DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendment filed 5/10/2026 is acknowledged. Applicant has amended claim 20 and 22; claim 21 is cancelled.
Claim Status
Claims 1, 4-5, 7-12, 15-20, and 22-23 are pending and under examination in the instant office action.
Withdrawal of Rejections
The rejection of claim 20 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification for scope of enablement is withdrawn in view of the amendment to the claims.
Claim Rejections - 35 USC § 103- Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 4-5, 7-12, 15-20, and 22-23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/068695 to Zhang et al, published 19 April 2018 (PTO-892 5/28/2025), in view of WO 2019/027903 to Wang et al, published 7 February 2019 (PTO-892 5/28/2025), WO 2018/137705 Qiu et al published 2 August 2018 (PTO-892 5/28/2025), Schwartz et al, "CTLA4 and CD47 Combinational Therapy to Extend Survival in Melanoma", J Clin Oncol. 35(15 suppl):e21025, Meeting Abstract from 2017 ASCO Annual Meeting I, 2017 (PTO-892 5/28/2025), and WO 2019/144895, Zhao et al (effectively filed 24 January 2019) (PTO-892 5/28/2025).
Zhang teaches a bispecific antibody comprising two antigen binding regions: (1) a first antigen binding portion, specifically a sdAB moiety recognizing CTLA-4 and (2) a second antigen binding portion comprising a heavy chain variable domain (VH) and a light chain variable domain (VL), wherein the VH and VL together form an antigen-binding site that binds a second epitope, wherein the first antigen binding portion and the second antigen binding portion are fused to each other. Zhang teaches the second epitope is not from CTLA-4 and the anti-CTLA-4 construct is bispecific [0014][0018][0020].
Zhang teaches the isolated anti-CTLA-4 construct, wherein the sdAb moiety comprises a VH domain comprising SEQ ID NO: 275. Instant amino acid sequences of the CDRs CDR1, CDR2, and CDR3 set forth in SEQ ID NO: 28, SEQ ID NO:30, and SEQ ID NO: 31 have 100% identity to Ref. SEQ ID NO: 275 (see sequence alignment below). (Claim 6)
Zhang teaches the second antibody moiety specifically recognizing a second antigen, not CTLA-4, is a full-length antibody consisting of two heavy chains and two light chains and in some embodiments, the antigen binding portion is an antibody fragment comprising a heavy chain comprising the VH and a light chain comprising the VL. Zhang teaches different fusion and construct formats for making bispecific antibodies. Among the different fusion and construct formats presented, one depiction is that the N-terminus of each sdAb is fused to the C-terminus of one light chain via an optional peptide linker. A second depiction shows the C-terminus of each sdAb is fused to the N-terminus of heavy chain or light chain of the full-length antibody via an optional linker (Figure 40-49) [0018-0020][0242-0247].
Zhang teaches the sdAB moiety specifically recognizing CTLA-4 and the second antibody moiety are optionally connected by a peptide linker, with SEQ ID NO. 162. Reference SEQ ID NO. 162 is a GS linker with 100% identity to instant SEQ ID NO. 37 (see sequence alignment below). [0242-0247, Claim 19]
Zhang teaches the sdAB moiety specifically recognizing CTLA-4 comprises a VH domain comprising the amino acid sequence SEQ ID NO: 275, which has 100% identity to instant SEQ ID NO: 28 (see sequence alignment below). [0014,0022]
Zhang teaches the isolated anti-CTLA-4 construct, wherein the full-length antibody comprises a heavy chain and a light chain, wherein at least one of the heavy chains of the full-length antibody is fused to the anti-CTLA-4 sdAb, and wherein the heavy chain fusion polypeptide comprises the amino acid sequence of SEQ ID No. 320. Instant SEQ ID NO.8 has 100% identity to Reference SEQ ID NO. 320. [0505]
Zhang teaches the anti-CTLA-4 sdAb moiety is camelid, chimeric, partially humanized, or fully humanized. [0163-0190]
Zhang teaches an isolated nucleic acid encoding the isolated anti-CTLA-4 constructs described. Zhang further teaches a vector comprising the isolated nucleic acid, and an isolated host cell comprising any one of the isolated nucleic acid or vector described. Zhang also teaches a method of producing the isolated anti-CTLA-4 construct described, comprising culturing a host cell comprising any one of the isolated nucleic acid or vector described, or culturing any one of the isolated host cell described, under conditions effective to express the encoded anti-CTLA-4 construct; and obtaining the expressed anti-CTLA-4 construct from said host cell. [0026-0030]
Zhang teaches pharmaceutical composition comprising the anti-CTLA-4 construct and a pharmaceutically acceptable carrier. [0024][0355-0370]
Zhang also teaches methods of treating an individual having a CTLA-4-related disease, comprising administering to the individual having a CTLA-4-related disease, comprising administering to the individual an effective amount of the pharmaceutical compositions comprising anti-CTLA-4 constructs, wherein the CTLA-4 related disease is cancer, wherein the cancer is a solid tumor, such as melanoma. Zhang teaches that anti-CTLA-4 antibody therapy has shown promise in a number of cancers, such as melanoma. [0025][0371-00379]
Zhang does not teach the second epitope bound by the bispecific antibody binds CD47.
Wang teaches a bispecific antibody wherein the first epitope is located on CD47 and the second epitope is located on CTLA-4. Wang teaches the antibody is a humanized or human antibody and is a single-chain antibody (scFv) or a single domain antibody (sdAb). [0070--0076]
Wang also teaches methods of treating cancer in a subject in need thereof, comprising administering to the subject a pharmaceutical composition of the antibody, wherein the cancer can be a solid cancer including melanoma. [0144, 0154, 0159]
Wang also teaches utilizing methods of determining a level of CD47 in a sample from a subject can lead to the diagnosis of abnormal CD47 levels in a disease (such as cancer, including melanoma), which can be used to make therapeutic decisions. [00164]
Qiu teaches a bispecific antibody wherein the first antigen binding moiety binds to CD47 and the second antigen binding moiety binds to an immune checkpoint including CTLA-4 [0119].
