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( 12 ) United States Patent US010292951B2 (12 ) United States Patent ( 10 ) Patent No. : US 10 ,292 , 951 B2 Glick et al. (45 ) Date of Patent: May 21, 2019 ( 54 ) METHODS AND COMPOSITIONS FOR (58 ) Field of Classification Search TREATING CONDITIONS ASSOCIATED CPC . .. .. .. .. A61K 31 / 167 WITH AN ABNORMAL INFLAMMATORY See application file for complete search history . RESPONSES (56 ) References Cited (71 ) Applicant: First Wave Bio , Inc ., Ann Arbor, MI U . S . PATENT DOCUMENTS (US ) 3 , 079 ,297 A 2 / 1963 Schraufstatter et al. (72 ) Inventors : Gary D . Glick , Ann Arbor, MI (US ) ; 5 ,663 , 155 A * 9 / 1997 McCaffrey .. A61K 31/ 70 Luigi Franchi, Ann Arbor, MI (US ) ; 514 / 45 Giancarlo Santus, Milan ( IT ) ( Continued ) ( 73 ) Assignee : First Wave Bio , Inc ., Ann Arbor , MI FOREIGN PATENT DOCUMENTS (US ) CN 105063018 A * 11 / 2015 ( * ) Notice : Subject to any disclaimer, the term of this EP 0938338 9 /2009 patent is extended or adjusted under 35 (Continued ) U . S . C . 154 (b ) by 0 days . OTHER PUBLICATIONS (21 ) Appl . No. : 15 /255 , 102 CureZone .org ( http : / /www . curezone .org / forums/ fm .asp ? i = ( 22 ) Filed : Sep . 1 , 2016 2146880 # i, accessed May 15 , 2017, dated Feb . 2 , 2014 ). * (Continued ) (65 ) Prior Publication Data Primary Examiner — Benjamin J Packard US 2017 /0056347 A1 Mar. 2 , 2017 ( 74 ) Attorney , Agent, or Firm — Fish & Richardson P . C . (57 ) ABSTRACT This disclosure features chemical entities ( e . g ., a compound Related U . S . Application Data exhibiting activity as a mitochondrial uncoupling agent or a (60 ) Provisional application No . 62/ 213 ,016 , filed on Sep . pharmaceutically acceptable salt and / or hydrate and /or coc 1 , 2015 , provisional application No . 62 / 241, 508 , filed rystal thereof ; e . g . , a compound , such as niclosamide or a on Oct. 14 , 2015 . pharmaceutically acceptable salt and /or hydrate and / or coc rystal thereof; e . g . , a compound , such as a niclosamide (51 ) Int. Ci. analog , or a pharmaceutically acceptable salt and / or hydrate A61K 31/ 167 ( 2006 .01 ) and / or cocrystal thereof ) that are useful, e . g ., for treating one A61K 9 /00 ( 2006 .01 ) or more symptoms of a pathology characterized by an (Continued ) abnormal inflammatory response ( e . g . , inflammatory bowel ( 52 ) U . S . CI. diseases ) in a subject ( e . g ., a human ) . This disclosure also CPC . .. A61K 31/ 167 (2013 .01 ) ; A61K 9 / 0031 features compositions as well as other methods of using and ( 2013 .01 ) ; A61K 9 / 10 ( 2013 .01 ) ; making the same. (Continued ) 60 Claims, 7 Drawing Sheets Effect of Niclosamide on Lamina propria T Cells Isolated from Inflamed Colon Tissue (biopsy from Crohn ' s patients ) 6 : 52 10 : 2048 :38 %celldeath 7AAD 100 101 19 10 % 10 " 10 " 102 190 Control Niclosamide 400V Anny Control Niclosamide Apoptosis of T cells (CD45 + CD3 + ) was detected ZADD uptake and Amexin V staining US 10 ,292 ,951 B2 Page 2 (51 ) Int . CI. OTHER PUBLICATIONS A61K 45 /06 ( 2006 .01 ) Sanphui et al (Cryst . Growth Des. , 2012 , 12 ( 9 ) , pp . 4588 -4599 ). * A61K 9 / 10 ( 2006 .01 ) Frizelle and Coils ( Dis Colon Rectum , Feb . 2005 , v48 n2 , 393 A61K 47 / 32 ( 2006 . 