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 .
1. Claims 59, 62, 64 – 68, and 75 – 84 are pending. Claims 59, 62, 64 – 68, 75 and 76 are under consideration.
Withdrawn Specification Objection
2. The objection to the specification for improper trade name or marker usage is withdrawn in view of Applicant’s amendment to the specification.
Withdrawn Claim Objections
3. The objection to claim 64 is withdrawn in view of Applicant’s amendment to the claim to depend from claim 62 instead of claim 59.
4. The objection to claim 66 is withdrawn in view of Applicant’s amendment to the claim.
Withdrawn Claim Rejections
5. The rejection of claim 66 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to the claim.
6. The rejection of claim 76 under 35 U.S.C. 112(b) is withdrawn in view of Applicant’s amendment to claim 59 to recite a second promoter.
7. The rejection of claim 76 under 35 U.S.C. 112(d) is withdrawn in view of Applicant’s amendment to claim 59 to recite a second promoter.
8. The rejection of claims 59 and 68 are rejected under 35 U.S.C. 101 is withdrawn in view of Applicant’s amendment to claim 59 requiring a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA.
9. The rejection of claim 59 under 35 U.S.C. 102(a)(1) is withdrawn in view of Applicant’s amendment to claim 59 requiring a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA.
10. The rejection of claims 59, 62, 64, 66, and 68 under 35 U.S.C. 102(a)(1) and (a)(2) is withdrawn in view of Applicant’s amendment to claim 59 requiring a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA.
11. The rejection of claims 59, 62, 64, 65, and 68 under 35 U.S.C. 102(a)(1) is withdrawn in view of Applicant’s amendment to claim 59 requiring a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA.
12. The rejection of claims 59, 62, 64, 67 and 68 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 59 requiring a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA.
13. The rejection of claims 59, 62, 64, 68, and 75 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 59 requiring a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA.
14. The rejection of claim 76 under 35 U.S.C. 103 is withdrawn in view of Applicant’s amendment to claim 59 requiring a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA.
Claim Interpretation
15. For the purpose of applying prior art, photoreceptor cell specific promoters that meet the limitations of claim 59 are interpreted to include Crx promoter, Grk promoter, and GnbQ501/3 promoter based on Applicant’s specification at para. 0010, 0013, 0016, and 0080, and Figure 1B.
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.
16. Claim(s) 59, 62, 64, 65, 68, and 75 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran, Nicholas Minh Abell. Understanding CRX-Associated Retinopathies Using Animal Models. Washington University in St. Louis, 2013; previously cited), hereinafter Tran in view of Cideciyan (Cideciyan, Artur V., et al. Proceedings of the National Academy of Sciences 115.36 (2018): E8547-E8556; previously cited), hereinafter Cideciyan.
Regarding claim 59, Tran teaches an expression construct comprising the GRK promoter (“photoreceptor cell specific promoter” and “a promoter that is trans-activated by wild-type CRX”) operably linked to CRX (page 128, para. 2; page 129, para. 1). Tran teaches a rAAV5 carrying Crx shRNA expressed under the GRK promoter that was injected into the subretinal space of mice to determine if silencing of Crx expression by shRNA was capable of affecting the expression of downstream CRX target genes (page 129, para. 1). Tran does not teach “a shRNA specific for a mutant CRX mRNA”. However, Tran teaches the results suggest that CRX shRNA effectively downregulated the expression of CRX target genes and that rAAV-mediated CRX and Crx shRNA gene therapy was effective at infecting photoreceptors and affecting the expression of a CRX target gene, suggesting it may be a viable approach for targeted therapy (page 129, para. 1). Tran teaches the E168d2 Crx mutant is associated with severely impaired retinal function (page xi, para. 2; page 5, para. 2; page 9; page 24; page 28, para. 2 – 3; page 32, para. 2 – 3). Tran teaches the E168d2 transcript is more stable than the wild type Crx transcript in vitro and in vivo (page 112, last para.; page 113 – 114). Tran teaches that this greater stability may play an important role in disease and has implications for designing mutation class-specific therapy strategies, possibly targeting mutant allele expression (page 114).
Regarding claims 62 and 64, Tran teaches the viral vector (claim 62) AAV5 (claim 64) comprises the construct (page 128, para. 2).
Regarding claim 68, Tran teaches the expression construct is injected into the subretinal space of Crx-KO mice (page 128, para. 2) and therefore the expression construct is formulated for subretinal administration.
