arg Tyr Leu Asp Thr Thr Phe Gin Arg Ile 55 As n Leu As n Ala Val 135 Leu Gly Asp Thr Glu Ser Asp Ile 105 Giu Pro Pro Val1 10 Giu Ser Arg Asp Leu 90 Val1 Thr Leu Asp Ala Ile Ile Ile Thr Lys Ala Tyr Tyr 140 Cys Val Val Ile Arg Ser Lys Thr Thr 125 Gly T yr Phe Leu Arg Ile Pro Cys Gin 110 Tyr Gi y Pro Ile Val1 Ser Ile Leu Asp Ser Asp Giu Asp <210> 7 <211> 1841 <212> DNA <213> Homo <220> <221> CDS <222> (18) sapiens (1838) <400> 7 gtcgattccc gggtacc atg gtg ctc ttc gtg ctc acc tgc ctg ctg gcg Met Val Leu Phe Val Leu Thr Cys Leu Leu Ala 1 5 gtc ttc cca gcc atc tcc acg aag agt ccc ata ttt ggt ccc gag gag Val Phe Pro Ala Ile Ser Thr Lys Ser Pro Ile Phe Gly Pro Giu Giu 20 qtg aat agt gtg gaa ggt aac tca gtg tcc atc acg tgc tac tac cca 98 146 WO 99/50403 PCTIUS99/06507 Val Asn Ser Val Giu Gly Asn Val Ser Ile Thr Cys Tyr Tyr Pro coo acc Pro Thr tct gtc aac cgg Ser Val Asn Arg cac His acc cgg aag tac Thr Arg Lys Tyr tgc cgg cag gga Cys Arg Gin Gly got Ala aga ggt ggc tgo Arg Gly Gly Cys aco ctc atc tc Thr Leu Ile Ser tcg Ser 70 gag ggc tao gto Glu Giy Tyr Val tcc Ser ago aaa tat gca Ser Lys Tyr Ala ggc Gly agg got aac otc Arg Ala Asn Leu acc Thr 85 aao tto ccg gag Asn Phe Pro Glu aac ggo Asn Gly aca ttt gtg Thr Phe Val tao aag tgt Tyr Lys Cys 110 aao att goo cag Asn Ile Ala Gin otg Leu 100 ago cag gat gao Ser Gin Asp Asp too ggg cgc Ser Gly Arg 105 ttt gat gto Phe Asp Val ggc ctg ggo ato Gly Leu Gly Ile ago oga ggc ctg Ser Arg Gly Leu ago ctg Ser Leu 125 gag gto ago cag Glu Val Ser Gin ggt Gly 130 cct ggg otc cta Pro Gly Leu Leu gao aot aaa gto Asp Thr Lys Val tao Tyr 140 aca gtg gac ctg Thr Val Asp Leu aga aog gtg aoo Arg Thr Vai Thr ato Ile 150 aao tgo cct tto Asn Cys Pro Phe act gag aat got Thr Glu Asn Ala oaa Gin 160 aag agg aag too Lys Arg Lys Ser ttg Leu 165 tao aag oag ata Tyr Lys Gin Ile ggc ctg Gly Leu 170 tac cct gtg Tyr Pro Vai aca gga aga Thr Giy Arg 190 ctg Leu 175 gto ato gao too Val Ile Asp Ser agt Ser 180 ggt tat gtg aat Gly Tyr Val Asn ccc aao tat Pro Asn Tyr 185 tta ctg tto Leu Leu Phe 578 626 ata cgo ctt gat Ile Arg Leu Asp oag ggt act ggo Gin Gly Thr Gly oag Gin 200 ago gtt Ser Vai 205 gto ato aac caa Val Ile Asn Gin otc Leu 210 agg otc ago gat Arg Leu Ser Asp ggg oag tat otc Gly Gin Tyr Leu oag got ggg gat Gin Aia Gly Asp too aat agt aat Ser Asn Ser Asn aag Lys 230 aag aat got gao Lys Asn Ala Asp otc Leu 235 oaa gtg ota aag Gin Val Leu Lys cc0 Pro 240 gag ccc gag otg Glu Pro Glu Leu gtt Val 245 tat gaa gac ctg Tyr Glu Asp Leu agg ggo Arg Gly 250 WO 99/50403 PCT/US99/06507 tca gtg acc ttc cac tgt gcc ctg ggc cct gag gtg gca aac gtg gcc 818 Ser Val Thr Phe His Cys Ala Leu Gly Pro Glu Val Ala Asn Val Ala 255 260 265 aaa ttt ctg tgc cga cag agc agt ggg gaa aac tgt qac gtg gtc gtc 866 Lys Phe Leu Cys Arg Gin Ser Ser Gly Glu Asn Cys Asp Val Val Val 270 275 280 aac acc ctg ggg aag aqg gcc cca gcc ttt gag ggc agg atc ctg ctc 914 Asn Thr Leu Gly Lys Arg Ala Pro Ala Phe Giu Gly Arg Ile Leu Leu 285 290 295 aac ccc cag gac aag gat ggc tca ttc agt gtg gtg atc aca ggc ctg 