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(12) United States Patent (10) Patent No.: US 8,080,578 B2 Liggett Et Al

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(12) United States Patent (10) Patent No.: US 8,080,578 B2 Liggett Et Al USO08080578B2 (12) United States Patent (10) Patent No.: US 8,080,578 B2 Liggett et al. (45) Date of Patent: *Dec. 20, 2011 (54) METHODS FOR TREATMENT WITH 5,998.458. A 12/1999 Bristow ........................ 514,392 BUCNDOLOL BASED ON GENETIC 6,004,744. A 12/1999 Goelet et al. ...... 435/5 6,013,431 A 1/2000 Söderlund et al. 435/5 TARGETING 6,156,503 A 12/2000 Drazen et al. ..... ... 435/6 6,221,851 B1 4/2001 Feldman ... 51446 (75) Inventors: Stephen B. Liggett, Clarksville, MD 6,316,188 B1 1 1/2001 Yan et al. .......................... 435/6 6,365,618 B1 4/2002 Swartz ... 514,411 (US); Michael Bristow, Englewood, CO 6,498,009 B1 12/2002 Liggett ............................. 435/6 (US) 6,566,101 B1 5/2003 Shuber et al. 435,912 6,586,183 B2 7/2003 Drysdale et al. .................. 435/6 (73) Assignee: The Regents of the University of 6,784, 177 B2 8/2004 Cohn et al. 514,248 Colorado, a body corporate, Denver, 6,797.472 B1 9/2004 Liggett ......... ... 435/6 6,821,724 B1 1 1/2004 Mittman et al. ... 435/6 CO (US) 6,861.217 B1 3/2005 Liggett ......... ... 435/6 7,041,810 B2 5/2006 Small et al. ... ... 435/6 (*) Notice: Subject to any disclaimer, the term of this 7, 195,873 B2 3/2007 Fligheddu et al. ... 435/6 patent is extended or adjusted under 35 7,211,386 B2 5/2007 Small et al. ....... ... 435/6 7,229,756 B1 6/2007 Small et al. ... ... 435/6 U.S.C. 154(b) by 280 days. 7,449,292 B2 11/2008 Liggett et al. ... 435/6 This patent is Subject to a terminal dis 7,572,603 B2 8/2009 Small et al. ... 435,912 7,642,052 B2 1/2010 Small et al. ....................... 435/6 claimer. 7,678,824 B2 * 3/2010 Liggett et al. 514,415 2001/0016338 A1 8/2001 Snapir et al. 435/69.1 (21) Appl. No.: 11/838,131 2001/0051712 A1 12/2001 Drysdale et al. 536,235 2002/0187491 A1 12/2002 Johnson ........ ... 435/6 (22) Filed: Aug. 13, 2007 2003/0039979 A1 2/2003 Liggett et al. ... 435/6 2003/009 1998 A1 5/2003 Drysdale et al. .. ... 435/6 Prior Publication Data 2003/01 13725 A1 6/2003 Small et al. ....... 536,231 (65) 2003/0124636 A1 7/2003 Leyland-Jones .. 435/7.92 US 2008/OO96982 A1 Apr. 24, 2008 2003/0143608 A1 7/2003 Filigheddu et al. ............... 435/6 2003/02331 18 A1 12/2003 Hui ............... ... 606,201 2004/0023967 A1 2/2004 Cohn et al. 514,248 Related U.S. Application Data 2004/0033524 A1 2/2004 Johnson ............................ 435/6 (62) Division of application No. 1 1/226,908, filed on Sep. (Continued) 14, 2005. (60) Provisional application No. 60/609.689, filed on Sep. FOREIGN PATENT DOCUMENTS 14, 2004, provisional application No. 60/610,706, EP O329822 6, 1994 filed on Sep. 17, 2004. (Continued) (51) Int. C. OTHER PUBLICATIONS A6 IK3I/405 (2006.01) A6 IK 47/00 (2006.01) Borjesson et al., “A novel polymorphism in the gene coding for the A6IP 43/00 (2006.01) beta 1-adrenergic receptor associated with Survival in patients with CI2O I/68 (2006.01) heart failure, Eur Heart J., 21:1853-1858, 2000. C7H 2L/02 (2006.01) Bouzamondo et al., “Beta-blocker treatment in heart failure.' Fun C7H 2L/04 (2006.01) damental & Clinical Pharmacology, 15:95-109, 2001. GOIN33/53 (2006.01) Bristow et al. “Selective versus nonselective beta-blockade for heart failure therapy: are there lessons to be learned from the COMET (52) U.S. C. ........ 