US009833513B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 ,833 ,513 B2 Larson et al. (45 ) Date of Patent: Dec . 5 , 2017 ( 54 ) LIQUID PROTEIN FORMULATIONS FOR CO7K 16 /241 ( 2013 .01 ) ; CO7K 16 / 2839 INJECTION COMPRISING ( 2013 . 01 ) ; COZK 16 /2863 (2013 .01 ) ; COOK 1 -BUTYL - 3 -METHYLIMIDAZOLIUM 16 / 2887 ( 2013 .01 ) ; CO7K 16 / 32 ( 2013 . 01 ) ; METHANESULFONATE AND USES A61K 38/ 00 ( 2013 .01 ) THEREOF (58 ) Field of Classification Search ( 71 ) Applicant : EAGLE BIOLOGICS , INC ., None Woodcliff Lake, NJ (US ) See application file for complete search history . (72 ) Inventors: Alyssa M . Larson , Dana Point, CA (US ) ; Kevin Love, Boston , MA (US ) ; (56 ) References Cited Alisha K . Weight, Mill Creek , WA (US ) ; Alan Crane , Waban , MA (US ) ; U . S . PATENT DOCUMENTS Robert S . Langer, Newton , MA (US ) ; 3 ,682 , 174 A 8 / 1972 Cohen Alexander M . Klibanov, Boston , MA 4 ,092 ,410 A 5 / 1978 Ogata et al . (US ) 4 ,171 , 698 A 10 / 1979 Genese 5 , 001 ,000 A 3 / 1991 Rohrbacher et al . 5 , 034 ,506 A 7 / 1991 Summerton et al . ( 73 ) Assignee : Eagle Biologics , Inc. , Woodcliff Lake, 5 , 142 ,047 A 8 / 1992 Summerton et al . NJ (US ) 5 , 166 ,315 A 11/ 1992 Summerton et al. 5 ,217 , 866 A 6 / 1993 Summerton et al. ( * ) Notice : Subject to any disclaimer , the term of this 5 ,334 , 162 A 8 / 1994 Harris patent is extended or adjusted under 35 5 , 356 , 802 A 10 / 1994 Chandrasegaran U . S . C . 154 ( b ) by 507 days . 5 ,454 ,786 A 10 / 1995 Harris 5 , 487 , 994 A 1 / 1996 Chandrasegaran (21 ) Appl. No. : 14/ 484 ,053 5 ,506 , 337 A 4 / 1996 Summerton et al. 5 ,521 , 063 A 5 / 1996 Summerton et al . 5 ,527 ,675 A 6 / 1996 Coull (22 ) Filed : Sep . 11, 2014 5 , 539 , 082 A 7 / 1996 Nielsen et al . 5 ,569 , 193 A 10 / 1996 Hofstetter et al . ( 65 ) Prior Publication Data 5 ,608 , 038 A 3 / 1997 Eibl et al . US 2015 / 0071922 A1 Mar . 12, 2015 5 ,623 ,049 A 4 / 1997 Lobberding et al . 5 ,698 ,685 A 12/ 1997 Summerton et al. 5 ,714 ,331 A 2 / 1998 Buchardt et al. Related U . S . Application Data 5 , 736 , 336 A 4 / 1998 Buchardt et al . (60 ) Provisional application No . 62 / 030 , 521, filed on Jul. ( Continued ) 29 , 2014 , provisional application No . 62 /026 ,497 , filed on Jul. 18 , 2014 , provisional application No . FOREIGN PATENT DOCUMENTS 62/ 008, 050 , filed on Jun . 5 , 2014 , provisional application No. 61 / 988 ,005 , filed on May 2 , 2014 , EP 1981824 10 /2008 provisional application No . 61/ 946 ,436 , filed on Feb . EP 2335725 6 / 2011 28 , 2014 , provisional application No . 61/ 943, 197 , (Continued ) filed on Feb . 21, 2014 , provisional application No . 61 / 940 ,227 , filed on Feb . 14 , 2014 , provisional OTHER PUBLICATIONS application No. 61/ 876 ,621 , filed on Sep . 11 , 2013 . Earle and Seddon , “ Ionic liquids green solvents for the future” , (51 ) Int . CI. Pure Appl . Chem ., 72 ( 7 ) : 1391 - 8 ( 2000 ) . A61K 39 /395 ( 2006 .01 ) (Continued ) A61K 47 /06 ( 2006 .01 ) A61K 47 / 24 ( 2006 .01 ) A61K 9 /00 ( 2006 .01 ) Primary Examiner — Yunsoo Kim A61K 47 / 20 ( 2006 . 