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 Application
Claims 1-17, 48, and 56 are pending.
Receipt and consideration of Applicants' amended claim set and remarks/arguments filed on 12/08/2025 are acknowledged. Claims 17, 48, and 56 remain withdrawn, as being drawn to an unelected invention or specie. Claims 1, 14 and 22 are amended and new claim 36 is added. Claims under consideration in the instant office action are claims 1-16.
Applicants' arguments, filed 12/08/2025, have been fully considered but they are not deemed to be persuasive. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. 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 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.
Claims 1 and 3-16 are rejected under 35 U.S.C. 103 as being unpatentable over Draper et al. (US 9,662,314, as disclosed in IDS) in view of Ekstrom et al. (Autism Spectrum Conditions in Myotonic Dystrophy Type 1: A Study on 57 Individuals With Congenital and Childhood Forms, American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 2008, 147B, pp. 918-926, as disclosed in IDS) and Bonora et al. (Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients, EMBO Molecular Medicine, 2014, 6(6), pp. 795-809).
Draper et al. teaches “methods of upregulating hnRNP L and hnRNP L targets by administering a therapeutically effective amount of an isoprenoid antibiotic.” (see abstract). Draper et al. teaches that “Proteome analysis has demonstrated that ascochlorin treatment of human osteosarcoma cells (U2OS) results in a ≥10 fold increase in the levels of three proteins, including the splicing factor hnRNP L (most up-regulated protein, 12x), as well as BINI (third most up-regulated protein, 10x).” (col. 6, lines 3-7). Draper et al. thus teaches “ascochlorin and structurally related compounds hold promise as potential therapeutics for the treatment of muscle degeneration/wasting linked to muscular dystrophy, myopathy, and aging. This effect might be mediated by an increase in the levels of the RNA binding protein hnRNP L and/or hnRNP L targets (some of them already associated with muscle disease, e.g., BINI), with or without effect on mRNA splicing.” (col. 16, lines 31-38). Draper et al. teaches the treatment of myotonic dystrophies by administering an isoprenoid antibiotic (claims 1, 3).
Draper et al. does not teach a method of treating a neurological disease comprising identifying the subject comprising a splicing defect in an autism spectrum disorder (ASD)-associated gene and administering a spliceopathy rescue agent such as ascochlorin.
Ekstrom et al. is drawn towards the comorbidity of ASD and myotonic dystrophy type 1 (DM1) (see abstract). Ekstrom et al. teaches that “ASD was significantly correlated with the DM1 form; the more severe the form of DM1, the higher the frequency of ASD. The frequency of ASD increased with increasing CTG repeat expansions. ASD and/or other neuropsychiatric disorders such as attention deficit hyperactivity disorder, and Tourette’s disorder were found in 54% of the total DM1 group.” (see abstract). Ekstrom et al. teaches “According to ICD-10 and DSM-IV the diagnosis of autistic disorder (AD) requires specific types of abnormalities in three key areas of functioning: reciprocal social interaction, language and communication, and restricted, repetitive and stereotyped behavior, together with evidence of delayed or deviant development in at least one of these areas before 36 months of age. The interview contains 84 questions and provides separate scores in the distinct areas, as well as early history, with specific threshold scores; 10 for reciprocal social interaction, 8 for communication for verbal individuals and 7 for non-verbal, 3 for restricted, repetitive behavior, and 1 for deviation in early
development.” (pp. 919-920, bridging paragraph).
Bonora et al. is drawn towards the presence of CADPS2 genetic variants in ASD patients (see abstract). Regarding claims 3-13, Bonora et al. teaches that “Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue- and temporal-specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent-of-origin effect.” (see abstract).
It would have been obvious to one of ordinary skill in the art to identify a patient comprising a splicing defect in an autism spectrum disorder (ASD)-associated gene, as suggested by Bonora et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since CADPS2 gene mutation may contribute to the development of ASD as taught by Bonora et al., with a reasonable expectation of success absent evidence of criticality of the particular steps.
