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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claim(s) 1-16 in the reply filed on 06/29/2026 is acknowledged.
Claims 23-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-16 and 23-25 are pending.
Claims 1-16 are under examination on the merits.
Priority
This application 18/261,953 filed on 07/18/2023 is a 371 national phase of PCT/US22/12822 filed on 01/18/2022 and claims the benefit of provisional U.S. Patent Application No. 63/139,095, filed on 01/19/2021.
The priority date of claim 1 and its dependent claims is determined to be 01/19/2021, the filing date of provisional U.S. Patent Application No. 63/139,095.
Drawings
The drawings are objected to because nucleotide sequences appear in Figs. 2C, 3B, 4, and 5 without SEQ ID NOs. See Nucleotide Sequence Disclosure Objection below. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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. 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 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.
See sequences in Figs. 2C, 3B, 4, and 5.
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (p. 36). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The use of terms which are trade names or marks used in commerce (including NEW ENGLAND BIOLABS® and SYBR® Green among others), has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM, or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Interpretation
Claims 2, 4 and 6 recite the limitation “wherein at least a portion of the more than one crRNAs comprise”: “a Cas12a repeat sequence” (claim 2); ”a Cas13 repeat sequence” (claim 4); or “a Cas12a repeat sequence and --- comprise a Cas13 repeat sequence”(claim 6). Under the broadest reasonable interpretation, the limitations are interpreted as comprising the recited Cas repeat sequence if the repeat is recognized by the respective Cas protein.
Claim Rejections - 35 USC § 112(b)
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.
Claims 9-11 are 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.
Claim 9 recites the limitation “wherein the Cas13 protein comprises a Cas13d protein and a Cas13b protein”. There is insufficient antecedent basis for “the Cas13 protein” in the limitation. Neither claim 4 nor claim 1, which claim 9 depends from, recites a “Cas13 protein”.
Claims 10 and 11 recite the limitation “wherein the average length of the crRNA is ---“. There is insufficient antecedent basis for “the crRNA“. Claim 1, which claims 10 and 11 depend from, recite a “more than one CRISPR RNA (crRNA)” and “each of the more than one crRNAs”.
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, 2, 8, 10-11, and 15-16 is/are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Zetsche et al. (Multiplex gene editing by CRISPR–Cpf1 using a single crRNA array. 2017. Nat Biotechnol 35: p. 1-18 with supplemental material).
Regarding claim 1, Zetsche teaches CRISPR arrays comprising crRNAs comprising spacers separated by repeats (p. 1, col.1 and Fig. 1). Zetsche teaches arrays with guides as spacers, the guides targeting specific target nucleic acids (Fig. 2a). Zetsche further teaches sequences preceding the repeats (separators) (Figs. 1a and Supp. Fig. 4a, annotated below):
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194
237
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Regarding claim 2, Zetsche teaches a crRNA comprises Cpf1 (Cas12a) repeat sequence (Fig. 1).
Regarding claim 8, Zetsche teaches target nucleic acids comprise 4 different target nucleic acids (Fig. 2).
Regarding claim 10, Zetsche teaches individual crRNAs (repeat + spacer after pre-crRNA processing) comprising lengths of 65 nucleotides (Fig. 1B) , which reads on “the average length of the crRNA is about 30 to about 70 nucleotides”.
Regarding claim 11, Zetsche teaches individual crRNAs (repeat + spacer after pre-crRNA processing) comprising lengths of ~ 42 nucleotides (Fig. 1B), which reads on “the average length of the crRNA is about 50 nucleotides”.
Regarding claim 15, Zetsche teaches in vitro synthesis of arrays (p. 5, col. 1), which reads on a nucleic acid encoding the engineered multiplex CRISPR array.
Regarding claim 16, Zetsche teaches vectors comprising the nucleic acids comprising CRIPR arrays (Fig. 2f).
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.
Claims 1 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Zetsche et al. (Multiplex gene editing by CRISPR–Cpf1 using a single crRNA array. 2017. Nat Biotechnol 35: p. 1-18 with supplemental material).
The teachings of Zetsche as they relate to claim 1 are stated in the 102 rejection above in this office action
Regarding claim 12, Zetsche teaches a separator sequence that is AU rich (Supp Fig. S4), which reads on an AT-rich sequence. Zetsche further teaches a separator sequence that is 15 nucleotides in length (Supp Fig. S4) and does not teach the separator sequence is about 3 to about 8 nucleotides in length.
However, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Zetsche to arrive at the instantly claimed invention. Determining an appropriate separator sequence length is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claims 1, 3-7, 13 and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Zetsche et al. (Multiplex gene editing by CRISPR–Cpf1 using a single crRNA array. 2017. Nat Biotechnol 35: p. 1-18 with supplemental material) in view of Zhang et al. (US20190071717).
The teachings of Zetsche as they relate to claim 1 are stated in the 102 rejection above in this office action.
Regarding claim 3, Zetsche does not teach the engineered multiplex CRISPR array is capable of upregulating the expression of the plurality of target nucleic acids simultaneously.
