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 .
DETAILED ACTION
Applicant’s amendment of 9 February 2026, in which claims 1, 8-11, 14, 19-21 have been amended, claims 2-5 have been cancelled, and new claims 24-40 have been added, is acknowledged.
Claims 1, 6-40 are pending in the instant application.
Claims 1, 6-40 are being examined on their merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on9 February 2026 and 16 March 2026, are acknowledged and considered.
Response to arguments of 9 February 2026
In view of Applicant’s amendment of 9 February 2026, all the objections and rejections to claims 2-5 are herein withdrawn. Claims 2-5 have been cancelled.
On 9 February 2026, Applicant has amended the claims substantially and has added new claims.
The amendment of 9 February 2026 necessitated the following new rejections.
As indicated in the non-final office action mailed on 22 October 2025, the claims are examined to the extent they read on the elected species, namely patients suffering from lactic acidosis as the patient population suffering from a specific disease, to be treated with DCA; and plasma as the biological samples used to measure BHB levels, lactate levels, in the method, and the following rejections are made below, based on Applicant’s amendment of 9 February 2026.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL--The specification shall contain a written description of theinvention, and of the manner and process of making and using it, in such full, clear, concise,and exact terms as to enable any person skilled in the art to which it pertains, or with which itis most nearly connected, to make and use the same, and shall set forth the best modecontemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of themanner and process of making and using it, in such full, clear, concise, and exact terms as toenable any person skilled in the art to which it pertains, or with which it is most nearlyconnected, to make and use the same, and shall set forth the best mode contemplated by theinventor of carrying out his invention.
Claims 1, 6-40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), firstparagraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as toreasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Independent claim 1, as amended, recites a patient on a ketogenic diet such that a ratio of calories from fat to carbohydrates and proteins is at least 3:1. The claim also recites a patient’s diet such as the ratio of calories from fat to carbohydrates and proteins is less than 2.5:1.
Newly added claims 24-26, which depend on claim 1, recite a patient's diet such that a ratio of calories from fat : (carbohydrates + proteins) is less than 1.5:1; or less than or equal to 1:1, or less than or equal to 0.7:1.
Similarly, independent claim 14 recites a patient on a ketogenic diet such that a ratio of calories from fat to carbohydrates and proteins is at least 3:1, and the claim also recites a patient’s diet such as the ratio of calories from fat to carbohydrates and proteins is less than 2.5:1. Newly added claims 27-29, which depend on claim 14, recite a patient's diet such that a ratio of calories from fat : (carbohydrates + proteins) is less than 1.5:1; or less than or equal to 1:1, or less than or equal to 0.7:1.
Further, newly added independent claim 33 recites a patient on a ketogenic diet such that a ratio of calories from fat to carbohydrates and proteins is at least 3:1, and the claim also recites a patient’s diet such as the ratio of calories from fat to carbohydrates and proteins is less than 2.5:1. Newly added claims 34-36, which depend on claim 3, recite a patient's diet such that a ratio of calories from fat : (carbohydrates + proteins) is less than 1.5:1; or less than or equal to 1:1, or less than or equal to 0.7:1.
Newly added independent claim 37 recites a patient on a ketogenic diet such that a ratio of calories from fat to carbohydrates and proteins is at least 3:1, and the claim also recites a patient’s diet such as the ratio of calories from fat to carbohydrates and proteins is less than 2.5:1. Newly added claims 38-40, which depend on claim 37, recite a patient's diet such that a ratio of calories from fat : (carbohydrates + proteins) is less than 1.5:1; or less than or equal to 1:1, or less than or equal to 0.7:1.
The original Specification discloses [0033] ketogenic diets ranging from 2:1 to 4.4:1 ratios of grams from fat to carbohydrates and protein. Commercially available [0043] products are disclosed KETOCAL® with products formulated to incorporate diets ranging from 2.5:1 to 4:1.
