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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 8 January 2026 has been entered.
Claim Status
Claims 1, 4-5, 7-12, and 15-23 are pending and under examination in the instant office action.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement- New
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating , does not reasonably provide enablement for a method of treating any disease related to abnormal expression of CD47 and/or CTLA4. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the method of the invention commensurate in scope with these claims.
In order to determine compliance with the enablement requirement of 35 U.S.C. 112(a), the Federal Circuit developed a framework of factors in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), referred to as the Wands factors to assess whether any necessary experimentation required by the specification is "reasonable" or is "undue." Consistent with Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Wands factors continue to provide a framework for assessing enablement in a utility application or patent, regardless of technology area. In In re Wands, 8 USPQ2d 1400 (Fed. Cir., 1988) eight factors included for determining enablement:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The following is an analysis of these factors in relationship to this application.
Scope of the claims and nature of the invention
Claim 20 is directed to a method of treating a disease “related to abnormal expression of CD47 and/or CTLA-4” comprising administering a CD47/CTLA-4 bispecific comprising 3 particular anti-CTLA-4 CDRs (VHH domain) and 6 particular anti-CD47 CDRs (VH/VL antibody domain) as in claim 1. The specification does not define “related to abnormal expression” and does not provide any examples of the degree or type of abnormal expression that could be used to determine the scope of the abnormal expression. The specification and the claims give the examples of cancers that are diseases related to abnormal CD47 and/or CTLA-4 expression (p. 11lines 13-22).
State of the Relevant Art; level of ordinary skill; and level of predictability in the art
Methods of treating cancer comprising administering monotherapies with antagonists of CD47/SIRPɑ and antagonists of CTLA-4 binding to CD80 are known in the art.
Methods of treating with anti-CTLA4 and anti-CD47 combinatorial therapy are also known in the art. For example, 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 (Of record, cited on IDS dated 1/3/2022) teaches a method of treating comprising administering an anti-CTLA-4 blocking antibody and an anti-CD47 translation-blocking morpholino in a mouse model of melanoma. WO2019027903 to Wang et. al. (Of record, IDS dated 9/1/2023) teaches a bispecific antibody comprising an anti-CD47 binding domain and a second epitope on the checkpoint molecules PD-1, PD-L1, TIM-3, CTLA-4 or on other tumor associated immune suppressors or surface antigens [0076].
Regarding diseases associated with abnormal CD47 expression, Gheibihayat, Seyed Mohammad, et al. "CD47 in the brain and neurodegeneration: an update on the role in neuroinflammatory pathways." Molecules 26.13 (2021): 3943 teaches that increased CD47 expression has been reported in a variety of cancers as well as Gaucher disease, multiple sclerosis, and stroke (Abstract). Gheibihayat et. al. teaches that CD47 and SIRPɑ have been correlated with the development of neurodegenerative pathologies and processes such as neuroinflammation, multiple sclerosis, Alzheimer’s, Stroke, and spinal cord injuries among others (p. 5 ¶2). Gheibihayat et. al. teaches that CD47 targeting has different therapeutic strategies in different neurodegenerative diseases and that in multiple sclerosis “modulating CD47 could be harmful and beneficial depending on the context” (Table 1). Oldenborg, Per-Arne. "Role of CD47 in erythroid cells and in autoimmunity." Leukemia & lymphoma 45.7 (2004): 1319-1327 teaches that in a model of non-obese diabetic mice, worsening of autoimmune hemolytic anemia was associated with CD47 deficiency (p. 1324 left column). Cham, Lamin B., et al. "CD47 as a potential target to therapy for infectious diseases." Antibodies 9.3 (2020): 44 teaches that blockade of CD47 increases both innate and adaptive immunity to promote an anti-viral effect. Kuriyama, Takuro, et al. "Engulfment of hematopoietic stem cells caused by down-regulation of CD47 is critical in the pathogenesis of hemophagocytic lymphohistiocytosis." Blood, The Journal of the American Society of Hematology 120.19 (2012): 4058-4067 teaches that downregulation of CD47 on hematopoietic stem cells is associated with hemophagocytic lymphohistiocytosis (HLH) (Abstract). Lastly, Hayat, Seyed Mohammad Gheibi, et al. "CD47: role in the immune system and application to cancer therapy." Cellular Oncology 43.1 (2020): 19-30 reviews the role of CD47 in the immune system and teaches that overexpression of CD47 is related to evasion of phagocytosis in tumors (p. 19 right column).
