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 4-11 are pending (claim set as filed on 05/11/2026).
Applicant’s election without traverse of Group I, product/composition claims, in the reply filed on 01/09/2026 is again acknowledged. Claim 6 stands withdrawn as being directed to the non-elected method claim.
Therefore, claims 1-2, 4-6, and newly added claims 7-11 are under 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.
Withdrawal of Rejections
The response and amendments filed on 05/11/2026 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated herein for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s response to arguments section.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Objection
Claim 9 is objected to for a minor informality because it is missing a period to conclude the sentence.
Maintained Rejections
Claim Rejections - 35 USC §103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-2, 4-5, and 7-11 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.
Examiner’s Response to Arguments
Applicant’s amendments and arguments filed on 05/11/2026 have been fully considered but they are not persuasive and deemed insufficient to overcome the prior arts of record.
In response to Applicant’s argument (addressing page 5 of the remarks) that “rather than motivating a PHOSITA to modify Choi by knocking out MIPEP instead of Crif1, Coenen suggests that MIPEP would not be a knockout target because it was not associated with deficiency in the OXPHOS system in patients”: this argument is not persuasive because it is first noted that the prior office action did not propose “knocking out MIPEP instead of Crif1” but rather to envisage “a totally or partially lost function of a MIPEP gene” following the guidance of the cited references by Choi and Coenen. As Applicant noted, Coenen explicitly states that “MIPEP clearly have a role in the functioning of more than one complex of the OXPHOS system” (see Coenen at page 1095, last ¶) and Coenen teaches the knockout of four nuclear genes that includes the MIPEP gene. Furthermore, the passage by Coenen alludes to human patients whereas the primary reference of Choi already addressed the claimed limitation of a non-human animal (e.g., mice). The determination of obviousness is not based upon a rigid application of teaching-suggestion-motivation (TSM) rationale explicit from the prior arts but rather whether one of ordinary skill in the art would find the claimed invention prima facie obvious after a fair reading of the cited prior arts. In other words, the MPEP 2141 states that “Prior art is not limited just to the references being applied, but includes the understanding of one of ordinary skill in the art”. Therefore, the “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.
In response to Applicant’s argument (addressing page 5 of the remarks) that there is no reasonable expectation of success as Coenen discloses a large number of genes involved in the whole process of OXPHOS system: this argument is not persuasive because both of the references are directed to deficiencies in the mitochondrial OxPhos system. The MPEP 2143.02(I) states that “Conclusive proof of efficacy is not required to show a reasonable expectation of success … reasoning that the expectation of success need only be reasonable, not absolute”. The secondary reference of Coenen is merely indicating that other genes may be involved but Coenen investigates and narrows down to four particular nuclear genes of interest (OXA1L, MRS2L, YME1L, and MIPEP) (see Coenen’s title). Said differently, it is within the purview of the ordinary artisan to knockout said genes of interest to affect the OxPhos system to upregulate mitokine production for beneficial therapeutic purposes.
Conclusion
No claims were allowed.
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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NGHI V NGUYEN whose telephone number is (571)270-3055. The examiner can normally be reached Mon-Fri: 9 - 3 pm (EST).
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653
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