DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/08/2026 has been entered.
Status of claim rejections
The rejection of record under 35 USC § 112(a) of claims 11-17 are withdrawn in view of Applicant’s amendments/arguments in the Response filed 03/08/2026.
The rejection of record under 35 USC § 103 is maintained and modified in view of Applicant’s arguments/amendments in the Response filed 03/08/2026.
New Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8-18 and 22-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Claims 8 and 22 have been amended to recite, inter alia, “a functional counterpart of a defective gene associated with manifestation of an ocular disease or condition wherein the functional counterpart is selected from the group consisting of CRX, AIPL1, TULP1, etc.” (see claim 8 and 22).
The examiner has interpreted this limitation to encompass any nebulous “functional” counterpart of the Markush group of genes claimed, including fragments between 3 nucleic acids to the full-length nucleic acid sequence. The specification does not reasonably provide support for possession of the claimed genera of ocular disease-related genes, nor does it provide any correlating structure that would allow for functional counterpart genes to retain functionality.
In the instant case, the genes listed in claim 8 must be a functional counterpart (interpreted to include fragments of the aforementioned genes) for use in a recombinant AAV vector. A “functional counterpart of a defective gene associated with ocular disease” encompasses a broad genus of functional genes, including the wildtype eye disease-associated genes, mutants, various fragments, etc. The broad genus of these functional gene counterparts greatly exceeds the species of ocular disease-associated genes supported in the specification.
In support of the claimed genus, the specification discloses 14 examples in which NR2E3 with AAV5, AAV2.8, and AAV8 is used in recombinant AAV vectors in murine models of retinal degeneration and retinitis pigmentosa (see pgs. 28-39 of the specification). However, there is no data in the specification that indicates the use of any other hNHR other than NR2E3, or fragments thereof in a recombinant AAV vector. Furthermore, the specification only discloses various examples of what the functional counterpart of defective genes associated with retinal degeneration could be (such as CRX, AIPL1, NRL, NR2E3, PRPH2, etc.) (see pg. 4 of the specification), but the examples are limited only to the use of wildtype murine NR2E3 and not any other “functional” gene counterparts. The specification only discloses speculative embodiments (see para 0012, 0019) of such functional counterparts. There is no disclosure of functional counterpart otherwise used in a recombinant AAV vector, except for the disclosure of full-length CRX (see Fig. 20; para 0062). The data generated for full-length CRX used in a recombinant AAV vector, as described in the specification, cannot reasonably be extrapolated and applied to support possession of the entire claimed genus of functional gene counterparts useful in a recombinant AAV vector, because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1966).
There is also no disclosure as to what structure(s) must be present or retained on the “functional counterpart” or functional characteristics that would distinguish a functional counterpart of a gene from a non-functional counterpart. Applicant has provided no information as to how a gene counterpart would be considered “functional”, distinguishing characteristics, or the amount of biological activity that is required for the gene counterpart to work. There is no sufficient structure-function relationship with respect to the broad genus as claimed. The data in the specification cannot be extrapolated to any and all possible counterparts of genes associated with ocular disease. Even with knowledge in the art regarding the modification of genes, one of ordinary skill would not reasonably know, based on the disclosure provided, what structures or functions are required for the outcome of creating a functional counterpart of a gene associated with ocular disease without a recognized correlation between structure and function. Therefore, the claims are rejected under 35 U.S.C. 112(a) for lack of written description.
Modified Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 8-10, 12, 16, and 22-25 are rejected under 35 U.S.C. 103 as being unpatentable over Haider (WO 2014134627 A1; 04 September 2024; prior art of record), and further in view of Agbandje-Mckenna et al (WO 2015134643 A1; 11 September 2015; hereinafter "Agbandje"; prior art of record) and Botta et al (EP3071592A2; published 28 Sept 2016; hereinafter “Botta”; prior art of record).
