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 .
Application Status
The preliminary amendment filed 07/17/2024 are acknowledged and have been entered. Claims 3 and 5 are amended. Claims 2, 17, 19, 21-37, 39-41, 44-55 are cancelled. Claims 1, 3-16, 18, 20, 38, and 42-43 are pending and being examined on the merits.
Priority
The application is a 371 PCT of US2022/034896 filed 06/24/2022 that claims priority to application 63/214,566 filed 06/24/2021.
Information Disclosure Statement
The information disclosure statements filed 11/25/2024 have been considered.
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.
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, 3-4, 6-7, 9, 12, 15-16, 18, 20, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Alkan (US 2020/0220488 A1) in view of Ruggero (US 20140243356A1).
Regarding claims 1 and 12, Alkan teaches exemplary transgenes and diseases to be treated with a synthetic AAV vector [VIII. Methods of Treatment, B]. Alkan teaches a synthetically produced AAV vector or a pharmaceutical composition thereof can be used in the treatment of glycogen storage disease (GSD) by delivering a nucleic acid sequence encoding an enzyme to correct aberrant glycogen synthesis or breakdown in subjects having GSD [0402]. Alkan specifically identifies phosphoglucomutase-1 (PGM-1) as one of the enzymes to be delivered and expressed [0402]. Alkan teaches that a partial restoration of enzyme activity compared to wild-type controls (e.g., at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99%) may be sufficient for reduction in at least one symptom of GSD and/or an improvement in the quality of life for a subject having GSD [0403]. Alkan teaches that nucleic acid encoding an enzyme to correct aberrant glycogen storage can be inserted behind the albumin endogenous promoter for in vivo protein replacement [0403]. Alkan teaches the transgene in an expression cassette or vector [0437]. Thereby Alkan expressly teaches an AAV vector carrying a nucleic acid encoding PGM1 for expression in a subject with a glycogen-storage disorder, in order to restore PGM1 enzyme activity and reduce symptoms.
Regarding claims 3, and 6-7, Alkan teaches the expression cassette included the CAG (or CMV) promoter, green fluorescent protein CDS (GFP), WPRE 5' UTR and bovine growth hormone poly Adenylation sequence (bGH polyA) [0498, claim 48].
Regarding claim 4, Alkan teaches where the expression cassette comprises ITRs as ITRs plays a critical role in mediating replication, viral particle and DNA packaging, DNA integration and genome and provirus rescue [0012, 0471, 0487, claim 1].
Regarding claim 9, Alkan teaches were the expression cassette can comprise a Kozak sequence [0053, Fig. 11A)
Claims 15-16, 18, and 20, Alkan teaches that pharmaceutical composition comprises a synthetic AAV vector produced using the synthetic process as described herein and a pharmaceutically acceptable carrier or diluent [0288] and a method of treating a disease in a subject comprising introducing into a target cell in need thereof of the subject a therapeutically effective amount of a synthetically produced closed-ended DNA vector [0386].
Regarding claim 42, Alkan teaches isolated DNA vectors and [claims 63-64, 0032] and that the synthetic AAV vector can be codon optimized [0409-0411, 0438].
Alkan does not teach a nucleotide sequence as set forth in SEQ ID NO: 1.
Ruggero teaches human phosphoglucomutase 1 transcript variant 1 (PGM1) as SEQ ID NO: 121. SEQ ID NO: 121 comprises a sequence that is 100% identical to SEQ ID NO: 1 (nucleotides 214-1902).
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to use Ruggero’s known human PGM1 coding sequence as the PGM1-encoding transgene expressly taught by Alkan because Alkan teaches to deliver and express PGM1 to restore enzyme activity in subjects with glycogen-storage disease. The combination would have predictably produced an AAV expression construct capable of expressing human PGM1 for enzyme-replacement therapy.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Alkan (US2020/0220488 A1) in view of Ruggero (US20140243356A1) as applied to claims 1 and 3 and further in view of Widdowson (US 2018/0353621 A1)
The teachings of Alkan and Ruggero are discussed as applied to claims 1 and 3 and similarly apply to claim 5.
Alkan and Ruggero do not teach wherein the CAG promoter has a nucleotide sequence of SEQ ID NO: 2.
Widdowson teaches genetic constructs and recombinant vectors comprising such constructs that can be used in gene therapy methods for treating a range of disorders [abstract]. Widdowson teaches that the promoter in the genetic construct of the first aspect may be any nucleotide sequence that is capable of inducing RNA polymerase to bind to and transcribe the first and second coding sequences [0028]. Widdowson teaches that the promoter can be a CAG promoter of SEQ ID NO: 2. SEQ ID NO: 2 of Widdowson is 100% to SEQ ID NO: 2 of the current application.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to utilize the known CAG promoter sequence taught by Widdowson in the expression cassette as taught and suggested by Alkan and Ruggero because Alkan teaches using a CAG promoter and the CAG promoter was a well-known constitutive mammalian promoter routinely used to achieve robust transgene expression. Substituting the known CAG promoter sequence for the generic CAG promoter taught by Alkan merely employs a known promoter according to its established function and would have yielded the predictable result of constitutive expression of the PGM1 transgene.
