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 .
Response to Arguments
Applicant’s arguments, see “Objections to the Claims”, filed 08/05/2026, with respect to claim 2 have been fully considered and are persuasive. The objection of claim 2 has been withdrawn.
Applicant’s arguments, see “Rejections under 35 U.S.C. § 112”, filed 08/05/2026, with respect to claims 2-8, 10-11, and 16 have been fully considered and are persuasive. The 112(b) rejections of claim 2-8, 10-11, and 16 have been withdrawn.
Applicant’s arguments with respect to claim(s) 1-25 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Claim Interpretation
Claim 4 is directed to the preamble statement of claim 1 (preamble: “a method of treating a mitochondrial disorder”). Claim 4 specifies that the mitochondrial disorder comprises Leigh syndrome (with or without Complex 1 mutations) or Lebers Hereditary Neuropathy. Preamble statements are only given patentable weight when it recites structural limitations to the claimed invention. In this case, the claimed invention is a method/process, and the body of the claim outlines all of the steps of the method. The mitochondrial disorder only represents the intended use of the method outlined in claim 1 and its dependent claims. Therefore, dependent claim 4 is also interpreted to be the intended use of the disclosed invention, and is not granted patentable weight. See MPEP 2111.02.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-23 and 25 and 24 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims will be analyzed below according to MPEP 2106.
Inquiry 1: Is the claim directed to a statutory category of invention (process, machine, manufacture, or composition of matter)?
Yes, claim 1 (and its dependent claims) and claim 24 are both directed to processes.
Inquiry 2A Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Yes, claim 1 recites “selecting an anaplerotic therapy based on the amount of the 2- hydroxyglutarate enantiomer present in the biological sample…” Claim 1 also recites “determining an amount of 2-hydroxyglutarate enantiomer present…” As worded, these steps are mental processes, which are abstract ideas; specifically, “determining” would be performed in the human mind by simply observing data collected in an unrecited analytical method (LC-MS, etc.) and deciding how much metabolite is present, and “selecting” is a function of the human mind which would occur by contemplating appropriate anaplerotic therapies based on the aforementioned determination. See MPEP 2106.04(a).
Claim 3 recites “determining an amount of a lactate enantiomer... the amount of the 2-hydroxyglutarate enantiomer and the amount of the lactate enantiomer are determined” As worded, this is a mental processes, which is an abstract idea; specifically, “determining” would be performed in the human mind by simply observing data collected in an unrecited analytical method (LC-MS, etc.) and deciding how much metabolite is present. See MPEP 2106.04(a).
Claim 24 recites “determining and amount of 2-hydroxyglutarate enantiomer and an amount of a lactate enantiomer” and “selecting a therapy based on an amount of a metabolite present in a biological sample…” As worded, these steps are mental processes, which are abstract ideas; specifically, “determining” would be performed in the human mind by simply observing data collected in an unrecited analytical method (LC-MS, etc.) and deciding how much metabolite is present, and “selecting” is a function of the human mind which would occur by contemplating appropriate anaplerotic therapies based on the aforementioned determination. See MPEP 2106.04(a).
Inquiry 2A Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
No they do not. Claim 1, its dependent claims, and claim 24 will be further analyzed below.
Claim 1 contains step “i. determining an amount of …” and step “ii. Selecting an anaplerotic therapy…”; these are both judicial exceptions, and, at best, they amount to mere data-gathering because they are intended to generate a value that represents an amount of 2-hydroxyglutarate enantiomer. See MPEP 2106.05(g). Claim 1 also contains step “iii. administering the anaplerotic therapy to the subject if the amount of the metabolite present in the biological sample is less than a predetermined amount.” This is not a particular treatment or prophylaxis; “administering the anaplerotic therapy to treat the Complex I deficient mitochondrial” generally describes the clinical approach and broader class of disorders/diseases which the method is intended for. See MPEP 2106.04(d)(2) for examples of specific treatments or prophylaxes.
Furthermore, steps ii-iii of claim 1 are conditional and not required; regardless that the subject has or is suspected of having Complex I deficient mitochondrial disorder, if the amount of metabolite is greater than the predetermined amount, then no action is taken and therefore there is no particular practical application. The removal of the “if” phraseology does not make the method unconditional.
Claims 2-3 and 14-18 are dependent on claim 1 and pertain to step “i. determining an amount of a metabolite…”; this is an insignificant extra-solution activity that amounts to mere data-gathering. See MPEP 2106.05(g).
Claim 4 is dependent on claim 1 and pertains to the preamble statement “method of treating a mitochondrial disorder”; this list of specific mitochondrial disorders may be, at best, interpreted as a field of use. See MPEP 2106.05(h).
Claims 5-13, 11, 19, 21-23, and 25 are dependent on claim 1 and all pertain to the claimed anaplerotic treatment. These claims only limit the anaplerotic treatments that may be “selected” from, but they do not amount to a specific treatment or prophylaxis. Furthermore, the claim language does not positively recite how the selection of the anaplerotic therapy relates to the anaplerotic agents themselves. For example, regarding claim 5, the claim language does not positively recite why a short chain fatty acid would be selected over a triglyceride. Therefore, these claims do not improve upon nor apply the judicial exception in a meaningful way, nor do they amount to a particular treatment or prophylaxis. See MPEP 2106(d)(2).
In addition to the “determining” and “selecting” judicial exceptions cited in step 2A prong 1, claim 24 contains steps: i. “contacting…” but this amounts to the insignificant extra-solution (pre-solution) activity of mere data-gathering (See MPEP 2106.05(g)); and step “iv. administering the anaplerotic therapy to the subject to treat the Complex I deficient mitochondrial disorder.” This is not a particular treatment or prophylaxis; “administering the anaplerotic therapy to treat the Complex I deficient mitochondrial” generally describes the clinical approach and broader class of disorders/diseases which the method is intended for. See MPEP 2106.04(d)(2) for examples of specific treatments or prophylaxes.
