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 .
Election/Restriction
Applicant’s election without traverse of Invention I (i.e., claims 1-14 and 39) and species of A) artificial peptide linker: SEQ ID NO: 150; B) first and second antigen: VEGF/PD-1; C) VH-A, VH-B, and VL sequences: SEQ ID NOs: 20, 11, and 15 respectively; and D) polypeptide chain and common light chain sequences of claim 14: none correspond to elected SEQ ID NOs: 20, 11, and 15, in the reply filed on 28MAR2025 is acknowledged. Upon further consideration claim 12 has been withdrawn as the VHA or VHB of SEQ ID NO: 83 is drawn to a nonelected species of the PD-1 VHA or VHB of SEQ ID NO: 11 (see OA.APPENDIX for comparison of SEQ ID NO: 83 and SEQ ID NO: 11 of the instant application).
Claims 12, 14-20 and 23-38 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 28MAR2025.
Claim Status
Applicant’s amendments received 06OCT2025 are acknowledged.
Claims 4, 11, 21-22, 28, 35, and 39-40 have been canceled.
Claims 1, 3, 5, 13-17, 25, 29, and 37-38 have been amended.
Claims 1-3, 5-10, 12-20, 23-27, 29-34, and 36-38 (i.e., Claims 1 and 25 are independent) are pending in the instant application.
Claims 12, 14-20, 23-27, 29-34, and 36-38 remain withdrawn.
Claims 1-3, 5-10, and 13 are examined on the merits.
Priority
The present application is a 371 National Stage of PCT International Application No. PCT/CN2021/088153, filed 19APR2021, which claims foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy of CN202010357134.4 filed on 29APR2020 has been received and is acknowledged.
Information Disclosure Statement
The information disclosure statement(s) (IDS) submitted on 06OCT2025 (2x) is/are acknowledged and the references cited therein have been considered.
Specification
Applicant’s arguments, see p 19, filed 06OCT2025, with respect to objections to the specification for minor informalities have been fully considered and said objections to the specification have been withdrawn in view of amendments to the specification filed as part of said response.
Upon further consideration the disclosure is objected to because of the following informalities:
The CROSS-REFERENCE TO RELATED APPLICATIONS section is missing.
The SEQ ID NO used to identify “three GGGGS (SEQ ID NO: 156 in tandem)” should be updated to “(GGGGS)3 (SEQ ID NO: 150)” for the purpose of clarity on p 29, line 28 and p 30, line 1 for example. All other locations should be updated appropriately.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-3, 6-10, and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the peptide linker is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the lengths of the artificial peptide linkers is going to result in a variety of overall HC or polypeptide chain conformations (e.g., in the instance of GS vs (GGGGS)3, the GS linker is going to constrict the structure more than the highly flexible (GGGGS)3 linker) and there is an expansive list of alternatives (i.e., 37 different artificial linker peptide sequences). Claims 2-3, 6-10, and 13 are also rejected since they depend on claim 1, but do not remedy this deficiency.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim 9 contains the mutation of “S228P” in the IgG4; however there is no numbering scheme such as Kabat or EU numbering, which renders the claim indefinite.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Scope of Enablement
Claims 1-3, 5-10, and 13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for:
“A tetravalent bispecific antibody, characterized in that, the tetravalent bispecific antibody comprises:
two identical polypeptide chains, wherein each of the identical peptide chains comprises VHB-CH1-SEQ ID NO: 150-VHA-CH1-CH2-CH3; and
four identical common light chains, wherein each identical common LC comprises VL-CL;
wherein the VHA/VHB is VEGF/PD1 or PD1/VEGF; wherein the VH of PD1 comprises SEQ ID NO: 11; the VH of VEGF comprises SEQ ID NO: 20; and the VL comprises SEQ ID NO: 15; and wherein each of the polypeptide chains comprise the S228P mutation in the hinge region of an IgG4 (Kabat numbering);” does not reasonably provide enablement for more. Claims 2-3, 5-10, and 13 are also rejected since they depend on claim 1, but do not remedy this deficiency. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Scope of the claim:
