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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 03/02/2026 is acknowledged. Claims 24-25 were cancelled. Claims 14 and 32 were amended. Claims 14-18,21-23,26-28,30-32,34 and 35 are pending and under examination.
Oath/Declaration
A Declaration is due full consideration and weight for all that it discloses.
Declarations are reviewed for the following considerations: 1) whether the Declaration presents a nexus such as a side-by-side or single-variable comparison (In re Huang, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996)), 2) whether the Declaration presents a comparison to the closest art, 3) whether the Declaration is commensurate in scope with the scope of the claims (In re Kulling, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)), 4) whether the Declaration shows the difference in results are in fact unexpected and unobvious and of both statistical and practical significance (Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992)), and 5) whether the prima facie case is sufficiently strong that allegedly superior results are insufficient to overcome the case for obviousness (Pfizer Inc. v. Apotex, Inc., 82 USPQ2d 1321, 1339
(Fed. Cir. 2007)).
The Declaration under 37 CFR 1.132 filed 03/02/2026 is insufficient to overcome the rejection of claims 14-18,21-23,26-28,30-32,34 and 35 under 35 U.S.C. 103 because: The Declaration simply provides the exact same explanation and same arguments regarding ‘405 and Roger et al. that were provided in the Arguments of the response to the 103 rejections in the non-final rejection. The Declaration provides arguments regarding what ‘405 and Rogers et al. pertains to vs. the present invention, but does not show the difference in results are in fact unexpected and unobvious and of both statistical and practical significance. Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Examples of statements which are not evidence and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint
Inventor.
Regarding Applicants arguments on pages 2-4 of the Declaration regarding the state of the art prior to the effective filing date as only treating CRX-disease in newborn or pre-symptomatic models before establishment of a disease phenotype and before photoreceptor cell fate establishment, this is not found persuasive. Roger shows rescue of the phenotype caused by the expression of LCA- associated dominant mutation that mimics the CrxRip phenotype, which means in this case, the dominant mutant caused disease can be treated by overexpressing wild type protein. Roger shows that dominant mutations in CRX as causing congenital blindness and LCA, and that expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the CrxRip phenotypes which was rescued by overexpression of WT CRX (Abstract). Roger et al. also teaches that the photoreceptor layer in CrxRIP/RIP and Crx-/- retinas underwent rapid degeneration between 5 and 10 weeks, and only a few nuclei persisted at 9 months of age (Fig. 2B, page 635, left column). Therefore, Roger does show that photoreceptor degeneration occurred in the mouse models.
Applicant states on page 4 that the present invention demonstrates that CRX expression in models comprising already formed photoreceptors with arrested differentiation and/or degeneration unexpectedly re-initiates a photoreceptor differentiation program and points to FIG. 6. However Applicant does not explain any unexpected results. The specification (page 15) discloses FIG. 6 shows differentiated PR with outer segment can be observed in CrxRip/+ retina using a lower dose of AAV-CRX vector. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
See also the response to Applicants arguments pertaining to the 103 rejections below.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Withdrawn Rejections
Applicant’s arguments and amendments, see page 5, filed 03/02/2026, with respect to the objection to claim 14, the 35 U.S.C. 112(a) Written description, New Matter and enablement rejections of claims 14-18,21-28,30-32,34 and 35, and 35 U.S.C. 112(b) rejection of claim 32 have been fully considered and are persuasive due to the amendments to claim 14 correcting a typo and the amendment to recite “or” rather than “and” regarding the dominant mutation in the CRX gene or a hypomorphic mutation in the CRX target gene PDE6B, and the amendment to claim 32 which is no longer indefinite. The objection to claim 14 and 35 U.S.C. 112(a) Written description, New Matter and Enablement rejections of claims 14-18,21-28,30-32,34 and 35 and 35 U.S.C. 112(b) rejection of claim 32 have been withdrawn.
Claim Objections
Claim 32 is objected to because of the following informalities: the amendment to claim 32 recites “results from said hylomorphic mutation” and therefore there is a typo, “hylomorphic” and should be corrected to “hypomorphic”. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 14,15,21-23,26-28,30,31,34 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Scaria et al. (WO 2015168666, Published 5 Nov 2015) in view of Roger et al. (J Clin Invest. 2014; 124(2):631-643) and US 20180161405 (‘405), previously cited.
Regarding claims 14,30 and 31, Scaria et al. teach methods comprising subretinal delivery of rAAV particles comprising a rAAV vector encoding a heterologous nucleic acid used in treatment of an ocular disorder in an individual, the heterologous nucleic acid encodes a CRX polypeptide (paragraph 0025), and teaches the ocular disorders being treated include Leber’s Congenital Amaurosis, cone dystrophy, retinitis pigmentosa (paragraphs 0012,0020,0027,0035,0074). Scaria et al. teach the heterologous nucleic acid is under the control of a promoter sequence that is expressed in the retina, including in photoreceptor cells, and in some embodiments the promoter is a rhodopsin kinase (RK) promoter, an opsin promoter (paragraphs 0012,0020,0026,0034,0074).
