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 .
Status of Claims
This application was filed on 8/3/23 with claims 1-25. On 12/7/23, applicant canceled claims 21, 22, 24, and 25 and amended claims 3-20 and 23. Claims 1-20 and 23 are pending and under examination.
Specification
The specification is objected to because it refers to skipped sequences within the sequence listing. Under ST.26, amino acid sequences less than 4 amino acids long are prohibited and are “skipped” within the listing. See MPEP 2422.01(I); Annex C, Instructions Relating to the Presentation of Nucleotide and Amino Acid Sequence Listings in International Patent Applications Under the PCT at (7). Reference within the specification to a skipped sequence is therefore improper. For example, SEQ ID NO: 31 is skipped, presumably because it contains three or fewer amino acids. The same is true of SEQ ID NOs: 37 and 62. The specification must be amended to replace each reference to a skipped sequence with the amino-acid sequence itself. In this case, since neither the specification nor the sequence listing provides the sequences for SEQ ID NOs: 31, 37, and 62, applicant must take care not to introduce new matter into the disclosure.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-20 and 23 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is drawn to a therapeutic combination comprising two bispecific antibodies. It gives options for the first bispecific antibody (lines 3-24) and the second bispecific antibody (lines 25-46), but it is unclear whether both of these sets of requirements must be met. There is no “or” or “and” at line 24 after “respectively,” so the scope of the claim is unclear. See MPEP 2173.05(h) (open lists of alternatives are indefinite).
Claim 1 also refers to SEQ ID NOs: 31, 37, and 62, among others (lines 12 and 34, e.g.). The sequence listing indicates that SEQ ID NO:31 is “000” because it was skipped; see MPEP 2422.01, setting a lower bound of four nonbranched amino acids as the threshold for a sequence listing. The same is true for SEQ ID NOs: 37 and 62. The as-filed specification provides no information about the contents of SEQ ID NOs: 31, 37, and 62. Because there is no definition in the application for SEQ ID NOs: 31, 37, and 62, the claims containing those limitations are indefinite. The claims must be amended to remove any reference to the skipped SEQ ID NOs. Applicants are cautioned about adding new matter in making these amendments.
Because claims 2-20 and 23 depend from claim 1 and do not rectify the sources of indefiniteness, they must also be rejected under 35 U.S.C. 112(b).
In addition, claims 2, 6, 10, 12, 17, 20, and 23 recite “preferable” limitations. Description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. In those instances where it is not clear whether the claimed narrower range is a limitation, a rejection under 35 U.S.C. 112(b) should be made. MPEP 2173.05(d).
Claims 6, 10, and 13 refer to “the number” of the first and second protein functional regions. Claim 1 does not recite or imply a “number.” The meaning of these limitations is therefore indefinite because there is no clear antecedent basis for them. See MPEP 2173.05(e).
Furthermore, claim 19 refers to an anti-tumor chemotherapeutic drug “such as” one selected from a list. It is unclear whether the items on the list are preferences, examples, or limitations. See MPEP 2173.05(d), in particular example C.
Claim Rejections - 35 USC § 103
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.
Claims 1-8, 11-20, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Xia et al. (2021, CA 3146780; reference N on PTO-892) in view of Li et al. (US 20210340239; reference A on PTO-892).
Xia was published on 2/11/21 and qualifies as prior art under 35 U.S.C. 102(a)(1) outside the section 102(b) grace period.
Li was effectively filed 8/30/18 and names another inventor, so it is prior art under 35 U.S.C. 102(a)(2). It was published on 11/4/21, which is within one year of the filing of the claimed foreign-priority application. Foreign priority, however, has not been perfected since there is no certified English translation of CN 202211101982.4 in this record. Li is therefore currently prior art under 35 U.S.C. 102(a)(1) outside the grace period.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Xia does not teach a composition comprising the CTLA-4/PD-1 bispecific antibody and a VEGFA/PD-1 bispecific antibody. Regarding claims 7 and 8, Xia does not teach that the immunoglobulin or single-chain antibody have HCVR and LCVR of SEQ ID NOs: 45 and 47, respectively. Regarding claim 15, Xia does not teach providing two different bispecific antibodies mixed together in a combination composition. Regarding claim 16, Xia does not teach providing two different bispecific antibodies in separate packages. Regarding claim 17, Xia does not teach providing two different bispecific antibodies in the claimed ratios.
Li teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Li teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Paragraphs 28-30.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Li, SEQ ID NO: 9) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Li, SEQ ID NO: 11). Li teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 58-60 and a LCVR comprising CDRs identical to SEQ ID NOs: 61 and 63 (see Li, SEQ ID NOs: 5 and 7); this is termed bevacizumab. Xia therefore also teaches that when the immunoglobulin is bevacizumab, the single-chain antibody is 14C12H1L1. Li teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraphs 21, 76, 110, and 113.)
Regarding claims 7 and 8 (options 5 and 11), Li’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Li teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 74.)
Regarding claims 17 and 18, Li teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 72.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with Li’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claim 15, it would have been obvious to provide Xia’s and Li’s bispecific antibodies together in a single composition because Xia and Li both teach that their antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and Li’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and Li’s bispecific antibodies in the claimed ratios because both Xia and Li teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Li’s antibody (as suggested in paragraph 72) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Claims 1-20 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Xia et al. (2021, CA 3146780; reference N on PTO-892) in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
Xia was published on 2/11/21 and qualifies as prior art under 35 U.S.C. 102(a)(1) outside the section 102(b) grace period. Zhang was published on 6/3/21 and is likewise prior art outside the grace period. This Office action refers to a WIPO English translation of Zhang, provided with this Office action as reference U.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Xia does not teach a composition comprising the CTLA-4/PD-1 bispecific antibody and a VEGFA/PD-1 bispecific antibody. Regarding claims 7 and 8, Xia does not teach that the immunoglobulin or single-chain antibody have HCVR and LCVR of SEQ ID NOs: 45 and 47, respectively. Regarding claims 9 and 10, Xia does not teach a VEGFA/PD-1 bispecific antibody having HCVR and LCVR of SEQ ID NOs: 54 and 56. Regarding claim 15, Xia does not teach providing two different bispecific antibodies mixed together in a combination composition. Regarding claim 16, Xia does not teach providing two different bispecific antibodies in separate packages. Regarding claim 17, Xia does not teach providing two different bispecific antibodies in the claimed ratios.
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claim 15, it would have been obvious to provide Xia’s and Zhang’s bispecific antibodies together in a single composition because Xia and Zhang both teach that their antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and Zhang’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Comment on Reference Patents and Copending Applications
There are numerous reference patents and copending applications that name applicant and/or one or more joint inventors and claim bispecific antibodies for either PD-1/CTLA-4 or PD-1/VEGFA. As detailed above in the rejections under 35 U.S.C. 103, it would have been obvious to combine these two types of bispecific antibodies based on the prior-art teachings of at least Xia and Zhang. The following rejections account for the examined claims’ combination composition with respect to the reference patents and copending applications. They rely on substantially the same rationales as those set forth above under section 103.
