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 .
Priority
The Amendments and Remarks filed 15 April 2026 are acknowledged and have been entered. Claims 1, 4-6, 8-12, 16, and 21 are amended. Claims 3, 7, 13, 17, 23, and 25 have been canceled. Claims 1, 2, 4-6, 8- 12, 14-16 and 18-22 and 24 are pending and being examined on the merits.
Any objection or rejection not reiterated herein has been overcome by applicant’s claim amendments.
Priority
This application is a 371 PCT of US21/53116 filed 10/01/2021 which claims priority to 63/182,508 filed 04/30/2021 and 63/087,111 filed 10/02/2020.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 14-16, 18-22 and 24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. This rejection has been modified in view of applicants claim amendments. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
MPEP 2163.II.A.3.(a).i) states, “Whether the specification shows that applicant was in possession of the claimed invention is not a single, simple determination, but rather is a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention”.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).”
Claims 1 and 21 are directed to a method for treating a disease comprising administering to the subject a therapeutically effective amount of a mitofusin (Mfn) modulator that directly or indirectly selectively inhibits expression or activity of Mfn2 and act downstream of VPS13D. Possession of these claims requires the possession of the functional genus of mitofusin 2 (Mfn) modulators that are known to treat a disease associated with mitochondria dysfunction.
The current specification, as filed, discloses that “a Mfn modulator directly modulates expression or activity of a mitofusin by increasing or inhibiting expression or activity of a mitofusin’ [pg. 2, lines 4-10]. The specification also teaches examples of a modulator [pg. 2, lines 11-20; pg. 15-16]. The specification also teaches that a modulator can directly or indirectly alter Mfn transcriptional activity by interacting with another factor (e.g., protein) that modulates expression and/or the epigenetic state of a Mfn gene [paragraph bridging pages 15-16]. The specification also teaches that a Mfn modulator is a nucleic acid, polypeptide, or small
molecule; where a small molecule comprises, a proteolysis targeting chimera (PROTAC), a kinase modulator, or an E3 ubiquitin ligase modulator. The specification demonstrates that RNAi mediated inhibition of Mfn2 suppresses the abnormal mitochondria phenotype in VPS13D-mutated fibroblast [Fig. 14]. However, claim 1 is not limited to RNAi-mediated inhibition. Rather, claim 1 encompasses any Mfn modulator that directly or indirectly selectively inhibits expression or activity of Mfn2 and acts downstream of VPS13D, regardless of its structure or mechanism of inhibition.
Casals (Casals et al. 2018, Cell Chemical Biology 25, 268–278) discloses the identification of new activator of MFN1/2 expression [abstract]. Casals teach that leflunomide and teriflunomide increased MFN2 transcriptional activity and mitofusin mRNA levels in HeLa cells (pg. 270-271, bridging paragraph; Figs. S1E and S1F]. Casals teaches that leflunomide and teriflunomide induce the upregulation of mitofusins, and also mitochondrial elongation by depletion of the cellular pyrimidine pool secondary to dihydroorotate dehydrogenase inhibition [pg. 271, col. 2, para 2]. Therefore, Casals teach a small molecule modulator of Mfn that does not comprise a PROTAC, a kinase modulator, or an E3 ubiquitin ligase modulator.
Zhang (Zhang et al. Chemistry 2022, 4, 655–668) discloses a new chemical class of mitofusin activators, piperine analogs [abstract]. Therefore, not all Mfn modulators were known at the time of filing.
The claimed genus contains numerous unrelated technologies as disclosed yet the specification provides working examples only for RNA-mediated inhibition. Given the vast majority of modulators that could potentially modulate Mfn2 expression, either directly or indirectly, the specification does not disclose of provide support for the full genus of Mfn modulators.
The additional dependent claims do not further limit the genus of Mfn modulators so as to resolve the issues above, and are therefore not sufficiently described for at least the reasons above.
Response to Arguments
Applicant's arguments filed 15 April 2026 have been fully considered but they are not persuasive. Although applicant has narrowed claim 1, the claim still encompass a broad functional genus of Mfn2 modulators defined by the results achieved rather than by structural characteristics. The specification provides working examples only for RNAi-mediated inhibition of Mfn2 and does not disclose a representative number of species of common structural features sufficient to demonstrate possession of the full scope of the claimed genus of Mfn2 modulators.
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, 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 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.
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.
