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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date 1 June 2017 (01.06.2017) W PO WO 2017/088974 A3 PCT AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (51) International Patent Classification: C07K 16/28 (2006.01) (21) International Application Number: PCT/EP20 16/00 1970 (22) International Filing Date: 22 November 2016 (22.1 1.2016) (25) Filing Language: English (26) Publication Language: English (30) Priority Data: 62/258,626 23 November 2015 (23. 11.2015) 16164879.5 12 April 2016 (12.04.2016) US EP (71) Applicant: MERCK PATENT GMBH [DE/DE]; Frank furter Strasse 250, 64293 Darmstadt (DE). (72) Inventors: CELIK, Ilhan; Stuckerstrasse 8, 64673 Zwingenberg (DE). STAUB, Eike; Gewuerzapfelweg 13, 64297 Darmstadt (DE). URBAN, Miriam; Talblick 4, 63849 Leidersbach (DE). RAAB, Sabine; Kapersburgstrasse 13, 6 1 19 1 Rosbach (DE). SAMY, Eileen; 53 Summer St., Unit 1, Arlington, MA 02474 (US). BENDER, Andrew; 210 Lowell Street, Reading, MA 01867 (US). HIGGINBOTHAM, Georgianna; 28 Veranda Avenue, Tewksbury, MA 01876 (US). WU, Yin; 7 Apache Avenue, Andover, MA 01810 (US). XU, Daigen; 1 Hyacinth Drive, Westford, MA 01886 (US). (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). Published: — with international search report (Art. 21(3)) — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) (88) Date of publication of the international search report: 13 July 2017 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, < ¾ o— - (54) Title: ANTI- ALPHA- V INTEGRIN ANTIBODY FOR THE TREATMENT OF FIBROSIS AND/OR FIBROTIC DISORDERS (57) Abstract: The invention relates to the prophylaxis and/or treatment of fibrosis and/or fibrotic diseases by means of antibodies. Above all, the invention relates to the administration of an anti-alpha-v integrin (receptor) antibody to patients suffering from , fibrosis and/or fibrotic diseases, including but not limited to systemic sclerosis (SSc). More specifically, the instant invention relates to the treatment of fibrotic diseases of the skin, lung, heart, liver and/or kidney by means of said antibody. Even more specifically, the instant invention relates to the administration of a recombinant, de- immunized monoclonal antibody targeting av-integrins pa tients suffering from systemic sclerosis, including, but not limited to systemic sclerosis of the skin, lung, heart and/or kidney by means of the anti-alpha-v integrin antibody DI17E6 and structural mutants or modifications thereof. A . CLASSIFICATION INV. O F SUBJECT MATTER A61K39/395 C07K16/28 A61P35/00 C12Q3/00 A61P17/02 ADD. According t o International B . FIELDS (IPC) o r t o both national classification and IPC SEARCHED Minimum documentation C07K A61K Documentation Electronic Patent Classification searched searched other than minimum data base consulted EPO-Internal C . DOCUMENTS Category* (classification system followed b y classification symbols) C12Q documentation during the international , BIOSIS, CONSIDERED Citation of document, to the extent that such documents are included search (name of data base and, where practicable, CHEM ABS Data, EMBASE, SCISEARCH in the fields searched search terms used) , WPI Data T O B E RELEVANT with indication, where appropriate, of the relevant passages Relevant t o claim No. NEI L C HENDERSON ET AL: "Targeti ng of [alphaj v i ntegrin i denti fies a core molecul ar pathway that regulates f i brosi s i n several organs" , NATURE MEDICINE. , vol . 19 , no. 12 , 1 November 2013 (2013-11-10) , pages 1617-1624, XP055338299 , 1-25 , 28-46 US ISSN : 1078-8956, D0I : 10. 