DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response to restriction requirement filed on August 14, 2025 have been received and entered. Claims 1-2, 10-14, 16-19, 21-25, 28-31 and 32 are pending in the instant application.
Election/Restrictions
Applicant’s election of claims 1-2, 10-14, 16-19, 21-25 and 28 (group I) in the reply filed on August 14, 2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). Applicant’s further election of species of XPG is also acknowledged. Claims 1, 2, 10, 21-25 and 28 read on the elected species.
Claims 11-14, 16-19, 29-32 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on August 14, 2205.
Priority
This application is a 371 of PCT/US2021/023254 filed on 03/19/2021, which claims priority from an US provisional application no 62/992,729 filed on 03/20/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/17/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claims 1, 2, 10, 21-25 and 28 are under consideration.
Claim Rejections - 35 USC § 112-Scope of enablement
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 1, 2, 10, 21-25 and 28 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
A method of treating a subject with one or more mutations in an ERCC5 gene exhibiting Cockayne Syndrome (CS), said method comprising intravenously administering a dose of 1x1012 vg/kg to 3x1014 vg/kg a replication-incompetent Adeno-associated Virus-9 (riAAV-9) to the subject in need thereof, wherein the riAAV comprises a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein under the control of a promoter, wherein the nucleotide sequence is a human codon optimized sequence of SEQ ID NO: 3 or the nucleotide sequence as set forth in SEQ ID NO: 12, thereby treating CS in the subject does not reasonably provide enablement for delivering via any other route or using any other serotype of AAV to treat or delay to the onset of CS caused by any other mutation in any other gene. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
In determining whether Applicant’s claims are enabled, it must be found that one of skill in the art at the time of invention by applicant would not have had to perform “undue experimentation” to make and/or use the invention claimed. Such a determination is not a simple factual consideration, but is a conclusion reached by weighing at least eight factors as set forth in In re Wands, 858 F.2d at 737, 8 USPQ 1400, 2d at 1404. Such factors are: (1) The breadth of the claims; (2) The nature of the invention; (3) The state of the art; (4) The level of one of ordinary skill in the art; (5) The level of predictability in the art; (6) The amount of direction and guidance provided by Applicant; (7) The existence of working examples; and (8) The quantity of experimentation needed to make and/or use the invention.
The office has analyzed the specification in direct accordance to the factors outlines in In re Wands. MPEP 2164.04 states: “[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection.” These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform “undue experimentation” to make and/or use the invention and therefore, applicant’s claims are not enabled.
Nature of the Invention:
The claims are directed to a method of treating a subject with Cockayne Syndrome (CS) or delaying the onset of CS, comprising administering to the subject a replication-incompetent Adeno-associated Virus (riAAV) comprising a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein in an amount effective to treat CS in the subject or delay the onset of CS or a symptom thereof. Dependent claims limit the subject comprises one or more mutations in an ERCC5 gene and the subject has XPG. Claims further limits the subject has XPG and the riAAV comprises a nucleotide sequence encoding an XPG protein, wherein the nucleotide sequence is a human codon optimized sequence of SEQ ID NO: 3 or comprises the sequence of SEQ ID NO: 12 Claims 24 and 25 limit the riAAV is an AAV9 serotype and wherein the riAAV is administered to the subject intravenously, intraventricularly or intrathecally, or through the cisterna magna, or a combination thereof.
Breadth of the claims:
The claims are broadly directed to a method comprising: administering via any mean into any site any amount of a replication-incompetent Adeno-associated Virus (riAAV) of any serotype comprising a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein effective to treat CS in the subject or delay the onset of CS or a symptom thereof that may or may not have XPG. It is emphasized that instant rejection is based on four separate issues: 1) administering via any route any amount effective of any serotype of replication defective adeno-associated virus (AAV) vector to have an effect on a subject that may or may not have XPG to treat Cockayne Syndrome (CS) of any etiology and pathology, 2) the absence of an enabling disclosure of correlating the local expression of any nucleotide encoding XPG at a level sufficient to delay symptom of genu of Cockayne Syndrome (CS) or delaying the onset of CS in a mammal, and in particular human; (3) delivering an AAV vector of any serotype encoding XPG in any predictable animal model of genus of Cockayne Syndrome (CS) or delaying the onset of CS ; and 4) nexus between cellular pathology associated with Cockayne Syndrome (CS) or delaying the onset of CS to local expression in cells that exhibit treatment of CS. The deficiencies were identified by the Office after analysis of the disclosure provided in the instant application. Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 USC 112, first paragraph, have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404.
