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. This action is in response to the papers filed March 13, 2026. 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 new grounds of rejection presented in this Office Action are necessitated by Applicant's amendments. Any rejections or objections not reiterated herein have been withdrawn. This action is made FINAL.
Claims 1, 6-10, and 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 March 13, 2026 to show evidence of non-obviousness. The declaration is not persuasive for the reasons set forth below in paragraph 7.
Claim Rejections - 35 USC § 103
4. 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.
5. Claims 1, 6-10 and 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 Claim 1 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 each of the patients having PDCD is a fast metabolizer of DCA or a slow metabolizer of DCA based on a GSTZ1 haplotype of each patient and administering a DCA dose to the patients based on the GSTZ1 haplotype of each 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 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 patients with PDCD have 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 mortality relative to patients having PDHA1-releated PDCD not treated with DCA (clm 1). The combined references do not teach a method that reduces the hazard/odds ratio of death to less than 0.2 (clm 1). 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 hazard/odds ratio of death to less than 0.10 (clm 9). The combined references do not teach that the method reduces the hazard/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 patients by administering a DCA dose to the patient based on the GSTZ1 haplotype of the patient. Thus, reducing the likelihood of mortality in the patients 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.
6. Claims 1, 6-10 and 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 each of the patients having PDCD is a fast metabolizer of DCA or a slow metabolizer of DCA based on a GSTZ1 haplotype of each 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 12.5mg/kg/day (clm 1). 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 (12.5mg/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 (12.5mg/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 mortality relative to patients having PDHA1-releated PDCD not treated with DCA (clm 1). The combined references do not teach a method that reduces the hazard/odds ratio of death to less than 0.2 (clm 1). 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 hazard/odds ratio of death to less than 0.10 (clm 9). The combined references do not teach that the method reduces the hazard/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
7. In the response, the Applicants traversed the rejections made under 35 USC 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). The Applicants argue that the cited documents fail to disclose a method of reducing the likelihood of mortality in patients with PDHA1-related pyruvate dehydrogenase complex deficiency (PDCD), wherein the method reduces the hazard/odds ratio of death to less than 0.20. They argue that the cited documents at least fail to expect this degree of improvement in survival. To support the above arguments, Applicants submit herewith a Declaration under 37 CFR 1.132 by co-inventor Peter Stacpoole.
In the declaration (page 2), Dr. Stacpoole states the following:
Based on my review of the cited documents and as discussed in more detail below, the
documents cited in the Office Action do not disclose dichloroacetate (DCA) dosing resulting in a
hazard/odds ratio of death less than 0.2 in patients with PDHA1-related pyruvate dehydrogenase
complex deficiency (PDCD). More specifically, the cited documents do not disclose a hazard/odds ratio of death less than 0.2 as a result of administering a DCA dose to patients with PDHA1-related PDCD based on the GSTZ1 haplotype of each patient, the DCA dose being 25 mg/kg/day when the patient is identified as a fast metabolizer of DCA and the DCA dose being 12.5 mg/kg/day when the patient is identified as a slow metabolizer of DCA. In addition, prior to conducting the study disclosed in the present application, I did not expect a hazard/odds ratio of death less than 0.2. This magnitude of improvement was not expected.
The Examiner agrees that the cited documents do not specifically teach that administering DCA to patients with PDHA1-related PDCD will reduce the hazards/odds ratio of death to less than 0.2 as recited in claim 1. However the prior arts are not required to teach this for the rejection to be proper. The reduction of the hazard/odds ratio of death to less than 0.2 is a necessary property that flows from the administration of DCA to these patients based on GSTZ1 haplotype dosing. The cited references teach treating the same patients (those with PDHA1-related PDCD), the same haplotype (GSTZ1), and the same dosing (25 mg/kg/day to fast metabolizers or 12.5 mg/kg/day to slow metabolizers) so it would be expected that the hazard/odds ratio would also be the same.
In the declaration (pages 3 and 4), Dr. Stacpoole states the following regarding the Stacpoole (Pediatrics 2008) publication:
Stacpoole 2008 showed survival of 9 out of 10 patients with PDCD based on follow-up of the patients enrolled in the CLA study. While these PDCD patients on chronic DCA administration of 25 mg/kg/day had few deaths, the result was not statistically significant.
Most of the patients (7/10) in Stacpoole 2008 were female and the mean age at DCA start was 4.3 years.
