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 .
Summary
Receipt of Applicant’s Disclosure document filed on 04/17/2026 is acknowledged. Claims 1-12 are pending.
Claims 1, 3, 6-12 are amended.
Claims are pending and under examination in this application.
Claim Objections - Withdrawn
The objections to claims 7 and 9 relating to the standalone use of the abbreviation “ASADH” are withdrawn in view of Applicant’s amendments, which now introduce the full term “aspartate β-semialdehyde dehydrogenase” before use of the acronym or otherwise eliminate the informality.
Claim Rejections - 35 USC § 102 - Withdrawn
The rejection of claims 1–12 under 35 U.S.C. § 102(a)(1) as anticipated by Design, Synthesis, and Evaluation of Irreversible Peptidyl Inhibitors for Clan CA and Clan CD Cysteine Proteases (Götz) is withdrawn in view of Applicant’s amendments. As amended, independent claim 1 now recites that the enzyme target is specifically aspartate β-semialdehyde dehydrogenase (ASADH) and that the compound comprises a vinyl sulfone or a sulfonyl acrylamide. Götz does not disclose ASADH as an enzyme target. Accordingly, the § 102 rejection based on Götz is not sustained.
Modified Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
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.
Claims 1-12 are rejected under 35 U.S.C. 103 as being unpatentable over A Fragment Library Screening Approach to Identify Selective Inhibitors against an Essential Fungal Enzyme (hereinafter the reference is referred as Dahal) in view of
Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases (hereinafter the reference is referred as Powers) and further in view of A Diels-Alder approach to biaryls (DAB): synthesis of the western portion of TMC-95 (hereinafter the reference is referred as Ashburn).
Detailed Claim Mapping (Amended Claims):
Regarding claim 1 (amended): Dahal teaches a method comprising: (i) providing a compound having selective inactivation activity against aspartate β-semialdehyde dehydrogenase (ASADH), an essential microbial enzyme target (Dahal, abstract; pp. 521, 524–525); (ii) providing ASADH as the enzyme target (Dahal, pp. 521–522); and (iii) a basis for inactivating that enzyme target, in that Dahal explicitly acknowledges that ASADH’s active site contains a cysteine nucleophile that can be covalently modified to lead to an inactivated enzyme (Dahal, p. 524, right col. ¶ 2–3).
Dahal fails to specifically teach that the compound is a vinyl sulfone or a sulfonyl acrylamide, or that inhibition proceeds irreversibly via covalent bonding with the specific compounds tested.
Powers teaches that vinyl sulfones and sulfonyl-containing Michael acceptors function as irreversible covalent warheads for enzymes containing active-site cysteine nucleophiles, forming stable covalent bonds with the catalytic cysteine residue, thereby irreversibly inactivating the enzyme target (Powers, pp. 4639, 4645 right col. ¶ 2; pp. 4683, 4687, 4740). Regarding the “sulfonyl acrylamide” alternative of claim 1, Powers teaches acrylamide-class Michael acceptors and sulfonyl-containing warheads as established chemical tools for targeting cysteine nucleophiles in enzyme active sites (Powers, p. 4645, right col. ¶ 2; Table 2.1). A sulfonyl acrylamide — combining an acrylamide Michael acceptor with a sulfonyl group — represents a straightforward structural hybrid of these two known covalent warhead classes. It would have been obvious to one of ordinary skill in the art to design and employ such a sulfonyl acrylamide compound as a covalent inactivator of a cysteine-nucleophile–containing enzyme, including ASADH.