Guidance of the Specification and The Existence of Working Examples:
The specification discloses Cockayne syndrome (CS) is a rare disease characterized by neurodegeneration and premature aging throughout the body. CS is caused by mutations in various genes involved in DNA repair mechanisms including excision repair cross-complementing (ERCC) genes. The rarest version of CS in humans is caused by mutations in Xeroderma Pigmentosum group G (XPG) protein. (see para, 3 of the published application). The mutations in ERCC5 can lead to xeroderma pigmentosum (XP) and (CS) cockayne syndrome (see para. 7 of the specification). Examples teaches intravenous injections of AAV9-ERCC5 using several doses and compared to WT healthy mice. A vector map of the AAV9-ERCC5 used in this study is shown in Figure 16. A codon optimized ERCC5 sequence (SEQ ID NO: 12) is cloned into an AAV9 comprising ITRs of SEQ ID NOs: 10 and 13 and a CMV promoter of SEQ ID NO: 11. WT mice or the hybrid Xpg-/- knockout mice were either untreated or treated with the AAV9-ERCC5. It is further disclosed that one of the following doses was administered: 5 x 1012vg/kg, 1 x 1013vg/kg, 3 x 1013 vg/kg, or 3 x 1014 vg/kg. As shown in Figure 2A, the % survival for Xpg- mice treated with AAV9-ERCC5 was generally higher relative to the untreated Xpg-- mice. Twenty percent of mice given the highest dose of AAV9-ERCC5 survived to 23 weeks, whereas 0% of untreated Xpg- mice survived to 20 weeks. Interestingly, almost 40% of mice given the second-highest dose of AAV9-ERCC5 survived past 21 weeks. About 35% of mice given the third-highest dose of AAV9-ERCC5 survived past 21 weeks. On average, each higher dose extended survival by an additional 1-2 weeks. Figures 4A and 4B, the 100% of untreated Xpg- mice exhibited these CS symptoms by Week 15, whereas, at this timepoint 0% of mice treated with the highest dose of AAV9- ERCC5 demonstrated kyphosis and tremors. Treatment delayed the onset of kyphosis and tremors. Figures 4A and 4B. This study demonstrated that AAV9-mediated gene delivery of the ERCC5 gene led to gene expression. The highest dose treatment cohort displayed improvements in several functional domains including survival. The treated mice demonstrated improved quality of life and a delayed onset of neurodegeneration.
