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 .
Amendments
In the reply filed 09/12/2025, Applicant has amended claims 42, 52, 59 and 60, has newly canceled claim 67.
Claim Status
Claims 42-43 and 52-66 are pending and are considered on the merits.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/12/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Withdrawn Claim Objections
The prior objection to claims 59 and 60 because of typographic errors is withdrawn in light of Applicant’s amendment to the claims.
Maintained Claim Objections
Claims 58 and 66 stand objected to because of the following informalities:
Applicant is advised that should claims 57 and 65 be found allowable, claims 58 and 66 will be objected to under 37 CFR 1.75 as being a duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 706.03(k).
Appropriate correction is required.
Withdrawn Claim Rejections - 35 USC § 112(a)
(Scope of Enablement)
The prior rejection of claims 42-43 and 53-59 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for a method of preventing optic neuropathy by administering a rAAV-SIRT1, is withdrawn in light of Applicant’s amendment to claim 42 to remove the limitation of “preventing”.
Withdrawn Claim Rejections - 35 USC § 103
The prior rejection of claims 42-43, 52-55 and 59-63 under 35 U.S.C. 103 as being unpatentable over Zuo et al (Invest Ophthalmol Vis Sci. 2013; 54: 5097–5102, cited in IDS 11/08/2023) in view of Hauswirth et al. (Human Gene Therapy. 2008, 19: 979-990. Prior art of record), Jacobson et al. (Molecular Therapy. 2006; 13(6): 1074-1084. Prior art of record) and Bosch Tubert et al (US20160354489A1, cited in IDS 11/08/2023) is withdrawn in light of Applicant’s amendment to claims 42 and 52 to recite new limitations of the AAV capsid “that is capable of transducing retinal ganglion cells (RGC)” and “wherein transduction of RGC by the recombinant AAV results in …”, that are not taught by Zuo, Hauswirth, Jacobson or Bosch Tubert.
The prior rejection of claims 56-58 and 64-66 under 35 U.S.C. 103 as being unpatentable over Zuo et al (Invest Ophthalmol Vis Sci. 2013; 54: 5097–5102, cited in IDS 11/08/2023) in view of Hauswirth et al. (Human Gene Therapy. 2008, 19: 979-990. Prior art of record), Jacobson et al. (Molecular Therapy. 2006; 13(6): 1074-1084. Prior art of record) and Bosch Tubert et al (US20160354489A1, cited in IDS 11/08/2023), and further in view of Chaffiol et al (Molecular Therapy. 2017; 25(11): 2546-2560. Available online 20 July 2017. Cited in IDS 11/08/2023) is withdrawn in light of Applicant’s amendment to claims 42 and 52 to recite new limitations of the AAV capsid “that is capable of transducing retinal ganglion cells (RGC)” and “wherein transduction of RGC by the recombinant AAV results in …”, that are not taught by Zuo, Hauswirth, Jacobson, Bosch Tubert or Chaffiol.
New 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.
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 42-43, 52-55 and 59-63 are rejected under 35 U.S.C. 103 as being unpatentable over Zuo et al (Invest Ophthalmol Vis Sci. 2013; 54: 5097–5102, cited in IDS 11/08/2023) in view of Patrício et al (Molecular Therapy: Nucleic Acids. 2017; 6: 198-208. Cited in IDS 11/08/2023) and Bosch Tubert et al (US20160354489A1, cited in IDS 11/08/2023).
With respect to independent claims 42 and 52, Zuo teaches a method of treating optic neuropathy in a mouse model by overexpressing SIRT1 to promote RGC survival and to delay its loss of function (abstract), thus teaches preambles of claims 42 and 52.