As can clearly be seen, but was not known in 2008, mortality in PDCD patients stabilizes
after 4 years of age. The patients of Stacpoole 2008 were relatively older. Most of these patients
(7 of 10) started DCA treatment at 3 years and 9 months or later, and the youngest treatment
starting age was 1 year and 4 months. Based on today's knowledge, these patients were biased to
survive.
Had we attempted to assess the difference in survival in a matched similarly rigorous
manner to what has been done in the current study, there likely would have been minimal benefit
given that mortality stabilizes around the age most of the patients began taking DCA. As such,
there would have likely been minimal risk reduction (hazard / odds ratio ~1).
These teachings in the declaration have been fully considered. First of all it is relevant to note that the claims are NOT rejected over the Stacpoole (Pediatrics 2008) publication. Instead the rejections are based on the Stacpoole (Advanced Drug Delivery Reviews 2008) and Stacpoole (Mitochondrion 2018) publications. Figure 2 in Stacpoole (Pediatrics 2008) shows that 1 patient (10%) out of 10 being treated with DCA died during follow-up over a period of 11 years.
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The instant specification teaches the following with respect to mortality in patients with PDCD:
[0004] PDCD is associated with high morbidity and mortality. Two natural history studies have been conducted evaluating the natural course of the disease. One study [DeBrosse, et al 2012] was conducted at a single site in a cohort of 59 patients. In-depth chart reviews and family interviews were conducted to establish the most common symptomology, different medical interventions and whether the patient remained alive or had passed away. 23 of the 59 patients in the study (39%) had passed away at the time of the publication and at least 2 additional patients passed away following a later review. Another study [Patel, et al 2012] conducted a global meta-analysis using data on published data that included subjects, primarily in case report form, with PDCD. This review included 371 patients, of which 294 reported survival outcomes at the time of publication. Of the 294, 108 patients (37%) had died. Both studies reported higher rates of mortality at younger ages. Patients that survived past one year of life had a higher likelihood of surviving in early childhood. If patients survived past 4 years of age, they had a much higher likelihood of surviving into adolescence. Despite improved lifespan, most patients had very severe mental and physical deficits that often made them completely dependent on care.
Based on the teachings in the specification, the mortality rate of PDCD patients not treated with DCA is 37-39%. Based on the teachings in Stacpoole (Pediatrics 2008) reference, the mortality rate of PDCD patients treated with DCA is only 10%. Thus Stacpoole (Pediatrics 2008) clearly shows that the PDCD patients that were treated with DCA had better survival rates than PDCD patients that were not treated with DCA. With respect to arguments that the mortality rates in Stacpoole (Pediatrics 2008) are biased with respect to the age and gender of the patients, it is noted that the claims are not directed to any particular gender or age group. Thus this argument is not commensurate in scope with the claimed invention.
The response states that even the documents cited in the rejection (Berendzen (Mitochondrion 2006), Stacpoole (Advanced Drug Delivery Reviews 2008), and Stacpoole (Mitochondrion 2018)) fail to teach a hazard/odds ratio of death less than 0.20.
They argue that Berendzen indicates that DCA has not been associated with improvement in survival:
"However, although DCA has been demonstrated to significantly improve
hyperlactatemia and lactic acidosis in numerous open label studies and in four
randomized, placebo-controlled trials in acquired (Stacpoole et al., 1992, Agbenyega et
al., 2003) and congenital (Duncan et al., 2004; Stacpoole et al., 2006) forms of lactic
acidosis, this effect has not been associated with improvement in important clinical outcome measures, including survival." Berendzen at 128 (emphasis added); and see
id. at 132
This argument has been fully considered. The Examiner agrees that Berendzen does not teach that DCA improves survival in patients with PDCD. However, Berendzen is not being relied upon to teach this in the 103 rejections.
They argue that Stacpoole (Advanced Drug Delivery Reviews, 2008) also fails to expect a hazard/odds ratio of death less than 0.20. It discloses a three-year survival of 79% (36 patients), which does not appear to be an improvement to standard of care and does not provide a comparison to well- matched, untreated controls, which is necessary to assess a hazard ratio. It therefore fails to expect a hazard/odds ratio of death less than 0.20.
