DETAILED ACTION
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 .
Status of the Claims
Claims 1-2 and 4-6 are pending (claim set as filed on 08/04/2023).
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-2 and 4-5, in the reply filed on 01/09/2026 is acknowledged.
Claim 6 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Therefore, claims 1-2 and 4-5 are presented for examination.
Priority
This application is a 371 of PCT/JP2022/006200 filed on 02/16/2022, which has a foreign application to JP 2021-023574 filed on 02/17/2021.
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 08/04/2023 and 09/18/2024 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the Examiner.
Drawings
The drawings filed on 08/04/2023 have been accepted.
Claim Objection
Claim 1 is objected to because it recites the abbreviation of “Mipep” which is presumed to stand for ‘mitochondrial intermediate peptidase’ (see specification at ¶ [0020]). An abbreviation should be preceded in its first occurrence by the specific identity of the entity which said abbreviation is intended to represent. Thereafter, the use of the abbreviation in the claims will be understood.
Claim Rejections - 35 USC §103, Obviousness
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
Claims 1-2 and 4-5 are rejected under 35 U.S.C. 103 as being unpatentable over Choi (An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models, 2020) in view of Coenen (Mutation detection in four candidate genes (OXA1L, MRS2L, YME1L and MIPEP) for combined deficiencies in the oxidative phosphorylation system, 2005) - both references cited by the ISA and in the IDS filed on 08/04/2023.
Choi’s discloses that “oxidative phosphorylation (OxPhos), a process in which electrons are transported along five multimeric complexes embedded in the inner mitochondrial membrane to generate a proton gradient for ATP production” (see page 838, right col.: Introduction). Choi further relates to “high interest in the role of mitochondrial function and quality control in energy metabolism, relatively little is known about the roles of OxPhos function and mitokines in mammalian adipocytes. We, therefore, investigated whether UPRmt and mitokine production caused by lower OxPhos in adipocytes regulates systemic energy metabolism and glucose homeostasis” (see page 839, left col.).
Choi teaches generating mitokine double knockout mice where “all animal experiments used male mice and they were fed a normal chow diet (NCD) for 10 weeks or a high-fat diet … After euthanasia, liver, gastrocnemius, epididymal and inguinal adipose tissue, and brown adipose tissue (BAT) were dissected” (claim interpretation: this reads on a non-human animal or part thereof) (see page 839: Methods). Choi discloses comparison with wild-type controls and the VO2 in Crif1-depleted adipose-derived mesenchymal stem cells was lower than that in controls (see page 839, left col. 1st ¶) and “analysis revealed an apparent decrease in assembly of complexes I, III, and V in AdKO mouse adipose tissue compared with wild-type control mice” (see page 840, right col.: Results).
Choi teaches “Genetic or pharmacological inhibition of adipocyte mitochondrial OxPhos function induces the UPRmt in vitro and in vivo. Mitochondrial OxPhos deficits cause proteotoxic stress, which initiates the UPRmt to induce mitochondrial proteostasis, a highly conserved mitoprotective mechanism. Therefore, we measured expression of mitochondrial chaperones and proteases in AdKO mice and controls under both NCD- and HFD fed conditions” (see page 844, left col.). Choi teaches “Adipocyte-specific impairment of OxPhos function is associated with greater synthesis of adipo-mitokines in vivo … In particular, expression of major mitokines, such as GDF15 and FGF21, was much higher in the adipose tissue of AdKO mice compared with control mice” (see page 845, bridging ¶).
Regarding claims 4-5 pertaining to the mitokines’ therapeutic effects, Choi teaches that the “data suggest that adipocyte-specific impairment of OxPhos improves glucose metabolism and protects against diet-induced obesity and insulin resistance in the context of HFD feeding” (see page 843, left col.). Choi teaches “GDF15 and FGF21 attenuates progression of diet-induced obesity in AdKO … These findings suggest that mitokines regulate body weight and alleviate diet induced obesity in AdKO mice, and may therefore be responsible for the protective effects of adipocyte specific disruption of OxPhos” (see page 847, left col.). “Paradoxically, accumulating evidence also suggests that mitochondrial stress or OxPhos dysfunction-induced UPRmt, which is evolutionarily conserved from worms to mammals, has beneficial effects on whole-body metabolism … also a potential therapeutic modality for metabolic diseases … obesity, hepatic and adipose inflammation” (see page 849: Discussion). Choi also teaches blood samples were collected from the hearts of mice under general anesthesia where the supernatant was used for insulin assay; GDF15 and FGF21 (see page 839, right col., Serum measurements).
However, Choi does not teach: a totally or partially lost function of a MIPEP gene.
Coenen discloses “five complexes embedded in the mitochondrial inner membrane, together constituting the oxidative phosphorylation (OXPHOS) system, comprise the final steps in cellular energy production … Numerous mutations have been described in nuclear genes that are involved in the functioning of a single complex of the OXPHOS system. However, little attention has been paid to patients with a deficiency of more than one complex of this particular system. In this study we have investigated four nuclear genes (OXA1L, MRS2L, YME1L and MIPEP) that might be involved in the pathology of combined enzymatic deficiencies of the OXPHOS system. Based on the results of yeast knockouts of these four proteins” (see abstract). Coenen further teaches mitochondrial intermediate peptidase (MIPEP) “is involved in the processing of nuclear-encoded subunits of the OXPHOS system. The protein cleaves octapeptides from the precursor subunits of the OXPHOS system, resulting in mature subunits. Disruption of this gene in yeast leads to a severe defect in complex III and IV of the OXPHOS system” (see pages 1092-1093, bridging ¶).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to envisage “a totally or partially lost function of a MIPEP gene” following the guidance of the cited references by Choi and Coenen. The ordinary artisan would have been motivated to do so is because Choi first suggests that “impairment of OxPhos function is associated with greater synthesis of adipo-mitokines in vivo … In particular, expression of major mitokines, such as GDF15 and FGF21” (see Choi at page 845, bridging ¶) which thereby provides beneficial therapeutic effects. Arriving at the disclosure of Coenen which discloses investigating four nuclear genes (OXA1L, MRS2L, YME1L, and MIPEP) that might be involved in the pathology of combined enzymatic deficiencies of the OXPHOS system. Based on the results of yeast knockouts of these four proteins” (see Coenen’s abstract). Thus, an ordinary artisan would have reasonably envisaged the knockout of the MIPEP gene (as part of the OxPhos system) from the small genus disclosed by Coenen for the disclosure of Choi in generating the expression of therapeutic mitokines such as GDF15 and FGF21. The ordinary artisan would have had a reasonable expectation of success because both references are directed to deficiencies in the mitochondrial OxPhos system.
Conclusion
No claims were allowed.
Correspondence Information
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653