|MO NAMAN ATTITUUNIKAUS009962450B2 MITATTI (12 ) United States Patent (10 ) Patent No. : US 9 , 962 , 450 B2 Kraynov et al. ( 45) Date of Patent : May 8 , 2018 ( 54 ) METHOD OF TREATING HEART FAILURE 4 ,659 ,839 A 4 / 1987 Nicolotti et al . WITH MODIFIED RELAXIN POLYPEPTIDES 4 ,670 ,417 A 6 / 1987 Iwasaki et al. 4 ,671 , 958 A 6 / 1987 Rodwell et al. 4 ,680 , 338 A 7 / 1987 Sundoro ( 71) Applicant : AMBRX , INC . , La Jolla , CA (US ) 4 ,689 ,406 A 8 / 1987 Banks et al . 4 ,699 ,784 A 10 / 1987 Shih et al . ( 72 ) Inventors : Vadim Kraynov , San Diego , CA (US ) ; 4 ,738 , 921 A 4 / 1988 Belagaje et al. Nick Knudsen , San Diego , CA (US ) ; 4 ,755 ,465 A 7 / 1988 Gray et al. 4 ,837 , 148 A 6 / 1989 Cregg Amha Hewet, Chula Vista , CA (US ) ; 4 ,859 ,600 A 8 / 1989 Gray et al . Kristine De Dios, San Diego , CA (US ) ; 4 , 876 , 197 A 10 / 1989 Burke et al. Jason Pinkstaff , Encinitas, CA (US ) ; 4 , 880 ,734 A 11/ 1989 Burke et al . Lorraine Sullivan , San Diego , CA 4 , 902 ,502 A 2 / 1990 Nitecki et al . 4 , 904 , 584 A 2 / 1990 Shaw ( US ) 4 ,929 , 555 A 5 / 1990 Cregg et al. 5 ,021 , 234 A 6 / 1991 Ehrenfeld (73 ) Assignee : AMBRX , INC. , La Jolla , CA (US ) 5 ,089 ,398 A 2 / 1992 Rosenberg et al . 5 , 122 ,614 A 6 / 1992 Zalipsky ( * ) Notice : Subject to any disclaimer , the term of this 5 , 145 , 962 A 9 / 1992 Hudson et al. patent is extended or adjusted under 35 5 , 162 ,601 A 11/ 1992 Slightom U . S . C . 154 ( b ) by 86 days . 5 , 219 , 564 A 6 / 1993 Zalipsky et al . 5 , 229 , 490 A 7 / 1993 Tam 5 , 231, 178 A 7 / 1993 Holtz et al. ( 21) Appl. No. : 15 /239 , 277 5 ,252 ,714 A 10 / 1993 Harris et al . 5 , 281, 698 A 1 / 1994 Nitecki ( 22 ) Filed : Aug. 17, 2016 5 , 290 ,686 A 3 / 1994 Kendal et al . 5 , 324 ,639 A 6 / 1994 Brierley et al . (65 ) Prior Publication Data 5 , 324 , 844 A 6 / 1994 Zalipsky 5 , 382 ,657 A 1 / 1995 Karasiewicz et al. US 2017 /0035897 A1 Feb . 9 , 2017 5 ,446 , 090 A 8 / 1995 Harris 5 ,468 , 478 A 11/ 1995 Saifer et al . Related U . S . Application Data 5 ,473 ,034 A 12 / 1995 Yasui et al . 5 ,476 ,653 A 12 / 1995 Pitt et al. (62 ) Division of application No . 14 / 152 , 302 , filed on Jan . 5 , 516 ,657 A 5 / 1996 Murphy et al . 10 , 2014 , now Pat. No . 9 ,452 ,222 , which is a division 5 ,516 ,673 A 5 / 1996 Margel et al . of application No . 13 /212 , 101, filed on Aug . 17 , 2011, 5 , 532 , 142 A 7 / 1996 Johnston et al . now Pat . No. 8 ,735 ,539 . ( Continued ) ( 60 ) Provisional application No . 61 / 374 , 582, filed on Aug . FOREIGN PATENT DOCUMENTS 17 , 2010 . CA 2300362 2 / 1999 (51 ) Int. Cl. CA 2707840 2 / 2009 A61K 38 / 17 ( 2006 . 01 ) (Continued ) COZK 14 /64 ( 2006 .01 ) A61K 47 / 48 ( 2006 . 