CHA KUNA TAITEIT US009974774B2UIT EN UNA MAN UNITA ANT IN (12 ) United States Patent (10 ) Patent No. : US 9 , 974 , 774 B2 Garner et al. ( 45) Date of Patent: May 22, 2018 ( 54 ) COMBINATORIAL METHODS TO IMPROVE 5 ,077 , 282 A 12 / 1991 Murdock et al . THE THERAPEUTIC BENEFIT OF 5 , 077 , 283 A 12 / 1991 Murdock et al. 5 , 116 ,827 A 5 / 1992 Murdock et al . BISANTRENE AND ANALOGS AND 5 , 143 , 661 A 9 / 1992 Lawter et al. DERIVATIVES THEREOF 5 ,212 ,291 A 5 / 1993 Murdock et al . 5 , 378 ,456 A 1 / 1995 Tsou @( 71) Applicant : UPDATE PHARMA INC ., Lebanon , 5 , 387 , 584 A 2 / 1995 Schnur 5 , 436 , 243 A 7 / 1995 Sachs et al . NJ (US ) 5 , 550 , 149 A 8 / 1996 Powell et al. 5 , 561, 141 A 10 / 1996 Powell et al. @(72 ) Inventors : William J . Garner, San Francisco , CA 5 , 573 , 781 A 11/ 1996 Brown et al. (US ) ; Amie Franklin , Pacifia , CA 5 ,609 , 867 A 3 / 1997 Tsou (US ) ; John Rothman , Lebanon , NJ 5 ,639 , 887 A 6 / 1997 Powell et al . (US ) 5 , 786 , 344 A 7 / 1998 Ratain et al. 5 , 994 , 130 A 11/ 1999 Shyjan 6 , 011 , 069 A 1 / 2000 Inomata et al. @( 73 ) Assignee : RACE ONCOLOGY LTD ., West Perth 6 ,054 ,437 A 4 / 2000 Eilon et al. ( AU ) 6 , 238 , 687 B1 5 / 2001 Mao et al. 6 , 245 , 790 B1 6 / 2001 Hattori et al. @( * ) Notice : Subject to any disclaimer , the term of this 6 , 306 , 897 B1 10 / 2001 Uckun et al. patent is extended or adjusted under 35 6 , 368, 598 B1 4 / 2002 D ' Amico et al. 6 , 428 , 968 B1 8 / 2002 Molnar- Kimber et al . U . S . C . 154 (b ) by 0 days . days . 6 , 443 , 898 B1 9 /2002 Unger et al . 6 ,495 , 582 B1 12 / 2002 Hale et al . ( 21) Appl. No .: 14 / 907, 729 6 ,610 ,677 B28 / 2003 Davies et al . 6 , 638 , 926 B2 10 / 2003 Davies et al. ( 22 ) PCT Filed : Jul. 25 , 2014 6 , 649 , 640 B2 11 / 2003 Hale et al . 6 ,653 , 301 B2 11/ 2003 Bebbington et al. 6 ,660 , 731 B2 12 /2003 Bebbington et al. ( 86 ) PCT No. : PCT/ US2014 /048137 6 , 664 , 247 B2 12 /2003 Bebbington et al . 8 371 ( c ) ( 1 ) , 6 , 670 ,167 B1 12 / 2003 Chen et al. 6 , 743 , 791 B2 6 / 2004 Cao et al . ( 2 ) Date : Jan . 26 , 2016 6 , 753 , 348 B2 6 / 2004 Uckun et al. 6 , 872 , 715 B2 3 / 2005 Santi et al. (87 ) PCT Pub . No .: WO2015 /013581 6 , 875 , 863 B1 4 / 2005 Tian et al. 6 , 887 , 993 B1 5 / 2005 Tian et al. PCT Pub . Date : Jan . 29 , 2015 6 , 903 , 116 B2 6 / 2005 Yokota et al . 6 , 967, 198 B2 11 /2005 Benedict et al . (65 ) Prior Publication Data 6 , 989 , 385 B2 1 / 2006 Bebbington et al. 7 ,008 , 948 B2 3 / 2006 Bebbington et al. US 2016 / 0166546 A1 Jun . 16 , 2016 7 , 041 , 687 B2 5 / 2006 Binch et al . 