Some of the below rejections are provisional, but not all provisional nonstatutory double patenting rejections are withdrawn when they are the final outstanding rejection. See MPEP 804(I)(B)(1)(a). In addition, any provisional rejection below that is based on a copending application that issues as a patent will convert to a nonprovisional rejection.
Reference Patents and Applications Claiming PD-1/CTLA-4 Bispecific Antibodies
US Patent 11,578,128
Claims 1-20 and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 4, 22, and 25 of U.S. Patent No. 11,578,128 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’128 patent claims a bispecific antibody comprising a first protein area that binds to PD-1 and comprises six CDRs with SEQ ID NOs: 29-34; the ’128 patent’s SEQ ID NOs: 29-32 and 34 are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a second protein area that binds to CTLA-4. The second protein area comprises six CDRs that may be SEQ ID NOs: 35-40; the ’128 patent’s SEQ ID NOs: 35-38 and 40 are identical to examined SEQ ID NOs: 33-36 and 38, respectively. (Claims 1 and 22.) The ’128 patent claims that the first and second protein areas may each be an immunoglobulin, for example IgG, or single-chain antibody. (Claims 3 and 4.) The ’128 patent claims that the bispecific antibody has a HCVR and LCVR of SEQ ID NOs: 20 and 22, respectively, which are identical to examined SEQ ID NOs: 18 and 20, respectively. (Claim 25.)
The ’128 patent does not expressly claim that the PD-1-binding functional area is an immunoglobulin and the CTLA-4-binding functional area is a single-chain antibody or vice versa. The ’128 patent also does not claim a composition comprising two bispecific antibodies. Regarding claim 6, the ’128 patent does not claim that the bispecific antibodies contain SEQ ID NOs: 40, 24, 43, and 44. Regarding examined claims 9 and 10, the ’128 patent does not claim SEQ ID NOs: 54 and 56. Regarding claims 11 and 12, the ’128 patent does not claim that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n. Regarding claim 14, the cited claims of the ’128 claim do not recite that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. Regarding claim 16, the ’128 patent does not claim providing the bispecific antibody with a second agent in separate packages. Regarding claims 17 and 18, the ’128 patent does not claim any particular dosage for the antibody. Regarding claim 19, the ’128 patent does not claim providing the bispecific antibody with an anti-tumor chemotherapeutic drug. Regarding claim 20, the ’128 patent does not claim providing the bispecific antibody with an adjuvant. Regarding claim 23, the ’128 patent does not claim treating the listed cancers with the composition.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.)
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine the ’128 patent’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
It would have been further obvious to generate a bispecific antibody with the PD-1-binding functional area as an immunoglobulin and the CTLA-4-binding functional area as a single-chain antibody because the ’128 patent claims that these are options for the configuration. (Claims 1 and 3.) It would have also been obvious to generate a bispecific antibody with the CTLA-4-binding functional area as an immunoglobulin and the PD-1-binding functional area as a single-chain antibody for the same reason.
Regarding claim 6, it would have been obvious to substitute Xia’s bispecific antibody (which contains sequences identical to the examined SEQ ID NOs) for that of the ’128 patent because both are taught to bind CTLA-4 and PD-1. See MPEP 2144.06(II) (substitution of art-recognized equivalents is prima facie obvious).
Regarding claim 15, it would have been obvious to provide the ’128 patent’s and Zhang’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide the ’128 patent’s and Zhang’s bispecific antibodies in separate packages because Xia teaches providing two different agents, including a bispecific antibody, in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide the ’128 patent’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that cancer-therapeutic bispecific antibodies with the same binding targets as those claimed can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
US Patent 12,479,919
Claims 1-5, 7-20, and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 12,479,919 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’919 patent claims a bispecific antibody comprising a first protein area that comprises an immunoglobulin six CDRs with SEQ ID NOs: 29-34; the ’919 patent’s SEQ ID NOs: 29-32 and 34 are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a single-chain antibody with a second protein area that comprises six CDRs that may be SEQ ID NOs: 35-40; the ’919 patent’s SEQ ID NOs: 35-38 and 40 are identical to examined SEQ ID NOs: 33-36 and 38, respectively. (Claim 1.) The ’919 patent claims that the bispecific antibody has a HCVR and LCVR of SEQ ID NOs: 20 and 22, respectively, which are identical to examined SEQ ID NOs: 18 and 20, respectively. (Claim 16.)
The ’919 patent does not claim a composition comprising two bispecific antibodies. Regarding examined claims 9 and 10, the ’919 patent does not claim SEQ ID NOs: 54 and 56. Regarding claims 11 and 12, the ’919 patent does not claim that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n. Regarding claim 14, the cited claims of the ’919 patent do not recite that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. Regarding claim 16, the ’919 patent does not claim providing the bispecific antibody with a second agent in separate packages. Regarding claims 17 and 18, the ’919 patent does not claim any particular dosage for the antibody. Regarding claim 19, the ’919 patent does not claim providing the bispecific antibody with an anti-tumor chemotherapeutic drug. Regarding claim 20, the ’919 patent does not claim providing the bispecific antibody with an adjuvant. Regarding claim 23, the ’919 patent does not teach treating the listed cancers with the composition.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine the ’919 patent’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claim 15, it would have been obvious to provide the ’919 patent’s and Zhang’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide the ’919 patent’s and Zhang’s bispecific antibodies in separate packages because Xia teaches providing two different agents, including a bispecific antibody, in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide the ’919 patent’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that cancer-therapeutic bispecific antibodies with the same binding targets as those claimed can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Copending Application 17/630,467
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 34, 37-39, 42-46, and 52-56 of copending application 17/630,467 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’467 application claims a bispecific antibody comprising a first protein functional region that is an immunoglobulin and targets PD-1. It contains CDRs of SEQ ID NOs: 27-30 and 32, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a second protein functional region that is a single-chain antibody and comprises SEQ ID NOs: 33-36 and 38, which are identical to examined SEQ ID NOs: 33-36 and 38, respectively. Regarding examined claim 2, it contains certain amino-acid mutations in the heavy chain constant region of the immunoglobulin. (Claim 1.) Regarding examined claims 3 and 4, the ’467 application’s SEQ ID NOs: 18, 20, 2, and 4 are identical to examined SEQ ID NOs: 18, 20, 2, and 4, respectively. (Claims 37 and 38.) Regarding examined claim 5, the ’467 application’s SEQ ID NOs: 40 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. (Claim 39.) Regarding examined claim 6, the ’467 application’s SEQ ID NOs: 40, 24, 43, and 44 are identical to examined SEQ ID NOs: 40, 24, 43, and 44, respectively. (Claim 46.) Regarding examined claims 11 and 12, the ’467 application claims that the two protein functional regions are connected by a linker, for example (GGGGS)n. (Claims 42 and 43.) Regarding examined claim 13, the ’467 application claims that “the number” of each of the functional regions is 1, 2, or more. (Claim 44.) Regarding examined claim 14, the ’467 application claims that the single chain antibody is linked to the C-terminus of the immunoglobulin’s heavy chain. (Claim 45.) Regarding examined claims 15, 19, and 20, the ’467 application claims a composition comprising the bispecific antibody an a second therapeutic (for example, an anti-tumor chemotherapeutic agent) along with a pharmaceutically acceptable carrier or excipient (“adjuvant”). (Claim 53.) Regarding examined claim 16, the ’467 application claims providing the bispecific antibody and an additional therapeutic in a separate package. (Claim 54.) Regarding examined claim 23, the ’467 application claims treating or preventing a tumor. (Claim 55.)