Scaria et al. does not teach wherein the Leber’s Congenital Amaurosis, cone dystrophy or retinitis pigmentosa is a result of a dominant mutation in the CRX gene.
However, before the effective filing date, Roger et al. taught that Leber congenital amaurosis (LCA) encompasses a set of early-onset blinding diseases characterized by vision loss, involuntary eye movement and nonrecordable electroretinogram (ERG), and that mutations in homeodomain transcription factor CRX lead to an autosomal dominant form of LCA (Abstract). Roger et al. taught a mouse mutant with a frameshift mutation in Crx (CrxRip), and that CrxRip is a dominant mutation that results in congenital blindness with nonrecordable responses by ERG and arrested photoreceptor differentiation with no associated degeneration, and that expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the CrxRip phenotype, which was rescued by overexpression of WT CRX (Abstract). Roger et al. also taught a range of diverse clinical phenotypes, from cone-rod dystrophy and retinitis pigmentosa to congenital blindness in LCA, associated with CRX mutations in humans reveal its more complex role in photoreceptor development and/or function (page 631, right paragraph), and that the majority of missense and truncation mutations in the CRX homeodomain are associated with cone-rod dystrophy and alter its DNA binding properties or transcriptional synergy with NRL, thereby influencing gene expression and photoreceptor maturation, and many human CRX framework mutations identified downstream of the homeodomain result in dominant and more severe LCA phenotypes (page 634, left column). Roger et al. taught in humans, almost 50 CRX mutations have been identified in patients with retinopathy, and the majority act in a dominant manner (page 640).
Scaria et al. and Roger et al. do not teach wherein the vector is administered after initiation of photoreceptor degeneration or that the vector is administered as long as there are functional cone and/or rod photoreceptors.
Before the effective filing date, ‘405 taught improved methods for treating ocular diseases, in particular inherited retinal degenerative disorders such as rod-cone dystrophies with an rAAV carrying a nucleic acid sequence encoding a functional gene by sub-retinal injections in each quadrant of retina (paragraph 0001) and that rod-cone dystrophies encompass retinitis pigmentosa and Leber congenital amaurosis (paragraph 0002). Rod-cone dystrophy, Leber congenital amaurosis (LCA) may be caused by mutations in more than 10 genes, including the CRX gene causing LCA7 (paragraph 0025). ‘405 taught that “rescue” means to prevent progression of the disease to total blindness, prevent spread of damage to uninjured photoreceptor cells and/or RPE cells or to improve damage in injured photoreceptor cells and/or RPE cells (paragraph 0039), and administering a pharmaceutical composition comprising the rAAV vector after initiation of photoreceptor loss, and may be administered when less than 10-90% of the photoreceptors are functioning or remaining (paragraph 0040).
Regarding claim 15, Scaria et al. teach wherein the rAAV particle comprises an AAV serotype 2 (AAV2) (paragraphs 0007,0079,0081-0083,0146).
Regarding claims 21-22, Scaria et al. teach intravitreal or subretinal injection of AAV2 particles, and the number of vector genomes injected is 108 or 109 vg (paragraph 0079).
Regarding claim 23, Scaria et al. teach as a guide, the number of particles administered per injection is generally between about 1x106 and about 1x1014 particles, and between about 1x109 and 1x1012 particles, and may be administered by one or more subretinal injections (paragraph 0201) and also teaches the dose of recombinant viral particles administered is 1x108 to about 1x1013 genome copies (paragraph 0209).
Regarding claims 27 and 28, Scaria et al. teach also provided herein are pharmaceutical compositions comprising a rAAV particle comprising a heterologous nucleic acid encoding a therapeutic polypeptide or therapeutic nucleic acid, and a pharmaceutically acceptable carrier, and the pharmaceutical compositions may be suitable for any mode of administration, for example by subretinal administration (paragraph 0253). Scaria et al. teach the pharmaceutical compositions comprising a rAAV described herein and a pharmaceutically acceptable carrier are suitable for administration to humans (paragraph 0254).
Regarding claim 34, Scaria et al. teach in the case of diseases resulting in progressive degenerative visual function, treating the subject at an early age may not only result in a slowing or halting of the progression of the disease, it may also ameliorate or prevent visual function loss due to acquired amblyopia, and that in some embodiments the human treated is less than 13,12,10,8 or less than 6 years of age (page 0214).