State of the Art and Predictability of the Art and the Amount of Experimentation Necessary:
The state of the art teaches twelve natural serotypes of AAV (1-12) that have been characterized to date, having differential tropism and transduction potential in vasculature, retina, brain, muscle, liver, and lung. The process of gene therapy involves several critical steps: selecting the appropriate AAV serotype, choosing the most effective administration route, precisely delivering the vectors to the desired cells, and ensuring the sustained expression of the therapeutic genes, which ultimately leads to the correction or mitigation of the underlying genetic disorder (see page 110, col. 2, para. 1, Liu et al). The art further report that adeno-associated virus (rAAV) vectors can target a wide array of tissues with high specificity. For instance, serotype like AAV1 show strong affinity for skeletal and cardiac muscle, making them ideal for treating muscular dystrophies and cardiomyopathies (Vulin et al Molecular Therapy, 2012, vol. 20 no. 11, 2120–2133). It is further known that AAV9, AAVrh10, and AAV2 are particularly effective in targeting the CNS, which is crucial for treating neurodegenerative diseases such as SMA and Parkinson’s disease (see Liu et al Cytokine and Growth Factor Reviews 80 (2024) 109–120 and references therein). Additionally, AAV5 is often used for targeting the airway epithelium, which is important in treating respiratory diseases such as cystic fibrosis (see page 110, col. 2, para. 2). Liu emphasizes that strategic selection of AAV serotypes based on their tropism ensures that gene therapies can be tailored to specific tissues. Liu teaches that AAV-based therapies are directed to targets that include the liver, CNS…and the most common administration routes for these therapies are intravenous injection, intrathecal injection or intraparenchymal injection (see page 110, col. 2, last para.). Liu continue to teach that BBB is a highly selective barrier that serves to protect the brain from pathogens and toxins, but it also poses a significant challenge for the delivery of AAV vectors to the CNS. For instance, serotypes like AAV9 and AAVrh10 have demonstrated the ability to cross the BBB when administered systemically, such as through intravenous injection. AAV9, in particular, is favored because of its ability to effectively transduce and express therapeutic genes within the human CNS (See page 113, col. 2, para. 1 to page 114, col. 1, para. 2). This is further supported by the teaching of Zhou who reported IV injection is the optimal brain-targeting rAAV injection route because it is minimally invasive, especially when widespread gene therapy is needed in the brain and in some disease conditions in which widely targeting both the CNS and peripheral system is required (Gessler et al., 2019). However, most rAAVs cannot cross the blood–brain barrier (BBB), and different rAAV stereotypes recognize different cell receptors and thus have different tropisms for distinct tissues and cell types, which causes difficulties in delivering rAAVs into the brain by IV administration. Moreover, the required high concentration of virus vectors, rapid immune responses, immunotoxicity, and potential off-targeting to the peripheral tissues may limit the use of IV for rAAV delivery into the brain (see Zhou et al Frontiers in Molecular Neuroscience, 2022, 1-13, page 02, col. 1, last para. to col. 2, para. 1). In a post filing publication, Batista et al (bioRxiv preprint doi: https://doi.org/10.1101/2025.06.06.658349; posted 2025, 1-33). states “treatment with AAV9-CSA resulted in a significant increase in lifespan, and broad distribution of human CSA in the brain and heart. Despite clear therapeutic benefit, we also observed neuroradiological abnormalities, neuropathologic alterations including hypo-myelination, astrocytosis, microgliosis, and likely life limiting transcriptomic alterations in liver at endpoint” (see abstract).
The art further teaches apparat from the choice of viral vector, transduction efficiency is also dependent on the promoter chosen to drive transgene expression. Moreover, the choice of promoter impacts the expression of reporter genes in different cell types. Liu evaluated the expression of enhanced green fluorescent protein (EGFP) driven by 6 different promoters in AAV for transgene expression in cochlea in vivo. The results show transgene expression using EF-1α promoter was only marginal expression; while the RSV promoter failed to drive expression (see Liu et al Exp Mol Med, 2007 39(2): page. 170–175). The specification fails to teach choice of promoter that is known to influence the transduction efficiency and specificity in the CNS and peripheral tissue in the treatment of CS. The specification fails to teach to which extent, riAAV vectors transduce cell types present in the CNS and peripheral tissue like liver, nor do they show any expression and/or secretion of ERCC5 can be expressed by delivering any vector via any route in vivo that exert any therapeutic effect other than an effective dose of an AAV9 comprising a codon optimized ERCC5 sequence as set forth in SEQ ID NO: 12 under the control of a CMV promoter. There is no in vitro to in vivo correlation of using any other AAV serotype delivered via any other route to express ERCC5 in a predictable model of CS. Thus, given the breadth of the claims, it is apparent that one of skilled in the art would require the identification and characterization of all the different serotype of AAV serotype delivered via different route by testing their ability to infect the different cells of CNS and peripheral tissue affected by the plurality of CS disorder in a predictable animal model having a mutation in ERCC5 gene to make use of the invention. Given, the variable and unpredictable expression pattern of different serotype of AAV delivered via different route and the lack of guidance provided by the specification with respect to using any titer of any serotype of AAV encoding nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein operably linked to any promoter intended to treat CS of different etiology and pathology would require undue experimentation for one of skill in the art to make and use the invention, without a reasonable expectation of success.