Qui teaches that CD47 is a key molecule in governing macrophage phagocytosis and the CD47 expression is elevated in several human cancers including solid tumors such as melanoma. Qui also teaches methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of antigen binding units. Qui discloses solid tumors such as melanoma among the cancers treated. [00165]
Schwartz teaches that CTLA-4 is up-regulated post-T cell activation and blockade enhances tumor responses in immunocompetent humans with melanoma, and that CD47 blockade on tumor cells significantly enhances immune-targeted tumor cell killing post-irradiation compared to irradiation alone. The results of Schwartz’s study show that the combination of CD47/CTLA4 blockade with irradiation significantly increased survival by 25% compared to irradiation/CTLA4 alone at 50 days.
Zhang, Wang, Qiu and Schwartz (the combined references) teach a bispecific antibody comprising a first antigen portion comprising a VH and VL binding to CD47 and a second antigen binding portion comprising a sdAb that binds to CTLA-4, a pharmaceutical composition comprising the bispecific antibody, and a method of treating cancer including melanoma, as set forth above.
The combined references do not disclose the instantly claimed sequences of the CD47 antibody.
Zhao teaches an anti-CD47 antibody comprising at least one antibody -antigen binding site, wherein the antibody comprises a variable heavy chain that is at least 90% identical to SEQ ID NO: 365, and a variable light chain that is at least 90% identical to SEQ ID NO: 378. The instantly claimed VH of the first antigen binding portion comprising heavy chain complementarity-determining regions (CDRs) HCDR1, HCDR2, and HCDR3, with amino acid sequences set forth in SEQ ID NO: 21, SEQ ID NO: 22, and SEQ ID NO: 23 have 100% identity to Reference SEQ ID NO: 365, and the instantly claimed VL of the first antigen binding portion comprising light chain CDRs LCDR1, LCDR2, and LCDR3, with amino acid sequences set forth in SEQ ID NO: 24, SEQ ID NO: 25, and SEQ ID NO: 26 have 100% identity to Reference SEQ ID NO: 378 (see sequence alignments below). (Claim 13 of Zhao)
Zhao also teaches the anti-CD47 antibody is a humanized or human antibody having a variable heavy region (VH) and/or variable light (VL) chain region with at least 90% identical to SEQ ID NO: 401 and SEQ ID NO: 402 (Claim 31 of Zhao). Instant SEQ ID NO: 4 and SEQ ID NO: 6 have 100% identity to Reference SEQ ID NO: 401 and SEQ ID NO: 402 (see sequence alignment below).
Zhao teaches the CD47 antibody can be formulated as a bispecific antibody that binds a second different antigen, and teaches methods of making bispecific antibodies are known in the art. [00288-00298]; [00363-00365].
Zhao also teaches pharmaceutical compositions of the disclosed CD47 antibodies and methods of treating CD47+ cancers and tumors, including melanoma. [0010]; [0049]; [00355-00356]
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention was filed to make an isolated anti-CD47/anti-CTLA-4 bispecific antigen-binding protein or a fragment thereof, comprising the bispecific anti-CTLA-4 antibody of Zhang, in one of the bispecific antibody formats linking the anti-CTLA4 VHH domain to the heavy chain of an IgG antibody as taught by Zhang, and the anti-CD47 antibody of Zhao, and used in methods of treating cancer. This would result in an anti-CTLA4/anti-CD47 bispecific antibody comprising a heavy chain 100% identical to instant SEQ ID NO: 8 or 12 (for instance, comprising the CD47 heavy chain SEQ ID NO: 401 of Zhao linked substituted into the bispecific antibody of Zhang, for example SEQ ID NO: 320 wherein the antibody heavy chain is linked by an IgG hinge peptide linker to the anti-CTLA4 VHH domain 100% identical to the anti-CTLA4 VHH of Zhang at the C-terminus of the heavy chain; and further comprising a light chain SEQ ID NO: 402 of Zhao 100% identical to instant SEQ ID NO: 6).
One of ordinary skill in the art would have been motivated to, and have a reasonable expectation of success to, because: (1) Zhang teaches making a bispecific antibody comprising one antigen binding portion comprising a sdAb that binds to CTLA-4, and a second antigen binding portion comprising VH and VL domains that bind to a different antigen for treatment of cancer including melanoma, and teaches known methods of bispecific antibody construction; (2) Wang teaches a bispecific antibody binding one epitope on CD47 and the second epitope on CTLA-4, for the treatment of cancer including melanoma; (3) Qiu teaches a bispecific antibody binding to both CD47 and immune checkpoints like CTLA-4 for cancer treatment including melanoma; (4) Schwartz demonstrates the combination CD47/CTLA-4 blockade successfully treats melanoma, and significantly increases survival when combined with irradiation, and (5) Zhao suggests utilizing their CD47 antibody for the treatment of CD47+ cancers including melanoma and suggests making bispecific antibodies with their CD47 antibody that bind to an additional antigen, and teach methods of making bispecific antibodies are known in the art.
Given the cited prior art teach both the motivation and methods to make bispecific antibodies binding to CD47 and CTLA-4, particularly for the treatment of CD47/CTLA-4 expressing cancers including melanoma, and given the success demonstrated by the prior art for treating melanoma by combined CD47/CTLA-4 blockade, one of skill in the art would have pursued modifying the CTLA-4 bispecific antibody of Zhang to bind to CD47 using the antibody taught by Zhao, and to treat melanoma with the bispecific antibody, with a reasonable expectation of success.
