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 01/19/2024 is acknowledged. Claims 1-12 are pending and under examination in this application.
Priority
The instant application is a continuation application of a national stage entry of PCT/US2022/037601 filed on 07/19/2022, and have a provisional status from the application # 63/223,339 filed on 07/19/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/19/2024 are in compliance with the provisions of 37 CFR 1.98. Accordingly, the information disclosure statements has been considered by the examiner. Signed copies have been attached to this office action.
Claim Objections
Claims 7 and 9 are objected to because of the following informalities: Claims 7 and 9 recites ASADH. For better legibility and clarity, it is suggested to spell out the word followed by the acronym (ASADH) in the first usage, then subsequently use of the acronym (ASADH) is more clear.
Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Design, Synthesis, and Evaluation of Irreversible Peptidyl Inhibitors for Clan CA and Clan CD Cysteine Proteases (hereinafter the reference is referred as Götz).
Götz teaches the development of novel potent and selective inhibitors for cysteine proteases, design, synthesis and evaluation of several peptidyl inhibitors for clan CA and Clan CD cysteine proteases involving vinyl sulfones (page xvii, ¶ Summary) and evaluation of potent and selective inhibitors of S. mansoni Legumain (Chapter 4).
Regarding claim 1, Götz teaches inhibitor design comprising highly selective inhibitors, the physiological function of a particular class of enzymes within an organism, and the design of irreversible inhibitors for proteases, and the design of irreversible inhibitors for proteases generally involves a peptide chain with a so-called warhead replacing the scissile peptide bond, and the optimal peptide sequence for the inhibitor is derived from the best peptide substrate sequence, which can be determined through enzyme subsite mapping using a peptide library, thus it is therefore possible to design inhibitors specific for a particular enzyme, wherein the inhibitor can then be used to investigate the physiological significance of the target enzyme (page 8-9, ¶ Inhibitor Design). Moreover, Götz discloses The warhead consists of a reactive functionality that is attacked by the enzyme’s catalytic nucleophile. A covalent bond is formed between the inhibitor and the catalytic residue and hence the enzyme is irreversibly inactivated. A variety of irreversible warheads have been developed so far. It is known in prior art (Powers et al) have extensively reviewed the irreversible inhibitors for serine, cysteine, and threonine proteases reported, and alkylating agents include halomethyl ketones, diazomethyl ketones, acyloxymethyl ketones, epoxides, aziridines, vinyl sulfones, and azodicarboxamides (page 9, ¶ 2). Therefore, the limitations of providing a compound having a selective inactivation activity, enzyme target and inactivating the enzyme target is anticipated by the teachings of Götz.
Regarding claims 2 and 3, Götz teaches vinyl sulfones (page 9, ¶ 2), Table 2.1, and page 20).
Regarding claim 4, Götz teaches carboxyl group (page 2, ¶ 2, and page 80 last line to page 81 ¶ 1) and nitrogen group (page 69, ¶ Inhibitor Design, and page 82 ¶ chemistry, and pages 83 and 87).
Regarding claim 5, Götz teaches the subject matter, composition comprising selective inhibitors, inactivation activity, and enzyme target
Götz teaches the compound inhibitor’s warhead reacts with thioalkylating agents, such as DTT, and that the progress of this reaction is dependent on the pH and the electron withdrawing nature of P1’ substituent, and conclude from the difference in reactivity with thioalkylating agents and from the difference in the IC values of the inhibition assay with legumain, and our 1H NMR study that the mechanism of inhibition occurs by attack of the active site cysteine on the carbon immediately next to the scissile bond. This insight provides us with new possibilities in the design of more potent inhibitors (page 97). Therefore, the compound exhibits at least one of antifungal and antibacterial properties is anticipated by Götz.
Regarding claims 11 and 12, Götz teaches irreversible inhibitors and covalent bonding (pages 9 and 12) and a covalent bond forms and the inhibitor is irreversibly bound to the enzyme (page 94, ¶ Mechanism of Inhibition).
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 1) in view of
Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases (hereinafter the reference is referred as Powers) and further in view of A DielseAlder approach to biaryls (DAB): synthesis of the western portion of TMC-95 (hereinafter the reference is referred as Ashburn).