Furthermore, steps iii.-iv. of claim 24 are conditional and not required; regardless of the subject having or being suspected of having Complex I deficient mitochondrial disorder, if the amount of metabolite is greater than the predetermined amount, then no action is taken and therefore there is no particular practical application. The removal of the “if” phraseology does not make the method unconditional.
Inquiry 2B: Does the claim recite additional limitations that amount to significantly more than the judicial exception?
No, they do not. Claims 1, its dependent claims, and claim 24 will each be discussed further below.
Claim 1 does not include additional elements that amount to significantly more than the judicial exception. Claim 1 contains step “i. determining an amount of …” and step “ii. Selecting an anaplerotic therapy…”; these are both judicial exceptions, and, at best, they amount to mere data-gathering because they are intended to generate a value that represents an amount of 2-hydroxyglutarate enantiomer. See MPEP 2106.05(g). Claim 1 also contains step “iii. administering the anaplerotic therapy to the subject if the amount of the metabolite present in the biological sample is less than a predetermined amount.” This is not a particular treatment or prophylaxis; “administering the anaplerotic therapy to treat the Complex I deficient mitochondrial” generally describes the clinical approach and broader class of disorders/diseases which the method is intended for. See MPEP 2106.04(d)(2) for examples of specific treatments or prophylaxes.
Furthermore, steps ii-iii of claim 1 are conditional and not required; regardless that the subject has or is suspected of having Complex I deficient mitochondrial disorder, if the amount of metabolite is greater than the predetermined amount, then no action is taken and therefore there is no particular practical application. The removal of the “if” phraseology does not make the method unconditional.
Furthermore, the concept of measuring levels of a metabolite in a biological sample is a well-understood, routine, and conventional practice that is synonymous with “metabolomics”; Liu teaches an overview of metabolomics and discusses its utilities and limitations (Liu et al, Non Patent Literature, “Metabolomics: a Primer”; see abstract), and Roessner et al teaches techniques to measure an amount of a metabolite in a sample (Roessner et al, Non-Patent Literature, “Metabolite Measurements”; see section 3.2). Therefore, step “i.” does not amount to significantly more than the judicial exception. Claim 1’s step “iii.” involves the administration of the selected anaplerotic therapy. This is a contingent limitation that is not required; for example, if the amount of metabolite present is more than the predetermined amount then no action is taken and this step would not amount to significantly more than the exception. Furthermore, the concept of administering anaplerotic therapy based on metabolite deficiency is well-understood, routine, and conventional in the arts; Roe teaches the concept of anaplerotic therapy, the motivation behind it, and its therapeutic efficacy in treating metabolic disorders (Roe et al., Non-Patent Literature, “Anaplerotic diet therapy in inherited metabolic disease: Therapeutic potential”; see abstract); McCain et al. (University of South Carolina Scholar Commons, Fall 2021, pgs. 1-179) teaches a method of simultaneous detection of lactate enantiomers and 2-hydroxyglutarate enantiomers for the treatment of Complex I deficient mitochondrial disorders. Therefore, none of the additional elements of claim 1 amount to significantly more than the judicial exception.
The dependent claims of claim 1 will also be analyzed to determine if they amount to significantly more than the judicial exception:
Claims 2-3 and 14-18 pertain to claim 1’s step “i. determining an amount of a metabolite…”; these elements all represent insignificant extra-solution activities that amount to mere data-gathering. See MPEP 2106.05(g).
Claim 4 pertains to the preamble statement “method of treating a mitochondrial disorder”, where the list of specific mitochondrial disorders may be, at best, interpreted as a field of use. See MPEP 2106.05(h).
Claims 5-13, 19-23, and 25 all pertain to the claimed anaplerotic therapy, the elements of which are well-understood, routine, and conventional in the arts. Regarding claims 5, 9, and 20, Roe (US20060004099) teaches that triheptanoin, a triglyceride, may be used as an anaplerotic agent at a dose of 0.1-2 g/kg (paragraph [109]). Regarding claims 11, 19, and 21, Roe also teaches the use of short chain fatty acids (paragraph [10]) at a dose of 0.1-2.0 g/kg (paragraph [11]) as well as the concurrent use of B complex vitamins (paragraph [115]) for anaplerotic therapy. Regarding claims 6, 7, 10, and 25, Borges (US20160263071) teaches the use of propionic acid (paragraph [83]), propionylcarnitine (paragraph [21]), C5 ketones (paragraph [79]), and a triglyceride of propionic acid (formula 1 and paragraph [88]) as potential anaplerotic agents. Regarding claim 8, Kuratsune (US5576348) teaches the use of valerylcarnitine as an anaplerotic agent (abstract). Regarding claims 12, 13, and 23, Pereira (WO202200) teaches the use of the α-ketoglutarate ester α-dimethyl ketoglutarate (Pg 13, line 21) at a dose of about 100-3000mg (Pg 13, line 26) as an anaplerotic agent. Regarding claim 22, Clarke (US20200268825) teaches the use of a vitamin at a dosage of about 0.1 mcg to 1.5 mcg (paragraph [59]). Furthermore, the specification of the instant application further supports that the anaplerotic therapies are well-understood, routine, and conventional in the arts. See MPEP 2106.05(d)(1). Therefore, none of the elements of the dependent claims of claim 1 amount to significantly more than the judicial exception.
Regarding claim 24, in addition to the “determining” and “selecting” judicial exceptions cited in step 2A prong 1, claim 24 contains steps: i. “contacting…” but this amounts to the insignificant extra-solution (pre-solution) activity of mere data-gathering (See MPEP 2106.05(g)); and step “iv. administering the anaplerotic therapy to the subject to treat the Complex I deficient mitochondrial disorder.” This is not a particular treatment or prophylaxis; “administering the anaplerotic therapy to treat the Complex I deficient mitochondrial” generally describes the clinical approach and broader class of disorders/diseases which the method is intended for. See MPEP 2106.04(d)(2) for examples of specific treatments or prophylaxes.
