(12) United States Patent (10) Patent No.: US 7482,124 B2 Ranade Et Al

USOO7482124B2

(12) United States Patent (10) Patent No.: US 7482,124 B2 Ranade et al. (45) Date of Patent: Jan. 27, 2009

(54) METHOD OF IDENTIFYINGA 5,349,053 A 9, 1994 Landolfi PPARGAMMA-AGONIST COMPOUND 5,359,046 A 10/1994 Capon et al. HAVING A DECREASED LIKELIHOOD OF 5,403.484 A 4/1995 Ladner et al. INDUCING DOSE-DEPENDENT 5,413,923 A 5/1995 Kucherlapati et al. PERPHERAL EDEMA 5,427,908 A 6/1995 Dower et al. 5,441,050 A 8, 1995 Thurston et al. 5.447,851 A 9, 1995 Beutler et al. (75) Inventors: Koustubh Ranade, Princeton, NJ (US); 5,474,981 A 12/1995 Leder et al. Terrye Aigeldinger Delmonte, Ewing, 5,478,925 A 12/1995 Wallach et al. NJ (US); William J. Geese, Doylestown, 5,516,637 A 5/1996 Huang et al. PA (US) 5,530,101 A 6/1996 Queen et al. 5,545,806 A 8/1996 Lonberg et al. (73) Assignee: Bristol-Myers Squibb Company, 5,545,807 A 8, 1996 Surani et al. Princeton, NJ (US) 5,565,332 A 10/1996 Hoogenboom et al. 5,569,825 A 10/1996 Lonberg et al. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 0 days. FOREIGN PATENT DOCUMENTS (21) Appl. No.: 11/483,290 EP 232262 2, 1987 EP O 367 166 5, 1990 (22) Filed: Jul. 7, 2006 EP O 394 827 10, 1990 EP O 307434 9, 1993 (65) Prior Publication Data EP O 396387 12/1993 EP O 239 400 8, 1994 US 2007/OOO9945A1 Jan. 11, 2007 EP O 401 384 3, 1996 EP O 439 095 5, 1998 Related U.S. Application Data EP 1 OO7712 2, 1999 EP O 592 106 11, 2004 (60) Provisional application No. 60/697.727, filed on Jul. 8, 2005, provisional application No. 60/706,171, filed on Aug. 5, 2005, provisional application No. 60/705,995, (Continued) filed on Aug. 5, 2005. OTHER PUBLICATIONS (51) Int. Cl. Abali, H. et al., “Circulating and Local Bone Marrow Renin CI2O I/68 (2006.01) angiotensin System in Leukemic Hematopoiesis: Preliminary Evi GOIN 33/53 (2006.01) dences”, Hematology, vol. 7, No. 2, pp. 75-82 (2002). (52) U.S. Cl...... 435/6: 435/7.21 (Continued) (58) Field of Classification Search ...... None See application file for complete search history. Primary Examiner Robert Landsman (74) Attorney, Agent, or Firm—Stephen C. D'Amico (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS 4,179,337 A 12/1979 Davis et al. The invention provides novel polynucleotides and polypep 4,376, 110 A 3, 1983 David et al. tides associated with the incidence of PPAR-agonist induced 4,444,887 A 4, 1984 Hoffmann edema. The invention also provides polynucleotide fragments 4.474,893 A 10/1984 Reading corresponding to the genomic and/or coding regions of these 4,631,211 A 12/1986 Houghten 4,676.980 A 6/1987 Segal et al. polynucleotides which comprise at least one polymorphic 4,683, 195 A 7, 1987 Mullis et al. locus per fragment. Allele-specific primers and probes which 4,714,681 A 12/1987 Reading hybridize to these regions, and/or which comprise at least one 4,716,111 A 12/1987 Osband et al. polymorphic locus are also provided. The polynucleotides, 4,741,900 A 5, 1988 Alvarez et al. primers, and probes of the present invention are useful in 4,816,397 A 3, 1989 BOSS et al. phenotype correlations, medicine, and genetic analysis. Also 4,816,567 A 3/1989 Cabilly et al. provided are vectors, host cells, antibodies, and recombinant 4,925,648 A 5, 1990 Hansen et al. and synthetic methods for producing said polynucleotides 4.946,778 A 8, 1990 Ladner et al. and/or polypeptides. The invention further relates to diagnos 4,980,286 A 12/1990 Morgan et al. tic and therapeutic methods for applying these novel poly 5,073,627 A 12/1991 Curtis et al. nucleotides and polypeptides to the diagnosis, treatment, and/ 5, 112,946 A 5, 1992 Maione 5,122,464 A 6, 1992 Wilson et al. or prevention of various diseases and/or disorders, 5,205.290 A 4/1993 Unger particularly PPAR-agonist induced edema or related indica 5,223,409 A 6, 1993 Ladner et al. tions. The invention further relates to screening methods for 5,225,539 A 7, 1993 Winter identifying agonists of PPAR proteins with decreased risk of 5,258.498 A 11/1993 Huston et al. inducing peripheral edema in patients. 5,314,995 A 5/1994 Fell, Jr. et al. 5,336,603 A 8/1994 Capon et al. 17 Claims, 112 Drawing Sheets US 7482,124 B2 Page 2

U.S. PATENT DOCUMENTS WO WO98,50433 11, 1998 WO WO99,04813 2, 1999 5,571,698 A 11/1996 Ladner et al. WO WOOO,22166 4/2000 5,573,920 A 1 1/1996 Randle WO WO 2004.014308 2, 2004 5,580,717 A 12/1996 Dower et al. WO WO 2004/035822 4/2004 5,585,089 A 12/1996 Queen et al. WO WO 2004f10O871 11, 2004 5,601,819 A 2/1997 Wong et al. WO WO 2005/089731 9, 2005 5,622,929 A 4/1997 Willner et al. 5,625,126 A 4/1997 Lonberg et al. OTHER PUBLICATIONS 5,633,425 A 5/1997 Lonberg et al. 5,641,670 A 6, 1997 Treco et al. Agapitov, A.V. et al., “Role of endothelin in cardiovascular disease'. 5,658,727 A 8, 1997 Barbas et al. Journal of the Renin-Angiotensin-Aldosterone System, vol. 3, No. 1, 5,661,016 A 8/1997 Lonberg et al. pp. 1-15 (2002). 5,661,106 A 8, 1997 Baumann et al. Ahmad, U. et al., “Strong Association of a Renin Intronic Dimor 5,698,426 A 12, 1997 Huse phism with Essential Hypertension'. Hypertens. Res., vol. 28, No. 4. 5,716,805 A 2, 1998 Srinivasan et al. pp. 339-344 (2005). 5,733,743 A 3, 1998 Johnson et al. Albertin, G. et al., “Endothelin-1 and adrenomedullin enhance the 5,733,761 A 3, 1998 Treco et al. growth of human adrenocortical carcinoma-derived SW-13 cell line 5,750,753 A 5, 1998 Kimae et al. by stimulating proliferation and inhibiting apoptosis'. International 5,780,225 A 7/1998 Wigler et al. Journal of Molecular Medicine, vol. 15, pp. 469-474 (2005). 5,807,715 A 9, 1998 Morrison et al. Alberts, G.F. et al., “Constitutive Endothelin-1 Overexpression Pro 5,814,318 A 9/1998 Lonberg et al. motes Smooth Muscle Cell Proliferation via an External Autocrine 5,821,047 A 10, 1998 Garrard et al. Loop'. The Journal of Biological Chemistry, vol. 269, No. 13, pp. 5,837,832 A 11/1998 Chee et al. 101 12-10118 (1994). 5,856,104 A 1/1999 Chee et al. Altschul, S.F. et al., “Basic Local Alignment Search Tool”, J. Mol. 5,856,174 A 1/1999 Lipshutz et al. Biol., vol. 215, pp. 403-410 (1990). 5,858,659 A 1/1999 Sapolsky et al. Ames, R.S. et al., "Conversion of murine Fabs isolated from a 5,874,219 A 2f1999 Rava et al. combinatorial phage display library to full length immunoglobulins'. 5,885,793 A 3, 1999 Griffiths et al. Journal of Immunological Methods, vol. 184, pp. 177-186 (1995). 5,916,771 A 6, 1999 Hori et al. Amiri, F. et al., “Endothelium-Restricted Overexpression of Human 5,939,598 A 8/1999 Kucherlapati et al. Endothelin-1 Causes Vascular Remodeling and Endothelial Dys 5,969,108 A 10/1999 McCafferty et al. function'. Circulation, vol. 110, pp. 2233-2240 (2004). 6,028,066 A 2/2000 Unger Andersen, U.B. et al., “Left Ventricular Structure and Diastolic Func 6,414,002 B1 7/2002 Cheng et al. tion in Subjects with Two Hypertensive Parents'. Blood Pressure, 2005/0288.343 A1 12/2005 Rusowicz et al. vol. 10, pp. 193-198 (2001). Arenkov, P. et al., “Protein Microchips: Use for Immunoassay and FOREIGN PATENT DOCUMENTS Enzymatic Reactions'. Analytical Biochemistry, vol. 278, pp. 123 131 (2000). EP O 519596 2, 2005 Arinami, T. et al., “Chromosomal Assignments of the Human WO WO 86,05807 10, 1986 Endothelin Family Genes: The Endothelin-1 Gene (EDN1) to 6p23 WO WO 98.01.036 2, 1989 p24, the Endothelin-2 Gene (EDN2) to 1p34, and the Endothelin-3 WO WO 89.12624 12/1989 Gene (EDN3) to 20g 13.2-q13.3". Am. J. Hum. Genet., vol. 48, pp. WO WO90,02809 3, 1990 990-996 (1991). WO WO91/OO360 1, 1991 Arnon, R. et al., “Monoclonal Antibodies for Immunotargeting of WO WO91,06570 5, 1991 Drugs in Cancer Therapy”, Monoclonal Antibodies and Cancer WO WO91,09967 7, 1991 Therapy, Alan R. Liss, Inc., publ., Reisfeld, R.A. et al., eds., pp. WO WO 91/10737 7, 1991 243-256 (1985). WO WO91f10741 7, 1991 Arun, C. et al., “Endothelin-1 is a novel prognostic factor in non WO WO 91/14438 10, 1991 Small cell lung cancer. The International Journal of Biological WO WO92fO1047 1, 1992 Markers, vol. 19, No. 4, pp. 262-267 (2004). WO WO 92,05793 4f1992 Asakura, H. et al., “Changes in Plasma Endothelin-1 After Elective WO WO92fO8495 5, 1992 Cesarean Section in Women with Preeclampsia and the Relationship WO WO92,08802 5, 1992 to Thrombocytopenia'. J. Nippon Med. Sch., vol. 70, No. 6, pp. WO WO92, 18619 10, 1992 480-489 (2003). WO WO92/2O373 11, 1992 Asham, E. et al., “Increased endothelin-1 in colorectal cancer and WO WO92,22324 12/1992 reduction of tumour growth by ETA receptor antagonism'. British WO WO93,08829 5, 1993 Journal of Cancer, vol. 85, No. 11, pp. 1759-1763 (2001). WO WO93, 11236 6, 1993 Ashkenazi, A. et al., “Protection against endotoxic shock by a tumor WO WO 93/17715 9, 1993 necrosis factor receptor immunoadhesin'. Proc. Natl. Acad. Sci. WO WO93,21232 10, 1993 USA, vol. 88, pp. 10535-10539 (1991). WO WO94f10308 5, 1994 Ausubel, F.M. et al., eds. Current Protocols in Molecular Biology, WO WO94/12650 6, 1994 vols. 1, 2, 3 and 4. John Wiley & Sons, Inc., publ., pp. 1-11 (table of WO WO95/15982 6, 1995 contents) (2001). WO WO95/2O401 8, 1995 Ausubel, F.M. et al., eds., Unit 10.8: "Immunoblotting and WO WO96,04388 2, 1996 Immunodetection'. Current Protocols in Molecular Biology, vol. 2, WO WO96,22024 T 1996 John Wiley & Sons, Inc., publ., pp. 10.8.1-10.8.21 (1997). WO WO96,294.11 9, 1996 Ausubel, F.M. et al., eds., Unit 10.16: “Immunoprecipitation'. Cur WO WO96,33735 10, 1996 rent Protocols in Molecular Biology, vol. 2, John Wiley & Sons, Inc., WO WO96,34096 10, 1996 publ., pp. 10.16.1-10.16.29 (1999). WO WO98, 16654 4f1998 Ausubel, F.M. et al., eds., Unit 11.2: "Enzyme-Linked WO WO 98.24893 6, 1998 Immunosorbent Assays (ELISA). Current Protocols in Molecular WO WO98,46645 10, 1998 Biology, vol. 2, John Wiley & Sons, Inc., publ., pp. 11.2.1.-11.2.22 WO WO 98.493.05 11, 1998 (1991). US 7482,124 B2 Page 3

Bajora, R. et al., “Brain natriuretic peptide and endothelin-1 in the Cambiaggi. C. et al., “Gene Expression of Endothelin-1 (ET-1) and pathogenesis of polyhydramnios-oligohydramnios in Release of Mature Peptide by Activated Human Neutrophils'. monochorionic twins'. Am. J. Obstet. Gynecol., vol. 189, No. 1, pp. Cytokine, vol. 14, No. 4, pp. 230-233 (2001). 189-194 (2003). Camsari, A. et al., “Endothelin-1 and Nitric Oxide Concentrations Barish, G.D. et al., “PPARö: a dagger in the heart of the metabolic and Their Response to Exercise in Patients With Slow Coronary syndrome'. The Journal of Clinical Investigation, vol. 116, No.3, pp. Flow”. Circulation Journal, vol. 67, pp. 1022-1028 (2003). 590-597 (2006). Casares, M.T.G. et al., “Renin Expression in Hematological in Bartlett, R.J. et al., “In vivo targeted repair of a point mutation in the Hematological Malignancies and its Role in the Regulation of canine dystrophin gene by a chimeric RNA/DNA oligonucleotide'. Hematopoiesis'. Leukemia and Lymphoma, vol. 43, No. 12, pp. Nature Biotechnology, vol. 18, pp. 615-622 (2000). 2377-2381 (2002). Bebbington, C.R. et al., Chapter 8: “The use of vectors based on gene Casey, M.L. et al., “Endothelin-1 Gene Expression and Regulation of amplification for the expression of cloned genes in mammalian Endothelin mRNA and Protein Biosynthesis in Avascular Human cells'. DNA Cloning, vol. 3: A Practical Approach, IRL Press Lim Amnion'. The Journal of Biological Chemistry, vol. 266, No. 9, pp. ited, publ., Glover, D.M., ed., pp. 163-188 (1987). 5762-5768 (1991). Benatti, L. et al., “Two Preproendothelin 1 mRNAS Transcribed by Castellano, M. et al., “The Cardiac B-Adrenoceptor-Mediated Sig Alternative Promoters”. J. Clin. Invest., vol. 91, pp. 1149-1156 naling Pathway and Its Alterations in Hypertensive Heart Disease'. (1993). Hypertension, vol. 29, No. 3, pp. 715-722 (1997). Bengtsson, K. et al., “Polymorphism in the f-Adrenergic Receptor Cauduro, R.L. et al., “Cyclosporine Increases Endothelin-1 Plasma Gene and Hypertension'. Circulation, vol. 104, pp. 187-190 (2001). Levels in Renal Transplant Recipients'. Transplantation Proceed Bennett, D. et al., "Kinetic Characterization of the Interaction of ings, vol. 36, pp. 880-881 (2004). Biotinylated Human Interleukin 5 with a Fc Chimera of its Receptor Charloux, A. et al., “Circulating endothelin parallels arterial blood OSubunit and Development of an ELISA Screening Assay using pressure during sleep in healthy Subjects'. Regulatory Peptides, vol. Real-Time Interaction Biosensor Analysis”, Journal of Molecular 119, pp. 133-138 (2004). Recognition, vol. 8, pp. 52-58 (1995). Chen, H.H. et al., “Angiotensin II AT receptor antagonism prevents Berg, J.M. et al., “Lessons from Zinc-Binding Peptides'. Annu. Rev. detrimental renal actions of acute diuretic therapy in human heart Biophys. Biomol. Struct., vol. 26, pp. 357-371 (1997). failure”, Am. J. Physiol. Renal Physiol., vol. 284, pp. F1 115-F1119 Berger, J. et al., “Physiological and Therapeutic Roles of Peroxisome (2003). Proliferator-Activated Receptors', Diabetes Technology & Thera Chen, M.-C. et al., “Increased Circulating Endothelin-1 in Rheumatic peutics, vol. 4. No. 2, pp. 163-174 (2002). Mitral Stenosis: Irrelevance to Left Atrial and Pulmonary Artery Better, M. et al., “Escherichia coli Secretion of an Active Chimeric Pressures”, Chest, vol. 125, No. 2, pp. 390-396 (2004). Antibody Fragment'. Science, vol. 240, pp. 1041-1043 (1988). Chen, X. et al., “Fluorescence Polarization in Homogeneous Nucleic Bitter, G.A. et al., “Expression and Secretion Vectors for Yeast”. Acid Analysis”. Genome Research, vol. 9, pp. 492-498 (1999). Methods in Enzymology, vol. 153, pp. 516-544 (1987). Cheng, C.-M. et al., “Crucial Role of Extracellular Signal-Regulated Bloch, K.D. et al., “Structural Organization and Chromosomal Kinase Pathway in Reactive Oxygen Species-Mediated Endothelin-1 Assignment of the Gene Encoding Endothelin'. The Journal of Bio Gene Expression Induced by Endothelin-1 in Rat Cardiac Fibro logical Chemistry, vol. 264, No. 18, pp. 10851-10857 (1989). blasts'. Molecular Pharmacology, vol. 63, No. 5, pp. 1002-1011 Boerner, P. et al., “Production of Antigen-Specific Human (2003). Monoclonal Antibodies from InVitro-Primed Human Splenocytes'. Chow, M. et al., “Synthetic peptides from four separate regions of the The Journal of Immunology, vol. 147, No. 1, pp. 86-95 (1991). poliovirus type 1 capsid protein VP1 induce neutralizing antibodies'. Brewster, U.C. et al., “The Renin-Angiotensin-Aldosterone System: Proc. Natl. Acad. Sci. USA, vol. 82, pp. 910-914 (1985). Cardiorenal Effects and Implications for Renal and Cardiovascular Chruscinski, A. et al., “Differential Distribution of B-Adrenergic Disease States'. The American Journal of the Medical Science, vol. Receptor Subtypes in Blood Vessels of Knockout Mice Lacking B 326, No. 1, pp. 15-24 (2003). or B-Adrenergic Receptors'. Molecular Pharmacology, vol. 60, No. Brinkmann, U. et al., “Phage display of disulfide-stabilized Fv frag 5, pp. 955-962 (2001). ments”, Journal of Immunological Methods, vol. 182, pp. 41-50 Chun, T.-H. et al., “Modification of GATA-2 Transcriptional Activity (1995). in Endothelial Cells by the SUMO E3 Ligase PIASy”, Circulation Brodeur, B.R. et al., Chapter 4: “Mouse-Human Myeloma Partners Research, vol. 92, pp. 1201-1208 (2003). for the Production of Heterohybridomas'. Monoclonal Antibody Clark, A.G., “Inference of Haplotypes from PCR-amplified Samples Production Techniques and Applications, Marcel Dekker, Inc., publ., of Diploid Populations'. Mol. Biol. Evol., vol. 7, No. 2, pp. 111-122 Schook, L.B., ed., pp. 51-63 (1987). (1990). Bruno, C.M. et al., “Pathophysiology of endothelin and medical Clark, A.G. et al., “Haplotype Structure and Population Genetic emergencies'. Panminerva Med., vol. 45, No. 2, pp. 151-154 (2003). Inferences from Nucleotide-Sequence Variation in Human Bruno, C.M. et al., “Plasma endothelin-1 levels and albumin excre Lipoprotein Lipase'. Am. J. Hum. Genet., vol. 63, pp. 595-612 tion rate in normotensive, microalbuminuric type 2 diabetic (1998). patients'. Journal of Biological Regulators and Homeostatic Agents, Cockett, M.I. et al., “High Level Expression of Tissue Inhibitor of vol. 16, pp. 114-117 (2002). Metalloproteinases in Chinese Hamster Ovary Cells Using Buchwald, H. et al., “Long-term, continuous intravenous heparin Glutamine Synthetase Gene Amplification'. Bio/Technology, vol. 8, administration by an implantable infusion pump in ambulatory pp. 662-667 (1990). patients with recurrent venous thrombosis'. Surgery, vol. 88, No. 4. Colbere-Gerapin, F. et al., “A New Dominant Hybrid Selective pp. 507-516 (1980). Marker for Higher Eukaryotic Cells'. J. Mol. Biol., vol. 150, pp. 1-14 Bullido, M.J. et al., “Polymorphism in genes involved in adrenergic (1981). signaling associated with Alzheimers'. Neurobiology of Aging, vol. Cole, S.P.C. et al., “The EBV-Hybridoma Techniques and Its Appli 25, pp. 853-859 (2004). cation to Human Lung Cancer. Monoclonal Antibodies and Cancer Burchiel, S.W. et al., Chapter 13: “Immunopharmacokinetics of Therapy, Alan R. Liss, Inc., publ., Reisfeld, R.A. et al., eds., pp. 77-96 Radiolabeled Antibodies and Their Fragments”. Tumor Imaging: The (1985). Radioimmunochemical Detection of Cancer, Masson Publishing Cormack, B., Unit 8.5: “Directed Mutagenesis Using the Polymerase USA, Inc., publ., Burchiel, S.W. et al., eds, pp. 125-139 (1982). Chain Reaction'. Current Protocols in Molecular Biology, vol. 1, Burt, D.W. et al., “Identification of Negative and Positive Regulatory Suppl. 37, John Wiley & Sons, Inc., publ. Ausubel, F.M. et al., eds., Elements in the Human Renin Gene'. The Journal of Biological pp. 8.5.1-8.5.10 (1997). Chemistry, vol. 264, No. 13, pp. 7357-7362 (1989). Costa, C. et al., “Endothelin-1 Plasma Levels in Cyclosporine Burton, D.R. et al., “Human Antibodies from Combinatorial Librar Treated Stable Renal Transplant Patients'. Transplantation Proceed ies'. Advances in Immunology, vol. 57, pp. 191-280 (1994). ings, vol. 34, pp. 487-488 (2002). US 7482,124 B2 Page 4

Cote, R.J. et al., “Generation of human monoclonal antibodies reac Dzimiri, N., “Regulation off-Adrenoceptor Signaling in Cardiac tive with cellular antigens'. Proc. Natl. Acad. Sci. USA, vol. 80, pp. Function and Disease'. Pharmacological Reviews, vol. 51, No. 3, pp. 2026-2030 (1983). 465-501 (1999). Creighton, T.E., Proteins: Structures and Molecular Properties, Sec Eberle, J. et al., “Edothelin-1 Decreases Basic Apoptotic Rates in ond Edition, W.H. Freeman and Company, publ., pp. v-x (table of Human Melanoma Cell Lines”. The Journal of Investigative Derma contents) (1993). tology, vol. 119, No. 3, pp. 549-555 (2002). Crouse, G.F. et al., “Expression and Amplification of Engineered Egholm, E. et al., “PNA hybridizes to complementary Mouse Dihydrofolate Reductase Minigenes', Molecular and Cellu oligonucleotides obeying the Watson-Crick hydrogen-bonding lar Biology, vol. 3, No. 2, pp. 257-266 (1983). rules”, Nature, vol. 365, pp. 566-568 (1993). Danser, A.H.J. et al., “Prorenin Uptake in the Heart: a Prerequisite for El-Gamal, Y. et al., “Plasma endothelin-1 immunoreactivity in asth Local Angiotensin Generation?”. J. Mol. Cell Cardiol., vol. 34, pp. matic children'. Annals of Allergy, Asthma & Immunology, Vol. 88, 1463-1472 (2002). pp. 370-373 (2002). David, G.S. et al., “Protein Iodination with Solid State Elies, R. et al., “Structural and Functional Analysis of the B Cell Lactoperoxidase'. Biochemistry, vol. 13, No. 5, pp. 1014-1021 Epitopes Recognized by Anti-Receptor Autoantibodies in Patients (1974). with Chagas' Disease'. The Journal of Immunology, vol. 157, pp. Davis, L.G. et al., Basic Methods in Molecular Biology, Elsevier 4203-4211 (1996). Science Publishing Co., Inc., publ., pp. v.-viii (table of contents) Ellis, S.B. et al., “Isolation of Alcohol Oxidase and Two Other Metha (1986). nol Regulatable Genes from the Yeast Pichia pastoris’, Molecular De Groote, P. et al., “Association between bata-1 and beta-2 and Cellular Biology, vol. 5, No. 5, pp. 1111-1121 (1985). adrenergic receptor gene polymorphisms and the response to beta El-Sharkawy, I.M.A. et al., "Serum Levels of Endothelin-1 (ET-1), blockade in patients with stable congestive heart failure'. Interleukin-2 (IL-2) and Amino-Terminal Propeptide Type III Pharmacogenetics and Genomics, vol. 15, No.3, pp. 137-142 (2005). Procollagen (PIIINP) in Patients with Acute and Chronic Filariasis'. Delerive, P. et al., “Peroxisome Proliferator-Activated Receptor Acti Journal of the Egyptian Society of Parasitology, vol. 31, No. 1, pp. vators Inhibit Thrombin-Induced Endothelin-1 Production in Human 169-176 (2001). Vascular Endothelial Cells by Inhibiting the Activator Protein-1 Sig Erdem, M. et al., “Immunohistochemical Localization of naling Pathway'. Circulation Research, vol. 85, pp. 394-402 (1999). Endothelin-1 in Human Placenta from Normal and Growth-Re Deutscher, M.P. ed., Methods in Enzymology, vol. 182, Academic stricted Pregnancies'. Pediatric and Developmental Pathology, vol. Press, Inc., publ., pp. v.-viii (table of contents) (1990). 6, pp. 307-313 (2003). Dhanaraj, V. et al., "X-ray analyses of peptide-inhibitor complexes Ergul, S. et al., “Vasoactive Factors in Sickle Cell Disease: In Vitro define the structural basis of specificity for human and mouse renins'. Evidence for Endothelin-1-Mediated Vasoconstriction'. American Nature, vol. 357, pp. 466-472 (1992). Journal of Hematology, vol. 76, pp. 245-251 (2004). Di Paolo, S. et al., “Increased placental expression of tissue factor is Erkan, E. et al., “Role of Nitric Oxide, Endothelin-1, and Inflamma associated with abnormal uterine and umbilical Doppler waveforms tory Cytokines in Blood Pressure Regulation in Hemodialysis in severepreeclampsia with fetal growth restriction”. J. Nephrol., vol. Patients'. American Journal of Kidney Diseases, vol. 40, No. 1, pp. 16, pp. 650-657 (2003). 76-81 (2002). Didier, N. et al., “HIV-1-induced production of endothelin-1 in an in Erlich, H.A., ed., PCR Tecnology: Principles and Applications for vitro model of the human blood-brain barrier'. NeuroReport, vol. 13, DNA Amplification, Stockton Press, publ., pp. ix-x (table of con No. 9, pp. 1179-1183 (2002). Diep, Q.N. et al., “Structure, Endothelial Function, Cell Growth, and tents) (1989). Inflammation in Blood Vessels of Angiotensin II-Infused Rats: Role Erlich, H.A. et al., “Recent Advances in the Polymerase Chain Reac of Peroxisome Proliferator-Activated Receptor-Y. Circulation, vol. tion”, Science, vol. 252, pp. 1643-1651 (1991). 105, pp. 2296-2302 (2002). Evans, J.J. et al., “Effects of endothelin-1 on release of adrenomedul Ding, K.-H. et al., “Glucose-dependent insulinotropic peptide stimu lin and C-type natriuretic peptide from individual human vascular lates thymidine incorporation in endothelial cells: role of endothelin endothelial cells”, Journal of Endocrinology, vol. 175, pp. 225-232 1”, Am. J. Physiol. Endocrinol. Metab., vol. 285, pp. E390-E396 (2002). (2003). Excoffier, L. et al., “Maximum-Likelihood Estimation of Molecular Dionne, I.J. et al., “Association between obesity and a polymorphism Haplotype Frequencies in a Diploid Population'. Mol. Biol. Evol., in the B-adrenoceptor gene (Gly389 Arg ADRBI) in Caucasian vol. 12, No. 5, pp. 921-927 (1995). women', International Journal of Obesity, vol. 26, pp. 633-639 Fahimi-Vahid, M. et al., “Distinct Signaling Pathways Mediate (2002). Cardiomyocyte Phospholipase D Stimulation by Endothelin-1 and Dong, Y. et al., “Endothelin-1 Gene and Progression of Blood Pres Thrombin”. J. Mol. Cell Cardiol., vol. 34, pp. 441-453 (2002). sure and Left Ventricular Mass: Longitudinal Findings in Youth', Fallin, D. et al., "Accuracy of Haplotype Frequency Estimation for Hypertension, vol. 44, pp. 884-890 (2004). Biallelic Loci, via the Expectation-Maximization Algorithm for Dosanjh, A. et al., “Endothelin-1 (ET-1) Decreases Human Bronchial Unphased Diploid Genotype Data'. Am. J. Hum. Genet., vol. 67, pp. Epithelial Cell Migration and Proliferation: Implications for Airway 947-959 (2000). Remodeling in Asthma, Journal of Asthma, vol. 40, No. 8, pp. Fell, H.P. et al., “Genetic Construction and Characterization of a 883-886 (2003). Fusion Protein Consisting of a Chimeric F(ab') with Specificity for Douglas, M.L. et al., “Endothelin Axis Expression in Markedly Dif Carcinomas and Human IL-2'. The Journal ofImmunology, vol. 146, ferent in the Two Main Subtypes of Renal Cell Carcinoma'. Cancer, No. 7, pp. 2446-2452 (1991). vol. 100, No. 10, pp. 21 18-2124 (2004). Ferree, “The Biology of Peroxisome Proliferator-Activated Recep Dracopoli, N.C. et al., eds., Chapter 12: “Vectors for Gene Therapy'. tors: Relationship with Lipid Metabolism and Insulin Sensitivity”. Current Protocols in Human Genetics, vol. 3, John Wiley & Sons, Diabetes, vol. 53, Suppl. 1, pp. S43-S50 (2004). Inc., pp. 12.0.1-12. 12.15 (1999). Fishwild, D.M. et al., “High-avidity human IgGK monoclonal anti Dracopoli, N.C. et al., eds., Chapter 13: "Delivery Systems for Gene bodies from a novel strain of minilocus trasgenic mice'. Nature Therapy'. Current Protocols in Human Genetics, vol. 3, John Wiley Biotechnology, vol. 14, pp. 845-851 (1996). & Sons, Inc., pp. 13.0.1-13.10.7 (2000). Foecking, M.K. et al., “Powerful and versatile enhancer-promoter Dunigan, C.D. et al., “Complexity of Agonist- and Cyclic AMP unit for mammalian expression vectors'. Gene, vol. 45, pp. 101-105 Mediated Downregulation of the Human B-Adrenergic Receptor: (1986). Role of Internalization, Degradation, and mRNA Destabilization'. Forse, R.A. et al., “The Effect of Escherichia coli Endotoxin on the Biochemistry, vol. 41, No. 25, pp. 8019-8030 (2002). Adrenergic Control of Lipolysis in the Human Adipocyte'. Journal of During, M.J. et al., “Controlled Release of Dopamine from a Poly Surgical Research, vol. 46, No. 1, pp. 41-48 (1989). meric Brain Implant. In Vivo Characterization'. Annals of Neurol Foster, N. et al., “Lysosomal traffic of liganded endothelin B recep ogy, vol. 25, No. 4, pp. 351-356 (1989). tor'. Biochimica et Biophysica Acta, vol. 1642, pp. 45-52 (2003). US 7482,124 B2 Page 5

Fountoulakis, M. et al., “Interferon Y Receptor Extracellular Domain Giaid, A. et al., “Endothelin 1, an endothelium-derived peptide, is Expressed as IgG Fusion Protein in Chinese Hamster Ovary Cells'. expressed in neurons of the human spinal cord and dorsal root gan The Journal of Biological Chemistry, vol. 270, No. 8, pp. 3958-3964 glia, Proc. Natl. Acad. Sci. USA, vol. 86, pp. 7634-7638 (1989). (1995). Giannessi. D. et al., “The Role of Endothelins and Their Receptors in Francis, M.J. et al., “Immunological Priming with Synthetic Peptides Heart Failure'. Pharmacological Research, vol.43, No. 2, pp. 111 of Foot-and-Mouth Disease Virus'. J. Gen. Virol., vol. 66, pp. 2347 126 (2001). 2354 (1985). Gillies, S.D. et al., “Antibody-targeted interleukin 2 stimulates T-cell Frielle, T. et al., “Cloning of the cDNA for the human B-adrenergic killing of autologous tumor cells'. Proc. Natl. Acad. Sci. USA. vol. receptor', Proc. Natl. Acad. Sci. USA, vol. 84, pp. 7920-7924 (1987). 89, pp. 1428-1432 (1992). Frielle, T. et al., "Human?-and?-adrenergic receptors: structurally Gillies, S.D. et al., “High-level expression of chimeric antibodies and functionally related receptors derived from distinct genes'. using adapted cDNA variable region cassettes'. Journal of Immuno Trends in Neurosciences, vol. 11, No. 7, pp. 321-324 (1988). logical Methods, vol. 125, pp. 191-202 (1989). Fuchs, S. et al., “Functionality of two new polymorphisms in the Goding, J.W., Chapter 3: “Production of Monoclonal Antibodies'. human renin gene enhancer region'. Journal of Hypertension, vol. Monoclonal Antibodies: Principles and Practice, Second Edition, 20, No. 12, pp. 2391-2398 (2002). Academic Press Limited, publ., pp. 59-103 (1986). Fuchs, S. et al., “Implication of Ref-1 in the repression of renin gene Goldspiel, B.R. et al., “Human gene therapy”, Clinical Pharmacy, transcription by intracellular calcium'. Journal of Hypertension, vol. vol. 12, pp. 488-505 (1993). 21, No. 2, pp. 327-335 (2003). Goodfriend, T.L. et al., “Angiotensin Receptors and Their Antago Fuchsjäger-Mayrl, G. et al., "Ocular hyperperfusion following onset nists'. The New England Journal of Medicine, vol. 334, No. 25, pp. of intensified insulin therapy is inversely correlated with plasma 1649-1654 (1996). endothelin-1 in Type I diabetes', Diabetologia, vol. 45, pp. 883-889 Goodson, J.M., Chapter 6: “Dental Applications'. Medical Applica (2002). tions of Controlled Release, vol. II: Applications and Evaluation, Fukamizu, A. et al., “Human renin gene of renin-secreting tumor'. CRC Press, Inc., publ., Langer, R.S. et al., eds., pp. 115-138 (1984). Gene, vol. 49, pp. 139-145 (1986). Gordon, D. et al., “Consed: A Graphical Tool for Sequence Finish Fukunaga, Y. et al., “Thiazolidinediones, peroxisome proliferator ing”. Genome Research, vol. 8, pp. 195-202 (1998). activated receptor Y agonists, regulate endothelial cell growth and Greenspan, N.S. et al., “Idiotypes: structure and immunogenicity'. secretion of vasoactive peptides'. Atherosclerosis, vol. 158, pp. 113 The FASEB Journal, vol. 7, pp. 437-444 (1993). 119 (2001). Grubbs, A.L.. et al., “Saphenous Vein Endothelin System Expression Fullerton, S.M. et al., “Apollipoprotein E Variation at the Sequence and Activity in African American Patients'. Arterioscler. Thromb. Haplotype Level: Implications for the Origin and Maintenance of a Vasc. Biol., vol. 22, pp. 1122-1127 (2002). Major Human Polymorphism'. Am. J. Hum. Genet., vol. 67, pp. Guan, Y. et al., “Thiazolidinediones expand body fluid volume 881-900 (2000). through PPARY stimulation of ENaC-mediated renal salt absorp Funalot, B. et al., “Genes encoding endothelin-converting enzyme-l tion', Nature Medicine, vol. 11, No. 8, pp. 861-866 (2005). and endothelin-1 interact to influence blood pressure in women: The Guruli. G. et al., "Function and Survival of dendritic cells depend on EVA study”. Journal of Hypertension, vol. 22, No. 4, pp. 739-743 endothelin-1 and endothelin receptor autocrine loops”. Blood, vol. 104, No. 7, pp. 2107-2115 (2004). (2004). Gusella, J.F., “DNA Polymorphism and Human Disease”. Ann. Rev. Galindo-Fraga, A. et al., “Elevation of Plasmatic Endothelin in Biochem., vol. 55, pp. 831-854 (1986). Patients with Heart Failure', Archives of Medical Research, vol. 34, Hafizi. S. et al., “Profibrotic Effects of Endothelin-1 via the ETA pp. 367-372 (2003). Receptor in Cultured Human Cardiac Fibroblasts”. Cellular Physi Gao, J. et al., “Changes in the Protein Expression of Yeast as a ology and Biochemistry, vol. 14, pp. 285-292 (2004). Function of Carbon Source.” Journal of Proteome Research, vol. 2, Hämmerling, G.J. et al., eds., “Production of Antibody-Producing No. 6, pp. 643-649 (2003). Hybridomas in the Rodent Systems'. Monoclonal Antibodies and Gao, J. et al., “Identification of in vitro protein biomarkers of idio T-Cell Hybridomas: Perspectives and technical advances, Elsevier/ syncratic liver toxicity'. Toxicology in Vitro, vol. 18, pp. 533-541 North-Holland Biomedical Press, publ., pp. 563-587 (1981). (2004). Hansen, L. et al., “The Pro12 Ala Variant of the PPARG Gene is a Risk Gardner, L.A. et al., “Role of the Cyclic AMP-dependent Protein Factor for Peroxisome Proliferator-Activated Receptor-y?o. Agonist Kinase in Homologous Resensitization of the f-Adrenergic Recep Induced Edema in Type 2 Diabetic Patients'. The Journal of Clinical tor'. The Journal of Biological Chemistry, vol. 279, No. 20, pp. Endocrinology & Metabolism, vol. 91, No. 9, pp. 3446-3450 (2006). 21135-21 143 (2004). Hardman, J.A. et al., “Primary Structure of the Human Renin Gene'. Gavi, S. et al., “The 15-Amino Acid Motif of the C Terminus of the DNA, vol. 3, No. 6, pp. 457-468 (1984). f-Adrenergic Receptor is Sufficient to Confer Insulin-Stimulated Harlow, E. et al., Antibodies: A Laboratory Manual, Cold Spring Counterregulation to the f-Adrenergic Receptor. Endocrinology, Harbor Laboratory, publ., pp. iii-ix (table of contents) (1988). vol. 146, No. 1, pp. 450-457 (2005). Harrity, T. et al., “Muraglitazar, a Novel Dual (of Y) Peroxisome Gentz, R. et al., “Bioassay for the trans-activation using purified Proliferator-Activated Receptor Activator, Improves Diabetes and human immunodeficiency virus tai-encoded protein: Trans-activa Other Metabolic Abnormalities and Preseves B-Cell Function in tion requires mRNA synthesis'. Proc. Natl. Acad. Sci. USA, vol. 86. db/db Mice', Diabetes, vol. 55, pp. 240-248 (2006). pp. 821-824 (1989). He, J. et al., "Glycosylation off-adrenergic receptors regulates Germain, A.M. et al., “Endothelin receptor mRNAs in human fetal receptor Surface expression and dimerization'. Biochemical and Bio membranes, chorionic vessels, and decidua parietalis'. Molecular physical Research Communications, vol. 297, pp. 565-572 (2002). and Cellular Endocrinology, vol. 132, pp. 161-168 (1997). Hegarty, B.D. et al., “Peroxisome Proliferator-Activated Receptor Germain, S. et al., “Dissection of silencer elements in first intron (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid controlling the human renin gene'. Journal of Hypertension, vol. 17. Uptake and Metabolism in Vivo–A Study Using the Novel PPAROfy No. 7, pp. 899-905 (1999). Agonist Tesaglitazar”. Endocrinology, vol. 145, No. 7, pp. 3158 Germain, S. et al., “New Elements in Human Renin Promoter 3164 (2004). Involved in Cell-Specific Expression'. Clinical and Experimental Hellström, K.E. et al., Chapter 15: "Antibodies for Drug Delivery'. Pharmacology and Physiology, vol. 28, pp. 1056-1059 (2001). Controlled Drug Delivery: Fundamentals and Applications, Second Germain, S. et al., “Regulation of human renin Secretion and gene Edition, Marcel Dekker, Inc., publ., Robinson, J.R. et al., eds., pp. transcription in Calu-6 cells'. FEBS Letters, vol. 407, pp. 177-183 623-653 (1987). (1997). Hewage, C.M. et al., “Design of ET receptor agonists: NMR spec Geysen, H.M. et al., “Use of peptide synthesis to probe viral antigens troscopic and conformational studies of ET7-21 Leu7, Aib11, for epitopes to a resolution of a single amino acid. Proc. Natl. Acad. Cys(Acm)15'. Protein Engineering, vol. 15, No. 3, pp. 161-167 Sci., USA, vol. 81, pp. 3998-4002 (1984). (2002). US 7482,124 B2 Page 6