Dahal 1 teaches Pathogenic fungi represent a growing threat to human health, with an increase in the frequency of drug-resistant fungal infections. Identifying targets from among the selected metabolic pathways that are unique to microbial species presents an opportunity to develop new antifungal agents against new and untested targets to combat this growth threat. Aspartate semialdehyde dehydrogenase (ASADH) catalyzes a key step in a uniquely microbial amino acid biosynthetic pathway and is essential for microbial viability. This enzyme, purified from four pathogenic fungal organisms Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Blastomyces dermatitidis), has been screened against fragment libraries to identify initial enzyme inhibitors. The binding of structural analogs of the most promising lead compounds was measured against these fungal ASADHs to establish important structure–activity relationships among these different inhibitor classes. The most potent of these inhibitors have been docked into structures of this fungal enzyme target to identify important structural elements that serve as critical binding determinants. Several inhibitors with low micromolar inhibition constants have been identified that showed selectivity against these related enzymes from different fungal species. Subsequent screening against a library of drugs and drug candidates identified some additional inhibitors containing a consistent set of functional groups required for fungal ASADH inhibition (abstract).
Regarding claims 1, 5, 6, 7, Dahal 1 teaches a method comprising providing aspartate β-semialdehyde dehydrogenase (ASADH), an enzyme that catalyzes the committed step in the aspartate biosynthetic pathway, is responsible for the biosynthesis of several essential amino acids and other cellular metabolites critical for the survival of microorganisms. ASADH, coded by the asd gene, catalyzes the reductive dephosphorylation of the substrate aspartyl phosphate to product aspartate semialdehyde (ASA). Previous studies have shown that deletion of the asd gene in Salmonella typhimurium has lethal consequences for microorganisms, and the asd gene is on the list of the minimum set of genes required for survival of microorganisms such as Bacillus subtilis. Because this critical pathway is present only in plants and microbes but absent in mammals, disruption of the enzymes in this pathway should have minimum toxicity to the human host. Therefore, enzymes in this pathway are attractive and untested targets for antifungal drug development. In this study, we have identified some selective compounds that inhibit ASADHs from several pathogenic fungi at low micromolar levels. Selective and potent inhibitors of ASADH will be lethal to these fungi, and further development of these inhibitors can lead to potent antifungal agents (page 521, left column ¶ 1). Moreover, Dahal 1 discloses several inhibitors show selectivity between the bacterial and the fungal species and some compounds also showed selectivity between the ASADHs from different fungal species (page 524, ¶ Selectivity of Initial Fungal ASADH Inhibitors). Therefore, the subject matter and limitations of a compound having a selective inactivation activity, enzyme target and inactivating the enzyme target ASADH, exhibiting at least one of antifungal and antibacterial properties, microbial enzyme target a are explicitly taught.
Regarding claim 4, Dahal 1 teaches nitro or carboxyl groups in various combinations and in various positions (page 525, right column, ¶ 1 last 3 lines).
Regarding claim 9, Dahal 1 teaches replacing one of the aldehyde groups
with a nitro group (2-nitrobenzaldehyde, Ki = 180}19 μM) results in a threefold loss of potency, whereas extending the benzene ring to a naphthalene (Ki = 45}8 μM) leads to a slight improvement in potency. Each of these CalASADH inhibitors possesses very good ligand efficiencies that are used to select fragment library hits for further structural
elaboration (page 525, right column, ¶ 1). Furthermore, Dahal 1 discloses four structures of different fungal ASADHs are currently available in the Protein Data Bank, the CalASADH structure has the best resolution, and molecular docking studies were performed with the best inhibitors into the active site of CalASADH using AutoDock Vina (page 522, right column, ¶ Protein Structure Preparation for Docking Studies and page 522, right column ¶ 2 & 3; and page 523 ¶ entire Results and Discussion). Therefore, the subject matter and limitations of the compound is configured to match a binding pocket of ASADH is explicitly taught.
Dahal 1 fails to specifically teach sulfonyl group, vinyl sulfone, irreversibly inhibited by covalent bonding. However, Dahal 1 discloses because the enzyme active site contains a cysteine nucleophile, it is possible that some of these inhibitors could function by covalently modifying the active site thiol group, thereby leading to an inactivated enzyme, and confirming that the observed inhibition by these compounds
is freely reversible, and to examine the type of reversible inhibition, the concentration
of each inhibitor was varied at different ASA concentrations, and the kinetic data were fit to different models of reversible inhibition. p-Benzoquinone was found to be a competitive inhibitor versus ASA, confirming that this class of inhibitors bind at the active site of ASADH. Phthaldehyde inhibits fungal ASADHs by binding at the subunit interface and causing dissociation into dimers, consistent with this mode of inhibition,
phthaldehyde was found to be noncompetitive with respect to ASA (page 524, right column, ¶ 2-3). Furthermore, Dahal 1 discloses optimization and SAR (structure-activity relationship) studies, and CalASADH as the model enzyme, concluded with a found discrepancy in the accessible active site can be exploited to generate inhibitors encompassing the full active-site environment, and can be used to develop selective inhibitors to potentially disrupt the tetrameric interface, which would present a novel route to develop inhibitors with a unique mode of action (page 525, left column, ¶ 2-3). Therefore, it would have been obvious to a person skilled in the art to be motivated and explore alternatives compounds and functional groups to provide better potency at the accessible binding site of ASADHs, and better potency would lead to irreversible covalent binding vs reversible binding.
