CTNF 18/712,613 CTNF 101773 DETAILED ACTION 07-03-aia AIA 15-10-aia 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 1-3, and 11-24 are pending. Priority This application is filed 5/22/2024 and claims the benefit of domestic priority as below: PNG media_image1.png 57 534 media_image1.png Greyscale Information Disclosure Statements One IDS(s) received on 5/22/2024 have been considered unless marked with a strikethrough. Drawings New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because: a. The lines, numbers and lettering are not well-defined in Figure(s) 2A, 2B, 5A, 5C, 8A, 8C, 9A, and 14A. See 37 CFR 1.84(l) and (q). The graphs, in particular, have significant overlap, making them difficult to interpret. b. In Fig 7, the structure used for docking is different from the structure shown in the same figure. A heterocyclic ring was used instead of cyclopentane. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance. 07-30-03-h AIA Claim Interpretation Claims are interpreted in accordance with the broadest reasonable interpretation (BRI) standard consistent with the specification (See MPEP 2111). With respect to claims 11, 13, 15, and 21, the phrase “cell-potent inhibitors”, “bisubstrates for nicotinamide N-methyltransferase (NNMT) and its cofactor”, and “other closely related methyltransferases” are interpreted as functional properties or capabilities of the recited compound, not as separate structural limitations requiring uncited numerical values or assay-specific parameters. Therefore, the phrase “cell-potent inhibitors” is interpreted as encompassing a compound that inhibits nicotinamide N-methyltransferase (NNMT) and exhibits any cellular or cell based activity; the phrase “bisubstrates for NNMT and its cofactor” is interpreted as encompassing a bisubstrate type NNMT inhibitor including but not limited a compound designed or capable of engaging the NNMT substrate binding region and the cofactor associated binding region; and the phase “other closely related methyltransferases” is interpreted as requiring NNMT selectivity relative to other methyltransferases, but not a particular selective ratio, assay panel, comparator list, concentration, or fold selective cutoff. Claim Objections 12-151-08 AIA 07-43 12-51-08 Claim 2 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claim Rejections - 35 USC § 112, first paragraph 07-30-01 AIA 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. 07-31-03 AIA Claim s 16-19, and 23-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for extensive chemical synthesis, renal cancer cell line experiments for multiple compounds, and describes pharmaceutical compositions , does not reasonably provide enablement for the full scope of the claimed disease directed therapeutic methods involving cancer, diabetes, liver disease, scleroderma, and Parkinson’s disease without undue experimentation . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright , 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated: The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands , 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: 1) the quantity of experimentation necessary, 2) the amount of direction or guidance provided, 3) the presence or absence of working examples, 4) the nature of the invention, 5) the state of the prior art, 6) the relative skill of those in the art, 7) the predictability of the art, and 8) the breadth of the claims. These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher , 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons: The nature of the invention, and state and predictability of the art The instant claims relates to a method of inhibiting nicotinamide N-methyltransferase (NNMT) by administering an NNMT inhibiting effective amount of a compound or pharmaceutical composition. The state and predictability of the art must be evaluated in view of the breadth of the claimed disease recitations, the amount of guidance provided in the specification, and the working examples. (see MPEP 2164.03) The instant specification describes biochemical NNMT inhibition data for measuring a compound's ability to directly block NNMT's enzymatic function; cellular target engagement for verifying that an inhibitor can successfully enter the cell, bind to the target, and alter relevant intracellular pathways; and renal cancer cell line effects for evaluating the drug's impact on viability, migration, and metabolism in specific cancer models. Such data may be predictive of NNMT enzymatic inhibition, cellular target engagement, and effects in selected renal cancer cell lines. However, therapeutic use of NNMT inhibitors across the full scope of the claimed disease subject matter remains unpredictable because biochemical NNMT inhibition data, cellular target engagement data, and selected renal cancer cell line effects in the specification do not reasonably establish that the claimed compounds can be used to achieve the claimed NNMT inhibition method in subjects across cancer generally, diabetes, liver disease, scleroderma, or Parkinson’s disease. Moreover, the specification does not provide working examples of disease specific experimental data showing that the claimed compounds treat diabetes, liver