DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on July 22, 2025 has been entered. Applicant’s remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any rejections or objections not reiterated herein have been withdrawn.
Claims 1, 6-10, and 12-13 are currently pending and have been examined herein.
Declaration Under 37 CFR 1.132
3. A declaration was filed under 37 CFR 1.132 filed July 22, 2025 to show evidence of non-obviousness. The declaration is not persuasive for the reasons set forth below in paragraph 8.
Claim Rejections - 35 USC § 112
4. 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, 6-10 and 12-13 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.
Claims 1, 6-10 and 12-13 are drawn to a method of reducing the likelihood of mortality in patients (plural) with PDHA1-related pyruvate dehydrogenase complex deficiency (PDCD). However, step 1 requires identifying whether the patient (singular) having PDHA1-related PDCD is a fast metabolizer of dichloroacetate (DCA) or a slow metabolizer of DCA, based on a GSTZ1 haplotype of the patient and step 2 requires reducing the likelihood of mortality in the patients (plural) by administering a DCA dose to the patient (singular). Thus the claims are confusing because it is unclear if the method is practiced on a single patient or a plurality of patients. If it is the later, it is unclear how administering treatment to a single patient would result in reducing the mortality of multiple patients. Clarification is requested.
Claims 1, 6-10 and 12-13 are drawn to a method of reducing the likelihood of mortality in patients with PDHA1-related pyruvate dehydrogenase complex deficiency (PDCD). The claims are indefinite because it’s not clear what the reduced mortality is in comparison to. For example does the method reduce the likelihood of mortality in comparison to (i) non-PDCD patients treated with DCA, PDCD patients not treated with DCA, PDCD patients treated with DCA but not getting dosed based on their GSTZ1 haplotype. Clarification is requested.
Claims 1, 6-10 and 12-13 are rejected over the recitation of “wherein the standard dose is 25 mg/kg/day and the reduced dose is between 12.5 mg/kg/day and 25 mg/kg/day”. In the instant case the claims are confusing since they state that 25 mg/kg/day can be considered a “standard” dose and a “reduced” dose. Clarification is requested.
Claim Rejections - 35 USC § 103
5. 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.
6. Claims 1, 6-10 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Langaee (US 2013/0090382 Pub 4/11/2013) in view of Berendzen (Mitochondrion 6 (2006) 126-135), Stacpoole (Advanced Drug Delivery Reviews 60 (2008) 1478-1487), and Stacpoole (Mitochondrion 42 (2018) 59-63).
Regarding Claims 1 and 12 Langaee teaches that it has been determined that polymorphisms in the GSTZ1 modify the kinetics of DCA and, consequently, the risk of adverse effects from the drug. GSTZ1 haplotype clearly segregated subjects into fast and slow DCA metabolizers. Those who metabolized DCA slowly showed markedly delayed plasma clearance, increased excretion of unmetabolized drug and increased urinary accumulation of potentially toxic tyrosine metabolites. Thus, GSTZ1 haplotype predicts the toxic genetics of DCA. This information can be used prospectively to adjust drug dosing and mitigate risk of adverse events when using DCA (para 0049). Langaee teaches that knowledge of GSTz1/MAAI genotype can be used to determine if the subject is at a heightened risk (or a slow metabolizer of DCA) for developing adverse drug effects to DCA. Once an individual is known to include certain alleles, dose adjustments can be made so that the individual can tolerate the DCA (para 0050). Langaee teaches that in general, a patient is given a standard dosing regimen (e.g., daily dosage of DCA, frequency of administration, and the like) based on age, size, health, and the like, but as noted herein, the standard dosing regime is not appropriate for some subjects having certain GSTZ1 haplotypes (e.g., slow metabolizers of DCA). In general, the standard dosing regimen for a healthy adult is about 5 to 25 mg/kg/day. In an embodiment, the amount of the reduction of the standard dosing regimen for a subject that is a slow DCA metabolizer (e.g., having one of allele identified herein) should be about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more. In an embodiment, the amount of the reduction can initially be small and increased based on the response of the subject (para 0053). Further Langaee teaches administering DCA to patients with pyruvate dehydrogenase deficiency (para 0078). Thus Langaee teaches a method of identifying whether a PDCD patient is a fast metabolizer of DCA or a slow metabolizer of DCA based on a GSTZ1 haplotype of the patient and administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient, the DCA dose being a standard dose (25 mg/kg/day) when the patient is identified as a fast metabolizer of DCA and the DCA dose being a reduced dose (12.5-25 mg/kg/day) when the patient is identified as a slow metabolizer of DCA.