01 ) 396 ) . * A61K 47 / 38 ( 2006 .01 ) Transcript of a telephonic : hearing before the Honorable Leonard P . A61K 9 / 16 ( 2006 .01 ) Stark , which included counsel for Plaintiffs and counsel for Defen ( 52 ) U .S . CI. dants , concerning Plaintiffs ' motion for a temporary restraining CPC order , Jun . 9 , 2017 . Case IFM Therapeutics, Inc. , First Wave Bio , . .. A61K 45 / 06 ( 2013 .01 ) ; A61K 9 / 1635 Inc. , Gary D . Glick and Luigi Franchi v . Lycera Corporation ( 2013 .01 ) ; A61K 47 /32 ( 2013 . 01 ) ; A61K 47/ 38 ( 17 - CV - 608 ) ( D . Del. ) . ( 2013. 01 ) Memorandum Order issued by the Honorable Leonard P . Stalk on Jun . 12 , 2017, Case IFM Therapeutics , Inc ., First Wave Bio , Inc. , ( 56 ) References Cited Gary D . Glick, and Luigi Franchi v . Lycera Corporation (17 -cv 608 ) ( D . Del . ) . U . S . PATENT DOCUMENTS Answer and Counterclaim filed by the Defendant on Jun . 16 , 2017 ., 5 , 905 , 090 A 5 / 1999 Bertolini Case IFM Therapeutics , Inc. , First Wave Bio , Inc. , Gary D . Glick , 7 , 132 , 546 B2 11/ 2006 Kato et al. and Luigi Franchi v . Lycera Corporation ( 17 -cv -608 ) ( D . Del. ) . 7 ,691 , 578 B2 4 / 2010 Spiegelman Grifasi et al. , “ Using Salt Cosrystals to Improve the Solubility of 7 ,927 ,613 B2 4 / 2011 Almarsson et al. Niclosamide , " Cryst . Growth Des. 2015 , 15 : 1939 - 1948 . 7 ,989 , 498 B2 8 / 2011 Saunders CureZone .org , dated Feb . 2 , 2014 , retrieved on May 15, 2017 , 8 , 097 , 759 B2 1 / 2012 Muto et al. retrieved from http : / /www .curezone . org / forums/ fm .asp ? i = 8 , 148 , 328 B2 4 / 2012 Fogelman 2146880 # i , 2 pages. 8 , 262 ,657 B2 9 / 2012 Muto et al . Filipski et al ., “ Intestinal targeting of drugs : rational design approaches 9 , 308 ,213 B2 4 / 2016 Bannister et al . and challenges , ” Current Topics in Medicinal Chemistry . , 13 ( 7 ) :776 9 , 546 ,211 B2 1 /2017 Singh 802 , 2013 . 9 ,598 , 422 B2 3 / 2017 Beck et al. Imramovsky et al . , “ Crystal Structure of the 5 - Chloro Salicylamides : 2004 / 0091523 A1 * 5 / 2004 Weibel . .. A61K 9 /0095 424 /452 Three Different Types of the H -bonding Influenced Linear Chain 2005 / 0123571 A1 6 / 2005 Rossini et al. Formation in the Solid State , ” Crystals. , 2 :349 - 361, Epub May 3 , 2009 / 0062396 Al 3 / 2009 Olesen et al. 2012 . 2012 / 0035106 Al 2 / 2012 Betancourt et al. International Search Report and Written Opinion in International 2013 / 0078226 A 3 / 2013 Nakauchi et al. Application No . PCT/ US2016 /050012 , dated Jan . 23 , 2017 , 22 2013/ 0231312 AL 9 / 2013 Jin pages . 2013 / 0243886 AL 9 / 2013 Hu et al. Lawrance et al. , “ A murine model of chronic inflammation - induced 2014 /0256661 A1 * 9 / 2014 Armstrong .. .. .. .. .. A61K 9 / 0031 intestinal fibrosis down - regulated by antisense NF -kappa B , ” Gas 514 / 29 troenterology. , 125 (6 ) : 1750 -1761 , Dec . 2003 . 2015 /0056160 A1 2 / 2015 Bachynsky et al . Luedeker et al ., “ Crystal Engineering of Pharameutical Co -crystals : 2015 /0133405 Al 5 / 2015 Pelletier et al . “ NMR Crystallography " of Niclosamide Co - crystals ,” Cryst. Growth 2016 /0243117 AL 8 /2016 Menon et al . Des. 2016 16 :3087 - 3100 . Mook et al ., Bioorg . Med Chem 2015 , 23, 5829 . FOREIGN PATENT DOCUMENTS Morin et al ., “ Niclosamide Prevents Systemic Sclerosis in a Reac tive Oxygen Species - Induced Mouse Model, ” J Immunol , 2016 , EP 3168211 5 / 2017 197 :3018 - 3028 . WO WO 2004 /006906 1 / 2004 Sanphui et al ., “ Pharmaceutical Cocrystals of Niclosamide, " Cryst . WO WO 2006 / 120178 11/ 2006 WO WO 2010 / 048114 4 / 2010 Growth Des . 