DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed October 10, 2025 is pending.
Claims 1-33, 35, 36 are canceled.
Claims 34 and 37-57 are pending.
Claims 47-49, 51, and 54-57 have been withdrawn under 37 CFR 1.142(b) as being drawn to a nonelected group.
Claims 34, 37-46, 50, 52, and 53 are currently under consideration.
In view of the applicant’s amendment filed on October 10, 2025, the following rejections are set forth.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 34, 37, 38, 40-45, 50, 52, and 53 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) in view of McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025).
Li et al. teach a bifunctional antibody comprising a first functional area that targets PD-1 and a second function area that targets CTLA4 (e.g. see claim 1). The first and second functional areas are independently an immunoglobulin or an antigen-binding fragment, for example, a single-chain antibody (e.g. see claim 1). Li et al. also disclose that the immunoglobulin is IgG1 and the bifunctional antibody has the same CDRs as recited in instant claim 1 (e.g. see antibodies 4G10 and 14C12 and claims 5 and 7). Li et al. also teach the instantly claimed VH amino acid sequences of SEQ ID NOs: 2, 6, 10, and 14; and VL amino acid sequences of SEQ ID NOs: 4, 8, 12, and 16. See sequences alignments for VH and VL in the Office Action mailed on July 11, 2025.
Li et al. also teach that the first protein function area and the second protein function area are directly connected to or are connected by a junction fragment; preferably, the junction fragment is(GGGGS)n, where n is a positive integer, such as 1, 2, 3, 4, 5 or 6 (e.g. see claim 2). Li et al. also teach that the single-chain antibody is connected to the C-terminal of the heavy chain of immunoglobulin (e.g. see claim 6). Li et al. further teach a conjugate that includes the bispecific antibody and coupling moiety, wherein the coupling moiety is a detectable marker; specifically a radioisotope, fluorescent material, luminescent substance, coloring matter or enzyme (e.g. see claim 16); and a pharmaceutical composition that includes the bispecific antibody and pharmaceutically acceptable carrier and/or excipient (e.g. see claim 19).
Li et al. also teach that their bispecific antibodies, BiAb003, BiAb004 and 14C12H1L1, were combined with the T cell antibodies 4G10H3L3, Nilolumab, and Ipilimumab, which are considered to be anti-tumor chemotherapeutics (e.g. see page 34, example 3.3). This antibody combination was applied to CD4+ PBMCs in the presence of buffer (e.g. see page 34, example 3.3).
The reference teachings differ from the instant invention by not teaching that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A according to the EU numbering system.
McCarthy et al. teach antibody and other Fc-containing molecules with variations in the Fc region with reduced binding to Fc gamma receptors and resulting activity that can be used in the treatment of various diseases and disorders (e.g. see Abstract). McCarthy et al. also teach recombinant polypeptides comprising (a) a binding domain capable of binding a target molecule; and (b) an Fc domain comprising a mutated IgG1 constant domain comprising mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; wherein the binding molecule is capable of binding the target molecule without triggering significant complement dependent lysis or cell mediated destruction of the target (e.g. see [0011]). Specifically, the mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S in IgG1 reduce binding to FcγRI, FcγRII, and FcγRIII, and reduce ADCC and CDC activities (e.g. see [0050]). CDC refers to the form of cytotoxicity in which the complement cascade is activated by the complement component C1q binding to antibody Fc (e.g. see [0034]).
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Li et al. to incorporate the teachings of McCarthy et al. to include that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A. Given the well-known and favorable effector-function-reducing properties of antibodies that comprise the Fc mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; it would have been obvious to a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to have experimented with modifying Li et al.’s anti-PD-1/CTLA-4 bispecific antibody to further comprise the L234A, L235A, and G237A mutations described by McCarthy et al. in the Fc domain with a reasonable expectation of success.
It is noted that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03. This applies to the instant case where claim 34 recites that the heavy chain constant region “comprises amino acid mutations consisting of L234A, L235A, and G237A.” Therefore, given the broadest reasonable interpretation, the heavy chain may comprise additional mutations to the L234A, L235A, and G237A, such as those recited in McCarthy et al. (i.e. P238A, H268A, A330S and P331S).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
The Applicant’s arguments have been fully considered but have not been found persuasive.