Tran does not teach “a second promoter operably linked to a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA” of claim 59 or the AAV vector is AAV2/5 of claim 65 or the “second promoter is constitutively active” of claim 75. However, Tran teaches modulating the ratios of WT:mutant CRX might be effective at improving retinal integrity and function (page 128, para. 2). Tran teaches the antimorphic nature of the E168d2/+ CRX mutation may necessitate not only the delivery of a WT copy of the CRX gene but also the silencing of the antimorphic allele (page 128, para. 2). Tran teaches collectively, these experiments suggest that AAV-mediated CRX and Crx shRNA gene therapy was effective at infecting photoreceptors and affecting the expression of a CRX target gene, suggesting it may be a viable approach for targeted therapy (page 129, para. 1). Tran teaches the greatest limitation of the AAV5 constructs was the low infection efficiency of the viral vector because while local infection rates near the site of injection site could reach ~50 – 60%, overall only ~1.5% of photoreceptors were infected across the entire retina (page 129, para. 2).
Regarding “a second promoter operably linked to a nucleic acid molecule encoding a shRNA” of claim 59 and “AAV2/5” of claim 65 and “second promoter is constitutively active” of claim 75, Cideciyan teaches a single AAV2/5 vector (claim 65) comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid encoding rhodopsin and further comprising a second constitutively active promoter (“second promoter is constitutively active” of claim 75) that is H1 operably linked to a nucleic acid encoding a shRNA (claim 59) for rhodopsin in Figure S10E (Abstract; page 8551, right col. para. 2; page 8552; page 8555, right col. para. 3). Cideciyan teaches coinjecting separate AAV2/5 constructs (one expression construct for rhodopsin expression and one for shRNA expression) and the result pointed toward a beneficial effect of the combination of knockdown and replacement function but there was incomplete rod protection and treatment resulted in severe retinal complications (page 8550, right col.). Cideciyan teaches to circumvent these limitations, a single AAV vector that combined the knockdown (shRNA) and replacement (rhodopsin) was developed to lower viral load and thus achieve better protection from retinal degeneration and improved safety (page 8550, right col.; page 8551, right col. para. 1). Cideciyan teaches a single viral vector that combines both knockdown (shRNA) and replacement function can efficiently preserve the integrity of the entire structure of the rod photoreceptors and confers long-term protection of retinal structure and function from the degeneration that otherwise occurs rapidly in untreated rhodopsin-mutant eyes (page 8552, right col.; page 8553, left col. para. 4).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Tran regarding an AAV expression construct comprising the GRK promoter operably linked to a nucleic acid encoding CRX and an AAV5 expression construct comprising Crx shRNA under the GRK promoter and the E168d2 Crx mutant is associated with severely impaired retinal function and the E168d2 transcript is more stable than the wild type Crx transcript in vitro and in vivo with the teachings of Cideciyan regarding a single AAV vector comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to rhodopsin and further comprising a constitutively active promoter operably linked to rhodopsin shRNA to arrive at the claimed composition comprising an expression construct comprising: (i) a photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a cone rod homeobox transcription factor (CRX), wherein the promoter is a promoter that is trans-activated by wild-type CRX; and (ii) a second promoter operably linked to a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA. One would have been motivated to combine the teachings of Tran and Cideciyan in an expression construct to downregulate the E168d2 Crx mutant and provide wild type Crx to treat retinal disease as Tran teaches modulating the ratios of WT:mutant CRX might be effective at improving retinal integrity and function and Tran teaches the antimorphic nature of the E168d2 CRX mutation may necessitate not only the delivery of a WT copy of the CRX gene but also the silencing of the antimorphic allele and Tran teaches the greater transcript stability of the E168d2 may play an important role in disease and has implications for designing mutation class-specific therapy strategies, possibly targeting mutant allele expression and Tran teaches the E168d2 Crx mutant is associated with severely impaired retinal function and Cideciyan teaches coinjecting separate AAV2/5 constructs pointed toward a beneficial effect of the combination of knockdown and replacement function but there was incomplete rod protection and treatment resulted in severe retinal complications and to circumvent these limitations, a single AAV vector that combined the knockdown (shRNA) and replacement (rhodopsin) was developed to lower viral load and thus achieve better protection from retinal degeneration and improved safety. One would have a reasonable expectation of success in combining the teachings as Tran teaches the shRNA expression construct reduced expression of CRX target genes and the CRX expression construct expressed CRX in vivo and Cideciyan teaches a single viral vector that combines both knockdown (shRNA) and replacement function can efficiently preserve the integrity of the entire structure of the rod photoreceptors and confers long-term protection of retinal structure and function from the degeneration that otherwise occurs rapidly in untreated rhodopsin-mutant eyes.
