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 without traverse of a glycolysis inhibitor (compound), glucose analog (glycolysis inhibitor grouping) and 2DG (representative species), in the reply filed on 06/12/2026 is acknowledged.
Claims 8-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Status of Claims
Claims 1-21, 28-30, 32 and 35 are currently pending.
Claims 1-7, 15-21, 28-30, 32 and 35 are under consideration, as claims 8-14 are withdrawn.
Priority
The present application claims status as a 371 (National Stage) of PCT/GB2022/052910 filed on November 16, 2022 and claims priority to international application GB2116499.1 filed on 11/16/2021. Acknowledgment is made of applicant' s claim for foreign priority and papers submitted under 35 U.S.C. 119 (a)-(d). The present application and all claims are being examined with an effective filing date of 11/16/2021. In future actions, the effective filing date may change due to amendments or further review of priority documents.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 05/15/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
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 1-7, 15-21, 28-30 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 treatment of heteroplasmic mitochondrial DNA disorders using glycolysis inhibitors that selectively reduce mutant mtDNA heteroplasmy, does not reasonably provide enablement for the full scope of the claimed method of treating any mitochondrial DNA disorder. 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.
The specification fails to enable the claim (or the full scope of the claim) if a person of ordinary skill in the art would be faced with an undue burden of experimentation when trying to implement the invention based on the disclosure. In re Wands (858 F.2d 731 at 737, 8 USPQ2d 1400 at 1404 (Fed. Cir. 1988)) sets forth a non-exclusive list of factors by which this burden of experimentation may be judged to be due or undue; factors that are germane to the instant case include the breadth of the claims, nature of the invention, the amount of direction provided by the inventor, the existence of working examples and the state of the prior art.
Claim 1 recites a method of treating a mitochondrial DNA disorder by administering a therapeutically effective amount of a glycolysis inhibitor. In summary, the nature of the invention is the treatment of mitochondrial DNA disorders through selective inhibition of mutant mitochondrial DNA replication, thereby promoting replication of wild-type mitochondrial DNA, reducing intracellular heteroplasmy, and restoring mitochondrial function. The disclosure consistently attributes the therapeutic effect of the claimed glycolysis inhibitors to this mechanism and states that glycolysis inhibitors “select wild-type mtDNA molecules,” “inhibit replication of the mutant mtDNA but not the wild-type mtDNA,” and thereby reduce the level of mutant mtDNA and improve mitochondrial function. The specification further states that the mitochondrial DNA disorder treated by the compound is a heteroplasmic mitochondrial DNA disorder and that treatment reduces intracellular heteroplasmy.
The amount of direction provided by the inventor is limited to treatment using a small number of representative glycolysis inhibitors, principally 2-deoxy-D-glucose (2DG), 5-thioglucose (5TG), and limited data relating to oxamate. Although the specification lists numerous additional classes of glycolysis inhibitors and representative compounds, it provides little or no experimental guidance demonstrating that these additional inhibitors produce the claimed therapeutic effect. Instead, the disclosure relies primarily upon the proposed mechanism of preferential replication of wild-type mitochondrial DNA to extrapolate therapeutic efficacy across the broadly claimed genus of glycolysis inhibitors and mitochondrial DNA disorders.
The existence of working examples is likewise limited. The disclosure provides experimental support primarily for cells harboring the m.3243A>G mutation treated with 2DG and 5TG, with more limited data relating to oxamate. These experiments demonstrate a reduction in mutant mtDNA load, preferential replication of wild-type mtDNA, and improvement in mitochondrial function. However, the disclosure does not provide representative working examples demonstrating treatment across the full scope of glycolysis inhibitors or across the full breadth of mitochondrial DNA disorders encompassed by the claims.