Furthermore, steps iii.-iv. of claim 24 are conditional and not required; regardless of the subject having or being suspected of having Complex I deficient mitochondrial disorder, if the amount of metabolite is greater than the predetermined amount, then no action is taken and therefore there is no particular practical application. The removal of the “if” phraseology does not make the method unconditional.
Furthermore, steps iii.-iv. of claim 24 are conditional limitations that are not required, as discussed above in the Step 2A Prong 2 analysis. Thus, the administration step does not integrate the mental analysis step into a practical application. Therefore, none of the additional elements in claim 24 amount to significantly more than the judicial exception.
Furthermore, the concept of administering a therapy to a subject based on an amount of a metabolite present is a well-understood, routine, and conventional practice in the arts, as discussed in Balashova et al. (Non-Patent Literature “A Metabolomics Approach to Pharmacotherapy Personalization”; see abstract) and Roe et al. (in US 20060004099); McCain et al. (University of South Carolina Scholar Commons, Fall 2021, pgs. 1-179) teaches a method of simultaneous detection of lactate enantiomers and 2-hydroxyglutarate enantiomers for the treatment of Complex I deficient mitochondrial disorders.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1-3, 5, 9-11, 14-21, 24, is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), further in view of McCain et al. (University of South Carolina Scholar Commons, Fall 2021, pgs. 1-179). For simplicity, references to McCain throughout this office action will use the page numbers listed at the bottom of each page.
Regarding claim 1, Roe teaches a method of treating a mitochondrial disorder (examples 1 and 2; paragraphs [106]-[124]), comprising:
i. determining an amount of a metabolite present in a biological sample of a subject having or suspected of having Pompe disease (paragraphs [106] or [112] or [121]) (glycogen deposition in lysosomes and cytosol (2.0%-normal 1.03+/-0.18%) or 3-OH-butyrate (BOB) and acetoacetate (AcAc) was 1633 and 1211 mmmol/mol creatine, respectively or Blood acylcarnitine analysis revealed… reduced level of propionylcarnitine (1.08, normal <2.71uM));
ii. selecting an anaplerotic therapy for the subject based on the amount of the metabolite present in the biological sample (paragraphs [108] or [122]) (The patient was… placed on… diet containing triheptanoin or Patient diet was initially adjusted… C7 [triheptanoin oil] represented 22% of his daily Kcal intake.); and
iii. administering the anaplerotic therapy to the subject to treat the Complex I deficient mitochondrial disorder (paragraphs [108] or [122] of Roe) (The patient was… placed on… diet containing triheptanoin or Patient diet was initially adjusted… C7 [triheptanoin oil] represented 22% of his daily Kcal intake.).
Roe is silent to a subject having or suspected of having a Complex I deficient mitochondrial disorder.
In the analogous art of determining amounts of metabolites in subjects with mitochondrial disorders, McCain teaches of treating patients with a Complex I mitochondrial deficiency using anaplerotic therapy (pg. 22 first paragraph of McCain) (Riboflavin is part of flavin mononucleotide, a prosthetic group of Complex I. Treatment with riboflavin is especially important and effective in patients with a Complex I deficiency… Folinic acid is a supplement used to correct deficiencies in folate). McCain teaches that the anaplerotic therapy extends the lifespan of patients by a few years (pg. 22 first paragraph of McCain) (these treatments only prolong a patient’s lifespan by a few years).
It would have been obvious to substitute the subject having or suspected of having Pompe disease as taught by Roe with the subject having or suspected of having a Complex I deficient mitochondrial disorder as taught by McCain because doing so would extent the lifespan of the subject by a few years with a reasonable expectation of success (examples 1 and 2; paragraphs [106]-[124] of Roe; pg. 22 first paragraph of McCain).
Roe is silent to determining an amount of a 2-hydroxyglutarate enantiomer, wherein the 2-hydroxyglutarate enantiomer comprises L-2- hydroxyglutarate, D-2-hydroxyglutarate, or a combination thereof.
In the analogous art of metabolite detection in a biological sample, McCain discloses a method of detecting L-2-hydroxyglutarate and D-2-hydroxyglutarate (pg. 104 first paragraph of McCain) (the levels of L-2-HG were decreased 28% in NDUFS4 KO serum versus WT (Figure 4.10A-B). In addition, we quantified a remarkable 61% decrease in D-2-HG in NDUFS4 KO serum versus WT). McCain teaches that that L/D-2-HG are of interest because their levels are selectively decreased in subjects with complex I deficient metabolic disorder (see examples 1 and 2; paragraphs [106]-[124] of Roe; pg. 104 first paragraph of McCain) (the decrease in L-2-HG or D-2-HG was surprising in select brain regions, the serum measurements validate these findings and suggest that both enantiomers are selectively reduced in tissues of the NDUFS4 KO versus WT).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to combine the detected metabolites of Roe with the detected D/L-2-HG metabolites of McCain because doing so would lead to the predictable outcome of detecting Complex I deficient mitochondrial disorder with a reasonable expectation of success, especially when considering that L/D-2-HG are selectively reduced in subjects with Complex I deficient mitochondrial disorder, (see examples 1 and 2; paragraphs [106]-[124] of Roe; pg. 104 first paragraph of McCain). See MPEP 2143(I)(A).
Regarding claim 2, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches wherein the biological sample is selected form the group consisting of blood, serum, plasma, and tissue (paragraph [106] or [121] of Roe) (a muscle biopsy revealed or routine blood chemistry on admission).
Regarding claim 3, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches of determining an amount of racemic lactate ([0141] of Roe) (Blood Samples for glucose, lactate, ketones, FFA, amino acids and acylcarnitine concentrations will be obtained).
Modified Roe is silent to further comprising determining an amount of a lactate enantiomer present in the biological sample, wherein the lactate enantiomer comprises D-lactate, L-lactate, or a combination thereof, and wherein the amount of the 2-hydroxyglutarate enantiomer and the amount of the lactate enantiomer are determined.