The Applicant argues that:
The effect of Fc mutations in the context of antibodies is unpredictable. This is demonstrated by the data provided in the application which shows that the same Fc mutations result in disparate effect on the Fc region of antibodies having different variable domains. As shown in Example 7 and Table 7 of the present application, a control anti-PD-L1 antibody 5C10H2L2-IgG1mt, which contains the same Fc mutations (i.e., L234A, L235A, and G237A) as the instantly claimed antibody but different variable regions that target PD-L1, exhibited binding activity to complement Clq that is responsible for complement-dependent cytotoxicity (CDC). In stark contrast, the instantly claimed antibody as represented by BiAb004(hGITM) displays no measurable binding to complement Clq. Thus, the effect of Fc mutations comprising L234A, L235A, and G237A depends heavily on the context of the rest of the antibody (e.g., the variable domains). The abolished C1q binding and inhibition of CDC is therefore an unexpected benefit of the presently claimed antibodies that cannot be predicted from the performance of these mutations in the context of another antibody.
This is not found persuasive for the following reasons:
Contrary to the Applicant’s argument that the L234A, L235A, and G237A mutations unexpectedly resulted in abolished C1q binding and inhibition of CDC, a benefit which cannot be predictably translated to another antibody; it is noted that McCarthy et al. clearly teach that the L234A, L235A, G237A, P238A, H268A, A330S and P331S mutations in IgG1 antibodies, in general, reduce binding to FcγRI, FcγRII, and FcγRIII, and reduce ADCC and CDC activities. It is noted that CDC is a form of cytotoxicity in which the complement cascade is activated by C1q binding to antibody Fc (McCarthy et al.). Thus, the reduced CDC activity by McCarthy et al.’s IgG1 Fc mutants would presumably be the result of inhibiting C1q binding to Fc. Fc region mutations are generally known to be transferable to any antibody with a reasonable expectation of success.
Furthermore, while the Applicant asserts that the effect of Fc mutations comprising L234A, L235A, and G237A depends heavily on the context of the rest of the antibody (e.g., the variable domains); Li et al. disclose an antibody comprising a variable domain that is identical to instant BiAb004(hGITM). Thus, the anti-PD-1/CTLA-4 bispecific antibody comprising the L234A, L235A, and G237A mutations taught by Li et al. in view of McCarthy et al. would have the same structure as the BiAb004(hGITM) disclosed in the specification and would necessarily have the same function of no measurable binding to complement Clq as asserted by the Applicant, especially in the absence of evidence to the contrary.
Thus, McCarthy et al. provides the motivation for a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to combine Li et al.’s teachings with McCarthy et al.’s and experiment with modifying Li et al.’s anti-PD-1/CTLA-4 bispecific antibody to further comprise the L234A, L235A, and G237A mutations described by McCarthy et al. in the Fc domain with a reasonable expectation of success.
As such, the applicant’s arguments have not been found persuasive.
Thus, claims 34, 37, 38, 40-45, 50, 52, and 53 stand rejected under 35 U.S.C. 103.
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.
Anticipation-type
As noted above, the Applicant requested that the anticipation-type NSDP rejections over the claims in co-pending Application Nos. 18/264,191, 18/291,128, 18/286,755, and 18/840,378 as set forth in the Office Action mailed on July 11, 2025 be held in abeyance until the claims are otherwise allowable.
Claim 52 stands provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 2 of copending Application No. 18/264,191 (the ‘191 Application) for the reasons of record.
Claim 52 stands provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 18/291,128 (the ‘128 Application) for the reasons of record.
Claims 34-36 and 40-44 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 9 of copending Application No. 18/286,755 (the ‘755 Application) for the reasons of record.
Claim 52 stands provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 9-18 and 20-22 of copending Application No. 18/840,378 (the ‘378 Application) for the reasons of record.
Obviousness-type
Claims 34 and 37-46 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 18/291,128 (the ‘128 Application) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) for the reasons of record.
Claims 34-46 stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 9-18 and 20-22 of copending Application No. 18/840,378 (the ‘378 Application) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) for the reasons of record.
Claims 34, 37, 38 and 40-45 stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claim 16 of co-pending Application 17/996,878 (the ‘878 Application) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) for the reasons of record.
Claims 34-38, 40-45, 50, 52 and 53 stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over the following co-pending applications in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) for similar reasons as discussed in the obviousness-type nonstatutory double patenting rejection to the ‘878 Application above for the reasons of record.
New Grounds of Obviousness-type NSDP
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 34, 37, 38, 40-45, 50, 52, and 53 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-12, 17, 20, and 22-28 of U.S. Patent No. 11,578,128, a reference of record, (the ‘128 Patent) in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025).
