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 .
Priority
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/US2021/030055 (filed 04/30/2021). Acknowledgement is made of Applicants’ claim for benefit of U.S. Provisional Application No. 63/018,140 (filed 04/30/2020).
Response to Amendment
The amendment filed on 01/27/2026 has been received and entered into the application file.
Status of Prior Rejections/Response to Arguments
RE: Objection to claims 1, 3, and 5 for informalities:
The cancellation of claims 1 and 5 renders the objections thereto moot.
The amendment to claim 3 rectifying the informality is sufficient to obviate the remaining objection of record; accordingly, the objection is withdrawn.
RE: Rejection of the following under 35 U.S.C. 103:
claims 1-4, 7-11, and 14-15 over Maguire in view of Chiorini and Choudhury;
claims 5-6 over Maguire in view of Chiorini and Choudhury, further in view of Yoshimura and Kundakci; and
claims 12-13 over Maguire in view of Chiorini and Choudhury, further in view of Hopkins:
The cancelation of claims 1-2, 4-6, and 12-13 render the rejections thereof moot.
Claim 3 has been amended to recite the cochlear disorder or balance disorder as acute unilateral vestibulopathy (AUV), sudden sensorineural hearing loss (SSNHL), ototoxicity, benign paroxysmal positional vertigo (BPPV), tinnitus, Ménière's Disease, vestibular migraine, labyrinthitis, vestibular neuronitis, perilymph fistula, or Mal de Debarquement syndrome (MdDS).
Applicants assert the Maguire disclosure does not teach treating the disorders recited in amended claim 3. This argument is found persuasive as it pertains to treating a subject; however, claim 3 recites limitations directed to preventing and/or inhibiting said disorders, as well. The scope of the population in need of treatment for the disorders of claim 3 encompasses subjects having said disorders; the scope of the population in need of prevention or inhibition of said disorders encompasses the entirety of remaining subjects (i.e., subjects without one of the recited disorders). Therefore, by administering the rAAV in the modified method of Maguire set forth in the non-final Office action dated 10/28/2025, the method necessarily achieves the effect of preventing or inhibiting the disorders recited in amended claim 3.
Accordingly, the remaining rejections of record are modified and set forth below.
RE: Rejection of the following under 35 U.S.C. 103:
claims 1-4, 7-11, and 14-15 over Stankovic in view of Chiorini and Choudhury;
claims 5-6 over Stankovic in view of Chiorini and Choudhury, further in view of Yoshimura and Kundakci; and
claims 12-13 over Stankovic in view of Chiorini and Choudhury, further in view of Hopkins:
The cancelation of claims 1-2, 4-6, and 12-13 render the rejections thereof moot.
The amendment to claim 3 reciting the cochlear disorder or balance disorder as acute unilateral vestibulopathy (AUV), sudden sensorineural hearing loss (SSNHL), ototoxicity, benign paroxysmal positional vertigo (BPPV), tinnitus, Ménière's Disease, vestibular migraine, labyrinthitis, vestibular neuronitis, perilymph fistula, or Mal de Debarquement syndrome (MdDS) is sufficient to obviate the remaining rejections of record.
Accordingly, the rejections are withdrawn. New grounds of prior art rejections are set forth below.
RE: Rejection of claims 1-4, 7-11, and 14-15 on the ground of nonstatutory double patenting over claims 1-12 of U.S. Patent No. 11,447,797 in view of Maguire:
The cancelation of claims 1-2 and 4 renders the rejections thereof moot.
Claim 1 of U.S. Patent No. 11,447,797 recites an adeno-associated viral (AAV) vector comprising a nucleic acid sequence encoding a capsid comprising the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 9, wherein the AAV vector further comprises a heterologous nucleic acid sequence. SEQ ID NO: 4 shares 100% sequence identity with instant SEQ ID NO: 1 comprising a serine at residue 470; SEQ ID NO: 9 shares 100% sequence identity with instant SEQ ID NO: 1 comprising an asparagine at residue 470. Thus, the vector used in the method of the instant claims is rendered obvious by the vector taught in the claims of U.S. Patent No. 11,447,797.