In the analogous art of determining amounts of metabolites in subjects with mitochondrial disorders, McCain teaches the amount of the 2-hydroxyglutarate enantiomer and the amount of the lactate enantiomer are determined (pg. 102 first paragraph of McCain) (we report the successful adaptation of this method to simultaneously detect 2-HG levels in parallel with lactate quantification). McCain teaches that the simultaneous determination of lactate with D/L-2-HG allows for the confirmation of lactic acidosis, which is expected in Complex I deficient subjects (pg. 104 second paragraph) (~1.5-fold increase in lactate with knockout of NDUFS4, which confirmed the expected lactic acidosis throughout the body). Note that the NDUFS4 KO mouse model modulates Complex I deficiency (pg. 17 second paragraph of McCain) (Leigh Syndrome resulting from Complex I deficits has a significant reduction in cellular ATP production due to reduced proton pumping at Complex I. The loss of NDUFS4 results in the assembly of a smaller complex with significantly reduced electron shuttling ability).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the lactate and D/L-2-HG detection method of Modified Roe to simultaneously detect both lactate and D/L-2-HG as taught by McCain to provide: further comprising determining an amount of a lactate enantiomer present in the biological sample, wherein the lactate enantiomer comprises D-lactate, L-lactate, or a combination thereof, and wherein the amount of the 2-hydroxyglutarate enantiomer and the amount of the lactate enantiomer are determined. Doing so would have led to the predictable outcome of confirming the presence of lactic acidosis that is expected in subjects with Complex I deficient mitochondrial disorders with a reasonable expectation of success (see [0141] of Roe; pg. 102 first paragraph, pg. 104 second paragraph, and pg. 17 second paragraph of McCain).
Regarding claim 5, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches wherein the anaplerotic therapy is selected from the group consisting of a triglyceride (paragraph [109] or [122] of Roe) (composition was (% Kcal)… triheptanoin (C7) accounted for 26%) or Patient diet was adjusted… C7 represented 22% of his daily Kcal intake).
Regarding claim 9, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. Roe teaches wherein the anaplerotic therapy is the triglyceride, and the triglyceride is triheptanoin (paragraph [108] or [117] of Roe) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil).
Regarding claim 10, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above, wherein the anaplerotic therapy is triheptanoin (paragraph [108] or [117] of Roe) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil).
Roe does not specifically disclose within a single example embodiment wherein the anaplerotic therapy is the ketone, and the ketone is a C3 ketone or a C5 ketone.
Earlier in the disclosure, Roe teaches that C5 ketone bodies may be used directly treat Pompe disease (paragraph [92]) (In addition, the C5 ketone bodies BHP [beta-hydroxypentanoate] and BKP [beta-ketopentanoate], as stated above, could also be used directly for therapy).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute Roe’s triheptanoin therapy with Roe’s C5 ketone therapy because both may be used to lead to the predictable outcome of treating Pompe disease with a reasonable chance of success (see paragraphs [108] and [92] of Roe). See MPEP 2143(I)(B).
Regarding claim 11, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. The anaplerotic agent is triheptanoin (paragraph [108] or [117] of Roe) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil).
Roe does not specifically disclose within a single example embodiment wherein the anaplerotic therapy is the vitamin, and the vitamin is selected from the group consisting of vitamin C, coenzyme Q10, B complex vitamins, α-lipoic acid, L-carnitine, creatine, and L- arginine.
Earlier, Roe discloses that their anaplerotic treatment may include the b complex vitamins biotin (vitamin B7) and vitamin B12 to supplement the citric acid cycle (CAC) with acetyl-CoA or succinyl-CoA (paragraph [115] of Roe) (Additional co factors and Vitamins (e.g., Biotin and B-12) may be added to the patient’s diet to improve the metabolism of Propionyl-CoA to Succinyl-CoA and/or entry into the CAC as Acetyl-CoA.).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to combine the triheptanoin treatment at disclosed by Roe with B complex vitamins in order to lead to the predictable outcome of improving citric acid cycle metabolism with a reasonable chance of success (see paragraph [115] of Roe). See MPEP 2143(I)(A).
Regarding claim 14, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches that organic acid analyses found in example 1 and 2 are performed using GC-MS (paragraph [104] of Roe) (Organic acids in urine specimens are determined with isolation by liquid partition chromatography (LPC) and quantitative Gas Chromatography-Mass Spectrometry (GCMS)).
Roe does not specifically disclose wherein the biological sample is analyzed using liquid chromatography mass spectrometry.
McCain discloses a method of detecting metabolites using liquid chromatograph-tandem mass spectrometry (pg. 102 first paragraph of McCain) (DATAN derivatization followed by liquid chromatography-mass spectrometry (LC-MS) reduces the time, cost, and racemization of analytes compared to gas chromatography-mass spectrometry protocols.). The phrase “liquid chromatography mass spectrometry” is reasonably interpreted to mean a technique in which liquid chromatography precedes mass spectrometric analysis. Tandem mass spectrometry (MS/MS) collects ion mass-to-charge ratio data before and after the second MS step (in order to show parent/daughter ions in fragmentation, for example). Furthermore, the specification of the instant application clarifies that tandem mass spectrometry (fragmentation) is employed in applicant’s technique of “liquid chromatography mass spectrometry” (paragraph [68]) (Precursor ions… were isolated by the quadrupoles and fragmented…). McCain teaches that their LC-MS method is advantageous over GC-MS because it can save time and cost (pg. 102 first paragraph of McCain) (DATAN derivatization followed by liquid chromatography-mass spectrometry (LC-MS) reduces the time, cost, and racemization of analytes compared to gas chromatography-mass spectrometry protocols).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute the GC-MS method of Roe with the liquid chromatography mass spectrometry as disclosed by McCain to lead to the predictable outcome of saving time and cost with a reasonable expectation of success (see paragraph [104] of Roe; pg. 102 first paragraph of McCain). See MPEP 2143(I)(G).
Regarding claim 15, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches further comprising contacting a derivatization standard to the biological sample (paragraphs [104] and [105] of Roe) (the specimen is derivatized to form pentafluorobenzyl oximes… after drying, the organic acids are derivatized to form volatile and acylcarnitines are extracted… extract is derivatized). In both cases, the act of “derivatizing” metabolites inherently implies that the samples were contacted with a derivatization standard.