Paragraph [0046] recites “It is recommended that patients alter their diet in a stepwise fashion. If a patient has a diet that exceeds 4:1, it is recommended that carbohydrates be increased to bring the patient to a 4:1 ratio. If they are between 3:1 and 4:1, they are recommended to adhere to a 3:1 ratio. If between 2.5:1 and 3:1, it is recommended that they adhere to a 2.5:1 ratio. If the patient is at or below a 2.5:1 ratio, has controlled lactate (below 2.0 mM) and high levels of BHB (>3.0 mM), it is recommended that the physician and patient seek to use further discretion at ratios less than 2.5:1, so as to maintain lactate at 2.0 mM or less at the lowest possible BHB level, even if it exceeds 3.0 mM.”
There is no support for the now claimed method with a patient on a ketogenic diet of at least 3:1 and modifying the diet to less than 2.5:1 in that patient. Rather, the Specification teaches that if patient has a keto diet that exceeds 4:1, diet is to be modified to 4:1. And if patient is on keto diet of 3:1 to 4:1, diet is to be modified to 3:1.
Example 1 discloses a patient who entered the study with a restrictive ketogenic diet. Table 1 discloses the following keto ratios (calories from fat: carb + protein):
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166
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.Table 2, Example 2, discloses the following keto ratios:
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156
222
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. Example 3, Table 3 discloses the following keto ratios:
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.
The original Specification does not specifically disclose a ketogenic diet such that a ratio of calories from fat to carbohydrates and proteins is at least 3:1, less than 2.5:1; less than 1.5:1; less than or equal to 1:1, or less than or equal to 0.7:1.
Rather, the Specification exemplifies (see above) a number of ketogenic diets with specific ratios of calories from fat to carbohydrates and proteins as above. The limitation ketogenic diet such that a ratio of calories from fat to carbohydrates and proteins is at least 3:1, does not meet the written description requirement because the phrase “at least” has no upper limit and causes the claims to read literally on embodiments outside the actual range disclosed in the Specification.
Further the limitations ketogenic diet such that a ratio of calories from fat to carbohydrates and proteins is less than 2.5:1; less than 1.5:1; less than or equal to 1:1, or less than or equal to 0.7:1, do not meet the written description requirement because the phrase “less than” has no lower limit and causes the claim to read literally on embodiments outside the actual range disclosed in the Specification. It is noted that 1.5:1 and 1:1 are ratios not disclosed in the Specification, nor is there any disclosure of a ratio being less than or equal to 1.5:1 or 1:1.
This is new matter and does not have support in the specification. In re Wertheim, 541 F.2d 257, 191 USPQ90 (CCPA 1976).
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 1, 6-40 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claim 1, as amended, is indefinite for a number of reasons. Claim 1 is drawn to a method of treating PDCD with DCA in a patient on a ketogenic diet such that a ratio from fat: carbohydrate + protein is at least 3:1, and the claim recites two steps, namely
measuring the patient’s BHB level, the patient having received treatment with DCA, and
modifying the patient’s diet such that a ratio from fat: carbohydrate + protein is less than 2.5:1 to reduce the patient’s BHB level.
It is unclear what is meant by “the patient having received treatment with DCA”, since the claimed method does not comprise a step of administering DCA and does not recite a dose of DCA being administered, nor does it recite repeated administration of doses of DCA (to justify the dose being “maintained”). Further, there is confusion regarding the relationship between the recitation “the patient having received treatment with DCA” and the last two “wherein” statements in the claim, which refer to the dose of DCA “identified to be administered” and the dose of DCA “administered and maintained”. The recitation “the patient having received treatment with DCA” seems to refer to treatment received by the patient in the past (even 10 years ago?, no limit exists), and it is unclear how such past treatment is linked to the current method of treatment, which does not recite a step of administering DCA.
Further, the expression “measuring the patient’s BHB levels, the patient having received treatment” seems to indicate that the step of measuring BHB levels occurs after treatment with DCA.
