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 and Responses
On 7/29/26, applicant responded to the 1/30/26 nonfinal Office action. The claim listing amended claims 1-12 and 15-19; canceled claims 13, 14, 20, and 23; and added new claims 26-33. Applicant also supplied a substitute specification (clean and marked-up copies) and a declaration under 37 CFR 1.132. The response’s cover sheet indicates that the declaration was signed by Baiyong Li, but the declaration itself does not name the declarant either in the introduction or the signature box:
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On 7/30/26, the examiner contacted applicant’s representative, Sarah Robbins, to request a correctly signed declaration. Agent Robbins indicated that securing a replacement declaration by the statutory deadline would not be possible. Later that day, applicants submitted a second reply containing the same claim amendments, the same substitute specification, and essentially the same remarks but lacking a reference to the Rule 1.132 declaration. The 7/30/26 reply instructed that it was “intended to replace the response filed on July 29, 2026.” (Reply at 1.)
On 7/31/26, the examiner spoke with Agent Robbins and confirmed that no replacement declaration had been supplied and that the remarks had been modified solely to remove any reference to the Rule 1.132 declaration.
The 7/30/26 response cannot “replace” the 7/29/26 response. The 7/29/26 response complied with 37 CFR 1.111(b) and was therefore complete, so the 7/30/26 response was supplemental to the 7/29/26 response. Supplemental replies will not be entered as a matter of right, except when a supplemental reply is filed within a suspended period under 37 CFR 1.103. MPEP 714.03(a). The Office may enter a supplemental reply under clearly prescribed conditions such as claim cancellation, placement of the application in condition for allowance, and correction of informalities. See MPEP 714.03(a). Since the 7/30/26 reply appears to be a bona fide attempt to adopt an examiner suggestion (i.e., to address the legal deficiency in the Rule 1.132 declaration), the examiner has considered the remarks supplied with that supplemental response in conjunction with the entire 7/29/26 reply.
Claims 1-12, 15-19, and 26-33 are pending and under examination.
Claim Objections
The examiner objects to claim 26 because it does not end in a period.
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.
Xia in view of Li ’239
Claims 1-8, 11, 12, 15-18, 26-30, 32, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Xia et al. (2021, CA 3146780) in view of Li et al. (US 20210340239).
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 ’239 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 ’239 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. 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.)
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 claims 3 and 32, 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, option 4, 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 claims 6 and 32, 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 (option 5), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11, 12, and 26-29, 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.)
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 ’239 teaches a bispecific antibody for VEGFA and PD-1. (Title.) Specifically, Li ’239 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 ’239 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 ’239 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 ’239, SEQ ID NOs: 5 and 7); this is termed bevacizumab. Li ’239 therefore also teaches that when the immunoglobulin is bevacizumab, the single-chain antibody is 14C12H1L1. Li ’239 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 (option 5), Li ’239’s SEQ ID NOs: 5 and 7 are identical to examined SEQ ID NOs: 45 and 47, respectively.
Regarding claim 15, Li ’239 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 ’239 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 ’239’s VEGFA/PD-1 bispecific antibody to treat a tumor 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 ’239’s bispecific antibodies together in a single composition because Xia and Li ’239 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 ’239’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 ’239’s bispecific antibodies in the claimed ratios because both Xia and Li ’239 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 ’239’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).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Xia et al. (2021, CA 3146780) in view of Li et al. (US 20210340239) as applied to claims 1-8, 11, 12, 15-18, 26-30, 32, and 33 above and further in view of Li et al. (US 20210179706; reference A on PTO-892). Li ’706 was published on 6/17/21 and is prior art outside the 35 U.S.C. 102(b) grace period.
The teachings of Xia and Li ’239 are relied upon as above.
Xia and Li ’239 do not specify co-administering the antibodies along with the particular anti-tumor chemotherapeutic drug types recited in claim 19.
Li ’706 teaches that conventional tumor chemotherapeutic drugs capable of coadministration with cancer-therapeutic antibodies include alkylating agents, antimetabolites, anti-tumor antibiotics, plant-based anticancer agents, hormones, and immunological agents. (Paragraphs 42-43.)
It would have been obvious to combine the antibodies of Xia and Li ’239 with the tumor chemotherapeutic drugs of Li ’706 because Li ’706 teaches that these are conventional drug types suitable for coadministration with anti-tumor antibodies. See MPEP 2144.06(I) (combining equivalents known for the same purpose is prima facie obvious).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Xia et al. (2021, CA 3146780) in view of Li et al. (US 20210340239) as applied to claims 1-8, 11, 12, 15-18, 26-30, 32, and 33 above and further in view of Pantaleo et al. (US 20170166642; reference B on PTO-892).