Claims are directed to aa method of treating a subject with Cockayne Syndrome (CS) or delaying the onset of CS, comprising administering to the subject a replication-incompetent Adeno-associated Virus (riAAV) comprising a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein. In the instant case the issues relate to the predictability of animal model with respect to the breadth of claims intended to deliver an AAV encoding XPG for treating CS caused by any mutation within ERCC gene in a subject. Claims are directed to method of treating a subject with Cockayne Syndrome (CS) or delaying the onset of CS. Jaarsma et al (Mechanisms of Ageing and Development 2013, Vol 134, 5–6, 180-195) teaches Cockayne syndrome (CS) is a rare multisystem disorder characterized by cachectic dwarfism, nervous system abnormalities and features of premature aging. CS symptoms are associated with mutations in 5 genes, CSA, CSB, XPB, XPD and XPG encoding for proteins involved in the transcription-coupled subpathway of nucleotide excision DNA repair (NER) (see abstract). It is disclosed that the CSA and CSB mutations result in severe TC-NER dysfunction, but it has become clear that most of the CS symptoms cannot be explained by the sole loss of TC-NER function (see page 181, col. 1, para. 3). Jaarsma teaches a spectrum of mild-to-severe CS-like symptoms occurs in Xpb, Xpd, and Xpg mice that genetically mimic patients with a disorder that combines CS symptoms with another NER syndrome, xeroderma pigmentosum (see abstract). The specification describes the generation of replication-incompetent AAV9 serotype viral vectors that are tested in a xpg -/- murine model of CS. Thus, the guidance provided in the specification is limited to a gene therapy of mutated ERCC5 is envisioned, which gene codes for the XPG protein and for which specific mutations are associated with a particular CS phenotype. The specification lacks nexus between delivery of AAV to treat CS caused by mutations in XPG genes to mutation in any other CSA, CSB, XPB, XPD gene. The specification is silent on correlating any pathology observed in mutated ERCC5 mouse model with phenotype observed in mutation with CSA, CSB, XPB, XPD gene following delivery of instantly claimed AAV nor do the specification provide any guidance on improvement or slowing the onset of CS in a predictable animal model. Absent of any teaching or recognition in the art that AAV vectors encoding XPG are capable of transducing cells of CNS and peripheral tissue (eg liver) of mammals with plurality one or more mutation in CSA, CSB, XPB, XPD and XPG gene. The lack of guidance in the specification would force the skilled practitioner to establish animal models of different etiology with associated pathology in different species of mammal to study the effect of AAV encoding XPG as broadly claimed and determine the resulting effect of different serotype of AAV in the treatment of CS disorder caused by mutation with in CSA, CSB, XPB, XPD and XPG gene or delivery of nucleic acid encoding XPG in the treatment of CS disorder caused by mutation in CSA, CSB, XPB and XPD gene. Such guessing would require extensive and undue experimentation. Applicant should note that “case law requires that the disclosure of an application shall inform those skilled in the art how to use applicants’ alleged discovery, not to find out how to use it for themselves.” In re Gardner 166 USPQ 138 (CCPA) 1970. An artisan would have to carry out extensive experimentation to make use of the invention without reasonable expectation of success, and such experimentation would have been undue because of the treatment of CS by delivering AAV of any other serotype via any other route other than direct or intravenous injection into CNS in vivo is unpredictable and specification fails to provide any guidance as to how the claimed method would have been practiced commensurate with full scope of the claims. Although, specific vectors, promoters, nucleic acid encoding XPG protein, and route of administration might be or may have been effective for treatment of specific CS providing specific therapeutic effect. Gene therapy as a broad-based art is clearly