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 .
Election/Restrictions
Applicant’s election of the species, a protocadherin 15 (PCDH15) promoter, in the reply filed on 26 January 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
The non-elected promoters; Espin, PTPRQ, and TMHS; are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 26 January 2026.
Claim Status
Claims 1-11 were previously cancelled and claims 12-31 have been considered on their merits.
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 12-31 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of restoring hearing and vestibular function in a subject with an USH1C mutation related disorder, the method comprising injecting to inner ear cells of a P0-P1 mouse, an AAV vector comprising an Anc80 capsid, a PCHD15 promoter, and a polynucleotide encoding harmonin-b1, does not reasonably provide enablement for a method of restoring hearing and vestibular function in any subject with any hearing or vestibular disorder, the method comprising injecting to inner ear cells of any subject, any AAV vector comprising any USH1C polynucleotide.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)”. The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQd 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Breadth of the claims
Claim 12 discloses a method of restoring function and vestibular function in any subject with a hearing disorder or vestibular disorder, the method comprising injecting to inner ear cells of the subject, a synthetic inner ear hair cell targeting AAV vector, wherein the vector: encodes a capsid having at least 85% sequence identity to Anc80 of SEQ ID NO: l, comprises a PCDH15 promoter (elected species), and comprises a USH1C polynucleotide, wherein the promoter directs expression of the USH1C polynucleotide, thereby restoring hearing function and vestibular function in the subject.
The scope of claim 12 is broad to include restoring hearing and vestibular function in a subject with any hearing disorder or vestibular disorder. The instant specification discloses vectors and treatment methods only directed to Usher syndrome, specifically USH1C, which is both a hearing and vestibular disorder. Other disorders, such as nonsyndromic autosomal recessive deafness-18 (DFNB18), is caused by homozygous mutation in the USH1C gene. Jain (Genomics 50, 290-292 (1998)) teaches DFNB18 and USH1C are allelic variants of the same gene (Abstract). Jain teaches subjects with DFNB18 possess normal vestibular and vision functions (p. 290). Additionally, other hearing or vestibular disorder exist that are unrelated to a mutation in the USH1C gene; such as acoustic neuroma, which is a benign tumor on the vestibular nerve causing hearing loss and dizziness or autoimmune inner ear disease, which causes rapid hearing and balance loss. Thus, not all disorders with a USH1C mutation would result in a subject with a vestibular disorder and not all hearing and vestibular disorders would be restored by administering a USH1C polynucleotide, making the method disclosed in claim 12 of restoring both hearing and vestibular functions highly unpredictable.
Further, claim 12 is broad to include any subject with a hearing or vestibular disorder. The disclosure in the art and instant specification demonstrate successful hearing and vestibular restoration only in P0-P1 mice with transduction of inner ear hair cells with an AAV vector encoding harmonin-b1. At this stage of development, mice are deaf and do not possess fully developed ears. It would be unpredictable to expect similar results in a fully developed subject, for example, a human generally possess fully developed inner ears at birth. Therefore, the results of a treatment utilizing the information from the art and the instant disclosure of any subject to include any stage of development for any hearing or vestibular disorder would be highly unpredictable.
Claims 13-14 further limit the USH1C polynucleotide, to encoding any isoform of harmonin-a, harmonin-b, or harmonin-c.
The scope of claims 13-14 narrow the scope of which USH1C polynucleotide is encoded, what is known in the art and disclosed in the specification discuss the effectiveness of administering harmonin-b1, while harmonin-a1 is noted as not being effective as restoring hearing and vestibular functions on its own. Additionally, methods utilizing harmonin-c were not found in the art nor specification, therefore, utilizing a vector encoding this polynucleotide would be highly unpredictable as only one specific isoform of harmonin-b, harmonin-b1, was found to be successful in restoring both hearing and vestibular function in P0-P1 mice.
Claim 15 limits the promoter to PCDH15.
Claims 16-18 limit the serotype of the AAV vector.
Claim 19 limits the Anc80 capsid to 100% identity to SEQ ID NO: 1.
Claims 20-25 are directed to the types of inner ear hair cells and the vector efficiency of transduction.
Claims 26-29 are directed to limitations involving the treatment aspect of the claims.
