CTFR 17/831,745 CTFR 88557 Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Amendments In the reply filed 2/17/2026 , Applicant has amended Claim 49. Claims 35, 47-48 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim. Claims 31-34, 37-46 and 49-50 are under consideration. Information Disclosure Statement 06-52 AIA The information disclosure statement (IDS) submitted on 2/19/2026 was filed after the mailing date of the non-final Office action on 10/17/2025 . The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. Withdrawn 35 USC § 112 The prior rejection of Claim 49 under 35 U.S.C. § 112(b) pre-AIA 2 nd paragraph as being indefinite is withdrawn in light of Applicant’s amendments of instant claim to describe the genetic disease. Maintained Claim Rejections - 35 USC § 103 07-20-aia AIA 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. 07-23-aia AIA The factual inquiries set forth in Graham v. John Deere Co. , 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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. 07-20-02-aia AIA 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. 07-21-aia AIA Claim s 31-34, 36-38, 40-46 and 49-50 stand rejected under 35 U.S.C. 103 as being unpatentable over Glucksmann et al., (WO 2015/048577, filed 9/26/2014, with priority to 61/883,925 filed 9/27/2013 and 61/898,043 filed 10/31/2013, see Third Party IDS filed 5/23/2017), in view of Edge et al. (US 2013/0210145, filed 2/5/2013, published 8/15/2013) In regard to claim 31 , Glucksmann teaches the CRISPR-Cas9 system comprising: a CRISPR-Cas system chimeric guide RNA comprising a guide sequence, tracr mate and tracr polynucleotides ([0188-0204] of WO ’577, see pgs. 24-25 of priority document 61/898,043), and a Cas9 nuclease, wherein the Cas9 protein is capable of forming a complex with the CRISPR-Cas system chimeric guide RNA (Summary of Invention, WO ’577, see pgs. 9-12, 22 and Fig. 6 of priority document 61/898,043). In regard to the composition being formulated for local administration, Glucksman teaches the composition is delivered via localized injection to the target organ and is in a pharmaceutical composition (pgs. 134-135 of WO ’577, see p. 9, last two para., p. 10, p. 185, last para. of priority document 61/898,043) In regard to the guide RNA sequence being capable of hybridizing to a target sequence associated with an auditory genetic disease, Glucksman teaches targeting the ATOH1 gene in hair cells so as to treat impaired hearing (pgs. 294, last para. to p. 296 of WO ‘577, see p. 196, XVII to p.198, 7 th para. of priority document 61/898,043). Although, Glucksman is silent to a preferred embodiment of a composition for treating an auditory genetic disease comprising Cas9 and a gRNA that targets the ATOH1 gene and formulated for localized administration to a subjects cochlea, it would have been obvious to one having ordinary skill in the art at the time the invention was filed to produce said composition with a reasonable expectation of success. In regard to the reasonable expectation of success of targeting the ATOH1 gene to treat an auditory genetic disease, the prior art of Edge (US2013) describes the ATOH1 gene and teaches gene therapy methods for increasing ATOH1 expression in hair cells of a subject to treat hearing impairments [0004, 0019-0020, 0073-0074]. It would have been therefore predictably obvious to use a combination of these elements in said composition. In regard to claim 32 , Glucksmann teaches the Cas9 can be multiplexed with multiple CRISPR guide RNAs capable of hybridizing to different target sequences (p. 4, 9 th para., p. 6, 3 rd and last para. and Table VII-8 of priority document 61/898,043). In regard to claims 33 and 34 , Glucksmann teaches the CRISPR Cas9 protein comprises two NLS (Fig. 6 of WO ‘577, see p. 22, Fig. 6 of priority document 61/898,043). In regard to claim 36 , Glucksmann teaches the CRISPR Cas9 comprises a mutation in its catalytic domain, and is a nickase that cleaves only a single strand ( of WO ‘577, see p. 39, 3 rd & 4 th para., p. 41, 6 th para., pgs. 49-50 of priority document 61/898,043). In regard to claims 37 and 38 , Glucksmann teaches the Cas9 comprises mutations in its catalytic domain and further comprises a transcriptional activation domain ([0709] of WO ‘577, see pgs. 54-55, p. 75, 2 nd para. of priority document 61/898,043), which would have been obvious choose for the upregulation of ATOH1, which Edge teaches would lead to treating hearing loss. In regard to claim 40 , Glucksmann teaches the Cas9 is a Streptococcus pyogenes Cas9 (Fig. 1 of WO ‘577, see p. 22, Fig. 5 of priority document 61/898,043). In regard to claims 41 and 42 , Glucksmann teaches the guide polynucleotides are chiRNA (alias “unimolecular” guide RNA) for complexing the Cas protein ([0567] of WO ‘577, see p. 21, Fig. 1 of priority document 61/898,043). In regard to claim 43, Glucksmann teaches the Cas9 polynucleotide is an mRNA which transiently expresses the Cas9 and improves specificity and safety ([0082] of WO ‘577, see p. 9, last para., p. 11, 3 rd para. p. 56, 3 rd para. pgs. 187-188, 7 th para. of priority document 61/898,043). In regard to claim 44, Glucksmann teaches the CRSIPR Cas system is formulated in a liposomes ([0965-0969] of WO ‘577, see pgs. 184-185. of priority document 61/898,043). In regard to claim 45, Glucksmann teaches the CRISPR system further comprises a recombination template (alias “swap” nucleic acid) that up-regulates a gene (i.e., ATOH1) that promotes the generation of hair cells (p. 106 of WO ‘577, see p. 4, 4 th – last para., p. 196, 2 nd to last para. of priority document 61/898,043). In regard to claim 46, Glucksmann teaches the composition is to be used in a human cell (p. 12, 10th para. of priority document 61/898,043), which is obvious because of the clinical relevance. Furthermore, Edge discloses the human ATOH1 gene [0020, 0073], thereby providing a reasonable expectation of success for using the composition in human cells. In regard to claim 49 , as stated supra, Glucksmann teaches targeting the ATOH1 gene, and Edge teaches that the auditory disease to be treated by ATOH1 gene therapy include deafness, hearing loss, vestibular dysfunction because of a genetic defect [0099, 0101]. In regard to claim 50 , as stated supra, Glucksman teaches the composition is delivered via localized injection to the target organ and is in a pharmaceutical composition. Note that the formulation for localized intravitreal injection is directed to the intended use of the claimed composition does not appear to limit the formulation beyond a pharmaceutical composition. Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary . RESPONSE TO ARGUMENTS Applicant's arguments filed on 2/17/2026 are acknowledged. First, Applicant argues that instant claims require the composition is formulated for localized administration to a subjects eye or cochlea. Applicant states that the Examiner indicates that Glucksmann does not disclose a composition for treating auditory disease comprising Cas9 and gRNA, and uses Edge to cure this deficiency as directed to methods of gene therapy for increasing ATOH1 expression in hair cells of a subject. Applicant argues that one would not have combined the teachings of Glucksmann with Edge because they directed to disparate systems, wherein one is modifying a gene and the other is transgenesis, with a lack of overlap in mechanism, molecular components, and therapeutic strategies. Second, Applicant argues that even if one were motivated to formulate a Cas9/gRNA capable of targeting a sequence associated with an auditory disease for local administration to the cochlea, there would not have been a reasonable expectation of succuss in doing so. Applicant argues that the technical consideration for localized administration of CRISPR-Cas to the cochlea are substantially different from conventional gene therapy, while Edge provides no teachings regarding the feasibility, safety, or efficacy of administration of CRISPR components to the cochlea, nor form a functional Cas9/gRNA complex. Third, Applicant argues the claimed composition yields surprising results. Applicant argues that Examples 3-6 describe gRNA selection and validation for ocular or auditory diseases, followed by in vivo localized delivery to the retina or cochlea, wherein the composition exhibited localized, highly specific genome editing in the ocular or cochlear tissue. 07-37 Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's f irst argument, a 35 U.S.C. § 103(a) based test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller , 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In instant case, the secondary reference of Edge is primarily provided for supporting the reasonable expectation of success of targeting the Atoh1 gene in order to treat an auditory genetic disease. Furthermore, although Edge is concerned with gene replacement therapy, Glucksmann too is concerned with similar intended uses wherein the composition includes a “ swap nucleic acid…that up-regulates a gene that promotes hair growth ” (p. 196 of 61/898,043 priority document). Thus, contrast to Applicant’s assertion, Glucksmann and Edge do overlap in mechanism and share therapeutic strategy, albeit with different molecular components. In regard to the composition itself, Glucksmann teaches “ a pharmaceutical composition, comprising a gRNA molecule ”, as well as “ a pharmaceutical composition, comprising, (a) nucleic acid sequence, e.g., a DNA, that encodes one or more gRNA molecules ”, wherein “ the composition further comprises a