(12) United States Patent (10) Patent No.: US 8,501450 B2 N-N-1
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USOO85O145OB2 (12) United States Patent (10) Patent No.: US 8,501450 B2 Lin et al. (45) Date of Patent: Aug. 6, 2013 (54) HEPATITIS CVIRUS VARIANTS (56) References Cited (75) Inventors: Chao Lin, Winchester, MA (US); Tara U.S. PATENT DOCUMENTS Kieffer, Brookline, MA (US); 4,835,168 A 5/1989 Paget, Jr. et al. Christoph Sarrazin, Saarland (DE); 5,484.801 A 1/1996 Al-RaZZak et al. Ann Kwong, Cambridge, MA (US) 5,631,128 A 5/1997 Kozal et al. 5,807,876 A 9, 1998 Armistead et al. 5,866,684 A 2f1999 Attwood et al. (73) Assignee: Vertex Pharmaceuticals Incorporated, 5.948,436 A 9, 1999 Al-Razzak et al. Cambridge, MA (US) 5.990,276 A 1 1/1999 Zhang et al. 6,018,020 A 1/2000 Attwood et al. (*) Notice: Subject to any disclaimer, the term of this 6,037,157 A 3/2000 Norbeck et al. patent is extended or adjusted under 35 6,054,472 A 4/2000 Armistead et al. U.S.C. 154(b) by 521 days. (Continued) (21) Appl. No.: 12/718,340 FOREIGN PATENT DOCUMENTS WO WO92fO3918 A1 3, 1992 (22) Filed: Mar. 5, 2010 WO WO94f1443.6 A1 T 1994 (65) Prior Publication Data (Continued) US 2011/0244549 A1 Oct. 6, 2011 OTHER PUBLICATIONS Timm, J., et al., 2007. “Human leukocyte antigen-associated Related U.S. Application Data sequence polymorphisms in Hepatitis C Virus reveal reproducible (62) Division of application No. 1 1/599,162, filed on Nov. immune responses and constraints on viral evolution'. Hepatology, 13, 2006, now Pat. No. 7,705,138. vol. 46, pp. 339-349.* (60) Provisional application No. 60/854,598, filed on Oct. (Continued) 25, 2006, provisional application No. 60/735,577, filed on Nov. 11, 2005. Primary Examiner — Manjunath Rao (51) Int. Cl. Assistant Examiner — William W. Moore CI2N 9/50 (2006.01) (74) Attorney, Agent, or Firm — Ropes & Gray LLP CI 2N 15/51 (2006.01) CI 2N 15/57 (2006.01) (57) ABSTRACT CI 2N 15/74 (2006.01) CI 2N 15/79 (2006.01) The present invention relates to HCV variants, particularly CI2P 19/34 (2006.01) variants that are resistant to a protease inhibitors such as (52) U.S. Cl. VX-950. Also provided are methods and compositions USPC ..................... 435/219; 435/252.3:435/320.1; related to the HCV variants. Further provided are methods of 536/23.2:536/23.72 isolating, identifying, and characterizing multiple viral vari (58) Field of Classification Search ants from a patient. None See application file for complete search history. 13 Claims, 33 Drawing Sheets R155 Substitutions Confer Low-level Resistance to Telaprevir Replicon ICs 10 1. o 1 /tatutu u ult R(WT) K T s M N-N-1 Residue 155 US 8,501450 B2 Page 2 U.S. PATENT DOCUMENTS WO WOOO. 59929 A1 10, 2000 6,127.422 A 10/2000 Colacino et al. W8 W88-39. 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