Regarding claim 35, Scaria et al. teach the human treated can be less than 30 years of age (paragraph 0214) and teach adult mice subjects used in the in vivo experiments (paragraph 0319).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, that the diseases being treated (Leber’s Congenital Amaurosis, cone dystrophy, retinitis pigmentosa) by the method of Scaria et al. would have resulted from a dominant mutation in the CRX gene with a reasonable expectation of success. There would be a reasonable expectation of success, because Scaria et al. teaches treating the same diseases (Leber’s Congenital Amaurosis, cone dystrophy, retinitis pigmentosa) comprising subretinal delivery of rAAV particles comprising a rAAV vector encoding a heterologous nucleic acid used in treatment of an ocular disorder in an individual and wherein the heterologous nucleic acid encodes a CRX polypeptide, and Roger et al. teaches the association of mutations including dominant mutations in CRX with LCA, cone-rod dystrophy and retinitis pigmentosa. One of ordinary skill in the art would have been motivated to provide a method of treating retinitis pigmentosa, Leber’s congenital amaurosis or cone-rod dystrophy which resulted from a dominant mutation in the CRX gene by administering to the subject an rAAV vector comprising a polynucleotide encoding CRX of Scaria et al., because Roger et al. taught dominant mutations in CRX associated with LCA, cone-rod dystrophy, and retinitis pigmentosa. Roger et al. taught the majority of missense and truncation mutations in the CRX homeodomain are associated with cone-rod dystrophy and alter its DNA binding thereby influencing gene expression and photoreceptor maturation, and many human CRX framework mutations identified downstream of the homeodomain result in dominant and more severe LCA phenotypes and that a range of diverse clinical phenotypes, from cone-rod dystrophy and retinitis pigmentosa to congenital blindness in LCA, associated with CRX mutations in humans reveal its more complex role in photoreceptor development and/or function (page 631, right paragraph), and that expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the CrxRip phenotype, which was rescued by overexpression of WT CRX (Abstract).
It would have been obvious at the time of the effective filing date, that the method of Scaria et al. and Roger et al. administer the vector after initiation of photoreceptor degeneration or as long as there are functional cone and/or rod photoreceptors based on the teachings of ‘405. There would be a reasonable expectation of success because ‘405 also pertains to gene therapy using rAAVs carrying a nucleic acid encoding a functional gene for treating retinal degenerative disorders. One of ordinary skill in the art would have been motivated to do so in order to reduce progression to blindness and spread of damage because ‘405 taught that rescue means to prevent progression of the disease to total blindness, prevent spread of damage to uninjured photoreceptor cells and/or RPE cells or to improve damage in injured photoreceptor cells and/or RPE cells (paragraph 0039) and administering an rAAV vector after initiation of photoreceptor loss and the rAAV may be administered when less than 10-90% of the photoreceptors are functioning or remaining (paragraph 0040).
Accordingly, the limitations of claims 14,15,21-23,26-28,30,31,34 and 35 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant’s arguments, see page 6, filed 03/02/2026 with respect to the rejection(s) of claim(s) 14,15,21-23,27,28,30,31,34 and 35 under 35 U.S.C. 103 as unpatentable over Scaria et al. in view of Roger et al. have been fully considered and are persuasive, due to the amendment to claim 14 incorporating the subject matter of claim 25 (now canceled) which was not rejected as unpatentable over Scaria in view of Roger. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 14 incorporating the subject matter of claim 25 which was rejected under 35 U.S.C. 103 as unpatentable over Scaria et al. in view of Roger et al. and further in view of US 20180161405 (‘405).
Applicant argues on page 7 of response, that the Examiner’s reliance on US ‘405 is misplaced because ‘405 does not provide an enabling teaching nor would there be any reasonable expectation of success for the claimed invention. Applicant points to the Declaration of Jerome Roger which states that while ‘405 broadly lists CRX among numerous genes associated with retinal dystrophies, the references actual technical teaching and guidance is limited to classical gene replacement therapy for recessive loss-of-function disorders, exemplified by RPE65 where the addition of a functional gene copy is biologically straightforward and may be administered at various disease stages, while in the present invention, CRX mutations are dominantly acting and often exert dominant-negative effects such that simple gene replacement presents significant and non-trivial biological challenges.
This is not found persuasive. The rejection is made under 103 and does not need to exemplify all embodiments, only suggest. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. In this case, ‘405 was not relied upon solely for the CRX gene, as Scaria et al. was used for the base reference teaching that limitation, but rather for the teaching regarding administering a pharmaceutical composition comprising the rAAV vector after initiation of photoreceptor loss, including when less than 10-90% of the photoreceptors are functioning or remaining (paragraph 0040). The examiner did not provide any statements in the rejection regarding applying an RPE65-type gene replacement paradigm to CRX and was not relying on the teachings regarding RPE65 gene replacement therapy in ‘405. The fact that ‘405 also discloses treating the same diseases encompassed by the instant claims by administering an rAAV by sub-retinal injection and disclosed the CRX gene as one of the genes causing LCA7 provides support that ‘405 is relevant art. ‘405 provides motivation for why one of ordinary skill in the art would want to administer an rAAV gene therapy vector to a subject after initiation of photoreceptor loss in order to “rescue” or prevent progression of the disease to total blindness, and prevent spread of damage to uninjured photoreceptor cells (paragraph 0039-0040). Roger shows that rescue of the phenotype caused by the expression of LCA- associated dominant mutation that mimics the CrxRip phenotype, which means in this case, the dominant mutant caused disease can be treated by overexpressing wild type protein. The instant claims do not recite any function related to the dominant mutant. In addition, Applicant’s argument that CRX mutations are dominantly acting and often exert dominant-negative effects is not relevant because this limitation is not recited in the claim.