WO2018068695, Zhang SEQ ID NO. 275 aligned with Instant SEQ ID NO. 28
RESULT 1
BFF06553
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
ID BFF06553 standard; protein; 130 AA.
AC BFF06553;
DT 31-MAY-2018 (first entry)
DE Humanized anti-CTLA-4 single domain antibody VHH domain, SEQ ID 275.
CC PN WO2018068695-A1.
CC PD 19-APR-2018.
CC PF 10-OCT-2017; 2017WO-CN105506.
PR 11-OCT-2016; 2016WO-CN101777.
PR 20-JUL-2017; 2017WO-CN093644.
CC PA (NANJ-) NANJING LEGEND BIOTECH CO LTD.
CC PI Zhang Y, Wu S, Yang S, Chou C;
DR WPI; 2018-30471L/30.
Isolated anti-CTLA-4 construct used in pharmaceutical composition for treating individual having CTLA-4-related disease, which is cancer, comprises single-domain antibody moiety specifically recognizing CTLA-4, where sdAb moiety has CDR1.
Claim 6; SEQ ID NO 275; 391pp; English.
SQ Sequence 130 AA;
Query Match 100.0%; Score 699; Length 130;
Best Local Similarity 100.0%;
Matches 130; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGYTYSRHCLGWFRQAPGKGREAVSTIDSDGSTSYA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVESGGGLVQPGGSLRLSCAASGYTYSRHCLGWFRQAPGKGREAVSTIDSDGSTSYA 60
Qy 61 DSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAIGPNPRYCSGAPNTRGAEHYFGYW120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 DSVKGRFTISRDNAKNTLYLQMNSLRPEDTAVYYCAIGPNPRYCSGAPNTRGAEHYFGYW120
Qy 121 GQGTLVTVSS 130
||||||||||
Db 121 GQGTLVTVSS 130
WO 2018/068695, Zhang SEQ ID NO: 162 aligned with Instant SEQ ID NO.37
RESULT 1: 162 DUPLICATES:
===================================
ALIGNMENT:
Query Match 100.0%; Score 50; Length 9;
Best Local Similarity 100.0%;
Matches 9; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGGGSGGGS 9
|||||||||
Db 1 GGGGSGGGS 9
US-16-341-034-162
Filing date in PALM: 2019-04-10
Sequence 162, US/16341034
Patent No. 11472881
GENERAL INFORMATION
APPLICANT: NANJING LEGEND BIOTECH CO., LTD.
TITLE OF INVENTION: SINGLE-DOMAIN ANTIBODIES AND VARIANTS
TITLE OF INVENTION: THEREOF AGAINST CTLA-4
FILE REFERENCE: 76142-20003.00
CURRENT APPLICATION NUMBER: US/16/341,034
CURRENT FILING DATE: 2019-04-10
PRIOR APPLICATION NUMBER: PCT/CN2017/105506
PRIOR FILING DATE: 2017-10-10
PRIOR APPLICATION NUMBER: PCT/CN2016/101777
PRIOR FILING DATE: 2016-10-11
PRIOR APPLICATION NUMBER: PCT/CN2017/093644
PRIOR FILING DATE: 2017-07-20
NUMBER OF SEQ ID NOS: 379
SEQ ID NO 162
LENGTH: 9
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: Linker peptide
WO 2018/068695, Zhang SEQ ID NO. 275 aligned to Instant amino acid sequences of the CDRs CDR1, CDR2, and CDR3 in SEQ ID NO: 29, SEQ ID NO:30, and SEQ ID NO: 31
RESULT 1
BFF06630
ID BFF06630 standard; protein; 130 AA.
AC BFF06630;
DT 31-MAY-2018 (first entry)
DE Humanized anti-CTLA-4 single domain antibody VHH domain, SEQ ID 352.
CD245; CTLA-4 protein; Cytotoxic T-lymphocyte protein-4;
Cytotoxic T-lymphocyte-associated protein 4; antibody therapy; cancer; colon tumor; cytostatic; heavy chain variable region; humanized antibody; infection; single domain antibody; solid tumor; therapeutic; viral infection.
OS Unidentified.
CC PN WO2018068695-A1.
CC PD 19-APR-2018.
CC PF 10-OCT-2017; 2017WO-CN105506.
PR 11-OCT-2016; 2016WO-CN101777.
PR 20-JUL-2017; 2017WO-CN093644.
CC PA (NANJ-) NANJING LEGEND BIOTECH CO LTD.
CC PI Zhang Y, Wu S, Yang S, Chou C;
DR WPI; 2018-30471L/30.
CC PT Isolated anti-CTLA-4 construct used in pharmaceutical composition for
CC PT treating individual having CTLA-4-related disease, which is cancer,
CC PT comprises single-domain antibody moiety specifically recognizing CTLA-4,
CC PT where sdAb moiety has CDR1.
CC PS Claim 6; SEQ ID NO 352; 391pp; English.
SQ Sequence 130 AA;
Query Match 91.0%; Score 249.4; Length 130;
Best Local Similarity 51.1%;
Matches 48; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GYTYSRHCLG--------------TIDSDGSTSYADSVKG-------------------- 26
|||||||||| ||||||||||||||||
Db 26 GYTYSRHCLGWVRQAPGKGLEWVSTIDSDGSTSYADSVKGRFTISRDNSKNTLYLQMNSL 85
Qy 27 ------------GPNPRYCSGAPNTRGAEHYFGY 48
||||||||||||||||||||||
Db 86 RAEDTAVYYCARGPNPRYCSGAPNTRGAEHYFGY 119
WO2018/068695, Zhang SEQ ID NO.320 aligned with Instant SEQ ID No. 8
RESULT 3
BFF06598
ID BFF06598 standard; protein; 592 AA.