In the instance of claim 1, drawn to a tetravalent bispecific antibody against PD-1/VEGF, wherein the tetravalent bispecific antibody comprises: two identical polypeptide chains, wherein each of the identical polypeptide chains comprises VHB-CH1-peptide linker-VHA-CH1-CH2-CH3 from N- to C-terminus and four identical common light chains, wherein each identical LC comprises VL-CL; and wherein the peptide linker is an artificial peptide linker selected from the group consisting of G, GS, SG, GGS, SGG, GGG, GGGS, etc. (i.e., 37 different linker peptides), is not fully enabled. Claim 1 is not fully enabled because:
The breadth of PD1 and VEGF VH-CH1 regions and then the necessary screening to identify four identical VL-CL regions which will effectively pair with the PD1 and VEGF VH-CH1 regions;
The breadth of artificial peptide linker (see discussion supra);
The lack of predictability in the art; and
Therefore the undue experimentation required of one of ordinary skill in the art to make and use the tetravalent bispecific antibody as currently claimed.
Direction provided by the inventor and existence of working examples:
The specification discloses a variety of tetravalent bispecific antibodies comprising two identical polypeptide HCs and four identical LCs targeting a variety of antigens: VEGF x PD1, TGFß x PD1, HER2 x CD47, HER2 x CD137, PD1 x CD137, PD1 x CD40, PD1 x CTLA4, PD1 x EGFR, PD1 x PDL1, and PD1 x LAG3. Working example 1 of the specification discloses, construction of bispecific antibodies comprising VEGF x PD1, wherein the polypeptide HCs comprise the VH of known anti-VEGF antibodies of bevacizumab (i.e., SEQ ID NO: 1) and Y0313-1 (i.e., SEQ ID NO: 20), a CH1 region, a peptide linker of SEQ ID NO: 150, a known murine anti-human PD1 monoclonal antibody (i.e., clone 20) which was humanized resulting in SEQ ID NO: 11, a CH1-CH2-CH3 IgG4 region having the S228P mutation in the hinge sequence and the four identical LCs were a identified by screening eight point mutated LCs of bevacizumab (i.e., 601) resulting in 601-LC-V94L (i.e., SEQ ID NO: 15) being able to maintain binding affinity to both PD1 and VEGF when paired with the corresponding HC (p 26-36). Although, this example supports a tetravalent bispecific antibody of PD1 x VEGF, it is unclear whether the same effect could be observed, (i.e., binding of PD1 and VEGF with the same four identical light chains) if an alternative anti-PD1 and/or anti-VEGF VH were used, for example pembrolizumab and/or aflibercept, respectively, or if an alternative linker were used. In this instance, there is no disclosure or guidance provided regarding making or using the tetravalent bispecific antibody without identification of specific VHA, VHB, peptide linker, VL with appropriate point mutation, and appropriate mutation of S228P in the IgG4 sequences.
State of prior art and level of predictability in the art:
Furthermore, the literature teaches unless you know that the VL is not essential for binding the epitope of interest, finding a common light chain is an intensive process. For example, Shiraiwa, et al., (Methods, 2019 (available online 13OCT2018), 154, 10-20) teaches the methods up to 2018 for identifying common LCs in a bispecific antibody, as well as a combination of methods for engineering a bispecific antibody by FR/CDR shuffling to identify a common LC, followed by additional back mutations of the LC to improve binding affinity, wherein screening of point mutations at positions 25, 27a, 27b, 33, 34, 56, and 89 of the LC were used to identify the LC which was able to maintain binding affinity to both antigens (Abstract, Section 4.5, Table 1 and Table 3). Alternatively, Zhao, et al., (Mabs, 2022, 14, 1-14) teach that in the instance of anti-PD1 Fab clone 609, the VL is negligibly involved in binding the PD1 antigen according to the solved crystal structure and therefore the LCs of unrelated antibodies were able to pair with the VH of anti-PD1 Fab clone 609 and maintain binding to PD1 without mutation to the LCs (i.e., 7 of the 12 hybrids were able to efficiently bind PD1) (see abstract, Fig 1 and Fig 2A, and Table 3). Therefore the literature supports that the process of making bispecific common LC antibodies requires significant screening or a very precise understanding of the VL involvement in antigen binding to be able to pair a variety of LC without significant mutation or back mutation and maintain binding.
