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.
Priority
The instant application is a 371 of PCT/US2022/024604 filed on 04/13/2022, which claims domestic benefit to US provisional application no. 63/310,881 filed on 02/16/2022 and US provisional application no. 63/174,456 filed on 04/13/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 12/01/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The claim amendments and remarks filed on 12/01/2025 is acknowledged. Claims 1, 30, 33, 81-82, 98-99, and 104-105. Claims 2-26, 28-29, 31-32, 34-63, 65-71, 73-79, 83-89, 92-97, 101-103, and 106. Claims 107-112 are newly added.
Accordingly, claims 1, 27, 30, 33, 64, 72, 80-82, 90-91, 98-100, 104-105, and 107-112 are pending and being examined on the merits herein.
Withdrawn Objections/Rejections
The objection to the drawings, specification, and claims are withdrawn in view of the newly filed drawings, specification, and amended claims addressing the previously stated minor informalities.
The 35 USC 112(b) rejection for claims 99 and 105 are withdrawn in view of claim 99 having proper antecedence, and claim 105 now depending from claim 82.
The 35 USC 112(a) rejection for claims 81-82, 90-91, 98-100, and 104-105 are withdrawn in view of the removal of the “preventing” in claims 81-82.
The following grounds of rejections are either maintained from the previous Office Action dated
04/15/2025 or modified as necessitated by Applicant’s amendments.
Claim Rejections - 35 USC § 112
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.
Claim 104 is 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 104 recites “… cognitive dysfunction (e.g., dementia) … “.
A broad limitation together with a narrow limitation that falls within the limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 104 recites the broad recitation “cognitive dysfunction”, and the claim also recites (e.g., dementia), which is the narrower statement of the limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Response to Arguments
Applicant indicates that the phrase “(e.g., dementia)” was removed in instant claim 104. However, the exemplary phrase is still recited in the claim, and therefore the 112(b) rejection for claim 104 is maintained.
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.
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.
Claim(s) 1, 27, 30, 33, 64, 72, 80-82, 90-91, 98-99, 104-105, and 107-108 are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et al. (US20200397807A1 in IDS filed 08/21/2023).
Pranesh et al. discloses nicotinamide riboside (NR), the reduced form of NR (NRH), nicotinic acid riboside (NAR), the reduced form of NAR (NARH), derivatives thereof, compositions thereof and uses thereof to increase cellular NAD+ levels and enhance mitochondrial and cellular function and cell viability (see Abstract).
Pranesh discloses that when NAD+ levels are depleted, cellular functioning is impaired due to both reduced level of energy production and disruption of cellular homeostasis (paragraph 0005). Pranesh discloses that reduction in NAD+ levels is observed in physiological states such as in aging, and across a wide range of pathological states ranging from acute injury to chronic metabolic and inflammatory conditions (paragraph 0005). Pranesh discloses several approaches to enhance NAD+ levels including vitamin B3 compounds in diets such as nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) (paragraph 0006). Pranesh discloses that in animal models, both NR and NMN elevate NAD+ levels and improve organ function (paragraph 0007).
Pranesh et al. discloses that their compositions can be effectively administered to treat a mitochondrial disease, a mitochondria-related disease or condition, or a disease or condition characterized by acute NAD+ depletion due to DNA damage (see embodiment 49 in paragraph 0678). Pranesh et al. discloses that the mitochondrial disease include lipodystrophy (including congenital and acquired, partial and generalized, and severe), metabolic syndrome, obesity, types 1 and 2 diabetes, liver disorders, and others. (see embodiment 53 in paragraph 0678). Pranesh et al. also discloses that the mitochondrial disease is a neurodegenerative disorder (see embodiment 52 in paragraph 0678), and that a neurodegenerative disorder includes dementias (e.g., Alzheimer's disease [AD], vascular dementia, dementia with Lewy bodies and frontotemporal dementia [Pick's disease]), motor neuron disorders (e.g., Parkinson's disease), amyotrophic lateral sclerosis [ALS or Lou Gehrig's disease], and others listed in paragraph 0223.
