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United States Patent ( 10 ) Patent No.: US 10,478,439 B2 Honigberg Et Al

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United States Patent ( 10 ) Patent No.: US 10,478,439 B2 Honigberg Et Al US010478439B2 United States Patent ( 10 ) Patent No.: US 10,478,439 B2 Honigberg et al . (45 ) Date of Patent: * Nov . 19 , 2019 ( 54 ) USE OF INHIBITORS OF BRUTON'S ( 2013.01) ; A61K 31/4745 ( 2013.01 ) ; A61K TYROSINE KINASE (BTK ) 31/573 (2013.01 ) ; A61K 31/606 (2013.01 ) ; A61K 31/664 ( 2013.01 ) ; A61K 31/675 (71 ) Applicant: Pharmacyclics LLC , Sunnyvale , CA ( 2013.01 ) ; A61K 31/69 ( 2013.01) ; A61K (US ) 31/704 ( 2013.01 ) ; A61K 31/7032 (2013.01 ) ; A61K 31/7076 (2013.01 ) ; A61K 39/395 ( 72 ) Inventors : Lee Honigberg, San Francisco , CA ( 2013.01 ) ; A61K 39/3955 ( 2013.01) ; A61K (US ) ; David J. Loury , Incline Village , 39/39533 ( 2013.01 ) ; A61K 45/06 (2013.01 ) ; NV (US ) C07D 487/04 ( 2013.01 ) (58 ) Field of Classification Search (73 ) Assignee : Pharmacyclics LLC , Sunnyvale, CA CPC .. A61K 31/195 ; A61K 31/436 ; A61K 31/454 ; (US ) A61K 31/475 ; A61K 31/519 ; A61K 31/573 ; A61K 31/606 ; A61K 31/675 ; ( * ) Notice: Subject to any disclaimer , the term of this A61K 31/69 ; A61K 31/704 ; A61K patent is extended or adjusted under 35 31/7076 ; A61K 31/337 ; A61K 31/4184 ; U.S.C. 154 ( b ) by 0 days . A61K 31/437 ; A61K 31/4745 ; A61K This patent is subject to a terminal dis 31/664 ; A61K 31/7032 ; A61K 39/395 ; claimer . A61K 39/39533 ; A61K 39/3955 ; A61K 45/06 ; A61K 2300/00 , A61K 47/10 ; (21 ) Appl. No.: 15 / 965,114 A61K 47/12 ; A61K 47/14 ; A61K 47/20 ; A61K 47/26 ; A61K 47/36 ; A61K 47/38 ; ( 22 ) Filed : Apr. 27 , 2018 A61K 9/0014 ; A61K 9/0019 ; A61K 9/0031 ; A61K 9/0048 ; A61K 9/0056 ; (65 ) Prior Publication Data A61K 9/007 ; A61K 9/0078 ; A61K 9/06 ; US 2018/0256581 A1 Sep. 13 , 2018 A61K 9/4866 ; CO7D 487/04 See application file for complete search history . Related U.S. Application Data (63 ) Continuation of application No. 15 /715,995 , filed on (56 ) References Cited Sep. 26 , 2017 , now Pat. No. 10,016,435 , which is a U.S. PATENT DOCUMENTS ( Continued ) 3,547,119 A 12/1970 Farb ( 51) Int. Cl. 4,311,137 A 1/1982 Gerard A61K 9/00 (2006.01 ) ( Continued ) A61K 9/06 ( 2006.01 ) A61K 47/10 ( 2017.01 ) FOREIGN PATENT DOCUMENTS A61K 47/12 (2006.01 ) CA 2663116 A1 4/2008 A61K 47/14 ( 2017.01 ) CA 2847852 A1 4/2008 A6IK 47/20 ( 2006.01) A61K 47/26 ( 2006.01 ) (Continued ) A61K 47/36 ( 2006.01 ) A61K 4738 (2006.01 ) OTHER PUBLICATIONS A61K 9/48 (2006.01 ) Kimby ( Acta Oncologica , 2001, 224-230 ) . ( Year: 2001 ). * A61K 31/519 ( 