unpredictable in terms of achieving levels and duration of expression of a gene of interest, which results in a therapeutic effect. A showing that enough of a nucleic acid encoding XPG is expressed in the target cell (one or more of CNS and/or liver cells that are affected by the disease), enough nucleic acid is incorporated into the target cells, that such nucleic acid is properly incorporated into such cells as DNA, enough mRNA is produced therefrom, and enough protein is produced and enhanced ERCC 5 gene expression that have an effect on the target cells and such effect is enough of an effect for a long enough period of time to treat CS in a subject having mutation in ERCC 5 gene in a predictable animal model. Absent of any specific dose of riAAV in a specific volume of liquid suspension that is delivered to maintain an effective concentration of the transgene product at the target site an artisan of skill would have to perform undue experimentation to make and use the invention, without reasonable expectation of success. This is because transport barriers for vector selection, sorting targets to maximize efficiency, characterizing the optimum therapeutic window for treatment, and identifying the best route were known to be critical and unpredictable parameter in achieving more favorable AAV gene therapy outcomes for the treatment of CS as supported by the observations in the art record. In conclusion, in view of breadth of the claims and absence of a strong showing by Applicant, in the way of specific guidance and direction, and/or working examples demonstrating the same, such invention as claimed by Applicant is not enabled for the full scope of the claimed inventions.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 2, 10 and 24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Suzuki-Hatano et al (International Symposium on Xeroderma Pigmentosum and other Nucleotide Excision Repair disorders Downing College, University of Cambridge, Cambridge, UK. 20–22 March 2019) or (British Journal of Dermatology (2019) 180, ppe216–e233).
Claims are directed to a method administering to the subject an adeno-associated Virus (riAAV) comprising a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein. Instant rejection is applied to the breadth of the claim directed to active method step and not necessarily to treating any condition.
With respect to claim 1-2, 10, 24 Suzuki-Hatano teaches a method of injecting to the subject having a mutation in XPG protein that is encoded by EPCC5 gene, an adeno-associated Virus (AAV) serotype 9 comprising a coding sequence as set forth in ERCC5 and were evaluated weekly resulting in improving the survival of XPG-/- KO mouse (see e218, oral presentation 07).
Accordingly, Suzuki-Hatano anticipates claims 1-2, 10 and 24.
Claims 1, 2, 10, 24, 25 and 28 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Witko et al (Molecular Therapy, (May 2018) Vol. 26, No. 5, Supp. Supplement 1, pp. 132-133. Abstract Number: 282.).
Claims are directed to a method administering to the subject an adeno-associated Virus (riAAV) comprising a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein
With respect to claims 1, 2, 10, 21-25 and 28, Witko teaches a gene therapy method of treating CS, said method comprising intravenous injections of AAV9-CMV-codon optimizied ERCC5 gene to mouse whose genome comprises homozygous inactivation of XPG-/- (see abstract). The results show improvements in several neurological exams and activity tests for all AAV-treated mice show the upregulation of XPG gene expression in both AAV-treated groups as compared to untreated XPG-/- controls. Witko further discloses intravenously administered therapy at 5x1013 vector genomes/kg (see abstract).
Accordingly, Witko anticipates claim 1, 2, 10, 24, 25 and 28,
Claim Rejections - 35 USC § 103
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.
Claims 1, 2, 10, 21, 24, 25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Witko et al (Molecular Therapy, (May 2018) Vol. 26, No. 5, Supp. Supplement 1, pp. 132-133. Abstract Number: 282.) as evidenced by NCBI accession no D16305, dated 09/26/2008, Fath et al (PLoS One 2011, 6e17596, 1-14).