Claims 1, 4-6, 9-10, 14-16, 21-22 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Milane (US 2020/0054718 A1) in view of Wang (Wang et al. Current Biology 28, R66–R88, January 22, 2018) and Seong (Annals of neurology 83.6 (2018): 1075-1088, cited on the information disclosure statement) and Decker (Decker et al. Biochemistry and biophysics reports 24 (2020):100824). This is a modified rejection necessitated by applicants claim amendments.
Regarding claim 1, Milane teaches a method of treating cancer using nanoparticles that deliver an Mfn2-peptide for blocking Mfn2 (i.e, Mfn-2 modulator] [0006]. Milane teaches that cancer cell mitochondria have long been established as dysfunctional increased mtDNA mutations, increased ROS production, decreased OXPHOS, and failure to induce apoptosis [0018]. Milane teaches that transient blocking of Mfn2 (i.e., inhibiting the activity) reduces cellular energy capacity (through decreased mitochondrial fusion), decrease total protein production (by decreased mitochondrial coupling to the endoplasmic reticulum), increases the susceptibility of the cell to apoptosis activators (increased efficacy of lower dose), with minimal toxicity to normal cells (as Mfn2 blocking inhibits mitochondrial fusion not mitochondrial function) [0006]. Milane teaches administering at least one exogenous agent in a therapeutically effective dose which substantially prevents fusion of mitochondria with each other and with the endoplasmic reticulum [claim 1].
Milane does not teach wherein the subject comprises one or more mutations in vps13d and the Mfn modulator and acts downstream of vacuolar protein sorting 13 d (vps13d). Milane does not teach where the one or more mutations comprise a frameshift, missense, or partial duplication mutation. Milane does not teach a method of treating a subject having Vps13d-associated disease, the method comprising identifying the subject as having the Vps13d-associated disease by detecting in a biological sample obtained from a subject an increased level of mitofusin (Mfn) expression or activity relative to a control sample, and administering to the subject one or more Mfn modulators.
Wang teaches that mitophagy involves the selective sequestration of damaged and/or excess mitochondria in a double-membrane autophagosome, which subsequently fuses with the vacuole/lysosome for degradation [pg. R66, col. 1] and maintains mitochondrial homeostasis and cell health [abstract]. Wang teaches that the ubiquitin-binding activity of Vps13d is essential for its function in midgut mitophagy; and that Vps13d mutant cells had enlarged mitochondria and had a defect in mitochondria clearance [pg. R66, col. 2, para 2]. Wang teaches that simultaneous knockdown of the mitochondrial fusion factor Marf (the Drosophila homolog of mammalian mitofusin) rescued the defect in Vps13d mutants; therefore, the impaired mitophagy in Vps13d mutant midgut cells is caused by a block in mitochondrial fission [pg. R67, col. 1, para 1].
Seong teaches Vps13d missense and frameshift mutations (regarding claim 16) [pg. 4-5, bridging paragraph]. Seong teaches that mutations in Vps13d/VPS13D cause embryonic lethality in animals and led to severe alterations in mitochondrial morphology [pg. 7, col. 2, para 2; pg. 8]. Seong teaches that reduction of Vps13d in motoneurons led to strong impairment in the distribution of mitochondria that resembles previously described defects for mutations in mitochondrial fission/fusion machinery [pg. 9-10, bridging paragraph].
Decker teaches the use of CRISPR/Cas9 to knockdown Mfn2 and measuring Mfn2 expression in comparison to a control [abstract; pg. 2, para 2; Section 3.4; Fig. 4A].
Regarding claim 1, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to apply the mammalian Mfn2 inhibition approach taught by Milane to the Vps13d-associated disease described by Seong because Wang teaches that inhibition of mitofusin-mediated fusion, such as Mfn2, rescues mitochondria phenotype caused by Vps13d deficiency. A skilled artisan would have reasonably expected success because Wang explicitly demonstrated rescue of vps13d phenotype by suppressing mitofusin-mediated fusion, Marf was known in the art to be a homolog of mitofusin, and Milane provided practical mammalian methods for inhibiting the Mfn2 mitofusin. One of ordinary skill would be motivated to use the inhibitor in the subject for the advantage maintaining mitochondrial homeostasis and cell health in the subject.
