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. 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. This office action is a response to applicant’s communication submitted November 3, 2023 , wherein claims 1-8, 11, and 14-15 were preliminarily amended, and claims 9-10 and 12-13 were canceled. Claims 1-8, 11, and 14-15 are pending in this application . Priority This application is a 371 of PCT/EP2022/060882 filed 04/25/2022 and claims foreign priority to EP 21172203.8 filed 05/05/2021 . Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been received. Claim Interpretation The phrase “NARH” is interpreted to mean dihydronicotinic acid riboside as defined on page 4 of the specification (figure 1 description). The instant specification states that NARH is the reduced form of nicotinic acid riboside (NAR) (pg. 14, para. 3). The phrase “NR” is interpreted to mean nicotinamide riboside as defined on page 4 of the instant specification (figure 1 description). The phrase “metabolic fatigue” is interpreted as reduced mitochondrial function due to a shortage of substrates and/or accumulation of metabolites that interfere with mitochondrial function as defined on page 12 of the instant specification (para. 4). Claim Objections Claim s 1-8, 11, and 14-15 objected to because of the following informalities: In claims 1, 5, and 8 the acronyms NARH and NH should be defined. Regarding claims 2-3, 6-7 , 11, and 14-15 : When referencing a previous claim, the phrase “according to Claim 1” for example, the term “Claim” should not be capitalized. Regarding claims 2-4 which recite “Method according to” should read, “The method according to” to clarify they are dependent claims. In claim s 5 and 8 , the phrase “NAD+” should be defined as it is in claim 1 for consistency . Regarding claims . Appropriate correction is required. Claim Rejections - 35 USC § 112 (a) 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 8, 11, and 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, as failing to comply with the enablement requirement. The specification, while being enabling for the treatment of metabolic fatigue in one or more cells or treatment of muscle fatigue or metabolic fatigue , does not reasonably provide enablement for the prevention of the same. The specification does not enable any person skilled in the art to which is pertains, or with which it is most clear connected, to make and use the invention commensurate in scope with these claims. Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). These include: (1) breadth of the claims; (2) nature of the invention; (3) state of the prior art; (4) amount of direction provided by the inventor; (5) the level of predictability in the art; (6) the existence of working examples; (7) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) relative skill in the art. All of the factors have been considered with regard to the claim, with the most relevant factors discussed below: (1& 2) The breadth of the claims and nature of the invention: The claims are directed to methods of increasing NAD+ in an individual comprising administering a composition comprising a combination of NARH and NR. The claims are also directed towards compositions of NARH and NR. The claims are also directed to methods of achieving at least one result selected from ( i ) increased mitochondrial energy in one or more cells, (ii) improvement in a physiological state linked to metabolic fatigue in one or more cells, (iii) treatment or prevention of metabolic fatigue in one or more cells, (iv) treatment or prevention of muscle fatigue, (v) improved mobility and (vi) improved longevity comprising administering a composition comprising NARH and NR in amount effective to increase NAD+ biosynthesis. (3) The state of the prior art: While there are publications that describe methods of treating metabolic or muscle fatigue, weakness, and degeneration caused by for example neuromuscular diseases , there is no evidence in the prior art that the claimed composition would prevent muscle /metabolic fatigue from ever occurring. For example, Ryu et al ( Sci . Transl . Med. , 20 16, cited on PTO-892 ) teaches that NAD+ repletion can be beneficial in patients with muscular dystrophies ( abstract ). Ryu teaches NAD+ repletion provides protection from metabolic diseases and mitochondrial dysfunction induced by diet or aging, of which muscle fatigue can be a symptom (pg. 2, para. 2). Ryu teaches NAD+ repletion could delay both age-related and muscle stem cell senescence (pgs. 2-3, bridging para.). Hennesy (Metabolites, 2024, cited on PTO-892) discloses daily dietary nicotinamide riboside (NR) can delay subjective muscle fatigue onset in swine (abstract). Hennesy discloses that NAD+ has a direct impact on mitochondrial ATP production within muscle and NR-dosed mice have increased running distance (pg. 2, para. 3). Thus, in short, the art recognizes treatment or reduction in diseases characterized by muscle /metabolic fatigue aimed at NAD+ repletion and nicotinamide riboside supplementation can delay the onset of muscle fatigue , but not in the absolute prevention thereof. The instant specification states that “ "Prevention" includes reduction of risk, incidence and/or severity of a condition or disorder. ”, but this is not an explicit definition (pg. 10, last para.). It is noted that the term “prevent” does not necessarily mean that something is kept from ever occurring, but such is an interpretation available to the Examiner that falls under the “broad and reasonable” standard for claim term interpretation as set forth in the MPEP at § 2111 and thus is proper. (4 & 6) The amount of direction provided by the inventor and the existence of working examples: Applicant has not provided examples that demonstrate that the composition claimed would prevent muscle /metabolic fatigue from ever occurring . The instant specification has demonstrated that the composition when administered induces NAD+ biosynthesis (specification, pgs. 28-29, examples 2-5) . Applicant has not demonstrated that when the composition is administered to a subject, it would prevent muscle/metabolic fatigue from occurring. (5) The level of predictability in the art: The prior art does not teach a method of preventing muscle /metabolic fatigue by administering a therapeutic composition. Although some methods may aid in the reduction of muscle /metabolic fatigue and other diseases that result in muscle/metabolic fatigue , there is nothing in the prior art that indicates that prevention is possible. (7) The quantity of experimentation: Neither the instant specification nor the state of the art have demonstrated how therapeutic compositions, such as the composition claimed, can “prevent” muscle /metabolic fatigue