With respect to the state of the prior art, primary mitochondrial diseases were recognized as a highly heterogeneous group of disorders exhibiting substantial genetic, biochemical, and clinical complexity, arising from numerous distinct mitochondrial DNA mutations and resulting in highly variable clinical presentations. The prior art further recognized that mitochondrial DNA mutations may be either heteroplasmic or homoplasmic, with different diseases being associated with each type of mutation. For example, heteroplasmic mutations were known to cause disorders such as MELAS, MERRF, NARP, and many cases of Leigh syndrome, whereas Leber’s Hereditary Optic Neuropathy (LHON) was recognized as the principal disease associated with homoplasmic mtDNA mutations. (Bottani et al., Therapeutic Approaches to Treat Mitochondrial Diseases: “One-Size-Fits-All” and “Precision Medicine” Strategies, Pharmaceutics 2020, 12, 1083, cited in PTO-892). The prior art additionally recognized that treatment of mitochondrial diseases was highly unpredictable. Bottani et al. classified available therapeutic approaches into broad “one-size-fits-all” strategies and mutation- or disease-specific “precision medicine” strategies, while emphasizing that mitochondrial diseases exhibit extensive genotype-phenotype variability, that no approved cure existed for most mitochondrial diseases, and that the heterogeneity of these disorders had significantly hindered the development of effective therapies. (pg. 1–3). Moreover, Bottani et al. demonstrates that therapeutic responses differed depending upon the underlying mitochondrial defect. For example, certain dietary interventions and pharmacological approaches showed beneficial effects in some mitochondrial disease models while proving ineffective or even detrimental in others, leading the authors to conclude that disease-specific therapeutic approaches are often required and that further investigation was necessary before broadly applying individual therapeutic strategies across the spectrum of mitochondrial diseases. (pg. 5–12).
Accordingly, given the breadth of the claim, the limited number of representative working examples, the amount of direction provided by the specification, and the unpredictable nature of therapeutic efficacy across the full scope of the claimed genus, a person of ordinary skill in the art would be required to engage in undue experimentation to practice the full scope of the claimed invention. Therefore, the specification does not enable the invention commensurate in scope with the claims.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-7, 21, 28 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al. (WO2015157409, cited in the IDS).
Regarding claims 1-7, Dhar et al. teaches Pt(IV) prodrugs and nanoparticle formulations for treating mitochondrial diseases by targeting mitochondrial DNA, explaining that mitochondrial DNA plays an important role in disease and that targeting mitochondrial DNA may provide effective therapies for mitochondrial diseases (para 6-13). Dhar et al. further teaches compounds having Formula (I), wherein R³ is a mitochondria-targeting moiety and R² is OH or -(L²)x(R⁴)y, wherein R⁴ is selected from a conjugated cyclooxygenase inhibitor, a targeting moiety, a fluorophore, a glycolysis inhibitor, or a mitochondria-acting therapeutic agent (para 8 and 38). Dhar et al. further teaches that, in various embodiments, R⁴ is a glycolysis inhibitor and expressly identifies 2-deoxy-D-glucose (2DG), lonidamine, 3-bromopyruvate, imatinib, and oxythiamine as suitable glycolysis inhibitors (para 51). Dhar et al. additionally teaches administering the disclosed Pt(IV) prodrugs or nanoparticle formulations to treat a patient having a mitochondrial disease (e.g., para 12 and 123). Accordingly, Dhar et al. teaches administering a Pt(IV) prodrug compound for the treatment of mitochondrial disease, wherein the administered compound comprises an R⁴ substituent that is expressly taught to be a glycolysis inhibitor, including 2-deoxy-D-glucose (para 8, 38, 51). Thus, in embodiments where R⁴ is 2-deoxy-D-glucose, Dhar et al. teaches administering a compound that is a glycolysis inhibitor for the treatment of mitochondrial disease.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to select 2-deoxy-D-glucose (2DG) as the glycolysis inhibitor incorporated into the compounds of Dhar et al., because Dhar et al. expressly teaches that the R⁴ substituent may be a glycolysis inhibitor (para 8 and 38) and further expressly identifies 2-deoxy-D-glucose as one of a finite number of suitable glycolysis inhibitors for the R⁴ substituent (para 51). Selecting 2-deoxy-D-glucose therefore merely constitutes the predictable selection of one expressly disclosed species from Dhar et al.’s finite list of suitable glycolysis inhibitors for use in the disclosed compounds, yielding no more than the expected result.
Regarding claims 21 and 28, Dhar et al. teaches the compound described above can be administered “orally in capsules, suspensions or tablets” (para 132).
Regarding claim 30, Dhar et al. teaches embodiments of the compound described above, where the R4 of said compound is a conjugated mitochondria acting therapeutic agent, and expressly teaches metformin as a mitochondria acting therapeutic agent. Pursuant to MPEP 2144.06, "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). Accordingly, it would have been obvious to a person of ordinary skill in the art, to administer the compound of Dhar et al., as described above, comprising a glycolysis inhibitor, in combination with mannose, for the purpose of treating a mitochondrial disease. There is a reasonable expectation of success because both compounds are disclosed by Dhar et al. as suitable compounds for treating any mitochondrial disease and because both agents are taught by Dhar et al. as therapies for mitochondrial disease, and combining therapeutic agents directed to the same disease to achieve additive or improved therapeutic efficacy was well known in the art.