Regarding diseases associated with abnormal CTLA4 expression, these are known in the art. For example, Mao, Wei, et al. "Effect of CTLA-4 Inhibition on Inflammation and Apoptosis After Spinal Cord Injury." Neurochemical Research 49.5 (2024): 1359-1372 teaches that in a spinal cord injury of rats, the expression of CTLA-4 was protective against neurological impairment and severe neuroinflammation and that inhibition of CTLA4 with inhibitory antibodies was associated with increased impairment (Abstract). Santos, Rodrigo Ribeiro, et al. "Reduced frequency of T lymphocytes expressing CTLA-4 in frontotemporal dementia compared to Alzheimer's disease." Progress in Neuro-Psychopharmacology and Biological Psychiatry 48 (2014): 1-5 teaches that CTLA4 is downregulated in CD4+ T cells in frontotemporal dementia as compared with controls and Alzheimer’s disease (Fig. 2B). Verma, Nisha, et al. "Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations." Clinical & Experimental Immunology 190.1 (2017): 1-7 teaches that loss of function mutations are seen in common variable immunodeficiency disorders through genetic analysis of families (p. 3 left column- right column, Table 1). Kaufmann, Daniel E., et al. "Upregulation of CTLA-4 by HIV-specific CD4+ T cells correlates with disease progression and defines a reversible immune dysfunction." Nature immunology 8.11 (2007): 1246-1254 teaches that upregulation of CTLA-4 is associated with disease progression and immune suppression in HIV (Abstract, Fig. 1). Buchbinder, Elizabeth I., and Anupam Desai. "CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition." American journal of clinical oncology 39.1 (2016): 98-106 teaches that CTLA-4 and PD-1 pathways have distinct immune effects and that CTLA-4 is thought to regulate T-cell proliferation early in an immune response, primarily in lymph nodes. Buchbinder et. al. teaches “The exact mechanism by which anti-CTLA-4 antibodies induce an antitumor response is unclear, although research to date suggests that CTLA-4 blockade affects the immune priming phase by supporting the activation and proliferation of a higher number of effector T cells, regardless of TCR specificity, and by reducing Treg-mediated suppression of T-cell responses (Fig. 4).2 […] findings suggest that effective CTLA-4 blockade may depend on the ability to retain preexisting high-avidity T cells with relevance to the antitumor response” (p. 101- p. 103, left column).
Thus, because expression of CTLA4 and CD47 can be abnormally up or downregulated across many etiologically distinct diseases and the relationships between the CD47 and CTLA4 pathways are not predictable across each of these diseases, it would not have been predictable which diseases associated with expression of CTLA4 and/or CD47 may be treated with the instant antagonist CTLA4/CD47 antibody without additional direction from the inventor.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quantity of experimentation needed to make or use the invention based on the content of the disclosure
The instant specification discloses 6 species of anti-CTLA/anti-CD47 bispecific binding proteins comprising the instantly claimed CDRs (Table 3 p. 18). Of these, 3 appears to have reduced binding to CTLA4 and 3 appear to have similar or increase binding to CTLA4 (Fig. 1), but all bind to CTLA4. The specification teaches that CTLA4-G15-HC blocks (one of the six antibodies) CTLA4 binding to CD28 in an in vitro assay similar to an IgG4 fusion protein of the sdAb alone but will lower than an anti-CTLA-4 monoclonal antibody control (Fig. 3, see specification p. 31 lines 23-29). The specification teaches that all 6 bispecific antibodies bind to CD47 (Fig. 2) and that CTLA4-G15-HC induces cell phagocytosis but at a lower rate compared to the anti-CD47 monoclonal antibody (Fig. 4). There is no guidance about the phagocytosis assay or whether this is phagocytic activity against cancer cells, or if not what type of disease. There are no methods of administering the bispecific antibody disclosed whatsoever. There are no cytotoxicity assays performed with the bispecific antibodies in vitro or in vivo. There is no guidance or disclosure on what diseases apart from cancer are considered to be associated with abnormal expression of CTLA4 or CD47.
Conclusion
The Applicant does not have enablement for the method of treating any generic disease or disorder associated with the expression of CTLA4 or CD47. It would take undue experimentation for a person of ordinary skill in the art to determine which diseases or disorders associated with CTLA4 or CD47 expression can be treated. Dependent claims 21 and 22 resolved the scope of enablement issues as described for claim 20 and are therefore excluded from the rejection.
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, and 15-23 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/068695, Zhang et al, published April 19, 2018, in view of WO 2019/027903, Wang et al, WO 2018/137705, Qiu et al, 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, and WO 2019/144895, Zhao et al (filed January 2019).
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 11/28/2025 have been fully considered but are not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations 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 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).
Applicant argues that “even if the cited references could be read to suggest that CD47 and CTLA-4 were each of interest in immunotherapy, the universe of possible bispecific combinations in vast. Qiu and Wang alone list dozens of alternative pairings with CD47, ranging from PD-1, PD-L1, and LAG-3 to non-immune targets such as toxins, viral proteins, and detection molecules” (Remarks 9/29/2025 p. 8). This is not persuasive because, as described in the Office Action dated 5/28/2025, the combination of references including Qiu and Wang motivates a specific CD47/CTLA-4 bispecific. 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, and Schwartz teaches that there is a synergistic effect with inhibition of CD47 and CTLA-4 inhibition combined. Thus, an artisan would have motivation to choose CD47 from the list of targets in Qiu and Wang because Schwartz provides a reasonable expectation that choosing an anti-CD47 domain as the second antigen target would allow an artisan to design a better cancer therapy with the synergistic effect of CD47 and CTLA-4 inhibition taught by Schwartz.
