Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
Status of claims
The amendment filed on March 27, 2026 is acknowledged. Claims 1-15, 18, and 25 have been canceled. Claims 16-17, 19-24, and 26-32 are under examination in the instant office action.
Applicants' arguments, filed on March 27, 2026, have been fully considered but they are not found to be persuasive or moot in view of new ground rejection necessitated by the amendments (newly added limitation in claim 16). Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Duplicate Claims, Warning
Applicant is advised that should claim 26 as amended be found allowable, claim 27 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 16-17, 19-24, and 26-32 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0003721 (hereafter, DAVIS) in view of Schapira (J. Inherit, Metab. Dis. 25: 207-214, 2002) and Piekutowska-Abramczuk et al. (The American Journal of Human Genetics, volume 102, Issue 3, p460-467, March 01, 2018).
DAVIS teaches a method for treating a patient suffering from a disorder characterized by dysfunction of neuronal mitochondrial mitostasis or dysfunction of ATP generation (mitochondrial disease), comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound includes alverine citrate (abstract and claims 13-15). DAVIS further teaches MnMs protect mitochondria in primary neurons from Aβ(1-42) toxicity, glutamate toxicity, increased oxidative stress and the toxic cellular environment associated with Alzheimer's disease (abstract). DAVIS further teaches that the function of the electron transport chain in mitochondria (mitochondrial respiratory chain) is reduced in neurodegenerative disorders leading to reduced synthesis of ATP and the number of mitochondria per neuron is reduced due to a defect in the biogenesis of mitochondria in the disease and/or due to increased turnover ([0006]).
DAVIS discloses that mitochondrial fragmentation caused by treatment with peroxide (PO) and glutamate was fully protected by alverine and alverine significantly increased ATP production of mitochondria in primary neurons ([0151], [0152] and Fig. 6).
Also, DAVIS teaches that a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof can be administered orally in oral unit dosage forms such as tablets and capsules ([0090]-[0091] and [0065]).
In addition, DAVIS teaches that the dosage form may contain from about 10 mg to about 100 mg of the compound or a pharmaceutically acceptable salt thereof and can be administered once a day or twice per day ([0065]).
DAVIS does not specifically disclose treating a primary mitochondrial disease (PMD) which is a mitochondrial respiratory chain disease and is associated with mitochondrial complex I deficiency as recited in amended claim 16. Also, DAVIS does not specifically teach that the disease has a gene defect in NDUFS8 and is Leigh syndrome.
Schapira teaches that mitochondria are ubiquitous organelles in mammalian systems responsible for the production of ATP by oxidative phosphorylation (p208, para 1). Schapira further teaches that primary respiratory chain defects are caused by mutations in genes encoding subunit of the respiratory chain, which include mutations of mtDNA as well as of nuclear DNA genes encoding respiratory chain subunits (p208, para 4). Schapira further teaches that secondary respiratory chain defects may encompass all the etiologies other than the primary gene mutations of respiratory chain subunits (p211, para 4). Also, Schapira teaches that while these various mitochondrial disorders may have different underlying etiologies, they have defective oxidative phosphorylation as a common pathway in their pathogenesis and thus treatments designed to improve respiratory chain function may ameliorate the progression of these disorders as evidenced by Schapira (Summary).
