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. Election/Restrictions Applicant’s election without traverse of Group I (claims 59, 62, 64 – 68, 75, and 76) in the reply filed on 02/24/2026 is acknowledged. Claims 77 – 84 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 02/24/2026. Priority 2. This application claims priority of U.S. provisional application No. 63/172,978, filed April 9, 2021 . Information Disclosure Statement 3. The information disclosure statement (IDS) submitted on 05/06/2024 are acknowledged. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. 4. The Moen reference (citation no. 25) has not been considered because the copy provided only contains 2 or the 9 pages. Drawings 5 . The drawings filed on 10/09/2023 are acknowledged. Specification 6 . The use of the term TetON , TetOff , which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term . Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Claim Objections 7 . Claim 64 is objected to because of the following informalities: “The composition of claim 59” should read “The composition of claim 62” because claim 59 does not recite “a viral vector” but claim 62 recites “a viral vector”. Claim 64 is being examined as depending from claim 62. Appropriate correction is required. 8 . Claim 66 is objected to because of the following informalities: “ GnbQ50 ” should read “ GnbQ501/3 ” because the specification defines GnbQ501/3 as a photoreceptor specific promoter at para. 00208 . Appropriate correction is required. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(b): (b ) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the appl icant regards as his invention. 9 . Claim s 66 and 76 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. 10 . Claim 66 recites the limitation "the expression vector" in line 2. There is insufficient antecedent basis for this limitation in the claim. 11 . Regarding claim 76 that depends from claim 75 , it is unclear how a U6 promoter is also a “ photoreceptor cell specific promoter” required by claim 75. In other words, the U6 promoter is not recognized in the art as being a photoreceptor cell specific promoter and therefore cannot meet the limitation required by claim 75 but does meet the limitation of “constitutively active”. Claim Rejections - 35 USC § 112 The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. 12 . Claim 76 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 75 requires a second photoreceptor cell specific promoter but claim 76 that depends from claim 75 broadens the second promoter to recite U6 promoter, which is not a photoreceptor cell specific promoter . Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Interpretation 13 . 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. 14 . For the purpose of applying prior art, claim 64 is being examined as depending from claim 62 because claim 59 does not recite “viral vector” , while claim 62 recites “wherein the viral vector comprises the expression construct” . 15 . For the purpose of applying prior art, “the expression vector” of claim 66 is interpreted as “the expression construct” of claim 59 based on Applicant’s specification at para. 0021, 0026, 0033, and 0064 and because claim 59 does not recite “vector” . 16 . For the purpose of applying prior art, the second promoter of claim 75 is interpreted as a constitutively active promoter based on Applicant’s Figure 15 – 16 or a photoreceptor cell specific promoter based on Applicant’s specification at para. 0018, 0024, 0025 , and 0030 . Claim Rejections - 35 USC § 101 35 U.S.C. 101 reads as follows: Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. 17 . Claims 59 and 68 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX without significantly more. The claim(s) recite(s) photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX which is not shown to differ from that in nature . Claim 59 is drawn to a composition comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a cone rod homeobox transcription factor (CRX), wherein (a) the promoter is a promoter that is active in retinal photoreceptors but not repressed by a CRX mutant; or (b) a promoter that is transactivated by wild-type CRX . The Office published Office's new guidance document entitled 2019 Revised Patent Subject Matter Eligibility Guidance, published January 7, 2019. Applicant is directed to the Federal Register, Volume 4, No. 4, pages 50-57 at page 74621. Step 1 of the USPTO' s eligibility analysis entails considering whether the claimed subject matter falls within the four statutory categories of patentable subject matter identified by 35 U.S.C. 101: Process, machine, manufacture, or composition of matter. The claims are directed to a composition of matter (step 1, Yes). Step 2A of the 2019 Revised Patent Subject Matter Eligibility Guidance is a two-prong inquiry. In Step 2A Prong One, examiners evaluate whether the claim recites a judicial exception. The composition of matter ( photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX ) is directed to a natural phenomenon (Step 2A, prong 1, Yes). Because the claim recites a nature-based product limitation ( photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX ), the markedly different characteristics analysis is used to determine if the nature-based