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(12) United States Patent (10) Patent No.: US 8,877,688 B2 Vasquez Et Al

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(12) United States Patent (10) Patent No.: US 8,877,688 B2 Vasquez Et Al US008877688B2 (12) United States Patent (10) Patent No.: US 8,877,688 B2 Vasquez et al. (45) Date of Patent: *Nov. 4, 2014 (54) RATIONALLY DESIGNED, SYNTHETIC (56) References Cited ANTIBODY LIBRARIES AND USES THEREFOR U.S. PATENT DOCUMENTS 4.946,778 A 8, 1990 Ladner et al. (75) Inventors: Maximiliano Vasquez, Palo Alto, CA 5,118,605 A 6/1992 Urdea (US); Michael Feldhaus, Grantham, NH 5,223,409 A 6/1993 Ladner et al. 5,283,173 A 2f1994 Fields et al. (US); Tillman U. Gerngross, Hanover, 5,380,833. A 1, 1995 Urdea NH (US); K. Dane Wittrup, Chestnut 5,525.490 A 6/1996 Erickson et al. Hill, MA (US) 5,530,101 A 6/1996 Queen et al. 5,565,332 A 10/1996 Hoogenboom et al. (73) Assignee: Adimab, LLC, Lebanon, NH (US) 5,571,698 A 11/1996 Ladner et al. 5,618,920 A 4/1997 Robinson et al. (*) Notice: Subject to any disclaimer, the term of this 5,658,727 A 8, 1997 Barbas et al. patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 747 days. FOREIGN PATENT DOCUMENTS This patent is Subject to a terminal dis claimer. DE 19624562 A1 1, 1998 WO WO-88.01649 A1 3, 1988 (21) Appl. No.: 12/404,059 (Continued) OTHER PUBLICATIONS (22) Filed: Mar 13, 2009 Rader et al. (Jul. 21, 1998) Proceedings of the National Academy of (65) Prior Publication Data Sciences USA vol. 95 pp. 8910 to 8915.* US 201O/OO5638.6 A1 Mar. 4, 2010 (Continued) Primary Examiner — Heather Calamita Related U.S. Application Data Assistant Examiner — Christian Boesen (63) Continuation-in-part of application No. 12/210,072, (74) Attorney, Agent, or Firm — Choate, Hall & Stewart LLP filed on Sep. 12, 2008. (57) ABSTRACT (60) Provisional application No. 60/993,785, filed on Sep. The present invention overcomes the inadequacies inherent in the known methods for generating libraries of antibody-en 14, 2007. coding polynucleotides by specifically designing the libraries (51) Int. Cl. with directed sequence and length diversity. The libraries are C40B 40/08 (2006.01) designed to reflect the preimmune repertoire naturally created (52) U.S. Cl. by the human immune system, with or without DH segments USPC ............................................................ 506/17 derived from other species, and are based on rational design (58) Field of Classification Search informed by examination of publicly available databases of None antibody sequences. See application file for complete search history. 8 Claims, 26 Drawing Sheets 88. Exeter: &: Exists: 3. fiss:f3d 83. & st St.G R - 8. 33. 3. 3 . SSXX s s x s : s s Pereitage US 8,877,688 B2 Page 2 (56) References Cited 6,489,123 B2 12/2002 Osbournet al. 6,492,107 B1 12/2002 Kauffman et al. 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