DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/21/2026 has been entered.
Claim Status
As of the Final Office Action mailed 4/21/2026, claims 102-115 were pending.
In Applicant's Response filed on 7/21/2026, claim 114 was amended.
As such, claims 102-115 are pending and have been examined herein.
This action is FINAL.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of record of claim 114 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment to claim 114.
The rejection of record of claims 102-108 and 111-115 under 35 USC § 103 as being unpatentable over Stankovic et al (WO2017100791 A1, 12 Dec 2016; Published 15 June 2017; Ref. B15 of Foreign Patent Documents in IDS filed 1 Oct 2024; previously cited) in view of Limberis et al (Molecular Therapy, May 2012; 20(1):S31; previously cited) as evidenced by Suzuki et al (Sci Rep., 3 April 2017; 7:45524, p. 1-11. Ref. C179 of NPL in IDS filed 8/19/2025) has been recast below.
The rejection of record of claims 109-110 under 35 USC § 103 as being unpatentable over Stankovic in view of Limberis as applied to claims 102-108 and 111-115, and further in view of Taylor-Parker (AddGene, 31 Mar 2016; Retrieved from the Internet 5/13/2025 from https://blog.addgene.org/plasmids-101-terminators-and-polya-signals; previously cited) has been recast below.
Claim Interpretation
Claim 102 recites SEQ ID NO: 95. Applicant indicates SEQ ID NO: 95 is ranibizumab (Lucentis) in para 222 of the instant specification. As such, the use of ranibizumab in a vector reads on “a nucleotide sequence comprising a coding sequence . . . wherein the coding sequence encodes a vascular endothelial growth factor binding agent” as in instant claim 102 absent evidence to the contrary.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 102-108 and 111-115 are rejected under 35 U.S.C. 103 as being unpatentable over Stankovic et al (WO2017100791 A1, 12 Dec 2016; Published 15 June 2017; Ref. B15 of Foreign Patent Documents in IDS filed 1 Oct 2024; previously cited) in view of Limberis et al (Molecular Therapy, May 2012; 20(1):S31; previously cited) as evidenced by Suzuki et al (Sci Rep., 3 April 2017; 7:45524, p. 1-11. Ref. C179 of NPL in IDS filed 8/19/2025).
Regarding claim 102, Stankovic teaches a method of delivering a transgene to one or more cells in the inner ear in a subject, the method comprising administering an adeno-associated virus (AAV) to the inner ear in a subject, wherein the AAV comprises an Anc80 capsid protein and a transgene (see claim 2 of Stankovic).
Regarding claim 102 and 113, Stankovic continues to teach that adeno-associated virus (AAV) containing an Anc80 capsid protein provide highly efficient gene transfer to inner ear cells including both IHCs and OHCs (p. 1, lines 24-30). The one or more cells of the inner ear also include supporting cells (see claim 5 of Stankovic).
Regarding claim 102, 107, and 108, Stankovic teaches that the transgene is under control of a heterologous promoter sequence such as CMV promoter or CBA promoter (p. 3, lines 19-21).
Regarding claims 103 through 105, Stankovic teaches that nucleic acids can be used to deliver transgenes to the inner ear while suspended in an artificial perilymph solution (p. 21, lines 21-27).
Regarding claim 111, Stankovic teaches that the virus particle containing the Anc80 capsid protein has a construct carrying the transgene that is flanked by suitable inverted terminal repeats (ITRs) that allow the transgene to be packaged within the Anc80 capsid (p. 19, lines 8-11).
Regarding claim 112, Stankovic also teaches that AAV2 ITRs were used in the vector (“Viral vector generation,” para 2).
Stankovic does not teach:
(i) the transgene is a VEGF binding agent (SEQ ID NO: 95; ranibizumab; see claim interpretation above).
Limberis teaches AAV8 mediated expression of ranibizumab (title). The reference teaches that macaques were injected intravitreally or subretinally with 1011 genome copies of AAV8 vector expressing ranibizumab under the transcriptional control of the CMV promoter. The AAV-8 expressed ranibizumab inhibited VEGF-induced proliferation by ~75% (p. S31, col 2, top para). This shows that ranibizumab is a VEGF binding agent that can be delivered in an AAV vector.
Regarding claim 106, Limberis teaches a vector containing the nucleic acid sequence for ranibizumab. The instant specification states that SEQ ID NO 102 encodes for ranibizumab (para 222 of specification) such that, absent evidence to the contrary, the nucleic acid sequence of Limberis renders obvious on “wherein the coding sequence comprises the nucleic acid sequence of SEQ ID NO: 102” as in instant claim 106.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a vector containing Anc80 capsid protein as taught by Stankovic, where the vector contains ranibizumab as taught by Limberis, to arrive at the instantly claimed invention. As Limberis shows that a vector can contain ranibizumab, one of ordinary skill would have been motivated to simply substitute the transgene of Stankovic for the ranibizumab as taught by Limberis with a reasonable expectation of advantageously having a transgene be able to be efficiently inhibit VEGF expression and proliferation in target cells as taught by the prior art.