01 ) OTHER PUBLICATIONS A61K 38 /22 ( 2006 .01 ) A61K 47 /60 ( 2017 .01 ) Büllesbach EE , et al. “ Functional importance of the A chain loop in A61K 38 /00 ( 2006 .01 ) relaxin and insulin , ” J Biol Chem . May 6 , 1994 ; 269 ( 18 ) : 13124 - 8 . (52 ) U . S . CI. Feng S , et al . “ Relaxin promotes prostate cancer progression ,” Clin Cancer Res . Mar . 15 , 2007 ; 13 ( 6 ) : 1695 - 702 . CPC . A61K 47/ 48215 (2013 .01 ) ; A61K 38 /2221 Roy SS , et al. " A new cell secreting insulin ,” Endocrinology . Apr . (2013 . 01 ) ; A61K 47 /60 ( 2017 .08 ) ; COZK 14 /64 2003; 144 ( 4 ): 1585 -93 . (2013 .01 ); A61K 38/ 00 (2013 . 01 ) Sudo S , et al . “ H3 relaxin is a specific ligand for LGR7 and activates ( 58 ) Field of Classification Search the receptor by interacting with both the ectodomain and the None exoloop 2 , " J Biol Chem . Mar. 7 , 2003 ; 278 ( 10 ) :7855 -62 . See application file for complete search history . Teerlink JR , et al. “ Relaxin for the treatment of patients with acute heart failure ( Pre - RELAX - AHF ) : a multicentre , randomised , pla (56 ) References Cited cebo - controlled , parallel- group , dose - finding phase Ilb study, " Lan cet . Apr. 25 , 2009 ;373 ( 9673 ) : 1429 -39 . U . S . PATENT DOCUMENTS (Continued ) 3 , 773 , 919 A 11/ 1973 Boswell et al . 4 , 289 ,872 A 9 / 1981 Denkewalter et al. Primary Examiner — Christine J Saoud 4 ,412 , 989 A 11/ 1983 Iwashita et al . 4 ,414 , 148 A 11/ 1983 Jansen et al . ( 74 ) Attorney , Agent, or Firm — Robin L . Teskin ; 4 ,485 ,045 A 11/ 1984 Regen LeClairRyan PLLC 4 , 511 , 502 A 4 / 1985 Builder et al. 4 , 511 , 503 A 4 / 1985 Olson et al . (57 ) ABSTRACT 4 ,512 , 922 A 4 / 1985 Jones et al. 4 ,544 , 545 A 10 / 1985 Ryan et al . Modified relaxin polypeptides and their uses thereof are 4 ,551 ,433 A 11/ 1985 Deboer provided . 4 , 569 ,789 A 2 / 1986 Blattler et al. 4 ,619 , 794 A 10 / 1986 Hauser 21 Claims, 26 Drawing Sheets US 9 , 962 ,450 B2 Page 2 (56 ) References Cited 6 , 586, 207 B2 7 / 2003 Tirrell et al . 6 , 602 , 498 B2 8 / 2003 Shen U . S . PATENT DOCUMENTS 6 , 608 , 183 B1 8 / 2003 Cox , III 6 , 610 , 281 B2 8 / 2003 Harris 5 ,559 ,213 A 9 / 1996 Hakimi et al. 6 , 646, 110 B2 11/ 2003 Nissen et al . 5 ,571 , 709 A 11 / 1996 Devauchelle et al . 6 , 852, 507 B1 2 / 2005 Cerutti et al . 5 , 580 ,723 A 12 / 1996 Wells et al. 6 , 927 , 042 B2 8 /2005 Schultz et al. 5 , 583 , 023 A 12 / 1996 Cerutti et al . 7 , 045, 337 B2 5 /2006 Schultz et al. 5 ,602 ,034 A 2 / 1997 Tekamp - Olson 7 ,083 ,970 B2 8 / 2006 Schultz et al . 5 ,605 , 827 A 2 / 1997 Jackwood et al. 7 , 230, 068 B2 6 /2007 Wilson 5 ,612 , 460 A 3 / 1997 Zalipsky 7 , 332 , 571 B2 2 /2008 Miao 5 ,629 , 203 A 5 / 1997 Shuster 7 ,385 , 028 B2 6 /2008 Miao 5 ,629 , 384 A 5 / 1997 Veronese et al. 7 , 632 , 823 B2 12 / 2009 Tian 5 ,643 ,575 A 7 / 1997 Martinez et al . 