Haider teaches methods for modulating development and function of photoreceptor cells (title) and also teaches a composition comprising a nucleic acid encoding a nuclear hormone receptor or fragment thereof for local administration to an ocular or adnexal tissue of a subject suffering from or at risk of developing an ocular disease or disorder for treating or reducing the severity of an ocular disease or disorder in a subject (pg. 1, paragraph 4; see claim 9). The nuclear hormone receptor of fragment encodes NR1D1, NR2E3 RORA, NUPR1, NR2C1 or a fragment thereof (pg. 2, paragraph 1; see claims 11-13) in a vector or a nucleic acid construct, e.g., a vector containing the nucleic acids such as recombinant AAV (rAAV) nucleic acid vectors (an rAAV vector comprising a human nuclear hormone receptor gene or fragment wherein said hNHR gene is selected from NR2E3, NR1D1, RORA, NUPR1, NR2C1 as in claim 8) (pg. 20, paragraph 5). Haider also teaches that the subject treated is in need of a treatment of an ocular disorder, and specifically that the disorder is age-related macular degeneration (AMD) (pg. 2, paragraph 3).
Haider does not explicitly teach that the AAV capsid protein is AAV5 or AAV8 (as in claim 8).
However, Agbandje teaches improved rAAV vectors and methods for transduction of photoreceptors and RPE cells (title) used as delivery agents for diagnosis, treatment, or amelioration of disorders/diseases of the mammalian eye (abstract). Agbandje also teaches that rAAV has many properties that favor its use as a gene delivery vehicle, including that: 1) the wild-type virus is not associated with any pathologic human condition; 2) the recombinant form does not contain native viral coding sequences; and 3) persistent transgenic expression has been observed in a variety of mammalian cells, facilitating their use in many gene therapy-based applications (paragraph 0006). Agbandje also teaches that AAV5 and AAV8 (as in claim 8) are AAV serotypes commonly used to deliver transgenes to cells (paragraph 0012).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to modify the construct of Haider by including the AAV5 or AAV8 capsid protein and arrive at the claimed invention. As Haider teaches an rAAV construct with nuclear hormone receptor genes and Agbandje teaches that AAV5 and AAV8 are commonly used to deliver transgenes to cells, one of ordinary skill would have been motivated to use AAV5 or AAV8 with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Agbandje teaches that recombinant AAVs such as AAV5 or AAV8 are capable of advantageously being used in many gene therapy-based applications, especially as delivery agents for diagnosis, treatment, or amelioration of disorders/diseases of the mammalian eye.
Neither Haider nor Agbandje teaches a functional counterpart of a defective gene associated with manifestation of said ocular condition or disease, wherein said functional counterpart of a defective gene is selected from the group consisting of CRX, AIPLI, TULP1, CABP4, RPE65, CEP290, NRL, PRPH2, RHO, ROM1, ABCA4, MERTK, PDE6A, PDE6B, SAG, CNGB3, RAB28, CACNA1F, ELOV4, ANCA4, GNAT1, GRK1, CANAIF, CACNA2D4, XLRS, BBS2, BBS4, BBS6, MYO7A, USH2A, and a combination thereof.
However, Botta teaches vectors comprising nucleic acids useful for the treatment of eye disorders (see abstract; claims 11-12). Botta teaches various genes and nucleotides that can be utilized in various vectors including adenoviral vectors, lentiviral vectors, retroviral vectors, adeno-associated vectors, and plasmid DNA vectors (see claim 13-14), and that the vector can include nucleotide sequences of (including, but not limited to) RHO, CRX, NRL, PRPH2, RPE65, MERTK (see claim 15; throughout document).
Therefore, it would been prima facie obvious to one of ordinary skill at the time of filing to modify the construct of Haider and Agbandje by including the gene nucleotide sequences as taught by Botta to arrive at the claimed invention. As Haider and Agbandje teaches an rAAV construct with nuclear hormone receptor genes with AAV5 and AAV8 are commonly used to deliver transgenes to cells, and Botta teaches genes capable of use in a vector for treatment of ocular disease, one of ordinary skill would have been motivated to use the genes of Botta a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Botta teaches such nucleotide sequences are capable of advantageously being used in vectors for the treatment of eye disorders.
Regarding claim 9, Agbandje teaches AAV5 and AAV8, which are naturally occurring AAV serotype capsid proteins.
Regarding claim 10, Haider teaches that the hNHR gene is NR1D1, NR2E3 RORA, NUPR1, NR2C1.
