DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s amendments received 24APR2026 are acknowledged.
Claims 1-13, 20, 22, and 24-25 have been canceled.
Claim 14 has been amended.
Claims 14-19, 21, 23, and 26-44 are pending in the instant application (i.e., Claim(s) 14, 29, and 40 is/are independent).
Claims 15-17, 23, 26, 28, 31-34, and 36-44 remain withdrawn.
Claims 14, 18-19, 21, 27, 29-30, and 35 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/CN2020/131447, filed 25NOV2020, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of CN 201911164156.2 filed on 25NOV2019 has been received and is acknowledged. Examiner notes that there is no English translation of CN 201911164156.2 filed on 25NOV2019.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 24APR2026 (2x) is/are acknowledged and the references cited therein have been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Applicant’s arguments, see p 11, Nucleotide and/or amino acid sequence disclosures section, filed 24APR2026, with respect to specific sequence deficiencies have been fully considered and said deficiencies have been withdrawn in view of amendments to the specification filed as part of said response.
Claim Objections
Applicant’s arguments, see p 11-12, Claim objection section, filed 24APR2026, with respect to objections to claim(s) 14 for informalities have been fully considered and said objections to claim(s) 14 have been withdrawn in view of claim amendments filed as part of said response.
Withdrawn Rejections
35 USC §102
Applicant’s arguments, see p 12-20 and the Declaration by Baiyong Li, Rejections under 35 USC §102 section, filed 24APR2026, with respect to the rejection(s) of claim(s) 14, 27, and 29-30 under 35 USC §102 as being anticipated by WO 2018/167320 (CUREVAC AG, et. al, 20SEP2018), as evidenced by Ivonescimab, Drug Detail, CKB, and KEGG, Ivonescimab, have been fully considered and said rejections of claim(s) 14, 27, and 29-30 have been withdrawn. The declaration under 37 CFR 1.132 filed 24APR2026 is sufficient to overcome the rejection of claim14, 27, and 29-30 because per the declaration, VP101(hG1DM), also known as AK112 and ivonescimab was maintained as a trade secret by Akeso prior to the 25NOV2019 priority date and because no public sale of VP101(hG1DM) occurred at the time of the WO 2018/167320 (CUREVAC AG, et. al, 20SEP2018) application.
35 USC §103
Applicant’s arguments, see p 20-21, Rejections under 35 USC §103 section, filed 24APR2026, with respect to the rejection(s) of claim(s) 18-19, 21, and 35 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/167320 (CUREVAC AG, et. al, 20SEP2018), as evidenced by Ivonescimab, Drug Detail, CKB, and KEGG, Ivonescimab, and in further view of CA 3052670 A1 (Genentech, Inc., et al., 07SEP2018), under 35 USC §103 have been fully considered and said rejections of claim(s) 18-19, 21, and 35 have been withdrawn as discussed supra.
Double Patenting
Applicant’s arguments, see p 22-23, Double patenting rejection section, filed 24APR2026, with respect to the provisional rejection(s) of claim(s) 14, 21, 27, 29-30, and 35 under provisional nonstatutory double patenting have been fully considered and found persuasive. As such said rejections of claim(s) 14, 21, 27, 29-30, and 35 have been withdrawn. Examiner notes that although the instantly claimed bispecific antibody is 100% query match to the bispecific anti-VEGFAxPD1, (i.e., VP101 or AK112), as a part of a composition of the reference applications, the combination or use of said bispecific antibody in combination with additional pharmaceutically active agents (¶0062 of the instant specification, filed 24MAY2022) is not recited in the instantly claimed invention.
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.