In regard to SIRT1 gene therapy in the eyes of the mouse model, Zuo teaches overexpressing SIRT1 gene in the mouse eyes by recombining a SIRT1 gene into mouse beta-actin locus (page 5097, last para, line 3, also see Fig 2A&2B for SIRT1 overexpression in retina) prevents RGC loss (see Fig 3) and attenuates loss of RGC function (see Fig 4A). Zuo teaches this neuroprotection is dependent on SIRT1 expression in neurons as SIRT activator resveratrol fails to prevent RGC loss in homozygous neuron-specific SIRT1-KO mouse eyes that underwent optic nerve crush (Fig 3A, page 5099, col 2, para 1, last 5 lines). Thus, Zuo teaches a SIRT1 gene sequence is engineered to be overexpressed in the eyes for treating optic neuropathy and to preserve RGC function in a mouse model in claims 42 and 52.
However, Zuo is silent on administering to the eye a recombinant AAV virus comprising human SIRT1 in claims 42 and 52, nor teach the dose of the AAV (claims 43 and 60), the AAV capsid being an AAV2 capsid (claims 53 and 61), a hybrid promoter comprising a CMV enhancer and a chicken-beta actin promoter (claims 54 and 62), or the ITR sequencies being from AAV2 (claims 55 and 63).
Patrício teaches a recombinant AAV vector for gene therapy by administering to an eye of a subject (e.g., abstract, page 199, results section line 1, and page 205, right col, “Subretinal Injections”), related to claims 42 and 52. Patrício teaches the AAV2 virus is delivered at 1 x 109 vector genomes/eye (Figs. 2-3&5, page 200, last para), and teaches a previous study has used a dose of 2.7 x 1010 vg/eye (page 204, right col, line 2 from bottom), related to the dose range in claims 43 and 60. Patrício teaches the AAV2 vectors express a human therapeutic transgene Rab escort protein 1 (REP1, encoded by CHM gene) that is used in a clinical trial as a gene therapy for choroideremia (page 199, Result section “Generation of AAV Vectors”), related to claims 53 and 61. In the Result section “Generation of AAV Vectors” (page 199, right col), Patrício teaches the AAV2-CAG-REP1-WPRE-pA virus comprises a CAG promoter (hybrid of the human cytomegalovirus upstream enhancer with the chicken b-actin promoter, see Fig 1A legend), related to claims 54 and 62. Patrício teaches the AAV2 virus comprises AAV2 inverted terminal repeats (ITR) (see Fig 1A legend), related to claims 55 and 63.
Regarding the new limitations of the AAV capsid “that is capable of transducing retinal ganglion cells (RGC)” and “wherein transduction of RGC by the recombinant AAV results in expression of the human SIRT1”, Patrício teaches “subretinal delivery of an AAV2 vector coding the CHM gene with the WPRE leads to transduction of all retina layers up to the ganglion cells” (p. 204, left col, para 1, last sentence, also see Fig 3H&3M for GFP expression in ganglion cell layer “GCL” and see Fig 6G-6H for REP1 expression in all layers of retina including ganglion cell layer “GCL”). Thus, Patrício teaches the AAV2 capsid is capable of transducing retinal ganglion cells (RGC) and the transduction of RGC by the recombinant AAV results in expression of the human therapeutic transgene in the RGCs, related to claims 42 and 52. Patrício teaches various serotypes of AAV have been tested and “the demonstration of safety and efficacy of serotype 2 … justified its used in the first AAV gene therapy trials in the human eye” (page 198, col 2, end of para 1).