With respect to claims 1, 2, 10, 21-25 and 28, Witko teaches a gene therapy method of treating CS, said method comprising intravenous injections of AAV9-CMV-codon optimizied ERCC5 gene to mouse whose genome comprises homozygous inactivation of XPG-/- (see abstract). The results show improvements in several neurological exams and activity tests for all AAV-treated mice show the upregulation of XPG gene expression in both AAV-treated groups as compared to untreated XPG-/- controls. Witko further discloses intravenously administered therapy at 5x1013 vector genomes/kg (see abstract). Witko differs from claimed invention by not disclosing the nucleotide sequence is a human codon optimized sequence of SEQ ID NO: 3.
However, before the effective filing date of instant application, wildtype ERCC5 coding sequence was known in prior art as evidenced from the teaching of accession no D16305 that has 100% sequence identity to SEQ ID NO: 3. Suzuki-Hatano embraced the potential of increasing the expression of gene of interest by codon optimization (page 36, last 2 lines). Fath et al disclose optimizing various candidate genes’ coding regions taking the following sequence-based parameters into account (i) Codon choice, (ii) increase in GC-content, (iii) avoiding UpA- and introducing CpG-dinucleotides, (iv) removing destabilizing RNA elements, (v) removing cryptic splice-sites, (vi) avoiding intragenic poly(A)-sites, (vii) removing direct repeats, (viii) avoiding RNA secondary structures, and (ix) deleting internal ribosomal entry sites (See page 2, col. 1, last para.).
Accordingly, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Witko to use codon optimized ERCC5 sequence of the human ERCC5 known in prior art as evident form the teaching of accession number, with a reasonable expectation of success, before effective filing date of instant invention, in order to improve ERCC5 expression and resulting therapeutic outcome. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use optimized human ERCC5 sequence with reasonable expectation of success in achieving the predictable results as the Artisan was well aware of the required structures, the results of optimized coding sequence of ERCC5 and was well aware of the results of codon optimization of ERCC5, that could be delivered using riAAV9 as in Witko, before the effective filing date of instant invention. One of skill in the art would have been expected to have a reasonable expectation of success because prior art successfully reported using a codon optimized coding sequence of ERCC5 as suggested in Witko and Gruntman to improve the therapeutic outcome. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Claims 1, 2, 10, 21-25 and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Suzuki-Hatano et al (International Symposium on Xeroderma Pigmentosum, University of Cambridge, Cambridge, UK. 20–22 March 2019 or British Journal of Dermatology (2019) 180, ppe216–e233)/ Witko et al (Molecular Therapy, (May 2018) Vol. 26, No. 5, Supp. Supplement 1, pp. 132-133. Abstract Number: 282.) as evidenced by NCBI accession no D16305, dated 09/26/2008, Fath et al (PLoS One 2011, 6e17596, 1-14), Gruntman (Doctoral dissertation on Translational Pathway for Recombinant Adena-Associated Virus Human Gene Therapy: From Target Identification and Animal Modeling of the Disease to Non-Human Primate and Human Studies", 203 (2016), IDS) and Xiao (US7001761, dated 02/21/2006), Kaplitt (US 8067156, dated 11/29/2011).
Claims are directed to a method administering to the subject an adeno-associated Virus (riAAV) comprising a nucleotide sequence encoding a Xeroderma Pigmentosum group G (XPG) protein
With respect to claim 1-2, 10, 24 Suzuki-Hatano teaches a method of injecting to the subject having a mutation in XPG protein that is encoded by EPCC5 gene, an adeno-associated Virus (AAV) serotype 9 comprising a coding sequence as set forth in ERCC5 and were evaluated weekly resulting in improving the survival of XPG-/- KO mouse (see e218, oral presentation 07). It is relevant to note that wildtype ERCC5 coding sequence was known in prior art as evidenced from the teaching of accession no D16305 that has 100% sequence identity to SEQ ID NO: 3. Suzuki-Hatano embraced the potential of increasing the expression of gene of interest by codon optimization (page 36, last 2 lines).
