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
This action is written in response to applicant’s correspondence received 16 February 2024. Claims 1-4, 20-21, 23-24, 26, 28-29, 36, 43, 45, 72, 77, and 79-80 are currently pending. Accordingly, claims 1-4, 20-21, 23-24, 26, 28-29, 36, 43, 45, 72, 77, and 79-80 are examined herein.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. The file size is currently listed in kilobytes and must be listed in bytes. See item 1) a) or 1) b) above.
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 incorporation-by-reference paragraph, 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.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings, specifically FIGs. 4B and 13A-D, are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, 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 § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 45 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 45, MPEP 2173.05(s) states "Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted)." In the instant case, it would be practical to define the invention using the very same SEQ ID NOs or species of Acr proteins found Tables 1 and 2.
Claim Rejections - 35 USC § 102
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 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.
Claim(s) 1-4, 43, 72, 77, and 79-80 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Fremaux (PG Pub No. US 2020/0190492 A1, published 18 June 2020, filed 24 April 2018).
Regarding claims 1 and 79, Fremaux is drawn towards an invention concerned with methods and compositions utilizing anti-CRISPR proteins in plants (Abstract). Fremaux teaches the use of a method comprising introducing together (a) a Cas endonuclease (i.e., a Cas effector protein), (b) an anti-CRISPR (i.e., “ACR”) polypeptide, wherein the ACR is provided as a polynucleotide encoding a polypeptide, and (d) a guide polynucleotide ([0031]). Fremaux teaches that (c) the nucleotide sequence encoding the ACR protein can be operably linked to a translational initiation or termination region (i.e., a translational control element) ([0242]). Fremaux teaches that (b) the ACR protein is an inhibitor of the Cas protein ([0294]). Fremaux teaches that the ACR proteins can reduce the ability of the Cas protein to cleave a target polynucleotide (i.e., the Cas protein mediates one or more edits to a target sequence of a target nucleic acid) ([0225]). Fremaux teaches that the reduction in activity of the Cas protein can be measured (i.e., detected) as the cleavage activity of the Cas protein ([0302]).
Regarding claim 2, Fremaux teaches that the modulated activity of the Cas protein may be modulated cleavage activity ([0100], [0302]).
Regarding claim 3, Fremaux teaches that the modulated activity of the Cas protein may be modulated binding specificity ([0100]).
Regarding claim 4, Fremaux teaches that (i) utilizing the ACR protein reduces the off-target DNA cleavage of the Cas protein (i.e., the amount of on-target activity is increased by the system as compared with a similar system lacking the translational control element) ([0306]-[0307]).
Regarding claim 43, Fremaux teaches that the Cas protein may be a Cas9 protein ([0014]).
Regarding claims 72 and 80, Fremaux teaches that the cell may be a human cell ([0299]).
Regarding claim 77, Fremaux teaches that the reduced activity of the Cas protein can be assayed in a bacterial host ([0302]). Fremaux teaches that the host may be in vitro ([0158]).
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.
Claim(s) 20-21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fremaux (PG Pub No. US 2020/0190492 A1, published 18 June 2020, filed 24 April 2018) as applied to claims 1-4, 43, 72, 77, and 79-80 above, and further in view of Jang (RNA binding proteins: new concepts in gene regulation. Boston, MA: Springer US, 2002. 1-33).
Regarding claims 20-21, Fremaux anticipates claims 1-4, 43, 72, 77, and 79-80 as described above. Fremaux further teaches that the expression vector may comprise a ribosome binding site for translation initiation ([0252]).
Fremaux does not teach or suggest the use of a translational control element selected from an IRES sequence (Claim 20), wherein the IRES sequence is EMCV (Claim 21).
However, one of ordinary skill in the art would have considered the teachings of Jang as both references are common fields of endeavor pertaining to the use of ribosome binding sites in nucleic acids.
