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 .
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
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 3-11, 14-17, 19, 23-25, and 28-32 remain and claims 47-55 and 66 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.
The broadest reasonable interpretation (BRI) of the claimed method is administering a pharmaceutically composition comprising an antisense oligomer selected from SEQ ID NOs: 36, 92-96, or 166-169 to a subject having a disease or condition associated with OPA1 deficiency, wherein the deficient amount is associated with haploinsufficiency of an OPA1 gene, and the subject has an allele encoding a functional OPA1 protein and a second allele from which the OPA1 protein is not produced or produced at reduced level or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein.
The antisense oligomers target a OPA1 pre-mRNA and promote exclusion of a non-sense mediated RNA decaying inducing exon (NMD exon) from the OPA1 pre- mRNA. Examples 19 and 20 of the specification show that the claimed antisense oligomer (ASO-14) upregulates OPA1 haploinsufficiency in HEK293 cell line and cells with OPA1 mutation from patients diagnosed with Autosomal domain optic atrophy (ADOA). Page 152 summarizes the data from the examples and the data suggest that the ASO-14 mediated increased OPA1 protein expression in disease modifying in ADOA in a mutation-independent manner.
The claimed method broadly reads on treating a disease or condition associated with a deficient amount or activity of an OPA1 protein in a subject, wherein the deficient amount is associated with haploinsufficiency of an OPA1 gene, and the subject has an allele encoding a functional OPA1 protein and a second allele from which the OPA1 protein is not produced or produced at reduced level or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein.
The OPA1 gene was well known in the prior art and plays a role in the maintenance and function of mitochondria. The art indicates that various genetic disorders or conditions are associated with the OPA1 gene, including optic atrophy (ADOA) and other mitochondrial disorders. See OPA gene reviews (Genetics https://genetiics.ca, 2023, pages 1-47, retrieved on the line 4/2/25, of record). In addition, to optic atrophy, mutations in the OPA1 gene have also been linked to other neurological disorders, such as hereditary spastic paraplegia and mitochondrial encephalopathy. OPA1-related disorders are a complex group of conditions that can have a wide range of symptoms and severity. Sciezynka et al. (PLOS One, pages 1-9, 2017, of record) disclose that only a few studies have addressed the importance aspects of the fate of mutated OPA1 transcripts. The art of record indicates that ongoing research and reviews of the gene are required to further understand these disorders and develop potential treatments.
With respect to any disease or condition associated OPA1 (claim 1), the skilled artisan would possess the knowledge that there are some diseases or conditions associated OPA1 expression. However, neither the prior art nor the as-filed specification disclose that the diseases or conditions embraced by the instant claims are considered an OPA1 disease or condition that can be treated with the claimed oligomers. In addition, the specification of the instant disclosure does not describe treating these conditions or diseases with the claimed antisense oligomers. The specification discloses that OPA1 gene is associated with optic atrophy type 1; autosomal dominant optic atrophy (ADOA) (pages 109-110). The specification contemplates the claimed methods. The specification appears to disclose that the antisense oligomers used in the method promote exclusion of a non-sense mediated RNA decaying inducing exon (NMD exon) from the OPA1 pre-mRNA in a cell or increase a level of a processed mRNA that is processed from the OPA1 pre-mRNA and that lacks the NMD exon in the cell.
In view of the lack of written description in the instant specification of the disclosure, the skilled artisan would have to further experiment with any disease or condition embraced by the claimed method and determine if the disease or condition is associated with a subject having a first allele encoding a functional OPA1 and a second allele from which the OPA1 protein is not produced or produced at a reduced level, or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein. Then, determine if the claimed method would result in treating or reducing the likelihood of developing the disease or condition.
The written description requirement for the claimed genus of treating or reducing any disease or condition having an OPA1 deficiency in a subject in need thereof is not satisfied through sufficient description of a representative number of species (the disease or condition comprises autosomal optic atrophy (ADOA)). The contemplation of the method and limited description directed to one disease (optic atrophy type 1) does not represent the genus of diseases or condition. The species (optic atrophy type 1) does not adequately described or considered to be representative of the entire genus of diseases and conditions. For example, in view of the prior art, a skilled artisan would not envision any other disease or condition listed in dependent claim 19 or new claim 66 to be treatable by the claimed method without further experimentation. Sciezynka et al. disclose that there are no known effective treatments for ADOA (page 2). Therapy for each disease or condition embraced by the claimed method would have to be empirically determined. Other than ADOA-plus syndrome, there appears to be known correlation between nonsense-mediated mRNA decay-inducing exons in an OPA1 gene and the diseases or conditions set forth in instant claims. For example, a search of the prior art does not indicate that any disease or condition (e.g., brain disfunction, deafness, Charcot-Marie Tooth disease, age-related macular degeneration, Behr syndrome, Parkinson’s disease, prion disease, cognitive function decline in healthy aging, kidney disease, heart and brain ischemic damage) are associated with haploinsufficiency of an OPA1 gene and can be treated using the claimed antisense oligomer. As shown by new claim 66, there is a substantial variation within the genus of diseases and conditions embraced by the claimed method and the specification of the instant disclosure does not describe a sufficient variety of species that can be treated using the OPA1 antisense oligomers to reflect the variation within the genus. See Enzo Biochem., 323 F.3d at 966, 63 USPQ2d at 1615; Noelle V. Lederman, 355 F.3d 1348, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004)("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). See also MPEP 2163.