The ’467 application does not claim a composition comprising the two bispecific antibodies required in examined claim 1. Regarding examined claims 9 and 10, the ’467 application does not claim SEQ ID NOs: 54 and 56. Regarding claims 17 and 18, the ’467 application does not claim any particular dosage for the antibody. Regarding claim 23, the ’467 application does not claim treating the listed cancers with the composition.
The teachings of Xia and Zhang are relied upon as set forth above with respect to US Patent 11,578,128; that discussion is incorporated into this rejection.
In particular, Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.) Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.) Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
It would have been obvious before the effective filing date to combine the ’467 application’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claims 17 and 18, it would have been obvious to provide the ’467 application’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Regarding claim 23, it would have been obvious to treat the cancers on the list because the ’067 application claims that its antibodies are therapeutic and prophylactic for tumors and Xia teaches that in particular, PD-1/CTLA-4 bispecific antibodies treat the cancers on examined claim 23’s list. Zhang teaches the same for PD-1/VEGFA antibodies. The skilled artisan would therefore have expected success in treating those cancers with a combination of the ’067 application’s and Zhang’s antibodies.
Copending Application 18/286,755
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 16-18 of copending application 18/286,755 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’755 application claims a bispecific antibody comprising a first protein functional region that is an immunoglobulin or single-chain antibody and targets PD-1. It contains CDRs of SEQ ID NOs: 27-30 and 32, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a second protein functional region that is a single-chain antibody or immunoglobulin and comprises SEQ ID NOs: 33-36 and 38, which are identical to examined SEQ ID NOs: 33-36 and 38, respectively. (Claim 1.) Regarding examined claim 2, the ’755 application’s antibody contains certain amino-acid mutations in the heavy chain constant region of the immunoglobulin. (Claim 9.) Regarding examined claims 3 and 4, the ’755 application’s SEQ ID NOs: 18, 20, 2, and 4 are identical to examined SEQ ID NOs: 18, 20, 2, and 4, respectively. (Claims 2 and 3.) Regarding examined claim 5, the ’755 application’s SEQ ID NOs: 40 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. (Claim 4.) Regarding examined claim 6, the ’755 application’s SEQ ID NOs: 40, 24, 43, and 44 are identical to examined SEQ ID NOs: 40, 24, 43, and 44, respectively. (Claim 10.) Regarding examined claims 11 and 12, the ’755 application claims that the two protein functional regions are connected by a linker, for example (GGGGS)n. (Claims 5 and 6.) Regarding examined claim 13, the ’755 application claims that “the numbers” of each of the functional regions is 1, 2, or more. (Claim 7.) Regarding examined claim 14, the ’755 application claims that the single chain antibody is linked to the C-terminus of the immunoglobulin’s heavy chain. (Claim 8.) Regarding examined claims 15, 19, and 20, the ’755 application claims a composition comprising the bispecific antibody an a second therapeutic (for example, an anti-tumor chemotherapeutic agent) along with a pharmaceutically acceptable carrier or excipient (“adjuvant”). (Claim 11.) Regarding claims 17 and 18, the ’755 application claims providing the antibody at 0.1-10000mg, preferably 200mg or 100mg. (Claim 17.) Regarding examined claim 23, the ’755 application claims treating or preventing a tumor from the list in examined claim 23. (Claims 16 and 18.)
The ’755 application does not claim a composition comprising the two bispecific antibodies required in examined claim 1. Regarding examined claims 9 and 10, the ’755 application does not claim SEQ ID NOs: 54 and 56.
The teachings of Xia and Zhang are relied upon as set forth above with respect to US Patent 11,578,128; that discussion is incorporated into this rejection.
In particular, Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.) Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.) Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
It would have been obvious before the effective filing date to combine the ’755 application’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claims 17 and 18, it would have been obvious to provide the ’755 application’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of the ’755 application’s antibody (as suggested at page 17 of Xia) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Copending Application 18/291,128
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of copending application 18/291,128 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’128 application claims a composition comprising two antibodies. The first is an antibody to TIGIT. The second is a bispecific antibody comprising a first protein functional region that is an immunoglobulin or single-chain antibody and targets PD-1. It contains CDRs of SEQ ID NOs: 29-32 and 34, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a second protein functional region that is a single-chain antibody or immunoglobulin and comprises SEQ ID NOs: 37-40 and 42, which are identical to examined SEQ ID NOs: 33-36 and 38, respectively. (Claim 1.) Regarding examined claim 2, the ’128 application’s antibody contains certain amino-acid mutations in the heavy chain constant region of the immunoglobulin. (Claim 3.) Regarding examined claims 3 and 4, the ’128 application’s SEQ ID NOs: 43, 44, 35, and 36 are identical to examined SEQ ID NOs: 18, 20, 2, and 4, respectively. (Claim 3 at page 6/27.) Regarding examined claim 5, the ’128 application’s SEQ ID NOs: 53 and 54 are identical to examined SEQ ID NOs: 40 and 24, respectively. (Claim 3, page 22/27.) Regarding examined claim 6, the ’755 application’s SEQ ID NOs: 53, 54, 74, and 75 are identical to examined SEQ ID NOs: 40, 24, 43, and 44, respectively. (Claim 3, page 23/27.) Regarding examined claims 15, 19, and 20, the ’128 application claims a composition comprising the bispecific antibody an a second therapeutic (for example, an anti-tumor chemotherapeutic agent) along with a pharmaceutically acceptable carrier or excipient (“adjuvant”). (Claims 6 and 9-11.) Regarding examined claim 16, the ’128 application claims packaging the two antibodies in its composition separately. (Claim 5, e.g.) Regarding examined claims 17 and 18, the ’128 application claims providing the bispecific antibody at 10-1000mg, preferably 200mg, and claims providing each of the two antibodies at numerous dosages. (Claims 6 and 7.) Regarding examined claim 23, the ’755 application claims treating or preventing a tumor from the list in examined claim 23. (Claim 6.)
