CTNF 18/567,629 CTNF 100291 DETAILED ACTION Notice of Pre-AIA or AIA Status 07-03-aia AIA 15-10-aia The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA. Claim Status Claims 4, 6, 8-12, 14 are amended. Claims 15-16 are cancelled. Claims 1-14 and 17-26 are examined on the merits. Priority This application is a national stage application, of International Patent Application No. PCT/US2022/032647, filed 06/08/2022, which claims priority from U.S. Provisional Application 63208280, filed 06/08/2021 is acknowledged. Specification 07-29 AIA The disclosure is objected to because of the following informalities: The specification describing Figures 3A, 3B, 3E, 3F, 6A indicates “red”, it should be changed . Appropriate correction is required. Claim Rejections - 35 USC § 112 07-30-01 AIA 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. 07-31-01 Claims 1-14, 17-26 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. Claim 1 requires “an expression cassette comprising a coding sequence for a hypoxanthine- guanine phosphoribosyltransferase (HPRT) having a nucleic acid sequence of SEQ ID NO: 3 or a sequence at least 80% identical to SEQ ID NO: 3”. The specification does not provide adequate support for the limitation “ having a nucleic acid sequence of SEQ ID NO: 3” “or a sequence at least 80% identical to SEQ ID NO: 3”. Under the broadest reasonable interpretation, the phrase “ having a nucleic acid sequence of SEQ ID NO: 3 ” encompasses any nucleic acid sequence that includes the sequence of SEQ ID NO 3, including embodiments in which only a portion of SEQ ID NO 3 is present. For example, the claim language reads on sequences containing two or more consecutive nucleotides of SEQ ID NO 3. The specification does not provide adequate support for the limitation “ a sequence at least 80% identical to SEQ ID NO 3 ”, this represent possession of a broader genus of nucleic acid sequences encompassed by the claimed 80% identity limitation. The specification does not disclose identify of which nucleotide substitutions, deletions or insertions are permissible while maintaining expression of a functional HPRT protein. Claims 17, 20, 24, 26, requires the provision of a genus of “ therapeutic gene for Lesch-Nyhan disease”. The specification does not provide adequate support for the limitation “therapeutic gene”. The term “therapeutic gene” encompasses a broad genus of genes that could potentially be used to treat Lesch-Nyhan disease. The claims are not limited to any particular gene. Under its broadest reasonable interpretation, the claims encompasses any gene that may be therapeutically useful in treating Lesch-Nyhan disease. The specification discloses a particular therapeutic gene, such as HPRT, such disclosure does not provide support for the much broader genus of any therapeutic gene for Lesch-Nyhan disease. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification envisions A therapeutic recombinant (r), replication defective adeno-associated virus (AAV) is provided herein which is useful for treating and/or reducing symptoms associate with Lesch-Nyhan syndrome or a disorder associated with deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme levels. A recombinant adeno-associated virus (rAAV) comprising an adeno-associated virus (AA V) capsid and packaged therein a vector genome, wherein the vector genome comprises: (a) an AAV 5' inverted terminal repeat (ITR), (b) an expression cassette comprising a coding sequence for a hypoxanthine-guanine phosphoribosyltransferase (HPRT) having a nucleic acid sequence of SEQ ID NO: 3 or a sequence at least 80% identical to SEQ ID NO: 3 which encodes amino acid sequence of SEQ ID NO: 4, which coding sequence is operably linked to expression control sequences which direct expression of the HPRT, and (c) an AAV 3' ITR is provided herein. In certain embodiments, the AA V capsid is selected which is suitable in targeting to dopaminergic neurons. In some embodiments, the AAV capsid is capable of targeting cells in substantia nigra (SN) and/or ventral tegmental area (VTA). In some embodiments, the AAV capsid is selected from those comprising Clade F. In certain embodiments, the AAV capsid is AAVhu68. (e.g., line 8, page 2). The specification envisions method of treating Lesch-Nyhan Disease, wherein method comprises direct delivery of a therapeutic gene to the dopaminergic neurons of a patient in a need thereof. In certain embodiments, the delivery comprises injection into the substantia nigra and/or ventral tegmental area. In certain embodiments, the therapeutic gene is hypoxanthine-guanine phosphoribosyltransferase (HPRT). In some embodiments, the method comprises direct delivery of an rAAV comprising the therapeutic gene. (e.g., line 7, page 3). The specification envisions Recombinant adeno-associated virus (rAAV) based compositions and methods