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 .
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). See in particular table 1 and paragraphs 27, 29 and 37.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
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.
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 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (US 2023/0357766).
Liu et al. teach at paragraph 3 that prime editing (PE) is a nucleic acid editing platform that enables the targeted and programmable installation of defined changes in a nucleotide sequence at a desired locus. It involves targeting of a prime editor to a target site in the genome, wherein the prime editor comprises a nucleic acid programmable DNA binding protein (napDNAbp) fused to a polymerase (e.g., a reverse transcriptase (RT)) associated with a prime editing guide RNA (pegRNA).
With regard to claims 1-3, Liu et al. teach at paragraph 12 that their disclosure provides prime editing complexes comprising a prime editor complexed with an engineered pegRNA, as well as expression vectors encoding said modified pegRNAs. These may be encoded on the same or different vector molecules.
With regard to the first plasmid of claims 1 and 2, Liu et al. teach at paragraph 14 a pegRNA for prime editing comprising a guide RNA and at least one nucleic acid extension arm comprising a DNA synthesis template and a primer binding site. The extension arm further comprises a nucleic acid moiety at either the 3’ or 5’ ends. At paragraph 12 Liu et al. teach appending this nucleic acid moiety to the end of the extension arm of a pegRNA achieves a consistent increase in editing efficiency.
At paragraph 17 and claim 6 Liu et al. teach the nucleic acid moiety that modifies a pegRNA is an evopreq1 aptamer having a nucleotide sequence such as SEQ ID NO: 219, which is identical to instant SEQ ID NO: 12.
With regard to the second plasmid of claims 1 and 3, Liu et al. teach prime editors, which are defined at paragraph 309 as fusion constructs comprising a napDNAbp (e.g., Cas9 nickase) and a reverse transcriptase, which are capable of carrying out prime editing on a target nucleotide sequence in the presence of a pegRNA. At paragraph 610 Liu et al. further teach the prime editor may have the following amino acid sequence (referred to as “PE2”), which includes a Cas9 variant comprising an H840A mutation (i.e., a Cas9 nickase) and an M-MLV RT comprising mutations D200N, T330P, L603W, T306K, and W313F, as well as an N-terminal NLS sequence and an amino acid linker that joins the C-terminus of the Cas9 nickase domain to the N-terminus of the RT domain. The PE2 fusion protein has the following structure: [NLS]-[Cas9(HS40A)]-[linker]-[MMLV-RT (D200N) (T330P) (L603W) (T306K) (W313F)]. At paragraphs 1275-1278 Liu et al. teach that PE2 installs single-nucleotide transversion, insertion, and deletion mutations with substantially higher efficiency than PE1, and is compatible with shorter PBS pegRNA sequences, consistent with an enhanced ability to productively engage transient genomic DNA:PBS complexes.
With regard to claim 7, Liu et al. teach at paragraphs 44 and claims 42-53 a method of prime editing comprising contacting a target DNA sequence with a modified pegRNA and a prime editor comprising a napDNAbp and a domain having an RNA-dependent DNA polymerase activity, wherein the editing efficiency is increased as compared to the same method using a pegRNA not comprising the modification.
Liu et al. do not explicitly teach a two-plasmid system for prime editing in yeast or a method of using such plasmids in yeast. However, Liu et al. further teach in paragraph 1034 that the vectors of their invention may encode the prime editors, and/or the pegRNAs. The vectors may be capable of driving expression of one or more coding sequences in a cell. In some embodiments, the cell may be a eukaryotic cell, such as a yeast cell. Suitable promoters to drive expression in different types of cells are known in the art. Also, paragraphs 1268-1271 demonstrate the successful use of prime editors and pegRNAs in yeast.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the prime editors and pegRNAs taught by Liu et al. as plasmids capable of expression in yeast and use such vectors to perform prime editing in yeast.
One of ordinary skill in the art would choose to use a first plasmid comprising a pegRNA with a nucleic acid moiety because Liu et al. teach that inclusion of such a moiety achieves a consistent increase in editing efficiency, and one would choose to include the aptamer comprising instant SEQ ID NO: 12 because Liu et al. explicitly teach this aptamer sequence as a preferred sequence as evidenced by claim 6 of Liu et al.
One of ordinary skill in the art would choose to use the fusion protein designated as PE2 because Liu et al. teach that PE2 is a more efficient prime editor than PE1.
One of ordinary skill in the art would have reason to make the prime editor and pegRNA as separate vectors because Liu et al. specifically contemplate such an embodiment. Additionally, one of ordinary skill would have been motivated to make such vectors suitable for use in yeast because Liu et al. both specifically suggest vectors that can be expressed in yeast and demonstrate that their system works in yeast cells.
Allowable Subject Matter
Claims 4-6 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
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tracy Vivlemore whose telephone number is (571)272-2914. The examiner can normally be reached Mon-Fri 7:30-4:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Dan Sullivan can be reached at 571-272-0900. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Tracy Vivlemore
Supervisory Primary Examiner
Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638