Regarding claim 12 and 16, teaches suitable sequences of NR1D1 (SEQ ID NO: 5) that has 100% similarity to instant SEQ ID NO: 5 (see claim 34), and NUPR1 (SEQ ID NO: 28) that has 100% similarity to instant SEQ ID NO: 9. Please see screenshots below of the duplicate sequence disclosures and alignments:
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Regarding claim 22-25, Haider, Agbandje, and Botta teach (in combination) a recombinant DNA (nucleic acid) composition comprising the hNHR genes selected from NR2E3 and RORA, a functional counterpart of a defective gene associated with an ocular disease, and a delivery vehicle, where the delivery vehicle is AAV5 or AAV8 (see rejection above). Haider also teaches that gene delivery of genes such as NR2E3 or NR1D1 suppresses retinal spotting, dysplasia, and rescues retinal degeneration in NR2E3 deficient mice (i.e., the ocular condition is ameliorated by transfection as in claim 22) (see pg. 10, Fig. 3-5).
Accordingly, the claimed invention was prima facie obvious at the time of filing, especially in the absence of evidence to the contrary.
Second rejection
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Haider, Agbandje, and Botta as applied to claims 8-10, 12, 16, and 22-25 above, and further in view of Moore (WO200183556 A2).
As discussed above, claims 8-10, 12, 16, and 22-25 were rendered prima facie obvious by the teachings of Haider, Agbandje, and Botta.
The difference between Haider, Agbandje, Botta, and the instant claims is that none of the references explicitly teach the NR2E3 gene comprises SEQ ID NO: 1 (as in claim 11).
However, Moore teaches a nuclear receptor, RetinaX Receptor, including polynucleotides encoding RetinaXR, polypeptides and vectors and recombinant host cells containing RetinaXR-encoding sequences for gene therapy treatment of various disorders including including age-related macular degeneration, diabetic retinopathy, non-diabetic retinopathies, retinopathy of prematurity, and retinitis pigmentosa, neovascular glaucoma, uveitis, corneal inflammation (see abstract; see pg. 15). Moore teaches a sequence (see SEQ ID NO: 1, claim 13 of Moore) that has 100% sequence identity to instant SEQ ID NO: 1 (see alignment below).
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Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to use the NR2E3 gene of Moore in the recombinant AAV vector of Haider, Agbandje, and Botta to arrive at the claimed invention. As Haider, Agbandje, and Botta teach an AAV vector with nuclear hormone receptor genes, Moore teaches polynucleotide sequences for treatment of diseases like AMD, including NR2E3 gene, one of ordinary skill would have been motivated to use the gene in the vector with a reasonable expectation of success. As the claimed invention relies on the creation of a recombinant AAV vector, one of ordinary skill would have reasonably performed a simple substitution of one known element (any of the hNHR genes of Haider) with another (the NR2E3 gene of Moore) with a reasonable expectation of success (creating a recombinant AAV vector with a gene associated with eye disease). One of ordinary skill would have been motivated to make the substitution because Moore teaches RetinaXR-encoding sequences for gene therapy treatment of various disorders including including age-related macular degeneration.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Third rejection
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Haider, Agbandje, and Botta as applied to claims 8-10, 12, 16, and 22-25 above, and further in view of Bancel et al (US 20140010861 A1, 29 March 2007; prior art of record; hereinafter “Bancel”) and Choudhary & Malek (J Biomol Screen. 2016 Dec;21(10):1007-1018; prior art of record; hereinafter “Choudhary”).
As discussed above, claims 8-10, 12, 16, and 22-25 were rendered prima facie obvious by the teachings of Haider, Agbandje, and Botta.
The difference between Haider, Agbandje, Botta, and the instant claims is that none of the references explicitly teach the RORA gene comprises SEQ ID NO:7 (as in claim 13).