Regarding Claim 13 Langaee teaches they treated 6 children (3 with pyruvate dehydrogenase deficiency and 3 with one or more defects in a respiratory chain enzyme) with DCA for 12 months. Langaee teaches that the patients ranged in age from 2-10 years at the time the DCA administration commenced (para 0078). Thus Langaee teaches a method wherein the patient is above the age of 0.9 years old.
Langaee does not teach a method wherein the patient with PDCD has PDHA1-related PDCD (clm 1).
However Berendzen teaches that they analyzed 46 patients with PDC deficiency treated with DCA (page 129). Berendzen teaches that molecular diagnostic studies identified 16 patients with a mutation in a PDC gene (page 130). As shown in Table 2, 14 of the patients treated with DCA had mutations in the E1α subunit of the pyruvate dehydrogenase complex (PDH). Berendzen further teaches that four patients with a mutation in the E1α gene have continued to be evaluated and have received DCA for at least 5 years (page 131). It is noted that PDHA1 is the gene that encodes the E1α subunit of the pyruvate dehydrogenase complex (PDH). Thus Berendzen teaches treating a patient having PDHA1-related PDCD with DCA.
Additionally Stacpoole (2008) teaches that DCA should be most effective in patients with congenital defects in the PDH complex, in particular, with mutations in the E1α subunit. This hypothesis is founded upon both the primary site and mechanism of action of DCA on fuel metabolism and on the sum of the evidence regarding drug safety and efficacy from both open label and controlled trials (page 1485).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Langaee such that the PDCD patients being treated are those known to have PDHA1 related PDCD as suggested by Berendzen and Stacpoole (2008). The skilled artisan would have been motivated to treat patients having PDHA1-related PDCD with DCA since the prior art already teaches treatment of these patients with DCA and teaches that DCA should be most effective in PDCD patients with mutations in the E1α subunit (which is encoded by PDHA1).
The combined references do not teach that administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient will reduce the mortality of the patient (clm 1).
However Stacpoole (2018) teaches that “Open label studies in PDCD patients also suggest DCA may improve clinical functionality within 24h of initiating treatment, and may also increase survival (Stacpoole et al., 2008, and personal observ.)” (page 60 col 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Langaee, Berendzen, and Stacpoole (2008) by administering DCA to a patient having PDCD with the goal of reducing the likelihood of mortality in the patient based on the teachings of Stacpoole (2018). The claim would have been obvious because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
The combined references do not teach that the method reduces the likelihood of PDCD-related mortality to less than 10% (clm 6). The combined references do not teach that the method reduces the likelihood of PDCD-related mortality to less than 5% (clm 7). The combined references do not teach that the method reduces the likelihood of PDCD-related mortality to less than 2% (clm 8). The combined references do not teach that the method reduces the odds ratio of death to less than 0.10 (clm 9). The combined references do not teach that the method reduces the odds ratio of death to less than 0.05 (clm 10).
However, the result of reducing mortality would be an inherent property of practicing the “administering” step. It is well settled that “the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Moreover, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Further when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. In reMay, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds, as well as a method of using them for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the inventors had merely found a new property of the compound and such a discovery did not constitute a new use. The court went on to reverse the obviousness rejection of claims 2-5 and 7-10 which recited a process of using a new compound. The court relied on evidence showing that the nonaddictive property of the new compound was unexpected.). See also In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966) (The claim was directed to a process of inhibiting light degradation of polypropylene by mixing it with one of a genus of compounds, including nickel dithiocarbonate. A reference taught mixing polypropylene with nickel dithiocarbonate to lower heat degradation. The court held that the claims read on the obvious process of mixing polypropylene with the nickel dithiocarbamate and that the preamble of the claim was merely directed to the result of mixing the two materials. “While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition.” 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)).
The teachings of the Court are instructive to the instant action. The claims require reducing the likelihood of mortality in the patient by administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient. Thus, reducing the likelihood of mortality in the patient must be an inherent result of practicing the administering step. The Examiner finds that the administering step is obvious in view of the teachings of Langaee, Berendzen, and Stacpoole. The examiner therefore finds that the references inherently and necessarily teach reduction of mortality.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
7. Claims 1, 6-10 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Langaee (Genetic Testing and Molecular Biomarkers Vol 22 No 4 2018) in view of Langaee (US 2013/0090382 Pub 4/11/2013), Berendzen (Mitochondrion 6 (2006) 126-135), Stacpoole (Advanced Drug Delivery Reviews 60 (2008) 1478-1487), and Stacpoole (Mitochondrion 42 (2018) 59-63).