product limitation is a product of nature exception. The claim also recites “wherein (a) the promoter is a promoter that is active in retinal photoreceptors but not repressed by a CRX mutant; or (b) a promoter that is transactivated by wild-type CRX ” . The markedly different characteristics analysis is performed by comparing the nature-based product limitation in the claim to its naturally occurring counterpart to determine if it has markedly different characteristics from the counterpart. Here, the closest natural counterpart is naturally occurring photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX . Furukawa ( Furukawa, Akiko, et al. "The mouse Crx 5′-upstream transgene sequence directs cell-specific and developmentally regulated expression in retinal photoreceptor cells." Journal of Neuroscience 22.5 (2002): 1640-1647 ) teaches the endogenous mouse Crx locus encoding the Crx promoter and Crx protein in Figure 1A. Furukawa teaches the Crx promoter directs expression to retinal photoreceptor cells (page 1641, left col. para. 2). When the claimed photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX is compared to this counterpart, the comparison indicates that there are no differences in structure, function or other characteristics. Further, the claimed photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX is not markedly different from the natural counterpart as a result of recitation of “active in retinal photoreceptors but not repressed by a CRX mutant” or “a promoter that is trans-activated by wild-type CRX as Furukawa teaches Crx transactivates itself to maintain its expression in vivo by positive feedback (page 1 641 , left col. paragraph 2; page 1645, left col. last para. ). Therefore, the claimed photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX is a product of nature exception and recites a judicial exception. In Step 2A Prong Two, examiners evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception. This evaluation is performed by (a) identifying whether there are any additional elements recited in the claim beyond the judicial exception, and (b) evaluating those additional elements individually and in combination to determine whether the claim as a whole integrates the exception into a practical application. Besides the judicial exception, the claim recites the judicial exception is “ an expression construct ”. An evaluation of whether this limitation is insignificant extra-solution activity is then performed. Note that because Step 2A Prong Two analysis excludes consideration of whether a limitation is well-understood, routine, conventional activity, this evaluation does not take into account whether or not the limitation is well-known. When so evaluated, this additional element is insignificant extra-solution activity because the judicial exception can is naturally occurring and the Crx protein is expressed from the naturally occurring Crx locus . Accordingly, “expression construct” does not integrate the recited judicial exception into a practical application and the claim is therefore directed to the judicial exception (Step 2A, prong 2, No). In Step 2B, the eligibility analysis evaluates whether the claim as a whole amounts to significantly more than the recited exception, i.e., whether any additional element, or combination of additional elements adds an inventive concept into the claim. As discussed with respect to Step 2A Prong Two, the claim recites generically recites “ expression construct ”, which is at best the equivalent of merely adding the words “apply it” to the judicial exception. Mere instructions to apply an exception cannot provide an inventive concept. At Step 2B, the evaluation of the insignificant extra-solution activity consideration takes into account whether or not the extra-solution activity is well-known. Here, recitation of the photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding CRX being an expression construct is recited at a high level of generality and does not amount to significantly more and does not provide an inventive concept (Step 2B: No). Markedly different characteristics can be expressed as the product' s structure, function, and/or other properties. In accordance with this analysis, a product that is purified or isolated, for example, will be eligible when there is a resultant change in characteristics sufficient to show a marked difference from the product' s naturally occurring counterpart. If the claim recites a nature-based product limitation that does not exhibit markedly different characteristics, the claim is directed to a ‘‘product of nature” exception (a law of nature or naturally occurring phenomenon), and the claim will require further analysis to determine eligibility based on whether additional elements add significantly more to the exception. Limitations that were found not to be enough to qualify as ‘‘significantly more” when recited in a claim with a judicial exception include: Adding the words ‘‘apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer; simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are well-understood, routine and conventional activities previously known to the industry; adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea; or generally linking the use of the judicial exception to a particular technological environment or field of use. In the instant case, the limitations of the claim does not impose limits on the claim scope such that they are not markedly different in structure from a naturally occurring product. Claim Rejections - 35 USC § 102 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action: A person shall be entitled to a patent unless – (a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale , or otherwise available to the public before the effective filing date of the claimed invention. (a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention. 