However, Bancel teaches modified polynucleotides for production of proteins associated with human disease (title). The primary constructs or mmRNA of the present invention may be designed to encode polypeptides of interest selected from any of several target categories including, but not limited to, biologics, antibodies, vaccines, therapeutic proteins or peptides, cell penetrating peptides, secreted proteins, plasma membrane proteins, cytoplasmic or cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease, targeting moieties or those proteins encoded by the human genome for which no therapeutic indication has been identified but which nonetheless have utility in areas of research and discovery (paragraph 0093). The polynucleotides may encode one or more biologics used to treat, cure, mitigate, prevent, or diagnose a serious or life-threatening disease or medical condition (paragraph 0097). Bancel discloses a sequence (SEQ ID NO: 25524) that has 100% sequence similarity to instant SEQ ID NO: 7 (see alignment below):
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Instant SEQ ID No 7 vs SEQ ID No 25524 of Bancel
Similarly, Choudhary teaches nuclear hormone receptors as potential therapeutic targets for retinal diseases (title). Choudhary also teaches human nuclear receptor (NR) superfamily is composed of 48 evolutionarily related transcription factors that regulate a myriad molecular pathways modulated by NRs, and functions such as inflammation, lipid metabolism, apoptosis, EM regulation, energy metabolism, and angiogenesis are compromised in various eye diseases such as diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinitis pigmentosa (RP) (pg. 1 paragraph 1, pg. 2, paragraph 1). Choudhary further teaches that retinoic acid receptor-related orphan receptor alpha (RORα; NR1F1) is a lipid-sensing NR that has been shown to regulate the inflammatory response in allergy and autoimmune diseases (pg. 6, paragraph 3). The absence of RORα inhibited pathological angiogenesis in a model of oxygen-induced retinopathy, by directly impacting the expression of suppressor of cytokine signaling 3 (SOCS3), which is a critical regulator of tissue inflammation (pg. 6, paragraph 3). RORα may also serve as a novel target for drug development to treat pathological retinal angiogenesis without directly altering levels of angiogenic growth factors, such as VEGF, which are essential for physiological angiogenesis (pg. 6, paragraph 3).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to use the RORA gene of Bancel, as a retinopathy-related nuclear receptor as taught by Choudhary, in the recombinant AAV vector of Haider, Agbandje, and Botta to arrive at the claimed invention. As Haider, Agbandje, and Botta teach an AAV vector with nuclear hormone receptor genes, Bancel teaches modified polynucleotide sequences for treatment of human disease, including a RORA gene, and Choudhary teaches that RORA may serve as a novel target for drug development to treat pathological retinal angiogenesis/retinopathy, one of ordinary skill would have been motivated to use the RORA of Bancel with a reasonable expectation of success. As the claimed invention relies on the creation of a recombinant AAV vector, one of ordinary skill would have reasonably performed a simple substitution of one known element (any of the hNHR genes of Haider) with another (the RORA gene of Bancel) with a reasonable expectation of success (creating a recombinant AAV vector with a gene associated with eye disease). One of ordinary skill would have been motivated to make the substitution because Bancel teaches an RORA gene that can be used to treat human diseases, and Choudhary teaches that RORA is a candidate target for drug development in retinopathy.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Fourth rejection
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Haider, Agbandje, and Botta as applied to claims 8-10, 12, 16, and 22-25 above, and further in view of Rossi and Warren (WO2011130624 A2, 20 October 2011; prior art of record; hereinafter “Rossi”) and Choudhary.
As discussed above, claims 8-10, 12, 16, and 22-25 were rendered prima facie obvious by the teachings of Haider, Agbandje, and Botta.
The difference between Haider, Agbandje, Botta, and the instant claims is that none of the references explicitly teach an NR1C3 gene comprising SEQ ID NO: 3.