In regard to making and using an AAV comprising SIRT1 in gene therapy, Bosch Tubert teaches an AAV8-SIRT1 virus for overexpressing SIRT1 in liver to treat non-alcoholic fatty liver disease (see example 1 and Figure 2).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating optic neuropathy or preserving RGC function by overexpressing SIRT1 gene in the eyes disclosed by Zuo, by substituting the SIRT1 knocking-in approach with administering a recombinant AAV comprising SIRT1 gene to the eyes of the subjects as suggested by Patrício and Bosch Tubert with a reasonable expectation of success. Since Zuo teaches SIRT1 activation (by resveratrol) fails to prevent RGC loss in SIRT1 neuronal knockout mouse eyes, “confirming the importance of SIRT1 expression in neurons for resveratrol-mediated neuroprotection” (p. 5099, right col, para 1), suggesting SIRT1 overexpression in retinal neurons (RGC, see e.g., Fig 2A and 2B for SIRT1 overexpression in retina) accounts for its neuroprotection and RGC preservation, since Patrício teaches the AAV2 virus is capable of transducing RGC resulting in expression of the therapeutic transgene in the RGCs (p. 204, left col, para 1) and AAV2 virus demonstrates safety and efficacy that justify its use in the first AAV gene therapy trials in the human eye (page 198, right col, end of para 1), and since Bosch Tubert reduces to practice a method of treating diseases by administering an AAV comprising SIRT1 (example 1), one of ordinary skill in the art would have had a reason to substitute with the AAV2 gene delivery approach suggested by Patrício in the method of Zuo in order to safely and efficiently transduce SIRT1 gene into RGC to obtain SIRT1 expression in the RGCs to treat optic neuropathy or to preserve RGC function in human patients.
Furthermore, since Zuo aims to study the mechanisms of SIRT1 function to treat human patients (see 5097, para 1), and since Patrício teaches AAV2 virus is used in the first AAV gene therapy trials in the human eye (page 198, right col, end of para 1), one of ordinary skill in the art would have had a reason to use a sequence encoding human SIRT1 in the AAV in order to treat human patients.
Additionally, one of the ordinary skill in the art would have had a reason to have used the AAV comprising an AAV2 capsid and a genome comprising flanking AAV2 ITRs and a hybrid promoter in the taught dose and form of Patrício since Patrício has reduced to practice the AAV that has been used in human clinical trial and has demonstrated capability of transducing RGC resulting in expression of transgene expression in the RGC to treat eye disease.
Finally, in regard to the reasonable expectation of success in using an AAV-SIRT1 in gene therapy, it would be predictably obvious to use AAV gene therapy when practicing a method of Zuo. In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988) (citations omitted) (The court held the claimed method would have been obvious over the prior art relied upon because one reference contained a detailed enabling methodology, a suggestion to modify the prior art to produce the claimed invention, and evidence suggesting the modification would be successful.). Therefore, one of ordinary skill in the art could have pursued the known potential option of using AAV-SIRT1 gene therapy to treat optical neuropathies or to preserve RGC function with a reasonable expectation of success. This reasonable expectation of success is supported by: (1) Zuo provides a suggestion to treat optical neuropathies and to preserve RGC function by SIRT1 gene overexpression in the retinal neurons (e.g., RGC), (2) the reference of Patrício contains a detailed enabling methodology for AAV gene therapy that could easily be applied to other genes (i.e., SIRT1) to transduce RGCs to treat eye diseases, and (3) the success of making and using AAV-SIRT1 for gene therapy as taught by Bosch Tubert suggests modification of the method of Zuo to substitute with AAV-SIRT1 gene therapy would be successful.
With respect to claim 59, directed to the optic neuropathy being optic neuritis or traumatic optic neuropathy, Zuo teaches the SIRT1 overexpression, as well as a SIRT1 activator treatment, is used to treat a mouse model having experimental optic neuritis induced by traumatic optic nerve crush injury (see e.g., abstract).
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 09/12/2025 are acknowledged.
Applicant first argues that Zuo only describes a traumatic optic injury model using either SIRT1 knock-in mice or conditional neuron-specific SIRT1-KO mice and alternatively resveratrol-induced SIRT1 expression. There is widespread and chronic overexpression of SIRT1 so it is not obvious that overexpression selectively in RGCs would be therapeutically effective (Remarks, p. 7-8).
