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 amendments to the claims and arguments filed on January 12, 2026 have been received and entered. Claims 1, 21 have been amended, while claims 2-9, 15, 20, 24-27, 29-34 have been canceled. Claims 1, 10-14, 16-19, 21-23 and 28 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Claims 11-14 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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.
Claims 1, 10, 21-23 and 28 are under consideration.
Maintained-Claim Rejections - 35 USC § 112-in modified form
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, 10, 21-23 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 CS in a subject. 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.
Applicants disagree with the rejection arguing Examples 1- 3 provide an exemplary method for one skilled in the art to be able to practice the invention of amended claim 1. For mutations within the ERCC8 gene and ERCC6 gene, Examples 4 and 5 provide further guidance for one skilled in the art to practice the invention of amended claim 1. Additionally, the claims have been amended to characterize the route of administration as intravenous, intraventricular, intrathecal, or administration through the cisterna magna, as well as characterize the AAV as being serotype 9 or 2. Applicant demonstrated 1.5- to 2-fold increased expression of therapeutic protein in all tissues assessed, and a therapeutic benefit was observed at all doses tested. Paragraph [0079] reports that "[b]oth low dose treatment groups also showed on average 3 to 4 weeks of increased survival as compared to untreated controls and brain histological analyses demonstrate normalization of nucleus sizes in treated mice," implicating improvement in the underlying DNA repair disorder. Paragraph [0080]. Examples 2 and 3 establish that all doses employed in the working example achieved a beneficial, therapeutic response, in a clinically relevant animal model. Applicant continue to argue that the specification describes AAV and codon- optimized sequences of therapeutic proteins (see, e.g., paragraph [0044] and [0048]-[0055]); appropriate routes of administration (see, e.g., paragraphs [0066]); dosages (see, e.g., paragraph [0044]); and subjects (see, e.g., paragraph [0013]). Applicants’ arguments have been fully considered, but are not found persuasive.
In response, the previous office action indicated an enabled scope 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. Applicant’s amendments to the base claim only in part obviates the grounds for rejection. It was indicated that the disclosure is not enabled for delivering via any other route or using any other serotype of AAV to treat CS by all the recited route of administration.
Applicant’s argument in part relying on the Examples 1- 3 that provide an exemplary method well as characterize the AAV as being serotype 9 or 2 and amended route of administration is not found persuasive. This is because guidance provided in examples 1-2 is limited to an intravenous administration of AAV9-ERCC5 to Xpg-/- mouse that is 1-day old neonate (n ≥ 8 per cohort) at doses 5x10¹², 1x10¹³, 3x10¹³, or 3x10¹⁴ vg/kg via the temporal vein (see para. 78 of the specification). In this context, previous office action explicitly reported 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 Liu Cytokine and Growth Factor Reviews 80 (2024) 109–120 and references therein, page 113, col. 2, para. 1 to page 114, col. 1, para. 2). Liu continue to teaches direct intracranial offers high delivery efficiency to targeted brain areas with minimal systemic distribution, it presents significant risks, including the invasive nature of the procedure, potential for infection, hemorrhage, and neurotoxicity, as well as limitations in treating disorders that affect multiple brain regions. In fact, intraputamenal delivery of AAV2-neurturin in patients with advanced Parkinson’s disease, the occurrence of serious adverse events, including bleeding and infection, highlighted the risks associated with invasive surgical procedures (see page 114, col. 1, para. 2). There is no evidence on record that an intravenous injection of AAV2-ERCC5 would transduce and express therapeutic genes cross as it is not expected to cross BBB to have any effect in a subject in need thereof. Further, 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. As stated in the previous office action, 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 riAAV2 or AAV9 delivered via plurality of different route as embraced by the breadth of the claim in any 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.
Withdrawn-Claim Rejections - 35 USC § 102
Claims 1, 2, 10 and 24 were 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). The rejection is withdrawn in view of the Pacak’s declaration indicating that cited art is not by others. Therefore, previous rejection is hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Claims 1, 2, 10, 24, 25 and 28 were 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.). In view of Applicants’ amendment of base claims introducing the limitation of claim 21, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Withdrawn-Claim Rejections - 35 USC § 103
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). In view of Applicants’ amendment of base claims and upon further consideration, the previous rejection is rendered moot and hereby withdrawn. Applicants’ arguments with respect to the withdrawn rejections are thereby rendered moot.
Maintained-Claim Rejections - 35 USC § 103
Claims 1, 10, 21-23 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), Gruntman (Doctoral dissertation on Translational Pathway for Recombinant AAV Human Gene Therapy: From Target", 203 (2016), IDS) and Xiao (US7001761, dated 02/21/2006), Kaplitt (US 8067156, dated 11/29/2011). Please note Suzuki-Hatano that was applied alternative to Witko reference is withdrawn from the statement of rejection in view of Pacak’s declaration indicating that cited art is not by others.