Higgins, D.R. et al., eds., Methods in Molecular Biology: Pichia Iwai, C. et al., “Suppressive Effect of the Gly389 Allele of the Protocols, Humana Press Inc., publ., pp. vii-viii (table of contents) 3-Adrenergic Receptor Gene on the Occurrence of Ventricular (1998). Tachycardia in Dilated Cardiomyopathy'. Circulation Journal, vol. Hillier, C. et al., “Effect of adrenomedullin on the production of 66, pp. 723-728 (2002). endothelin-1 and on its vasoconstrictor action in resistance arteries: Izzo, Jr., J.L. et al., eds., Hypertension Primer: The Essentials of High evidence for a receptor-specific functional interaction inpatients with Blood Pressure, American Heart Association, publ., pp. v.-viii (table heart failure'. Clinical Science, vol. 101, pp. 45-51 (2001). of contents) (1993). Hobart, PM. et al., “Human renin gene: Structure and sequence Jakoby, W.B., ed., Methods in Enzymology, vol. 104, Academic analysis”. Proc. Natl. Acad. Sci. USA, vol. 81, pp. 5026-5030 (1984). Press, Inc., publ., pp. v.-vii (table of contents) (1984). Hoehe, M.R. et al., “Genetic mapping of adrenergic receptor genes in Jalkanen, M. et al., “Cell Surface Proteoglycan of Mouse Mammary humans”, J. Mol. Med., vol. 73, pp. 299-306 (1995). Epithelial Cells is Shed by Cleavage of Its Matrix-binding Hoh, F. et al., “High-Resolution X-ray Structure of the Unexpectedly Ectodomain from Its Membrane-associated Domain'. The Journal of Stable Dimer of the Lys-Arg-des(17-21)|Endothelin-1 Cell Biology, vol. 105, No. 6, Pt. 2, pp. 3087-3096 (1987). Peptide”, Biochemistry, vol.43, No. 48, pp. 15154-15168 (2004). Jalkanen, M. et al., “Heparan Sulfate Proteoglycans from Mouse Hollenberg, N.K., "Considerations for Management of Fluid Mammary Epithelial Cells: Localization on the Cell Surface with a Dynamic Issues Associated with Thiazolidinediones”. The American Monoclonal Antibody”. The Journal of Cell Biology, vol. 101, pp. Journal of Medicine, vol. 115, No. 8A, pp. 111S-115S (2003). 976-984 (1985). Holmer, S.R. et al., “Beta-adrenergic stimulation of renin expression Jamal, S. et al., “UV-induction of keratinocyte endothelin-1 in vivo”. Journal of Hypertension, vol. 15, No. 12, Pt. 1, pp. 1471 downregulates E-cadherin in melanocytes and melanoma cells'. The 1479 (1997). Journal of Clinical Investigation, vol. 110, No. 4, pp. 443-452 (2002). Hoppe, H.-J. et al., “A parallel three stranded C-helical bundle at the Janknecht, R. et al., “Rapid and efficient purification of native nucleation site of collagen triple-helix formation'. FEBSLetters, vol. histidine-tagged protein expressed by recombinant vaccinia virus', 344, pp. 191-195 (1994). Proc. Natl. Acad. Sci. USA, vol. 88, pp. 8972-8976 (1991). Hosmer, D.W. et al., Applied Logistic Regression, Second Edition, Jespers, L.S. et al., “Guiding the Selection of Human Antibodies from John Wiley & Sons, Inc., publ., pp. v.-vii (table of contents) (2000). Phage Display Repertoires to a Single Epitope of an Antigen'. Bio/ Hotta, J. et al., “Polymorphisms of Renin-Angiotensin System Genes Technology, vol. 12, pp. 899-903 (1994). with High-Altitude Pulmonary Edema in Japanese Subjects', Chest, Jin, J.J. et al., “Association of Endothelin-1 Gene Variant with Hyper vol. 126, No. 3, pp. 825–830 (2004). tension'. Hypertension, vol. 41, pp. 163-167 (2003). Houghten, R.A., “General method for the rapid solid-phase synthesis Johanson, K. et al., “Binding Interactions of Human Interleukin 5 of large numbers of peptides: Specificity of antigen-antibody inter with Its Receptor C. Subunit'. The Journal of Biological Chemistry, action at the level of individual amino acids'. Proc. Natl. Acad. Sci. vol. 270, No. 16, pp. 9459-9471 (1995). USA, vol. 82, pp. 5131-5135 (1985). Johnson, B.C., ed., Posttranslational Covalent Modifications of Pro Howard III, M.A. et al., “Intracerebral drug delivery in rats with teins, Academic Press, publ., pp. 1-12 (1983). lesion-induced memory deficits”. J. NeuroSurg., vol. 71, pp. 105-112 Johnson, J.A. et al., “f-Adrenergic receptor polymorphisms and (1989). antihypertensive response to metoprolol. Clinical Pharmacology & Hu, L.A. et al., “B-Adrenergic Receptor Association with PSD-95”. Therapeutics, vol. 74, No. 1, pp. 44-52 (2003). The Journal of Biological Chemistry, vol. 275, No. 49, pp. 38.659 Joliot, A. et al., “Antennapedia homeobox peptide regulates neural 38666 (2000). morphogenesis'. Proc. Natl. Acad. Sci. USA. vol. 88, pp. 1864-1868 Hunkapiller, M. et al., “A microchemical facility for the analysis and (1991). synthesis of genes and proteins', Nature, vol. 310, pp. 105-111 Jones, P.T. et al., “Replacing the complementarity-determining (1984). regions in a human antibody with those from a mouse'. Nature, vol. Hunter, W.M. et al., “Preparation of Iodine-131 Labelled Human 321, pp. 522-525 (1986). Growth Hormone of High Specific Activity”. Nature, vol. 194, pp. Kang, J.S. et al., "Zinc Finger Proteins as Designer Transcription 495-496 (1962). Factors'. The Journal of Biological Chemistry, vol. 275, No. 12, pp. Huston, J.S. et al., “Protein Engineering of Single-Chain Fv Analogs 8742-8748 (2000). and Fusion Proteins”. Methods in Enzymology, vol. 203, pp. 46-88 Kawana, M. et al., “Cooperative Interaction of GATA-2 and AP1 (1991). Regulates Transcription of the Endothelin-1 Gene'. Molecular and Iglarz, M. et al., “Effect of Peroxisome Proliferator-Activated Recep Cellular Biology, vol. 15, No. 8, pp. 4225-4231 (1995). tor-O. and -y Activators on Vascular Remodeling in Endothelin-De Kermani, A. et al., “Thiazolidinedione-Associated Congestive Heart pendent Hypertension'. Arterioscler. Thromb. Vasc. Biol., vol. 23, Failure and Pulmonary Edema', Mayo Clin. Proc., vol. 78, pp. 1088 pp. 45-51 (2003). 1091 (2003). Imai, T. et al., “Cloning and sequence analysis of cDNA for human Kettleborough, C.A. et al., “Isolation of tumor cell-specific single renin precursor'. Proc. Natl. Acad. Sci. USA. vol. 80, pp. 7405-7409 chain Fv from immunized mice using phage-antibody libraries and (1983). the re-construction of whole antibodies from these antibody frag Imokawa, G. et al., “Endothelins Secreted from Human ments”, Eur, J. Immunol., vol. 24, pp. 952-958 (1994). Keratinocytes are Intrinsic Mitogens for Human Melanocytes'. The Kim. T.H. et al., "B-Catenin activates the growth factor endothelin-1 Journal of Biological Chemistry, vol. 267, No. 34, pp. 24.675-24680 in colon cancer cells'. Oncogene, vol. 24, pp. 597-604 (2005). (1992). Kimmel, C.B. et al., “Endothelin 1-mediated regulation of pharyn Innis, M.A. et al., eds., PCR Protocols: A Guide to Methods and geal bone development in zebrafish'. Development, vol. 130, pp. Applications, Academic Press, Inc., publ., pp. V-X (table of contents) 1339-1351 (2003). (1990). Kinugawa, T. et al., “Plasma Endothelin-1 Levels and Clinical Cor Inoue, A. et al., “The Human Preproendothelin-1 Gene'. The Journal relates in Patients with Chronic Heart Failure'. Journal of Cardiac of Biological Chemistry, vol. 264, No. 25, pp. 14954-14959 (1989). Failure, vol. 9, No. 4, pp. 318-324 (2003). Inoue, K. et al., “Further Evidence for Endothelin as an Important Kitamura, A. et al., “Endothelin-1 is a potent stimulator of O. 11 Mediator of Pancreatic and Intestinal Ischemia in Severe Acute integrin-mediated collagen matrix remodeling by rat mesangial Pancreatitis'. Pancreas, vol. 26, No. 3, pp. 218-223 (2003). cells'. Biochemical and Biophysical Research Communications, vol. Inouye, S. et al., "Up-promoter mutations in the Ipp gene of 299, pp. 555-561 (2002). Escherichia coli, Nucleic Acids Research, vol. 13, No. 9, pp. 3101 Knapp. M. et al., “The Haplotype-Relative-Risk (HRR) Method for 3 110 (1985). Analysis of Association in Nuclear Families'. Am. J. Hum. Genet. Itoh, Y. et al., "Cloning and sequence analysis of cDNA encoding the vol. 52, pp. 1085-1093 (1993). presursor of a human endothelium-derived vasoconstrictor peptide, Kocik, M. et al., “The effect of cyclosporin A on the level of big endothelin: identity of human and porcine endothelin', FEBS Let endothelin in patients one year after orthotopic heart transplanta ters, vol. 231. No. 2, pp. 440-444 (1988). tion'. Transpl. Int., vol. 17, pp. 65-70 (2004). US 7482,124 B2 Page 7

Köhler, G., “Immunoglobulin chain loss in hybridoma lines'. Proc. Liang, W. et al., “Resistance of the Human f3-Adrenergic Receptor to Natl. Acad. Sci. USA, vol. 77, No. 4, pp. 2197-2199 (1980). Agonist-induced Ubiquitination'. The Journal of Biological Chem Köhler, G. et al., “Continuous cultures of fused cells secreting anti istry, vol. 279, No. 45, pp. 46882-46889 (2004). body of predefined specificity”. Nature, vol. 256, pp. 495-497 (1975). Link, A.J., “Multidimensional peptide separations in proteomics'. Koller, B.H. et al., “Inactivating thef-microglobulin locus in mouse Trends in Biotechnology, vol. 20, No. 12 (Suppl.), pp.S8-S13 (2002). embryonic stem cells by homologous recombination'. Proc. Natl. Logan, J. et al., “Adenovirus tripartite leader sequence enhances Acad. Sci. USA, vol. 86, pp. 8932-8935 (1989). translation of mRNAs late after infection'. Proc. Natl. Acad. Sci. Kostelny, S.A. et al., “Formation of a Bispecific Antibody by the Use USA, vol. 81, pp. 3655-3659 (1984). of Leucine Zippers'. The Journal of Immumology, vol. 148, No. 5, Lohse, M.J. et al., “What is the Role of B-Adrenergic Signaling in pp. 1547-1553 (1992). Heart Failure?”, Circulation Research, vol. 93, pp. 896-906 (2003). Koutz, P. et al., “Structural Comparison of the Pichia pastoris Alco Lonberg, N. et al., “Antigen-specific human antibodies from mice hol Oxidase Genes”. Yeast, vol. 5, pp. 167-177 (1989). comprising four distinct genetic modifications'. Nature, vol. 368, pp. Kozák, M. et al., “Endothelin-1 gene polymorphism in the identifi 856-859 (1994). cation of patients at risk for malignant ventricular arrhythmia', Med. Lonberg, N. et al., “Human Antibodies from Transgenic Mice'. Sci. Monit., vol. 8, No. 5, pp. BR164-BR167 (2002). Intern, Rev. Immunol., vol. 13, pp. 65-93 (1995). Kozbor, D. et al., “A Human Hybrid Myeloma for Production of Long, J.C. et al., “An E-MAlgorithm and Testing Strategy for Mul Human Monoclonal Antibodies'. The Journal of Immunology, vol. tiple-Locus Haplotypes'. Am. J. Hum. Genet., vol. 56, pp. 799-810 133, No. 6, pp. 3001-3005 (1984). (1995). Kozbor, D. et al., “The production of monoclonal antibodies from Lopez-Berestein, G., “Treatment of Systemic Fungal Infections with human lymphocytes'. Immunology Today, vol. 4. No. 3, pp. 72-79 Liposomal-Amphotericin B. Liposomes in the Therapy of Infec (1983). tious Diseases and Cancer, Alan R. Liss, Inc., publ., Lopez-Berestein, Kriegler, M., Gene Transfer and Expression: A Laboratory Manual, G. et al., eds., pp. 317-327 (1989). Stockton Press, publ., pp. vii-x (table of contents) (1990). Lowy, I. et al., “Isolation of Transforming DNA: Cloning the Hamster Kumazaki, T. et al., “Aging- and Growth-Dependent Modulation of aprt Gene”. Cell, vol. 22, pp. 817-823 (1980). Endothelin-1 Gene Expression in Human Vascular Endothelial Lischer, T.F.. et al., “Endothelins and Endothelin Receptor Antago Cells'. Experimental Cell Research, vol. 211, pp. 6-11 (1994). nists: Therapeutic Considerations for a Novel Class of Cardiovascu Landschulz, W.H. et al., “The Leucine Zipper: A Hypothetical Struc lar Drugs'. Circulation, vol. 102, pp. 2434-2440 (2000). ture Common to a New Class of DNA Binding Proteins”. Science, Maack, C. et al., “Partial Agonist Activity of Bucindolol is Dependent vol. 240, pp. 1759-1764 (1988). on the Activation State of the Human B-Adrenergic Receptor'. Cir Lang, J.A. et al., “Endogenous Human Renin Expression and Pro culation, vol. 108, pp. 348-353 (2003). moter Activity in CALU-6, a Pulmonary Carcinoma Cell Line”, Maggi, M. et al., “Expression and Biological Effects of Endothelin-1 Hypertension, vol. 25, No. 4, Pt. 2, pp. 704-710 (1995). in Human Gonadotropin-Releasing Hormone-Secreting Neurons'. Langer, R., “New Methods of Drug Delivery”, Science, vol. 249, pp. The Journal of Clinical Endocrinology & Metabolism, vol. 85, No. 4. 1527-1533 (1990). pp. 1658-1665 (2000). Langer, R. et al., “Chemical and Physical Structure of Polymers as Malik, F. et al., “Polyethylene Glycol (PEG)-modified Granulocyte Carriers for Controlled Release of Bioactive Agents: A Review”. Macrophage Colony-stimulating Factor (GM-CSF) with Conserved JMS Rev. Macromol. Chem. Phys., vol. C23, No. 1, pp. 61-126 Biological Activity”. Experimental Hematology, vol. 20, pp. 1028 (1983). Langer, R.S. et al., eds., Medical Applications of Controlled Release, 1035 (1992). vol. I: Classes of Systems, CRC Press, Inc., publ. (1984) (table of Mangahas, C.R. et al., “Endothelin-1 Upregulates MCAM in contents). Melanocytes'. The Journal of Investigative Dermatology, vol. 123, Langer, R.S. et al., eds., Medical Applications of Controlled Release, pp. 1135-1139 (2004). vol. II: Applications and Evaluation, CRC Press, Inc., publ. (1984) Marinoni, E. et al., “Follicular fluid adrenomedullin concentrations (table of contents). in spontaneous and stimulated cycles: relationship to ovarian func Lavoie, C. et al., “ff-Adrenergic Receptor Heterodimerization tion and endothelin-1 and nitric oxide', Regulatory Peptides, vol. Regulates f-Adrenergic Receptor Internalization and ERK Signal 107, pp. 125-128 (2002). ing Efficacy”. The Journal of Biological Chemistry, vol. 277, No. 38. Marks, J.D. et al., “By-Passing Immunization: Building High Affin pp. 35402-35410 (2002). ity Human Antibodies by Chain Shuffling”. Bio/Technology, vol. 10, Lee-Kirsch, M.A. et al., “Distinct Renin Isoforms Generated by pp. 779-783 (1992). Tissue-Specific Transcription Initiation and Alternative Splicing'. Marx. N. et al., “PPARY Activation in Human Endothelial Cells Circulation Research, vol. 84, pp. 240-246 (1999). Increases Plasminogen Activator Inhibitor Type-1 Expression: Leff, T. et al., “The Antidiabetic PPARY Ligands: An Update on PPARY as a Potential Mediator in Vascular Disease'. Arteriorscler, Compounds in Development'. Curr. Med. Chem.—Immun., Endoc. Thromb. Vasc. Biol., vol. 19, pp. 546-551 (1999). & Metab. Agents, vol. 2, No. 1, pp. 33-47 (2002). Masharani, U. et al., “Mbol RFLP at the human renin (ren) gene Lennon, G. et al., “The I.M.A.G.E. Consortium: An Integrated locus'. Nucleic Acids Research, vol. 16, No. 5, p. 2357 (1988). Molecular Analysis of Genomes and Their Expression”. Genomics, Mason, D.A. et al., “A Gain-of-function Polymorphism in a G-pro vol. 33, pp. 151-152 (1996). tein Coupling Domain of the Human f3-Adrenergic Receptor. The Leon, O. et al., "Zinc fingers: DNA binding and protein-protein Journal of Biological Chemistry, vol. 274, No. 18, pp. 12670-12674 interactions'. Biol. Res., vol. 33, pp. 21-30 (2000). (1999). Levy, R.J. et al., “Inhibition of Calcification of Bioprosthetic Heart Massai, L. et al., “Prepro-endothelin-1 mRNA and its mature peptide Valves by Local Controlled-Release Diphosphonate”. Science, vol. inhuman appendix'. Am. J. Physiol. Gastrointest. Liver Physiol., vol. 228, pp. 190-192 (1985). 284, pp. G340-G348 (2003). Li, J.-M. et al., “Endothelin-1 Expression and Quantitative Analysis Matise, T.C., "Genome Scanning for Complex Disease Genes Using in Astrocytomas'. Ai Zheng (Chinese Journal of Cancer), vol. 21,No. the Transmission/Disequilibrium Test and Haplotype-based 10, pp. 1109-1111 (2002). Haplotype Relative Risk”. Genetic Epidemiology, vol. 12, pp. 641 Li, T. et al., "Case-control, haplotype relative risk and transmission 645 (1995). disequilibrium analysis of a dopamine D2 receptor functional pro Mawi, I.A. et al., “Role of the 3'-Untranslated Region of Human moter polymorphism in Schizophrenia'. Schizophrenia Research, Endothelin-1 in Vascular Endothelial Cells'. The Journal of Biologi vol. 32, pp. 87-92 (1998). cal Chemistry, vol. 279, No. 10, pp. 8655-8667 (2004). Liang, W. et al., “Differences in endosomal targeting of human f McColl, D.J. et al., “Structure-based design of an RNA-binding zinc and 3- adrenergic receptors following clathrin-mediated finger”, Proc. Natl. Acad. Sci. USA, vol. 96, pp. 9521-9526 (1999). endocytosis”, Journal of Cell Science, vol. 117. No. 5, pp. 723-734 McDonald, W.H. et al., "Shotgun proteomics and biomarker discov (2003). ery'. Disease Markers, vol. 18, pp. 99-105 (2002). US 7482,124 B2 Page 8

Medinger, M. et al., “Angiogenesis and the ET-1/ETA receptor Sys Nygren, H., “Conjugation of Horseradish Peroxidase to Fab Frag tem: Immunohistochemical expression analysis in bone metastases ments with Different Homobifunctional and Heterobifunctional from patients with different primary tumors'. Angiogenesis, vol. 6, Cross-Linking Reagents'. The Journal of Histochemistry and pp. 225-231 (2003). Cytochemistry, vol. 30, No. 5, pp. 407-412 (1982). Mehta, C.R. et al., “Exact Logistic Regression: Theory and O'Hare, K. et al., “Transformation of mouse fibroblasts to methotrex Examples', Statistics in Medicine, vol. 14, pp. 2143-2160 (1995). ate resistance by a recombinant plasmid expressing a prokaryotic Mercier, J.-F. et al., “Quantitative Assessment of B- and dihydrofolate reductase'. Proc. Natl. Acad. Sci. USA. vol. 78, No. 3, 3-Adrenergic Receptor Homo- and Heterodimerization by pp. 1527-1531 (1981). Bioluminescence Resonance Energy Transfer”. The Journal of Bio Oi, V.T. et al., "Chimeric Antibodies'. BioTechniques, vol. 4, No. 3, logical Chemistry, vol. 277, No. 47, pp. 44925-44931 (2002). pp. 214-221 (1986). Milstein, C. et al., "Hybrid hybridomas and their use in Ong, A.C.M. et al., “Expression and Cellular Localisation of Renal immunohistochemistry”. Nature, vol. 305, pp. 537-540 (1983). Endothelin-1 and Endothelin Receptor Subtypes in Autosomal Miyazaki, H. et al., “Structure of the human renin gene'. Proc. Natl. Dominant Polycystic Kidney Disease'. Nephron Experimental Acad. Sci. USA, vol. 81, pp. 5999-6003 (1984). Nephrology, vol. 93, pp. e80-e86 (2003). Morgan, R.A. et al., “Human Gene Therapy'. Ann. Rev. Biochem. Opgaard, O.S. et al., “Endocradial expression and functional charac vol. 62, pp. 191-217 (1993). terization of endothelin-1”, Molecular and Cellular Biochemistry, Morris, B.J., “New possibilities for intracellular renin and inactive vol. 224, pp. 151-158 (2001). renin now that the structure of the human renin gene has been eluci Order, S.E., Chapter 15: "Analysis, Results, and Future Prospective dated”. Clinical Science, vol. 71, pp. 345-355 (1986). of the Therapeutic Use of Radiolabeled Antibody in Cancer Morrison, S.L., “Transfectomas Provide Novel Chimeric Antibod Therapy”, Monoclonal Antibodies for Cancer Detection and ies”, Science, vol. 229, pp. 1202-1207 (1985). Therapy, Academic Press Inc., publ., Baldwin, R.W. et al., eds., pp. Mulligan, R.C., “The Basic Science of Gene Therapy”, Science, vol. 303-316 (1985). 260, pp. 926-932 (1993). Ott, J., “Statistical Properties of the Haplotype Relative Risk”, Mulligan, R.C. et al., “Selection for animal cells that express the Genetic Epidemiology, vol. 6, pp. 127-130 (1989). Escherichia coli gene coding for Exanthine-guanine Padlan, E.A., “A Possible Procedure for Reducing the Immunogenic phosphoribosyltransferase'. Proc. Natl. Acad. Sci. USA. vol. 78, No. ity of Antibody Variable Domains While Preserving Their Ligand 4, pp. 2072-2076 (1981). Binding Properties'. Molecular Immunology, vol. 28, No. 4/5, pp. Mullinax, R.L. et al., “Expression of a Heterodimeric Fab Antibody 489-498 (1991). Protein in One Cloning Step”, BioTechniques, vol. 12, No. 6, pp. Padmanabhan, N. et al., “Genetic basis of cardiovascular 864-869 (1992). disease—the renin-angiotensin-aldosterone system as a paradigm'. Mullis, K. et al., “Specific Enzymatic Amplification of DNA InVitro: Journal of the Renin-Angiotensin-Aldosterone System, vol. 1, No. 4. The Polymerase Chain Reaction'. Cold Spring Harbor Symposia on pp. 316-324 (2000). Quantitative Biology, vol. 51, pp. 263-273 (1986). Pain, D. et al., “Preparation of Protein A-Peroxidase Monoconjugate Munson, P.J. et al., "LIGAND: A Versatile Computerized Approach Using a Heterobiofunctional Reagent, and Its Use in Enzyme for Characterization of Ligand-Binding Systems'. Analytical Bio Immunoassays”, Journal of Immunological Methods, vol. 40, pp. chemistry, vol. 107, pp. 220-239 (1980). 219-230 (1981). Nagai, M. et al., “Role of Endothelin-1 Induced by Insulin in the Pak, Y. et al., “Direct Binding of the B1 Adrenergic Receptor to the Regulation of Vascular Cell Growth'. American Journal of Hyper Cyclic AMP-Dependent Guanine Nucleotide Exchange Factor tension, vol. 16, No. 3, pp. 223-228 (2003). Namiki, A. et al., “Endothelin-1 Concentrations in Pericardial Fluid CNrasGEF Leads to Ras Activation'. Molecular and Cellular Biol are More Elevated in Patients with Ischemic Heart Disease than in ogy, vol. 22, No. 22, pp. 7942-7952 (2002). Patients with Nonischemic Heart Disease”, Jpn. Heart J., vol. 44, No. Pang, J.X. et al., “Biomarker Discovery in Urine by Proteomics'. 5, pp. 633-644 (2003). Journal of Proteome Research, vol. 1, No. 2, pp. 161-169 (2002). Naramura, M. et al., “Mechanisms of cellular cytotoxicity mediated Perez, J.M. et al., “f-adrenergic receptor polymorphisms confer by a recombinant antibody-IL2 fusion protein against human mela differential function and predisposition to heart failure', Nature noma cells'. Immunology Letters, vol.39, pp. 91-99 (1994). Medicine, vol. 9, No. 10, pp. 1300-1305 (2003). Narayan, S. et al., “Endothelin-1 Synthesius and Secretion in Human Persic, L. et al., “An integrated vector system for the eukaryotic Retinal Pigment Epithelial Cells (ARPE-19): Differential Regulation expression of antibodies or their fragments after selection from phage by Cholinergics and TNF-O'. Invest. Ophthalmol. Vis. Sci., vol. 44. display libraries'. Gene, vol. 187, pp. 9-18 (1997). No. 11, pp. 485-4894 (2003). Pinto-SietSma, S.-J. et al., “Role of the Endothelin-1 Gene Locus for Nesto, R.W. et al., “Thiazolidinedione Use, Fluid Retention, and Renal Impairment in the General Nondiabetic Population”, Journal Congestive Heart Failure'. Ciculation, vol. 108, pp. 2941-2948 of the American Society of Nephrology, vol. 14, pp. 2596-2602 (2003). (2003). Neuberger, M., “Generating hih-avidity human Mabs in mice'. Podlowski, S. et al., “f-Adrenoceptor gene variations: a role in Nature Biotechnology, vol. 14, p. 826 (1996). idiopathic dilated cardiomyopathy?”. J. Mol. Med., vol. 78, pp. 87-93 Ng, T.M.H. et al., “Neurohormonal Activation does not explain (2000). Elevated Tissue Factor Expression in Heart Failure'. Thromb. Pomerantz, J.L. et al., “Structure-Based Design of a Dimeric Zinc Haemost., vol. 87, pp. 176-177 (2002). Finger Protein', Biochemistry, vol. 37, No. 4, pp. 965-970 (1998). Nguyen, G. et al., “Pivotal role of the renin?prorenin receptor in Pontiroli, A.E. et al., “Body weight and glucose metabolism have a angiotensin II production and cellular responses to renin'. The Jour different effect on circulating levels of ICAM-1, E-selectin, and nal of Clinical Investigation, vol. 109, No. 11, pp. 1417-1427 (2002). endothelin-1 in humans'. European Journal of Endocrinology, vol. Nicherson, D.A. et al., “PolyPhred: automating the detection and 150, pp. 195-200 (2004). genotyping of single nucleotide Substitutions using fluorescence Presta, L.G., “Antibody engineering”. Current Opinion in Structural based resequencing. Nucleic Acids Research, vol. 25, No. 14, pp. Biology, vol. 2, pp. 593-596 (1992). 2745-2751 (1997). Proudfoot, N.J., “Transcriptional interference and termination Nicolaidou, P. et al., “Urinary excretion of endothelin-1 in children between duplicated O-globin gene constructs suggests a novel with absorptive idiopathic hypercalciuria'. Pediatr. Nephrol. vol. 18, mechanism for gene regulation”. Nature, vol. 322, pp. 562-565 pp. 1157-1160 (2003). (1986). Nielsen, P.E. et al., “Sequence-Selective Recognition of DNA by Qin, H. et al., “Reassignment of Human Renin Gene to Chromosome Strand Displacement with a Thymine-Substitute Polyamide'. Sci 1q32 in Studies of a (1:4)(q42;p16) Translocation'. Hum. Hered. ence, vol. 254, pp. 1497-1500 (1991). vol.43, pp. 261-264 (1993). Nisonoff, A., “Idiotypes: Concepts and Applications'. The Journal of Quehenberger, P. et al., “Leptin Induces Endothelin-1 in Endothelial Immunology, vol. 147, No. 8, pp. 2429-2438 (1991). Cells in Vitro'. Circulation Research, vol. 90, pp. 711-718 (2002). US 7482,124 B2 Page 9

Ranade, K. et al., “A Polymorphism in the B1 Adrenergic Receptor is Seifter, S. et al., “Analysis for Protein Modifications and Nonprotein Associated with Resting Heart Rate'. Am. J. Hum. Genet., vol. 70, Confactors'. Methods in Enzymology, vol. 182, pp. 626-646 (1990). pp. 935-942 (2002). Shephard, P. et al., “Dissecting the roles of endothelin, TGF-B and Ranade, K. et al., "High-Throughput Genotyping with Single GM-CSF on myofibroblast differentiation by keratinocytes'. Nucleotide Polymorphisms”. Genome Research, vol. 11, pp. 1262 Thromb. Haemost., vol. 92, pp. 262-274 (2004). 1268 (2001). Shiina, T. et al., “Interaction with B-Arrestin Determines the Differ Rattan, S.I.S. et al., “Protein Synthesis, Posttranslational Modifica ence in Internalization Behavior between 3-Adrenergic Receptors'. tions, and Aging”. Annals New York Academy of Sciences, vol. 663, The Journal of Biological Chemistry, vol. 275, No. 37, pp. 29082 pp. 48-62 (1992). 29090 (2000). Rebuffat, P. et al., “Signaling pathways involved in the A and B Shine, J. et al., “Structure of the Human Renin Gene'. Transactions of receptor-mediated cortisol secretagogue effect of endothelins in the the Association of American Physicians, vol.97, Waverly Press, Inc., human adrenal cortex', International Journal of Molecular Medicine, publ., pp. 63-69 (1984). vol. 7, pp. 301-305 (2001). Shioji, K. et al., “Association between Hypertension and the O-Ad Ricote, M. et al., “The peroxisome proliferator-activated receptor-Y is ducin, Bl-Adrenoreceptor, and G-Protein B3 Subunit Genes in the a Negative regulator of macrophage activation'. Nature, vol. 391, pp. Japanese Population; the Suita Study”. Hypertens. Res., vol. 27. No. 79-82 (1998). 1, pp. 31-37 (2004). Riechmann, L. et al., “Reshaping human antibodies for therapy'. Shiu, Y-T. et al., "Sickle erythrocytes increase prostacyclin and Nature, vol. 332, pp. 323-327 (1988). endothelin-1 production by cultured human endothelial cells under Roguska, M.A. et al., “Humanization of murine monoclonal antibod flow conditions'. European Journal of Haematology, vol. 68, pp. ies through variable domain resurfacing'. Proc. Natl. Acad. Sci. 163-169 (2002). USA, vol. 91, pp. 969-973 (1994). Shi-wen, X. et al., “Endothelin-1 Induces Expression of Matrix Roy-Beaudry, M. et al., “Endothelin 1 Promotes Osteoarthritic Car associated Genes in Lung Fibroblasts through MEK/ERK'. The tilage Degradation Via Matrix Metalloprotease 1 and Matrix Metal Journal of Biological Chemistry, vol. 279, No. 22, pp. 23098-23103 loprotease 13 Induction'. Arthritis & Rheumatism, vol. 48, No. 10, (2004). pp. 2855-2864 (2003). Shi-Wen, X. et al., “Endothelin-1 Promotes Myofibroblast Induction Rozen, S. et al., Chapter 20: “Primer3 on the WWW for General through the ETA Receptor via a rac/Phosphoinositide 3-Kinase/Akt Users and for Biologist Programmers'. Methods in Molecular Biol dependent Pathway and is Essential for the Enhanced Contractile ogy, vol. 132: Bioinformatics Methods and Protocols, Humana Press Phenotype of Fibrotic Fibroblasts'. Molecular Biology of the Cell, Inc., publ., Misener, S. et al., eds., pp. 365-386 (2000). vol. 15, pp. 2707-2719 (2004). Rither, U. et al., “Easy identification of cDNA clones'. The EMBO Shu, L. et al., “Secretion of a single-gene-encoded immunoglobulin Journal, vol. 2, No. 10, pp. 1791-1794 (1983). from myeloma cells'. Proc. Natl. Acad. Sci. USA. vol. 90, pp. 7995 Ryan, M.J. et al., “Endothelin-1 increase calcium and attenuates 7999 (1993). renin gene expression in AS4.1 cells'. Am. J. Physiol. Heart Circ. Sielecki, A.R. et al., “Structure of Recombinant Human Renin, a Physiol, vol. 283, pp. H2458-H2465 (2002). Target for Cardiovascular-Active Drugs, at 2.5 A Resolution”, Sci Saiki, R.K. et al., “Primer-Directed Enzymatic Amplification of DNA ence, vol. 243, pp. 1346-1351 (1989). with a Thermostable DNA Polymerase'. Science, vol. 239, pp. 487 Skerra, A. et al., “Assembly of a Functional Immunoglobulin F 491 (1988). Fragment in Escherichia coli'. Science, vol. 240, pp. 1038-1041 Sambrook, J. et al., Molecular Cloning: A Laboratory Manual, Sec (1988). ond Edition, Books 1, 2 and 3, Cold Spring Harbor Laboratory Press, Smolen, V.F. et al., eds., Controlled Drug Bioavailability, vol. 1: Drug publ., pp. xi-XXXviii (table of contents) (1989). Product Design and Performance, John Wiley & Sons, Inc., publ., p. Santerre, R.F. et al., “Expression of prokaryotic genes for xiii (table of contents) (1984). hygromycin B and G418 resistance as dominant-selection markers in Sofowora, .G.G. et al., “A common f31-adrenergic receptor mouse L cells'. Gene, vol. 30, pp. 147-156 (1984). polymorphism (Arg389Gly) affects blood pressure response to Satoh, H. et al., “Thiazolidinediones Suppress Endothelin-1 Secre B-blockade'. Clinical Pharmacology & Therapeutics, vol. 73, No. 4. tion from Bovine Vascular Endothelial Cells: A New Possible Role of pp. 366-371 (2003). PPARY on Vacular Endothelial Function'. Biochemical and Bio Soubrier, F. et al., “Molecular cloning and nucleotides sequence of a physical Research Communications, vol. 254, No. 3, pp. 757-763 human renin cDNA fragment'. Nucleic Acids Research, vol. 11, No. (1999). 20, pp. 7181-7190 (1983). Saudek, C.D. et al., “A Preliminary Trial of the Programmable Soubrier, F. et al., "Segmental homology between the promoter Implantable Medication System for Insulin Delivery'. The New region of the human renin gene and the mouse ren I and ren2 pro England Journal of Medicine, vol. 321, No. 9, pp. 574-579 (1989). moter regions'. Gene, vol. 41, pp. 85-92 (1986). Saunders, R. et al., “Ouabain stimulates endothelin release and Spinella, F. et al., “Endothelin-1 Decreases Gap Junctional Intercel expression in human endothelial cells without inhibiting the Sodium lular Communication by Inducing Phosphorylation of Connexin 43 pump”. Eur, J. Biochem. vol. 271, pp. 1054-1062 (2004). in Human Ovarian Carcinoma Cells'. The Journal of Biological Sawai, H. et al., “Direct Production of the Fab Fragment Derived Chemistry, vol. 278, No. 42, pp. 41294-41301 (2003). from the Sperm Immobilizing Antibody. Using Polymerase Chain Spinella, F. et al., “Endothelin-1-induced Prostaglandin E2-EP2, EP4 Reaction and cDNA Expression Vectors'. American Journal of Signaling Regulates Vascular Endothelial Growth Factor Production Reproductive Immunology, vol. 34, pp. 26-34 (1995). and Ovarian Carcinoma Cell Invasion'. The Journal of Biological Schiffrin, E.L., “Role of Endothelin-1 in Hypertension and Vascular Chemistry, vol. 279, No. 45, pp. 46700-46705 (2004). Disease'. American Journal of Hypertension, vol. 14, No. 6, Pt. 2, pp. Stachon, A. et al., “The Secretion of Endothelin-1 by Microvascular 83S-89S (2001). Endothelial Cells from Human Benign Prostatic Hyperplasia is Schiffrin, E.L. et al., “Peroxisome Proliferator-Activated Receptors: Inhibited by Vascular Endothelial Growth Factor'. Growth Factors, Vascular and Cardiac Effects in Hypertension'. Hypertension, vol. vol. 22, No. 4, pp. 281-289 (2004). 42, Pt. 2, pp. 664-668 (2003). Staels, B. et al., “Activation of human aortic Smooth-muscle cells is Scopes, R.K., Protein Purification: Principles and Practice, Second inhibited by PPARO but not by PPARy activators', Nature, vol. 393, Edition, Springer-Verlag New York Inc., publ., pp. xiii-xv (table of pp. 790-793 (1998). contents) (1987). Stannard, C. et al., “Rapid Changes in the Phosphoproteome Show Sefton, M.V., “Implantable Pumps”. CRC Critical Reviews in Bio Diverse Cellular Responses Following Stimulation of Human Lung medical Engineering, vol. 14, No. 3, pp. 201-240 (1987). Fibroblasts with Endothelin-1”, Biochemistry, vol. 42, No. 47, pp. Segal, D.J. et al., “Toward controlling gene expression at will: Selec 13919-13928 (2003). tion and design of Zinc finger domains recognizing each of the Stein, M.B. et al., “A Polymorphism of the B-Adrenergic Receptor is 5'-GNN-3"DNA target sequences'. Proc. Natl. Acad. Sci. USA. vol. Associated with Low Extraversion'. Biol. Psychiatry, vol. 56, pp. 96, pp. 2758-2763 (1999). 217-224 (2004). US 7482,124 B2 Page 10