disease, scleroderma, or Parkinson’s disease. For claims 16, 18, and 23, the claimed disease condition is “cancer”. Cancer is not a single disease operating through a single uniform biological mechanism. Rather, cancer encompasses many tumor types and subtypes, with different tissues of origin, mutations, tumor microenvironments, metastatic behavior, drug sensitivities, resistance mechanisms, and clinical endpoints. Paragraph [0004] of the instant specification also reinforces that the claims encompass a heterogeneous class of disease. The subsequent examples concerning biochemical NNMT inhibition, cellular target engagement, and selected renal cancer cell line effects do not provide a reliable basis for extrapolating to cancer generally. Dagogo-Jack et al. (Tumour heterogeneity and resistance to cancer therapies, Nat. Rev. Clin. Oncol, 15(2), 81-94, pub’d 11/08/2017) explains that cancer is characterized by tumor heterogeneity and clonal architecture, which have important consequences for therapeutic resistance and treatment response (abstract section). Moreover, Roberti et al. (Nicotinamide N-methyltransferase: At the crossroads between cellular metabolism and epigenetic regulation, Mol. Metab. 45, 101165, pub’d 1/14/2021) describes that NNMT biology context dependent, and discuss NNMT as a druggable target in diseases in which NNMT is improperly activated, not as a universal therapeutic target for all NNMT associated diseases (abstract and introduction). Moreover, Roberti states that NNMT depletion contributes to liver cancer progression by promoting autophagy under nutrient starvation, and, as a proof of concept, autophagy inhibitor treatment might represent a possible strategy for treatment of cancers characterized by NNMT repression (NNMT inhibitors section). Dagogo-Jack and Roberti support that the renal cancer cell line data do not establish all claimed NNMT inhibitor compounds would operate though the same mechanism or could be used in the same way, across cancer generally. For claims 17, 19, and 24, the claimed diseases conditions are diabetes, a liver disease, scleroderma, or Parkinson's disease. These are not a single disease class with a common biological or pharmacological framework. They are separately recited disease conditions, and at least representative claimed conditions are themselves biologically heterogeneous. For example, Ahlqvist et al. (Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables, Lancet Diabetes Endocrinol., 6(5), 361-369, pub’d 05/05/2018) explains that adult onset diabetes can be separated into distinct subgroups with different disease progression and different risks of diabetic complications (abstract and discussion section). Ahlqvist supports that diabetes related therapeutic response cannot be assumed to be uniform across all diabetic subjects. The NNMT related metabolic literature is also limited to particular metabolic contexts. Kraus et al., (Nicotinamide N-methyltransferase knockdown protects against diet-induced obesity, Nature, 508(7495), 258-62, pub’d 4/10/2014) reports NNMT involvement in white adipose tissue and liver in obesity and diabetic mouse models . These references supports a metabolic rationale tied to obesity, adipose tissue, liver, insulin resistance, and type 2 diabetes related contexts, but they do not teach how to practice the claimed method across diabetes generally, including autoimmune type 1 diabetes, or across the other disease states recited in the claims (abstract section). A liver disease is also not a single therapeutic context. It includes heterogeneous etiologies and clinical settings, including fatty liver conditions, viral infections, alcohol misuse, and genetic or autoimmune disorders. Asrani et al. (Burden of liver diseases in the world, J. Hepatol., 70(1), 151-171, pub’d 9/26/2018) describes liver disease as a broad category involving multiple disease burdens, including cirrhosis, viral hepatitis, and hepatocellular carcinoma (summary section). Thus, even if some NNMT related metabolic studies involve liver tissue, such studies do not enable therapeutic use for liver disease generally. Moreover, Scleroderma is a group of autoimmune diseases characterized by the hardening and tightening of the skin and connective tissues, and Parkinson's disease is a group of the origin and spread of abnormal proteins (the Braak staging and SOC models) or direct molecular, mitochondrial, and genetic dysfunctions. Several different references describe Scleroderma and Parkinson's disease are supported that these disease are also heterogeneous etiologies and clinical settings, not a predictable disease context in which therapeutic efficacy may be extrapolated from renal cancer cell line data or general NNMT inhibition including Varga et al. (Systemic sclerosis: a prototypic multisystem fibrotic disorder, J. Clin. Invest., 117(3), 557-567, pub’d 03/01/2007) and Parsons et al. (High expression of nicotinamide N-methyltransferase in patients with idiopathic Parkinson's disease, Neurosci. Lett., 342(1-2), 13-16, pub’d 05/15/2003). Instant specification disclosure underscores the breadth and unpredictability of the claimed subject matter. Paragraphs [0003] and [0005] describe NNMT only at the level of