for treating Lesch-Nyhan syndrome (also referred to as Lesch-Nyhan disease, Lesch-Nyhan syndrome, Lesch-Nyhan disease, or LNS), or a disease associated with deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme levels. An engineered coding sequence for HPR T is provided herein having the sequence of SEQ ID NO: 3 or a sequence about 80% identical thereto which encodes SEQ ID NO: 4. In certain embodiments, the sequence is about 85% identical, about 90% identical, about 95% identical, about 97% identical, about 98% identical, 99% identical, or values therebetween. Suitably, the engineered HPRT coding sequence is engineered into an expression cassette comprising at least one open reading frame (ORF) and is operably linked to regulatory sequences which direct expression thereof in a target cell, e.g., dopaminergic neurons. (e.g., line 11, page 5). The specification envisions the promoter is a tissue-specific (e.g., neuron specific) promoter. In certain embodiments, a suitable promoter may include without limitation, an elongation factor 1 alpha (EF1 alpha) promoter, a Synapsin 1 promoter, a shorted synapsin promoter, a neuron-specific enolase (NSE) promoter, the promoter is human tyrosine hydroxylase (TH) promoter (THa) (expresses in several cell groups within the brain, including the dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, and the noradrenergic neurons of the locus coeruleus) (e.g., line 15, page 9). The specification envisions suitable route of administration may be selected, for rAAV.HPRT, e.g., intravenous, intrathecal, intracerebroventricular, or direct injection. Conventional and pharmaceutically acceptable routes of administration include, but are not limited to, direct delivery to a desired organ (e.g., brain, CSF, substantia nigra (SN), ventricular tegmental area (VTA)), oral, inhalation, intranasal, intrathecal, intratracheal, intraarterial, intraocular, intravenous, intramuscular, subcutaneous, intradermal, intraparenchymal, intracerebroventricular, intrathecal, ICM, lumbar puncture and other parenteral routes of administration. Routes of administration may be combined, if desired (e.g., line 1, page 34). The working examples disclose the generation of rAAV HPRT viral particle (AAV2 - 5' ITR, spacer sequences, a CB7 promoter, a chicken beta-actin intron, a HPRT coding sequence (full length 660 bp) , a rabbit beta globin poly A, spacer sequences, and a shorted 130 nucleotide AAV2 - 3' ITR), rAAV.hHPRT having an AAVhu68 capsid (e.g., line 1, example 1, page 43). The examples described in the specification disclose the AAV-mediated HPRT expression in adult mouse brain in restoration of dopamine levels in adult mouse brain following postnatal HPRT expression by using adeno-associated virus (AAV) gene replacement of HPRT as a strategy for enzyme replacement and restoration of dopamine levels in a mouse model of LNS. A dose of 100 μL of vehicle or rAAV.PHP.eB.CB7.CI.hHPTR.rBG (3 x 1011 GC) was injected intravenously into the tail vein of male HPRT knock-out (KO) mice (3 months old at injection). The HPRT KO mouse model demonstrates no neuronal phenotype, but has decreases striatal dopamine with a morphologically normal brain. Four week-post administration of rAAV-PHP.eB.CB7.CI.hHPTR.rBG, HPRT expression levels were assessed using western blot and microscopy imaging analysis. Additionally, HPRT expression levels are assessed in dopaminergic neurons, e.g., using a marker for tyrosine hydroxy lase which identifies dopaminergic neurons in CNS (e.g., line 2, example 3, page 44; Fig. 3). The working examples disclose that treatment with rAAV.PHP.eB.hHPRT restored HPRT expression in the brain of the HPRT knock-out mice (KO) following intravenous administration of rAAV.PHP.eB comprising HPRT transgene. These data show that a widespread expression of HPRT in the brain of HPRT KO mice restored dopamine levels in the striatum to normal (e.g., line 3, page 45; Fig. 4). Additionally, we observed that post-natal HPRT expression reversed striatal dopamine deficit in adult HPRT knock-out mice (e.g., line 12, page 45; Fig. 5). The working examples disclose transgene delivery to dopaminergic cell bodies with stereotaxic (i.e., direct delivery to the Substantia Nigra (SN)) delivery ofrAAVhu68.CB7.eGFP and rAAVhu68.hHPRT , and intravenous delivery of rAAV9.PHP.eB.TH.hHPRT. 