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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 02/06/2026 is acknowledged. Claims 4-5 were cancelled. Claims 1,16 and 23 were amended. Claim 25 is new. Claims 1-3 and 6-25 are pending.
Applicant elected OTOF from Species B in the reply filed on 07/07/2025 without traverse, and the examiner expanded Species B to include TMCI, USHIC, MYO7A, CDH23, PCDH15, WHRN, PDZD7, TMPRSS3, STRC, MYO15A, MYO6, LOXHD1, POU3F4, TMIE, SYNE4 and FAM65B due to the cited art.
Claims 2 and 6-7 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1,3 and 8-25 are under examination.
Response to Arguments
Applicant’s arguments and amendments, see page 7, filed 02/06/2026, with respect to the objection to the drawings have been fully considered and are persuasive due to applicant providing replacement drawings correcting the labeling issues. The objection to the drawings has been withdrawn.
Applicant’s arguments and amendments, see page 7, filed 02/06/2026, with respect to the objection to claim 13 have been fully considered and are persuasive due to correction of the misspelling. The objection to claim 13 has been withdrawn.
Applicant’s arguments and amendments, see pages 7-8, filed 02/06/2026, with respect to the 35 U.S.C. 112(a) scope of enablement rejection of claims 9-24 have been fully considered and are persuasive due to the amendment to claim 1 reciting AAV8BP2 capsid and an inner ear cell-specific promoter and amendment to claims 9 and 16 reciting administration to the inner ear of the subject and removing preventing. The 35 U.S.C. 112(a) scope of enablement rejection of claims 9-24 has been withdrawn.
Priority
This application is a 371 of PCT/US21/14553 filed 01/22/2021 which claims benefit of 62/965,506 filed 01/24/2020 as reflected in the filing receipt dated 07/27/2022.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1,3,8-12,14-19 and 21-25 are rejected under 35 U.S.C. 103 as being unpatentable over Holt et al. (WO 2019/173367, Published 12 September 2019) in view of Cronin et al. EMBO Molecular Medicine, Vol. 6, 4 August 2014, 16 pages) and Ramachandran et al. (Human Gene Therapy, Vol. 28, No. 2, 1 February 2017), both cited on an IDS.
Regarding claims 1,3 and 25, Holt et al. teach AAV9-php.b vectors comprising a transgene encoding a polypeptide of interest (e.g. TMC1, TMC2, MY07A, USCH1C, CDH23, PCDH15, SANS, CIB2, USH2A, VLGR1, WHRN, CLRN1, PDZD7, KCNQ4, TMPRSS3, STRC, EYA4, USH1C (e.g., harmonin-a, b, or c), OTOF, GPR98, MY06, MY015A, LOXHD1, POU3F4, EYA1, WFS1, ACTG1, TMIE, PJVK, SYNE4, and FAM65B) and methods for administering the vector to the inner ear of a subject having a genetic defect in auditory and/or vestibular mechanosensation, thereby treating the subject (page 1, lines 28-31-page 2 lines 1-3). Holt et al. teach an AAV9-php.b vector that encodes a capsid and contains a promoter, that is a CAG promoter that directs expression of a downstream polynucleotide (page 2, lines 15-18).
Holt et al. teach compositions and methods for delivering and expressing a protein (e.g. TMC1, TMC2, MY07A, USCH1C, CDH23, PCDH15, SANS, CIB2, USH2A, VLGR1, WHRN, CLRN1, PDZD7, KCNQ4, TMPRSS3, STRC, EYA4, USH1C (e.g., harmonin-a, b, or c), OTOF, GPR98, MY06, MY015A, LOXHD1, POU3F4, EYA1, WFS1, ACTG1, TMIE, PJVK, SYNE4, and FAM65B) required for mechanosensation, including hearing, and/or vestibular function, in a cell of the inner ear of a subject such as the cochlear cell, wherein the subject has a loss or reduction in the level or activity of that protein (page 39 lines 13-20).
While Holt et al. teach an AAV9 vector comprising a transgene encoding a polypeptide of interest, and CAG promoter, it does not teach an AAV8PB2 capsid protein.