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Claims 14, 21, 27, 29-30, and 35 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12,195,527 B2 (included in IDS filed 10SEP2025, herein referred to as “’527.” Although the claims at issue are not identical, they are not patentably distinct from each other because the bispecific anti-VEGFA x PD1 antibody of the ‘527 patent anticipates the bispecific anti-VEGFA x PD1 antibody of the instant application. Specifically, both products are drawn to a bispecific antibody comprising an anti-VEGFA IgG antibody having the same VH and VL and two anti-PD1 single chain antibodies comprising the same VH and VL and the same linkers for the VH/VL of the single chain antibodies and to link the single chain antibodies to the HC of the Ig antibody and pharmaceutical compositions thereof. In this instance, because the VH and VL of the anti-VEGFA IgG1 are the same as the instant application, the VH and VL comprise constant regions of an IgG antibody, the VH and VL of the anti-PD1 scFvs are the same as the instant application, the linkers are the same as the instant application, and the pharmaceutical compositions comprise the bispecific antibody and a pharmaceutically acceptable excipient there is no clear difference in the scope between the products of the instant application and the ’527 patent (see OA.APPENDIX).
Applicants argue (p 21-22) that Examiner failed to establish a prima facie case of unpatentability, accounting for each and every feature of the claims, as recited in the claims, and that the assertions with reference to the sequence alignments do not establish that the claims of ‘527 recite “the same” amino acid sequences and arrangements thereof as in the present claims, let alone identify why the differences between the present claims and the claims of ‘527 are allegedly obvious.
RESPONSE
Applicant’s arguments have been fully considered but are found non-persuasive essentially for the reasons of record and as described further below.
In response to Applicant’s argument that the Examiner failed to establish a prima facie case of unpatentability, the ‘527 patent fails to show all features of the invention, and why the ‘527 is allegedly obvious, it is expanded upon that both bispecific antibodies of the ‘527 patent and the instant application comprise or consist of an anti-VEGFA immunoglobulin and two anti-PD1 scFv antibodies, wherein the anti-VEGFA Ig comprises or consists of a VH (i.e., SEQ ID NO: 5 of the ‘527 patent)-IgG1 constant region HC (i.e., SEQ ID NO: 24 of the instant application) and a VL (i.e., SEQ ID NO: 7 of the ‘527 patent)-Ig kappa constant region LC (i.e., SEQ ID NO: 26), wherein the two anti-PD1 scFv comprise or consist of a VH-linker-VL or VL-linker-VH (i.e., SEQ ID NOs: 9-13-11 or 11-13-9 of the ‘527 patent or SEQ ID NOs: 9-18-17 or 17-18-9 of the instant application, see OA.APPENDIX), and wherein an anti-PD1 scFv is linked via SEQ ID NO: 13 (i.e., 100% query match to SEQ ID NO: 18) to each C-terminus of the HC of the anti-VEGFA Ig (i.e., the HC of the anti-Ig comprises or consists of SEQ ID NO:5-IgG1 constant region-SEQ ID NO: 13-SEQ ID NOs: 9-13-11 or 11-13-9, which anticipates the fusion of SEQ ID NOs: 24-18-9-18-17 or 24-18-17-18-9 of the instant application, see OA.APPENDIX).
Issued claims of the ‘527 patent:
Instant Application patent claims, underline corresponds to direct mapping to claim 1 of the ‘527 patent and italics corresponds to the additional claim limitations.
1. A bispecific antibody, wherein the bispecific antibody comprises: (a) an anti-VEGFA IgG1 immunoglobulin that binds to human VEGFA, wherein the anti-VEGFA IgG1 immunoglobulin comprises two pairs of polypeptide chains, wherein each of the two pairs of polypeptide chains comprises a heavy chain polypeptide and a light chain polypeptide, wherein: (i) the heavy chain polypeptide comprises: a heavy chain variable region (VH region), wherein the amino acid sequence of the VH region is set forth in SEQ ID NO:5, and a human Ig gamma-1 chain constant region; and (ii) the light chain polypeptide comprises: a light chain variable region (VL region), wherein the amino acid sequence of the VL region is set forth in SEQ ID NO:7, and a human Ig kappa constant region; and (b) two anti-PD-1 single chain antibodies that bind to human PD-1, wherein each of the two anti-PD-1 single chain antibodies comprises: (i) a VH region, wherein the amino acid sequence of the VH region is set forth in SEQ ID NO:9, and (ii) a VL region, wherein the amino acid sequence of the VL region is set forth in SEQ ID NO:11, wherein the VH region and the VL region of one of the two anti-PD-1 single chain antibodies are linked by a first linker having the amino acid sequence set forth in SEQ ID NO:13, and the VH region and the VL region of the other of the two anti-PD-1 single chain antibodies are linked by a second linker having the amino acid sequence set forth in SEQ ID NO:13; and wherein one terminus of one of the two anti-PD-1 single chain antibodies is linked to the C-terminus of one of the two heavy chain polypeptides of the anti-VEGFA IgG1 immunoglobulin via a third linker having the amino acid sequence set forth in SEQ ID NO:13 and wherein one terminus of the other of the two anti-PD-1 single chain antibodies is linked to the C-terminus of the other of the two heavy chain polypeptides of the anti-VEGFA IgG1 immunoglobulin via a fourth linker having the amino acid sequence set forth in SEQ ID NO:13.
