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 .
DETAILED ACTION
Claims 1, 8, 13, 19-20 and 26-37 are pending. Claims 8 and 26-37 are withdrawn.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/25/2025 has been entered.
Priority
Acknowledgment is made of applicant's claim for priority under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) based upon applications filed in Korea on 02/02/2018 and 01/29/2019.
The claim for priority cannot be based on application filed in Korea on 02/02/2018 because the limitation of independent claim 1 specifically require C69T and G100V, which are not disclosed in the priority application, but are disclosed in the application filed on 01/29/2019. Thus, the instant application effective filing date is considered as 01/29/2019.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1, 13 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Schreiber (US 2017/0095531 A1, of record in Office Correspondence mailed on 04/25/2025) in view of Giaccia (WO 2016164428, of record in Office Correspondence mailed on 12/13/2023), Betts (Bioinformatics for geneticists (2003): 289-316, of record in Office Correspondence mailed on 12/13/2023, hereinafter “Betts”), University of Arizona (University of Arizona, The Biology Project, www.biology.arizona.edu/biochemistry/problem_sets/aa/isoleusine.html, 2003, of record in Office Correspondence mailed on 12/13/2023), and Li (Cancer Science 109.8 (2018): 2435-2445, of record in Office Correspondence mailed on 11/21/2024), and as evidenced by Appendix B (Protein alignment of reference SEQ ID NO:32 of Giaccia and instant SEQ ID NO 61, 2025, of record in Office Correspondence mailed on 04/25/2025).
Regarding claim 1, Schreiber teaches CD279 variant (i.e., PD-1 variant) having the amino acid sequence of SEQ ID NO: 32 (column 121 first row). Appendix B shows SEQ ID NO: 32 is 100% identical to instant SEQ ID NO 61.
Schreiber does not teach the PD-1 variant has C69T, F13I, M46I, and G100V substitutions.
However, Giaccia teaches a modified human PD-1 fragment with one or more mutations selected from a group of residues including C93S, F37L, M70I, N49S, N116S, and G124S enumerated according to amino acid sequence of full-length WT PD-1 (i.e., C69S, F13L, M46I, N25S, N92S, and G100S respectively) ([0008], [0011], Tables 1 and 2). Giaccia teaches these amino acid modifications can be used to alter properties of PD-1, affecting its binding activity and/or specificity to PD-L1 ([0107], FIG. 4). See below for alignment of instant SEQ ID NO: 61 and WT PD-1. Wildtype residues and positions F13, N25, M46, C69, N92 and G100 are highlighted.
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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 modify the PD-1 variant taught by Schreiber by mutating one or more of the amino acids at positions 13, 46, 69 and 100 to F13L, M46I, C69S and G100S, and combining different substitutions, as suggested by Giaccia. One of ordinary skill in the art would be motivated to do so in order to select a variant with increased binding affinity to PD-L1. Since Giaccia teaches a desire to improve binding affinity of PD-1 variant to PD-L1, there is a reasonable expectation of success.
Schreiber and Giaccia do not teach C69T, F13I and G100V mutations.
However, Betts teaches serine can be substituted by other polar or small amino acids, in particular, threonine (para. “14.5.16.1 Substitutions”).
University of Arizona teaches isoleucine is interchangeable with leucine (page 1 para.1).
Li teaches PD-1 variant with G124V substitution (Figure 4). Li teaches this mutation played major roles in enhancing the affinity of PD‐1 binding to its ligands (Abstract, page 2439 right column para. 3).
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 further modify the PD-1 sequence taught by Schreiber by substituting threonine (T) as suggested by Betts for the serine (S) at position 69, substituting isoleucine (I) as suggested by University of Arizona for the Leucine (L) at position 13, and substituting valine (V) as suggested by Li for the glycine (G) at position 100. One of ordinary skill in the art would be motivated to do so in order to increase the affinity of the variant to PD-L1. Since Giaccia and Li teach a desire to form an improved PD-1 variant and Betts and University of Arizona teach safe substitution of serine to threonine and leucine to isoleucine, respectively, there is a reasonable expectation of success.