AC BFF06598;
DT 31-MAY-2018 (first entry)
DE Anti-CTLA-4/PD1 bispecific antibody heavy chain fusion protein, SEQ 320.
KW CD245; CTLA-4 protein; Cytotoxic T-lymphocyte protein-4;
KW Cytotoxic T-lymphocyte-associated protein 4; Immunoglobulin G1;PD1 protein; antibody therapy; bispecific antibody; cancer; colon tumor; cytostatic; fusion protein; heavy chain; infection; mutein; solid tumor; therapeutic; viral infection.
Homo sapiens.
Synthetic.
Unidentified.
CC PN WO2018068695-A1.
CC PD 19-APR-2018.
CC PF 10-OCT-2017; 2017WO-CN105506.
PR 11-OCT-2016; 2016WO-CN101777.
PR 20-JUL-2017; 2017WO-CN093644.
CC PA (NANJ-) NANJING LEGEND BIOTECH CO LTD.
CC PI Zhang Y, Wu S, Yang S, Chou C;
DR WPI; 2018-30471L/30.
CC PT Isolated anti-CTLA-4 construct used in pharmaceutical composition for treating individual having CTLA-4-related disease, which is cancer, comprises single-domain antibody moiety specifically recognizing CTLA-4, where sdAb moiety has CDR1.
CC PS Claim 30; SEQ ID NO 320; 391pp; English.
Query Match 94.3%; Score 2967.5; Length 592;
Best Local Similarity 93.8%;
Matches 557; Conservative 17; Mismatches 13; Indels 7; Gaps 2;
Qy 1 EVQLVQSGAEVKKPGSSVKVSCKASGYSFTHHWIHWVRQAPGQGLEWMGMIDASDSETRL 60
:||||||| ||||||:|||||||||||:||:::::|||||||||||||| |: |: |
Db 1 QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF 60
Qy 61 SQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARLGRYY-----FDYWGQGTTVTV 115
::|||:|||:| | ||:|||||| ||: :||||||||| | | ||||||||||||
Db 61 NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCAR--RDYRFDMGFDYWGQGTTVTV 118
Qy 116 SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 175
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 119 SSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQ 178
Qy 176 SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGP 235
|||||||||||||||||||||||||||||||||||||||||||||||||||||||| |||
Db 179 SSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGP 238
Qy 236 SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS 295
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 239 SVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS 298
Qy 296 TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM 355
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 299 TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEM 358
Qy 356 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ 415
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 359 TKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQ 418
Qy 416 EGNVFSCSVMHEALHNHYTQKSLSLSLGKEPKSSDKTHTSPPSPEVQLVESGGGLVQPGG 475
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 419 EGNVFSCSVMHEALHNHYTQKSLSLSLGKEPKSSDKTHTSPPSPEVQLVESGGGLVQPGG 478
Qy 476 SLRLSCAASGYTYSRHCLGWFRQAPGKGREAVSTIDSDGSTSYADSVKGRFTISRDNAKN 535
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 479 SLRLSCAASGYTYSRHCLGWFRQAPGKGREAVSTIDSDGSTSYADSVKGRFTISRDNAKN 538
Qy 536 TLYLQMNSLRPEDTAVYYCAIGPNPRYCSGAPNTRGAEHYFGYWGQGTLVTVSS 589
||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 539 TLYLQMNSLRPEDTAVYYCAIGPNPRYCSGAPNTRGAEHYFGYWGQGTLVTVSS 592
WO 2019/144895, Zhao SEQ ID NO. 365 aligned to Instant SEQ ID NO. 21, 22, 23
RESULT 1
BGP82446
ID BGP82446 standard; protein; 117 AA.
AC BGP82446;
DT 19-SEP-2019 (first entry)
DE Anti-CD47 humanized antibody (108VH.M4) VH region, SEQ 365.
KW CD47; Cluster of Differentiation 47; IAP protein; antibody; antibody therapy; cancer; cytostatic; heavy chain variable region; humanized antibody; integrin associated protein; mutein; neoplasm; prophylactic to disease; therapeutic.
OS Homo sapiens.
OS Chimeric.
OS Synthetic.
FH Key Location/Qualifiers
FT Region 26..35
FT /note= "CDR1 region"
FT Region 50..66
FT /note= "CDR2 region"
FT Misc-difference 53
FT /note= "Wild-type Pro substituted by Ala"
FT Region 99..106
FT /note= "CDR3 region"
CC PN WO2019144895-A1.
CC PD 01-AUG-2019.
CC PF 24-JAN-2019; 2019WO-CN072929.
PR 24-JAN-2018; 2018WO-CN074055.
CC PA (NANJ-) NANJING LEGEND BIOTECH CO LTD.
CC PI Zhao T, Zhang H, Yang S, Zhang Y, Chou C, Wu S;
DR WPI; 2019-675597/61.
CC PS Claim 13; SEQ ID NO 365; 118pp; English.
SQ Sequence 117 AA;
Query Match 87.6%; Score 173.4; Length 117;
Best Local Similarity 43.2%;
Matches 35; Conservative 0; Mismatches 0; Indels 46; Gaps 2;
Qy 1 GYSFTHHWIH--------------MIDASDSETRLSQKFKD------------------- 27
|||||||||| |||||||||||||||||
Db 26 GYSFTHHWIHWMKQRPGQGLEWIGMIDASDSETRLSQKFKDKATLTVDASSSTAYMQLNS 85
Qy 28 -------------LGRYYFDY 35
||||||||
Db 86 PTSEDSALYFCARLGRYYFDY 106
WO 2019/144895, Zhao SEQ ID NO. 378 aligned to Instant SEQ ID NO. 24, 25, 26
RESULT 2
BGP82459
ID BGP82459 standard; protein; 107 AA.