6. A pharmaceutical composition comprising the bispecific antibody according to claim 1 and a pharmaceutically acceptable excipient.
8. A bispecific antibody in IgG-scFv form, wherein: (a) the IgG portion of the bispecific antibody is an anti-human VEGFA immunoglobulin, wherein the anti-human VEGFA immunoglobulin comprises two pairs of polypeptide chains, wherein each of the two pairs of polypeptide chains comprises a heavy chain polypeptide and a light chain polypeptide, wherein: (a)(i) the heavy chain polypeptide comprises a heavy chain variable region (VH region), wherein the amino acid sequence of the VH region is set forth in SEQ ID NO:5; and (a)(ii) the light chain polypeptide comprises a light chain variable region (VL region), wherein the amino acid sequence of the VL region is set forth in SEQ ID NO:7; and (b) the scFv portion of the bispecific antibody is two anti-human PD-1 single chain antibodies, wherein each of the two anti-human PD-1 single-chain antibodies comprises: (b)(i) the amino acid sequence set forth in SEQ ID NO:9, linked via (b)(ii) a linker to (b)(iii) the amino acid sequence set forth in SEQ ID NO:11, wherein one terminus of each of the two anti-human PD-1 single chain antibodies is linked to the C-terminus of one of the two heavy chain polypeptides of the anti-human VEGFA immunoglobulin via a linker, and wherein the linker of (b)(ii) and the linker linking a terminus of an anti-human PD-1 single chain antibody to the C-terminus of one of the two heavy chain polypeptides are each independently a [GGGGS (SEQ ID NO: 14)]m linker, wherein m is 1, 2, 3, 4, 5, or 6.
14. A bispecific antibody, comprising: two anti-PD1 single chain antibodies and an anti-VEGFA immunoglobulin, wherein the amino acid sequence of the HC of the anti-VEGFA Ig is set forth in SEQ ID NO: 24, and the amino acid sequence of the LC of the anti-VEGFA Ig is set forth in SEQ ID NO: 26; and for each of the two anti-PD1 single chain antibodies: the amino acid sequence of the heavy chain variable region of the single chain antibody is set forth in SEQ ID NO: 9, and the amino acid sequence of the light chain variable region of the single chain antibody is set forth in SEQ ID NO: 17; the single chain antibody is linked to the C-terminus of one HC of Ig; the single chain antibody is linked to the Ig via a first linker fragment; and the heavy chain variable region of the single chain antibody is linked to the light chain variable region of the single chain antibody via a second linker fragment; and the first linker fragment and the second linker fragment are the same or different, wherein the amino acid sequences of the first linker fragment and second linker fragment are independently selected from SEQ ID NO: 18 and SEQ ID NO: 19.
21. A pharmaceutical composition, comprising the bispecific antibody of claim 14 and a pharmaceutically acceptable vector and/or excipient.