The instant claims are drawn to a bispecific antibody or an antigen-binding fragment thereof; a conjugate comprising the bispecific antibody or an antigen-binding fragment thereof and a conjugated moiety; and a pharmaceutical composition comprising the bispecific antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier or excipient.
Claims 1-12, 17, 20, and 22-28 of the ‘128 Patent are drawn to a bispecific antibody, or an antigen-binding fragment thereof, comprising the instantly claims CDRs; a conjugate, comprising the bispecific antibody, or the antigen-binding fragment thereof, and a conjugating partner as a detectable marker; and a pharmaceutical composition comprising the bispecific antibody, or the antigen-binding fragment thereof, and a pharmaceutically acceptable carrier or excipient.
The claims of the ‘128 Patent differ from the instant invention by not reciting that the immunoglobulin is of the human IgG1 subtype; or that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A according to the EU numbering system.
The teachings of Li et al. and McCarthy et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the ‘128 Patent’s anti-PD-1/CTLA-4 bispecific antibody to include that the immunoglobulin is of the human IgG1 subtype; and that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A.
IgG1 is the most common antibody subclass and widely used for the generation of bispecific antibody-based therapeutics. Thus, given the well-known applications of IgG1 in bispecific antibody-based therapeutics and favorable effector-function-reducing properties of antibodies that comprise the Fc mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; it would be obvious to a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to experiment with modifying the ‘128 Patent’s anti-PD-1/CTLA-4 bispecific antibody to be an IgG1-type antibody comprising the L234A, L235A, and G237A mutations described by McCarthy et al. with a reasonable expectation of success.
It is noted that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03. This applies to the instant case where claim 34 recites that the heavy chain constant region “comprises amino acid mutations consisting of L234A, L235A, and G237A.” Therefore, given the broadest reasonable interpretation, the heavy chain may comprise additional mutations to the L234A, L235A, and G237A, such as those recited in McCarthy et al. (i.e. P238A, H268A, A330S and P331S).
Therefore, the claims in the ‘128 Patent would render the instant claims obvious.
These are New Grounds of Rejection necessitated by applicant's amendment. Claims 34, 37, 38, 40-45, 50, 52, and 53 (and claims 39 and 46 in the case of the ‘755, ‘128, and ‘722 Applications) are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over the following co-pending applications in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025) for similar reasons as discussed in the obviousness-type nonstatutory double patenting rejection to the ‘128 Patent.
The instant claims are drawn to a bispecific antibody or an antigen-binding fragment thereof; a conjugate comprising the bispecific antibody or an antigen-binding fragment thereof and a conjugated moiety; and a pharmaceutical composition comprising the bispecific antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier or excipient).
Claims 1-15, and 17-19 of co-pending Application No. 18/024,471 are drawn to a pharmaceutical composition comprising the instantly claimed anti-PD-1/CTLA-4 bispecific antibody; a kit comprising the instantly claimed anti-PD-1/CTLA-4 bispecific antibody; a unit formulation comprising the instantly claimed anti-PD-1/CTLA-4 bispecific antibody; and a single dose unit comprising the instantly claimed anti-PD-1/CTLA-4 bispecific antibody.
Claims 1 and 3-20 of co-pending Application No. 18/264,191 are drawn to a therapeutic combination comprising an effective amount of a first bispecific antibody and an effective amount of a second bispecific antibody, wherein the first bispecific antibody is the instantly claimed anti-PD-1/CTLA-4 bispecific antibody.
Claims 1-8, 10-12, 14, 15, and 17 of co-pending Application 18/286,755 are drawn to the instantly claimed anti-PD-1/CTLA-4 bispecific antibody; a pharmaceutical composition for treating a tumor (particularly a malignant tumor), comprising an effective amount of the anti-CTLA4-anti-PD-1 bispecific antibody; use of the anti-CTLA4-anti-PD-1 bispecific antibody in preparing a medicament or a kit for preventing and/or treating a tumor (particularly a malignant tumor); a kit for preventing and/or treating a tumor (particularly a malignant tumor), comprising the anti-CTLA4-anti-PD-1 bispecific antibody; a unit formulation preferably used for treating a tumor (particularly a malignant tumor) comprising the anti-CTLA4-anti-PD-1 bispecific antibody; and a single dose unit, preferably used for treating a tumor (particularly a malignant tumor), and comprising the anti-CTLA4-anti-PD-1 bispecific antibody.
