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 .
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 Objections
Claim 2 is objected to because of the following informalities: after “claim 1,” there should be the word “wherein”; “comprising” should read “comprises”. 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 2-8, 10-11, and 16 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.
Regarding claims 2-8 and 10, each of these claims recite an open-ended list of alternatives that may be selected from. These lists may best be described as Markush Groups, and in such cases, they must be limited to only the recited alternatives; they must not use an open-ended transitional phrase such as “comprising”. Because the transitional phrase for each of these claims is “comprises”, this allows for unrecited alternatives to be included in the claim. Therefore, the claims are indefinite in their scope. See MPEP 2117, 2111.03, and 2173.03(h)(1). Examiner recommends amending the transitional phrase “comprises” to instead use closed language, such as for claim 2 “the biological sample is blood serum, plasma or tissue”. Similar amendments are suggested for claims 3-8 and 10. Appropriate correction is required.
Regarding claim 11, the limitation “the vitamin is selected from vitamin C, coenzyme Q10, B complex vitamins, α-lipoic acid, L-carnitine, creatine, and L-arginine” renders the claim unclear and indefinite on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of vitamins in claim 11 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: not all of the alternatives in the Markush grouping are in the art-recognized class of vitamins; α-lipoic acid and coenzyme Q10 are antioxidants, L-carnitine and creatine are amino acid derivatives, and L-arginine is an amino acid. It is generally accepted in the art that there are 13 vitamins (A, B1-3, B5-7, B9, B12, C, D, E, K).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Regarding claim 16, "the derivatization standard" is recited in line 1 of the claim. There is insufficient antecedent basis for this limitation in the claim. Examiner recommends amending the preamble to be dependent on claim 15, which does recite a derivatization standard. In the interest of compact prosecution, the Examiner interprets claim 16 to depend from claim 15.
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 a process.
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 metabolite present in the biological sample…”. Claim 1 also recites “determining an amount of a metabolite present…” Claim 24 recites “selecting a therapy based on an amount of a metabolite present in a biological sample…” These steps may each be described as a mental process, which is an abstract idea. 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 an additional step “i. determining an amount of a metabolite…”; this is a judicial exception that prefaces another judicial exception, and it amounts to mere data-gathering. 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; it generally applies the exception through instruction. See MPEP 2106.04(d)(2) and MPEP 2106.05(f). Furthermore, this is a conditional limitation that is not required; “if” the amount of metabolite is greater than the predetermined amount, then no action is taken and therefore there is no particular practical application.
Claims 2-23 and 25, which depend from claim 1, will also be analyzed for practical applications of the judicial exception.
Claims 2-3 and 14-18 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 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 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 judicial exception, claim 24 contains step “ii. administering the 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. See MPEP 2106.04(d)(2). Furthermore, this is a conditional limitation that is not required; “if” the amount of metabolite is greater than the predetermined amount, then no action is taken and therefore there is no particular practical application.
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.” of “determining an amount of a metabolite present in a biological sample of a subject”, but this itself is a judicial exception and, at best, amounts to mere data gathering. See MPEP 2106.05(g). 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). 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.
Claim 24 does not contain elements that amount to significantly more than the judicial exception. Claim 24 contains an additional element in step “ii. administering the therapy to the subject if the amount of the metabolite present in the biological sample is less than a predetermined amount.” This step is highly general and is not particular; instead, it reads as merely instructions to “apply” the exception in a general way. 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). Furthermore, this is a conditional limitation that is not required. 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.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 5, 9, 15, 17, 18, 20, and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Roe (US 20060004099).
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 (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 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 if the amount of the metabolite present in the biological sample is less than a predetermined amount (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.).
Regarding claim 2, Roe teaches the method of claim 1 as rejected above. Roe teaches the biological sample comprising blood, serum, plasma, or tissue (paragraph [106] or [121]) (a muscle biopsy revealed or routine blood chemistry on admission).
Regarding claim 5, Roe teaches the method of claim 1 as rejected above. Roe teaches wherein the anaplerotic therapy comprises a triglyceride (paragraph [109] or [122]) (composition was (% Kcal)… triheptanoin (C7) accounted for 26%) or Patient diet was adjusted… C7 represented 22% of his daily Kcal intake).