The teachings of Xia and Li ’239 are relied upon as above.
Xia and Li ’239 do not specify that the cancer being treated is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
Pantaleo teaches that antibodies targeted to PD-1 treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. (Paragraph 73.)
It would have been obvious to use the antibodies of Xia and Li ’239 to treat Hodgkin’s lymphoma or non-Hodgkin’s lymphoma because Xia’s antibody targets PD-1 and Pantaleo teaches that anti-PD-1 antibodies are therapeutic for those conditions.
Xia in view of Zhang
Claims 1-12, 15-18, 26-30, 32, and 33 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 the first Office action on the merits.
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. 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.)
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 claims 3 and 32, 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, option 4, 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 claims 6 and 32, 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 (option 5), Xia’s SEQ ID NOs: 18 and 20 are identical to examined SEQ ID NOs: 18 and 20, respectively.
Regarding claims 11, 12, 26, and 27, 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.)
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, 10, and 33, 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 (option 5), 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 to treat a tumor 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).
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Xia et al. (2021, CA 3146780) in view of Zhang et al. (WO 2021104302) as applied to claims 1-12, 15-18, 26-30, 32, and 33 above and further in view of Li et al. (US 20210179706). Li ’706 was published on 6/17/21 and is prior art outside the 35 U.S.C. 102(b) grace period.
The teachings of Xia and Zhang are relied upon as above.
Xia and Zhang do not specify co-administering the antibodies along with the particular anti-tumor chemotherapeutic drug types recited in claim 19.
Li ’706 teaches that conventional tumor chemotherapeutic drugs capable of coadministration with cancer-therapeutic antibodies include alkylating agents, antimetabolites, anti-tumor antibiotics, plant-based anticancer agents, hormones, and immunological agents. (Paragraphs 42-43.)
It would have been obvious to combine the antibodies of Xia and Zhang with the tumor chemotherapeutic drugs of Li ’706 because Li ’706 teaches that these are conventional drug types suitable for coadministration with anti-tumor antibodies. See MPEP 2144.06(I) (combining equivalents known for the same purpose is prima facie obvious).
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Xia et al. (2021, CA 3146780) in view of Zhang et al. (WO 2021104302) as applied to claims 1-12, 15-18, 26-30, 32, and 33 above and further in view of Pantaleo et al. (US 20170166642).
The teachings of Xia and Zhang are relied upon as above.
Xia and Zhang do not specify that the cancer being treated is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
Pantaleo teaches that antibodies targeted to PD-1 treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. (Paragraph 73.)
It would have been obvious to use the antibodies of Xia and Zhang to treat Hodgkin’s lymphoma or non-Hodgkin’s lymphoma because Xia’s antibody targets PD-1 and Pantaleo teaches that anti-PD-1 antibodies are therapeutic for those conditions.
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 1-12, 15-18, and 26-30 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. The ’128 patent does not claim treating a tumor, for example the cancers in claim 30, with the composition. 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, 12, and 26-29, 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.
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 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.)
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, 12, and 26-29, 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.)
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 (option 5), 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, 7-12, 15-18, 26-29, 32, and 33 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. The ’919 patent does not teach treating the listed cancers with the composition. Regarding examined claims 9 and 10, the ’919 patent does not claim SEQ ID NOs: 54 and 56. Regarding claims 11, 12, and 26-29, 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.
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 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.)
Regarding claims 11, 12, and 26-29, 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.)
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 (option 5), 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 1-12, 15-18, 26-30, 32, and 33 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. The ’467 application claims treating or preventing a tumor. (Claim 55.) 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 claim 15, the ’467 application claims a composition comprising the bispecific antibody and 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.)
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)).
It would have been obvious to treat tumors, including those in claim 30, 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.
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).
Copending Application 18/286,755
Claims 1-12, 15-18, and 26-33 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.) The ’755 application claims treating or preventing a tumor from the list in examined claims 30 and 31. (Claims 16 and 18.) 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, 4, and 32, 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, 12, and 26-29, 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 claims 15 and 19, 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.)
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 1-12, 15-18, and 26-33 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.) The ’755 application claims treating or preventing a tumor from the list in examined claims 30 and 31. (Claim 6.) 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, 4, and 32 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 and 19, 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 claims 26-29, the ’128 application claims including a linker of sequence (GGGGS)n, where n=1-6. (Claim 3.)