18 . Claim(s) 59 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Furukawa ( Furukawa, Akiko, et al. "The mouse Crx 5′-upstream transgene sequence directs cell-specific and developmentally regulated expression in retinal photoreceptor cells." Journal of Neuroscience 22.5 (2002): 1640-1647 ), hereinafter Furukawa . Claim 59 is drawn to a composition comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a cone rod homeobox transcription factor (CRX), wherein (a) the promoter is a promoter that is active in retinal photoreceptors but not repressed by a CRX mutant; or (b) a promoter that is transactivated by wild-type CRX . Furukawa teaches the endogenous mouse Crx locus encoding the Crx promoter and Crx protein in Figure 1A. Furukawa teaches the Crx promoter directs expression to retinal photoreceptor cells (page 1641, left col. para. 2). Furukawa teaches Crx transactivates itself to maintain its expression in vivo by positive feedback (page 1 641 , left col. paragraph 2; page 1645, left col. last para. ). Therefore, Furukawa anticipates claim 59 . 19 . Claim(s) 59 , 62, 64, 66, and 68 is/are rejected under 35 U.S.C. 102 (a)(1) and (a)(2) as being anticipated by Swaroop ( US-20230066585-A1 ; Filed 01/15/2021; Published 03/02/2023), hereinafter Swaroop as evidenced by Furukawa ( Furukawa, Akiko, et al. "The mouse Crx 5′-upstream transgene sequence directs cell-specific and developmentally regulated expression in retinal photoreceptor cells." Journal of Neuroscience 22.5 (2002): 1640-1647 ), hereinafter Furukawa . Claim 59 is drawn to a composition comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a cone rod homeobox transcription factor (CRX), wherein (a) the promoter is a promoter that is active in retinal photoreceptors but not repressed by a CRX mutant; or (b) a promoter that is transactivated by wild-type CRX . Regarding claim 59 , Swaroop teaches an expression construct comprising a CRX promoter (“photoreceptor cell specific promoter” and “a promoter that is trans-activated by wild-type CRX”) operably linked to a nucleic acid encoding CRX (page 8, para. 0081 – 0083; page 25, para. 0205 – 0206). The CRX promoter is trans-activated by wild-type CRX as evidenced by Furukawa (page 1 641 , left col. paragraph 2; page 1645, left col. last para. ). Regarding claim s 62 and 64 , Swaroop teaches the viral vector (claim 62 ) AAV2 (claim 64 ) comprises the expression construct (page 22, para. 0196). Regarding claim 66 , Swaroop teaches dendrimers or nanoparticles can comprise the expression construct (page 4, para. 0033; page 11 – 12, para. 0116; page 17, para. 0154 – 0155; page 18, para. 0159). Regarding claim 68 , Swaroop teaches the expression construct is formulated for local delivery to the eye by subretinal administration (page 15, para. 0140 and 0142 – 0143 ). Therefore, Swaroop anticipates claims 59, 62, 64, 66, and 68 . 20 . Claim(s) 59 , 62, 64 , 65 , and 68 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Watanabe ( Watanabe, Satoshi, et al. PloS one 8.1 (2013): e54146. ), hereinafter Watanabe as evidenced by Furukawa ( Furukawa, Akiko, et al. "The mouse Crx 5′-upstream transgene sequence directs cell- specific and developmentally regulated expression in retinal photoreceptor cells." Journal of Neuroscience 22.5 (2002): 1640-1647 ), hereinafter Furukawa . Claim 59 is drawn to a composition comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a cone rod homeobox transcription factor (CRX), wherein (a) the promoter is a promoter that is active in retinal photoreceptors but not repressed by a CRX mutant; or (b) a promoter that is transactivated by wild-type CRX . Regarding claim 59 , Watanabe teaches an expression construct comprising a Crx promoter (“photoreceptor cell specific promoter” and “a promoter that is trans-activated by wild-type CRX”) operably linked to a nucleic acid encoding Crx (page 3, right col. last para.; Figure 3A; page 9, left col. last para.). The CRX promoter is trans-activated by wild-type CRX as evidenced by Furukawa (page 1 641 , left col. paragraph 2; page 1645, left col. last para. ). Regarding claims 62, 64, and 65 , Watanabe teaches the viral vector (claim 62 ) AAV2/5 (“or any combination thereof” of claim 64 and “AAV2/5” of claim 65 ) comprises the expression construct (page 3, right col. last para.; page 9, left col. last para. and right col. para. 1). Regarding claim 68 , Watanabe teaches the expression construct was injected subretinally into mice (page 3, right col. last para.; page 5, left col. para. 1 ; page 9, right col. para. 2 ) and was therefore formulated for subretinal administration. Therefore, Watanabe anticipates claims 59 , 62, 64, 65, and 68 . 