This argument has been fully considered. The instant specification teaches the following with respect to mortality in patients with PDCD:
[0004] PDCD is associated with high morbidity and mortality. Two natural history studies have been conducted evaluating the natural course of the disease. One study [DeBrosse, et al 2012] was conducted at a single site in a cohort of 59 patients. In-depth chart reviews and family interviews were conducted to establish the most common symptomology, different medical interventions and whether the patient remained alive or had passed away. 23 of the 59 patients in the study (39%) had passed away at the time of the publication and at least 2 additional patients passed away following a later review. Another study [Patel, et al 2012] conducted a global meta-analysis using data on published data that included subjects, primarily in case report form, with PDCD. This review included 371 patients, of which 294 reported survival outcomes at the time of publication. Of the 294, 108 patients (37%) had died. Both studies reported higher rates of mortality at younger ages. Patients that survived past one year of life had a higher likelihood of surviving in early childhood. If patients survived past 4 years of age, they had a much higher likelihood of surviving into adolescence. Despite improved lifespan, most patients had very severe mental and physical deficits that often made them completely dependent on care.
Based on the teachings in the specification, the mortality rate of PDCD patients not treated with DCA is 37-39%. Based on the teachings in the Stacpoole (Advanced Drug Delivery Reviews, 2008) reference, the mortality rate of PDCD patients treated with DCA is only 21%. Thus Stacpoole (Advanced Drug Delivery Reviews, 2008) clearly shows that the PDCD patients that were treated with DCA had better survival rates than PDCD patients that were not treated with DCA.
They argue that Stacpoole (Mitochondrion 2018) also fails to expect a hazard/odds ratio of death less than 0.20. This reference primarily refers to Stacpoole (Pediatrics 2008) and personal experience primarily related to treating patients in that cohort. They argue that Stacpoole (Mitochondrion 2018) only indicates that DCA might improve survival and therefore fails to expect a hazard/odds ratio of death less than 0.20.
This argument has been fully considered. Stacpoole (Mitochondrion 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).
Thus at least two of the references being relied upon to reject the claims and one reference not being relied upon to reject the claims teach or suggest that administering DCA to a patient with PDCD will reduce mortality/increase survival. The references do not specifically teach that the method will reduce the hazards/odds ratio of death to less than 0.2, however the prior arts are not required to teach this for the rejection to be proper. The reduction of the hazard/odds ratio of death to less than 0.2 is a necessary property that flows from the administration of DCA to these patients based on GSTZ1 haplotype dosing. The cited references teach treating the same patients (those with PDHA1-related PDCD), the same haplotype (GSTZ1), and the same dosing (25 mg/kg/day to fast metabolizers or 12.5 mg/kg/day to slow metabolizers) so it would be expected that the hazard/odds ratio would also be the same.
The Applicants argue that the observed degree of reduction in mortality would have been nonobvious. They argue that the magnitude of improvement was not expected. They argue that there would have been no reasonable expectation of success in reducing the hazard/odds ratio of death to less than 0.20.
These arguments have been fully considered but are not persuasive. Presence of a property not possessed by the prior art is evidence of non-obviousness. However the Applicants have not met the burden of establishing that the claimed properties ((i) the ability to reduce mortality and (ii) the ability to reduce the hazard/odds ratio of death to less than 0.2) was not possessed by the prior art. The reduction of mortality and the reduction of the hazard/odds ratio of death to less than 0.2 is a necessary property that flows from the administration. The references teach the same patients, the same haplotype, and the same dosing so it would be expected that the reduction of mortality and the reduction of the hazard/odds ratio would also be the same. The Applicants have not provided any reasons as to why the prior art methods which treat the same patients, the same haplotype, and the same dosing would not be able to achieve (i) the ability to reduce mortality and (ii) the ability to reduce the hazard/odds ratio of death to less than 0.2. Applicants are reminded that obviousness does not require absolute predictability, but at least some degree of predictability is required. Based on the teachings in the prior art there was more than a reasonable expectation of success.
The Applicants argue that obviousness based on inherency is inappropriate in the present case. They argue that because the present rejection is based on picking and choosing from the disclosures of several cited documents and the cited documents fail to expect the recited degree of improvement in survival, obviousness based on inherency is inappropriate in the present case.
This argument has been fully considered but is not persuasive. A proper finding of inherency does not require that all limitations are taught in a single reference. In relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art. In the instant case this has been done since the references teach the same patients, the same haplotype, and the same dosing. Based on these similarities it would be expected that the reduction of mortality and the reduction of the hazard/odds ratio would also be the same. It appears that Applicants have done nothing more than recognize a new property of a pre-existing method of treatment.