1038/nm.3282 abstract page 1619 page 1622 , right-hand col umn page 164 /-- Further documents * Special categories are listed in the continuation of cited documents "A" document defining t o b e of particular "E" earlier application filing date the general relevance of Box C . : state of the art which is not considered o r patent but published o n o r after the international "L" documentwhich may throw doubts o n priority claim(s) orwhioh is cited t o establish the publication date of another citation o r other special reason (as specified) Ό " document means referring t o a n oral disclosure, use, exhibition o r other "P" document published prior t o the international the priority date claimed filing date but later than Date of the actual completion search of the international "X" document of particular relevance; the claimed invention cannot be considered novel o r cannot b e considered to involve a n inventive step when the document is taken alone "Y" document of particular relevance; the claimed invention cannot b e considered t o involve a n inventive step when the document is combined with one o r more other such documents, such combination being obvious t o a person skilled in the art member of the same patent family Date of mailing of the international search report 24/05/2017 of the ISA/ European Patent Office, N L - 2280 HV Rijswijk Tel. (+31-70) 340-2040, Fax: (+31-70) 340-3016 "T" later document published after the international filing date o r priority date and not in conflict with the application but cited to understand the principle o r theory underlying the invention "&" document 18 May 2017 Name and mailing address See patent family annex. Authorized P.B. 5818 Patentlaan officer 2 Domi ngues , Hel ena DOCUMENTS CONSIDERED TO BE RELEVANT C(Continuation). Category* Citation Y WO Y W0 of document, with indication, where appropriate, of the relevant passages Relevant 2007/008712 A2 (BIOGEN IDEC INC [US] ; VIOLETTE SHELIA [US] ; K00PMAN LOUISE A [US] ; SIM) 18 January 2007 (2007-01-18) page 143 - page 144 page 186 - page 187 exampl e 15 t o claim No. 1-25 , 28-46 2009/010290 A2 (MERCK PATENT GMBH [DE] ; [DE] ; HAHN DIANE [DE] ; MITJANS F) 22 January 2009 (2009-01-22) exampl e s 1 , 6 , 12 1-25 , 28-46 GOODMAN SIMON Y GERALD S H0RAN ET AL: " Parti a l i nhibi t i on o f i ntegri n a l pha(v)beta6 prevents pulmonary f i brosi s wi thout exacerbati ng i n l ammati on" , AMERICAN JOURNAL OF RESPI RATORY AND CRITICAL CARE MEDICINE, AMERICAN THORACIC SOCI ETY, UNITED STATES, vol . 177 , no. 1 , 1 January 2008 (2008-01-01) , pages 56-65 , XP002725452, ISSN : 1535-4970, D0I : 10. 1164/RCCM.200706-8050C the whole document 1-25 , 28-36 Y, P C0NR0Y KYLI E P ET AL: 1-25 , 28-46 Y, P X " [al pha]v i ntegri n s : key regul ators o f t i ssue f i brosi s " , CELL AND TISSUE RESEARCH , SPRINGER, DE, vol . 365 , no. 3 , 2 May 2016 (2016-05-02) pages 511-519 , XP036047046, ISSN : 0302-766X, DOI : 10. 1007/S00441-016-2407-9 [retri eved on 2016-05-02] the whole document BARBARA ULMASOV ET AL: " Inhi b i tors o f Arg-Gly-Asp-Bi ndi ng Integri n s Reduce Devel opment of Pancreati c Fibrosi s i n Mi c " CMGH CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY, vol . 2 , no. 4 , 1 July 2016 (2016-07-01) pages 499-518, XP055338304, ISSN : 2352-345X, DOI : 10. 1016/j .jcmgh .2016.03 .004 the whole document WO 2013/148232 HOFFMANN Al (GENENTECH INC [US] ; [CH] ) (2013-10-03) LA ROCHE 3 October 2013 page 4 7 page 52 - page 53 ; table 4 -/-- , 1-25 , 28-46 , 26 DOCUMENTS CONSIDERED TO BE RELEVANT C(Continuation). Category* Citation o f document, with indication, where appropriate, of the relevant passages AUSRA MI LANO ET AL: "Mol ecul ar Subsets the Gene Expressi on Si gnatures of Scleroderma Ski n " , Relevant in t o claim No. 26 PLOS ONE, vol . 3 , no. 7 , 16 July 2008 (2008-07-16) page e2696, XP055369805 , D0I : 10. 1371/journal .pone. 0002696 page 3 , r i ght-hand col umn , paragraph 3 f i gure I E , 2010/008543 A2 (DARTMOUTH COLLEGE [US] ; WHITFI ELD MICHAEL L [US] ; SARGENT JENNI FER L [ ) 2 1 January 2010 (2010-01-21) page 42 , l i ne 20 - l ine 24 26 M0NIQUE HINCHCLI FF ET AL: 26,28-46 W0 Si gnatures i n Ski n Associ Cl ini cal Improvement duri Treatment i n Systemi c Scl JOURNAL OF INVESTIGATIVE vol . 133 , no. 8 , 1 August 2013 (2013-08-01) 1979-1989 , XP055369808, "Molecul ar ated wi t h ng Mycophenol ate erosi s " , DERMATOLOGY, , pages US ISSN : 0022-202X, D0I : 1 . 1038/ the whole document . G13 . 130 . INTERNATIONAL SEARCH REPORT Box No. II PCT/EP2O16/0O1970 Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet) This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons: 1. I I Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely: □ 3. □ I Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: I Claims Nos.: because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a). Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet) This International Searching Authority found multiple inventions in this international application, as follows: see addi tional sheet As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims. □ ' 4. As all searchable claims could be searched without effort justifying an additional fees, this Authority did not invite payment of additional fees. As only some of the required additional search fees were timely paid by the applicant, this international search report covers ' only those claims for which fees were paid, specifically claims Nos. : I I No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos. : Remark on Protest I I The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. ' The additional search fees were accompanied by the applicant's protest but the applicable protest ' fee was not paid within the time limit specified in the invitation. I INo protest accompanied Form PCT/ISA/21 0 (continuation of first sheet (2)) (April 2005) the payment of additional search fees. International Application No. FURTHER INFORMATION CONTINUED FROM PCT/ISA/ PCTY EP2016/ 001970 210 Thi s Internati onal Searchi ng Authori t y found mul tipl e (groups of) i nventions i n thi s internati onal appl i cati on , as fol lows: 1. claims : 1-25, 3 7 (completely) ; 34-36, 38-46(parti al ly) Concerns aspects rel ated t o the treatment of pati ents sufferi ng from f i brosi s and/or fibroti c di sorders wi t h anti -?v i ntegri n anti body D117E6 (abi tuzumab) . 2 . claims : 26, 28-36, 38-46(al l parti al ly) Concerns aspects rel ated t o a f i brosi s gene signature compri sing two or more of the genes defi ned i n cl aim 26 or compri sing the genes defi ned i n cl aim 2 7 ; a moni tori ng method based on tracki ng the changes of a score cal cul ated from a mul t i -gene si gnature compri sing 2 or more, preferably 5 or more, more preferably 9 or more, even more preferably 15 or more and especi al l y 16, 17 , 18 or 19 genes defi ned i n cl aim 30; and a method of treati ng f i brosi s i n subjects characteri zed by the gene signatures referred t o i n cl aims 28 and 29 using the anti -?v i ntegri n antibody D117E6 (abi tuzumab) . Patent document cited in search report WO 2007008712 Patent family member(s) Publication date A2 18-01-2007 2006269266 PI0612778 2614183 101287841 102875681 104072614 200800278 1920065 2447372 2458012 2458013 5116671 5780599 2009500041 2012183077 20080031049 20130042636 20140068200 2008286269 2011305629 2014294809 2007008712 Al 2008277907 PI0815567 2693863 101687039 1113493 2167128 201070150 2167128 2526967 2395799 1143523 P20120949 203269 5341889 2010533480 20100057010 2167128 2167128 2010254977 2009010290 201001124 Al B 22-01-2009 18-02-2015 22-01-2009 31-03-2010 22-06-2016 03-12-2012 30-08-2010 31-03-2010 28-11-2012 15-02-2013 12-09-2014 31-12-2012 30-11-2014 13-11-2013 28-10-2010 28-05-2010 24-01-2013 31-01-2013 07-10-2010 22-01-2009 24-11-2010 090339 2013240344 CA 2864884 CN 104334744 EP 2831280 HK 1206796 JP 2015522246 K R 20140143196 NZ 628458 RU 2014139546 S G 11201405830V US 2016230226 WO 2013148232 Al Al Al A Al Al A A A A A Al Al 05-11-2014 18-09-2014 03-10-2013 04-02-2015 04-02-2015 15-01-2016 06-08-2015 15-12-2014 25-11-2016 20-05-2016 30-10-2014 11-08-2016 03-10-2013 AU BR CA CN CN CN EA EP EP EP EP P P P P KR KR KR US US US O WO 2009010290 A2 22-01-2009 AU BR CA CN CY DK EA EP EP ES HK HR IL JP JP KR PT SI US O ZA W0 2013148232 Al 03-10-2013 Publication date AR AU A2 Al A A A Al A2 A2 Al Al B2 B2 A A A A A Al Al Al A2 A2 Al A Tl T3 Al A2 Al T3 Al Tl A B2 A A E Tl Al A2 18-01-2007 05-05-2009 18-01-2007 15-10-2008 16-01-2013 01-10-2014 30-06-2008 14-05-2008 02-05-2012 30-05-2012 30-05-2012 09-01-2013 16-09-2015 08-01-2009 27-09-2012 07-04-2008 26-04-2013 05-06-2014 20-11-2008 15-12-2011 02-10-2014 18-01-2007 page 1 of 2 Patent document cited in search report WO 2010008543 Patent family member(s) Publication date A2 21-01-2010 US W0 2011190156 A l 2010008543 A2 Publication date 04-08-2011 21-01-2010 page 2 of 2