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 on 7/7/2026. Claims 1-6, 8-13, 23, and 34-40 are pending. All pending claims are currently under examination.
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’s electronic filing system (see Section I.1 of the Legal Framework for EFS-Web or Patent Center (https://www.uspto.gov/patents-application- process/filing-online/legal-framework-efs-web), 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 EFS-Web or Patent Center 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 EFS-Web or Patent Center 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 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.
Figures 12, 14, 22, 26, 29, and 30 contain nucleotide sequences that are not identified by sequence identifiers (i.e., SEQ ID NOs) in the drawings or in the brief description of the drawings. Drawings containing nucleotide sequences must be accompanied with their proper SEQ ID numbers, either in the drawings themselves or in the brief description of the drawings in the specification. For instance, the brief description of Figure 12 does not include SEQ ID NOs for the sequences listed in Figure 12. Additionally, SEQ ID numbers of the sequences shown in Figure 12 are not shown in the figure itself. The remaining figures listed above have similar deficiencies, wherein the figures contain nucleotide sequences that are not identified with SEQ ID numbers and have no corresponding SEQ ID numbers recited in the brief description of said figures.
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 § 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.
Claims 1-5, 8-13, 23, and 34-40 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Shilobeth (WO 2021/084533, published 5/6/2021). The rejection is further evidenced by Grover (Grover A et al. Syst Synth Biol. 2010 Dec;4(4):323-9).
Regarding claim 1, Shibioleth teaches a nucleoprotein complex comprising a targeting nucleic acid and a modular polypeptide component (see Figure 2 and page 2, second paragraph). Shilobeth teaches that the targeting nucleic acid comprises a targeting nucleic acid element that is complementary to a target nucleic acid sequence (“sgRNA,” Figure 2, page 9 second paragraph, and page 16 final two paragraphs). Shilobeth teaches that the sgRNA comprises a tracrRNA which is a scaffold region that interacts with the modular polypeptide component, and therefore teaches that the targeting nucleic acid comprises a recognition element (“tracrRNA” of the sgRNA molecules) which interacts with a nucleic acid recognition module of the modular polypeptide (page 16, final two paragraphs describing tracRNA/sgRNA structure, Figure 2, page 9 second paragraph).
Shiboleth teaches that the modular polypeptide component comprises a dsDNA binding domain (“NSDB”, Figure 2, page 9, second paragraph). Regarding the non-sequence specific DNA binding domain, Shilobeth teaches that the non-sequence specific DNA binding domain (NSDB) can also be a sequence-specific DNA binding domain which recognizes dsDNA, including zinc finger domains and RVDs which recognize specific sequences of DNA (see page 26, paragraphs 4-6, which teaches that the non-sequence specific NSDB can also in fact be sequence-specific DNA binding domains which recognize predetermined sequences). Furthermore, Shilobeth also teaches that the nucleoprotein comprises an effector domain for modifying a target DNA (“FokI nuclease monomer,” page 9, second paragraph).
Shilobeth therefore teaches each of the elements of claim 1, where the practitioner can immediately envision the recited invention of claim 1 given that Shilobeth teaches each of the presently recited components of the invention configured in a nucleoprotein complex as taught in Figure 2 (and see page 9, second paragraph).
Regarding claim 2, Shilobeth teaches that the DBD and dCas9 are linked, where furthermore the dCas9 is linked with the effector domain (Figure 2, page 9 second paragraph). Thus, the DBD and effector are linked via amino acids. Furthermore, Shilobeth teaches that the chimeric protein orientation can be arranged as “dScCas9-FokI-ZF1,” and therefore teaches that the DBD (Zinc Finger 1, ZF1) can be directly linked with the effector (i.e., FokI, see page 45, final paragraph). Shilobeth further teaches that the chimeric fusion elements can be linked together (page 60, fourth paragraph). Thus, the practitioner can immediately envision the present claim limitations, where embodiments of the present orientation are taught by Shilobeth who also teaches that such components can be linked via linkers (above).