514/415: 514/789; 435/6.1; 435/6.11; trial?” J Card Fail. 9:444-53, 2003. 435/6.17; 435/7.1:536/23.5; 536/24.31; 530/350 Bristow et al., “Effect of baseline or changes in adrenergic activity on (58) Field of Classification Search ........................ None clinical outcomes in the beta-blocker evaluation of Survival trial.” See application file for complete search history. Circulation. 110:1437-42, 2004. Bristow et al., “The role of third-generation beta-blocking agents in (56) References Cited chronic heart failure.” Clinical Cardiology, 21 (Suppl I):I-3-I-13. 1998. U.S. PATENT DOCUMENTS (Continued) 4,234,595 A 11/1980 Kreighbaum et al. ........ 424/274 4,873,191 A 10/1989 Wagner et al. ...... 435/1723 Primary Examiner — Carla Myers 4,965,188 A 10, 1990 Mullis et al. ... 435/6 5,002,867 A 3, 1991 Macevicz ..... ... 435/6 (74) Attorney, Agent, or Firm — Fulbright & Jaworski L.L.P. 5,130,238 A 7, 1992 Malek et al. 435/91 5,169,766 A 12/1992 Schuster et al. 435/91 (57) ABSTRACT 5,202,231 A 4, 1993 Drmanac et al. ... 435/6 5,302,509 A 4, 1994 Cheeseman ..... ... 435/6 The present invention concerns the use of methods for evalu 5,595,880 A 1/1997 Weinshank et al. 435/721 ating bucindolol treatment for a patient, particularly one with 5,648,482 A 7/1997 Meyer ................. 536, 24.33 heart failure. It concerns methods for determining whether to 5,679,524. A 10, 1997 Nikiforov et al. ................. 435/6 5,766,851 A 6, 1998 Shuldiner et al. ................. 435/6 administer or prescribe bucindolol to a patient based on 5,846,710 A 12/1998 Bajaj............ 435/6 whether the patient is homozygous for the Arg 389 polymor 5,856,092 A 1/1999 Dale et al. 435/6 phism in the B1-adrenergic receptor (AR). 5,888,819 A 3, 1999 Goelet et al. 435/5 5,981,174 A 11/1999 Wolfetal. ........................ 435/6 28 Claims, 29 Drawing Sheets US 8,080,578 B2 Page 2 U.S. PATENT DOCUMENTS Gene Card for ADRA2CO2c-AR available via url: <genecards.org/ 2004/0106954 A1 6/2004 Whitehurst et al. .............. 6O7.3 cgi-bin/carddisp.pl?gene=Adra2cc, Feb. 6, 2008. 2004/O192625 A1 9/2004 Liggett .......... 514,44 Gene Card for ADRBIB1-AR available via url: <genecards.org/cgi 2006/0073508 A1* 4/2006 Small et al. ....................... 435/6 bin/carddisp.pl?gene=ADRBD, Feb. 6, 2008. 2008/0269346 A1 10, 2008 Johnson etal 514,651 Goldstein et al., “Metoprolol controlled release extended release in 2009/0092964 A1 4/2009 Liggett ....... 435/5 patients with severe heart failure.” J of Am College of Cardiology, 2009/0228995 A1 9/2009 Liggett et al. ................... 