DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicants’ amendments to the claims and arguments filed on August 14, 2026, have been received and entered. Claims 1-50, 52-53, 56-57, 59, 71 and 72 have been canceled, while claims 51 and 63 have been amended. Claims 73-80 are newly added. Claims 51, 54-55, 58, 60-70, 73-80 are pending in the instant application.
Election/Restrictions
Applicants’ election without traverse of claims 51-62 in the reply filed on July 15, 2025, was acknowledged. Claims 63-70 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 15, 2025.
Claims 51-55, 57-61, 73-79 are directed to an allowable product. Pursuant to the procedures set forth in MPEP § 821.04(B), claims 63-70, 73-80, directed to the process of using an allowable product, previously withdrawn from consideration as a result of a restriction requirement, claims 62-70, 82-84 are hereby rejoined and fully examined for patentability under 37 CFR 1.104.
Because all claims previously withdrawn from consideration under 37 CFR 1.142 have been rejoined, the restriction requirement as set forth in the Office action mailed on May 15, 2025, is hereby withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 51, 54-55, 58, 60-70, 73-80 are under consideration.
Priority
This application is a Divisional of US application no 18/134,095 filed on 04/13/2023, which is a continuation of PCT/US21/61205 filed on 11/30/2021, which claims priority from US provisional 63/152,832 filed on 02/23/2021 and 63/120,189 filed on 12/01/2020
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/14/226 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 51, 54-55, 58, 60-70, 73-80 are under consideration.
Withdrawn-Claim Rejections - 35 USC § 103
Claims 51, 54-55, 58, 60-62 and 72 were rejected under 35 U.S.C. 103 as being unpatentable Vandenberghe (WO/2015/054653, 4/15/2015, IDS), as evidenced by Ambion Catalogue (PBS, Catalog #: AM9624-AM9625, 2006, page 1), Suzuki (Scientific Reports, 2017, 7: 45524, 1-10, IDS), Simons (WO2019126329, dated 6/27/2019, IDS), Bennicelli et al (Molecular Therapy, 2008, 16 (3), 458-465, art of record)/Mathur (US 20230242939, EFD, 01/29/2020) and Colosi (WO2015038625, dated 03/19/2015).
In view of Applicants’ amendment to the base claim introducing the limitation “a nucleic acid construct comprising the nucleotide sequence of SEQ ID NO: 91 or SEQ ID NO: 92” obviate the basis of the rejection. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
New-Claim Rejections - 35 USC § 112 -necessitated by amendments
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 63-70, 82-84 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 delivering a nucleic acid encoding anti-VEGF polypeptide in a mammalian subject, said method comprising
directly introducing into cochlea of the mammalian subject, a composition comprising an effective amount of an adeno-associated virus (AAV) particle, and wherein the AAV particle comprises (i) a nucleotide sequence construct comprising the nucleotide sequence of SEQ ID NO: 91 or 92 and (ii) an AAV Anc80 capsid,
wherein the composition comprises:(i) 8.1 mM sodium phosphate dibasic,(ii) 1.5 mM monopotassium phosphate,(iii) 2.7 mM potassium chloride,(iv) 172 mM sodium chloride, and(v) 0.001 % Poloxamer 188., and wherein said administration results in anti-VEGF protein expression in the inner ear hair cells of the cochlea,
does not reasonably provide enablement for delivering a pharmaceutical composition comprising adeno-associated virus (AAV) particles to the inner ear of a subject via any other route, administering to any and all inner ear disorder including vestibular schwannoma or neurofibromatosis type II. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
The claims are directed to a method of delivering a pharmaceutical composition to the inner ear of a subject, wherein the pharmaceutical composition comprises an adeno- associated virus (AAV) particle, wherein the AAV particle comprises:(i) a nucleic acid construct comprising the nucleotide sequence set forth in SEQ ID NO: 91 or SEQ ID NO: 92, and(ii) an AAV Anc80 capsid, wherein the composition comprises:(i) 8.1 mM sodium phosphate dibasic,(ii) 1.5 mM monopotassium phosphate,(iii) 2.7 mM potassium chloride,(iv) 172 mM sodium chloride, and(v) 0.001 % Poloxamer 188. Dependent claims limit the composition is delivered via a round window membrane injection. wherein the inner ear disorder is vestibular schwannoma or neurofibromatosis type II (NF2) and wherein the AAV Anc80 capsid is an AAV Anc80L65 capsid.
