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
Examiner acknowledges receipt of the replies filed 6/16/2025 and 8/25/2025, in response to the nonfinal office action mailed 3/14/2025.
Claims 1 and 13-16 are pending. Claims 2-12 have been canceled. Claims 13-16 remain withdrawn from further consideration for the reasons made of record.
Claim 1 is being examined on the merits in this office action.
Claim Objections- withdrawn
The objection of claim 1 is objected is withdrawn in view of the amendment filed 8/25/2025.
Trademark in the Specification - withdrawn
The objection to the specification for a trademark is withdrawn in view of the amendment filed 6/16/2025.
Improper Markush Grouping- withdrawn
The rejection of claims 1-9, 11, and 12 on the judicially-created basis that it contains an improper Markush grouping of alternatives, is withdrawn in view of the amendment filed 8/25/2025.
Claim Rejections - 35 USC § 112- withdrawn
The rejection of claims 1-9 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of the amendment filed 8/25/2025.
The rejection of claims 1-6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment filed 8/25/2025.
Claim Rejections - 35 USC § 102- withdrawn
The rejection of claims 1-6 under 35 U.S.C. 102(a)(1) as being anticipated by Miller et al. (WO 2014/151634 A1), is withdrawn in view of the amendment filed 8/25/2025.
The rejection of claims 1-6 under 35 U.S.C. 102(a)(1) as being anticipated by Allen et al. (WO2017/151830-previously cited), is withdrawn in view of the amendment filed 8/25/2025.
The rejection of claims 1-6 under 35 U.S.C. 102(a)(1) as being anticipated by Sun et al. (U.S. 20160176928), is withdrawn in view of the amendment filed 8/25/2025.
The rejection of claims 1-6 under 35 U.S.C. 102(a)(1) as being anticipated by Miller et al. (U.S. 20170260237), is withdrawn in view of the amendment filed 8/25/2025.
Claim Rejections - 35 USC § 103- withdrawn
The rejection of claims 1-6 under 35 U.S.C. 103 as being unpatentable over Mapelli et al. (U.S. 20160175386), is withdrawn in view of the amendment filed 8/25/2025.
Double Patenting- withdrawn
The rejection of claims 1-6 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 9861680 (hereinafter referred to as the ‘680 patent”- cited in IDS filed 4/12/2022), is withdrawn in view of the amendment filed 8/25/2025.
The rejection of claims 1-6 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 9944678 (hereinafter referred to as the ‘678 patent”- cited in IDS filed 4/12/2022), is withdrawn in view of the amendment filed 8/25/2025.
The rejection of claims 1-6 on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 10538555 (hereinafter referred to as the ‘555 patent”- cited in IDS filed 4/12/2022), is withdrawn in view of the amendment filed 8/25/2025.
Response to Arguments
Applicant’s amendment and arguments with respect to the above objections and rejections have been fully considered and are persuasive. Therefore, the objections and rejections have been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment filed 8/25/2025.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Claim Objections- New objection
Claim 1 is objected to because of the following informalities:
Claim 1 should be amended at p. 4, l. 7 to recite “hydroxy group a piperidine ring”; and at p. 4, l. 16 “a pyrrolidine[[,]] ring”.
Claim 1 should be amended at p. 5, l. 5 to recite “C1-C6alkyl; and”; and at l. 10 to recite “other than hydrogen[[;]]” .
Appropriate correction is required.
New Rejections
35 U.S.C. 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.
Claims 1 is 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. This is a new rejection necessitated by the amendment filed 8/25/2025.
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 courts have stated:
“To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.” MPEP 2163.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
“A written description of an invention involving a chemical genus, like a description of a chemical species, 'requires a precise definition, such as by structure, formula, [or] chemical name,' of the claimed subject matter sufficient to distinguish it from other materials. Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus. . . ."). Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. The MPEP does state that for generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP 2163. Although the MPEP does not define what constitute a sufficient number of representative, the Courts have indicated what do not constitute a representative number species to adequately describe a broad generic. In Gostelli, the Court determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618.