However, before the effective filing date, Cronin et al. teach the development of a modified adeno-associated virus capsid as a promising vehicle for further development toward potential clinical use (Abstract). Cronin et al. teach the identification of a favorable AAV variant from directed selection from a library of serotype AAV8 capsid mutants (Introduction, page 1176, left column). Cronin et al. teach a 9-amino acid stretch of a conformationally variable region of the AAV8 capsid protein between positions 585 and 593 was specifically selected for its potential to alter receptor attachment and cellular transduction properties of the virus, and that the residues from amino acids 585-594 of the AAV8 capsid protein encompass finger-like loops for one VP subunit, and that the amino acid sequences and structural topology of these large outer loops have been reported to facilitate tissue tropism and transduction efficiency (Results, page 1176, right column). Cronin et al. teach this loop formed by residues from 585-594 holds a prominent position on the capsid and includes sites shown in some serotypes to be critical for heparan sulfate binding and cellular uptake and that this surface exposed epitope region of residues 585-594 in AAV8 is amenable to changes that may influence tissue tropism and transduction characteristics and still yield viable capsids (Results, page 1176, right column). Cronin et al. teach residues from amino acids 585-593 of the AAV8 capsid were replaced with a mixture of sequences to produce randomized codons and produce an AAV capsid library and the mutated capsid region was cloned into an AAV8 vector for AAV library production (Results, pages 1176-1177). Cronin et al. teach AAV vectors were created with the selected mutant sequences in place of the wild-type AAV8 capsid gene, and that AAVs were made comprising a mutant capsid, AAV8BP2 (page 1177, right column).
Additionally, Ramachandran et al. teach many novel AAVs have been engineered in order to enhance transduction properties, including efficiency of targeting particular cell types, onset of expression and the ability to penetrate across tissue planes for use in gene therapy (page 155, left column), and teach work from their group generated a novel capsid called AAV8BP2 by in vivo directed evolution (page 155, right column). Ramachandran et al. teach that AAV8BP2 produced lower immune reactivity and had a better safety profile than AAV7m8 even at the highest doses administered (Abstract, page 163 right column, page 166 left column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to utilize AAV8BP2 as the capsid protein in place of AAV9-php.b of Holt et al. to deliver expression of proteins TMC1, TMC2, MY07A, USCH1C, CDH23, PCDH15, SANS, CIB2, USH2A, VLGR1, WHRN, CLRN1, PDZD7, KCNQ4, TMPRSS3, STRC, EYA4, USH1C (e.g., harmonin-a, b, or c), OTOF, GPR98, MY06, MY015A, LOXHD1, POU3F4, EYA1, WFS1, ACTG1, TMIE, PJVK, SYNE4, or FAM65B with a reasonable expectation as both AAV8BP2 and AAV9-pbp.b are known serotypes for gene therapy and gene transfer. An artisan would have been motivated to utilize AAV8BP2, as Cronin et al. teach residues from amino acids 585-594 of the AAV8 capsid protein encompass finger-like loops for one VP subunit, and that the amino acid sequences and structural topology of these large outer loops have been reported to facilitate tissue tropism and transduction efficiency and identified AAV8BP2 as one of the mutant capsids, and according to Ramachandran et al. the mutant capsid has been shown to produce lower immune reactivity and have a better safety profile even at the highest doses administered.
Regarding claims 8,10 and 17, Holt et al. teach delivery of one or more of the nucleic acids described herein to inner ear cells can be used to treat any number of inherited or acquired hearing disorders, including recessive deafness, dominant deafness, Usher syndrome and other syndromic deafness, as well as hearing loss due to trauma or aging (page 44, lines 3-8)
Regarding claims 9 and 16, Holt et al. teach that the inner ear, e.g. cochlear, particularly the inner and outer hair cells in the cochlear is an attractive target for polynucleotide therapy approaches in hearing loss and deafness of various etiologies (Page 1, lines 21-23). Holt et al. teach methods for administering the vector comprising a transgene encoding a polypeptide of interest (e.g. TMC1, TMC2, MY07A, USCH1C, CDH23, PCDH15, SANS, CIB2, USH2A, VLGR1, WHRN, CLRN1, PDZD7, KCNQ4, TMPRSS3, STRC, EYA4, USH1C (e.g., harmonin-a, b, or c), OTOF, GPR98, MY06, MY015A, LOXHD1, POU3F4, EYA1, WFS1, ACTG1, TMIE, PJVK, SYNE4, or FAM65B) to the inner ear of a subject having a genetic defect in auditory and/or vestibular mechanosensation, thereby treating the subject (page 1, lines 28-31-page 2 lines 1-3).