Breadth of the claims:
The claims are broadly directed to a method comprising: delivering via any means a pharmaceutical composition comprising any amount or a dose of adeno-associated virus (AAV) particles to the inner ear of a subject into any site of an inner ear of a subject.
It is noted that while claims are directed to an active method of administering via any mean a pharmaceutical composition of adeno-associated virus (AAV) into an inner ear of a subject (claim 63) having inner ear disorder (claim 67), therefore, claims delivering a pharmaceutical composition in part are interpreted as method of treating a subject having inner ear disorder in view of disclosure of the specification (see para. 41-43 of the specification).
It is emphasized that instant rejection is based on four separate issues: 1) administering via any route a pharmaceutical composition comprising an adeno-associated virus (AAV) of the invention to have an effect on treating inner ear disorder of any etiology and pathology, 2) the absence of an enabling disclosure of correlating the local expression of anti VEGF protein in diseased cells/organ of inner ear that specifically bind VEGF proteins at a level sufficient to treat genus of inner ear disorder in a subject as embraced by the breadth of claims 63, 67-68; (3) delivering an AAV encoding anti-VEGF polypeptide in any predictable animal model of genus of inner ear disorder; and 4) nexus between cellular pathology associated with inner ear disease to local expression in cells of inner ear that exhibit treatment of inner ear disease. The deficiencies were identified by the Office after analysis of the disclosure provided in the instant application. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404.
Guidance of the Specification and The Existence of Working Examples:
The specification y provides a general description of a method that provides administration of anti-VEGF constructs, which can express anti-VEGF proteins ( ranibizumab, bevacizumab, and/or aflibercept) can be useful in treating conditions, diseases, or disorders associated with neovascularization. (see para, 5 of the published application).
Example 1 teaches construction of viral AAV encoding Ranibizumab-PC, and Bevacizumab (see fig. 6). Example 2 teaches purifying rAAVAnc80-Ranibizumab, rAAVAnc80-Ranibizumab-PC, and rAAVAnc80-Bevacizumab-PC particles. Example 3 teaches formulation of rAAVAnc80-antiVEGF particles. Examples 5and 6 teaches the transduction and/or transfection of exemplary constructs, and expression and secretion of exemplary proteins described herein. Subsequent disclosure pertains to binding activity of anti-VEGF proteins produced from cell lines. Example 7 teaches ex-vivo demonstration of anti-VEGF protein production. n these experiments, an organ of Corti was dissected and mounted on coverslips, followed by incubation for three to four days with either vehicle or a range of doses of rAAV particles-rAAVAnc80-ranibizumab-PC particles or rAAVAnc80-bevacizumab-PC particles. An rAAVAnc80-bevacizumab-PC particle was transduced at 1.2E10, 2.4E10, and 3.5E10 vg/explant, while an rAAVAnc80-ranibizumab-PC particle was transduced at 1.4E10, 2.8E10, and 4.2E10 vg/explant. Anti-VEGF RNA was detected in the explants receiving rAAVAnc80-antiVEGF particles, but not those receiving vehicle (FIG. 16, Panel (A)), and secreted anti-VEGF protein was detected in the media of the explants receiving rAAVAnc80-antiVEGF particles, but not those receiving vehicle (FIG. 16, Panel (B)). Example 9 teaches evaluating and measuring anti-VEGF levels in CSF and serum, after intracochlear delivery of rAAV particles as described herein comprising constructs encoding anti VEGF. rAAVAnc80-ranibizumab-PC particles or rAAVAnc80-bevacizumab-PC particles. The results out of 17 cochleae, 14 also showed expression in a subset of OHCs and/or non-hair cells. No substantial difference was detected in the cell identity and expression pattern between ears receiving rAAVAnc80-ranibizumab-PC particles compared to those receiving rAAVAnc80-bevacizumab-PC particles (see fig. 23 and 24). Example 10 provides general methodology of performing phenotypic analysis of transgenic expression of Anti-VEGF protein encoding mRNA and protein expression in murine models of vestibular schwannoma (VS). The specification contemplates evaluating the potential for inner ear toxicity, following gross examination, a cochleae that could be processed, dissected, and stained, and a cytocochleogram analysis could be performed to evaluate loss of IHCs and/or OHCs. The opposite cochlea/ear can be processed for middle- and inner-ear histopathology and microscopic evaluation. This assertion clearly shows that instant specification fails to enable a method of treating any inner ear disorder in a subject, comprising: administering a dose of an adeno-associated virus (AAV) particle to the inner ear of the subject suggesting the prophetic nature of the invention that was not reduced to practice before the effective filing date of the invention.