Finally the Applicants argue that the claimed method addresses a long-felt need in that treatment of PDCD without negative side effects such as peripheral neuropathy and death. were not present in the art. See MPEP 716.04; and see Declaration under 37 CFR 1.132 of David Penake, filed May 8, 2025.
This argument has been fully considered but is not persuasive. The declaration does not establish a long felt need and failure of others. A successful showing of a long felt need should include evidence of three factors (i) the need must have been a persistent one that was recognized by those of ordinary skill in the art, (ii) the long felt need must not have been satisfied by another before the invention by the applicant, and (iii) the invention must in fact satisfy the long felt need. The declaration does not establish that the long felt need was not satisfied by another before the invention by the applicant. The invention satisfies the need by identifying if a patient is a fast or slow metabolizer of DCA based on a GSTZ1 haplotype and administering a DCA dose based on whether the patient is a fast or slow metabolizer. However since this was already being done in the prior art, the need had already been met. The declaration does not provide sufficient evidence to overcome the rejection, as it merely summarizes the state of the art. The rejections are maintained.
Additionally the Applicants traversed the rejections made under 35 USC 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). The response asserts that for the same reasons as discussed above, the claims are non-obvious over these references.
This argument has been fully considered but is not persuasive. The Applicants arguments and the declaration have been fully addressed above. The Examiners response to the arguments and the declaration, as set forth above, applies equally to the present ground of rejection.
Double Patenting
8. 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.
9. Claims 1, 6-10, and 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). 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 Stacpoole (2018) teaches that they conducted a double blind, placebo controlled, crossover trial of 24 children, aged 6 months to 17 years with genetically proven PDCD. Stacpoole teaches that patients will initially be screened for eligibility and genotyped to determine GSTZ1 haplotype status, which will stratify subjects into one of the two dose regimens. EGT carriers will receive 12.5 mg/kg/12 h DCA, which is the standard dose administered in most prior trials. EGT non-carriers will receive half that dose (page 61, col 2 Fig 3). Stacpoole further teaches that haplotype variations in GSTZ1 influence the kinetics and biotransformation of DCA, distinguishing “slow” from “fast” drug metabolizers. Fast metabolizers possess at least one wild type (EGT) GSTZ1 allele, while slow metabolizers lack this allele (page 59, col 2 to page 60 col 1). 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 Stacpoole (2018). 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 since Stacpoole teaches this dose is appropriate for EGT non-carriers which are slow metabolizers. Further one would have been motivated to treat patients of all ages, including those above the age of 0.9 years since these patients also suffer from this disease. Regarding the recitations that the method reduces the hazard/odds ratio (clms 1, 9, and 10) and reduces the likelihood of PDCD related mortality (clms 6-8), it is noted that these limitations merely recite necessary properties of the administering step.
Response To Arguments-Double Patenting
10. In the response the Applicants traversed the double patenting rejection. Initially the Applicants note that the 9,765,393 Patent and Langaee US 2013/0090382 are family members corresponding to U.S. Application No. 13/703,990. They further argue that the cited documents fail to disclose a method of reducing the likelihood of mortality in patients with PDHA1-related pyruvate dehydrogenase complex deficiency (PDCD), wherein the method reduces the hazard/odds ratio of death to less than 0.20. The cited documents at least fail to expect this degree of improvement in survival. They argue that there would have been no reasonable expectation of reducing the hazard/odds ratio of death to less than 0.20. Also, obviousness based on inherency is inappropriate in the present case at least because (1) the present rejection is based on picking and choosing from the disclosures of several cited documents; and (2) the cited documents fail to expect the recited degree of improvement in survival. Additionally, the claimed method addresses a long-felt need in that treatment of PDCD without negative side effects such as peripheral neuropathy and death were not present in the art.
These arguments have been fully considered but are not persuasive. Even without Langaee US 2013/0090382 the claims are unpatentable over the Patent. The limitations that Langaee US 2013/0090382 was being relied upon are also present in Stacpoole (Mitochondrion 42 (2018) 59-63) and therefore Langaee US 2013/0090382 is not even necessary. Further applicants arguments pertaining the extent that mortality was reduced have been fully addressed above. The response, as set forth above, applies equally to the double patenting rejections.
11. THIS ACTION IS MADE FINAL. 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 extension fee 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.
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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