The claim recites a method of treatment with DCA, yet there is no clear step of administration. We learn that the patient has undergone genetic testing “to identify the dose of DCA to be administered”, yet the claim does not specify whether the dose “identified” is actually administered to the patient.
Even more confusing is the last “wherein” recitation: we learn that “the dose of DCA administered to the patient is maintained”, yet the claim makes no reference to a dose of DCA administered (only to a dose identified to be administered), and the claim makes no reference to repeated administration, which is a pre-requisite for the limitation “the dose is maintained”.
Regarding the two steps recited in the method, measuring BHB levels and modifying keto diet to reduce patient’s BHB level, it appears that claims 1, 6-13, 24-26, 31-32 are directed towards measuring levels of biological molecules/ketone levels/BHB levels in two different biological samples and comparing said levels between the two different biological samples to determine a decrease in ketone levels/BHB levels; however, the claims fail to clearly establish the origins of the two different biological samples, or the reference or standard by which one would make a comparison of levels of the one or more biological molecules. Claims recite BHB level and lactate level (claim 6, 7, 8, 9, 10, 11, 12, 13), without specifying the origin of the samples used for measurement.
Claims 6-9 depend on claim 1, and recite “further” measuring the patient’s BHB levels; yet claim 1 already recites measuring the patient’s BHB level. Appropriate clarification of the claim language is required.
Claims 8-11 recite “increasing” carbohydrate intake, without specifying a reference level.
Claim 8 depends on claim 1 and recites two unrelated limitations; one of the limitations is an additional step in the method of claim 1, namely a step of measuring lactate levels, although no biological sample is mentioned. The other limitation refers to “increasing carbohydrate intake”, without providing the threshold or standard used to measure the claimed increase.
Regarding claims 8-11, for clarity, it is suggested that one new limitation, not two, be added to the claims at a time. Claim 9 is not clear, at least because it depends on claim 1 and refers to an increase in BHB levels “following initiation of DCA therapy”; yet claim 1 does not recite an initiation of DCA therapy. As such, there is insufficient antecedent bais for this limitation of claim 9, in claim 1. Further, claims 9-11 depend on claim 1 and recite increasing carbohydrate intake relative to fat compared to a prior carbohydrate intake relative to fat, yet it is unclear what is the threshold or reference used. Which prior intake? And how does it relate to the method in claim 1?
Claim 10 depends on claim 1 and recites lactate levels prior to DCA therapy, yet claim 1 does not recite DCA therapy, does not recite measuring lactate levels and certainly does not recite measuring lactate levels prior to DCA therapy. There is insufficient antecedent basis for these limitations of claim 10, in claim 1.
Claim 12 depends on claim 1 and recites “reducing measuring the patient’s BHB levels and lactate levels beyond regular check-ins”; yet claim 1 does not recite measuring the patient’s BHB levels at regular check-ins, and claim 1 does not recite lactate levels being measured at all. As such, there is insufficient antecedent basis for the limitation “measuring the patient’s BHB levels and lactate levels at regular check-ins” of claim 12, in claim 1. Further, it is unclear what is a regular check-in (as opposed to perhaps an irregular one?), and it is unclear how one can reduce the measuring of a parameter. One may reduce the frequency with which some parameter is measured, but not the measuring, as in instant claim 12.
Claim 13 suffers from similar issues of lack of antecedent basis for the limitation related to measuring patient lactate levels, and for the recitation related to patients who adhere to a carbohydrate-restricted diet. Nowhere does claim 1 recite anything related to the patient “adhering” to a carbohydrate-restricted diet.
Much of the analysis above to claim 1 applies to claim 14, as well, with the added note that claim 14 recites an additional step of instructing the patient to modify the diet. It is unclear how such a step is relevant to a method of treatment, since instructing the patient can occur via mail, email, verbal means, but it may not result in a modification of diet, it is just delivering instructions- which the patient may or may not follow. The question about relevance extends to dependent claims 19-21, 27-29.