AC BGP82459;
DT 19-SEP-2019 (first entry)
DE Anti-CD47 humanized antibody (108VL2.M1) VL region, SEQ 378.
CC PN WO2019144895-A1.
CC PD 01-AUG-2019.
CC PF 24-JAN-2019; 2019WO-CN072929.
PR 24-JAN-2018; 2018WO-CN074055.
CC PA (NANJ-) NANJING LEGEND BIOTECH CO LTD.
CC PI Zhao T, Zhang H, Yang S, Zhang Y, Chou C, Wu S;
DR WPI; 2019-675597/61.
Claim 13; SEQ ID NO 378; 118pp; English.
Sequence 107 AA;
Query Match 82.7%; Score 118.3; Length 107;
Best Local Similarity 36.5%;
Matches 27; Conservative 0; Mismatches 0; Indels 47; Gaps 2;
Qy RASENVGTYIS---------------GASNRYT---------------------------18
||||||||||| |||||||
Db 24 RASENVGTYISWYQQKPGQAPRLLIYGASNRYTGVPARFSGSGSGTDFTLTISSLEPEDF 83
Qy 19 -----GESYGHLYT 27
|||||||||
Db 84 AVYHCGESYGHLYT 97
WO 2019/144895, Zhao SEQ ID NO. 401 aligned to Instant SEQ ID NO. 4
RESULT 1
BGP82482
(NOTE: this sequence has 4 duplicates in the database searched.
See complete list at the end of this report)
ID BGP82482 standard; protein; 444 AA.
AC BGP82482;
DT 19-SEP-2019 (first entry)
DE Anti-CD47 antibody VH variant/IgG4 (IgG4PE) fusion protein, SEQ 401.
FH Key Location/Qualifiers
FT Region 26..35
FT /note= "CDR1 region"
FT Region 50..66 /note= "CDR2 region"
FT Region 99..106/note= "CDR3 region"
FT Misc-difference 225/note= "Wild type Ser substituted by Pro"
FT Misc-difference 232 /note= "Wild type Leu substituted by Glu"
CC PN WO2019144895-A1.
CC PD 01-AUG-2019.
CC PF 24-JAN-2019; 2019WO-CN072929.
PR 24-JAN-2018; 2018WO-CN074055.
CC PA (NANJ-) NANJING LEGEND BIOTECH CO LTD.
CC PI Zhao T, Zhang H, Yang S, Zhang Y, Chou C, Wu S;
DR WPI; 2019-675597/61.
DR N-PSDB; BGP82500, BGP82501, BGP82502.
CC PT Anti-CD47 antibody binds human CD47, inhibits, interferes with CD47 expression, activity and/or signaling, and does not cause significant agglutination of cells, comprises one antibody-antigen binding site.
CC PS Claim 31; SEQ ID NO 401; 118pp; English.
SQ Sequence 444 AA;
Query Match 100.0%; Score 2366; Length 444;
Best Local Similarity 100.0%;
Matches 444; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLVQSGAEVKKPGSSVKVSCKASGYSFTHHWIHWVRQAPGQGLEWMGMIDASDSETRL 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EVQLVQSGAEVKKPGSSVKVSCKASGYSFTHHWIHWVRQAPGQGLEWMGMIDASDSETRL 60
Qy 61 SQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARLGRYYFDYWGQGTTVTVSSAST 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 SQKFKDRVTITADKSTSTAYMELSSLRSEDTAVYYCARLGRYYFDYWGQGTTVTVSSAST 120
Qy 121 KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 KGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLY 180
Qy 181 SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 SLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFEGGPSVFLF 240
Qy 241 PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 PPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVV 300
Qy 301 SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 SVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQV 360
Qy 361 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 SLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVF 420
Qy 421 SCSVMHEALHNHYTQKSLSLSLGK 444
||||||||||||||||||||||||
Db 421 SCSVMHEALHNHYTQKSLSLSLGK 444
WO 2019/144895, Zhao SEQ ID NO. 402 aligned to Instant SEQ ID NO. 6
RESULT 1
BGP82483
(NOTE: this sequence has 5 duplicates in the database searched.
See complete list at the end of this report)
ID BGP82483 standard; protein; 214 AA.
AC BGP82483;
DT 19-SEP-2019 (first entry)
DE Anti-CD47 antibody VL variant/IgK CL domain fusion protein, SEQ 402.
CD47; Cluster of Differentiation 47; IAP protein; antibody therapy; cancer; chimeric protein; cytostatic; fusion protein; immunoglobulin; immunoglobulin kappa; integrin associated protein; neoplasm; prophylactic to disease; therapeutic.
OS Homo sapiens.
OS Mus sp.
OS Chimeric.
OS Synthetic.
CC PN WO2019144895-A1.
CC PD 01-AUG-2019.
CC PF 24-JAN-2019; 2019WO-CN072929.
PR 24-JAN-2018; 2018WO-CN074055.
CC PA (NANJ-) NANJING LEGEND BIOTECH CO LTD.
CC PI Zhao T, Zhang H, Yang S, Zhang Y, Chou C, Wu S;
DR WPI; 2019-675597/61.
DR N-PSDB; BGP82495, BGP82497, BGP82499.
Anti-CD47 antibody binds human CD47, inhibits, interferes with CD47 expression, activity and/or signaling, and does not cause significant agglutination of cells, comprises one antibody-antigen binding site.
Claim 31; SEQ ID NO 402; 118pp; English.
