DETAILED ACTION
Notice of 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 with partial traverse of Group I, claims 1, 4-5, 7, 11-13, 15, 17-19, 21, 25, 31, 35-37 and 40 in the reply filed on 04 March 2026 is acknowledged. The traversal is on the ground(s) that the kit claim of Group III has the same three subsections utilized in the method claims of Group III. This is not found persuasive because additional search and consideration is required for two Groups, placing an undue examination burden upon the Examiner.
The requirement is still deemed proper and is therefore made FINAL.
Status of Application
Claims 1, 4-5, 7, 11-13, 15, 17-19, 21, 25, 31, 35-37 and 44 are pending; Claim 44 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter, there being no allowable generic or linking claim. Thus, claims 1, 4-5, 7, 11-13, 15, 17-19, 21, 25, 31, 35-37 and 40 are subject to examination on the merits.
Priority
The instant application is a 371 of PCT/GB22/50004 filed 05 January 2022 which claims benefit of US Provisional applications 63133942 and 63133942, both filed 05 January 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 17 December 2025, 11 July 2023 (x2) and 10 July 2023 (x2) have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on p. 35, line 5. 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.
Compliance with Sequence Rules
The sequence listing, filed in computer readable form (.txt) on 05 July 2023, has been received and entered. This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to fully comply with the requirements of 37 C.F.R. § 1.821 through 1.825.
The following Figures/parts of the specification contain sequences that contain four or more specifically defined amino acids or ten or more specifically defined nucleotides without any corresponding SEQ ID NO: and/or no reference to any SEQ ID NO: in the Brief Description of the Drawings.
In Figure 1, a polynucleotide sequence having 10 or more specifically defined nucleotides is disclosed.
In Figure 5, a polynucleotide sequence having 10 or more specifically defined nucleotides is disclosed.
* If the noted sequences are in the sequence listing as filed, Applicants must amend the specification to identify the sequences appropriately by SEQ ID NO:. If the noted sequences are not in the sequence listing as filed, Applicants must provide (1) an updated copy of the sequence listing containing the requisite sequences in computer readable form (.txt), (2) an amendment directing its entry into the specification, (3) a statement that no new matter has been added and (4) an amendment to the specification to identify the identified sequences by SEQ ID NO:, which can be in the Brief Description of the Drawings section of the specification and (5) an updated incorporation by reference statement with the new date of creation, sequence file name and size. – See also MPEP 2422.
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, 4-5, 12-13, 17-19, 21, 31, 35-37 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Jin and Collantes (WO 2018/129129 – cited on IDS 07/11/2023; hereafter Jin).
Jin teaches:
Regarding claims 1, 5, 18-19, 31, 35-36,
A method of genetically modifying a cell comprising transforming said cell with a two different systems which can edit one or more locations within a locus, comprising:
The first system comprises: (i) a first sequence-targeting, single-strand DNA
(ssDNA) nicking protein (STP), (ii) a first RNA scaffold comprising: (a) a first nucleic acid-targeting motif comprising a first guide RNA sequence that is complementary to a first target nucleic acid sequence in the target DNA, (b) a first CRISPR motif capable of binding to the first sequence-targeting protein, and (c) a first recruiting RNA motif, and (iii) a first non-nuclease effector fusion protein, comprising: (a) a first RNA binding domain capable of binding to the first recruiting RNA motif, (b) a first linker, and (c) a first effector domain. The first non-nuclease effector fusion protein has an enzymatic activity.
The second system comprises (i) a second sequence-targeting, ssDNA nicking protein for targeting a second target nucleic acid sequence in the target DNA. This sequence-targeting, ssDNA nicking protein can be the same as the one in the first system – Said second system specifically comprises one of three options:
Option A: the second system comprises (ii) a second RNA scaffold comprising: (a) a second nucleic acid-targeting motif comprising a second guide RNA sequence that is complementary to a second target nucleic acid sequence in the target DNA, (b) a second CRISPR motif capable of binding to the second sequence- targeting protein, and (c) a second recruiting RNA motif, and (iii) a second non-nuclease effector fusion protein, comprising: (a) a second RNA binding domain capable of binding to the second recruiting RNA motif, (b) a second linker, and (c) a second effector domain. The second recruiting RNA motif in (ii) and all components in (iii) can be the same as, or can be different from the components the first system. The second effector fusion protein may or may not have enzymatic activity.
Option B: the second system comprises (ii) a second RNA scaffold comprising (a) a second nucleic acid-targeting motif comprising a second guide RNA sequence that is complementary to a second target nucleic acid sequence in the target DNA and (b) a second CRISPR motif capable of binding to the second sequence- targeting protein. Preferably, the second RNA scaffold does not have a recruiting RNA motif so that no effector protein is recruited to the second target nucleic acid sequence.
Option C: the second system further comprises (ii) a second RNA scaffold comprising: (a) a second nucleic acid-targeting motif comprising a second guide RNA sequence that is complementary to a second target nucleic acid sequence in the target DNA, (b) a second CRISPR motif capable of binding to the second sequence- targeting protein, and (c) a second recruiting RNA motif, and (iii) a local DNA repair inhibitor fusion protein, comprising: (a) a second RNA binding domain capable of binding to the second recruiting RNA motif, (b) a second linker, and (c) a local DNA repair inhibitor domain. See p. 2 , line 19 to p. 4, line 10; p. 5, line 11-24; Claims 1-4.