Claim 30 limits the hearing or vestibular disorder to Usher syndrome.
The scope of claim 30 is broad to include any form of Usher syndrome. Treating any form of Usher syndrome would be unpredictable, considering the USH1C gene is only associated with the USH1C form of the disorder. While other forms of the syndrome are associated with mutations in other genes.
Claim 31 limits the method of administration to injecting through a round window membrane.
Nature of the invention
The nature of the invention is a treatment method for USH1C, Usher syndrome type 1C, which is known to effect hearing, vestibular function, and vision. However, the disclosed methods are specific to the inner ear hair cells. The claims are directed broadly to restoring hearing and vestibular function in any subject with hearing or vestibular function.
State of the prior art
The state of the art in the field treatment methods for treating Usher syndrome with AAV gene therapy is relatively low. However, there is a fair amount of information regarding Usher syndrome and the related gene mutations which cause said syndrome.
Aparisi (Molecular Vision, 2010), discusses mutations in the USH1C gene, and teaches Usher syndrome IC is caused by mutations in the USH1C gene, which is a rare form of Usher syndrome (p. 2948). Aparisi teaches Usher syndrome type I (USH1) is associated with five genes, to include USH1C (Abstract).
Géléoc (Science Vol 334, 2014) discusses gene therapy for genetic deafness, to include a prominent example Usher syndrome and discloses gene therapy trials for treatment of retinitis pigmentosa are underway, as of 2014, for Usher syndrome 1B and suggests this approach could be tested in mouse ears to treat auditory dysfunction in mouse models (Gene Therapy for Genetic Deafness). Géléoc discusses the numerous studies demonstrating AAV vector transfection of rodent hair cells in vitro, however, Géléoc does not discuss gene therapy methods directed to USH1C.
Nagel-Wolfrum (Retinal Degenerative Diseases, 2014) discusses gene augmentation using AAV but focuses on the retina, not hearing or vestibular functions, however, Nagel-Wolfrum suggests restoring USH protein expression should reverse clinical phenotypes.
Level of predictability in the art
Landegger (Nature Biotechnology, 2017, IDS ref.) teaches safety and efficiency of Anc80L65 for transgene delivery to the cochlea of mice (Abstract). Landegger teaches additional methods to maximize specificity and minimize biodistribution should be considered to limit expression outside of the therapeutic cochlear cell target (p. 283), which suggests the use of a cell specific promoter. This concept has been exemplified by the examples in the instant specification.
Additionally, Pan (Nature Biotechnology, 2017, IDS ref.) teaches delivery of wild-type Ush1c into the inner ear of mice using the same AAV vector, Anc80L65 (Abstract). Pan teaches Anc80L65 efficiently transduces both auditory and vestibular hair cells in vivo and designed Anc80L656 vectors encoding harmonin-a1 or harmonin-b1 (p. 265). Pan teaches early postnatal round window membrane injection of harmonin vectors successfully restored auditory and vestibular function to near wild-type levels in otherwise deaf and dizzy c.216AA mice, demonstrating early reintroduction of wild-type harmonin with vectors that efficiently target IHCs and OHCs can improve auditory sensitivity by over a thousand-fold relative to first-generation inner ear gene therapy approaches (p. 265). Pan teaches delivery of harmonin-b1 via RWM injection at early stages can restore mechanotransduction in IHCs noting the combination of harmonin-a1 and harmonin-b1 did not result in significant improvement (p. 266, 1st column). Pan teaches none of the P0-P1 mice injected with AAV2/Anc80L65.CMV.harmonin-a1 recovered auditory function at 6 weeks and suggests exogenous expression of harmonin-a1 was insufficient for auditory rescue (p. 266, 2nd column). Pan teaches, to determine whether injections at a later developmental stage might lead to partial auditory rescue, RWM injections of AAV2/Anc80L65.CMV.harmonin-b1 (0.8 μl) at P10-P12 and assessed auditory thresholds at 6 weeks, wherein none of these mice had detectable DPOAEs, and their ABR thresholds did not differ from the uninjected c.216AA control mice (p. 268, 1st column). Pan teaches cochlear development begins at the basal end, by P0 these hair cells may have matured beyond the point of repair and suggests prenatal intervention may be more effective (p. 271, 1st column).
