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 .
Claim Status
Claims 1, 4-5, 16, 47, 49, 52, 57-58, 92-93, 106, 132, 134, and 139-140 are pending.
Claims 2-3, 6-15, 17-20, 22-46, 48, 50-51, 53-56, 59-91, 94-105, 107-131, 133, 135-138 and 141-146 were cancelled.
Claims 57-58, 134, and 139-140 are withdrawn as being directed to a non-elected species, the election having been made on 4/4/2024.
Claims 1, 4-5, 16, 47, 49, 52, 92-93, 106 and 132 have been examined.
Priority
This application has PRO 63/313,575 02/24/2022
This application has PRO 63/202,564 06/16/2021
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 6/29/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Withdrawn Objection and Rejection
The objection of claims 1 and 106 is withdrawn because the amendment to the claims overcome the objection.
The rejection of claim 106 under 35 U.S.C. 112(d) is withdrawn because the amendment to claim 106 overcomes the rejection.
Maintained Rejection
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.
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.
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, 4-5, 16, 47, 49, 52, 92-93, 106 and 132 are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (J. Med. Chem. 2017; 60: 9290-9298, previously cited 8/18/2025).
Claim 1 is drawn to a compound formula (I) as follows.
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Shi et al. teach synthesis of cyclic γ-AApeptide library (p9291, col 2, last para to p9293 col 1, para 1 and S3, 2. Preparation of One-bead Two-compound library to S7) comprising chemically coupling building blocks with side chain modified amino acid analogs to make 135, 000 compounds with defined R and R’ moieties shown above (p9291, Fig 1). Shi’s R and R' moieties correlate with the claimed moieties of R1-R7 further shown as follows.
Shi et al. teach the bead can be removed after synthesis to generate an amine group as
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follows (S15, Molecular dynamics simulations) and the compound 1 shown in Scheme S2 at page (S18).
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Shi et al. teach to ensure the development of relatively unbiased cyclic library, a diverse set of hydrophobic, cationic, and negatively charged side chains were chosen (p9291, col 2, Library Diversity and Decoding) shown in figure 1 (p9291). Although Shi et al. do not explicitly show a specific compound structure of the claimed compound formula (I), Shi’s unbiased cyclic library comprises all combinations of R and R' moieties either intrinsically containing the claimed compounds or obvious to substitute side chains within R and/or R' groups shown above to generate individual 135000 unbiased cyclic library because the claimed compounds and Shi’s compound library are produced by the same building blocks. Thus, it is expected that the claimed compound formula is intrinsic in Shi’s compound library for a diverse set of hydrophobic, cationic, and negatively charged side chains in the absence of contrary. In one example, Shi et al. show a compound 4 in Shi’s unbiased cyclic library as follows, reading on R1=C4 alkyl, R2= C(O)-C1 alkyl substituted with C3 cycloalkyl, R4=C(O)-C1 alkyl substituted with methylenedioxyphenyl, R5= C1 alkyl substituted with C6 aryl, and R7 = C(O)-C3 alkyl substituted with NH2.
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With respect to the R3 moiety, Shi et al. suggest to ensure the development of relatively unbiased cyclic library for a diverse set of compounds comprising a hydrophobic side chain to substitute a negatively charged side chains at R3 and/or other R moieties (p9291, col 2, Library Diversity and Decoding). Thus, it would be obvious to substitute the carboxylic acid side chain of R3 moiety in compound 4 with a hydrophobic moiety of phenylmethyl group during the compound library synthesis by selecting a building block with a desired side chain of phenylmethyl group shown as follows (p, S7), reading on R3 = phenylmethyl.
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With respect to the R6 moiety, Shi et al. suggest to ensure the development of relatively unbiased cyclic library for a diverse set of compounds comprising a hydrophobic side chain to substitute a positively charged side chains at R6 and/or other R moieties (p9291, col 2, Library Diversity and Decoding). Thus, it would be obvious to substitute the positively charged amine side chain of R6 moiety in compound 4 during the compound library synthesis by using a building block with a desired alkyl side chain shown as follows (p, S7), reading on R6 = unsubstituted C4-alkyl in claims 1 and 106.