Instant claim 114 recites, inter alia, “wherein the transduction of one or more supporting cells results in expression of anti-VEGF in one or more supporting cells in the inner ear of a mammal” which raises a question as to its limiting effect (see MPEP 2111.04). Limitations in a claim are not given weight when it simply expresses an intended result or use. Furthermore, the combination of Stankovic and Limberis render obvious the composition of instant claim 102 and shows that the composition can transduce inner ear supporting cells via the Anc80 capsid protein. Thus, absent evidence to the contrary, the vector of Stankovic and Limberis in combination would result in “expression of anti-VEGF in one or more supporting cells of the inner ear of a mammal” as instantly claimed in instant claim 114.
Regarding claim 115, Stankovic teaches that Anc80 containing vectors can transduce supporting cells of the inner ear but does not explicitly state that the vector transduces supporting cells “comprising Hensen’s cells, Claudius cells, Dieter cells, inner and outer pillar cells, inner border cells, inner phalangeal cells, or any combination thereof” as instantly claimed. However, evidentiary reference Suzuki evidences that inner ear gene therapy containing Anc80 capsid protein can be used to transduce inner ear cells (abstract). The reference evidences that injections targets virtually 100% of IHCs throughout the cochlear spiral, as well as a significant fraction of OHCs (Introduction, para 4). The AAV vector transduced virtually all of the supporting cells (“Transduction in the vestibular epithelia” para 1; Fig. 5). This evidences that Anc80 containing vectors can transduce all supporting cells of the inner ear. Thus, absent evidence to the contrary, the vector of Stankovic and Limberis in combination can induce expression in the supporting cells as instantly claimed in instant claim 115.
Response to Arguments
Applicant’s arguments and the Declaration by Dr. Robert Ng (“the Ng Declaration”) have been fully considered but are not persuasive.
On p. 6-11, Applicant argues in sum that the obviousness rejections posited against the instant claims fail to provide a reasoned explanation to combine the teachings of Stankovic and Limberis and does not explain how or why the results of the combination of the reference would have been predictable. Applicant argues that the Office Action foes not state any reason to select ranibizumab as the transgene for use in an AAV vector containing ANc80 capsid in the context of expression in the inner ear, does not point to any disclosure suggesting that ranibizumab could be delivered to the ear using such a vector, nor that the combination would result in anti-VEGF expression and achieve VEGF inhibition. Applicant argues that the rejection relies on impermissible hindsight. Applicant uses the Ng Declaration to support the argued unpredictability of 100-fold to 10,000-fold increase in anti-VEGF protein levels in the cochlea when the instant composition is administered and purported unexpected safety and tolerability of the claimed composition.
While Applicant’s arguments and the Ng Declaration have been fully considered, it has not been found persuasive. 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 response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Stankovic teaches vectors containing Anc80 capsid protein can efficiently deliver transgenes to cells of the inner ear; specifically “the transgene is delivered to at least 80% of inner hair cells and at least 80% of outer hair cells . . . consisting of spiral ganglion neurons, vestibular hair cells, vestibular ganglion neurons, supporting cells, and cells in the stria vascularis.” Figures 8C and 8D of Stankovic are graphs showing quantitative comparison of inner and outer hair cell transduction efficiency following round window injection of C57BL/6 mice. Figure 8E are images showing dose-dependency of Anc80 hair cell transduction. Stankovic further contemplates safe and effective gene transfer in the cochlea due to the ancestral Anc80 capsid protein and confirmed maintained vestibular function via rotarod tests in injected mice (see, e.g., Example 1E of Stankovic). While it does not contemplate the use of ranibizumab as the transgene, Limberis shows that ranibizumab can be successfully delivered in an AAV vector and suppress VEGF expression.
A claimed compound may be obvious because it was suggested by, or structurally similar to, a prior art compound even though a particular benefit of the claimed compound asserted by patentee is not expressly disclosed in the prior art. It is the differences, in fact, in their respective properties which are determinative of nonobviousness. If the prior art compound does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, applicant’s recognition of the benefit is not in itself sufficient to distinguish the claimed compound from the prior art. In re Dillon, 919 F.2d 688, 693, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990) (en banc) (see MPEP 2144.09(VII)). Here, at least reference Stankovic shows that an AAV vector containing Anc80 capsid possesses the particular benefit of targeting cells of the inner ear. Limberis shows that an AAV vector containing ranibizumab possesses the particular benefit of reducing VEGF expression in targeted cells.