Claims 1, 2, 4, 5, and 7-11 of copending Application No. 18/291,128 are drawn to a pharmaceutical composition comprising the instantly claimed anti-PD-1/CTLA-4 bispecific antibody or an antigen-binding fragment thereof; a kit; a unit formulation; and a single dose unit.
Claim 11 of copending Application 18/250,010 is drawn to an anti-CD73 antibody or the antigen-binding fragment which is contained in a kit comprising the instantly claimed anti-PD-1/CTLA-4 bispecific antibody or an antigen-binding fragment thereof.
Claims 9-18 and 20-22 of 18/840,378 Application are drawn to a therapeutic combination comprising the instantly claimed anti-PD-1/CTLA-4 bispecific antibody or an antigen-binding fragment thereof. The phrases “therapeutic combination” and “pharmaceutical composition” can be used interchangeably.
Claims 1-19 and 22 of copending Application No. 19/162,722 are drawn to a therapeutic combination, comprising an anti-CTLA4-anti-PD-1 bispecific antibody and gemcitabine or a pharmaceutically acceptable salt thereof; a kit; and a method for treating or preventing a tumor.
Claims 1-25 of copending Application No. 19/365,106 are drawn to a bispecific antibody thereof, wherein, the first protein functional area binds to PD-1, and, the second protein functional area binds to CTLA4; an isolated nucleic acid molecule; a vector, a host cell line; a method for preparing the bispecific antibodies thereof; Conjugates; Reagent kits; Preparation of reagent kits; a pharmaceutical composition; Methods of producing drugs; the use of the said bispecific antibodies thereof; an in vivo or in vitro method to apply to cells or subjects in need with an effective dose of the said bispecific antibodies thereof; Usage of the bispecific antibodies thereof; and a method for the prevention and/or treatment and/or adjuvant treatment and/or diagnosis of tumors or anemia.
Claims 1-45 of copending Application No. 19/473,423 are drawn to uses of an anti-CTLA4-anti-PD-1 bispecific antibody or a pharmaceutical composition comprising the bispecific antibody; anti-CTLA4-anti-PD-1 bispecific antibodies; and methods for treating or preventing a malignant tumor of vulva.
The claims of the copending Applications differ from the instant invention by not reciting that the immunoglobulin is of the human IgG1 subtype; or that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A according to the EU numbering system.
The teachings of Li et al. and McCarthy et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to modify the copending Applications’ anti-PD-1/CTLA-4 bispecific antibodies to include that the immunoglobulin is of the human IgG1 subtype; and that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A.
IgG1 is the most common antibody subclass and widely used for the generation of bispecific antibody-based therapeutics. Thus, given the well-known applications of IgG1 in bispecific antibody-based therapeutics and favorable effector-function-reducing properties of antibodies that comprise the Fc mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; it would be obvious to a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to experiment with modifying the copending Applications’ anti-PD-1/CTLA-4 bispecific antibodies to be an IgG1-type antibody comprising the L234A, L235A, and G237A mutations described by McCarthy et al. with a reasonable expectation of success.
It is noted that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See MPEP 2111.03. This applies to the instant case where claim 34 recites that the heavy chain constant region “comprises amino acid mutations consisting of L234A, L235A, and G237A.” Therefore, given the broadest reasonable interpretation, the heavy chain may comprise additional mutations to the L234A, L235A, and G237A, such as those recited in McCarthy et al. (i.e. P238A, H268A, A330S and P331S).
Therefore, the claims in the copending Applications would render the instant claims obvious.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 34, 37, 38, 40-45, 50, 52, and 53 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-13 of U.S. Patent No. 11,479,608, a reference of record, (the ‘608 Patent) in view of in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025).
The instant claims are drawn to a bispecific antibody or an antigen-binding fragment thereof; a conjugate comprising the bispecific antibody or an antigen-binding fragment thereof and a conjugated moiety; and a pharmaceutical composition comprising the bispecific antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier or excipient).
Claims 1-13 of the ‘608 Patent are drawn to an antibody or antigen binding fragment thereof that binds to human CTLA4 and comprises the instantly claimed anti-CTLA4 CDRs (SEQ ID NOs: 33-38); and a pharmaceutical composition comprising the anti-CTLA antibody.
The claims of the ‘608 Patent differ from the instant invention by reciting an anti-PD-1/CTLA-4 bispecific antibody; that the immunoglobulin is of the human IgG1 subtype; or that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A.