01 ) ( 74 ) Attorney , Agent, or Firm — Baker & Hostetler LLP A61K 47 / 22 ( 2006 . 01 ) CO7K 16 /22 ( 2006 .01 ) COOK 16 / 24 ( 2006 . 01 ) (57 ) ABSTRACT COZK 16 / 28 ( 2006 . 01 ) A61K 47 / 18 ( 2017 .01 ) Concentrated , low - viscosity , low - volume liquid pharmaceu A61K 9 / 19 ( 2006 .01 ) tical formulations of proteins have been developed . Such CO7K 16 /32 ( 2006 . 01 ) formulations can be rapidly and conveniently administered A61K 38 /00 ( 2006 .01 ) by subcutaneous or intramuscular injection , rather than by (52 ) U . S . CI. lengthy intravenous infusion . These formulations include CPC . .. A61K 47 / 06 ( 2013 .01 ) ; A61K 9 / 0019 low -molecular -weight and / or high -molecular - weight pro (2013 .01 ) ; A61K 9 / 19 (2013 .01 ) ; A61K teins , such as mAbs, and viscosity - reducing ionic liquids. 39 / 3955 ( 2013 .01 ) ; A61K 47/ 186 ( 2013 .01 ) ; A61K 47/ 20 (2013 . 01) ; A61K 47 / 22 (2013 . 01) ; A61K 47 / 24 ( 2013 .01 ) ; C07K 16 / 22 ( 2013 .01 ) ; 26 Claims, No Drawings US 9 ,833 Page, 513 2 B2 (56 ) References Cited 2016 /0074515 Al 3 /2016 Soane et al . 2016 /0090419 Al 3 / 2016 Morichika et al. U . S . PATENT DOCUMENTS 2016 /0193346 A17 / 2016 Houston et al . 2016 /0367675 Al 12 /2016 Liu et al. 5 , 773 ,571 A 6 / 1998 Nielsen et al. 2017 /0049888 AL 2 /2017 Liu et al. 5 , 779 ,668 A 7 / 1998 Grabenkort 5 , 786 , 571 A 7 / 1998 Bethel et al. FOREIGN PATENT DOCUMENTS 5 ,819 , 988 A 10 / 1998 Sawhney et al. 5 . 871, 736 A 2 / 1999 Bruegger et al . EP 2538973 1 / 2013 5 , 962 ,405 A 10 / 1999 Seelich wo W00244321 A2 6 / 2002 6 ,065 ,645 A 5 /2000 Sawhney et al . WO 2004089335 10 / 2004 6 ,171 , 586 B1 1 / 2001 Lam et al . WO 2006071693 7 / 2006 6 , 267 , 958 B1 7 / 2001 Andya et al. WO 2009015367 1 / 2009 6 , 394 , 314 B1 5 / 2002 Sawhney et al . WO 2009026122 2 / 2009 6 , 443 , 612 B1 9 / 2002 Keller Wo 2009043049 4 / 2009 6 , 457 , 609 B1 10 / 2002 Keller WO 2010132047 11 / 2010 6 , 525 , 102 B1 2 / 2003 Chen et al. WO WO2010132047 Al 11 / 2010 6 , 551 , 840 B2 4 / 2003 Ono et al. WO 2011069037 6 / 2011 6 , 564 ,972 B2 5 / 2003 Sawhney et al. WO WO2011072246 A2 6 / 2011 6 , 685 , 940 B2 2 / 2004 Andya et al. WO 2011095543 8 / 2011 6 , 698 , 622 B2 3 / 2004 Sawhney et al. WO 2011109415 9 / 2011 6 , 730 , 328 B2 5 / 2004 Maskiewicz WO 2011139718 11 / 2011 6 , 875 , 432 B2 4 / 2005 Liu WO WO2012010832 A1 1 /2012 7 ,390 , 786 B2 6 / 2008 Warne et al . WO 2012141978 10 / 2012 7 ,501 , 000 B2 3 / 2009 Rosenflanz et al . WO 2013096791 6 / 2013 7 ,666 , 413 B2 2 / 2010 Liu WO WO2013176772 AL 11/ 2013 7 , 740 , 842 B2 6 / 2010 Arvinte wo WO2014018423 A2 1 / 2014 7 , 758, 860 B2 7 / 2010 Warne WO 2014023816 2 / 2014 8 , 142 , 776 B2 3 / 2012 Liu 8 ,383 , 114 B2 2 / 2013 Sloey et al . 8 , 476, 239 B2 7 / 2013 Dali et al. OTHER PUBLICATIONS 8 , 500 , 681 B2 8 / 2013 Gonnelli et al . 8 ,703 , 126 B2 4 / 2014 Liu et al . International Search Report for PCT/ US2014 /055245 dated May 8 , 715 , 651 B2 5 / 2014 Maestro et al. 29 , 2015 . 8 , 779, 094 B2 7 / 2014 Johnston et al . 