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 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 1-12, 15-19, and 26-33 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.) The ’378 application claims treating or preventing a tumor from the list in examined claims 30 and 31. (Claim 26.) 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, 4, and 32, 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, 12, and 26-29, 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 and 19, the ’378 application claims a composition comprising the bispecific antibody and a second therapeutic (chiauranib, an anti-tumor chemotherapeutic agent that is an immunological agent) along with a pharmaceutically acceptable carrier or excipient (“adjuvant”). (Claims 1, 23.)
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 1-12, 15-19, and 26-33 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.) The ’722 application claims treating or preventing a tumor from the list in examined claims 30 and 31. (Claim 22.) 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, 4, and 32 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 and 33, 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, 12, and 26-29, 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 claims 15, 16, and 19, the ’722 application claims a composition comprising the bispecific antibody and a second therapeutic (gemcitabine, an anti-tumor chemotherapeutic agent that is an antimetabolite) along with a pharmaceutically acceptable carrier or excipient (“adjuvant”), either together or separately in multiple packages. (Claims 1, 8.)
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).
Reference Patents and Applications Claiming PD-1/VEGFA Bispecific Antibodies
US Patent 12,195,527
Claims 1-12, 15-18, and 26-32 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.) The ’527 patent discloses that the utility of its bispecific antibody is to treat cancers and tumors selected from the list in claims 30 and 31. (Column 4, lines 12-24, e.g.) Regarding examined claims 11, 12, and 26-29, 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.)
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. The ’527 patent does not claim treating or preventing the tumors and cancers on the recited list. 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.
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. 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.)
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 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.)
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)). Specifically, it would have been obvious to treat or prevent the tumors on the list in claims 30 and 31 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.
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).
Copending Application 17/272,121
Claims 1-12, 15-18, and 26-33 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.) The ’121 application claims treating the tumors on the list in claims 30 and 31, for example non-small cell lung cancer. (Claims 35-39 and 79, e.g.) Regarding examined claims 11, 12, and 26-29, 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.)
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. 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.)
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 claims 3 and 32, 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, 12, and 26-29, 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.)
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)). In particular, 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.
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).
Copending Application 17/779,425
Claims 1-12, 15-18, 26-29, 32, and 33 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.) The ’425 application claims treating tumors (Claim 23, e.g.) Regarding examined claims 11, 12, and 26-29, 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.)
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 claims 3 and 32, 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, option 4, 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, 12, and 26-29, 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 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)). 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.
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).
Claims 30 and 31 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 and Zhang as applied to claims 1-12, 15-18, 26-29, 32, and 33 above, and further in view of Pantaleo (US 20170166642).
The claims of the ’425 application and the teachings of Xia and Zhang are relied upon as above.
The ’425 application does not claim, and Xia and Zhang do not teach, that the cancer being treated is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
Pantaleo teaches that antibodies targeted to PD-1 treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. (Paragraph 73.)
It would have been obvious to use the antibodies of the ’425 application, Xia, and Zhang to treat Hodgkin’s lymphoma or non-Hodgkin’s lymphoma because Xia’s antibody targets PD-1 and Pantaleo teaches that anti-PD-1 antibodies are therapeutic for those conditions.
Copending Application 18/024,478
Claims 1-12, 15-18, 26-30, 32, and 33 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.) The ’478 application claims treating tumors with the bispecific antibody combined with a PARP inhibitor. (Claims 3 and 23, 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, 12, and 26-29, 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.)
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. 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.)
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 claims 3 and 32, 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, 12, and 26-29, 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.)
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)). In particular, 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.
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).
Claim 31 is 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 and Zhang as applied to claims 1-12, 15-18, 26-30, 32, and 33, above, and further in view of Pantaleo (US 20170166642).
The claims of the ’478 application and the teachings of Xia and Zhang are relied upon as above.
The ’478 application does not claim, and Xia and Zhang do not teach, that the cancer being treated is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
Pantaleo teaches that antibodies targeted to PD-1 treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. (Paragraph 73.)
It would have been obvious to use the antibodies of the ’478 application, Xia, and Zhang to treat Hodgkin’s lymphoma or non-Hodgkin’s lymphoma because Xia’s antibody targets PD-1 and Pantaleo teaches that anti-PD-1 antibodies are therapeutic for those conditions.
Copending Application 18/264,138
Claims 1-12, 15-18, 26-30, 32, and 33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 15, 16, 21-29, and 35-37 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.) The ’138 application claims treating tumors with the bispecific antibody. (Claim 37, 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.)
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. 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.)
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 claims 3 and 32, 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, 12, and 26-29, 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.)