Both Landegger and Pan were published on the 6 February 2017, which is the effective filing date of the instant application. Both of these publications also share at least one author with the instant applicants.
Direction provided by the Inventors/Working examples
The working examples in the instant specification are in line with that of Pan, above. The instant specification discloses significant recovery was observed when P1 mice were treated with RWM injections of AAV2/Anc80L65.CMV.harmonin-b1, stating the results suggest delivery of exogenous harmonin-b1 via RWM injection at early stages can restore mechanotransduction in IHCs (p. 56, lines 6-24). The instant specification also discloses none of the mice injected with AAV2/Anc80.CMV.harmonin-al recovered auditory function at 6 weeks and mice injected with
AAV2/Anc80.CMV.harmonin-b1 recovered significant auditory function at 6 weeks with similar results to that of wild-type mice (p. 59, lines 6-12). The instant specification provides evidence that suggests harmonin-a1 may be dispensable for auditory function and harmonin-b1 alone is sufficient for significant restoration of auditory thresholds at low frequencies (Fig. 9 and pp. 59-60 lines bridging the pages). However, while the instant specification discloses harmonin-a1 alone being insufficient to recover hearing function, data is presented demonstrating at least a partial recovery of vestibular function to the level of control mice (p. 63, lines 29-31 and p. 64, lines 7-10).
Therefore, the instant specification provides examples of successfully recovering both hearing and vestibular function when administering AAV2/Anc80.CMV.harmonin-b1 via RWM injection in mice at P0-P1. No examples directed to the utilization of harmonin-c, nor was the utilization of harmonin-a1 demonstrated to restore both hearing and vestibular function. The PCDH15 gene is described as one of six Usher genes, however, no working examples were provided wherein the PCDH15 promoter was utilized with the AAV vector to express a harmonin protein, however, expressing transgenes with heterologous promoters is well-known in the art.
Based on the examples provided in the specification it would be highly unpredictable to expect restoration of hearing and vestibular function with any USH1C polynucleotide to a subject at any stage of development. One of ordinary skill would not have predicted to recover hearing and vestibular function by administering harmonin-a1 to a subject, nor would one have predicted success in recovering hearing and vestibular function by administering any USH1C polynucleotide to a subject at a fully developed stage.
Accordingly, claim 12 fails to satisfy the enablement requirement for the full scope of the claim. Claims 13-31 are included in the rejections because they ultimately depend from claim 12 and do not remedy the issue.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12-31 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites a list of promoters, in lines 10-12 of the claim, to include “…and a tetraspan membrane protein of hair cell stereocilia (TMHS) (lipoma HMGIC fusion partner-like 5, LHFPL5) promoter…”, which renders the claim indefinite because it is unclear whether the limitation in parenthesis are part of the claimed invention. MPEP § 2173.05(d) states, description of examples or preferences is properly set forth in the specification rather than the claims. If stated in the claims, examples and preferences may lead to confusion over the intended scope of a claim. Therefore, it is unclear whether the information in parentheses is exemplary or a limitation of the claim.
Claims 13-31 are included in the rejections because they ultimately depend from claim 12 and do not remedy the issue.
Double Patenting
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 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 12-27 and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-14, 16-19, and 21-28 of U.S. Patent No. 12,102,692 B2 in view of Gyӧrgy et al. (Molecular Therapy, Vol. 25 No. 2, published 01 February 2017, IDS ref.).
Regarding instant claims 12, 15, and 19-21, patented claims 1, 22, and 25 describes an AAV vector comprising an Anc80 capsid protein and a transgene comprising USH1C. Patented claim 2 describes a method of delivering a transgene to at least 80% of IHC and OHC (instant claims 20-21) in a subject’s inner ear to treat a hearing disorder by administering the AAV vector of claim 1 to the inner ear in a subject. Patented claim 4 describes the Anc80 capsid protein amino acid sequence, SEQ ID NO: 1, which has a 100% similarity match to instant SEQ ID NO: 1 (instant claim 19). The patented claims to not specifically require restoring hearing and vestibular function, however, this limitation is considered a result of administering the claimed vector. As such, it would be reasonable to expect the same results when administering the same vector.
Patented claim 6 describes the transgene is under control of a heterologous promoter, but does not point to the heterologous promoter, PCDH15.
