MANKANN UT MIUS009775889B2 A TOMUTAN UNTUK (12 ) United States Patent (10 ) Patent No. : US 9 ,775 , 889 B2 Keller et al. (45 ) Date of Patent: Oct . 3 , 2017 ( 54 ) METHODS OF TREATMENT OF CELLULITE 4 ,645 ,668 A * 2 / 1987 Pinnell .. .. .. 424 / 94 . 2 4 , 769 , 027 A 9 / 1988 Baker et al . .. .. 424 /493 ( 71) Applicant: HALOZYME , INC ., San Diego , CA 4 , 952 ,496 A 8 / 1990 Studier et al . .. .. 435 /91 . 41 (US ) 4 , 983 , 164 A 1 / 1991 Hook et al. .. .. .. .. .. 604 / 139 5 , 033 ,252 A 7 / 1991 Carter . 53 /425 (72 ) Inventors : Gilbert Keller , Belmont, CA (US ) ; 5 ,051 , 449 A 9 / 1991 Kligman .. .. 514 /559 5 , 052 ,558 A 10 / 1991 Carter . .. .. 206 /439 Gregory I . Frost , Palm Beach , FL (US ) 5 , 059 , 595 A 10 /1991 Le Grazie . .. .. .. 424 /468 5 ,073 ,543 A . 514 / 21 (73 ) Assignee : Halozyme, Inc. , San Diego, CA (US ) 5 , 120 ,548 A 6 / 1992 McClelland et al. .. .. .. 424 /473 5 , 122 ,614 A 6 / 1992 Zalipsky .. .. .. .. .. .. 548 / 520 ( * ) Notice : Subject to any disclaimer, the term of this 5 , 171 ,081 A 12 / 1992 Pita et al . .. .. 362 / 101 patent is extended or adjusted under 35 5 , 323 , 907 A 6 / 1994 Kalvelage .. .. .. 206 / 531 U . S . C . 154 ( b ) by 0 days . 5 ,324 , 844 A 6 / 1994 Zalipsky . .. 548 /520 This patent is subject to a terminal dis 5 , 342 ,756 A 8 / 1994 Risteli et al. .. .. 435 / 7 . 21 claimer . 5 ,395 , 326 A 3 / 1995 Haber et al . .. .. .. .. 604 / 191 5 ,446 ,090 A 8 / 1995 Harris . 525 /54 . 1 5 , 523 ,090 A 6 / 1996 Znaiden et al. .. 424 /401 (21 ) Appl. No. : 14 / 243, 805 5 ,536 , 499 A 7 / 1996 Znaiden et al. 424 /401 5 , 538 , 853 A 7 / 1996 Risteli et al. .. .. .. .. 435 / 7 . 9 ( 22 ) Filed : Apr. 2 , 2014 5 ,589 , 171 A 12 / 1996 Wegman .. .. .. 424 / 94 .67 5 ,591 , 767 A 1/ 1997 Mohr et al. 514 / 413 (65 ) Prior Publication Data 5 ,612 ,460 A 3 / 1997 . .. 530 / 391. 9 US 2014 /0271609 A1 Sep . 18 , 2014 5 ,639 ,476 A 6 / 1997 Oshlack et al . .. .. 424 /468 (Continued ) Related U . S . Application Data FOREIGN PATENT DOCUMENTS (63 ) Continuation of application No. 12 / 381, 063, filed on Mar. 6 , 2009 . 0576953 1 / 1994 EP 0822199 9 /2004 ( 60 ) Provisional application No. 61/ 068 , 667, filed on Mar. 6 , 2008 , provisional application No . 61/ 127 ,725 , filed (Continued ) on May 14 , 2008 . OTHER PUBLICATIONS ( 51 ) Int . Ci. Hexel et al , Subcision : a treatment for cellulite . Int J Dermatol . Jul . A61K 38 /48 ( 2006 .01 ) 2000 ; 39 ( 7 ): 539 -44 . * C12N 9 /64 ( 2006 .01 ) Turk et al , Acidic pH as a physiological regulator of human (52 ) U . S . CI. cathepsin L activity . Eur J Biochem . Feb . 1999 ;259 ( 3 ) :926 - 32 . * CPC .. .. .. A61K 38 / 4873 ( 2013 .01 ) ; A61K 38 /482 PIR _ 80 :* database Acc # Khhul from Mason et al, Biochem J . Dec . ( 2013 . 01 ) ; A61K 38 / 488 ( 2013 . 01 ) ; A61K 1 , 1986 ; 240 ( 2 ) : 373 - 7 . Alignment with SEQ ID No : 1 . * 38 /4813 ( 2013 .01 ) ; C12N 9 /6472 ( 2013 .01 ) ; Mason et al , The N - terminal amino acid sequences of the heavy and C12N 9 /6491 (2013 .01 ) ; C12Y 304 / 22015 light chains of human cathepsin L . Biochem J . Dec . 