Stiles, G.L. et al., “The Cardiac B-Adrenergic Receptor'. The Journal Infectious Diseases and Cancer, Alan R. Liss, Inc., publ., Lopez of Biological Chemistry, vol. 258, No. 13, pp. 8443-8449 (1983). Berestein, G. et al., eds., pp. 353–365 (1989). Studnicka, G.M. et al., “Human-engineered monoclonal antibodies Treiber, F.A. et al., “Endothelin-1 Gene LYS198ASN Polymorphism retain full specific binding activity by preserving non-CDR and Blood Pressure Reactivity'. Hypertension, vol. 42, pp. 494-499 complementarity-modulating residues'. Protein Engineering, vol.7. (2003). No. 6, pp. 805-814 (1994). Trends in Biotechnology, vol. 11, No. 5, pp. 155-215 (1993). Sugawara, A. et al., “Transcriptional Suppression of Type 1 Tschopp, J.F. et al., “Expression of the lacz gene from two methanol Angiotensin II Receptor Gene Expression by Peroxisome Prolifera regulated promoters in Pichia pastoris’. Nucleic Acids Research, tor-Activated Receptor-Y in Vascular Smooth Muscle Cells”. Endo vol. 15, No. 9, pp. 3859-3876 (1987). crinology, vol. 142, No. 7, pp. 3125-3134 (2001). Tutt, A. et al., “Trispecific F(ab'). Derivatives that Use Cooperative Suresh, M.R. et al., “Bispecific Monoclonal Antibodies from Hybrid Signaling via the TCR/CD3 Complex and CD2 to Activate and Redi Hybridomas'. Methods in Enzymology, vol. 121, pp. 210-228 rect Resting Cytotoxic T Cells'. The Journal of Immunology, vol. (1986). 147, No. 1, pp. 60-69 (1991). Sutcliffe, J.G. et al., “Antibodies that React with Predetermined Sites Van Heeke, G. et al., “Expression of Human Asparagine Synthetase on Proteins”. Science, vol. 219, pp. 660-666 (1983). in Escherichia coli. The Journal of Biological Chemistry, vol. 264. Suzuki, F. et al., “Human Prorenin Has 'Gate and Handle' Regions for No. 10, pp. 5503-5509 (1989). Its Non-proteolytic Activation'. The Journal of Biological Chemis Varagic, J. et al., “Local Cardiac Renin-Angiotensin System: Hyper try, vol. 278, No. 25, pp. 22217-22222 (2003). tension and Cardiac Failure'. J. Mol. Cell Cardiol., vol. 34, pp. Suzuki, M. et al., “Single-nucleotide polymorphisms in the 17B 1435-1442 (2002). hydroxysteroid dehydrogenase genes might predict the risk of side Vasku, “The Double Heterozygote of Two Endothelin-1 Gene effects of estramustine phosphate Sodium in prostate cancer Polymorphisms (G8002A and -3A/-4A) is Related to Big Endothelin patients'. International Journal of Urology, vol. 12, pp. 166-172 Levels in Chronic Heart Failure'. Experimental and Molecular (2005). Pathology, vol. 73, pp. 230-233 (2002). Sventek. P. et al., “Vascular and cardiac overexpression of endothelin-1 gene in one-kidney, one clip Goldblatt hypertensive rats Verhoeyen, M. et al., “Reshaping Human Antibodies: Grafting an but only in the late phase of two-kidney one clip Goldblatt hyperten Antilysozyme Activity”. Science, vol. 239, pp. 1534-1536 (1988). sion”, Journal of Hypertension, vol. 14, No. 1, pp. 57-64 (1996). Vié, H. et al. “Human fusion proteins between interleukin 2 and IgM Szybalska, E.H. et al., “Genetics of Human Cell Lines, IV. DNA heavy chain are cytotoxic for cells expressing the interleukin 2 recep Mediated Heritable Transformation of a Biochemical Trait”. Proc. tor', Proc. Natl. Acad. Sci. USA, vol. 89, pp. 11337-11341 (1992). Natl. Acad. Sci., vol. 48, pp. 2026-2034 (1962). Wahl, R.L. et al., “Improved Radioimaging and Tumor Localization Takashima, H. et al., “Hydrophobic Core around Tyrosine for Human with Monoclonal F(ab')”. The Journal of Nuclear Medicine, vol. 24. Endothelin-1 Investigated by Photochemically Induced Dynamic No. 4, pp. 316-325 (1983). Nuclear Polarization Nuclear Magnetic Resonance and Matrix-As Wang, B.S. et al., “Dimerization of zinc fingers mediated by peptides sisted Laser Desorption Ionization Time-of-Flight Mass Spectrom evolved in vitro from random sequences”. Proc. Natl. Acad. Sci. etry”, Biochemistry, vol.43, No. 44, pp. 13932-13936 (2004). USA, vol. 96, pp. 9568-9573 (1999). Takeda, K. et al., “Peroxisome Proliferator-Activated Receptor Y Wang, G.-X. et al., “Shear-Induced Changes in Endothelin-1 Secre Activators Downregulate Angiotensin II Type 1 Receptor in Vascular tion of Microvascular Endothelial Cells', Microvascular Research, Smooth Muscle Cells”. Circulation, vol. 102, pp. 1834-1839 (2000). vol. 63, pp. 209-217 (2002). Tamura, K. et al., “Recent Advances in the Study of Renin and Wenzel-Seifert, K. et al., “Similarities and differences in the coupling Angiotensinogen Genes: From Molecules to the Whole Body”. of human f3- and 32-adrenoceptors to G, splice variants'. Bio Hypertens. Res., vol. 18, No. 1, pp. 7-18 (1995). chemical Parmacology, vol. 64, pp. 9-20 (2002). Tanaka, C. et al., “Evaluation of the Lys198ASn and -134delA Wigler, M. et al., “Transfer of Purified Herpes Virus Thymidine Genetic Polymorphisms of the Endothelin-1 Gene'. Hypertens. Res., Kinase Gene to Cultured Mouse Cells”. Cell, vol. 11, pp. 223-232 vol. 27, No. 5, pp. 367-371 (2004). (1977). Templeton, A.R. et al., “Recombinational and Mutational Hotspots Wilson, I.A. et al., “The Structure of an Antigenic Determinant in a within the Human Lipoprotein Lipase Gene'. Am. J. Hum. Genet. Protein', Cell, vol. 37, pp. 767-778 (1984). vol. 66, pp. 69-83 (2000). Wolfe, S.A. et al., “Analysis of Zinc Fingers Optimized via Phage Terwilliger, J.D. et al., “A Haplotype-Based “Haplotype Relative Display: Evaluating the Utility of a Recognition Code'. J. Mol. Biol. Risk Approach to Detecting Allelic Associations'. Hum. Hered., vol. vol. 285, pp. 1917-1934 (1999). 42, pp. 337-346 (1992). Wolfe, S.A. et al., “Combining structure-based design with phage Thorpe, P.E., "Antibody Carriers of Cytotoxic Agents in Cancer display to create new Cys-His Zinc finger dimers'. Structure, vol. 8, Therapy: A Review”, Monoclonal Antibodies 84: Biological and Clinical Applications, Editrice Kurtis S.r.l., publ., Pinchera, A. et al., No. 7, pp. 739-750 (2000). eds., pp. 475-506 (1985). Woods, M. et al., “Endothelin-1 is Induced by Cytokines in Human Thorpe, P.E. et al., “The Preparation and Cytotoxic Properties of Vascular Smooth Muscle Cells: Evidence for Intracellular Antibody-Toxin Conjugates'. Immunological Rev., vol. 62, pp. 119 Endothelin-Converting Enzyme'. Molecular Pharmacology, vol. 55. 158 (1982). pp. 902-909 (1999). Tilly, N. et al., “Endothelin-1 Levels in Patients with Disorders of the Wu, G.Y. et al., “Delivery systems for genetherapy'. Biotherapy, vol. Thyroid Gland”. Exp. Clin. Endocrinol. Diabetes, vol. 111, pp. 80-84 3, pp. 87-95 (1991). (2003). Wu, G.Y. et al., “Receptor-mediated in Vitro Gene Transformation by Tiret, L. et al., “The Lys198ASn Polymorphism in the Endothelin-1 a Soluble DNA Carrier System'. The Journal of Biological Chemis Gene is Associated with Blood Pressure in Overweight People'. try, vol. 262, No. 10, pp. 4429-4432 (1987). Hypertension, vol. 33, pp. 1169-1174 (1999). Wülfing, C. et al., “Expression of endothelin-1 and endothelin-A Tolstoshev, P., “Gene Therapy, Concepts, Current Trials and Future and -B receptors in invasive bladder cancer. Oncology Reports, vol. Directions'. Annu. Rev. Pharmacol. Toxicol., vol. 32, pp. 573-596 13, pp. 223-228 (2005). (1993). Wülfing, P. et al., “Endothelin-1-. Endothelin-A-, and Endothelin-B- Traunecker, A. et al., "Bispecific single chain molecules (Janusins) Receptor Expression is Correlated with Vascular Endothelial Growth target cytotoxic lymphocytes on HIV infected cells'. The EMBO Factor Expression and Angiogenesis in Breast Cancer. Clinical Can Journal, vol. 10, No. 12, pp. 3655-3659 (1991). cer Research, vol. 10, pp. 2393-2400 (2004). Traunecker, A. et al., “Soluble CD4 molecules neutralize human Wülfing, P. et al., “Expression of Endothelin-1, Endothelin-A, and immunodeficiency virus type 1", Nature, vol. 331, pp. 84-86 (1988). Endothelin-B Receptor in Human Breast Cancer and Correlation Treat, J. et al., “Liposome Encapsulated Doxorubicin: Preliminary with Long-Term Follow-Up'. Clinical Cancer Research, vol. 9, pp. Results of Phase I and Phase II Trials”. Liposomes in the Therapy of 4125-4131 (2003). US 7482,124 B2 Page 11

Wunderlich, K. et al., “Vasospastic persons exhibit differential Allogeneic Islet Transplantation'. The Journal of Immunology, vol. expression of ABC-transport proteins”. Molecular Vision, vol. 9, pp. 154, pp. 5590-5600 (1995). 756-761 (2003). Zijlstra, M. et al., “Germ-line transmission of a disrupted Xu, J. et al., “f-Adrenergic Receptor Association with the Synaptic 3-microglobulin gene produced by homologous recombination in Scaffolding Protein Membrane-associated Guanylate Kinase embryonic stem cells', Nature, vol. 342, pp. 435-438 (1989). Inverted-2 (MAGI-2)”. The Journal of Biological Chemistry, vol. Zill, P. et al., “Beta-1-Adrenergic Receptor Gene in Major Depres 276, No. 44, pp. 41310-14317 (2001). sion: Influence on Antidepressant Treatment Response'. American Xu, J. et al., “Heterodimerization of OA- and fl-Adrenergic Recep Journal of Medical Genetics, Part B (Neuropsychiatric Genetics), tors'. The Journal of Biological Chemistry, vol. 278, No. 12, pp. vol. 120B, pp. 85-89 (2003). 10770-10777 (2003). Zola, H., Monoclonal Antibodies: A Manual of Techniques, CRC Yang-Feng, T.L. et al., “Chromosomal organization of adrenergic Press, Inc., publ., pp. 147-158 (1987). receptor genes'. Proc. Natl. Acad. Sci. USA. vol. 87, pp. 1516-1520 Zurfluh, L.L. et al., “Auxin-induced changes in the patterns of protein (1990). synthesis in soybean hypocotyl”. Proc. Natl. Acad. Sci. USA. vol. 77. Yin, J.J. et al., “A causal role for endothelin-1 in the pathogenesis of No. 1, pp. 357-361 (1980). osteoblastic bone metastases'. Proc. Natl. Acad. Sci., vol. 100, No. NCBI Entrez. Accession No. AL5921 14 (gi:20386829), Clark, S., 19, pp. 10954-10959 (2003). Jan. 16, 2007. Yokoyama, Y. et al., “Endothelin Receptor Remodeling Induces the NCBI Entrez. Accession No. AL592146 (gi: 16973122), Tracey, A., Portal Venous Hyper-Responsive to Endothelin-1 Following Jan. 18, 2007. Endotoxin Pretreatment'. Shock, vol. 17. No. 1, pp. 36-40 (2002). NCBI Entrez. Accession No. NC 000001 (gi:42406218), Interna Zhang, H. et al., "Collecting duct-specific deletion of peroxisome tional Human Genome Sequencing Consortium, Feb. 20, 2004. proliferator-activated receptor Y blocks thiazolidinedione-induced NCBI Entrez. Accession No. NM 00 1955 (gi:21359861), fluid retention'. Proc. Natl. Acad. Sci., vol. 102, No. 26, pp. 9406 Tamilselvan, S. et al., Apr. 15, 2007. 941 1 (2005). NCBI Entrez. Accession No. NP 000675 (gi:4557265), Hicks, S.W. Zhang, L. et al., “Expression of local renin and angiotensinogen et al., Apr. 15, 2007. mRNA in cirrhotic portal hypertensive patient'. World J. NCBI Entrez. Accession No. NP 001946 (gi:21359862), Gastroenterol, vol. 9, No. 7, pp. 1584-1588 (2003). Tamilselvan, S. et al., Apr. 15, 2007. Zhao, R.-Z. et al., “TNF-O induces interleukin-8 and endothelin-1 NCBI Single Nucleotide Polymorphism No. rs2368564, Sep. 20, expression in human endothelial cells with different redox path 2001. ways'. Biochemical and Biophysical Research Communications, NCBI Single Nucleotide Polymorphism No. rs6676458, Jun. 27. vol. 327, pp.985-992 (2005). 2003. Zheng, X.X. et al., “Administration of Noncytolytic IL-10/Fc in NCBI Single Nucleotide Polymorphism No. rs11571092, Jan. 16, Murine Models of Lipopolysaccharide-Induced Septic Shock and 2004. U.S. Patent Jan. 27, 2009 Sheet 1 of 112 US 7482,124 B2

FIG. 1A

GGTCTTTGTAAAATAATAATTATTCATTTCACAAAAGTGATAATTAAAAGACTTTAATAG 60

6. CAATACAGAAAGTTACATGAATATAAAGACTTAACCTTTcTAAAGCTCAGTTTTCCTAAG 120

2. TAATCAAAAãcCTGATAAAGATAACAAGAATGAGGAATTATCTTGAGAAAATGTAAAATC 18O

181 TTTCCTTTTáttr TGAGACAGGGTCrcáCTCTGTCAtcCAGGCTAAAGTGCAGTGGCA 24 O

241 CAATCATAccTCACTACAGcCTTGAACTccTGGACTCAAGTGATCCT.cccGCCTCAGCCf 3OO

30 cCCCAGTAGöTAAGACTACAGGCACGCAccACCACACCCAGCTAATTTTTTTCAGAGATG 360

36 GGGTCTTGciaTATTGcccigGCTGGTCTigAACGAGCticAAGTGAGcGTGAGCCTcci 42O

42. ACCTCATcciccCAAAGCACTAGGATTACAGGCATGAGcéACTGTTTCC(AGCCTAAAAt 480

A 81 AATTGTTTCiTAGGCCAGCiACCAAAAACGCAAAGAAAAACTTTCTGTAGTGTGATTGct 54 O

54. TCTTCTTATGGGAAGccCATTAGATAAccTGTAAGTCAiiACCTGATGAÁAACAATACT 6OO

6O1 GAATGTAATcAGACACAGA?AGACTGTTCAAGGCTATGAGTAGCTGAGTcCAAGCTCGTA 660

661 TCACTTGccACACAACAGccAATAAGTCTAGAGACAAGGiATTGTGGCAAGGAAAGCTAc 72O

72 CTTATTCAGAGAACCAGAAAACCAAGAAGATGGTGGACCACCATCATAAAGAACCATCTG 78O

781 AAGTCAGCAiGAAcGTTAGGCTCTTCTTTATGTTAAGGGAAGGGGAAGAAGAAGGGGATT 84 O

84. GGGATCAAGAGGTGACTGAiGACCACAGACACCTGGGTGcCAGCAAGGGTCTGAGGACGT 9 OO

901 TGTAAAACTicTTTTTTCTAGGTCAGGTCACAATGTTcci ATACATCTTi AACATAACAt 96.O

961. TGTTATTTgicTGTATAtticCTTATCTccTTGGGGGTTAGTTTGGGGAAAGGAACTGT 1020

1021 AccATTTTT iTTAAAGTTGäACTGCAAGCiAAACTCCTATAATTAGCTGGTCTATGTACA 1080

1081 GAGCTAAGCAGAAGCTTTTAGCCTAAAGGATAATACCCCTGGGGGTCAGAGGCAAAATGG 1140 U.S. Patent Jan. 27, 2009 Sheet 2 of 112 US 7482,124 B2

F.G. B

141 AGTCAGTCAiGCTAAGTCTccCTCCACTcfcTTTCTTTTTGAGATGGAATTTCACTCTf 1200

12O1 AtTGCCCAGGCCGGAGTGCAGTGGCATGAfCTCAGCTCAcTGCAAcCTccGCCTCCTGGG 1260

1261 TTCAAGCAATTCTCTTGcci CAGCCTCCTGAGTAGCTGAGATTACAGGTGTCCATCACCA 32O

1321 CAccCAGCTÁATTTTTGTAGTTTAGTGGAGATGGGGTTTcACCATTGTTéGTCAGGCTGG 38O

138 TCTGGAACTcCTGAccTCAGGTGATCTAccCACCTTGGccTCCCAAAGTcCTGGGACAGG 1440

441 TGTGAGCCAcCATGCCTGGccCCTCTACTct TATAATTAAACCAGCTGTfGCTTTTCCTG 1500

15O1 CCAAGAAAccAGTCATGAAGATTCACCCAFGTTCTAGATGGGAAAACTGGGCTGTAGCCF 1560

15 61 GGGAGAGGccAGTCAGGGACAAAGCCAAAGTTAATATAGAGAATGGAGCFTCCAGGGTAf 1620

1621 AGGGGTTGGGTCTGGGCTAGGGAGCTGGAAACCTAGGTTi TACGCTTGTccCAGTTTTGA 168O

681 TGTTAGccCTGAGCAGTGciGTTTCTCATcAGCCTCTGccTGCTCCAGGGGTCACAGGGc 1740

1741 CAAGCCAGAT AGAGGGCTGCTAGcGTCAcigGACACAAGATTGCTTTcccACAGCTGTcc 1800

180 TTCCTCCAGcccCTCTGCT.cccCATCCGGAAACCTGGGTAccCTTCACccACCTAGCTct 1860

1861 GTCCCGCAGiGAGATTTATiGCTGACTGccCTGCCATCTAccCCAGGGTAATAAATCAGG 1920

1921. GCAGAGCAGAATTGCAATCAccCCATGCATGGAGTGTATAAAAGGGGAAGGGCTAAGGGA 1980

1981 GCCACAGAAccTCAGTGGAfCTCAGAGAGAGCCCCAGAcigAGGGAAGCATGGATGGATG 2O4. O

2O41 GAGAAGGATGCCTCGCTGGGACTGCTGciGCTGCTCTGGGGCTCCTGTACCTTTGGTcf 2100

21 Ol CCCGACAGACACCACCAcci TTAAACGGTAATTGGTAAcfcAGGCAGAGAAGGGGTGGGA 2160

21 61 GGGGTGCAGGGTTccCAccitcCCAACAccCTGGCTTTTcCACATGcGGiGTCATTCAGi 2220

222 CCTTACGATCAGCTGGACAGGGAAGTATGGACCTGTTCAGAGAGGTCAAGTGACTTGCCC 228O U.S. Patent Jan. 27, 2009 Sheet 3 of 112 US 7482,124 B2

F.G. 1C

2281 AATAAATGACACTAGTAGTcAGGTCTAGAGCTGTGACTitTGCTTCCTGccCAGAGCAc 234. O

234 CATGCTAAct AAGCACTGTAGAGAACTCAGAAGTATTAGGACATGcccci TGCACTTGAG 24 OO

24O1 GAGCTCACAGCCTGAATAti AAGAAGGGCATGGGTGGTTGGGCGCGGTGGCTCCTGCCTG 24 60

246 TAATCCCAGcACTTTGGGAGGCTGAGACGGATCACTTGAGGTCAGGAGTi TGAGACCAGc 252O

252 CTGGCCAACATGGGGAAAccCCATCTCTACTAAAAATACAAAAATTAGccGGGCATGGTG 2580

2581 GCAGGCACTTGTAATCCCCAGCTACTCGGGAAGCTGAGG?AGGAGAATCGTTTGAGCCCG 2640

264. GAAGGTGGAGATTGCTGAGcCAAGATCGT6CCACTGCACfCCAGCCTGAGTGACAGAACA 27 OO

27 O. AGACTCCATcTCAAAAAAAAAAAGACGGGGGTCGGGGCATGGGTACAGiTAACTGTAcc 2760

2761 AGGGAAGCAGCTTGATATCGTGGTTAAATGCAAGGCTTATAGAGTTAGATTGCCTTCATf 282O

2821 TAAATTTTGcTTCACTAGCAGAACAAACTAGGTCTGGAATCATGGGCAAGTTATTTAAcc 288O

2881 TCTCCAAGTcTCAGTTTArcATTTTAAACAGGTATGATAATAACAGTAccTACTTGATGG 294 O

2941 GGCTGCTTTGGGGATTTTAGGAGATAAGGCATAGAAAGCTGGGCACGTTGTAAGAGCCCA 3OOO

3001 GCTACTGTTAGTACTACAGGATAGATTCTTACAAATATCAAAAGCAAGGTTTGGCCGGGA 3O 60

3O 61 GCAGTGGCT?ACGCCTATAATCCCAACACTTTGGGAGGccGAGGGGGGCAGATCACCCGA 31.2O

3.21 GGTCAGGAGFTCAAGACCAGCCTGACCAAcATGGAGAAAccCTGTCTCTACTAAAAATAC 318O

3.81 AAAATTAGccGGGCGTGGTGGCACATGCCFGTAATTCCAGCTACTTGGGAGGCTGAGGCA 3240

3241 GGAGAATCGöTTGAACCTGcGAGCCTGAGGTTGCAGTGAGCCGACATAccGCCATTGCAc 33OO

33O. TCCAGCCTGGTCAACAAGAGCAAAACTCAGTCTAAAAAAAAAAAAGAAAGAAAAAAACAA 3360

3361 GGCTTTAGGTAGCCCACAATTAGAAGGAGAAAACCTTAGCATCCCCTAGGTGCCAGGCCT 342O U.S. Patent Jan. 27, 2009 Sheet 4 of 112 US 7482,124 B2

FIG. 1D

3421 TGTGGGAACAAGTGATTCAFTAAGACTGTAGAAGGAAGciGGGCACGCGGCTCATGCTTG 3480

348 TAATTCCAGCACTTTGAGAGGCTGAGGTGGGCAGATCGCTGAGCTCACGAGTTCAAGAc 35 40

3541 CAGCCTAGG?AACATGGTGAAACCTTGTCiGTACAAATACAAAAATTAGöTAGGTGTGGi 3600

36O1 GGTGCAAATcTGTAGTCCCAGCTACTCGGGAGGCTGAGGiGGGAGCATCACTTCAGCCT6 3660

366 GGAGGTGGAGGCTGCAGTGAGCAGAGACTGACCCACTGTGCTCTAGCCTGGGTGATAGAG 3.720

3721 CCAGACCTTâTGTAAAAAAAAAAAAAAAAAAAAAAAAGACTGAAGAAGGGGAAGAGACAG 3780

378 CATTTGAGAAAAGGCCTCAcAGAGAAAGGGGTTTTCAAtcTGGGGACAGcAGATATGAcc 3840

3841 AGCAGTCCTGAAGGTAGGGAGGCACACTTAATAATGGTAATAGTTGCTAAGCCTATAAA 3900

39 O. ATGCTTAGGGTGTCACAGGATCTTTTCACATGTCTCATcfcAAGTCATGccCCCAACAAc 3960

3961 TCAGCATTccCACTTTGCAGATGAGGACAcTGAGCCTCAGGGAGGTGATATGTAAGAGce 4020

4021 TAAGCCTCAÁCACACACTGGGCCTTTTGcitcCGAAACTGCTTTCCCTTGCTCTGAGGCf 4080

408 CTCGGAGAGTAATTGCTGGGTTGTGAGCACTGGGTAAGAGGATGGGTGcitCAAAGCAGc 4140

4.141 TGCACTCCAGGATAAAGGTAGAGGAAAGTAAAAACATCriccCCTGCTGitATCCAAAAG 4200

420.1 AGAAAAAGAATGGRATTGGGCAAGGGGTGGAGGGGGAATcCAGCTTTTGAAACAGTATTA 4260

4261 TAGGAATTTfGCTAccCGCFATGTGCAGAGCATCATGcGiGGCACTTGGGACAGCTGAAi 4320

4321 GAATGAGCTcCATTCTCAAGGTGAACATGiACATATACAcACCTACAATTTACATTTAti 4380

4381 GAGCAGTGGrcGCATGGTTTCATCTGCACAGTGACTCTGAGGTAGGTACFACCATTAGGc 4 440

4 441 CCATTGTTAGAGAGGGGTTAATGGAGACTTAGAAGAGGccCAGAGAGGTi AGGTAGCTTf 4500

4501 CTCAGAATCACATAAGTGGTAAGGGGATTCAGGCATGCCCCCTGCAACCACTGTCTTCAC 4560 U.S. Patent Jan. 27, 2009 Sheet 5 of 112 US 7482,124 B2

FIG. 1E

456 CAccGTACGGCACCAGTTccACAAGCTGTACAGTGTGGGcTGTGAGAcccAAGGAAAAAc 4 620

462. AGAGCTGAGGCCCACGGGAåGGTGAGGCCGGTGTGGGCTGGAGGCCTTGGGGTAAGCTTc 4680

4681 CTGGAGGTGGGGGTACATGTTGGGCCTTGGAGGACTAAAGAACTGGGGGGAAAAGGAAcc 4740

4741 GAAGAAGGAAAGGATTTTcf GAAAAGGAAATCGCAAGAAGTAAACGTCCAAAGCATAGce 4800

48O1 TGTTGTGAGTAAACAGTGGGAAATCCAAccTCTTTGGGGcCAAACCTCTGAccCTCCAcG 4860

486. TTCCCAGCTGTGAAGTGGGAGTAATAAAATCATCCACCTTATGAGAGCAAATAAAATAAt 4920

4921 GATTGTGAAAATATTTTGGTAACAGTAAccTGTGATAGGAAGATAACAATCATTTCTGi 498O

4981 TACAATACCATGCTGATAGGCATAAAAGTfGCATTCATGiTCATGGGCAÅAATGGGGGTA 5040

SO4. AGTAGAATGCATGGGACGCAAGAAGGATGTAGGAAGGAAAGGGTAGTGTGAGTATAGGAG 500

510 GACTAGCCACTGAGAAGAAAGTAGAAGAAAGAGGGAATCFTTGTGTGTATGGGAAAGTCi 560

516.1 ATTGCAGAGFCAACTTGGGCTTCCATCCTGGGACCTTCccGTGAACAGCiAGAGACAtci. 5220

5221 TCCTCTGGGcTTTGGCAGCCTTTATGTCGGGACCCAGGGGACCCTATAT6GGAAATAGGG 5280

5281 CCAGACACAFGCTCTGAATccCTGCTTCAACATTTCTGAGTCACCTTTGiccCTGTGAGc 5340

5341 CTTCATTTTTCTCATCTATAAAATGGATGACAGCTAGCTfGTTGGTGTGATTTCAGTAGc 5400

54O1 GGCTCAGTAGAGTCAGTTTcCTAGGTCTCitTAATTCTGcCTCTCAAAGGTGATGGGAAA 54.60

5461 ACATCTAGACAAGAAGCCAAGGGACCGGGACACATCTCTcCAAGGACGAGGTGCATGGCG 55.20

552. CTCTGAAGATGCTGGCATcf CTCTAGGCccAACCCAGCTcAGGGGGTCCACTCCACCACA 5580

5581 GCCCTGGCTGGGTGCCTGT.cccCTGGTATcCTGGAGAcci TGCAGCTGciGTGGGCATcf 5640

564, GCTGCCACCTAGCGGCCCCCATGGCACTGTCTCCCCGCCAGCCCCTAGTTTTGACAGGG 5700

U.S. Patent Jan. 27, 2009 Sheet 7 of 112 US 7482,124 B2

F.G. 1G

6841 AGCCAGGCAÄGAccCCAAGAccCAAGGTccCCTGAGCCccTCCAGCCCTöTCTTTTTAcc 69 OO

69 Ol cCCACAGAccCAGTACTATGGCGAGATTGGCATCGGCAccCCACCCCAGACCTTCAAAGT 6960

696.1 cGTCTTTGAcACTGGTTCGrcCAATGTTT6GGTGccCTccTCCAAGTGCAGCCGTCTCTA 7020

7 O2 CACTGcCTGiGGTGAGAcci AAGAccCACAGTGCCTCTccTcCATccc.ccTGccCTACTG 708O

7 O81. TGCATGAGCAATCCTGccCAACACCCAGCiccCATCCCTctTGCCACCAAGGGAGTGGCf 71.4 O

7 141 TcCTCTCTGcCTCTGTG.cccACTGACATGTAGGGGAGAGGGGAAGATGTcTccCGTTTTT 7200

72 Ol CTGATACAGCCACCAAGGTTAAAAACAAAAAAAGGTCCAAGAACCCCTGAGCACCCAGAA 7260

7261 GGCCACTTccCAGTCTTcciGAGATTGAGACAGGACTGAATTCTCAAAccCATCCCAGGc 732O

7321 ACTCGGAAci CTTCCATccöTAGTCTTAAiCAACAAccret TACTAGGCACTTACTCTGT 738O

381 GCCTGGCATcTTCTCTGGT&TTATCAGTGiTAGTGATTACTTTAAATTccTTCATTTAGG 744. O

4 4. ACAAAATTcfcGATGTATGGGCACATTAGGAGAGCCCAAGAAACCCAGTcCTTGATTGAf T5 OO

7 501 GAAGCACATATTCCAAG.cccCCTGACCCTAGGGCCACTCATCCCTGCAccTAAGCTAAcc 75 6.O

75 6. AGCCATAcccACAATGCAccCTGcCTCTGAGTCCCCCTGTCTGGGCCAct CTTGGACAAA 762O

7621 cCTGAGCCTcTGTCCCCCTGCCAGTGTAT?ACAAGCTCTicGATGCTTCGGATTCCTCCA 7680

768 GCTACAAGCACAATGGAAcAGAACTCACccTCCGCTATTcAACAGGGACAGTCAGTGGCf TAO

77 All TTCTCAGCCAGGACATCATcACCGTAAGTfGGGCCGCCCiAGGTCATCTGCCCCGGACcc 7800

780. circrgTcccCAGccCTCTCCTGAccCrcCAGGGccCAcáccTGcGGGGAGSTACACrce 7860

7861 AGCCCACTTGGAGCCTGGGGAGCTGAGGAiCACCCTACT(TGCCACATcfgGCTGTTGci 7920

7921 GCAAAGCAGCAGTACCTATGGGGGAGCAAGCCTGGGCTACGGGCT CACCGTTGGGTGGTT 7980 U.S. Patent Jan. 27, 2009 Sheet 8 of 112 US 7482,124 B2

FIG. 1H

7981 TGTGGATGTTTTTGCATCTAACTTGCATGTAGGGCTTGTcCTGAGCCCc(TGGCTGCAGi 8040

804. CAAGTAACTcGTCCAAGTTcACCAGCTCTGACTGGGCTACACCCTAGAcrgAAATCCAGG 81 OO

81.01 GTCAGAGTCAGGCTGAGTTTTAGGGTCAGGCATAGGTTTTAAGGTCACAGTTGAGGTTGA 81 60

861 CTCTGGGAci CAGGTCAAGGCCTGCTTTTcTTTTCCATGiGGCCCATGTcTGAccGTTTc 8220

8221 CTCATCCTGGAGTTTCTCAGGCCCTGCTccATCAGAGTTAGGGGAGGGG?ACACGTGGCA 8280

8281 CCTGAGAGGAAATCAGGGTGATTCCTGccfccCTTCCTTTTTCTGTGAACTCAGATATAA 8340

8341 AGGAGGGAGAAGGGCAAGCitGTCTGTGciaAAGAAAcccTTCGCCCATóATAAGGGTGG 8400

84O1 GGGCCAAGAccCAGTCCTGcCAGGCACGAAAGTCTGGCCACTGGGGAGGGGAGGAGCTcf 84 60

8461 TGGCAGCTTi TCTTTTGCTGCTTGGCAGGACCACCCTCTcAGCCTCTGci CTCCGATCCc 8520

852. TGGTCAACTcTAGCTCTCTcTGGGCTCCGöAGCAGAGATGTGTATTGGCACAGAGTGTGi 8580

8581 GCGTGCAGGGTTGAGGAAAACTCTTAcccCGATTTCTGiaccCTGGAGöATGTGTG.ccc 8640

864 1. CTGGGATCCCTAGTGTGGAAGCCCAGACCAGACTCCAAccAAGGAGTGGGCAGTGGGCTf 87 OO

87 O. GGTCTCCTCTCGTCCTTCCiCCCACAGGTGGGTGGAATCACGGTGACACAGATGTTTGGA 87 60

8761 GAGGTCACGGAGATGcccGcCTTACCCTTcATGCTGGCCGAGTTTGATGGGGTTGTGGGö 8820

882 ATGGGCTTCATTGAACAGGcCATTGGCAGGGTCACCCCTATCTTCGACAACATCATCTcc 888O

888 CAAGGGGTGcTAAAAGAGGACGTCTTCTCitTCTACTACAACAGGTGGGGACTGGGACTc 894 O

8941 CAAGGGCTGAGGTGGGGGGACAGGAGGGGAGAAGAGATGGGGAGTGGAAGGAGAGTCTGG 9 OOO

9001 GCCAGAATTGTAAAGTGTTfGTAATTAGGiGACAGCCAATCAATATCTAGAGCTGTACTA 90 60

906 GCCAATATGGAAGGCACTATTGAAATTTAAATTAATTAAATACAGTTAAGCATCAATTAA 912O U.S. Patent Jan. 27, 2009 Sheet 9 of 112 US 7482,124 B2

F.G. 1

912 GCATTCAAcigGTGGCTCTTAGTTGTACTAGCCACACGTcAAATGCCTGGCAGCCACGGi 980

91.81 GGCTAGTAACTACAGTCTTATGACAGTGCAGATAGAGAAiATTCCCAGCATGACAGGACA 9240

924. TTCTAATAGACAGCGCCACTCTGGAGCAAGAGGAGATGCAAGGTGGGGGcGATGGTAAAt 93OO

9301 AAGGGATTACTGTGACCTGFAGCCCTGcciGTTAGGGCCATGGCTCCTccCACACAGAGA 9360

9361 CAGCCAACTTCAGTCATCCATTAGATCCTTCATTCGTTTGTTTGCTCAcicATCAGTTCA 942O

94.21 GTAAATGCTATGTGCCAAGcACTGTGGTAGGCTCTGGGGGTGCAGCAGTGAACACAGTGA 94.80

948. ACAAGGCAGAATCTGTACTcCCCTACCCACATAGAGCTTACAGGCTAACAGGGAAGACAA 954 O

9541 GACATATTCCAACATAAAGAGTGTCACAGGCAGGCAGCAAGTGTGGTGciGAAAACCATG 96.OO

96.01. GATGCTTTTcAATTCTAGGöTGAGCTTATATGCAGCTCAGCCAGCCTTGGGGAAGCTCTf 9660

9661 GAGCAGGGTTGGGCTCTAcfcCAAACTGciGGGCTTAGAAAGATGGCATGAGTTGGAGAc 972O

9721 AAGAGAGCTGGAGCCAAAAGGGGCTGGGT6CAGTGGCTCATGCCTGTAAFCCCAGCACT 978O

978. TGGGAGGCCAAGGCGAGAGGATCGCATGAGCCCAGGAGTAAGGCTTCAGTGAGCAGTGA 98 40

98.41 TTGTGCCAcfcCACTCCAG(TAAGGCAAcAGAGTGAGArcCAGTCTCAAAAAAAAAAAAA 9900

990 AAAAAAAAAAAGTCACAAGGGTAAGAACAFGAGGCCAGTGGCAAAAAGA&TAGAGGAGAG 9960

99.61 GATCAGAGTTCAGAGAAATcTCACAGTAAAATGGAGAGGAGTCTCCGGTTGGTGATAGA 10O20

OO2 AAGTGAGGcc TTGAGAAAAGGCCAATTGGcGGCTCTGCATTCAGGGGTGGTCTTTAGAAG O080

10081 AACTGTTTTAGAGGAAGTGGGGGCAAGGccAGATGGCAAGAAGTTAAGAGGTGGACGACG 101 40

101 41 TGGGTGTCAGGAAGTGGAGGTCATGAGATGTAGGCTGccöTGGGACATTéAACAGGGAAG O2OO

O2O GGAATGGGGGGTGGCGTGGGGGGTGAGATCCAGAAGCAGAAGAGGAAGGGTGGGTGTTTT 10260 U.S. Patent Jan. 27, 2009 Sheet 10 of 112 US 7482,124 B2

FIG. J.

O26 TAAATGCTAGAGGATGCTCGAGTGATGcci GTAGGTGGAGGAAGAAGCCAATGGAAAGAÁ O320

10321 AGAGATTAAAAATGTGGAAÄGAAGAGGAGöTAAATGGGGGCACTGGAGTi TGGAGGCCTf 1038O

1038. GAAAGAGATGAGGTTCCAG?AGACAGGAAGAAGCCAGGTTTGCAGAGGAGAGGGCTGGc O44 O

10441 CTCTTCTTTTATCTTGGGATGGGAAGGAGGGAACATCCAGAGAGATACTéAAGTGTTGAG O500

1050 AGACAGCCAGGAGGGAATTfGTGCTAGCATATACACATACATTCCGAAti TATAAAAACA 105 6.O

1056. CAAGTAGTTfGCAGTTGCACAAAATAACAATGCACAcciACACACCCATGCACACATGT 10620

O621 GCATGTGTGAATTCTAGTAiGAATTCTGGAAAAACACATcACACACACAGGCATGCCCTG 10680

O68 GAGACTAGGcCTACAGTAGiCCCTGAGCCAAGTGCAGTGAGGAGGAAAGGAAGGTGAGGG 1040

1074 GAATCAGCTcCAGACGGGGcACCAGGAGCCTGGCTCCAGiccCCCACTTGTTCACTCATG 10800

108O1 GACTGGGTAñCTTCAGGCAÄGTGACTTCGcCTCTTGGTGACTCCATTGccTGAAGGGCAA OB 60

10861 AGAGAGTACATAACACCCAccCTGCCAAACAGCAGGGCTGATGAGGCTGGCATGAAATGA O920

O92. AGCTTCCTT icTGCTGTCTcTCTTTCTCTGCAGAGATTccGAGTAAGGAGACAAAACccc O980

1098 CACATGGCTGTGACCTTCCAGTACTCCCCGAGCACCTGAccTAGAATTACACACGCCAcc 1040

11 O 41 GGCCCAAAAcTCACATCAccAAGCCCAGccTCCGCTAGATGCCGAAGTTCTCTGTCTCTc 1100

11101 CTTCCTGCT(TCTCCATGccACCTGCCCAccCCATACCCAATAGCCTCCcCAGGGTCCCc 1160

1116 TCCCATGCACCTGCTCAATCAGCAGCAAccCAAGAGTGAGGGGTGTCCATTTGTGTCTTG 11220

122 TTCACATcCACTCACTGTccTTGTACCTGcTCCTTTTCTGTGACCTCTCiGGGGATGCT i. 1280

28 TTTGGGGGAACAGCTGGACTAccCTGGAACAACCTCTGGTTGGTCTTGGGGAGGGGAAGA 34 O

11341 AAGGCAGAGAAGCAGTATGTTCTGCATGCTTCCCAACGACAGCTCCGAGCCTGGCTGTCT 14 OO U.S. Patent Jan. 27, 2009 Sheet 11 of 112 US 7482,124 B2

FIG. 18.

114 O1 GTCCCACAticcTCTGCTciaGAGCCCTCicTCCT.cccciGCAccCTTGiGCAAccTTcc 11460

1461 CCAATTGcci GAGTTGCTGGGTCCTGGAGGTTATGGGTTTCCAAGAGCTTCTGATCTTTc 11520

1152. CTTTAGGAAt TCCCAATCGCTGGGAGGACAGATTGTGCTGGGAGGCAGcGACCCCCAGCA 11580

1581 TTACGAAGGéAATTTCCAciATATCAAccicATCAAGAcigGTGTCTGGöAGATTCAAAT 11640

1164. GAAGGGGTCAGAAATCCTCAACCCTCCCCGGGCTCCAAAAAATGCTGCCGTCACTCGGGT 11700

117 O. TGGGGAGGGiGGGGAAGGAcTGCATTACCATCCTGCCCTcTTTCCAAATGCAGCCACTTc 11760

11761 TTAAGCACAGCCACCATTTGCTCTCTGccigCTCTGTcciGGCTGGGGAACAGAGAAGGG 11820

11821 AGGGGCCTGGGGAGAAGTGGTGGAGGGTGACAGTACCTTccCTCCTCTACTCACTGCCTc 1880

1881 AACAGGCCAcCAGCGTGGccTCCACCCAccCACCCACAct CAGGAAGGAcATGCAGCCTG 11940

11941 GAGGTG.cccdATCAGCCTTcTGTCTGTCT(TCTGTCTGTcTGTCTGACT&TGGCCTcccd 12 OOO

200 CAGGGTGTciGTGGGGTCAtcCACCTTGcicTGTGAAGAcGGCTGCCTGGCATTGGTAGA 12060

12061 CAccGGTGcitcCTACATcfcAGGTTCTAccAGCTCCATAGAGAAGCTCATGGAGGCCTf 12120

1221 GGGAGCCAAGAAGAGGCTGFTTGATGTAAGAAGCCAAAGAGGGAAGGTGCTGTGGGTGGG 2180

1218. GGGAGCGCCiCCTGGTATCGGCTCACAAATCCCCCAGGCAAATGAGGCCATCTCAGGcci 12240

1224 TCGCTTGTTcACCTCACAcfcTCCACACATGTGGCTGGTcAccCATGGGGCGGGGCACTg 12300

12301 TCCCCAGccöTCTCCAGCAGAGAGACCAGGCCACCAGcGcAGGACTCCTfGTCTGCTGAG 12360

1236 ACGTCTTCCATACTCAAGAGGCTCTCTTTGCCCCCCAcccCAGTATGTcGTGAAGTGTA 12420

12421 ACGAGGGCccTACACTCCCCGACATCTCTTTCCACCTGGGAGGCAAAGAATACACGCTCA 12480

12481 CCAGCGCGGACTATGTATTTCAGGTGAGGTTCGAGTCGGCCCCCTCGGTGGCAGGGAGAA 1254 O U.S. Patent Jan. 27, 2009 Sheet 12 of 112 US 7482,124 B2

FIG, 1.