Regarding Claim 1 Langaee (2018) teaches that dichloroacetate (DCA) represents the first targeted therapy for pyruvate dehydrogenase complex deficiency; it is metabolized by glutathione transferase zeta1 (GSTZ1). Variation in the GSTZ1 haplotype is the principal variable influencing DCA kinetics and dynamics in humans. Langaee teaches that they developed a sensitive and rapid clinical genetic screening test for determining GSTZ1 haplotype status in individuals who would be treated with DCA, and then applied the test for the investigation of the plasma pharmacokinetics (PK) of DCA as a function of GSTZ1 haplotype. Langaee teaches that DNA samples from 45 healthy volunteer study participants were genotyped for three functional GSTZ1 single nucleotide polymorphisms (rs7975, rs7972, and rs1046428) by TaqMan®. Prior studies showed that subjects with at least one EGT haplotype (EGT carrier) metabolized DCA faster than EGT noncarriers. The EGT haplotype carrier group demonstrated significantly faster metabolism of DCA and higher rates of plasma DCA clearance after 5 days of drug exposure compared with EGT noncarriers (p = 0.04). Langaee teaches that these preliminary data establish the validity and practicality of our rapid genotyping/haplotyping procedure for genetic-based DCA dosing to mitigate or prevent adverse effects in patients treated chronically with this drug (abstract). Thus Langaee teaches a method of identifying whether a PDCD patient is a fast metabolizer of DCA or a slow metabolizer of DCA based on a GSTZ1 haplotype of the patient. Langaee further suggests administering a DCA dose based on the haplotype to mitigate or prevent adverse effects.
Langaee (2018) does not teach a method further comprising administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient, the DCA dose being a standard dose when the patient is identified as a fast metabolizer of DCA and the DCA dose being a reduced dose when the patient is identified as a slow metabolizer of DCA wherein the standard dose is 25 mg/kg/day and the reduced dose is between 12.5mg/kg/day and 25mg/kg/day (clm 1). Langaee does not teach a method wherein the standard dose is 25 mg/kg/day and the reduced dose is 12.5mg/kg/day (clm 12). Additionally Langaee does not teach a method wherein the patient is above the age of 0.9 years old (clm 13).
However Langaee (US 2013/0090382) teaches that it has been determined that polymorphisms in the GSTZ1 modify the kinetics of DCA and, consequently, the risk of adverse effects from the drug. GSTZ1 haplotype clearly segregated subjects into fast and slow DCA metabolizers. Those who metabolized DCA slowly showed markedly delayed plasma clearance, increased excretion of unmetabolized drug and increased urinary accumulation of potentially toxic tyrosine metabolites. Thus, GSTZ1 haplotype predicts the toxic genetics of DCA. This information can be used prospectively to adjust drug dosing and mitigate risk of adverse events when using DCA (para 0049). Langaee teaches that knowledge of GSTz1/MAAI genotype can be used to determine if the subject is at a heightened risk (or a slow metabolizer of DCA) for developing adverse drug effects to DCA. Once an individual is known to include certain alleles, dose adjustments can be made so that the individual can tolerate the DCA (para 0050). Langaee teaches that in general, a patient is given a standard dosing regimen (e.g., daily dosage of DCA, frequency of administration, and the like) based on age, size, health, and the like, but as noted herein, the standard dosing regime is not appropriate for some subjects having certain GSTZ1 haplotypes (e.g., slow metabolizers of DCA). In general, the standard dosing regimen for a healthy adult is about 5 to 25 mg/kg/day. In an embodiment, the amount of the reduction of the standard dosing regimen for a subject (a healthy adult or child) that is a slow DCA metabolizer (e.g., having one of allele identified herein) should be about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more. In an embodiment, the amount of the reduction can initially be small and increased based on the response of the subject (para 0053). Langaee they treated 6 children (3 with pyruvate dehydrogenase deficiency and 3 with one or more defects in a respiratory chain enzyme) with DCA for 12 months. Langaee teaches that the patients ranged in age from 2-10 years at the time the DCA administration commenced (para 0078).