Regarding claim 3, Shilobeth teaches that the TE is RNA (“sgRNA,” Figure 2, page 9, second paragraph).
Regarding claim 4, Shilobeth teaches that the sgRNA comprises an RNA scaffold to which the modular polypeptide/dCas interacts with and binds (e.g., page 16, third paragraph).
Regarding claim 5, Shilobeth teaches that the targeting element and recognition elements are bound together via a sequence (i.e., the sgRNA is taught to be the synthetic fusion via a sequence of the targeting crRNA and recognition tracrRNA elements, page 16, third paragraph).
Regarding claim 8, Shilobeth teaches that the DBD can be fewer than 75 amino acids in length (e.g., zinc fingers which are 24 residues in length, page 26, second to last paragraph).
Regarding claims 9-10, Shilobeth teaches that the zinc fingers can be Cys2His2 (C2H2 zinc finger domains) finger domains (page 26, second to last paragraph). As evidenced by Grover, C2H2 zinc finger domains are 30 or fewer amino acids in length and recognize specific DNA sequences which are 3 bases in length (page 324, left column). Shilobeth therefore inherently teaches that zinc fingers which are fewer than 30 amino acids in length and recognize DNA triplets by teaching C2H2 zinc finger domains as evidenced by Grover (above).
Regarding claim 11, Shilobeth teaches that the zinc fingers can comprise broad sequence specificity, and therefore teaches that the DBD is capable of binding more than one predetermined sequence (page 26, second to last paragraph).
Regarding claim 12, Shilobeth teaches that the modular polypeptide comprises an NLS (Figure 2, page 9 second paragraph).
Regarding claim 13, Shilobeth teaches that the effector is FokI nuclease (Figure 2, page 9 second paragraph).
Regarding claim 23, Shilobeth teaches that the modular polypeptide component can further comprise fusion effector domains, where the effector can be a transcription activator (page 59, paragraphs 3-4).
Regarding claims 34-35, Shilobeth teaches that the DBD and effector are separate modules, where furthermore the DBD is linked to a dCas protein which is linked with the effector via a linker (Figure 2, page 9 second paragraph). Thus, the DBD and effector are linked via amino acids (i..e, the dCas protein and amino acid linker, Figure 2, page 9, second paragraph). Furthermore, Shilobeth teaches that the orientation of the chimeric fusion linked proteins can be for instance dScCas9-FokI-ZF1 (page 45, final paragraph). Furthermore, Shilobeth teaches that the general components of the fusion constructs are linked via linkers (e.g., page 60, fourth paragraph). Thus, a practitioner could at once envision linking the components using linkers.
Regarding claim 36, Shilobeth teaches that the DBD, dCas9, and effector are linked together via amino acids, as each of these components are proteins comprising amino acids which are linked together (Figure 9, page 9 second paragraph). Furthermore, Shilobeth teaches that the DBD is linked with the Cas enzyme, which binds with the targeting nucleic acid molecule (sgRNA, Figure 2). Thus, the DBD is linked via amino acid (i.e., the Cas protein) with the targeting nucleic acid (sgRNA, Figure 2).
Regarding claim 37, Shilobeth teaches that the nucleic acid recognition module is a dead Cas enzyme, and is therefore devoid of enzymatic activity (Figure 2, “dCas”).
Regarding claims 38-39, Shilobeth teaches that the DBD can be for instance a zinc finger which is 24 residues in length (page 26, paragraphs 4-5).
Regarding claim 40, Shilobeth teaches the FokI nuclease as an effector (Figure 2, page 9 second paragraph). Furthermore, the specification recites that, with regards to the phrase “devoid of target binding ability,” such an effector can still comprise “some target, e.g., DNA, recognition activity,” (specification, page 5, fifth paragraph) Thus, the FokI effector taught by Shilobeth broadly reads on claim 40, as this is also an “effector” as defined in the specification to fulfill such requirements (page 5, paragraph 7).