2541 AGGCTGGACAGAGACCCTCAAAGAGTGACAGATTACAATGCACAGGTCAiGTTAGAACTé 12600

12601 TAGTTCTCAAACTTGGCTGiGCATGTCAccTGGAGAGCT iTGAAAAATCCTGGTACCTGG 12660

12661 GCCACAtCccATAccTATTAAATCAGAAccTCTAGAAGT&GCACCTGGGGTTCAGTTTcc 1272O

272 CCAGGTGATTCCAATGTGTGGCCATGTTTGGGCATCACTATGCCTGTTccCTCATCTCCA 12780

12781 TTTTCTCATcAAATACT.cccAAGAATCCTñTGCTCCTATATTCTTACCCiCTTTTCATAA 1284 O

2841 TCAATAGGCFTAGAGAAGTfGAATAACTTGTCTAGGATCAGAAGCTAAGGCAAACTGTAÁ 29 OO

12901 GCTCCTGAAGGAAGCACGGiGCCTGATGCATTGTTTGcci GGGATCTAGöACAGGGGCTA 12960

1296. AACATAGGAGTGGTGCAGTcCACGATGGGGCAAAATGGCCATGATGTGAGGGAGGCCCAG 13020

13021 TGTGGCTAGGGGAGAGATGGGGGCGAGAGGGGGAATGTTGCTGAAGACAGTTGCTGGGGG 13O80

13O8. TCAGGCAAGGTGAAAGGAGAATGCTCATGiGCTGGGTATGGAGAAACTcfcCCCCTTCC 1314 O

1341 GCCAGGAATcCTACAGTAGAAAAAGCTGiGCACACTGGcCATCCACGc?ATGGATATcc 32OO

132O1 CGCCACCCACTGGACCCAccTGGGCCCTGGGGGCCACCTTCATCCGAAAGTTCTACACAG 13260

3261 AGTTTGATCGGCGTAACAAccGCATTGGCiTCGCCTTGGccCGCTGAGGccCTCTGCCAc 13320

13321 cCAGGCAGGccCTGCCTTCAGCCCTGGCccAGAGCTGGAACACTCTCTGAGATGCCCCTc 3380

1338 TGCCTGGGcitATGccCTCAGATGGAGACATTGGATGTGGAGCTCCTGciGGATGCGTGc 13440

34 41 cCTGAccccigCACCAGcccTTCCCTGCTtTGAGGACAAAGAGAATAAAGACTTCATGT 13500

135O1 CACAGCCTGiTGCATCTGGGTTCACTAGGGTTTAGAACAGAGGGAGGGGCTGcGTGATCA 13560

1356. TGTGTGGACAGGAATGTGAcACAGACAAccTACACATTCGCCTAGCGCACAGGTTCTTGc 13620

13621 GTGCAGGGATGAGCCATCCATCTGCCATCAACGGGACT CAGGGGAGCTGTTTACACAA 3680 U.S. Patent Jan. 27, 2009 Sheet 13 of 112 US 7482,124 B2

FIG. 1M

13681 CCTCAGGTGcGAAGTCTGAAAAGAGCCGGAACCAAGCTccCTCTAGTCccTCAGGGACCA 1340

1374 AGGCTAATGöTGTGGCAGTAGACTGTGGGiCAGAAAGTTötCCCAGCTCACAGAAGCCAG 13800

38O1 CTCTGAGTTcAGACTCTGcircTGCTGAGCTAGTCAGCCciGTCTCTTGTccCTGCAAAAc 386O

13861 TccCCTCAGcTGTCCTTATcCACTGCAGAiGCCCCCGCccTGCCCCATGAGCCATTTAC 13920

13921. ACAGGCATTöTAAGGCACTACCACCTAAAATCATAGAAcÁCCAGAGATccAGGCAATAct 398O

1398. TCCACTTTACAGGTGGGGAAACTGAGGCCCAGAGAATGGAAGGCCTTGccCAAGATTAct 1 AOAO

14 O 41 CGGTCAAGAATCAAGTAGTGAAGAATACTGAAAGATAGTGAAGAATCAAGACTGGAACCC 1 400

1410 AGccCGTCTGACTTGGGTccTGGGGGTTTcCACCTTATCATAAGCAGTTGGTAccGTCAt 1460

46 AAGTACAGTGCTTCACGCACGCTGGTACAGGGCCACGTGCACAAGCACACAGGTGCACAc 14220

14221 ACACACTGci ATCCTCCATccCATcCAccicGGACTCGTcAGGCTGAAGicTCTTCTCCc 428O

14281 ACTCTCACTcCTTGGGCTGict TCAGGGCACATGTAACTfGGGGAATGAGAAATTAGCAt A340

14341 CCACCTGGAGCCACTGAAGcCATCCCTCricACCATAGTFGCTCACCTCCTTTTGACAG 14400

440 AAAGTCGTGAGGCACTGAAiGGCCCAAccAGGCCCTCAGTACCTCTGGGáGCCATCTGci 1. A 460

14461 AGAGTCCCTGTGTAGCGCCAAGAGCCGGAGCCTGGGCTTCAGG 1 A503 U.S. Patent Jan. 27, 2009 Sheet 14 of 112 US 7482,124 B2

FG. 2A

1. GGTCTTTGTAAAATAATAATTATTCATTTCACAAAAGTGATAATTAAAAGACTTTAATAG 60

6. CAATACAGAAAGTTACATGAATATAAAGAct AACCTTTcTAAAGCTCAGTTTTCCTAAG 2O

121 TAATCAAAAACCTGATAAAGATAACAAGAATGAGGAATTATCTTGAGAAAATGTAAAATc 18O

18 TTTCCTTTTáttTTTTGAGACAGGGTCTCACTCTGTCAtcCAGGCTAAAGTGCAGTGGCi 24O

241 CAATCATAGötCACTACAGcCTTGAACTccTGGACTCAAGTGATCCT.cccGCCTCAGCC 3OO

301 CCCCAGTAGCTAAGACTACAGGCACGCACCACCACACCCAGCTAATTTTTTTCAGAGATG 360

36. GGGTCTTGciaTATTGcccigGCTGGTCTfGAAcGAGCTiCAAGTGAGcGTGAGCCTcci 42O

421 AccTCATcciccCAAAGCAcTAGGATTACAGGCATGAGCeACTGTTTCCcAGCCTAAAAt 48O

48 AATTGTTTCiTAGGCCAGCiACCAAAAACGCAAAGAAAAACTTTCTGTAGTGTGATTGCf 540

5. A TCTTCTTATGGGAAGCCCAFTTAGATAAccTGTAAGTCAiiACCTGATGAAAACAATACT'? 600

6O1 GAATGTAATcAGACACAGAAAGACTGTTCAAGGCTATGAGTAGCTGAGTcCAAGCTCGTA 66O

661 TCACTTGCCACACAACAGcöAATAAGTCTAGAGACAAGGTATTGTGGCAAGGAAAGCTAC 72O

721 CTTATTCACAGAACCAGAAAACCAAGAAGATGGTGGACCAGCATCATAAAGAACCATCTG 780

781 AAGTCAGCATGAACGTTAGGCTCTCTTTATGTTAAGGGAAGGGGAAGAAGAAGGGGATf 840

841 GGGATCAAGAGGTGACTGAiGACCACAGAcACCTGGGTGcCAGCAAGGGTCTGAGGACG't 900

90. TGTAAAACTicTTTTTTCTAGGTCAGGTCACAATGTTcciATACATCTTi AACATAACAt 96.O

961. TGTTATTTGircTGTATATTrcCTTATCTCCTTGGGGGTTAGTTTGGGGAAAGGAACTGT 102O

1021 ACCATTTTTTTTAAAGTTGAACTGCAAGCiAAACTCCTATAATTAGCTGGTCTATGTACA 1080

108 GAGCTAAGCAGAAGCTTTTAGCCTAAAGGATAATACCCCTGGGGGTCAGAGGCAAAATGG 1140 U.S. Patent Jan. 27, 2009 Sheet 15 of 112 US 7482,124 B2

FIG. 2B

141 AGTCAGTCATGCTAAGTCTccCTCCACTCiCTTTCTTTTTTGAGATGGAäTTTCACTCTf 2OO

201 ATTGccCAGGccGGAGTGCAGTGGCATGATCTCAGCTCAcTGCAAccTccGCCTCCTGGG 260

26. TTCAAGCAATCTCTTGCCiCAGCCTCCTGAGTAGCTGAGATTACAGGTGTCCATCACCA 1320

1321 CACCCAGCTAATTTTTGTAGTTTAGTGGAGATGGGGTTTcACCATTGTT6GTCAGGCTG6 1380

138 TCTGGAACTCCTGACCTCAGGTGATCTAccCACCTTGGCCTCCCAAAGTGCTGGGACAGG 14 AO

1441 TGTGAGCCACCATGCCTGGccCCTCTACT(TTATAATTAAACCAGCTGTfGCTTTTCCTG 15 OO

501. CCAAGAAAccAGTCATGAAGATTCACCCATGTTCTAGAT&GGAAAACTGGGCTGTAGCCT 560

15 61 GGGAGAGGCCAGTCAGGGACAAAGCCAAAGTTAATATAGAGAATGGAGCiTCCAGGGTAf 62O

1621 AGGGGTTGGGTCTGGGCTAGGGAGCTGGAñACCTAGGTTTACGCTTGTccCAGTTTTGA 1680

681 TGTTAGCCCiCAGCAGTGciGTTTCTCATcAGCCTCTGccTGCTCCAGGGGTCACAGGGC 740

1741 CAAGCCAGATAGAGGGCTGöTAGCGTCAcrgGACACAAGATTGCTTTCC(ACAGCTGTcc 1800

18O1 TTCCTCCAGcccCTCTGCT.cccCATccGGAAAccTGGGTAccCTTCAcccACCTAGCTct 1860

1861 GTCCCGCAGiGAGATTTATfGCTGACTGccCTGCCATCTACCCCAGGGTAATAAATCAGG 1920

1921 GCAGAGCAGAATTGCAATCAccCCATGCATGGAGTGTATAAAAGGGGAAGGGCTAAGGGA 98O

198 GCCACAGAAccTCAGTGGAiCTCAGAGAGAGCCCCAGAcigAGGGAAGCATGGATGGArg 204 O

20 41. GAGAAGGATécCTCGCTGGGGACTGCTGcGCTGCTCTGGGGCTCCTGTACCTTTGGTcf 21 OO

2O1 CCCGACAGACACCACCACCTTTAAACGGTAATTGGTAACfCAGGCAGAGAAGGGGTGGGA 2160

261 GGGGTGCAGöGTTCCCACCitcCCAACAccCTGGCTTTTcCACATGcGGiGTCATTCAGi 2220

222 CCTTACGATCAGCTGGACAGGGAAGTATGGACCTGTTCAGAGAGGTCAAGTGACTTGCCC 228O U.S. Patent Jan. 27, 2009 Sheet 16 of 112 US 7482,124 B2

FG. 2C

2281 AATAAATGACACTAGTAGTcAGGTCTAGAAGCTGTGACTitTGCTTCCTGccCAGAGCAC 234 O

234 CATGCTAACTAAGCACTGTAGAGAACTCAGAAGTATTAGGACATGccCcitGCACTTGAG 24 OO

24 O1 GAGCTCACAGCCTGAATAti AAGAAGGGCATGGGTGGTTGGGCGCGGTGGCTCCTGCCTG 246O

2461 TAATCCCAGcACTTTGGGAGGCTGAGACGGATCACTTGAGGTCAGGAGTi TGAGACCAGC 252O

252. CTGGCCAACATGGGGAAAccCCATCTCTACTAAAAATACAAAAATTAGccGGGCATGGTG 258O

2581 GCAGGCACTfGTAATCCCCAGCTACTCGGGAAGCTGAGGcAGGAGAATCGTTTGAGCCCG 264 O

2641 GAAGGTGGAGATTGCTGAGCCAAGATCGTGcCACTGCAcfcCAGCCTGAGTGACAGAAcÁ 2700

27 O1 AGACTCCAtcTCAAAAAAAAAAAGACGGGGGTCGGGGCATGGGTACAGiTAACTGTAcc 276O

2761 AGGGAAGCAGCTTGATATcGTGGTTAAATGCAAGGCTTATAGAGTTAGATTGCCTTCATf 2820

2821 TAAATTTTGcTTCACTAGCAGAACAAACTAGGTCTGGAAiCATGGGCAAGTTATTTAAcc 288O

2.881 TCTCCAAGTcTCAGTTTATcATTTTAAACAGGTATGATAATAACAGTAccTACTTGATGG 294 O

294, GGCTGCTTTGGGGATTTTAGGAGATAAGGCATAGAAAGCTGGGCACGTTGTAAGAGCCCA 3000

3001 GCTACTGTTAGTACTACAGGATAGATTCTTACAAATATCAAAAGCAAGGTTTGGCCGGGA 3O 60

3061 GCAGTGGCTcACGCCTATAATCCCAACAct TTGGGAGGccGAGGGGGGCAGATCACCCGA 312O

321 GGTCAGGAGTTCAAGACCAGCCTGACCAAcATGGAGAAAccCTGTCTCTACTAAAAATAC 318O

3.18. AAAATTAGccGGGCGTGGTGGCACATGCCi GTAATTCCAGCTACTTGGGAGGCTGAGGCA 324 O

3241 GGAGAATCGCTTGAACCTGGGAGGCTGAGGTTGCAGTGAGCCGACATAGcGCCATTGCAC 3300

3301 TCCAGCCTGGTCAACAAGAGCAAAACTCAGTCTAAAAAAAAAAAAGAAAGAAAAAAACAA 3360

33 61 GGCTTTAGGTAGCCCACAATTAGAAGGAGAAAACCTTAGCACCCCTAGGTGCCAGGCCT 342O U.S. Patent Jan. 27, 2009 Sheet 17 of 112 US 7482,124 B2

FIG. 2D

3421 TGTGGGAACAAGTGATTCATAAGACTGTâGAAGGAAGciGGGCACGCGGCTCATGCTTg 348O

3481 TAATTCCAGcACTTTGAGAGGCTGAGGTGGGCAGATCGCitGAGCTCACGAGTTCAAGAc 3540

3.54 CAGCCTAGGcAACATGGTGAAACCTTGTcfgTACAAATAcAAAAATTAGöTAGGTGTGGi 36OO

3601 GGTGCAAATcTGTAGTCCCAGCTACTCGGGAGGCTGAGGTGGGAGCATCACTTCAGCCTG 366O

366 GGAGGTGGAGGCTGCAGTGAGCAGAGACTGAccCACTGTGCTCTAGCCTGGGTGATAGAG 3720

3.21. CCAGACCTTATGTAAAAAAAAAAAAAAAAiiAAAAAAAGACTGAAGAAGGGGAAGAGACAG 378O

3781 CATTTGAGAAAAGGCCTCAcAGAGAAAGGGGTTTTCAATcTGGGGACAGéAGATATGAcc 384 O

38A1 AGCAGTCCTGAAGGTAGGGAGGCACACTTAATAATGGTáATAGTTGCTAAGCCTATAAA 3900

3901 ATGCTTAGGGTGTCACAGGATCTTTTCACATGTCTCATCiCAAGTCATGccCCCAACAAc 396 O

3961 TCAGCATTccCACTTTGCAGATGAGGACAcTGAGGCTCAGGGAGGTGATATGTAAGAGGc 4020

4 O21 TAAGCCTCAACACACACTGGGCCTTTTGcitcCGAAACTGCTTTCCCTTGCTCTGAGGCf 4080

4 O8. CTCGGAGAGTAATTGCTGGGTTGTGAGCACTGGGTAAGAGGATGGGTGciTCAAAGCAGö 414 O

A 141 TGCACTCCAGGATAAAGGTAGAGGAAAGTAAAAACATCTFCCCCTGCTGiTATCCAAAAG 4200

42O1 AGAAAAAGAATGGAATTGGGCAAGGGGTGGAGGGGGAATcCAGCTTTTGAAACAGTATTA 4260

4261 TAGGAATTTfGCTAccCGCTATGTGCAGAGCATCATGCGAGGCACTTGGGACAGCTGAAt 4320

A321 GAATGAGCTcCATTCTCAAGGTGAACATGTACATATACACACCTACAATTTACATTTATf A380

4381 GAGCAGTGGicGCATGGTTTCATCTGCACAGTGACTCTGAGGTAGGTAct ACCATTAGGc 4 440

4 441 CCATTGTTAGAGAGGGGTTAATGGAGACTTAGAAGAGGccCAGAGAGGTi AGGTAGCTTi 4500

450 CTCAGAATCACATAAGTGGTAAGGGGATTCAGGCATGCCCCCTGCAACCACTGTCTTCAC 45 60 U.S. Patent Jan. 27, 2009 Sheet 18 of 112 US 7482,124 B2

FIG. 2E

4561 CACCGTACGGCACCAGTTccACAAGCTGTACAGTGTGGGöTGTGAGAccCAAGGAAAAAc 462O

4621 AGAGCTGAGGCCCACGGGAAGGTGAGGCCGGTGTGGGCTGGAGGCCTTGGGGTAAGCTTc 4680

468 CTGGAGGTGGGGGTACATGiTGGGCCTTGGAGGACTAAAGAACTGGGGGGAAAAGGAAGG 474 O

4741 GAAGAAGGAAAGGATTTTCiGAAAAGGAAATGGCAAGAAGTAAAGGTCCAAAGCATAGGc 4800

48O1 TGTTGTGAGFAAACAGTGGGAAATGCAAccTCTTTGGGGcCAAACCTCTGAccCTCCAC6 4860

4861 TTCCCAGCTGTGAAGTGGGAGTAATAAAATCATCCACCTTATGAGAGCAAATAAAATAAt 4920

4921 GATTGTGAAAATATTTTGGiAACAGTAAccTGTGATAGGAAGATAACAAATCATTTCTGi 498O

4.981 TACAATACCATGCTGATAGGCATAAAAGTfGCATTCATGiTCATGGGCAAAATGGGGGTA 5040

5041 AGTAGAATGCATGGGACGCAAGAAGGATGTAGGAAGGAAAGGGTAGTGTGAGTATAGGAG 5 OO

51O. GACTAGCCAcTGAGAAGAAAGTAGAAGAAAGAGGGAATCitTGTGTGTAiGGGAAAGTct 5160

561 ATTGCAGAGicAACTTGGGöTTCCATCCTGGGACCTTCccGTGAACAGCiAGAGACATcf 522O

522 TCCTCTGGGöTTTGGCAGcc TTTATGTCGGGAccCAGGGGACCCTATATGGGAAATAGGG 528O

5281 cCAGACACAt GCTCTGAATccCTGCTTCAãCATTTCTGAGTCACCTTTGiccCTGTGAGc 534. O

5341 CTTCATTtticTCATCTATAAAATGGATGACAGCTAGCTfGTTGGTGTGATTTCAGTAGc 54OO

54O1 GGCTCAGTAGAGTCAGTTTcCTAGGTCTCiTTAATTCTGcCTCTCAAAGGTGATGGGAAA 54.60

546. ACATCTAGACAAGAAGCCAAGGGACCGGGACACATCTCTcCAAGGACGAGGTGCATGGCG 552O

5521 CTCTGAAGAiGCTGGCATcf CTCTAGGCccAAccCAGCTcAGGGGGTCCACTCCACCACA 558O

558 GCCCTGGCTGGGTGCCTGTccCCTGGTATcCTGGAGAccitGCAGCTGciGTGGGCATct 564 O

56.41 GCTGCCACCTAGCGGCCTCCCATGGCACTGTCTCCCCGCCAGCCCCTAGTTTTGACAGGG 57 OO U.S. Patent Jan. 27, 2009 Sheet 19 of 112 US 7482,124 B2

FIG. 2F

57 Ol GCACTCCCTccCATTAATcfcTTCAGAGGGAATGTCTGTGCCTGTTTCCTGTCTGTCCTc 5760

576. ccGCCAGGTGGAGTTCCTTAAAGGCAGTCATGATCATTATCTTTCTAGCTCCAGTGTCCA 5820

5821 GCACAGTGAGGCACAAAGTAGTTGTTCAGCAGGTGATTACGGAATAAATGAATGAACGGA 588O

5881 CCAATAAACAAATAGCCTTGTCTAATCAAAATTAGGCAAcAGAAGGAAGTCACTTCAGGG 5940

594 TTATTTAAT.cccCGGGCAccTGACTCCTCTAAATTGACTcTTGACAAGAAGTAACTCTTA 6000

6001 TAAATGCTccAGAGGCCCTcAGCGACAGAGGTGATTTCCAGGTGGCTGGGCTAACGTTA? 6060

6061 AGGTGGTTGTACTAAAAGCAGGGGTTTGGCCTCAGGGACfCCACCACTGiGGTGGAGGTA 61.20

61.21 CAGCACTTTTCTATTTTTGöttcCTCCAccCTGGGCCAGGATCTTCCTCAAGAGAATGcc 680

681 CTCAATCCGAGAAAGCCTGAAGGAACGAGGTGTGGACATGGCCAGGCTTGGTCCCGAGTG 6240

624 GAGCCAAcccATGAAGAGGCTGACACTTGGCAACACCACCTCCTCCGTGATCCT CACCAA 6300

6301 CTACATGGAcGTGAGTGCTfGGCTCAGCCcCTCGCTCCCiCCCTGTCTccTTTCCCTCA 6360

6361 GGACCTAGGGCTTTCTTTGcTGCAAGACTcACCCTTTCCAAGCTGTGTTfGACGAAGGcG 6420

6 421 CTGAGTAGCACGTGAGCAccCTAGAAAAticcCATTTTccAGCTGGAAAGCCTGAGCACA 64.80

6481. GAAGACAGGAAGGCATCCAGGGGCCATTCAGGGGCAGGGTTAGGTTTGGAACTCAGCCCA 6540

6541 GGCCTCAAccCAGGTGTCACAGGTGGGTGGGAAGGGGTGiGTGACTCAGGTGGGGGTTTé 6600

66O1 TGTGACCTGécCCAGCACAACCTGATGGcitcCTGccCCAGAGGATCCTcAAGAGTCAAG 6660

6661. TTTGCTTccrgCTTCATTCrCAATGTTTTGATTTTGCCCiCTTGTCTTACTGAGACTcco 6720

6721 ACTTTCTGGGATGCCATGGGGAGATGCTAAGCCTCCTAccAGTTCCTGCAGGAAAATGGi 678 O

6781 AACCCCGAGAGGCTATAGGACCTCGCCTGGGCCAAGTCTCACACCGAGAGCCAAGAGTGA 6840 U.S. Patent Jan. 27, 2009 Sheet 20 of 112 US 7482,124 B2

FIG. 2G

6841 AGCCAGGCAAGAccCCAAGAccCAAGGTccCCTGAGCCccTCCAGCCCT(TCTTTTTAcc 69 OO

690 ccCACAGAcccAGTACTATGGCGAGATTGGCATCGGCAccCCACCCCAGACCTTCAAAGf 6960

696.1 cGTCTTTGACACTGGTTCGrcCAATGTTTGGGTGCCCTccTCCAAGTGCAGCCGTCTCTA 7020

7021 CACTGCCTGiGGTGAGAcci AAGAccCACAGTGCCTCTCCTCCATCCCCCTGCCCTACTG 708O

7081 TGCATGAGCAATCCTGccCAACACCCAGCiccCATCCCTctTGCCACCAñGGGAGTGGCf 714. O

T 14 TCCTCTCTGcCTCTGTGccöACTGACATGiAGGGGAGAGGGGAAGATGTcTCCCGTTTTT 72 OO

72O1 CTGATACAGéCACCAAGGTi AAAAACAAAAAAAGGTCCAñGAAccCCTGAGCACCCAGAA T260

7261 GGCCACTTccCAGTCTTcciGAGATTGAGACAGGACTGAATTCTCAAAccCATCCCAGGc 7320

7321 ACTCGGAAct CTTCCAT.cccTAGTCTTAATCAACAAccTcTTACTAGGCACTTACTCTGT 7380

738. GCCTGGCATcTTCTCTGGTGTTATCAGTGiTAGTGATTACTTTAAATTccTTCATTTAGG 744. O

7441 ACAAAATTcfcGATGTATGGGCACATTAGGAGAGCCCAAGAAACCCAGTcCTTGATTGAf 7 500

75O1 GAAGCACATATTCCAAG.cccCCTGACCCTAGGGCCACTCATCCCTGCAccTAAGCTAAcc 7560

7561. AGCCATAcccACAATGCAccCTGCCTCTGAGTCCCCCTGiCTGGGCCACfCTTGGACAA? 7 620

7621 CCTGAGCCTcTGTCCCCCTGCCAGTGTATCACAAGCTCTCGATGCTTCGGATTCCTCCA 768O

768 GCTACAAGCACAATGGAACAGAACTCAcccTCCGCTATTcAACAGGGACAGTCAGTGGCf 774 O

774l TTCTCAGCCAGGACATCATcACCGTAAGTfGGGCCGCCCTAGGTCATCTGCCCCGGAccc 7800

7801 CTTCTGT.cccCAGGCCTCTCCTGACCCTCCAGGGCCCACACCTGCGGGGAGGTACACTGc 7860

786 AGCCCACTTGGAGCCTGGGGAGCTGAGGAñCACCCTACTcTGCCACATcf GGCTGTTGCf 7920

792 GCAAAGCAGCAGTACCTATGGGGGAGCAAGCCTGGGCTACGGGCT CACCGTTGGGTGGTT 798O

U.S. Patent Jan. 27, 2009 Sheet 22 of 112 US 7482,124 B2

FG. 2

921 GCATTCAAciGGTGGCTCTTAGTTGTACTAGCCACACGTCAAATGCCTGGCAGCCACGGif 918O

91.81 GGCTAGTAACTACAGTCTTATGACAGTGCAGATAGAGAAATTCCCAGCATGACAGGACA 9240

924. 1 TTCTAATAGACAGCGCCACTCTGGAGCAAGAGGAGATGCAAGGTGGGGGcGATGGTAAAt 9300

9301 AAGGGATTACTGTGACCTGTAGCCCTGcci GTTAGGGCCATGGCTCCTccCACACAGAGA 9360

9361 CAGCCAACTTCAGTCATCCATTAGATCCTTCATTCGTTTGTTTCCTCACTCATCAGTTCA 9420

94.21 GTAAATGCTATGTGCCAAG?ACTGTGGTAGGCTCTGGGGGTGCAGCAGTGAACACAGTGA 94.80

9481 ACAAGGCAGAATCTGTACTcCCCTACCCACATAGAGCTTACAGGCTAACAGGGAAGACAA 954 O

9541 GACATATTCCAACATAAAGAGTGTCACAGGCAGGCAGCAAGTGTGGTGciGAAAACCATG 96.00

96O1 GATGCTTTT CAATTCTAGGCTGAGCTTATATGCAGCTCAGCCAGCCTTGGGGAAGCTCT 9660

9661 GAGCAGGGTiGGGCTCTAcfcCAAACTGciGGGCTTAGAAAGATGGCATGAGTTGGAGAC 97.20

972. AAGAGAGCTGGAGGCAAAAGGGGCTGGGTGCAGTGGCTCATGCCTGTAAFCCCAGCACT 9780

978 TGGGAGGCCAAGGCGAGAGGATCGCATGAGCCCAGGAGTi AAGGCTTCAGTGAGCAGTGA 984 O

98.41 TTGTGCCAcigCACTCCAGöTAAGGCAACAGAGTGAGATcCAGTCTCAAAAAAAAAAAAA 99 OO

9901 AAAAAAAAAAAGTCACAAGGGTAAGAACAFGAGGCCAGTGGCAAAAAGAATAGAGGAGAG 9960

99.61 GATCAGAGTTCAGAGAAATcTCACAGTAAAATGGAGAGGAGTCTCCGGTTTGGTGATAGA 10020

1 0021 AAGTGAGGccTTGAGAAAAGGCCAATTGGöGGCTCTGCATTCAGGGGTGGTCTTTAGAAG 0080

10O8. AACTGTTTTAGAGGAAGTGGGGGCAAGGccAGATGGCAAGAAGTTAAGAGGTGGACGACG 101 4 0

101 41 TGGGTGTCAGGAAGTGGAGGTCATGAGATGTAGGCTGCccTGGGACATTcAACAGGGAAG 1 O 200

10201 GGAATGGGGGGTGGCGTGGGGGGTGAGATCCAGAAGCAGAAGAGGAAGGGTGGGTGTTTT 10260 U.S. Patent Jan. 27, 2009 Sheet 23 of 112 US 7482,124 B2

FIG. 2J

10261 TAAATGCTAGAGGATGCTcGAGTGATGCCTGTAGGTGGAGGAAGAAGCCAATGGAAAGAA 10320

10321 AGAGATTAAAAATGTGGAAAGAAGAGGAGct AAATGGGGGCACTGGAGTFTGGAGGCCTf 10380

10381 GAAAGAGATGAGGTTCCAccAGACAGGAAGAAGCCAGGTTTTGCAGAGGAGAGGGCTGGC 04 40

104 41 CTCTTCTTTTATCTTGGGATGGGAAGGAGGGAACATCCAGAGAGATACTGAAGTGTTGAG 10500

10501 AGACAGGCAGGAGGGAATTfGTGCTAGCATATACACATAcATTCCGAAtitATAAAAACA 10560

10561. CAAGTAGTTfGCAGTTGCAcAAAATAACAATGCACAcci ACACACCCATGCACACATGT 10620

10 621 GCATGTGTGAATTCTAGTATGAATTCTGGAAAAACACAtcACACACACAGGCATGCCCTG 10680

10681 GAGACTAGGCCTACAGTAGTCCCTGAGCCAAGTGCAGTGAGGAGGAAAGGAAGGTGAGG6 10740

O741 GAATCAGCTCCAGACGGGGcACCAGGAGCCTGGCTCCAGTCCCCCACTTGTTCACTCATG 10800

1080 GACTGGGTAACTTCAGGCAAGTGACTTCGcCTCTTGGTGäCTCCATTGc(TGAAGGGCAA 10860

10861 AGAGAGTACATAACACCCAccCTGCCAAACAGCAGGGCTGATGAGGCTGGCATGAAATGA 10920

10921 AGCTTCCTTi CTGCTGTCTCTCTTTCTCTGCAGAGATTccGAGTAAGGAGACAAAAcccc 10980

10981 CACATGGCTGTGACCTTCCAGTACT.ccccGAGCACCTGAccTAGAATTACACAcGCCAcc 11040

1041 GGCCCAAAACTCACATCAGCAAGCCCAGCCTCCGCTAGATGCCGAAGTTcTCTGTCTCTc 11100

11101 CTTCCTGCTCTCTCCATGccACCTGccCAcccCATAccCAATAGCCTcccCAGGGT.cccc 1160

11161 TccCATGCAccTGCTCAAtcAGCAGCAAccCAAGAGTGAGGGGTGTCCATTGTGTCTTG 11220

11221 TTCACATCCACTCACTGTccTTGTACCTGcTCCTTTTCTGTGACCTCTCiGGGGATGCT'i 11280

1281 TTTGGGGGAACAGCTGGACTACCCTGGAACAAccTCTGGTTGGTCTTGGGGAGGGGAAGA 11340

11341 AAGGCAGAGAAGCAGTATGTTCTGCATGCTTCCCAACGACAGCTCCGAGCCTGGCTGTCT 1 400 U.S. Patent Jan. 27, 2009 Sheet 24 of 112 US 7482,124 B2

FIG. 2K

11 4 01 GTCCCACATTCCTCTGCTCTAGAGCCCTCTCTCCTCCCCTGCACCCTTGiGCAACCTTcc 11460

1146. CCAATTGccrGAGTTGCTGGGTCCTGGAGGTTATGGGTTTCCAAGAGCTicTGATCTTTc 11520

1521 CTTTAGGAATTCCCAATCGGTGGGAGGACAGATTGTGCTGGGAGGCAGcGACCCCCAGCA 1158O

581 TTACGAAGGGAATTTCCAct ATATCAAccicATCAAGACTGGTGTCTGGöAGATTCAAAt 1164 O

1164. GAAGGGGTCAGAAATCCTCAAccCTCCCCGGGCTCCAAAAAATGCTGCCGTCACTGGGGi 117OO

17 O1 TGGGGAGGGiGGGGAAGGACTGCATTACCATCCTGCCCTcTTTCCAAATGCAGCCACTTc 1760

6. TTAAGCACAGCCACCATTTGCTCTCTGCCTGCTCTGTCCAGGCTGGGGAACAGAGAAGGG 1820

11821 AGGGGCCTGGGGAGAAGTGGTGGAGGGTGACAGTACCTTcCCTCCTCTAcTCACTGCCTc 11880

1881 AACAGGCCAccAGCGTGGccTCCACCCAccCACCCACACfCAGGAAGGACATGCAGCCTG 119 AO

11941 GAGGTG.cccdATCAGCCTTcTGTCTGTCTGTCTGTCTGTcTGTCTGACTGTGGCCTCCcc 2OOO

2001 CAGGGTGTcigTGGGGTCAtcCACCTTGcicTGTGAAGAcGGCTGCCTGGCATTGGTAGA 12O60

12061 CAccGGTGcitcCTACATcfcAGGTTCTAccAGCTCCAT?GAGAAGCTCATGGAGGCCTf 12120

121.21 GGGAGCCAAGAAGAGGCTGiTTGATGTAAGAAGCCAAAGAGGGAAGGTGCTGTGGGTGGG 1280

12181 GGGAGCGCCiCCTGGTATCGGCTCACAAATCCCCCAGGCAAATGAGGCCATCTCAGGCCF 1224 0

12241 TcGCTTGTTcAccTCACAcfcTCCACACAFGTGGCTGGTéACCCATGGGGCGGGGCACTG 12300

23 O. TccCCAGccöTCTCCAGCAGAGAGACCAGGCCACCAGCGéAGGACTCCTfGTCTGCTGAG 12360

12361 ACGTCTTCCATACTCAAGAñGGCTCTCTTfGCCCCCCAccCCAGTATGTcGTGAAGTGTA 2420

12421. AcGAGGGCccTACACTCCccGACATCTCT, TCCACCTGGGAGGCAAAGAATACACGCTCA 12480

124 81 CCAGCGCGGACTATGTATTTCAGGTGAGGTTCGAGTCGGCCCCCTCGGTGGCAGGGAGAA 2540 U.S. Patent Jan. 27, 2009 Sheet 25 of 112 US 7482,124 B2

FIG. 2L

125 41 AGGCTGGACAGAGACCCTCAAAGAGTGACAGATTACAATGCACAGATCATGTTAGAACTG 12600

1260) TAGTTCTCAAACTTGGCTGFGCATGTCAccTGGAGAGCTFTGAAAAATccTGGTACCTGG 12660

1266 GCCACAT.cccATACCTATTAAATCAGAAccTCTAGAAGTGGCACCTGGGGTTCAGTTTCc 272O

12721 CCAGGTGATTCCAATGTGTGGCCATGTTTGGGCATCACTATGCCTGTTccCTCATCTcci 12780

1278) TTTTCTCATcAAATACTccCAAGAATCCTATGCTCCTATATTCTTAcccfcTTTTCATAA 128 40

128A1 TCAATAGGCFTAGAGAAGTTGAATAACTTGTCTAGGATCAGAAGCTAAGGCAAACTGTAA 12900

12901 GCTCCTGAAGGAAGCACGGTGCCTGATGCATTGTTTGCCTGGGATCTAGcACAGGGGCTA 12960

12961 AACATAGGAGTGGTGCAGTcCACGATGGGGCAAAATGGccATGATGTGAGGGAGGCCCAG 13020

3O21 TGTGGCTAGGGGAGAGATGGGGGCGAGAGGGGGAATGTTGCTGAAGACAGTTGCTGGGGG 13O80

13081 TCAGGCAAGGTGAAAGGAGAATGCTCATGiGCTGGGTATGGAGAAACTcfccCCCTTcci 1314 O

1314 GCCAGGAATcCTACAGTAGTAAAAAGCTGiGCACACTGGcCATCCAcGccATGGATATcc 13200

1320.1 cGCCACCCAcTGGAccCAccTGGGCCCTGGGGGCCACCTTCATCCGAAAGTTCTACACAG 13260

1326 AGTTTGATcGGCGTAACAAccGCATTGcci TCGCCTTGGccCGCTGAGGccCTCTGCCAC 1332O

3321 cCAGGCAGGccCTGCCTTCAGCCCTGG.cccAGAGCTGGAACACTCTCTGAGATGccCCTc 13380

13381 TGCCTGGGCTATGccCTCAGATGGAGACATTGGATGTGGAGCTCCTGcitcGATGcGTGc 13440

13441 cCTGAcccci GCACCAGcccTTccCTGCT'? TGAGGACAAAGAGAATAAAGACTTCATGTf 13500

1350 CACAGCCTGiTGCATCTGGGTTCACTAGGGTTTAGAACAGAGGGAGGGGöTGcGTGATCA 13560

13561 TGTGTGGACAGGAATGTGACACAGACAAGcTACACAt TCGCCTAGCGCAcAGGTTCTTGc 13620

13621 GTGCAGGGATGATGCCATCCATCTGCCATCAACGGGACTCAGGTGGAGCTGTTTACACAA 13 680 U.S. Patent Jan. 27, 2009 Sheet 26 of 112 US 7482,124 B2

FIG. 2M

1368. CCTCAGGTGGGAAGTCTGAÅAAGAGCCGGAACCAAGCTccCTCTAGTCCCTCAGGGACCA 13740

13741 AGGCTAATGcTGTGGCAGTAGACTGTGGGTCAGAAAGTTCTCCCAGCTCACAGAAGCCAG 13800

13801 CTCTGAGTTcAGACTCTGcicTGCTGAGCTAGTCAGCCCTGTCTCTTGTccCTGCAAAAc 13860

1386 TccCCTCAGcTGTCCTTATcCACTGCAGATGccCCCGCccTGCCCCATGTAGCCATTTAC 13920

13921. ACAGGCATTcTAAGGCACTACCACCTAAAATCATAGAACACCAGAGATccAGGCAATAct 13980

13981 TCCACTTTACAGGTGGGGAAACTGAGGCccAGAGAATGGAAGGCCTTGccCAAGATTAct 14040

14041 CGGTCAAGAATCAAGTAGTGAAGAATACTGAAAGATAGTGAAGAATCAAGACTGGAACcc , 14 100

141 01 AGCCCGTCTGACTTGGGTccTGGGGGTTTcCACCTTATCATAAGCAGTTGGTAccGTCAt 14160

141 61 AAGTACAGTGCTTCACGCACGCTGGTACAGGGCCACGTGcACAAGCACACAGGTGCACAC 14220

14221 ACACACTGciATCCTCCATccCATCCAccigGGACTCGTcAGGCTGAAGicTCTTCTccc 14280

428 ACTCTCACTcCTTGGGCTGiCTTCAGGGCACATGTAACTTGGGGAATGAGAAATTAGCAt 4340

1434 CCACCTGGAGCCACTGAAGcCATCCCTCTCACCATAGTfGCTCACCTcf CTTTTGACAG 14400

14401 AAAGTCGTGAGGCACTGAATGGCCCAAccAGGCCCTCAGTACCTCTGGGAGCCATCTGCA 14. 460

14461 AGAGTCCCTGTGTAGCGCCAAGAGCCGGAGCCTGGGCTTCAGG 14503 U.S. Patent Jan. 27, 2009 Sheet 27 of 112 US 7482,124 B2

FIG. 3A

1. GGTCTTTGTAAAATAATAATTATTCATTTcACAAAAGTGATAATTAAAAGACTTTAATAG 6O

61 CAATACAGAAAGTTACATGAATATAAAGACTTAACCTTTct AAAGCTCAGTTTTCCTAAG 120

121 TAATCAAAAACCTGATAAAGATAACAAGAATGAGGAATTATCTTGAGAAAATGTAAAATc 180

181 TTTCCTTTTATTTTTTGAGACAGGGTCTCACTCTGTCATcCAGGCTAAAGTGCAGTGGCA 240

24. CAATCATAGötCACTACAGcCTTGAACTccTGGACTCAAGTGATCCTCccGCCTCAGCCf 300

301 cCCCAGTAGcTAAGACTACAGGCACGCAccACCACACCCAGCTAATTTTTTTCAGAGATG 360

361 GGGTCTTGciaTATTGcccigGCTGGTCTfGAAcGAGCTicAAGTGAGcGTGAGCCTcci 420

421 ACCTCATCCFCCCAAAGCACTAGGATTACAGGCATGAGCCACTGTTTCCcAGCCTAAAA 480

481 AATTGTTTC'? TAGGCCAGCiACCAAAAACGCAAAGAAAAACTTTCTGTAGTGTGATTGCf 540

541 TCTTCTTATGGGAAGccCATTTAGATAAccTGTAAGTCAiiACCTGATGAñAACAATACT'? 600

601 GAATGTAATcAGACACAGAAAGACTGTTCAAGGCTATGAGTAGCTGAGTcCAAGCTCGTA 660

66 TCACTTGCCACACAACAGCCAATAAGTCTAGAGACAAGGTATTGTGGCAAGGAAAGCTAc 720

72. CTTATTCAGAGAACCAGAAAACCAAGAAGATGGTGGACCAGCATCATAAAGAACCATCTG 780

781. AAGTCAGCATGAACGTTAGGCTCTTCTTTATGTTAAGGGAAGGGGAAGAñGAAGGGGATf 840

84 GGGATCAAGñGGTGACTGAfGACCACAGACACCTGGGTGcCAGCAAGGGiCTGAGGACGi 900

901. TGTAAAACTicTTTTTTCTAGGTCACGTCACAATGTTcci ATACATCTTi AACATAACA 960

961 TGTTATTTGicTGTATATTi CCTTATCTccTTGGGGGTTAGTTTGGGGAAAGGAACTGTf 1 O2O

1021 ACCATTTTTTTTAAAGTTGAACTGCAAGCiAAACTCCTATAATTAGCTGGTCTATGTACA O80

1081 GAGCTAAGCAGAAGCTTTTAGCCTAAAGGATAATACCCCTGGGGGTCAGAGGCAAAATGG 1140 U.S. Patent Jan. 27, 2009 Sheet 28 of 112 US 7482,124 B2