7 , 067, 506 B2 6 / 2006 Keegan et al . Related U . S . Application Data 7 , 087 , 603 B2 8 /2006 Bebbington et al. (60 ) Provisional application No. 61/ 858 ,729 , filed on Jul. (Continued ) 26 , 2013 . FOREIGN PATENT DOCUMENTS (51 ) Int. Cl. EP 1332755 AL 8 /2003 A61K 31/ 4178 ( 2006 . 01 ) WO 199739768 A1 10 / 1997 A61K 45 /06 ( 2006 .01 ) (Continued ) A61K 31 /4168 ( 2006 .01 ) A61K 31/ 473 ( 2006 .01 ) A61K 47 / 48 ( 2006 .01 ) OTHER PUBLICATIONS (52 ) U .S . Ci. Alberts et al CAS : 115 : 41444 , 1991. * CPC . A61K 31/ 4178 ( 2013 .01 ) ; A61K 31/ 4168 ( 2013 .01 ) ; A61K 31/ 473 ( 2013 .01 ) ; A61K (Continued ) 45 /06 ( 2013 . 01 ) ; A61K 47/ 48 (2013 . 01 ) Primary Examiner — Rei Tsang Shiao (58 ) Field of Classification Search (74 ) Attorney , Agent, or Firm — Ditthavong & Steiner , ??? . .. .. .. .. .. A61K 31 /4178 ; A61K 47 / 48 See application file for complete search history. P . C . (56 ) References Cited (57 ) ABSTRACT The present invention describes methods and compositions U . S . PATENT DOCUMENTS for improving the therapeutic efficacy of therapeutic agents 4 ,258 ,181 A * 3 / 1981 Murdock .. .. .. .. C07C 17 /32 previously limited by suboptimal therapeutic performance 540 /467 by either improving efficacy as monotherapy or reducing 4 , 261, 989 A 4 / 1981 Sasaki et al . side effects . Such methods and compositions are particularly 4 ,784 , 845 A 11/ 1988 Desai et al. applicable to bisantrene or derivatives, analogs , or prodrugs 4 , 816 , 247 A 3 / 1989 Desai et al . 4 , 900 , 838 A 2 / 1990 Murdock thereof. 5 , 000 , 886 A 3 / 1991 Lawter et al. 5 , 070 ,082 A 12 / 1991 Murdock et al. 7 Claims , No Drawings US 9 ,974 , 774 B2 Page 2 (56 ) References Cited 8 , 008 , 281 B2 8 / 2011 Prendergast et al. 8 ,008 , 318 B2 8 / 2011 Beckmann et al. U . S . PATENT DOCUMENTS 8 , 008 , 491 B2 8 / 2011 Jiang et al. 8 , 012 ,976 B2 9 / 2011 Wang et al . 7 , 091, 213 B28 / 2006 Metcalf , III et al . 8 , 026 , 355 B2 9 / 2011 Hansen et al . 7 , 094 , 798 B18 / 2006 Booth et al . 8 , 067 , 395 B2 11/ 2011 Jankowski et al. 7 , 098, 330 B2 8 / 2006 Bebbington et al . 8 , 067 , 412 B2 11/ 2011 Winssinger et al. 7 , 101 , 576 B2 9 / 2006 Hovey et al. 8 , 088 , 760 B2 1 / 2012 Chu et al . 7 , 115 , 619 B2 10 /2006 Stevens et al. 8 ,093 ,050 B2 1 / 2012 Cho et al . 7 , 115 , 739 B2 10 / 2006 Bebbington et al . 8 , 093 ,244 B2 1 / 2012 Diaz et al. 7 ,129 , 244 B2 10 / 2006 Kasibhatla et al . 8 , 097, 622 B2 1 / 2012 Nakayama et al. 7 , 132 , 533 B2 11 / 2006 Benedict et al . 8 , 101 , 623 B2 1 / 2012 Luke et al. NN7 ,148 , 211 B2 12 / 2006 Mazess et al . 8 , 114 , 870 B2 2 / 2012 Xiao et al . 