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 .
Election/Restrictions
Applicant’s election of claim 11 species, long covid-19 species, treatment/treating species, delta variant SARS-Cov-2 species, and encephalomyelitis/chronic fatigue syndrome in the reply filed on 07/07/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 19 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Priority
This application is the 35 U.S.C. 371 national phase of International Patent Application No. PCT/IB22/00597, filed August 30, 2022, which claims the benefit of priority to U.S. Provisional Patent Application No. 63/238,659, filed August 30, 2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/24/2024, 09/30/2024, and 07/07/2026 has been considered by the examiner.
Status of Claims
Claims 11-12, 15, 17-19, 29, 34, 36-37, 39, 41, and 48-52 are pending. Claims 1-10, 13-14, 16, 20-28, 30-33, 35, 38, 40, and 42-47 are canceled. Claim 19 is withdraw. Claims 11-12, 15, 17-18, 29, 34, 36-37, 39, 41, and 48-52 are examined in accordance to the elected species.
Claim Objections
Claim 11 is objected to because of the following informalities: claim 11 recites “administering to the subject a therapeutically effective amount of an urolithin.” The indefinite article “an” should be replaced with “a” such that the claim recites “a therapeutically effective amount of a urolithin.”. Appropriate correction is required.
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.
Claims 36, 39, and 41 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 36 recites “wherein the subject concurrently administered a nutrient, a coenzyme, a nicotinamide adenine dinucleotide (NAD+) precursor.” It is unclear whether the absence of a conjunction between “a nutrient,” “a coenzyme,” and “a nicotinamide adenine dinucleotide (NAD+) precursor” means that all three categories must be concurrently administered or whether the three categories are intended as alternatives, i.e., a nutrient, a coenzyme, or a nicotinamide adenine dinucleotide (NAD+) precursor.
The ambiguity is material because dependent claim 37 further defines “the nutrient,” claim 39 further defines “the coenzyme,” and claim 41 further defines “the … NAD+ precursor,” suggesting that Applicant may have intended the three recitations of claim 36 to be alternative embodiments. However, claim 36 as presently written does not contain language establishing that relationship.
Accordingly, one of ordinary skill in the art would not be reasonably apprised whether the scope of claim 36 requires concurrent administration of each of a nutrient, a coenzyme, and an NAD+ precursor, or instead requires only one member selected from those three categories. Claims 37, 39, and 41 inherit the ambiguity by dependency.
For purposes of examination under the prior art below, and without waiving the foregoing rejection, claim 36 is interpreted as encompassing the alternative administration of a nutrient, a coenzyme, or an NAD+ precursor, consistent with the separate dependent-claim structure of claims 37, 39, and 41.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 11, 12, 15, 17, 29, 34, and 48–52 are rejected under 35 U.S.C. 103 as being unpatentable over D’Amico et al. (“Impact of the Natural Compound Urolithin A on Health, Disease, and Aging,” Trends in Molecular Medicine, Vol. 27, No. 7, July 2021, pp. 687–699) in view of Morris et al. (“Mitochondrial dysfunctions in Myalgic Encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways,” Metabolic Brain Disease 29:19–36 (2014)) and further in view of Maccarone et al. (“Post COVID-19 persistent fatigue: a proposal for rehabilitative interventions in the spa setting,” International Journal of Biometeorology 65:2241–2243 (March, 2021)).
D’Amico teaches urolithin A (UA), a member of the claimed genus of urolithins, and teaches direct supplementation of UA as a nutritional intervention in humans. D’Amico teaches that UA enhances cellular health by increasing mitophagy and mitochondrial function and reducing detrimental inflammation and identifies UA as particularly promising for conditions involving mitochondrial and muscle dysfunction (D’Amico, p. 687, Abstract and Highlights).
D’Amico further teaches that improvement of mitochondrial health is the most consistent effect of UA across species and explains that UA promotes clearance and recycling of dysfunctional mitochondria by mitophagy (D’Amico, p. 688, left column, section “Mitophagy and Mitochondrial Function”). D’Amico additionally reports induction of mitochondrial OXPHOS proteins, increased mitochondrial respiratory capacity, and systemic and skeletal-muscle regulation of mitochondrial function in humans (D’Amico, p. 689, left column). D’Amico further teaches attenuation of detrimental inflammatory responses by UA and specifically reports decreases in the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α (D’Amico, p. 690, left column, section “Inflammation”). D’Amico also teaches improvement in skeletal-muscle performance, including enhanced skeletal-muscle strength, aerobic performance, endurance, grip strength, and running activity (D’Amico, p. 691, left column, section “Skeletal Muscle Function”).