Thus, claims 1-7, 21 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al.
Claims 15-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al. as applied to claim 1 above, and further in view of Tranah et al. (Mitochondrial DNA m.3243A > G heteroplasmy affects multiple aging phenotypes and risk of mortality, Scientific RePoRTS | (2018) 8:11887, cited in PTO-892).
The teachings of Dhar et al., as they apply to claim 1, have already been discussed above and are relied upon.
Regarding claims 15-17 and 19-20, Dhar et al. teaches a method of treating mitochondrial DNA disorders as described above, and further teaches that any mitochondrial disease may be treated using the disclosed Pt(IV) prodrugs or nanoparticle formulations, described above, and expressly identifies mitochondrial myopathy, diabetes mellitus and deafness, Leber’s hereditary optic neuropathy, Wolff-Parkinson-White syndrome, multiple sclerosis, Leigh syndrome, neuropathy, ataxia, retinitis pigmentosa, mitochondrial neurogastrointestinal encephalopathy, and myoclonic epilepsy with ragged-red fibers (MERRF), among others, as mitochondrial diseases that may be treated using the disclosed compounds (para 134). However, Dhar et al. does not expressly disclose the particular mitochondrial DNA mutation associated with the mitochondrial disease being treated.
Tranah et al. teaches that the pathogenic mitochondrial DNA mutation m.3243A>G is one of the most thoroughly studied mitochondrial DNA mutations and causes several mitochondrial diseases and physiological dysfunctions, including mitochondrial myopathy. Tranah et al. further teaches that mitochondrial function is cell-type specific and that a single mitochondrial DNA mutation may lead to a variety of mitochondrial diseases depending upon the tissue in which the mutation is expressed (p. 1). Tranah et al. therefore identifies patients having the recited m.3243A>G mutation as patients suffering from mitochondrial diseases of the type that Dhar et al. expressly teaches treating.
An invention would have been obvious to a person having ordinary skill in the art if some teaching in the prior art would have led that person to combine the prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Dhar et al., that “any mitochondrial disease”, including mitochondrial myopathy, may be treated using the disclosed Pt(IV) prodrugs or nanoparticle formulations, and the teachings of Tranah et al., that the pathogenic mitochondrial DNA mutation m.3243A>G causes mitochondrial myopathy, thereby identifying patients having the recited mutation as patients suffering from mitochondrial diseases treatable according to Dhar et al., would have led said practitioner to administer the compounds disclosed by Dhar et al. to a patient suffering from a mitochondrial DNA disorder associated with the m.3243A>G mutation. Given that Dhar et al. demonstrates a successful method for treating mitochondrial diseases using the disclosed compounds, a person having ordinary skill in the art would have reasonably expected that applying Dhar et al.’s disclosed treatment to patients identified by Tranah et al. as having mitochondrial myopathy or chronic progressive external ophthalmoplegia resulting from the m.3243A>G mutation would successfully result in a method of treating a mitochondrial DNA disorder associated with the m.3243A>G mutation by administering a therapeutically effective amount of the disclosed compound. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art, before the effective filing date of the claimed invention.
Thus, claims 15-17 and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al. further in view of Tranah et al.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al. as applied to claim 1 above, and further in view of Xi et al. (2-Deoxy-D-glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion, Cancer Chemother Pharmacol (2011) 67:899–910, cited in PTO-892).
The teachings of Dhar et al., as they apply to claim 1, have already been discussed above and are relied upon. Dhar et al. does not teach administration of mannose to a patient suffering from a mitochondrial DNA disorder.
Xi et al. teaches that 2-deoxy-D-glucose (2-DG) is a glycolysis inhibitor that not only inhibits glycolysis, thereby reducing cellular ATP levels, but also interferes with N-linked glycosylation, resulting in endoplasmic reticulum (ER) stress and an unfolded protein response (Abstract). Xi et al. further teaches that the addition of exogenous mannose reverses the 2-DG-induced ER stress and autophagy without restoring the lowered ATP levels caused by 2DG (Abstract). Xi et al. additionally teaches that exogenous mannose reverses the 2DG-induced ER stress without affecting the lowered ATP levels produced by 2DG (p. 900, left column, second full paragraph; p. 900, right column, first full paragraph).