Specific examples comprise: The first system having: (i) dCas9 from S. pyogenes as the sequence targeting protein, (ii) a RNA scaffold containing a guide RNA sequence, a CRISPR RNA motif, and a MS2 operator motif, and (iii) an effector fusion containing a human AID fusing to MS2 operator binding protein MCP
Regarding claims 4 and 12-13, the sequence targeting protein is a dCas9 or nCas9 enzyme, wherein Cas9 enzymes are Type II Cas proteins – See p. 11-19.
Regarding claim 21, the effector protein can comprise deamination activity, cytidine or adenosine specifically – See p. 4, line 30 to p.5, line 7; claim 13.
Regarding claim 35, the RNA-ligand binding motif comprises a single RNA molecule which will necessarily result in the ligand binding motif either: 3’, 5’ or within the gRNA (See p. 22, line 12).
Regarding claim 17 and 37, the RNA motif and RNA binding domain pairs are selected from: telomerase Ku binding motif and Ku protein or a RNA-binding section thereof, a telomerase Sm7 binding motif and Sm7 protein or a RNA-binding section thereof, a MS2 phage operator stem-loop and MS2 coat protein (MCP) or a RNA-binding section thereof, a PP7 phage operator stem-loop and PP7 coat protein (PCP) or a RNA-binding section thereof, a SfMu phage Com stem- loop and Com RNA binding protein or a RNA-binding section thereof, and a non-natural RNA aptamer and corresponding aptamer ligand or a RNA-binding section thereof – See p. 4 line 20-28; Claim 9.
Finally, given there is nothing in the claims that the method utilizes a single editing system, then the dual system of Jin is taken as anticipatory.
Claim(s) 1, 4-5, 7, 11-13, 15, 17-19, 21, 25, 31, 35-37 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Kim, Y (US 2021/0130827 – cited herein; published May 6, 2021; with an effectively filed date of October 30, 2019).
Kim teaches:
Regarding claims 1, 4, 5, 7, 12, 17-18, 25, 31 a method for genetically modifying a cell comprising base editing with a system comprising contacting a target nucleic acid with:
(a) a Type V Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated (Cas) (CRISPR-Cas) targeting effector protein;
(b) a deaminase, optionally wherein the target nucleic acid is contacted with two or more deaminases; and
(c) a guide nucleic acid, wherein the deaminase is recruited to the Type V CRISPR-Cas effector protein, thereby modifying the target nucleic acid, optionally wherein the Type V CRISPR-Cas effector protein, the deaminase and guide nucleic acid are co-expressed (See Claim 1). In addition, said system further stipulates:
wherein the guide nucleic acid is a recruiting guide nucleic acid comprising a guide RNA linked to an RNA recruiting motif, and
wherein the deaminase is a deaminase fusion protein comprising a deaminase fused to an affinity polypeptide that binds to the RNA recruiting motif (See claim 4);
It is further taught said recruiting guide nucleic acid is linked to two or more RNA recruiting motifs (See Claim 9); and wherein,
Regarding claims 17 and 37, the RNA recruiting motif is a telomerase Ku binding motif and the affinity polypeptide is a Ku polypeptide; the RNA recruiting motif is a telomerase Sm7 binding motif and the affinity polypeptide is a Sm7 polypeptide; the RNA recruiting motif is an MS2 phage operator stem-loop and the affinity polypeptide is a MS2 Coat Protein (MCP); the RNA recruiting motif is a PP7 phage operator stem-loop and the affinity polypeptide is a PP7 Coat Protein (PCP); the RNA recruiting motif is an SfMu phage Com stem-loop and the affinity polypeptide is a Com RNA binding protein; the RNA recruiting motif is a Pumilio/fem-3 mRNA binding factor (PUF) and the affinity polypeptide is a PUF binding site (PBS) polypeptide; and/or the RNA recruiting motif is a synthetic RNA-aptamer and the affinity polypeptide is the corresponding aptamer ligand (See claim 10; paragraph 0118).
Here, the deaminase is the same as the instant “effector domain” and the Type V Cas enzyme is the same as the instant “sequence targeting protein”
Regarding claim 11, said Type V Cas protein is fused to a protein of interest, specifically a uracil glycosylase inhibitor (See claims 28-29; paragraph 0113).
Regarding claim 15, said Type V targeting sequence comprises a Cas protein comprising a nuclease active site mutation rendering it either as a nickase or dead (See claims 11, 31-32; paragraph 0099-0101).
Regarding claims 18 and 21, said method comprises contacting with two or more deaminases which have the same or different functions (See claim 13) and said deaminase is a cytosine or adenine deaminase (See claim 12).
Regarding claims 31 and 35, the RNA-ligand binding motif can comprise a single RNA molecule which will necessarily result in the ligand binding motif either: 3’, 5’ or within the gRNA (See paragraph 0093).
Reference of Interest – Not Relied Upon
Li et al., “SWISS: multiplexed orthogonal genome editing in plants with a Cas9 nickase and engineered CRISPR RNA scaffolds”, Genome Biology, 2020, 21:141. Li et al. teach: “…a CRISPR simultaneous and wide-editing induced by a single system (SWISS), in which RNA aptamers engineered in crRNA scaffold recruit their cognate binding proteins fused with cytidine deaminase and adenosine deaminase to Cas9 nickase target sites to generate multiplexed base editing. By using paired sgRNAs, SWISS can produce insertions/deletions in addition to base editing.” (Abstract).
Conclusion
Claims 1, 4-5, 7, 11-13, 15, 17-19, 21, 25, 31, 35-37 are rejected. Claim 40 is 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUZANNE M NOAKES whose telephone number is (571)272-2924. The examiner can normally be reached M-F (7-4).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Manjunath Rao can be reached at 571-272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SUZANNE M NOAKES/Primary Examiner, Art Unit 1656
08 April 2026