The analysis above of claims 12, 13 can be applied to claims 22, 23.
Claims 33-36 are unclear as they recite a method of reducing BHB level in a patient on a ketogenic diet. It is unclear how the decrease/reducing is to be measured, as the claims fail to establish a standard or threshold level. For example, the reducing could be relative to another sample taken from the same subject previously (for example, before receiving DCA treatment). Alternatively, the reducing could be relative to a healthy subject, or relative to another subject suffering from the same disease/condition as the patient treated with DCA, i.e., a different subject than the subject currently treated with DCA. Further, the level of biomarker may vary over time (for example, during treatment). The term “reducing a BHB level” requires a comparison with a predetermined standard level, yet the claim fails to clearly set forth whether this predetermined standard level is a standard established from a healthy subject, from another subject suffering from the same disease/condition but not treated with DCA, or from the same subject from a previously acquired sample. Claims 33-36 recite BHB level and lactate level, without specifying the origin of the samples used for measurement.
Further, claim 33 recites “wherein a dose of DCA administered to the patient is maintained”, without the claim making any reference to a dose of DCA being administered. The claim states that patient is “receiving” DCA treatment, it is unclear how the patient “receives” DCA treatment- for example, by mail, using kits, etc. If the patient is administered DCA in a method of treatment, the claim should state that. Claim 33 does not recite a dose of DCA, and it is unclear whether the treatment involves one dose or several /repeated doses of DCA or whether the method comprises a step of administering DCA.
This analysis is not exhaustive.
Appropriate clarification/correction is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 16 depends on claim 14, which recites a ketogenic ratio of at least 3:1, which is consistent with a carbohydrate-restricted diet. As such, claim 16 fails to further limit the subject matter of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections- 35 USC 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6-40 are rejected under 35 U.S.C. 103 as being unpatentable over NCT02616484 (Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex deficiency (DCA/PDCD), version of 2022-09-12, cited in PTO-892 of 22 October 2025) and Sofou et al. (J. Inherit Metab Dis 2017, 40, 237-245, cited in IDS).
NCT02616484 (Trial of Dichloroacetate in Pyruvate Dehydrogenase Complex deficiency (DCA/PDCD), version of 2022-09-12) teaches a method of treating a patient with deficiency of the pyruvate dehydrogenase complex (PDC), which is the most common cause of congenital lactic acidosis (page 6, first paragraph in the attached document), comprising
administering DCA to the patient (page 8, Arms and Interventions), and measuring the patient’s plasma beta-hydroxybutyrate concentrations (page 10, point 3, under Secondary Outcome Measures), which are steps in instant claims.
NCT02616484 teaches (page 9, Arms and Interventions, right column, first paragraph) that participants will be genotyped to determine GSTZ1 haplotype status, as in instant claims, which will stratify this group into 1 of 2 dose regimens, as in instant claim 37.
NCT02616484 teaches (page 10, point 2, under Secondary Outcome Measures) that the measurement of blood lactate level will be performed, and (page 10, point 3, under Secondary Outcome Measures) the measurement of plasma β-hydroxybutyrate (β-BHB) concentrations will be performed.
NCT02616484 does not teach that the patient’s blood lactate levels and plasma β-hydroxybutyrate levels are measured prior to initiation of the DCA treatment, as in instant claim 6, 17, or for at least three months during DCA treatment, as in instant claim 7, 18, or after 4 months, as in instant claim 22.
NCT02616484 does not teach instructing the patient to modify their diet to obtain a target plasma β-hydroxybutyrate (β-BHB) concentration, as in instant claims.
NCT02616484 does not teach instructing the patient to increase their carbohydrate intake, as in instant claims 8-11, 19, 20, 21, until the plasma β-hydroxybutyrate (β-BHB) concentration is <3.0 mM, and the blood lactate level is <2.0 mM, as in instant claim 11, 21.