Regarding claims 11,12,18 and 19, Holt et al. teach the method of expressing a polypeptide in the inner ear of a subject by contacting a cell of the inner ear with a AAV9-php.b vector encoding a polypeptide of interest, wherein the AAV9-bph.b vector transfects at least about 85% or more of inner and outer hair cells (page 2, lines 23-26). Holt et al. teach, as used herein, inner ear cells refer to, without limitation, inner hair cells (IHCs), outer hair cells (OHCs), spiral ganglion neurons, stria vascularis, vestibular hair cells, vestibular ganglion neurons, and supporting cells (page 43, lines 30-33). Therefore, Holt et al. teach that the AAV vector transfects the stria vascularis.
Regarding claims 14,15,21 and 22, Holt et al. teach expression of a transgene delivered using an AAV-PHP.B vector can result in regeneration of inner hair cells, outer hair cells, spiral ganglion neurons, stria vascularis, vestibular hair cells and/or vestibular ganglion neurons such that hearing or vestibular function is restored for an extended period of time (page 49, lines 32-33- page 50, lines 1-3).
Regarding claims 23 and 24, Holt et al. teach a virus and a transgene (OTOF) as described herein can be delivered to inner ear cells (e.g. cells of the cochlea) by injection through the round window, or the utricle (page 49 lines 3-8) or can be delivered to the appropriate position within the ear during surgery (e.g. canalostomy) (page 49 lines 13-14), and exemplifies in vivo injection of the AAV vector via the round window membrane (Example 1, page 52 and Example 5, page 55). Holt et al. teach injection methods to deliver the virus also include through the posterior semicircular canal (Example 8, page 57).
Accordingly, claims 1,3,8-12,14-19 and 21-25 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 02/06/2026 have been fully considered but they are not persuasive.
Applicant argues on page 8, that the claims have been amended to recite an AAV8BP2 capsid protein, an inner ear cell-specific promoter, and inner ear administration, and that when the cited references are considered together, they do not teach nor suggest the claimed combination nor provide a reasonable expectation of success. Applicant argues Holt et al. discusses inner ear therapy at a general level and does not address capsid engineering, capsid tropism or promoter specificity relevant to the amended claims, and Cronin et al. discloses the AAV8BP2 capsid solely in the context of retinal gene delivery, where the capsid was identified through empirical directed evolution and in vivo selection for ON-bipolar cell transduction in the retina and nothing in Cronin suggests the AAV8BP2 capsid as suitable for transduction of inner ear cells particularly in combination with an inner ear cell specific promoter. Applicant argues that considering Cronin and Ramachandran et al. together, the cited art does not teach AAV8BP2 as a broadly applicable capsid, but a narrowly optimized construct whose performance is unpredictable, and the teachings would have cautioned one skill in the art against applying AAV8BP2 to a distinct and highly protected anatomical environment such as the inner early, particular in combination with an inner ear hair cell specific promoter and inner ear administration. Applicant argues the art fails to provide a reasonable expectation of success and impermissible hindsight reconstruction.
This is not found persuasive. Regarding claims 1,3,8 and 25, these claims are product claims. Per MPEP 2111.02, "the patentability of apparatus or composition claims depends on the claimed structure, not on the use or purpose of that structure." Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801,809 (Fed. Cir. 2002). Therefore, there would be a reasonable expectation of success to utilize AAV8BP2 as the capsid protein in place of AAV9-php.b of Holt et al. to deliver expression of the proteins taught by Holt et al. and the inner ear hair cell-specific promoter which is CAG of Holt et al., as both AAV8BP2 and AAV9-pbp.b are known serotypes for gene therapy and gene transfer.
Regarding the method of treating claims (claims 9-12,14-19, and 21-24), the examiner maintains that there would be a reasonable expectation of success that administering the recombinant AAV virion of Holt et al. in view of Cronin et al. and Ramachandran et al. to the recited subject would result in the method being carried out regarding treating cochlear damage in a subject or treating hearing loss or dizziness in a subject. Holt et al. teach administering the vector to the inner ear of a subject as well as using a CAG specific promoter, which would be an inner ear hair cell-specific promoter.
