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 .
Application Status
This action is written in response to applicant’s correspondence received 04/29/2026. Claims 1, 4-6, 8-9, 11-14 are currently pending.
Any rejection or objection not reiterated herein has been overcome by amendment.
Applicant’s amendments and arguments have been thoroughly reviewed, but are not
persuasive to place the claims in condition for allowance for the reasons that follow.
Priority
Acknowledgment is made of applicant's claim for foreign priority based on an application filed in EP-4008788-A1 on 12/03/2021.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Withdrawn Claim Rejections – 35 USC §112(a) Written Description
The timely filing of Declaration under 37 C.F.R. § 1.132 by Axel Schambach ("Schambach Declaration") filed on 04/29/2026 meets the formal requirements and has been considered on the merit. It is sufficient to overcome the rejection of claim 7 based upon 35 USC §112(a) Written Description,
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.
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 1, 4-6, 8-9, 11, and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Pan (Neural Regen Res. 2013 Jun 15;8(17):1551-9; Cited on the IDS submitted on 05/26/2023) in view of Poletti (Viruses. 2021 Aug 2;13(8):1526) and further in view of Bauche (US20150182617A1, published on 07/02/2015). All references cited herein were cited in the previous office action mailed on 12/29/2025.
Pan (2013) teaches that a 3rd generation self-inactivating (SIN) lentiviral vector pseudo typed with VSVG comprising a cargo sequence encoding reporter gene green fluorescent protein and an Atoh1 transgene, commonly associated with sensorineural hearing loss (SNHL) in certain types of genetic mutations, can be successfully delivered to the inner ear of a subject (normal rats with no SNHL) via local microinjections at sufficiently high titers (3x108 TU/ml) and led to reporter and transgene expression in inner ear cells including inner and outer hair cells, which in turn augments Myo7a expression in hair cells, without damage to the hair cells or cause loss of hearing function based on ABR threshold measurement (Page 1552, right column, second¶ and Figure 1).
Pan (2013) does not teach detailed third generation lentivirus genomic structure.
Poletti (2021) teaches updated third generation lentiviral vectors with all structural features as claimed (Page 4 of 14, Figure 1A, see below):
wherein the lentiviral vector comprises a cargo nucleic acid selected from the group consisting of a protein-coding gene, a miRNA, or an shRNA (Page 4, Figure 1 legends, last 3 lines), and wherein the lentiviral vector comprises a) a 5' LTR with a deleted (SIN) U3 region, a repeat region (R) and a U5 region, b) a 5' UTR comprising a primer binding site (PBS), a splice donor site (SD), a packaging signal (p), a Rev-responsive element, and, optionally, a splice acceptor (SA) site, c) an internal enhancer/promoter region operably linked to a cargo sequence, d) RNA processing elements optionally comprising a Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE), and e) a 3' LTR with a deleted U3 (SIN) region, a repeat region (R) and a U5 region. See schematic below. Poletti further teaches a cargo sequence encoding protein-encoding transgenes, microRNA, shRNA, etc. in the legends of Figure 1.
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Neither Pan nor Poletti teaches MARAV-G or COCV-G glycoproteins.
However, Bauche (2015) teaches that the commonly used VSV-G envelop glycoprotein could induce immune responses from the host that interfere with the in vivo performance of lentiviral vectors (¶[0013]) and that additional pseudo typed envelop glycoproteins, such as MARAV-G and COCV-G are known in the art as alternatives to enhance targeted transgene product delivery using lentiviral vectors (Page 10, ¶[0083], Page 15, ¶[0155]).
Regarding claim 1, It would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified the 3rd generation lentiviral vector used by Pan (2013) to comprise the updated lentiviral genomic structures, taught by Poletti (2021) because of nearly a decade of advancements and improved performance and safety features in 3rd generation lentiviral vector designs since Pan’s publication, for the delivery of a variety of cargos that cover diverse molecular structures. It would also have been obvious to modify Pan’s original VSV-G envelop glycoprotein with additional varieties, such as Bauche (2015)’s MARAV-G or COCV-G glycoproteins such that the versatility and durability of 3rd gen lentiviral vectors can be further expanded to adapt to expanding clinical demands, such as avoiding immune responses in multiple administrations. It would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results. One would have been motivated to do so because Poletti (2021) teaches that “LVs have proven their safety and efficacy as flexible gene delivery vectors in clinical applications of gene therapy for genetic diseases” (Page 10, Conclusion, line 1). One would have reasonable expectation of success because Poletti’s summary of clinical applications (Page 6, first¶).