However, Rossi teaches modified RNAs used for changing the phenotype of a cell such as expressing a polypeptide or altering the developmental potential of a cell (title, abstract). Rossi teaches various modified RNAs that can be used to treat a variety of diseases such as ocular disorders (paragraph 00390). One such gene is the NHR peroxisome proliferative activated receptor gamma (PPAR-gamma, also known as NR1C3) (pg. 133, table 1, SEQ ID NO: 793). SEQ ID NO: 793 (NM_005037) of Rossi has 94.7% similarity to instant SEQ ID NO: 3 (see screenshot below of duplicate sequence disclosure and alignment):
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Similarly, Choudhary also teaches that PPAR-gamma (NR1C3) is a diabetic retinopathy candidate receptor, as it has been shown to play an important role in a variety of biological processes dysregulated in diabetes and DR, including adipogenesis, glucose metabolism, angiogenesis, and inflammation (pg. 5, paragraph 4; pg. 6, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to use the NR1C3 nuclear hormone receptor as taught by Rossi, as a diabetic retinopathy-related nuclear receptor as taught by Choudhary in the recombinant AAV vector of Haider, Agbandje, and Botta to arrive at the claimed invention. As Haider, Agbandje, and Botta teach an AAV vector with nuclear hormone receptor genes, Rossi teaches various modified mRNAs useful for treating diseases such as ocular disorders including an NR1C3 gene, and Choudhary teaches that NR1C3 is a diabetic retinopathy candidate receptor, one of ordinary skill would have been motivated to use the NR1C3 of Rossi with a reasonable expectation of success. As the claimed invention relies on the creation of a recombinant AAV vector, one of ordinary skill would have reasonably performed a simple substitution of one known element (any of the hNHR genes of Haider) with another (the NR1C3 of Rossi) with a reasonable expectation of success (creating a recombinant AAV vector with a gene associated with eye disease). One of ordinary skill would have been motivated to make the substitution because Rossi teaches an NR1C3 gene that can be used to treat ocular diseases, and Choudhary teaches that NR1C3 is a candidate receptor for targeting in diabetic retinopathy.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Fifth rejection
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Haider, Agbandje, and Botta as applied to claims 8-10, 12, 16, and 22-25 above, and further in view of Venter et al (US 20070037165 A1, 15 February 2007; prior art of record) and Olivares et al (Developmental Biology, Volume 429, Issue 1, 1 September 2017, Pages 343-355; hereinafter “Olivares”).
As discussed above, claims 8-10, 12, 16, and 22-25 were rendered prima facie obvious by the teachings of Haider, Agbandje, and Botta.
The difference between Haider, Agbandje, Botta, and the instant claims is that none of the references explicitly teach the NR2C1 gene comprises SEQ ID NO:11 (as in claim 15).
However, Venter teaches polymorphisms in known genes associated with human disease, methods of detection and uses thereof (title) based on the discovery of novel polymorphisms (SNPs) in the genes known in the art to contribute to human disease (abstract, paragraph 0001, paragraph 0028, and 0032). Venter teaches a sequence (SEQ ID NO: 5796) that has 100% sequence identity to instant SEQ ID NO: 11 (see alignment below):
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Instant SEQ ID NO 11 vs SEQ ID NO 5796 of Venter
Similarly, Olivares teaches nuclear hormone receptors (NHRs) are a highly conserved group of transcriptional regulators that are involved in numerous functions including development, reproduction, metabolism, circadian cycle, and immunological responses (pg. 343, col 1 paragraph 1) and that NR2C1 is a critical regulator of early retina cell patterning, and that loss of NR2C1 causes a severe vision deficit and impacts early retina cell types (title, abstract; pg. 345 col 2, paragraph 3). In NR2C1+/- and NR2C1-/- mutant mice showed severe vision loss due to disruption in phototransduction (pg. 346, Fig. 3C; pg. 347, col 1, paragraph 2). Olivares also teaches that NR2C1 is clearly an important transcription factor in the central nervous system and likely also plays an important role in stem cell and cancer biology and could serve as a novel factor to be considered for targeted therapeutics (pg. 351, col 1, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to use the NR2C1 gene sequence associated with human disease as taught by Venter, as a nuclear hormone receptor associated with severe vision deficit as taught by Olivares, in the recombinant AAV vector of Haider, Agbandje, and Botta to arrive at the claimed invention. As Haider, Agbandje, and Botta teach an AAV vector with nuclear hormone receptor genes, Venter teaches a suitable gene sequence of NR2C1 associated with human disease, and Olivares teaches that NR2C1 is a could serve as a novel factor to be considered for targeted therapeutics for treatment of eye disease, one of ordinary skill would have been motivated to use the NR2C1 of Rossi with a reasonable expectation of success. As the claimed invention relies on the creation of a recombinant AAV vector, one of ordinary skill would have reasonably performed a simple substitution of one known element (any of the hNHR genes of Haider) with another (the NR2C1 of Venter) with a reasonable expectation of success (creating a recombinant AAV vector with a gene associated with eye disease). One of ordinary skill would have been motivated to make the substitution because Venter teaches an NR2C1 gene associated with human disease, and Olivares teaches that NR2C1 is a critical regulator of early retina cell patterning, loss of NR2C1 causes severe vision deficit, and NR2C1 could serve as a novel factor to be considered for targeted therapeutics.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Sixth rejection
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Haider, Agbandje, and Botta as applied to claims 8-10, 12, 16, and 22-25 above, and further in view of Tavazoie & Pencheva (WO2014028461 A2, 20 February 2014; prior art of record; hereinafter “Tavazoie”) and Choudhary.