However, a PCDH15 promoter would be obvious to utilize in a vector intended to be administered to the inner ear of a subject as this would be considered a cell specific promoter and cell specific promoters would reduce off target expression of a transgene (instant claim 15).
Regarding instant claim 13, the patented claims do not claim the USH1C encodes harmonin, however, the USH1C is known to encode harmonin as disclosed in the instant specification.
Regarding instant claim 14, the patented claims are silent to specific isoform of harmonin, however, selecting a known isoform would be considered obvious.
Regarding instant claims 16-18, the patented claims disclose an AAV vector, yet are silent to the serotype. Gyӧrgy teaches AAV transduction of inner ear hair cells using serotype AAV1 (Abstract). Therefore, it would have been obvious to utilize AAV1 as the serotype in the patented claims. Additionally, the patented specification discloses utilizing AAV1 and AAV2 (column 20 and Fig. 1).
Regarding instant claims 22-25, these claims recite intended results. Intended result are not given weight and since the method steps have been made obvious over the patented claims, the results, even if given weight, would necessarily occur.
Regarding instant claims 26 and 27, these claims recite intended results. Intended results are not given weight and since the method steps have been made obvious over the patented claims, the results, even if given weight, would necessarily occur. Additionally, patented claim 2 discloses treating a hearing disorder, which reads as reversing hearing loss (instant claim 26), partial hearing loss or complete deafness (instant claims 27).
Regarding instant claim 31, patented claim 8 discloses injecting the AAV vector through the round window.
Claims 12-27 and 31 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 and 7-14 of U.S. Patent No. 11,167,042 B2 in view of Gyӧrgy et al. (Molecular Therapy, Vol. 25 No. 2, published 01 February 2017).
Regarding instant claims 12, 15, and 19, patented claim 1 disclose an AAV vector comprising an Anc80 capsid protein and a transgene, USH1C. Patented claim 2 disclose a method of delivering a transgene to at least 80% IHCs and OHCs in a subject’s inner ear to treat a hearing disorder. Patented claim 3 discloses the Anc80 capsid sequence, SEQ ID NO: 1, which has a 100% similarity match to instant SEQ ID NO: 1 (instant claim 19). The patented claims to not specifically require restoring hearing and vestibular function, however, this limitation is considered a result of administering the claimed vector. As such, it would be reasonable to expect the same results when administering the same vector.
Patented claims 5 and 14 describes the transgene is under control of a heterologous promoter, but does not point to the heterologous promoter, PCDH15.
However, a PCDH15 promoter would be obvious to utilize in a vector intended to be administered to the inner ear of a subject as this would be considered a cell specific promoter and cell specific promoters would reduce off target expression of a transgene (instant claim 15).
Regarding instant claim 13, the patented claims do not claim the USH1C encodes harmonin, however, the USH1C is known to encode harmonin as disclosed in the instant specification.
Regarding instant claim 14, the patented claims are silent to specific isoform of harmonin, however, selecting a known isoform would be considered obvious.
Regarding instant claims 16-18, the patented claims disclose an AAV vector, yet are silent to the serotype. Gyӧrgy teaches AAV transduction of inner ear hair cells using serotype AAV1 (Abstract). Therefore, it would have been obvious to utilize AAV1 as the serotype in the patented claims. Additionally, the patented specification discloses utilizing AAV1 and AAV2 (column 18 and Fig. 1).
Regarding instant claims 20-21, patented claim 10 discloses a method wherein the transgene results in regeneration of IHCs and OHCs. This reads as the vector transduces inner hair cells (instant claim 20) and outer hair cells (instant claim 21).
Regarding instant claims 22-25, these claims recite intended results. Intended result are not given weight and since the method steps have been made obvious over the patented claims, the results, even if given weight, would necessarily occur.
Regarding instant claims 26 and 27, these claims recite intended results. Intended results are not given weight and since the method steps have been made obvious over the patented claims, the results, even if given weight, would necessarily occur. Additionally, patented claim 2 discloses treating a hearing disorder, which reads as reversing hearing loss (instant claim 26), partial hearing loss or complete deafness (instant claims 27).
Regarding instant claim 31, patented claim 7 discloses injecting the Anc AAV through the round window.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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