Applicant argues on pages 7-8 that gene replacement therapy for a gene such as RPE65 is fundamentally different from therapeutic approaches involving CRX, as RPE65 encodes an enzyme of the visual cycle and disease causing mutations are recessive loss-of-function mutations such that addition of a functional gene copy is biologically additive and compensates for the missing enzymatic activity while CRX is a photoreceptor-specific transcription factor that regulates the expression of numerous downstream genes essential for photoreceptor differentiation, maintenance, and survival, and CRX mutations are predominantly dominant and exert dominant-negative or gain-of-function effects. Therefore, a person of ordinary skill in the art could not have reasonably predicted or expected that a gene augmentation or replacement strategy could provide therapeutic benefit, and merely increasing or reintroducing CRX expression could not have been reasonably predicted to neutralize the pathogenic mutant protein and could have been expected to aggravate transcriptional imbalance. The skilled person would have lacked any reasonable expectation of success in applying an RPE65-type gene replacement paradigm to CRX, particularly in a therapeutic context when intervention occurs after retinal differentiation is complete and after photoreceptor degeneration has begun and therefore the present invention runs counter to the prevailing technical assumptions in the field.
This is not found persuasive. Applicant has not provided any evidence that the teachings of ‘405 will not work for CRX, as Rogers et al. provides evidence that CRX gene replacement works. Given the teachings of Roger, one would have a reasonable expectation of success for the therapeutic benefit of providing wild type CRX. Instant claim 14 only recites a single-step of administering to the subject in need thereof a rAAV vector comprising a polynucleotide encoding CRX and no specific structures of the AAV or CRX gene is recited in the claim. Applicant’s argument that ‘405 does not provide an enabling teaching are not relevant because Applicants do not provide any specific guidance regarding this. The examiner directs applicant’s attention to MPEP 2121: PRIOR ART IS PRESUMED TO OPERABLE/ENABLING. Once such a reference is found, the burden is on applicant to provide facts rebutting the presumption of operability. In re Sasse, 629 F.2d 675, 207 USPQ 107 (CCPA 1980). Also see MPEP 716.07. The examiner further points to MPEP 2121.01 (II): “Even if a reference discloses an inoperative device, it is prior art for all that it teaches.” Clearly, ‘405 teaches treating ocular diseases, in particular inherited retinal degenerative disorders including rod-cone dystrophies, with an rAAV carrying a nucleic acid sequence encoding a functional gene by sub-retinal injections into the retina (paragraph 0001), that LCA7 is caused by mutations in the CRX gene, and teaches general embodiments of the invention regarding “rescue” to prevent total blindness and preventing spread of damage to uninjured photoreceptor cells and administering the composition after initiation of photoreceptor loss (paragraphs 0039-0040).
In addition, Applicant is providing arguments without evidence of unexpected results. “The arguments of counsel cannot take the place of evidence in the record.” In re Schulze, 346 F.2d 600, 145 USPQ 716, 718 (CCPA 1965), In re Huang, 40 USPQ 2d 1685 (Fed. Cir. 1996), In re De Blauwe et al., 222 USPQ 191, (Fed. Cir. 1984). Applicant has not provided any factual evidence establishing unobviousness. MPEP 716.01(c). Neither Applicant’s arguments nor the examples in the instant specification provide guidance as to how this would be different than what is taught in the art (Scaria). Applicant provides no arguments regarding the base reference, Scaria et al., which was relied upon for teaching the majority of the claim limitations. It is noted that instant claim 14 only recites a single-step of administering to the subject in need thereof a rAAV vector comprising a polynucleotide encoding CRX and wherein the polynucleotide is under the control of a promoter that drives expression in rod and cone photoreceptors and wherein the vector is administered subretinally or intravitreally, all of which is taught by Scaria et al. and provided in the rejection. Other than arguments, Applicant has not provided evidence of unexpected results that one of ordinary skill in the art would not have had a reasonable expectation of success.
Applicant argues on pages 8-9, that the state of the art prior to the effective filing date of the invention treated only CRX-associated disease, if at all, in newborn or pre-symptomatic models (before establishment of the disease phenotype at a developmental stages when the retina is composed of only retinal progenitor prior photoreceptor cell fate establishment). Applicant argues such work was conducted at an early developmental stage when the retina was composed primarily of retinal progenitor cells, i.e. before photoreceptor fate commitment and the prior art provides no guidance for therapeutic intervention in a differentiated or degenerating retina. Roger et al. relies exclusively on neonatal mouse models in which photoreceptor fate commitment has not yet occurred and the retina is largely composed of retinal progenitor cells undergoing active differentiation and Roger et al. fails to address therapeutic intervention in a mature or degenerating retina and provides no guidance for treatment under these conditions. The absence of degeneration is critical: the non-recordable ERG response observed in CrxRIP mice result from a failure of maturation not from photoreceptor loss or degeneration. Therefore the problem solved by the instant invention is fundamentally distinct from that of Roger et al.. Applicant provides a figure from Roger et al. and argues on page 10 of response that expression of NRL partially restored the development in CrxRIP/+ mice but NRL is expressed in rod and not in cone as CRX and is not comparable, and that NRL expression does not restore the photoreceptor outer segments formation, a critical component of the photoreceptor to capture light (Figure 7), and also cites page 634, second paragraph of Roger et al. Applicant argues without proper outer segment formation, functional vision cannot be achieved, which indicates that early embryonic transgenic expression of NRL may bias towards a rod-like fate, however outer segment morphogenesis remains defective and this impairment is consistent with the dominant-negative effect of CRXRIP. Applicant argues on page 11 that the skilled person in the art would have concluded from Roger et al. that outer segment regeneration is not achievable in this dominant-negative CRX context, particularly when treatment is administered after retinal development is complete.