3-month-old HPRT KO mice received an AAVhu68.Cb7.HPRT via stereotaxic intraparenchymal injection to the SN, observing restoration of HPRT expression in SN improving dopamine levels in the striatum (e.g., line 1, page 46; Fig. 7). Furthermore, the working example discloses an MRI-guided AAV.HPRT delivery to the SN in a nonhuman primate (NHP). These data show showed that injection of an rAAV.HPRT transgene into the SN of HPRT KO mice restored enzyme function and dopamine levels in the brain. Further, NHP studies assess vector toxicity and expression following intraparenchymal delivery to the brain (e.g., line 11, page 46; Fig. 8). The examples described in the specification does not meet the limitation of the rejected claims “ having a nucleic acid sequence of SEQ ID NO: 3” “or a sequence at least 80% identical to SEQ ID NO: 3” and “therapeutic gene”. The state of the art with respect to using HPRT for treatment of Lesch-Nyhan disease is under developed and unpredictable. Southgate et al. (Metabolic Brain Disease, 1999) teaches that the Lesch-Nyhan syndrome is an X-linked disorder caused by a virtually complete absence of the key enzyme of purine recycling, hypoxanthine-guanine phosphoribosyltransferase (HPRT) (e.g., abstract). Southgate teaches replacement of HPRT in HPRT-deficient cells using adenoviral vectors can restore the biochemical phenotype to normal, and provide a survival advantage in negative selection media. The biochemical phenotype assessed was the expression of the HPRT enzyme, and the restoration of normal rates of purine salvage and metabolism. The physiological phenotype tested was the growth of infected cells in HAT medium, which is permissive only for HPRT expressing cells (e.g., paragraph 1 st , page 217; Table 1). However, many mutations responsible for either full (causing classic LND) or partial (causing LNV, Lesch-Nyhan variants) deficiency of HPRT have been identified, Torres and Puig (Orphanet Journal of Rare Diseases, 2007) teaches that mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the gene : deletions, insertions, duplications, and point mutations have been described as the cause of HPRT deficiency . To date, more than 300 disease associated mutations have been found (e.g., paragraph 4 th , page 6). Thus, the prior art does not overcome the deficiency of the specification with regard to the description of a genus of HPRT variants. The teachings are consistent with the prior art demonstrating the underdeveloped and unpredictability of the nature of the invention. The claims encompasses significantly more than what is disclosed in the specification and does not satisfy the written description requirement under 35 U.S.C 112(a). Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-14 and 17-21, 24, 26. 07-31-03 AIA Claim s 1-14, 17-26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for treatment of Lesch-Nyhan disease comprising administering to the subject an adeno-associated vector (AAV) comprising an expression cassette encoding the hypoxanthine-guanine phosphoribosyltransferase (HPRT) protein, and wherein the HPRT sequence is SEQ ID NO 3, and wherein the administration is direct delivery to the substantia nigra in the brain guided via magnetic resonance imaging (MRI) , does not reasonably provide enablement for treating Lesch-Nyhan disease with a therapeutic gene or with HPRT variants or for other methods of administration . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to the invention commensurate in scope with these claims. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Wands states, on page 1404: Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex part Forman. These include: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and the quantity of experimentation needed to make or use the invention. All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below. Nature of the invention : The instant claim 17 is drawn to a method for treating Lesch-Nyhan disease comprising delivery of a therapeutic gene. The nature of the claim is complicated, because the claim requires the outcome of treating Lesch-Nyhan disease , yet the claim is drawn to administering a therapeutic gene to the dopamine neurons. The instant claim 20 is drawn to a method for treating Lesch-Nyhan disease comprising delivery of a therapeutic gene to the substantia nigra. The nature of the claim is complicated, because the claim requires the outcome of treating Lesch-Nyhan disease , yet the claim is drawn to administering a therapeutic gene. The instant claim 26 is drawn to a method for treating Lesch-Nyhan disease comprising delivery of a rAAV comprising the therapeutic gene and wherein the rAAV according to claim 1 to the patient. The nature of the claim is complicated, because the claim requires the outcome of treating Lesch-Nyhan disease, yet the claim is drawn to administering a rAAV of claim 1. The specification does not provide adequate support for the limitation “ having a nucleic acid sequence of SEQ ID NO: 3” “or a sequence at least 80% identical to SEQ ID NO: 3” in claim 1. Breadth of the claim : The claims encompass a method for treating Lesch-Nyhan disease comprising administering to the subject a therapeutic gene. The claims are broad with respect to the therapeutic gene for treatment of Lesch-Nyhan disease. The claims are broad with respect