With respect to claims 4-5 and 16, Shi et al. show R1 moiety as isobutyl moiety in a compound and further suggest an isobutyl moiety can be substituted by phenylmethyl (p9291, Fig 1) by selecting a desired building block during the compound library synthesis (p, S7) to prevent bias and increase the diversity of a cyclic library. See compound 3 at page S18 showing R1 moiety as phenylmethyl.
With respect to claim 47, Shi et al. show R5 moiety as phenylmethyl in a compound and further suggest an phenylmethyl moiety can be replaced by an unsubstituted C1-6 alkyl (p9291, Fig 1) by selecting a desired building block during the compound library synthesis (p, S7) to prevent bias and increase the diversity of a cyclic library. See compound 3 at page S18 showing R5 moiety as an isobutyl moiety.
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With respect to claim 49, Shi et al. suggest to ensure the development of relatively unbiased cyclic library for a diverse set of compounds comprising a hydrophobic side chain to substitute a positively charged side chains at R6 (p9291, col 2, Library Diversity and Decoding). Thus, it would be obvious to substitute the positively charged amine side chain of R6 moiety in compound 4 during the compound library synthesis by using a building block with a desired alkyl side chain shown above (p, S7), reading on R6 = unsubstituted C4-alkyl. See compounds 5 and 7 at
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page S18 showing R6 moiety as an isobutyl moiety.
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With respect to claim 52, Shi et al. show R2 as in compound 4.
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With respect to claim 92-93, Shi et al. suggest substitution of a positively charged side chain with a Cl-C6 alkyl substituted with methylenedioxyphenyl at R7 position to create an unbiased cyclic library for a diverse set of compounds (p9291, col 2, Library Diversity and Decoding) shown in figure 1 (p9291), reading on R7 = .
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With respect to claim 132, Shi et al. show a compound 4 in Shi’s unbiased cyclic library as follows. Shi et al. teach to ensure the development of relatively unbiased cyclic library, a diverse set of hydrophobic, cationic, and negatively charged side chains were chosen (p9291, col 2, Library Diversity and Decoding) shown in figure 1 (p9291). To make relatively unbiased cyclic library as taught by Shi et al., one of ordinary skill in the art would have found it obvious to modify compound 4 to maximize the diversity of the cyclic peptide compound library by selecting different building blocks with different side chains shown page S7.
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With respect to the R1 moiety in compound M-2-2, it would be obvious to select phenylmethyl to substitute isobutyl in the moiety by using the building block shown as follows (pS7) to increase the diversity of the compound library according to substitution of R moiety in figure 1 (p9291).
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With respect to the R2 moiety in compound M-2-2, it would be obvious to substitute the C3 cycloalkyl moiety by the C6 cycloalkyl moiety to increase the diversity of the compound library according to Shi’s teachings (p9291, Fig 1).
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With respect to the R3 moiety in compound M-2-2, it would be obvious to select phenylmethyl to substitute isobutyl in the moiety by using the building block shown as follows (pS7) to increase the diversity of the compound library according to substitution of R moiety in figure 1 (p9291).
With respect to the R4 moiety in compound M-2-2, Shi et al. show R4 moiety made from a compound as follows.
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With respect to the R5 moiety in compound M-2-2, it would be obvious to select isobutyl to substitute phenylmethyl in the moiety by using the building block shown as follows (pS7) to increase the diversity of the compound library according to substitution of R moiety in figure 1 (p9291).
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With respect to the R6 moiety in compound M-2-2, it would be obvious to select isobutyl to substitute a positively charged side chain in the moiety by using the building block shown as follows (pS7) to increase the diversity of the compound library according to substitution of R moiety in figure 1 (p9291).