Jang is drawn towards a paper concerned with the role of RNA-binding proteins in IRES-dependent translation (Abstract). Jang teaches that EMCV is an IRES that comprises a ribosome binding site that allows for the translation of mRNA (pg. 9). Jang teaches that the EMCV IRES was able to successfully drive expression of a reporter gene present within a bicistronic mRNA in vitro (i.e., the EMCV IRES is a translational control element) (pg. 4-5; see FIG. 1A). Jang teaches that the EMCV IRES was able to direct excellent translation of the reporter gene in rabbit reticulocyte lysates (pg. 3-4).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the translational initiation region of Fremaux for an EMCV IRES, as described by Jang. A person of ordinary skill in the art would have had a reasonable expectation of success because both Fremaux and Jang teach the use of translation initiation regions that were individually known to have the same function of translational control in nucleic acids encoding proteins of interest.
Claim(s) 23-24, 26, and 39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fremaux (PG Pub No. US 2020/0190492 A1, published 18 June 2020, filed 24 April 2018) as applied to claims 1-4, 43, 72, 77, and 79-80 above, and further in view of Liu (Scientific reports 7.1 (2017): 2193).
Regarding claims 23-24 and 26, Fremaux anticipates claims 1-4, 43, 72, 77, and 79-80 as described above.
Fremaux further teaches that the ACR protein may be combined with other genes in a polycistron separated by sequences encoding self-cleaving 2A peptides ([0111]). Fremaux teaches that the nucleic acids encoding the ACR protein may be comprised with expression cassettes encoding the Cas protein ([0244]). Although Fremaux teaches the use of 2A peptides, it does so in the context of separating the ACR protein from downstream proteins (see FIG. 10). However, the instant claims 23-24 and 26 require that the nucleic acid comprises a translation control element that comprises a 2A peptide that regulates translation of the Cas effector protein or the ACR protein.
Fremaux does not teach or suggest that the translational control element encodes one or more 2A peptides (Claim 23) selected from P2A and T2A (Claim 24). Fremaux does not teach or suggest that the translational control element encodes two or more 2A peptides in tandem (Claim 26). Fremaux does not teach or suggest the use of a promoter operably linked to the first nucleotide sequence, and the first nucleotide sequence is 5’ to the translational control element and the second nucleotide sequence (Claim 39).
However, one of ordinary skill in the art would have considered the teachings of Liu as both references are common fields of endeavor pertaining to the use of translational control elements.
Liu is drawn towards a study concerned with a systematic comparison of 2A peptides for cloning multi-genes in a polycistronic vector (Abstract). Liu teaches that utilizing a polycistronic or bi-cistronic vector allows for multigene co-expression in a target organism (pg. 1). Liu teaches the use of a bi-cistronic construct comprising a Mef2c gene and a GFP gene that are separated by two tandem P2A and T2A peptide sequences (pg. 3; see Figure 2A). Liu teaches that utilizing the tandem P2A and T2A peptide sequences in the bi-cistronic construct allowed for the highest efficiency of expression of the encoded genes (pg. 2, 4).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the method and composition of Fremaux such that the first nucleotide sequence was linked to a promoter and 5’ of two tandem P2A and T2A peptide sequences followed by the second nucleotide sequence, as described by Liu. A person of ordinary skill in the art would have been motivated to do so in order to allow for the co-expression of both the ACR protein and the Cas protein in a target cell of interest. A person of ordinary skill in the art would have had a reasonable expectation of success because Fremaux teaches that the ACR protein may be combined with other genes in a polycistronic vector comprising 2A peptides and Liu teaches that utilizing tandem 2A peptides to express two genes of interest was known in the art to be a method of efficiently expressing both genes in a target cell.
Claim(s) 28-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fremaux (PG Pub No. US 2020/0190492 A1, published 18 June 2020, filed 24 April 2018) as applied to claims 1-4, 43, 72, 77, and 79-80 above, and further in view of Kearse (Genes & development 31.17 (2017): 1717-1731).
Regarding claims 28-29, Fremaux anticipates claims 1-4, 43, 72, 77, and 79-80 as described above.
Fremaux does not teach or suggest that the translational control element is a non-AUG start codon selected from CUG (Claim 28). Fremaux does not teach or suggest that the non-AUG start codon is at the 5’ end and in-frame with the first nucleotide sequence and wherein the first nucleotide sequence does not comprise a native in-frame AUG start codon (Claim 29).
However, one of ordinary skill in the art would have considered the teachings of Kearse as both references are common fields of endeavor pertaining to the use of translational control elements.