its known enzymatic activity (i.e., methyl group transfer from S-adenosyl-L-methionine (SAM) to nicotinamide (NAM)), and identifies bisubstrate analogs as a general methyltransferase inhibitor design strategy. These disclosures support the conclusion that the application begins from a broad target disease association and a general inhibitor design concept, not from a demonstrated therapeutic method across the full scope of the disease recited claims. The claims require practicing the claimed NNMT inhibition method in subject across broad and heterogeneous disease, while the specification provides only selected compound synthesis, in vitro NNMT inhibition assay, cellular assays, and limited renal cancer cell line data. Paragraphs [0003]-[0005] in the instant specification highlight the gap between general knowledge that NNMT is an enzymatic target implicated in many diseases, and possession of an enabled method of inhibiting NNMT in subjects across cancer generally, diabetes, liver disease, scleroderma, and Parkinson’s disease. The specification does not provide guidance commensurate with the full scope of disease including working examples, disease models, dosing guidance, patient selection criteria, or pharmacodynamic endpoints for those conditions. Moreover, the specification does not identify a general quality running through the claimed genus and the recited disease conditions that would give the claimed compounds a peculiar fitness for treating or inhibiting NNMT in all claimed disease contexts. Therefore, the disclosure provides a starting point for further research rather than an enabling teaching for the full claimed methods. Accordingly, in view of the prior arts above, which collectively show mechanism dependent variability in inhibitor response in broad and heterogeneous disease, the claims require practicing the claimed NNMT inhibition method in subjects across broad and heterogeneous disease. Thus, even apart from the cited literature, the specification dose not teach how to use the claimed NNMT inhibitors across each recited broad disease context without undue experiment, and , the therapeutic utility of the full scope of claims 16-19, and 23-24 would not have been reasonably predictable. The breadth of the claims The claims are very broad insofar as they recite methods of treatment based on pharmaceutical compositions comprising compounds from a broad Markush genus. Claim 16, 18, 23 are directed to subjects having cancer. "Cancer" as a proliferative disease is not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, something seen especially in, for example, the cancers of the breast, brain and salivary glands. They can occur in pretty much every part of the body. To be able to simply stop cancer cells generally from being able to proliferate. Specifically, the prior art knows that there never has been a compound capable of treating cancers generally. A similar statement appears at In re Application of Hozumi et al., 226 USPQ 353: "In spite of the vast expenditure of human and capital resources in recent years, no one drug has been found which is effective in treating all types of cancer. Cancer is not a simple disease, nor is it even a single disease, but a complex of a multitude of different entities, each behaving in a different way". There are compounds that treat a modest range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers. Claims 17, 19, and 24 are directed to subjects having diabetes, a liver disease, scleroderma, or Parkinson's disease. Although, these disease are recited within the same dependent claims, they do not share a single biological or pharmacological framework that would make practicing the claimed NNMT inhibition method predictable from the specification’s data. As discussed above, Ahlqvist explains that diabetes can be separated into distinct subgroups with different disease progression and different risks of diabetic complications (abstract). Similarly, the cited liver disease, systemic sclerosis and Parkinson’s disease references by Asrani, Varga, and Parsons support that those claimed disease are heterogeneous and biologically distinct from the renal cell line systems disclosed in the specification. Although the specification provides synthetic disclosure for many compounds and in vitro NNMT inhibitory activity data for multiple compounds, it does not provide representative therapeutic data commensurate with the breadth of the treatment claims. The specification also does not provide a predictive structure activity relationship or disease context activity relationship that would allow one of ordinary skill in the art to determine, without substantial additional experiments, which embodiments within the claimed genus would be therapeutically effective across the full scope of the claims. In view of the specific heterogeneity and context dependent NNMT biology described by the cited references, the breadth of the present claims exceeds what would have been reasonably enabled by the disclosed data. The amount of direction or guidance provided and the presence or absence of working examples The specification provides synthetic disclosure for many compounds and for testing biochemical or cellular NNMT inhibition. It