While Cronin et al. and Ramachandran et al. do pertain to using the AAV8BP2 for retinal gene delivery, Cronin et al. taught that the modified AAV8 capsid protein had been reported to facilitate tissue tropism and transduction efficiency (page 17 of office action) and Ramachandran et al. taught AAV8BP2 produced lower immune reactivity and had better safety profile than AAV7m8 even at the highest doses (page 17 of office action). One of ordinary skill in the art would have been motivated by these findings to apply this capsid variant for use in other tissues and cells other than the eye, including the ear.
The reasonable expectation of success is further supported by Kim et al. (Molecular Therapy: Methods and Clinical Development Vol. 13, June 2019), who taught that AAV has become a more recognized vehicle for successful gene delivery to the inner ear, facilitating gene function research and the development of treatments for hereditary hearing loss, and that previous studies have validated several AAV vectors in the murine inner ear, including AAV1, AAV2, AAV5, AAV6, AAV8, AAV9 and Anc80L65, leading to substantial advancement of cochlear gene therapy investigations (Discussion, page 199). Therefore, it can be seen that both AAV8 and AAV9 vectors have been used and validated in the inner ear of mice. This further supports the reasonable expectation of success of using an AAV8 capsid protein including a modified capsid protein in place of an AAV9 capsid protein.
In addition, Isgrig et al. (Nature Communications (2019)10:427), cited on an IDS, taught most conventional AAVs infect inner hair cells with various efficiencies (Abstract). Isgrig et al. taught in order for inner ear gene therapy to achieve complete hearing restoration, a viral vector with high infection efficiency is required, and also discussed the synthetic AAVs, AAV2.74m8 and AAV8BP2 have shown enhanced cellular transduction in the retina, and examined the infection patterns of AAV2.7m8 and AAV8BP2 in the mouse inner ear (page 2, left column). Isgrig et al. taught when AAV2.7m8-GFP and AAV8BP2-GFP were delivered to neonatal mouse inner ears, GFP was expressed in vestibular organs (page 2, right column). Therefore, the state of the art shows the same capsid protein AAV8BP2 as instantly claimed, which was shown as enhancing cellular transduction in the retina as being evaluated for infection and delivery to the inner ear. Therefore, the art provides a suggestion and motivation as well as a reasonable expectation of success.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In addition, regarding the combination of Holt et al. in view of Cronin et al. and Ramachandran et al., any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
Therefore, the examiner is maintaining the 35 U.S.C. 103 rejection of claims 1,3,8-12,14-19 and 21-24, as the amendments to the claims are taught by the cited references, and the limitation of the CAG promoter in new claim 25 is taught by Holt et al.
Claims 13 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Holt et al., Cronin et al. and Ramachandran et al. as applied to claims 1,3,8-12,14-19 and 21-25 above, and further in view of Nyberg et al. (Science Translational Medicine, Vol. 11, No. 485, Published 6 March 2019).
The teachings of Holt et al., Cronin et al., and Ramachandran et al. as applicable to claims 1,3,8-12,14-19 and 21-25 are described above. Holt et al. teach that the AAV vector transfects the stria vascularis (Page 2, lines 23-26 and page 43, lines 30-33).
Holt et al., Cronin et al., and Ramachandran et al. do not teach that the recombinant AAV virion infects the marginal cells, the intermediate cell and/or the basal cells of the stria vascularis.