962 Asn Pro Gin Asp Lys Asp Gly Ser Phe Ser Val Val Ile Thr Giy Leu 300 305 310 315 agg aag gag gat gca ggg cgc tac ctg tgt gqa gcc cat tcg gat ggt 1010 Arg Lys Giu Asp Ala Giy Arq Tyr Leu Cys Gly Ala His Ser Asp Gly 320 325 330 cag ctg cag gaa ggc tcg cct atc cag gcc tgg caa ctc ttc gtc aat 1058 Gin Leu Gin Glu Gly Ser Pro Ile Gin Ala Trp Gin Leu Phe Val Asn 335 340 345 gag gag tcc acg att ccc cgc agc ccc act gtg gtg aag ggg gtg gca 1106 Giu Giu Ser Thr Ile Pro Arg Ser Pro Thr Vai Vai Lys Gly Val Ala 350 355 360 gga agc tct gtg gcc gtg ctc tgc ccc tac aac cgt aag gaa agc aaa 1154 Gly Ser Ser Val Ala Val Leu Cys Pro Tyr Asn Arg Lys Glu Ser Lys 365 370 375 agc atc aag tac tgg tgt ctc tgg gaa ggg gcc cag aat ggc cgc tgc 1202 Ser Ile Lys Tyr Trp Cys Leu Trp Giu Gly Ala Gin Asn Gly Arg Cys 380 385 390 395 ccc ctg ctg gtg gac agc gag ggg tgg gtt aag gcc cag tac gag ggc 1250 Pro Leu Leu Val Asp Ser Glu Gly Trp Val Lys Ala Gin Tyr Giu Gly 400 405 410 cgc ctc tcc ctg ctg gag gag cca ggc aac ggc acc ttc act gtc atc 1298 Arg Leu Ser Leu Leu Glu Giu Pro Gly Asn Gly Thr Phe Thr Val Ile 415 420 425 ctc aac cag ctc acc agc cgg gac gcc ggc ttc tac tgg tgt ctg acc 1346 Leu Asn Gin Leu Thr Ser Arg Asp Ala Gly Phe Tyr Trp Cys Leu Thr 430 435 440 aac ggc gat act ctc tgg agg acc acc gtg gag atc aag att atc gaa 1394 Asn Gly Asp Thr Leu Trp Arg Thr Thr Val Giu Ile Lys Ile Ile Giu 445 450 455 gga gaa cca aac ctc aag gtt ccc ggg aat gtc acg gct gtg ctg gga 1442 WO 99/50403 WO 9950403PCTIUS99/06507 Gly 460 Giu Pro Asn Leu Val Pro Gly Asn Val1 470 Thr Ala Val Leu gag act ctc aag Glu Thr Leu Lys gtc Val 480 ccc tgt cac ttt Pro Cys His Phe tgc aaa ttc tcc Cys Lys Phe Ser tcg tao Ser Tyr 490 1490 gag aaa tac Glu Lys Tyr agc caa gao Ser Gin Asp 510 tgg T rp 495 tgo aag tgg aat Cys Lys Trp Asn aac Asn 500 aeg ggc tgo cag Thr Gly Cys Gin gcc ctg 000 Ala Leu Pro 505 gac gag aac Asp Glu Asn 1538 1586 gaa ggc coo agc Giu Gly Pro Ser gcc ttc gtg aac Ala Phe Val Asn agc cgg Ser Arg 525 ctt gto tcc otg Leu Val Ser Leu acc Thr 530 otg aac otg gtg Leu Asn Leu Val agg gct gat gag Arg Ala Asp Glu ggc Gly 540 tgg tac tgg tgt Trp Tyr Trp Cys gga Gly 545 gtg aeg cag ggc Val Lys Gin Giy cac His 550 ttc tat gga gag Phe Tyr Gly Glu act Thr 555 1634 1682 1730 gca gcc gtc tat Ala Ala Val Tyr gca gtt gaa gag Ala Val Glu Glu aag gca gcg ggg Lys Ala Ala Gly tcc cgc Ser Arg 570 gat gtc agc Asp Val Ser gac tot ggt Asp Ser Gly 590 ota Leu 575 gog aag gca gao Ala Lys Ala Asp got Al a 580 got cot gat gag Ala Pro Asp Giu aag gtg ota Lys Val Leu 585 gat coo agg Asp Pro Arg 1778 1826 ttt ogg gag att Phe Arg Glu Ile gag Giu 595 aao aaa goc att Asn Lys Ala Ile cag Gin 600 ott ttt goa gag tga Leu Phe Ala Glu 605 1841 'c210> 8 <211> 607 <212> PRT <213> Homo sapiens <400> Met Val Leu 1 Ser Thr Lys Gly Asn Ser Arg His Thr Phe Val Leu Thr Cys Leu Leu 5 10 Ser Pro Ile Phe Gly Pro Glu 25 Val Ser Ile Thr Cys Tyr Tyr Ala Val Phe Pro Ala Ile Giu Val Asn Pro Pro 40 Cys Thr Arg Ser Val Glu Ser Val Asn Gly Gly Cys Arg Lys Tyr Trp Arq Gin Gly