As set forth in the Office action dated 10/28/2025, it has been held that a claim to a method of using a composition is not patentably distinct from an earlier claim to the identical composition in a patent disclosing the identical use. See Pfizer, 518 F.3d at 1363; Geneva, 349 F.3d at 1385-86, and Sun Pharmaceutical Industries v. Eli Lilly and Co., 611 F. 3d 1381, 1387 (CAFC 2010). See MPEP 804(II)(B)(1).
However, Applicants assert the subject matter of the specification of U.S. Patent No. 11,447,797 is specific to methods of treating methylmalonic acidaemia, wherein cells targeted for transduction are in the liver, as well as methods of treating hypoparathyroidism, wherein cells targeted for transduction are in salivary glands. This argument is found persuasive, as the methods disclosed by the patent under discussion differ in scope from the claimed method of the instant application.
Accordingly, the remaining rejections of record are withdrawn.
Claim Interpretation
The following comments are made to establish broadest reasonable interpretation for the record.
Regarding claim 8: The instant claim recites a number of genes the heterologous nucleic acid sequence of claim 1 may encode, including USH3. As evidenced by Västinsalo, et al. (pg. 30; col. 1, par. 2. Eur J Hum Genet. 2011), the gene encoding clarin-1 was initially known as USH3A but has since been renamed to CLRN1. Therefore, the term USH3 as recited in claim 8 is interpreted as an alternative term for the gene encoding clarin-1.
Claim Objections
Claim 3 is objected to for the following informality: Line 8 recites “…vertibular migraine…”; this should read “…vestibular migraine…”.
Appropriate correction is required.
Modified Grounds of Prior Art Rejections
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.
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.
Claims 3, 7-11, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Maguire, et al. (US 2021/0079406), in view of Chiorini, et al. (US 2018/0355376) and Choudhury, et al. (Invest Ophthalmol Vis Sci. 2018); as evidenced by Beranova-Giorgianni and Giorgianni (Proteomes. 2018), Atkinson, et al. (Development. 2015), and Holt and Vandenberghe (Mol Ther. 2012).
Maguire, et al. teaches compositions and methods useful for treating hereditary hearing loss (Abstract).
Chiorini, et al. teaches an adeno-associated virus isolate and fusion protein (Title).
Choudhury, et al. teaches a novel capsid protein that efficiently transduces photoreceptors and retinal pigment epithelium (Title).
Regarding claims 3, 8, 10, 14: Maguire, et al. teaches a method for transducing an outer hair cell or inner hair cell with an rAAV (par. 0017), wherein the rAAV comprises a transgene encoding clarin-1 (par. 0005), and an AAV9.PHP.B capsid protein (par. 0011). Maguire, et al. further teaches administering to a subject an effective amount of rAAV to express clarin-1 (par. 0018). As set forth above, the scope of the population in need of treatment for the cochlear or balance disorders recited in claim 3 encompasses subjects having said disorders; the scope of the population in need of prevention or inhibition of said disorders encompasses the entirety of remaining subjects (i.e., subjects without one of the recited disorders). Maguire, et al. teaches the rAAV for treating hereditary hearing loss (par. 0018); therefore, the population of subjects with hereditary hearing loss necessarily comprises subjects in need of prevention or inhibition of AUV, SSNHL, ototoxicity, BPPV, tinnitus, Ménière's Disease, vestibular migraine, labyrinthitis, vestibular neuronitis, perilymph fistula, MdDS. Thus, the administering to a subject an effective amount of the rAAV, as taught by Maguire, necessarily achieves the effect of preventing or inhibiting the disorders recited in claim 3.
Thus, Maguire, et al. renders obvious:
the method of preventing or inhibiting a cochlear disorder or balance disorder in a subject comprising administering to the subject an AAV vector, wherein the AAV vector comprises a heterologous nucleic acid sequence, thereby preventing or inhibiting the cochlear disorder in the subject, wherein the cochlear disorder or balance disorder is acute unilateral vestibulopathy (AUV), sudden sensorineural hearing loss (SSNHL), ototoxicity, benign paroxysmal positional vertigo (BPPV), tinnitus, Ménière's Disease, vestibular migraine, labyrinthitis, vestibular neuronitis, perilymph fistula, Mal de Debarquement syndrome (MdDS) limitations recited in claim 3; and
the wherein the heterologous nucleic acid sequence encodes USH3 limitation recited in claim 8.