As discussed above, claims 8-10, 12, 16, and 22-25 were rendered prima facie obvious by the teachings of Haider, Agbandje, and Botta.
The difference between Haider, Agbandje, Botta, and the instant claims is that none of the references explicitly teach an LXRa gene comprising SEQ ID NO: 13.
However, Tavazoie teaches a method of inhibiting endothelial recruitment, inhibiting tumor cell invasion, or treating metastatic cancer in a subject using an agent that can be an antibody, nucleic acid, polypeptide (pg. 8, paragraph 2). Tavazoie also teaches that the subject can also have a disorder characterized by pathological angiogenesis, including an eye disorder (see claim 79 and 80; pg. 8, paragraph 2). Tavazoie further teaches an mRNA sequence of LXRa (SEQ ID NO: 21) that has 100% similarity to instant SEQ ID NO: 13 (see screenshot below of duplicate sequence disclosure and alignment):
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Instant SEQ ID NO: 13 vs Tavazoie SEQ ID NO: 21
Similarly, Choudhary teaches that another nuclear receptor of interest in diabetic retinopathy is the liver x receptor (LXRa, LXRb; NR1H2/NR1H3) (pg. 6, paragraph 4). LXRs serve as cholesterol sensors and regulate cholesterol homeostasis and appear to be at the intersection of lipid metabolism and inflammation, and links between LXR expression in endothelial progenitor cells, critical for mediating vascular repair, and micro- and macrovascular complications have been observed (pg. 7, paragraph 1). Mice in which LXR was absent developed acellular capillaries and endothelial progenitor cell dysfunction similar to that observed in diabetic mice fed a high-fat diet, and the treatment of diabetic mice with the LXR agonist GW3965 resulted in decreased micro- and macrovascular changes, including fewer acellular capillaries and reduced activated retinal glial cells, as demonstrated by glial fibrillary acidic protein (GFAP) immunoreactivity (pg. 7, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to use the LXRa nuclear hormone receptor as taught by Tavazoie, as a diabetic retinopathy-related nuclear receptor as taught by Choudhary, in the recombinant AAV vector of Haider, Agbandje, and Botta to arrive at the claimed invention. As Haider, Agbandje, and Botta teach an AAV vector with nuclear hormone receptor genes, Tavazoie teaches a suitable gene of LXRa that can be used for eye disorders, and Choudhary teaches that LXRa is a nuclear receptor of interest in diabetic retinopathy, one of ordinary skill would have been motivated to use the LXRa of Tavazoie with a reasonable expectation of success. As the claimed invention relies on the creation of a recombinant AAV vector, one of ordinary skill would have reasonably performed a simple substitution of one known element (any of the hNHR genes of Haider) with another (the LXRa of Tavazoie) with a reasonable expectation of success (creating a recombinant AAV vector with a gene associated with eye disease). One of ordinary skill would have been motivated to make the substitution because Tavazoie teaches a suitable gene of LXRa for disorders such as eye disease, and Choudhary teaches that LXRa is a potential candidate receptor for targeting in diabetic retinopathy.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Seventh rejection
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable Haider, Agbandje, and Botta as applied to claims 8-10, 12, 16, and 22-25 above, and further in view of Vega et al (US 20030129203A1, 10 July 2003; prior art of record; hereinafter “Vega”).
As discussed above, claims 8-12, 16, and 22-25 were rendered prima facie obvious by the teachings of Haider, Agbandje, and Botta.
The difference between Haider, Agbandje, Botta, and the instant claims is that none of the references explicitly teach a capsid protein having SEQ ID NO: 73 or 74.