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The art summarized by the references of Qi et al (Fundamental Research, 2025, 192-202) teaches hearing loss could be due to congenital abnormalities, degenerative changes in old age, and acquired injuries such as virus or ototoxic drug-induced diseases (abstract). The art teaches relatively closed structure of the inner ear and the presence of the blood-labyrinth barrier between the inner ear and the systemic blood circulation leads to difficulty in achieving effective doses of drugs in the inner ear via systemic administration (see page 197, col. 2, para. 3). In the organ of Corti, the scala media is filled with endolymph, while the other two chambers are filled with perilymph. Viral vectors can be directly delivered to the endolymph or the perilymph in order to access sensory cells by fluid diffusion. Viruses can be injected through the RWM, the cochlear duct, or the semicircular canal, and these are referred to as RWM injection, cochleostomy, and canalostomy, respectively (see page 197, col. 2, para. 3). In the instant case, guidance provided in the specification is limited to intracochlear delivery of rAAV particles (see example above). The teaching of specification is consistent with the state of art showing RWM injection has been successfully applied for virus delivery into the inner ear in both neonatal and adult mice with no resulting cochlear damage or hearing impairment (see Qi, page 107, col. 2, para. 4 and reference therein). Qi in part rely on the teaching of Landegger et al. (prior art of record, Nature Biotechnology volume 35, pages280–284, 2017, IDS) discovered that Anc80L65 can simultaneously transduce the OHCs and IHCs of the mouse cochlea with nearly 100% infection efficiency (see page 198, col. ,1, para. 4).
The art teaches “deafness cannot be treated by simple gene delivery when the target cells are absent or have been severely damaged, So, it is important to choose the appropriate time windows for treatment in mice models” (see page 199, col. 2, para. 2). Qi states “Anc80L65 can simultaneously transduce the OHCs and IHCs of the mouse cochlea with nearly 100% infection efficiency in neonatal mice but rarely infects outer hair cells in adult mice and nonhuman primate model (NHP)”. It is further disclosed that Over 250 genes are associated with syndromic and nonsyndromic types of hearing loss. “most mutation-induced deafness” belongs to rare diseases. A variety of deafness genes only affect a few families, raising concerns about the rationality and feasibility of developing personalized treatments for these types of deafness. However, due to the large population of inherited deafness and the large proportion of rare mutations in deafness patient, translational therapeutic solutions still need to be developed. (see page 199, col. 1, para. 2 and 3). Further, in the instant case the issues relate to the predictability of animal model with respect to the breadth of claims intended to deliver an AAV encoding an anti VEGF antibody for treating plurality of different inner ear disorder in a mammal, which lacks nexus between delivery of AAV to inner ear to reversal or improvement of any cellular pathology associated with any of the inner ear disorder. Gehlhausen et al (Human Molecular Genetics, 2015, Vol. 24, No. 1, 1-8) teach Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disorder resulting from germline mutations in the NF2 gene. The art reports that the development of cranial nerve VIII tumors correlates with functional impairments in hearing and balance, as measured by auditory brainstem response and vestibular testing (abstract). Gehlhausen et al teaches “short-term improvements in hearing with Bevacizumab treatment of vestibular schwannomas in NF2 patients are not consistently associated with a reduction in tumor size. It has also been suggested that biochemical disturbance of the inner-ear fluids could be the underlying cause of hearing loss related to these tumors. Otoacoustic-emission studies in patients with vestibular schwannomas support the hypothesis that some degree of hearing loss is cochlear in origin. Altogether, the degree to which hearing loss in these patients is retro cochlear or cochlear in origin remains an open question (see page 5, col. 2, last para. to page 6, col. 1, para. 1). The specification is silent on correlating any CN VIII lesions with potential functional hearing deficits that are reduced following delivery of instantly claimed AAV nor do the specification provide any guidance on click-evoked auditory brainstem response (ABR) or any means to show hearing improvement in a hearing loss observed in a predictable animal model. There is no nexus between cellular pathology associated with any inner ear disease that could be overcome by local expression in anti-VEGF antibody in cells of inner ear that exhibit treatment of inner ear disease. Absent of any teaching or recognition in the art that AAV encoding