Maguire, et al. does not teach the capsid protein as comprising the amino acid sequence of SEQ ID NO: 1, as required by the remaining limitation recited in the instant claim.
Chiorini, et al. teaches a capsid protein comprising the amino acid sequence as set forth in SEQ ID NO: 4, which corresponds to capsid protein VP1 of AAV44.9 (par. 0021); SEQ ID NO: 4 comprises a serine at residue 470, and shares 100% sequence identity with SEQ ID NO: 1 comprising a serine at residue 470. Chiorini, et al. also teaches nucleic acid sequence SEQ ID NO: 5, which encodes the capsid (par. 0033); SEQ ID NO: 5 shares 100% sequence identity with instant SEQ ID NO: 2. Please see end of Office action for all sequence alignments.
Thus, Chiorini, et al. reads on:
the nucleic acid sequence encoding a capsid comprising the amino acid sequence of SEQ ID NO:1 limitation recited in claim 3;
the wherein the capsid is encoded by the nucleic acid sequence of SEQ ID NO: 2 limitation recited in claim 10; and
the wherein residue 470 of the amino acid sequence of SEQ ID NO: 1 is serine limitation recited in claim 14.
It would have been prima facie obvious to a person having ordinary skill in the art to have substituted the AAV44.9 VP1 capsid protein encoded by SEQ ID NO: 4 as taught by Chiorini, et al. for the AAV9.PHP.B capsid protein in the method taught by Maguire, et al. This conclusion of obviousness is based on the ‘substitution rationale’. The use of the AAV44.9 VP1 capsid protein in place of the AAV9.PHP.B capsid protein is a predictable use of prior art elements according to their established functions of facilitating viral entry into a host cell, leading to the predictable result of delivery of genetic material into the host cell.
Further, Choudhury, et al. teaches AAV44.9 resulted in extensive transduction of RPE cells with subretinal injections of mice (Abstract: Results). As evidenced by Beranova-Giorgianni and Giorgianni, RPE cells are polarized cells in the retina which interact with outer segments of photoreceptors by receiving and processing input from systemic circulation via the choroid capillary system, i.e., mechanoreceptors (pg. 1; par. 2); as evidenced by Atkinson, et al., hair cells residing in the inner ear sensory organs including the cochlea are mechanoreceptors (pg. 1561; col. 1, par. 1). Thus, a person having ordinary skill in the art would have a reasonable expectation of success in substituting the AAV44.9 VP1 capsid protein capable of transducing mechanoreceptor RPE cells for the AAV9.PHP.B capsid protein in a method comprising transduction of mechanoreceptor hair cells. This rationale aligns with the principle of a simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(B).
Thus, the limitations recited in claims 3, 8, 10, and 14 are rendered obvious.
Regarding claim 7: Following the above discussion, Maguire, et al. teaches an embodiment wherein the transgene encoding clarin-1 further comprises a promoter, such as a chicken β-actin (CBA) promoter (par. 0007); as evidenced by Holt and Vandenberghe, the chicken β-actin promoter has strong activity in inner hair cells (pg. 1837; col. 1, par. 1). Thus, the modified method of Maguire, et al. in which the transgene is under the control of a chicken β-actin promoter reads on the wherein the heterologous nucleic acid sequence is operably linked to regulatory sequences which direct expression of the heterologous nucleic acid sequence in hairs of the inner ear limitation recited in claim 7.
Regarding claim 9: Following the above discussion, Maguire, et al. teaches an embodiment wherein the rAAV comprises a first region comprising an AAV inverted terminal repeat, a second region comprising a transgene encoding clarin-1, and a third region comprising a second AAV inverted terminal repeat (pars. 0005, 0008); this reads on the wherein the heterologous nucleic acid sequence is flanked by one or more inverted terminal repeat (ITR) sequences limitation recited in claim 9.
Regarding claim 11: Following the above discussion, Maguire, et al. teaches a pharmaceutical composition comprising the rAAV and a pharmaceutically acceptable carrier (par. 0016); this reads on the wherein the AAV vector is in a composition with a pharmaceutically acceptable carrier limitation recited in claim 11.