D’Amico expressly teaches intervention clinical trials in which subjects directly received UA by oral administration (D’Amico, p. 695, left col., section “UA in Clinical Studies”). D’Amico further reports single oral administration up to 2000 mg and repeated oral dosing up to 1000 mg daily for 28 days, with UA bioavailable at all tested doses (D’Amico, p. 696, col. 1).
D’Amico does not expressly teach administering UA to a subject afflicted with long COVID-19.
Morris teaches that ME/CFS is a neuroimmune disorder characterized by chronic low-grade inflammation and increased oxidative/nitrosative stress and further teaches mitochondrial abnormalities in ME/CFS, including lowered ATP production and impaired oxidative phosphorylation. Morris additionally explains that defects in ATP production and the electron-transport complexes are associated with increased superoxide/hydrogen-peroxide production and mitochondrial damage. Morris further teaches that mitochondrial dysfunction, including lowered ATP production, may contribute to the onset of ME/CFS symptoms such as fatigue and post-exertional malaise (Morris, p. 19, Abstract, cols. 1–2). The Morris publication is specifically directed to mitochondrial dysfunction in ME/CFS. Morris expressly concerns myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and teaches mitochondrial dysfunction, impaired ATP generation, oxidative/nitrosative stress, and immuno-inflammatory abnormalities in that disorder (Morris, p. 19, Abstract).
Maccarone teaches that, following recovery from acute SARS-CoV-2 infection, many subjects fail to return to full health and experience persistent disabling outcomes; persistent fatigue was reported in 53.1–72% of recovered subjects, and chronic post-COVID syndrome was known to persist beyond 12 weeks (Maccarone, p. 2241, cols. 1–2). Maccarone additionally teaches a mechanistic relationship between post-COVID persistent fatigue and inflammation. Maccarone states that the virus-induced cytokine storm had been hypothesized to contribute to chronic fatigue, that accumulation of pro-inflammatory cytokines in the CNS may contribute to unremitting fatigue, and that IL-6 overexpression was linked to persistent inflammation and fatigue (Maccarone, p. 2242, col. 1). Thus, although D’Amico does not expressly administer UA for long COVID, Morris and Maccarone provide the reason for applying D’Amico’s mitochondrial-function-enhancing and anti-inflammatory intervention to the claimed post-viral condition.
It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to administer a therapeutically effective amount of urolithin A, as taught by D’Amico, to a subject suffering from persistent post-COVID disease as taught by Maccarone to treat myalgic encephalomyelitis/chronic fatigue associated with Covid-19 (Mec/Cfs). D’Amico expressly teaches that UA improves mitochondrial function and mitophagy, decreases detrimental inflammatory responses, and improves muscle function. Morris teaches that mitochondrial dysfunction, impaired ATP production, oxidative/nitrosative stress, and inflammatory abnormalities are mechanistically associated with ME/CFS and symptoms including fatigue and post-exertional malaise. Maccarone teaches that subjects recovering from COVID-19 commonly experience a persistent chronic-fatigue syndrome and associates that fatigue with persistent pro-inflammatory cytokine activity, including IL-6.
Accordingly, one of ordinary skill would have been motivated to employ the mitochondrial-function-enhancing and anti-inflammatory effects of UA to ameliorate the mitochondrial/inflammatory abnormalities and resulting fatigue associated with persistent post-COVID disease. The proposed modification uses D’Amico’s known intervention for the same categories of physiological dysfunction identified by Morris and Maccarone, rather than relying merely upon the fact that UA and long COVID were independently known.
One of ordinary skill would also have had a reasonable expectation that administration of UA would beneficially affect at least one manifestation of the post-COVID condition, including post-Covid-19 mec/cfs). D’Amico reports that UA actually increases mitochondrial respiratory function and mitochondrial biomarkers and produces anti-inflammatory and muscle-functional effects. Moreover, D’Amico reports direct oral administration of UA to humans in a randomized, double-blind, placebo-controlled Phase I study (D’Amico, p. 695, left column). D’Amico further reports no observed adverse effects following a single oral UA dose up to 2000 mg or repeated administration up to 1000 mg/day for 28 days, favorable bioavailability, increased mitochondrial gene-set expression in skeletal muscle, and improved systemic mitochondrial biomarkers (D’Amico, p. 696, col. 1). Thus, the prior art supplied not merely a theoretical mechanism, but experimental evidence that UA produced the mitochondrial, inflammatory, and muscle-related biological effects that the combined teachings identified as relevant to the claimed condition. A reasonable expectation of success does not require certainty that every subject or every symptom would respond.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over D’Amico et al. in view of Morris et al. and Maccarone et al., as applied to claims 11, 12, 15, 17, 29, 34, and 48–52 are above, and further in view of Columbia University Mailman School of Public Health, “Is Long COVID Really Chronic Fatigue Syndrome by Another Name?” published August 6, 2021.