also provides renal cancer cell lines data. However, the specification does not provide sufficient guidance how to use substantially the full claimed genus to treat the full scope of the claimed disease settings and mutation defined populations without undue experimentation. MPEP 2164.02 recognizes that working examples are relevant to enablement, but the lack of working example for every embodiment is not, by itself, the basis for this rejection. Rather, the basis for the rejection is that the disclosure provides limited working examples, limited disease specific guidance, broad disease recited claims, unpredictable physiological activity, and no demonstrated correlation between the disclosed renal cancer cell line assays and the full scope of the claimed diseases. In view of the prior arts above, they reinforce the deficiency by showing that therapeutic response and disease biology vary by cancer type, metabolic context, tissue context, and disease context, such that simple extrapolation from general NNMT inhibitory activity or renal cancer cell line data would not reasonably enable the full claimed therapeutic scope. Accordingly, the instant specification lacks sufficient therapeutic direction and representative working examples commensurate with the full scope of the claimed methods of treatment. The quantity of experimentation necessary Given the limited predictability of the art, the breadth of the claims, and absence of sufficient guidance or representative working examples, a person having ordinary skill in the art would be required to engage in extensive experimentations to determine which compounds retain activity against each of the disease recited in claims 16-19, and 23-24, and establishing therapeutic efficacy in the various claimed disease contexts. In view of the prior arts above, they show that the recited diseases are heterogeneous and involve different biological mechanisms, tissue context, and therapeutic response profiles. Practicing the full scope of the claims would require substantial screening, selection and optimization across both compound structure and disease context. Such work would include determining which compounds within the broad genus have appropriate potency, selectivity, pharmacokinetics, tissue distribution, safety, dosing profile, target engagement, pharmacodynamic effect, and therapeutic efficacy in each claimed disease context. Given the breadth of the claims, the heterogeneous nature of the recited disease, the context dependent biology of NNMT, the limited disease specific guidance, the absence of representative working examples across the recited disease conditions, and the substantial experimentation required to identify operative compounds, dosing regimens, patient populations, pharmacodynamic endpoints, and therapeutic efficacy in each disease context, the specification does not enable the full scope of claims. Accordingly, the instant claims 16-19, and 23-24 do not comply with the enablement requirement of §112, because practicing the claimed invention would require undue experimentation by a person of ordinary skill in the art without reasonable assurance of success. Claim Rejections - 35 USC § 112, second paragraph 07-30-02 AIA 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. 07-34-01 Claims 3, 11, and 13-24 are 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. Claim 3 recites the limitation "R1 is H" in the last compound as shown in below. There is PNG media_image2.png 173 343 media_image2.png Greyscale insufficient antecedent basis for this limitation in the claim. Claim 1 recites a compound having a structure represented by Formula (I) and dependent claim 3 recites that the specific compound of claim 1. The definition of R1 in Formula (I) is an alkyl, a haloalkyl, an alkenyl, an alkynyl, an aminoalkcanoic acid, an acyl, an arylalkylacyl, an arylacyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an arylalkyl, or a heteroarylalkyl, but one of the compounds in claim 3 as shown in below does not fall within the limitations of R1 in Formula (I) (i.e., hydrogen at R1). Claims 14 and 20 each recite both a compound and a pharmaceutical composition comprising the same. MPEP 2173 provides that claims must particular point out and distinctly claim the subject matter which the inventor regard as the invention, so that the public can determine the metes and bounds of he claimed invention. Claim 14 is drawn to “a method for inhibiting NNMT in a subject in need thereof comprising administering an NNMT inhibiting effective amount of the compound of claim 1 or a pharmaceutical composition comprising same”. For claim 14, the method steps and the subject matter administered must be clearly set forth. (see MPEP 2173.05(q)). Claim 20 is drawn to both a compound and a pharmaceutical composition comprising the same. Applicant appears to intend to claim both the compound itself and pharmaceutically comprising the compound. However, the claim dose not clearly set forth whether the claimed subject matter is directed to the compound, pharmaceutically acceptable salt thereof, or both. In addition, the phrase “comprising the same” is unclear because it does not clearly identify whether “same” refers to the recited