to the treatment of Lesch-Nyhan with any therapeutic gene. Furthermore, the claims broadly encompass the administration of any sequence encoding HPRT variant that can differ in any number of mutations relative to SEQ ID NO 3; the claim is broad with respect to SEQ ID NO 3, the phrase “ having a nucleic acid sequence of SEQ ID NO: 3 ” encompasses any nucleic acid sequence that includes the sequence of SEQ ID NO 3, including embodiments in which only a portion of SEQ ID NO 3 is present. For example, the claim language reads on sequences containing two or more consecutive nucleotides of SEQ ID NO 3. The complex nature of the subject matter of this invention is greatly exacerbated by the breadth of the claims. Guidance of the specification and existence of working examples: The specification envisions a therapeutic recombinant (r), replication defective adeno-associated virus (AAV) is provided herein which is useful for treating and/or reducing symptoms associate with Lesch-Nyhan syndrome or a disorder associated with deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme levels. A recombinant adeno-associated virus (rAAV) comprising an adeno-associated virus (AA V) capsid and packaged therein a vector genome, wherein the vector genome comprises: (a) an AAV 5' inverted terminal repeat (ITR), (b) an expression cassette comprising a coding sequence for a hypoxanthine-guanine phosphoribosyltransferase (HPRT) having a nucleic acid sequence of SEQ ID NO: 3 or a sequence at least 80% identical to SEQ ID NO: 3 which encodes amino acid sequence of SEQ ID NO: 4, which coding sequence is operably linked to expression control sequences which direct expression of the HPRT, and (c) an AAV 3' ITR is provided herein. In certain embodiments, the AA V capsid is selected which is suitable in targeting to dopaminergic neurons. In some embodiments, the AAV capsid is capable of targeting cells in substantia nigra (SN) and/or ventral tegmental area (VTA). In some embodiments, the AAV capsid is selected from those comprising Clade F. In certain embodiments, the AAV capsid is AAVhu68. (e.g., line 8, page 2). The specification envisions method of treating Lesch-Nyhan Disease, wherein method comprises direct delivery of a therapeutic gene to the dopaminergic neurons of a patient in a need thereof. In certain embodiments, the delivery comprises injection into the substantia nigra and/or ventral tegmental area. In certain embodiments, the therapeutic gene is hypoxanthine-guanine phosphoribosyltransferase (HPRT). In some embodiments, the method comprises direct delivery of an rAAV comprising the therapeutic gene. (e.g., line 7, page 3). The specification envisions Recombinant adeno-associated virus (rAAV) based compositions and methods for treating Lesch-Nyhan syndrome (also referred to as Lesch-Nyhan disease, Lesch-Nyhan syndrome, Lesch-Nyhan disease, or LNS), or a disease associated with deficiency in hypoxanthine-guanine phosphoribosyltransferase (HPRT) enzyme levels. An engineered coding sequence for HPR T is provided herein having the sequence of SEQ ID NO: 3 or a sequence about 80% identical thereto which encodes SEQ ID NO: 4. In certain embodiments, the sequence is about 85% identical, about 90% identical, about 95% identical, about 97% identical, about 98% identical, 99% identical, or values therebetween. Suitably, the engineered HPRT coding sequence is engineered into an expression cassette comprising at least one open reading frame (ORF) and is operably linked to regulatory sequences which direct expression thereof in a target cell, e.g., dopaminergic neurons. (e.g., line 11, page 5). The specification envisions the promoter is a tissue-specific (e.g., neuron specific) promoter. In certain embodiments, a suitable promoter may include without limitation, an elongation factor 1 alpha (EF1 alpha) promoter, a Synapsin 1 promoter, a shorted synapsin promoter, a neuron-specific enolase (NSE) promoter, the promoter is human tyrosine hydroxylase (TH) promoter (THa) (expresses in several cell groups within the brain, including the dopaminergic (DA) neurons of the substantia nigra and ventral tegmental area, and the noradrenergic neurons of the locus coeruleus) (e.g., line 15, page 9). The specification envisions suitable route of administration may be selected, for rAAV.HPRT, e.g., intravenous, intrathecal, intracerebroventricular, or direct injection. Conventional and pharmaceutically acceptable routes of administration include, but are not limited to, direct delivery to a desired organ (e.g., brain, CSF, substantia nigra (SN), ventricular tegmental area (VTA)), oral, inhalation, intranasal, intrathecal, intratracheal, intraarterial, intraocular, intravenous, intramuscular, subcutaneous, intradermal, intraparenchymal, intracerebroventricular, intrathecal, ICM, lumbar puncture and other parenteral routes