anti-VEGF antibody are capable of transducing inner ear cells located in inner ear of mammals with vestibular schwannoma, or neurofibromatosis type II. The lack of guidance in the specification would force the skilled practitioner to establish animal models with associated pathology in different species of mammal to study the effect of AAVanc80 encoding an anti VEGF antibody as broadly claimed and determine the resulting effect of AAVanc80 in the treatment of vestibular schwannoma, or neurofibromatosis type II or delivery of antibody that binds to any isoform of mammalian VEGF in the treatment of vestibular schwannoma, or neurofibromatosis type II. Such guessing would require extensive and undue experimentation. Applicant should note that “case law requires that the disclosure of an application shall inform those skilled in the art how to use applicants’ alleged discovery, not to find out how to use it for themselves.” In re Gardner 166 USPQ 138 (CCPA) 1970.
The specification fails to teach to which extent, AAV particles transduce cell types present in the genus of inner ear disorder, nor do they show any expression and/or secretion of anti-VEGF antibody in an inner ear can be expressed by delivering the vector via any route in vivo that exert any therapeutic effect. There is no in vitro to in vivo correlation of AAV particles delivered via any route into inner ear to express an anti VEGF antibody in a predictable model of inner ear disorder. Thus, given the breadth of the claims, it is apparent that one of skilled in the art would require the identification and characterization of all the different serotype of AAVAnc80 serotype delivered via any route into inner ear by testing their ability to infect the different cells of inner ear affected by the plurality of inner ear disorder in a predictable animal model of different inner ear disorder including acoustic neuroma, genetic mutation, vestibular schwannoma, or neurofibromatosis type II to make use of the invention. Given, the variable and unpredictable expression pattern of AAVanc80 particle delivered into inner ear via different route and the lack of guidance provided by the specification with respect to determine the extent of transduction of AAV particle in cell types present in a subject having a genus of inner ear disorder embraced by the breadth of the claim would require undue experimentation for one of skill in the art to make and use the invention, without a reasonable expectation of success. An artisan would have to carry out extensive experimentation to make use of the invention without reasonable expectation of success, and such experimentation would have been undue because of the treatment of inner ear disorder by delivering AAV via any other route other than direct injection into RWM or cochlea in vivo is unpredictable and specification fails to provide any guidance as to how the claimed method would have been practiced commensurate with full scope of the claims. Although, specific viruses, vectors, promoters, nucleic acid encoding antibody that binds to different isoform of mammalian VEGF, and route of administration might be or may have been effective for treatment of specific inner ear disease providing specific therapeutic effect. Gene therapy as a broad-based art is clearly unpredictable in terms of achieving levels and duration of expression of a gene of interest, which results in a therapeutic effect. A showing that enough of a nucleic acid encoding antibody that binds to VEGF and thereby inhibits the activity of a vascular endothelial growth factor is expressed in the target cell (one or more of inner ear cells that are affected by the disease), enough nucleic acid is incorporated into the target cells, that such nucleic acid is properly incorporated into such cells as DNA, enough mRNA is produced therefrom, and enough protein is produced and enhanced antibody expression that inhibits the activity of a vascular endothelial growth factor expression have an effect on the target cells ((inner ear cells that are affected by different inner ear disease)) and such effect is enough of an effect for a long enough period of time to any inner ear disorder in a predictable animal model. Absent of any specific dose of rAAV in a specific volume of liquid suspension that is delivered to maintain an effective concentration of the transgene product at the target site in a predictable animal model for genus of inner ear disorder, an artisan of skill would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. This is because of transport barriers for AAV particles, sorting targets to maximize efficiency, characterizing the optimum therapeutic window for treatment, and identifying the best route were known to be critical and unpredictable parameter in achieving more favorable AAV gene therapy for the treatment of inner ear disorder as supported by the observations in the art record. In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled for the full scope of the claimed inventions.