Regarding claim 15: Following the above discussion, Chiorini, et al. teaches an embodiment wherein the capsid protein comprises the amino acid sequence as set forth in SEQ ID NO: 9, which corresponds to capsid protein VP1 of AAV44.9 (par. 0022). As the sequence set forth as SEQ ID NO: 9 of Chiorini, et al. comprises an asparagine at residue 470, this reads on the amino acid sequence of SEQ ID NO: 1 limitation recited in claim 1 as well as the wherein residue 470 of the amino acid sequence of SEQ ID NO: 1 is asparagine limitation recited in claim 15. (See end of Office action for sequence alignments.) For the same reasons set forth above in the rejection of claim 1, it would have been prima facie obvious to a person having ordinary skill in the art to have substituted the AAV44.9 VP1 capsid protein encoded by SEQ ID NO: 9 as taught by Chiorini, et al. for the AAV9.PHP.B capsid protein in the method taught by Maguire, et al., rendering obvious the limitations recited in claim 15.
New Grounds of Prior Art Rejections
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.
Claims 3, 7-11, and 14-15 are rejected under 35 U.S.C. 103 as being unpatentable over Burns, et al. (WO 2019/210181), in view of Chiorini, et al. (US 2018/0355376) and Choudhury, et al. (Invest Ophthalmol Vis Sci. 2018); as evidenced by Beranova-Giorgianni and Giorgianni (Proteomes. 2018), and Atkinson, et al. (Development. 2015).
Burns, et al. teaches polynucleotides containing regions of the Myosin 15 promoter and vectors containing the same, used for expression of a transgene specifically in hair cells (Abstract).
The teachings of Chiorini, et al. and Choudhury, et al. are set forth above.
Regarding claims 3, 7-8, 10, 14: Burns, et al. teaches nucleic acid vectors containing regions of the Myosin 15 (Myo15) promoter operably linked to a transgene (pg. 14, par. 1; pg. 15, par. 2), wherein the Myo15 promoter is capable of expressing a transgene specifically in cochlear hair cells (pg. 14, par. 1); the transgene may be ATOH1, OTOF, USH1C, CLRN1, BDNF, or HSP70 (pg. 3, par. 4). Burns, et al. also teaches methods of treatment wherein the AAV is administered to a subject for the treatment of sensorineural hearing loss or tinnitus (pg. 32, pars. 2-3), as well as to prevent or reduce ototoxic drug-induced hair cell damage or death (pg. 33, par. 3).
Thus, Burns, et al. renders obvious:
the method of treating a cochlear disorder or balance disorder in a subject comprising administering to the subject an AAV vector, wherein the AAV vector comprises a heterologous nucleic acid sequence, thereby treating the cochlear disorder in the subject, wherein the cochlear disorder or balance disorder is sudden sensorineural hearing loss (SSNHL), ototoxicity, or tinnitus limitations recited in claim 3;
the method of preventing or inhibiting a cochlear disorder or balance disorder in a subject comprising administering to the subject an AAV vector, wherein the AAV vector comprises a heterologous nucleic acid sequence, thereby preventing or inhibiting the cochlear disorder in the subject, wherein the cochlear disorder or balance disorder is acute unilateral vestibulopathy (AUV), benign paroxysmal positional vertigo (BPPV), Ménière's Disease, vestibular migraine, labyrinthitis, vestibular neuronitis, perilymph fistula, Mal de Debarquement syndrome (MdDS) limitations recited in claim 3 (for the same reasons as stated in the claim 3 rejection over Maguire);
the wherein the heterologous nucleic acid sequence is operably linked to regulatory sequences which direct expression of the heterologous nucleic acid sequence in hairs of the inner ear limitation recited in claim 7; and
the wherein the heterologous nucleic acid sequence encodes ATOH1, BDNF, USH1, USH3, HSP70-1, and OTOF limitations recited in claim 8.
Additionally disclosed is an embodiment wherein the vector is an rAAV virion comprising capsid proteins encoded by an AAV cap gene (pg. 30, par. 1). However, Burns, et al. does not teach specific sequences to encode the capsid proteins.