compound, pharmaceutically acceptable salt thereof, or both. Accordingly, the metes and bounds of claims 14, and 20 are unclear and the claims fail to particularly point out and distinctly claim the subject matter which the inventor regards as the invention. Claims 15-19, and 21-24 as the dependent claims from claims 14 and 20 are rejected under 35 USC 112(b) as indefinite for at least the same reasons set forth above. The terms “ cell-potent” and “closely related methyltransferases” in claims 11, 13, 15 and 21 are a relative term which renders the claim indefinite. The terms “cell-potent” and “closely related methyltransferases” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification also does not provide an object standard, threshold value, assay condition, comparator, or structural or functional criterion by which one of ordinary skill in the art could determine whether a compound is “cell-potent” or selective over “closely related methyltransferases.” Claims 18-19, and 22-24 as the dependent claims from claims 15 and 21 are rejected under 35 USC 112(b) as indefinite for at least the same reasons set forth above. Claim Rejections - 35 USC § 112, fourth paragraph 07-36 AIA The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 07-36-01 AIA Claim s 11 and 13 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 11 depends from claim 1 and recites that "compound is a cell-potent inhibitor for nicotinamide N-methyltransferase (NNMT), a bisubstrate for NNMT and its cofactor, and selective for NNMT over other closely related methyltransferases." Claim 13 depends from claim 12 and recites that “the one or more compounds are cell-potent inhibitors for nicotinamide N-methyltransferase (NNMT), bisubstrates for NNMT and its cofactor, and selective for NNMT over other closely related methyltransferases.” The recitation in claims 11 and 13 appears to state intended use of the compound or composition, rather than additional structural, chemical, compositional limitations or objectively measurable limitation on the claimed product, the dependent claims do not further limit the product claimed in the parent claim . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC § 102 07-06 AIA 15-10-15 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. 07-07-aia AIA 07-07 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 – 07-12-aia AIA (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 07-15-03-aia AIA Claim(s) 1 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Martin et al. (WO 2022/211627 A1, priority date 03/30/2021 of NL 2027866 B1) . With respect to claim 1 , the claim recites that a compound having the Formula (I) or a pharmaceutically acceptable salt thereof, defined by a Markush group of Formula (I). Martin teaches compounds of Formula (I), (II), and (III), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, as inhibitors of nicotinamide NNMT. Martin further teaches an NNMT inhibitor design space that permits scaffold, heteroatom, linker, side chain, and masking group/prodrug variation. Martin also teaches pharmaceutical formulations, methods of treating conditions modulated by NNMT inhibition, and method of inhibiting NNMT in vitro or in vivo . Martin states that, in certain embodiments, a compound of Formula (I), (II), or (III) are subject to a proviso excluding compounds of Formula (IV). However, Matin’s technical disclosure is not limited only to compounds of Formula (IV) falling outside the proviso. For example, Martin expressly discloses GYZ-655 in table 4 (paragraph [00269]), as a bisubstrate NNMT inhibitor having a 3-carbon alkynyl linker attached to a substituted phenyl group. Table 4 further reports biological evaluation data and HRMS data for GYZ-655. Martin also identifies GYZ-655 as a reference compound previously described in Chen (paragraph [00269]). Thus, even if certain Formula (IV) compounds are excluded from particular claim embodiments by proviso, Martin’s disclosure of the structure, synthesis, and biological activity of GYZ-655 remains relevant prior art. Accordingly, the proviso is properly treated as a claim scope exclusion in Martin, not as a technical teaching away from the use of GYE-655 or closely related alkyne linked bisubstrate NNMT inhibitors. (see MPEP 2123 and 2145) Martin directly discloses a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof as inhibitors of NNMT (paragraph [0017], and abstract). Martin further teaches a broad Markush genus encompassing NNMT inhibitor scaffold and linker variation. For example, Martin discloses embodiments in which the relevant structural variables as tetrahydrofuran or cyclopentane ring with substitution variations as Y is O and CH2, X is N or CH, R3/R5/R6/R7 are hydrogens, R4 is amide, R is aminoalkanoic acid, and X’ is an amine in Martin’s Formula (I) (claim 1), as corresponding to the claimed substitution of Formula (I) in instant claim 1. Martin’s GYZ-655 is one of alternative species of Martin’s Formula (I). Accordingly, Martin’s associated genus teaches each structural genus limitation of instant Formula (I) in claim 1. PNG media_image3.png 367 326 media_image3.png Greyscale PNG media_image4.png 228 338 media_image4.png Greyscale PNG media_image5.png 167 338 media_image5.png Greyscale Instant Formula (I) Martin’s Formula (I) Martin’s GYZ-655 Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-20-02-aia AIA 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 following prior art rejection is made in the alternative. Although the claims are rejected under 35 USC 112 for lack of enablement and indefiniteness, this rejection applies to the claimed subject matter can reasonably understood by specification. 