Regarding claim 4, Bauche (2015) further teaches a 3rd generation lentiviral vector pseudo typed with envelop glycoprotein from Marabavirus (MARAV), i.e. MARAV-G (Page 10, ¶[0083]).
Regarding claim 5, Bauche (2015) further teaches a 3rd generation lentiviral vector pseudo typed with envelop glycoprotein from Cocal virus (COCV), i.e. COCV-G (Page 10, ¶[0083]).
Regarding claim 6, both Pan (2013) and Bauche (2015) teach a 3rd generation lentiviral vector pseudo typed with envelop glycoprotein from glycoprotein of the vesicular stomatitis virus (VSV), i.e. VSV-G (Bauche, Page 3, ¶[0036]).
Regarding claim 8, Pan (2013) teaches that a 3rd generation lentiviral vector comprising a cargo sequence that encodes Atoh1 (Page 1551, title), which is a highly conserved essential transcription factor and an ortholog of ATOH1 in humans. And the versatility of using 3rd gen lentiviral vectors to deliver diverse protein coding transgenes and regulatory RNAs was taught by Poletti (2021).
Regarding claim 9, Pan (2013) further teaches that a 3rd generation lentiviral vector derived from HIV-1, i.e. “human immunodeficiency virus-1 rev” on (Page 1556, last ¶), can be used for local delivery to the inner ear for transgene product to be expressed in cell types in the inner ear of a subject.
Regarding claim 11, Pan (2013) teaches that a 3rd generation lentiviral vector is able to transduce hair cells in the inner ear of a subject, i.e. delivery of transgenes to a cell of the inner ear of a subject. And Poletti (2021) confirms that diverse cargo nucleic acid sequences encoding protein coding genes and regulatory RNAs can be delivered using the 3rd gene lentiviral vectors of claim 1.
Regarding claim 13, Pan (2013) teaches that round window microinjection can be a chosen route for administering a 3rd generation lentiviral vector-based composition to the inner ear of a subject.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Pan (2013) in view of Poletti (2021) and Bauche (2015) as applied to claims 1, 4-6, 8-9, 11, and 13 above, and further in view of Benskey (Lentivirus Production and Purification. In: Manfredsson, F. (eds) Gene Therapy for Neurological Disorders. Methods in Molecular Biology, vol 1382. Humana Press, New York, NY. 2016).
The teachings of Pan (2013), Poletti (2021) and Bauche (2015) have been discussed above.
None of Pan, Poletti, and Bauche teaches the use of non-integrating lentiviral vectors.
However, Benskey (2016; pages 107-114) teaches that 3rd generation lentiviral vectors can be concentrated and purified using a variety of methods including ultracentrifugation, precipitation, etc., which are known in the art.
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3rd generation lentiviral vector used by Pan (2013) and updated based on Poletti (2021) and Bauche (2016), following the protocols of concentration and purification of lentiviral vectors described by Benskey (2016) to have achieved greater transduction efficiency using sufficiently high titers of lentiviral particles for therapeutic purpose and would have arrived at the same claimed invention based on a simple combination rationale using proven methods to achieve predictable results based on the proven success described by Pan, Poletti, Bauche, and Benskey. One would have reasonable expectation of success because of decades of advancements in the art with proven results summarized by Poletti.
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Pan (2013) in view of Poletti (2021) and Bauche (2015) as applied to claims 1, 4-6, 8-9, 11, and 13 above, and further in view of Shaw (Design and Potential of Non-Integrating Lentiviral Vectors. Biomedicines. 2014 Jan 27;2(1):14-35; listed in IDS submitted on 05/26/2023). The recitation “non-integrating lentiviral vector” is interpreted to encompass vectors wherein alterations in the viral integrase or vector Long Terminal Repeats have been used to generate vectors that lack the ability to integrate under the broadest reasonable interpretation (BRI).