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Langaee (2018) by administering a DCA dose to a patient based on the GSTZ1 haplotype of the patient, the DCA dose being a standard dose (25 mg/kg/day) when the patient is identified as a fast metabolizer of DCA and the DCA dose being a reduced dose (between 12.5mg/kg/day and 25mg/kg/day) when the patient is identified as a slow metabolizer of DCA as suggested by Langaee (US 2013/0090382). In the instant case both Langaee references teach the correlation between the GSTZ1 haplotype and metabolism rate of DCA. Langaee (2018) suggests administering a DCA dose based on the haplotype to mitigate or prevent adverse effects (abstract). Langaee (US 2013/0090382) teaches administering a dose of DCA based on GSTZ1 haplotype. Langaee teaches administering a standard (dose 25 mg/kg/day) or a reduced dose (between 12.5mg/kg/day and 25mg/kg/day) to a patient that is a slow metabolizer (para 0052-0053). One of skill in the art would have been motivated to administer different dosages to fast and slow metabolizers for the benefit of being able to mitigate or prevent adverse side effects (abstract). Further one of skill in the art would have been motivated to administer different dosages to fast and slow metabolizers for the benefit of being able to adjust the dose so that an individual can tolerate the DCA (para 0050). Finally it would have been obvious to treat patients above the age of 0.9 years since PDCD also effects this age group.
The combined Langaee references do not teach a method wherein the patient with PDCD has PDHA1-related PDCD (clm 1).
However Berendzen teaches that they analyzed 46 patients with PDC deficiency treated with DCA (page 129). Berendzen teaches that molecular diagnostic studies identified 16 patients with a mutation in a PDC gene (page 130). As shown in Table 2, 14 of the patients treated with DCA had mutations in the E1α subunit of the pyruvate dehydrogenase complex (PDH). Berendzen further teaches that four patients with a mutation in the E1α gene have continued to be evaluated and have received DCA for at least 5 years (page 131). It is noted that PDHA1 is the gene that encodes the E1α subunit of the pyruvate dehydrogenase complex (PDH). Thus Berendzen teaches treating a patient having PDHA1-related PDCD with DCA.
Additionally Stacpoole teaches that DCA should be most effective in patients with congenital defects in the PDH complex, in particular, with mutations in the E1α subunit. This hypothesis is founded upon both the primary site and mechanism of action of DCA on fuel metabolism and on the sum of the evidence regarding drug safety and efficacy from both open label and controlled trials (page 1485).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the methods of Langaee and Langaee such that the PDCD patients being treated are those known to have PDHA1 related PDCD as suggested by Berendzen and Stacpoole. The skilled artisan would have been motivated to treat patients having PDHA1-related PDCD with DCA since the prior art already teaches treatment of these patients with DCA and teaches that DCA should be most effective in PDCD patients with mutations in the E1α subunit (which is encoded by PDHA1).
The combined references do not teach that administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient will reduce the mortality of the patient (clm 1).
However Stacpoole (2018) teaches that “Open label studies in PDCD patients also suggest DCA may improve clinical functionality within 24h of initiating treatment, and may also increase survival (Stacpoole et al., 2008, and personal observ.)” (page 60 col 1).
Accordingly, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Langaee, Berendzen, and Stacpoole (2008) by administering DCA to a patient having PDCD with the goal of reducing the likelihood of mortality in the patient based on the teachings of Stacpoole (2018). The claim would have been obvious because “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.
The combined references do not teach that the method reduces the likelihood of PDCD-related mortality to less than 10% (clm 6). The combined references do not teach that the method reduces the likelihood of PDCD-related mortality to less than 5% (clm 7). The combined references do not teach that the method reduces the likelihood of PDCD-related mortality to less than 2% (clm 8). The combined references do not teach that the method reduces the odds ratio of death to less than 0.10 (clm 9). The combined references do not teach that the method reduces the odds ratio of death to less than 0.05 (clm 10).