Claims 8 and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Alkan (US2020/0220488 A1) in view of Ruggero (US20140243356A1) as applied to claims 1, 6, 7, and 9 and further in view of Swartz (US 2022/0033851 A1)
The teachings of Alkan and Ruggero are discussed as applied to claims 1, 6, 7, and 9 and similarly apply to claims 8 and 10.
Alkan and Ruggero do not teach wherein the wherein the bgh polyadenylation tail signal has a nucleotide sequence of SEQ ID NO: 3 or wherein the Kozak sequence has a nucleotide
sequence of SEQ ID NO: 4.
Swartz teaches an AAV expression vector comprising a Kozak sequence comprising gccacc (current application’s SEQ ID NO: 4) and a polyadenylation element [0025]. Swartz teaches the Bovine Growth Hormone (BGH) polyadenylation (polyA) of SEQ ID NO: 5 [0123]. SEQ ID NO: 5 is 100% identical to the current application’s SEQ ID NO: 3.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to utilize the known bGH polyadenylation sequence and kozak sequence taught by Swartz in the expression cassette as taught and suggested by Alkan and Ruggero because Alkan teaches using a bGH polyadenylation and kozak sequence in the expression cassette and the bGH polyadenylation sequence and kozak sequence were well-known sequences routinely used to achieve transgene expression. Substituting the known bGH polyadenylation sedquence and kozak sequence for the generic bGH polyadenylation and kozak sequence taught by Alkan merely employs a known bGH polyadenylation sequence and kozak sequence according to its established function and would have yielded the predictable result of constitutive expression of the PGM1 transgene.
Claims 13 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Alkan (US2020/0220488 A1) in view of Ruggero (US20140243356A1) as applied to claims 1, 12, and 42 and further in view of Yi (Yi et al. Human gene therapy 28.3 (2017): 286-294).
The teachings of Alkan and Ruggero are discussed as applied to claims 1, 12, and 42 and similarly apply to claims 13 and 38.
Alkan and Ruggero do not teach vector is an adeno-associated viral vector of serotype 9 (AAV9) comprising an AAV9 capsid.
Yi teaches expressly teaches and AAV9 vector containing a human enzyme-expression cassette and intravenously administering the AAV9 vector to treat glycogen storage disease [abstract]. Although Yi does not repeatedly use the word ‘capsid’, Yi expressly identifies the administered recombinant viral vector as an AAV serotype 9 vector. A skilled artisan would have understood that the serotype designation of the administered recombinant AAV particle identifies its capsid serotype. Accordingly, Yi’s AAV9 vector necessarily comprise an AAV9 capsid surrounding the packaged enzyme-expression vector genome.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to package the PGM1 expression cassette as taught and suggested by Alkan and Ruggero in a AAV9 capsid vector as taught by Yi. A skilled artisan would have been motivated to make the modification because Yi demonstrated that an AAV9-packaged human enzyme-expression cassette effectively delivered the replacement enzyme to cardiac and skeletal muscle tissues and corrected biochemical abnormalities in a multisystem glycogen storage disease [abstract].
Claim 14 is rejected under 35 U.S.C. 103 as being unpatentable over Alkan (US2020/0220488 A1) in view of Ruggero (US20140243356A1) and Yi (Yi et al. Human gene therapy 28.3 (2017): 286-294) as applied to claims 1, 12 and 13 and further in view of Wilson (US 2007/0036760 A1)
The teachings of Alkan, Ruggero, and Yi are discussed as applied to claims 1, 12 and 13 and similarly apply to claim 14.
Alkan, Ruggero, and Yi do not teach wherein the AAV serotype has a capsid that is at least 95% identical to SEQ ID NO: 10.
Wilson teaches AAV-mediated delivery of therapeutic and immunogenic genes using the vectors [abstract]. Wilson teaches a human AAV serotype previously unknown, designated herein as clone 28.4/hu.14, or alternatively, AAV serotype 9 [0008]. Wilson teaches the invention provides an AAV of serotype 9 composed of AAV capsid which is serologically related to a capsid of the sequence of amino acids 1 to 736 of SEQ ID NO: 123 [0008]. SEQ ID NO 123 of Wilson is 100% identical to the current application’s SEQ ID NO: 10.
It would have been obvious to one ordinary skilled in the art before the effective filing date of the claimed invention to utilize the known AAV9 capsid sequence taught by Wilson in the expression cassette as taught and suggested by Alkan, Ruggero and Yi because Yi teaches using a AAV9 serotype to achieve transgene expression. Substituting the known AAV9 capsid sequence for the generic AAV9 taught by Yi merely employs a known AAV9 capsid according to its established function and would have yielded the predictable result of constitutive expression of the PGM1 transgene.
Allowable Subject Matter
The following is an examiner’s statement of reasons for allowance: The closest art is discussed above. The prior art fails to teach or suggest the specific recombinant nucleic acid constructs of SEQ ID NO: 8 or 9. Although the individual components of the CAG promoter, Kozak, hPGM1, WPRE, bgh polyA, and ITRs are known, the prior art does not disclose or render obvious the specific arrangement and nucleotide sequence of the claimed expression cassette. Therefore, claims 11 and 43 are found free of the art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Claims 11 and 43 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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