D’Amico, Morris, and Maccarone render obvious treatment of a subject afflicted with long COVID-19 by administration of urolithin A for the reasons set forth above but do not expressly identify the antecedent SARS-CoV-2 infection as infection with the Delta variant.
Columbia expressly teaches that the proliferation of the “extra-contagious Delta variant” gave the threat of Long COVID “new urgency.” Columbia further teaches in the same discussion that mild and asymptomatic SARS-CoV-2 infections remained capable of giving rise to Long COVID (Columbia, p. 5, paragraph beginning “The proliferation of the extra-contagious Delta variant…”).
It would have been obvious to one of ordinary skill in the art to carry out the treatment suggested by D’Amico, Morris, and Maccarone in a Long-Covid-19 subject whose preceding SARS-CoV02 infection caused by the then-known Delta Variant. Columbia places Delta infection expressly in the context of the continuing risk of Long Covid, including following mild or symptomatic infections. The selection of Long-Covid patient whose antecedent infection was Delta therefore represents application of the suggested treatment to one of the known SARS-CoV-2 viral variants giving rise to the patient population of interest.
One of ordinary skill would have had a reasonable expectation of success because the proposed UA therapy is directed to the post-infectious mitochondrial, inflammatory, and muscle/energy abnormalities associated with persistent disease, rather than to neutralization of a particular viral variant. The prior art provides no indication that UA’s mitochondrial or anti-inflammatory activity would cease to operate merely because the antecedent SARS-CoV-2 infection was caused by Delta.
Claims 36, 37, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over D’Amico et al. in view of Morris et al. and Maccarone et al., as applied to claims 11, 12, 15, 17, 29, 34, and 48–52 above, and further in view of Paul et al., “Redox imbalance links COVID-19 and myalgic encephalomyelitis/chronic fatigue syndrome,” PNAS 118(34):e2024358118 (published August 16, 2021).
As discussed above, D’Amico in view of Morris and Maccarone renders obvious treatment of long COVID with UA but does not expressly teach the additional concurrent nutritional/coenzyme, including vitamin C CoQ10.
Paul teaches that long COVID is reminiscent of ME/CFS and describes ME/CFS as including profound fatigue, post-exertional malaise, unrefreshing sleep, and cognitive deficits. Paul further identifies redox imbalance, systemic and neuroinflammation, impaired ATP generation, and a hypometabolic state as biological abnormalities relevant to COVID-19 and ME/CFS (Paul, p. 1, Abstract and introductory text). Paul specifically explains that mitochondrial dysfunction has long been associated with fatigue, can cause elevated oxidative stress, and could contribute to fatigue in acute COVID-19 and ME/CFS. Paul further describes dysregulated mitochondrial bioenergetics in SARS-CoV-2 infection and impaired ATP production and structural/functional mitochondrial abnormalities in ME/CFS (Paul, p. 3, section “Impaired Energy Metabolism in COVID-19 and ME/CFS”). Paul further depicts redox imbalance, mitochondrial dysfunction, and chronic inflammation as bidirectionally related and capable of causing symptoms of both long COVID and ME/CFS (Paul, Fig. 2 and accompanying text, p. 4).
Paul identifies multiple nutrient/coenzyme interventions directed to the relevant redox abnormalities and reports clinical benefit from small studies involving ubiquinol and a combination of NADH and CoQ10. Paul additionally identifies nicotinamide, selenium, vitamin C, vitamin D, and vitamin E among potential therapies targeting redox imbalance (Paul, p. 5, section “Potential Redox-Based Therapeutics”).
It therefore would have been obvious to concurrently administer a nutrient or coenzyme, including vitamin C or CoQ10 as taught by Paul with the UA treatment suggested by D’Amico, Morris, and Maccarone because Paul expressly teaches such adjuncts as approaches for correcting redox/energy abnormalities implicated in COVID-19 and ME/CFS.
