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 .
Priority
The instant application is a national stage entry under 35 U.S.C. § 371 of PCT/US2022/014926 (filed 02/02/2022). Acknowledgement is made of Applicants’ claim for benefit of U.S. Application Nos. 63/221,682 (filed 07/14/2021) and 63/145,123 (filed 02/03/2021).
Election/Restrictions
Applicant’s election without traverse of Group I in the reply filed on 08/04/2026 in response to a Restriction requirement is acknowledged.
Applicant’s election of SEQ ID NO: 40 as the nucleic acid sequence comprised in the UBE3A-ATS shRNA in the same reply in response to an Election of Species requirement 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)).
Claims 1-15 and 18-20 are pending in the instant application; claims 19-20 are withdrawn as directed to inventions nonelected.
Claims 1-15 and 18 read on Applicants’ elections and are examined on the merits herein.
Claim Interpretation
The following comments are made to establish broadest reasonable interpretation for the record.
Regarding claims 1-2, 15: These claims are directed to an rAAV vector comprising a polynucleotide sequence encoding at least one UBE3A-ATS shRNA. The term UBE3A-ATS is interpreted as referring to ubiquitin protein ligase E3A antisense transcript, as supported by the instant specification (par. 0003).
Regarding claim 3: Claim 3 recites the rAAV vector as further comprising a second polynucleotide sequence which is substantially a reverse complement of the first polynucleotide sequence. As supported by the definition set forth in the specification, a substantially reverse complement is interpreted as a sequence that is the reverse complement of a first polynucleotide sequence except for one, two, three, or four mismatches (par. 0044); under broadest reasonable interpretation, an exact reverse complement is encompassed within the scope of a substantially reverse complement.
Regarding claims 7-8, 11: These claims recite the rAAV vector as further comprising a CBh promoter sequence. The CBh promoter is interpreted as referring to a ubiquitous chicken β-actin hybrid promoter, as supported by the specification (par. 0081).
Regarding claims 9-11: These claims recite the rAAV vector as further comprising a BGH polyA sequence. The BGH polyA is interpreted as referring to a bovine growth hormone polyadenylation sequence, as supported by the specification (par. 0094).
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4 and 13-15 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Chamberlain and Germain (US 2021/0332368).
Chamberlain and Germain (hereinafter Chamberlain) teaches compositions and methods for activating expression from the paternally-inherited allele of UBE3A in human Angelman's Syndrome neurons using viral vector delivery of short hairpin RNAs (Abstract).
Regarding claims 1-4: Chamberlain teaches a polynucleotide comprising a nucleotide sequence encoding a short hairpin RNA (shRNA) which inhibits a UBE3A antisense transcript (UBE3A-ATS), wherein the polynucleotide is contained within an adeno-associated viral (AAV) vector (pars. 0023, 0025, 0059). In an embodiment, the nucleotide sequence encoding the shRNA has the nucleotide sequence as set forth in SEQ ID NO: 2, wherein the bold nucleotides therein are replaced by SEQ ID NO: 48, and wherein the italicized nucleotides therein are replaced by the nucleotides complementary to SEQ ID NO: 48 (par. 0027). The shRNA is generated by annealing two complementary polynucleotides with the desired sequences; specifically, the target sequence (i.e., SEQ ID NO: 48) and its reverse complement (par. 0102).
Chamberlain discloses SEQ ID NO: 48 and reverse complement thereof in DNA format (pg. 41); thus, these sequences encoding the shRNA of Chamberlain are necessarily transcribed in order to generate the shRNA molecule. The transcribed reverse complement of SEQ ID NO: 48 shares 100% identity to the sequence as set forth in instant SEQ ID NO: 40 (please see pg. 2 of Office Action Appendix I for sequence alignments); thus, the polynucleotide sequence comprising the reverse complement of SEQ ID NO: 48 of the shRNA molecule of Chamberlain reads on the SEQ ID NO: 40 limitations recited in claims 1 and 2. Additionally, transcribed SEQ ID NO: 48 shares 100% identity to the reverse complement sequence of instant SEQ ID NO: 40 (pg. 2; OA Appendix I); thus, the polynucleotide sequence comprising SEQ ID NO: 48 of the shRNA molecule of Chamberlain reads on the reverse complement of the first polynucleotide limitations recited in claims 3 and 4.