L

WO 99/50403 WO 9950403PCT/US99/06507 Ile Arg Ile Gly Gin Gly 145 Lys Ile Leu Gin Asp 225 Giu Cys Gin Arg Asp 305 Gly Ser Pro Val1 Cys 385 Ser Glu Ser T rp Lys 465 Pro Thr Aia Aila Ile Giy 130 Arg Arg Asp Asp Leu 210 Ser Pro Aila Ser Aila 290 Giy Arg Pro Ar g Leu 370 Leu Glu Giu Arg Arg 450 Val1 Cys Leu Asn Gin Asn 115 Pro Thr Lys Ser Ile 195 Arq As n Giu Leu Ser 275 Pro Ser Tyr Ile Ser 355 Cys Trp Gi y Pro Asp 435 Thr Pro His Ile Leu Leu 100 Ser Giy Vai Ser Ser 180 Gin Leu Ser Leu Giy 260 Giy Aia Phe Leu Gin 340 Pro Pro Giu T rp Gly 420 Al a Thr Giy Phe Ser Thr Ser Arg Leu Thr Leu 165 Gly Gly Ser As n Val1 245 Pro Glu Phe Ser Cys 325 Ala Thr Tyr Giy Val 405 Asn Giy Vai As n Pro 485 Se r 70 Asn Gin Giy Leu Ile 150 Tyr Tyr Thr Asp Lys 230 T yr Giu Asn Giu Val1 310 Giy Trp Vai Asn Aia 390 Lys Gly Phe Giu Vai 470 Cys Giu Phe Asp Leu Asn 135 Asn Lys Val1 Gi y Aia 215 Lys Giu Val Cys Giy 295 Val Ala Gin Vai Arg 375 Gin Ala Thr Tyr Ile 455 Thr Lys Gly Pro Asp Ser 120 Asp Cys Gin Asn Gin 200 Gly Asn Asp Ala Asp 280 Arg Ile His Leu Lys 360 Lys Asn Gin Phe T rp 440 Lys Aila Phe Val Asn 90 Giy Asp Lys Phe Giy 170 As n Leu Tyr Asp Arg 250 Val Val Leu Gly Asp 330 Val Val Ser Arg Glu 410 Val Leu Ile Leu Ser 490 Ser 75 Gly Arg Val Vai Lys 155 Leu Tyr Ph e Leu Leu 235 Gi y Al a Val Leu Leu 315 Gi y Asn Al a Lys Cys 395 Gly Ile Thr Giu Gly 475 Tyr Ser Thr Tyr Ser Tyr 140 Thr Tyr Thr Ser Cys 220 Gin Ser Lys As n Asn 300 Arg Gin Giu Gly Ser 380 Pro Arg Leu Asn Gly 460 Glu Gi u Lys Phe Lys Leu 125 Thr Giu Pro Gly Val1 205 Gin Val1 Val Phe Thr 285 Pro Lys Leu Giu Ser 365 Ile Leu Leu Asn Gly 445 Glu Thr Lys Tyr Vai Cys 110 Giu Val As n Val Arg 190 Val Ala Leu Thr Leu 270 Leu Gin Glu Gin Ser 350 Ser Lys Leu Ser Gin 430 Asp Pro Leu Tyr Al a Vali Gi y Val1 Asp Al a Leu 175 Ile Ile Gly Lys Phe 255 Cys Gi y Asp Asp Glu 335 Thr Val Tyr Val Leu 415 Leu Thr As n Lys TrpD 495 Gi y Asn Leu Ser Leu Gin 160 Val Arg Asn Asp Pro 240 His Arg Lys Lys Ala 320 Gly Ile Al a T rp Asp 400 Leu Thr Leu Leu Val1 480 Cys WO 99/50403 WO 9950403PCTIUS99/06507 Lys Pro Leu Gly 545 Ala Lys Glu Trp Ser Thr 530 Val1 Val Al a Ile Asn Lys 515 Leu Lys Glu Asp Giu 595 Asn 500 Ala Asn Gin Glu Ala 580 Asn Thr Phe Leu Gly Arg 565 Ala Lys Gly Val1 Val1 His 550 Lys Pro Al a Cys Asn Thr 535 Phe Ala Asp Ile Gin Cys 520 Arg Tyr Ala Glu Gin 600 Leu Giu Asp Giu Ser 570 Val Pro Pro Asn Giu Thr 555 Arg Leu Arg Ser Ser Gly 540 Ala Asp Asp Leu Gin Arg 525 T rp Ala Val Ser Phe 605 Asp 510 Leu Tyr Val Ser Gly 590 Ala Gly Ser Cys Val 560 Al a Arg