Regarding claim 16, Modified Roe (Roe in view of McCain) teaches the method of claim 15 as rejected above. Roe discloses a method of analyzing metabolites utilizing trimethyl silyl (TMS) derivatization and gas chromatography mass-spectrometry (GC-MS) as a detection method (paragraph [104] of Roe) (derivatized to form volatile trimethyl silyl (TMS) derivatives for… Gas Chromatography… Detection is by Mass Spectrometry).
Modified Roe does not specifically disclose wherein the derivatization standard is diacetly-l-tartaric anhydride (DATAN) or malate.
In the analogous art of metabolite detection in a biological sample, McCain teaches a method of analyzing D/L-lactate and D/L-2-hydroxyglutarate using diacetyl-L-tartaric anhydride (DATAN) as a derivatization standard and liquid chromatography mass-spectrometry (LC-MS) as a detection method (pg. 102 first paragraph of McCain) (DATAN derivatization followed by liquid chromatography-mass spectrometry (LC-MS) reduces the time, cost, and racemization of analytes compared to gas chromatography-mass spectrometry protocols). McCain further teaches that their LC-MS method using DATAN saves experiment time and cost and reduces racemization of the chiral metabolites when compared to GC-MS (pg. 102 first paragraph of McCain) (DATAN derivatization followed by liquid chromatography-mass spectrometry (LC-MS) reduces the time, cost, and racemization of analytes compared to gas chromatography-mass spectrometry [GC-MS] protocols).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute Roe’s metabolite analysis method using TMS and GC-MS with McCain’s analysis method using DATAN and LC-MS to lead to the predicable outcome of reducing experiment time and cost and reducing the degree of racemization of the chiral metabolites with a reasonable expectation of success (pg. 102 first paragraph of McCain). See MPEP 2143(I)(B).
Regarding claim 17, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches wherein the predetermined amount is the amount of metabolite present in the same biological sample from a non- mitochondrial disorder subject (paragraph [112] or [121] of Roe) (decrease in propionylcamitine (1.25, normal <2.71 uM) or creatinine was… 0.6 (normal 0.7-1.2 units)). It is interpreted by the Examiner that the term ‘normal’ is “a value obtained from a non-disordered individual”.
Regarding claim 18, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches wherein the amount of the metabolite present is less than about 20% of the predetermined amount (paragraph [123] of Roe) (Succinate and α-ketoglutarate levels were reduced (6 n1<42), and 4 n1<75)… This profile persisted during the study). Each of these two measurements show values that are less than 20% of the predetermined amount; it is interpreted by the Examiner that in the Roe reference where it recites “This profile persisted during the study”, it reads on “the amount of the metabolite present is less than about 20% of the predetermined amount” because anaplerotic treatment followed these measurements.
Regarding claim 19, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. Roe discloses an anaplerotic therapy using 1 gm/Kg per day of triheptanoin (C7) (paragraph [109] or [118] of Roe) (both paragraphs read: C7 dose of 1 gm/Kg/Day).
Roe does not specifically disclose within a single example embodiment wherein the short chain fatty acid and the vitamin are administered concurrently or sequentially.
Earlier, Roe discloses that their anaplerotic treatment may include the b complex vitamins biotin (vitamin B7) and vitamin B12 to supplement the citric acid cycle with acetyl-CoA or succinyl-CoA (paragraph [115] of Roe) (Additional co factors and Vitamins (e.g., Biotin and B-12) may be added to the patient’s diet to improve the metabolism of Propionyl-CoA to Succinyl-CoA and/or entry into the CAC as Acetyl-CoA.). Roe discloses that triheptanoin and short chain fatty acids (C5) may be used in the same manner to treat glycogen storage disease (paragraph [100] of Roe) (Triheptanoin or other odd carbon fatty acids (C15, C5 or BHP) can permit the gradual reduction of excessive Stored glycogen or polysaccharide resulting from any of the various types of glycogen Storage disease).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the treatment of Roe (triheptanoin) to use a combination of a short chain fatty acid and a vitamin to lead to the predictable outcome of improving citric acid cycle metabolism while treating glycogen storage disease with a reasonable chance of success (see paragraph [100] and [115] of Roe). See MPEP 2143(I)(G).
Regarding claim 20, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. Roe teaches wherein the anaplerotic therapy is administered at a dose of about 0.1 g/kg to about 2.0 g/kg (paragraph [109] or [118] of Roe) (both paragraphs read: C7 dose of 1 gm/Kg/Day).
Regarding claim 21, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. Roe discloses an anaplerotic therapy using 1 gm/Kg per day of triheptanoin (C7) (paragraph [109] or [118] of Roe) (both paragraphs read: C7 dose of 1 gm/Kg/Day).
Roe does not specifically disclose within a single example embodiment wherein the short chain fatty acid is administered at a dose of about 0.1 g/kg to about 2.0 g/kg.
Earlier, Roe discloses that triheptanoin and short chain fatty acids (C5) may be used in the same manner to treat glycogen storage (Pompe) disease (paragraph [100] of Roe) (Triheptanoin or other odd carbon fatty acids (C15, C5 or BHP) can permit the gradual reduction of excessive Stored glycogen or polysaccharide resulting from any of the various types of glycogen Storage disease). Roe discloses that the short chain fatty acids (C5) may be dosed between 0.1 gm/Kg and 2 gm/Kg (paragraph [11] of Roe) (For example, the composition of the present invention may be an odd carbon fatty acid that is adapted for a dosage of between 0.1, 1, 1.5, 2, 3 or even 4 gr/kg/day).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute 1 g/Kg/day triheptanoin with 0.1-2.0 gm/Kg of a short chain fatty acid to lead to the predictable outcome of treating glycogen storage disease with a reasonable chance of success (see paragraph [100] of Roe). See MPEP 2143(I)(B).