This is not found persuasive. Roger et al. was relied upon for the teaching regarding dominant mutations in CRX as causing congenital blindness and LCA, and that expression of LCA-associated dominant CRX frameshift mutations in mouse retina mimicked the CrxRip phenotypes which was rescued by overexpression of WT CRX (Abstract). Roger et al. also teaches that the photoreceptor layer in CrxRIP/RIP and Crx-/- retinas underwent rapid degeneration between 5 and 10 weeks, and only a few nuclei persisted at 9 months of age (Fig. 2B, page 635, left column).
Applicant argues on page 11 that the present invention demonstrates the CRX expression in models comprising already formed photoreceptors with arrested differentiation and/or degeneration unexpectedly re-initiates a photoreceptor differentiation program and points to Figure 6. Therefore, Roger et al. provides no guidance, examples, or data addressing treatment of dominant CRX mutations, nor does it suggest that administration of a CRX vector after initiation of photoreceptor degeneration would be effective, and the skilled artisan would have been discouraged from carrying out the subject matter of the claims since there is not reasonable expectation of success in prior art when administering AAV therapy for CRX mutant mice.
This is not found persuasive. Applicant repeatedly refers to the deficiencies of Roger et al. and provides no arguments regarding the teachings of the base reference Scaria et al. which was relied upon for teaching the majority of the claim limitations. As stated above instant claim 14 only recites a single-step of administering to the subject in need thereof a rAAV vector comprising a polynucleotide encoding CRX and wherein the polynucleotide is under the control of a promoter that drives expression in rod and cone photoreceptors and wherein the vector is administered subretinally or intravitreally, all of which is taught by Scaria et al. and provided in the rejection. Roger et al. was relied upon for the teachings that dominant mutations in the CRX gene cause the recited diseases, and ‘405 was relied upon for motivation of administering treatment after initiation of photoreceptor degeneration for the recited diseases. Applicant refers to FIG. 6 but does not explain any unexpected results. The specification (page 15) discloses FIG. 6 shows differentiated PR with outer segment can be observed in CrxRip/+ retina using a lower dose of AAV-CRX vector. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. An unexpected property or result must actually be unexpected and of statistical and practical significance. The burden is on the applicant to establish the results are in fact unexpected, unobvious and of statistical and practical significance. See MPEP 716.02.
Claims 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Scaria et al. in view of Roger et al. and ‘405 as applied to claims 14,15,21-23,26-28,30,31,34 and 35 above, and further in view of Khani et al. (Invest Ophthamol Vis Sci. Vol. 48, No. 9, 1 Sept 2007, pages 3954-3961), cited on an IDS and in the office action dated 08/16/2024.
The teachings of Scaria et al., Roger et al. and ‘405 as applicable to claims 14,15,21-23,26-28,30,31,34 and 35 are described above.
Additionally regarding claims 17-18, Scaria et al. teach a rhodopsin kinase promoter (paragraph 0012,0020,0074) and that "Rhodopsin kinase (RK) promoter" refers to a polynucleotide sequence derived from a rhodopsin kinase gene (e.g., human RK, represented by GenBank Entrez Gene ID 6011) that drives expression specifically in rod and cone photoreceptor cells [0136].
Scaria et al., Roger et al. and ‘405 do not teach wherein the AAV vector is an AAV2/5 or AAV2/8 serotype and does not explicitly recite the promoter is GRK1.
However, before the effective filing date, Khani et al. taught that gene based therapies offer a potential treatment for photoreceptor degeneration where gene constructs are delivered to the retina using AAV vectors, as well as the need for a promoter with photoreceptor-restricted transcriptional activity (right column, page 3954). AAV2 vectors were among the first to be developed for gene delivery to retinal photoreceptors, and that pseudotyped AAV2/5 vectors are more efficient than AAV-2 vectors in mediated gene delivery to photoreceptors and RPE cells (page 3954, right column).
Khani et al. taught the small carrying capacity of AAV vectors limits the promoters to being short, and that a number of promoters that have been studied have had variable success in driving expression of foreign genes in photoreceptors right column, page 3954). Khani et al. taught a short derivative of the human rhodopsin kinase promoter, also known as GRK1 (Abstract), plays a role in light adaptation and abundant expression in rods and cones and is the most favorable promoter configuration (right column, page 3959). Khani et al. taught the delivery of a AAV2/5 vector containing the hRK promoter by subretinal injection into animals and concluded that the RK promoter was active in rods and cones (page 3957).