New -Double Patenting Rejection- necessitated by amendments
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 63-70, 73-80 are provisionally rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 27, 29-40, 51-60 of copending Application No 19254653 in view of Mathur (US 20230242939, EFD, 01/29/2020). Although the claims at issue are not identical, they are not patentably distinct from each other because both method overlaps delivering a composition to a subject having inner ear disorder. In the instant case, claims are directed to a method of delivering a pharmaceutical composition to the inner ear of a subject, wherein the pharmaceutical composition comprises an adeno- associated virus (AAV) particle, wherein the AAV particle comprises:(i) a nucleic acid construct comprising the nucleotide sequence set forth in SEQ ID NO: 91 or SEQ ID NO: 92, and(ii) an AAV Anc80 capsid wherein the composition comprises:(i) 8.1 mM sodium phosphate dibasic,(ii) 1.5 mM monopotassium phosphate,(iii) 2.7 mM potassium chloride,(iv) 172 mM sodium chloride, and(v) 0.001 % Poloxamer 188 9claim 63). Dependent claim limits the method, wherein the AAV Anc80 capsid is an AAV Anc80L65 capsid comprising the sequence of SEQ ID NO: 114. Claims further limits the method, wherein the composition has a volume of 0.01 mL to 2.00 mL and wherein method comprises delivering the pharmaceutical composition is administered via a round window membrane injection or via intracochlear administration.. In contrast, claims in ‘653 are directed to a method of method comprising contacting an inner ear cell with an adeno- associated virus (AAV) particle, comprising:(i) a nucleic acid construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof; and(ii) AAV Anc80 capsid (claim 27). Claims are also directed to a method comprising introducing into an inner ear of a subject an adeno-associated virus (AAV) particle, comprising:(i) a nucleic acid construct comprising a coding sequence operably linked to a promoter, wherein the coding sequence encodes a vascular endothelial growth factor (VEGF) binding agent or a portion thereof; and(ii) AAV Anc80 capsid Dependent claims limit the AAV Anc80 capsid is an AAV Anc80L65 capsid comprises an amino acid sequence according to SEQ ID NO: 113 or SEQ ID NO: 114 and wherein the nucleic acid construct comprises a nucleic acid sequence according SEQ ID NOs: 91 or 92.Claims further limit the method, wherein the pharmaceutical composition is formulated for intra-cochlear delivery or wherein the AAV particle is introduced into the inner ear of the subject via intra-cochlear administration or wherein the AAV particle is introduced into the inner ear of the subject via a round window membrane injection. The claims in ‘653 differ from claimed invention by not disclosing the composition comprises :(i) 8.1 mM sodium phosphate dibasic, (ii) 1.5 mM monopotassium phosphate, (iii) 2.7 mM potassium chloride,(iv) 172 mM sodium chloride, and(v) 0.001 % Poloxamer 188. Mathur cures the deficiency by disclosing reported formulating AAV particles in PBS that may comprise sodium chloride, potassium chloride, disodium phosphate, monopotassium phosphate, and distilled water (see para. 572), wherein dibasic sodium phosphate may be 8.1-8.6 mM (see para. 575) and monopotassium phosphate is in a range of 1.2-1.7 mM, Sodium chloride may be in formulation ranging from 171-172mM (see para. 582), KCl ranging from 1.2-1.7 mM (see para. 587) and 0.001% poloxamer 188 (See claim 91 of ‘939). Accordingly, it would have been prima facie obvious for one of ordinary skill in the art seeking to use an AAV particle suitable for gene therapy to modify the AAV particle composition of ‘653 by formulating in PBS with PF-68 as suggested in Mathur, for successful delivery and transduction of virus particles in inner ear cells, with reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 63-70, 73-80 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of USP 12365726 in view of Simons (WO2019126329, dated 6/27/2019, IDS)/ Mathur (US 20230242939, EFD, 01/29/2020). Although the claims at issue are not identical, they are not patentably distinct from each other because claims in the instant application uses the composition comprising an adeno-associated virus (AAV) particle of ‘726.