It would have been obvious to one of ordinary skill in the art to apply the vinyl sulfone or sulfonyl acrylamide warhead chemistry of Powers to the ASADH target of Dahal, in view of Dahal’s explicit identification of an active site cysteine nucleophile susceptible to covalent modification (Dahal, p. 524, right col. ¶ 2–3), with a reasonable expectation that such compounds would irreversibly inactivate ASADH via covalent bonding with that cysteine. The motivation is provided by Dahal’s SAR optimization discussion, which identifies that more potent inhibitors could exploit the full active site environment of ASADH (Dahal, p. 525, left col. ¶ 2–3), and by Dahal’s affirmative identification of covalent cysteine modification as a mechanistic possibility. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
Regarding claims 2 and 3 (claim 2 original; claim 3 amended): Claim 2 recites the compound comprises a sulfonyl group. Powers teaches vinyl sulfones and sulfonylating compounds comprising sulfonyl group–containing warheads as irreversible enzyme inactivators (Powers, p. 4645, right col. ¶ 2; Table 2.1; p. 4683; p. 4736, right col. ¶ Other Sulfonylating Compounds). Claim 3 (amended) recites the compound comprises an electrophile moiety. Powers teaches a broad class of electrophilic warheads including vinyl sulfones, vinyl sulfonamides, and other Michael acceptors as irreversible covalent inactivators of cysteine-nucleophile enzymes (Powers, p. 4645, right col. ¶ 2). The “electrophile moiety” limitation of claim 3, as amended, is fully encompassed by Powers’ teaching of electrophilic warheads.
Regarding claims 4 and 5 (original): Dahal teaches compounds bearing nitro and carboxyl groups in various combinations and positions, screened against ASADH for inhibitory activity (Dahal, p. 525, right col. ¶ 1, last 3 lines; abstract). The antifungal and antibacterial properties recited in claim 5 are taught by Dahal, which discloses selective ASADH inhibitors active against pathogenic fungal and bacterial species (Dahal, p. 521, left col. ¶ 1; pp. 524–525).
Regarding claim 6 (amended): Claim 6 recites that the compound bonds with a cysteine residue nucleophile. Dahal explicitly teaches that the ASADH active site contains a cysteine nucleophile susceptible to covalent modification (Dahal, p. 524, right col. ¶ 2–3). Powers teaches covalent bond formation between vinyl sulfone warheads and active-site cysteine nucleophiles (Powers, pp. 4639, 4645, 4683).
Regarding claim 7 (amended): Claim 7 recites the compound is a dipeptide. Powers teaches peptidyl and peptidomimetic vinyl sulfone inhibitors, including dipeptide-based scaffolds, as established irreversible inactivators of cysteine-nucleophile–containing enzymes (Powers, pp. 4683–4687, including dipeptide-derived vinyl sulfone structures in Figures 67–68). Ashburn further teaches the design and synthesis of dipeptide-containing biaryl structures used as frameworks for enzyme inhibitor scaffolds (Ashburn, pp. 856–865).
Regarding claim 8 (amended): Claim 8 recites the vinyl sulfone is configured as an isostere of a mixed phosphoric carboxylic anhydride. As further addressed in the Response to Arguments below, the prior office action’s erroneous construction of “isostere” as “isomer” is withdrawn. The rejection of claim 8 is maintained on corrected grounds: Dahal establishes that ASADH’s natural substrate is aspartyl phosphate, which contains a phosphoryl group (Dahal, pp. 521–522). Dahal’s inhibitor design studies identify that structural complementarity with the active site is critical to potency and selectivity (Dahal, pp. 522–525). Powers discloses that sulfonyl groups — as present in vinyl sulfones — function as bioisosteres of phosphoryl groups in the design of covalent enzyme inhibitors targeting active-site nucleophiles (Powers, pp. 4683, 4687). It would therefore have been obvious to design a vinyl sulfone compound wherein the sulfonyl group serves as a bioisostere (i.e., isostere) of the phosphoryl-containing intermediate of the ASADH catalytic cycle, specifically the mixed phosphoric carboxylic anhydride substrate.
Regarding claim 9 (amended): Claim 9 recites the compound is configured to match a binding pocket of the enzyme target ASADH. Dahal teaches molecular docking studies performed with lead inhibitors into the active site of CalASADH using AutoDock Vina, identifying structural elements that serve as critical binding determinants (Dahal, p. 522, right col. ¶ Protein Structure Preparation for Docking Studies; p. 522, right col. ¶ 2–3; p. 523, Results and Discussion). The limitation that the compound is configured to match the ASADH binding pocket is therefore explicitly taught by Dahal.
