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 Application/Amendments/Claims
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office Action.
Applicant’s response filed on 12/29/2025 has been considered.
Claim 15 has been canceled. Claims 14, 16, 17-23 and 26 have been amended. Claims 14 and 16-26 are the subject of the present Official action.
Priority
Applicant’s claim for the benefit of a prior-filed application EP20305620.5 and 371 of PCT/EP2021/065430 published 6/9/2020 and 6/9/2021, respectively, under 35 U.S.C 119(e) or under 35 U.S.C 120, 121 or 365(c) is acknowledged.
Accordingly, the effective priority date of the instant application is granted as 6/9/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 9/3/2025 and 3/18/2026 were received. The submissions were in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements were considered by the examiner.
Withdrawn Rejections
The objection of claim 14 has been withdrawn in light of applicants claim amendments which define the acronym NRF2 as nuclear factor erythroid-related factor 2.
The under 35 U.S.C. 102(a)(1) and 102(a)(2) rejection of claims 14 and 24-26 has been withdrawn in light of the amendments moving the limitations of claim 15 into independent claim 14.
Maintained Rejections in response to Applicants’ arguments or amendments
Claim Interpretation
A transgene encoding human NRF2 or a variant thereof will be interpreted broadly to read on any transgene that shares any sequence homology to human NRF2.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claims 14, 18-21 and 23-26 stand rejected under 35 U.S.C. 103 as being unpatentable over Vignier et al. US 2019/0350955, published 11/21/2019 (hereinafter Vignier, reference of record) in view of Cepko et al. US 2016/0279265, published 9/29/2016 (hereinafter Cepko, reference of record). This rejection is maintained with respect to the Office action mailed on 8/27/2025. A response to applicant’s traversal follows the rejection below.
Claim 14: Vignier describes a method for treating dilated cardiomyopathies comprising the administration of a therapeutically effective amount of nicotinamide riboside (Vignier, abstract). Vignier shows that the nicotinamide riboside kinase Nmrk2 gene involved in the NAD+ synthetic pathway is strongly induced in the heart of mouse models with dilated cardiomyopathy (Vignier, abstract and para 7-12). Vignier found that diet supplementation with nicotinamide riboside markedly improved cardiac functions and reduced dilated cardiomyopathies (Vignier, para 135-137). Vignier shows that nicotinamide riboside increases expression of NRF2 and is thus considered a NRF2 activator. Vignier does not describe the NRF2 activator as a nucleic acid construct comprising a transgene encoding human NRF2 or a variant thereof.
Claims 24-25: Vignier describes treating dilated cardiomyopathies which are genetically induced by mutations to the dystrophin gene including Emery Dreiffus Muscular Dystrophy and Duchenne and Becker Muscular Dystrophy among others (Vignier, claim 9).
Claims 26: Vignier describes the administration of nicotinamide riboside (NRF2 activator) and pharmaceutically acceptable excipients (Vignier, claim 26).
Claim 18-21: Cepko describes packaging the nucleic acid constructs into adeno-associated viral (AAV) particles including AAV capsid proteins derived from AAV8 serotypes (Cepko, para 87). Cepko describes using 5’ and 3’ ITRs from AAV2 serotypes (Cepko, para 87).
Claim 23: Cepko describes intravenous administration (Cepko, para 94).
It would have been prima facie obvious to one of ordinary skill in the art to administer the AAV vector encoding human NRF2 as described by Cepko rather than administering a NRF2 activator like nicotinamide riboside as a treatment for dilated cardiomyopathies as described by Vignier since vector expression would allow for direct and sustained expression of NRF2 in target cells. It would have been a matter of combining prior art elements according to known methods to yield predictable results since Cepko shows that sustained human NRF2 expression can be achieved using AAV vectors. One would have been motivated to make this combination since AAV vectors can be designed to provide continuous endogenous production of NRF2 in target cells rather than intermittently administering NRF2 activator. One would have a reasonable expectation of success given that using gene therapy approaches for NRF2 expression are proven in the art as shown by Cepko and a clear mechanism exists showing how these approaches can be applied towards treating cardiomyopathies as described by Vignier. Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered claims 14, 18-21 and 23-26 to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing that Vignier only discloses the use of NR as a dietary supplement and does not disclose the role of NRF2 in dilated cardiomyopathy. Applicant argues that the overexpression or modulation of NRF2 does not necessarily treat cardiac deterioration, and argues that the cited art does not discuss the role of NRF2 in treating cardiac deterioration.