The teachings of Pan (2013), Poletti (2021) and Bauche (2015) have been discussed above. None of Pan, Poletti, and Bauche teaches using non-integrative 3rd generation lentiviral vectors. However, Shaw (2014) discloses the strategy of using a non-integrating 3rd gen lentiviral vector (Page 19, Figure 3) and teaches that “lentiviral vectors that do not integrate are predicted to have a safer profile compared to integrating vectors and should be considered for applications where transient expression is required or for sustained episomal expression such as in quiescent cells” (Page 14, Abstract, lines 5-8). Shaw further teaches that “alterations in the viral integrase or vector Long Terminal Repeats have been used to generate vectors that lack the ability to integrate” (Page 14, Abstract, lines 9-10).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to have modified the 3rd generation lentiviral vector used by Pan (2013) and updated based on Poletti (2021) and Bauche (2016), using the methods described by Shaw (2014) and would have reduced the concern of insertional mutagenesis and oncogenesis associated with integrative lentiviral vectors and enhance safety profile in vivo, following the therapeutic applications directed by Poletti (2021), and would have arrived at the same claimed invention, with a simple combination rationale using proven methods to achieve predictable results based on the proven success described by Pan, Poletti, Bauche, and Shaw. One would have reasonable expectation of success because of decades of advancements in the art with recent clinical applications summarized by Poletti.
Response to Arguments
Applicants argue that:
(Remarks, filed on 04/29/2026, pages 13-14)
“These rejections all rely primarily on Pan allegedly disclosing delivery of a gene to inner- ear cells using a third-generation lentiviral vector. …Pan reports that a third-generation self-inactivating human immunodeficiency virus-1- based lentiviral vector carrying the Atoh1 gene can infect cochlear tissue and lead to expression …
First and foremost, Pan does not disclose the specific structural configuration of the lentiviral vector now required by amended claim 1. … merely refers in rather general terms to a lentiviral construct without much structural detail.
Furthermore, Pan is restricted to a single protein-coding gene (Atoh1) and does not provide any teaching or suggestion that such a system could be used as a general delivery platform for multiple classes of nucleic acid cargo, … constitutes a broadly applicable and functionally validated delivery platform.
… the skilled person would not have derived from Pan a reasonable expectation that lentiviral vectors could be used to reliably and efficiently deliver diverse nucleic acid cargos to inner-ear cells. On the contrary, prior work had highlighted substantial challenges in achieving transduction of relevant inner-ear cell types, in particular sensory hair cells, which were often not transduced at all despite the use of lentiviral vectors. These findings would have reinforced the perception that the inner ear constitutes a technically demanding and unpredictable target for gene delivery.”
Applicant's arguments filed on 04/29/2026 have been fully considered but they are not persuasive. The amendments necessitated new rejections. See office action above for detailed reasons.
(Remarks, filed on 04/29/2026, pages 14-15)
“The additional references cited by the Examiner do not remedy these deficiencies. Bauche … does not provide any teaching that the specific glycoproteins recited in claim 1, in combination with the claimed vector architecture, would be suitable for inner-ear delivery. … Benskey … demonstrate transduction only of neuronal or neuron-like cell types in vitro and within the rat striatum in vivo (Fig. 1), … Shaw … describe systems for generating lentiviral vectors that have alterations in the viral integrase or vector Long Terminal Repeats … Even when all cited references are considered in combination, they do not provide a teaching or suggestion that would lead the skilled person to the presently claimed method. … The additional post-filing data further reinforce this conclusion ...Taken together, the cited prior art neither discloses nor suggests the claimed combination of features, nor does it provide a reasonable expectation of success ... The amended claims therefore define subject matter that would not have been obvious to the skilled person at the relevant date.”
Applicant's arguments filed on 04/29/2026 have been fully considered but they are not persuasive. The amendments necessitated new rejections. See office action above for detailed reasons.
Conclusion
No claims are allowable.
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 Delphinus D. Yu whose telephone number (571) 272-1576. The examiner can normally be reached Mon-Thr 7:30am to 4:30pm Fri 10am to 2pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil P Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DELPHINUS DOU YI YU/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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