800/13 38:932-8, 2001. FOREIGN PATENT DOCUMENTS Goldstein, “Beta blocker therapy in African American patients with EP O874.048 10, 1998 heart failure.' Heart Fail Rev., 9:161-7, 2004. JP 06-121686 5, 1994 Hein et al., “Two functionally distincta-adrenergic receptors regu WO WO 88,10315 12, 1988 late sympathetic neurotransmission.” Nature, 402:181-184, 1999. WO WO 89,06700 7, 1989 Humma and Terra, “Pharmacogenetics and cardiovascular disease: WO WO 89,10414 11, 1989 impact on drug response and applications to disease management.” WO WO 90/01069 2, 1990 Am J Health-Syst Pharm, 59:1241-1252, 2002. WO WO90,0945.5 8, 1990 Iwai et al., “Arg389Gly polymorphism of the human beta1 WO WO91/02087 2, 1991 WO WO 92.15712 9, 1992 adrenergic receptor inpatients with nonfatal acute myocardial infarc WO WO94,03630 2, 1994 tion. Am. Heart J., 146:106-109, 2003. WO WO95/17676 6, 1995 Johnson and Terra. “B-adrenergic receptor polymorphisms: cardio WO WO95/33048 12/1995 vascular disease associations and pharmacogenetics. Pharmaceuti WO WO 97.11698 4f1997 cal Research, 19:1779-1787, 2002. WO WO99,13721 3, 1999 Johnson et al., “f-adrenergic receptor polymorphisms and WO WO99, 19512 4f1999 antihypertensive response to metoprolol.” Clin Pharmacol Ther. WO WOOOf2O450 4/2000 74:44-52, 2003. WO WOOO,22166 4/2000 WO WOOO.31307 6, 2000 Joseph et al., “Markedly reduced effects of(-)-isoprenalinebut not of WO WOO1? 11039 2, 2001 (-)-CGP12177 and unchanged affinity of beta-blockers at Gyl389 WO WOO1/29082 4/2001 31 adrenoceptors compared to Arg589- 31 adrenoceptors. British WO WOO1 (79.561 10, 2001 J of Pharmacology, 142:51-56, 2004. WO WO O2/O9760 2, 2002 Karlsson et al., “Beta 1-adrenergic receptor gene polymorphisms and WO WO O2/O71070 9, 2002 response to beta1-adrenergic receptor blockade in patients with WO WOO3,0579.20 T 2003 essential hypertension.” Clin Cardiol. 27(6):347-50, 2004. WO WOO3,088978 10, 2003 Kaye et al., “Interaction between cardiac sympathetic drive and heart WO WO 2004/011018 2, 2004 rate in heart failure: modulation by adrenergic receptor genotype.”J WO WO 2004,0231.01 3, 2004 Am Coll Cardiol. 44:2008-15, 2004. WO WO 2005/025409 3, 2005 La Rosee, “The Arg389Gly beta1-adrenoceptor gene polymorphism determines contractile response tO catecholamines.” OTHER PUBLICATIONS Pharmacogenetics, 14:711-716, 2004. Bristow et al., “O-adrenergic receptor 322-325 Del polymorphism Lechat et al., “The cardiac insufficiency bisoprolol study II (CIBIS enhance the sympatholytic effect of bucindolol, and adversely II): a randomised trial.” The Lancet, 353:9-13, 1999. affected clinical outcomes in the BEST trial.” Circulation 112:II-351, Leineweber, "Beta-adrenergic receptor polymorphism in human car 2005. diovascular disease.” Ann Med, 36(suppl 1):64-69, 2004. Bristow, "Antiadrenergic therapy of chronic heart failure: Surprises Liggett et al. A polymorphism within a conserved f-adrenergic and new opportunities.” Circulation, 107:1100-2, 2003. receptor motif alters cardiac function and 3-blocker response in Bristow, "Beta-adrenergic receptor blockade in chronic heart fail human heart failure.” (Under review at PNAS.).
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