COMPOSITIONS AND METHODS FOR TREATING CLRN1-ASSOCIATED HEARING LOSS AND/OR VISION LOSS

Detailed Office 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 Claims Acknowledgement is hereby made of receipt and entry of the communication filed 16 March, 2026. Applicant’s election of Group I without traverse is noted. Claims 1, 10, 11, 13-16, 38-44, 46, 47, and 51-62 are pending in the instant application. 37 C.F.R. § 1.98 The information disclosure statements filed 10 October, 2023, 12 February, 2024, 05 March, 2024, 01 April, 2024, 01 October, 2024, 04 December, 2024, 04 February, 2025, 24 March, 2025, 28 May, 2025, 06 August, 2025, 16 March, 2026, 25 June, 2026, and 24 August, 2026, have been placed in the application file and the information referred to therein has been considered. Joint Inventors, Common Ownership Presumed 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 at the time any inventions covered therein were effectively filed absent any evidence to the contrary. Applicant is advised of the obligation under 37 C.F.R. § 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned at the time a later invention was effectively filed 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. Graham v. Deere Analysis The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 U.S.P.Q. 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. § 103(a) 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. 35 U.S.C. § 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 of this title, 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 1, 10, 13-16, 38, 51, and 54-61, are rejected under 35 U.S.C. § 103 as being unpatentable over Corey et al. (U.S. Pat. No. 12,129,287 B2, issued 29 October, 2024; claiming priority to Prov. Appl. No. 63/078,319, filed 14 September, 2020; hereinafter referred to as “Corey et al. (‘287)”). The claims are directed toward a recombinant adeno-associated virus (AAV) particle comprising a construct with the following elements: i) a 5’ inverted terminal repeat (ITR); ii) a cytomegalovirus (CMV) enhancer; iii) a chicken β-actin (CBA) promoter; iv) a chimeric intron; v) a 5’ untranslated region (UTR); vi) a clarin 1 protein coding sequence encoding the protein of SEQ ID NO.: 1; vii) a 3’ UTR; viii) a polyadenylation signal; and ix) a 3’ ITR (claim 1). Corey et al. (‘287) disclose a recombinant adeno-associated virus comprising: (i) an AAV capsid protein; (ii) a nucleic acid comprising, from 5′ to 3′: (a) a 5′ ITR; (b) a Human Cytomegalovirus Major Immediate-Early Enhancer (CMV IE enhancer); (c) a Chicken beta-actin (CBA) promoter; (d) a beta-actin exon; (e) a chimeric intron; (f) a 5′ UTR; (g) a Kozak sequence; (h) a nucleotide sequence encoding a human clarin-1 protein; (i) a 3′ UTR; (j) a bovine growth hormone poly A signal; and (k) a 3′ ITR. This teaching does not disclose a rAAV particle comprising the clarin protein of SEQ ID NO.: 10. However, this teaching clearly provides various murine and human clarin 1 isoforms, including human isoform A set forth in SEQ ID NO.: 10 (see SEQ ID NOS.: 5 or 6, col. 14). Moreover, the 5’ ITR and 3’ ITR flank the CMV enhancer and poly(A) sequence as required by claim 10. Recombinant AAV particles, pharmaceutical compositions comprising said particles, and ex vivo cells are also disclosed as required by claims 13-15 (see cols. 35-40, Example 2). Kits comprising the aforementioned compositions are also contemplated (claim 38; see cols. 43-44). Claim 51 further references a polynucleotide encoding the protein of SEQ ID NO.: 10 which is also described in the examples. This teaching clearly states that the AAV capsid can be selected from AAV2 (see col. 12). The remaining claims (54-61) are directed toward kits comprising a pharmaceutical composition comprising the rAAV particle. Suitable pharmaceutical compositions, kits comprising said compositions, and methods of administration are also clearly set forth (cols. 37-40, 43, and 44). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to prepare a rAAV with the aforementioned elements to express different isoforms of human clarin 1, including that set forth in SEQ ID NO.: 1. Compositions comprising the clarin 1-encoding rAAV would be useful for the treatment of inner ear disorders. Claims 11, 39-44, 46, 47, 52, 62 are rejected under 35 U.S.C. § 103 as being unpatentable over Corey et al. (‘287), as applied supra to claim 1, and further in view of Choi et al. (U.S. Pat. No. 10,550,404 B2, issued 04 February, 2020; claiming priority to Prov. Appl. No. 61/642,630, filed 04 May, 2012; hereinafter referred to as “Choi et al. (‘404)”), Simons and Ng (U.S. Pat. No. 11,807,867 B2, issued 07 November 2023; claiming priority to Prov. Appl. No. 62/979,792, filed 21 February, 2020; hereinafter referred to as “Simons and Ng (‘867)”), Simons and Ng (WO 2020/005974 A1 published 02 January, 2020; claiming priority to Prov. Appl. No. 62/689,660, filed 02 January, 2020; hereinafter referred to as “Simons and Ng (‘974)”), and Simons and Ng (U.S. Pat. No. 12,226,493 B2, issued 18 February, 2025; claiming priority to Prov. Appl. No. 62/697,652, filed 13 July, 2018; hereinafter referred to as “Simons and Ng (‘493)”). The claims further require specific vector elements (e.g., a 5’ ITR comprising SEQ ID NO.: 20 or 21 (claim 39); a 3’ ITR comprising SEQ ID NO.: 18 or 22 (claim 40); a CMV element comprising SEQ ID NO.: 38 (claim 41); a CBA promoter comprising SEQ ID NO.: 23 or 24 (claim 42); an intron comprising SEQ ID NO.: 39 (claim 43); a 5’ UTR comprising SEQ ID NO.: 40 (claim 44); a 3’ UTR comprising SEQ ID NO.: 41 (claim 46); or a poly(A) sequence comprising SEQ ID NO.: 44 (claim 47)). Claim 52 requires the utilization of an AAV2 capsid. Claims 11 and 62 are directed toward rAAVs comprising the sequences of SEQ ID NOS.: 64 or 68, respectively. Choi et al. (‘404) provide rAAV vectors for the treatment of various pathological conditions comprising 5’ and 3’ ITRs corresponding to SEQ ID NOS.: 20 (SEQ ID NOS.: 16, 36, and 9), 21 (SEQ ID NO.: 17), 18 (SEQ ID NOS.: 16, 36, and 9), and 22 (SEQ ID NO.: 17). Simons and Ng (‘867) provide rAAV vectors for the treatment of hearing impairment in humans. The rAAV vectors contained a CMV enhancer corresponding to SEQ ID NO.: 38 (SEQ ID NO.: 98), CBA promoter corresponding to SEQ ID NO.: 23 (SEQ ID NO.: 99), and chimeric intron corresponding to SEQ ID NO.: 39 (SEQ ID NO.: 100). Simons and Ng (‘974) provide rAAV vectors expressing CLRN1 for the treatment of hearing disorders. In particular, recombinant vectors comprising the 5’ and 3’ UTRs of SEQ ID NOS.: 40 and 41, respectively were disclosed (see SEQ ID NOS.: 12 and 60, respectively). This teaching also provides rAAV vectors corresponding to SEQ ID NOS.: 64 and 68 (see SEQ ID NO.: 42). Simons and Ng (‘493) provide recombinant AAV vectors encoding CLRN1 for the treatment of hearing loss. These vectors contained the polynucleotide of SEQ ID NO.: 10 (SEQ ID NOS.: 5 and 6) and encoded the CLRN1 protein of SEQ ID NO.: 1 (SEQ ID NOS.: 10 and 19). These constructs also contained a poly(A) signal corresponding to SEQ ID NO.: 44 (SEQ ID NO.: 34). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include well-known rAAV structural components such as 5’ and 3’ ITRs, CMV enhancers, CBA promoters, chimeric introns, 5’ and 3’ UTRs, and poly(A) sequences as provided by Choi et al. (‘404), Simons and Ng (‘867), Simons and Ng (‘974), and Simons and Ng (‘493), in the rAAV vector of Corey et al. (‘287). Absent evidence to the contrary, one of ordinary skill in the art would have reasonably been motivated to employ these different elements because they produce a rAAV vector that produces high-level expression of the transgene, particularly CRLN1. Claim 53 is rejected under 35 U.S.C. § 103 as being unpatentable over Corey et al. (‘287), as applied supra to claim 13, and further in view of Stankovic et al. (U.S. Pat. Pub. No. 2018/0369414 A1, published 27 December, 2018; claiming priority to Prov. Appl. No. 62/266,477, filed 11 December, 2015; hereinafter referred to as “Stankovic et al. (‘414)”). The claim further requires the utilization of an Anc80 capsid. Stankovic et al. (‘414) provide rAAV vectors for the treatment of cochlear disorders containing the Anc80 capsid. The AAV Anc80 capsid is an in silico product derived from AAV serotypes 1-3 and 6-9. Vectors carrying this capsid are potent gene therapy vectors. Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to include the Anc80 capsid protein of Stankovic et al. (‘414), in the rAAV vector of Corey et al. (‘287), to produce a more robust and potent rAAV vector. Correspondence Any inquiry concerning this communication should be directed to Jeffrey S. Parkin, Ph.D., whose telephone number is (571) 272-0908. The Examiner can normally be reached Monday through Friday from 10:00 AM to 6:00 PM. A message may be left on the Examiner's voice mail service. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. 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Respectfully, /JEFFREY S PARKIN/Primary Examiner, Art Unit 1671 24 September, 2026