7 , 632 , 924 B2 12/ 2009 Cho 5 ,650 , 234 A 7 / 1997 Dolence et al. NNNNNN.7 , 638 , 299 B2 | 12/ 2009 Cho 5 ,672 ,662 A 9 / 1997 Harris et al . 7 ,638 , 491 B2 12 / 2009 Miao 5 ,674 , 706 A 10 / 1997 Shuster 7 , 696 , 312 B2 4 / 2010 Miao RE35 , 749 E 3 / 1998 Rosenberg et al . 7 , 736 , 872 B2 6 / 2010 Paulsel 5 , 736 ,625 A 4 / 1998 Callstrom et al. 7 , 737, 226 B2 6 /2010 Wilson 5 , 739 ,208 A 4 / 1998 Harris 7 , 816, 320 B2 10 / 2010 Hays 5 , 747 ,646 A 5 / 1998 Hakimi et al. 7 , 820, 766 B2 10 / 2010 Wilson 5 , 750 , 373 A 5 / 1998 Garrard et al . 7 , 829 , 310 B2 11 / 2010 Paulsel 5 , 753 , 220 A 5 / 1998 Suzuki et al . NNNNN7 , 838 , 265 B2 11/ 2010 Paulsel 5 , 762 ,939 A 6 / 1998 Smith et al. 7 , 846 , 689 B2 . 12 / 2010 Paulsel 5 , 766 , 885 A 6 / 1998 Carrington et al. 7 , 858, 344 B2 12 / 2010 Paulsel 5 , 808 , 096 A 9 / 1998 Zalipsky 7 , 883 , 866 B2 2 / 2011 Paulsel 5 , 824 , 778 A 10 / 1998 Ishikawa et al . 7 , 888 , 533 B2 2 / 2011 Tian 5 , 824 , 784 A 10 / 1998 Kinstler et al. 7 , 919 , 591 B2 4 / 2011 Sheffer 5 ,834 ,250 A 11/ 1998 Wells et al . 7 , 928, 163 B2 4 / 2011 Miao 5 , 834 , 594 A 11 / 1998 Hakimi et al . 7 , 939 , 496 B2 5 / 2011 Cho 5 , 843 , 733 A 12 / 1998 Estes NNNN7 , 947 ,473 B2 5 / 2011 Buechler 5 , 849 , 860 A 12 / 1998 Hakimi et al . 7 , 959 , 926 B2 6 / 2011 Buechler 5 , 858 , 368 A 1 / 1999 Smith et al . 8 , 008 , 428 B2 8 / 2011 Wilson 5 , 861, 279 A 1 / 1999 Zhang et al. 8 , 008, 456 B2 8 / 2011 Miao 5 , 871, 986 A 2 / 1999 Boyce 8 , 012, 931 B2 9 / 2011 Cujec 5 , 891, 676 A 4 / 1999 Estes 8 , 022 , 186 B2 9 / 2011 Sheffer 5 , 900 , 461 A 5 / 1999 Harris 8 , 048 ,988 B2 11/ 2011 Miao 5 ,911 , 997 A 6 / 1999 Schwabe et al. 8 , 053 ,560 B2 11 / 2011 Sheffer 5 , 932 ,462 A 8 / 1999 Harris et al. 8 , 071, 809 B2 12 / 2011 Tian 5 ,939 , 285 A 8 / 1999 Devauchelle et al. 8 ,080 , 391 B2 12 / 2011 Buechler 5 , 965 ,393 A 10 / 1999 Hasnain et al. 8 , 093 , 356 B2 1 / 2012 Hays 5 , 898 , 868 A 11/ 1999 Harrison et al. 8 , 097, 702 B2 | 1 / 2012 Cho 5 , 980 , 948 A 11/ 1999 Goedemoed et al. 8 , 114 , 630 B2 2 /2012 Kraynov 5 , 990 , 237 A 11/ 1999 Bentley et al. 8 , 119, 603 B2 2 / 2012 Cho 6 , 004 ,573 A 12 / 1999 Rathi et al . 8 , 143, 216 B2 3 / 2012 Cho 6 ,013 ,433 A 1 / 2000 Pellett et al. 8 , 153 , 758 B2 4 / 2012 Miao 6 ,013 , 478 A 1 / 2000 Wells et al. 8 , 163, 695 B2 4 / 2012 Hays 6 ,017 , 731 A 1 / 2000 Tekamp -Olson et al. 8 , 178, 108 B2 5 / 2012 Buechler 6 ,083 , 723 A 7 / 2000 Tekamp -Olson 8 ,178 , 494 B2 5 / 2012 Hays 6 ,096 , 304 A 8 / 2000 McCutchen 8 , 232 , 371 B2 7 / 2012 Cho 6 , 126 , 944 A 10 / 2000 Pellett et al .