Regarding claim 9, Roe teaches the method of claim 5 as rejected above. Roe teaches wherein the triglyceride comprises triheptanoin (paragraph [108] or [117]) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil).
Regarding claim 15, Roe 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]) (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 17, Roe 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]) (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, Roe 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]) (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 20, Roe 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]) (both paragraphs read: C7 dose of 1 gm/Kg/Day).
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]), comprising:
i. selecting a therapy based on an amount of a metabolite present in a biological sample (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
ii. administering the therapy to the subject if the amount of the metabolite present in the biological sample is 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.).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 3, 14, and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), and further in view of Struys et al. (Non-Patent Literature, Clinical Chemistry, Vol. 50, No. 8, pgs. 1391-1395, 05/05/2004, as cited in the IDS submitted on 01/08/2024).
Regarding claim 3, Roe teaches the method of claim 1 as rejected above. Roe discloses that the metabolite comprises glycogen, acetoacetate, hydroxybutryate, or acylcarnitine (paragraphs [106] or [112] or [121]).
Roe does not specifically disclose wherein the metabolite comprises L-2- hydroxyglutarate, D-2-hydroxyglutarate, D-lactate, or L-lactate.
In the analogous art of metabolite detection in a biological sample, Struys discloses a method of detecting L-2- hydroxyglutarate and D-2-hydroxyglutarate (abstract, second paragraph) (We used… for the determination of D- and L-2-HG). Note that D-2-HG and L-2-HG are abbreviations of L-2-hydroxyglutarate and D-2-hydroxyglutarate (see abstract, first paragraph). Struys teaches that that L/D-2-HG are of interest because their levels are dysregulated in subjects with certain metabolic disorders (pg. 1, right column, first sentence) (reliable test for the differential diagnosis of D-2-hydroxyglutaric aciduria). Struys further teaches that D-2-HG is associated with the citric acid (Krebs) cycle intermediate α-ketoglutarate, (pg. 1, right column, last sentence) (there is a strong metabolic relationship between D-2-HG and the Krebs cycle intermediate 2-ketoglutarate).
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 Struys because doing so would lead to the predictable outcome of detecting the metabolic abnormalities that are associated with metabolic, neurodegenerative, and mitochondrial disorders with a reasonable expectation of success, especially when considering that D-2-HG is associated with metabolites in the Krebs cycle, (See Struys, pg. 1, right column, last sentence). See MPEP 2143(I)(A).
Regarding claim 14, Roe 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]) (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.
In the analogous art of metabolite detection in a biological sample, Struys discloses a method of detecting metabolites using liquid chromatograph-tandem mass spectrometry (abstract, paragraph 2) (We used liquid chromatography–tandem mass spectrometry (LC-MS/MS) for the determination of D- and L-2-HG). 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…). Struys teaches that LC-MS is advantageous over GC-MS because it can save time and cost (pg. 1392) (it [GC-MS] has the disadvantage of being time-consuming and… expensive. We therefore developed a reliable, robust, and simple SID LC-MS/MS method for the enantiomeric analysis.).
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 GC-MS method of Roe to instead use liquid chromatography mass spectrometry as disclosed by Struys to lead to the predictable outcome of saving time and cost with a reasonable expectation of success (see Struys pg. 1392) (it [GC-MS] has the disadvantage of being time-consuming and… expensive. We therefore developed a reliable, robust, and simple SID LC-MS/MS method for the enantiomeric analysis.). See MPEP 2143(I)(G).
Regarding claim 16, Roe teaches the method of claim 1 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]) (derivatized to form volatile trimethyl silyl (TMS) derivatives for… Gas Chromatography… Detection is by Mass Spectrometry).
Roe does not specifically disclose wherein the derivatization standard is diacetly-l-tartaric anhydride.
In the analogous art of metabolite detection in a biological sample, Struys teaches a method of analyzing certain metabolites using diacetyl-L-tartaric anhydride (DATAN) as a derivatization standard and liquid chromatography mass-spectrometry (LC-MS) as a detection method (abstract, conclusions section) (The analytes were derivatized by use of diacetyl-L-tartaric anhydride (DATAN)… separated on an achiral C18 HPLC column and detected by MS/MS). Struys further teaches that their LC-MS method using DATAN is a known equivalent to GC-MS (pg. 1395, left column, third paragraph) (LC-MS/MS method… is a good alternative for our current GC-MS method).
