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
1. Claims 308-337 are pending in the current application.
2. This application is a CON of PCT/CN2025/075611 01/30/2025. FOREIGN APPLICATIONS: PCTCN2024074986 01/31/2024, PCTCN2024124776 10/14/2024, PCTCN2024137503 12/06/2024.
Response to Restriction Election
3. Applicant’s election of the species, compound 109,
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in the reply filed on December 8, 2025 is acknowledged. The election was made without traverse. According to applicants’ representative claims 308-320, 323-337 read on the elected species. As detailed in the following rejections, the generic claim encompassing the elected species was not found patentable. The search and examination was continued until prior art was found that anticipated or rendered obvious a non-elected species that falls within the scope of the generic Markush claim reading on the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 321-322, which do not read on the elected species are withdrawn.
Information Disclosure Statements
4. The information disclosure statement filed September 30, 2025 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because reference 197 is cited without a date. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
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.
5. Claim(s) 308-318, 323, 326-331, 336 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bondebjerg WO 2004110988 A1 (cited on the IDS) in view of Furber “Cathepsin C Inhibitors: Property Optimization and Identification of a Clinical Candidate” J. Med. Chem. 2014, 57, 2357−2367 (cited on the IDS) and Lew “Substrate analogues incorporating b-amino acids: potential application for peptidase inhibition.” FASEB Journal, 2001, 15(9), 1664-1666. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art
(MPEP 2141.01)
Bondebjerg WO ‘988 teaches compounds that are analogs of the compounds of the instant case that have the same utility on page 11 ff. as Formula (I) reproduced here:
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R4 is defined as the structure:
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A and B are various rings which correspond to the groups L (A) and (R1), where the methylene in claim 1 linking L-R1 accounts for the L in Bondebjerg defined as C1-alkyl. The R2 defined as C1alkoxy accounts for the group of the elected species.
A specific subgenus of this design is described on page 14:
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A number of specific R4 groups which are the L-A-B construct are listed by name on page 15 ff. and include the claimed arylene and aryl and heteroaryl definitions of L-R1. Examples include compound Example 5 which has the biaryl group:
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Subsequent to the work of Bondebjerg, Furber discusses issues with the compounds of Bondebjerg, such as Example 5:
Amidoacetonitrile derivatives have, in some studies, shown a low potential for such nonspecific covalent binding,9 and Combio was the first company to describe amidoacetonitrile-based inhibitors of CatC (e.g., compound 1 in 2004).10 [page 2357 col. 2, page 2358 col 1.]…. Indeed, on further investigation, compound 11 and related examples from the series were shown to be subject to rapid proteolysis in the cell assay medium, indicating a level of instability that could not be carried forward. Hydrolysis of the amide bond was shown to be enzymatic in nature because the instability could be repeated in plasma (t1/2 rat plasma, 1.1 h; t1/2 human plasma, 3.1 h), whereas the compounds were chemically stable at pH 2, 7.4, and 10 (t1/2 > 100 h). Although plasma instability was viewed as problematic for a lead compound, it was anticipated this could be resolved by substitution around the amide bond, and this could form part of an initial chemistry exploration….
Furber tackles the hydrolytic stability problem with “a series of compounds was prepared wherein the α position was incorporated within a ring” [page 2360].
Besides the solution given by Furber, incorporation of the α position within a ring, other techniques exist to solve issues with proteolysis in peptide drugs. According to Lew, “We hypothesize that substitution of a-amino acids at or around the scissile bond of a peptide substrate with b-amino acids (containing an extra carbon in the peptide backbone) will confer resistance to proteolytic cleavage without necessarily abolishing enzyme binding; indeed, such a stabilized analogue may act as a specific inhibitor of the peptidase.” [abstract] Lew showed that for a series of b-amino acid containing Bradykinin analogs, hydrolytic cleavage was prevented. “In conclusion, substitution of b-amino acids at the scissile bond can stabilize peptides against hydrolysis with only a moderate decrease in enzyme affinity. Thus,
peptidomimetics incorporating b-amino acids may have utility in the design and development of novel, specific, substrate-based peptidase inhibitors.” [abstract]
Ascertainment of the difference between the prior art and the claims
The prior art differs only in the presence of a methylene group in the amino terminal residue of the known dipeptidic DPP1 inhibitors disclosed by Bondebjerg.2
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Vs.