FG. 3B

1141 AGTCAGTCATGCTAAGTCTccCTCCACTcf CTTTCTTTTTTGAGATGGAATTTCACTCti 1200

1201. ATTGCCCAGGCCGGAGTGCAGTGGCATGArcTCAGCTCACTGCAAccTccGCCTCCTGGG 1260

1261 TTCAAGCAATTCTCTTGccicAGCCTCCTGAGTAGCTGAGATTACAGGTGTCCATCAcci, 1320

1321 CAccCAGCTAATTTTTGTAGTTTAGTGGAGATGGGGTTTcACCATTGTTGGTCAGGCTGG 1380

1381 TCTGGAACTcCTGAccTCAGGTGATCTAccCACCTTGGccTCCCAAAGTGCTGGGACAGG 1440

1441 TGTGAGCCAccATGCCTGGccCCTCTACTCTTATAATTAAACCAGCTGTiGCTTTTCCTG 1500

50. CCAAGAAAccAGTCATGAAGATTCACCCATGTTCTAGATGGGAAAACTGGGCTGTAGCC 15 60

56. GGGAGAGGccAGTCAGGGACAAAGCCAAAGTTAATATAGAGAATGGAGCTCCAGGGTAf 1620

1621 AGGGGTTGGGTCTGGGCTAGGGAGCTGGAAACCTAGGTTTTACGCTTGTcCCAGTTTTGA 1680

1681 TGTTAGccci GAGCAGTGcigTTTCTCATcAGCCTCTGccTGCTCCAGGGGTCACAGGGc 1740

1741 CAAGCCAGATAGAGGGCTGöTAGcGTCAcfcGACACAAGATTGCTTTCCóACAGCTGTcc 1800

1801 TTCCTCCAGccCCTCTGCTccCCATCCGGAAACCTGGGTACCCTTCACccACCTAGCTCi 1860

1861 GTCCCGCAGiGAGATTTATfGCTGACTGccCTGCCATCTACCCCAGGGTAATAAATCAGG 1920

1921 GCAGAGCAGAATTGCAATCACCCCATGCATGGAGTGTATAAAAGGGGAAGGGCTAAGGGA 1980

1981 GCCACAGAAccTCAGTGGAfCTCAGAGAGAGCCCCAGAcigAGGGAAGCATGGATGGATG 2O4 O

204 GAGAAGGATGccTCGCTGGGGACTGCTGciGCTGCTCTGGGGCTCCTGTácCTTTGGTci 2100

2101 CCCGACAGACACCACCAcci TTAAACGGTAATTGGTAAci CAGGCAGAGAAGGGGTGGGA 21 60

21 61 GGGGTGCAGcGTTCCCAcci TCCCAACAccCTGGCTTTTcCACATGcGGiGTCATTCAGi 2220

2221 CCTTACGATCAGCTGGACAGGGAAGTATGGACCTGTTCAGAGAGGTCAAGTGACTTGCCC 228O U.S. Patent Jan. 27, 2009 Sheet 29 of 112 US 7482,124 B2

FIG. 3C

2281 AATAAATGACACTAGTAGTcAGGTCTAGAAGCTGTGACTitTGCTTCCTGCCCAGAGCAC 2340

2341 CATGCTAAct AAGCACTGTAGAGAACTCAGAAGTATTAGGACATGCCCCTTGCACTTGAG 2400

240 GAGCTCACAGCCTGAATAti AAGAAGGGCATGGGTGGTTGGGCGCGGTGGCTCCTGCCTG 24 60

246 TAATCCCAGcACTTTGGGAGGCTGAGACGGATCACTTGAGGTCAGGAGTTTGAGACCAGc 2520

2521 CTGGCCAACATGGGGAAAccCCATCTCTACTAAAAATACAAAAATTAGccGGGCATGGTG 2580

258 GCAGGCACTfGTAATCCCCAGCTACTCGGGAAGCTGAGG?AGGAGAATCGTTTGAGCCCG 2640

2641 GAAGGTGGAGATTGCTGAGCCAAGATCGTGCCACTGCACfCCAGCCTGAGTGACAGAACA 2700

270 AGACTCCATcTCAAAAAAAAAAAAGACGGGGGTCGGGGCATGGGTACAGiTAACTGTAcc 27 60

2761 AGGGAAGCAGCTTGATATCGTGGTTAAATGCAAGGCTTATAGAGTTAGATTGCCTTCATf 2820

2821 TAAATTTTGcTTCACTAGCAGAACAAACTAGGTCTGGAATCATGGGCAAGTTATTTAAcc 2880

2881 TCTCCAAGTcTCAGTTTAtcATTTTAAACAGGTATGATAATAACAGTAccTACTTGATGG 2940

2941 GGCTGCTTTGGGGATTTTAGGAGATAAGGCATAGAAAGCTGGGCACGTTGTAAGAGCCCA 3000 3001 GCTACTGTTAGTACTACAGGATAGATTCTTACAAATATCAAAAGCAAGGTTTGGCCGGGA 3060

3061 GCAGTGGCT(ACGCCTATAATCCCAACAct TTGGGAGGccGAGGGGGGCAGATCACCCGA 31.20

3121 GGTCAGGAGTTCAAGACCAGCCTGACCAACATGGAGAAAccCTGTCTCTACTAAAAATAC 31.80

3.81 AAAATTAGccGGGCGTGGTGGCACATGCCFGTAATTCCAGCTACTTGGGAGGCTGAGGCA 3240

324 GGAGAATCGöTTGAACCTGGGAGGCTGAGGTTGCAGTGAGCCGACATAGcGCCATTGCAC 3300

330. TCCAGCCTGGTCAACAAGAGCAAAACTCAGTCTAAAAAAAAAAAAGAAAGAAAAAAACAA 3360

3361 GGCTTTAGGTAGCCCACAATTAGAAGGAGAAAACCTTAGCATCCCCTAGGTGCCAGGCCT 3420 U.S. Patent Jan. 27, 2009 Sheet 30 of 112 US 7482,124 B2

FIG. 3D

342. TGTGGGAACAAGTGATTCATAAGACTGTAGAAGGAAGcicGGCAcGCGGCTCATGCTTg 3480

3481 TAATTCCAGcACTTTGAGAGGCTGAGGTGGGCAGATCGCitGAGCTCAcGAGTTCAAGAc 3540

3541 CAGCCTAGG?AACATGGTGAACCTTGTCiGTACAAATAcAAAAATTAGcTAGGTGTGGi 3600

36O1 GGTGCAAATcTGTAGTCCCAGCTACTCGGGAGGCTGAGGiGGGAGCATCACTTCAGCCTg 3660

3661 GGAGGTGGAGGCTGCAGTGiGCAGAGACTGACCCACTGTGCTCTAGCCTGGGTGATAGAG 3.720

3721 CCAGACCTTATGTAAAAAAAAAAAAAAAAAAAAAAAAGACTGAAGAAGGGGAAGAGACAG 378O

3781 CATTTGAGAAAAGGCCTCACAGAGAAAGGGGTTTTCAATCTGGGGACAGCAGATATGAcc 384 O

3841 AGCAGTCCTGAAGGTAGGGAGGCACACTTTAATAATGGTAATAGTTGCTAAGCCTATAAA 39 OO

39 O. ATGCTTAGGGTGTCACAGGATCTTTTCACATGTCTCATCiCAAGTCATGcCCCCAACAAc 39 60

3961 TCAGCATTccCACTTTGCAGATGAGGACACTGAGGCTCAGGGAGGTGATATGTAAGAGGc 4O20

4021 TAAGCCTCAACACACACTGGGCCTTTTGcitcCGAAACTGCTTTCCCTTGCTCTGAGGCf 408O

4.08 CTCGGAGAGTAATTGCTGGGTTGTGAGCACTGGGTAAGAGGATGGGTGciTCAAAGCAGC 440

4.141 TGCACTCCAGGATAAAGGTAGAGGAAAGTAAAAACATCTiCCCCTGCTGiTATCCAAAAG 4200

42O1 AGAAAAAGAATGGAATTGGGCAAGGGGTGGAGGGGGAAtcCAGCTTTTGAAACAGTATTA 4260

4.261 TAGGAATTTfGCTAccCGCiATGTGCAGAGCATCATGcGAGGCACTTGGGACAGCTGAAt 4320

4.32 GAATGAGCTcCATTCTCAAGGTGAACATGiACATATACACACCTACAAt itACATTTATf 4380

4381 GAGCAGTGGrcGCATGGTTTCATCTGCACAGTGACTCTGAGGTAGGTAct ACCATTAGGö 4 440

4 44 CCATTGTTAGAGAGGGGTTâATGGAGACTiaGAAGAGGccCAGAGAGGTTAGGTAGCTTf 4500

4501 CTCAGAATCACATAAGTGGTAAGGGGATTCAGGCATGCCCCCTGCAACCACTGTCTTCAC 45 60 U.S. Patent Jan. 27, 2009 Sheet 31 of 112 US 7482,124 B2

FIG.3E

45 61 CACCGTACGGCACCAGTTccACAAGCTGTACAGTGTGGGöTGTGAGACccAAGGAAAAAc 462O

4621 AGAGCTGAGGCCCACGGGAAGGTGAGGCCGGTGTGGGCTGGAGGCCTTGGGGTAAGCTTc 4 680

4681 CTGGAGGTGGGGGTACATGTTGGGCCTTGGAGGACTAAAGAACTGGGGGGAAAAGGAAGG 474. O

474. GAAGAAGGAAAGGATTTTCTGAAAAGGAAATGGCAAGAAGTAAAGGTCCAAAGCATAGGc 4800

480 TGTTGTGAGTAAACAGTGGGAAATGCAAccTCTTTGGGGcCAAACCTCTGACCCTCCACG 4860

486. TTCCCAGCTGTGAAGTGGGAGTAATAAAATCATCCACCTTATGAGAGCAAATAAAATAAF 4920

4921 GATTGTGAAAATATTTTGGiAACAGTAAccTGTGATAGGAAGATAACAAATCATTTCTGi 498O

498 TACAATACCATGCTGATAGGCATAAAAGTfGCATTCATGi TCATGGGCAAATGGGGGTA 5040

504 AGTAGAATGcATGGGACGCAAGAAGGATGTAGGAAGGAAAGGGTAGTGTGAGTATAGGAG 5100

5101 GACTAGCCAcTGAGAAGAAAGTAGAAGAAAGAGGGAATcf TTGTGTGTATGGGAAAGTcf 5160

5 161 ATTGCAGAGTCAACTTGGGcTTCCATCCTGGGACCTT.cccGTGAACAGCTAGAGACATcf 5220

5221 TCCTCTGGGöTTTGGCAGccTTTATGTCGGGACCCAGGGGACCCTATATGGGAAATAGGG 5280

5281 CCAGACACAFGCTCTGAATccCTGCTTCAACATTTCTGAGTCACCTTTGiccCTGTGAGc 5340

534. CTTCATTTTTCTCATCTATAAAATCGATGACAGCTAGCTfGTTGGTGTGATTTCAGTAGc 5 400

54 O1 GGCTCAGTAGAGTCAGTTTcCTAGGTCTCitTAATTCTGcCTCTCAAAGGTGATGGGAAA 5 460

5461 ACATCTAGACAAGAAGCCAAGGGACCGGGACACATCTCTcCAAGGACGAGGTGCATGGCG 552O

5521 CTCTGAAGATGCTGGCATCTCTCTAGGCccAACCCAGCTcAGGGGGTCCACTCCACCACA 5580

5581 GCCCTGGCTGGGTGCCTGTccCCTGGTATcCTGGAGAcci TGCAGCTGciGTGGGCATcf 5640

56.41 GCTGCCACCTAGCGGCCTCCCATGGCACTGTCTCCCCGCCAGCCCCTAGTTTTGACAGGG 57 OO U.S. Patent Jan. 27, 2009 Sheet 32 of 112 US 7482,124 B2

FIG, 3F

57 Cl GCACTccCTGGCATTAATCfCTTCAGAGGGAATGTCTGTécCTGTTTCCTGTCTGTCCTc 57 60

576. ccGCCAGGTGGAGTTCCTTAAAGGCAGTCATGATCATTACTTTCTAGCiccAGTGTcci 5820

582. GCACAGTGAGGCACAAAGTAGTTGTTCAGCAGGTGATTACGGAATAAATGAATGAACGGi 5880

588. CCAATAAACAAATAGCCTTGTCTAATCAAAATTAGGCAACAGAAGGAAGFCACTTCAGGG 594 O

594 TTATTTAAT.cccCGGGCAGCTGACTccTct AAATTGACTctTGACAAGAAGTAACTCTTA 6000

60 Ol TAAATGCTccAGAGGCCCTcAGCGACAGAGGTGATTTCCAGGTGGCTGGGCTAACGTTAA 6060

606 AGGTGGTTGiACTAAAAGCAGGGGTTTGGcCTCAGGGAcicCAccACTGiGGTGGAGGTi, 62O

61.21 CAGCACTTTTCTATTTTTGcTTCCTCCAccCTGGGCCAGGATCTTCCTCAAGAGAATGcc 618O

6181 CTCAATCCGAGAAAGCCTGAAGGAACGAGGTGTGGACATGGCCAGGCTTGGTCCCGAGTG 6240

6241 GAGCCAAcccATGAAGAGGöTGACACTTGGCAACACCAccTCCTCCGTGATCCTCACCAA 63OO

6301 CTACATGGAcGTGAGTGCTigGCTCAGcccCTCGCTCccrccCTGTCTccTTTCCCTCA 6360

636. GGAccTAGGGCTTTCTTTGcTGCAAGACTcAccCTTTCCAAGCTGTGTTfGACGAAGGcG 642O

6.421 CTGAGTAGCACGTGAGCAccCTAGAAAAttcCCATTTTC6AGCTGGAAAGCCTGAGCACA 64.80

6481 GAAGACAGGAAGGCATCCAGGGGCCATTCAGGGGCAGGGTTAGGTTTGGAACTCAGCCCA 6540

65 41 GGCCTCAAGCCAGGTGTCACAGGTGGGTGGGAAGGGGTGiGTGACTCAGGTGGGGGTTTC 6600

660 TGTGACCTGGCCCACCACAácCTGATGGCitcCTGCCCCAGAGGATCCT(AAGAGTCAAG 6660

6661 TTTGCTTccrgCTTCATT circAATGTTTTGATTTTGCCCiCTTGTCTTACTGAGACTccc 6720

6721 ACTTTCTGGéATGCCATGGGGAGATGCTAñGCCTCCTAccAGTTCCTGciGGAAAATGGA 6780

678. AACCCCGAGAGGCTATAGGACCTCGCCTGGGCCAAGTCT CACACCGAGAGCCAAGAGTGA 6840 U.S. Patent Jan. 27, 2009 Sheet 33 of 112 US 7482,124 B2

FIG, 3G

6841 AGCCAGGCAÁGACCCCAAGACCCAAGGTccCCTGAGCCccTCCAGCCCTcTCTTTTTAcc 69 OO

6901 CCCACAGAccoAGTACTATGGCGAGATTGGCATCGGCAccCCACCCCAGACCTTCAAAG? 6960

696. CGTCTTTGACACTGGTTCGTCCAATGTTTGGGTGCCCTccTCCAAGTGCAGCCGTCTCTA 7020

702 CACTGcCTGTGGTGAGAccra.AGAccCACAGTGCCTCTccTCCATCCCccTGCCCTACTG 708O

708 TGCATGAGCAATCCTGccCAACACCCAGCfccCATccCTctTGCCACCAAGGGAGTGGCf 740

714. TCCTCTCTGccTCTGTG.cccACTGACATGTAGGGGAGAGGGGAAGATGTCTCCCGTTTTT 7200

720. CTGATACAGCCACCAAGGTFAAAAACAAAAAAAGGTCCAAGAAccCCTGACCACCCAGAñ 7260

7261 GGCCACTTccCAGTCTTCCTGAGATTGAGACAGGACTGAATTCTCAAAccCATCCCAGGé 732O

7321 ACTCGGAAcfcTTCCAT.cccTAGTCTTAACAACAAccTctTACTAGGCACTTACTCTGi 738O

7381 GCCTGGCATcTTCTCTGGTGTTATCAGTGitAGTGATTACTTTAAATTccTTCATTTAGG 7440

7441. ACAAAATTcfcGATGTATGGGCACATTAGGAGAGCCCAAGAAACCCAGTcCTTGATTGAf 75OO

750 GAAGCACATATTCCAAGCccCCTGACCCTAGGGCCACTCATCCCTGCAccTAAGCTAAcc 7560

7561. AGCCATAccCACAATGCAccCTGCCTCTGAGTCCCCCTGiCTGGGCCACCTTGGACAAñ 762O

762 CCTGAGCCTcTGTCCCCCTGCCAGTGTATcACAAGCTcticGATGCTTCGGATTCCTCCA 768O

7681 GCTACAAGCACAATGGAACAGAACTCAcccTCCGCTATTcAACAGGGACAGTCAGTGGCf 7740

774 TTCTCAGCCAGGACATCATcACCGTAAGTfGGGCCGCcci AGGTCATCTGCCCCGGAccc 7800

78O1 CTTCTGT.cccCAGGCCTCTcCTGACCCTccAGGGCCCACACCTGCGGGGAGGTACACTGc 7860

7861 AGccCACTTGGAGCCTGGGGAGCTGAGGAACAccCTACTcTGCCACAtcrgGCTGTTGCf 7920

7921 GCAAAGCAGCAGTACCTATGGGGGAGCAAGCCTGGGCTACGGGCT CACCGTTGGGTGGTT 798O

U.S. Patent Jan. 27, 2009 Sheet 35 of 112 US 7482,124 B2

FIG. 3

921 GCATTCAAcfcGTGGCTCTTAGTTGTACTAGCCACACGTcAAATGccTGGCAGCCACGGi 918O

91.81 GGCTAGTAACTACAGTCTTATGACAGTGciGATAGAGAAATTCCCAGCATGACAGGACA 9240

9241 TTCTAATAGACAGCGCCAcircTGGAGCAAGAGGAGATGCAAGGTGGGGGcGATGGTAAAt 9300

9 301 AAGGGATTACTGTGACCTGTAGCCCTGcci GTTAGGGCCATGGCTCCTccCACACAGAGA 9360

9361 CAGCCAACTTCAGTCATcCATTAGATCCTTCATTCGTTTGTTTGCTCAcfcATCAGTTCA 9420

94.21 GTAAATGCTATGTGCCAAGCACTGTGGTAGGCTCTGGGGGTGCAGCAGTGAACACAGTGi 94.80

9481 ACAAGGCAGAATCTGTACTccCCTAccCACATAGAGCTTACAGGCTAACAGGGAAGACAA 95 40

954 GACATATTCCAACATAAAGAGTGTCACAGGCAGGCAGCAAGTGTGGTGciGAAAACCAT& 96.00

96.01 GATGCTTTTcAATTCTAGGcTGAGCTTATATGCAGCTCAGCCAGCCTTGGGGAAGCTCTf 96.60

9661 GAGCAGGGTTGGGCTCTACTCCAAACTGciGGGCTTAGAAAGATGGCATGAGTTGGAGAC 97.20

97.21 AAGAGAGCTGGAGGCAAAAGGGGCTGGGTGCAGTGGCTCATGCCTGTAAtcCCAGCACT 9780

9781 TGGGAGGCCAAGGCGAGAGGATCGCATGAGCCCAGGAGTAAGGCTTCAGTGAGCAGTGA 984 O 984.1 TTGTGcCAcrgCACTCCAGöTAAGGCAAcAGAGTGAGATcCAGTCTCAAAAAAAAAAAAA 9900

99.01 AAAAAAAAAAAGTCACAAGGGTAAGAACATGAGGCCAGTGGCAAAAAGAATAGAGGAGAG 9960

996. GATCAGAGTFCAGAGAAAtcTCACAGTAAAATGGAGAGGAGTCTCCGGTi TGGTGATAGA 10O20

100.21 AAGTGAGGCCTTGAGAAAAGGCCAATTGGcGGCTCTGCAt TCAGGGGTGGTCTTTAGAAG OO 8O

1008. AACTGTTTTAGAGGAAGTGGGGGCAAGGccAGATGGCAAGAAGTTAAGAGGTGGACGACG 1040

101 41 TGGGTGTCAGGAAGTGGAGGTCATGAGATGTAGGCTGccCTGGGACATTcAACAGGGAAG 10200

1020 GGAAGGGGGGTGGCGTGGGGGGTGAGATCCAGAAGCAGAAGAGGAAGGGTGGGTGTTTT 10260 U.S. Patent Jan. 27, 2009 Sheet 36 of 112 US 7482,124 B2

FIG. 3J

10261 TAAATGCTAGAGGATGCTCGAGTGATGCCFGTAGGTGGAGGAAGAAGCCAATGGAAAGA O32O

O321 AGAGATTAAAAATGTGGAAAGAAGAGGAGCTAAATGGGGGCACTGGAGTi TGGAGGCCTf 10380

10381 GAAAGAGATGAGGTTCCAccAGACAGGAAGAAGCCAGGTTTGCAGAGGAGAGGGCTGGC 104 40

04 4. CTCTTCTTTFATCTTGGGAfgGGAAGGAGGGAACATCCAGAGAGATACTGAAGTGTTGAG 105OO

105O1 AGACAGGCAGGAGGGAATT'iGTGCTAGCATATACACATACAFTCCGAAt itATAAAAACA O560

1056. CAAGTAGTTfGCAGTTGCAcAAAATAACAATGCACAcci ACACAccCaigCACACATG 10620

1062 GCATGTGTGAATTCTAGTATGAATTCTGGAAAAACACATCACACACACAGGCATGCCCTG O68O

1068. GAGACTAGGCCTACAGTAGiccCTGAGCCAAGTGCAGTGiGGAGGAAAGGAAGGTGAGGG 1. Of AO

10741 GAATCAGCTcCAGACGGGGéACCAGGAGCCTGGCTCCAGfccCCCACTTGTTCACTCATG 108OO

O8O1 GACTGGGTAACTTCAGCCASGTGACTTCGcCTCTTGGTGiCTCCATTGccTGAAGGGCAA 10860

10861 AGAGAGTAc?TAACAccCAccCTGCCAAACAGCAGGGCTGATGAGGCTGGCATGAAATGA 10920

1092 AGCTTCCTticTGCTGTCT(TCTTTCTCT&CAGAGATTccGAGTAAGGAGACAAAAccce O980

O981 CACATGGCT&TGAccrccigTact.ccccéAGCAccTGAccTAGAATTACACAcGCCAce 11040

104. GGCCCAAAAcTCACATCAccAAGCCCAGccTCCGCTAGAiGCCGAAGTTCTCTCTCTCTc 1100

11101 CTTCCTGCT&TCTCCATGccACCTGccCAccCCATAccCAATAGCCTCccCAGGGTcccd. 11160

1161. TccCATGCAccTGCTCAATCAGCAGCAAccCAAGAGTGAGGGGTGTCCATTGTGTCTTG 11220

22. TTCACAFCCiCTCACTGTccTTGTAccTGöTCCTTTTCT&TGACCTCTCigGGGATGcti 11280

128 TTTGGGGGAACAGCTGGACAccCTGGAACAACCTCTGGTTGGTCTTGGGGAGGGGAAGA 1340

1341 AAGGCAGAGAAGCAGTATGTTCTGCATGCTTCCCAACGACAGCTCCGAGCCTGGCTGTCT 14 OO

U.S. Patent Jan. 27, 2009 Sheet 38 of 112 US 7482,124 B2

FG. 3L

2541 AGGCTGGACAGAGACCCTCiAAGAGTGACAGATTACAATGCACAGGTCAiGTTAGAACTG 12600

260 TAGTTCTCAAACTTGGCTGiGCATGTCAccTGGAGAGCT iTGAAAAATccTGGTACCTGG 12660

2661 GCCACAT.cccATACCTATTAAATCAGAAccTCTAGAAGTGGCACCTGGGGTTCAGTTTcc 12720

2721 cCAGGTGATiccAATGTGTGGCCATGTTTGGGCATCACT?TGCCTGTTccCTCATCTCCA 12780

12781 TTTTCTCATcAAATACT.cccAAGAATCCTATGCTCCTATATTCTTACCCiCTTTTCATAA 12840

2841 TCAATAGGCitAGAGAAGTfGAATAACTT&TCTAGGATCAGAAGCTAAGGCAAACTGTAA 129 OO

2901 GCTCCTGAAGGAAGCACGGFGCCTGATGCATTGTTTGCCTGGGATCTAGCACAGGGGCTA 12960

12961 AACATAGGAGTGGTGCAGTCCACGATGGGGCAAAATGGCCATGATGTGAGGGAGGCCCAG 13020

3021 TGTGGCTAGGGGAGAGATGGGGGCGAGAGGGGGAATGTTGCTGAAGACAGTTGCTGGGGG 1308O

1308 TCAGCCAAGGTGAAAGGAGAATGCTCATGiGCTGGGTATGGAGAAACTcfc.cccCTTcci 13140

13141 GCCAGGAAtcCTACAGTAGAAAAAGCTGiGCACACTGccCATCCACGccATGGATATcc 13200

1320.1 CGCCACCCACTGGACCCAccTGGGCCCTGGGGGCCACCTTCATCCGAAAGTTCTACACAG 13260

13261 AGTTTGATCGGCGTAACAAccGCATTGGCitcGCCTTGGccCGCTGAGGccCTCTGCCAc 3320

13321 CCAGGCAGGccCTGCCTTCAGCCCTGGCccAGAGCTGGAACACTCTCTGAGATGCCCCTc 13380

.3381 TGCCTGGGCiTATGccCTCAGATGGAGACATTGGATGTGGAGCTCCTGciGGATGCGTGc 34 40

13441 CCTGAcccci GCACCAGcccTTCCCTGCTTGAGGACAAAGAGAATAAAGACTTCATGT 13500

13501 CACAGCCTGTTGCATCTGGGTTCACTAGGGTTTAGAACAGAGGGAGGGGöTGCGTGATCA 13560

13561 TGTGTGGACAGGAATGTGACACAGACAAccTACACATTCGCCTAGCGCACAGGTTCTTGc 1362O

3621 GTGCAGGGATGATGCCATCCATCTGCCATCAACGGGACTCAGGTGGAGCTGTTTACACAA 13 680 U.S. Patent Jan. 27, 2009 Sheet 39 of 112 US 7482,124 B2

FIG. 3M

13681 CCTCAGGTGGGAAGTCTGAAAAGAGCCGGAACCAAGCTccCTCTAGTCCCTCAGGGACCA 13740

13741 AGGCTAATGcTGTGGCAGTAGACTGTGGGTCAGAAAGTTcTCCCAGCTCACAGAAGCCAG 13800 13801 CTCTGAGTTcAGACTCTGct CTGCTGAGCTAGTCAGCCcigTCTCTTGTccCTGCAAAAc 13860

13861 TccCCTCAGcTGTCCTTATcCACTGCAGATGccCCCGCccTGccCCATGiAGCCATTTAC 13920

392. ACAGGCATTcTAAGGCACTACCACCTAAAATCATAGAACACCAGAGATccAGGCAATAct 13980

1398 TCCACTTTAcAGGTGGGGAAACTGAGGCccAGAGAATGGAAGGCCTTGccCAAGATTAct 14 O40

14 O 41 CGGTCAAGAATCAAGTAGTGAAGAATACTGAAAGATAGTGAAGAATCAAGACTGGAAccc 1400

141 01 AGCCCGTCTGACTTGGGTccTGGGGGTTTcCACCTTATCATAAGCAGTTGGTACCGTCAT 14160

14161 AAGTACAGTGCTTCACGCAcGCTGGTACAGGGCCACGTGCACAAGCACACAGGTGCACAC 14220

14221 ACACACTGCfATCCTCCATccCATCCAccfcGGACTCGTcAGGCTGAAGTCTCTTCTCCc 14280

14281 ACTCTCACTcCTTGGGCTGicTTCAGGGCACATGTAACTfGGGGAATGAGAAATTAGCAt 14340

1 4 341 CCACCTGGAGCCACTGAAGcCATCCCTCTiCACCATAGTfGCTCACCTCfCTTTTGACAG 144 OO

4 401 AAAGTCGTGAGGCACTGAAiGGCCCAACCAGGCCCTCAGTACCTCTGGGAGCCATCTGCA 14460

14461 AGAGTCCCTGTGTAGCGCCAAGAGCCGGAGCCTGGGCTTCAGG 14503 U.S. Patent Jan. 27, 2009 Sheet 40 of 112 US 7482,124 B2

FIG. 4A

1. GGTCTTTGTAAAATAATAAFTATTCATTTcACAAAAGTGATAATTAAAAGACTTTAATAG 60

6. CAATACAGAAAGTTACATGAATATAAAGACTTAACCTTTCTAAAGCTCAGTTTTCCTAAG 2O

21 TAATCAAAAAccTGATAAAGATAACAAGAATGAGGAATTATCTTGAGAAAATGTAAAAtc 80

18. TTTCCTTTTATTTTTTGAGACAGGGTCTCACTCTCTCATcCAGGCTAAAGTGCAGTGGCA 2 AO

241 CAATCATAGöTCACTACAccCTTGAACTccTGGACTCAAGTGATCCT.cccGCCTCAGcci 3OO

30 CCCCAGTAGcTAAGACTACAGGCACGCAccACCACACCCAGCTAATTTTTTCAGAGATG 350

361 GGGTCTTGci ATATTGCCCiCGCTGGTCTiGAACGAGCTiCAAGTGAGCGTGAGCCTcci 42O

421 AccTCATcciccCAAAGCAcTAGGATTACAGGCATGAGccACTGTTTcccAGCCTAAAAt 48O

A8. AATTGTTTcf TAGGCCAGCiACCAAAAAccCAAAGAAAAACTTTCTGTAGTGTGATTGci 540

541 TCTTCTTATGGGAAGCCCATTAGATAAccTGTAAGTCAAACCTGATGAAAACAATACT 6OO

6O1 GAATGTAATöAGACACAGAAAGACTGTTCAAGGCTATGAGTAGCTGAGTcCAAGCTCGTA 660

661 TCACTTGccACACAACAGccAATAAGTCTAGAGACAAGGFATTGTGGCAAGGAAAGCTAC 2O

721 CTTATTCAGAGAACCAGAAAACCAAGAAGATGGTGGACCAGCATCATAAAGAACCATCTG 780

781 AAGTCAGCAiGAAcGTTAGGCTCTTCTTTATGTTAAGGGAAGGGGAAGAñGAAGGGGATT 840

841 GGGATCAAGAGGTGACTGATGACCACAGACACCTGGGTGcCAGCAAGGGTCTGAGGACGT 9 OO

9 Ol TGTAAAACTTCTTTTTTCTAGGTCAGGTCACAATGTTCCTATACATCTTAACATAACAF 950

96. TGTTATTTgicTGTATATTTCCTTATCTccTTGGGGGTTAGTTTGGGGAAAGGAACTGT 102O

O2 ACCATTTTTTTTAAAGTTGAACTGCAAccia AACTCCTATAATTAGCTGöTCTATGTACA 1080

1081 GAGCTAAGCAGAAGCTTTTAGCCTAAAGGATAATACCCCTGGGGGTCAGAGGCAAAATGG O U.S. Patent Jan. 27, 2009 Sheet 41 of 112 US 7482,124 B2

FIG. 4B

1141 AGTCAGTCAGCTAAGTCTccCTCCACTCiCTTTCTTTTTTGAGATGGAATTTCACTCTf 1200

1201. ATTGCCCAGGCCGGAGTGCAGTGGCATGAfCTCAGCTCActGCAACCTccGCCTCCTGGG 260

1261 TTCAAGCAAitcTCTTGCCiCAGCCTCCT6AGTAGCTGAGATTACAGGT6tcCATCAcci, 1320

132 CACCCAGCTAATTTTTGTAGTTTAGTGGAGATGGGGTTTCACCATTGTTGGTCAGGCTGG 1380

138. TCTGGAACTCCTGACCTCAGGTGATCTAccCACCTTGGccTCCCAAAGTGCTGGGACAGG 1440

14 A1 TGTGAGCCACCATGCCTGGcCCCTCTACTcTTATAATTAAACCAGCTGTfGCTTTTCCTG 1500

1501 CCAAGAAAccAGTCATGAAGATTCACCCAFGTTCTAGATGGGAAAACTGGGCTGTAGcci 560

156) GGGAGAGGCCAGTCAGGGAcAAAGCCAAAGTTAATATAGAGAATGGAGCTCCAGGGTAt 1620

62 AGGGGTTGGGTCTGGGCTAGGGAGCTGGAAAccTAGGTTTTACGCTTGTccCAGTTTTGA 68O

1681 TGTTAGccci GACCAGTGciGTTTCTCATcAGCCTCTGccTGCTCCAGGGGTCACAGGGc 1740

T41 CAAGCCAGATAGAGGGCTccTAGCGTCAcigGACACAAGATTGCTTTcccACAGCTGTcc 1800

1801 TTCCTCCAccCCCTCTCCT.cccCATCCGGAAAccTGGGTAccCTTCACccACCTAGCTct 1860

1861 GTCCCGCAGTGAGATTTATfGCTGACTGccCTGcCATCTâccCCAGGGTAATAAATCAGG 1920

1921 GCAGAGCAGAATTGCAATCACCCCATGCATGGAGTGTATAAAAGGGGAAGGGCTAAGGGA 1980

1981 GCCACAGAAccTCAGTGGArcTCAGAGAGAGCCCCAGAcicAGGGAAGCATGGATGGATG 2040

2041 GAGAAGGAT&cCTCGCTGGGGACTGCTGciGCTGCTCTGGGGCTCCTGTACCTTTGGTcf 200

2101 CCCGACAGAcACCACCAccitTAAACGGTAATTGGTAAcicAGGCAGAGAAGGGGTGGGA 21 60

21 61 GGGGTGCAGGGTTCCCAcci TCCCAACAcccTGGCTTTTcCACATGCGGiGTCATTCAGi 2220

222 CCTTACGATCAGCTGGACAGGGAAGTATGGACCTGTTCAGAGAGGTCAAGTGACTTGCCC 2280 U.S. Patent Jan. 27, 2009 Sheet 42 of 112 US 7482,124 B2

FIG. 4C

2281 AATAAATGACACTAGTAGTcAGGTCTAGAñGCTGTGActiTTGCTTCCT&ccCAGAGCAc 2340

234 CATGCTAACTAAGCACTGTAGAGAACTCAGAAGTATTAGéACATGcccci TGCACTTGAG 2400

24O1 GAGCTCACAGCCTGAATAttaAGAAGGGCATGGGTGGttégGCGCGGTGGCTcCTGCCTG 24 60

24 61 TAATCCCAGcACTTTGGGAGGCTGAGACGGATCACTTGAGGTCACGAGT iTGAGACCAGé 2520

2521. CTGGCCAAcATGGGGAAAccCCATCTCTAct AAAAATACAAAAATTAGccGGGCATGGTG 2580

258 GCAGGCACTfGTAAtcCCCAGCTACTCGGGAAGCTGAGGcAGGAGAATCGTTTGAGCCCG 2640

2641 GAAGGTGGAGATTGCTGAccCAAGATCGTGCCACTGCACTCCAGCCTGAGTGACAGAACA 2700

27 O1 AGACTCCATcTCPAAAAAAAAAAAGACGGGGGTCGGGGCATGGGTACAGiTAACTGTAcc 27 60

261. AGGGAAGCAGCTTGATATcGTGGTTAAATGCAAGCCTTATAGACTTAGATTGCCTTCATf 2820

282 TAAATTTTGCTTCACTAGCAGAACAAACTAGGTCTGGAATCATGGGCAAGTTATTTAAcc 288O

2881 TCTCCAAGTcTCAGTTTATcATTTTAAACAGGTATGATAATAACAGTAccTACTTGATGG 2940

2941 GGCTGCTTTGGGGATTTTAGGAGATAAGGCATAGAAAGCTGGGCACGTTGTAAGAGCCCA 3OOO 3001 GCTACTGTTAGTACTACAGGATAGATTCTTACAAATATCAAAAGCAAGGTTTGGCCGGGA 3060

306. GCAGTGGCTéACGCCTATAATCCCAACACitTGGGAGGccGAGGGGGGCAGATCACCCGA 32O

31.21 GGTCAGGAGirCAAGACCAGCCTGACCAAcATGGAGAAAccCTGTCTCTACTAAAAATAC 38O

3181 AAAATTAGccGGGCGTGGTécCACATGccigTAATTCCAGCTACTTGGGAGGCTGAGGCA 324 O

3241 GGAGAATCGöTTGAACCTGöGAGGCTGAGGTTGCAGTGAGCCGACATAGcGCCATTGCAc 3300

3301 TCCAGCCTGGTCAACAAGAGCAAAACTCAGTCTAAAAAAAAAAAGAAAGAAAAAAACAii 3360

3361 GGCTTTAGGTAGCCCACAATTAGAAGGAGAAAACCTTAGCATCCCCTAGGTGCCAGGCCT 3420 U.S. Patent Jan. 27, 2009 Sheet 43 of 112 US 7482,124 B2

F.G. 4D

3421 TGTGGGAACAAGTGATTCATAAGACTGTAGAAGGAAGCTGGGCACGCGGCTCATGCTTG 3480

34 81 TAATTCCAGcACTTTGAGAGGCTGAGGTGGGCAGATCGCiTGAGCTCACGAGTTCAAGAc 3540

3541 CAGCCTAGGcAACATGGTGAAACCTTGTcf GTACAAATACAAAAATTAGGTAGGTGTGGT 3600

360 GGTGCAAAtcTGTAGTCCCAGCTACTCGGGAGGCTGAGGiGGGAGCATCACTTCAGCCTG 3660

3661 GGAGGTGGAGGCTGCAGTGAGCAGAGACTGACCCACTGTGCTCTAGCCTGGGTGATAGAG 3.720

3721 CCAGACCTTATGTAAAAAAAAAAAAAAAAAAAAAAAAGACTGAAGAAGGGGAAGAGACAG 378O

3781 CATTTGAGAAAGGCCTCACAGAGAAAGGGGTTTTCAAtcTGGGGACAGCAGATATGAcc 384 O

3841 AGCAGTCCTGAAGGTAGGGAGGCACACTTi AATAATGGTAATAGTTGCTAAGCCTATAAA 3900

390. ATCCTTAGGGTGTCACAGGATCTTTTCACATGTCTCATcf CAAGTCATGccCCCAACAAc 3960

396 TCAGCATTccCACTTTGCAGATGAGGACACTGAGGCTCAGGGAGGTGATATGTAAGAGGc 4020

402 TAAGCCTCAACACACACTGcGCCTTTTGcitccGAAACTGCTTTCCCTTGCTCTGAGGCf 4 080

4081 CTCGGAGAGTAATTGCTGGGTTGTGAGCACTGGGTAAGAGGATGGGTGcitCAAAGCAcc 41. 40

4141 TGCACTCCAGGATAAAGGTAGAGGAAAGTAAAAACATcticcCCTGCTGf TATCCAAAAG 4200

42O1 AGAAAAAGAATGGAATTGGGCAAGGGGTGGAGGGGGAATcCAGCTTTTGAAACAGTATTA 4260

4.261 TAGGAATTTfGCTAccCGCfATGTGCAGAGCATCATGCGAGGCACTTGGGACAGCTGAAt 4320

A321 GAATGAGCTcCATTCTCAAGGTGAACATGTACATATACACACCTACAATTACATTTATf 4.380

4381 GAGCAGTGGrcGCATGGTTTCATCTGCACAGTGACTCTGAGGTAGGTAct ACCATTAGGc 4 440

444 l CCATTGTTAGAGAGGGGTTAATGGAGACTTAGAAGAGGccCAGAGAGGTTAGGTAGCTTf 4500

450 CTCAGAATCACATAAGTGGTAAGGGGATTCAGGCATGCCCCCTGCAACCACTGTCTTCAC 45 60 U.S. Patent Jan. 27, 2009 Sheet 44 of 112 US 7482,124 B2