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date, to replace the AAV2 vector used in the method of Scaria et al. with the AAV2/5 vector of Khani et al. in order to improve efficiency of the delivery to the target cells. There would be a reasonable expectation of success, because both Scaria et al. and Khani et al. taught AAV2 vectors for delivering genes to photoreceptors and RPE cells. One of ordinary skill in the art would have been motivated to replace the AAV2 vector used in the method of Scaria et al. with an AAV2/5 vector because Khani et al. taught that pseudotyped AAV2/5 vectors are more efficient than AAV-2 vectors in mediated gene delivery to photoreceptors and RPE cells (page 3954, right column), and would make obvious the limitations of claim 16.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date, to use the GRK1 promoter of Khani et al. in the method of Scaria et al. and Roger et al. for the purpose of improving expression of the CRX gene in rod and cone photoreceptor cells. There would be a reasonable expectation of success because Scaria et al. also taught using a promoter which is human RK that drives expression specifically in rod and cone photoreceptor cells. One of ordinary skill in the art would have been motivated to use GRK1 as the promoter in the method of Scaria et al. and Roger et al. because Khani et al. taught that the hRK1 promoter is the most favorable promoter configuration due to the small size, and that the promoter is active in both rods and cones, and would make obvious the limitations of claims 17 and 18.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
No additional arguments pertaining to claims 16-18 have been provided by Applicant. Applicant provided arguments pertaining to Rogers and ‘405 and the Examiner responded to those arguments above.
Claims 14,15,21-23,26-28,30,32,34 and 35 are rejected under 35 U.S.C. 103 as being unpatentable over Scaria et al. (WO 201516866, Published 5 Nov 2015) in view of Pittler et al. (The Journal of Biological Chemistry, Vol. 279, No. 19, Issue of May 7 2004, pp. 19800-19807), Muradov et al. (Vision Research 57 (2012) 1-8) and US 20180161405 (‘405).
Regarding claims 14,30 and 32, Scaria et al. teach methods comprising subretinal delivery of rAAV particles comprising a rAAV vector encoding a heterologous nucleic acid used in treatment of an ocular disorder in an individual, the heterologous nucleic acid encodes a CRX polypeptide (paragraph 0025), and teaches the ocular disorders being treated include Leber’s Congenital Amaurosis, cone dystrophy, retinitis pigmentosa (paragraphs 0012,0020,0027,0035,0074). Scaria et al. teach the heterologous nucleic acid is under the control of a promoter sequence that is expressed in the retina, including in photoreceptor cells, and in some embodiments the promoter is a rhodopsin kinase (RK) promoter, an opsin promoter (paragraphs 0012,0020,0026,0034,0074).
Scaria et al. does not teach wherein the that Leber’s Congenital Amaurosis, cone dystrophy or retinitis pigmentosa is a result of a hypomorphic mutation in the CRX target gene Phosphodiesterase 6B (PDE6B).
However, before the effective filing date, Pittler et al. taught the type 6 cGMP phosphodiesterase (PDE6) in rod photoreceptors is a heterotrimeric enzyme essential for phototransduction, functioning to lower cytoplasmic cGMP levels in response to light activation of the receptor rhodopsin, and the alpha and beta subunits comprise the catalytic core of the enzyme (page 19800, right column). The PDE6A promoter requires Nrl and Crx for full transcriptional activity, and their data and that from other studies of the PDE6B gene promoter shows greater activity but contains essentially the same binding sites (page 19801, left column). mRNA levels of Pde6a and Pde6b in Crx knockout mice were 13% and 55% respectively of that observed in the Crx+/+, and therefore Crx is necessary to achieve wild type transcription levels (page 19804, right column). Pittler et al. taught a critical role for Crx in achieving full promoter activity of both the Pde6a and Pde6b promoters and this is in contrast to other published results suggesting that Crx does not have a significant involvement in the activation of the Pde6b promoter (page 19804, Discussion, right column).
Additionally, Muradov et al. taught mutations in the key rod phototransduction enzyme phosphodiesterase 6 (PDE6) are known to cause recessive retinitis pigmentosa in humans, and that mutation N605S in the PDE6B subunit is linked to atypical retinal degeneration in mice (Abstract, page 1). The rd1 mouse is a classical loss-of-function model with disruption of the PDE6B gene causing elevation of cGMP levels and rapid retinal degeneration (page 1, right column).
Scaria et al., Pittler et al., and Muradov et al. do not teach wherein the vector is administered after initiation of photoreceptor degeneration or that the vector is administered as long as there are functional cone and/or rod photoreceptors.
‘405 taught improved methods for treating ocular diseases, in particular inherited retinal degenerative disorders such as rod-cone dystrophies with an rAAV carrying a nucleic acid sequence encoding a functional gene by sub-retinal injections in each quadrant of retina (paragraph 0001) and that rod-cone dystrophies encompass retinitis pigmentosa and Leber congenital amaurosis (paragraph 0002). ‘405 taught that the rod-cone dystrophy, Leber congenital amaurosis (LCA) may be caused by mutations in more than 10 genes, including the CRX gene causing LCA7 (paragraph 0025). ‘405 taught that “rescue” means to prevent progression of the disease to total blindness, prevent spread of damage to uninjured photoreceptor cells and/or RPE cells or to improve damage in injured photoreceptor cells and/or RPE cells (paragraph 0039). ‘405 taught administering a pharmaceutical composition comprising the rAAV vector after initiation of photoreceptor loss, and may be administered when less than 10-90% of the photoreceptors are functioning or remaining (paragraph 0040).