Zhang teaches CRISPR systems including CRISPR arrays (for example fig. 96A) and the use of Cpf1 (cas12a) as the Cas protein (para 205, Fig. 96A). Zhang teaches a gene of interest may be upregulated (para 1049). Zhang teaches upregulation of a target may be used to regulate target expression in gain of function screens (para 861).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zetsche and Zhang to arrive at the instantly claimed invention. The modification would have entailed using the CRISPR array of Zetsche teaches to upregulate targets as taught by Zhang. One would have been motivated to select the target modulation (upregulation of Zhang) to expand control of target modifications, for example in the context of gain of function screens as taught by Zhang. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 4 and 5, Zetsche does not teach at least a portion of the more than one crRNAs comprise a Cas13 repeat sequence (claim 4) or the engineered multiplex CRISPR array is capable of downregulating the expression of the plurality of target nucleic acids simultaneously (claim 5).
Zhang teaches CRISPR systems including CRISPR arrays (for example fig. 96A) and the use of C2c2 (cas13a) as the Cas protein (para 205). Zhang further teaches a gene of interest may be downregulated (para 1049). Zhang teaches downregulation may be used in screening for functional elements (para 1049)
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zetsche and Zhang to arrive at the instantly claimed invention. The modification would have entailed using the CRISPR array of Zetsche teaches to downregulate targets as taught by Zhang. One would have been motivated to select the target modulation (downregulation of Zhang) to expand control of target modifications, for example in the screening for functional elements as taught by Zhang. One would have been motivated to expand the use of the CRISPR array of Zetsche. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 6 and 7, Zetsche does not teach at least a portion of the more than one crRNAs comprise a Cas12a repeat sequence and at least a portion of the more than one crRNAs comprise a Cas13 repeat sequence (claim 6) or wherein the engineered multiplex CRISPR array is capable of upregulating and downregulating the expression of the plurality of target nucleic acids simultaneously (claim 7).
Zhang teaches embodiments wherein the Type V/Type VI RNA-targeting Cas enzyme is Cpf1 (Cas12a)/C2c1/C2c2 (Cas13a) (para 205).
Zhang further teaches genes of interest may be upregulated or downregulated (para 1049).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zetsche and Zhang to arrive at the instantly claimed invention. The modification would have entailed substituting the Cas proteins of Zhang in the CRISPR array of Zetsche. Absent an unexpected result it would have been prima facie obvious to one of skill in the art at the time of the invention to modify the array of Zetsche wherein the Cas repeats of Zhang are used as the Cas proteins. The motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose (RNA editing and manipulation). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art. One would have been motivated by the expanded modification abilities gained by using two known Cas proteins and designing for two modes of modification or regulation. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Regarding claims 13 and 14, Zetsche does not teach the plurality of target nucleic acids are RNAs (claim 13) or the plurality of target nucleic acids are double-stranded DNAs (dsDNAs) (claim 14).
Regarding claim 13, Zhang teaches targets can be RNAs (199)
Zetsche teaches the CRISPR array targets DNA. Zetsche does not teach the DNA is dsDNA.
Regarding claim 14, Zhang teaches targets can be DNA (para 220) and guides that induce double-stranded breaks (para 421).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zetsche and Zhang to arrive at the instantly claimed invention. The modification would have entailed selecting the targets of Zhang as the targets of the Zetsche CRISPR array. One would have been motivated to take advantage of the repeat-spacer modularity of Zetsche (incorporating multiple guides to different targets) using the guidance of Zhang to expand the capability to specifically target RNAs or dsDNA breaks as desired. There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Zetsche et al. (Multiplex gene editing by CRISPR–Cpf1 using a single crRNA array. 2017. Nat Biotechnol 35: p. 1-18 with supplemental material) in view of Zhang et al. (US20190071717) as applied to claims 1, 3-7, 13 and 14 above, and further in view of Cheng et al. (US20190002875).
Regarding claim 9, neither Zetsche nor Zhang teach the Cas13 protein comprises a Cas13d protein and a Cas13b protein.
Cheng teaches engineered CRISPR systems, including CRISPR arrays (Fig. 1). Cheng further teaches Cas proteins Cas13a and Cas13d (paras 101, 308). Cheng teaches expanding the repertoire of Cas nucleases for RNA manipulation (para 308).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Zetsche and Zhang with Cheng to arrive at the instantly claimed invention. The modification would have entailed substituting the Cas proteins of Cheng in the CRISPR array of Zetsche and Zhang. Absent an unexpected result it would have been prima facie obvious to one of skill in the art at the time of the invention to modify the array of Zetsche and Zhang wherein the Cas repeats of Cheng are used as the Cas 13 proteins of Zhang. The motivation to combine arises from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose (RNA editing and manipulation). There would have been a reasonable expectation of success given the underlying materials and methods are widely known, successfully demonstrated, and commonly used as evidenced by the prior art.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JESSICA GRAY whose telephone number is (571)272-0116. The examiner can normally be reached Monday-Friday 8-5 with second Fridays off.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, WINSTON SHEN can be reached at (571)272-3157. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JESSICA GRAY/Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682
Prosecution Insights