Regarding claims 21 and 24, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention that an increased cellular level of Mfn2 in a subject can be used to identify a subject as having the Vps13d-associated disease relative to a control and that the Mfn-2 inhibitor of Milane can be used to treat such subject. One of ordinary skill would be motivated to measure Mfn2 expression levels in the subject, as taught by Decker, and treat the subjects with the Mfn2 inhibitor given Wangs teaching that knockdown of the mitochondrial fusion factor Marf (the Drosophila homolog of mammalian mitofusin) rescued the defect in Vps13d mutants.
Regarding claims 5-6 and 9, Milane also teaches the use of an siRNA as a Mfn-2 modulator [0021].
Regarding claims 14-15 and 22, Milane teach treating human cells [0019].
Regarding claims 4 and 10, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Milane by substituting the peptide inhibitor with the CRISPR-CAS nuclease of Decker. This modification would amount to a simple substitution of one known mechanism of inhibition of Mfn-2 for another.
Claims 2 and 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Milane (US 2020/0054718 A1) in view of Wang (Wang et al. Current Biology 28, R66–R88, January 22, 2018), Seong (Annals of neurology 83.6 (2018): 1075-1088, cited on the information disclosure statement) and Decker (Decker et al. Biochemistry and biophysics reports 24 (2020):100824), as applied to claims 1 and further in view of Kolliputi (US 20190262308 A1). This is a new rejection necessitated by applicants claim amendments.
The teachings of Milane, Wang, Seong, and Decker are discussed above as applied to claim 1 and similarly apply to claims 2, 11-12.
Milane, Wang, Seong, and Decker do not teach there the Mfn modulator is a small molecule that comprises a PINK modulator.
Kolliputi teaches that Alda-1 decreases levels of Mfn-2 and PINK1 [0137, claim 5].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Milane by substituting the peptide inhibitor with Alda-1. This modification would amount to a simple substitution of one known inhibitor of Mfn-2 for another.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Milane (US 2020/0054718 A1) in view of Wang (Wang et al. Current Biology 28, R66–R88, January 22, 2018), Seong (Annals of neurology 83.6 (2018): 1075-1088, cited on the information disclosure statement) and Decker (Decker et al. Biochemistry and biophysics reports 24 (2020):100824), as applied to claims 1 and 6 and further in view of Rossomando (US20130164851 A1). This is a new rejection necessitated by applicants claim amendments.
The teachings of Milane, Wang, Seong, and Decker are discussed above as applied to claims 1 and 6 and similarly apply to claim 8.
Milane, Wang, Seong, and Decker do not teach wherein the interfering nucleic acid is antisense oligonucleotide (ASO).
Rossomando teaches generating a cell line by the administration of an RNA effector molecule that inhibits expression of an endogenously expressed gene [0008] and that effector molecules such as antisense RNA, siRNA, shRNA, etc. can be used for inhibiting expression of a target RNA [0129].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Milane by substituting the siRNA inhibitor with an antisense RNA. This modification would amount to a simple substitution of one known molecule known to inhibitor expression a target RNA for another; where the antisense RNA targets Mfn2.
Claims 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Milane (US 2020/0054718 A1) in view of Wang (Wang et al. Current Biology 28, R66–R88, January 22, 2018), Seong (Annals of neurology 83.6 (2018): 1075-1088, cited on the information disclosure statement) and Decker (Decker et al. Biochemistry and biophysics reports 24 (2020):100824), as applied to claims 1 and further in view of Dorn (US 20190169138 A1). This is a new rejection necessitated by applicants claim amendments.
The teachings of Milane, Wang, Seong, and Decker are discussed above as applied to claim 1 and similarly apply to claims 18-20.
Milane, Wang, Seong, and Decker do not teach where the disease associated with mitochondrial dysfunction is a neurological movement disorder; delivery to a neuron of a subject, and where the therapeutically effective amount restores normal mitochondrial function in the subject.
Dorn teaches that mitofusin modulating agents are useful for treating diseases or disorders associated with a mitochondria-associated disease, disorder, or condition such as diseases or disorders associated with mitofusin 1 and/or Mfn2, or mitochondrial dysfunction [abstract]. Dorn teaches a method that comprises administering to a subject a therapeutically effective amount of a composition comprising one or more of a mitofusin modulating agent or a pharmaceutically acceptable salt thereof, wherein the mitofusin modulating agent is a mitofusin agonist or the mitofusin modulating agent regulates mitochondrial fusion [0006]. Dorn teaches the mitochondria-associated disease, disorder, or condition is selected from one or more of the group consisting of: a chronic neurodegenerative condition wherein mitochondrial fusion, fitness, or trafficking are impaired [0009]. Dorn teaches where the Mfn modulator is delivered to a neuron of the subject [0048, 0103]. Dorn teaches that the mitofusin modulating agent corrects mitochondrial dysfunction and cellular dysfunction and repairs defects in neurons with mitochondrial mutations [0013].