FIG. 4E

456) CACCGTAccGCACCAGTTccACAAGCTGTACAGTGTGGGCTGTGAGAcccAAGGAAAAAC 4 620

4621 AGAGCTGAGéccCACGGGAñGGTGAGGccGGTGTGGGCTGGAGGCCTTGGGGTAAGCTTC 4680

468 CTGGAGGTGGGGGTACATGTGGGCCTTGGAGGACTAAAGAACTGGGGGGAAAAGGAAGG 4740

4741 GAAGAAGGAAAGGATTTTCigAAAAGGAAATGGCAAGAAGTAAAGGTCCAAAGCATAGGC 4800

4801 TGTTGTGAGAAACAGTGGGAAATGCAAccTCTTTGGGGcCAAACCTCTGAccCTCCAcG 4860

A 861. TTCCCAGCTGTGAAGTGGGAGTAATAAAATCATCCACCTTATGAGAGCAAATAAAATAAt 4920

49.21 GATTGTGAAAATATTTTGGTAACAGTAAccTGTGATAGGAAGATAACAAATCATTTCTGT 4980

4981 TACAATACCATGCTGATAGGCATAAAAGTfGCATTCATGiTCATGGGCAAAATGGGGGTA 5040

5041 AGTAGAATGcATGGGACGCAAGAAGGATGTAGGAAGGAAAGGGTAGTGTGAGTATAGGAG 51OO

5 O. GACTAGCCACTGAGAAGAAAGTAGAAGAAAGAGGGAATCitTGTGTGTATGGGAAAGTct 5160

5 161 ATTGCAGAGlicAACTTGGGöTTCCATCCTGGGACCTTCccGTGAACAGCiAGAGACAtci. 5220

5221 TCCTCTGGGöTTGGCAGccTTTATGTCGGGACCCAGGGGACCCTATATGGGAAATAGGG 5280

5281 CCAGACACAiGCTCTGAATcCCTGCTTCACATTTCTGAGTCACCTTTGiccCTGTGAcc 5340

5341. CTTCAtticTCATCTATñAAATGGATGáCAGCTAGCTigtTGGTGTGäTTTCAGTAcc 54.00

5401 GGCTCAGTAGAGTCAGTTTCCTAGGTCTCitTAATTCTGcCTCTCAAAGGTGATGGGAAA 54.60

546 ACATCTAGACAAGAAGCCAAGGGAccGGGACACATCTCTcCAAGGACGAGGTGCATGGce 55.20

5521 CTCTGAAGAiGCTGGCATcfcTCTAGGcceAACCCAGCTcAGGGGGTcc?CTCCACCACA 5580 5581 GccCTGGCTGGGTCCCTGT.cccCTGGTArcCTGGAGAcci TGCAGCTGciGTGGGCAtci. 5640

56.41 GCTGCCACCTAGCGGCCTCCCAGGCACTGTCTCCCCGCCAGCCCCTAGTTTTGACAGGG 5700

U.S. Patent Jan. 27, 2009 Sheet 47 of 112 US 7482,124 B2

FIG. 4H

7981 TGTGGATGTTTTTGCATCTAACTTGCATGTAGGGCTTGTcCTGAGccccGTGGCTGCAct 804 O

8041 CAAGTAACTcGTCCAAGTTcACCAGCTCTGACTGGGCTACACCCTAGAct GAAATCCAGG 800

8101 GTCAGAGTCAGGCTGAGTTTTAGGGTCAGGCATAGGTTTTAAGGTCACAGTTGAGGTTGA 81 60

8161. CTCTGGGAcfcAGGTCAAGGCCTGCTTTTcTTTTCCATGiGGccCATGTcTGAccGTTTc 8220

8221 CTCATCCTGGAGTTTCTCAGGCCCTGCTccATCAGAGTTAGGGGAGGGGöACACGTGGCA 828O

8281 CCTGAGAGGAAATCAGGGTGATTCCTGCCiCCCTTCCTTTTTCTGTGAACTCAGATATAA 8340

8341 AGGAGGGAGAAGGGCAAGCTTGTCTGTGci AAAGAAAcccTTCGCCCATGATAAGGGTGG 84 OO

84 O1 GGGCCAAGAccCAGTCCTGcCAGGCACGAAAGTCTGGCCACTGGGGAGGGGAGGAGCTct 84 60

8461 TGGCAGCTTTTCTTTTGCTGCTTGGCAGGACCACCCTCTcAGCCTCTCCiCTCCGATCCc 8520

852. TGGTCAACTcTAGCTCTCTCTGGGCTCCGcAGCAGAGATGTGTATTGGCACAGAGTGTGi 8580

8581 GCGTGCAGGGTTGAGGAAATACTCTTACccCGATTTCTGTACCCTGGAG?ATGTGTG.ccc 864 O

8641 CTGGGATCccTAGTGTGGAAGCCCAGACCAGACTCCAAccAAGGAGTGGGCAGTGGGCTf 8 700

87 O1 GGTCTCCTcf GGTCCTTCCiccCACAGGTGGGTGGAATCACGGTGACACAGATGTTTGGA 8 7 60

8761 GAGGTCACGGAGATGCCCGcCTTACCCTTcATGCTGGCCGAGTTTGATGGGGTTGTGGGé 882O

8821 ATGGGCTTCATTGAACAGGcCATTGGCAGGGTCACCCCTATCTTCGACAÁCATCATCTcc 8880

8881 CAAGGGGTGcTAAAAGAGGACGTCTTCTCitTCTACTACAACAGGTGGGGACTGGGACTc 8940

8941 CAAGGGCTGAGGTGGGGGGACAGGAGGGG?GAAGAGATGGGGAGTGGAAGGAGAGTCTGG 9000

9 OO GCCAGAATTGTAAAGTGTTfGTAATTAGGTGACAGCCAATCAATATCTAGAGCTGTACTA 90 60

9061 GCCAATATGGAAGGCACTATTGAAATTTAAATTAATTAAATACAGTTAAGCATCAATTAA 912O U.S. Patent Jan. 27, 2009 Sheet 48 of 112 US 7482,124 B2

FIG. 4

912 GCATTCAAcicGTGGCTCTTAGTTGTACTAGCCACACGT CAAATGCCTGGCAGCCACGGr 9180

91.81 GGCTAGTAActACAGTCTTATGACAGTGCAGATAGAGAAATTCCCAGCATGACAGGACA 9240

9241 TTCTAATAGACAGCGCCAci CTGGAGCAAGAGGAGATGCAAGGTGGGGGcGATGGTAAAt 9300

9301 AAGGGATTACTGTGACCTGTAGCCCTGcci GTTAGGGCCATGGCTCCTccCACACAGAGA 9360

9361 CAGCCAActicAGTCATcc?TTAGATCCTTCATTCGTTT GTTTGCTCAcicATCAGTTCA 9420

94.21 GTAAATGCTATGTGCCAAGcACTGTGGTAGGCTCTGGGGGTGCAGCAGT6AACACAGTGA 94.80

9481 ACAAGGCAGAATCTGTACTccCCTACCCACATAGAGCTTACAGGCTAACAGGGAAGACAA 95.40

9541 GACATATTccAACATAAAGAGTGTCACAGGCAGCCAGCAAGTGTGGTGciGAAAACCATG 96.OO

96O1 GATGCTTTTcAATTCTAGGöTGAGCTTATATGCAGCTCAGCCAGCCTTGGGGAAGCTCT? 9 660

9661 GAGCAGGGrigGGCTCTAcicCAAACTGciGGGCTTAGAAAGATGGCATéAGTTGGAGAC 972O

97.21 AAGAGAGCTGGAGCCAAAAGGGGCTGGGTGCAGTGGCTCATGCCTGTAAFCCCAGCACTf 978O

9781 TGGGAGGCCAAGGCGAGAGGATCGCATGAGCCCAGGAGTi AAGGCTTCAGTGAGCAGTGA 984 O

98.41 TTGTGCCAcigCACTCCAGöTAAGGCAACAGAGTGAGATcCAGTCTCAAAAAAAAAAAAA 9900

99.01 AAAAAAAAAAAGTCACAAGGGTAAGAACAFGAGGCCAGTGGCAAAAAGAATAGAGGAGAG 9960

99.61 GATCAGAGTiCAGAGAAATéTCACAGTAAAATGGAGAGGñGTCTCCGGTTTGGTGATAGA OO20

10O21 AAGTGAGGCCTTGAGAAAAGGCCAATTGGcGGCTCTGCATTCAGGGGTGGTCTTTAGAAG 10O80

10081 AACTGTTTTAGAGGAgSTGGGGGCAAGGCCAGATGGCAAGAAGTTAAGAGGTGGACGACG O140

101.41 TGGGTGTCAGGAAGTGGAGGTCATGAGATGTAGGCTGccöTGGGACATT?AACAGGGAAG 10200

10201 GGAATGGGGGGTGGCGTGGGGGGTGAGATCCAGAAGCAGAAGAGGAAGGGTGGGTGTTTT O260 U.S. Patent Jan. 27, 2009 Sheet 49 of 112 US 7482,124 B2

FIG. 4.J.

10261 TAAATGCTAGAGGATGCTCGAGTGATGccfgtAGGTGGAGGAAGAAGCCAATGGAAAGAA 1032O

1032 AGAGATTAAAAATGTGGAAAGAAGAGGAccTAAATGGGGGCACTGGAGTFTGGAGGCCT 10380

10381 GAAAGAGATGAGGTTCCAGcAGACAGGAAGAAGCCAGGTTTTGCAGAGGAGAGGGCTGGc 104 40

10A 41 CTCTTCTTTTATCTTGGGArcGGAAGGAGGGAACATCCAGAGAGATACTGAAGTGTTGAG 10500

10501 AGACAGGCAGGAGGGAATTfGTGCTAGCAiiATACACATACATTCCGAAti TATAAAAACA 10560

1056 CAAGTAGTTfGCAGTTGCAcAAAATAACAATGCACAcci ACACAccCATGCACACATGi 10620

10621 GCATGTGTGAATTCTAGTATGAATTCTGGAAAAACACATcACACACACAGGCATGCCCTé 10680

1068. GAGACTAGGcCTACAGTAGTCCCTGAGCCAAGTGCAGTGAGGAGGAAAGGAAGGTGAGGG 10740

10741. GAATCAGCTcCAGACGGGGcACCAGGAGCcTGGCTCCAGTCCCCCACTTGTTCACTCATG 10800

10801 GACTGGGTAÁCTTCAGGCAÄGTGACTTCGcCTCTTGGTGACTCCATTGccTGAAGGGCAA 10860

1086 AGAGAGTACATAACACCCAccCTGCCAAACAGCAGGGCTGATGAGGCTGGCATGAAATGA 10920

10921 AGCTTCCTTi CTGCTGTCrcTCTTTCTCTGCAGAGATTccGAGTAAGGAGACAAAAcccc. 10980

10981 CACATGGCTGTGACCTTCCAGTACTCCCCGAGCACCTGAccTAGAATTACACACGCCAcc 1040

11041 GGCCCAAAACTCACATCAG?AAGCCCAGccTCCGCTAGATGCCGAAGTTcTCTGTCTCTc 11100

1110 CTTCCTGCTCTCTCCATGccACCTGccCAccCCATAccCAATAGCCTcccCAGGGTccce 11160

1116 TCCCATGCAccTGCTCAAtcAGCAGCAAccCAAGAGTGAGGGGTGTCCATTGTGTCTTG 11220

11221 TTCACATcCACTCACTGTccTTGTACCTGcTCCTTTTCT GTGAccTCTcf GGGGATGCTf 1128O

11281 TTTGGGGGAACAGCTGGAciACCCTGGAACAACCTCTGGiTGGTCTTGGGGAGGGGAAGA 11340

11341 AAGGCAGAGAAGCAGTATGTTCTGCATGCTTCCCAACGACAGCTCCGAGCCTGGCTGTCT 1 400 U.S. Patent Jan. 27, 2009 Sheet 50 of 112 US 7482,124 B2

FIG. 4K

140 GTCCCACAttcCTCTGCTct AGAGCCCTcigTCCTCCCcigCAccCTTGiGCAAccTTcc 11460

11461 CCAATTGcci GAGTTGCTGGGTCCTGGAGGTTATGGGTTicCAAGAGCticTGATCTTTé 1152O

1152. CTTTAGGAATTCCCAATCGCTGGGAGGACAGATTGTGCTGGGAGGCAGcGACCCCCAGCA 1580

11581 TTACGAAGGGAATTTCCActATATCAAccicATCAAGAciGGTGTCTGG?AGATTCAAAt 1164 O

1164. GAAGGGGTCAGAAATCCTCAACCCTCCCCGGGCTCCAAAAAATGCTGCCGTCACTGGGGi 11700

1170. TGGGGAGGGTGGGGAAGGACTGCATTACCATCCTGCCCTctTTCCAAATéCAGCCActre 11760

1176 TTAAGCACAGCCACCATTTGCTCTCTGCCTGCTCTGTCCAGGCTGGGGAACAGAGAAGGG 11820

11821 AGGGGCCTGGGGAGAAGTGGTGGAGGGTGACAGTACCTTccCTCCTCTACTCACTGCCTc 11880

11881 AACAGGCCACCAGCGTGGCCTCCACCCAccCACCCACACTCAGGAAGGACATGCAGCCT6 1940

119A1 GAGGTG.ccccATCAGCCTTcTGTCTGTCTGTCTGTCTGTcTGTCTGACTGTGGCCTCCCc 12 OOO

12001 CAGGGTGTcf GTGGGGTCATCCACCTTGcircTGTGAAGAcGGCTGCCTGGCATTGGTAGA 12060

12O6 CAccGGTGcitcCTACATcf CAGGTTCTAccAGCTCCATAGAGAAGCTCATGGAGGCCTf 12120

1212 GGGAGCCAAGAAGAGGCTGiTTGATGTAAGAAGCCAAAGAGGGAAGGTGcTGTGGGTGGG 1280

1218. GGGAGCGCCACCTGGTATCGGCTCACAAATCCCCCAGGCAAATGAGGCCATCTCAGGCct 12240

2241 TCGCTTGTTcACCTCACAct CTCCACACAiGTGGCTGGTcAccCATGGGGCGGGGCACTG 12300

1230 TcccCAG.cccTCTCCAGCAGAGAGACCAGGCCACCAGCGöAGGACTCCTfGTCTGCTGAG 2360

12361 ACGTCTTccATACTCAAGAAGGCTCTCTTfGCCCCCCAcccCAGTATGTcGTGAAGTGTA 12420

12421 AcGAGGGcccTACACTcccGACATCTCritcCACCTGGGAGGCAAAGAATACACGCTCA 248O

24 81 CCAGCGCGGACTATGTATTTCAGGTGAGGTTCGAGTCGGCCCCCTCGGTGGCAGGGAGAA 1.25 40 U.S. Patent Jan. 27, 2009 Sheet 51 of 112 US 7482,124 B2

FIG. 4L

12541 AGGCTGGACAGAGACCCTCAAAGAGTGACAGATTACAATGCACAGGTCATGTTAGAACTG 2600

26O1 TAGTTCTCAÅACTTGGCTGiGCATGTCAccTGGAGAGCTtTGAAAAATccTGGTACCTGG 1266 O

12661 GCCACAT.cccATACCTATTAAATCAGAAccTCTAGAAGT&GCACCTGGGGTTCAGTTTcc 1272O

12721 cCAGGTGAticcAATGTGTGGCCATGTTTGGGCATCACTATGCCTGTTccCTCATCTCCA 12780

278. TTTTCTCATcAAATACTcccAAGAATCCTATGCTCCTATATTCTTACCCiCTTTTCATAA 284 O

1284 TCAATAGGCitAGAGAAGTfGAATAACTTGTCTAGGATCAGAAGCTAAGGCAAACTGTAA 12900

12901 GCTCCTGAAGGAAGCACGGiGCCTGATGCATTGTTTGccigGGATCTAccACAGGGGCTA 12960

12961 AACATAGGAGTGGTGCAGTcCACGATGGGGCAAAATGGCCATGATGTGAGGGAGGCCCAG 1302O

1302. TGTGGCTAGGGGAGAGATGGGGGCGAGAGGGGGAATGTTGCTGAAGACAGTTGCTGGGGG 3O8O

3081 TCAGGCAAGGTGAAAGGAGAATGCTCATGFGCTGGGTATGGAGAAACTcfcCCCCTTCCT 13140

13141 GCCAGGAAtcCTACAGTAGFAAAAAGCTGiGCACACTGGcCATCCACGCCATGGATATcc 13200

132O1 CGCCACCCAcTGGACCCAccTGGGCCCTGGGGGCCACCTiCATCCGAAAGTTCTACACAG 1326O

13261 AGTTTGATCGGCGTAACAAccGCATTGGCitcGCCTTGGccCGCTGAGGccCTCTGCCAc 1332O

1332 cCAGGCAGGccCTGCCTTCAGCCCTGGccöAGAGCTGGA?CACTCTCTGAGATGCCCCTc 1338O

13381 TGCCTGGGCitATGccCTCAGATGGAGACATTGGATGTGGAGCTCCTGciGGATGCGTGc 1.34 40

13441 CCTGACCCCFGCACCAGCCóTTCCCTGCTitGAGGACAAAGAGAATAAAGACTTCATGT 13500

1350 CACAGCCTGTGCATCTGGGTTCACTAGGGTTTAGAACAGAGGGAGGGGGTGcGTGATCA 13560

13561 TGTGTGGACAGGAATGTGACACAGACAAGCTACACATTCGCCTAGCGCACAGGTTCTTGc 13620

1362. GTGCAGGGATGATGCCATCCATCTGCCATCAACGGGACT CAGGTGGAGCTGTTTACACAA 1368O U.S. Patent Jan. 27, 2009 Sheet 52 of 112 US 7482,124 B2

FIG. 4M

13681 CCTCAGGTGGGAAGTCTGAAAAGAGCCGGAACCAAGCTccCTCTAGT.cccTCAGGGACCA 13740

13741 AGGCTAATGcTGTGGCAGTAGACTGTGGGiCAGAAAGTTctCCCAGCTCACAGAAGCCAG 13800

1380 CTCTGAGTTcAGACTCTGcicTGCTGAGCfAGTCAGCCciGTCTCTTGTccCTGcAAAAc 13860

13861 TcccCTCAccTGTCCTTATccACTGCAGATGccCCCGCccTGCCCCATGTAGCCATTTAC 13920

13921. ACAGGCATTöTAAGGCACTACCACCTAAAATCATAGAAcÁCCAGAGATccAGGCAATAct 1398O

13981 TCCACTTTACAGGTGGGGARACTGAGGCCCAGAGAATGGAAGGCCTTGccCAAGATTAct 14040

14041 CGGTCAAGAATCAAGTAGTGAAGAATACTGAAAGATAGTGAAGAATCAAGACTGGAACce 14100

1410 AG.cccGTCTGACTTGGGTccTGGGGGTTTcCACCTTATCATAAGCAGTTGGTAccGTCAt 14160

1461 AAGTACAGTéCTTCACGCAcGCTGGTACAGGGCCACGTGcACAAGCACAcAGGTGCACAC 14220

14221 ACACACTGciaTCCTCCATccCATCCACCiCGGACTCGTcAGGCTGAAGicTCTTCTccc 1428O

14281 ACTCTCACTCCTTGGGCTGTCTTCAGGGCACATGTAACTTGGGGAATGAGAAATTAGCAF 4340

14341 CCACCTGGAGCCACTGAAGcCATCCCTCTTCACCATAGTfGCTCACCTCiCTTTTGACAG 14400

14401 AAAGTCGTGAGGCACTGAAiGGCCCAAcc?GGCCCTCAGTACCTCTGGGAGCCATCTGCA 14. 460

14461 AGAGTCCCTGTGTAGCGCCAAGAGCCGGAGCCTGGGCTTCAGG 14503 U.S. Patent Jan. 27, 2009 Sheet 53 of 112 US 7482,124 B2

FIG. 5A

GGTCTTTGTAAAATAATAAiTATTCATTTCACAAAAGTGATAATTAAAAGACTTTAATAG 60

61 CAATACAGAAAGTTACATGAATATAAAGACTTAACCTTTcTAAAGCTCAGTTTTCCTAAG 12O

121 TAATCAAAAACCTGATAAAGATAACAAGAATGAGGAATTATCTTGAGAAAATGTAAAATc 18O

181 TTTCCTTTTATTTTTTGAGACAGGGTCTCACTCTGTCATcCAGGCTAAAGTGCAGTGGCA 24 O

241 CAATCATAGötCACTACAGcCTTGAACTccTGGACTCAAGTGATCCT.cccGCCTCAGcci 300

301 CCCCAGTAGcTAAGACTACAGGCACGCACCACCACACCCAGCTAATTTTTTCAGAGATG 360

361 GGGTCTTGciatATTGcccigGCTGGTCTTGAACGAGCTiCAAGTGAGcGTGAGCCTcci 420

421 ACCTCATCCiCCCAAAGCACTAGGATTACAGGCATGAGccACTGTTTCCcAGCCTAAAAt 48O

48 AATTGTTTcf TAGGCCAGCiACCAAAAAcGCAAAGAAAAACTTTCTGTAGTGTGATTGCf 54 O

541 TCTTCTTATGGGAAGCCCATTAGATAAccTGTAAGTCAAACCTGATGAAAACAATACTf 600

601 GAATGTAAtcAGACACAGAAAGACTGTTCAAGGCTATGAGTAGCTGAGTcCAAGCTCGTA 660

661 TCACTTGCCACACAACAGCCAATAAGTCTAGAGACAAGGTATTGTGGCAAGGAAAGCTAc 72O

721 CTTATTCAGAGAACCAGAAAACCAAGAAGATGGTGGACCAGCATCATAAAGAACCATCTG 780

781 AAGTCAGCATGAACGTTAGGCTCTTCTTTATGTTAAGGGAAGGGGAAGAAGAAGGGGATf 840

841 GGGATCAAGAGGTGACTGATGACCACAGACACCTGGGTGcCAGCAAGGGTCTGAGGACGi 900

901 TGTAAAACTicTTTTTTCTAGGTCAGGTCACAATGTTCCTATACATCTTi AACATAACAF 96.O 961 TGTTATTTgicTGTATATriccTTATCTccTTGGGGGTTâGTTTGGGGAAGGAACTGTi 1020

1021 ACCATTTTTTTTAAAGTTGAACTGCAAGCiAAACTCCTATAATTAGCTGGTCTATGTACA 108O

1081 GAGCTAAGCAGAAGCTTTTAGCCTAAAGGATAATACCCCTGGGGGTCAGAGGCAAAATGG 114 O U.S. Patent Jan. 27, 2009 Sheet 54 of 112 US 7482,124 B2

FIG.SB

114 1 AGTCAGTCATGCTAAGTCTccCTCCACTCTCTTTCTTTTTTGAGATGGAATTTCACTCTf 1200

1201. ATTGccCAGGCCGGAGTGCAGTGGCATGArcTCAGCTCAcTGCAAccTccGCCTCCTGGG 1260

261 TTCAAGCAATTCTCTTGccrCAGCCTCCTGAGTAGCTGAGATTACAGGTGTCCATCACCA 1320

1321 CAccCAGCTAATTTTTGTAGTTTAGTGGAGATGGGGTTTcACCATTGTTGGTCAGGCTGG 1380

138 TCTGGAACTcCTGACCTCAGGTGATCTAccCACCTTGGccTCCCAAAGTGCTGGGACAGG 1440

144. TGTGAGCCAcCATGCCTGGccCCTCTACTcTTATAATTAAACCAGCTGTfGCTTTTCCTG 500

150 CCAAGAAAccAGTCATGAAGATTCACCCAiGTTCTAGATGGGAAAACTGGGCTGTAGcci 15 60

15 61. GGGAGAGGCCAGTCAGGGACAAAGCCAAAGTTAATATAGAGAATGGAGCitcCAGGGTAf 1620

621 AGGGGTTGGGTCTGGGCTAGGGAGCTGGAAAccTAGGTTTTACGCTTGTccCAGTTTTGA 1680

1681 TGTTAGcccrgAGCAGTGciGTTTCTCAT CAGCCTCTGccTGCTCCAGGGGTCACAGGGc 1740

1741 CAAGCCAGATAGAGGGCTGCTAGCGTCAcfcGACACAAGATTGCTTTCCöACAGCTGTcc 800

1801 TTCCTCCAccccCTCTGCTcccCATCCGGAAccTGGGTAccCTTCAccöAccTAGCTcf 1860 1861 GTCCCGCAGTGAGATTTATfGCTGACTGccCTGCCATCTAccCCAGGGTAATAAATCAGG 1920

1921 GCAGAGCAGAATTGCAATCACCCCATGCATGGAGTGTATAAAAGGGGAAGGGCTAAGGGA 1980

1981. GCCACAGAAccTCAGTGGAFCTCAGAGAGAGCCCCAGAcrgAGGGAAGCATGGATGGATG 2O40

2041 GAGAAGGATGCCTCGCTGGGGACTGCTGciGCTGCTCTGGGGCTCCTGTACCTTTGGTcf 2100

2101 CCCGACAGAcACCACCACCTTAAACGGTAATTGGTAAcfcAGGCAGAGAAGGGGTGGGA 260

21 61 GGGGTGCAGGGTTCCCAcci TccCAACAcccTGGCTTTTcCACATGcGGiGTCATTCAGi 2220

2221 CCTTACGATCAGCTGGACAGGGAAGTATGGACCTGTTCAGAGAGGTCAAGTGACTTGCCC 2280 U.S. Patent Jan. 27, 2009 Sheet 55 of 112 US 7482,124 B2

F.G. SC

2281 AATAAATGACACTAGTAGTcAGGTCTAGAAGCTGTGACTitTGCTTCCTGCCCAGAGCAC 2340

2341 CATGCTAAct AAGCACTGTAGAGAACTCAGAAGTATTAGGACATGccCCTTGCACTTGAG 2400

24 O1 GAGCTCACAGCCTGAATAti AAGAAGGGCATGGGTGGTTGGGCGCGGTGGCTCCTGCCTG 2460

246 TAATCCCAccACTTTGGGAGCCTGAGACGGATCACTTGAGGTCAGGAGTTTGAGACCAcc 2520

2S21 CTGGCCAAcATGGGGAAAccCCATCTCTACTAAAAATACAAAAATTAGccGGGCATGGTG 2580

2581 GCAGGCACTigTAATccCCAGCTACTCGGGAAGCTGAGGöAGGAGAATCGTTTGAGCCCG 2640

2641 GAAGGTGGAGATTGCTGAccCAAGATCGTGcCACTGCAcfcCAGCCTGAGTGACAGAACA 27 OO

2701 AGACTCCATcTCAAAAAAAAAAAGACGGGGGTCGGGGCATGGGTACAGFTAACTGTAcc 2760

2761 AGGGAAGCAGCTTGATATcGTGGTTAAATGCAAGGCTTATAGAGTTAGAiTGCCTTCATf 2820

2821 TAAATTTTGcTTCACTAGCAGAACAAACTAGGTCTGGAATCATGGGCAAGTTATTTAAcc 2880

288 TCTCCAAGTCTCAGTTTATcATTTTAAACAGGTATGATAATAACAGTAccTACTTGATGG 2940

2941 GGCTGCTTTGGGGATTTTAGGAGATAAGGCATAGAAAGCTGGGCACGTTGTAAGAGCCCA 3000 3001 GCTACTGTTAGTACTACAGGATAGATTCTTACAAATATCAAAAGCAAGGTTTGGCCGGGA 3060

3061 GCAGTGGCTCACGCCTATATCCCAACAct TTGGGAGGccGAGGGGGGCAGATCACCCGA 31.20

321 GGTCAGGAGFTCAAGACCAGCCTGACCAAcATGGAGAAAccCTGTCTCTACTAAAAATAC 318O

3.81 AAAATTAGccGGGCGTGGTGGCACATGCCFGTAATTCCAGCTACTTGGGAGGCTGAGGCA 324 O

324 GGAGAATCGCTTGAACCTGGGAGGCTGAGGTTGCAGTGAGCCGACATAGcGCCATTGCAC 3300

33O1 TCCAGCCTGGTCAACAAGAGCAAAACTCAGTCTAAAAAAAAAAAAGAAAGAAAAAAACAA 3360

336 GGCTTTAGGTAGCCCACAATTAGAAGGAGAAAACCTTAGCATCCCCTAGGTGCCAGGCCT 342O U.S. Patent Jan. 27, 2009 Sheet 56 of 112 US 7482,124 B2

FIG.SD

3421 TGTGGGAACAAGTGATTCAFTAAGACTGTAGAAGGAAGCfcGGCACGCGGCTCATGCTTG 3480

3481 TAATTCCAGCACTTTGAGAGGCTGAGGTGGGCAGATCGCitGAGCTCAcGAGTTCAAGAc 3540

3541 CAGCCTAGG?AACATGGTGAACCTTGTCiGTACAAATACAAAAATTAG?TAGGTGTGGi 3600

360 GGTGCAAATctGTAGTCCCAGCTACTCGGGAGGCTGAGGiGGGAGCATCACTTCAGCCTG 3660

3661 GGAGGTGGAGGCTGCAGTGAGCAGAGACTGAccCACTGTGCTCTAGCCTGGGTGATAGAG 3.720

3721 CCAGACCTTATGTAAAAAAAAAAAAAAAAAAAAAAAAGACTGAAGAAGGGGAAGAGACAG 3780

3781 CATTTGAGAñAAGGCCTCACAGAGAAAGGGGTTTTCAATcTGGGGACAGcAGATATGAcc 3840

3841 AGCAGTCCTGAAGGTAGGGAGGCACACTriAATAATGGTAATAGTTGCTAAGCCTATAAA 3900

3901 ATGCTTAGGGTGTCACAGGATCTTTTCACATGTCTCATcfcAAGTCATGccCCCAACAAc 3960

3961 TCAGCATTccCACTTTGCAGATGAGGACACTGAGGCTCAGGGAGGTGATATGTAAGAGGc 4020

4021 TAAGCCTCAÄCACACACTGGGCCTTTTGcitcCGAAACTGCTTTCCCTTGCTCTGAGGCf 408O

4081 CTCGGAGAGTAATTGCTGGGTTGTGAGCAcTGGGTAAGAGGATGGGTGci TCAAAGCAGé 4140

441 TGCACTCCAGGATAAAGGTAGAGGAAAGTAAAAACATCTTCCCCTGCTGFTATCCAAAAG 4200

42O1 AGAAAAAGAATGGAATTGGGCAAGGGGTGGAGGGGGAATcCAGCTTTTGAAACAGTATTA 4260

4261 TAGGAATTTfGCTACCCGCiATGTGCAGAGCATCATGCGAGGCACTTGGGACAGCTGAAt 4320

4321 GAATGAGCTcCATTCTCAAGGTGAACATGiACATATACACACCTACAATTACATTTATf A380

4381 GAGCAGTGGicGCATGGTTTCATCTGCACAGTGACTCTGAGGTAGGTAct ACCATTAGGc 4 440

4 441 CCATTGTTAGAGAGGGGTTAATGGAGACTiAGAAGAGGccCAGAGAGGTTAGGTAGCTTf 4500

4501 CTCAGAATCACATAAGTGGTAAGGGGATTCAGGCATGCCCCCTGCAACCACTGTCTTCAC 45 60 U.S. Patent Jan. 27, 2009 Sheet 57 Of 112 US 7482,124 B2

F.G. S.E

4561 CACCGTACGGCACCAGTTccACAAGCTGTACAGTGTGGGcTGTGAGAcccAAGGAAAAAC 462O

4621 AGAGCTGAGGCCCACGGGAÄGGTGAGGCCGGTGTGGGCTGGAGGCCTTGGGGTAAGCTTc 4,680

4 681 CTGGAGGTGGGGGTACATGf TGGGCCTTGGAGGACTAAAGAACTGGGGGGAAAAGGAAGG 4740

474. GAAGAAGGAAAGGATTTTCTGAAAAGGAAATGGCAAGAAGTAAAGGTCCAAAGCATAGGC 4800

480 TGTTGTGAGTAAACAGTGGGAAATGCAAccTCTTTGGGGCCAAACCTCTGACCCTCCAcG 4860

4861 TTCCCAGCTGTGAAGTGGGAGTAATAAAATCATCCACCTTATGAGAGCAñATAAAATAAt 4920

4921 GATTGTGAAAATATTTTGGiAACAGTAAccTGTGATAGGAAGATAACAAATCATTTCTGi 498O

4981 TACAATACCATGCTGATAGGCATAAAAGTfGCATTCATGiTCATGGGCAiiAATGGGGGTA 5040

5 O4. AGTAGAATGcATGGGACGCAAGAAGGATGTAGGAAGGAAÄGGGTAGTGTGAGTATAGGAG 500

5101 GACTAGCCAcTGAGAAGAAAGTAGAAGAAAGAGGGAATCitTGTGTGTAiGGGAAAGTCi 5160

5 161 ATTGCAGAGiCAACTTGGG?TTCCATCCTGGGACCTTCccGTGAACAGCfAGAGACATCi 5220

5221 TCCTCTGGGCTTTGGCAGcc TTTATGTCGGGACCCAGGGGACCCTATATGGGAAATAGGG 5280

5281 CCAGACACAt GCTCTGAATccCTGCTTCAACATTTCTGAGTCACCTTTGiccCTGTGAGc 5340

534. CTTCATTTTTCTCATCTATAAAATGGATGACAGCTAGCTTGTTGGTGTGATTTCAGTAGc 5400

5 401 GGCTCAGTAGAGTCAGTTTcCTAGGTCTCitTAATTCTGcCTCTCAAAGGTGATGGGAAà 5 460

5461 ACATCTAGACAAGAAGCCAAGGGACCGGGACACATCTCTcCAAGGACGAGGTGCATGGCG 552O

5521 CTCTGAAGATGCTGGCATCfCTCTAGGCCCAACCCAGCTcAGGGGGTCCACTCCACCACA 5580

5581 GCCCTGGCTGGGTGCCTGTccCCTGGTATCCTGGAGAcci TGCAGCTGciGTGGGCATcf 5640

56.41 GCTGCCACCTAGCGGCCTCCCATGGCACTGTCTCCCCGCCAGCCCCTAGTTTTGACAGGG 57 00 U.S. Patent Jan. 27, 2009 Sheet 58 of 112 US 7482,124 B2

FIG.SF

57 O1 GCACTCCCTGGCATTAATCfCTTCAGAGGGAATGTCTGTGCCTGTTTCCTGTCTGTCCTc 57 60

5761 CCGCCAGGTGGAGTTCCTTAAAGGCAGTCATGATCATTATCTTTCTAGCTCCAGTGTCCA 582O

5821 GCACAGTGAGGCACAAAGTAGTTGTTCAGCAGGTGATTACGGAATAAATGAATGAACGGA 588O

588 CCAATAAACAAATAGCCTTGTCTAATCAAAATTAGGCAAcAGAAGGAAGFCACTTCAGGG 594 O

594 TTATTTAATccCCGGGCAccTGACTCCTciaAATTGACTcTTGACAAGAAGTAACTCTTA 6000

600 TAAATGCTccAGAGGCCCT?AGCGACAGAGGTGATTTCCAGGTGGCTGGGCTAACGTTAA 6060

606 AGGTGGTTGiACTAAAAGCAGGGGTTTGGCCTCAGGGAcfcCACCACTGTGGTGGAGGTA 61.20

61.21 CAGCACTTTTCTATTTTTGcTTCCTCCAccCTGGGCCAGGATCTTCCTCAAGAGAATGcc 618O

618 CTCAATCCGAGAAAGCCTGAAGGAACGAGGTGTGGACATGGCCAGCCTTGGTCCCGAGTG 624 O

624 1 GAGCCAAcccATGAAGAGGöTGACACTTGGCAACACCAccTCCTCCGTGATCCTCACCAA 63OO

63O CTACATGGAcGTGAGTGCTigGCTCAGCCcCTCGCTCCCiCCCTGTCTccTTTCCCTCAt 636O

636 GGACCTAGGGCTTTCTTTGöTGCAAGACTCACCCTTTCCAAGCTGTGTTTGACGAAGGCG 642O

642 CTGAGTAGCACGTGAGCAccCTAGAAAAticCCATTTTCCAGCTGGAAAGCCTGAGCACA 64.80

6481 GAAGACAGGAAGGCATCCAGGGGCCATTCAGGGGCAGGGiTAGGTTTGGAACTCAGCCCA 65 AO

6541 GGCCTCAAGcCAGGTGTCACAGGTGGGTGGGAAGGGGTGiGTGACTCAGGTGGGGGTTTc 6600

660 TGTGACCTGGCCCAGCACAACCTGATGGCitcCTGccCCAGAGGATCCTcAAGAGTCAAG 666O

66.61. TTTGCTTcci GCTTCATTcfcAATGTTTTGATTTTGCCCiCTTGTCTTACTGAGACTccc 672O

672 ACTTTCTGGGATGCCATGGGGAGATGCTAAGCCTCCTAccAGTTCCTGCAGGAAAATGGA 6780

678, AACCCCGAGAGGCTATAGGACCTCGCCTGGGCCAAGTCTCACACCGAGAGCCAAGAGTGA 6840 U.S. Patent Jan. 27, 2009 Sheet 59 of 112 US 7482,124 B2

6841 AGCCAGGCAAGACCCCAAGACCCAAGGTccCCTGAGCCCCTCCAGCCCTcTCTTTTTAcc 6900

6901 CCCACAGAccCAGTACTATGGCGAGATTGGCATCGGCAccCCACCCCAGACCTTCAAAGf 6960

696.1 CGTCTTTGACACTGGTTCGrcCAATGTTTGGGTGccCTccTCCAAGTGCAGCCGTCTCTA 7020

702. CACTGccTGTGGTGAGAcci AAGAccCACAGTGCCTCTccTCCATccCccTGccCTACTG 7080

708 TGCATGACCAATCCTGccCAACACCCAGCiccCATccCTctTGCCACCAGGGAGTGGCf 71.40

7141 TCCTCTCTGccTCTGTG.cccACTGACATGiaGGGGAGAGGGGAAGATGTcTccCGTTTTT 7200

720 CTGATACAGccACCAAGGTi AAAAACAAAAAAAGGTCCAñGAACCCCTGAGCACCCAGAA 7260

726 GGCCACTTccCAGTCTTCCFGAGATTGAGACAGGACTGAATTCTCAAAccCATCCCAGGc 732O

7321 ACTCGGAAcfcTTCCATCC(TAGTCTTAAiCAACAACCTCTTACTAGGCACTTACTCTGT 7380

7381. GCCTGGCATcTTCTCTGGT&TTATCAGTGiTAGTGATTAcTTTAAATTccTTCATTTAGG 744 O

7441 ACAAAATTcfcGATGTATGGGCACATTAGGAGAGCCCAAGAAAccCAGTcCTTGATTGAf 7500

75 O1. GAAGCACATATTCCAAGCccCCTGACCCTAGGGCCACTCATCCCTGCAccTAAGCTAAcc 7560

75 61 AGCCATAcccACAATGCAccCTGCCTCTGiGTCCCCCTGiCTGGGCCAccTTGGACAAA 7620

7621 CCTGAGCCTcTGTCCCCCT6CCAGTGTATcACAAGCTCTicGATGCTTc(GATTCCTCCA 7680

7681 GCTACAAGCACAATGGAAcÁGAACTCAcccTCCGCTATT?AACAGGGACAGTCAGTGGCf 7740

774. TTCTCAGCCAGGACATCATcACCGTAAGTiGGGCCGCCCTAGGTCATCTGCCCCGGACCC 7800

7801 CTTCTGTCccCAGGCCTCTcCTGACCCTccAGGGCCCACACCTGcGGGGAGGTACACTGc 7860

786 AGCCCACTT&GAGCCTGGGGAGCTGAGGAACAccCTACT(TGCCACATcigGCTGTTGCf 7920

7921 GCAAAGCAGCAGTACCTATGGGGGAGCAAGCCTGGGCTACGGGCTCACCGTTGGGTGGTT 7980 U.S. Patent Jan. 27, 2009 Sheet 60 of 112 US 7482,124 B2

F.G. SH

7981 TGTGGATGTTTTTGCATCTAACTTGCATGiAGGGCTTGTcCTGAGCCCCGTGGCTGCAGT 8040

8041 CAAGTAACTcGTCCAAGTTcACCAGCTCTGACTGGGCTACACCCTAGACTGAAATCCAGG 81.00

81.01 GTCAGAGTCAGGCTGAGTTTAGGGTCAGGCATAGGTTTTAAGGTCACAGTTGAGGTTGA 81 60

861 CTCTGGGAci CAGGTCAAGGCCTGCTTTTcTTTTCCATGiGGCCCATGTcTGACCGTTTc 822O

8221 CTCATCCTGGAGTTTCTCAGGCCCTGCTccATCAGAGTTAGGGGAGGGG?ACACGTGGCA 828O

8281 cCTGAGAGGAAATCAGGGTGATTCCTGcciccCTTCCTTTTTCTGTGAACTCAGATATAA 8340

83 All AGGAGGGAGAAGGGCAAGCiTGTCTGTGciaAAGAAAcccTTCGCCCATGATAAGGGTGG 8400

840 GGGCCAAGAccCAGTCCTGcCAGGCACGAiiAGTCTGGCCACTGGGGAGGGGAGGAGCTcf 84 60

8461 TGGCAGCTTi TCTTTTCCTGCTTGGCAGGACCACCCTCTcAGCCTCTGcircTCCGATccc 8520

8521 TGGTCAACTcTAGCTCTCTcTGGGCTCCGöAGCAGAGATGTGTATTGGCACAGAGTGTGi 8580

8581 GCGTGCAGGGTTGAGGAAAACTCTTAccccGATTTCTGiAccCTGGAccATGTGTG.ccc 864 O

864. 1 CTGGGAT.cccTAGTGTGGAAGCCCAGAcc?gACTCCAAccAAGGAGTGGGCAGTGGGCti 87 OO

870. GGTCTCCTcf GGTCCTTccfccCACAGGTGGGTGGAATCACGGTGACACAGATGTTTGGA 87 60

876 GAGGTCACGGAGATGCCCGCCTTACCCTTCATGCTGGCCGAGTTTGATGGGGTTGTGGGC 882O

8821 ATGGGCTTCATTGAACAGGcCATTGGCAGGGTCAccCCTATCTTCGACAACATCATCTcc 888O

8881 CAAGGGGTGcTAAAAGAGGACGTCTTCTCitTCTACTACAACAGGTGGGGACTGGGACTc 8940

8941 CAAGGGCTGAGGTGGGGGGACAGGAGGGGAGAAGAGATGGGGAGTGGAAGGAGAGTCTGG 9 OOO

9001 GCCAGAATTGTAAAGTGTTfGTAATTAGGiGACAGCCAATCAATATCTAGAGCTGTACTA 9060

9061 GCCAATATGGAAGGCACTATTGAAATTTAAATTAATTAAATACAGTTAAGCATCAATTAA 92O U.S. Patent Jan. 27, 2009 Sheet 61 of 112 US 7482,124 B2

FIG.S.