07-21-aia AIA Claim s 1, and 11-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Martin et al. (WO 2022/211627 A1, priority date 03/30/2021 of NL 2027866 B1), in view of Chen et al. (Novel Propargyl-Linked Bisubstrate Analogues as Tight-Binding Inhibitors for Nicotinamide N-Methyltransferase, J. Med. Chem., 62(23), 10783-10797, pub’d 11/14/2019), and further in view of Gao et al., (Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT) with Enhanced Activity, J. Med. Chem. 2019, 62, 6597−6614, pub’d 07/02/2019) . Martin teaches the compound having the Formula (I) or a pharmaceutically acceptable salt thereof, defined by a Markush group of Formula (I), as set forth in the rejection of claim 1 under 35 USC 102(a)(2) above, and at least those teachings are incorporated by reference herein. In addition, Martin teaches pharmaceutical compositions comprising NNMT inhibiting compounds, methods of administering such compounds or compositions, and methods of treating or inhibiting conditions modulated by NNMT inhibition, including in vitro or in vivo NNMT inhibition. With respect to claims 11, and 13, the claim recites that the compound or composition is cell potent for NNMT, is a bisubstrate inhibitor for NNMT and its cofactor, and is selective for NNMT over closely related methyltransferases. As the claim interpretation, Martin teaches the bisubstrate and NNMT inhibitory aspects because it discloses alkyne linked bisubstrate NNMT inhibitors and specifically reports GYZ-655 with biological activity (paragraph [00269]). Martin fails to teach that the compound or composition is a bisubstrate inhibitor for NNMT’s cofactor, and is selective for NNMT over closely related methyltransferases. Chen teaches that the NNMT analogs including GYZ-655 is clearly delineated the occupancies of bisubstrate analogs at both nicotinamide and SAM binding sites (introduction section). Chen describes propargyl linked bisubstrate analogs designed to engage both the nicotinamide substrate binding region and the SAM/cofactor binding region of NNMT (introduction). Chen further teaches that such propargyl linker compounds expand the linker pool for designing bisubstrate analogs for methyltransferases and provides an approach to develop potent and selective inhibitors (introduction section). Therefore, Chen supports the alkyne linked bisubstrate scaffold and provides additional motivation to select and modify such compounds for improved NNMT inhibitory activity. Gao further teaches bisubstrate NNMT inhibitors with enhanced activity and demonstrates that modification of the linker, nicotinamide mimetic portion, and amino acid/cofactor mimetic portion can affect potency and cellular activity (figure 4-5, and results and discussion section). Therefore, Gao provides additional guidance that structurally related bisubstrate NNMT inhibitors could be modified through routine medicinal chemistry modifications to improve NNMT inhibition, including cell potency and activity relevant properties. It would have been obvious to a PHOSITA at the time of the invention to select and modify the known alkyne linked bisubstrate NNMT inhibitor scaffold taught by Martin and Chen in view of the optimization guidance taught by Gao to obtain a compound or composition that is cell potent for NNMT, acts as a bisubstrate for NNMT and its cofactor, and exhibits selectivity for NNMT over related methyltransferases. The motivation would have been to obtain the advantage of improved NNMT inhibitory activity, improved cellular potency, and improved selectivity of bisubstrate NNMT inhibitors. A person of ordinary skill in the art would have had a reasonable expectation of success because Martin, Chen, and Gao each teach bisubstrate NNMT inhibitor scaffolds directed to the same enzyme target and disclose that structural variation within these scaffolds can produce active NNMT inhibitors. The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. Examples of rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results; (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; (E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success; (F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art; (G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Applying KSR example rationale (B) and (E) in claims 11, and 13 , it would have been prima facie obvious to select the claimed Formula (I) compounds from the known cyclopentane and alkyne-linked bisubstrate NNMT inhibitor design space taught by Martin, in view of Chen and Gao. Martin discloses a finite number of identified structural variables for NNMT inhibitor compounds, including scaffold, heteroatom, linker, moiety, terminal amide, and masking group/prodrug variation. Chen teaches GYZ-655 and related propargyl linked bisubstrate NNMT