of administration. Routes of administration may be combined, if desired (e.g., line 1, page 34). The working example, does teach treatment of Lesch-Nyhan disease, the working examples disclose the generation of rAAV HPRT viral particle (AAV2 - 5' ITR, spacer sequences, a CB7 promoter, a chicken beta-actin intron, a HPRT coding sequence (full length 660 bp) , a rabbit beta globin poly A, spacer sequences, and a shorted 130 nucleotide AAV2 - 3' ITR), rAAV.hHPRT having an AAVhu68 capsid (e.g., line 1, example 1, page 43). The examples described in the specification disclose the AAV-mediated HPRT expression in adult mouse brain in restoration of dopamine levels in adult mouse brain following postnatal HPRT expression by using adeno-associated virus (AAV) gene replacement of HPRT as a strategy for enzyme replacement and restoration of dopamine levels in a mouse model of LNS. A dose of 100 μL of vehicle or rAAV.PHP.eB.CB7.CI.hHPTR.rBG (3 x 1011 GC) was injected intravenously into the tail vein of male HPRT knock-out (KO) mice (3 months old at injection). The HPRT KO mouse model demonstrates no neuronal phenotype, but has decreases striatal dopamine with a morphologically normal brain. Four week-post administration of rAAV-PHP.eB.CB7.CI.hHPTR.rBG, HPRT expression levels were assessed using western blot and microscopy imaging analysis. Additionally, HPRT expression levels are assessed in dopaminergic neurons, e.g., using a marker for tyrosine hydroxy lase which identifies dopaminergic neurons in CNS (e.g., line 2, example 3, page 44; Fig. 3). The working examples disclose that treatment with rAAV.PHP.eB.hHPRT restored HPRT expression in the brain of the HPRT knock-out mice (KO) following intravenous administration of rAAV.PHP.eB comprising HPRT transgene. These data show that a widespread expression of HPRT in the brain of HPRT KO mice restored dopamine levels in the striatum to normal (e.g., line 3, page 45; Fig. 4). Additionally, we observed that post-natal HPRT expression reversed striatal dopamine deficit in adult HPRT knock-out mice (e.g., line 12, page 45; Fig. 5). The working examples disclose transgene delivery to dopaminergic cell bodies with stereotaxic (i.e., direct delivery to the Substantia Nigra (SN)) delivery ofrAAVhu68.CB7.eGFP and rAAVhu68.hHPRT , and intravenous delivery of rAAV9.PHP.eB.TH.hHPRT. 3-month-old HPRT KO mice received an AAVhu68.Cb7.HPRT via stereotaxic intraparenchymal injection to the SN, observing restoration of HPRT expression in SN improving dopamine levels in the striatum (e.g., line 1, page 46; Fig. 7). Furthermore, the working example discloses an MRI-guided AAV.HPRT delivery to the SN in a nonhuman primate (NHP). These data show showed that injection of an rAAV.HPRT transgene into the SN of HPRT KO mice restored enzyme function and dopamine levels in the brain. Further, NHP studies assess vector toxicity and expression following intraparenchymal delivery to the brain (e.g., line 11, page 46; Fig. 8). Predictability and state of the art: The state of the art with respect to HPRT for treatment of Lesch-Nyhan disease is under developed and unpredictable. Southgate et al. (Metabolic Brain Disease, 1999) teaches that the Lesch-Nyhan syndrome is an X-linked disorder caused by a virtually complete absence of the key enzyme of purine recycling, hypoxanthine-guanine phosphoribosyltransferase (HPRT) (e.g., abstract). Southgate teaches replacement of HPRT in HPRT-deficient cells using adenoviral vectors can restore the biochemical phenotype to normal, and provide a survival advantage in negative selection media. The biochemical phenotype assessed was the expression of the HPRT enzyme, and the restoration of normal rates of purine salvage and metabolism. The physiological phenotype tested was the growth of infected cells in HAT medium, which is permissive only for HPRT expressing cells (e.g., paragraph 1st, page 217; Table 1). However, many mutations responsible for either full (causing classic LND) or partial (causing LNV, Lesch-Nyhan variants) deficiency of HPRT have been identified, Torres and Puig (Orphanet Journal of Rare Diseases, 2007) teaches that mutations in HPRT deficiency show a high degree of heterogeneity in type and location within the gene: deletions, insertions, duplications, and point mutations have been described as the cause of HPRT deficiency. To date, more than 300 disease associated mutations have been found (e.g., paragraph 4th, page 6). Valechha et al. (World Academy od Sciences J. 2025) teaches due to the rarity of LNS and an incomplete understanding of its complex pathophysiology, to date, no therapies exist that can fully address the root cause of the disease (e.g., abstract; Tables I-III). Valechha teaches that the etiology of LNS, is caused by >2,000 identified genetic alterations in the hgprt gene www.lesch ‑ nyhan.org/en/research/mutations ‑ database/). Mutations are distributed throughout the gene, and no hotspots or clusters have been identified. This indicates that multiple mutations in hgprt can cause unique LND. Of note, >600 pathogenic variations linked to LND have been identified to date (e.g., right column, paragraph 3 rd , page 2). Thus, the teachings of the post-filing art are consistent with the prior art demonstrating the underdeveloped and unpredictable nature of the invention. Amount of experimentation necessary: Lesch ‑ Nyhan Syndrome (LNS) is a rare inborn error of metabolism caused by a deficiency in the hypoxanthine ‑ guanine phosphoribosyl transferase enzyme is highly complex and different etiologies and gene-based therapies are still in developmental stages. It would require a large amount of experimentation to make use of a “therapeutic gene” and/or HPRT variants for treatment of Lesch-Nyhan disease. For a specific gene therapy to be efficacious, it would require to address: (1) the specific means of delivery, expression, activity, (2) to define the specific dosage of therapeutic molecules delivered to the cells or to the subjects in time course, (3) the potential deleterious effect of continuous expression of the therapeutic gene or HPRT variants on cells and tissues. In view as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 1-14, 17-21, 24, 26 are not considered to be fully enabled by the instant disclosure. In view of the breadth of the claims, the lack of guidance provided by the specification, the lack of the predictability of the art to which the invention pertains, undue amount of experimentation would be required to make and use the claimed invention to treat Lesch-Nyhan disease in a subject, with a reasonable expectation of success. Because the specification does not contain a detailed description of how to make and use the method based on administration of rAAV comprising the claimed nucleic acid encoding the HPRT variant proteins, or a therapeutic gene according to the invention, and absent working examples that provide evidence that is reasonably predictive of the ability of treating Lesch-Nyhan disease in subject’s brain, the claims are not enabled commensurate in scope with the claimed invention . 07-30-02 AIA 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 applicant regards as his invention. 07-34-01 Claims 11-13 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. Claim 11 recites “wherein the vector genome further comprises a spacer sequence of about 66 nucleotides between the AAV 5' ITR and the promoter”. The phrase “about 66 nucleotides” renders the claim indefinite because the metes and bounds of the claimed spacer sequence cannot be determined with reasonable certainty. The claim does not define the degree of variation encompassed by the term “about”. Claim 12 recites “wherein the vector genome further comprises a spacer sequence of about 88 nucleotides between the polyA and the AAV 3' ITR”. The phrase “about 88 nucleotides” renders the claim indefinite because the metes and bounds of the claimed spacer sequence cannot be determined with reasonable certainty. The claim does not define the degree of variation encompassed by the term “about”. Claim Rejections - 35 USC § 103 07-06 AIA 15-10-15 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. 07-20-aia AIA 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. 07-23-aia AIA 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. 07-21-aia AIA Claim s 1-9, 14 and 17-26 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (“Wilson” US 2020/0056159 A1, cited as reference 15 on IDS filed 03/12/2024) in view of Fotin-Mleczek et al. (“Fotin-Mleczek”, US 2019/0241633 A1, cited as reference 14 on IDS filed 03/12/2024), Bankiewicz et al. (“Bankiewicz”, 2016) and Southgate et al. (“Southgate”, Metabolic Brain Disease, 1999) . Regarding claims 1, 4-9, Wilson teaches a nucleic acid sequences and amino acids of a novel isolated adeno-associated virus (AAV), which is termed herein AAVhu68 , which is within clade F . AAVhu68 (previously termed herein AAV3G2) varies from another Clade F virus AAV9 (e.g., paragraph 0046). Wilson teaches a vector genome contains, at a minimum, from 5' to 3', an AAV 5' ITR , coding sequence(s), and an AAV 3' ITR (e.g., paragraph 0048). Wilson teaches AAV vector, the vector also includes conventional control elements necessary which are operably linked to the transgene in a manner which permits its transcription, translation and/or expression in a cell transfected with the plasmid vector or infected with the virus produced (e.g., paragraph 0097). Wilson teaches that the AAV vector contain a promoter sequence chicken beta-actin promoter, an intron, e.g., the chicken beta-actin intron , Rabbit β-globin poly A sequence (e.g., paragraphs 0098, 0260). Regarding claim 14, Wilson