Applicant’s argument has been fully considered but it is not persuasive. As stated supra, Zuo teaches SIRT1 activation (by resveratrol) fails to prevent RGC loss in SIRT1 neuron-specific knockout mouse eyes, “confirming the importance of SIRT1 expression in neurons for resveratrol-mediated neuroprotection” (p. 5099, right col, para 1. Underline added), thus suggests SIRT1 overexpression in retinal neurons (including RGC) accounts for its role in preventing RGC loss and preserving RGC function. Accordingly, one of ordinary skill in the art would have had a reasonable expectation of success in overexpressing SIRT1 in retinal neurons including RGCs to obtain therapeutically effective prevention of RGC loss and preservation of RGC function.
Applicant further argues that the present disclosure demonstrates a neuroprotective role when SIRT1 is augmented in RGC “as described in the specification at Example 2” and in post-filing art McDougald and Chaqour (Remarks, p. 8).
Applicant’s argument has been fully considered but it is not persuasive. As a first matter, it is noted that Example 2 in the specification is directed to an in vitro study of transfection of ARPE19 cells with an AAV-SIRT1 vector (specification, p. 44, last para) in which the ARPE19 cells are a human retinal pigment epithelial (RPE) cell line that is not even an RGC. Thus, Applicant fails to specifically point out the objective factual evidences supporting the arguments in the art.
Furthermore, regarding Applicant’s referring to post filing art teaching AAV-SIRT1 treating optic neuropathy and preserving RGC function that is not predictable based on the teachings of Zuo (Remarks, p. 8), Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that Applicant' s “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304. In the instant case, as stated supra, Zuo teaches overexpressing SIRT1 gene in the mouse eyes (see Fig 2A&2B for SIRT1 overexpression in retina) prevents RGC loss (see Fig 3) and attenuates loss of RGC function (see Fig 4A). Zuo teaches this neuroprotection is dependent on SIRT1 expression in neurons (including RGC) as SIRT activator resveratrol fails to prevent RGC loss in neuron-specific SIRT1-KO mouse eyes (Fig 3A, page 5099, col 2, para 1, last 5 lines). Prior art Patrício is cited to teach “subretinal delivery of an AAV2 vector coding the CHM gene with the WPRE leads to transduction of all retina layers up to the ganglion cells” (p. 204, left col, para 1, last sentence, also see Fig 3H&3M and Fig 6G-6H for GFP or REP1 expression in all layers of retina including ganglion cell layer “GCL”), thus teaches the AAV2-mediated gene delivery is capable of transducing retinal ganglion cells (RGC) and resulting in expression of the human therapeutic transgene in the RGCs. Therefore, one of ordinary skill would have had a reasonable degree of predictability in obtaining transduction of RGC by Patrício’s AAV2 in the method of Zuo that results in expression of SIRT1 in RGC to treat optic neuropathy and to preserve RGC function.
Applicant finally argues that Hauswirth, Jacobson and Bosch Tubert fail to provide additional motivation to express SIRT1 in RGC (Remarks, p. 8).
Applicant’s argument has been fully considered and it is persuasive as Hauswirth, Jacobson and Bosch Tubert are silent on the AAV being capable of transducing RGC and resulting in transgene expression in RGC. Therefore, the prior rejection has been withdrawn. However, as necessitated by amendment, a new ground of rejection has been made over Zuo in view of Patrício and Bosch Tubert as discussed above. Specifically, Zuo suggests the neuroprotective role of SIRT1 is dependent on SIRT1 expression in retinal neurons (see above). Patrício is cited to teach an AAV2 virus that is capable of transducing retinal neurons including RGCs and that is safe and efficient for use in human clinical trial.
Claims 56-58 and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Zuo et al (Invest Ophthalmol Vis Sci. 2013; 54: 5097–5102, cited in IDS 11/08/2023) in view of Patrício et al (Molecular Therapy: Nucleic Acids. 2017; 6: 198-208. Cited in IDS 11/08/2023) and Bosch Tubert et al (US20160354489A1, cited in IDS 11/08/2023), as applied to claims 42 and 52 above, and further in view of Chaffiol et al (Molecular Therapy. 2017; 25(11): 2546-2560. Available online 20 July 2017. Cited in IDS 11/08/2023).