2006.01 ) A61K 31/195 ( 2006.01 ) ( Continued ) A61K 31/436 (2006.01 ) A61K 31/454 ( 2006.01) Primary Examiner — Umamaheswari Ramachandran A61K 31/475 (2006.01 ) (74 ) Attorney , Agent, or Firm — Foley Hoag LLP A6IK 31/573 ( 2006.01 ) A61K 31/606 ( 2006.01 ) A61K 31/675 ( 2006.01) (57 ) ABSTRACT A61K 31/69 ( 2006.01 ) Disclosed herein are methods for treating a cancer compris A61K 31/704 ( 2006.01 ) ing: a . administering a Btk inhibitor to a subject sufficient to (Continued ) result in an increase or appearance in the blood of a (52 ) U.S. CI. subpopulation of lymphocytes defined by immunophenotyp CPC A61K 31/519 ( 2013.01 ) ; A61K 9/007 ing; b . determining the expression profile of one or more ( 2013.01 ) ; A61K 9/0014 (2013.01 ) ; A61K biomarkers from one or more subpopulation of lympho 9/0031 (2013.01 ) ; A61K 9/0048 ( 2013.01) ; cytes ; and c . administering a second agent based on the A61K 9/0056 ( 2013.01) ; A61K 9/06 ( 2013.01) ; determined expression profile . A61K 31/195 ( 2013.01) ; A61K 31/337 ( 2013.01 ) ; A61K 31/4184 ( 2013.01 ) ; A61K 31/436 ( 2013.01 ) ; A61K 31/437 (2013.01 ) ; 17 Claims, 39 Drawing Sheets A61K 31/454 ( 2013.01) ; A61K 31/475 Specification includes a Sequence Listing . US 10,478,439 B2 Page 2 Related U.S. Application Data 6,303,652 B1 10/2001 Uckun et al . 6,306,897 B1 10/2001 Uckun et al . continuation of application No. 14 /091,196 , filed on 6,326,469 B1 12/2001 Ullrich et al. Nov. 26 , 2013 , now Pat. No. 9,801,881 , which is a 6,344,316 B1 2/2002 Lockhart et al. 6,344,465 B1 2/2002 Armistead et al . continuation of application No. 13 / 869,700 , filed on 6,498,178 B2 12/2002 Stamos et al. Apr. 24 , 2013 , now abandoned , which is a continu 6,506,769 B2 1/2003 Snow et al. ation of application No. 13 / 153,317 , filed on Jun . 3 , 6,660,744 B1 12/2003 Hirst et al . 2011 , now abandoned . 6,753,348 B2 6/2004 Uckun et al. 6,770,639 B2 8/2004 Snow et al. 6,824,768 B2 11/2004 Stalgis et al . ( 60 ) Provisional application No. 61/ 472,138, filed on Apr. 6,893,638 B2 5/2005 Anderson et al. 5 , 2011 , provisional application No.61 / 419,764 , filed 6,921,763 B2 7/2005 Hirst et al. on Dec. 3 , 2010 , provisional application No. 7,083,784 B2 8/2006 Dall'Acqua et al . 61/ 351,655 , filed on Jun. 4 , 2010, provisional 7,138,420 B2 11/2006 Bentzien et al. application No. 61 /351,793 , filed on Jun . 4 , 2010 , 7,332,497 B2 2/2008 Hirst et al . provisional application No. 61/ 351,762 , filed on Jun . 7,514,444 B2 4/2009 Honigberg et al . 7,547,689 B2 6/2009 Sessler et al. 4 , 2010 , provisional application No.61 /351,130 , filed 7,718,662 B1 5/2010 Chen et al. on Jun . 3 , 2010 . 