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( 12 ) United States Patent US010155803B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 155, 803 B2 Dixit et al. (45 ) Date of Patent: * Dec. 18 , 2018 ( 54 ) MULTIVALENT HETEROMULTIMER ( 56 ) References Cited SCAFFOLD DESIGN AND CONSTRUCTS U . S . PATENT DOCUMENTS (71 ) Applicant : Zymeworks Inc ., Vancouver (CA ) 4 ,179 ,337 A 12 / 1979 Davis et al . 4 , 857 , 467 A 8 / 1989 Sreekrishna et al . 4 , 946 , 778 A 8 / 1990 Ladner et al . ( 72 ) Inventors : Surjit Bhimarao Dixit, Richmond 4 ,980 , 286 A 12 / 1990 Morgan et al . (CA ) ; Igor Edmondo Paolo D ' Angelo , 5 , 073 ,627 A 12 / 1991 Curtis et al. Port Moody (CA ) ; David Kai Yuen 5 , 108 , 910 A 4 / 1992 Curtis et al. Poon , Richmond (CA ) 5 ,258 , 498 A 11/ 1993 Huston et al. 5 ,482 ,858 A 1 / 1996 Huston et al. 5 , 576 , 195 A 11 / 1996 Robinson et al . ( 73 ) Assignee : ZYMEWORKS INC ., Vancouver BC 5 ,641 ,670 A 6 / 1997 Treco et al . (CA ) 5 , 731 , 168 A 3 / 1998 Carter et al. 5 ,780 , 594 A 7 / 1998 Carter 5 ,837 , 846 A 11/ 1998 Huston et al. ( * ) Notice : Subject to any disclaimer , the term of this 5 , 846 , 818 A 12 / 1998 Robinson et al . patent is extended or adjusted under 35 5 , 856 , 456 A 1 / 1999 Whitlow et al . U . S . C . 154 (b ) by 26 days. 5 , 869, 620 A 2 / 1999 Whitlow et al . 5 , 990 ,275 A 11 / 1999 Whitlow et al . This patent is subject to a terminal dis 6 , 001, 606 A 12 / 1999 Ruben et al. claimer . 6 ,077 ,692 A 6 / 2000 Ruben et al. 6 ,096 ,289 A * 8 / 2000 Goldenberg .. A61K 47 /48753 424 / 1 . 49 ( 21 ) Appl . No . : 15 / 355 , 007 6 , 350 ,430 B1 2 /2002 Dooley et al. 6 ,492 , 123 B1 12 / 2002 Holliger et al. 6 ,686 , 179 B2 2 / 2004 Fleer et al . ( 22 ) Filed : Nov. 17 , 2016 6 , 905 ,688 B2 6 / 2005 Rosen et al. 6 , 926 , 898 B2 8 /2005 Rosen et al . (65 ) Prior Publication Data 6 , 946 , 134 B1 9 / 2005 Rosen et al. 6 , 972 , 322 B2 12 /2005 Fleer et al . US 2017/ 0174745 A1 Jun . 22 , 2017 6 , 987 ,006 B2 1 / 2006 Fleer et al . 6 ,989 , 365 B2 1 / 2006 Fleer et al. 6 , 994 , 857 B2 2 /2006 Rosen et al . 7 , 041, 478 B2 5 / 2006 Fleer et al . Related U . S . Application Data 7 ,056 ,701 B2 6 /2006 Fleer et al. 7 ,094 ,577 B2 8 / 2006 Fleer et al. (63 ) Continuation of application No. 13 /411 , 353 , filed on 7 , 138 , 497 B2 11/ 2006 Houston et al. Mar. 2 , 2012 , now Pat . No . 9 ,499 , 605 . 7 , 141, 547 B2 11 / 2006 Rosen et al. ( Continued ) ( 60 ) Provisional application No . 61/ 449, 016 , filed on Mar . 3 , 2011 . FOREIGN PATENT DOCUMENTS EP 0201239 A1 11 / 1986 (51 ) Int. Ci. EP 0251744 A2 1 / 1988 CO7K 14 / 79 ( 2006 .01 ) ( Continued ) CO7K 14 /765 ( 2006 .01 ) CO7K 14 /47 ( 2006 .01 ) OTHER PUBLICATIONS CO7K 14 /485 ( 2006 . 01 ) CO7K 14 / 605 ( 2006 .01 ) U . S . Appl. No . 13 / 941, 450 , “ Corrected Notice of Allowability ” , COZK 14 / 76 ( 2006 . 01 ) dated Jul. 10 , 2015 , 10 pages . CO7K 16 / 28 ( 2006 . 01 ) (Continued ) CO7K 16 / 32 ( 2006 .01 ) Primary Examiner — Karen Cochrane Carlson CO7K 19 /00 ( 2006 . 01 ) (74 ) Attorney , Agent, or Firm — Kilpatrick Townsend & C12N 9 /64 ( 2006 .01 ) Stockton LLP (52 ) U .S . CI. CPC . .. .. .. COZK 14 / 765 (2013 . 01 ) ; CO7K 14 / 47 (57 ) ABSTRACT Provided herein are multifunctional heteromer proteins. In ( 2013 .01 ) ; CO7K 14 /4721 (2013 .01 ) ; CO7K specific embodiments is a heteromultimer that comprises : at 14 /485 ( 2013. 01 ) ; CO7K 147605 (2013 .01 ) ; least two monomeric proteins , wherein each monomeric CO7K 14 / 76 ( 2013 .01 ) ; CO7K 14 / 79 ( 2013 .01 ) ; protein comprises at least one cargo polypeptide , attached to CO7K 16 / 283 ( 2013 .01 ) ; CO7K 16 / 32 a transporter polypeptide , such that said monomeric proteins (2013 . 01 ) ; COOK 19 / 00 ( 2013 .01 ) ; C12N associate to form the heteromultimer . These therapeutically 9 /6454 ( 2013 . 01 ) ; C12Y 304 / 21061 ( 2013 . 01) : novel molecules comprise monomers that function as scaf CO7K 2317 /622 ( 2013 .01 ) ; COZK 2319 /00 folds for the conjugation or fusion of therapeutic molecular ( 2013 .01 ) ; C07K 2319 /31 ( 2013 .01 ) entities resulting in the creation of bispecific or multivalent (58 ) Field of Classification Search molecular species . CPC . CO7K 14 /79 ; CO7K 14 /4721 ; CO7K 14 /485 ; C07K 14 /605 ; CO7K 14 /76 27 Claims, 53 Drawing Sheets See application file for complete search history. Specification includes a Sequence Listing . US 10 ,155 ,803 B2 Page 2 References Cited WO 0121658 A1 3 / 2001 ( 56 ) WO 0149866 A1 7 / 2001 U . S . PATENT DOCUMENTS WO 03012069 A2 2 / 2003 WO 03031464 A2 4 / 2003 7 , 189 ,690 B2 3 / 2007 Rosen et al. WO 03060071 A2 7 / 2003 7 , 271, 149 B2 9 / 2007 Glaesner et al . WO 2004029207 A 4 / 2004 7 , 385 ,032 B2 6 / 2008 Tschopp et al. 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