The ’128 application does not claim a composition comprising the two bispecific antibodies required in examined claim 1. Regarding examined claims 9 and 10, the ’128 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 11 and 12, the ’128 application does not claim that the two protein functional regions are connected by a linker, for example (GGGGS)n. Regarding examined claim 14, the ’128 application does not claim that the single chain antibody is linked to the C-terminus of the immunoglobulin’s heavy chain.
The teachings of Xia and Zhang are relied upon as set forth above with respect to US Patent 11,578,128; that discussion is incorporated into this rejection.
In particular, Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.) Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.) Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.) Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.) Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
It would have been obvious before the effective filing date to substitute the ’128 application’s TIGIT antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claims 17 and 18, it would have been obvious to provide the ’128 application’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Copending Application 18/840,378
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 9-11, 13-15, 18, 20-23, and 26 of copending application 18/840,378 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’378 application claims a composition comprising a bispecific antibody that binds CTLA-4 and PD-1. (Claim 1.) The bispecific antibody comprises a first protein functional region that is an immunoglobulin or single-chain antibody and targets PD-1. It contains CDRs of SEQ ID NOs: 27-30 and 32, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a second protein functional region that is a single-chain antibody or immunoglobulin and comprises SEQ ID NOs: 33-36 and 38, which are identical to examined SEQ ID NOs: 33-36 and 38, respectively. (Claim 9.) Regarding examined claim 2, the ’378 application’s antibody contains certain amino-acid mutations in the heavy chain constant region of the immunoglobulin. (Claims 9 and 10.) Regarding examined claims 3 and 4, the ’378 application’s SEQ ID NOs: 18, 20, 2, and 4 are identical to examined SEQ ID NOs: 18, 20, 2, and 4, respectively. (Claims 13 and 14.) Regarding examined claim 5, the ’378 application’s SEQ ID NOs: 40 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. (Claim 15.) Regarding examined claims 6-8, the ’378 application’s SEQ ID NOs: 40, 24, 43, and 44 are identical to examined SEQ ID NOs: 40, 24, 43, and 44, respectively. (Claim 14.) Regarding examined claims 11 and 12, the ’378 application claims that the two protein functional regions are connected by a linker, for example (GGGGS)n. (Claim 18.) Regarding examined claim 13, the ’378 application claims that “the numbers” of each of the functional regions is 1, 2, or more. (Claim 20.) Regarding examined claim 14, the ’378 application claims that the single chain antibody is linked to the C-terminus of the immunoglobulin’s heavy chain. (Claim 21.) Regarding examined claims 15, 19, and 20, the ’378 application claims a composition comprising the bispecific antibody and a second therapeutic (chiauranib, an anti-tumor chemotherapeutic agent) along with a pharmaceutically acceptable carrier or excipient (“adjuvant”). (Claims 1, 23.) Regarding examined claim 23, the ’378 application claims treating or preventing a tumor from the list in examined claim 23. (Claim 26.)
The ’378 application does not claim a composition comprising the two bispecific antibodies required in examined claim 1. Regarding examined claims 9 and 10, the ’378 application does not claim SEQ ID NOs: 54 and 56.
The teachings of Xia and Zhang are relied upon as set forth above with respect to US Patent 11,578,128; that discussion is incorporated into this rejection.
In particular, Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.) Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.) Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
It would have been obvious before the effective filing date to combine the ’378 application’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claims 17 and 18, it would have been obvious to provide the ’378 application’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of the ’378 application’s antibody (as suggested at page 17 of Xia) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Copending Application 19/162,722
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 8-10, 12-19, and 22 of copending application 19/162,722 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’722 application claims a composition comprising a bispecific antibody that binds CTLA-4 and PD-1. (Claim 1.) The bispecific antibody comprises a first protein functional region that is an immunoglobulin or single-chain antibody and targets PD-1. It contains CDRs of SEQ ID NOs: 27-30 and 32, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a second protein functional region that is a single-chain antibody or immunoglobulin and comprises SEQ ID NOs: 33-36 and 38, which are identical to examined SEQ ID NOs: 33-36 and 38, respectively. (Claim 1.) Regarding examined claim 2, the ’722 application’s antibody contains certain amino-acid mutations in the heavy chain constant region of the immunoglobulin. (Claim 10.) Regarding examined claims 3 and 4, the ’722 application’s SEQ ID NOs: 18, 20, 2, and 4 are identical to examined SEQ ID NOs: 18, 20, 2, and 4, respectively. (Claims 12 and 13.) Regarding examined claim 5, the ’722 application’s SEQ ID NOs: 40 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. (Claim 14.) Regarding examined claims 6-8, the ’722 application’s SEQ ID NOs: 40, 24, 43, and 44 are identical to examined SEQ ID NOs: 40, 24, 43, and 44, respectively. (Claim 13.) Regarding examined claims 11 and 12, the ’722 application claims that the two protein functional regions are connected by a linker, for example (GGGGS)n (SEQ ID NO: 45 of the ’722 application). (Claim 15.) Regarding examined claim 13, the ’722 application claims that “the numbers” of each of the functional regions is 1, 2, or more. (Claim 16.) Regarding examined claim 14, the ’722 application claims that the single chain antibody is linked to the C-terminus of the immunoglobulin’s heavy chain. (Claim 17.) Regarding examined claims 15, 16, 19, and 20, the ’722 application claims a composition comprising the bispecific antibody and a second therapeutic (gemcitabine, an anti-tumor chemotherapeutic agent) along with a pharmaceutically acceptable carrier or excipient (“adjuvant”), either together or separately in multiple packages. (Claims 1, 8.) Regarding examined claim 23, the ’722 application claims treating or preventing a tumor from the list in examined claim 23. (Claim 22.)
The ’722 application does not claim a composition comprising the two bispecific antibodies required in examined claim 1. Regarding examined claims 9 and 10, the ’722 application does not claim SEQ ID NOs: 54 and 56.
The teachings of Xia and Zhang are relied upon as set forth above with respect to US Patent 11,578,128; that discussion is incorporated into this rejection.
In particular, Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.) Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.) Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
It would have been obvious before the effective filing date to combine the ’722 application’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding claims 17 and 18, it would have been obvious to provide the ’722 application’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of the ’378 application’s antibody (as suggested at page 17 of Xia) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Copending Application 19/365,106
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 and 25 of copending application 19/365,106 in view of Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS) and Xia et al. (2021, CA 3146780).