7 , 160 ,867 B2 1 / 2007 Abel et al. 8 , 119 , 366 B2 2 / 2012 Stylianou 7 , 169 , 817 B2 1 / 2007 Pan et al. 8 , 119 , 654 B2 2 / 2012 Jagtap et al . 7 , 202 ,244 B2 4 /2007 Boyle et al . 8 , 119 , 689 B2 2 / 2012 Ebensen et al. 7 , 250, 409 B2 7 / 2007 Boger 8 ,124 , 630 B2 2 /2012 Riedl et al. 7 , 253 , 187 B2 8 / 2007 Cao et al . 8 , 129 , 371 B2 3 /2012 Zask et al . 7 , 304 , 061 B2 12 / 2007 Hale et al. 8 , 133 , 857 B2 3 / 2012 Aikawa 7 , 311 , 901 B2 12 / 2007 Seo et al . 8 , 148, 393 B2 4 /2012 Van Dalen et al . 7 , 318, 931 B2 1 / 2008 Okumu et al . 8 , 158, 616 B2 4 /2012 Rodgers et al. 7 , 345 , 054 B2 3 / 2008 Hale et al . 8 , 158 , 638 B2 4 / 2012 Ohsuki et al. 7 , 354 , 919 B2 4 / 2008 Hale et al. 8 , 163 , 755 B2 4 / 2012 Jin et al. 7 ,390 , 815 B2 6 / 2008 Davies et al . 8 , 168 , 651 B2 5 / 2012 Chua et al . 7 , 402 , 556 B2 7 / 2008 Trouet et al . 8 , 178 , 125 B2 5 / 2012 Wen et al. 7 ,405 , 295 B2 7 / 2008 Currie et al . 8 , 178 , 131 B2 5 / 2012 Le Huerou et al . 7 , 410 , 988 B2 8 /2008 Dickson , Jr . et al . 8 , 178 , 527 B2 5 /2012 Chen et al. 7 , 445 , 897 B2 11/ 2008 Ho et al . 8 , 183 ,249 B2 5 / 2012 Cheng et al. ????????? 8 ,183 , 250 B2 5 /2012 Penning et al. 7 , 446 ,122 B2 11/ 2008 Chao et al . 7 ,449 , 477 B2 11 / 2008 Barda et al . 8 ,183 , 342 B2 5 / 2012 Matsuyama 7 ,462 , 713 B2 12 / 2008 Benedict et al. 8 , 188 , 103 B2 5 / 2012 Van Der Aa et al. 7 ,470 , 709 B2 12 / 2008 Barsanti et al. 8 , 202 , 876 B2 6 / 2012 Albaugh et al. NNN7 ,485 , 649 B2 2 / 2009 Brnardic et al. 8 ,207 , 195 B2 6 / 2012 Navratil et al. 7 , 501 , 435 B2 3 / 2009 Arrington et al . 8 , 211 , 054 B2 7 / 2012 Dewey 7 , 504 ,397 B2 3 / 2009 Hummersone et al . 8 , 211 , 669 B2 7 / 2012 Reed et al . 7 , 514 , 444 B2 4 /2009 Honigberg et al . 8 , 217, 070 B2 7 / 2012 Zhu et al . 7 , 531 , 556 B2 5 / 2009 Green 8 , 227 , 605 B2 7 /2012 Shipps, Jr. et al. 7 , 550 , 477 B2 6 / 2009 Brnardic et al . 8 ,227 ,807 B2 7 /2012 Yamazaki et al. 7 ,560 , 462 B2 7 / 2009 Gaudino et al. 8 , 231 , 898 B2 7 / 2012 Oshlack et al. 7 ,608 , 618 B2 10 /2009 Kesicki et al. 8 , 232 , 277 B2 7 / 2012 Chen et al. 7 , 625 , 890 B2 12 / 2009 Heerding et al. 8 , 232 , 280 B2 7 / 2012 Honigberg et al. 7 , 625 , 913 B2 12 / 2009 Bebbington et al . 8 , 236 , 802 B2 8 /2012 Xu et al. 7 , 648 , 996 B2 1 / 2010 Beckmann et al . 8 , 236 , 812 B2 8 / 2012 Honigberg et al. 7 , 652 , 027 B2 1 / 2010 Lee et al. 8 ,242 ,103 B2 8 / 2012 Lewis et al. 7 , 652 , 135 B2 1 / 2010 Binch et al . 8 , 242 ,147 B2 8 /2012 Dumas et al . 7 , 655 , 673 B2 2 / 2010 Zhang et al. 8 , 242 ,270 B2 8 / 2012 Lajeunesse et al . 7 , 659 , 274 B2 2 / 2010 Crew et al.