teaches compositions may contain, in addition to the rAAV and carrier(s), other conventional pharmaceutical ingredients, such as preservatives, or chemical stabilizers (e.g., paragraph 0159). Wilson does not teach HPRT SEQ ID NO 3, as required by the instant claims. Wilson does not teach AAV capsid capable of targeting dopaminergic neurons, as required by the instant claims. Wilson does not teach AAV capsid capable of targeting substantia nigra, as required by the instant claims. Wilson does not teach a method of treating Lesch-Nyhan disease, as required by the instant claims. However, this is cured by Fotin-Mleczek, Bankiewicz and Southgate. Fotin-Mleczek teaches a system for expressing a therapeutic protein , preferably by stabilization of the mRNA and/or an increase of the translational efficiency of such an mRNA with respect to such nucleic acids known from the prior art. It is a further object of the invention to provide such a system, which allows treatment and/or prophylaxis of inherited or acquired diseases, particularly as defined herein, in a safe and effective manner (e.g., paragraph 0013). Fotin-Mleczek total hypoxanthine-guanine phosphoribosyl transferase deficiency (Lesch-Nyhan syndrome) (e.g., paragraph 0302). Fotin-Mleczek teaches SEQ ID NO 18203 with 86.9% identity to SEQ ID NO 3 of the instant claims. Bankiewicz teaches a method for AAV delivery using real-time visualization of the infusion. Regardless of the encoded transgene , co- infusion of AAV2 and Gadoteridol with MRI monitoring shows an excellent correlation with the transgene expression as assessed in NHP brain by immunohistochemistry (e.g., right column, page 435, Figs. 1-2). Bankiewicz teaches a MRI-compatible delivery platform that includes a skull-mounted aiming device, a reflux-resistant CED cannula and an MRI-integrated software package that communicates with both the console and the operating neurosurgeon in the MRI suite. This device results in cannula tip placement that is within <1 mm of the visually identified target site, greatly increasing our ability to safely and reliably deliver gene therapy vectors as evaluated in the NHP model for infusion into different regions of the brain (e.g., paragraph 4 th , page 435; Fig. 3). Bankiewicz teaches that striatal infusion of AAV6 resulted in extensive transduction of cortical and substantia nigra pars compacta (SNpc) neurons (e.g., right column, paragraph 2 nd , page 438). Southgate teaches that the Lesch-Nyhan syndrome is an X-linked disorder caused by a virtually complete absence of the key enzyme of purine recycling, hypoxanthine-guanine phosphoribosyltransferase (HPRT). A possible long-term solution is gene therapy, and recombinant adenoviruses have been proposed as vectors for gene transfer of HPRT into postmitotic neuronal cells (e.g., abstract). Southgate teaches the ability of adenoviral vector expressing the human HPRT cDNA under the transcriptional control of a short human cytomegalovirus major immediate early promoter (RAd-HPRT) to correct the altered biochemical phenotype of human and murine HPRT-deficient cells, and to rescue them from cell death in the negative selection medium, HAT (hypoxanthine, aminopterin, thymidine) (e.g. paragraph 2 nd , page 208; Figs. 3-4; Table 1). Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Wilson -an AAV vector AAVhu68 comprising from 5' to 3', an AAV 5' ITR, coding sequence(s), and an AAV 3' ITR, the vector also includes a promoter sequence chicken beta-actin promoter, an intron the chicken beta-actin intron, Rabbit β-globin poly A sequence, with the teachings of Fotin-Mleczek -a system for expressing a therapeutic protein HPRT comprising SEQ ID NO 18203, with the teachings of Bankiewicz -a method for direct AAV carrying a transgene delivery using real-time visualization of the infusion with MRI monitoring to target cells in the substantia nigra in the brain, and the teachings of Southgate - an adenoviral vector expressing the human HPRT to correct the altered biochemical phenotype of human and murine HPRT-deficient cells such in Lesch-Nyhan syndrome; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining a AAVhu68 vector carrying the HPRT gene to treat Lesch-Nyhan disease using an MRI guided injection into the brains of patients. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to treat Lesch-Nyhan disease using an AAV vector carrying the HPRT gene to rescue cells deficient in HPRT . 