In addition, it was known in the art that respiratory chain complex I deficiency is the most frequently identified biochemical defect in childhood mitochondrial diseases and clinical symptoms range from fatal infantile lactic acidosis to Leigh syndrome and other encephalomyopathies or cardiomyopathies as evidenced by Piekutowska-Abramczuk et al. (abstract). Piekutowska-Abramczuk et al. teach NDUFB8 as a relevant gene in childhood-onset mitochondrial disease and as an essential component for the stability and activity of complex I (abstract and p466, col 1 para 2). Piekutowska-Abramczuk et al. further teach that respiratory chain complex I (CI; NADH:ubiquinone oxidoreductase), one of the largest membrane-bound protein complexes in the human cell, is essential for oxidative energy metabolism as it powers ATP synthesis by using the reducing potential of NADH to proton translocation across the inner mitochondrial membrane (p460, col 1, para 1). Piekutowska-Abramczuk et al. further teach that mammalian complex I is composed of 44 different subunits including 14 highly conserved (from bacteria to humans) core subunits and their 9 cofactors (a flavin mononucleotide [FMN] and eight iron-sulfur [Fe-S] clusters) that house the catalytic machinery, wherein seven subunits (encoded by NDUFS1 [MIM: 157655], NDUFS2 [MIM: 602985], NDUFS3 [MIM: 603846], NDUFS7 [MIM: 601825], NDUFS8 [MIM: 602141], NDUFV1 [MIM: 161015], and NDUFV2 [MIM: 600532]) are hydrophilic proteins encoded by nuclear genes while the remaining (encoded by MT-ND1 [MIM: 516000], MT-ND2 [MIM: 516001], MT-ND3 [MIM: 516002], MT-ND4 [MIM: 516003], MT-ND4L [MIM: 516004], MT-ND5 [MIM: 516005], and MT-ND6 [MIM: 516006]) are hydrophobic membrane-bound proteins, encoded by the mitochondrial genome (p460, col 1, para 1). Thus, one of ordinary skill in the art would have recognized that Leigh syndrome is a disorder associated with mitochondrial chain complex I deficiency and a defect in NDUFB8 is one of causative gene defects in mitochondrial chain complex I deficiency, which is associated with reduced ATP synthesis and mitochondrial dysfunction.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use alverine citrate for treating a primary mitochondrial disease associated with mitochondrial complex I deficiency such as Leigh syndrome, which may comprise a defect in genes such as NDUFB8 because of the following reasons. DAVIS teaches and suggests the use of alverine citrate for treating a disorder characterized by mitochondrial dysfunction and dysfunction of ATP generation and specifically discloses that alverine citrate increases ATP production of mitochondria. Also, both primary and secondary chain defects share defective oxidative phosphorylation as a common pathway in their pathogenesis, which necessarily results in decreased ATP production due to mitochondria respiratory chain dysfunction, and thus similar treatments designed to improve respiratory chain function including increasing ATP production may ameliorate the progression of these disorders as evidenced by Schapira. In addition, the skilled artisan would have recognized a primary mitochondrial respiratory chain disease such as Leigh syndrome as a disorder associated with reduced ATP synthesis due to mitochondrial chain complex I deficiency and a defect in NDUFB8 as evidenced by Piekutowska-Abramczuk et al. Accordingly, the skilled artisan would have been motivated to use alverine citrate for treating the primary mitochondrial respiratory chain disease including Leigh syndrome on the reasonable expectation that alverine citrate, which is a treatment to improve respiratory chain function, i.e., ATP production, would be useful for ameliorating the progression of the primary mitochondrial respiratory chain disease, which has the same defective oxidative phosphorylation and reduced ATP production as the mitochondrial diseases disclosed in Davis.
As to the amount of alverine recited in claim 32, DAVIS teaches the range overlapping those claimed. Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the amount of alverine citrate based on the range disclosed in DAVIS. In the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). See MPEP 2144.05 Obviousness of Ranges. In addition, it is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 USPQ 33; In re Russell, 169 USPQ 426. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”)
As to claims 26-27, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use alverine citrate in combination with other treatment for the same disease or another compound for treating the same disease with a reasonable expectation of success. According to M.P.E.P. § 2144.06, “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). In this case, one would be motivated to use alverine citrate in combination with other treatment for the same disease or another compound for treating the same disease based on their independent efficacy in treating the same disease (i.e., disease associated with mitochondrial dysfunction). One would have a reasonable expectation of success, as noted above, that two independently successful treatments would be similarly successful when combined.
Response to Applicant’s arguments
Responses are limited to Applicants' arguments relevant to either reiterated or newly applied rejections.
