Anti-alpha-v Integrin Antibody For The Treatment Of Fibrosis And/or Fibrotic Disorders

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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
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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



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