17. Claim(s) 66 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran, Nicholas Minh Abell. Understanding CRX-Associated Retinopathies Using Animal Models. Washington University in St. Louis, 2013; previously cited), hereinafter Tran in view of Cideciyan (Cideciyan, Artur V., et al. Proceedings of the National Academy of Sciences 115.36 (2018): E8547-E8556; previously cited), hereinafter Cideciyan as applied to claims 59, 62, 64, 65, 68, and 75 above, and further in view of Han (Han, Zongchao, et al. PloS one 7.12 (2012): e52189.), hereinafter Han.
Tran in view of Cideciyan make obvious the limitations of claim 59 and 62 as set forth above. Tran teaches AAV5 carrying Crx was injected into the subretinal space of mice (page 128, para. 2). Cideciyan teaches subretinal injection of AAV2/5 (Abstract; page E8548, right col. last para.; page E8555, right col. para. 2). Tran and Cideciyan do not teach the composition comprises a nanoparticle or a dendrimer that comprises the viral vector.
Regarding “nanoparticle” of claim 66, Han teaches a comparison of subretinal injection of AAV and nanoparticles using matched plasmids with a photoreceptor-specific promoter or a ubiquitous promoter (Abstract; page 1, right col. para. 2’ page 2, left col. para. 1; page 8, right col.). Han teaches nanoparticles can drive persistent gene expression at levels comparable to AAV and with longevity comparable to AAV (Abstract; page 2, right col. para. 2; page 3, left col. para. 2; page 6, right col. para. 2; page 7, right col. para. 1; page 8, left col. para. 3). Han teaches the nanoparticles are well-tolerated, even after repeated injection, and do not induce an inflammatory response after delivery to the eye (page 7, right col. para. 1). Han teaches the nanoparticles subretinally injected do not leave the eye, while AAVs were detected in the visual pathways of the brain (Abstract; page 8, left col. para. 1 and 3). Han teaches nanoparticles have several benefits for intraocular use including their safety and they are nontoxic to the eye (page 8, left col. last para.). Han teaches nanoparticles have the potential to become a successful alternative for ocular gene therapy (Abstract).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Tran regarding an AAV expression construct comprising the GRK promoter operably linked to a nucleic acid encoding CRX and an AAV5 expression construct comprising Crx shRNA under the GRK promoter and the E168d2 Crx mutant is associated with severely impaired retinal function and the E168d2 transcript is more stable than the wild type Crx transcript in vitro and in vivo with the teachings of Cideciyan regarding a single AAV vector comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to rhodopsin and further comprising a constitutively active promoter operably linked to rhodopsin shRNA with the teachings of Han regarding nanoparticles comprising an identical vector to AAV can be subretinally injected into mice and drive gene expression to arrive at the claimed composition comprising a nanoparticle or a dendrimer, wherein the nanoparticle or dendrimer comprises the viral vector. One would have been motivated to combine the teachings of Tran, Cideciyan, and Han in an expression construct to downregulate the E168d2 Crx mutant and provide wild type Crx to treat retinal disease as Tran teaches the E168d2 Crx mutant is associated with severely impaired retinal function and Cideciyan teaches a single AAV vector that combined the knockdown (shRNA) and replacement (rhodopsin) was developed to lower viral load and thus achieve better protection from retinal degeneration and improved safety and Han teaches nanoparticles have the potential to become a successful alternative for ocular gene therapy and Han teaches the nanoparticles subretinally injected do not leave the eye, while AAVs were detected in the visual pathways of the brain. One would have a reasonable expectation of success in combining the teachings as Han teaches nanoparticles can drive persistent gene expression at levels comparable to AAV and with longevity comparable to AAV and Han teaches the nanoparticles are well-tolerated, even after repeated injection, and do not induce an inflammatory response after delivery to the eye.
18. Claim(s) 67 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran, Nicholas Minh Abell. Understanding CRX-Associated Retinopathies Using Animal Models. Washington University in St. Louis, 2013; previously cited), hereinafter Tran in view of Cideciyan (Cideciyan, Artur V., et al. Proceedings of the National Academy of Sciences 115.36 (2018): E8547-E8556; previously cited), hereinafter Cideciyan as applied to claims 59, 62, 64, 65, 68, and 75 above, and further in view of Murphy (Murphy, Daniel P., et al. Elife 8 (2019): e48216; previously cited), hereinafter Murphy in view of Hulliger (Hulliger EC, et. al. Mol Ther Methods Clin Dev. 2020 Mar 13; previously cited), hereinafter Hulliger.