Claims (45)

1. An enzymatic nucleic acid molecule with RNA cleaving activity, wherein said enzymatic nucleic acid molecule specifically cleaves RNA encoded by an aryl hydrocarbon nuclear transporter (ARNT) gene.

2. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid molecule is in a hammerhead configuration.

3. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid molecule comprises a stem II region of length greater than or equal to 2 base pairs.

4. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid molecule is in a hairpin motif. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid is in a hepatitis delta virus, group I intron, group II intron, VS nucleic acid or RNase P nucleic acid configuration.

6. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic •nucleic molecule is a DNAzyme. i 7. The enzymatic nucleic acid of claim 4, wherein said enzymatic nucleic acid molecule comprises a stem II region of length between three and seven base-pairs.

8. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic S 20 nucleic acid molecule comprises between 12 and 100 bases complementary to said RNA.

9. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid molecule comprises between 14 and 24 bases complementary to said mRNA. The enzymatic nucleic acid molecule of claim 2 wherein said enzymatic nucleic acid molecule consists essentially of any sequence defined as Seq. I.D. Nos 1-393, 25 911-1611, 2449-3587, and 4915-5701.

11. The enzymatic nucleic acid molecule of claim 4, wherein said enzymatic nucleic acid molecule consists essentially of any sequence defined as Seq. ID Nos 787- 848, 2313-2380, 4727-4820 and 6489-6568.

12. The enzymatic nucleic acid molecule of claim 2, wherein said enzymatic S 30 nucleic acid molecule comprises at least five ribose residues, phosphorothioate linkages Sin at least three of the 5' terminal nucleotides, a 2'-C-allyl modification at position No. 4 of said nucleic acid, at least ten 2'-O-methyl modifications, and a 3'-end modification.

13. The enzymatic nucleic acid of claim 12, wherein said enzymatic nucleic acid comprises a linked inverted ribose moiety at said 3' end.

14. The enzymatic nucleic acid molecule of claim 2, wherein said enzymatic nucleic acid molecule comprises at least five ribose residues, phosphorothioate linkages in at least three of the 5' terminal nucleotides, a 2'-amino modification at position No. 4 and/or at position No. 7 of said enzymatic nucleic acid molecule, at least ten 2'-O-methyl modifications, and a 3'-end modification.

15. The enzymatic nucleic acid molecule of claim 2, wherein said enzymatic nucleic acid molecule comprises at least five ribose residues, phosphorothioate linkages ifi at least three of the 5' terminal nucleotides, abasic substitution at position No. 4 and/or AS24183spci I 280 at position No. 7 of said enzymatic nucleic acid molecule, at least ten 2'-O-methyl modifications, and comprises a 3'-end modification.