1 , (2013 .01 ) ; C12Y 304 / 24007 (2013 .01 ) 1986 ;240 ( 2 ): 373 - 7 .* (58 ) Field of Classification Search (Continued ) None See application file for complete search history . Primary Examiner — Sheridan Swope ( 56 ) References Cited ( 74 ) Attorney , Agent, or Firm — Dentons US LLP ; U . S . PATENT DOCUMENTS Stephanie Seidman 3 , 536 ,809 A 10 / 1970 Applezweig . .. .. .. .. 424 /28 3 ,539 ,794 A 11/ 1970 Rauhut et al . .. .. .. .. .. 240 / 2 . 25 (57 ) ABSTRACT 3 , 598 , 123 A 8 / 1971 Zaffaroni . .. .. .. .. .. .. 424 / 435 3 ,630 , 200 A 12 / 1971 Higuchi .. 424 / 427 3 , 710 , 795 A 1 / 1973 Higuchi et al . 424 /424 Methods and combinations are provided for controlling the 3 , 845 , 770 A 11/ 1974 Theeuwes et al . .. .. .. .. 424 / 427 duration of action , in vivo , of matrix - degrading enzymes. 3 , 916 , 899 A 11/ 1975 Theeuwes et al. .. .. 424 / 424 The methods and combinations permit temporary in - vivo 4 ,002 , 531 A 1 / 1977 Royer .. .. .. 435 / 188 activation ofmatrix - degrading enzymes upon administration 4 ,008 , 719 A 2 / 1977 Theeuwes et al . .. 424 / 427 4 ,044 , 126 A 8 / 1977 Cook et al. .. 514 / 180 to the extra cellular matrix (or “ ECM ” ) . Matrix -degrading 4 , 179 , 337 A 12 / 1979 Davis et al. .. .. 435 / 181 enzymes having a controlled duration of action can be used 4 , 202 , 314 A 5 / 1980 Smirnov et al . .. .. .. .. .. 128 /218 to treat ECM -mediated diseases or disorders characterized 4 ,214 ,584 A 7 / 1980 Smirnov et al . .. 128 / 218 by increased deposition or accumulation of one or more 4 , 288 ,433 A 9 / 1981 Koulbanis et al . .. 514 / 161 ECM components . 4 ,364 , 923 A 12 / 1982 Cook et al. 424 / 46 4 , 397 , 951 A 8 / 1983 Taki et al . .. .. 435 / 188 4 ,414 , 209 A 11 / 1983 Cook et al. .. .. .. .. .. .. 514 / 180 4 , 529 ,403 A 7 / 1985 Kamstra 604 / 136 23 Claims, 11 Drawing Sheets US 9 , 775 , 889 B2 Page 2 (56 ) References Cited 2003 /0012778 A1 1 /2003 Zimmerman et al. .. .. 424 / 94 .64 2003 / 0026794 A1 * 2 / 2003 Fein . .. .. .. 424 / 94 . 2 U . S . PATENT DOCUMENTS 2003 / 0045495 Al 3 / 2003 Li et al . .. .. 514 /44 R 2003 /0114647 A1 6 / 2003 Harris et al . .. .. .. .. .. 530 / 402 5 ,643 , 575 A 7 / 1997 Martinez et al . 424 / 194 . 1 2003/ 0143596 Al 7 / 2003 Bentley et al . .. .. .. 435 / 6 5 ,667 , 793 A 9 / 1997 Cho et al . 424 / 401 2003/ 0158333 A1 8 / 2003 Roberts et al. .. .. .. .. .. 530 /402 5 ,672 ,662 A 9 / 1997 Harris et al. .. .. .. .. .. .. .. 525 / 408 2003 /0220447 Al 11/ 2003 Harris .. .. .. .. .. 528 /322 5 ,674 ,533 A 10 / 1997 Santus et al . 424 / 493 2004 / 0013637 Al 1 / 2004 Bentley et al. .. 424 /78 . 17 5 ,705 , 170 A 1 / 1998 Kong et al. .. 424 / 401 2004 /0235734 AL 11/ 2004 Bossard . .. 514 / 12 5 , 705 , 364 A 1 / 1998 Etcheverry et al. .. 435 / 70 . 3 2005 / 0042213 Al 2 / 2005 Gelder et al. .. .. .. 424 / 94 .64 5 ,733 , 566 A 3 / 1998 Lewis 424 / 426 2005 / 0114037 Al 5 / 2005 Desjarlais et al. .. .. .. .. .. 702 / 19 5 , 747 ,027 A 5 / 1998 Stern et al. .. 