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

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(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. 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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). 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