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 6 is rejected under 35 U.S.C. 103 as being unpatentable over Shilobeth (WO 2021/084533 A1, published May 2021) as applied to claims 1-5, 8-13, 23, and 34-40 above, and further in view of Zalatan (Zalatan JG et al. Cell. 2015 Jan 15;160(1-2):339-50).
Regarding claims 1-5, 8-13, 23, and 34-40, as discussion of these claims is given above in the 102 rejection and incorporated here.
Shilobeth anticipates the claim limitations of claims 1-5. Furthermore, Shilobeth teaches that their constructs are modular, and can therefore be adapted and changed to suit different DNA targeting strategies (page 72, fourth paragraph). Shilobeth teaches that gRNA comprise RNA motifs which can bind with and recruit proteins such as the tracrRNA motif (page 16, final two paragraphs). Shilobeth further teaches additional recognition regions/RNA-protein binding motifs, such as the MS2 RNA binding motif and RNA recognition motif (RRM) domains (page 77, final paragraph). Additionally, Shilobeth teaches that effectors of their constructs can be transcriptional activators and/or repressors (e.g., page 26, fourth paragraph, page 59 paragraphs 4-5, and page 156 first paragraph).
Shilobeth, while teaching the concept of recognition elements such as RNA scaffold binding motifs, and teaches that the targeting nucleic acid comprises one recognition element, does not teach that the targeting nucleic acid comprises two recognition elements.
Zalatan is a research article which focuses on uses of gRNA scaffolding to recruit effector domains to specific genetic loci to affect gene expression (Title, Abstract, and throughout). Thus, Zalatan and Shilobeth directly overlap in subject matter and filed of endeavor because both teach the goals and inventive concepts of using gRNA with RNA scaffolds to recruit effector domains to specific target sites. Furthermore, similar to Shilobeth, Zalatan teaches that transcriptional activators and repressor can be coupled with RNA scaffolds in order to recruit such effectors to a desired location within a target genome (e.g., Abstract, see Figure 1). Furthermore, Zalatan teaches that such RNA scaffolds (i.e., recognition elements which are fused with the targeting element or gRNA) can be used in the context of recruiting two different effectors (e.g., Figure 1A and Graphical Abstract). Thus, Zalatan teaches that the concept of using targeting elements comprising two recognition elements (RNA scaffolds) is a known technique in order to recruit desired effector proteins to a site, where such effectors can be effectors such as activators or repressors (Figure 1, Graphical Abstract). Furthermore, Zalatan teaches that “CRISPR-associated RNA scaffolds provide a powerful way to construct synthetic gene expression programs for a wide range of applications, including rewiring cell fates or engineering metabolic pathways,” (Abstract). Thus, Zalatan teaches that their constructs are a useful, powerful tool with a broad range of biotechnology applications, where a practitioner would be motivated to adopt such recruitment strategies of multiple effectors using two or more recognition elements depending on a desired gene regulation or modification goal (Zalatan Abstract, graphical abstract, Figure 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the modular nucleoprotein complexes taught by Shiboleth to include multiple recognition elements/RNA scaffolds as taught by Zalatan because such a combination is the simple combination of known prior art elements with predictable results. In the present case, Zalatan has already taught the inventive concept of targeting elements (gRNA) comprising two recognition elements, where furthermore Zalatan teaches that such constructs are useful and broadly applicable in order that a practitioner can recruit multiple effector proteins to the same location for a desired outcome. Furthermore, the result is predictable because both Zalatan and Shilobeth teach the same effector proteins (i.e., activators and repressors) and also teach similar molecular tools to be used in such nucleoprotein complexes (i.e., fusion RNA molecules with scaffold recognition domains and dCas9).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOUGLAS CHARLES RYAN whose telephone number is (571)272-8406. The examiner can normally be reached M-F 8AM - 5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ram Shukla can be reached at (571)-272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/D.C.R./Examiner, Art Unit 1635
/RAM R SHUKLA/Supervisory Patent Examiner, Art Unit 1635
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