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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 02/13/2026 has been entered.
Response to Amendment
The rejection of claim 42 under 35 USC 112(d) is withdrawn in view of the amendment to claim 42 clarifying the sequence only differs by said W142H.
The rejection of claims under 35 USC 112(a) is withdrawn in view of the amendment to claim 34 reciting particular structural limitations; although, see new rejection under 35 USC 112(b) below.
Election/Restrictions
The restriction requirement for species of anti-human PD-1 antibodies, as set forth in the Office action mailed on 5/31/2024, has been reconsidered. The restriction requirement for anti-PD-1 antibody species is hereby withdrawn. Claims 37-39 and remainder of species in 40, directed to other species of anti-human PD-1 antibodies are no longer withdrawn from consideration.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claim Objections
Claims 41 and 44 are objected to because of the following informalities: In claim 41, line 3, the phrase “the sequence of” is missing after “having”. In claim 44, line 3, it appears after “or”, the group should be “C47S, C92S, C34S and C129S. If this was not the intent for claim 44, then clarity is required.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 34, 35, 48 and dependent claims 36, 40-49 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.
Claims 34 and 35 are indefinite because they recite, respectively, “full-length IgG Fc domain containing a constant heavy and constant light chain” and ”the heavy chain and/or the light chain of the Fc domain”. Fc domains are only part of the heavy chain. The light chain is separate and comprises its own constant domain.
Claim 48 is indefinite because it recites the IL-7 variant is linked to the PD-1 antibody or antigen-binding fragment thereof, however, the IL-7 variant is linked to the C-terminus of the Fc region or the light chain constant region, making the claim confusing. This rejection could be obviated by replacing “the anti-human PD-1 antibody or antigen-binding fragment thereof is linked to the IL-7 variant “ with --the covalent linkage is--.
Claim Rejections - 35 USC § 112(a)
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.
Claim 40 is 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 wherein the anti-PD-1 antibody has a publicly known sequence or is readily available, does not reasonably provide enablement for wherein the antibody sequence is not publicly known or readily available. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 40 recites a laundry list of antibodies by name only that bind human PD-1. Some have sequences that were known, e.g., nivolumab, and/or were commercially available before the instant invention was effectively filing. Others are listed by name and have no disclosed sequence or cannot be obtained. When the invention requires access to specific biological material, that material must be both known and readily available to meet the requirements under 35 USC 112(a), enablement. For an antibody, this can include it being commercially available or described by sequence so that the artisan of ordinary skill could readily obtain or make it. According to MPEP § 2404.01, “The concepts of "known and readily available" are considered to reflect a level of public accessibility to a necessary component of an invention disclosure that is consistent with an ability to make and use the invention. To avoid the need for a deposit on this basis, the biological material must be both known and readily available - neither concept alone is sufficient.”
The specification does not provide a repeatable method for obtaining all the antibodies listed in claim 40, e.g., AM-0001 or BAT-1306¸ and they do not all appear to be a known and readily available material. Biological deposit of the antibodies would satisfy the requirements of 35 USC §112(a). For each deposit made pursuant to these regulations, the specification shall contain: (1) The accession number for the deposit; (2) The date of the deposit; (3) A description of the deposited biological material sufficient to specifically identify it and to permit examination; and (4) The name and address of the depository. [See MPEP § 2404-2410.02, which list further requirements directed to whether or not the deposit is made under the Budapest Treaty, and see also 37 CFR 1.806-1.808.]
Claims 37 and 38 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims 37 and 38 depend from the bifunctional molecule of claim 34 and set forth the species of anti-human PD-1 antibody, of which there are 28 possible: 14 defined by heavy chain CDR1-3 and 2 defined by light chain CDR1-3 (see claim 37). Claim 38 recites the full VH and VL sequence with the variant amino acids instead of only reciting the CDRs as in claim 37. The recited variability occurs in the heavy chain CDR3 (HCDR3) and light chain CDR1 (LCDR1). However, this genus is not commensurate in scope with the disclosure, which states in the last paragraph, “The following antibodies and bifunctional molecules have been used in the different experiments disclosed herein: pembrolizumab (KEYTRUDA®, Merck) nivolumab (OPDIVO®, Bristol-Myers Squibb), and the bifunctional molecules as disclosed herein comprising an anti-PD-1 humanized antibody comprising a heavy chain as defined in SEQ ID NO: 19, 22 or 24 and a light chain as defined in SEQ ID NO: 28 or an anti- PD-1 chimeric antibody comprising an heavy chain as defined is SEQ ID NO: 71 and a light chain as defined in SEQ ID NO: 72. This antibody represents four disclosed species shown to function in a manner sufficient to bind PD-1 and have activity in the claimed bispecific molecule.