16. The enzymatic nucleic acid molecule of claim 2, wherein said enzymatic nucleic acid molecule comprises of at least five ribose residues, phosphorothioate linkages in at least three of the 5' terminal nucleotides, a 6-methyluridine substitution at position No. 4 and/or at position No. 7 of said enzymatic nucleic acid molecule, at least ten 2'-O-methyl modifications, and comprises a 3'-end modification.

17. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid comprises sequences that are complementary to any of sequences defined as Seq ID Nos 394-786 and 849-910.

18. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid comprises at least one 2'-sugar modification.

19. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic nucleic acid comprises at least one nucleic acid base modification.

20. The enzymatic nucleic acid molecule of claim 1, wherein said enzymatic S•" nucleic acid comprises at least one phosphorothioate modification. S:i• ~21. The enzymatic nucleic acid molecule of any one of claims 1 to 20, wherein said enzymatic nucleic acid molecule is chemically synthesized.

22. An enzymatic nucleic acid molecule with RNA cleaving activity, wherein said 20 enzymatic nucleic acid molecule specifically cleaves RNA encoded by an aryl hydrocarbon nuclear transporter (ARNT) gene, substantially as hereinbefore described.

23. A mammalian cell including an enzymatic nucleic acid molecule of any one of claims 1 to 22.

24. The mammalian cell of claim 23, wherein said mammalian cell is a human cell. 25 25. A mammalian cell including an enzymatic nucleic acid molecule with RNA cleaving activity, wherein said enzymatic nucleic acid molecule specifically cleaves RNA encoded by an aryl hydrocarbon nuclear transporter (ARNT) gene, substantially as hereinbefore described.

26. An expression vector comprising a nucleic acid sequence encoding at least one 30 enzymatic nucleic acid molecule of any one of claims 1 to 22 in a manner which allows expression of that enzymatic nucleic acid molecule.

27. The expression vector of claim 26, wherein said expression vector comprises: a) a transcription initiation region; b) a transcription termination region; and c) a gene encoding at least one said nucleic acid molecule, wherein said gene 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.

28. The expression vector of claim 26, wherein said expression vector comprises: a) a transcription initiation region; 4b) a transcription termination region; \S c) an open reading frame; and t k' (4 281 d) a gene encoding at least one said nucleic acid molecule, which gene is operably linked to the 3'-end of said open reading frame, wherein said gene 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.

29. The expression vector of claim 26, wherein said expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; and d) a gene encoding at least one said nucleic acid molecule, wherein said gene 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. The expression vector of claim 26, wherein said vector comprises: a) a transcription initiation region; b) a transcription termination region; an intron; d) an open reading frame; and e) a gene encoding at least one said nucleic acid molecule, which gene is operably 20 linked to the 3' end of said open reading frame, wherein said gene 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.

31. An expression vector comprising a nucleic acid sequence encoding at least one 25 enzymatic nucleic acid molecule with RNA cleaving activity in a manner which allows expression of that enzymatic nucleic acid molecule, wherein said enzymatic nucleic acid molecule specifically cleaves RNA encoded by an aryl hydrocarbon nuclear transporter 0. (ARNT) gene, said expression vector being substantially as hereinbefore described.

32. A mammalian cell including an expression vector of any one of claims 26 to 30 31.

33. The mammalian cell of claim 32, wherein said mammalian cell is a human cell.

34. A mammalian cell including an expression vector comprising a nucleic acid sequence encoding at least one enzymatic nucleic acid molecule with RNA cleaving activity in a manner which allows expression of that enzymatic nucleic acid molecule, wherein said enzymatic nucleic acid molecule specifically cleaves RNA encoded by an aryl hydrocarbon nuclear transporter (ARNT) gene, said mammalian cell being substantially as hereinbefore described. A pharmaceutical composition comprising the enzymatic nucleic acid molecule of any one of claims 1 to 22. S36. A pharmaceutical composition comprising the expression vector of any one of i hs 26 to 31. 4 I (I 282

37. A method for treatment of cancer, diabetic retinopathy, age related macular degeneration (ARMD), inflammation, or arthritis comprising the step of administering to a patient an enzymatic nucleic acid molecule of any one of claims 1 to 22, or a pharmaceutical composition of claim

38. A method for treatment of cancer comprising the step of administering to a patient, an expression vector of any one of claims 26 to 31, or a pharmaceutical composition of claim 36.