21 . Claim(s) 59 , 62, 64, and 68 is/are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Tran ( Tran, Nicholas Minh Abell. Understanding CRX-Associated Retinopathies Using Animal Models . Washington University in St. Louis, 2013. ), hereinafter Tran . Claim 59 is drawn to a composition comprising an expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a cone rod homeobox transcription factor (CRX), wherein (a) the promoter is a promoter that is active in retinal photoreceptors but not repressed by a CRX mutant; or (b) a promoter that is transactivated by wild-type CRX . 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). 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. Therefore, Tran anticipates claims 59 , 62, 64, and 68 . 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. 22 . Claim (s) 59 , 62, 64, 67 and 68 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. ), hereinafter Tran in view of Murphy ( Murphy, Daniel P., et al. Elife 8 (2019): e48216. ), hereinafter Murphy in view of Hulliger ( Hulliger EC, et. al . Mol Ther Methods Clin Dev. 2020 Mar 13 ), hereinafter Hulliger . Tran anticipates claim 59 , 62, 64, and 68 as set forth above but does not teach “the promoter is GnbQ50” of claim 67 . However, Tran teaches the CRX expression construct expresses CRX in vivo when subretinally injected into Crx -/- mice (page 128, last para.; 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). 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). 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 expression construct comprising a photoreceptor cell specific promoter operably linked to a nucleic acid encoding CRX with the teachings of Murphy regarding a Gnb3 promoter in which K50 motifs 1 and 3 were replaced with a Q50 motif 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 GnbQ50. One would have been motivated to combine the teachings of Tran, Murphy, and Hulliger in an expression construct to selectively express CRX 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 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 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 the expression construct results in expression of CRX in vivo and Murphy teaches the modified Gnb3 promoter maintains expression in photoreceptor cells while decreasing expression in bipolar cells. 23 . Claim (s) 59 , 62, 64, 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. ), hereinafter Tran in view of Cideciyan ( Cideciyan , Artur V., et al. Proceedings of the National Academy of Sciences 115.36 (2018): E8547-E8556.), hereinafter Cideciyan . Tran anticipates claims 59, 62, 64, and 68 as set forth above. Regarding “an expression construct comprising a second photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a shRNA” of claim 75 , Tran teaches a n AAV5 construct comprising Crx shRNA (“shRNA”) under the GRK promoter (“photoreceptor cell specific promoter”) was injected into the subretinal space of WT mice and silencing of Crx expression by shRNA was capable of downregulating the expression downstream CRX target genes (page 129, para. 1). Tran teaches an AAV5 expression construct comprising the GRK promoter and nucleic acid sequence encoding CRX was subretinally injected into Crx -KO mice where CRX was expressed (page 128, para. 2; page 129, para. 1; Figure 5.2). Tran does not teach the Crx expression construct further comprises the shRNA expression construct or that the shRNA is specific for a mutant CRX mRNA or a constitutively active promoter. However, Tr an 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 “the expression construct further comprises” and “second promoter is constitutively active”, Cideciyan teaches a single AAV 2/5 vector comprising a n 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”) that is H1 operably linked to a nucleic acid encoding a shRNA 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 rho do psin 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 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 expression construct wherein the expression construct further comprises a second photoreceptor cell specific promoter operably linked to a nucleic acid molecule encoding a shRNA specific for a mutant CRX mRNA, wherein the second promoter is constitutively active. One would have been motivated to combine the teachings of Tran and Cideciyan in an expression construct to downregulate Crx mutants 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 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. 24 . 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. ), hereinafter Tran in view of Cideciyan ( Cideciyan , Artur V., et al. Proceedings of the National Academy of Sciences 115.36 (2018): E8547-E8556.), hereinafter Cideciyan as applied to claim s 59 , 62, 64, 68, and 75 above, and further in view of Liao ( Liao, Hsi -Wen, et. al. Biotechniques 42.3 (2007): 285-288 ), hereinafter Liao . Tran anticipates claim s 59 , 62, 64, and 68 as set forth above. Tran in view of Cideciyan make obvious the limitations of claim 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. Conclusion No claims allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT ZANNA M BEHARRY whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)270-0411 . 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