For an antibody, it is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework (FR) sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Chen et al. (EMBO J. 14 (12): 2784-2794, 1995) teach that the substitution of a single amino acid in CDR-H2 of an antibody can totally ablate antigen binding and that the same substitution in closely related antibodies can have opposite effects on binding (e.g., see entire document, including Figure I). The authors compared the effects of identical substitutions in related anti-phosphocholine antibodies DI6 and TI5, and as shown in Figure 3, some substitutions increased antigen binding in one antibody while ablating it in the other. While other amino acid changes in antibodies produced only small or insignificant changes in binding affinity, the complexity of antigen binding and affinity by antibodies is high. There are publications which acknowledge that CDR-H3 is important, but the conformations of other CDRs as well as framework residues (FRs) influence binding. MacCallum et al. (J. Mol. Biol 262:732, 1996) analyzed a variety of antibodies for their interaction with their antigen and found that although CDR3 of the variable heavy chain dominated the interaction, a number of residues outside the CDRs make antigen contact and residues in the CDR which do not contact antigen are important for backbone conformations (e.g., p. 733, section beginning at the end of col. 1, and p. 735, paragraph bridging cols. 1-2). Similarly, Herold et al. (Sci Rep. 2017 Sep 25;7(1):12276) performed single- and double-point mutations in exemplary antibodies and found that a single point mutation in the VH CDR region can completely abolish antigen binding (page 8, paragraph 1, line 11). The art underscores the importance of fully defined CDRs and combinations thereof.
In light of the guidance taught in the specification and the state of the relevant art, the disclosure does not fully support the claims under the written description provision of 35 USC 112(a). Claims 37 and 38 are directed to at least 14 different heavy chains and 2 different light chains, producing at least 28 unique antibodies. However, the specification only provides evidence that the inventors were in possession of four different antibodies. In light of the claim language that permits CDR sequences not disclosed in the specification, one of skill in the art could neither expect nor predict the appropriate functioning of the antigen-binding molecules with disclosed substitutions of the claimed genus. Given the limited number of species described, they cannot be considered representative of the broad genus. It does not appear Applicant was in possession of the full breadth of anti-human PD-1 antibodies claimed.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
With the exception of the four disclosed antibodies referred to above, i.e., comprising the variable heavy chain region of SEQ ID NO:19, 22 or 24 and variable light chain region of SEQ ID NO:28, the skilled artisan cannot envision the detailed chemical structure of the encompassed polynucleotides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991).
Therefore, only an anti-human PD-1 antibody comprising the variable heavy chain region of SEQ ID NO:19, 22 or 24 and variable light chain region of SEQ ID NO:28, but not the full breadth of the claim meets the written description provision of 35 U.S.C. § 112(a). Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
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.
Claims 34-49 and 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 25-48 of copending Application No. 17/785,427 ('427, reference application) in view of Zetti et al. (Cancer Res. 78 (13_Supplement):4558, July 2018).