The ’106 application claims a bispecific antibody comprising a first protein functional region that is an immunoglobulin (e.g., IgG1) and targets PD-1. It contains CDRs of SEQ ID NOs: 29-32 and 34, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. The bispecific antibody also comprises a second protein functional region that is a single-chain antibody and comprises SEQ ID NOs: 35-38 and 40, which are identical to examined SEQ ID NOs: 33-36 and 38, respectively. (Claims 1-5 and 7.) Regarding examined claims 3 and 4, the ’106 application’s SEQ ID NOs: 18, 20, 2, and 4 are identical to examined SEQ ID NOs: 18, 20, 2, and 4, respectively. (Claim 8.) Regarding examined claim 6, the ’106 application’s SEQ ID NOs: 40, 24, 43, and 44 are identical to examined SEQ ID NOs: 40, 24, 43, and 44, respectively. (Claim 10.) Regarding examined claim 13, the ’106 application claims that “the numbers” of each of the functional regions is 1, 2, or more. (Claim 4.) Regarding examined claim 14, the ’106 application claims that the single chain antibody is linked to the C-terminus of the immunoglobulin’s heavy chain. (Claim 6.) Regarding examined claim 23, the ’106 application claims treating or preventing a tumor from the list in examined claim 23. (Claim 25.)
The ’106 application does not claim a composition comprising the two bispecific antibodies required in examined claim 1. Regarding examined claims 9 and 10, the ’106 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 11 and 12, the ’106 application does not claim that the immunoglobulin and single-chain antibody are connected by a linker, for example (GGGGS)n. Regarding examined claims 15 and 16, the ’106 application does not claim a mixture of two bispecific antibodies or a combination in which they are provided in separate packages. Regarding examined claims 17 and 18, the ’106 application does not claim any particular dose of the PD-1/CTLA-4 bispecific antibody. Regarding examined claims 19 and 20, the ’106 application does not claim including an anti-tumor chemotherapeutic drug or an adjuvant.
The teachings of Xia and Zhang are relied upon as set forth above with respect to US Patent 11,578,128; that discussion is incorporated into this rejection.
In particular, Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.) Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.) Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.) Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.) Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.) Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
It would have been obvious before the effective filing date to combine the ’106 application’s CTLA-4/PD-1 bispecific antibody with Zhang’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding examined claims 11 and 12, it would have been obvious to link the ’106 application’s immunoglobulin and single-chain antibody by a linker, for example (GGGGS)n, because Xia teaches that this structure is useful for that purpose.
Regarding examined claims 15 and 16, it would have been obvious to provide two bispecific antibodies or a combination in which they are provided in separate packages based on the teachings of Xia and Zhang.
Regarding examined claims 17 and 18, it would have been obvious to provide the ’106 application’s and Zhang’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of the ’106 application’s antibody (as suggested at page 17 of Xia) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Regarding examined claims 19 and 20, it would have been obvious to provide the ’106 application’s and Zhang’s bispecific antibodies with another anti-tumor drug based on the teachings of Xia and Zhang about the antibodies’ cancer-therapeutic activity and the suggestion to include a chemotherapeutic drug and a carrier (“adjuvant”) in the composition.
Reference Patents and Applications Claiming PD-1/VEGFA Bispecific Antibodies
US Patent 12,195,527
Claims 1-20 and 23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 12,195,527 in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
The ’527 patent claims a bispecific antibody that binds VEGFA and PD-1. The antibody contains an anti-VEGFA IgG1 portion comprising a HCVR of SEQ ID NO: 5 and a LCVR of SEQ ID NO: 7, which are identical to examined SEQ ID NOs: 45 and 47, respectively. Examined SEQ ID NO: 45 contains fragments that are SEQ ID NOs: 58-60, and examined SEQ ID NO: 47 contains fragments that are SEQ ID NOs: 61 and 63. The ’527 patent’s bispecific antibody also contains two anti-PD-1 single-chain antibodies comprising VH of SEQ ID NO: 9 and VL of SEQ ID NO: 11, which are identical to examined SEQ ID NOs: 18 and 20, respectively. Examined SEQ ID NO: 18 contains fragments that are SEQ ID NOs: 27-29, and examined SEQ ID NO: 20 contains fragments that are SEQ ID NOs: 30 and 32. (Claims 1 and 2.) Regarding examined claims 11 and 12, the ’527 patent’s bispecific antibody links the immunoglobulin and single-chain-antibody elements by a linker of SEQ ID NO: 13 (which is (GGGGS)4). (Claims 3-5.) Regarding examined claim 20, the ’527 patent claims a composition comprising the bispecific antibody and a pharmaceutically acceptable excipient (“adjuvant”). Regarding examined claim 23, the ’527 patent discloses that the utility of its bispecific antibody is to treat cancers and tumors selected from a list. (Column 4, lines 12-24, e.g.)
The ’527 patent does not claim a combination of its VEGF/PD-1 bispecific antibody with a CTLA-4/PD-1 bispecific antibody as set forth in the examined claims. Regarding examined claims 9 and 10, the ’527 patent does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 15 and 16, the ’527 patent does not claim providing two bispecific antibodies either in a single composition or in separate packages. Regarding examined claims 17 and 18, the ’527 patent does not claim the recited ratios or dosage amounts. Regarding claim 19, the ’527 patent does not claim a composition that further comprises an anti-tumor chemotherapeutic drug. Regarding claim 23, the ’527 patent does not claim treating or preventing the tumors and cancers on the recited list.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with the ’527 patent’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding examined claims 9 and 10, it would have been obvious to substitute Zhang’s VP101(hG1DM) for the ’527 patent’s bispecific antibody (which is VP101) because both can be linked to 14C12H1L1 single-chain antibodies to make a bispecific antibody.
Regarding claim 15, it would have been obvious to provide Xia’s and the ’527 patent’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and the ’527 patent’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and the ’527 patent’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Regarding examined claim 23, it would have been obvious to treat or prevent the tumors on the list with a mixture of Xia’s and the ’527 patent’s bispecific antibodies because Xia, Zhang, and the ’527 patent all disclose that each bispecific antibody is useful for achieving this outcome.
Copending Application 17/272,121
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24, 35-40, 43-55, 58-69, and 71-79 of copending application 17/272,121 in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
The ’121 application claims a method of treating a malignant tumor with a bispecific antibody that binds VEGFA and PD-1. The antibody contains an anti-VEGFA IgG1 portion comprising a HCVR of SEQ ID NO: 5 and a LCVR of SEQ ID NO: 7, which are identical to examined SEQ ID NOs: 45 and 47, respectively. Examined SEQ ID NO: 45 contains fragments that are SEQ ID NOs: 58-60, and examined SEQ ID NO: 47 contains fragments that are SEQ ID NOs: 61 and 63. The ’121 application’s bispecific antibody also contains two anti-PD-1 single-chain antibodies comprising VH of SEQ ID NO: 9 and VL of SEQ ID NO: 11, which are identical to examined SEQ ID NOs: 18 and 20, respectively. Examined SEQ ID NO: 18 contains fragments that are SEQ ID NOs: 27-29, and examined SEQ ID NO: 20 contains fragments that are SEQ ID NOs: 30 and 32. (Claim 24, e.g.) Regarding examined claims 11 and 12, the ’121 application’s bispecific antibody links the immunoglobulin and single-chain-antibody elements by a linker of SEQ ID NO: 14 (which is (GGGGS)n). (Claim 24, e.g.) Regarding examined claim 19, the ’121 application claims coadministering a chemotherapeutic drug. (Claim 40, e.g.) Regarding examined claim 20, the ’121 application claims combining the bispecific antibody and a pharmaceutically acceptable excipient (“adjuvant”). Regarding examined claim 23, the ’121 application claims treating the tumors on the list (Claims 35-39, e.g.)