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).
Claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9, 15, 16, 21-29, and 35-37 of copending application 18/264,138 in view of Xia et al. and Zhang as applied to claims 1-12, 15-18, 26-30, 32, and 33, above, and further in view of Pantaleo (US 20170166642).
The claims of the ’138 application and the teachings of Xia and Zhang are relied upon as above.
The ’138 application does not claim, and Xia and Zhang do not teach, that the cancer being treated is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
Pantaleo teaches that antibodies targeted to PD-1 treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. (Paragraph 73.)
It would have been obvious to use the antibodies of the ’138 application, Xia, and Zhang to treat Hodgkin’s lymphoma or non-Hodgkin’s lymphoma because Xia’s antibody targets PD-1 and Pantaleo teaches that anti-PD-1 antibodies are therapeutic for those conditions.
Copending Application 18/264,2421
Claims 1-12, 15-18, and 26-33 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 18/264,242 in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS).
The ’242 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 ’242 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.) The ’242 application claims treating tumors, for example non-squamous non-small cell lung cancer, with the bispecific antibody. (Claims 31 and 34, e.g.) Regarding examined claim 2, the ’242 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, 12, and 26-29, the ’242 application’s bispecific antibody links the immunoglobulin and single-chain-antibody elements by a linker of (GGGGS)n. (Claim 27, e.g.)
The ’242 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 ’242 application does not claim SEQ ID NOs: 54 and 56. Regarding examined claims 15 and 16, the ’242 application does not claim providing two bispecific antibodies either in a single composition or in separate packages. Regarding examined claims 17 and 18, the ’242 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. 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.)
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, 12, and 26-29, 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.)
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 ’242 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).
Claim 19
Claim 19 is rejected on the ground of nonstatutory double patenting as being unpatentable over each of the sets of claims of the above-identified patents and co-pending applications, each individually taken in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS), and further in view of
Li et al. (US 20210179706). Li ’706 was published on 6/17/21 and is prior art outside the 35 U.S.C. 102(b) grace period.
The claims of the patents and co-pending applications, and the teachings of Xia and Zhang, are relied upon as above.
The patents and co-pending applications do not claim, and Xia and Zhang do not specify, co-administering the antibodies along with the particular anti-tumor chemotherapeutic drug types recited in claim 19.
Li ’706 teaches that conventional tumor chemotherapeutic drugs capable of coadministration with cancer-therapeutic antibodies include alkylating agents, antimetabolites, anti-tumor antibiotics, plant-based anticancer agents, hormones, and immunological agents. (Paragraphs 42-43.)
It would have been obvious to combine the antibodies of the claims of each of the patents and co-pending applications, Xia, and Zhang with the tumor chemotherapeutic drugs of Li ’706 because Li ’706 teaches that these are conventional drug types suitable for coadministration with anti-tumor antibodies. See MPEP 2144.06(I) (combining equivalents known for the same purpose is prima facie obvious).
Claim 31
Claim 31 rejected on the ground of nonstatutory double patenting as being unpatentable over each of the sets of claims of the above-identified patents and co-pending applications, each individually taken in view of Xia et al. (2021, CA 3146780) and Zhang et al. (WO 2021104302; citation 006 on 2/12/25 IDS), and further in view of Pantaleo et al. (US 20170166642).
The claims of the patents and co-pending applications, and the teachings of Xia and Zhang, are relied upon as above.
The patents and co-pending applications do not claim, and Xia and Zhang do not specify, that the cancer being treated is Hodgkin’s lymphoma or non-Hodgkin’s lymphoma.
Pantaleo teaches that antibodies targeted to PD-1 treat Hodgkin’s lymphoma and non-Hodgkin’s lymphoma. (Paragraph 73.)
It would have been obvious to use the antibodies of each of the patents and co-pending applications, Xia, and Zhang to treat Hodgkin’s lymphoma or non-Hodgkin’s lymphoma because Xia’s antibody targets PD-1 and Pantaleo teaches that anti-PD-1 antibodies are therapeutic for those conditions.
Response to Arguments
Regarding the obviousness rejection of record, applicant argues that nothing in Xia, Li ’239, or Zhang suggests combining the bispecific antibodies. (Reply at 23.) As discussed in the rejection, however, when two compositions are each taught by the prior art to be useful for the same purpose, and they are claimed to be combined for that same purpose, “the idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (quoted in MPEP 2144.06). Here, all of the antibodies are taught by the prior art as being useful for treating cancer, and applicant claims them as useful for that same purpose. Combining them would have been prima facie obvious.