Regarding claim 15, Scaria et al. teach wherein the rAAV particle comprises an AAV serotype 2 (AAV2) (paragraphs 0007,0079,0081-0083,0146).
Regarding claims 21-22, Scaria et al. teach intravitreal or subretinal injection of AAV2 particles, and the number of vector genomes injected is 108 or 109 vg (paragraph 0079).
Regarding claim 23, Scaria et al. teach as a guide, the number of particles administered per injection is generally between about 1x106 and about 1x1014 particles, and between about 1x109 and 1x1012 particles, and may be administered by one or more subretinal injections (paragraph 0201) and also teaches the dose of recombinant viral particles administered is 1x108 to about 1x1013 genome copies (paragraph 0209).
Regarding claims 27 and 28, Scaria et al. teach also provided herein are pharmaceutical compositions comprising a rAAV particle comprising a heterologous nucleic acid encoding a therapeutic polypeptide or therapeutic nucleic acid, and a pharmaceutically acceptable carrier, and the pharmaceutical compositions may be suitable for any mode of administration, for example by subretinal administration (paragraph 0253). Scaria et al. teach the pharmaceutical compositions comprising a rAAV described herein and a pharmaceutically acceptable carrier are suitable for administration to humans (paragraph 0254).
Regarding claim 34, Scaria et al. teach in the case of diseases resulting in progressive degenerative visual function, treating the subject at an early age may not only result in a slowing or halting of the progression of the disease, it may also ameliorate or prevent visual function loss due to acquired amblyopia, and that in some embodiments the human treated is less than 13,12,10,8 or less than 6 years of age (page 0214).
Regarding claim 35, Scaria et al. teach the human treated can be less than 30 years of age (paragraph 0214) and teach adult mice subjects used in the in vivo experiments (paragraph 0319).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date, that the diseases being treated (Leber’s Congenital Amaurosis, cone dystrophy, retinitis pigmentosa) by the method of Scaria et al. would have resulted from a hypomorphic mutation in PDE6B with a reasonable expectation of success. There would be a reasonable expectation of success, because Pittler et al. taught the association and relationship of PDE6B and CRX and Muradov et al. taught mutations in PDE6B that are associated with atypical retinal degeneration. One of ordinary skill in the art would have been motivated to provide a method of treating retinitis pigmentosa, Leber’s congenital amaurosis or cone-rod dystrophy which resulted from a hypomorphic mutation in PDE6B by administering to the subject an rAAV vector comprising a polynucleotide encoding CRX of Scaria et al., because Pittler et al. taught the PDE6A promoter requires Nrl and Crx for full transcriptional activity, and their data and that from other studies of the PDE6B gene promoter shows greater activity but contains essentially the same binding sites, and teach a critical role for Crx in achieving full promoter activity of both the Pde6a and Pde6b promoters which is in contrast to other published results suggesting that Crx does not have a significant involvement in the activation of the Pde6b promoter (page 19804, Discussion, right column), and because Muradov et al. taught mutations in the key rod phototransduction enzyme phosphodiesterase 6 (PDE6) are known to cause recessive retinitis pigmentosa in humans, and that mutation N605S in the PDE6B subunit is linked to atypical retinal degeneration in mice (Abstract, page 1) and that the rd1 mouse is a classical loss-of-function model with disruption of the PDE6B gene causing elevation of cGMP levels and rapid retinal degeneration (page 1, right column) which shows these mutations in PDE6B result in retinal degeneration.
It would have been obvious at the time of the effective filing date, that the method of Scaria et al. modified by Pittler et al. and Muradov et al. administer the vector after initiation of photoreceptor degeneration or as long as there are functional cone and/or rod photoreceptors based on the teachings of ‘405. There would be a reasonable expectation of success because ‘405 also pertains to gene therapy using rAAVs carrying a nucleic acid encoding a functional gene for treating retinal degenerative disorders. One of ordinary skill in the art would have been motivated to do so in order to reduce progression to blindness and spread of damage because ‘405 taught that rescue means to prevent progression of the disease to total blindness, prevent spread of damage to uninjured photoreceptor cells and/or RPE cells or to improve damage in injured photoreceptor cells and/or RPE cells (paragraph 0039) and administering an rAAV vector after initiation of photoreceptor loss and the rAAV may be administered when less than 10-90% of the photoreceptors are functioning or remaining (paragraph 0040).