However, the result of reducing mortality would be an inherent property of practicing the “administering” step. It is well settled that “the discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
Moreover, there is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
Further when a claim recites using an old composition or structure and the “use” is directed to a result or property of that composition or structure, then the claim is anticipated. In reMay, 574 F.2d 1082, 1090, 197 USPQ 601, 607 (CCPA 1978) (Claims 1 and 6, directed to a method of effecting nonaddictive analgesia (pain reduction) in animals, were found to be anticipated by the applied prior art which disclosed the same compounds, as well as a method of using them for effecting analgesia but which was silent as to addiction. The court upheld the rejection and stated that the inventors had merely found a new property of the compound and such a discovery did not constitute a new use. The court went on to reverse the obviousness rejection of claims 2-5 and 7-10 which recited a process of using a new compound. The court relied on evidence showing that the nonaddictive property of the new compound was unexpected.). See also In re Tomlinson, 363 F.2d 928, 150 USPQ 623 (CCPA 1966) (The claim was directed to a process of inhibiting light degradation of polypropylene by mixing it with one of a genus of compounds, including nickel dithiocarbamate. A reference taught mixing polypropylene with nickel dithiocarbamate to lower heat degradation. The court held that the claims read on the obvious process of mixing polypropylene with the nickel dithiocarbamate and that the preamble of the claim was merely directed to the result of mixing the two materials. “While the references do not show a specific recognition of that result, its discovery by appellants is tantamount only to finding a property in the old composition.” 363 F.2d at 934, 150 USPQ at 628 (emphasis in original)).
The teachings of the Court are instructive to the instant action. The claims require reducing the likelihood of mortality in the patient by administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient. Thus, reducing the likelihood of mortality in the patient must be an inherent result of practicing the administering step. The Examiner finds that the administering step is obvious in view of the teachings of Langaee, Langaee, Berendzen, and Stacpoole. The examiner therefore finds that the references inherently and necessarily teach reduction of mortality.
Accordingly, the claimed invention is prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response To Arguments
8. In the response the Applicants traversed the rejections made under 35 USC 103. The response notes that claim 1 has been amended to (i) limit the claim to a method of reducing mortality, (ii) to recite the standard and reduced dosage, and (iii) to recite that the patient has PDHA1-related PDCD.
The response states that PDHA1-related PDCD patients have a defect in the E1 subunit. Other forms of PDCD include DLD-related PDCD, which leads to a defect in the E3 subunit. The Applicants argue that Langaee 2018 and Langaee ‘382 are silent as to this subject matter. Additionally, as noted above, Ganetzky 2021 and Patel 2012 demonstrate that the different genetic presentations cause different phenotypical presentations. At the time the invention was filed, it was not recognized whether DCA is effective against all types of PDCD, or only particular subtypes.
This argument has been fully considered. It is noted that the rejections have been modified to address the claims as amended. The newly cited Berendzen reference (Mitochondrion 6 (2006) 126-135) teaches that they analyzed 46 patients with PDC deficiency treated with DCA (page 129). As shown in Table 2, 14 of the patients treated with DCA had mutations in the E1α subunit of the pyruvate dehydrogenase complex (PDH). Berendzen further teaches that four patients with a mutation in the E1α gene have continued to be evaluated and have received DCA for at least 5 years (page 131). Thus Berendzen teaches treating patients having PDHA1-related PDCD with DCA and the treatment must have had some beneficial response if the patients continued the treatment for greater than 5 years. Additionally the newly cited Stacpoole (Advanced Drug Delivery Reviews 60 (2008) 1478-1487) reference teaches that DCA should be most effective in patients with congenital defects in the PDH complex, in particular, with mutations in the E1α subunit. This hypothesis is founded upon both the primary site and mechanism of action of DCA on fuel metabolism and on the sum of the evidence regarding drug safety and efficacy from both open label and controlled trials (page 1485). Based on these two prior art references there was knowledge in the art that DCA was effective for treating PDHA1-related PDCD.
The Applicants argue that the prior art does not teach a reduction in mortality. They argue that the prior art of Langaee only relates to reducing toxicity of DCA treatment, but is silent as to improving survival.
This argument has been fully considered. It is noted that the rejections have been modified to address the claims as amended. The newly recited Stacpoole (Mitochondrion 42 (2018) 59-63) reference actually teaches that “Open label studies in PDCD patients also suggest DCA may improve clinical functionality within 24h of initiating treatment, and may also increase survival (Stacpoole et al., 2008, and personal observ.)” (page 60 col 1). Therefore the prior art does in fact teach that DCA can reduce mortality in patients with PDCD.
The Applicants noted that as explained in the Declaration under 37 CFR 1.132 filed on May 22, 2025, it was expected that the study would result in a 20% dropout rate due to death or peripheral neuropathy. In particular in the prior study described on page 3 of the Declaration, 7% of patients dropped out due to death during the six month treatment course, and it was implausible that no subjects would die in the Applicant’s study. However, zero deaths were reported.