In the instant case, the claims are drawn to a macrocyclic peptide of formula I or a pharmaceutically acceptable salt thereof. The peptide has 13 amino acid residues connected via variable A:
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. The R variables are further defined in the claim. The limitation pharmaceutically acceptable salt thereof further imparts a functional utility to the claim for administration that is broadly construed to be pharmaceutical, e.g., administered to treat a disease/condition.
The specification indicates that the compounds are useful for blocking the interaction of PD-1 and PD-L1, thereby modulating the immune system and treating infectious disease and cancer (e.g., para. [0003]).
As stated earlier, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable claims 1 encompasses broad generics with respect all possible compounds encompassed by the claim. The possible structural variations are limitless to any class of peptide or a peptide-like molecule that can form peptide bonds. It must not be forgotten that the MPEP states that if a peptide is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP 2163. Here, though the claims may recite some functional characteristics, the claims lack written description because there is no disclosure of a correlation between function and structure of the compounds beyond compounds disclosed in the examples in the specification.
Formula I encompasses macrocyclic peptides of 13 amino acids linked by a variable A. The sequence of the ring peptide is unlimited, and includes natural and unnatural amino acids at each position. Some of the ring peptide amide nitrogens may be methylated, and some may form ring structures with the alpha-carbon side chain. The prior art pertaining to the development of small molecule inhibitors of the PD- 1/PD-L1 interaction underscores the unpredictability in the field. Barakat (J Pharma Care Health Sys 1(4):1-2, (2014)- previously cited) teaches on p. 1: “Despite all these advantages over current immune checkpoint’s antibodies, very limited efforts have been directed to development of small molecules toward these targets. This is mainly due to the limited structural information on these proteins. For example, current PD-1 crystal structures describe PPIs of mouse PD-1 and human PD-L1 or with mouse PD-L2. Similarly, there is only one structure for the mouse TIM-3. Lacking the detailed human protein-protein interactions is a barrier to rationally design small molecule inhibitors for these targets.”
Tables 1 and 2 indicate that 76 peptides were prepared. The specification is limited to binding assays with highly variable results - compare Example Numbers 1003-1007, 1013-1015, and 1032 (Table 3; pp. 122-124). Despite Examples 1003 and 1004 having similar ring structures, the binding assays results were highly variable Examples 1003 (37 nM) and 1004 (>10000 nm). See Table 3. Thus, the binding assay results underscore the critical and nuanced correlation between structural changes and functional utility required for blocking the interaction of PD-1 and PD-L1. There are no examples in which a pharmaceutical compound was used in any disease model.
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate"). Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
35 U.S.C. 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.
Claim 1 is 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. This is a new rejection necessitated by the amendment filed 8/25/2025.
The metes and bounds of claim 1 are deemed to be indefinite. Claim 1 recites at page 4 “Rn .. when p is 0, Rv and Rn”. The variable “p” was deleted in the amendment filed 8/25/2025 (p. 3, l. 12). Thus, recitation of an undefined variable renders the claim indefinite.
Claim recites “R1 … is optionally substituted with one, halo or hydroxy group”. It is unclear from the claim and the specification as to what Applicant intends by this claim limitation. For instance, it is unclear if Applicant intended for the claim scope to encompass optional substitution with one group selected from a halogen and hydroxy.
The claim should be amended to more precisely define the claim scope.
Closest Prior Art
Compound 1048, elected species, appears to be free of the prior art. The closest prior art is Miller et al (U.S. 20170369530-previously cited). Miller et al teach macrocyclic inhibitors of the PD-1/PD-L1 interaction that are closely related to the elected compound 1048. For instance, but not limited to, compounds 1048 and 1049 of Miller et al have the following respective structures.
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(para. [1342]) and
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(para. [1343]). Miller et al do not teach or suggest the combination of side chains at positions R5, R9, and R10.
Allen et al. (WO2017/151830-previously cited) disclose intermediate compounds 10502 and 10503 (structures previously presented). Allen et al do not teach or suggest the combination of side chains at the recited in instant claim 1.
Conclusion
No claims are allowed.
Claims 1 and 13-16 are pending. Claims 13-16 are withdrawn.
Claims 1 is rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
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/KRISTINA M HELLMAN/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654