inhibitors can be modified to enhance NNMT inhibitory activity. Therefore, selecting and modifying the known bisubstrate NNMT inhibitor scaffold to obtain a compound or composition that is cell potent for NNMT, acts as a bisubstrate for NNMT and its cofactor, and exhibits selectivity for NNMT over related methyltransferases would have been a predictable variation yielding the expected results in NNMT inhibition. (see MPEP 2141) With respect to claim 12 , the claim recites that a pharmaceutical composition comprising one or more compounds of claim 1, together with one or more pharmaceutically acceptable diluents, excipients, or carriers. Martin teaches the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers for larger animals, such as humans. (paragraph [00258]) With respect to claim 14 , the claim recites a method for inhibiting nicotinamide N-methyltransferase (NNMT) in a subject in need thereof, which method comprises administering to the subject an NNMT- inhibiting effective amount of a compound of claim 1 or a pharmaceutical composition comprising same, together with one or more pharmaceutically acceptable diluents, excipients, or carriers , whereupon NMT in the subject is inhibited. Martin teaches the pharmaceutical compounds of the invention may be administered orally, topically, or parenterally to a host to obtain a protease-inhibitory effect. In the case of larger animals, such as humans, the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers (paragraph [00249] and [00258]). With respect to claim 15 , the claim recites the compound is a cell-potent inhibit or for NNMT, a bisubstrate for NNMT and its cofactor, and selective for NNMT over other closely related methyltransferases. Martin fails to teach that the compound or composition is a bisubstrate inhibitor for NNMT’s cofactor, and is selective for NNMT over closely related methyltransferases. Chen teaches that the NNMT analogs including GYZ-655 is clearly delineated the occupancies of bisubstrate analogs at both nicotinamide and SAM binding sites (introduction section). Moreover, these propargyl linker compounds expand the linker pool to devise bisubstrate analogs for methyltransferases and provides a valuable approach to develop potent and selective inhibitors (introduction section). Martin teaches administration of NNMT inhibiting compounds and compositions for treating NNMT modulated conditions, and Martin, Chen , and Gao collectedly teaches bisubstrate NNMT inhibitors with potent activity. Therefore, the claimed method using such a compound would have been obvious for the same reason discussed above with respect to claims 11, and 13. With respect to claims 16-19 , the claim recites a method wherein the subject as cancer including has diabetes, a liver disease, scleroderma, or Parkinson's disease. Martin teaches a compound or pharmaceutical composition for use, wherein the condition is selected from the group consisting of: cancer (such as lung cancer, bladder cancer, renal cancer, oral cancer, skin cancer, breast cancer, colorectal cancer, gastric cancer, hepatocellular cancer, ovarian cancer, pancreatic cancer, prostate cancer and glioblastoma), metabolic disorders, diabetes, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, Huntington's diseases, schizophrenia, functional disorders of the endothelium, thrombosis, high blood pressure, atherosclerosis, inflammation and pulmonary hypertension (paragraph [00254]). Conclusion Claim(s) 1, 3, and 11-24 is/are rejected. Claim(s) 2 is/are objected to. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEONG JONG KIM whose telephone number is (571)272-6918. The examiner can normally be reached 7:00am-3:30pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /SEONG JONG KIM/ Examiner, Art Unit 1621 /CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621 Application/Control Number: 18/712,613 Page 2 Art Unit: 1621 Application/Control Number: 18/712,613 Page 3 Art Unit: 1621 Application/Control Number: 18/712,613 Page 4 Art Unit: 1621 Application/Control Number: 18/712,613 Page 5 Art Unit: 1621 Application/Control Number: 18/712,613 Page 6 Art Unit: 1621 Application/Control Number: 18/712,613 Page 7 Art Unit: 1621 Application/Control Number: 18/712,613 Page 8 Art Unit: 1621 Application/Control Number: 18/712,613 Page 9 Art Unit: 1621 Application/Control Number: 18/712,613 Page 11 Art Unit: 1621 Application/Control Number: 18/712,613 Page 12 Art Unit: 1621 Application/Control Number: 18/712,613 Page 13 Art Unit: 1621 Application/Control Number: 18/712,613 Page 14 Art Unit: 1621 Application/Control Number: 18/712,613 Page 15 Art Unit: 1621 Application/Control Number: 18/712,613 Page 16 Art Unit: 1621 Application/Control Number: 18/712,613 Page 17 Art Unit: 1621 Application/Control Number: 18/712,613 Page 18 Art Unit: 1621 Application/Control Number: 18/712,613 Page 19 Art Unit: 1621 Application/Control Number: 18/712,613 Page 20 Art Unit: 1621 Application/Control Number: 18/712,613 Page 21 Art Unit: 1621 Application/Control Number: 18/712,613 Page 22 Art Unit: 1621 Application/Control Number: 18/712,613 Page 23 Art Unit: 1621 Application/Control Number: 18/712,613 Page 24 Art Unit: 1621
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