Regarding claim 24, Roe teaches a method for determining an amount of a metabolite present in a subject (examples 1 and 2; paragraphs [106]-[124] of Roe), comprising:
contacting a biological sample obtained from a subject having or suspected of having Pompe disease with a derivatization standard (paragraph [104] of Roe) (derivatized to form volatile trimethyl silyl (TMS) derivatives for… Gas Chromatography… Detection is by Mass Spectrometry)
determining an amount of a metabolite present in the biological sample (paragraphs [106] or [112] or [121]) (glycogen deposition in lysosomes and cytosol (2.0%-normal 1.03+/-0.18%) or 3-OH-butyrate (BOB) and acetoacetate (AcAc) was 1633 and 1211 mmmol/mol creatine, respectively or Blood acylcarnitine analysis revealed… reduced level of propionylcarnitine (1.08, normal <2.71uM))
selecting a therapy based on an amount of a metabolite present in the biological sample being less than a predetermined amount (paragraphs [121] and [122]) (Blood acylcarnitine analysis revealed… reduced level of propionylcarnitine and Patient diet was initially adjusted… C7 [triheptanoin oil] represented 22% of his daily Kcal intake.); and
administering the therapy to the subject to treat Pompe disease (paragraphs [121] and [122]) (Blood acylcarnitine analysis revealed… reduced level of propionylcarnitine and Patient diet was initially adjusted… C7 [triheptanoin oil] represented 22% of his daily Kcal intake.).
Roe is silent to treating a subject having or suspected of having the Complex I deficient mitochondrial disorder.
In the analogous art of determining amounts of metabolites in subjects with mitochondrial disorders, McCain teaches of treating patients with a Complex I mitochondrial deficiency using anaplerotic therapy (pg. 22 first paragraph of McCain) (Riboflavin is part of flavin mononucleotide, a prosthetic group of Complex I. Treatment with riboflavin is especially important and effective in patients with a Complex I deficiency… Folinic acid is a supplement used to correct deficiencies in folate). McCain teaches that the anaplerotic therapy extends the lifespan of patients by a few years (pg. 22 first paragraph of McCain) (these treatments only prolong a patient’s lifespan by a few years).
It would have been obvious to substitute the subject having or suspected of having Pompe disease as taught by Roe with the subject having or suspected of having a Complex I deficient mitochondrial disorder as taught by McCain because doing so would extent the lifespan of the subject by a few years with a reasonable expectation of success (examples 1 and 2; paragraphs [106]-[124] of Roe; pg. 22 first paragraph of McCain).
Modified Roe is silent to the metabolite being 2-hydroxyglutarate enantiomer.
In the analogous art of metabolite detection in a biological sample, McCain discloses a method of detecting L-2- hydroxyglutarate and D-2-hydroxyglutarate (pg. 104 first paragraph of McCain) (the levels of L-2-HG were decreased 28% in NDUFS4 KO serum versus WT (Figure 4.10A-B). In addition, we quantified a remarkable 61% decrease in D-2-HG in NDUFS4 KO serum versus WT). McCain teaches that that L/D-2-HG are of interest because their levels are selectively decreased in subjects with complex I deficient metabolic disorder (pg. 104 first paragraph of McCain) (the decrease in L-2-HG or D-2-HG was surprising in select brain regions, the serum measurements validate these findings and suggest that both enantiomers are selectively reduced in tissues of the NDUFS4 KO versus WT).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to combine the detected metabolites of Roe with the detected D/L-2-HG metabolites of McCain because doing so would lead to the predictable outcome of detecting Complex I deficient mitochondrial disorder with a reasonable expectation of success, especially when considering that L/D-2-HG are selectively reduced in subjects with Complex I deficient mitochondrial disorder, (see examples 1 and 2; paragraphs [106]-[124] of Roe; pg. 104 first paragraph of McCain). See MPEP 2143(I)(A).
Modified Roe is silent to the derivatization standard comprising diacetyl-l-tartaric anhydride (DATAN).
In the analogous art of metabolite detection in a biological sample, McCain teaches a method of analyzing D/L-lactate and D/L-2-hydroxyglutarate using diacetyl-L-tartaric anhydride (DATAN) as a derivatization standard and liquid chromatography mass-spectrometry (LC-MS) as a detection method (pg. 102 first paragraph of McCain) (DATAN derivatization followed by liquid chromatography-mass spectrometry (LC-MS) reduces the time, cost, and racemization of analytes compared to gas chromatography-mass spectrometry protocols). McCain further teaches that their LC-MS method using DATAN saves experiment time and cost and reduces racemization of the chiral metabolites when compared to GC-MS (pg. 102 first paragraph of McCain) (DATAN derivatization followed by liquid chromatography-mass spectrometry (LC-MS) reduces the time, cost, and racemization of analytes compared to gas chromatography-mass spectrometry [GC-MS] protocols).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute Roe’s metabolite analysis method using TMS and GC-MS with McCain’s analysis method using DATAN and LC-MS to lead to the predicable outcome of reducing experiment time and cost and reducing the degree of racemization of the chiral metabolites with a reasonable expectation of success (pg. 102 first paragraph of McCain). See MPEP 2143(I)(B).
Claim(s) 4, 6, 7, and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), further in view of McCain et al. (University of South Carolina Scholar Commons, Fall 2021, pgs. 1-179), as applied to claim 1 above, further in view of Borges (US20160263071).
Regarding claim 4, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above to treat Pompe disease, also called “glycogen storage disease”. Roe teaches that Pompe disease causes dysfunction to various organelles (including mitochondria) (paragraph [005] of Roe) (Excessive glycogen storage within lysosomes interrupts the normal functioning of other organelles).
Modified Roe does not specifically disclose wherein the Complex I deficient mitochondrial disorder is selected from the group consisting of Leigh Syndrome, Leigh Syndrome with Complex I mutations, and Lebers Hereditary neuropathy.