However, Vega teaches mutant recombinant adeno-associated viruses (title) for high throughput directed evolution of peptides and proteins (abstract). Vega teaches that AAV and rAAV have many applications, including uses of the recombinant viruses for treatment of diseases and vectors for gene therapy (paragraph 0002), use as a gene transfer vector, introducing heterologous nucleic acids into cells, and for genetic therapy (paragraph 0008). Vega further teaches an AAV that has the serotype of AAV1-AAV6, and a sequence of AAV-5 that is the same sequence as instant SEQ ID NO: 73 (see claim 5, screenshot below):
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Instant SEQ ID NO 73 vs Vega SEQ ID NO 748
Therefore, it would have been prima facie obvious to one of ordinary skill at the time of filing to use the AAV capsid protein as taught by Vega in the recombinant AAV vector of Haider, Agbandje, and Botta to arrive at the claimed invention. As Haider, Agbandje, and Botta teach an AAV vector with nuclear hormone receptor genes, and Vega teaches suitable sequence of AAV-5 for use in recombinant AAV vectors, one of ordinary skill would have been motivated to use the AAV-5 of Vega with a reasonable expectation of success. As the claimed invention relies on the creation of a recombinant AAV vector, one of ordinary skill would have reasonably performed a simple substitution of one known element (the AAV5 or AAV8 serotype of Agbandje) with another (the specific AAV-5 serotype gene of Vega) with a reasonable expectation of success (creating a recombinant AAV vector with a gene associated with eye disease). One of ordinary skill would have been motivated to make the substitution because Vega teaches that the AAV-5 serotype can advantageously be used to make vectors for gene therapy.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill at the time of filing, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 03/08/2026 have been fully considered but they are not persuasive.
On pg. 7-10 of the remarks, Applicant argues that the Botta reference is use of an artificial DNA binding domain which may be combined with DNA vectors such as RHO, CRX, NRL, etc. Applicant argues that the Office uses claims 13-15 of Botta to disclose the genes and nucleotides and is an incorrect reading of the reference. Applicant argues that all of the vectors of Botta require a DBD protein which can also include the nucleotide sequences (citing to the abstract and summary of the invention, pg. 8, and pg. 48). Applicant then argues that the combination of the references would lead one of ordinary skill to create a vector including the nHR of Haider, rAAV vector (as taught by Agbandje) and a DBD as “required” by Botta. Applicant further argues that the present claims are absent of any protein DBD and that there is no motivation to combine the references to arrive at the claimed invention.
In response, the examiner disagrees. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, it is noted that the claims are drawn generally to a recombinant AAV5 or AAV8 vector (i.e., a composition) comprising a human nuclear hormone receptor gene and one of the genes recited in (b) (e.g., CRX, TULP1, etc.). The claim (which uses comprising language), does not exclude the inclusion of a DBD protein. The Haider (primary) reference discusses treating or reducing the severity of an ocular disease (see claim 1) with a nucleic acid composition encoding a nuclear hormone receptor using Applicant’s claimed hNHRs (see claims 1 and 3; claims 9-15).
With this in mind, Botta does exemplify the use of protein DNA binding domains in the disclosed vectors. However, one must look at the disclosure of Haider, Abganje, and Botta, and balance the totality of the combination of teachings of the prior art. Haider provides one of ordinary skill the necessary teaching, suggestion, and motivation to use a human nuclear hormone receptor in a vector to treat eye disease by modulating expression of photopigment genes, Agbanje teaches Applicant’s claimed AAV vectors, and Botta teaches the use of genes such as CRX in a vector to treat eye disease by modulating rhodopsin in a diseased state (see rejections above). Thus, the prior art, in combination, provides one of ordinary skill the teaching, suggestion, and motivation to use CRX in a vector (generally; e.g., via simple substitution of one known element for another) to treat ocular disorders. This teaching thus renders prima facie obvious Applicant’s recombinant vector and the rejections are maintained as set forth above.
Conclusion
NO CLAIMS ALLOWED.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Santiago et al. A Drug-Tunable Gene Therapy for Broad-Spectrum Protection against Retinal Degeneration. Mol Ther. 2018 Oct 3;26(10):2407-2417
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672