Thus, the rAAV vector of Chamberlain anticipates:
the rAAV vector comprising a first polynucleotide sequence encoding at least one UBE3A-ATS shRNA, wherein the at least one UBE3A-ATS shRNA comprises a nucleic acid sequence as set forth in SEQ ID NO: 40 limitation recited in claim 1;
the wherein the at least one UBE3A-ATS shRNA comprises a nucleic acid sequence as set forth in SEQ ID NO: 40 limitation recited in claim 2;
the wherein the rAAV vector further comprises a second polynucleotide which is substantially a reverse complement of the first polynucleotide sequence limitation recited in claim 3; and
the wherein the second polynucleotide sequence is the reverse complement of the first polynucleotide sequence except for no more than four mismatches limitation recited in claim 4.
Regarding claims 13-14: Following the above discussion, Chamberlain teaches the rAAV comprises an AAV capsid protein (par. 0085); in an embodiment, the AAV serotype is AAV9 (par. 0084). This anticipates:
the rAAV viral vector comprising an AAV capsid protein, and the rAAV vector of claim 1 limitation recited in claim 13; and
the wherein the AAV capsid protein is an AAV9 capsid protein limitation recited in claim 14.
Regarding claim 15: Following the above discussion, Chamberlain teaches the viral particle of the disclosure can be formulated for administration in a pharmaceutical composition, wherein the composition comprises a pharmaceutically acceptable excipient (pars. 0089, 0093); this anticipates the pharmaceutical composition comprising the rAAV viral vector and at least one pharmaceutically acceptable excipient limitation recited in claim 15.
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.
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 1-4, 13-15, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Chamberlain and Germain (US 2021/0332368).
The teachings of Chamberlain are set forth above; claims 1-4 and 13-15 are anticipated by the same.
Regarding claim 18: Following the above discussion, Chamberlain teaches for general guidance, a composition based on viral particles is formulated at a dose of at least 105 viral genomes per cell (par. 0095), but does not explicitly teach the limitations recited in the instant claim.
However, the dose of the viral genomes per cell would have been routinely optimized by a person having ordinary skill in the art. Chamberlain teaches the pharmaceutical composition is administered in a therapeutically effective amount (par. 0094), but discloses the appropriate dosage will vary depending upon known factors; e.g., pharmacodynamic characteristics, age, health, and weight of the host organism, nature and extent of symptoms, any concurrent treatment, frequency of treatment, the need for prevention or therapy and/or the effect desired (par. 0095). The disclosure further states the dosage will be calculated based on the route of administration, and further refinement of the appropriate dosage is made by a practitioner (par. 0095).
Thus, Chamberlain clearly teaches the pharmaceutical composition is administered at a dose effective to achieve a therapeutic effect. That means the conditions necessarily to achieve the therapeutic effect are result effective variables. Result effective variables would be optimized by routine experimentation by one having ordinary skill in the art. Furthermore, differences in dosage will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such a dose is critical. See MPEP 2144.05(II)(A).
This renders obvious the comprising a dose of about 1011 to about 1018 viral vector particles limitations recited in claim 18.
Claims 1-4, 7-8, and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Chamberlain and Germain (US 2021/0332368), in view of Zhang, et al. (US 2021/0155911) and Gray (WO 2019/094061).
The teachings of Chamberlain are set forth above; claims 1-4 and 13-15 are anticipated by the same.
Zhang, et al. (hereinafter Zhang) teaches systems, methods, and compositions for targeting nucleic acids (Abstract).
Gray teaches methods of using vectors for delivery of an open reading frame to a cell or a subject (Abstract).
Regarding claims 7-8: Following the above discussion, Chamberlain teaches an embodiment wherein the vector further comprises a promoter sequence (par. 0067), but does not disclose the promoter as a CBh promoter, as required by the limitations recited in the instant claims.