Regarding claims 1, 10, 21-25 and 28, Witko teaches a gene therapy method of treating CS, said method comprising intravenous injections of 5x1013 vg/Kg AAV9-CMV-codon optimized 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 (i) codon optimized sequence is set forth in SEQ ID NO: 12 (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
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.). The combination of references differs from claimed invention by not disclosing (i) riAAV comprises a promoter comprising the sequence of SEQ ID NO: 11 and (ii) 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 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.
Response to arguments
Applicant disagree with the rejection arguing Witko is silent on the nucleotide sequence of the vector payload, does not teach or describe administration of a nucleotide sequence encoding a CSA or CSB protein, or disclose that the subject comprises one or more mutations in an ERCC5 gene, an ERCC8 gene, an ERCC6 gene, or a combination thereof. Fath fails to cure the deficiencies of Witko, as the Office has not demonstrated that one skilled in the art following the teachings of Witko in view of Fath would necessarily arrive at a nucleotide sequence encoding a XPG protein comprising the nucleotide sequence of SEQ ID NO: 12. Accession No. D16305 recites both the amino acid sequence and the DNA sequence of human ERCC5. However, D16305 does not comprise the nucleotide sequence set forth in SEQ ID NO: 12 and in fact, demonstrates about 75% sequence identity with SEQ ID NO: 12. Taking the teachings of Fath into account for optimizing the sequence of D16305 does not necessarily lead one skilled in the art to the nucleotide sequence set forth in SEQ ID NO: 12 with any particularity. Thus, there is nothing in Fath suggesting or guiding a skilled artisan to specifically arrive at a nucleotide sequence encoding an XPG protein comprising the nucleotide sequence set forth in SEQ ID NO: 12 to use in a method of treating a subject with Cockayne Syndrome. Applicant continue to argue none of the secondary references teach or suggest the codon- optimized sequences required by the instant claims. Applicants’ arguments have been fully considered, but are not found persuasive.
In response, it appears that applicant in part agree that primary art of Witko teaches a gene therapy method of treating CS, said method comprising intravenous injections of 5x1013 vg/Kg AAV9-CMV-codon optimized 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 (elected species) gene expression in both AAV-treated groups as compared to untreated XPG-/- controls. It is relevant to note that the teaching of Witki further discloses Cockayne Syndrome (CS) is a rare, autosomal recessive disorder characterized by neurodegeneration and premature aging. CS that is caused by mutations in genes involved in DNA repair mechanisms including mutations that affects the XPG protein, an endonuclease required for nucleotide excision repair, which is encoded by the ERCC5 gene. Thus, teaching of Witko teaches all the limitation of base claim 1 except the references does not explicitly disclose the codon optimized coding sequence of ERCC5 gene as set forth in SEQ ID NO: 12. As previously indicated, codon optimization was routine in prior art that typically included (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 s to improve and optimize the gene sequences to boost the protein expression of the genes in any mammalian cells. The cited art of record as summarized by Fath explicitly discloses A variety of vessels suitable for this purpose are well-known in the art, including GeneOptimizer H expert software to optimize coding sequence. Thus, Fath et al. cure the deficiency in Witko. for optimizing the coding sequence of ERCC5. To the extent that Witko. describe the use of codon optimized sequence capable of improving in several neurological exams and activity tests for all AAV-treated mice show the upregulation of XPG (elected species) gene expression , the rejection is applicable to the instant case. Applicants' selective reading of Peled et al. ignores the teachings of the primary reference of Peled et al. There is no requirement for Witko. to teach that which is clearly taught by Fath. 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, specifically in the case of a finite number of variants is a specific variant obvious.
Absent evidence to an unexpected superior result with any specific sequence as set forth in SEQ ID NO: 12 as compared to any other optimized or wild type coding sequence of ERCC5,
it would be obvious to one of ordinary skill in the art to try optimizing the coding sequence of
ERCC5 using method and software disclosed in prior art by optimizing the coding sequence of ERCC5 gene to arrive at finite numbers of codon optimize sequences that includes the codon optimized sequence set forth in SEQ ID NO: 12 and select a synthetic codon optimized ERC5 from the finite sequence that exhibits improved expression of ERCC5 using the method/assay disclosed in Fath in a host/cell, with reasonable expectation of success.
Examiner’s note: Should applicant provide evidence of unexpected superior result using coding sequence set forth in SEQ ID NO: 12 as compared to other codon optimized coding sequence, instant obviousness rejection may be overcome pending rejection.
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).
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ANOOP K SINGH/Primary Examiner, Art Unit 1632
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