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Borges discloses a method of treating a series of neuromuscular and neurodegenerative disorders, which they specify to include Leigh syndrome (paragraph [67] of Roe) (neuromuscular disorders may include… Leigh syndrome). Borges teaches that these disorders involve mitochondrial dysfunction (paragraph [65]) (neuromuscular disease… may involve… mitochondrial dysfunction).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify Roe’s method of treating Pompe disease to treat Leigh syndrome as disclosed by Borges with a reasonable chance of success because both disorders negatively impact mitochondrial functioning (see paragraph [5] of Roe and [65] of Borges). See MPEP 2143(I)(G).
Regarding claim 6, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. Roe teaches an anaplerotic therapy using triheptanoin (paragraph [108] or [117] of Roe) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Roe discloses that triheptanoin (C7) improves propionate levels in a subject (paragraph [99] of Roe) (it was found that the odd chain fatty acids optimized the supply of propionate).
Modified Roe does not specifically disclose wherein the anaplerotic therapy is the short chain fatty acid, and the short chain fatty acid is propionic acid or valeric acid.
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Borges discloses a method of treating neurodegenerative/neuromuscular diseases using anaplerotic agents, which includes propionic acid (paragraph [77] and [83] of Borges) (anaplerotic agent is a precursor of propionyl-CoA and the precursor of propionyl-CoA is an uneven chain fatty acid… The uneven chain fatty acid may be … propionic acid). It is known in the art that propionic acid is a carboxylic acid (pKa ~5) that would immediately be converted propionate at physiological pH (~7), therefore consuming propionic acid would lead to increased propionate levels in a subject.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute Roe’s triheptanoin with Borges’ propionic acid to lead to the predictable outcome of increasing propionate levels in a subject with a reasonable chance of success (see paragraph [99] of Roe and [83] of Borges). See MPEP 2143(I)(B).
Regarding claim 7, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above, where the anaplerotic agent is triheptanoin (paragraph [108] or [117] of Roe) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Roe discloses that subjects with Pompe disease are subject to reduced levels of propionylcarnitine (paragraph [121] of Roe) (Blood acylcarnitine analysis revealed… a reduced level of propionylcarnitine (1.08, normal <2.71 uM).
Roe does not specifically disclose wherein the anaplerotic therapy is the short chain acylcarnitine, and the short chain acylcarnitine is propionylcarnitine or butenylcarnitine.
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Borges discloses a method using propionylcarnitine as an anaplerotic agent, including (paragraph [10] and [17] and [21]) (administering… anaplerotic agents and anaplerotic agents… are… precursors of propionyl-CoA and the precursor of propionyl-CoA is propionyl-carnitine).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the treatment of Roe using triheptanoin to use propionylcarnitine as disclosed by Borges because it would lead to the predicable outcome of alleviating the subject’s propionylcarnitine deficiency with a reasonable chance of success (see Roe paragraph [121]; Borges paragraph [21]). See MPEP 2143(I)(G).
Regarding claim 25, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. Roe teaches the use of triheptanoin as an anaplerotic agent (paragraph [108] or [117] of Roe) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Roe teaches that their anaplerotic therapy supplies propionyl-CoA (C3-CoA) to the citric acid cycle (CAC) in patients with a compromised CAC (paragraph [98]) (providing additional C2-CoA and C3-CoA [propionyl-CoA] into the CAC [citric acid cycle]… circumvent and avoid the enzymes that are deficient or lacking).
Roe does not specifically disclose wherein the short chain fatty acid comprises a triglyceride of propionic acid (C3).
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Borges discloses a method of treatment that utilizes a triglyceride of propionic acid (C3), which is a precursor to propionyl-CoA; (paragraphs [85] and [88], and formula 1 below of Borges) (precursor of propionyl-CoA may be one or more compounds of formula I and R1, R2, and R3 are independently selected from C1 to C20 alkyl…). Borges teaches that triheptanoin is metabolized to propionyl-CoA (paragraph [006]) (Triheptanoin provides the body with heptanoate, which [is]… metabolized to propionyl-CoA). Borges further teaches that propionyl-CoA is capable of supplying metabolites to the citric acid cycle (paragraph [6]) (propionyl-CoA produces methyl-malonyl-CoA, which can be metabolized to succinyl CoA… refilling of deficient… intermediates of the TCA cycle).
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It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute Roe’s triheptanoin with Borges’ triglyercide of propionic acid because both anaplerotic agents are able to supply propionyl-CoA to patients with compromised metabolisms with a reasonable chance of success (see paragraph [6] and [85] of Borges). See MPEP 2143(I)(B).
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), further in view of McCain et al. (University of South Carolina Scholar Commons, Fall 2021, pgs. 1-179), as applied to claim 5 above, and further in view of Kuratsune (US5576348).
Regarding claim 8, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. The anaplerotic agent is triheptanoin (paragraph [117]) (dietary therapy with triheptanoin oil). Roe teaches that patients with Pompe disease have reduced levels of acylcarnitine (paragraphs [121]) (Blood acylcarnitine analysis revealed… reduced level of propionylcarnitine (1.08, normal <2.71uM)).
Roe does not specifically disclose wherein the anaplerotic therapy is the short chain acylcarnitine, and the short chain acylcarnitine is selected from the group consisting of hydroxypropionylcarnitine, propenoylcarnitine, hydroxybutyrylcarnitine, valerylcarnitine, methylglutarylcarnitine, tiglylcarnitine, glutaconylcarnitine, hydroxyvalerylcarnitine, and methylmalonylcarnitine.
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Kuratsune discloses a treatment that utilizes valerylcarnitine (abstract) (administering an acylcarnitine… The acylcarnitine may be… valerylcarnitine). Kuratsune teaches that treatment with acylcarnitines (such as valerylcarnitine) increase the intracellular/extracellular concentration of acylcarnitines in a subject (column 5 lines 37-45) (acylcarnitine or a salt thereof can cause the increase of serum and cellular acylcarnitine concentration…).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the anaplerotic treatment of Roe that uses triheptanoin to use valerylcarnitine as disclosed by Kuratsune because it would lead to the predictable outcome of correcting the decreased acylcarnitine levels in a subject with a reasonable chance of success (see paragraph [121] of Roe and column 5 lines 37-45 of Kuratsune). See MPEP 2143(I)(G).
