DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1, 5, 7, 9-10, 12, 15, 18-19, 24-25, 27-28, 41-42, and 44 are currently amended, claims 2-4, 8, 13-14, 21-23, 33, 35-40, and 45-55 are canceled, and claims have been considered on their merits.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 5-7, 9-12, 15-20, 24-25, 27-32, 41-42, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Keravala et al. (WO 2019/210325, published 31 October 2019, IDS ref.).
Regarding claim 1, Keravala et al. teach compositions and methods for treating, central nervous system degeneration using a recombinant gene therapy vector comprising a PARK2 or functional fragment or variant thereof (Abstract). PARK2 is also known as PRKN (p. 105, lines 10) and the gene name presented in all capital letters indicates a Human gene. Keravala et al. teach the PARK2 gene and the polynucleotide comprise a sequence having 70-99% identity to a PARK2 isoform polynucleotide sequence (p.3 lines 8-11). Keravala et al. teach in some embodiments the polynucleotide is codon-optimized (p. 3, lines 11-12). Keravala et al. teach the disclosure provides recombinant gene therapy vector, comprising a transgene polynucleotide encoding PARK2 gene, wherein the transgene polynucleotide is operably linked to a eukaryotically active promoter sequence (p. 52, lines 13-17). Keravala et al. teach the codon-optimized Parkin transgene sequences are SEQ ID NOs: 35-38 (p. 96, Example 1).
Keravala et al. is silent the PRKN protein nucleic acid sequence comprising instant SEQ ID NO: 2 or 3.
However, it would have been obvious to one of ordinary skill in the art to utilize codon optimization to arrive at the claimed SEQ ID NOs in the method of Keravala et al. because it would have been obvious to try other codon-optimized nucleic acid sequences to arrive at the same polypeptide as the person of ordinary skill would be choosing from a finite number of identified, predictable solutions with a reasonable expectation of success. MPEP 2143(E) Example 3 states, “when there is motivation to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to anticipated success, it is likely the product not of innovation but of ordinary skill and common sense.” KSR, 550 U.S. at 402-03, 82 USPQ2d at 1390.”
Keravala et al. teach in some embodiments, a codon-optimized polynucleotide encoding PARK2 is disclosed (p. 52, lines 18-25). Keravala et al. teach codon optimization refers to the discovery that the frequency of occurrence of synonymous codons in coding DNA is biased in different species (p. 52, lines 18-25). Such codon degeneracy allows an identical polypeptide to be encoded by a variety of nucleotide sequences and a variety of codon optimization methods are known in the art (p. 52, lines 18-25). Additionally, codon optimization in heterologous expression systems, can overcome species-specific codon usage differences and boost protein production.
Utilizing the codon-optimized sequence disclosed by Keravala et al. would ultimately arrive at the identical PRKN protein. When comparing the translation of instant SEQ ID NO: 2 and SEQ ID NO: 38 of Keravala et al., both codon-optimized sequences arrive at Human E3 ubiquitin-protein ligase parkin isoform 1, NP_004553.2, with 100% identity as seen below:
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Therefore, substituting SEQ ID NO: 38 of Keravala et al. with SEQ ID NO: 2 of the instant application would have led to a reasonable expectation of success because both sequences encode the identical protein and codon-optimization is dependent on the intended application of the sequence in question.
Regarding claims 5-7, and 9-11, Keravala et al. teach a plasmid (claim 11) AAV expression cassette comprising 5’ AAV2 ITR, CMV enhancer, CBA promoter (claim 6), codon-optimized Parkin transgene variant, WPRE), and 3’ AAV2 ITR (claims 7 and 9) (p. 100, Example 2, Fig. 7, and Fig. 8). The plasmid reads as a vector (claim 10) and the CBA promoter reads as a constitutive promoter (claim 5).
Regarding claims 12 and 15-17, Keravala et al. teach various viral or non-viral vectors can be used, wherein the recombinant gene therapy vector is a recombinant adeno-associated virus (rAAV) (claim 12), to include AAV9 (claim 17) (p. 3, lines 17-20). Keravala et al. teach the AAV comprises a capsid protein having at least 95% identity to a wild-type VP1, VP2, or VP3 capsid protein (claim 15) (p. 3, lines 24-25). The recombinant gene therapy vector reads as the isolated nucleic acid of claim 1. The capsid of AAV9 is known to cross the blood-brain barrier (claim 16).
Regarding claim 18, Keravala et al. teach capsid proteins of a rAAV may be modified so that the rAAV is targeted to a particular target tissue of interest such as neurons or more particularly a dopaminergic neuron (p. 80, lines 12-14). Keravala et al. teach methods of administering or delivering recombinant gene therapy vectors which express a gene related to a CNS degeneration to a mammalian subject, to include transducing neuronal calls and brain tissues directed by neuron-specific control elements (p. 82, lines 9-10 and 15-19).
Regarding claim 19 and 20, Keravala et al. teach for purposes of administration, e.g., by injection, various solutions can be employed, such as sterile aqueous solutions (pharmaceutically acceptable carrier) (p. 80, lines 20-21). The combination of a pharmaceutically acceptable carrier and vector read as a composition comprising the isolated nucleic acid.