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Xi et al., that exogenous mannose reverses the 2DG-induced ER stress without affecting the lowered ATP levels produced by the glycolysis inhibitor, would have led a person of ordinary skill in the art to administer mannose in combination with the glycolysis inhibitor (e.g., 2DG) containing compound taught by Dhar et al. There is a reasonable expectation of success because Xi et al. teaches that exogenous mannose is effective against 2DG induced ER stress. Furthermore, a person of ordinary skill in the art would have been motivated to administer mannose in combination with the glycolysis inhibitor-containing compound taught by Dhar et al. in order to reduce the known ER stress associated with administration of 2-deoxy-D-glucose, because Xi et al. teaches that mannose reduces ER stress while preserving the glycolysis-inhibiting activity of 2-deoxy-D-glucose. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Thus, claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al., further in view of Xi et al.
Claims 15-16 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al. as applied to claim 1 above, and further in view of Russell and Turnbull (Mitochondrial DNA disease—molecular insights and potential routes to a cure, EXPERIMENTAL CELL RESEARCH 325 (2014) 38–43, herein “Russell”, cited in PTO-892).
The teachings of Dhar et al., as they apply to claim 1, have already been discussed above and are relied upon.
Regarding claims 15-16 and 18, Dhar et al. teaches a method of treating mitochondrial DNA disorders as described above, and further teaches that any mitochondrial disease may be treated using the disclosed Pt(IV) prodrugs or nanoparticle formulations, described above, and expressly identifies mitochondrial myopathy, diabetes mellitus and deafness, Leber’s hereditary optic neuropathy, Wolff-Parkinson-White syndrome, multiple sclerosis, Leigh syndrome, neuropathy, ataxia, retinitis pigmentosa, mitochondrial neurogastrointestinal encephalopathy, and myoclonic epilepsy with ragged-red fibers (MERRF), among others, as mitochondrial diseases that may be treated using the disclosed compounds (para 134). However, Dhar et al. does not expressly disclose the particular mitochondrial DNA mutation associated with the mitochondrial disease being treated.
Russell et al. teaches that the common mitochondrial DNA deletion nt.8467_13446del4977 is a single large-scale mitochondrial DNA deletion responsible for common mitochondrial diseases (Russell et al., “Large scale, single mtDNA deletions”). Russell et al. further teaches that the phenotypes associated with single large-scale mitochondrial DNA deletion diseases include Pearson syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia (CPEO) and that these phenotypes represent a spectrum of mitochondrial disease associated with the common deletion (Russell et al., “Large scale, single mtDNA deletions”).
An invention would have been obvious to a person having ordinary skill in the art if some teaching in the prior art would have led that person to combine the prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Dhar et al., that any mitochondrial disease may be treated using the disclosed Pt(IV) prodrugs or nanoparticle formulations, and the teachings of Russell et al., that the claimed mitochondrial DNA deletion nt.8467_13446del4977 is associated with several mitochondrial diseases including Pearson syndrome, Kearns-Sayre syndrome, and chronic progressive ophthalmoplegia, would have led said practitioner to administer the compounds disclosed by Dhar et al. to a patient suffering from a mitochondrial DNA disorder associated with the claimed deletion. Given that Dhar et al. demonstrates a successful method for treating mitochondrial diseases using the disclosed compounds, a person having ordinary skill in the art would have reasonably expected that applying Dhar et al.’s disclosed treatment to patients having mitochondrial diseases resulting from the nt.8467_13446del4977 deletion would successfully result in a method of treating a mitochondrial DNA disorder associated with the claimed deletion by administering a therapeutically effective amount of the disclosed compound.
Thus, claims 15-16 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al., further in view of Russell.
Claims 32 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al. (WO2015157409, cited in the IDS) and Pereira and Moraes (Current strategies towards therapeutic manipulation of mtDNA heteroplasmy, Frontiers in Bioscience, Landmark, 22, 991-1010, January 1, 2017, herein “Pereira”, cited in PTO-892).