07-22-aia AIA Claim s 11, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Wilson et al. (“Wilson” US 2020/0056159 A1, cited as reference 15 on IDS filed 03/12/2024), Fotin-Mleczek et al. (“Fotin-Mleczek”, US 2019/0241633 A1, cited as reference 14 on IDS filed 03/12/2024), Bankiewicz et al. (“Bankiewicz”, 2016) and Southgate et al. (“Southgate”, Metabolic Brain Disease, 1999) as applied to claim s 1-9, 14 and 17-26 above, and further in view of Logan et al. (“Logan”, Nature Genetics, 2017) . Wilson, Fotin-Mleczek, Bankiewicz and Southgate do not teach the spacer sequence between AAV 5’ ITR and the promoter, and the poly A and AAV 3’ ITR, as required by the instant claims. However, this is cured by Logan. Logan teaches that sequence analysis of the AAV-ΔLSP1-eGFP vector construct identified a 105-nt sequence between the left-hand ITR and the Kozac consensus sequence , which is an element that encompasses the start codon and is known to enhance translation initiation. The first 46 nt were from the native AAV2 sequence , which is normally located immediately adjacent to the right-hand ITR ( it reads on spacer sequence between the AAV 5’ ITR and the promoter ) in the genome of WT AAV2, whereas the remaining 59 nt were a remnant polylinker sequence. The same native 46-nt sequence from WT AAV2 was also present in the 3′ UTR , adjacent to the right-hand ITR ( it reads on spacer sequence between the poly A and 3’ ITR ) (e.g., paragraph 2 nd , page 1268; Fig. 2A [see below]). Logan teaches unmodified pSub201-derived AAV vectors retain 46 nt of the WT AAV2 genome adjacent to the left- and right-hand ITRs. Depending on vector configuration, this could modulate expression from heter-ologous liver-specific promoters or confer unintended hepatic expres-sion of vectors that carry promoters intended to achieve specificity for nonhepatic tissues. The second point is whether retention of these elements might have safety implications in human clinical trials (e.g., paragraph left column, paragraph 5 th , page 1272). PNG media_image1.png 200 400 media_image1.png Greyscale Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to combine the teachings of Wilson, Fotin-Mleczek, Bankiewicz and Southgate -an AAVhu68 vector coding sequence HPRT and the teachings of Logan - an spacer sequence of 46 nucleotides at the right of the AAV 5’ ITR before the promoter and at the left of the 3’ ITR after the poly A sequence; for someone skilled in the art would have been obvious to use these teachings to achieve the predictable result of obtaining an AAVhu68 vector carrying the HPRT gene and spacers at the AAV 5’ and 3’ ITRs. One of ordinary skill in the art before the effective filing date of the invention would have been motivated to include spacers at the 5’ and 3’ ITR of the AAV vector to modulate expression of the HPRT gene. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIO GOMEZ RODRIGUEZ whose telephone number is (571)270-0991. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 5712722916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /JULIO WASHINGTON GOMEZ RODRIGUEZ/Examiner, Art Unit 1637 /Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637 Application/Control Number: 18/567,629 Page 2 Art Unit: 1637 Application/Control Number: 18/567,629 Page 3 Art Unit: 1637 Application/Control Number: 18/567,629 Page 4 Art Unit: 1637 Application/Control Number: 18/567,629 Page 5 Art Unit: 1637 Application/Control Number: 18/567,629 Page 6 Art Unit: 1637 Application/Control Number: 18/567,629 Page 7 Art Unit: 1637 Application/Control Number: 18/567,629 Page 8 Art Unit: 1637 Application/Control Number: 18/567,629 Page 9 Art Unit: 1637 Application/Control Number: 18/567,629 Page 10 Art Unit: 1637 Application/Control Number: 18/567,629 Page 11 Art Unit: 1637 Application/Control Number: 18/567,629 Page 12 Art Unit: 1637 Application/Control Number: 18/567,629 Page 13 Art Unit: 1637 Application/Control Number: 18/567,629 Page 14 Art Unit: 1637 Application/Control Number: 18/567,629 Page 15 Art Unit: 1637 Application/Control Number: 18/567,629 Page 16 Art Unit: 1637 Application/Control Number: 18/567,629 Page 17 Art Unit: 1637 Application/Control Number: 18/567,629 Page 18 Art Unit: 1637 Application/Control Number: 18/567,629 Page 19 Art Unit: 1637 Application/Control Number: 18/567,629 Page 20 Art Unit: 1637 Application/Control Number: 18/567,629 Page 21 Art Unit: 1637 Application/Control Number: 18/567,629 Page 22 Art Unit: 1637 Application/Control Number: 18/567,629 Page 23 Art Unit: 1637 Application/Control Number: 18/567,629 Page 24 Art Unit: 1637 Application/Control Number: 18/567,629 Page 25 Art Unit: 1637 Application/Control Number: 18/567,629 Page 26 Art Unit: 1637 Application/Control Number: 18/567,629 Page 27 Art Unit: 1637 Application/Control Number: 18/567,629 Page 28 Art Unit: 1637 Application/Control Number: 18/567,629 Page 29 Art Unit: 1637 Application/Control Number: 18/567,629 Page 30 Art Unit: 1637 Application/Control Number: 18/567,629 Page 31 Art Unit: 1637 Application/Control Number: 18/567,629 Page 32 Art Unit: 1637 Application/Control Number: 18/567,629 Page 33 Art Unit: 1637 Application/Control Number: 18/567,629 Page 34 Art Unit: 1637
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