Accordingly, the limitations of claims 14,15,21-23,26-28,30,32,34 and 35
would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
Applicant’s arguments, see page 6, filed 03/02/2026 with respect to the rejection(s) of claim(s) 14,15,21-23,27,28,30,32,34 and 35 under 35 U.S.C. 103 as unpatentable over Scaria et al. in view of Pittler et al. and Muradov et al. have been fully considered and are persuasive, due to the amendment to claim 14 incorporating the subject matter of claim 25 (now canceled) which was not rejected as unpatentable over Scaria in view of Pittler and Muradov. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of the amendment to claim 14 incorporating the subject matter of claim 25 which was rejected under 35 U.S.C. 103 as unpatentable over Scaria et al. in view of Pittler and Muradov and further in view of US 20180161405 (‘405).
Applicant does not provide any arguments pertaining to Scaria, Pittler or Muradov, and only provides arguments regarding US ‘405 which are the same arguments provided for the rejections of Scaria, Rogers and ‘405 that are provided above in the Response to Arguments section for the 103 rejection regarding Scaria, Roger, and ‘405. Applicant provides no arguments regarding the references teaching the hypomorphic mutation in PDE6B (Pittler and Muradov). As Applicant provided the same arguments to ‘405 for both of the 103 rejections (Scaria in view of Rogers and ‘405, and Scaria in view of Pittler, Muradov and ‘405), the Examiner’s response to arguments is provided above.
Claims 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Scaria et al., Pittler et al. and Muradov et al. as applied to claims 14,15,21-23,26-28,30,32,34 and 35 above, and further in view of Khani et al. (Invest Ophthamol Vis Sci. Vol. 48, No. 9, 1 Sept 2007, pages 3954-3961), cited on an IDS.
The teachings of Scaria et al., Pittler et al., Muradov et al. and ‘405 as applicable to claims 14,15,21-23,26-28,30,32,34 and 35 are described above.
Additionally regarding claims 17-18, Scaria et al. teach a rhodopsin kinase promoter (paragraph 0012,0020,0074) and that "Rhodopsin kinase (RK) promoter" refers to a polynucleotide sequence derived from a rhodopsin kinase gene (e.g., human RK, represented by GenBank Entrez Gene ID 6011) that drives expression specifically in rod and cone photoreceptor cells [0136].
Scaria et al., Pittler et al., Muradov et al. and ‘405 do not teach wherein the AAV vector is an AAV2/5 or AAV2/8 serotype and do not explicitly recite the promoter is GRK1.
However, before the effective filing date, Khani et al. taught that gene based therapies offer a potential treatment for photoreceptor degeneration where gene constructs are delivered to the retina using AAV vectors, as well as the need for a promoter with photoreceptor-restricted transcriptional activity (right column, page 3954). Khani et al. taught AAV2 vectors were among the first to be developed for gene delivery to retinal photoreceptors, and that pseudotyped AAV2/5 vectors are more efficient than AAV-2 vectors in mediated gene delivery to photoreceptors and RPE cells (page 3954, right column).
Khani et al. taught the small carrying capacity of AAV vectors limits the promoters to being short, and that a number of promoters that have been studied have had variable success in driving expression of foreign genes in photoreceptors right column, page 3954). A short derivative of the human rhodopsin kinase promoter, also known as GRK1 (Abstract), plays a role in light adaptation and abundant expression in rods and cones and is the most favorable promoter configuration (right column, page 3959). Khani et al. taught the delivery of a AAV2/5 vector containing the hRK promoter by subretinal injection into animals and concluded that the RK promoter was active in rods and cones (page 3957).
Therefore, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date, to replace the AAV2 vector used in the method of Scaria et al. modified by the teachings of Pittler et al. and Muradov et al., with the AAV2/5 vector of Khani et al. in order to improve efficiency of the delivery to the target cells. There would be a reasonable expectation of success, because both Scaria et al. and Khani et al. taught AAV2 vectors for delivering genes to photoreceptors and RPE cells. One of ordinary skill in the art would have been motivated to replace the AAV2 vector used in the method of Scaria et al. with an AAV2/5 vector because Khani et al. taught that pseudotyped AAV2/5 vectors are more efficient than AAV-2 vectors in mediated gene delivery to photoreceptors and RPE cells (page 3954, right column), and would make obvious the limitations of claim 16.
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date, to use the GRK1 promoter of Khani et al. in the method of Scaria et al. modified by the teachings of Pittler et al. and Muradov et al., for the purpose of improving expression of the CRX gene in rod and cone photoreceptor cells. There would be a reasonable expectation of success because Scaria et al. also taught using a promoter which is human RK that drives expression specifically in rod and cone photoreceptor cells. One of ordinary skill in the art would have been motivated to use GRK1 as the promoter in the method of Scaria et al. modified by the teachings of Pittler et al. and Muradov et al., because Khani et al. taught that the hRK1 promoter is the most favorable promoter configuration due to the small size, and that the promoter is active in both rods and cones, and would make obvious the limitations of claims 17 and 18.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Response to Arguments
No additional arguments pertaining to claims 16-18 have been provided by Applicant. Applicant only provided arguments pertaining to ‘405 and the Examiner responded to those arguments above.
Conclusion
Claims 14-18,21-23,26-28,30-32,34 and 35 are rejected.
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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/STEPHANIE L SULLIVAN/
Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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