Regarding claim 10 (amended): Claim 10 recites the compound comprises an amino acid. Powers teaches amino acid– and peptidomimetic-based vinyl sulfone inhibitor scaffolds as established tools for irreversible cysteine-enzyme inactivation (Powers, pp. 4683–4687, including amino acid–derived vinyl sulfone structures).
Regarding claim 11 (amended): Claim 11 recites the compound comprises a trifluoromethyl functional group. Powers specifically teaches that trifluoromethyl ketones function as potent, selective mechanism-based inactivators of serine and cysteine enzymes, and describes the incorporation of trifluoromethyl groups into inhibitor scaffolds as a known strategy for modulating the electrophilicity and reactivity of covalent warheads targeting active-site nucleophiles (Powers, pp. 4700–4703; ¶ Trifluoromethyl Ketones; Table 3.1). It would have been obvious to one of ordinary skill in the art to incorporate a trifluoromethyl functional group into a vinyl sulfone or sulfonyl acrylamide scaffold targeting ASADH, given this established precedent in covalent inhibitor design for cysteine-nucleophile enzymes.
Regarding claim 12 (amended): Claim 12 recites the compound comprises a carbonyl group. Powers teaches carbonyl-containing irreversible inhibitor scaffolds for cysteine and serine enzyme targets, including α,β-unsaturated carbonyl compounds and other carbonyl-bearing warheads (Powers, Figure 39; p. 4667, left col. ¶ 1). Dahal’s lead inhibitor compounds include carbonyl-bearing structures (Dahal, pp. 524–525).
It would have been obvious to one of ordinary skill in the art at the time of the instant application to have combined the teachings of Dahal and Powers to achieve the instant invention. Dahal teaches the subject matter of a method comprising providing a compound having selective inactivation activity against ASADH as an essential microbial enzyme target. Both Dahal and Powers provide motivation for developing irreversible, covalently-bonding inhibitors to achieve greater potency. Powers discloses the use of vinyl sulfones, sulfonyl-containing Michael acceptors, and vinyl sulfonamides as established irreversible covalent warheads for cysteine-nucleophile enzymes. A person of ordinary skill in the art would have combined the teachings of Dahal and Powers with a reasonable expectation of successfully achieving a method of providing a vinyl sulfone or sulfonyl acrylamide compound that selectively and irreversibly inactivates ASADH via covalent bonding. It is obvious to combine prior art elements according to known methods to yield predictable results. See MPEP § 2141(III)(A)–(G).
Response to Arguments
Applicant’s arguments have been considered but are not found persuasive for the following reasons.
Regarding the § 102/Götz rejection: The Examiner withdraws this rejection as discussed above. Götz does not disclose ASADH as an enzyme target. No further response to Applicant’s arguments on this point is required.
Regarding the § 103 rejection — Dahal “teaches away”:
Applicant argues that Dahal teaches away from the claimed invention because the inhibition observed in Dahal was freely reversible, and therefore one of ordinary skill in the art would not have been motivated to develop irreversible covalent ASADH inhibitors. This argument is not persuasive for three independent reasons.
First, Dahal explicitly acknowledges that the active site of ASADH contains a cysteine nucleophile, and Dahal specifically states that it is possible that some of the identified inhibitors could function by covalently modifying the active site thiol group, thereby leading to an inactivated enzyme (Dahal, p. 524, right col. ¶ 2). While Dahal’s observed inhibition for the specific compounds tested was reversible, Dahal itself identifies the mechanistic possibility of covalent ASADH inactivation via its active-site cysteine. This is not teaching away from the claimed method — it is an affirmative disclosure in the reference that covalent modification of ASADH via its cysteine nucleophile is recognized as a possibility.