Applicant supplies a declaration under 37 CFR 1.132 in support of patentability. (7/29/26 reply.) As discussed above, however, the declaration is noncompliant because the evidence itself does not identify the declarant. (See pages 1 and 6, giving no name.) It therefore cannot be viewed as having evidentiary weight. As a supplement to the declaration, applicant supplies “Figure A” within the 7/30/26 reply as alleged evidence of a ”mechanistically meaningful and therapeutically relevant anti-tumor effect.” (Reply at 23-24.) The remarks do not, however, provide any meaningful explanation of the data in Figure A. The burden of explaining data proffered as evidence of unexpected results lies with applicant. See MPEP 716.02(b)(II).
While the 1.132 declaration is noncompliant, the examiner notes that it appears to characterize Figure A as a study on the effects of various antibodies on IL-2 secretion in various cell types. (Declaration at ¶ 8.) Even if that information were provided as proper evidence, Figure A would still not be convincing of error because it only appears to demonstrate that a combination of the two antibodies results in greater IL-2 secretion than either antibody alone. It is unclear why this would have been “truly unexpected and nonobvious.” See MPEP 716.02(b)(I). As discussed in the previous Office action, 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 Figure A that applicants observed a greater-than-additive effect; see MPEP 716.02(a)(I). Figure A 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 additive at most:
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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). While Figure A does appear to show statistical significance based on the asterisks, it is not clear on the record that this documented increase would have had practical significance.
Furthermore, while evidence pertaining to secondary considerations must be taken into account whenever it has been properly presented, it does not necessarily control the obviousness conclusion. Putting aside the fact that Figure A has not been properly presented, it does not overcome the strong showing of obviousness established under 35 U.S.C. 103. See, e.g., Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1372, 82 USPQ2d 1321, 1339 (Fed. Cir. 2007) ("the record establish[ed] such a strong case of obviousness" that allegedly unexpectedly superior results were ultimately insufficient to overcome obviousness conclusion) (quoted in MPEP 2145).
Finally, the evidence in Figure A appears to be 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).
Regarding the double-patenting rejections of record, applicant alleges that the use of secondary references is improper. (Reply at 26-28.) This is incorrect. A nonstatutory double-patenting rejection grounded in obviousness is “analogous to [a failure to meet] the nonobviousness requirement of 35 U.S.C. 103” except that the patent disclosure principally underlying the double patenting rejection is not considered prior art. MPEP 804(II)(B)(3). Section 804(II)(B)(3) explicitly requires that “[a]ny secondary reference used to support an obviousness analysis for a nonstatutory double patenting rejection must be prior art,” compelling a conclusion that secondary references may be relied upon in obviousness-type double-patenting rejections. See also form paragraphs 8.36 and 8.37, setting forth the Office’s language for rejecting on the ground of nonstatutory double patenting in view of secondary references.
Regarding the rejection over the ’755 application, applicant contends that the claims are silent regarding a VEGF-binding-domain-containing bispecific antibody. (Reply at 28.) This feature, however, is fully addressed by the cited secondary references.
Regarding the rejection over the ’128 application, applicant contends that the claims are silent regarding a PD-1/CTLA-4-binding-domain-containing bispecific antibody and that it would not have been obvious based on the claims alone to make the substitution set forth in the rejection. (Reply at 29.) This feature, however, is fully addressed by the cited secondary references.
Regarding the rejection over the ’242 application, applicant contends that the claims are silent regarding a PD-1/CTLA-4-binding-domain-containing bispecific antibody and that it would not have been obvious based on the claims alone to make the substitution set forth in the rejection. (Reply at 29-30.) This feature, however, is fully addressed by the cited secondary references.
Regarding the rejection over the ’467, ’378, ’722, and ’478 applications, applicant contends that the claims are silent regarding a PD-1/CTLA-4-binding-domain-containing bispecific antibody and that it would not have been obvious based on the claims alone to make the substitution set forth in the rejection. (Reply at 30-31.) This feature, however, is fully addressed by the cited secondary references.
Regarding the rejection over the ’722 application (“Rejection 7”), applicant argues that the rejection must fall because the ’722 application was filed after this application, citing a non-precedential PTAB decision. (Reply at 32-33.) MPEP 804(I)(B)(1)(b)(iii) makes clear, however, that provisional nonstatutory double-patenting rejections may be made in these scenarios and that the rejection should only be withdrawn when it is the only rejection remaining in the application.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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/Lora E Barnhart Driscoll/Primary Examiner, Art Unit 3991
1 See 4/7/26 interview summary in this application.
Prosecution Insights