Tran and Cideciyan do not teach “the promoter is GnbQ50” of claim 67. However, Tran teaches mice with the E168d2 Crx mutant have photoreceptor damage (page 128, para. 1). Tran teaches AAV-mediated CRX and CRX shRNA gene therapy can transduce photoreceptors (page 128, para. 2; page 129, para. 1). Tran teaches the vast majority of genetic retinopathies have few, if any, viable therapeutic strategies (page 124, para. 1). Tran teaches there are no treatment strategies for CRX-associated diseases and since CRX influences many cellular processes, designing targeted therapy is exceptionally difficult (page 125, para. 3). Tran teaches the next challenge in developing effective therapy is delivering therapeutic agents to photoreceptor cells (page 124, para. 2). Tran teaches because CRX regulates the expression of many downstream target genes, the expression level needs to be carefully titrated as wild type overexpression could be just as damaging as the disease itself (page 125, para. 1). Cideciyan teaches AAV5 capsids permit efficient transduction of photoreceptor cells following subretinal injection (Supporting Information page 7, para. 2).
Murphy teaches a construct comprising a Gnb3 promoter in which K50 motifs 1 and 3 were replaced with a Q50 motif operably linked to a nucleic acid encoding a reporter (DsRed and GFP) and that this promoter caused a selective decrease of reporter expression in bipolar cells while maintaining expression in photoreceptor cells (page 13, last para.; Figure 6C, D). One would have been motivated to combine the teachings of Tran, Cideciyan and Murphy as each are drawn to transducing photoreceptor cells.
Hulliger teaches targeting therapeutic genes to specific cell types to achieve precise intervention is often imperative (page 505, left col.). Hulliger teaches photoreceptor cells are targets for gene therapy at early stages of retinal degeneration while bipolar cells make promising targets for gene therapy at late stages of retinal degeneration when most photoreceptors are lost (page 505, left col.). Hulliger teaches optogenetic and gene supplementation therapies to restore vision are already performed on human patients (page 505, left col.).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Tran regarding an AAV expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid encoding CRX and an AAV5 expression construct comprising Crx shRNA under the GRK promoter and the E168d2 Crx mutant is associated with severely impaired retinal function and the E168d2 transcript is more stable than the wild type Crx transcript in vitro and in vivo with the teachings of Cideciyan regarding a single AAV vector comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to rhodopsin and further comprising a constitutively active promoter operably linked to rhodopsin shRNA with the teachings of Murphy regarding a Gnb3 promoter in which K50 motifs 1 and 3 were replaced with a Q50 motif that maintains expression in photoreceptor cells with the teachings of Hulliger regarding photoreceptor cells are targets for gene therapy at early stages of retinal degeneration to arrive at the claimed composition where the promoter is GnbQ501/3. One would have been motivated to combine the teachings of Tran, Cideciyan, Murphy, and Hulliger in an expression construct to selectively express CRX in photoreceptor cells and reduce mutant CRX expression in photoreceptor cells for gene therapy of retinal diseases as Tran teaches there are no treatment strategies for CRX-associated diseases and since CRX influences many cellular processes, designing targeted therapy is exceptionally difficult and Tran teaches mice with the E168d2 Crx mutant have photoreceptor damage and Hulliger teaches targeting therapeutic genes to specific cell types to achieve precise intervention is often imperative. One would have a reasonable expectation of success in combining the teachings as Tran teaches AAV-mediated CRX and CRX shRNA gene therapy can transduce photoreceptors and Murphy teaches the modified Gnb3 promoter maintains expression in photoreceptor cells while decreasing expression in bipolar cells.
19. Claim(s) 76 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tran (Tran, Nicholas Minh Abell. Understanding CRX-Associated Retinopathies Using Animal Models. Washington University in St. Louis, 2013; previously cited), hereinafter Tran in view of Cideciyan (Cideciyan, Artur V., et al. Proceedings of the National Academy of Sciences 115.36 (2018): E8547-E8556; previously cited), hereinafter Cideciyan as applied to claims 59, 62, 64, 65, 68, and 75 above, and further in view of Liao (Liao, Hsi-Wen, et. al. Biotechniques 42.3 (2007): 285-288; previously cited), hereinafter Liao.
Tran in view of Cideciyan make obvious the limitations of claims 59 and 75 as set forth above. Cideciyan teaches the expression construct comprises the H1 promoter operably linked to a shRNA in Figure S10E (Abstract; page 8551, right col. para. 2; page 8552; page 8555, right col. para. 3) but Tran and Cideciyan do not teach U6 promoter of claim 76. However, Cideciyan teaches the U6 promoter is more potent, which leads to a very high level of shRNA expression (page 8554, right col. last para.).