8 , 802 , 095 B2 8 / 2014 Houston et al . Riduan and Zhang , “ Imidazolium salts and their polymeric mate 8 , 906 , 368 B2 12 / 2014 Bolli et al . rials for biological applications" , Chem . Soc Rev . , 42 :9055 - 70 9 ,072 , 668 B2 7 / 2015 Dai et al. ( 2013 ) . 9 , 084 , 743 B2 7 / 2015 Teschner et al. Sheldon , et al. , “ Biocatalysts in ionic liquids ” , Green Chem ., 9 , 084 , 777 B2 7 / 2015 Morichika et al. 4 : 147 - 51 (2002 ) . 9 , 309, 316 B2 4 / 2016 Dali et al . van Rantwijk and Sheldon , “ Biocatalysis in ionic liquids ” , Chem 9 , 320, 797 B2 4 / 2016 Sloey et al . 9 , 457 , 089 B2 10 / 2016 Soula Rev . , 107 : 2757 -65 (2007 ) . 9 , 605, 051 B2 3 / 2017 Soane et al . Baker , et al ., “ Fluorescence quenching immunoassay performed in 2002 / 0190082 Al 12 / 2002 Keller an ionic liquid ” , Royal Doc Chem ., (27 ) :2851 - 3 (2006 ) . 2003 /0113316 Al 6 / 2003 Kaisheva et al. Du and Klibanov , “ Hydrophobic salts markedly diminish viscosity 2004 /0191243 AL 9 / 2004 Chen et al. of concentrated protein solutions” , Biotechnol Bioeng . , 108 :632 - 6 2004 / 0197324 Al 10 / 2004 Liu et al. (2011 ) . 2005 /0158303 A1 7 / 2005 Liu et al. Guo , et al. , “ Structure - activity relationship for hydrophobic salts as 2006 /0142234 AL 6 / 2006 Chen et al. 2007 /0053900 A1 3 / 2007 Liu et al. viscosity - lowering excipients for concentrated solutions of mono 2008 /0071063 Al 3 / 2008 Allan et al. clonal antibodies ” , Pharm Res. , 29 : 3102 - 9 ( 2012 ) . 2008 / 0226689 Al 9 / 2008 Berry Jezek , et al. , “ Viscosity of concentrated therapeutic protein com 2009/ 0280129 Al 11 / 2009 Liu et al . positions” , Adv Drug Deliv Rev. , 63 : 1107 - 17 ( 2011 ) . 2010 /0061949 A1 3 / 2010 Schmidt- Jacobsen Miller , et al . , “ Low viscosity highly concentrated injectable 2010 /0239567 A1 9 / 2010 Esue nonaqueous suspensions of lysozyme microparticies” , Langmuir , 2011 /0145940 Al 6 / 2011 Voytas et al . 2011/ 0262626 Al 10 / 2011 Sun 26 : 1067 - 74 (2010 ) . 2011/ 0305734 Al 12 / 2011 Edelson et al . Shire , et al. , “ Challenges in the development of high protein 2012 /0230982 AL 9 / 2012 Zhou concentration formulations ” , J . Pharm . Sci. , 93 :1390 -1402 (2004 ) . 2012 /0231009 AL 9 / 2012 Ramani et al . Srinivasan , et al. , “ Non - aqueous suspensions of antibodies are much 2012 / 0263783 Al 10 / 2012 Messmer less viscous than equally concentrated aqueous solutions” , Pharm . 2013 / 0028907 AL 1 / 2013 Parshad et al . Res ., 30 : 1749 - 57 ( 2013 ) 2013 / 0028920 A 1 / 2013 Gurny Wang, et al ., “ Antibody structure, instability , and formulation ” , J . 2013 /0058958 Al 3 / 2013 Bowen et al. Pharm . Sci ., 96 : 1 - 26 ( 2007 ) . 2013 /0171128 A1 7 / 2013 Huang et al. 2013 / 0216525 AL 8 / 2013 Chen Hawe, et al. , Fluorescent molecular rotors as dyes to characterize 2013 /0309226 A1 11 / 2013 Armstrong et al . polysorbate -containing IgG formulations, Pharma Res . , 27 ( 2 ): 314 2014 / 0023655 Al 1 / 2014 Monck et al . 26 ( 2009 ) . 2014 /0127227 AL 5 / 2014 Chang Jacobson , et al ., “ 1 , 1 - Dicyano - 2 - [ 6 - (dimethylamino )naphthalen - 2 2014 / 0294859 Al 10 / 2014 Sloey et al.