However, before the effective filing date, Nyberg et al. teach mechanotransduction of auditory signals by cochlear sensor hair cells relies on the precise electrochemical composition of the cochlear fluids, and that the stria vascularis is a highly vascularized epithelial-mesodermal tissue in the lateral wall of the cochlea and is essential for generating and maintaining the unique ionic composition of the endolymph in the scala media (page 1, right column). Nyberg et al. teach the stria vascularis is composed of three cell layers that form a distinct compartment, and that on the medial surface, adjacent marginal cells are coupled together by apical tight junctions to form a continuous secretory barrier epithelium; on the lateral side, tight junctions between adjacent basal endothelial cells separate the stria vascularis from the fibrocytes populating the spiral ligament in the cochlear lateral wall; a perivascular intrastrial space, located between the marginal and basal cell layers, contains a dense network of strial capillaries together with pericytes and perivascular-resident macrophage-like melanocytes also called intermediate cells (page 1 right column- page 2, left column). Nyberg et al. teach malfunction of the stria vascularis can alter the electrochemical composition of the endolymph, resulting in loss of the endocochlear potential, elevated auditory thresholds, and hearing loss (page 2, right column).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, to have administered the recombinant AAV virion of Holt et al., Cronin et al., and Ramachandran et al. in order to infect the marginal cells, the intermediate cells, and/or the basal cells of the stria vascularis in order to treat cochlear damage or hearing loss with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to provide a method of treating cochlear damage or treating hearing loss in a subject by administering a recombinant AAV virion as taught by Holt et al., Cronin et al., and Ramachandran et al., that infects the marginal cells the intermediate cells, and/or the basal cells of the stria vascularis because Nyberg et al. teach these types of cells as making up the stria vascularis and that malfunction of the stria vascularis can alter the electrochemical composition of the endolymph, resulting in loss of the endocochlear potential, elevated auditory thresholds, and hearing loss. Therefore, an ordinary artisan would be motivated to infect these cells in the stria vascularis that may be malfunctioning and causing hearing loss, with the recombinant AAV virion to treat the hearing loss, and would make obvious the limitations of claims 13 and 20.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant's arguments filed 02/06/2026 have been fully considered but they are not persuasive.
Applicant argues on page 9 that the cited art does not provide a reasonable expectation of success as discussed above, and Nyberg et al. does not cure these deficiencies with respect to claims 13 and 20. Applicant argues the teachings of Nyberg et al. underscore the unpredictability of therapeutic access to stria vascularis cell layers, and the teachings of Nyberg et al. would have cautioned a person having ordinary skill in the art against speculative or unpredictable viral targeting of this tissue absence a clear and reliable expectation of control and success. Applicant again argues impermissible hindsight reconstruction using the instant application.
This is not found persuasive. The examiner has responded to the arguments pertaining to claims 1,3-5,8-12,14-19, and 21-24 above and impermissible hindsight, and as the 103 has been maintained but modified based on the amendments to the claims, the examiner is also maintaining the rejection of claims 13 and 20. In response to Applicant’s arguments about Nyberg et al., Nyberg et al. also teaches AAV vectors have been used in animal models to delivery neurotrophin genes to the cochlea to protect primary auditory neurons or sensory hair cells, and several AAV vector serotypes have enabled targeting of a therapeutic gene, such as a hair cell gene to the inner ear, and newer generations of AAV vectors are being developed to improve targeting and safety include the synthetic vector Anc80L65 that demonstrated targeting sensory hair cells in the cochlea safely and efficiently (page 5, left column).
It is also noted that the instant claims as amended recite administering to the inner ear of the subject and the cited art (Holt et al.) teach Holt et al. teach the method of expressing a polypeptide in the inner ear of a subject by contacting a cell of the inner ear with a AAV9-php.b vector encoding a polypeptide of interest, wherein the AAV9-bph.b vector transfects at least about 85% or more of inner and outer hair cells (page 2, lines 23-26) and that inner ear cells refer to, without limitation, inner hair cells (IHCs), outer hair cells (OHCs), spiral ganglion neurons, stria vascularis, vestibular hair cells, vestibular ganglion neurons, and supporting cells (page 43, lines 30-33). Holt et al. teach a virus and a transgene (OTOF) as described herein can be delivered to inner ear cells (e.g. cells of the cochlea) by injection through the round window, or the utricle (page 49 lines 3-8) or can be delivered to the appropriate position within the ear during surgery (e.g. canalostomy) (page 49 lines 13-14), and exemplifies in vivo injection of the AAV vector via the round window membrane (Example 1, page 52 and Example 5, page 55). Holt et al. teach injection methods to deliver the virus also include through the posterior semicircular canal (Example 8, page 57). Therefore, the claims and Holt et al. are not to systemic administration, but administration to the inner ear, and therefore the unpredictability taught by Nyberg regarding the BLB would not be a limitation when the delivery method is directly to the inner ear.
In addition, obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. NOTE: MPEP 2143.02.
Conclusion
Claims 1,3 and 8-25 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 STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636