from occurring. An undetermined number of experimental factors utilizing a composition and its method for preventing would have to be resolved by the practitioner and/or the patient for the following reasons: the factors are not sufficiently discussed in the specification to provide guidance to utilize the invention as claimed. (8) The level of skill in the art: The level of skill in the art would be high, mostly likely at the Ph.D. /MD level. Therefore, other than proposing an initial hypothesis, the entire burden of research involved in utilizing the compositions claimed to prevent all muscle/metabolic fatigue would fall on the shoulders of the skilled artisan attempting to practice the claimed invention, presenting an undue burden of unpredictable experimentation. Genentech, 108 F.3d at 1366, sates that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.” Therefore, in view of the Wands factors, as discussed above, particularly the state of the art and the lack of guidance or working examples, Applicant fails to provide information sufficient to practice the claimed invention without undue experimentation. Claim Rejections - 35 USC § 102 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. Claims 1-8, 11, and 14-15 are rejected under 35 U.S.C. 102(a)(1) as being FILLIN "Insert either—clearly anticipated—or—anticipated—with an explanation at the end of the paragraph." \d "[ 3 ]" anticipated by Dellinger (WO 2017/184885, IDS filed November 3, 2023). Regarding claims 1-8, 11, and 14-15 : Dellinger teaches, “ I -(2',3 ',5'triacetyl-beta-D-ribofuranosyl)-nicotinic acid ("NAR triacetate" or "NARTA"); or derivatives of a reduced form of nicotinic acid riboside ("NARH"), including I - (2',3',5 '- triacetyl -beta-D- ribofuranosyl )-1,4-dihydronicotinic acid ("NARH triacetate" or "NARJT-TA"); or derivatives of nicotinamide riboside ("NR"), including I -(2',3',5'-triacetyl- beta-D- ribofuranosyl )-nicotinamide ("NR triacetate" or "NRTA"); derivatives of a reduced form of nicotinamide riboside ("NRH"), including l-(2',3 ',5'-triacetyl-beta-Dribofuranosyl)-l ,4- dihydronicotinamide ("NRH triacetate" or "NRH-TA"); or salts or prodrugs thereof, for use in food or beverage applications, pharmaceutical formulations, or as a dietary supplement. Methods of using the compounds above to promote the increase of intracellular levels of nicotinamide adenine dinuc!eotide ("NAD+") or NADH in cells and tissues for improving cell and tissue survival or overall cell and tissue health are provided. ” (abstract). Dellinger teaches that Vitamin B3 deficiency yields to evidenced compromised cellular activity through NAD+ depletion, and the beneficial effect of additional NAD+ bioavailability through nicotinic acid ("NA"), nicotinamide C'Nam "), and nicotinamide riboside ("NR") supplementation is primarily observed in cells and tissues where metabolism and mitochondrial function had been compromised (pg. 2, para. 0005) . Dellinger teaches that food or beverage products containing at least one compound selected from nicotinamide riboside derivatives nicotinic acid riboside , and nicotinamide mononucleotide used in combination with each other would effectively provide higher levels of NAD+ to a subject in need thereof than when provided separately, in synergistic manner (i.e. combination, food product form, enterally administration, pgs. 15-16, para. 0075). Dellinger demonstrates that both NR and NARH supplementation increases NAD % relat i ve to control (pg. 38, para. 00167, table). Thus, even though Dellinger does not teach a composition specifically comprising NR and NARH, a person of ordinary skill in the art upon reading the reference would at once envisage the claimed combination (See MPEP 2131.02 (III). Dellinger teaches methods for treating diseases that would benefit from increasing mitochondrial activity (pg. 22, para. 00112). Dellinger teaches that mitochondria are in virtually any cell type and nondividing tissues with high energy requirements including skeletal muscle are particularly affected (pg. 00114, para. 00114). Dellinger teaches the methods can be used for reducing the rate of decline in muscular capacities and for improving muscular functional status in humans with muscular dystrophy (pg. 27, para. 00124). Dellinger teaches muscular dystrophy results in atrophy of skeletal muscle (pg. 27, para. 00124). Although Dellinger does not specifically state that NAD+ biosynthesis is increased in skeletal cells specifically, wherein the method can be applied for improving muscular functional status comprising the same ingredients for the purpose of increasing NAD+ biosynthesis as instantly claimed, the method of Dellinger necessarily results in increasing NAD+ biosynthesis in skeletal cells, absent evidence to the contrary. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer (See MPEP 2112 (I)). Claim Rejections - 35 USC § 103 The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action: A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made. Claims 1-8, 11, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Dellinger (WO 2017/184885, IDS filed November 3, 2023) as applied to claims 1-8, 11, and 14-15 above. Regarding claims 1-8, 11, and 14-15: As discussed above, Dellinger teaches all of the above. Even if assuming for the sake of argument that Dellinger does not specifically teach the specific combination of NARH and NR as claimed, the claims would still have been rendered obvious over Dellinger. Dellinger does not teach a specific combination of NARH and NR in the composition. However, as discussed previously, Dellinger demonstrates that both NR and NARH supplementation increases NAD % relative to control (pg. 38, para. 00167, table). Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to combine NARH and NR in the composition of Dellinger. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as Dellinger teaches that supplementation of these components increase NAD concentration for the purpose of treating muscular dystrophy in a subject, thereby alleviating symptoms (i.e. muscle weakness) by promoting NAD+ biosynthesis in skeletal muscle cells. Conclusion No claims are allowed in this action. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT SAMUEL L GALSTER whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)270-0933 . The examiner can normally be reached FILLIN "Work Schedule?" \* MERGEFORMAT Monday - Friday 8:00 AM - 5:00 PM . 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, FILLIN "SPE Name?" \* MERGEFORMAT Scarlett Y Goon can be reached at FILLIN "SPE Phone?" \* MERGEFORMAT 571-270-5241 . 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. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /SAMUEL L GALSTER/ Examiner, Art Unit 1693