The ’121 application does not claim using a combination of its VEGF/PD-1 bispecific antibody with a CTLA-4/PD-1 bispecific antibody as set forth in the examined claims. Regarding examined claims 9 and 10, the ’121 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 15 and 16, the ’121 application does not claim providing two bispecific antibodies either in a single composition or in separate packages. Regarding examined claims 17 and 18, the ’121 application does not claim the recited ratios or dosage amounts.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with the ’121 application’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding examined claims 9 and 10, it would have been obvious to substitute Zhang’s VP101(hG1DM) for the ’121 application’s bispecific antibody (which is VP101) because both can be linked to 14C12H1L1 single-chain antibodies to make a bispecific antibody.
Regarding claim 15, it would have been obvious to provide Xia’s and the ’121 application’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and the ’121 application’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and the ’121 application’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Regarding examined claim 23, it would have been obvious to treat or prevent the tumors on the list with a mixture of Xia’s and the ’121 application’s bispecific antibodies because Xia, Zhang, and the ’121 application all disclose that each bispecific antibody is useful for achieving this outcome.
Copending Application 17/779,425
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-19, 21, 23, 27, 29, 30, 35, 36, and 40-44 of copending application 17/779,425 in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
The ’425 application claims a bispecific antibody that binds VEGFA and PD-1. The antibody contains an anti-VEGFA IgG1 portion comprising a HCVR of SEQ ID NO: 24 and a LCVR of SEQ ID NO: 26, which are identical to examined SEQ ID NOs: 45 and 47, respectively. Examined SEQ ID NO: 45 contains fragments that are SEQ ID NOs: 58-60, and examined SEQ ID NO: 47 contains fragments that are SEQ ID NOs: 61 and 63. The ’425 application’s bispecific antibody also contains two anti-PD-1 single-chain antibodies comprising VH of SEQ ID NO: 9 and VL of SEQ ID NO: 17, which are identical to examined SEQ ID NOs: 18 and 20, respectively. Examined SEQ ID NO: 18 contains fragments that are SEQ ID NOs: 27-29, and examined SEQ ID NO: 20 contains fragments that are SEQ ID NOs: 30 and 32. (Claim 14, e.g.) Regarding examined claims 11 and 12, the ’425 application’s bispecific antibody links the immunoglobulin and single-chain-antibody elements by a linker of SEQ ID NO: 18 and 19 (which is (GGGGS)n). (Claim 14, e.g.) Regarding examined claim 20, the ’425 application claims combining the bispecific antibody and a pharmaceutically acceptable excipient (“adjuvant”). (Claim 21, e.g.) Regarding examined claim 23, the ’425 application claims treating the tumors (Claim 23, e.g.)
The ’425 application does not claim using a combination of its VEGF/PD-1 bispecific antibody with a CTLA-4/PD-1 bispecific antibody as set forth in the examined claims. Regarding examined claims 9 and 10, the ’425 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 15 and 16, the ’425 application does not claim providing two bispecific antibodies either in a single composition or in separate packages. Regarding examined claims 17 and 18, the ’425 application does not claim the recited ratios or dosage amounts.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with the ’425 application’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding examined claims 9 and 10, it would have been obvious to substitute Zhang’s VP101(hG1DM) for the ’425 application’s bispecific antibody (which is VP101) because both can be linked to 14C12H1L1 single-chain antibodies to make a bispecific antibody.
Regarding claim 15, it would have been obvious to provide Xia’s and the ’425 application’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and the ’425 application’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and the ’425 application’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Regarding examined claim 23, it would have been obvious to treat or prevent the tumors on the list with a mixture of Xia’s and the ’425 application’s bispecific antibodies because Xia, Zhang, and the ’425 application all disclose that each bispecific antibody is useful for achieving this outcome.
Copending Application 18/024,478
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-17, 20, 23-25, 28, and 30-37 of copending application 18/024,478 in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
The ’478 application claims a bispecific antibody that binds VEGFA and PD-1. The antibody contains an anti-VEGFA immunoglobulin or single-chain antibody comprising SEQ ID NOs: 28-30, 31, and 33, which are identical to examined SEQ ID NOs: 58-60, 61, and 63, respectively. The ’478 application’s bispecific antibody also contains an anti-PD-1 single-chain antibody or immunoglobulin comprising SEQ ID NOs: 34-37 and 39, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. (Claim 1, e.g.) Regarding examined claim 2, the ’478 application’s bispecific antibody’s Ig is IgG1 with particular mutations in the heavy chain constant region. (Claims 1 and 2, e.g.) Regarding examined claims 11 and 12, the ’478 application’s bispecific antibody links the immunoglobulin and single-chain-antibody elements by a linker of (GGGGS)n. (Claims 10 and 11, e.g.) Regarding examined claim 14, the ’478 application’s bispecific antibody links the single-chain antibody to the C-terminus of the immunoglobulin. (Claim 13, e.g.) Regarding examined claims 17 and 18, the ’478 application claims providing 0.1-100mg of the bispecific antibody. (Claim 25.) Regarding examined claim 19, the ’478 application claims combining the bispecific antibody and an anti-tumor chemotherapeutic agent. (Claims 3, 16, and 17, e.g.) Regarding examined claim 23, the ’478 application claims treating tumors with the bispecific antibody combined with a PARP inhibitor. (Claims 3 and 23, e.g.)
The ’478 application does not claim using a combination of its VEGF/PD-1 bispecific antibody with a CTLA-4/PD-1 bispecific antibody as set forth in the examined claims. Regarding examined claims 9 and 10, the ’478 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 15 and 16, the ’478 application does not claim providing two bispecific antibodies either in a single composition or in separate packages. Regarding examined claims 17 and 18, the ’478 application does not claim the recited ratios or dosage amounts for both bispecific antibodies.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with the ’478 application’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding examined claims 9 and 10, it would have been obvious to substitute Zhang’s VP101(hG1DM) for the ’478 application’s bispecific antibody (which is VP101) because both can be linked to 14C12H1L1 single-chain antibodies to make a bispecific antibody.
Regarding claim 15, it would have been obvious to provide Xia’s and the ’478 application’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and the ’478 application’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and the ’478 application’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Regarding examined claim 23, it would have been obvious to treat or prevent the tumors on the list with a mixture of Xia’s and the ’425 application’s bispecific antibodies because Xia, Zhang, and the ’425 application all disclose that each bispecific antibody is useful for achieving this outcome.