Applicant argued that Davis does not address mitochondrial dysfunction as a primary cause of disease, let alone teach or suggest that genetic mitochondrial mutations may be causative of neurological or psychiatric diseases. Also, Applicant dose not teach or suggest that any of the protective compound operate by compensating for genetic mutations in a gene encoding one of the 44 different subunits of mitochondrial complex I, let alone NDUFS8. Also, Applicant argued that Piekutowska-Abramczuk et al. only describe genetic mutations that directly cause mitochondrial dysfunction, which directly leads to disease development (Leigh syndrome) and in Leigh syndrome, mitochondrial dysfunction is the primary etiological cause. In addition, Applicant argued that given the fundamental differences between PMD and SMD as taught by Niyazov, the ordinary skilled artisan would not have been motivated to combine Davis and Piekutowska-Abramczuk et al. Finally, Applicant argued because the amended claim 16 recites a method of treating a PMD, the cited prior art references do not teach or reasonably suggest claimed method.
In response, the Examiner respectfully submits that the above rejection is based on a combination of references, not on Davis or Piekutowska-Abramczuk et al. taken in a vacuum. As such, Applicants' arguments pertaining to those references are not persuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In this case, DAVIS specifically teaches and suggest the use of alverine citrate for treating a patient suffering from a disorder characterized by dysfunction of neuronal mitochondrial mitostasis or dysfunction of ATP generation (mitochondrial disease) (see abstract and claims 13-15). DAVIS further teaches that the function of the electron transport chain in mitochondria (mitochondrial respiratory chain) is reduced in neurodegenerative disorders leading to reduced synthesis of ATP and the number of mitochondria per neuron is reduced due to a defect in the biogenesis of mitochondria in the disease and/or due to increased turnover (see [0006]). DAVIS specifically discloses that mitochondrial fragmentation caused by treatment with peroxide (PO) and glutamate was fully protected by alverine and alverine significantly increased ATP production of mitochondria in primary neurons (see [0151], [0152] and Fig. 6). Piekutowska-Abramczuk et al. was cited for evidencing that Leigh syndrome is associated with reduced ATP synthesis and mitochondrial dysfunction due to mitochondrial chain complex I deficiency and a defect in NDUFB8 is one of causative gene defects in mitochondrial chain complex I deficiency. While both primary and secondary chain defects may have different underlying cause, they share defective oxidative phosphorylation as a common pathway in their pathogenesis, which necessarily results in decreased ATP production due to mitochondria respiratory chain dysfunction, and thus similar treatments designed to improve respiratory chain function including increasing ATP production may ameliorate the progression of these disorders as evidenced by Schapira. In addition, the skilled artisan would have recognized a primary mitochondrial respiratory chain disease such as Leigh syndrome as a disorder associated with reduced ATP synthesis due to mitochondrial chain complex I deficiency and a defect in NDUFB8 as evidenced by Piekutowska-Abramczuk et al. “[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.” See MPEP 2144.01. Accordingly, the skilled artisan would have been motivated to use alverine citrate for treating the primary mitochondrial respiratory chain disease including Leigh syndrome on the reasonable expectation that alverine citrate, which is a treatment to improve respiratory chain function, i.e., ATP production, would be useful for ameliorating the progression of the primary mitochondrial respiratory chain disease, which has the same defective oxidative phosphorylation and reduced ATP production as the mitochondrial diseases disclosed in Davis. This is further supported by Niyazov reference applicant cited. Indeed, Niyazov teaches that even in the absence of the ability to distinguish between PMD and SMD, treating SMD with standard treatments for PMD can be effective (see abstract), supporting the same treatment can be used for both PMD and SMD. Further, it should be noted that the claimed treatment is not limited to addressing the underlying cause of the mitochondrial disease, but encompasses ameliorating or reducing it symptoms such as dysfunction of ATP generation.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See MPEP 2145(X)(A) (citing In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971)). As set forth in the rejection of the claims, the combination of each teaching was properly motivated by a rationale derived independently of applicant’s disclosure.
For the foregoing reasons, Applicant’s arguments have not been found to be persuasive.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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 date of this final action.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611
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