nucleic acid, e.g., a DNA or mRNA, that encodes a Cas9 molecule ”, as well as wherein “ the composition further comprises a Cas9 molecule ” (pgs. 9-10 of 61/898,043 priority document). Glucksmann goes on to teach the composition can be formulated for “ localized injection to (a) target organ ” (p. 185 of priority document). Finally, Glucksmann discloses a composition comprising “ a Cas9 molecule/gRNA molecule complex that up-regulates a gene that promotes the development of hair cells, or down-regulates a gene that inhibits the development of hair cells ” of the ear. Glucksmann goes on to teach the composition is to be used for “ contacting the cell with a Cas9 molecule/gRNA complex that results in turning on a maturation pathway. For hair cell this would include one or more of the following: Atoh1 ” (p. 196-197 of priority document). Although the Examiner indicated that Glucksmann did not provided a “preferred embodiment of a composition for local administration for treating an auditory genetic disease”, this is not the same as Applicant’s assertion that the Examiner acknowledged Glucksmann did “not disclose” such a composition. Applicant is reminded that patent documents are relevant as prior art for all they contain, and that a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. In regard to Applicant’s second arguments directed to the reasonable expectation of success of making such a formulation, as stated supra, Glucksmann clearly teaches all of the components necessary to make and use the claimed composition. Furthermore, Edge establishes in the background that it was well known endogenous cells of cochlea can be converted to hair cells when the proneural transcription factor, Atoh1, is expressed exogenously [004]. Thus, one of ordinary skill could have made the composition with a reasonable expectation of success of it being capable to edit the Atoh1 gene in the cochlea. Moreover, any conclusions of unpredictability have to be made in the context of this particular invention, i.e., a composition. The Federal Circuit would have found that the claims at issue would have been obvious, since there had been ample suggestion in the prior art that the claimed composition could have been made. Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit has concluded that Applicant’s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304. In regard to Applicant’s third arguments directed to their surprising results of using such a formulation, as a first matter, Applicant’s purported surprising results are not commensurate in scope with claimed invention. Specifically, all of Applicant’s working examples of in vivo treatments are limited to the unelected “ocular genetic diseases” and use a specific AAV vector (i.e., AAV1/2 or AAV8), delivered by specific routes (e.g., subretinal or intravitreal), for specific ocular conditions (e.g., retinitis pigmentosa or macular degeneration). As such the purported surprising results do not show objective evidence of nonobviousness commensurate in scope with the claims. As a second matter, in regard to the elected and examined “auditory genetic diseases”, Applicant only provides “in vitro validation” experiments for targeting Atoh1 expression in HEK cells (Example 6). Applicant is reminded that showing of surprising and unexpected results must be based on evidence, not argument or speculation. In re Mayne, 104 F.3d 1339, 1343-44, 41 USPQ2d 1451, 1455-56 (Fed. Cir. 1997) (conclusory statements regarding unusually low immune response or unexpected biological activity that were unsupported by comparative data held insufficient to overcome prima facie case of obviousness). Furthermore, in order to complete the art of record and to rebut Applicant's arguments, Applicant is directed to the review of Doudna et al., (US2014/0068797, filed 3/15/2013, see IDS filed 6/10/2022), which demonstrate that well before the time of filing of the invention it was known that CRISPR-Cas9 could target genes in human cells (see Example 2 & 4 of Doudna). Thus, it appears Applicant’s invention with respect to auditory genetic diseases is works as intended. Applicant’s arguments and working example amount to an affirmation that the claimed subject matter functions as it was intended to function as predicted by the prior art. This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. 