Chiorini, et al. teaches a capsid protein comprising the amino acid sequence as set forth in SEQ ID NO: 4, which corresponds to capsid protein VP1 of AAV44.9 (par. 0021); SEQ ID NO: 4 comprises a serine at residue 470, and shares 100% sequence identity with SEQ ID NO: 1 comprising a serine at residue 470. Chiorini, et al. also teaches nucleic acid sequence SEQ ID NO: 5, which encodes the capsid (par. 0033); SEQ ID NO: 5 shares 100% sequence identity with instant SEQ ID NO: 2. Please see end of Office action for all sequence alignments.
Thus, Chiorini, et al. reads on:
the nucleic acid sequence encoding a capsid comprising the amino acid sequence of SEQ ID NO:1 limitation recited in claim 3;
the wherein the capsid is encoded by the nucleic acid sequence of SEQ ID NO: 2 limitation recited in claim 10; and
the wherein residue 470 of the amino acid sequence of SEQ ID NO: 1 is serine limitation recited in claim 14.
It would have been prima facie obvious to a person having ordinary skill in the art to have modified the rAAV virion of Burns, et al. by using the sequence as set forth in SEQ ID NO: 4 to encode the capsid protein VP1 of AAV44.9, as taught by Chiorini, et al. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. A skilled artisan would have been motivated to use the capsid protein taught by Chiorini, et al. because of its high gene transfer activity in a number of cell types (par. 0020). Further, Choudhury, et al. teaches AAV44.9 resulted in extensive transduction of RPE cells with subretinal injections of mice (Abstract: Results). As evidenced by Beranova-Giorgianni and Giorgianni, RPE cells are polarized cells in the retina which interact with outer segments of photoreceptors by receiving and processing input from systemic circulation via the choroid capillary system, i.e., mechanoreceptors (pg. 1; par. 2); as evidenced by Atkinson, et al., hair cells residing in the inner ear sensory organs including the cochlea are mechanoreceptors (pg. 1561; col. 1, par. 1). Thus, a person having ordinary skill in the art would have a reasonable expectation of success in the modification set forth above.
Thus, the limitations recited in claims 3, 7-8, 10, and 14 are rendered obvious.
Regarding claim 9: Following the above discussion, Burns, et al. teaches an embodiment wherein the rAAV vector comprises flanking ITRs (pg. 29, par. 2); this reads on the wherein the heterologous nucleic acid sequence is flanked by one or more inverted terminal repeat (ITR) sequences limitation recited in claim 9.
Regarding claim 11: Following the above discussion, Burns, et al. teaches an embodiment wherein the rAAV is contained in a pharmaceutical composition (pg. 31, par. 1); this reads on the wherein the AAV vector is in a composition with a pharmaceutically acceptable carrier limitation recited in claim 11.
Regarding claim 15: Following the above discussion, Chiorini, et al. teaches an embodiment wherein the capsid protein comprises the amino acid sequence as set forth in SEQ ID NO: 9, which corresponds to capsid protein VP1 of AAV44.9 (par. 0022). As the sequence set forth as SEQ ID NO: 9 of Chiorini, et al. comprises an asparagine at residue 470, this reads on the amino acid sequence of SEQ ID NO: 1 limitation recited in claim 3, as well as the wherein residue 470 of the amino acid sequence of SEQ ID NO: 1 is asparagine limitation recited in claim 15. (See end of Office action for sequence alignments.) For the same reasons set forth above in the rejection of claim 3, it would have been prima facie obvious to a person having ordinary skill in the art to have used the AAV44.9 VP1 capsid protein encoded by SEQ ID NO: 9 as taught by Chiorini, et al. modify the rAAV virion of Burns, et al., rendering obvious the limitations recited in claim 15.
Conclusion
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 GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
SEQUENCE ALIGNMENTS
Query (instant SEQ ID NO: 1) vs. Subject (Chiorini, et al.; SEQ ID NO: 4)
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4
621
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Query (instant SEQ ID NO: 1) vs. Subject (Chiorini, et al.; SEQ ID NO: 9)
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3
618
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Query (instant SEQ ID NO: 2) vs. Subject (Chiorini, et al.; SEQ ID NO: 5)
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100
614
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Prosecution Insights