The teachings of Li et al. and McCarthy et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to apply the ‘608 Patent’s anti-CTLA4 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody. Given that Li et al. teach a bifunctional antibody comprising a first functional area that targets PD-1 and a second function area that targets CTLA4; wherein the first functional area targeting PD-1 comprises the instantly claimed CDRs (instant SEQ ID NOs: 27-32) and the second function area targeting CTLA4 comprises identical CDRs to the ‘608 Patent’s anti-CTLA4 antibody (instant SEQ ID NOs: 33-38); it would be obvious to a skilled artisan to apply the ‘608 Patent’s anti-CTLA4 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody with a reasonable expectation of success since it has already been done.
Furthermore, the rationale for combining the teachings of the ‘608 Patent in view of Li et al. and McCarthy et al. to arrive at an IgG1 bispecific antibody comprising the of L234A, L235A, and G237A mutations in the Fc domain is similar to that which is outlined in the in the obviousness-type nonstatutory double patenting rejection to the ‘128 Patent above.
IgG1 is the most common antibody subclass and widely used for the generation of bispecific antibody-based therapeutics. Thus, given the well-known applications of IgG1 in bispecific antibody-based therapeutics and favorable effector-function-reducing properties of antibodies that comprise the Fc mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; it would be obvious to a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to experiment with modifying the anti-PD-1/CTLA-4 bispecific antibody that comprises the ‘608 Patent’s anti-CTLA4 antibody to be an IgG1-type antibody comprising the L234A, L235A, and G237A mutations described by McCarthy et al. with a reasonable expectation of success.
Therefore, the claims in the ‘608 Patent would render the instant claims obvious.
This is a New Ground of Rejection necessitated by applicant's amendment. Claims 34, 37, 38, 40-45, 50, 52, and 53 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 2, and 6 of U.S. Patent No. 12,076,398, a reference of record,(the ‘398 Patent) in view of in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025).
The instant claims are drawn to a bispecific antibody or an antigen-binding fragment thereof; a conjugate comprising the bispecific antibody or an antigen-binding fragment thereof and a conjugated moiety; and a pharmaceutical composition comprising the bispecific antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier or excipient).
Claim 1, 2, and 6 of the ‘398 Patent are drawn to a monospecific monoclonal antibody that binds to PD-1 and comprises the instantly claimed anti-PD-1 CDRs; and a pharmaceutical composition comprising the anti-PD-1 monospecific monoclonal antibody.
The claims of the ‘398 Patent differ from the instant invention by reciting an anti-PD-1/CTLA-4 bispecific antibody; that the immunoglobulin is of the human IgG1 subtype; or that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A.
The teachings of Li et al. and McCarthy et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to apply the ‘398 Patent’s anti-PD-1 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody. Given that Li et al. teach a bifunctional antibody comprising a first functional area that targets PD-1 and a second function area that targets CTLA4; wherein the first functional area targeting PD-1 comprises identical CDRs to the ‘398 Patent’s anti-PD-1 antibody (instant SEQ ID NOs: 27-32) and the second function area targeting CTLA4 comprises the instantly claimed CDRs (instant SEQ ID NOs: 33-38); it would be obvious to a skilled artisan to apply the ‘398 Patent’s anti-PD-1 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody with a reasonable expectation of success since it has already been done.
Furthermore, the rationale for combining the teachings of the ‘398 Patent in view of Li et al. and McCarthy et al. to arrive at an IgG1 bispecific antibody comprising the of L234A, L235A, and G237A mutations in the Fc domain is similar to that which is outlined in the in the obviousness-type nonstatutory double patenting rejection to the ‘128 Patent above.
IgG1 is the most common antibody subclass and widely used for the generation of bispecific antibody-based therapeutics. Thus, given the well-known applications of IgG1 in bispecific antibody-based therapeutics and favorable effector-function-reducing properties of antibodies that comprise the Fc mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; it would be obvious to a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to experiment with modifying the anti-PD-1/CTLA-4 bispecific antibody that comprises the ‘398 Patent’s anti-CTLA4 antibody to be an IgG1-type antibody comprising the L234A, L235A, and G237A mutations described by McCarthy et al. with a reasonable expectation of success.
Therefore, the claims in the ‘398 Patent would render the instant claims obvious.
These are New Grounds of Rejection necessitated by applicant's amendment. Claims 34, 37, 38, 40-45, 50, 52, and 53 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over the following co-pending applications in view of Li et al. 2017 (CN106967172A, an IDS reference filed September 21, 2022, please see English translation attached) and McCarthy et al. 2015 (US20150337053A1, an IDS reference filed 10/10/2025) for similar reasons as discussed in the obviousness-type nonstatutory double patenting rejection to the ‘398 Patent.