Pranesh et al. discloses the NR or NAR derivative can be administered via any suitable route including orally (see paragraph 0265) and can be presented in a kit that contain all active and inactive ingredients in unit dosage form or the active ingredient and inactive ingredients in two or more separate containers (see paragraph 0214). Pranesh et al. discloses that an effective amount of their NR or NAR derivate is about 50 mg in addition to other amounts between 50-1000 mg as recited in paragraph 0259. Pranesh et al. discloses that their NR or NAR derivative can be administered one, two or more (e.g., three or four) times a day, once every two days, once every three days, twice a week or once a week, or as deemed appropriate by the treating physician (see paragraph 0261). Pranesh discloses that the length of treatment can administered over a period of 1-6 days, or about 1-6 weeks to treat an acute disease/disorder or condition (0263). Pranesh et al. discloses that these dosing amounts and regimens also apply to the therapeutic use of NR, NRH, NAR, and NARH, alone or in combination with one or more other therapeutic agents described (see paragraph 0269).
Pranesh et al. discloses that their compositions can further comprise administering a therapeutically effective amount of at least one other therapeutic agent selected from sirtuin-activating agents, AMPK-activating agents, etc. listed in embodiment 61 in paragraph 0678. Pranesh et al. discloses that the sirtuin-activating agents can include polyphenols and discloses that these polyphenols include but are not limited to butein, fisetin, isoliquiritigenin, piceatannol, quercetin, and analogs, derivatives and salts thereof (paragraph 0273). Pranesh et al. discloses that the additional therapeutic agent(s) and the NR/NAR derivative(s) can be administered in the same pharmaceutical composition or in separate compositions (see paragraph 0270). Pranesh discloses that the optional additional therapeutic agent(s) independently can be administered in any suitable mode including orally (paragraph 0503). Pranesh discloses that the optional additional therapeutic agent(s) an be administered in any suitable frequency, including without limitation daily (one, two or more times per day), once every two or three days, twice weekly or once weekly, or on a pro re nata (as-needed) basis, which can be determined by the treating physician (paragraph 504). Pranesh discloses that the length of treatment with the optional additional therapeutic agent(s) can be determined by the treating physician and can independently be, e.g., at least about 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks (1 month), 6 weeks, 2 months, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, 5 years or longer (paragraph 504).
Even though Pranesh does not exemplify a combination comprising the recited first and second formulations that are both suitable for oral administration, it would have been prima facie obvious before the effective filing date of the claimed invention to have selected NaR in an amount of 50 mg and further select fisetin from within the teachings of Pranesh as well as prepare the two compounds in separate formulations for oral administration as disclosed in Pranesh to arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because Pranesh provides guidance of using NaR at 50 mg in combination with additional therapeutic agents which include sirtuin-activating agents such as fisetin as disclosed in Pranesh. Furthermore, Pranesh discloses that both compounds can be administered orally, and that the two compounds can be administered in separate compositions.
In regards to instant claims 81-82 and 104-105, it would have also been prima facie obvious before the effective filing date of the claimed invention to have administered the combination of Pranesh as described above to a subject to treat a mitochondrial disease which include obesity, dementia, Parkinson’s disease, and others as disclosed in Pranesh to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Pranesh provides guidance that their compositions can be effectively administered to treat these diseases/conditions.
In regards to instant claims 90-91 and 98-99, it would have also been prima facie obvious before the effective filing date of the claimed invention to have further optimized the dosing cycles and regimen length as disclosed in Pranesh for the combination of Pranesh as described above to arrive at the recited dosing cycles and regimen length. One of ordinary skill in art could have performed routine optimization based off Pranesh discloses that both the NaR and additional therapeutics can be independently administered one, two or more (e.g., three or four) times a day, once every two days, once every three days, twice a week or once a week, or as well as over a period of several days to several months as deemed appropriate by the treating physician. See MPEP 2144.05 II.
