US010328157B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 , 328 , 157 B2 Zhao ( 45 ) Date of Patent: Jun . 25, 2019 ( 54 ) ACETYLENEDICARBOXYL LINKERS AND 45/ 06 ( 2013. 01 ) ; A61K 47/ 6809 (2017 . 08 ) ; THEIR USES IN SPECIFIC CONJUGATION A61K 47/ 6849 ( 2017 .08 ) ; A61K 47/ 6851 OF A CELL - BINDING MOLECULE ( 2017 . 08 ) ; A61K 47 /6889 ( 2017 .08 ) ; C07C 59 / 76 (2013 . 01 ) ; C07C 233 / 20 ( 2013 .01 ) ; (71 ) Applicant: SUZHOU M -CONJ BIOTECH CO . , C07C 237 /52 (2013 .01 ) ; C070 207 /46 LTD ., Suzhou (CN ) ( 2013 .01 ) ; C07D 277 / 56 (2013 .01 ) ; C07D 309/ 14 ( 2013 . 01 ) ; CO7D 403/ 14 ( 2013 .01 ) ; ( 72 ) Inventor: Robert Yongxin Zhao , Lexington , MA C07D 407 / 12 ( 2013 . 01 ) ; C07D 407/ 14 (US ) ( 2013 .01 ) ; CO7D 413 / 04 (2013 . 01 ) ; C07D ( 73 ) Assignee : HANGZHOU DAC BIOTECH CO . , 413 / 14 ( 2013 .01 ) ; C07D 417 / 12 ( 2013 . 01 ) ; LTD . , Hangzhou ( CN ) C07D 417 / 14 ( 2013 .01 ) ; C07D 493 /04 ( 2013 . 01 ) ; C07D 498 / 14 ( 2013 . 01 ) ; C07D ( * ) Notice : Subject to any disclaimer , the term of this 519 / 00 ( 2013 .01 ) ; C07K 16 / 28 ( 2013 . 01 ) ; patent is extended or adjusted under 35 CO7K 16 / 2863 ( 2013 .01 ) ; COOK 16 / 32 U . S . C . 154 ( b ) by 0 days . ( 2013 . 01 ) ; GOIN 33 /5014 (2013 .01 ) ; A61K 2039/ 505 ( 2013 .01 ); C07K 2317 /24 (2013 . 01 ) ; (21 ) Appl. No. : 15 /423 ,695 YO2A 50 /416 ( 2018 .01 ); YO2A 50 / 466 ( 22 ) Filed : Feb . 3 , 2017 ( 2018 . 01) ; YO2A 50 /473 (2018 .01 ) (58 ) Field of Classification Search (65 ) Prior Publication Data CPC .. A61K 47 /6803 US 2017 /0143845 A1 May 25 , 2017 See application file for complete search history . Related U . S . Application Data (56 ) References Cited (62 ) Division of application No . 14 / 799, 666 , filed on Jul. 15, 2015 , now Pat . No . 9 ,839 , 687 . U . S . PATENT DOCUMENTS 4 ,000 , 304 A 12 / 1976 Wu et al. (51 ) Int. Cl. 4 , 169 , 888 A 10 / 1979 Hanka et al. A61K 47 /68 ( 2017 . 01 ) 4 ,256 , 746 A 3 / 1981 Miyashita et al. CO7K 16 / 28 ( 2006 .01 ) 4 , 294 , 757 A 10 / 1981 Asai 4 , 307 , 016 A 12 / 1981 Asai et al. C07C 59 / 76 ( 2006 . 01 ) 4 ,313 , 946 A 2 / 1982 Powell et al . CO7D 417 / 14 ( 2006 . 01 ) 4 ,315 , 929 A 2 / 1982 Freedman et al. C07C 237 /52 ( 2006 . 01 ) 4 , 322 , 348 A 3 / 1982 Asai et al. A61K 39 / 395 ( 2006 . 01 ) 4 ,331 , 598 A 5 /1982 Hasegawa et al . A61K 45 / 06 ( 2006 .01 ) C070 207 / 46 ( 2006 . 01 ) (Continued ) C07C 233 /20 ( 2006 . 01 ) FOREIGN PATENT DOCUMENTS COD 413 / 14 ( 2006 .01 ) C07D 309 / 14 ( 2006 . 01 ) CA 2 710 693 A11 /2011 C07D 403 / 14 ( 2006 .01 ) CNCA 10172396127723981 A1A 6 /2010 C07D 407 / 12 ( 2006 . 01 ) ( Continued ) C07D 407 / 14 ( 2006 .01 ) CO7D 413 /04 ( 2006 .01 ) OTHER PUBLICATIONS C07D 417 / 12 ( 2006 . 01 ) C07D 493 / 04 ( 2006 .01 ) " Chromophore” , http : // goldbook . iupac. org /plain / C01076 - plain . CO7D 498 / 14 ( 2006 .01 ) html, 1994 ( Year : 1994 ) . * CO7D 277 /56 ( 2006 .01 ) (Continued ) C07D 519 /00 ( 2006 . 01 ) A61K 31 /337 ( 2006 . 01 ) A61K 31 /404 (2006 .01 ) Primary Examiner — Noble E Jarrell A6IK 31/ 537 ( 2006 . 01 ) ( 74 ) Attorney , Agent, or Firm — Buchanan Ingersoll & A61K 31 / 5517 ( 2006 .01 ) Rooney PC GOIN 33/ 50 ( 2006 .01 ) A61K 38 /05 ( 2006 .01 ) CO7K 16 / 32 ( 2006 .01 ) (57 ) ABSTRACT A61K 39 /00 ( 2006 .01 ) (52 ) U . S . CI. Cell binding agent - drug conjugates comprising bridge link CPC . .. A61K 47 /6803 ( 2017 .08 ) ; A61K 31 /337 ers , and methods of using such linkers and conjugates are ( 2013 .01 ) ; A61K 31/ 404 ( 2013 .01 ) ; A61K provided . 31/ 537 (2013 .01 ) ; A61K 31/ 5517 ( 2013 . 01 ) ; A61K 38 /05 (2013 . 01 ) ; A61K 39 / 395 ( 2013 .01 ) ; A61K 39 /3955 ( 2013 . 01 ) ; A61K 27 Claims, 11 Drawing Sheets US 10 ,328 ,157 B2 Page 2 (56 ) References Cited 5 ,416 , 064 A 5 / 1995 Chari et al. 5 , 427 , 908 A 6 / 1995 Dower et al . U . S . 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