7,732,454 B2 6/2010 Verner 7,741,330 B1 6/2010 Chen et al. ( 51 ) Int. CI. 7,825,118 B2 11/2010 Honigberg et al. A61K 31/7076 7,960,396 B2 6/2011 Honigberg et al. ( 2006.01 ) 8,008,309 B2 8/2011 Honigberg et al . A61K 45/06 ( 2006.01 ) 8,058,249 B2 11/2011 Krieg et al. A61K 31/4184 ( 2006.01 ) 8,088,781 B2 1/2012 Honigberg et al. A61K 31/4745 ( 2006.01 ) 8,158,786 B2 4/2012 Honigberg et al. A61K 31/7032 ( 2006.01 ) 8,232,280 B2 7/2012 Honigberg et al. A61K 39/395 8,236,812 B2 8/2012 Honigberg et al. ( 2006.01 ) 8,306,897 B2 11/2012 Yolles C07D 487/04 ( 2006.01 ) 8,377,946 B1 2/2013 Chen et al. A61K 31/337 ( 2006.01) 8,399,470 B2 3/2013 Honigberg et al . A61K 31/437 ( 2006.01) 8,476,284 B2 7/2013 Honigberg et al. A61K 31/664 ( 2006.01 ) 8,497,277 B2 7/2013 Honigberg et al . 8,501,724 B1 8/2013 Chen et al. 8,501,751 B2 8/2013 Honigberg et al. ( 56 ) References Cited 8,552,010 B2 10/2013 Honigberg et al. 8,557,803 B2 10/2013 Yamamoto et al . U.S. PATENT DOCUMENTS 8,563,563 B2 10/2013 Honigberg et al. 8,568,653 B2 10/2013 Thillen et al. 4,360,019 A 11/1982 Portner et al . 8,633,311 B2 1/2014 Bommer et al . 4,487,603 A 12/1984 Harris 8,642,604 B2 2/2014 Knight et al . 4,531,937 A 7/1985 Yates 8,658,653 B2 2/2014 Honigberg et al. 4,683,202 A 7/1987 Mullis 8,691,546 B2 4/2014 Honigberg et al . 4,692,147 A 9/1987 Duggan 8,697,711 B2 4/2014 Honigberg et al. 4,725,852 A 2/1988 Gamblin et al . 8,703,780 B2 4/2014 Honigberg et al . 4,755,173 A 7/1988 Konopka et al. 8,735,403 B2 5/2014 Honigberg et al. 4,843,155 A 6/1989 Chomczynski 8,735,404 B2 5/2014 Honigberg et al . 5,033,252 A 7/1991 Carter 8,741,908 B2 6/2014 Honigberg et al . 5,052,558 A 10/1991 Carter 8,748,438 B2 6/2014 Honigberg et al. 5,323,907 A 6/1994 Kalvelage 8,748,439 B2 6/2014 Honigberg et al . 5,384,261 A 1/1995 Winkler et al. 8,754,090 B2 6/2014 Buggy et al . 5,397,787 A 3/1995 Buzzetti et al. 8,754,091 B2 6/2014 Honigberg et al. 5,445,934 A 8/1995 Fodor et al . 8,759,516 B2 6/2014 Honigberg et al. 5,530,012 A 6/1996 Mattson et al . 8,809,273 B2 8/2014 Honigberg et al. 5,593,997 A 1/1997 Dow et al . 8,877,202 B2 11/2014 Govindan et al . 5,643,207 A 7/1997 Rise 8,883,435 B2 11/2014 Honigberg et al . 5,677,195 A 10/1997 Winkler et al . 8,883,803 B2 11/2014 Honigberg et al . 5,708,153 A 1/1998 Dower et al. 8,940,750 B2 1/2015 Honigberg et al. 5,744,305 A 4/1998 Fodor et al . 8,952,015 B2 2/2015 Honigberg et al . 5,770,358 A 6/1998 Dower et al . 8,957,079 B2 2/2015 Honigberg et al . 5,770,722 A 6/1998 Lockhart et al. 8,975,266 B2 3/2015 Honigberg et al. 5,789,162 A 8/1998 Dower et al . 3/2015 Pan et al.
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