Both applications claim a bifunctional molecule comprising (i) an anti-human PD- 1 antibody or antigen-binding fragment thereof (instant claims 34, 36, 40, and 46-47, and claims 30-34 and 41-44 of '427), and (ii) an IL-7 variant comprising the sequence of instant SEQ ID NO:56, i.e., the sequence of SEQ ID NO:51 but with the W142H substitution, which is identical to SEQ ID NO:5 of '427 (instant claim 34, 41 and 45, claims 25, 26 and 29 of '427). Additional identical IL-7 variants are claimed in both applications (instant claims 43 and 44, and claims 25, 27 and 28 of '427). IgG1 and IgG4 heavy chain substitutions are claimed in both (instant claims 46, 47 and 49, and claims 30 and 31 of '427). Both applications specify a linker between the anti-PD-1 antibody or fragment thereof and the IL-7 variant (instant claims 48-49, and claims 35- 40 of '427). Claim 36 of ‘427 specifies the linker is a GGGSn peptide, as in claim 49 of the instant application. A pharmaceutical composition comprising the bifunctional molecule is claimed (instant claim 54 and claim 47 of '427). Instant claims 37-39, further limiting the anti-PD-1 antibody by CDR and variable heavy chain (VH) and variable light chain (VL) sequences. correspond to claims 42-44 of '427 (see Table below). '427 does not claim wherein the anti- PD-1 antibody is BI-754091.
Zetti et al. teach humanized IgG4 anti-human PD-1 monoclonal antibody BI 754091 (first line of second paragraph, see instant claims 36 and 40). The antibody stimulated cytokine production in exhausted human T cells (middle of second paragraph; see claim 32 of '427). The antibody showed significant tumor growth inhibition in tumor-bearing mice and complete responses in some tumors (third paragraph). Also, the antibody binds cynomolgus monkey PD-1 with about the same affinity as human PD-1 (fourth paragraph). Repeated high doses of the antibody were well tolerated (fourth paragraph). The antibody is in a clinical trial (fifth paragraph).
It would have been obvious wherein the anti-PD-1 antibody was BI-754091 because of its known and expected antitumor properties.
This is a provisional nonstatutory double patenting rejection.
Claims 34-49 and 54 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43-60 and 63 of copending Application No. 18/267,795 ('795, reference application) in view of Zetti et al. (Cancer Res. 78 (13_Supplement):4558, July 2018).
Both applications claim a bifunctional molecule comprising (i) an anti-human PD- 1 antibody or antigen-binding fragment thereof (instant claims 34, 36, 40 and 46-47, and claims 43 and 55-60 of '795), and (ii) an IL-7 variant comprising the sequence of instant SEQ ID NO:56, i.e., the sequence of SEQ ID NO:51 but with the W142H substitution, which is identical to SEQ ID NO:5 of '795 (instant claim 34, 41 and 45, claims 43-44 and 46-47 of '795). Additional identical IL-7 variants are claimed in both applications (instant claims 43 and 44, and claim 44 of '795). IgG1 and IgG4 heavy chain substitutions are claimed in both (instant claims 46, 47 and 49, and claims 48-52 of '795). Both applications specify a linker between the anti-PD-1 antibody or fragment thereof and the IL-7 variant (instant claims 48-49, and claims 43 and 53 of '795). A pharmaceutical composition comprising the bifunctional molecule is claimed (instant claim 54 and claim 63 of '17/785,795). Instant claims 37-39, further limiting the anti-PD-1 antibody by CDR and variable heavy chain (VH) and variable light chain (VL) sequences, including SEQ ID NO:24 and 28, which corresponding to claims 56-58 of '795 (see Table below). '795 does not claim wherein the anti-PD-1 antibody is BI-754091.
Zetti et al. teach humanized IgG4 anti-human PD-1 monoclonal antibody BI 754091 (first line of second paragraph, see instant claims 36 and 40). The antibody stimulated cytokine production in exhausted human T cells (middle of second paragraph; see claim 32 of '427). The antibody showed significant tumor growth inhibition in tumor-bearing mice and complete responses in some tumors (third paragraph). Also, the antibody binds cynomolgus monkey PD-1 with about the same affinity as human PD-1 (fourth paragraph). Repeated high doses of the antibody were well tolerated (fourth paragraph). The antibody is in a clinical trial (fifth paragraph).
It would have been obvious wherein the anti-PD-1 antibody was BI-754091 because of its known and expected antitumor properties.
This is a provisional nonstatutory double patenting rejection.
17/785,427 & 18/267,795 17/414,970
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Applicant requests the double patenting rejections be vacated with the application is otherwise allowable (pp. 14-15 of the REMARKS). The argument has been fully considered but is not persuasive. Because claims remain rejected under 35 USC 112(b) and (a), the rejections under double patenting remain as set forth above.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
March 11, 2026