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to modify the method of Milane by delivering the Mfn2 modulator to a neuron of a subject a chronic neurodegenerative condition where a therapeutically effective amount restores normal mitochondrial function in the subject. One of ordinary skill would be motivated to make the modification because Dorn teaches that Mfn2 modulators can be used to treat a chronic neurodegenerative condition where the modulator can be delivered to a neuron of a subject, and where the modulator restores mitochondria function. One of ordinary skill would have a reasonable expectation of success since Milane and Dorn both teach the use of Mfn2 modulators for therapeutic purposes.
Response to Arguments
Applicant's arguments filed 15 April 2026 have been fully considered but they are not persuasive.
Applicants argue that Milane fails to disclose experimental data, peptide sequences, or working examples demonstrating efficiency and therefore cannot support the obviousness rejection. Milane is not relied upon for demonstrating successful vps13d-associated disease. Rather, Milane is relied upon for teaching therapeutic inhibition of mammalian Mfn2. The rejection relies on the combined teachings of the references, not Milane alone. Furthermore, the absence of experimental data or peptide sequence disclosure in Milane does not negate the reference’s express teaching that Mfn2 is a therapeutic target or its disclosure of multiple approaches for inhibiting Mfn2. A reference is available for all that it reasonably teaches to one of ordinary skill in the art, including its express disclosure and the reasonable inferences therefrom.
Applicant argue that amended claim 1 incorporates limitation previously recited in claim 16. While this amendment has been fully considered, the additional limitations do not overcome the rejection because Seong expressly teaches vps13d mutations and Wang teaches rescue of the vps13d mutant phenotype through inhibition of the mitochondria mitofusin factor Marf. It would have therefore been obvious to combine the references as discussed in the rejection above.
In response to applicant's arguments against the references individually, 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).
Applicants argue that the inventors surprisingly and unexpectedly discovered that inhibition of Mfn2 downstream of vsp13d rescues mitochondria dysfunction associated with vps13d mutations. This argument is nor persuasive. Wang expressly teaches that simultaneously knockdown of Marf, the Drosophila homologue of mammalian mitofusin, rescues defected observed in vps13d mutants. Therefore, Wang teaches that very rescue phenomenon relied upon by Applicants evidence of unexpected results. Applicant’s alleged discovery therefore amounts to recognition of the biological mechanism underlying the prior-art rescue phenomenon and application of that teaching to mammalian Mfn2 therapeutics. However, discovering the scientific explanation for an otherwise obvious combination does not render the claimed invention nonobvious. Furthermore, applicant has not provided comparative evidence demonstrating that the claimed methods exhibit results that are unexpected relative to the closest prior art. Accordingly, applicant’s assertion of unexpected results is not commensurate in scope with the claims and is insufficient to outweigh the prima facia case of obviousness.
Applicants argue that Wang merely describes the discovery that vps13d plays a role in mitophagy and does not teach that treatment of the vps13d mutant phenotype through the downstream inhibition of MFN2. This argument is not persuasive as Wang teaches that inhibition of mitofusion-mediated mitochondria fusion suppresses or rescues the vps13d mutant phenotype. Wang’s teaches that reduction of Marf activity rescues the mitochondria phenotype caused by loss od vps13d. A person of ordinary skill in genetic biology would understand that suppression of a mutant phenotype thought inhibition of a second gene indicated that the second gene functions downstream of, or epistatically to, the first gene within the relevant pathway. Thus, Wang teaches the functional relationship stated in the claims.
Applicants argue that the references do not teach selective inhibition of Mfn2. This argument is not persuasive because Milane teaches the inhibition of Mfn2 using specific Mfn2 inhibitors while Wang teaches that inhibition of Marf, the Drosophila homolog of mammalian Mfn2, rescues the vpsd13d phenotype. According one of ordinary skill would be motivated to combine the references as discussed in the rejection above.
Conclusion
No claims allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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