Likewise, regarding claims 1, 2, 10, 21-25 and 28, Witko teaches a gene therapy method of treating CS, said method comprising intravenous injections of AAV9-CMV-codon optimizied ERCC5 gene to mouse whose genome comprises homozygous inactivation of XPG-/- (see abstract). The results show improvements in several neurological exams and activity tests for all AAV-treated mice show the upregulation of XPG gene expression in both AAV-treated groups as compared to untreated XPG-/- controls. Witko further discloses intravenously administered therapy at 5x1013 vector genomes/kg (see abstract). However, before the effective filing date of instant application, it was routine to codon optimize a gene sequence for enhancing expression in mammalian cell. Fath et al disclose optimizing various candidate genes’ coding regions taking the following sequence-based parameters into account (i) Codon choice, (ii) increase in GC-content, (iii) avoiding UpA- and introducing CpG-dinucleotides, (iv) removing destabilizing RNA elements, (v) removing cryptic splice-sites, (vi) avoiding intragenic poly(A)-sites, (vii) removing direct repeats, (viii) avoiding RNA secondary structures, and (ix) deleting internal ribosomal entry sites (See page 2, col. 1, last para.).
Suzuki-Hatano/ Witko differs from claimed invention by not disclosing (i) riAAV is administered to the subject intravenously, intraventricularly or intrathecally, or through the cisterna magna, or a combination thereof (ii) riAAV comprises a promoter comprising the sequence of SEQ ID NO: 11 and (iii) the riAAV comprises an ITR comprising the sequence of SEQ ID NO: 10, SEQ ID NO: 13, or both
The deficiency is cured by Gruntman who intravenous injection of 1x1012 riAAV9 encoding CSA under the control of ubiquitous promoter, SV40 polyadenylation sequence and ITR to treat CS in subject (see figures 2.1 and 2.2 page 11 of the description) (limitation of claim 24, 25). The combination of references differs from claimed invention by not disclosing the requisite SEQ ID NO: for the coding sequence, promoter and ITR.
Xiao teaches SEQ ID NO: 36 that has 100% sequence identity to SEQ ID NO: 11 (see sequence search result), while Kaplitt teaches AAV ITR sequence as set forth in SEQ ID NO: 13 that has 100% sequence identity to SEQ ID NO: 13 (see sequence search result).
Accordingly, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the method of Suzuki-Hatano/ Witko by substituting ERCC5 coding sequence with another codon optimized ERCC5 sequence of the native human ERCC5 as suggested by Witko, Fath and Gruntman, with a reasonable expectation of success, before effective filing date of instant invention, in order to improve ERCC5 expression and resulting therapeutic outcome. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be motivated to use optimized human ERCC5 sequence with reasonable expectation of success in achieving the predictable results as the Artisan was well aware of the required structures, the results of optimized coding sequence of ERCC5. It is noted that while Applicant’s specific sequences as set forth in SEQ ID NO: 12 are not specifically taught, absent evidence of any unexpected and/or superior results, there is nothing in the art to demonstrate that the artisan would not expect to codon optimize the ERCC5 sequence using method and software known in as in Witko and Fath. Hence, it would appear that Applicant's contribution to the art is simply to claim codon optimized coding sequences, which is obvious to the Artisan before the effective filing of the instant application. Furthermore, KSR has already stated that motivation need not be specific, and only in the case of an infinite number of variants is a specific variant non-obvious. Given that one of ordinary skill in the art was well aware of the results of codon optimization, the requirements for codon optimization of ERCC5, and was already able to codon optimize coding sequence that could be delivered using riAAV9 as in Witko, before the effective filing date of instant invention. One of skill in the art would have been expected to have a reasonable expectation of success because prior art reported experimentation to substitute the wild type coding sequence with a codon optimized coding sequence of ERCC5 as suggested in Witko and Gruntman to improve the therapeutic outcome. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www.uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Thus, the claimed invention, as a whole, is clearly prima facie obvious in the absence of evidence to the contrary.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Fedler M (US20180303998, dated 10/25/2018) teaches a method of administering to the subject a replication-incompetent Adeno-associated Virus (riAAV) comprising a nucleotide sequence encoding a protein associated with ERCC5 (XPG) (see para. 23).
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632