DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ preliminary amendment, filed on 11/07/2024, in which claims 1-11 are cancelled and claims 12-40 are new.
Claims 12-40 are pending and are examined on the merits herein.
Priority
The instant application is a Continuation of 18/177,444 on filed on 03/02/2023, which claims domestic benefit to 63/315,640 filed on 03/02/2022.
Information Disclosure Statement
The information disclosure statement (IDS) dated 10/31/2024 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statement has been considered by the examiner.
Title of the Invention
Applicant is reminded that words such as “novel” are not considered part of the title of an invention. These words should not be included at the beginning of the title of the invention and will be deleted when the Office enters the title into the Office’s computer records, and when any patent issues (see MPEP 606).
Claim Rejections - 35 USC § 112(b)
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.
Claims 38 and 40 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 38 recites “a composition comprising the compound of claim 1,” however claim 1 was canceled by the applicant and therefore claim 38 depends from a canceled claim and is indefinite because the metes and bounds of the claim are not clear. For purposes of consideration on the merits, claim 38 is being interpreted as a composition comprising the compound of claim 12.
Claim 40 recites a method comprising administering a pharmaceutical composition of claim 38. Because claim 38 depends from a canceled claim and is indefinite because the metes and bounds of the claim are not clear, the metes and bounds of claim 40 are also indefinite. For purposes of consideration on the merits, claim 40 is being interpreted as a method comprising administering a pharmaceutical composition of claim 38, where claim 38 is being interpreted as a composition comprising the compound of claim 12.
Claim Rejections - 35 USC § 112(a) Scope of Enablement
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.
Claims 39-40 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 ameliorating metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders does not reasonably provide enablement for preventing metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders. 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.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (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 or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
The instantly claimed invention encompasses a method for treating metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders comprising administering a composition comprising a compound of claim 12. The instant specification defines treating as encompassing ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof) as well as preemptive or prophylactic administration to prevent the development of the
disease or at least one of the clinical symptoms [0081]. The instant specification defines metabolic disorders as including, among others, diabetes mellitus (including types 1 and 2), and diabetic complications [0193].
The breadth of the claims
The claim is broad in that it encompasses the prevention of all metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders. Wojtczak (Medical Teacher, 2002; PTO-892) teaches that “prevention” reflects the goal of preserving health and includes protection of health by personal and community wide effects. Thus in its broadest reasonable interpretation, the prevention of metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, and muscle disorders indicates that the onset of the metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, and muscle disorders, or symptoms thereof, never occurs such that health is protected. Thus, in its broadest reasonable interpretation, the prevention of metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, and muscle disorders indicates that that the onset of the metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders, or symptoms thereof, never occurs.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure describe analysis of effects of the compounds on cellular NAD+ levels in Jurkat cells (Example 8 beginning at [0326]), Huh-7 cells (Example 9 beginning at [0328]), primary human hepatocytes (Example 10 beginning at [0330]), and HepG2 cells (Example 11 beginning at [0332]). The instant disclosure further describes the binding of compounds to human plasma protein (Example 18 beginning at [0349]). The instant disclosure further describes the efficacy of a compound of claim 12 on a cisplatin induced kidney injury model in mice (Example 21 beginning at [0367]). The examples do not describe a study concerning the prevention of metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders. Additionally, the disclosure does not identify a method through which an ordinarily skilled artisan would be able to predictably determine that a subject or individual would have developed metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders in order to determine that the claimed method resulted in prevention of metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders.
The state of the prior art / the level of predictability in the art
The Harvard Medical School (Type 1 Diabetes Mellitus, website dated 13 January 2022) teaches that there is no proven way to prevent type 1 diabetes (page 5, paragraph 6). It also teaches that, although some patients can be genetically predisposed, it is not known why this autoimmune disease occurs in specific cases (page 2, paragraph 1).
Cole et al. (Nat Rev Nephrol., 2020) discusses the genetics of diabetes mellitus and teaches that clinical risk factors and glycemic control alone cannot predict the development of vascular complications. Numerous genetic studies have demonstrated a clear genetic component to both diabetes and its complications (abstract). Larger sample sizes of diabetes complications datasets will be needed to overcome phenotypic heterogeneity and moderate heritability to make
novel genetic discoveries (page 13, paragraph 1). Cole points to many research gaps that is urgently needed in order to improve the understanding of genetics in diabetes, including genetic studies of diverse populations, and improved phenotyping (page 13, paragraph 1). Diabetes and its complications are complex, multifactorial conditions with both major environmental and genetic components. Cole gives the example of family studies, which have demonstrated clear genetic components to diabetes, but as with most complex traits, linkage analysis was unable to identify loci with robust large effects, candidate gene studies are prone to false positives through the adoption of loose statistical thresholds, and early genome-wide association studies (GWAS) lacked large enough sample sizes to detect the modest effect sizes that underlie most complex
traits. The difficulties are further compounded when analyzing diabetes- induced microvascular and macrovascular complications, for which multiple intertwined risk factors exist, and which
have indirect diagnostics and unclear disease progression (paragraph bridging pages 2-3).
The teachings of Cole demonstrate that, while it is known that diabetes and its complications have a genetic factor, there are still research gaps in our understanding of this genetic factor, and clinical risk factors and glycemic control are not sufficient to allow prediction of the development of all diabetes complications. As such, there was no known method that could be used to predictably identify subjects or individuals for whom diabetes and complications such as diabetes- induced microvascular and macrovascular complications were prevented using the claimed methods.