It would have been obvious to one of ordinary skill in the art to treat a neurological disorder comprising administering a spliceopathy rescue agent such as ascochlorin, as suggested by Ekstrom et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since ascochlorin is an effective spliceopathy rescue agent of hnRNP L targets for patients with myotonic dystrophies as taught by Draper et al., which is a comorbidity of ASD as taught by Ekstrom et al., with a reasonable expectation of success absent evidence of criticality of the particular steps.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Draper et al. (US 9,662,314, as disclosed in IDS), Ekstrom et al. (Autism Spectrum Conditions in Myotonic Dystrophy Type 1: A Study on 57 Individuals With Congenital and Childhood Forms, American Journal of Medical Genetics Part B (Neuropsychiatric Genetics), 2008, 147B, pp. 918-926, as disclosed in IDS), and Bonora et al. (Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients, EMBO Molecular Medicine, 2014, 6(6), pp. 795-809) as applied to claims 1 and 3-16 above, and further in view of Sarajee et al. (Association of INPP1, PIK3CG, and TSC2 gene variants with autistic disorder: implications for phosphatidylinositol signalling in autism, J. Med. Genet., 2003, 40, pp. 1-5).
The teachings of Draper et al., Ekstrom et al., and Bonora et al. are presented above.
Draper et al., Ekstrom et al., and Bonora et al do not teach wherein said subject is from a cohort with neurofibromatosis comprising a splicing defect in a NF I gene or tuberous sclerosis comprising a splicing defect in a TSC I or TSC2 gene.
Sarajee et al. is drawn towards the association of gene variants and ASD (see abstract). Sarajee et al. teaches that “Several studies provide evidence suggesting linkage of autism for regions on chromosome 16p13.3, the location of the TSC2 gene.” (pg. 3, left column, first paragraph). Sarajee et al. teaches “that SNPs in three phosphatidylinositol signalling pathway genes, INPP1, PIK3CG, and TSC2, are in linkage disequilibrium with autism. TSC2 functions in the phosphatidylinositol-3-OH kinase (PI3K) pathway, downstream of the insulin / insulin-like growth factor receptor in the control of cell growth.” (pg. 4, left column, first paragraph).
It would have been obvious to one of ordinary skill in the art to select a subject from the cohort with neurofibromatosis comprising a splicing defect in a NF I gene or tuberous sclerosis comprising a splicing defect in a TSC I or TSC2 gene, as suggested by Sarajee et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do so since TSC2 gene mutations may contribute to the susceptibility of ASD as taught by Sarajee et al. (pg. 1, left column, first paragraph), with a reasonable expectation of success absent evidence of criticality of the particular steps.
Response to Arguments
Applicant argues that “Applicant traverses the rejection on the grounds that Draper, Ekstrom, and Bonora provide no motivation to combine. Draper discloses administering isoprenoid antibiotics to treat myotonic dystrophies with no teaching regarding ASD. The Office Action relies on Ekstrom and Bonora to cure this deficiency. However, Ekstrom only notes a potential correlation between myotonic dystrophy and ASD, without establishing a causative link. Similarly, Bonora only notes a correlation between CADPS2 mutations and ASD/ID, but provides no teaching regarding splicing defects. The Office Action fails to articulate a reasoned basis by which a skilled person in the art would have been motivated to combine Draper, Ekstrom, and Bonora to arrive at the claimed invention, beyond mere hindsight.” The Examiner respectfully disagrees since although Ekstrom does not provide a causative link to the development of ASD, Ekstrom does teach a correlation between the severity of DM1 and ASD, and the frequency of ASD increased with increasing CTG repeat expansions (see abstract). Given that ascochlorin is an effective spliceopathy rescue agent of hnRNP L targets for patients with myotonic dystrophies as taught by Draper, there is a sufficient nexus between the teachings of Ekstrom and Draper. Regarding Bonora, Bonora and Ekstrom are both drawn towards ASD.
Conclusion
Claims 1-16 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDREW P LEE whose telephone number is (571)270-1016. The examiner can normally be reached Monday-Friday 9am-5pm.
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/ANDREW P LEE/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691