Claim(s) 12, 13, 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), further in view of McCain et al. (University of South Carolina Scholar Commons, Fall 2021, pgs. 1-179), as applied to claim 1 above, and further in view of Pereira (WO2022006500).
Regarding claim 12, Modified Roe (Roe in view of McCain) teaches the method of claim 1 as rejected above. The anaplerotic agent is triheptanoin (paragraph [108] or [117] of Roe) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Roe teaches that their disclosed invention is useful in the treatment of muscle weakness (paragraph [14] of Roe) (present invention will be particularly useful for chronic muscle weakness).
Modified Roe does not specifically disclose wherein the anaplerotic therapy further comprises at least one α-ketoglutarate ester.
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Pereira discloses a treatment that uses an α-ketoglutarate ester (Pg. 13 lines 21) (the ester of α-ketoglutarate is a dimethyl ester of α-ketoglutarate). Pereira discloses that their treatments alleviate various forms of musculoskeletal decline (pg. 11, lines 30-31) (methods for treating and/or decreasing musculoskeletal decline are described herein).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute the therapy of Modified Roe (triheptanoin) with the therapy of Pereira (α-ketoglutarate ester) because both may be used to lead to the predictable outcome of improving muscle health with a reasonable chance of success (see paragraph [14] of Roe and pg. 11 lines 30-31 of Pereira). See MPEP 2143(I)(B).
Regarding claim 13, Modified Roe (Roe in view of McCain further in view of Pereira) teaches the method of claim 12 as rejected above. The anaplerotic agent is triheptanoin (paragraph [108] or [117]) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Modified Roe teaches that their disclosed invention is useful in the treatment of muscle weakness (paragraph [14]) (present invention will be particularly useful for chronic muscle weakness).
Modified Roe does not specifically disclose wherein the α-ketoglutarate ester is selected from α-dimethyl ketoglutarate, trifluoromethylbenzyl α-ketoglutarate, and octyl a-ketoglutarate.
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Pereira discloses a treatment that uses α-dimethyl ketoglutarate (Pg. 13 lines 21 of Pereira) (the ester of α-ketoglutarate is a dimethyl ester of α-ketoglutarate). Pereira discloses that their treatments alleviate various forms of musculoskeletal decline (pg. 11, lines 30-31) (methods for treating and/or decreasing musculoskeletal decline are described herein).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute the therapy of Roe (triheptanoin) with the therapy of Pereira (α-ketoglutarate ester) to lead to the predictable outcome of improving muscle function/health with a reasonable chance of success (see paragraph [14] of Roe and pg. 11 lines 30-31 of Pereira). See MPEP 2143(I)(B).
Regarding claim 23, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. The anaplerotic agent is triheptanoin (paragraph [108] or [117]) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Roe teaches that triheptanoin is dosed at 1gm/Kg/day (paragraph [109] or [118]) (both paragraphs read: C7 dose of 1 gm/Kg/Day). Roe teaches that their disclosed invention is useful in the treatment of muscle weakness (paragraph [14]) (present invention will be particularly useful for chronic muscle weakness).
Roe does not specifically disclose wherein the α-ketoglutarate ester is administered at a dose of about 100 mg to about 3000 mg.
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Pereira discloses a treatment that utilizes α-ketoglutarate esters that are dosed at about 100 mg to about 3000 mg (Pg. 13 lines 19-26 of Pereira) (an ester of a-ketoglutarate… daily doses include administering about 100 mg to about 3,000 mg). Pereira discloses that the dose may be selected based on the subject’s body weight (Pg. 13 lines 31-33 of Pereira) (pediatric and adolescent doses can be scaled based on subject body weight, where the adult daily doses are based on an average adult weight of about 70 kg). Pereira discloses that their treatments alleviate various forms of musculoskeletal decline (pg. 11, lines 30-31 of Pereira) (methods for treating and/or decreasing musculoskeletal decline are described herein).
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to substitute the therapy of Roe (triheptanoin dosed at 1gm/Kg/day) with the therapy of Pereira (α-ketoglutarate esters dosed at about 100 mg to about 3000 mg) because both may be used to lead to the predictable outcome of improving muscle health with a reasonable chance of success (see paragraph [14] of Roe and pg. 11 lines 30-31 of Pereira). See MPEP 2143(I)(B). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the α-ketoglutarate ester and the α-ketoglutarate ester is…”
Claim(s) 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), further in view of McCain et al. (University of South Carolina Scholar Commons, Fall 2021, pgs. 1-179), as applied to claim 5 above, and further in view of Clarke (US20200268825).
Regarding claim 22, Modified Roe (Roe in view of McCain) teaches the method of claim 5 as rejected above. The anaplerotic agent is triheptanoin (paragraph [108] or [117]) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Roe discloses that Pompe’s disease affects the intra-mitochondrial redox state (paragraph 113) (suggesting an alteration in the intra-mitochondrial redox state).
Roe does not specifically disclose wherein the vitamin is administered at a dose of about 0.1 mcg to about 1.5 mcg
In the analogous art of treating diseases that negatively impact metabolic/mitochondrial functioning, Clarke discloses a method of providing between 1 mcg to 5 mg of vitamins K2 (table 11-continued) (see modified table below) to treat neurological disorders (paragraph [2]) (therapy to treat neurological disorders).
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Clarke further teaches that Vitamins K2 may improve mitochondrial functioning, specifically the mitochondrial electron transport chain that is involved with redox reactions (table 8) (see modified table below).
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It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the treatment of Roe (triheptanoin) to include the treatment of Clarke (Vitamin K2, dosed at 1-5 mcg) to lead to the predictable outcome of improving the compromised intra-mitochondrial redox state that patients with Pompe disease experience with a reasonable chance of success (see paragraph [113] of Roe and table 8 of Clarke). See MPEP 2143(I)(G). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the vitamin and the vitamin is…”
Conclusion
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.
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/H.D.C./Examiner, Art Unit 1758
/CHRISTINE T MUI/Primary Examiner, Art Unit 1797
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