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 Struys’ analysis method using DATAN and LC-MS to lead to the predicable outcome of derivatizing, isolating, and analyzing metabolites with a reasonable chance of success (pg. 1395, left column, third paragraph) (LC-MS/MS method for the determination of D- and L-2-HG [D- and L-2-hydroxyglutarate] in urine is a good alternative for our current GC-MS method). 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), and further in view of Borges (US20160263071).
Regarding claim 4, Roe 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]) (Excessive glycogen storage within lysosomes interrupts the normal functioning of other organelles).
Roe does not specifically disclose wherein the mitochondrial disorder comprises Leigh Syndrome, Leigh Syndrome with Complex I mutations, or 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]) (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, Roe teaches the method of claim 5 as rejected above. Roe teaches an anaplerotic therapy using triheptanoin (paragraph [108] or [117]) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil). Roe discloses that triheptanoin (C7) improves propionate levels in a subject (paragraph [99]) (it was found that the odd chain fatty acids optimized the supply of propionate).
Roe does not specifically disclose wherein the short chain fatty acid comprises 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]) (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). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the short chain fatty acid and the short chain fatty acid is…”
Regarding claim 7, Roe teaches the method of claim 1 as rejected above, where the anaplerotic agent is triheptanoin (paragraph [108] or [117]) (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]) (Blood acylcarnitine analysis revealed… a reduced level of propionylcarnitine (1.08, normal <2.71 uM).
Roe does not specifically disclose wherein the short chain acylcarnitine comprises 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). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the short chain acylcarnitine and the short chain acylcarnitine is…”
Regarding claim 25, Roe teaches the method of claim 5 as rejected above. Roe teaches the use of triheptanoin as an anaplerotic agent (paragraph [108] or [117]) (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) (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).
PNG
media_image1.png
383
944
media_image1.png
Greyscale
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). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the triglyceride and the triglyceride is…”
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), and further in view of Kuratsune (US5576348).
Regarding claim 8, Roe 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 short chain acylcarnitine comprises hydroxypropionylcarnitine, propenoylcarnitine, hydroxybutyrylcarnitine, valerylcarnitine, methylglutarylcarnitine, tiglylcarnitine, glutaconylcarnitine, hydroxyvalerylcarnitine, or 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). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the short chain acylcarnitine and the short chain acylcarnitine is…”
Claim(s) 12, 13, 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe (US20060004099), and further in view of Pereira (WO2022006500).
Regarding claim 12, Roe teaches the method of claim 1 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 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 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 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, Roe 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). 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 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) (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, Roe 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) (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) (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) (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 in US20060004099, and further in view of Clarke US20200268825.
Regarding claim 22, Roe 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).
PNG
media_image2.png
491
419
media_image2.png
Greyscale
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).
PNG
media_image3.png
328
428
media_image3.png
Greyscale
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…”
Claim(s) 10, 11, 19, and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Roe in US20060004099.
Regarding claim 10, Roe teaches the method of claim 5 as rejected above. The anaplerotic agent is triheptanoin to treat Pompe disease (paragraph [108] or [117]) (diet containing triheptanoin was given or dietary therapy with triheptanoin oil).
Roe does not specifically disclose within a single example embodiment wherein the ketone comprises 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). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the ketone and the ketone is…”
Regarding claim 11, Roe 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 does not specifically disclose within a single example embodiment wherein the vitamin is selected from 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]) (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). 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 comprises…”
Regarding claim 19, Roe 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]) (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]) (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]) (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). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the combination of the short chain fatty acid and the vitamin and the combination of the short chain fatty acid and the vitamin is…”
Regarding claim 21, Roe 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]) (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]) (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]) (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). For clarity, Examiner suggests amending the language of the claim to positively recite the anaplerotic therapy by saying “wherein the anaplerotic therapy comprises the short chain fatty acid and the short chain fatty acid comprises…”
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Houston Cole whose telephone number is (571)272-8405. The examiner can normally be reached M-F, 9:00am-5:00pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maris Kessel can be reached at (571) 270-7698. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/H.D.C./Examiner, Art Unit 1758
/MARIS R KESSEL/Supervisory Patent Examiner, Art Unit 1758
Prosecution Insights