In KSR, the Supreme Court particularly emphasized "the need for caution in granting a patent based on the combination of elements found in the prior art," Id. at 415, 82 USPQ2d at 1395, and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." Id. at 415-16, 82 USPQ2d at 1395. The Supreme Court stated that there are "[t]hree cases decided after Graham [that] illustrate this doctrine." Id. at 416, 82 USPQ2d at 1395. (1) "In United States v. Adams, . . . [t]he Court recognized that when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result." Id. (2) "In Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., . . . [t]he two [pre-existing elements] in combination did no more than they would in separate, sequential operation." Id. at 416-17, 82 USPQ2d at 1395. (3) "[I]n Sakraida v. AG Pro, Inc., the Court derived . . . the conclusion that when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious." Id. at 417, 82 USPQ2d at 1395-96 (Internal quotations omitted.). The principles underlining these cases are instructive when the question is whether a patent application claiming the combination of elements of prior art would have been obvious (see MPEP 2141(I)). When considering obviousness of a combination of known elements, the operative question is thus "whether the improvement is more than the predictable use of prior art elements according to their established functions." Id.
Indeed, an obviousness rejection under 35 U.S.C 103 requires one of ordinary skill to balance each individual teaching of the prior art references with the totality of the references in combination. Applicant’s arguments must take into account the combination of teachings of the prior art references, and appreciate all of the evidence as a whole. Here, the combination of the Stankovic and Limberis references render prima facie obvious the composition components. Moreover, it would have been obvious to try, from a finite number of identifiable, predictable solutions, to make the AAV vector as claimed with a reasonable expectation of success as taught by the prior art. It would have been obvious for one of ordinary skill in the art, having good reason to pursue the known options of transgenes available within his or her technical grasp, to choose ranibizumab as the transgene within the Anc80-containing vector as a product of ordinary skill and common sense, especially given the teachings of Stankovic and Limberis. Thus, neither the arguments nor Declaration provide any evidence that the instantly claimed concentrations provide any benefits/unexpected results not previously contemplated by the prior art.
Claim(s) 109-110 are rejected under 35 U.S.C. 103 as being unpatentable over Stankovic et al (WO2017100791 A1, 12 Dec 2016; Published 15 June 2017; Ref. B15 of Foreign Patent Documents in IDS filed 1 Oct 2024; previously cited) in view of Limberis et al (Molecular Therapy, May 2012; 20(1):S31; previously cited) as applied to claims 102-108 and 111-112, and further in view of Taylor-Parker (AddGene, 31 Mar 2016; Retrieved from the Internet 5/13/2025 from https://blog.addgene.org/plasmids-101-terminators-and-polya-signals; previously cited).
The teachings of Stankovic and Limberis in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 102 of which claims 109-110 ultimately depend. The teachings will not be repeated here.
Neither Stankovic and Limberis teach:
the nucleotide sequence further comprises a polyadenylation sequence, or
that the polyadenylation sequence comprises a bovine growth hormone polyadenylation sequence, a mouse-beta-globin polyadenylation sequence, a mouse-alpha-globin polyadenylation sequence, a human collagen polyadenylation sequence, a polyoma virus polyadenylation sequence, a herpes simplex virus thymidine kinase polyadenylation sequence, an IgG heavy chain polyadenylation sequence, a human growth hormone polyadenylation sequence, or a SV40 polyadenylation sequence.
Regarding (i) and (ii), Taylor-Parker describes PolyA signals (title). The reference teaches that mammalian expression plasmids are primarily used to create mRNA and the commonly used mammalian terminators (SV40, hGH, BGH, and rbGlob) include the sequence motif AAUAAA which promotes both polyadenylation and termination.
Taylor-Parker continues to teach that, out of those listed, the SV40 late polyA and rbGlob polyA are thought to be more efficient in terminating transcription due to the presence of additional helper sequences.
Taylor-Parker continues to teach that the addition of the poly(A) tail is important for stability of the mRNA, protection from degradation, and is integral to the nuclear export and translation processes as well (“Eukaryotic termination and polyadenylation” para 3), showing why one of ordinary skill would include a polyadenylation signal in a vector construct.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a vector containing Anc80 and ranibizumab as taught by Stankovic and Limberis in combination, where the vector contains a polyadenylation signal as taught by Taylor-Parker, to arrive at the instantly claimed invention. As Taylor-Parker shows that polyadenylation is important in termination of transcription of nucleotide sequences, one of ordinary skill would have been motivated to modify the vector of Stankovic and Limberis in combination to include hGH, BGH, or SV40 polyA signal in the nucleotide sequence as taught by Taylor-Parker with a reasonable expectation of advantageously improving mRNA stability, protecting the synthesized RNA from degradation, and being able to have nuclear export as taught by the prior art.
Conclusion
No claim is allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/G.R./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