Sofou (J. Inherit Metab Dis 2017, 40, 237-245) teaches a method of treating a patient with deficiency of the pyruvate dehydrogenase complex (PDC), comprising
administering ketogenic diet (KD) to the patient.
Sofou teaches (Table 1) that patients with CLA (congenital lactic acidosis, patients 2, 6, 7, 10, 15, 17) were administered ketogenic diet (KD treatment duration 5 years, or 10 months, or 2 years and 6 months), with KD ratio start vs. last 1.5:1 vs. 3.0:1 (for patient 2), with carbohydrates (g/d) start vs. last 19 vs. 12 (patient 2), with blood lactate prior/last follow-up 12/2.1 (for patient 2), with improvement in symptoms (much improved on CGI-I clinical global impression scale).
Importantly, Sofou teaches (page 243, right column, last paragraph, under Concomitant medications) that some of the patients also received dichloroacetate (2 out of 19 patients). Thus, Sofou teaches co-administration of DCA and ketogenic diet (KD) in patients with deficiency of the pyruvate dehydrogenase complex (PDC), as in the instant claims.
Sofou measures blood lactate levels and plasma 3-hydroxybutyric acid levels at baseline, and during treatment, as in the instant claims.
Sofou teaches (page 243, left column, last paragraph) that increased blood lactate >2 mmol/l was found in 12 of 18 patients (67%) at baseline as opposed to four of 19 at last follow-up (21%) (p = 0.01). Thus, Sofou teaches that KD administration reduces blood lactate levels in patients to <2.0 mM, as in instant claim 21.
Sofou teaches (page 243, right column, second paragraph) that the majority of patients had plasma ketone levels (3-hydroxybutyric acid) >2 mmol/l.
Soufou teaches (page 244, left column, first paragraph) that optimal plasma ketone levels (plasma ketone levels at which patients achieved optimal functioning) are >2 mmol/l, with a median of 3.3 (2.1–4.5) mmol/l. Almost all patients who were considered by investigators as being at least much improved had ketone levels of ∼3– 3.5 mmol/l, as opposed to the remaining patients, with ketone levels 4 mmol/l.
Sofou teaches (page 244, right column, third paragraph) that ketosis is considered to improve lactate levels in PDC deficiency; this is also shown in the current study, as blood lactate significantly declined after KD initiation. In order to be effective, KD treatment must lead to adequate and sustained ketosis. Sofou teaches the level of ketosis as the most important variable in determining outcome of patients with PDC deficiency.
Sofou chooses to implement the ketogenic diet (KD) with a lower ketogenic ratio and relatively higher carbohydrate intake, with a ratio gradually increased: in Table 1, patients with CLA were administered ketogenic diet (KD), with KD ratio start vs. last 1.5:1 vs. 3.0:1 (for patient 2), with carbohydrates (g/d) start vs. last 19 vs. 12 (patient 2), with blood lactate prior/last follow-up 12/2.1 (for patient 2), with improvement in symptoms.
Sofou teaches the correlation between ketogenic ratio and carbohydrate intake: lower ketogenic ratios are correlated with higher carbohydrate intake.
Sofou does not implement the KD for PDC deficiency with a classic/strict/restrictive ketogenic diet with a ketogenic ratio of 3:1 to 4:1, as in the instant claims.
It would have been obvious to combine the teachings of NCT02616484 and Sofou to arrive at the instant invention. The person of ordinary skill in the art would have co-administered DCA and ketogenic diet (KD) in patients with pyruvate dehydrogenase complex deficiency, with monitoring/measuring plasma BHB levels and blood lactate levels in the patients prior and during treatment, because
NCT02616484 teaches a method of treating a patient with deficiency of the pyruvate dehydrogenase complex (PDC), comprising administering DCA to the patient, and measuring the patient’s plasma beta-hydroxybutyrate concentrations and blood lactate levels in the patient, and
Sofou teaches a method of treating a patient with deficiency of the pyruvate dehydrogenase complex (PDC), comprising administering ketogenic diet (KD) to the patient, measuring the patient’s plasma beta-hydroxybutyrate concentrations and blood lactate levels in the patient prior and during treatment, and Sofou also teaches co-administration of KD and DCA in patients with PDC deficiency, to treat said patients.