12 ( 9 ) : 4588 -4599 , 2012 . WO WO 2011 /035321 3 / 2011 IFM Therapeutics, Inc. , First Wave Bio , Inc ., Gary D . Glick , and WO WO 2012 /068274 5 / 2012 Luigi Franchi, Plantiff , v . , Lycera Corporation , Defendant, C . A . WO WO 2012 / 143377 10 / 2012 No . 17 -608 -LPS , Memorandun Opinion , Aug . 31 , 2018 , 25 pages . WO WO 2014 / 108571 7 / 2014 WO WO 2005 /017755 2 / 2015 * cited by examiner U . S . Patent May 21, 2019 Sheet 1 of 7 US 10 ,292 , 951 B2 . 10210% amilyaatau p 101 10*c:20.600C584 wwwa w 100 www - - - - -- - - - - - - - - - - - - - Niclosamide (*10. ttt*atututututusatatatatata Anny t WU Control fromInflamedColonTissue(biopsyCrohn'spatients) 10°C-+:8.82T . AS . FIG.1 EffectofNiclosamideonLaminaPropriaTCellsIsolated 7AAD ApoptosisofTcells(CD45+CD3)wasdetected7ADDuptakeandAnnexinVstaining 2233 innen nnnn . totototot ControlNiclosamide totototo death cell % U . S . Patent May 21, 2019 Sheet 2 of 7 US 10 ,292 ,951 B2 11111111111111111111111111111 TNBSColitisMice Enema .. S FIG.2 Enema Intraperitoneal atent May 21 , 2019 Sheet 3 of 7 US 10 ,292 ,951 B2 FIG . 3A 1 . 4 . 4 . 4 . rra Di LV TUTUTUTUTUTUTUTUTURUT . A .2 y.. * * Bottle R3K Material MP401 - LDPE PHARMALENE FC2OPH Cobrang . .. 13 - Remi fa kai K?, M & U . S . Patent May 21, 2019 Sheet 4 of 7 US 10 ,292 ,951 B2 FIG . 3B VAR. .. * rrrr Raw Material SVE n S ' f?rd ABW IZ ‘ 6107 p?ays S JO L sa 767?ol * 156 za 911 Of is,'Xrnisirinirinir. jenay ) uue mex jeuaren W 3007004 WHd# 3N37WW HOOZON AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA Mey eyalew aqejeos doldkod aua w ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' U . S . Patent May 21, 2019 Sheet 6 of 7 US 10 ,292 ,951 B2 FIG . 4 ooveyouBIOMKpOg FIG . 4B ColitisScore 1 111 . FIG . 4C ??????????????????????????? U . S . Patent May 21, 2019 Sheet 7 of 7 US 10 ,292 ,951 B2 FIG . 5 %Tcells TNF IFNY FIG . 6 US 10 , 292 ,951 B2 METHODS AND COMPOSITIONS FOR tory or immunosuppressive drugs . Salicylazosulfapyridine TREATING CONDITIONS ASSOCIATED and 5 -aminosalicylic acid are used to treat mild IBD and as WITH AN ABNORMAL INFLAMMATORY maintenance therapy if disease remission can be achieved . RESPONSES Corticosteroids are used in patients with moderate to severe disease . However, clinical remission can only be obtained in CROSS REFERENCE TO RELATED ~ 60 % of patients , and just about half of these stay in APPLICATIONS remission after treatment is discontinued . This last point is significant because long- term use of corticosteroids carries a This application claims the benefit of U . S . Provisional significant risk of serious side effects . Application No . 62 / 213 , 016 , filed on Sep . 1 , 2015 and U . S . 10 Immunosuppressive drugs can also be used to treat mod Provisional Application No . 62 / 241, 508 , filed on Oct . 14 , erate to severe cases of IBD , often as a replacement for 2015 ; each
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