Regarding claims 32 and 35, Dhar et al. teaches Pt(IV) prodrugs and nanoparticle formulations for treating mitochondrial diseases by targeting mitochondrial DNA, explaining that mitochondrial DNA plays an important role in disease and that targeting mitochondrial DNA may provide effective therapies for mitochondrial diseases (para 6-13). Dhar et al. further teaches compounds having Formula (I), wherein R³ is a mitochondria-targeting moiety and R² is OH or -(L²)x(R⁴)y, wherein R⁴ is selected from a conjugated cyclooxygenase inhibitor, a targeting moiety, a fluorophore, a glycolysis inhibitor, or a mitochondria-acting therapeutic agent (para 8 and 38). Dhar et al. further teaches that, in various embodiments, R⁴ is a glycolysis inhibitor and expressly identifies 2-deoxy-D-glucose (2DG), lonidamine, 3-bromopyruvate, imatinib, and oxythiamine as suitable glycolysis inhibitors (para 51). Dhar et al. additionally teaches administering the disclosed Pt(IV) prodrugs or nanoparticle formulations to treat a patient having a mitochondrial disease (e.g., para 12 and 123). Accordingly, Dhar et al. teaches administering a Pt(IV) prodrug compound for the treatment of mitochondrial disease, wherein the administered compound comprises an R⁴ substituent that is expressly taught to be a glycolysis inhibitor, including 2-deoxy-D-glucose (para 8, 38, 51). Thus, in embodiments where R⁴ is 2-deoxy-D-glucose, Dhar et al. teaches administering a compound that is a glycolysis inhibitor for the treatment of mitochondrial disease. It is further noted that claim 35 recites administering the compound to a cell. One of ordinary skill in the art would have understood that administration of the glycolysis inhibitor-containing compound to a patient for treatment of a mitochondrial disease necessarily results in administration of the compound to cells of the patient, including cells containing mitochondria affected by the mitochondrial disease. Accordingly, Dhar et al. teaches administration of the disclosed compound both to a patient and, inherently, to cells of the treated patient. However, although Dhar et al. expressly teaches administration of a glycolysis inhibitor-containing compound for the treatment of mitochondrial disease, Dhar et al. does not expressly disclose that administration of the glycolysis inhibitor reduces mitochondrial DNA heteroplasmy.
Pereira et al. teach that pathogenic mitochondrial DNA mutations frequently exist in a heteroplasmic state in which mutant and wild-type mitochondrial DNA coexist within the same cell and that therapeutic manipulation of mitochondrial DNA heteroplasmy is a strategy for treating mitochondrial disease. Pereira et al. further teach that metabolic strategies to shift mitochondrial DNA heteroplasmy have been tested and evaluated, including treatment with ketogenic supplements (glucose deprivation), which was sufficient “to shift mitochondrial DNA heteroplasmy toward wild-type mitochondrial DNA, thereby rescuing metabolic function” (pg. 996, bottom left). Pereira et al. additionally teach that metabolic intervention represents an approach for shifting mitochondrial DNA heteroplasmy.
An invention would have been obvious to a person of ordinary skill in the art if some teaching in the prior art would have led that person to combine prior art reference teachings to arrive at the claimed invention. Before the effective filing date of the claimed invention, the teachings of Pereira et al., which disclose that metabolic interventions, including ketogenic supplementation through glucose deprivation, shift mitochondrial DNA heteroplasmy toward wild-type mitochondrial DNA, and the teachings of Dhar et al., which disclose administration of compounds comprising glycolysis inhibitors, including 2-deoxyglucose, for the treatment of mitochondrial disease, would have led a person of ordinary skill in the art to administer the glycolysis inhibitor-containing compounds of Dhar et al. to a patient in need thereof with a reasonable expectation that inhibition of glycolysis, like the glucose deprivation achieved by ketogenic supplementation, would likewise reduce cellular glucose utilization and thereby shift mitochondrial DNA heteroplasmy. Furthermore, a person of ordinary skill in the art would have been motivated to administer the glycolysis inhibitor-containing compounds taught by Dhar et al. because Pereira et al. teach that reducing cellular dependence on glucose metabolism through metabolic intervention shifts mitochondrial DNA heteroplasmy toward wild-type mitochondrial DNA and provides a therapeutic benefit in heteroplasmic mitochondrial disease. Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention.
Thus, claims 32 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Dhar et al. Pereira.
Conclusion
No claim is in condition for allowance.
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/NAGHMEH NINA MOAZZAMI/Examiner, Art Unit 1652
/ROBERT B MONDESI/Supervisory Patent Examiner, Art Unit 1652
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