The instant claims are drawn to a bispecific antibody or an antigen-binding fragment thereof; a conjugate comprising the bispecific antibody or an antigen-binding fragment thereof and a conjugated moiety; and a pharmaceutical composition comprising the bispecific antibody or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier or excipient).
Claims 29-48 of copending Application 19/176,458 are drawn to a method for method for treating cancer in an entity, comprising administering to the entity a therapeutically effective amount of an anti-PD-1 antibody which comprises the anti-PD-1 CDRs of the instantly claims anti-PD-1/CTLA-4 bispecific antibody.
Claims 1-15 and 22 of copending Application 17/996,878 are drawn to an anti-CD73/anti-PD-1 bispecific antibody comprising the anti-PD-1 CDRs of the instantly claims anti-PD-1/CTLA-4 bispecific antibody.
Claims 16 and 19 of copending Application 18/696,546 are drawn to an anti-LAG3/anti-PD-1 bispecific antibodies comprising the anti-PD-1 CDRs of the instantly claims anti-PD-1/CTLA-4 bispecific antibody.
Claims 1, 2, 4, 5, 7, and 8 of copending Application 18/264,138 are drawn to a pharmaceutical composition comprising an anti-TIGIT antibody or an antigen-binding fragment thereof, and an anti-PD-1/anti-VEGFA bispecific antibody, wherein the anti-PD-1/anti-VEGFA bispecific antibody comprises the anti-PD-1 CDRs of the instantly claims anti-PD-1/CTLA-4 bispecific antibody; a kit; a unit formulation; and a single dose unit.
Claims 24, 35-39, 40, 43-55, and 58 of copending Application 17/272,121 are drawn to method for treating a malignant tumor in a human subject, the method comprising administering to the subject an effective amount of an anti-PD-1/VEGFA bispecific antibody which comprises the anti-PD-1 CDRs of the instantly claims anti-PD-1/CTLA-4 bispecific antibody.
The claims of the copending Applications differ from the instant invention by reciting an anti-PD-1/CTLA-4 bispecific antibody; that the immunoglobulin is of the human IgG1 subtype; or that the heavy chain constant region of the immunoglobulin comprises amino acid mutations consisting of L234A, L235A, and G237A.
The teachings of Li et al. and McCarthy et al. are outlined in the 103 rejection above.
It would be obvious to one of ordinary skill in the art to apply the copending Applications’ anti-PD-1 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody. Given that Li et al. teach a bifunctional antibody comprising a first functional area that targets PD-1 and a second function area that targets CTLA4; wherein the first functional area targeting PD-1 comprises identical CDRs to the ‘398 Patent’s anti-PD-1 antibody (instant SEQ ID NOs: 27-32) and the second function area targeting CTLA4 comprises the instantly claimed CDRs (instant SEQ ID NOs: 33-38); it would be obvious to a skilled artisan to apply the copending Applications’ anti-PD-1 antibody in Li et al.’s anti-PD-1/CTLA-4 bispecific antibody with a reasonable expectation of success since it has already been done.
Furthermore, the rationale for combining the teachings of the copending Application in view of Li et al. and McCarthy et al. to arrive at an IgG1 bispecific antibody comprising the of L234A, L235A, and G237A mutations in the Fc domain is similar to that which is outlined in the in the obviousness-type nonstatutory double patenting rejection to the ‘128 Patent above.
IgG1 is the most common antibody subclass and widely used for the generation of bispecific antibody-based therapeutics. Thus, given the well-known applications of IgG1 in bispecific antibody-based therapeutics and favorable effector-function-reducing properties of antibodies that comprise the Fc mutations L234A, L235A, G237A, P238A, H268A, A330S and P331S; it would be obvious to a skilled artisan, with the goal of designing an anti-PD-1/CTLA-4 bispecific antibody with reduced ADCC and CDC activity, to experiment with modifying the anti-PD-1/CTLA-4 bispecific antibody that comprises the copending Applications’ anti-PD-1 antibody to be an IgG1-type antibody comprising the L234A, L235A, and G237A mutations described by McCarthy et al. with a reasonable expectation of success.
Therefore, the claims in the copending Applications would render the instant claims obvious.
These are provisional nonstatutory double patenting rejections because the patentably indistinct claims have not in fact been patented.
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.
No claim is allowed.
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/GRACE H LUNDE/Examiner, Art Unit 1641
/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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