The Declaration filed on May 22, 2025 was previously considered by examiner and determined to be insufficient to overcome the rejection. It is noted that the expected dropout rate of 20% is based on the dropout rate of a study where patients with congenital lactic acidosis were treated with DCA. This is an entirely different disease than PDHA1-related PDCD. Further the 20% expected dropout rate is based on patients dropping out due to the combination of death and neuropathy. It not clear what the expected dropout rate due only to death would be. It is noted that once treatment was initiated, 3 patients died (7%) and 39 patients (92%) survived. Based on these numbers it does not seem unexpected that zero deaths would be reported in a follow up study.
The Applicants filed a second Declaration under 37 CFR 1.132 on July 22, 2025 to support their position that it was not expected that the mortality would be reduced to the extent observed. The declaration states that no reduction of mortality was expected, although it was surprisingly observed that mortality was reduced by 97%.
The Declaration (pages 2-4) states that a reduction in mortality rate was not expected.
The Declaration states that the inventors arrived at their expectation of a lack of a reduction in mortality rate due to treatment of PDHA1-related PDCD patients with DCA based on the teachings of Stacpoole (Pediatrics, Vol 121, No 5, May 2008). Patients with congenital lactic acidosis (CLA) that had previously completed a previous study with DCA were given the
opportunity to enroll in an open-label extension. These patients were followed for up to ~10 years. Although several patients had long-term follow-up, the median exposure was only 2.38 years. In Figure 2 of Stacpoole 2008, the authors provide what is described as a Kaplan-Meier curve showing that PDCD patients may appear to survive longer than other forms of CLA. Statistical information is not provided (log-rank statistics, patients at risk, censoring tick marks, etc.), making it not possible to reasonably assess the strength of evidence of Figure 2.
The declaration states that since statistical information was not provided in the Stacpoole 2008 paper, they did their own an analysis of whether or not there was a difference between the PDCD and non-PDCD cohorts in the curve of Stacpoole 2008. The declaration states that the log-rank statistic comparing the PDCD to non-PDCD survival outcomes is p=0.323, which is not statistically significant. Such analysis was completed by estimating how many patients were at-risk for each group (PDCD, all patients, non- PDCD CLA) by calculating the distance by which the curve dropped at each death. Based on this analysis, PDCD patients do not have different outcomes than the other CLA patients. This is due to most PDCD patients having a relatively short follow-up time, meaning that the long-term survival of many of the patients was unknown.
The declaration states that in scientific publications, typically the log-rank statistic and the necessary supporting information, including patients at risk are provided. In Stacpoole 2008, the underlying data of the Kaplan-Meier analysis are not provided. This further suggests that the PDCD patient group did not differ statistically from the rest of the cohort. This curve highlights the poor outcomes of patients with all forms of CLA and is unable to distinguish any subset of CLA that may have responded using standard statistical approaches.
The Declaration has been fully considered. The Examiner does not agree with Applicants analysis of Figure 2 in the Stacpoole (Pediatrics, Vol 121, No 5, May 2008) reference. An annotated copy of Figure 2 is shown below:
PNG
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446
564
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Greyscale
As shown in the box, 10 patients (28%) out of 36 patients died during the follow-up. Of the patients with PDH, 1 patient (10%) out of 10 died during the follow-up. Of the patients with non-PDH, 9 patients (35%) out of 26 died during the follow-up. Clearly this shows that PDH patients that were treated with DCA had better survival rates than non-PDH patients that were treated with DCA (90% survival versus 65% survival).
Further it is noted that the claims are now rejected in part over the teachings of Stacpoole (Advanced Drug Delivery Reviews 60 (2008) 1478-1487) and Stacpoole (Mitochondrion 42 (2018) 59-63).
Stacpoole (2018) teaches the following:
“Open label studies in PDCD patients also suggest DCA may improve clinical functionality within 24h of initiating treatment, and may also increase survival (Stacpoole et al., 2008, and personal observ.)” (page 60 col 1).
Stacpoole (2018) refers to Stacpoole (2008) which is Stacpoole (Advanced Drug Delivery Reviews 60 (2008) 1478-1487). This references teaches the following:
“At the end of this phase, 36 of the original 43 subjects chose to continue receiving open label DNA and to return every six months for evaluation. Exposure of this group to DCA totaled 110.42 patient years through May 2005 and their mean 3 year survival was 79% (page 1483, col 2).