However, Zhang teaches expression plasmid pY036 and associated nucleotide sequences (i.e., SEQ ID NO: 361), wherein residues 529-1324 of plasmid pY036 comprise a CBh promoter sequence (par. 0109; Figs. 18A-B); residues 529-1324 of SEQ ID NO: 361 share 100% identity to the sequence as set forth in instant SEQ ID NO: 63 (pgs. 3-4; OA Appendix I). Additionally, Gray teaches the CBh promoter is effective to drive strong gene expression (par. 0167).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have modified the rAAV vector of Chamberlain by using residues 529-1324 of SEQ ID NO: 361 as the promoter sequence. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so for the ability of the CBh promoter to drive strong gene expression, as disclosed by Gray (par. 0167); further, as Gray discloses use of the CBh promoter in an rAAV vector, and as Chamberlain discloses the vector further comprises a promoter sequence (par. 0067), the skilled artisan would have more than a reasonable expectation of success. This renders obvious:
the wherein the rAAV vector further comprises a CBh promoter sequence limitation recited in claim 7; and
the wherein the CBh promoter sequence comprises the nucleic acid sequence set forth in SEQ ID NO: 63 limitation recited in claim 8.
Claims 1-4, 9-10, and 13-15 are rejected under 35 U.S.C. 103 as being unpatentable over Chamberlain and Germain (US 2021/0332368), in view of Samulski (US 2017/0128528) and Gray (WO 2019/094061).
The teachings of Chamberlain and Gray are set forth above; claims 1-4 and 13-15 are anticipated by Chamberlain.
Samulski teaches a modified FXN gene providing for increased expression of the encoded protein frataxin (Abstract).
Regarding claims 9-10: Following the above discussion, Chamberlain teaches an embodiment wherein the vector further comprises a polyadenylation (polyA) sequence (par. 0067), but does not disclose the polyA sequence as a bovine growth hormone (bGH) polyA sequence, as required by the limitations recited in the instant claims.
However, Samulski teaches a bGH polyA signal sequence having the sequence of SEQ ID NO: 27 (par. 0026); SEQ ID NO: 27 shares 100% identity to the sequence as set forth in instant SEQ ID NO: 66 (pg. 5; OA Appendix I). Additionally, Gray teaches inclusion of a bGH polyA sequence is effective to drive strong gene expression (par. 0167).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art to have further modified the rAAV vector of Chamberlain by using SEQ ID NO: 27 as the polyA sequence. This conclusion of obviousness is based on the ‘teaching, suggestion, or motivation rationale’. One would be motivated to do so for the ability of the bGH polyA sequence to drive strong gene expression, as disclosed by Gray (par. 0167); further, as Gray discloses use of a bGH polyA sequence in an rAAV vector, and as Chamberlain discloses the vector further comprises a polyA sequence (par. 0067), the skilled artisan would have more than a reasonable expectation of success. This renders obvious:
the wherein the rAAV vector further comprises a BGH polyA sequence limitation recited in claim 9; and
the wherein the BGH polyA sequence comprises the nucleic acid sequence set forth in SEQ ID NO: 66 limitation recited in claim 10.
Claim Objections
Claims 3 and 15 are objected to because of the following minor informalities:
Claim 3 recites, “…wherein the rAAV vector further comprises a second polynucleotide which is…”; this should read “…wherein the rAAV vector further comprises a second polynucleotide sequence which is…” to be consistent with the language recited in corresponding claims (e.g., claim 4).
In claim 15, the “UBE3A” portion of the term “UBE3A-ATS” is not italicized. While it is standard in the art to italicize gene symbols, it is not required for claim language; however, the formatting should be consistent within the claim set (i.e., one of “UBE3A-ATS” or “UBE3A-ATS” recited in claims 1, 2, and 15).
Appropriate correction is required.
Claims 5-6 and 11-12 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.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
An AAV ITR sequence comprising a sequence as set forth in SEQ ID NOs: 56 or 58 (claims 5-6, 11), as well as an rAAV vector comprising a sequence as set forth in SEQ ID NO: 112 (claim 12) are free from the prior art before the effective filing date of the instant application.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GINA PRONZATI whose telephone number is (571)270-5725. The examiner can normally be reached Monday - Friday 9:00a - 5:00p ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, CHRISTOPHER BABIC can be reached at (571)272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GINA PRONZATI/Examiner, Art Unit 1633
/ALLISON M FOX/Primary Examiner, Art Unit 1633
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