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With respect to the R7 moiety in compound M-2-2, it would be obvious to substitute a positively charged side chain with heterocycle to increase the diversity of the compound library according to Shi’s teachings (p9291, Fig 1).
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Shi’s compound library synthesized by the process as follows (pS6) is expected to comprise all the building blocks shown in Scheme S2 at page (pS18) with all the building blocks comprising R
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and R' moieties to produce unbiased cyclic library, a diverse set of hydrophobic, cationic, and negatively charged side chains were chosen (p9291, col 2, Library Diversity and Decoding) shown in figure 1 (p9291). Since at least one synthesized compound in Shi’s compound library reads on the claimed compound formula (I) based the permutations and/or substitutions of building blocks in a reference compound structure shown as follows and M-2-2 is able to be synthesized as one of the permutation of building blocks taught by Shi, it would be expected that the claimed compound formula to be intrinsic in Shi’s compound library for a diverse set of hydrophobic, cationic, and negatively charged side chains in the absence of contrary.
One of ordinary skill in the art before the effective filing date of this invention would have found it obvious to synthesize individual compounds according to Shi’s substitutions among R and R' moieties to generate macrocyclic compound library, including the elected compound M-2-2, (p9291, Fig 1) because Shi et al. teach to ensure the development of relatively unbiased cyclic library, a diverse set of hydrophobic, cationic, and negatively charged side chains were chosen (p9291, col 2, Library Diversity and Decoding) shown in figure 1 (p9291). The modification of macrocyclic compound by using different building blocks for substitutions would have reasonable expectation of success to produce the claimed compounds because Shi’s compound library made by chemical synthesis in the process is coupling the same building blocks to produce the claimed compounds (p, S6).
Applicant’s Arguments
There is nothing in the disclosure of [the prior art] suggesting that one should select such variables (Remarks, p7, last para to p8, para 1-3).
The fact that the pending claims recite compounds encompassed within the genus disclosed in the prior art is not, by itself, sufficient to establish a prima facie case of obviousness (Remarks, p8, para 4-6 to p10).
PTAB in the Ex parte Alig case shows Yamazaki was found not to obviate the claims of the 15/301,347. Thus, Shi’s teaching of synthesizing multiple compounds to generation a library does not contain the claimed compounds and the instant claim formula is allowable (Remarks, p11-14).
Response to Arguments
Applicant's arguments filed 11/11/2025 have been fully considered but they are not persuasive for the reasons as follows.
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Applicant’s arguments (i) and (ii) are not persuasive because Shi et al. teach 135,000 synthesized cyclic peptides in a peptide library made by the process shown as follows (pS6). Each compound is equally important to contribute the diversity of the compound library as taught and/or suggested by Shi et al. described in the rejection above not repeated here. Since the elected compound M-2-2 is one of the compounds synthesized by the building blocks as a compound species in Shi’s library, one of ordinary skill in the art would expect the compound of M-2-2 to be intrinsically included in Shi’s diversified cyclic peptide library. See MPEP 2144.01. "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968). In the present case, one skilled in the art would “at once envisage” as well as reasonably expect that the compound of M-2-2 is synthesized by Shi’s building blocks described above and must be included in making the diversified cyclic peptide library described above. In particular, applicant failed to provide M-2-M2 cannot be synthesized by the process under the prior art conditions as taught by Shi (S6).
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Applicant’s argument (iii) is not persuasive because the case law is related to modify a prior art compound shown as follows, NOT apply to Shi’s 135,000 cyclic peptides by using various building blocks to synthesize 135,000 equally important compound species in a diverse peptide library made by the process taught by Shi et al. as follows (pS6).
Examiner’s comment:
Applicant should expect the examiner to maintain the rejection until applicant provide data to show that the elected species M-2-2 cannot be synthesized by the building blocks via Shi’s process. Any verbal arguments are insufficient to overcome the rejection of record.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
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/J.L/Examiner, Art Unit 1658
12-February-2026
/LI N KOMATSU/ Primary Examiner, Art Unit 1658