Clearly these additional Stacpoole references teach that treatment of PDCD with DCA may increase survival.
In totality, there are three different references, all authored by Stacpoole, who also happens to be an inventor listed on this application that are relevant to the determination as to whether a reduction if mortality was expected. The references are: (i) (Pediatrics, Vol 121, No 5, May 2008), (ii) (Mitochondrion 42 (2018) 59-63), and (iii) (Advanced Drug Delivery Reviews 60 (2008) 1478-1487). Based on the analysis of these references provided above, Examiner does not agree that a reduction in mortality rate was unexpected.
The Declaration (pages 4-6) discusses that the magnitude of the reduction of mortality was not expected.
The Declaration states that the inventors conducted a study (“SL1009-02”) to compare DCA-treated PDHA1-releated PDCD patients with their dosing based on the GSTZ1 haplotype, with appropriately matched natural history patients with similar background treatments who were not treated with DCA. The Declaration states that the resulting reduction in risk of death exceeded 97% across all analyses.
The Declaration states that in a Type-C meeting conducted with the FDA, the FDA encouraged Saol to conduct the study relating to survival as it is “an objective and clinically meaningful endpoint.” This and other interactions led to refinement of the study to incorporate the analyses listed in paragraph [0045] of the specification. The Declaration states that these analyses ultimately demonstrated highly statistically significant results with an overall reduction of the risk of death of 97.4% or greater (1-odds ratio) depending on the analysis that was conducted. These results demonstrate a clear and significant treatment effect, resulting in a near complete reduction in the risk of death.
The Declaration states that in addition to the data presented in the specification from the Phase III study, physicians have requested DCA to treat neonates considered to have cases that were imminently mortal with no other available treatment options. Three PDCD neonate patients were given access to medication. At this age, the 60-day mortality rate usually exceeds 50%, but to date all three patients survived and continue to do well (for up to 405 days).
The Declaration has been fully considered. The examiner does not agree the magnitude of the observed reduction in mortality was unexpected. As discussed above, Stacpoole (Pediatrics, Vol 121, No 5, May 2008) provides data showing that out of the patients with PDH, 1 patient (10%) out of 10 died during the follow-up over 10 years. That is a 90% survival rate for PDCD patients treated with DCA. Applicants have not met the burden of establishing that going from a 90% survival rate to 97% survival rate is in fact unexpected and of statistical and practical significance. The rejections are maintained.
Double Patenting
9. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
10a. Claims 1, 6-10, and 12-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9,765,393 in view of Berendzen (Mitochondrion 6 (2006) 126-135), Stacpoole (Advanced Drug Delivery Reviews 60 (2008) 1478-1487), Stacpoole (Mitochondrion 42 (2018) 59-63), and Langaee (US 2013/0090382 Pub 4/11/2013). Although the claims at issue are not identical, they are not patentably distinct from each other.
The instant claims are different from the Patent because they are drawn to a method comprising identifying whether a patient is a fast metabolizer of DCA or a slow metabolizer of DCA based on a GSTZ haplotype of the patient and then reducing the likelihood of mortality in the patient by administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient, the DCA dose being a standard dose when the patient is identified as a fast metabolizer or a reduced dose when the patient is identified as a slow metabolizer. However the claims of the Patent are drawn to an array for determining a GSTZ1 haplotype (see clm 1 of the Patent). The array is packaged in a kit and the kit is for treating a disease or disorder with dichloroacetate (DCA) (clm 2 of the Patent). The kit further comprises directions describing GSTZ1 haplotypes that have a risk of adverse drug effects if given a standard DCA dosing regimen (clm 2 of the Patent). The kit further comprises directions for reducing the standard DCA dosing regimen for a subject having certain GSTZ1 haplotypes (clm 3 of the Patent). Accordingly, it would have been obvious to have modified the patent by claiming a method of using the kit to identify the GSTZ1 haplotype of a patient and then administering a DCA dose based on the haplotype, wherein the dose is reduced in patients having a haplotype associated with a risk of adverse drug effects if the standard dose is given particularly since the directions in the kit say the kit is useful for this. The instant claims are different from the Patent because the claims state that the patient has PHDA1-related PDCD. However Berendzen teaches that they analyzed 46 patients with PDC deficiency treated with DCA (page 129). Berendzen teaches that molecular diagnostic studies identified 16 patients with a mutation in a PDC gene (page 130). As shown in Table 2, 14 of the patients treated with DCA had mutations in