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 29 March 2029 are acknowledged and have been entered. Claims 2, 4, 5, 8, 10, 12, 14, 16, 18-24 are amended. Claims 3, 7, 13, 17, 25 have been canceled. Claims 1, 2, 4-6, 8- 12, 14-16 and 18-24 are pending and being examined on the merits.
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.
Information Disclosure Statement
The information disclosure statement filed 03/29/2023 have been considered.
Drawings
The drawings are objected to because multiple figure numbers are on the same sheet. It would be remedial to place Figs. 10, 13A-C and 16A on a separate sheet. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the terms TOPO, AlexaFluor, Hoescht, Invitrogen, Vectashield, Leica, UC7, Phillips, Millipore Sigma, Abcam, Proteintech, Thermo Fisher, Halt, mCherry, to name a few, which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term. Please check the disclosure for other marks or names.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
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 1-2, 4-6, 8, 14-16, 18-24 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. 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. Possession of these claims requires the possession of the genus of mitofusin (Mfn) modulators and the genus of mitofusin (Mfn) modulator 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.
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.
Given the vast majority of modulators that could potentially modulate Mfn transcriptional activity, 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.
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.
Claims 1-2, 4, 14-15, and 18-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Dorn (US 20190169138 A1).
Regarding claim 1 and 4, Dorn teaches that mitofusin (Mfn) 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 (Mfn1) and/or mitofusin 2 (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].
Regarding claim 2, Dorn teaches that the small molecule Mfn regulators as described herein are allosteric agonists where they fully activate the receptor and fully stimulates mitofusin activity [0012, 0101, 0103, 0120]. Dorn teaches that the mitofusin modulating agents (e.g., mitofusin agonists) can modulate or enhance the transport ( e.g., trafficking, mobility, or movement) of mitochondria [0108].
Regarding claims 14 and 15, Dorn teaches delivering the Mfn modulators to a subject where the subject can be a human [0220].
Regarding claim 18, 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].
Regarding claim 19, Dorn teaches where the Mfn modulator is delivered to a neuron of the subject [0048, 0103].
Regarding claim 20, Dorn teaches that the mitofusin modulating agent corrects mitochondrial dysfunction and cellular dysfunction and repairs defects in neurons with mitochondrial mutations [0013].
Claims 1-2, 4-6, 8-9, and 14-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Milane (US 2020/0054718 A1).
Regarding claim 1-2, 4-6 and 8, 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].
Regarding claim 9, Milane also teaches the use of an siRNA as a Mfn-2 modulator [0021].
Regarding claims 14-15, Milane teach treating human cells [0019].
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 1-2, 4-6, 8-9, 11-12 and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Milane (US 2020/0054718 A1) in view of Kolliputi (US 20190262308 A1).
Regarding claim 1-2, 4-6 and 8, 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].
Regarding claim 9, Milane also teaches the use of an siRNA as a Mfn-2 modulator [0021].
Regarding claim 11-12, Milane does not teach there the Mfn modulator is a small molecule 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.
Regarding claims 14-15, Milane teach treating human cells [0019].
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over Milane (US 2020/0054718 A1) as applied to claim 1 and further in view of Decker (Decker et al. Biochemistry and biophysics reports 24 (2020):100824).
The teachings of Milane is discussed above as applied to claim 1 and similarly apply to claim 10.
Milane does not teach there the Mfn modulator is a polypeptide that comprises a CRISPR-Cas nuclease.
Decker teaches the use of CRISPR/Cas9 to knockdown Mfn2 [abstract; pg. 2, para 2].
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 16 and 21-24 are rejected under 35 U.S.C. 103 as being unpatentable over Milane (US 2020/0054718 A1) as applied to claim 1 and further 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).
The teachings of Milane is discussed above as applied to claim 1 and similarly apply to claims 16 and 21-24.
Milane does not teach where the subject comprises one or more mutations in vps13d, wherein 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 [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 16, it would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to use the Mfn-2 inhibitor of Milane in a subject that comprises a frameshift or missense mutation in Vps13D. 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 claim 21 and 23-24, 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 Mfn 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 Mfn expression levels in the subject, as taught by Decker, and treat the subjects with the Mfn 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 claim 22, Milane teach treating human cells [0019].
Conclusion
No claims allowed.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637