Second, a reference does not teach away merely because it pursues a different approach. In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). Teaching away requires that a reference actively discourage the claimed combination or indicate it would not work. Dahal contains no such discouragement. To the contrary, Dahal’s SAR and optimization discussion explicitly identifies that exploiting the full active site environment of ASADH can yield more potent inhibitors (Dahal, p. 525, left col. ¶ 2–3). The motivation to pursue irreversible covalent inhibitors for enhanced potency is thus expressly present in Dahal.
Third, the combination is mechanistically grounded, not hindsight-driven. The combination draws directly on Dahal’s identification of ASADH’s active-site cysteine nucleophile and its acknowledgment of covalent modification as a mechanistic possibility, combined with Powers’ established teaching that vinyl sulfones and sulfonyl-containing Michael acceptors irreversibly inactivate cysteine-containing enzymes by reacting with the active-site cysteine. The mechanistic bridge between the two references is the shared active-site cysteine chemistry, which is an objective feature of the prior art, not a product of hindsight reconstruction.
Regarding the § 103 rejection — enzyme class mismatch (Powers):
Applicant argues that Powers is directed to proteases and cannot supply the ASADH-specific context missing from the combination. This argument is not persuasive. The combination does not require Powers to disclose ASADH. Powers supplies the teaching that vinyl sulfones and sulfonyl-containing Michael acceptors are irreversible covalent warheads that function specifically by reaction with an active-site cysteine nucleophile (Powers, p. 4645, right col. ¶ 2; pp. 4683, 4687). Dahal independently establishes that ASADH’s active site contains a catalytic cysteine nucleophile susceptible to covalent modification (Dahal, p. 524). One of ordinary skill in the art would have recognized that vinyl sulfone warhead chemistry — which targets cysteine nucleophiles mechanistically — is directly applicable to ASADH, which Dahal confirms shares this active-site feature. The fact that Powers’ examples involve proteases does not negate the transferability of the warhead chemistry to any enzyme employing a cysteine catalytic nucleophile. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418–421 (2007) (combining familiar elements according to known methods to yield predictable results is obvious).
Regarding claim 8 and the term “isostere”:
Applicant correctly notes that “isostere” refers to two chemical groups of similar shape and size, not to structural isomers, and this correction is accepted. The prior office action’s construction of “isostere” as “isomer” was error, and that erroneous construction is withdrawn. The § 103 rejection of claim 8 is nonetheless maintained on the following corrected grounds: Dahal establishes that ASADH’s substrate is aspartyl phosphate containing a phosphoryl group, and that structural complementarity with the ASADH active site is critical to inhibitor potency (Dahal, pp. 521–525). Powers discloses that sulfonyl groups, as present in vinyl sulfones, are established bioisosteres (isosteres) of phosphoryl groups in the design of covalent enzyme inhibitors (Powers, pp. 4683, 4687). It would have been obvious to design a vinyl sulfone wherein the sulfonyl group serves as an isostere of the phosphoryl-containing mixed phosphoric carboxylic anhydride intermediate of the ASADH catalytic cycle. Notably, Applicant’s own Remarks acknowledge that the sulfonyl group in the claimed compounds is designed as a mimic of the phosphoryl group of the ASADH substrate (Remarks, p. 7), confirming that this design rationale flows directly from the combined teachings of Dahal and Powers.
Regarding Applicant’s synthesis argument:
Applicant argues that some synthetic methods used to prepare the claimed compounds would not have been available at the time of Dahal (2018) and that Powers (2002), as a protease-focused review, raises questions about the basis for the present claims. This argument is not persuasive. Claim 1, as amended, is a method of use claim reciting the steps of providing a compound, providing an enzyme target, and inactivating the enzyme target by irreversibly inhibiting ASADH via covalent bonding. The claim does not recite any particular synthetic route or method for preparing the compound. Whether specific synthetic methods for producing particular compound structures were or were not available at the time of any cited reference is irrelevant to the obviousness of the claimed method of using a vinyl sulfone or sulfonyl acrylamide compound to irreversibly inhibit ASADH via covalent bonding with its active-site cysteine. The same analysis applies equally to dependent claims 2–12, none of which recite any synthetic method.
Conclusion
No claims are 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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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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