Claims 56 and 64 are directed to the promoter sequence comprising nucleotides 1433-2362 of SEQ ID NO: 28, which is drawn to a human gamma-synuclein gene promoter. Claims 57-58 and 65-66 are drawn to a human gamma-synuclein gene promoter.
In regard to promoters used in overexpress SIRT1 and in the AAVs, Zuo teaches a beta-actin promoter in driving SIRT1 transgene overexpression (p. 5097, last para), Patrício uses a hybrid promoter comprising the cytomegalovirus (CMV) immediate early enhancer and a chicken beta-actin promoter (see Fig 1 legend), and Bosch Tubert teaches a liver-specific promoter (hAAT promoter) in the recombinant AAV8-hAAT-Sirt1 vector ([0118]). Bosch Tubert suggests to use AAV with a tissue-specific promoter to drive restricted SIRT1 expression to treat the diseased tissue (see e.g., [0010]).
However, Zuo, Patrício and Bosch Tubert do not teach a human gamma-synuclein gene promoter with a sequence of nucleotides 1433-2362 of SEQ ID NO: 28.
Chaffiol teaches a promoter to drive a therapeutic gene expression that allows optogenetic vision restoration with enhanced sensitivity in macaque retina (title, abstract). Chaffiol teaches a new promoter based on the regulatory region of the human gamma-synuclein gene (SNCG) allowing strong expression in ganglion cells across species, in combination with clinically proven adeno-associated virus 2 (AAV2), provides CatCh expression in peri-foveolar ganglion cells responding robustly to light under the illumination safety thresholds for the human eye up to 6 months post-injection (abstract, see Figs 1-5). Chaffiol teaches the promoter sequence in supplemental Figure S1B, which comprises a sequence 100% identical to nucleotides 1433-2362 of SEQ ID NO: 28 (see comparison below), related to claims 56-58 and 64-66.
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Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of treating optic neuropathy or preserving RGC function comprising administering to the eyes a recombinant AAV2 comprising a human SIRT1 driven by a CMV-chicken beta-actin hybrid promoter suggested by Zuo, Patrício and Bosch Tubert, by substituting the CMV-chicken beta-actin hybrid promoter with a human gamma-synuclein gene promoter with a sequence of nucleotides 1433-2362 of SEQ ID NO: 28 taught by Chaffiol with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so for multiple reasons. First, substituting a non-mammalian promoter with a human promoter for a human transgene in potentially a human subject would have been obvious. Furthermore, Zuo teaches that overexpression of SIRT1 in retina preserves the RGC function (see Figs 2 and 3) that is dependent on SIRT1 expression in neurons (including RGCs, p. 5099, right col, para 1), and Chaffiol teaches the human gamma-synuclein gene (SNCG) promoter in combination with AAV2 provides strong therapeutic gene expression in the retinal ganglion cells (RGCs) up to 6 months post-injection (abstract, see Figs 1-5). Since the combined cited art teaches each and every step and/or composition necessary to use a human gamma-synuclein gene promoter to drive SIRT1 in an AAV2 vector, one of ordinary skill in the art would have had a reasonable expectation of success as well.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Response to Traversal:
Applicant’s arguments filed on 09/12/2025 are acknowledged and have been discussed above.
Terminal Disclaimers
The terminal disclaimer filed on 09/12/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date
of US Patent No: 11,879,133 has been reviewed and is accepted. The terminal
disclaimer has been recorded.
The nonstatutory double patenting rejections of record are withdrawn.
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 extension fee 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 date of this final action.
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jianjian Zhu whose telephone number is (571)272-0956. The examiner can normally be reached M - F 8:30AM - 4PM (EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James Douglas (Doug) Schultz can be reached on (571) 272-0763. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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