SQ Sequence 214 AA;
Query Match 100.0%; Score 1115; Length 214;
Best Local Similarity 100.0%;
Matches 214; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EIVLTQSPATLSLSPGERATLSCRASENVGTYISWYQQKPGQAPRLLIYGASNRYTGIPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EIVLTQSPATLSLSPGERATLSCRASENVGTYISWYQQKPGQAPRLLIYGASNRYTGIPA 60
Qy 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCGESYGHLYTFGGGTKVEIKRTVAAPSVFIFPP120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 RFSGSGSGTDFTLTISSLEPEDFAVYYCGESYGHLYTFGGGTKVEIKRTVAAPSVFIFPP120
Qy 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 SDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLT 180
Qy 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
||||||||||||||||||||||||||||||||||
Db 181 LSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC 214
Response to Arguments
Applicant’s arguments dated 5/10/2026 have been fully considered but are not persuasive.
First, Applicant states that the secondary references do not specifically direct a skilled artisan toward the claimed CD47/CTLA-4 bispecific combination. Applicant points out that the ¶[119] of Qiu does not teach the limitation discussed by the Examiner. The Examiner thanks Applicant for noting the inadvertent error and notes that the citation was intended to be to both paragraphs [0119-0120], which teaches the use of the CD47 antibody in a bispecific broadly, and then specifically recites targets including CTLA-4.
Applicant argues that “a single undifferentiated mention of CTLA-4 among more than one hundred potential targets in a general definitional passage does not specifically direct a skilled artisan to select CTLA-4 over any other listed target” (Remarks 5/10/2026 p. 7). Applicant applies a similar argument to Wang, arguing that “paragraph [0076], cited as teaching a CD47/CTLA-4 bispecific, is a definitional section enumerating potential second epitopes—including PD-1, PD-L1, LAG-3, TIM-3, CTLA-4, EGFR, HER2, and many others. This is not persuasive because this interpretation is against Qiu and Wang individually rather than the combination of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In particular, Zhang, Wang, Qiu, and Schwartz teach a bispecific antibody comprising an anti-CD47 portion and the CTLA-4 sdAb of Zhang because an artisan seeking to make a bispecific based on the teaching of “any antigen” of Zhang would look for a mechanistic reason that would motivate a particular antigen; this is taught by Qiu, Wang, and Schwartz in combination because both Qiu and Wang teach that CD47 is one potential combination with CTLA-4 among other checkpoint molecules, in the context of a bispecific antibody, and Schwartz teaches that there is a synergistic effect with inhibition of CD47 and CTLA-4 inhibition combined. A person of ordinary skill in the art (POSA) would understand from both Qiu and Wang that CTLA-4 is one target antigen contemplated by the art for particular use in a bispecific with an anti-CD47 targeting domain; Schwartz particularly motivates the CD47/CTLA-4 bispecific combination suggested by Qiu and Wang because it teaches a mechanistic reason why a POSA would believe the combined CD47/CTLA-4 antibody would be more effective treatment for cancer.
Next, Applicant argues that Schwartz does not motivate construction of a fused bispecific antibody. Applicant Argues “The survival benefit is therefore attributable to the addition of the CD47 morpholino to a regimen that already included irradiation and CTLA-4 blockade, under highly specific experimental conditions in a syngeneic mouse model. This is a substantially narrower finding than "combined CD47 and CTLA-4 blockade is synergistic," and a skilled artisan would not have extrapolated from this specific irradiation-dependent, mouse-model result to a broadly applicable rationale for constructing a CD47/CTLA-4 bispecific antibody for use in human patients”. The Examiner disagrees. First, the conclusion of Schwartz explicitly states “Results herein suggest IR combined CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response” (“Conclusions” section) and the introduction specifically notes that the authors are exploring and teaches generically “Trials suggest that combinations of immune checkpoint inhibitors are more efficacious than single agents, but tumors remain resistant”. A POSA, therefore, would understand that the mouse model was one experiment to model a potential combinatorial therapy. Additionally, MPEP §2144.I states that “The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000)”. In this case, although Schwartz does not explicitly motivate a combination with a CTLA-4/CD-47 bispecific format, a person of ordinary skill in the art would understand that the scientific principle of improved survival in cancer in cancer by combining IR, anti-CTLA-4 checkpoint inhibition, and CD47 blockade could be met by treating with CTLA-4 checkpoint inhibitors and CD47 blockade in a variety of formats; Qiu and Wang teach that one of those formats is a CTLA-4/CD47 bispecific antibody. Thus, as described in the 103 rejection above, a POSA looking to design an anti-CTLA-4 bispecific antibody as taught by Zhang would be motivated to choose anti-CD47 for the second binding domain.
Applicant argues that the modalities for CD47 and CTLA-4 blockade used by Schwartz are mechanistically incompatible with the architecture of the claimed bispecific (Remarks 5/10/2026 p. 8). In response to applicant's argument that a skilled artisan reading Schwartz would not predictably conclude that a surface-binding bispecific antibody would replicate the intracellular mechanism of a morpholino or that the spatial constraints required for simultaneous dual surface engagement by a fused molecule would be satisfied, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Thus, although Schwartz teaches a morpholino, Schwartz explicitly states that the purpose of the morpholino is to blockade CD47. Both Wang and Qiu teach bispecific anti-CD-47 blocking antibodies in combination with checkpoint inhibitors such as anti-CTLA-4; thus, a POSA viewing the prior art in context would understand that the morpholino blockade of Schwartz is intended to serve the same mechanistic purpose of blocking CD47 as the bispecific antibodies of Wang and Qiu, and would have a reasonable expectation of success that a bispecific anti-CTLA-4/CD47 antibody would successfully perform both the CTLA-4 checkpoint inhibitory function and the CD47 blockade function taught to be useful for the treatment of cancer by Schwartz. The examiner also notes that there is no reason a POSA could not use the instantly claimed bispecific in further combination with IR treatment as taught by Schwartz, and there is not requirement in the claims that prevents combining the instantly claimed bispecific with additional treatment or using it in a particular context.