This argument has been fully considered, but is not found persuasive. Although it is acknowledged that Vignier only teaches the administration of a therapeutically effective amount of nicotinamide riboside, Vignier does describe treating dilated cardiomyopathies (Vignier, abstract). Vignier found that diet supplementation with nicotinamide riboside markedly improved cardiac functions and reduced dilated cardiomyopathies and further shows that nicotinamide riboside increases expression of NRF2 (Vignier, para 135-137). Thus, Vignier establishes a clear motivation for increasing expression of NRF2 as a treatment method for dilated cardiomyopathies.
Applicant further argues against Cepko, stating that no clear link exists between NRF2 expression and treating dilated cardiomyopathy. Applicant argues that there lacks any motivation to combine references and achieve the same therapeutic effect as claimed with a reasonable expectation of success.
This argument has been fully considered, but is not found persuasive since Cepko describes the viral expression of human NRF2 (Cepko, abstract and para 22, 29, 135, 147). Vignier outlines the treatment methodology between NRF2 expression and treating dilated cardiomyopathy. Thus, it would have been prima facie obvious to one of ordinary skill in the art to administer the AAV vector encoding human NRF2 as described by Cepko as a treatment for dilated cardiomyopathies to achieve more sustained and direct expression of NRF2 in target cells. One would have a reasonable expectation of success given that using gene therapy approaches for NRF2 expression are proven in the art as shown by Cepko and a clear mechanism exists showing how these approaches can be applied towards treating cardiomyopathies as described by Vignier.
Claims 16-17 and 22 stand rejected under 35 U.S.C. 103 as being unpatentable over Vignier (supra) and Cepko (supra) as applied to claims 14, 18-21 and 23-26 above in further view of Pacak et al. "Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice." Genetic vaccines and therapy 6.1 (2008): 13 (hereinafter Pacak, reference of record). This rejection is maintained with respect to the Office action mailed on 8/27/2025. A response to applicant’s traversal follows the rejection below.
A description of Vignier and Cepko can be found above. Neither Vignier nor Cepko describe the use of a human cardiac troponin T promoter (TNNT2) or the use of an AAV particle comprising an AAV capsid protein derived from an AAV-9 serotype.
Claims 16-17: Pacak describes the use of tissue specific promoters for improved specificity of transgene expression following intra-vascular gene delivery in neonatal mice (Pacak, abstract). Pacak demonstrates that human cardiac troponin T promoters drive targeted transgene expression in heart muscles (Pacak, pg 2 and Fig 1A).
Claim 22: Cepko describes the use of AAV particle comprising an AAV capsid protein derived from an AAV-9 serotype to drive targeted transgene expression in heart muscles (Pacak, pg 2 first para and Fig 1).
It would have been prima facie obvious to one of ordinary skill in the art to use the human cardiac troponin T promoters and AAV particles comprising an AAV capsid proteins derived from an AAV-9 serotype as described by Pacak to express human NRF2 as a treatment for dilated cardiomyopathies as described by Vignier in view of Cepko. It would have been a matter of combining prior art elements according to known methods to yield predictable results since the promoter and vector serotypes used by Cepko are optimized for expression in cardiac tissue. Thus, one would have been motivated to make this combination since human cardiac troponin T promoters and AAV9 serotypes provide tissue specificity to cardiac cells, thus providing a targeted treatment for dilated cardiomyopathies. One would have a reasonable expectation of success given that the exchange of known promoters and vector serotypes for gene therapy constructs is considered routine in the art and predictable methods exists for their modification as shown in Pacak (pg 2). Accordingly, in the absence of evidence to the contrary, one of ordinary skill in the art would have considered the claim invention to have been prima facie obvious to at the time the invention was made.
Response to Traversal
Applicant traverses the rejection by arguing since the limitations of claim 15 have been move into independent claim 14, the rejection is now moot.
This argument has been fully considered, but is not found persuasive since claim 14 and 15 were rejected under the first 103 and incorporated into the instant rejection in further view of Pacak to consider the limitations of claims 16-17 and 22.
Conclusion
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 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. ALEXANDER NICOL whose telephone number is (571)272-6383. The examiner can normally be reached on M-F 8-5 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria Leavitt can be reached on (571)272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Alexander Nicol
Patent Examiner
Art Unit 1633
/ALEXANDER W NICOL/Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634
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