the E1α subunit of the pyruvate dehydrogenase complex (PDH). Additionally Stacpoole (2008) teaches that DCA should be most effective in patients with congenital defects in the PDH complex, in particular, with mutations in the E1α subunit (page 1485). Accordingly, it would have been obvious to have modified the patent by claiming a method of using the kit to identify the GSTZ1 haplotype of a patient and then administering a DCA dose based on the haplotype to a patient having PDHA1-related PDCD as suggested by Berendzen and Stacpoole. The skilled artisan would have been motivated to treat patients having PDHA1-related PDCD with DCA since the prior art already teaches treatment of these patients with DCA and teaches that DCA should be most effective in PDCD patients with mutations in the E1α subunit (which is encoded by PDHA1). The instant claims are different from the Patent because they recite that administering DCA reduces the likelihood of mortality. Stacpoole (2018) teaches the following: Open label studies in PDCD patients also suggest DCA may improve clinical functionality within 24h of initiating treatment, and may also increase survival (Stacpoole et al., 2008, and personal observ.)” (page 60 col 1). Accordingly, it would have been obvious to have modified the patent by claiming a method of using the kit to identify the GSTZ1 haplotype of a patient and then administering a DCA dose based on the haplotype to a patient having PDHA1-related PDCD in order to reduce mortality as suggested by Stacpoole (2018) since this benefit was taught in the prior art at patients with PDCD typically have shorter life spans. Further the instant claims are different from the Patent because they state that the standard dose is 25 mg/kg/day and the reduced dose is 12.5 mg/kg/day. The instant claims are different from the Patent because they state that the patient is greater than 0.9 years old. However Langaee (US 2013/0090382) teaches that in general, a patient is given a standard dosing regimen (e.g., daily dosage of DCA, frequency of administration, and the like) based on age, size, health, and the like, but as noted herein, the standard dosing regime is not appropriate for some subjects having certain GSTZ1 haplotypes (e.g., slow metabolizers of DCA). In general, the standard dosing regimen for a healthy adult is about 5 to 25 mg/kg/day. In an embodiment, the amount of the reduction of the standard dosing regimen for a subject (a healthy adult or child) that is a slow DCA metabolizer (e.g., having one of allele identified herein) should be about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, or about 80% or more. In an embodiment, the amount of the reduction can initially be small and increased based on the response of the subject (para 0053). Lanagaee further teaches treating patients between 2-10 years old (para 0078). Accordingly, it would have been obvious to have modified the claims of the Patent such that the standard dose is 25 mg/kg/day and the reduced dose is 12.5 mg/kg/day as suggested by Langaee (US 2013/0090382). One of skill in the art would have been motivated to administer a 25 mg/kg dose since the prior art teaches that this was the standard dose and one of skill in the art would have been motivated to administer a 12.5 mg/kg dose based on the guidance of Langaee to reduce the dose by 50% in patients at high risk of adverse effects to mitigate or prevent those adverse side effects. Further one of skill in the art would have been motivated to administer different dosages to fast and slow metabolizers for the benefit of being able to adjust the dose so that an individual can tolerate the DCA (para 0050). Regarding Claims 6-10 it is noted that claim scope is not limited by claim language (such as wherein clauses) that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.
Response To Arguments
11. In the response the Applicants traversed the double patenting rejection. The Applicants argue that the claims have been amended to recite that patient has PDHA1-related PDCD. However, the ‘393 patent claims and cited arts (Langaee 2018 and Langaee ‘382) are silent as to PDHA1-related PDCD. The Applicants argue that at the time the ‘393 patent was filed, it was not recognized whether DCA is effective for treating all types of PDCD, or only particular subtypes. Further the claimed embodiments are additionally patentably distinct over the claims of the ‘393 patent in view of Langaee 2018 due to the above-noted unexpected results of reduced mortality.
It is noted that the double patenting rejection has been modified to address the claims as amended. In particular new references have been added which teach administering DCA to a patient that has PDHA1-related PDCD. Further applicants arguments and the declaration pertaining to unexpected results have been fully considered and addressed above. The response, as set forth above, applies equally to the double patenting rejections.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA HANEY whose telephone number is (571)272-8668. The examiner can normally be reached Monday-Friday, 8:15am-4:45pm EST.
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/AMANDA HANEY/Primary Examiner, Art Unit 1682
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