Quantity of experimentation needed to make or use the invention based on the disclosure:
Thus, one skilled in the art would be unable to make and/or use the tetravalent VEGF x PD1 bispecific antibody comprising two identical HC polypeptides and four identical LC polypeptides as currently claimed. Therefore, the implementation of the invention in view of the unclear nature (i.e., whether the point mutated LC of SEQ ID NO: 15 would work as a common LC for all anti-PD1 and/or anti-VEGF VH pairs), breadth of variables (i.e., anti-PD1 and anti-VEGF VH regions and linkers), lack of predictability in the art (i.e., amount of screening required to engineer bispecific common LC antibodies), and the lack of working examples utilizing alternate peptide linkers, non-S228P mutated IgG4, and alternative anti-PD1 VH with the VL of SEQ ID NO: 15, would require undue experimentation for one of ordinary skill in the art to make and/or use the tetravalent VEGF x PD1 bispecific antibody comprising two identical HC polypeptides and four identical LC polypeptides as instantly claimed.
Claim Rejections - 35 USC § 102
Applicant’s arguments, see p 19-20, Rejection under 35 USC §102(a)(1) section, filed 06OCT2025, with respect to the rejection(s) of claim(s) 1-3, 6-8, 10, 11, and 39 (claims 11 and 39 have been cancelled) under 35 USC §102 have been fully considered and are fully persuasive because of the claim amendments which add limitations not taught in the cited art. As such, said rejection of claims 1-3, 6-8, and 10 under 35 USC §102 have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant’s arguments, see p 21-23, Rejection under 35 USC §103 section, filed 06OCT2025, with respect to the rejection(s) of claim(s) 1 and 4-10 (claim 4 is cancelled) under 35 USC §103 have been fully considered and said rejections of claims 1 and 5-10 have been withdrawn in view of the claim amendments filed as part of said response.
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.
Applicant’s arguments, see p 23-25, Rejection for Double patenting section, filed 06OCT2025, with respect to the rejection(s) of claims 1-10, 12, and 39 (claims 4 and 39 have been cancelled) under nonstatutory double patenting as being unpatentable over U.S. Patent No. US 12,269,886 and provisional nonstatutory double patenting as being unpatentable over 17/572039 and 17/571975 have been fully considered and said rejections of claims 1-3, 5-10, and 12 have been withdrawn in view of the claim amendments filed as part of said response.
Applicant’s arguments, see p 23-25, Rejection for Double patenting section, filed 06OCT2025, with respect to the rejection(s) of claims 1-11 and 13 (claim 4 has been cancelled) under provisional nonstatutory double patenting as being unpatentable over 17/532039 have been fully considered. Applicant has asked that the provisional nonstatutory double patenting rejections be addressed once patentable subject matter in the reference application is identified. Given that the Applicant has not filed terminal disclaimers and has not amended the claims of the instant or reference applications to provide patentable distinctiveness the provisional nonstatutory double patenting rejections are maintained.