Next, Applicant argues that Schwartz teaches away from the claimed combination because Schwartz teaches that all groups treated with CD47 exhibited focal hemorrhage, which was more extensive when combined with CTLA-4 (Remarks 5/10/2026 p. 9). Regarding teaching away, MPEP §2145 teaches that “a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed”. Although Schwartz teaches that focal hemorrhage is a side effect of anti-CD47 treatment that was more extensive when combined with CTLA-4, Schwartz concludes that despite that that combining IR with CTLA4/CD47 checkpoint blockade provides a survival benefit by activating a beneficial adaptive immune response. This would suggest to a POSA that the focal adhesions are a side effect that is insufficiently concerning in the context of treatment of cancer to prevent pursuit of a combinatorial therapy; in cancer therapy, it is common to have a tolerance for adverse side effects because of the overall effect of mortality due to lack of treatments for the cancer. Thus, a POSA would not have been taught away from the instant invention by Schwartz and would have been motivated to combine Zhang, Wang, Qiu, Schwartz, and Zhao as described in the 103 rejection above.
Next, Applicant Argues that the combination does not support a reasonable expectation of success because “The relevant question is not whether bispecific construction was feasible in the abstract, but whether the prior art specifically predicted that these two CDR sets, derived from unrelated antibodies never previously combined, would retain dual functional binding activity when fused in a shared scaffold—and whether that success could be predicted across the range of fusion geometries encompassed by the claims” (Remarks 5/10/2026 p. 10-11). MPEP §2143.02 states that “The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016)”; that “reasonable expectation of success can be implicitly shown via the prior art teachings or as part of the obviousness analysis”; and that “the expectation of success need only be reasonable, not absolute”. Thus, a “success” in binding is whether a POSA would believe it was more likely than not that combining two antibody CDR sets, both taught as generically usable in a bispecific format, would have a reasonable expectation of making a bispecific antibody that retained a reasonable amount of the binding function of each individual antibody. First, the Examiner notes that regarding claim 1, this question relates to whether a POSA would have a reasonable expectation of combining the CDRs of the two unrelated antibodies in any bispecific format whatsoever with changes in the VH and VL domain, linkers, and other elements of the structure allowed. As taught implicitly by Zhang, Qiu, Wang, and Zhao, there was a general expectation by a POSA that antibodies could be combined together in bispecific formats and retain their binding properties substantially enough to make functional bispecific antibodies. Given two sets of CDRs each known to bind to particular antigens, a suggestion by the inventors that each set of CDRs would work in a bispecific format, a suggestion by one of the inventors that to use domains targeting the second antigen in particular, and work by other inventors particularly motivating choosing the anti-CTLA-4/anti-CD47 combination as a mechanistically favorable treatment, as described in the 103 above, an artisan would have a reasonable expectation of success of arriving at many suitable bispecific antibodies comprising the art-known domains. Applicant also points to claim 12 as requiring particular bispecific geometries. The Examiner notes that Applicant has claimed three particular sdAb anti-CTLA-4 antibody fusion structures in the alternate, and the claim does not require one particular structure over the others. Zhang teaches the particular anti-CTLA-4 VHH, and teaches that the anti-CTLA-4 VHH is useful in various bispecific formats including wherein the N-terminus of each sdAb is fused to the C-terminus of one light chain via an optional peptide linker. A second depiction shows the C-terminus of each sdAb is fused to the N-terminus of heavy chain or light chain of the full-length antibody via an optional linker (Figure 40-49) [0018-0020][0242-0247], as described in the 103 rejection above. Applicant argues that “Applicant's Exhibit 1 (Madsen et al., Front. Bioeng. Biotechnol. 2024) included in the previous response addresses this geometry-dependence with specific empirical data […]This is a targeted finding directly relevant to the claimed configurations: sdAb fusion to the light chain - one of the three configurations recited in claim 12 - is specifically identified in Madsen as the geometry more susceptible to binding interference” (Remarks p. 10). Madsen et. al. teaches “BsAbs are more than just the sum of their parts and selection of an optimal molecular architecture, is an important design consideration to obtain the desired functionality. This means that bsAbs that are constructed from the same molecular building blocks (and thus sharing the same total amino acid content) only differing in molecular geometry can exhibit varying activity (Dickopf et al., 2020; Madsen et al., 2023). The dual targeting is often complex because the bsAb configuration must account for both internal and external restraints to obtain the desired therapeutic functionality. Internal restraints are imposed by the molecular geometry in itself such as steric hindrance between the binding domains (Do et al., 2020; Madsen et al., 2023). One study examining a comprehensive set of symmetric sdAb-IgG bsAbs including mirroring the specificities found that the binding affinity of the antigen-binding domains was affected by inter-domain steric hindrance arising from the molecular geometry and that this effect was more pronounced when the sdAb was linked to the LC as compared to the HC (Madsen et al., 2023). Such internal restraints might be alleviated through engineering of the configuration, e.g., by extending linkers to increase the intramolecular flexibility and distance between target binding (Wu et al., 2007)”. As previously described by the Examiner, the study Madsen is citing does not match the scope of the instant claims; the 2023 Madsen study cited by Madsen 2024 is a comprehensive study using particular anti-PD-L1 and anti-HER2 antigen binding domains in a variety of formats relevant to the instant antibody + sdAb format (Madsen, Andreas V., et al. "Generation of robust bispecific antibodies through fusion of single-domain antibodies on IgG scaffolds: a comprehensive comparison of formats." MAbs. Vol. 15. No. 1. Taylor & Francis, 2023; See e.g. Fig. 1). Of the anti-PD-L1/anti-HER2 antibodies in the different formats tested, Madsen et. al. teaches that “The results show that all investigated bsAbs can bind each target individually and both targets at the same time (Figure 3a+)” (p. 5, right column). Thus, even if, en arguendo, the steric hinderance of Madsen et. al. was equivalent in scope to the instantly claimed anti-CTLA-4/CD47 antibody, the study teaches that despite steric hinderance concerns, there was more than a reasonable expectation of success (100% chance in this particular study) that combining sdAb onto a full length IgG would yield a bispecific antibody that bound to both targets. Even if some of the formats work better than others, and thus require design considerations as taught by Madsen, it was entirely reasonable inference as implicitly taught by Zhang and Zhao that these unrelated sets of CDRs could be combined in the formats taught by Zhang as described in the 103 rejection above. The Examiner would further like to note that, because claim 12 recites the geometries in the alternate, there only need be a reasonable expectation to arrive at one of the geometries taught by the claims; because Zhang et. al. also teaches linking to the heavy chain, which, en arguendo, would be expected to have less steric hinderance described by Madsen, there is a reasonable expectation that a POSA could arrive at one of those three formats with a functioning bispecific antibody that binding to both CTLA-4 and CD47.