91.21 GCATTCAAciGGTGGCTCTTAGTTGTACTâGCCACAcGTcAAATGCCTGGCAGCCACGGr 91.80

91.81 GGCTAGTAACTACAGTCTTATGACAGTGCAGATAGAGAATATTCCCAGCATGACAGGACA 9240

9241 TTCTAATAGACAGCGCCACTCTGGAGCAAGAGGAGATGCAAGGTGGGGGcGATGGTAAAt 93.00

9 301 AAGGGATTACTGTGACCTGTAGCCCTGcci GTTAGGGCCATGGCTCCTccCACACAGAGA 9360

936 CAGCCAACTTCAGTCATCCATTAGATccticATTCGTTT&TTTCCTCAct CATCAGTTCA 9420

94.2 GTAAATGCTATGTGCCAAGCACTGTGGTAGGCTCTGGGGGTGCAGCAGTGAACACAGTGA 94.80

9481 ACAAGGCAGAATCTGTACTcCCCTACCCACATAGAGCTTACAGGCTAACAGGGAAGACAA 95.40

9541 GACATATTccAACATAAAGAGTGTCACAGéCAGGCAGCAñGTGTGGTGcigAAAACCATG 96.00

96O1 GATGCTTTTcAATTCTAGGCTGAGCTTATATGCAGCTCAGCCAGCCTTGGGGAAGCTCT? 9660

966. GAGCAGGGTiGGGCTCTACfCCAAACTGcigGGCTTAGAAAGATGGCATGAGTTGGAGAc 97.20

9721 AAGAGAGCTGGAGGCAAAAGGGGCTGGGTGCAGTGGCTCATGCCTGTAAt CCCAGCACTf 9780

9781 TGGGAGGCCAAGGCGAGAGGATCGCATGAGCCCAGGAGTAAGGCTTCAGTGAGCAGTGA 984 O

984 TTGTGCCACCCACTCCAGCTAAGGCAAcAGAGTGAGATcCAGTCTCAAAAAAAAAAAAA 9900

990 AAAAAAAAAAAGTCACAAGGGTAAGAACATGAGGCCAGTGGCAAAAAGAATAGAGGAGAG 9960

99.61 GATCAGAGTiCAGAGAAAtcTCACAGTAAAATGGAGAGGAGTCTCCGGTTTGGTGATAGA OO20

10O2. AAGTGAGGccTTGAGAAAAGGCCAATTGGcGGCTCTGCATTCAGGGGTGGTCTTTAGAAG 1 OOBO

10081 AACTGTTTTAGAGGAAGTGGGGGCAAGGc(AGATGGCAAGAAGTTAAGAGGTGGACGAcG 101 4 0

101 41 TGGGTGTCAGGAAGTGGAGGTCATGAGATGTAGGCTGCccTGGGACAttcAACAGGGAAG 10200

102O GGAATGGGGGGTGGCGTGGGGGGTGAGATCCAGAAGCAGAAGAGGAAGGGTGGGTGTTTT 10260 U.S. Patent Jan. 27, 2009 Sheet 62 of 112 US 7482,124 B2

FIG.SJ

10261 TAAATGCTAGAGGATGCTCGAGTGATGCCFGTAGGTGGAGGAAGAAGCCAATGGAAAGAA 10320

10321 AGAGATTAAAAATGTGGAAAGAAGAGGAccTAAATCGGGGCACTGGAGTTTGGAGGCCri O380

10381 GAAAGAGATGAGGTTCCAGCAGACAGGAAGAAGCCAGGTTTTGCAGAGGAGAGGGCTGGc 104 40

10441 CTCTTCTTTi ATCTTGGGATGGGAAGGAGGGAACATCCAGAGAGATACTGAAGTGTTGAG 10500

10501 AGACAGGCAGGAGGGAATTfGTGCTAGCATATACACATACATTCCGAAtitATAAAAACA 10560

10561 CAAGTAGTTfGCAGTTGCACAAAATAACAATGCACAcci ACACACCCATGCACACATGi 10620

10621 GCATGTGTGAATTCTAGTATGAATTCTGGAAAAACACAtcACACACACAGGCATGCCCTG O680

10681 GAGACTAGGCCTACAGTAGTCCCTGAGCCAAGTGCAGTGAGGAGGAAAGGAAGGTGAGGG 10740

1041 GAATCAGCTcCAGACGGGGCACCAGGAGCcTGGCTCCAGTCCCCCACTTGTTCACTCATG 10800

10801 GACTGGGTAACTTCAGGCAAGTGACTTCGcCTCTTGGTGACTCCATTGccTGAAGGGCAå 10860

10861 AGAGAGTACATAACACCCAccCTGCCAAACAGCAGGGCTGATGAGGCTGGCATGAAATGA O920

10921 AGCTTCCTTi CTGCTGTCTcTCTTTCTCTGCAGAGATTccGAGTAAGGAGACAAAAcccc O980

10981 CACATGGCTGTGACCTTCCAGTACTCCCCGAGCACCTGACCTAGAATTAcACACGCCAcc 11040

1041 GGCCCAAAAcTCACATCAGcAAGCCCAGccTCCGCTAGAGCCGAAGTTcTCTGTCTCrc 1100

1101 CTTCCTGCTcTCTCCATGccACCTGccCAccCCATAccCAATAGCCTcccCAGGGT.cccd 1160

111 61 TccCATGCAccTGCTCAATcAGCAGCAAccCAAGAGTGAGGGGTGTCCATTTGTGTCTTG 11220

11221 TTCACATCCACTCACTGTccTTGTACCTGcTCCTTTTCTGTGACCTCTcfcGGGATGCT 11280

11281 TTTGGGGGAACAGCTGGAct ACCCTGGAAcAACCTCTGGiTGGTCTTGGGGAGGGGAAGA 11340

1341 AAGGCAGAGAAGCAGTATGTTCTGCATGCTTCCCAACGACAGCTCCGAGCCTGGCTGTCT 11400 U.S. Patent Jan. 27, 2009 Sheet 63 of 112 US 7482,124 B2

FIG.SK

1 4 01 GTccCACAriccTCTGCTciaGAGCCCTCigTcCTCCCcrgCACCCTTGiGCAAccTTcc 11460

114 61 cCAATTGcci GAGTTGCTGGGTCCTGGAGGTTATGGGTTTCCAAGAGCTTCTGATCTTTc 1520

1521 CTTTAGGAATTCCCAATCGöTGGGAGGACAGATTGTGCTGGGAGGCAGc(ACCCCCAGCA 1158O

1158. TTACGAAGGGAATTTCCActATATCAAccicATCAAGACTGGTGTCTGGCAGATTCAAAT 11640

1641 GAAGGGGTCAGAAATCCTCAACCCTCCCCGGGCTCCAAAAAATGCTGccGTCACTGGGGi 117OO

701 TGGGGAGGGiGGGGAAGGACTGCATTACCATCCTGCCCTcTTTCCAAATGCAGCCACTTc 1760

1176 TTAAGCACAGCCACCATTTGCTCTCTGcci GCTCTGTCCAGGCTGGGGAACAGAGAAGGG 1182O

11821 AGGGGCCTGGGGAGAAGTGGTGGAGGGTGACAGTACCTTccCTCCTCTAcTCACTGCCTc 1880

1188. AACAGGCCACCAGCGTGGccTCCACCCAccCACCCACACfCAGGAAGGACATGCAGCCTG 1940

11941 GAGGTGcccdATCAGCCTTcTGTCTGTCT(TCTGTCTGTcTGTCTGACTGTGGCCTCCcc 12000

2001 CAGGGTGTCicTGGGGTCATCCACCTTGciCTGTGAAGAcGGCTGCCTGGCATTGGTAGA 12060

12061 CACCGGTGCATCCTACATCfCAGGTTCTAccAGCTCCATAGAGAAGCTCATGGAGGCCTi 12120

12121 GGGAGCCAAGAAGAGGCTGTTTGATGTAAGAAGCCAAAGAGGGAAGGTGCTGTGGGTGGG 12180

12181 GGGAGCGCCiCCTGGTATCGGCTCACAAAiccCCCAGGCAAATGAGGCCATCTCAGGcci 2240

12241 TCGCTTGTTcACCTCACAci CTCCACACA GTGGCTGGTcACCCATGGGGcGGGGCACTG 12300

12301 TCCCCAGCCTCTCCAGCAGAGAGACCAGécCACCAGCGöAGGACTCCTfGTCTGCTGAG 12360

1236 ACGTCTTCCATACTCAAGAAGGCTCTCTTfGCCCCCCAcccCAGTATGTcGTGAACTGTi, 1242O

12421 AcGAGGGCccTACACTCCccGACATCTCTitcCACCTGGGAGGCAAAGAATACACGCTCA 1248O

12481 CCAGCGCGGACTATGTATTTCAGGTGAGGTTCGAGTCGGCCCCCTCGGTGGCAGGGAGAA 2540 U.S. Patent Jan. 27, 2009 Sheet 64 of 112 US 7482,124 B2

F.G. SL

12541 AGGCTGGACAGAGAccCTCiAAGAGTGACAGATTACAATGCACAGGTCATGTTAGAACTG 12600

12601 TAGTTCTCAAACTTGGCTGiGCATGTCAccTGGAGAGCT'? TGAAAAATccTGGTACCTGG 12660

2661 GCCACAT.cccATAccTATTAAATCAGAAccTCTAGAAGTGGCACCTGGGGTTCAGTTTCC 12720

12721 CCAGGTGAticCAATGTGTGGCCATGTTTGGGCATCACTATGCCTGTTccCTCATCTCCA 12780

12781 TTTTCTCATcAAATACTcccAAGAATCCTATGCTCCTATATTCTTACCCiCTTTTCATAA 284 O

12841 TCAATAGGCitAGAGAAGTfGAATAACTTGTCTAGGATCAGAAGCTAAGGCAAACTGTAA 12900

1290 GCTCCTGAAGGAAGCACGGiGCCTGATGcitTGTTTGcci GGGATCTAccACAGGGGCTA 12960

12961 AACATAGGAGTGGTGCAGTcCACGATGGGGCAAAATGGCCATGATGTGAGGGAGGCCCAG 13020

3021 TGTGGCTAGGGGAGAGATGGGGGCGAGAGGGGGAATGTTGCTGAAGACAGTTGCTgGGGG 3O80

13081 TCAGCCAAGGTGAAAGGAGAATGCTCATGiGCTGGGTATGGAGAAACTCTCCCCCTTcci 1314 O

13141 GCCAGGAAtcCTACAGTAGi AAAAAGCTGiGCACACTGGCCATCCACGccATGGATATcc 13200

1320 CGCCACCCAcTGGAccCAccTGGGCCCTGGGGGCCACCTTCATCCGAAAGTTCTACACAG 13260

13261 AGTTTGATCGGCGTAACAAccGCATTGGCitcGCCTTGGccCGCTGAGGccCTCTGcCAc 13320

1332. CCAGGCAGGCCCTGCCTTCAGCCCTGGCCCAGAGCTGGAACACTCTCTGAGATGCCCCTC 13380

13381 TGCCTGGGCiTATGCCCTCAGATGGAGAcATTGGATGTGGAGCTCCTGciGGATGcGTGc 13440

3441 CCTGAcccci GCACCAGCC(TTCCCTGCTitGAGGACAAñGAGAATAAAGACTTCATGTF 13500

135O1 CACAGCCTGitGCATCTGGGTTCACTAGGGTTTAGAACAGAGGGAGGGGétGCGTGATCA 13560

13561 TGTGTGGACAGGAATGTGAcACAGACAAGöTACACATTCGCCTAGCGCAcAGGTTCTTGc 13620

13621 GTGCAGGGATGATGCCATCCATCTGCCATCAACGGGACTCAGGTGGAGCTGTTTACACAA 1368O U.S. Patent Jan. 27, 2009 Sheet 65 of 112 US 7482,124 B2

FIG.SM

13681 cCTCAGGTGGGAAGTCTGAAAAGAGCCGGAACCAAGCTccCTCTAGTCccTCAGGGACCA 13740

1374 AGGCTAATGCTGTGGCAGTAGACTGTGGGrCAGAAAGTrcTccCAGCTcÁCAGAAGCCAG 13800

1380 CTCTGAGTtcAGACTCTGcircTGCTGAGCiAGTCAGCCCiCTCTCTTGTccCTGCAAAAc 13860

13861 TCCCCTCAGCTGTCCTTATcCACTGCAGATGCCCCCGCccTGCCCCATGiAGCCATTTAC 13920

1392. ACAGGCATTCTAAGGCACTACCACCTAAAATCATAGAACACCAGAGATccAGGCAATAct 1398O

13981 TCCACTTTACAGGTGGGGAAACTGAGGCccAGAGAATGGAAGGCCTTGccCAAGATTAct 14040

14041 CGGTCAACAATCAAGTAGTGAAGAATACTGAAAGATAGTGAAGAATCAAGACTGGAAccc 14 100

1410 AGCCCGTCTGACTTGGGTccTGGGGGTTTcCACCTTATCATAAGCAGTTGGTACCGTCA, 14160

14161 AAGTACAGTGCTTCACGCACGCTGGTACAGGGCCACGTGCACAAGCACACAGGTGCACAC 14220

14221 ACACACTGciaTcCTCCATccCATCCAccrgGGACTCGTcAGGCTGAAGrcTCTTCTCCc 428O

14281 ACTCTCACTcCTTGGGCTGicTTCAGGGCACATGTAACTfGGGGAATGAGAAATTAGCAt 14340

14341 cCAccTGGAGCCACTGAAccCATccCTCTTCACCATAGTfGCTCAccTcfcTTTTGACAG 14400

14401 AAAGTCGTGAGGCACTGAAGGCCCAAccAGGCCCTCAGTACCTCTGGGAGCCATCTCCA A 460

14461 AGAGTCCCTGTGTAGCGCCAAGAGCCGGAGCCTGGGCTTCAGG 14503 U.S. Patent Jan. 27, 2009 Sheet 66 of 112 US 7482,124 B2

FIG. 6A

1. GGTCTTTGTâAAATAATAAirATTCATTT&ACAAAAGTGATAATTAAAAGACTTTAATAG 50

6. CAATACAGAAAGTTACATGAATATAAAGAcTTAACCTTTct AAAccTCAGTTTTCCTAAG 2O

12l TAATCAAAAAccTGATAAAGATAACAAGAATGAGGAATTATCTTGAGAAAATGTAAAAte 18O

8. TTTCCTTTTATTTTTTGAGACAGGGTCrc?cTCTGTCArcCAGGCTAAAGTGCAGTGGCá 24 O

241. CAATCATAGöTCACTACAGCCTTGAACTccTGGACTCAAGTGATccTcccGCCTCAGcci 3OO

3O cCCCAGTAGct AAGACTACAGGCACGCAccACCACACCCAGCTAATTTTTTTCAGAGATG 350

36 GGGTCTTGciATATTGCCciGGCTGGTCTTGAACGAGCTTCAAGTGAGcGTGAGCCTCC 42O

421 ACCTCATCCiCCCAAAGCACTAGGATTACAGGCATGAGccACTGTTTCCCAGCCTAAAAi 48O

48 AATTGTTTCitAGGCCAGCiaccAAAAAcGCAAAGAAAAicTTTCTGTAGTGTGATTGci 50

541 TCTTCTTATGGGAAGCCCAiTTAGATAAccTGTAAGTCAiiAccTGATGAAAACAATACTf 600

6O1 GAATGTAATcAGACACAGAAAGACTGTTCAAGGCTATGAGTAGCTGAGTcCAAGCTCGTá 550

661 TCACTTGCCACACAACAGCCAATAAGTCTAGAGACAAGGiATTGTGGCAñGGAAAGCTAC 720

21 CTTATTCAGAGAACCAGAAAACCAAGAAGATGGTGGACCAGCATCATAAAGAACCATCTG 780

781 AAGTCAGCATGAACGTTAGGCTCTTCTTT?TGTTAAGGGAAGGGGAAGAAGAAGGGGAti 840

84. GGGATCAAGAGGTGACTGAfgACCACAGACACCTGGGTGcCAGCAAGGGTCTGAGGACGi 9CO

901 TGTAAAACTicTTTTTTCTAGGTCAGGTCACAATGTTCCTATACATCTTi AACATAACAi 96.O

961 TGTTATTTGircTGTATATTTCCTTATCTccTTGGGGGTTAGTTTGGGGAAAGGAACTGTi, O2O

102. ACCATTTTTTTAAAGTTGAACTCCAAGciaAACTccTaiAATTAGCTGGTCTATGTACA 1 O8O

108 GAGCTAAGCAGAAGCTTTTAGCCTAAAGGATAATACCCCTGGGGGTCAGAGGCAAAATGG A U.S. Patent Jan. 27, 2009 Sheet 67 of 112 US 7482,124 B2

FIG. 6B

14 AGTCAGTCAtcCTAAGTCTccCTCCACTCiCTTTCTTTTTTGAGATGGAATTTCACTCTt 200

2Ol ATTGccCAGGCCGGAGTGCAGTGGCATGATCTCAGCTCActGCAACCTccGCCTCCTGGG 1260

1261 TTCAAGCAATTCTCTTGcci CAGCCTCCTGAGTAGCTGAGATTACAGGTGTCCATCACCA 1320

321 CAccCAGCTAATTTTTGTAGTTTAGTGGAGATGGGGTTTcACCATTGTTGGTCAGGCTGG 1380

1381 TCTGGAACTcCTGACCTCAGGTGATCTAccCACCTTGGccTCCCAAAGTGCTGGGACAGG 1440

1441 TGTGAGCCAccATGcCTGGccCCTCTACTctTATAATTAAACCAGCTGTfGCTTTTCCTG 1500

150 cCAAGAAAccAGTCATGAAGATTCACCCAiGTTCTAGATécGAAAACTG6GCTGTAGCCF 15 60

15 61 GGGAGAGGccAGTCAGGGACAAAGCCAAAGTTAATATAGAGAATGGAGCitcCAGGGTAf 1620

1621 AGGGGTTGGGTCTGGGCTAGGGAGCTGGAAACCTAGGTTTTACGCTTGTccCAGTTTTGA 680

1681 TGTTAGccci GAGCAGTGcGTTTCTCATcAGCCTCTGccTGCTCCAGGGGTCACAGGGc 1740

1741 CAAGCCAGATAGAGGGCTGcTAGCGTCAcfcGACACAAGATTGCTTTCCóACAGCTGTcc 1800

18O TTCCTCCAGCCCCTCTGCTcCCCATCCGGAAACCTGGGTACCCTTCACccACCTAGCTct 1860

1861 GTcccGCAGTGAGATTTATTGCTGACTGccCTGCCATCTAccCCAGGGTAATAAATCAGG 1920

1921 GCAGAGCAGAATTGCAATCACCCCATGCATGGAGTGTATAAAAGGGGAAGGGCTAACGGA 1980

1981 GCCACAGAAccTCAGTGGAfCTCAGAGAGAGCCCCAGAcigAGGGAAGCATGGATGGATG 2040

204 GAGAAGGATGcCTCGCTGGGGACTGCTGciGCTGCTCTGGGGCTCCTGTAccTtTGGTct 2100

2101 CCCGACAGACACCACCACCitTAAACGGTAATTGGTAAci CAGGCAGAGAAGGGGTGGGA 21 60

261 GGGGTGCAGGGTTCCCAcci TCCCAACAccCTGGCTTTTcCACATGcGGiGTCATTCAGi 2220

2221 CCTTACGATCAGCTGGACAGGGAAGTATGGACCTGTTCAGAGAGGTCAAGTGACTTGCCC 2280 U.S. Patent Jan. 27, 2009 Sheet 68 of 112 US 7482,124 B2

FIG. 6C

2281 AATAAATGAcACTAGTAGTcAGGTCTAGAAGCTGTGActiTTGCTTCCTGCCCAGAGCAC 2340

2341 CATGCTAAct AAGCACTGTAGAGAACTCAGAAGTATTAGéACATGccCcitGCACTTGAG 2400

2401 GAGCTCACAGCCTGAATATAAGAAGGGCATGGGTGGTT6GGCGCGGTGGCTCCTGccré 2 4 50

246 TAATCCCAGcACTTTGGGAGGCTGAGACGGATCACTTGA6GTCAGGAGTitGAGACCAGc 25.20

2521 CTGGCCAACATGGGGAAAccCCATCTCTAct AAAAATACAAAAATTAGccGGGCATGGTG 2580

2581 GCAGGCACTfGTAATCCCCAGCTACTCGGGAAGCTGAGG?AGGAGAATCGTTTGAGCCCG 2640

2641 GAAGGTGGAGATTGCTGAccCAAGATCGTGCCACTGCAcfcCAGCCTGAGTGACAGAACA 2700

27 C1 AGACTCCATcTCAAAAAAAAAAAAGACGGGGGTCGGGGCATGGGTACAGiTAACTGTAcc 2T 60

27 61 AGGGAAGCAGCTTGATATCGTGGTTAAATGCAAGGCTTATAGACTTAGATGCCTTCATf 2820

2821 TAAATTTTccTTCACTAGCAGAACAAACTAGGTCTGGAATCATGGGCAAGTTATTTAAcc 288O

2881 TCTCCAAGTcTCAGTTTATcATTTTAAACAGGTATGATAATAACAGTAccTACTTGATGG 29A0

29 A1 GGCTGCTTTGGGGATTTTAGGAGATAAGGCATAGAAAGCTGGGCACGTTGTAAGAGCCCA 3OOO 300 GCTACTGTTAGTACTACAGGATAGATTCTTACAAATATCAAAAGCAAGGTTTGGCCGGGA 3060

306 GCAGTGGCT?ACGCCTATATCCCAACACitTGGGAGGccGAGGGGGGCAGATCACCCGA 320

3121 GGTCAGGAGFTCAAGACCAGCCTGACCAAcATGGAGAAAccCTCTCTCTACTAAAAATAc 380

38. AAAATTAGccGGGCGTGGT6GCACATGccigTAATTCCAGCTACTTGGGAGGCTGAGGCA 324 O

3241 GGAGAATCGöTTGAACCTGGGAGGCTGAGóTTGCAGTGAGCCGACATAGcGCCATTGCAc 3300

33Ol TCCAGCCTGGTCAACAAGAGCAAAACTCAGTCTAAAAAAAAAAAAGAAAGAAAAAAACAA 3360

336 GGCTTTAGGTAGCCCACAATTAGAAGGAGAAAACCTTAGCATCCCCTAGGTGCCAGGCCT 3420 U.S. Patent Jan. 27, 2009 Sheet 69 of 112 US 7482,124 B2

F.G. 6D

3421 TGTGGGAACAAGTGATTCATAAGACTGTAGAAGGAAGCiGGGCACGCGGCTCATGCTTG 3480

3481 TAATTCCAGcACTTTGAGAGGCTGAGGTGGGCAGATCGCitGAGCTCACGAGTTCAAGAC 3540

3541. CAGCCTAGGöAACATGGTGAAACCTTGTcf GTACAAATAcAAAAATTAGcTAGGTGTGGi 3600

360 GGTGCAAATcTGTAGTCCCAGCTACTCGGGAGGCTGAGGTGGGAGCATCACTTCAGCCTG 3660

3661 GGAGGTGGAGGCTGCAGTGAGCAGAGACTGACCCACTGTGCTCTAGCCTGGGTGATAGAG 3.720

372 CCAGACCTTATGTAAAAAAAAAAAAAAAAAAAAAAAAGACTGAAGAAGGGGAAGAGACAG 3780

3781 CATTTGAGAAAAGGCCTCACAGAGAAAGGGGTTTTCAAtcTGGGGACAGcAGATATGAcc 384 O

3841 AGCAGTCCTGAAGGTAGGGAGGCACACTTFAATAATGGTAATAGTTGCTAAGCCTATAA, 3900

3901 ATGCTTAGGGTGTCACAGGATCTTTTCACATGTCTCATCfCAAGTCATGcCCCCAACAAc 3960

3961 TCAGCATTccCACTTTGCAGATGAGGACACTGAGGCTCAGGGAGGTGATATGTAAGAGGC 4 O20

4021 TAAGCCTCAACACACACTGGGCCTTTTGcitcCGAAACTGCTTTCCCTTGCTCTGAGGCf 4080

4081 CTCGGAGAGTAATTGCTGGGTTGTGAGCACTGGGTAAGAGGATGGGTGcitCAAAGCAGC 4. 140

4141 TGCACTCCAGGATAAAGGTAGAGGAAAGTAAAAACATCTfcCCCTGCTGiTATCCAAAAG 4200

4 201 AGAAAAAGAATGGAATTGGGCAAGGGGTGGAGGGGGAATcCAGCTTTTGAAACAGTATTA 4260

4.261 TAGGAATTTfGCTACCCGCTATGTGCAGAGCATCATGCGAGGCACTTGGGACAGCTGAA 4320

4321 GAATGAGCTcCATTCTCAAGGTGAACATGTACATATACACACCTACAATTACATTTAT 4.380

4381 GAGCAGTGGicGCATGGTTTCATCTGCACAGTGACTCTGAGGTAGGTAct ACCATTAGGc 4 440

444 CCATTGTTAGAGAGGGGTTAATGGAGACTAGAAGAGGccCAGAGAGGTTAGGTAGCTTf 4500

4501 CTCAGAATCACATAAGTGGTAAGGGGATTCAGGCATGCCCCCTGCAACCACTGTCTTCAC 4560 U.S. Patent Jan. 27, 2009 Sheet 70 of 112 US 7482,124 B2

FIG. 6E

456 CACCGTACGGCACCAGTTCCACAAGCTGTACAGTGTGGGCTGTGAGACCCAAGGAAAAAC 4 620

4621 AGAGCTGAGGCCCACGGGAAGGTGAGGCCGGTGTGGGCTGGAGGCCTTGGGGTAAGCTTc 4 680

4 681 CTGGAGGTGGGGGTACATGTTGGGCCTTGGAGGACTAAAGAACTGGGGGGAAAAGGAAGG 4740

4741 GAAGAAGGAAAGGATTTTcfGAAAAGGAAATGGCAAGAAGTAAAGGTCCAAAGCATAGGc 4800

48O1 TGTTGTGAGAAACAGTGGGAAATGCAAccTCTTTGGGGcCAAACCTCTGACCCTCCAcG 4860

4861 TTCCCAGCTGTGAAGTGGGAGTAATAAAATCATCCACCTTATGAGAGCAAATAAAATAAt 4920

4921 GATTGTGAAñATATTTTGGTAACAGTAAccTGTGATAGGAAGATAACAAATCATTTCTGi 4980

4981 TACAATACCATGCTGATAGGCATAAAAGTfGCATTCATGiTCATGGGCAAAATGGGGGTA 5040

50 41 AGTAGAATGcATGGGACGCAAGAAGGATGiAGGAAGGAAÄGGGTAGTGTGAGTATAGGAG 5100

5101 GACTAGCCAcTGAGAAGAAAGTAGAAGAAAGAGGGAATCitTGTGTGTAiGGGAAAGTcf 5160

5, 61 ATTGCAGAGTCAACTTGGGöTTCCATCCTGGGACCTTCccGTGAACAGCTAGAGACATcf 522O

5221 TCCTCTGGGöTTTGGCAGccTTTATGTCGGGACCCAGGGGACCCTATATGGGAAATAGGG 5280

5281 CCAGACACAiGCTCTGAATccCTGCTTCAACATTTCTGAGTCACCTTTGiccCTGTGAGc 5340

5341. CTTCATTTTTCTCATCTATAAAATGGATGACAGCTAGCTfGTTGGTGTGATTTCAGTAGc 54.00

54O1 GGCTCAGTAGAGTCAGTTTcCTAGGTCTCiTTAATTCTGcCTCTCAAAGGTGATGGGAAA 54 60

5461 ACATCTAGACAAGAAGCCAAGGGACCGGGACACATCTCTcCAAGGACGAGGTGCATGGcG 55.20

5521. CTCTGAAGAiGCTGGCATCfCTCTAGGCccAACCCAGCTCAGGGGGTCCACTCCACCACA 5580

558 GCCCTGGCTGGGTGCCTGTccCCTGGTATcCTGGAGAcci TGCAGCTGcGTGGGCATcf 5640

56.41 GCTGCCACCTAGCGGCCTCCCATGGCACTGTCTCCCCGCCAGCCCCTAGTTTTGACAGGG 5700

U.S. Patent Jan. 27, 2009 Sheet 72 of 112 US 7482,124 B2

FIG. 6G

6841 AGCCAGGCAÄGACCCCAAGACCCAAGGTccCCTGAGCCccTCCAGCCCTcTCTTTTTAcc 6900

6901. CCCACAGAccCAGTACTATGGCGAGATTGGCATCGGCAccCCACCCCAGACCTTCAAAGf 6960

69 61 CGTCTTTGAcACTGGTTCGrcCAATGTTTGGGTGccCTccTCCAAGTGCAGCCGTCTCTA 7020

7021 CACTGCCTGiGGTGAGAcci AAGAccCACAGTGCCTCTccTcCATccccoTGccCTACTG 7080

7081 TGCATGAGCAATCCTGccCAACAccCAGCiccCATccCrcTTGCCACCAñGGGAGTGGCf 714. O

74.1 TCCTCTCTGcCTCTGTGccöACTGACATGiAGGGGAGAGGGGAAGATGTcTCCCGTTTTf 7200

72 Ol CTGATACAGcCACCAAGGTi AAAAACAAAAAAAGGTCCAAGAAccCCTGAGCACCCAGAA 7260

7261 GGCCACTTccCAGTCTTcci GAGATTGAGACAGGACTGAATTCTCAAAccCATccCAGGé 7320

7321 ACTCGGAAci CTTCCAT.cccTAGTCTTAATCAACAACCTctTACTAGGCACTTACTCTGi 7380

7381 GCCTGGCATcTTCTCTGGTGTTATCAGTGiTAGTGATTACTTTAAATTccTTCATTTAGG 7440

74. 41 ACAAAATTCfCGATGTATGGGCACATTAGGAGAGCCCAAGAAAccCAGTcCTTGATTGAf 7500

75 O1. GAAGCACATATTCCAAGccöcCTGAccCTAGGGCCACTCATCCCTGCAccTAAGCTAAcc 7560

75 61. AGCCATAcccACAATGCAccCTGCCTCTGAGTCCCCCTGiCTGGGCCAct CTTGGACAAA 7620

7621 CCTGAGCCTcTGTCCCCCT&cCAGTGTATcACAAGCTCTTCGATGCTTCGGATTCCTCCA 7680

7681 GCTACAAGCACAATGGAACAGAACTCAcccTCCGCTATTcAACAGGGACAGTCAGTGGCf 7740

7741 TTCTCAGCCAGGACATCATACCGTAAGTfGGGCCGCCCTAGGTCATCTGCCCCGGAcco 7800

78O1 CTTCTGT.cccCAGGCCTCTcCTGAccCTccAGGGccCACAccTGcGGGGAGGTACACTGc 7860

7861 AGccCACTTGGAGCCTGGGGAGCTGAGGAACAccCTACTcTGCCACATcf GGCTGTTGci 7920

7921 GCAAAGCAGCAGTACCTATGGGGGAGCAAGCCTGGGCTACGGGCTCACCGTTGGGTGGTT 798O U.S. Patent Jan. 27, 2009 Sheet 73 of 112 US 7482,124 B2

FIG. 6H

7981 TGTGGATGTittTGCATCTAACTTGCATGTAGGGCTTGTcCTGAGCCccGTGGCTGCAGT 80 40

8 O A1 CAAGTAACTcGTCCAAGTTcACCAGCTCTGACTGGGCTACAccCTAGAcigAAATCCAGG 81 OO

801 GTCAGAGTCAGGCTGAGTTTTAGGGTCAGGCATAGGTTTTAAGGTCACAGTTGAGGTTGA 81 60

816 CTCTGGGAct CAGGTCAAGécCTGCTTTTcTTTTCCATGiGGccCATGTcTGAccGTTTc 8220

8221 CTCATCCTGGAGTTTCTCAGGCCCTGCTccATCAGAGTTâGGGGAGGGGcACACGTGGCA 8280

8281 ccTGAGAGGAAATCAGGGTGATTCCTGccfccCTTCCTTi TTCTGTGAACTCAGATATAA 8340

8341 AGGAGGGAGAAGGGCAAGCiTGTCTGTGci AAAGAAAcccTTCGCCCATGATAAGGGTGG 84 OO

84 Ol GGGCCAAGAccCAGTCCTGcCAGGCACGAAAGTCTGGCCACTGGGGAGGGGAGGAGCTcf 84 60

8461 TGGCAGCTTi TCTTTTGCTGCTTGGCAGGACCACCCTCTcAGCCTCTGciCTCCGATccc 8520

8521 TGGTCAACTctAGCTCTCT(TGGGCTCCGcAGCAGAGAT(TGTATTGGCACAGAGTGTGi 8580

858 GCGTGCAGGGTTGAGGAAAiACTCTTACccCGATTTCTGTACCCTGGAGöATGTGTG.ccc 864 O

8641 CTGGGATccöTAGTGTGGAAccCCAGAccAGACTCCAAccAAGGAGTGGGCAGTGGGCTf 8 700

870 GGTCTCCTcf GGTCCTTCCiCCCACAGGTGGGTGGAATCACGGTGACACAGATGTTTGGA 8 7 60

8761 GAGGTCAccGAGATGcccGöcTTAccCTTcATGCTGGccGAGTTTGATGGGGTTGTGGGc 882O

8821 ATGGGCTTCATTGAACAGGcCATTGGCAGGGTCACCCCTATCTTCGACAACATCATCTcc 888O

8881 CAAGGGGTccTAAAAGAGGACGTCTTCTcf TTCTACTACAACAGGTGGGGACTGGGACTc 894 O

8941 CAAGGGCTGAGGTGGGGGGACAGGAGGGGAGAAGAGATGGGGAGTGGAAGGAGAGTCTGG 9 OOO

9 OO1 GCCAGAATTGTAAAGTGTTfGTAATTAGGFGACAGCCAAiCAATATCTAGAGCTGTACTA 906O

90.61 GCCAATATGGAAGGCACTATTGAAATTTAAATTAATTAAATACAGTTAAGCATCAATTAA 912O U.S. Patent Jan. 27, 2009 Sheet 74 of 112 US 7482,124 B2

FIG. 6

9121 GCATTCAAcicGTGGCTCTAGTTGTACTAGCCACACGTcAAATGCCTGGCAGCCACGGi 91.80

91.81 GGCTAGTAACTACAGTCTTATGACAGTGcAGATAGAGAAAttcCCAGCATGACAGGACA 9240

924 TTCTAATAGACAGCGCCAcicTGGAGCAAGAGGAGATGCAAGGTGGGGGcGATGGTAAAt 9300

93O1 AAGGGATTACTGTGACCTGTAGCCCTGcciGTTAGGGCCATGGCTCCTccCACACAGAGA 9360

9361 CAGCCAActicAGTCATCCATTAGATCCTiCATTCGTTTGTTTGCTCAcicATCAGTTCA 9420

94.21 GTAAATGCTATGTGCCAAGéACTGTGGTAGGCTCTGGGGGTGCAGCAGTGAACACAGTGA 94.80

9481 ACAAGGCAGAATCTGTACTcCCCTACCCAcATAGAGCTTACAGGCTAACAGGGAAGACAA 95.40

9541 GACATATTccAACATAAAGAGTGTCACAGGCAGGCAGCAAGTGTGGTGciGAAAACCATG 96.00

96O1 GATGCTTTT?AATTCTAGGöTGAGCTTATâTGCAGCTCAGCCAGCCTTGGGGAAGCTCTi 9660

9661 GAGCAGGGTiGGGCTCTAcfcCAAACTGciGGGCTTAGAAAGATGGCAT6AGTTGGAGAC 97.20

972 AAGAGAGCTGGAGGCAAAAGGGGCTGGGTGCAGTGGCTCATGCCTGTAATCCCAGCACT 9780

978. TGGGAGGCCAAGGCGAGAGGATCGCATGAGCCCAGGAGTTAAGGCTTCAGTGAGCAGTGA 98.40

98.41 TTGTCCCAcfcCACTCCAGöTAAGGCAAcÁGAGTGAGATcCAGTCTCAAAAAAAAAAAA, 9900

99 O1 AAAAAAAAAAAGTCACAAGGGTAAGAACAGAGGCCAGTGGCAAAAAGAATAGAGGAGAG 9960

99.61 GATCAGAGticAGAGAAAtcTCACAGTAAAATGGAGAGGAGTCTCCGGTTTGGTGATAGA 10O20

10021 AAGTGAGGCCTTGAGAAAAGGCCAATTGGcGGCTCTGCATTCAGGGGTGGTCTTTAGAAG 0080

10081 AACTGTTTTAGAGGAAGTGGGGGCAAGGc(AGATGGCAAGAAGTTAAGAGGTGGACGAcG 101 4 0

101 41 TGGGTGTCAGGAAGTGGAGGTCATGAGATGTAGGCTGccCTGGGACATTcAACAGGGAAG 10200

10201 GGAATGGGGGGTGGCGTGGGGGGTGAGATCCAGAAGCAGAAGAGGAAGGGTGGGTGTTTT 10260 U.S. Patent Jan. 27, 2009 Sheet 75 Of 112 US 7482,124 B2

FIG. 6J

O261 TAAATGCTAGAGGATGCTCGAGTGATGcci GTAGGTGGAGGAAGAAGCCAATGGAAAGAA 1032O

1032 AGAGATTAAÄAATGTGGAAAGAAGAGGAGCTAAATGGGGGCACTGGAGTi TGGAGGCCTT 10380

10381 GAAAGAGATGAGGTTCCAccAGACAGGAAGAAGCCAGGTTTGCAGAGGAGAGGGCTGGC 104 40

104 41 CTCTTCTTTi ATCTTGGGAiGGGAAGGAGGGAACATCCAGAGAGATACTGAAGTGTTGAG 10500

1050 AGACAGGCAGGAGGGAATTfGTGCTAGCATATACACATACATTCCGAATTATAAAAACA OS 60

O561 CAAGTAGTTfGCAGTTGCAcAAAATAACAATGCACAcci ACACACCCATGCACACATGi 10 62O

O621 GCATGTGTGAATTCTAGTAiGAATTCTGGAAAAACACAtcACACACACAGGCATGCCCTG O 680

10681 GAGACTAGGcCTACAGTAGiCCCTGAGCCAAGTGCAGTGAGGAGGAAAGGAAGGTGAGGG 0740

10741. GAATCAGCTcCAGACGGGG?ACCAGGAGCCTGGCTCCAGTCCCCCACTTGTTCACTCATG 108 OO

O801 GACTGGGTAãCTTCAGGCAAGTGACTTCGcCTCTTGGTGACTCCATTGccTGAAGGGCAA O 860

1086. AGAGAGTACATAACACCCACCCTGCCAAACAGCAGGGCTGATGAGGCTGGCATGAAATGA 1092O

10921 AGCTTCCTTi CTGCTGTCTcTCTTTCTCTGCAGAGATTccGAGTAAGGAGACAAAAcccc O98O

O98. CACATGGCTGTGACCTTCCAGTACTCCCCGAGCACCTGAccTAGAATTACACACGCCAcc 11040

11041 GGCCCAAAAcTCACATCAGöAAGCCCAGccTCCGCTAGAfGCCGAAGTTcTCTGTCTCTc 11 OO

1101 CTTCCTGCTcTCTCCATGccACCTGCCCAccCCATACCCAATAGCCTCccCAGGGTCCCc 1160

1116.1 TCCCATGCAcCTGCTCAATcAGCAGCAAccCAAGAGTGAGGGGTGTCCATTTGTGTCTTG 11220

11221 TTCACATCCiCTCACTGTccTTGTACCTGcTCCTTTTCTGTGACCTCTcfcGGGATGCT i 11280

1281 TTTGGGGGAÁCAGCTGGAciACCCTGGAACAACCTCTGGTTGGTCTTGGGGAGGGGAAGA 1340

134 AAGGCAGAGAAGCAGTATGTTCTGCATGCTTCCCAACGACAGCTCCGAGCCTGGCTGTCT 114 OO U.S. Patent Jan. 27, 2009 Sheet 76 of 112 US 7482,124 B2