424 / 94 .62 2005 /0171328 Al 8 / 2005 Harris .. .. .. .. ** ** . .. 528520 /322 5 , 747 , 322 A 5 / 1998 Crail et al . .. .. .. .. .. .. .. 435 / 226 2005 / 0209416 Al 9 /2005 Harris . 525 / 523 5 , 766 , 581 A 6 / 1998 Bartley et al . .. .. .. .. .. 424 /85 . 1 2005 /0287134 Al 12 / 2005 Klein . .. .. .. 424 / 94 .61 5 ,788 ,670 A 8 / 191998 Reinnnhard et al. .. .. .. 604 / 191 2007 / 0003541 Al 1 / 2007 Faudoa et al . .. .. .. 424 / 94 .65 5 , 795 , 569 A 8 / 1998 Bartley et al. 424 / 85 . 1 2007 / 0004036 A1 1 / 2007 Faudoa et al . .. .. .. 435 /325 5 . 808 , 096 A 9 / 1998 Zalipsky . .. .. .. .. .. .. .. 548 / 520 2007 /0128685 A1 6 / 2007 Faudoa et al . 435 / 34 5 , 827 , 721 A 10 / 1998 Stern et al. .. .. .. .. 435 / 201 2007 /0224183 A1 9 / 2007 Sabatino et al . .. .. .. .. 424 /94 .67 5 , 830 , 741 A 11/ 1998 Dwulet . .. .. .. .. .. 435 / 220 2007/ 0224184 Al 9 / 2007 Badalemente et al. .. 424 / 94 . 6 5 , 900 , 461 A 5 / 1999 Harris . .. .. .. .. .. .. .. .. 525 / 54 . 11 2008/ 0131500 A1 6 / 2008 Chang . 424 / 451 5 ,919 , 455 A 7 / 1999 Greenwald et al . .. .. 424 / 178 . 1 2009 / 0010918 A1 1 / 2009 Badalemente et al. .. 424 /94 .67 5 , 932 , 462 A 8 / 1999 Harris et al. 435 / 188 2010 /0003237 A1 1 / 2010 Keller et al . .. .. .. 424 / 94 .62 5 , 962 , 482 A 10 / 1999 Bissett 514 / 356 2010 / 0260739 A1 10 / 2010 Short et al. .. .. .. .. .. 424 / 94 . 5 5 , 971, 953 A 10 / 1999 Bachynnnsky .. .. .. .. .. .. 604 / 181 2010 /0284995 AL 11 /2010 Bookbinder et al . .. .. 424 / 94 .62 5 , 976 , 556 A 11/ 1999 Norton et al. .. .. .. .. 424 / 401 2011/ 0152359 Al 6 / 2011 Bookbinder et al. .. .. .. 435 / 200 5 ,985 , 263 A 11/ 1999 Lee et al . .. .. .. 424 / 85 . 2 2012 / 0108455 A1 5 / 2012 Kodandapani et al . .. .. .. 506 / 9 5 , 990 , 237 A 11/ 1999 Bentley et al. .. .. 525 /54 . 2 2012 /0148555 Al 6 /2012 Bookbinder et al. .. .. .. 435 / 200 6 ,022 , 539 A 2 / 2000 Wegman . .. .. .. .. 424 / 94 .67 2012 / 0251620 Al 10 /2012 Bookbinder et al . .. .. .. 424 / 450 6 , 054 , 569 A 4 / 2000 Benett et al. .. .. .. .. .. .. 424 / 945 2013 / 0058893 A1 3 / 2013 Bookbinder et al . .. .. .. 435 /200 6 , 060 ,474 A 5 / 2000 Williams et al . .. .. 514 / 253 .08 2013 /0266579 A1 10 / 2013 Wei et al. .. 424 / 158 . 1 6 ,071 ,526 A 6 / 2000 Schmidt et al . .. .. .. 424 / 401 6 ,086 , 872 A 7 / 2000 Wegman . .. .. .. .. 424 / 94 .67 FOREIGN PATENT DOCUMENTS 6 , 113 , 906 A 9 / 2000 Greenwald et al . .. .. .. 424 / 194 . 1 6 , 153 , 207 A 11/ 2000 Pugliese . .. .. .. .. .. 424 / 402 EP 1064951 8 / 2007 6 , 214 ,966 B1 4 / 2001 Harris 528 / 322 GB 2 323 530 9 / 1998 6 , 258 , 351 B1 . 7 / 2001 Harris . 424 / 78 . 3 JP 6 - 192124 4 / 1994 6 , 274 , 364 B1 8 / 2001 Bernard et al. .. .. 435 / 212 JP 7 - 075573 3 / 1995 6 ,294 ,350 B1 9 / 2001 Peterson .. .. 435 /29 2001 -523943 A 11/ 2001 6 , 340 , 742 B1 1 /2002 Burg et al. .. .. .. .. .. .. .. 530 / 351 MX 331943 7 / 2015 6 , 353 ,028 B2 3 / 2002 Easterling .. .. 514 /654 WO WO 94 / 15848 7 / 1994 6 ,399 , 348 B1 6 /2002 Will et al .