Kearse is drawn towards a review study concerned with non-AUG translation (Abstract). Kearse teaches that ORFs comprising non-AUG start codons (i.e., the ORF is at the 5’ end and in-frame with non-AUG start codon and does not comprise a native AUG codon) are expressed in when there is elevated cell stress that results in the overproduction of eIF2A (pg. 1723-1724; see Figure 5). Kearse teaches that eIF2A can initiate translation at CUG codons (i.e., non-AUG start codons) (pg. 1723).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute modify the method and composition of Fremaux such that the translational control element is a CUG start codon that is in-frame with the second nucleotide sequence that does not comprise a native in-frame AUG start codon, as described by Kearse. A person of ordinary skill in the art would have been motivated to do so in order to allow for the expression of the ACR protein in the presence of elevated cell stress. A person of ordinary skill in the art would have had a reasonable expectation of success because Fremaux teaches that the ACR protein may be linked to a translational control element while Kearse teaches that CUG start codons were known translational control elements that could drive expression of in-frame ORFs in response to cell stress.
Claim(s) 36 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fremaux (PG Pub No. US 2020/0190492 A1, published 18 June 2020, filed 24 April 2018) as applied to claims 1-4, 43, 72, 77, and 79-80 above, and further in view of Dong (Biochemical and biophysical research communications 482.4 (2017): 889-895).
Regarding claim 36, Fremaux anticipates claims 1-4, 43, 72, 77, and 79-80 as described above.
Fremaux does not teach or suggest that a spacer encoding sequence is positioned 5’ of the first nucleotide sequence and is operably linked to the first promoter, wherein the translational control element is positioned between the spacer encoding sequence and the first nucleotide sequence (Claim 36).
However, one of ordinary skill in the art would have considered the teachings of Dong as both references are common fields of endeavor pertaining to the use of polycistronic vectors encoding CRISPR proteins.
Dong is directed towards a study concerned with polycistronic tRNA and CRISPR guide-RNA (Abstract). Dong teaches the use of a vector system encoding, 5’ to 3’, a promoter, a guide RNA scaffold (i.e., a spacer encoding sequence), a T2A (i.e., a translational control element), and a Cas9 (pg. 890; see Fig. 1). Dong teaches that the vector system allows for the expression of multiple sgRNAs in one construct using a single promoter that can be processed by an endogenous tRNA processing system (Abstract).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the nucleic acid encoding the Cas protein and guide nucleic acid of Fremaux for the vector system encoding a Cas protein and guide nucleic acid of Dong. A person of ordinary skill in the art would have been motivated to do so in order to express multiple guide RNA sequences that can be processed by the endogenous tRNA processing system. A person of ordinary skill in the art would have had a reasonable expectation of success because both Fremaux and Dong teach the use of nucleic acids encoding Cas9 proteins and guide RNA molecules.
Claim(s) 45 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fremaux (PG Pub No. US 2020/0190492 A1, published 18 June 2020, filed 24 April 2018) as applied to claims 1-4, 43, 72, 77, and 79-80 above, and further in view of Bondy-Denomy (PG Pub No. US 2020/0087354 A1, published 19 March 2020, filed 16 November 2017).
Regarding claim 45, Fremaux anticipates claims 1-4, 43, 72, 77, and 79-80 as described above.
Fremaux does not teach or suggest that the Acr protein is selected from the claimed SEQ ID NO: 32 (Claim 45).
However, one of ordinary skill in the art would have considered the teachings of Bondy-Denomy as both references are common fields of endeavor pertaining to the use of Acr proteins that can inhibit Cas9.
Bondy-Denomy is drawn towards an invention concerned with Cas9-inhibiting polypeptides (Abstract). Bondy-Denomy teaches the use of an Acr protein having 100% identity to the claimed SEQ ID NO: 32 that can inhibit Cas9 ([0040], [0185]; see SEQ ID NO: 1 in attached sequence alignments).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the ACR protein of Fremaux for an Acr protein having 100% identity to the claimed SEQ ID NO: 32, as described by Bondy-Denomy. A person of ordinary skill in the art would have had a reasonable expectation of success because both Fremaux and Bondy-Denomy teach the use of Acr proteins that can inhibit Cas9 activity.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636