In the instant case, claims are directed to a method of delivering a pharmaceutical composition to the inner ear of a subject, wherein the pharmaceutical composition comprises an adeno- associated virus (AAV) particle, wherein the AAV particle comprises:(i) a nucleic acid construct comprising the nucleotide sequence set forth in SEQ ID NO: 91 or SEQ ID NO: 92, and(ii) an AAV Anc80 capsid wherein the composition comprises:(i) 8.1 mM sodium phosphate dibasic,(ii) 1.5 mM monopotassium phosphate,(iii) 2.7 mM potassium chloride,(iv) 172 mM sodium chloride, and(v) 0.001 % Poloxamer 188 9claim 63). Dependent claim limits the method, wherein the AAV Anc80 capsid is an AAV Anc80L65 capsid comprising the sequence of SEQ ID NO: 114. Claims further limits the method, wherein the composition has a volume of 0.01 mL to 2.00 mL and wherein method comprises delivering the pharmaceutical composition is administered via a round window membrane injection or via intracochlear administration. In contrast, claims in ‘726 are directed to an adeno-associated virus (AAV) particle or pharmaceutical composition comprising: (i) a nucleic acid construct that comprises the nucleotide sequence set forth in SEQ ID NO: 91 or 92, and (ii) an AAV Anc80 capsid. The claims in ‘726 differ from claimed invention by not disclosing the composition comprises :(i) 8.1 mM sodium phosphate dibasic, (ii) 1.5 mM monopotassium phosphate, (iii) 2.7 mM potassium chloride, (iv) 172 mM sodium chloride, and(v) 0.001 % Poloxamer 188. Mathur cures the deficiency by disclosing reported formulating AAV particles in PBS that may comprise sodium chloride, potassium chloride, disodium phosphate, monopotassium phosphate, and distilled water (see para. 572), wherein dibasic sodium phosphate may be 8.1-8.6 mM (see para. 575) and monopotassium phosphate is in a range of 1.2-1.7 mM, Sodium chloride may be in formulation ranging from 171-172mM (see para. 582), KCl ranging from 1.2-1.7 mM (see para. 587) and 0.001% poloxamer 188 (See claim 91 of ‘939). Accordingly, it would have been prima facie obvious for one of ordinary skill in the art seeking to use an AAV particle suitable for gene therapy would modify the AAV particle composition of ‘726 by formulating in PBS with PF-68 as suggested in Mathur, for successful delivery and transduction of virus particles in inner ear cells, with reasonable expectation of success.
Response to arguments
Applicants argue that the claims in the present divisional application (claiming priority to US '095) are directed to subject matter that was deemed to be patentably distinct compared to the subject matter elected and pursued in US '653 application divisional application. Thus, in view of the safe harbor provided by 35 U.S.C. § 121, the double patenting rejections over co-pending US 19/254,653 should be withdrawn. Applicants’ arguments have been fully considered but are not found persuasive.
To the extent, Applicants’ applicants’ argument pertains to claims 51, 54-55, 58, 60-70, asserting the claims should be accorded the safe harbor provided by 35 U.S.C. § 121, the double patenting rejections over co-pending US 19/254,653 is found persuasives, therefore, previous rejection of claims 51, 54-55, 58, 60-70 is hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot. The claims are however subject to new rejections over rejoined method claims 63-70, 73-80 as these claims were neither presented before nor restricted in parent application 18/134,095.
Conclusion
Claims 63-70, 82-84 are not allowed.
Applicants’ 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 ANOOP K. SINGH whose telephone number is (571)272-3306. The examiner can normally be reached Monday-Friday, 8AM-5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached at (571)272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632