07-66-05 AIA In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness. 07-21-aia AIA Claim 39 stands rejected under 35 U.S.C. 103 as being unpatentable over Glucksmann et al., (WO 2015/048577, filed 9/26/2014, with priority to 61/883,925 filed 9/27/2013 and 61/898,043 filed 10/31/2013, see IDS filed 6/10/2022), in view of Edge et al. (US 2013/0210145, filed 2/5/2013, published 8/15/2013), as applied to claim 31, in further view of Chylinski et al., (RNA Bio, 2013, 10:5, 726-737, published on-line 4/05/2013, see IDS filed 6/10/2022), and Kinnevey et al., (AAC, 2013, 57:524-531, published on-line 11/12/2012, see IDS filed 6/10/2022) , As stated supra, Glucksmann in view of Edge suggests a composition comprising CRISPR-Cas9 system for the treatment of an auditory disease. However, in regard to claim 39, although Glucksmann et al. cite the prior work of Chylinski et al., (2013) for a comparison of Cas9 orthologues (p. 21, last para, p. 40, last para. of priority document 61/898,043), they are silent with respect to a Cas9 orthologue from Staph aureus . In regard to claim 39 , Chylinski teaches the 1053 amino acid Staph aureus Cas9 (Table S1, p. 4, cluster 30). Accordingly, it would have been obvious to one of ordinary skill in the art at the time of filing to treat LCA as taught by Glucksmann and choose the Staph aureus Cas9 as taught by Chylinski with a reasonable expectation of success. The ordinary skilled artisan would have been motivated to do so for several reasons. First, as stated supra, Glucksmann explicitly cites the work of Chylinski and that the taught method is to include the cluster 30 Cas9 orthologues of Chylinski (p. 40 last para. of priority document 61/898,043). Note that Chylinski teaches that the use of other various tracrRNA and Cas9 proteins is a valuable tool for improving the design of single-guide chimeric RNA:Cas9 (p. 734, 3 rd para.). In regard to the reasonable expectation of success of choosing the Staph aureus Cas9 for the CRISPR method of Glucksmann, Chylinski teaches that Cas9 orthologs of closely related species (e.g., gram positive bacteria with a class II-A type Cas9) are exchangeable in DNA cleavage assays (p. 734, 1 st para.). Thus, because S. pyogenes and S. aureus are both gram positive bacterial with a class II-A type Cas9 (see Fig. 1 of Chylinski), there would be a reasonable expectation of success in using the closely related S. aureus Cas9. Furthermore, Chylinski cites the strain of S. aureus used (i.e., M06/0171), which was published by Kinnevey et al. in 2012, and explicitly teaches the software used for predicting strain specific tracrRNA and crRNA (p. 728, 3 rd & 4 th para.). Thus, it would be predictably obvious to use the Staph aureus Cas9 in the method of Glucksmann et al. Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary . RESPONSE TO ARGUMENTS Applicant's arguments filed on 2/17/2026 are acknowledged and have been addressed supra. Double Patenting 08-33 AIA The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg , 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b). Claims 31-34, 36-39, 41-42, 44-46 and 49-50 stand rejected on the grounds of nonstatutory double patenting over claims 1-20 of U.S. Patent No. 10,946,108 (Zhang et al., Patented 3/16/2021) in view of Edge et al. (US 2013/0210145, filed 2/5/2013, published 8/15/2013) The subject matter claimed in the instant application is fully disclosed in the referenced patent as follows: the composition comprising a CRISPR SaCas9 for targeting CDKN1B gene of Table 9 makes obvious the CRISPR Cas9 composition for treating an auditory genetic disease of instant application. It is clear that elements of the cited patent claims are to be found in instant claims. The difference between the cited patent claims do not indicate that targeting CDKN1B is capable of treating an auditory genetic disease. Nevertheless, Edge (US2013) teaches gene therapy methods for increasing CDKN1B gene (alias p27Kip) expression in hair cells of a subject to treat hearing impairments (see Claim 1 of Edge). Accordingly, it would have been obvious to prepare the patented CRISPR-SaCas9 composition targeting the CDKN1B gene and claim the intended use to treat auditory genetic disease with a reasonable expectation of success. Since the instant application claims are obvious over cited patent claims in view of Edge, said claims are not patentably distinct. RESPONSE TO ARGUMENTS Applicant's arguments filed on 2/17/2026 are acknowledged and have been addressed supra. Conclusion 07-39 AIA 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 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 date of this final action. No claims are allowed. Examiner Contact Information Any inquiry concerning this communication or earlier communications from the examiner should be directed to ARTHUR S LEONARD whose telephone number is (571)270-3073. The examiner can normally be reached on Mon-Fri 9am-5pm. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Doug Schultz can be reached on 571-272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /ARTHUR S LEONARD/Examiner, Art Unit 1631 Application/Control Number: 17/831,745 Page 2 Art Unit: 1631
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