Regarding claim 13, Giaccia teaches the PD-1 variant polypeptides also includes one or more modifications such as modifications of glycosylation by exposing the polypeptide to enzymes which affect glycosylation, such deglycosylating enzymes (i.e., aglycosylated) ([0118]). One of ordinary skill in the art would be motivated to form an aglycosylated PD-1 variant in order to improve the physicochemical properties of the protein.
Regarding claims 19-20, Giaccia teaches the PD-1 variant is contained in a pharmaceutical composition ([0155]). One of ordinary skill in the art would be motivated to do so in order to treat cancer as suggested by Giaccia (Abstract). Claim 20’s recitation “for preventing or treating a cancer disease or an infectious disease” is a recitation of intended use and is not considered to contribute to the patentability of the claimed composition. See MPEP 2111.02.
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 1, 13 and 19-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4 and 15 of copending Application No. 17/923,472. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are obvious over the copending claims.
Regarding instant claim 1, reference claim 1 recites programmed cell death protein-1 (PD-1) variant having increased binding ability to programmed death-ligand 1 (PD-L1), the PD-1 variant comprising amino acid substitutions of F13I, M46I, C69T and G100V in amino acids of wild-type PD-1 of SEQ ID NO: 1. Copending claim 2 recites the PD-1 variant having increased binding ability to PD-L1 of claim 1, comprising an amino acid sequence of SEQ ID NO: 2. Co-pending SEQ ID NO: 1 is 100% identical to instant SEQ ID NO: 61, co-pending SEQ ID NO: 2 is 100% identical to instant SEQ ID NO: 61 with substitutions C69T, F13I, M46I, and G100V .
Regarding instant claim 13, reference claim 4 recites wherein the variant is an aglycosylated variant.
Regarding instant claims 19-20, reference claim 15 recites a pharmaceutical composition for treating or preventing cancer, the pharmaceutical composition comprising a programmed cell death protein-1 (PD-1)variant having increased binding ability to programmed death-ligand1 (PD-L1), the PD-1variant comprising amino acid substitutions of F13I, M46I, C69T and G100V in amino acids of wild-type PD-1 of SEQ ID NO: 1
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant's arguments filed 07/25/2025 have been fully considered but they are not persuasive.
Applicant argues the claimed PD-1 variant consists of the amino sequence of SEQ ID NO: 61 but has the associated mutations and is thus a homoprotein and argues Schreiber does not teach or suggest CD279 alone or in isolation for further modification via amino acid mutations but rather heterologous chimeric protein constructs of which CD279 can be one component.
In response to the argument, Schreiber teaches amino acid sequence of PD-1 consisting of SEQ ID NO: 32, which is 100% identical to instant SEQ ID NO: 61. Schreiber teaches the protein can be fused to other proteins. However, this teaching does not obliterate that Schreiber teaches amino acid sequence of PD-1 consisting of SEQ ID NO: 32. One of ordinary skill in the art would be motivated and have reasonable expectation of success, to mutate the PD-1 variant taught by Schreiber in SEQ ID NO: 32 in order to increase its binding affinity to PD-L1. One of ordinary skill in the art would be motivated to modify Schreiber’s PD-1 by mutating one or more of the amino acid residues taught in Giaccia and Li in order to increase the binding affinity of the protein to PD-L1. One of ordinary skill in the art would be motivated to combine different substitutions from the teachings of Giaccia in order to select a variant with increased binding affinity. Since the prior art Schreiber teaches the instant SEQ ID NO 61 and Giaccia teaches the residues in the protein involved in increasing the bind affinity of the protein to PD-L1, there is a reasonable expectation of success.
Applicant argues that the provisional double patenting rejection should be withdrawn because the application under examination has the earlier patent term filing date.
The instant claims are obvious in view of the prior art as discussed above. Thus, the NSDP rejection of record has been maintained.
Citation of Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Mayer et al. (Journal of Nuclear Medicine 58.4 (2017): 538-546) teach a PD-1 variant with N49D mutation (i.e., N25D of instant SEQ ID NO 61) and teaches mutating this glycosylation site to aspartic acid to form aglycosylated variant (page 539 para. “Synthesis of Immuno-PET Binders”).
Conclusion
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/MARY A CRUM/Examiner, Art Unit 1657