In regards to instant claims 107-108, it would have also been prima facie obvious before the effective filing date of the claimed invention to have substituted the NaR in the combination of Pranesh as described above with NMN as disclosed in Pranesh to arrive at the claimed invention. One of ordinary skill in the art would have made this substitution with a reasonable expectation of success because Pranesh discloses that both NAR and NMN are known for the same purpose of elevating NAD+ levels. See MPEP 2144.06 II.
Lastly, the instant specification was considered but does not present any unexpected results over the rejection of record. Applicant demonstrates several dosage combinations of NaR and Fisetin, NMN and Fisetin, as well as NaR and Fisetin administered alone (Tables 1 and 2 page 36). However, Applicant has not provided any evidence that the recited combination has any unexpected result over the teachings of Pranesh.
Claim(s) 100 and 109-112 are rejected under 35 U.S.C. 103 as being unpatentable over Pranesh et al. (US20200397807A1 in IDS filed 08/21/2023), as applied to claims 1 and 81 above, and further in view of Hagemen et al. (WO2006024545A1 in PTO-892 dated 08/01/2025).
The teachings of Pranesh are as described above and teach the recited combination of instant claim 1 and the recited method of instant claim 81 as discussed above.
The difference between Pranesh and the claimed invention is that Pranesh does not teach the recited mg/kg amounts for the flavonoid.
Hageman et al. discloses the use of at least two compounds, of which the first compound is a natural compound identified as PARP-1 inhibitors and a second compound, which is an NAD+ precursor (see Abstract). Hagemen et al. discloses the first PARP-1 inhibitor compound can be fisetin and others (see page 7 lines 17-32). Hageman discloses that NAD+ precursor compounds include nicotinic acid (Niacin), nicotinamide, and others (page 12 lines 16-24). Hageman et al. discloses their compositions can be orally administered (see page 21 lines 34-35 through page 22 lines 1-3).
Hagemen et al. discloses that their composition is useful for the treatment of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease or amyotrophic lateral sclerosis (ALS) (see page 15 lines 3-25). Hagemen et al. discloses that their active ingredients can be administered daily for a period clinically desirable in the patient such as for example up to 1 month (see page 24 lines 24-35 through page 25 lines 1-8). Hagemen discloses that the PARP-1 inhibitor compounds can be orally administered between 0.1 mg to about 60 mg/kg (page 23 lines 30-35 through page 4 lines 1-11), and that NAD+ precursor can be orally administered between 0.1 mg to about 60 mg/kg as well (page 24 lines 12-23).
Hagemen et al. demonstrates in Example 4 the reduction of atherosclerotic plaque formation in a mouse model study by administering 5-50 mg/kg of fisetin per day (see page 35 lines 25-26 through all of page 36 and page 37 lines 1-5). Hagemen et al. discloses that other combinations disclosed in Table 8 provide the same results, which includes a combination of 50-100 mg nicotinamide, 25-500 mg theobromine, and 25-500 mg fisetin (see Table 8, first row on page 51).
It would have been prima facie obvious before the effective filing date of the claimed invention to have further modified the method of Pranesh as described above by preparing the NAD+ agonist in amounts disclosed in Pranesh as well as preparing the fisetin in amounts between 0.1 mg/kg to 60 mg/kg as disclosed in Hagemen to arrive at the claimed invention. One of ordinary skill in the art would have made these modifications with a reasonable expectation of success because Pranesh discloses administering the NAD+ agonist compounds in amounts between 50-1000 mg, which overlaps with the recited mg/kg amounts for a 60 kg human. See MPEP 2144.05 I. Furthermore, both Pranesh and Hageman et al. establish the use of a composition comprising a NAD+ agonist compound and fisetin for treating neurodegenerative disorders and age-related disorders such as cardiovascular/metabolic/lipid diseases, and Hageman et al. provides further guidance of administering fisetin in dosages that overlap in range. See MPEP 2144.05.