In view of the foregoing, it is clear that the instant specification fails to convey to the skilled artisan that the instant application has possession of the claimed genus of reducing a disease or condition in a subject having an OPA1 deficiency in need there using an antisense oligomer comprising the sequence set forth in SEQ ID NOs: 36, 92- 96, or 166-168 in the pending claims as of the effective filing date.
Response to Arguments
Applicant's arguments filed 1/23/26 have been fully considered but they are not persuasive.
Applicant argues that the amendment to the independent claim to limit the disease or condition in a subject to subject having a deficient or activity of an OPA1 protein, wherein the deficient amount of activity of an OPA1 protein is associated with haploinsufficiency of an OPA1 gene, and the subject has one allele encoding a functional OPA1 protein and a second allele from which the OPA1 protein is not produced or produced at reduced level or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein overcome the 112a rejection and the application as filed conveys with reasonable clarity that applicants were in possession of the claimed method as of the filing date of the application (See MPEP 2163.02).
Applicant’s argument is not found persuasive because contemplating or reciting the method does not provide written support because as of the filing date of the application only a limited number of diseases or disorders were associated with the claimed subject. As stated in the written description, the disorder or condition in instant claims 21 and 22 do not represent the genus of disorder or conditions embraced by the claimed genus. See MPEP 2163.03(V). A search of the prior art does not appear to disclose that a human, which would have one allele encoding a functional OPA1 protein and a second allele from which the OPA1 protein is not produced or produced at reduced level or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein would have any disease listed in new claim 66 (other than ADOA-plus syndrome). Neither the specification nor the prior art of record disclose that a subject would have any of the disorders or conditions set forth in new claim 66. The skilled artisan would have to further experiment with each disease or condition in new claim 66 to determine if the subject having these disease or condition has one allele encoding a functional OPA1 protein and a second allele from which the OPA1 protein is not produced or produced at reduced level or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein and then can be treated with the claimed method steps. The applicant is trying to pre-empt the future before it has arrived. A person would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed.
In response to applicant’s argument that the claims use antisense oligomers, which result in an increase in expression of functional OPA1 protein and the increase would treat any condition embraced by the claimed method, the argument is not found persuasive because while it is acknowledged that the claimed antisense oligomers can increase expression of a functional OPA1 protein by inhibiting expression of a nonfunctional or partially functional OPA1 protein, the skilled artisan would have to further experiment with what diseases or conditions have this issue and whether not the issue is a biomarker or an actual therapeutic target for treating these conditions or disorders. As stated above in the written description rejection, the antisense oligomers would result in treating only two diseases or conditions. One of ordinary skill in the art would not recognize what diseases or conditions are the result of the subject having one allele encoding a functional OPA1 protein and a second allele from which the OPA1 protein is not produced or produced at reduced level or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein. The two conditions described in the specification and claimed (claims 21 and 22) do not represent the genus of conditions or disorders embraced by the claimed invention. This is considered an unpredictable art, in view of the lack of disclosure in the specification and the prior art for what conditions or diseases can be treated with the antisense oligomers. See MPEP 2163(II)(A)(3)(a)(i)-(iii).
The argument (a person of skill in the art would understand, based on the disclosure of the present application and general knowledge in the art, that Applicant was in possession of the instantly claimed genus of treating "a disease or condition) is not found persuasive because other than applicant's assertion, there is no evidence of record to support applicant's assertion. “The arguments of counsel cannot take the place of evidence in the record.” See In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) (“An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness.”). The art of record appears to disclose to one of skill in the art that only claims 21 and 22 have written description and no other disease or condition embraced by the claimed method has written support. See OPA gene reviews (Genetics https://genetiics.ca, 2023, pages 1-47, retrieved on the line 4/2/25) and Sciezynka et al., both of record.
Applicant further argues that examples 19 and 20 use the antisense oligomers in claim 3 are sufficient to significantly address phenotypic deficits with mRNA and protein expression reduction associated with reduced expression of OPA1, including models of diseases associated with OPA1 haploinsufficiency.
Applicant’s arguments are not found persuasive because while it is acknowledged that the antisense oligomers can increase expression of a functional OPA1 protein by inhibiting expression of a nonfunctional or partially functional OPA1 protein, the skilled artisan would have to further experiment with what diseases or conditions have this issue and whether not the issue is a biomarker or an actual therapeutic target for treating these conditions or disorders. Even if the disease or conditions has this OPA1 haploinsufficiency deficiency, this would require a skilled artisan to establish a genotype-phenotype correlation, which would be a prerequisite for the implementation of targeted/precision medicine approaches. As stated above in the written description rejection, the antisense oligomers would result in treating only two diseases or conditions. One of ordinary skill in the art would not recognize what diseases or conditions are the result of the subject having one allele encoding a functional OPA1 protein and a second allele from which the OPA1 protein is not produced or produced at reduced level or a second allele encoding a nonfunctional OPA1 protein or a partially functional OPA1 protein The two conditions described in the specification and claimed (claims 21 and 22) do not represent the genus of conditions or disorders embraced by the claimed invention. This is considered an unpredictable art, in view of the lack of disclosure in the specification and the prior art for what conditions or diseases can be treated with the antisense oligomers. See MPEP 2163(II)(A)(3)(a)(i)-(iii).
Thus, the written description remains for the reasons of record.
.
Allowable Subject Matter
Claims 21-22 remain objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claims 27, 33-46, and 56-65 are in condition for allowance.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. 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 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.
See attached PTO-326 for disposition of claims.
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/BRIAN WHITEMAN/ Primary Examiner, Art Unit 1636