Thus, the person of ordinary skill in the art would have co-administered DCA and KD in patients with PDC deficiency, with the expectation that the combination is effective to treat PDC deficiency. One of ordinary skill in the art would have reasonably expected that combining DCA and KD known to be useful for the same purpose, i.e. treating PDC deficiency, would result in therapeutic effect. Since all compounds for co-administration herein are known to be useful to treat PDC deficiency, it is considered prima facie obvious to co-administer them in a method used for the same purpose. At least additive therapeutic effects would have been reasonably expected. See In re Kerkhoven, 205 USPQ 1069 (CCPA 1980).
Further, the person of ordinary skill in the art would have implemented the KD for PDC deficiency with a classic/strict/restrictive ketogenic diet with a ketogenic ratio of 3:1 to 4:1, as in the instant claims, rather than initiating KD with a lower ketogenic ratio and gradually increasing the ketogenic ratio (as in Sofou), because implementing a classic/strict/restrictive ketogenic diet with a ketogenic ratio of 3:1 to 4:1, using commercially available ketogenic diets, would lead to adequate and sustained ketosis faster. Sofou teaches that, in order to be effective, KD treatment must lead to adequate and sustained ketosis and Sofou teaches the level of ketosis as the most important variable in determining outcome of patients with PDC deficiency.
Further, the person of ordinary skill in the art would have monitored blood levels of lactate and BHB prior to treatment and at intervals of time during treatment, using the methodology of Sofou, until a target plasma concentration of BHB of ∼3 mmol/l, and a target blood lactate concentration of <2 mmol/l is achieved, as in instant claim 11, 21, because Sofou teaches that KD administration reduces blood lactate levels in patients to <2.0 mM, and Soufou teaches that optimal plasma ketone levels (plasma ketone levels at which patients achieved optimal functioning) are ∼3 mmol/l.
The person of ordinary skill in the art would have initiated the KD in the method of treatment with a classic/strict/restrictive ketogenic diet with a high ketogenic ratio of 3:1 to 4:1, would have monitored blood BHB levels during treatment, with the expectation that KD with high ketogenic ratio results in higher blood ketone levels in the patient, and would have taken steps to lower BHB blood levels, if too high, in order to maintain the blood BHB levels within the target taught by Sofou. The person of ordinary skill in the art would have considered decreasing the ketogenic ratio in the KD (which occurs by increasing carbohydrate to fat ratio, per definition of ketogenic ratio), with the expectation that decreasing ketogenic ratio in the diet inherently results in a decrease in blood ketone levels in the patient. Such iterations of gradually lowering ketogenic ratio in KD, with monitoring of blood BHB upon administering KD, with the aim of determining the optimum ketogenic ratio in KD resulting in the blood BHB and the blood lactate levels within the target taught by Sofou, to optimize treatment efficacy, is well within the skill of the artisan.
Further, regarding the dose of DCA administered in the method of treating PDCD, the person of ordinary skill in the art would have identified whether the patient with pyruvate dehydrogenase complex deficiency (PDCD) is a fast metabolizer of DCA or a slow metabolizer of DCA, based on a GSTZ haplotype of the patient, and would have administered different dose of dichloroacetate (DCA) to said patients, because NCT02616484 teaches that participants will be genotyped to determine GSTZ1 haplotype status, which will stratify this group into 1 of 2 dose regimens.
As such, claims 1, 6-40 are rejected as prima facie obvious.
Conclusion
Claims 1, 6-40 are rejected.
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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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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