Applicant argues that “claim 1 does not merely call for the general idea of combining CD47 and CTLA-4 binding activities. It recites a bispecific antibody defined by specific CDR sequences for both the CD47-binding and CTLA-4-binding domains” and submits the exhibit Madsen et. al. to show that bispecific antibodies “are often hampered by practical issues arising from the increased structural complexity” (Remarks 9/29/2025 p. 9). This is not persuasive. Applicant’s evidence is that bispecific antibodies in general could face steric hinderance problems; there is no evidence that the instantly claimed bispecific antibody suggested by the prior art would have steric hinderance problems. Applicant argues that this is not the correct framing of the issue and that the proper framing is whether one of skill could have reasonably expected that these two specific domains with specific CDR sequences could be successfully combined into a single functional bispecific without undue experimentation of loss of binding function (Remarks 11/28/2025 p. 10). This is unpersuasive because the scope of the Exhibit is not sufficient to suggest there would not be a reasonable expectation of success because although Madsen et. al. suggests that bispecific antibodies are “often” hampered by these design constraints in bispecific antibodies, both Zhang et. al. and Zhao et. al. teach the particular antibody domains with particular CDR sequences can be made into bispecific antibodies and described how a person of skill in the art would make a bispecific with those domains. Thus, a generic suggestion that building a bispecific antibody is “often” unpredictable is not sufficient to overcome the reasonable expectation of an artisan in view of the particular teachings of the prior art of Zhang, Wang, Qiu, Schwartz, and Zhao that these CDR sequences could and would make an improved anti-PD-1/anti-CD47 bispecific for the treatment of cancer. Further, Madsen teaches that “BsAbs are more than just a sum of their parts and selection of an optimal molecular architecture is an important design consideration to obtain the desired functionality”. Applicant’s claims are directed towards a bispecific antibody wherein the antibody is a sum of two sets of CDRs. Is applicant suggesting that they are not enabled for the scope of claim 1 and that it would take undue experimentation given two sets of CDRs to determine a bispecific structure that maintains any of the functionality of the original antibodies? This is not persuasive. 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-PD1/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.
Additionally, 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. Additionally, the scope of the instant claims is not commensurate in scope with what Madsen et. al. describes as unpredictable. Applicant has shown that one single species of bispecific antibody comprising a complete VH and VL region, with specific linkers, and the sdAb in a particular position is capable of still binding to CD47 and CTLA-4, but claims the entire genus of bispecific antibodies only comprising the CDRs of the instant bispecific. An artisan would not be able to read the instant specification and determine which of the bispecific antibodies with any framework regions, any linkers, and with the binding domains in any configuration would perform the binding functions as claimed. The Examiner recommends that additional evidence of non-obviousness commensurate in scope with the instant invention such as 1) failure of other bispecific antibodies comprising the instant CDRs to bind or be produced and/or 2) evidence of synergistic effects, anti-tumor efficacy, or decreased side effects of bispecific antibodies comprising the instant CDRs as suggested but not shown by the instant specification. The instant specification merely shows that a bi-specific antibody with the instantly claimed CDRs can 1) bind to CTLA-4 and CD47 and 2) perform inhibitory anti-CTLA-4 and anti-CD47 function. Although there is some unpredictability in bispecific antibodies, there is sufficient predictability that there is a reasonable expectation that the bispecific antibody with art-known CDRs can be made and would still bind to both targets. Currently, however, the CTLA4-G15-HC has only evidence that it has reduced inhibition of CTLA-4 and CD47, with speculation that this may help reduce side effects, but an artisan would not be able to determine whether this degree of loss of inhibition would still maintain anti-tumor efficacy while reducing side effects, and therefore there is a reasonable expectation of success at arriving at the instantly claimed genus of bispecific antibodies of any configuration, with any framework region, and art-known anti-CTLA-4 and anti-CD47 CDRs.
Applicant argues that the fact that anti-CD47 are not infinite “does not address which specific anti-CD47 domain would be chosen, how it would pair with the claimed anti-CTLA-4 domain, whether the two domains would sterically interfere, whether the bispecific scaffold would tolerate the domains’ spatial arrangements, or whether the claimed sequences would yield a functional molecule”. MPEP §2144 teaches the requirements of prima facie obviousness. This is not persuasive because, as described in the 103 rejection above, the cited art Zhang et. al. suggests particular bispecific formats including 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] (reads on claim 12). An artisan would have a reasonable expectation that the sdAb anti-CTLA4 antibody in those formats would work because it is particularly suggested by Zhang et. al. as described in the 103 rejection above. As described in the 103 above, in addition 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. Thus, a generic suggestion that often bispecific antibodies do not work entirely as expected or may face design obstacles is insufficient to show that there was less than a reasonable expectation of success that the two art-known antigen binding domain could be combined in a particular bispecific format particularly suggested by the prior art to benefit from an improved anti-cancer therapy suggested by the prior art.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678