In regards to instant claim 112, the recited improvements would flow naturally from the combined teachings of Pranesh and Hagemen described above because the combined teachings disclose administering the recited compounds in overlapping dosage amounts / cycles as disclosed in Tables 1 and 2 of the instant specification (page 36) for the same patient populations (e.g. age-related and neurodegenerative disorders).
MPEP 2145 II recites “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter.m 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc. v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) ("The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.").”
Response to Arguments
Applicant’s arguments filed on 12/01/2025 have been fully considered in so far as they apply to
the rejections of the instant office action, but were not persuasive.
Applicant states that Pranesh does not specifically teach a single combination containing a sirtuin-activating agent, let alone provide any motivation which would have led the skilled artisan to select a flavonoid, such as fisetin, from the numerous sirtuin-activating agents listed. Applicant states that, absent impermissible hindsight, there is nothing within the teachings of Pranesh which would have led the skilled artisan to selected to the recited combination from the millions of possible combinations taught in Pranesh. Applicant states that Hagemen does not cure this deficiency, since Hagemen does not mention a recited NAD+ agonist in combination with the recited flavonoids.
Applicant’s arguments described above were not persuasive because MPEP 2145 X. A. states that “Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” … Applicants may also argue that the combination of two or more references is "hindsight" because "express" motivation to combine the references is lacking. However, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness.”. Additionally, MPEP 2141 II C states that “"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.”
Here, even though Pranesh does not exemplify the recited combination, Pranesh discloses the use of a recited NAD+ agonist compound in combination with a sirtuin-activating agent and explicitly discloses fisetin as a suitable sirtuin-activating agent to use in this combination. Therefore, an ordinary skilled artisan could have considered this combination with a reasonable expectation of success. Furthermore, instant claim 1 recites the open-ended term “comprising”, which means the recited combination can include additional, unrecited elements. See MPEP 2111.03 I. Therefore, even if each and every sirtuin-activating agent disclosed in Pranesh was included, Pranesh would still meet the recited combination. Lastly, Hageman does not need to teach the recited NAD+ agonist as this limitation is already taught by Pranesh.
Applicant states that the routine optimization to arrive at the claimed dosages and regimens from the combined teachings of Pranesh and Hagemen is based on impermissible hindsight. Applicant states that obviousness cannot be established based on an unsupported allegation that an invention is the result of “routine optimization”, and that there is nothing in the teachings of Pranesh and Hagemen alone or in combination which would have led the skilled artisan to select the recited combination at the claimed dosage amounts / cycle / regimen.
Applicant’s arguments described above were not persuasive because MPEP 2145 X. A. states that “Applicants may argue that the examiner’s conclusion of obviousness is based on improper hindsight reasoning. However, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper.” … Applicants may also argue that the combination of two or more references is "hindsight" because "express" motivation to combine the references is lacking. However, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness.” Additionally, MPEP 2141 II C states that “"A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle." Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ." Id. at 418, 82 USPQ2d at 1396.”
Here, the routine optimization described above is based on Pranesh disclosing that both the NaR and additional therapeutics can be independently administered one, two or more (e.g., three or four) times a day, once every two days, once every three days, twice a week or once a week, or as well as over a period of several days to several months as deemed appropriate by the treating physician. Therefore, Pranesh provides guidance of dosing cycles and lengths that encompass the recited dosage cycles / lengths for both recited compounds such that an ordinary skilled could have performed routine optimization to arrive at the claimed invention. Furthermore, the combined teachings of Pranesh and Hagemen provide guidance of overlapping amounts for both the recited NAD+ compounds as well as the fisetin compound as described above. See MPEP 2144.05 I.
It is noted that MPEP 2144.05 III A states “Applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range."
Conclusion
No claim is found allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID H CHO whose telephone number is (571)270-0691. The examiner can normally be reached M-F 8AM-5PM.
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, Scarlett Goon can be reached at 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.
/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693