Regarding Applicant’s statement that the Examiner’s logic “that Zhang's bispecific success with one second antigen predicts success with any characterized antibody's CDR sequences in the same format - would, if applied consistently, render any sequence-defined bispecific antibody unpatentable over a platform reference plus a monospecific antibody reference. No bispecific antibody patent would ever survive such a standard” (Remarks p. 11), the Examiner makes no statement as to the patentability of other bispecific or monospecific antibodies under examination in other cases. As described in the 103 rejection above, Zhang, Wang, Qiu, and Schwartz teach a bispecific antibody comprising an anti-CD47 portion and the CTLA-4 sdAb of Zhang because an artisan seeking to make a bispecific based on the teaching of “any antigen” of Zhang would look for a mechanistic reason that would motivate a particular antigen; this is taught by Qiu, Wang, and Schwartz in combination because both Qiu and Wang teach that CD47 is one potential combination with CTLA-4 among other checkpoint molecules, and Schwartz teaches that there is a synergistic effect with inhibition of CD47 and CTLA-4 inhibition combined. Finally, Zhao teaches the particular sequences of an anti-CD47 antibody useful for the same purpose of CD47 blockade for cancer therapy. Thus, as described in the 103 rejection, the combination as taught by Zhao, Qiu, Wang, Schwartz, and Zhao is obvious to a person of ordinary skill in the art, as of the effective filing date, with a reasonable expectation of success. The Examiner suggests that, if Applicant indeed discovered steric hinderance in their particular antibody development with these CDRs or if the claimed combination of CDRs demonstrates properties that would be unexpected over the prior art (e.g. more stable, improved phagocytosis or CTLA-4 blockade, improved treatment of cancer better than expected by the generic combination), Applicant should make those data or facts of record so they can be included in the consideration of patentability.
Lastly, the Applicant argues that the selection of the claimed CDR sequences in driven by hindsight rather than prior art direction because there is no teaching in the prior art that would have directed a skilled artisan to select the Zhao anti-CD47 CDR sequences specifically over many other characterized anti-CD47 antibodies in the art. Applicant argues that this does not satisfy KSR’s requirement of a finite number of identified, predictable solutions (Remarks p. 12).
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As described in the 103 rejection above, the Examiner described what one with ordinary skill in the art would have done in designing a bispecific antibody. Applicant argues that “KSR’s ‘obvious to try” rationale requires not merely a finite number of alternatives but a finite number of “identified, predictable solutions”. As described related to predictability above, the genus of described anti-CD47 antibodies is a finite, identified, and predictable genus. First, although there are many anti-CD47 antibodies in the art, this number is not infinite as suggested by the applicant. An artisan would be motivated to choose art-defined, described anti-CD47 binding domains to benefit from the known anti-CD47 binding as described. These antibodies are “identified” by the disclosure by their inventors as anti-CD47 antibodies for blockade of CD47 useful for the treatment of cancer or increased immune response. MPEP §2144.06 states that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted)”. Thus, it would have been obvious to combine a disclosed anti-CD47 monoclonal antibody useful in bispecific format for the treatment of cancer with a disclosed anti-CTLA-4 sdAb in particular bispecific formats also useful for the treatment of cancer together in the formats disclosed. The references Qiu, Wang, and Schwartz provide additional context for the motivation to combine and strengthen the motivation to 1) to use bispecific antibody in particular and 2) to combine CD47 above the other generic antigen targets recited as described. As described in the 103 above, Zhang et. al. teaches known methods of bispecific antibody construction for the particular CTLA4 sdAb; (2) Wang teaches a bispecific antibody binding one epitope on CD47 and the second epitope on CTLA-4, for the treatment of cancer including melanoma; (3) Qiu teaches a bispecific antibody binding to both CD47 and immune checkpoints like CTLA-4 for cancer treatment including melanoma; (4) Schwartz demonstrates the combination CD47/CTLA-4 blockade successfully treats melanoma, and significantly increases survival when combined with irradiation, and (5) Zhao suggests utilizing their CD47 antibody for the treatment of CD47+ cancers including melanoma and suggests making bispecific antibodies with their CD47 antibody that bind to an additional antigen, and teach methods of making bispecific antibodies are known in the art. Thus, Wang, Qiu, and Schwartz teach a reasonable expectation that a generic anti-PD-1 anti-CTLA4 bispecific antibody would work by teaching the scientific mechanism and motivating that particular antigen target combination; Zhang et. al. gives a reasonable expectation that the sdAb would retain anti-CTLA4 binding and antagonist function in particular bispecific formats recited by the instant claims; and Zhao teaches that their anti-CD47 binding domain make a successful cancer treatment and suggests making bispecific antibodies.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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