F.G. 6K

11 4 01 GTCCCACATiccTCTGCTCiAGAGCCCTcfGTCCT.cccci GCAccCTTGiGCAAccTTcc 11460

1461 cCAATTGcci GAGTTGCTGGGTCCTGGAGGTTATGGGTTTCCAAGAGCTCTGATCTTTc 11520

11521 CTTTAGGAAiTccCAATCGcTGGGAGGACAGATTGTGCTGGGAGGCAGcGACCCCCAGCA 11580

1581 TTACGAAGGGAATTTCCAct ATATCAAccicATCAAGAcigGTGTCTGGcAGATTCAAAt 11640

11641 GAAGGGGTCAGAAATCCTCAAccCTCCCCGGGCTCCAAAAAATGCTGccGTCACTGGGGi 11 700

1701 TGGGGAGGGiGGGGAAGGACTGCATTACCATCCTGCCCT(TTTCCAAATGCAGCCACTTc 11760

1761 TTAAGCACAGCCACCATTTGCTCTCTGccigCTCTGTCCAGGCTGGGGAACAGAGAAGGG 11820

11821 AGGGGCCTGGGGAGAAGTGGTGGAGGGTGACAGTACCTTccCTCCTCTActCACTGCCTc 11880

1881 AACAGGCCAccAGCGTGGccTCCACCCAccCACCCACAci CAGGAAGGAcATGCAGCCTG 1940

11941 GAGGTGccccATCAGCCTTcTGTCTGTCTGTCTGTCTGTcTGTCTGACTGTGGCCTCCcc 12 OOO

2001 CAGGGTGTcigTGGGGTCAicCACCTTGcircTGTGAAGAcGGCTGCCTGGCATTGGTAG? 12O60

12061 CAccGGTGcitcCTACATCiCAGGTTCTAcCAGCTCCATAGAGAAGCTCATGGAGGCCTf 2120

121.21 GGGAGCCAAGAAGAGGCTGitTGATGTAAGAAGCCAAAGAGGGAAGGTGcTGTGGGTGGG 1218O

2181 GGGAGCGCCACCTGGTATCGGCTCACAAATCCCCCAGGCAAATGAGGCCATCTCAGGcci 12240

12241 TCGCTTGTtcACCTCACAcicTCCACACATGTGGCTGGTcAccCATGGGGCGGGGCACTG 12300

12301 TCCCCAGcccTCTCCAGCAGAGAGACCAGGCCACCAGCGöAGGACTCCTfGTCTGCTGAG 1236O

1236. ACGTCTTCCATACTCAAGAAGGCTCTCTTfGCCCCCCAccCCAGTATGTcGTGAAGTGTA 1242O

12421 ACGAGGGCccTACACTCCccGACATCTCTFTCCACCTGGGAGGCAAAGAATACACGCTCA 1248O

1248. CCAGCGCGGACTATGTATTTCAGGTGAGGTTCGAGTCGGCCCCCTCGGTGGCAGGGAGAA 1254 O U.S. Patent Jan. 27, 2009 Sheet 77 of 112 US 7482,124 B2

F.G. 6L

25 4. AGGCTGGAcÁGAGACCCTcÁAAGAGTGACAGATTACAATGCACAGGTCAGTTAGAACTG 2600

126O1 TAGTTCTCAAACTTGGCTGiGCATGTCAccTGGAGAGCT iTGAAAAATCCTGGTACCTGG 12660

12661 GCCACATccöATACCTATTAAATCAGAAccTCTAGAAGTGGCACCTGGGGTTCAGTTTCc 12720

12721 cCAGGTGATiccAATGTGTGGCCATGTTTGGGCATCACTATGCCTGTTccCTCATCTCCA 12780

1278 TTTTCTCATéAAATACTcccAAGAATCCT?TGCTCCTATATTCTTACCCiCTTTTCATAA 284 O

2841 TCAATAGGCitAGAGAAGTfGAATAACTTGTCTAGGATCAGAAGCTAAGGCAAACTGTAA 129 OO

1290 GCTCCTGAAGGAAGCACGGiGCCTGATGCATTGTTTGccigGGATCTAGCACAGGGGCTA 12960

12961 AACATAGGAGTGGTGCAGTcCACGATGGGGCAAAATGGCCATGATGTGAGGGAGGCCCAG 13020

1302 TGTGGCTAGGGGAGAGATGGGGGCGAGAGGGGGAATGTTGCTGAAGACAGTTGCT(1GGGG 13080

3O8. TCAGGCAAGGTGAAAGGAGAATGCTCATGiGCTGGGTATGGAGAAACTcfcCCCCTTCC 13140

3141 GCCAGGAATécTACAGTAGi AAAAAGCTGiGCACACTGGéCATCCACGc(ATGGATATcc 132OO

132O cGCCACCCAcTGGACCCAccTGGGCCCTGGGGGCCACCTiCATCCGAAAGTTCTACACAG 3260

3261 AGTTTGATcéGcGTAACAAccGCATTGGCitcGCCTTGGccCGCTGAGGccCTCTGCCAc 1332O

1332 cCAGGCAGGöCCTGCCTTCAGCCCTGGccöAGAGCTGGAñCACTCTCTGAGATGCCCCTc 3380

13381 TGCCTGGGCiTATGCCCTCAGATGGAGACATTGGATGTGGAGCTCCTGciGGATGCGTGc 1.34 4 O

13441 cCTGAcccci GCACCAGcccTTCCCTGCT iTGAGGACAAAGAGAATAAAGACTTCATGT't 13500

35O CACAGCCTGiTGCATCTGGGTTCACTAGGGTTTAGAACAGAGGGAGGGGcTGCGTGATCA 13560

135 61 TGTGTGGACAGGAATGTGAcACAGACAAGöTACACATTCGCCTAGCGCACAGGTTCTTGé 1362O

362. GTGCAGGGATGATGCCATCCATCTGCCATCAACGGGACT CAGGGGAGCTGTTTACACAA 13 680 U.S. Patent Jan. 27, 2009 Sheet 78 of 112 US 7482,124 B2

F.G. 6M

13681 CCTCAGGTGGGAAGTCTGAAAAGAGCCGGAACCAAGCTccCTCTAGTCC(TCAGGGAcci 13740

13741 AGGCTAATGcTGTGGCAGTAGACTGTGGGiCAGAAAGTTcTCCCAGCTCACAGAAGCCAG 13800

138O1 CTCTGAGTTcAGACTCTGciCTGCTGAGCiAGTCAGCCcigTCTCTTGTccCTGCAAAAc 13860

1386 TCCCCTCAGöTGTccTTATéCACTGCAGAiGCCCCCGccöTGccCCATGiAGCCATTTAc 13920

13921 ACAGGCATTcTAAGGCACTACCACCTAAAãTCATAGAAcÅcCAGAGATccAGGCAATAct 1398O

13981 TCCACTTTACAGGTGGGGAAACTGAGGCccAGAGAATGGAAGGCCTTGccCAAGATTACT 14 OAO

14041 CGGTCAAGAATCAAGTAGTGAAGAATACTGAAAGATAGTGAAGAATCAAGACTGGAACcc 14100

1401 AGCCCGTCTGACTTGGGTccTGGGGGTTTcCACCTTATCATAAGCAGTTGGTACCGTCAt 14160

1461 AAGTACAGTGCTTCACGCAcGCTGGTACAGGGCCACGTGcACAAGCACACAGGTGCACAc 14220

14221 ACACACTGciaTCCTCCATccCATCCAccigGGACTCGTcAGGCTGAAGiCTCTTCTCCc 1428O

14281 ACTCTCACtectTGGGCTGicTTCAGGGCACATGTAACTfGGGGAATGAGAAATTAGCAT 14340

14341 CCACCTGGAGCCACTGAAGcCATCCCTCTiCACCATAGTi GCTCACCTCiCTTTTGACAG 14400

144 O1 AAAGTCGTGAGGCACTGAATGGCCCAACCACGCCCTCAGTACCTCTGGGAGCCATCTCCA 14460

14461 AGAGTCCCTGTGTAGCGCCAAGAGCCGGAGCCTGGGCTTCAGG 14503 U.S. Patent Jan. 27, 2009 Sheet 79 of 112 US 7482,124 B2

F.G. 7A

1. GGTCTTTGTAAAATAATAATTATTCATTT (ACAAAAGTGATAATTAAAAGACTTTAATAG 60

61 CAATACAGAAAGTTACATGAATATAAAGActTAACCTTTcTAAAGCTCAGTTTTCCTAAG 120

121 TAATCAAAAACCTGATAAAGATAACAAGAATGAGGAATTATCTTGAGAAAATGTAAAATc 1BO

181 TTTCCTTTTATTTTTTGAGACAGGGTCTCACTCTGTCATcCAGGCTAAAGTGCAGTGGCA 240

24 CAATCATAGctCACTACAGCCTTGAACTccTGGACTCAAGTGATCCT.cccGCCTCAGCCF 300

301 CCCCAGTAGcTAAGACTACAGGCACGCAccACCACACCCAGCTAATTTTTTTCAGAGATG 360

361 GGGTCTTGciaTATTGcccicGCTGGTCTTGAACGAGCTTCAAGTGAGcGTGAGCCTcci 420

421 AccTCATcciccCAAAGCAcTAGGATTACAGGCATGAGccACTGTTTCCcAGCCTAAAAt 480

481 AATTGTTTCitAGGCCAGCiACCAAAAAcGCAAAGAAAAACTTTCTGTAGTGTGATTGci 540

54 TCTTCTTATGGGAAGCCCATTTAGATAAccTGTAAGTCAAACCTGATGAAAACAATACTf 600

601 GAATGTAATéAGACACAGAAAGACTGTTCAAGGCTATGAGTAGCTGAGTcCAAGCTCGTA 660

661 TCACTTGCCACACAACAGccAATAAGTCTAGAGACAAGGiATTGTGGCAAGGAAAGCTAC 72O

721 CTTATTCAGAGAACCAGAAAACCAAGAAGATGGTGGACCAGCATCATAAAGAACCATCT6 78O

781 AAGTCAGCATGAACGTTAGGCTCTTCTTTATGTTAAGGGAAGGGGAAGAAGAAGGGGATf 840

841 GGGATCAAGAGGTGACTGATGACCACAGACACCTGGGTGcCAGCAAGGGTCTGAGGACGT 900

901 TGTAAAACTTCTTTTTTCTAGGTCACGTCACAATGTTcci ATACATCTTFAACATAACAt 960

961 TGTTATTTGicTGTATATTrcCTTATCTccTTGGGGGTTAGTTTGGGGAAAGGAACTGTf 1020

1021 ACCATTTTT iTTAAAGTTGAACTGCAAGCiAAACTCCTATAATTAGCTGGTCTATGTACA 1080

1081 GAGCTAAGCAGAAGCTTTTAGCCTAAAGGATAATACCCCTGGGGGTCAGAGGCAAAATGG 1140 U.S. Patent Jan. 27, 2009 Sheet 80 of 112 US 7482,124 B2

FIG. 7B

114 1 AGTCAGTCATGCTAAGTCTccCTCCACTCiCTTTCTTTTTTGAGATGGAATTTCACTCTf 1200

1201. ATTGccCAGGCCGGAGTGCAGTGGCATGATCTCAGCTCACTGCAACCTccGCCTCCTGGG 1260

1261 TTCAAGCAATTCTCTTGcci CAGCCTCCTGAGTAGCTGAGATTACAGGTGTCCATCACCA 1320

1321 CAccCAGCTAATTTTTGTAGTTTAGTGGAGATGGGGTTTcACCATTGTTGGTCAGGCTGG 1380

1381 TCTGGAACTcCTGACCTCAGGTGATCTAccCACCTTGGccTCCCAAAGTGCTGGGACAGG 1440

1441 TGTGAGCCAccATGCCTGGccCCTCTACTctTATAATTAAACCAGCTGTfGCTTTTCCTG 1500

501 CCAAGAAAccAGTCATGAAGATTCACCCAiGTTCTAGATGGGAAAACTGGGCTGTAGcci 1560

561 GGGAGAGGccAGTCAGGGAcAAAGCCAAAGTTAATATAGAGAATGGAGCitcCAGGGTAf 1620

621 AGGGGTTGGGTCTGGGCTAGGGAGCTGGAAACCTAGGTTTTACGCTTGTcCCAGTTTTGA 1680

681 TGTTAGCccigAGCAGTGciGTTTCTCATcAGCCTCTGccTGCTCCAGGGGTCACAGGGc 1740

174 CAAGCCAGATAGAGGGCTGCTAGCGTCAct GGACACAAGATTGCTTTCCcACAGCTGTcc 800

18O TTCCTCCAGccCCTCTGCTccCCATCCGGAAACCTGGGTAccCTTCACccACCTAGCTcf 1860

1861 GTCCCGCAGTGAGATTTATfGCTGACTGccCTGCCATCTAccCCAGGGTAATAAATCAGG 1920

192. GCAGAGCAGAATTGCAATCAccCCATGCATGGAGTGTATAAAAGGGGAAGGGCTAAGGGA 1980

1981 GCCACAGAAccTCAGTGGAt CTCAGAGAGAGCCCCAGAcigAGGGAAGCATGGATGGATG 2040

2041 GAGAAGGATGcCTCGCTGGGGACTGCTGciGCTGCTCTG&GGCTCCTGTAccTtTGGTcf 2100

210 CCCGACAGAcACCACCACCTTTAAACGGTAATTGGTAACfCAGGCAGAGAAGGGGTGGGA 21 60

26. GGGGTGCAGGGTTCCCAcci TCCCAACAccCTGGCTTTTcCACATGcGGiGTCATTCAGi 2220

2221 CCTTACGATCAGCTGGACAGGGAAGTATGGACCTGTTCAGAGAGGTCAAGTGACTTGCCC 228O U.S. Patent Jan. 27, 2009 Sheet 81 of 112 US 7482,124 B2

FIG. 7C

2281 AATAAATGACACTAGTAGTcAGGTCTAGAAGCTGTGACTitTGCTTCCTGccCAGAGCAc 234 O

2341 CATGCTAAct AAGCACTGTAGAGAACTCAGAAGTATTAGGACATGCCCCTGCACTTGAG 2400

24 O1 GAGCTCACAGCCTGAATAti AAGAAGGGCATGGGTGGTTGGGCGCGGTGGCTCCTGCCTG 24 60

24 61 TAATCCCAGöACTTTGGGAGGCTGAGACGGATCACTTGAGGTCAGGAGTTTGAGACCAGc 252O

252. CTGGCCAACATGGGGAAAccCCATCTCTACTAAAAATACAAAAATTAGccGGGCATGGTG 2580

258 GCAGGCACTfGTAATCCCCAGCTACTCGGGAAGCTGAGGCAGGAGAATCGTTTGAGCCCG 2640

2641 GAAGGTGGAGATTGCTGAGcCAAGATCGTGCCACTGCAcfcCAGCCTGAGTGACAGAAcÁ 27 OO

2701 AGACTCCATcTCAAAAAAAAAAAAGACGGGGGTCGGGGCATGGGTACAGiTAACTGTAcc 27 60

27 6. AGGGAAGCAGCTTGATATCGTGGTTAAATGCAAGGCTTATAGAGTTAGATGCCTTCATf 282O

2821 TAAATTTTGöTTCACTAGCAGAACAAACTAGGTCTGGAATCATGGGCAAGTTATTTAAcc 2880

2881 TCTCCAAGTcTCAGTTTATcATTTTAAACAGGTATGATA?TAACAGTAccTACTTGATGG 294 O

294, GGCTGCTTTGGGGATTTTAGGAGATAAGGCATAGAAAGCTGGGCACGTTGTAAGAGCCCA 3000 3001 GCTACTGTTAGTACTACAGGATAGATTCTTACAAATATCAAAAGCAAGGTTTGGCCGGGA 3060

3O 61. GCAGTGGCT(ACGCCTATATCCCAACAcitTGGGAGGccGAGGGGGGCAGATCACCCGA 312O

3121 GGTCAGGAGiTCAAGACCAGCCTGACCAAcATGGAGAAAccCTGTCTCTACTAAAAATAc 318O

31.8 AAAATTAGccGGGCGTGGTGGCACATGccigTAATTCCAGCTACTTGGGAGGCTGAGGCA 324 O

3241. GGAGAATCGöTTGAACCTGGGAGGCTGAGGTTGCAGTGAGCCGACATAGöGCCATTGCAc 33OO

3301 TCCAGCCTGGTCAACAAGAGCAAAACTCAGTCTAAAAAAAAAAAAGAAAGAAAAAAACAA 3360

3361 GGCTTTAGGTAGCCCACAATTAGAAGGAGAAAACCTTAGCATCCCCTAGGTGCCAGGCCT 342O U.S. Patent Jan. 27, 2009 Sheet 82 of 112 US 7482,124 B2

F.G. 7D

3421 TGTGGGAACAAGTGATTCATTAAGACTGTAGAAGGAAGCfcGGCACGCGGCTCATGCTTG 3480

348 TAATTCCAccACTTTGAGAGGCTGAGGTGGGCAGATCGCTTGAGCTCACGAGTTCAAGAC 35 40

3541 CAGCCTAGGCAACATGGTGAAACCTTGTCigTACAAATAcAAAAATTAG(TAGGTGTGGi 36OO

360 GGTGCAAATcTGTAGTCCCAGCTACTCGGGAGGCTGAGGiGGGAGCATCACTTCAGCCTG 3660

3661 GGAGGTGGAGCCTCCAGTGAGCAGAGACTGACCCACTGTGCTCTAGCCTGGGTGATAGAG 3.720

372 CCAGACCTTATGTAAAAAAAAAAAAAAAAAAAAAAAGACTGAAGAAGGGGAAGAGACAG 3780

37.81. CATTTGAGAAAAGGCCTCAcAGAGAAAGGGGTTTTCAAtcTGGGGACAGéAGATATGAcc 3840

384 AGCAGTCCTGAAGGTAGGGAGGCACACTTAATAATGGTAATAGTTGCTAAGCCTATAAA 3900

3901 ATGCTTAGGGTGTCACAGGATCTTTTCACATGTCTCATCfCAAGTCATGcCCCCAACAAc 3960

396 TCAGCATTccCACTTTGCAGATGAGGACACTGAGGCTCAGGGAGGTGATATGTAAGAGGC 4020

4021 TAAGCCTCAñCACACACTGGGCCTTTTGcitccGAAACT&CTTTCCCTTGCTCTGAGGCf 4080

4081 CTCGGAGAGTAATTGCTGGGTTGTGAGCAcTGGGTAAGAGGATGGGTGcitCAAAGCAGc 440

441 TGCACTCCAGGATAAAGGTAGAGGAAAGTAAAAACATCTCCCCTGCTGitATCCAAAAG 4200

42O1 AGAAAAAGAñTGGAATTGGGCAAGGGGTGGAGGGGGRATcCAGCTTTTGAAACAGTATTA 4260

4261 TAGGAATTTfGCTAccCGCfATGTGCAGAGCATCATGcGAGGCACTTGGGACAGCTGAAt 4320

4.32 GAATGAGCTcCATTCTCAAGGTGAACATGiACATATACACACCTACAATTACATTTAtt 4380

4381 GAGCAGTGGrcGCATGGTTTCATCTGCACAGTGACTCTGAGGTAGGTACTACCATTAGGö 4 440

4 441 CCATTGTTAGAGAGGGGTTAATGGAGACTTAGAAGAGGccCAGAGAGGTi AGGTAGCTTf 4500

45 O1. CTCAGAATCACATAAGTGGTAAGGGGATTCAGGCATGCCCCCTGCAACCACTGTCTTCAC 45.60 U.S. Patent Jan. 27, 2009 Sheet 83 of 112 US 7482,124 B2

FIG. 7E

45 61 CAccGTACGGCACCAGTTccACAAGCTGTACAGTGTGGGCTGTGAGAccöAAGGAAAAAC 462O

4621 AGAGCTGAGGccCACGGGAAGGTGAGGCCGGTGTGGGCTGGAGGCCTTGGGGTAAGCTTc 4680

4681 CTGGAGGTGGGGGTACATGiTGGGCCTTGGAGGACTAAAGAACTGGGGGGAAAAGGAAGG 4740

4741 GAAGAAGGAAAGGATTTTCiGAAAAGGAAATGGCAAGAAGTAAAGGTCCAAAGCATAGGC 4800

480 TGTTGTGAGTAAACAGTGGGAAATGCAAccTCTTTGGGGcCAAACCTCTGACCCTCCAcG 4860

486 TTCCCAGCTGTGAAGTGGGAGTAATAAAATCATCCACCTTATGAGACCAAATAAAATAAt 4920

4921 GATTGTGAAAATATTTTGGTAACAGTAAccTGTGATAGGAAGATAACAAATCATTTCTGi 498O

498 TACAATACCATGCTGATAGGCATAAAAGTfGCATTCATGiTCATGGGCAAAATGGGGGTA 5040

50 41 AGTAGAATGcATGGGACGCAAGAAGGATGTAGGAAGGAAAGGGTAGTGT6AGTATAGGAG 5 OO

5101 GACTAGCCAcTGAGAAGAAAGTAGAAGAAAGAGGGAATCitTGTGTGTAiGGGAAAGTct 5,160

516. ATTGCAGAGTCAACTTGGGct TcCATCCTGGGACCTT.cccGTGAACAGct AGAGACAtci. 5220

522 TCCTCTGGGöTTTGGCAGccTTTATGTCGGGACCCAGGGGACCCTATATGGGAAATAGGG 528O

5281 CCAGACACAiGCTCTGAATccCTGCTTCAñCATTTCTGAGTCACCTTTGiccCTGTGAcc 534. O

5341. CTTCATTTTTCTCATCTATAAAATGGATGACAGCTAGCTfGTTGGTGTGATTTCAGTAGc 54 OO

54O1 GGCTCAGTAGAGTCAGTTTcCTAGGTCTCiTTAATTCTGcCTCTCAAAGGTGATGGGAA, 54.60

5461 ACATCTAGACAAGAAGCCAAGGGACCGGGACACATCTCTcCAAGGACGAGGTGCATGGCG 552O

5521 CTCTGAAGAFGCTGGCATCfCTCTAGGCC?AACCCAGCT(AGGGGGTCCACTCCACCACA 5580

558. GCCCTGGCTGGGTGCCTGTccCCTGGTATcCTGGAGAcci TGCAGCTGciGTGGGCATcf 5640

56.41 GCTGCCACCTAGCGGCCTCCCATGGCACTGTCTCCCCGCCAGCCCCTAGTTTTGACAGGG 57 OO U.S. Patent Jan. 27, 2009 Sheet 84 of 112 US 7482,124 B2

FIG. 7F

5701 GCACTCCCT6GCATTAATcfcTTCAGAGGGAATGTCTGTGCCTGTTTCCi GTCTGTCCTc 57 60

5761 cCGCCAGGTGGAGTTCCTTAAAGGCAGTCATGATCATTAiCTTTCTAGCfcCAGTGTCCA 5820

5821 GCACAGTGAGGCACAAAGTAGTTGTTCAGOAGGTGATTACGGAATAAATGAATGAACGGA 5880

5881 CCAATAAACAAATAGCCTTGTCTAATCAAAATTAGGCAACAGAAGGAAGTCACTTCAGGG S940

5941 TTATTTAATccCCGGGCAGCTGACTCCTciaAATTGACTctTGACAAGAAGTAACTCTTA 6000

6001 TAAATGCTCCAGAGGCCCTCAGCGACAGAGGTGATTTCCAGGTGGCTGGGCTAACGTTAA 6060

6061 AGGTGGTTGTACTAAAAGCAGGGGTTTGGccTCAGGGAcfcCACCACTGiGGTGGAGGTA 61.20

61.21 CAGCACTTTTCTATTTTTGcTTCCTCCAccCTGGGCCAGGATCTTCCTCAAGAGAATGcc 680

681. CTCAATCCGAGAAAGCCTGAAGGAACGAGGTGTGGACATGGCCAGGCTTGGTCCCGAGTG 6240

624 1. GAGCCAAccóATGAAGAGGCTGACACTTGGCAACACCAccTCCTCCGTGATCCTCACCAA 6300

6301 CTACATGGAcGTGAGTGcticCCTCAGCCcCTCGCTCCCiCCCTGTCTccTTTCCCTCAt 6360

636. GGACCTAGGGCTTTCTTTGcTGCAAGACTcACCCTTTCCAAGCTGTGTTi GACGAAGGcG 64 20

6421 CTGAGTAGCACGTGAGCAccCTAGAAAAticcCATTTTc(AGCTGGAAAGCCTGAGCACA 6480

6481 GAAGACAGGAAGGCATCCAGGGGCCATTCAGGGGCAGGGTTAGGTTTGGAACTCAGCCCA 65 40

6541 GGCCTCAAccCAGGTGTCAcAGGTGGGTGGGAAGGGGTGiGTGACTCAGGTGGGGGTTTc 6600

66O1 TGTGACCTGGCCCAGCACAAcCTGATGGCFTCCTGCCCCAGAGGATCCT?AAGAGTCAAG 6660

66.61 TTTGCTTcci GCTTCATTccAATGTTTT GATTTTGCCCiCTTGTCTTACTGAGACTcco 6720

6721 ACTTTCTGGGATGCCATGGGGAGATGCTAAGCCTCCTAccAGTTCCTGCAGGAAAATGGA 6780

6781 AACCCCGAGAGGCTATAGGACCTCGCCTGGGCCAAGTCTCACACCGAGAGCCAAGAGTGA 6840 U.S. Patent Jan. 27, 2009 Sheet 85 of 112 US 7482,124 B2

FIG. 7G

684. AGCCAGGCAAGACCCCAAGACCCAAGGTccCCTGAGCCccTCCAGCCCT(TCTTTTTAcc 6900

690 CCCACAGAccoAGTACTATGGCGAGATTGGCATCGGCAccCCACCCCAGACCTTCAAAGT 6960

696.1 CGTCTTTGACACTGGTTCGTCCAATGTTTGGGTGCCCTccTCCAAGTGCAGCCGTCTCTA 7020

7021 CACTGCCTGiGGTGAGAcci AAGACCCACAGTGCCTCTCCTCCATCCCccTGCCCTACTG 708O

7081 TGCATGAGCAATCCTGCCCAACACCCAGCfccCATCCCTcTTGCCACCAAGGGAGTGGCf 714. O

7141 TCCTCTCTGcCTCTGTG.cccACTGACATGTAGGGGAGAGGGGAAGATGTcTCCCGTTTTf 7200

720.1 CTGATACAGcCACCAAGGTTAAAAACAAAAAAAGGTCCAAGAACCCCTGAGCACCCAGAA 7260

7261 GGCCACTTccCAGTCTTcci GAGATTGAGACAGGACTGAATTCTCAAAccCATCCCAGGc 732O

732. ACTCGGAAcicTTCCATcccTAGTCTTAATCAACAAcCrcTTACTAGGCACTTACTCTGT 7380

7381 GCCTGGCATcTTCTCTGGTGTTATCAGTGiTAGTGATTACTTTAAATTccTTCATTTAGG 74 40

7441 ACAAAATTCfcGATGTATGGGCACATTAGGAGAGCCCAAGAAAccCAGTcCTTGATTGAf 7500

75O1 GAAGCACATATTCCAAGCCCCCTGACCCTAGGGCCACTCATCCCTGCAccTAAGCTAAcc 75 60

7561. AGCCATAcccACAATGCAccCTGCCTCTGAGTCCCCCTGicTGGGCCAcicTTGGACAAA 7620

7621 CCTGAGCCTcTGTCCCCCTGCCAGTGTATcACAAGCTCTTCGATGCTTCGGATTCCTCCA 7680

7 681 GCTACAAGCACAATGGAACAGAACTCACCCTCCGCTATTcAACAGGGACAGTCAGTGGCf 7740

7741 TTCTCAGCCAGGACATCATcACCGTAAGTfGGGCCGCCCTAGGTCATCTGCCCCGGAccc 7800

7801 CTTCTGTCccCAGGCCTCTcCTGACCCTCCAGGGCCCACACCTGcGGGGAGGTACACTGc 7860

7861 AGCCCACTTGGAGCCTGGGGAGCTGAGGAACACCCTACTcTGCCACATcfgGCTGTTGct 7920

7921 GCAAAGCAGCAGTACCTATGGGGGAGCAAGCCTGGGCTACGGGCT CACCGTTGGGTGGTT 7980 U.S. Patent Jan. 27, 2009 Sheet 86 of 112 US 7482,124 B2

F.G. 7H

7981 TGTGGATGTi TtTGCATCTAACTTGCATGTAGGGCTTGTcCTGAGCCccGTGGCTGCAGi 8040

8041 CAAGTAACTcGTCCAAGTTcACCAGCTCTGACTGGGCTACAccCTAGAcrgAAATCCAGG 8100

81.01 GTCAGAGTCAGGCTGAGTTTTAGGGTCAGGCATAGGTTTi AAGGTCACAGTTGAGGTTGA 81 60

81 61 CTCTGGGAccAGGTCAAGGCCTGCTTTTcTTTTCCATGiGGCCCATGTcTGACCGTTTc 8220

8221 CTCATCCTGGAGTTTCTCAGGCCCTGCTCCATCAGAGTTAGGGGAGGGG?ACACGTGGCA 8280

8281 ccTGAGAGGAAATCAGGGTGATTCCTGccrccCTTCCTTFTTCTGTGAAcTCAGATATA 8340

8341 AGGAGGGAGAAGGGCAAGcitGTCTGTGci AAAGAAAcccTTCGCCCATGATAAGGGTGG 8400

8401 GGGCCAAGACCCAGTCCTGcCAGGCACGAAAGTCTGGCCACTGGGGAGGGGAGGAGCTcf 84 60

84 61 TGGCAGCTTi TCTTTTGCTGCTTGGCAGGACCACCCTCTcAGCCTCTGcicTCCGATccc 8520

8521 TGGTCAACTcTAGCTCTCrcTGGGCTCCGCAGCAGAGATGTGTATTGGCACAGAGTGTGi 8580

8581 GCGTGCAGGGTTGAGGAAAACTCTTAcc?cGATTTCTGTAccCTGGAGéATGTGTGcce 864 O

864. CTGGGATccöTAGTGTGGAAccCCAGACCAGACTCCAAccAAGGAGTGGGCAGTGGGCTf 8700

8701 GGTCTCCTcf GGTCCTTCCTCCCACAGGTGGGTGGAATCACGGTGACACAGATGTTTGGA 87 60

8761 GAGGTCACGGAGATGCCCGCCTTACCCTTCATGCTGGCCGAGTTTGATGGGGTTGTGGGC 8820

8821 ATGGGCTTCATTGAACAGGCCATTGGCAGGGTCACCCCTATCTTCGACAÁCATCATCTcc 888O

8881 CAAGGGGTGöTAAAAGAGGACGTCTTCTCitTCTACTACAACAGGTGGGGACTGGGACTc 894 O

8941 CAAGGGCTGAGGTGGGGGGACAGGAGGGGAGAAGAGATGGGGAGTGGAAGGAGAGTCTGG 9 OOO

9 OO1 GCCAGAATT&TAAAGTGTTfGTAATTAGGTGACAGCCAATCAATATCTAGAGCTGTACTA 9060

9061 GCCAATATGGAAGGCACTATTGAAATTTAAATTAATTAAATACAGTTAAGCATCAATTAA 9120 U.S. Patent Jan. 27, 2009 Sheet 87 of 112 US 7482,124 B2

FIG. 7

9121 GCATTCAAcfcGTGGCTCTTAGTTGTACTAGCCACACGTcAAATGCCTGGCAGCCACGGr 918O

918. GGCTAGTAACTACAGTCTTATGACAGTGCAGATAGAGAAiATTCCCAGCATGACAGGACA 9240

9241 TTCTAATAGACAGCGCCActCTGGAGCAAGAGGAGATGCAAGGTGGGGGcGATGGTAAAt 93OO

9301 AAGGGATTACTGTGACCTGiAGCCCTGccigTTAGGGCCATGGCTCCTccCACACAGAGA 9360

9361 CAGCCAACTicAGTCATCCATTAGATCCticATTCGTTTGTTTGCTCAct CATCAGTTCA 9420

942. GTAAATGCTATGTGCCAAGCACTGTGGTAGGCTCTGGGGGTGCAGCAGTGAACACAGTGA 94.80

9481 ACAAGGCAGAATCTGTACTccCCTACCCACATAGAGCTTACAGGCTAACAGGGAAGACAA 95.40

95.41. GACATATTccAACATAAAGAGTGTCACAGGCAGGCAGCAAGTGTGGTGciGAAAACCATG 96.OO

96O1 GATGCTTTTcAATTCTAGGöTGAGCTTATATGCAGCTCAGCCAGCCTTGGGGAAGCTCTf 96.60

966. GAGCAGGGTfGGGCTCTAcfcCAAACTGciGGGCTTAGASAGATGGCAT&AGTTGGAGAC 97.20

97.21 AAGAGAGCTGGAGGCAAAAGGGGCTGGGTGCAGTGGCTCATGCCTGTAafcCCAGCACT 978O

9781 TGGGAGGCCAAGGCGAGAGGATCGCATGAGCCCAGGAGTi AAGGCTTCAGTGAGCAGTGA 984 O

984 TTGTGCCACigCACTCCAGCTAAGGCAACAGAGTGAGATcCAGTCTCAAAAAAAAAAAAA 9900

99.01 AAAAAAAAAAAGTCACAAGGGTAAGAACAFGAGGCCAGTGGCAAAAAGAATAGAGGAGAG 9960

99.61 GATCAGAGTiCAGAGAAATöTCACAGTAAAATGGAGAGGiGTCTCCGGTTGGTGATAGA 10O20

OC21 AAGTGAGGCCTTGAGAAAAGGCCAATTGGcGGCTCTCCATTCACGGGTGGTCTTTAGAAG 10080

10O81. AACTGTTTTAGAGGANGTGGGGGCAAGGCcAGATGGCAAGAAGTTAAGAGGTGGACGACG 101 40

101.41 TGGGTGTCAGGAAGTGGAGötCATGAGATGTAGGCTGcccTGGGACATTéAACAGGGAAG 10200

102O1 GGAATGGGGGGTGGCGTGGGGGGTGAGATCCAGAAGCAGAAGAGGAAGGGTGGGTGTTTT 10260 U.S. Patent Jan. 27, 2009 Sheet 88 of 112 US 7482,124 B2

FIG. 7J

10261 TAAAtGCTAGAGGATGCTCGAGTGATGCCTGTAGGTGGAGGAAGAAGCCAATGGAAAGAA 10320

10321 AGAGATTAAAAATGTGGAAñGAAGAGGAGCTAAATGGGGGCACTGGAGTi TGGAGGCCTf 10380

10381 GAAAGAGATGAGGTTCCAGöAGACAGGAAGAAGCCAGGTTTTGCAGAGGAGAGGGCTGGc O440

10441 CTCTTCTTTTATCTTGGGAiGGGAAGGAGGGAACATCCAGAGAGATACTGAAGTGTTGAG 1 O5 OO

105 O1 AGACAGGCAGGAGGGAATTfGTGCTAGCATATACACATAcATTCCGAAtitATAAAAACA O5 6.O

105 61 CAAGTAGTTfGCAGTTGCAcAAAATAACAATGCACAcci ACACACCCATGCACACATGT 10620

10621 GCATGTGTGAATTCTAGTAfGAATTCTGGAAAAACACATcACACACACAGGCATGCCCTG 10680

10681 GAGACTAGGCCTACAGTAGTCCCTGAGCCAAGTGCAGTGAGGAGGAAAGGAAGGTGAGGG 10740

10741. GAATCAGCTCCAGACGGGG(ACCAGGAGCTGGCTCCAGiCCCCCACTTGTTCACTCATG 10800

108O1 GACTGGGTAACTTCAGGCAñGTGACTTCGCCTCTTGGTGACTCCATTGccTGAAGGGCAA 10860

1086 AGAGAGTACATAACACCCACCCTGCCAAACAGCAGGGCTGATGAGGCTGGCATGAAATGA 1 O920

10921 AGCTTCCTTCTGCTGTCT(TCTTTCTCTGCAGAGATTccGAGTAAGGAGACAAAAcccc 10980

10981 CACATGGCTGTGACCTTcc?GTACTCCCCGAGCACCTGAccTAGAATTACACAcGCCAcc 11040

11041 GGCCCAAAACTCACATCAGCAAGCCCAGccTCCGCTAGAfGCCGAAGTTCTCTGTCTCTé 11 OO

11101 CTTCCTGCT(TCTCCATGccACCTGccCAccCCATAccCAATAGCCT.cccCAGGGTccco 11160

1116.1 TccCATGCAccTGCTCAAtcAGCAGCAAccCAAGAGTGAGGGGTGTCCAittgTGTCTTg 11220

11,221 TTCACATCCACTCACTGTCCTTGTACCTGcTCCTTTTCTGTGACCTCTCiGGGGATGCT i. 11280

11281 TTTGGGGGAACAGCTGGACACCCTGGAACAACCTCTGGTTGGTCTTGGGGAGGGGAAGA 11340

11341 AAGGCAGAGAAGCAGTATGTTCTGCATGCTTCCCAACGACAGCTCCGAGCCTGGCTGTCT 114 OO U.S. Patent Jan. 27, 2009 Sheet 89 of 112 US 7482,124 B2

FIG. TK

11401 GTCCCACATTCCTCTGCTCiAGAGCCCTcfgTCCTCCCCiccACCCTTGiGCAACCTTcc 11460

11461 CCAATTGccigAGTTGCTGGGTCCTGGAGGTTATGGGTTTCCAAGAGCticTGATCTTTc 1152O

11521 CTTTAGGAATTCCCAATCGöTGGGAGGACAGATTGTGCTGGGAGGCAGcGACCCCCAGCA 11580

1158. TTACGAAGGGAATTTCCAciATATCAAccfcATCAAGAcigGTGTCTGGöAGATTCAAAt 11640

11641 GAAGGGGTCAGAAATCCTc?ACCCTCCCCGGGCTCCAAAAAATGCTGccGTCACTGGGGr 11700

11.701 TGGGGAGGGTGGGGAAGGAcTGCATTACCATCCTGCCCTcTTTCCAAATGCAGCCACTTc 11760

176. TTAAGCACAGCCACCATTTGCTCTCTGcci GCTCTCTCCAGGCTGGGGAACAGAGAAGGG 11820

11821 AGGGGCCTGGGGAGAAGTGGTGGAGGGTGACAGTACCTTccCTCCTCTAcTCACTGCCTc 11880

1188. AACAGGCCACCAGCGTGGCCTCCACCCAccCACCCACAcfcAGGAAGGACATGCAGCCTG 11940

1941 GAGGTGCCCCATCAGCCTTcTGTCTGTCTGTCTGTCTGTcTGTCTGACTGTGGCCTCCcc 12 OOO

12001 CAGGGTGTCigTGGGGTCAFCCACCTTGCfCTGTGAAGAcGGCTGCCTGGCATTGGTAGA 12060

12061 CAccGGTGCATCCTACATcfcAGGTTCTAccAGCTCCATAGAGAAGCTCATGGAGGCCTf 12120

121.21 GGGAGCCAAGAAGAGGCTGiTTGATGTAAGAAGCCAAAGAGGGAAGGTGcTGTGGGTGGG 1218O

12 181 GGGAGCGCCACCTGGTATCGGCTCACAAATCCCCCAGGCAAATGAGGCCATCTCAGGCct 2240

12241 TCGCTTGTTcAccTCACAcicTcCACACAFGTGGCTGGTcACCCATGGGGCGGGGCACTG 123OO

230 TCCCCAGCCTCTCCAGCAGAGAGACCAGGCCACCAGCGéAGGACTCCTfGTCTGCTGAG 12360

12361 ACGTCTTCCATACTCAAGAAGGCTCTCTTfGCCCCCCAcccCAGTATGTcGTGAAGTGTA 12420

12421 ACGAGGGCCcTACACTCCccGACATCTCTiTCCACCTGGGAGGCAAAGAATACACGCTCA 12480

12481 CCAGCGCGGACTATGTATTTCAGGTGAGGTTCGAGTCGGCCCCCTCGGTGGCAGGGAGAA 12540