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 .
This action is in response to the papers filed August 28, 2025.
Claims 1-25 are currently pending in the application. Claims 2, 6, and 7 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 09/05/2024. Claims 9-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 09/05/2024.
No claims are amended, newly added or canceled in the claim set filed August 28, 2025.
Claims 1, 3-5, and 8 are examined on the merits.
Priority
This application is a 371 of PCT/US2019/068070 filed 12/20/2019. Applicant’s claim for the benefit of a prior-filed provisional application 62/784,306 filed on 12/21/2018 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Thus, the earliest possible priority for the instant application is December 21, 2018.
Response to arguments
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 1, 3-5 and 8 are rejected under 35 U.S.C. 103 as being unpatentable over Iizuka (Human Molecular Genetics, 2015, Vol. 24, No. 13) in view of Dalkara (In Vivo–Directed Evolution of a New Adeno-Associated Virus for Therapeutic Outer Retinal Gene Delivery from the Vitreous. Sci. Transl. Med. 5,189ra76-189ra76 (2013); IDS Reference).
Regarding claims 1 and 3-5, Iizuka teaches administering an AAV vector serotype 1 with a CMV promoter encoding Connexin26 protein (GJB2) (i.e. a heterologous nucleic acid encoding an expression product which as a polypeptide which reduces hearing loss) to drive expression of GJB2 through the inner ear (p. 3651, bridging paragraph; p. 3652, 2nd column; p. 3658, 1st column). Through administration of the AAV delivering GJB2 to neonatal GJB2-deficient mic, the Cx26 expression was rescued in cochleae (p. 3654, bridging paragraph). In non-rescued cochleae, organs of Corti collapsed and hair cells degenerated (p. 3655, 1st column).
However, Iizuka does not teach that the AAV capsid has been inserted with a peptide such as SEQ ID NO: 1 between ammo acids corresponding to amino acids 587 and 588 of AAV2-VP1.
Dalkara teaches an insertion of a peptide comprising the amino acid sequence of SEQ ID NO: 1 into a AAV2 major capsid protein at position 588 (p. 2-3, bridging paragraph; p. 3 “the AAV2 seven–amino acid library, and 67% of all clones (32 of 48) contained the same 7mer motif (LGETTRP)” p. 3 , legend Fig 2.). Dalkara teaches that the 588LALGETTRP insertion disrupted AAV2 binding to its primary receptor heparan sulfate proteoglycan (HSPG) and further altered virus tropism (p 3, col.2). The AAV2, 7m8 showed >10- to 100-fold more infectious than AAV2 in Chinese hamster ovary (CHO) cell lines (p. 3 last paragraph). Dalkara further teaches the AAV2.7m8 vector is utilized in gene therapy (p. 5, 2nd column). ). Dalkara further teaches the high infectivity of the 7m8 capsid compared to previous vectors may enable the use of relatively low dosages, thereby reducing the chance of immune response to vector capsid protein (p. 8).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to utilize AAV2.7m8 in place of AAV1 of Iizuka to deliver GJB2 expression with a reasonable expectation of success as they are both known AAV serotypes utilized for gene therapy and gene transfer. Furthermore, an artisan would be motivated to utilize AAV2.7m8 as the AAV2.7m8 capsid has been shown to have high infectivity compared to previous vectors (Dalkara; p. 8) that may enable the use of relatively low dosages (p. 8),.
Regarding claim 8, Iizuka teaches that the hearing loss associated with GJB2 mutations is genetic/hereditary hearing loss (p. 3651, 2nd column, Abstract).
Therefore the invention would have been prima facie obvious to one of ordinary skill in the art at the time of the effective filing date.
In response to Applicant’s arguments filed 08/28/2025 regarding the 103 rejection,
Applicant’s arguments filed 08/28/2025 have been considered, however they are not persuasive.
Applicant argues that “at the time of filing, while several AAV serotypes had been shown to infect mammalian cochlea inner hair cells (IHCs) effectively, the infection rates of outer hair cells (OHCs) had remained low. In addition, the infection efficiency of conventional AAVs for cochlear supporting cells was also low. In order for the inner ear gene therapy to achieve complete hearing restoration, a viral vector with higher infection efficiency than what was previously shown was required” (Remarks, p. 6).
Applicant does not cite any literature to support the state of the art at the time of filing regarding infection rates. Additionally, “low” is a relative term and is not compared to any data provided in the specification. Regardless, to be given substantial weight in the determination of obviousness or nonobviousness, evidence of secondary considerations must be relevant to the subject matter as claimed, and therefore the examiner must determine whether there is a nexus between the merits of the claimed invention and the evidence of secondary considerations. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 305 n.42, 227 USPQ 657, 673-674 n. 42 (Fed. Cir. 1985).
Applicant further argues, “It is only Applicants' specification that demonstrates that AAV2.7m8 is capable of infecting both cochlear IHCs and OHCs with high efficiency. Furthermore, Applicants show that AAV2.7m8 is capable of infecting the inner pillar cells and inner phalangeal cells with high efficiency, demonstrating that AAV2.7m8 is a uniquely powerful viral vector for inner ear gene delivery. Nothing in Iizuka, Dalkara, or their combination would have led a person having ordinary skill in the art to select AAV2.7m8 to deliver a therapeutic transgene to the inner ear with a reasonable expectation of success,” (Remarks, p. 6-7).
The examiner disagrees. The instant claims are product claims. The claims don't require any astounding levels of efficacy: all that is required under 103 is what KSR has told us. As shown above in the obviousness rejection, an artisan would be motivated to utilize AAV2.7m8 as the capsid has been shown to have high infectivity compared to previous vectors including at least Chinese hamster ovary (CHO) cell lines (p. 3, col.2) , RGCs and Müller cells, amacrine cells, bipolar cells, rods, cones, and RPE (Fig 1, Fg. 3 E and F) and (Dalkara; p. 8). Therefore, there is a motivation to improve upon a vector known in the art with the capsid described within in the invention to have high infectivity to enable the use of relatively low dosages, thereby reducing the chance of immune response to vector capsid protein.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634