39. A method for treatment of diabetic retinopathy, age related macular degeneration (ARMD), inflammation, or arthritis comprising the step of administering to a patient an expression vector of any one of claims 26 to 31, or a pharmaceutical composition of claim 36. A method for treatment of cancer comprising the steps of: a) isolating cells from a patient; b) administering to said cells an enzymatic nucleic acid molecule of any one of claims 1 to 22; and c) introducing said cells back into said patient.

41. A method for treatment of cancer comprising the steps of: a) isolating cells "°from a patient; b) administering to said cells an expression vector of any one of claims 26 to 31; and c) introducing said cells back into said patient. °42. A method of treatment of a patient having a condition associated with an elevated level of aryl hydrocarbon nuclear transporter (ARNT), comprising administering 20 to said patient an enzymatic nucleic acid molecule of any one of claims 1 to 22, or a pharmaceutical composition of claim

43. A method of treatment of a patient having a condition associated with an elevated level of aryl hydrocarbon nuclear transporter (ARNT), comprising administering to said patient an expression vector of any one of claims 26 to 31, or a pharmaceutical 25 composition of claim 36. SSSS*44. A method of treatment of a patient having a condition associated with the level "i :of aryl hydrocarbon nuclear transporter (ARNT), comprising the steps of: contacting i cells of said patient with an enzymatic nucleic acid molecule of any one of claims 1 to 22; I. and administering to said patient one or more additional drugs. 30 45. A method of treatment of a patient having a condition associated with the level of aryl hydrocarbon nuclear transporter (ARNT), comprising the steps of: contacting cells of said patient with an expression vector of any one of claims 26 to 31; and (b) administering to said patient one or more additional drugs.

46. Use of an enzymatic nucleic acid molecule of any one of claims 1 to 22 for the manufacture of a medicament for treating cancer, diabetic retinopathy, age related macular degeneration (ARMD), inflammation, or arthritis in a patient.

47. Use of an expression vector of any one of claims 26 to 31 for the manufacture of a medicament for treatment of cancer in a patient.

48. Use of an expression vector of any one of claims 26 to 31 for the manufacture of a medicament for treating diabetic retinopathy, age related macular degeneration inflammation, or arthritis in a patient. 283

49. Use of an enzymatic nucleic acid molecule of any one of claims 1 to 22 for the manufacture of a medicament for treating a patient having a condition associated with an elevated level of aryl hydrocarbon nuclear transporter (ARNT). Use of an expression vector of any one of claims 26 to 31 for the manufacture of a medicament for treating a patient having a condition associated with an elevated level of aryl hydrocarbon nuclear transporter (ARNT).

51. Use of an enzymatic nucleic acid molecule of any one of claims 1 to 22 for the manufacture of a medicament for treating a patient having a condition associated with the level of aryl hydrocarbon nuclear transporter (ARNT).

52. Use of an expression vector of any one of claims 26 to 31 for the manufacture of a medicament for treating a patient having a condition associated with the level of aryl hydrocarbon nuclear transporter (ARNT).

53. A method for modulating expression of ARNT gene in a mammalian cell comprising the step of administering to said cell an enzymatic nucleic acid molecule of any one of claims 1 to 22. V0@0

54. A method for modulating expression of ARNT gene in a mammalian cell comprising the step of administering to said cell an expression vector of any one of claims 26 to 31. S.

55. A method for modulating expression of ARNT gene in a mammalian cell 20 comprising the step of administering to said cell an enzymatic nucleic acid molecule of any one of claims 1 to 22 or an expression vector of any one of claims 26 to 31, said method being substantially as hereinbefore described.

56. A method of cleaving an ARNT RNA molecule comprising the step of, contacting the enzymatic nucleic acid molecule of any one of claims 1 to 22 with said 25 ARNT RNA molecule under conditions suitable for the cleavage of said ARNT RNA molecule.

57. The method of claims 56, wherein said cleavage is carried out in the presence of a divalent cation. o

58. The method of claim 57, wherein said divalent cation is Mg 2 30 59. A method of cleaving an ARNT RNA molecule as defined in any one of claims 56 to 58, substantially as hereinbefore described. Dated 10 December, 2002 Ribozyme Pharmaceuticals, Inc. Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 183spci