Powers teaches irreversible or covalent inhibitors of serine, cysteine, and threonine proteases. Serine, cysteine, and threonine proteases have many common active site features including an active site nucleophile and a general base, which are
often the target of irreversible inhibitors. Thus far, this group includes the majority of proteolytic enzymes and many significant enzymes with involvement in human diseases Moreover, Powers discloses inhibitors directed to commonly considered to be irreversible which includes inhibitors that form “stable” covalent bonds with the enzyme (page 4639, right column, ¶ II. Serine, Cysteine, and Threonine Proteases).
Regarding claims 1-6 and 10, Powers teaches a method of providing a compound comprising selective inactivation activity, an enzyme target, inactivating the enzyme target (Figure 30, and page 4658, left column, ¶ 1), vinyl sulfones and other Michael acceptors (page 4645, right column, ¶ 2), vinyl sulfonamide (Figure 69; page 4687, right column, ¶ 2); carboxyl group (Figure 39; page 4667, left column, ¶ 1); and currently, vinyl sulfone inhibitors of cruzain for the treatment of Chagas’ disease and vinyl sulfone inhibitors of the rhinovirus for the treatment of the common cold are undergoing clinical Trials, and the 3C protease inhibitors, such as AG7088, have good oral bioavailability. It is likely that irreversible protease inhibitors will be used in the future for the treatment of bacterial, viral, and parasitic diseases, and vinyl sulfones produced very potent inhibitors for the rhinovirus protease (page 4740, left column, ¶ 1-2). Moreover, Powers discloses other sulfonylating compounds comprising nitrophenyl esters of benzenesulfonic acid (corresponding to a type of sulfonyl group) and phenylmethane-sulfonic acid containing various positively charge groups on the benzene ring have been studied as inactivators of trypsin-like proteases, For example, p-nitrophenyl p-midinothiomethylbenzenesulfonate inactivates thrombin (page 4736, right column, ¶ other Sulfonylating Compounds).
Regarding claims 8 and 9, the claim language is unclear, and since it is unclear how the vinyl sulfonamide is being “configured”, Examiner interprets that the isotere to mean an isomer…that being said, Powers teaches structure isomers moiety, wherein the carboxylic acid is esterified or converted in to an amide derivative (page 4665, entire ¶ Nomenclature and Stereochemistry).
Regarding claims 11 and 12, Powers teaches one advantage of irreversible inhibitors is their irreversibility. Once the target enzyme is killed, it cannot usually be reactivated and the organism must resynthesize the enzyme. The inhibitor will usually
stay covalently bound to the inhibited enzyme until the enzyme is degraded into its constituent pieces, and if the protease inhibitor has an attached fluorophore or biotin molecule, the inhibitor can be used to localize various proteases in cells and tissues, irreversible inhibitors clearly have a distinct advantage in proteomic profiling and, in the future, it is likely that libraries of related reagents will be developed for other classes of proteases (page 4738, right column, ¶ 2). Therefore, the irreversible inhibition and covalent binding is taught.
It would have been obvious to one of ordinary skill in the art at the time of instant application to have combined the teachings of Dahal 1 and Powers to achieve the instant invention. Dahal 1 teaches the subject matter and limitations of a method comprising providing a compound having selective inactivation activity, an enzyme target and inactivating the enzyme target (ASADH). Both Dahal 1 and Powers provides motivation for irreversible or covalent bonding inhibitors to achieve potency. Powers discloses use of sulfonyl group, vinyl sulfones, vinyl sulfonamides and selective inactivation activity of an enzyme target. Therefore, a person of ordinary skill in the art would merely combine the teachings of Dahal 1 and Powers with a reasonable expectation of successfully achieving a method comprising of providing a compound having a selective inactivation activity, an enzyme target (ASADHs) and inactivating the enzyme target with covalently binding and irreversibly inhibition. From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. It is obvious to combine prior art elements according to the known methods to yield predictable results. Please see MPEP 2141 (III)(A)-(G).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615