27. The bispecific antibody of claim 14, consisting of the immunoglobulin and the two single chain antibodies.
28. A bispecific antibody, comprising: (a) an anti-VEGFA immunoglobulin comprising two pairs of polypeptide chains, wherein each of the two pairs of polypeptide chains comprises a heavy chain and a light chain, wherein the amino acid sequence of the heavy chain is set forth in SEQ ID NO: 24, and the amino acid sequence of the light chain is set forth in SEQ ID NO: 26; and (b) two anti-PD-1 single chain antibodies, wherein, for each of the two anti-PD-1 single chain antibodies: the amino acid sequence of the VH region is set forth in SEQ ID NO: 9; the amino acid sequence of the VL region is set forth in SEQ ID NO: 17; and the VH region and the VL region are linked by a linker fragment, wherein the amino acid sequence of the linker fragment is set forth in SEQ ID NO: 18,wherein the N-terminus of the VH region of one of the two anti-PD-1 single chain antibodies is linked to the C-terminus of one heavy chain of the immunoglobulin via a linker fragment, wherein the amino acid sequence of the linker fragment is set forth in SEQ ID NO: 18, and the N-terminus of the VH region of the other of the two anti-PD-1 single chain antibodies is linked to the C-terminus of the other heavy chain of the immunoglobulin via a linker fragment, wherein the amino acid sequence of the linker fragment is set forth in SEQ ID NO: 18.
30. The bispecific antibody of claim 29, consisting of the anti- VEGFA immunoglobulin and the two anti-PD-1 single chain antibodies.
35. A pharmaceutical composition, comprising the bispecific antibody of claim 29 and a pharmaceutically acceptable vector and/or excipient.
In this instance, because claims 1 and 8 of the ‘527 patent are silent on the IgG1 constant region and Ig kappa constant region, the specification was consulted to determine the scope of the bispecific anti-VEGFA x PD1 antibody, specifically the immunoglobulin construct. Per the specification of the ‘527 patent, the inventors have acquired a humanized bifunctional antibody named VP101, which is capable of simultaneously binding to VEGFA and PD1, wherein in some embodiments of the present application, the bispecific antibody is provided wherein the Ig comprises constant regions derived from a human antibody; preferably the constant regions of the Ig are selected from constant regions of human IgG1, IgG2, IgG3, and IgG4, or wherein the HC constant region is human IgG1 chain C region, or human IgG4 chain C region, and its LC constant region is human Ig kappa chain C region, or wherein the constant regions of the immunoglobulin are humanized, for example each HC constant region is IgG1 chain C region, UniProt #P01857 (i.e., 99.4% local similarity to aa 124-453 of SEQ ID NO: 24 of the instant application) and each LC constant region is Ig kappa chain C region, UniProt #P01834 (i.e., 100% local similarity to aa 109-214 of SEQ ID NO: 26 of the instant application) (see col 4, lines 7-9 and col 6, lines 22-40).
Therefore, the bispecific antibody of the ‘527 antibody anticipates the sequences of the bispecific antibody of the instant application, and additionally the arrangement of the ‘527 bispecific antibody (i.e., two anti-VEGFA HC each linked to an anti-PD1 scFv via the C-terminus and two anti-VEGFA LC) anticipates the arrangement of the bispecific antibody of the instant application. Furthermore, because the bispecific antibody of the ‘527 anticipates the sequences and arrangement of the bispecific antibody of the instant application, there is no clear difference in the scope between the products of the instant application and the ’527 patent.
Allowable Subject Matter
Claims 18-19 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Examiner notes that CN109053895 A (Li, Baiyong, et al., 21DEC2018, included in IDS) teaches a conjugate comprising VP101 and a detectable label and a kit comprising VP101 and further comprising a second antibody capable of specifically binding the bispecific antibody, optionally the second antibody further comprises a detectable label; however, upon perfection of priority for the instant application, the CN109053895 A art would be moot.
Conclusion
Claims 14, 21, 27, 29-30, and 35 are rejected.
Claims 18-19 are objected to.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMANTHA L. HOPKINS whose telephone number is (703)756-4666. The examiner can normally be reached Mon-Thurs 6:00 AM to 4:00 PM EST.
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/SAMANTHA LAKE HOPKINS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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