Copending Application 18/264,138
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-16 and 21-37 of copending application 18/264,138 in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
The ’138 application claims a bispecific antibody that binds VEGFA and PD-1. The antibody contains an anti-VEGFA immunoglobulin or single-chain antibody comprising SEQ ID NOs: 35-38 and 40, which are identical to examined SEQ ID NOs: 58-60, 61, and 63, respectively. The ’138 application’s bispecific antibody also contains an anti-PD-1 single-chain antibody or immunoglobulin comprising SEQ ID NOs: 45-48 and 50, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. (Claim 1, e.g.) Regarding examined claim 2, the ’138 application’s bispecific antibody’s Ig is IgG1 with particular mutations in the heavy chain constant region. (Claim 24, e.g.) Regarding examined claims 11 and 12, the ’138 application’s bispecific antibody links the immunoglobulin and single-chain-antibody elements by a linker of (GGGGS)n. (Claim 22, e.g.) Regarding examined claims 17 and 18, the ’138 application claims providing 0.1-100mg of the bispecific antibody and the TIGIT antibody in a particular range of mass ratios. (Claims 25 and 35, e.g.) Regarding examined claim 23, the ’138 application claims treating tumors with the bispecific antibody. (Claim 37, e.g.)
The ’138 application does not claim using a combination of its VEGF/PD-1 bispecific antibody with a CTLA-4/PD-1 bispecific antibody as set forth in the examined claims. Regarding examined claims 9 and 10, the ’138 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 15 and 16, the ’138 application does not claim providing two bispecific antibodies either in a single composition or in separate packages. Regarding examined claims 17 and 18, the ’138 application does not claim the recited ratios or dosage amounts for both bispecific antibodies.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with the ’138 application’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding examined claims 9 and 10, it would have been obvious to substitute Zhang’s VP101(hG1DM) for the ’138 application’s bispecific antibody (which is VP101) because both can be linked to 14C12H1L1 single-chain antibodies to make a bispecific antibody.
Regarding claim 15, it would have been obvious to provide Xia’s and the ’138 application’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and the ’138 application’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and the ’138 application’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Copending Application 18/264,272
Claims 1-20 and 23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 10-12, 19, 20, 27, 28, 30, and 31 of copending application 18/264,272 in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
The ’272 application claims a composition comprising a bispecific antibody that binds VEGFA and PD-1. The antibody contains an anti-VEGFA immunoglobulin or single-chain antibody comprising SEQ ID NOs: 31-34 and 36, which are identical to examined SEQ ID NOs: 58-60, 61, and 63, respectively. The ’272 application’s bispecific antibody also contains an anti-PD-1 single-chain antibody or immunoglobulin comprising SEQ ID NOs: 14-44 and 46, which are identical to examined SEQ ID NOs: 27-30 and 32, respectively. (Claims 10-12, e.g.) Regarding examined claim 2, the ’272 application’s bispecific antibody’s Ig is IgG1 with particular mutations in the heavy chain constant region. (Claims 19 and 20, e.g.) Regarding examined claims 11 and 12, the ’272 application’s bispecific antibody links the immunoglobulin and single-chain-antibody elements by a linker of (GGGGS)n. (Claim 27, e.g.) Regarding examined claim 23, the ’272 application claims treating tumors with the bispecific antibody. (Claim 31, e.g.)
The ’272 application does not claim using a combination of its VEGF/PD-1 bispecific antibody with a CTLA-4/PD-1 bispecific antibody as set forth in the examined claims. Regarding examined claims 9 and 10, the ’272 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 15 and 16, the ’272 application does not claim providing two bispecific antibodies either in a single composition or in separate packages. Regarding examined claims 17 and 18, the ’272 application does not claim the recited ratios or dosage amounts for both bispecific antibodies.
Xia teaches a bispecific antibody for CTLA-4 and PD-1. (Title.) Specifically, Xia teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Page 6.) Xia teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Xia, SEQ ID NO: 22) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Xia, SEQ ID NO: 24). Xia teaches that when the immunoglobulin is 14C12, the single-chain antibody contains an HCVR comprising CDRs identical to SEQ ID NOs: 33-35 and a LCVR comprising CDRs identical to SEQ ID NOs: 36 and 38 (see Xia, SEQ ID NOs: 2 and 4); this is termed 4G10. Xia therefore also teaches that when the immunoglobulin is 4G10, the single-chain antibody is 14C12H1L1.
Regarding claim 2, Xia teaches that the immunoglobulin is of human IgG1 subtype and can have mutations at L234A and L235A, L234A and G237A, L235A and G237A, or L234A, L235A and G237A. (Claims 2 and 3.)
Regarding claim 3, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 4, options 4 and 8, Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively. Xia’s SEQ ID NOs: 2 and 4 are identical to examined SEQ ID NOs: 2 and 4, respectively.
Regarding claim 5, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively.
Regarding claim 6, Xia’s SEQ ID NOs: 22 and 24 are identical to examined SEQ ID NOs: 40 and 24, respectively. Xia teaches that the heavy chain of 4G10 may be 4G10H3V (SEQ ID NO: 43), which is identical to examined SEQ ID NO: 43. Xia teaches that the light chain of 4G10 may be 4G10L3V(M) (SEQ ID NO: 44), which is identical to examined SEQ ID NO: 44. (Page 41.)
Regarding claims 7 and 8 (options 5 and 11), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11 and 12, Xia teaches that the first protein functional region is linked to the second protein functional region either directly or via a linker fragment; and/or the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody either directly or via a linker fragment, for example (GGGGS)n, wherein n is preferably 1-6. (Pages 14-15; claims 10 and 11.)
Regarding claim 14, Xia teaches that the single chain antibody is linked to the C terminus of the heavy chain of the immunoglobulin. (Page 15.)
Regarding claim 16, Xia teaches providing the bispecific antibody with a second agent in separate packages. (Page 17.)
Regarding claims 17 and 18, Xia teaches that the unit dose for the bispecific antibody is 100-1000mg, 200-800mg, 200-500mg, 300-600mg, 400-500mg, or 450mg. (Pages 17-18.)
Regarding claim 19, Xia teaches providing the bispecific antibody with an anti-tumor chemotherapeutic drug. (Page 17.)
Regarding claim 20, Xia teaches providing the bispecific antibody with one or more pharmaceutically acceptable excipients (i.e., adjuvants) and, preferably, a package insert. (Page 17.)
Regarding claim 23, Xia teaches that the bispecific antibodies are useful for treating various cancers including melanoma, renal cancer, prostate cancer, bladder cancer, colon cancer, rectal cancer, gastric cancer, liver cancer, lung cancer, etc. (Page 18.)