Regarding claim 24, Keravala et al. teach PRKN is the primary gene in which pathogenic variants are known to cause parkin type early-onset Parkinson disease (p. 105-106, Example 6 and Table 13). Keravala et al. teach human subjects having one or more mutations associated with Parkinson's Disease are treated with recombinant gene therapy vectors encoding wild-type or functional variants of the mutated gene (claim 24) (p. 106, lines 2-5).
Regarding claim 25 and 27, Keravala et al. teach administration of an effective dose of the compositions may be by routes standard in the art including, but not limited to, systemic, local, direct injection, parenteral, intravenous, cerebral, cerebrospinal, intrathecal, intracisternal, intraputaminal, intrahippocampal, intra-striatal, or intra-cerebroventricular administration (p. 79, lines 20-25). Cerebrospinal administration reads as direct injection to the CNS of the subject (claim 25). Intravenous injection reads as peripheral injection (claim 27).
Regarding claims 28 and 29, Keravala et al. teach mutations in the PARK2 include deletions, insertions, frameshifts, missense, and nonsense mutations in every exon; deletions and duplications of one or more exons are the most common mutations (Table 13).
Regarding claim 30, Keravala et al. teach 3’ to 5’: 3’ ITR, CMV enhancer, CBA promoter, transgene encoding Parkin, WPRE, Bovine growth hormone pA, 3’ ITR (p. 100, Example 2 and Fig. 8).
Regarding claims 31 and 32, Keravala et al. teach viral vectors can be used, wherein the recombinant gene therapy vector is a recombinant adeno-associated virus (rAAV), to include AAV9 (p. 3, lines 17-20). Keravala et al. teach the AAV comprises a capsid protein having at least 95% identity to a wild-type VP1, VP2, or VP3 capsid protein (AAV9 capsid) (claim 32) (p. 3, lines 24-25). The recombinant gene therapy vector reads as an rAAV comprising an AAV capsid protein and the rAAV vector of claim 30 (claim 31).
Regarding claim 41, Keravala et al. teach human subjects having one or more mutations associated with Parkinson's Disease are treated with recombinant gene therapy vectors encoding wild-type or functional variants of the mutated gene (claim 41) (p. 106, lines 2-5).
Regarding claims 42 and 44, Keravala et al. teach administration of an effective dose of the compositions may be by routes standard in the art including, but not limited to, systemic, local, direct injection, parenteral, intravenous, cerebral, cerebrospinal, intrathecal, intracisternal, intraputaminal, intrahippocampal, intra-striatal, or intra-cerebroventricular administration (p. 79, lines 20-25). Cerebrospinal administration reads as direct injection to the CNS of the subject (claim 42). Intravenous injection reads as peripheral injection (claim 44).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claims 26 and 43 are rejected under 35 U.S.C. 103 as being unpatentable over Keravala et al. (WO 2019/210325, published 31 October 2019, IDS ref.) as applied to claims 1, 5-7, 9-12, 15-20, 24-25, 27-32, 41-42, and 44 above, and further in view of Lam et al. (Journal of Clinical Neuroscience 18 (2011)).
Regarding claims 26 and 43, Keravala et al. are silent to direct injection to the CNS comprising convection enhanced delivery (CED).
However, Lam et al. teach convection-enhanced delivery (CED) is a promising neurosurgical technique for the delivery of potential therapeutic agents to the Parkinson’s disease (PD-affected striatum (Abstract). Therefore, it would have been obvious to one or ordinary skill in the art to utilize the CED method of Lam et al. to deliver the isolated nucleic acid construct or the rAAV comprising a nucleic acid of Keravala et al. with a reasonable expectation of success because Lam et al. teach infusions of rAAV vector-mediated transfer of GAD is a potential treatment for PD (p. 1166, Translation of convention-enhanced delivery in Parkinson’s disease). One would have been motivated to utilize the CED method of Lam et al. to deliver the isolated nucleic acid construct or the rAAV comprising a nucleic acid of Keravala et al. because Lam et al. suggest direct neurosurgical approaches with CED could be a solution to current problems of accurately delivering potentially therapeutic agents to deep brain targets in the treatment of PD (p. 1166, Conclusion).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Claim 34 is rejected under 35 U.S.C. 103 as being unpatentable over Keravala et al. (WO 2019/210325, published 31 October 2019, IDS ref.) as applied to claims 1, 5-7, 9-12, 15-20, 24-25, 27-32, 41-42, and 44 above, and further in view of Li et al. (Molecular Therapy Vol. 10, No. 6, December 2004).
Regarding claim 43, Keravala et al. is silent to a Baculovirus vector comprising the nucleic acid sequences of SEQ ID NO: 2 or 3.
However, Li et al. teach transgene expression from the baculovirus vectors driven by a neuron-specific promoter was detectable in target regions remote from injection sites (Abstract). Li et al. teach the attributes of baculovirus vectors in the bidirectional axonal transport and transneuronal transport in neural circuits of the central nervous system could be utilized for targeted gene delivery (Abstract). Therefore, it would have been obvious to one of ordinary skill in the art to utilize a Baculovirus vector comprising the nucleic acid sequence of Keravala et al. with a reasonable expectation of success because Li et al. teach current studies have contributed to more extensive use of the baculovirus as an effective neuronal gene delivery vector and also for as a gene therapy of PD (p. 1128, Discussion, 1st column). One would have been motivated to utilize a Baculovirus vector comprising the nucleic acid sequence of Keravala et al. because targeted gene delivery to neurons are crucial to effective gene therapy of neurodegenerative diseases (Abstract).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631