Liao teaches an expression construct comprising the U6 promoter operably linked to shRNA for melanopsin (Figure 1A; page 285, left col. last para.; page 286, right col.). Liao teaches administration of the construct to the eye of a mouse where the construct reduced the expression of melanopsin to an undetectable level (page 285, middle col.; page 286, right col. para. 1; Figure 2).
It would have been obvious prior to the effective filing date of the invention as claimed for the person of ordinary skill in the art to combine the teachings of Tran regarding an AAV expression construct comprising the GRK promoter operably linked to CRX and an AAV5 expression construct comprising Crx shRNA under the GRK promoter with the teachings of Cideciyan regarding a single AAV vector comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to rhodopsin and further comprising a constitutively active promoter operably linked to rhodopsin shRNA with the teachings of Liao regarding an expression construct comprising the U6 promoter operably linked to shRNA to arrive at the claimed expression construct wherein the second promoter is U6 promoter. One would have been motivated to combine the teachings of Tran, Cideciyan, and Liao in an expression construct to downregulate Crx mutant expression to undetectable levels and provide wild type Crx to determine the efficacy of the construct in an animal model of retinal disease as Tran teaches modulating the ratios of WT:mutant CRX might be effective at improving retinal integrity and function and Tran teaches the antimorphic nature of the E168d2/+ CRX mutation may necessitate not only the delivery of a WT copy of the CRX gene but also the silencing of the antimorphic allele and Cideciyan teaches coinjecting separate AAV2/5 constructs pointed toward a beneficial effect of the combination of knockdown and replacement function but there was incomplete rod protection and treatment resulted in severe retinal complications and to circumvent these limitations, a single AAV vector that combined the knockdown (shRNA) and replacement (rhodopsin) was developed to lower viral load and thus achieve better protection from retinal degeneration and improved safety and Cideciyan teaches and Cideciyan teaches the U6 promoter is more potent, which leads to a very high level of shRNA expression. One would have a reasonable expectation of success in combining the teachings as Tran teaches the shRNA expression construct reduced expression of CRX target genes and the CRX expression construct expressed CRX in vivo and Cideciyan teaches a single viral vector that combines both knockdown (shRNA) and replacement function can efficiently preserve the integrity of the entire structure of the rod photoreceptors and confers long-term protection of retinal structure and function from the degeneration that otherwise occurs rapidly in untreated rhodopsin-mutant eyes and Liao teaches the shRNA expression construct resulted in undetectable levels of the target of the shRNA.
Applicant’s Arguments/Response to Arguments
20. Applicant Argues: Applicant asserts that the therapeutic strategy of Cideciyan is fundamentally different from the presently claimed invention and one of ordinary skill in the art would understand that the therapeutic objective of Cideciyan is to eliminate all endogenous RHO expression and replacement of the endogenous gene product. Applicant asserts that one of ordinary skill in the art is motivated to combine the cited references, the art would not have provided a reasonable expectation that the resulting construct would successfully treat CRX-mediated disease.
Response to Argument: This is not found persuasive because the therapeutic strategy of Tran and Cideciyan are similar in that both aim to reduce endogenous mutant retinal protein expression and provide wild type retinal protein. Tran teaches an AAV vector that downregulates Crx function and an AAV vector that expresses wild type Crx. Tran teaches E168d2 Crx mutant is associated with severely impaired retinal function (page xi, para. 2; page 5, para. 2; page 9; page 24; page 28, para. 2 – 3; page 32, para. 2 – 3) and Tran teaches the E168d2 transcript is more stable than the wild type Crx transcript in vitro and in vivo (page 112, last para.; page 113 – 114) and Tran teaches that this greater stability may play an important role in disease and has implications for designing mutation class-specific therapy strategies, possibly targeting mutant allele expression (page 114). Cideciyan teaches to circumvent the limitations associated with separate AAV vectors for wild type gene expression and shRNA expression, a single AAV vector that combined the knockdown and replacement was developed to lower viral load and thus achieve better protection from retinal degeneration and improved safety (page 8550, right col.; page 8551, right col. para. 1). Thus, one of ordinary skill in the art would understand that combining the AAV vectors of Tran into an expression construct as taught by Cideciyan would reduce the mutant Crx transcript and provide wild type Crx expression for a therapeutic strategy for treating retinal disease. One would have a reasonable expectation of success in combining Tran and Cideciyan as Cideciyan teaches a single viral vector that combines both knockdown (shRNA) and replacement function can efficiently preserve the integrity of the entire structure of the rod photoreceptors and confers long-term protection of retinal structure and function from the degeneration that otherwise occurs rapidly in untreated rhodopsin-mutant eyes (page 8552, right col.; page 8553, left col. para. 4).
Conclusion
No claims allowed.
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.
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/Z.M.B./Examiner, Art Unit 1632
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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