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
Claims 16-32 are pending.
Election/Restrictions
Applicants’ election of the following species: Leigh syndrome and NDUFS8, in the reply filed on 8/29/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a))
Accordingly, claim 25 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 16-24 and 26-32 are under examination in the instant office action.
Claim Rejections - 35 USC § 112 (b)
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.
Claim 26 is 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 pre-AIA the applicant regards as the invention.
Claim 26 recites “the composition is associated with other treatment for the same disease”. However, it is unclear what this mean. Is it intended to recite “the composition is used in combination with other treatments for the same disease”? Appropriate correction is required.
The primary purpose of this requirement of definiteness of claim language is to ensure that the scope of the claims is clear so the public is informed of the boundaries of what constitutes infringement of the patent. A secondary purpose is to provide a clear measure of what applicants regard as the invention so that it can be determined whether the claimed invention meets all the criteria for patentability and whether the specification meets the criteria of 35 U.S.C. 112, first paragraph with respect to the claimed invention.", (see MPEP § 2173).
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 16-17 and 28-31 are rejected under 35 U.S.C. 102 (a)(2) as being anticipated by US 2023/0003721 (hereafter, DAVIS).
DAVIS teaches a method for treating a patient suffering from a disorder characterized by dysfunction of neuronal mitochondrial mitostasis or dysfunction of ATP generation (a disease associated with mitochondrial dysfunction), comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, wherein the compound includes alverine citrate, wherein the disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, mood disorders, and schizophrenia (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 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]).
As such, the instant claims are anticipated by DAVIS.
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 16-24 and 26-32 are rejected under 35 U.S.C. 103 as being unpatentable over US 2023/0003721 (hereafter, DAVIS) in view of 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 (a disease associated with mitochondrial dysfunction), 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 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 that the disorder is associated with mitochondrial complex I deficiency and has a gene defect in NDUFS8. Also, it does not specifically teach that the disorder is Leigh syndrome.
However, 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 disease associated with mitochondrial complex I deficiency such as Leigh syndrome, which may comprises a defect in genes such as NDUFB8 because alverine citrate is taught to be effective for treating a disorder characterized by mitochondrial dysfunction and increasing ATP production of mitochondria as taught by DAVIS. The skilled artisan would have been motivated to do so on the reasonable expectation that alverine citrate would be useful for treating Leigh syndrome as a disorder characterized by mitochondrial dysfunction as evidenced by Piekutowska-Abramczuk et al. by improving mitochondrial function and increasing ATP production as taught by 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.
Conclusion
No claims are allowed.
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/BONG-SOOK BAEK/Primary Examiner, Art Unit 1611
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