Kathiresan et al. (Cell, 2012) discloses the genetics of human cardiovascular disease (CVD) (see Abstract), and that cardiovascular diseases encompass a range of condition extending from myocardial infarction to congenital heart disease, most of which are heritable (see Abstract). Kathiresan et al. discloses that some forms of CVD exhibit a simple pattern of inheritance suggestive of a single causal gene that confers a large effect on phenotype (see page 1242, right column). However, Kathiresan et al. discloses most CVD traits, such as myocardial infarction or concentrations of plasma LDL cholesterol, show complex inheritance, suggestive of an interplay between multiple genes and nongenetic factors (see page 1242, right column).
Alberts (Stroke, 2004) discloses the role of genetic factors in the pathogenesis of stroke and cerebrovascular diseases (see first paragraph). Alberts et al. discloses that phosphodiesterase 4D (PDE4D) gene has a strong association with ischemic strokes due to carotid atherosclerosis and cariogenic strokes (see first paragraph). However, Alberts et al. discloses several limitations with this association in that several markers in and around the PDE4D gene also had significant associations and number polymorphisms were found, in which certain isoforms exhibited reduced expression (see fourth paragraph). Therefore, Alberts et al. discloses that while lower levels of certain forms of PDE4D gene lead to ischemic stroke remains unclear, and there are other aspects of these pathways that have not been fully explored, and if genetic and protein changes influence the development and progression of atherothrombosis in patients remains to be proven (see fifth paragraph). Alberts also discloses that there are numerous reports of various genetic polymorphisms that are associated with an increased or decreased risk of stroke. However, Alberts discloses that these studies suffer from several limitations inherent to these types of studies including small or limited patient population and diversity, failure to control other risk factors, and lack of functional changes related to the polymorphisms (see second to last paragraph).
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed in detail above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a subject or an individual would have predictably developed metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders in order to apply the claimed method as a preventative measure. Furthermore, as there is no known or disclosed method that could be used to establish that metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders were prevented using the claimed method as there is no way to conclusively know that the subject would have developed metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders without the claimed method. Therefore, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to find a method that could be used to determine that metabolic disorders, cardiovascular disorders, cerebrovascular disorders, liver disorders, kidney disorders, or muscle disorders was prevented.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Claim Rejections - 35 USC § 112(d)
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.
Claims 30 and 32 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.
Claims 30 and 32 depend on claims 29 and 31 respectively, which in turn ultimately depend from claim 28 and therefore include the limitations of claim 28. Claims 30 and 32 recite wherein R5 is aryl or arylalkyl. However, claim 28 recites the narrower scope wherein R5 is phenyl, napthyl, or benzyl. Similarly, claims 30 and 32 recite R6 is alkyl, substituted alkyl, arylalkyl or heteroarylalkyl. However, claim 28 recites the narrower scope wherein R6 is CH3, -C2H5. Finally, claims 30 and 32 recite R7 is alkyl, alkenyl or arylalkyl. However, claim 28 recites the narrower scope wherein R7 is -CH3, -C2Hs, -C3H7, -CH(CH3)2, -CH2CH(CH3)2, -CH(C2H5)(CH2)2CH3 or cyclopropyl. Thus, claims 30 and 32 fail to further limit claims 29 and 31 on which they depend. Instead claims 30 and 32 recite a broader scope of compounds and are therefore of improper dependent form.
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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 12-14, 27-28, and 38-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 12168673. Although the claims of ‘637 are directed to specific identified compounds, rather than the broader scope of a Markush of compounds as recited in the instant claims, and are thus not identical to the instant claims, they are not patentably distinct from each other because compounds of ‘673 are within the scope of the instant claims.
Claim 1 of ‘673 is directed to a compound of the below formula, which is a compound of instant Formula (III) in which R1, R2, and R3 are each H.
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Claim 13 of ‘673 is directed to a compound of the below formula, which is a compound of instant Formula (IV) in which R2, and R3 are each H, R5 is phenyl, and R6 and R7 are -CH3.
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Claims 2 and 14 of ‘673 are directed to pharmaceutical compositions comprising the compound of claims 1 and 13 of ‘673, respectively.
Claims 3 and 15 of ‘673 are directed to a method of treating, among others, a metabolic disorder comprising administering the compounds of claim 1 and 13 of ‘673, respectively.
Claims 4 and 16 of ‘673 are directed to a method of treating, among others, a metabolic disorder comprising administering the pharmaceutical composition of claim 2 and 14 of ‘673, respectively.
Regarding the limitations of instant claims 13-14, these claims depend from instant claim 12 and recite additional limitations of R8, R9, and R10. However, instant claim 12 recites the alternative limitations that R1, R2, and R3 may be either -H or R8C(O)-, R9C(O)-, and R10C(O)- respectively. Thus the limitations of instant claims 13-14 are anticipated by the compound of claim 1 of ‘673.
Allowable Subject Matter
Claims 15-26, 29, and 34-37 are 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.
The closest prior art is Ganapati (WO2018/236814; IDS 10/31/2024), which teaches nicotinamide riboside and nicotinic acid riboside derivatives which have improved stability and bioavailability compared to nicotinamide riboside and nicotinic acid riboside. The nicotinamide riboside and nicotinic acid riboside derivatives are taught as precursors or prodrugs of nicotinamide riboside and nicotinic acid riboside. The derivatives are taught as being useful for increasing cellular NAD+ levels and improving mitochondrial function. Ganapati teaches compounds such as, among others, MP-07 and MP-12, which comprise a ribosyl group bound to nicotinic acid to form the pyridinium.
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However, Ganapati does not teach compounds in which the ribosyl group is bound to the nicotinic acid through an ester bond, as required by the instant claims. Neither Ganapati nor the prior art more broadly provides motivation to alter the pyridinium bond of these compounds. Thus the instant claims are not obvious over the prior art
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sarah Grace Hibshman whose telephone number is (703) 756-5341. The examiner can normally be reached Monday-Thursday 7:30am-5:30pm (EST).
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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