Claims 1-3, 5-10, and 13 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of co-pending Application No. 17/571894; herein referred to as the “reference application.” Although the claims at issue are not identical, they are not patentably distinct from each other because the PD1xVEGF tetravalent bispecific antibody of the reference application anticipates the PD1xVEGF tetravalent bispecific antibody of the instant application. Specifically, both tetravalent bispecific antibodies comprise two polypeptide chains and four common light chains, wherein the polypeptide chains comprise a VHB-CH1-peptide linker-VHA-CH1-CH2-CH3 which are set forth in SEQ ID NO: 21 of the reference application, wherein in SEQ ID NO: 21, VHB binds PD-1 and VHA binds VEGF, the peptide linker consists of an artificial linker (GGGGS)3 (i.e., SEQ ID NO: 150), and the CH1 and CH1-CH2-CH3 regions are derived from an IgG4 containing the S228P mutation (i.e., 99.4% query match to the fusion of SEQ ID NOs: 11 fus 150 fus 20 fus 148 of the instant application) and wherein the four common light chains comprise VL-CL, which are set forth in SEQ ID NO: 13 (i.e., 100% query match to SEQ ID NO: 15 or the VL of the instant application).
The co-pending claim of the reference application recite: A tetravalent bispecific antibody against PD-1 and VEGF, wherein the tetravalent bispecific antibody comprises two polypeptide chains and four common light chains, an amino acid sequence of the polypeptide chain is shown as SEQ ID NO: 21 and an amino acid sequence of the common light chain is shown as SEQ ID NO: 13 (i.e., claim 1).
In this instance, because the VHB-CH1-peptide linker-VHA-CH1-CH2-CH3 polypeptide components of the instant application are equivalent to SEQ ID NO: 21 of the reference application and because the VL-CL common light chain components of the instant application are equivalent to SEQ ID NO: 13 of the reference application, there is no clear difference in the scope between the products of the instant and reference applications. Specifically, SEQ ID NO: 21 of the reference application, comprises 20-Fab-0313-IgG4 (see Table 1 of the reference application) (i.e., wherein “20-Fab” is equivalent to VHB-CH1 and “20” denotes the VH which binds PD-1, set forth in SEQ ID NO: 11 of the instant application; wherein the artificial peptide linker is equivalent to (GGGGS)3 set forth in SEQ ID NO: 150 of the instant application; wherein “0313” is equivalent to VHA and denotes the VH which binds VEGF, set forth in SEQ ID NO: 20 of the instant application; and wherein “IgG4” is equivalent to the CH1-CH2-CH3 IgG4 (S228P) set forth in SEQ ID NO: 148 of the instant application) (see OA.APPENDIX) and because SEQ ID NO: 13 of the reference application, comprises the VL-CL of 601-LC-V94L (see Table 1 of the reference application) wherein the VL is set forth in SEQ ID NO: 15 of the instant application (see OA.APPENDIX).
Furthermore, per MPEP §2113, even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself (i.e., the patentability of the product does not depend on its method of production). In this instance, the claimed product-by-process is a tetravalent bispecific antibody comprising two polypeptide chains which each comprise VHB-CH1-peptide linker-VHA-CH1-CH2-CH3 and four common light chains, which bind two antigens and the reference application teaches two polypeptide chains each of which comprise VH1-linker-VH2-CH1-CH2-CH3 and four common light chains, wherein the linker is CH1-hinge (i.e., CH1-peptide linker), which bind two antigens (i.e., tetravalent bispecific antibody) by determining the most suitable VH for a single VL via phage screening or the like. Given that the reference application teachings are drawn to antibodies comprising two polypeptide chains which each comprise VHB-CH1-peptide linker-VHA-CH1-CH2-CH3 and four common light chains, which bind two or more antigens (i.e., multispecific multivalent antibodies), while the instant claimed invention can be any PD1 x VEGF bispecific antibody comprising two polypeptide chains which each comprise VHB-CH1-peptide linker-VHA-CH1-CH2-CH3 and four common light chains, which bind two antigens, the reference application necessarily anticipates the breadth of the instant claimed invention.
In response, it is suggested that applicant either file a terminal disclaimer or amend the claims such that a clear and unmistakable line of separation exists between the products claimed in the instant application and those of the reference application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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