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Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to use analogs of those of Bondebjerg to produce the instant invention. Analogs differing only in a methylene, i.e. b amino acids versus the a amino acids, were known to offer improvements in peptidase inhibitors. “Thus, b-Amino acids contain an extra carbon between the amino and carboxyl termini; this modification generally renders the adjacent peptide bond resistant to hydrolysis (2,3).” [Lew, Page 2]
It would be routine for the chemist to insert a methylene in order to improve hydrolytic stability, a known problem with the compounds of Bondebjerg described by Furber. This is a so called exemplary rationale discussed in MPEP 2143, “(C) Use of known technique to improve similar devices (methods, or products) in the same way; (D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;” The modification of inserting “an extra carbon between the amino and carboxyl termini” was recognized to render “the adjacent peptide bond resistant to hydrolysis”. One of ordinary skill in the art would have been capable of applying this known technique disclosed by Lew, who suggests the application generally to peptidomimetics, to the compounds of Bondebjerg that were ready for improvement. The results would have been predictable to one of ordinary skill in the art.
6. Claim(s) 319-320, 324-325, 332-335, 337 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bondebjerg in view of Furber and Lew as applied to claims 308-318, 323, 326-331, 336 above, and further in view of Doyle “Discovery of Second Generation Reversible Covalent DPP1 Inhibitors Leading to an Oxazepane Amidoacetonitrile Based Clinical Candidate (AZD7986)” J. Med. Chem. 2016, 59, 9457−9472 (cited on the IDS). Most of the reported DPP1 inhibitors are dipeptidic structures based on preferred substrate motifs where the C-terminus has been modified to include an electrophilic warhead that reacts through covalent bond formation with the active site cysteine (Cys234). The warheads of Bondebjerg have described a generic diaryl structure but do not contain a benzoxazolone motif as disclosed in the elected species and other compounds of the instant claims. Doyle on page 9461-9462 discovered later that the benzoxazolone motif is superior to those of Bondebjerg.
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“[A] series of alternative right-hand side chains, based around bicyclic ring systems on the distal phenyl ring, for example, 20 (Chart 3), which had been shown to have excellent DPP1 enzyme and cellular potencies. On the basis of this observation, a series of analogues containing ring systems built around the distal phenyl ring were prepared, and some selected examples, 21−33, are shown in Table 5. Of these, the 2-oxo-1,3-benzothiazole example 29 and its equivalent 2-oxo-1,3-benzoxazole, 30, gave DPP1 enzyme potencies with pIC50 values of 8.6 and 8.4, respectively, that also translated into good DPP1 cell potencies, with pIC50 values of 8.5 and 8.4, respectively. Of these analogues, 29 had a higher log D of 1.5 compared to the lower log D of 0.8 for 30, leading to 30 having a better ligand lipophilicity efficiency (LLE)27,28 of 7.6 compared to an LLE of 7.1 for 29. On the basis of the better LLE for the 2-oxo-1,3-benzoxazole 30, a series of close analogues were prepared, 31−33, which all demonstrated good DPP1 enzyme and cellular potencies.” For these reasons a compound containing ring systems built around the distal phenyl ring (L) substituted with 2-oxo-1,3-benzothiazole, 2-oxo-1,3-benzoxazole, and other groups (R1) would be prepared. “[O]ne might envision a suggestion in the prior art to formulate a compound having certain structurally defined moieties, or moieties with certain properties. If a person of ordinary skill would have known how to synthesize such a compound, and the structural and/or functional result could reasonably have been predicted, then a prima facie case of obviousness of the claimed chemical compound might exist….” [MPEP 2143 B]. In this case all the moieties were known to give improved properties.
Conclusion
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
1 Compound 1 in Furber is the compound Example 5 of Bondebjerg and the assignee is Combio.
2 Claim 335 is an independent claim untethered from the claimed genus and is drawn to not only b-amino acids like the elected species but also a large number of a-amino acid compounds that simply fall under the genus of Bondebjerg.