Zhang teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Zhang teaches that the bispecific antibody targets each of these proteins in a first or second protein functional region; the first and second protein functional regions can be immunoglobulins or single-chain antibodies, respectively. (Claim 1.) Li teaches that within the immunoglobulin, which is termed 14C12H1L1, the heavy-chain variable region (HCVR) comprises three CDRs that are identical to SEQ ID NOs: 27-29 (see Zhang, SEQ ID NO: 9, paragraphs 354-355) and the light-chain variable region comprises two CDRs that are identical to SEQ ID NOs: 30 and 32 (see Zhang, SEQ ID NO: 11, paragraphs 358-359). Regarding claims 9 and 10, Zhang teaches that the bispecific antibody comprises the amino acid sequence of the heavy chain of the immunoglobulin in SEQ ID NO: 24 and the amino acid sequence of the light chain thereof in SEQ ID NO: 26. (Paragraphs 96-97.) Zhang’s SEQ ID NOs: 24 and 26 are identical to examined SEQ ID NOs: 54 and 56, respectively. This antibody is termed VP101(hG1DM). Zhang therefore also teaches that when the immunoglobulin is VP101(hG1DM), the single-chain antibody is 14C12H1L1. Zhang teaches that the bispecific antibody is useful for treating cancers including liver cancer, lung cancer, melanoma, renal tumor, ovarian cancer, lymphoma, colon cancer, rectal cancer, skin cancer, glioma, renal tumor, prostate cancer, bladder cancer, gastrointestinal cancer, breast cancer, brain cancer and leukemia. (Paragraph 194.)
Regarding claims 7 and 8 (options 5 and 11), Zhang’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Zhang teaches that the bispecific antibody can be used alone or in combination, or used in combination with additional pharmaceutically active agents. (Paragraph 147.)
Regarding claims 17 and 18, Zhang teaches that the unit dose of the bispecific antibody is at least 1 mg, at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. (Paragraph 145.)
It would have been obvious before the effective filing date to combine Xia’s CTLA-4/PD-1 bispecific antibody with the ’272 application’s VEGFA/PD-1 bispecific antibody because the skilled artisan would have predicted that each bispecific antibody would bind its intended target and would have treated various types of cancers. See MPEP 2143(I)(A); see also MPEP 2144.06(I) (prima facie obvious to combine two compositions taught by the prior art to be useful for the same purpose (quoting In re Kerkhoven, 626 F.2d 846, 850, 205 U.S.P.Q. 1069, 1072 (C.C.P.A. 1980)).
Regarding examined claims 9 and 10, it would have been obvious to substitute Zhang’s VP101(hG1DM) for the ’272 application’s bispecific antibody (which is VP101) because both can be linked to 14C12H1L1 single-chain antibodies to make a bispecific antibody.
Regarding claim 15, it would have been obvious to provide Xia’s and the ’272 application’s bispecific antibodies together in a single composition because Xia and Zhang both teach that bispecific antibodies can be mixed with additional agents.
Regarding claim 16, it would have been obvious to provide Xia’s and the ’272 application’s bispecific antibodies in separate packages because Xia teaches providing two different agents in different packages, preferably with a package insert.
Regarding claim 17, it would have been obvious to provide Xia’s and the ’272 application’s bispecific antibodies in the claimed ratios because both Xia and Zhang teach that their bispecific antibodies can be provided in a range of dosages. Optimizing within those disclosed dosages would also necessarily optimize the ratio between the two agents. For example, providing 450mg of Xia’s antibody (as suggested at page 17) and 100mg of Zhang’s antibody (as suggested in paragraph 145) would result in a mass ratio of 4.5:1, which is within the range set forth in claim 17. The dosage optimization and resulting effect on the mass ratio would have been obvious. See MPEP 2144.05(I) (overlapping ranges prima facie obvious); MPEP 2144.05(II) (obvious to optimize art-recognized result-effective variables).
Consideration of Alleged Unexpected Results
In preparing the rejections under 35 U.S.C. 103 and the nonstatutory double patenting rejections, the examiner gave full consideration to the as-filed disclosure and any evidence of unexpected results. See MPEP 2141(II) (“Objective evidence relevant to the issue of obviousness must be evaluated by Office personnel.”) In particular, the specification at page 6 states:
The inventors of the present invention have made intensive studies and creative efforts to combine the anti-CTLA4-anti-PD-1 bispecific antibody with the anti-PD-1-anti-VEGFA bispecific antibody, and surprisingly found that the combined antibody has a pharmacological effect of effectively inhibiting tumor growth, which is superior to that of the anti-VEGFA-anti-PD-1 bispecific antibody or the anti-CTLA4-anti-PD-1 bispecific antibody alone.
This is not, however, a clear demonstration of unexpected results. As discussed in the rejections, the cited prior art teaches both an anti-CTLA4-anti-PD-1 bispecific antibody and an anti-PD-1-anti-VEGFA bispecific antibody meeting the sequence requirements of the claims. The art also demonstrates that these bispecific antibodies were both known in the art to be useful for the same purpose, i.e. treating cancers. Providing them together for that same purpose would have been prima facie obvious. See MPEP 2144.06(I). There is no evidence in the specification to show that the person of ordinary skill in the art would not have expected an improved tumor-inhibition function by providing two agents that were already known to be tumor inhibitors.
It is also not clear from the specification that applicants observed a greater-than-additive effect; see MPEP 716.02(a)(I). Figure 1 appears to show a change in IL-2 release with a combination of BiAb004(hG1TM) (CTLA-4/PD-1 bispecific antibody) and VP101(hG1DM) (VEGF/PD-1 bispecific antibody) relative to either alone, but the increase is only one from either ~5800 or ~5000 to ~6000 at the highest antibody concentration:
PNG
media_image1.png
352
390
media_image1.png
Greyscale
(Arrows added by examiner.) It is not clear that the person of ordinary skill in the art would have found this modest increase in IL-2 production to be “in fact unexpected and unobvious and of both statistical and practical significance.” See MPEP 716.02(b)(I). For example, there is no clear statistical difference between the combination and the antibody alone because the error bars overlap. It is also not clear on the record that this documented increase would have had practical significance. The evidence in Figure 2 is not clearly relevant to the claimed invention, which does not include VEGF.
Finally, the evidence in Figures 1 and 2 is limited to a single bispecific-antibody combination (BiAb004(hG1TM) and VP101(hG1DM)), but the claims are not so limiting. The showing is not reasonably commensurate in scope with the claimed invention. See MPEP 716.02(d); see also MPEP 716.01(b) (nexus requirement).
In brief, the showing in the specification does not contain evidence of unexpected results that would overcome either the obviousness or double-patenting rejections. The examiner makes these observations in the interest of compact prosecution and in assisting applicants with responding to this Office action.
Conclusion
No claims are allowed. No claims are free of the art.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LORA E BARNHART DRISCOLL, whose telephone number is (571)272-1928. The examiner can normally be reached M-F 7:00-4:00 p.m. ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Patricia Engle, can be reached at 571-272-6660. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Lora E Barnhart Driscoll/ Primary Examiner, Art Unit 3991