The references provide a reasonable expectation of success because the agents act upon complementary aspects of the same interrelated mitochondrial, redox, inflammatory, and energy-metabolic abnormalities. Paul expressly explains that these abnormalities are bidirectionally connected and may establish a persistent self-reinforcing pathological process. Paul expressly identifies vitamin C/ascorbate and teaches that vitamin C has antiviral and immunomodulatory effects (Paul, p. 3). Paul thereafter expressly includes vitamin C among potential therapies targeting redox imbalance (Paul, p. 5). Paul teaches that subjects with ME/CFS reportedly have significantly reduced plasma CoQ10 and that CoQ10 levels inversely correlate with fatigue, impaired concentration and memory, and symptoms of autonomic dysfunction. Paul further teaches that CoQ10/ubiquinone is a component of the electron transport chain and possesses antioxidant and anti-inflammatory effects (Paul, p. 4). Paul additionally reports clinical benefit from small studies of ubiquinol and of NADH plus CoQ10 (Paul, p. 5).
Accordingly, one of ordinary skill in the art would have been motivated to select vitamin C and/or CoQ10 as the nutrient concurrently administered with UA to provide additional antioxidant/redox and immunomodulatory support in a disease state associated with mitochondrial dysfunction, oxidative stress, and inflammation.
A reasonable expectation of beneficial activity would have existed because Paul expressly identifies the antioxidant/redox abnormality and identifies vitamin C or CoQ10 as an agent directed to that abnormality. The claim does not require that zinc also be administered.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over D’Amico et al. in view of Morris et al. and Maccarone et al., further in view of Paul et al., as applied to claims 36, 37, and 39 above, and further in view of the October 6, 2020, About NAD publication reporting the Altay et al. clinical study, “Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19.”
The combination discussed with respect to claim 36 teaches concurrent supplementation directed to redox/energy metabolism but does not expressly teach that the NAD+ precursor is nicotinamide riboside, as specifically required by claim 41.
The AboutNAD/Altay disclosure reports clinical research involving 93 mild-to-moderate COVID-19 patients and teaches administration of a nutritional protocol containing nicotinamide riboside (NR), L-serine, N-acetyl-L-cysteine, and L-carnitine tartrate. The NR-containing protocol was administered together with then-standard therapy and reportedly reduced recovery time by 29%, from 9.3 days to 6.6 days (AboutNAD, p. 2, first and second substantive paragraphs). The reference further teaches that SARS-CoV-2 infection depletes NAD+ and identifies NAD+ precursors and related metabolic pathways as biologically relevant in COVID-19 (AboutNAD, p. 2).
Most importantly, the reference expressly states that nicotinamide riboside is important for mitochondrial function and explains that the investigators hypothesized that the metabolic-cofactor combination could improve COVID-19 clinical outcomes by regulating energy metabolism and carbohydrate, lipid, and amino-acid pathways (AboutNAD, p. 3, first substantive paragraph).
The reference also teaches that the nutrients participate in the NAD+ biosynthesis pathway and reports administration of the nutritional combination twice daily for 14 days in the randomized Phase 2 study, with significantly reduced recovery time compared with placebo (AboutNAD, p. 4).
The underlying Altay et al. study is identified in the reference as “Combined metabolic cofactor supplementation accelerates recovery in mild-to-moderate COVID-19,” medRxiv (2020).
Accordingly, one of ordinary skill would have been motivated to select nicotinamide riboside as the NAD+ precursor concurrently administered in the method suggested by D’Amico, Morris, Maccarone, and Paul. The motivation is not based merely upon NR being one of many known NAD+ precursors; the prior art expressly associates SARS-CoV-2 infection with NAD+ depletion, identifies NR as important to mitochondrial function, and reports administration of an NR-containing regimen to human COVID-19 patients.
One of ordinary skill in the art would likewise have had a reasonable expectation of success because the Altay disclosure reports an actual human clinical study in which an NR-containing metabolic-cofactor protocol significantly shortened recovery time, while D’Amico independently demonstrates biological improvement of mitochondrial function and human bioavailability of UA. The proposed combination therefore represents use of complementary known interventions directed toward mitochondrial/energy-metabolic abnormalities implicated in COVID-19 and its persistent sequelae.
The Examiner notes that the rejection does not rely upon any one reference as expressly teaching treatment of long COVID-19 with urolithin A. Rather, D’Amico teaches urolithin A and its demonstrated mitophagy-promoting, mitochondrial-function-enhancing, anti-inflammatory, muscle-functional, and human oral-administration properties; Morris teaches mitochondrial, bioenergetic, oxidative/nitrosative, and inflammatory dysfunction in ME/CFS; and Maccarone teaches persistent post-COVID fatigue and its association with persistent inflammatory abnormalities. The proposed modification therefore arises from the express physiological relationship among the teachings of the references and not from Applicant’s disclosure. The additional references are relied upon only for the further limitations recited in the respective dependent claims.
Conclusion
Claims 11-12, 15, 17-18, 29, 34, 36-37, 39, 41, and 48-52 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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