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 .
Applicant’s cancellation of claims 69-70, 72-73, amendment of claims 68 and 77, in the paper of 7/13/2026, is acknowledged. Applicants' arguments filed on 7/13/2026, have been fully considered and are deemed to be persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Claims 68, 71, 74-77, 80-82, 95-101 are still at issue and are present for examination.
Applicants attention is directed to the proper method of amending the claims as per MPEP 714, 37 CFR 1.121 Manner of making amendments in application. Applicants attention is directed to the claim 68 which appears to use underlining AND strike-through.
37 CFR 1.121 Manner of making amendments in applications
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters.
As per the above, applicants amendment of claim 68 which includes “underlined” and “strike-through” text (e.g. “ is noncompliant. In the interest of advancing prosecution the above text is interpreted as not existing.
Please use proper markings in all future amendments. This is required to clarify the record and prosecution and avoid issues that result from a lack of clarity of the record and prosecution.
Election/Restriction
Applicant’s election with traverse of the claims of Group I, claims 68-73, 75, 76, 95-101, drawn to an altered cytidine deaminase, in the paper of 3/6/3026 is acknowledged.
Claims 74, 77, 80-82 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claim Rejections - 35 USC § 112
The rejection of claim(s) 68-73, 75, 76 and 95-101 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention is withdrawn based upon applicants amendment of the claims and applicants arguments presented in the paper of 7/13/2026.
The rejection of claim(s) 68-73, 75, 76 and 95-101 under 35 U.S.C. 112, first paragraph, based on a lack of scope of enablement is withdrawn based upon applicants amendment of the claims and applicants arguments presented in the paper of 7/13/2026.
Claim Rejections - 35 USC § 103
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 rejection of claims 68-73, 75, 76, 95-101 under 35 U.S.C. 103 as being unpatentable over Chen et al. (US 2021/163913) and Univ Shangai Tech (WO 2019/042284) based upon applicants amendment of the claims and applicants arguments in the paper of 7/13/2026. Specifically as argued by applicants, Modification of the tyrosine residue at position 130 to alanine (Y130A) consistently resulted in an APOBEC protein with no activity (see FIG. 6c of Bulliard et al., 2011, J Virol., 85(4): 1765-1776, and FIG. 5a of Shi et al., 2017, Nat Struct Mol Biol., 24(2): 131-139).
Claims 68, 71, 75, 76, 95-101 is/are rejected under 35 U.S.C. 103 as being unpatentable over Joung and Gehrke (US 11,326,157 and US 20200172885), Chen et al. (US 2021/163913) and Univ Shangai Tech (WO 2019/042284).
Joung and Gehrke (US 11,326,157) disclose methods and compositions for improving the genome-wide specificities of targeted base editing technologies. Joung and Gehrke teach base Editors (BEs) that include a single strand nicking CRISPR-Cas9 (nCas9) protein fused to a cytidine deaminase domain. The taught cytidine deaminase domains include variants of a number of cytidine deaminases including hAPOBEC3A of SEQ ID NO:57 ( SEQ ID NO:57 of Joung and Gehrke is 100% identical to instant SEQ ID NO:3) comprising a mutation at one or more positions including Y130 (see Table 7 and supporting text). Joung and Gehrke teach a number of fusion proteins comprising a Cas9-like nickase (nCas9) linked to an engineered variant human apolipoprotein B mRNA editing enzyme catalytic subunit 3A (hAPOBEC3A) deaminase, wherein the engineered variant hAPOBEC3A deaminase has at least 85% sequence identity to SEQ ID NO:57 and comprises one or more mutations selected from R28 to A, E, or Q; K30 to A, E, Q, N, R, D, H, or S; N57 to A, G, D, E, K, Q, or 8; K60 to A, D, E, N, or Q; W98Y; Y130A; or D131 to R, K, N, Q, H, or S of SEQ ID NO:57. Joung and Gehrke teach that that the Y130A mutation enhances the sequence specificity of cytidine deaminase proteins by affecting the protein:substrate interaction interface (see Table 7 and supporting text). . Joung and Gehrke teach a number of fusion proteins comprising a Cas9-like nickase (nCas9) linked to an engineered variant human apolipoprotein B mRNA editing enzyme catalytic subunit 3A (hAPOBEC3A) deaminase, wherein the engineered variant hAPOBEC3A deaminase has at least 85% sequence identity to SEQ ID NO:57 and comprises one or more mutations comprising Y130A; and D131 to R, K, N, Q, H, or S of SEQ ID NO:57 (see claim 18 and supporting text).
Chen et al. (US 2021/163913) teach a fusion protein comprising an APOBEC3A protein and a Cas protein. The APOBEC3 may be a mutant, comprising amino acid substitutions at Y130 and Y132. Examples of combinatory mutations include Y130F+D131E+Y132D, Y130F+D131Y+Y132D, Y130E-D131E-Y132D, and Y130E-D131Y-Y132D (see claims 1, 4, 5 and paragraph 0084). Chen et al. further teach the above APOBEC3 substitution mutants in the SEQ ID NO:16 and SEQ ID NO:40 which are 100% identical to instant SEQ ID NO:3. Chen et al. further teach the use of the above APOBEC3 mutant fusion proteins in methods of editing a target polynucleotide including the use of the mutant APOBEC3 mutant in a composition comprising a DNA comprising a 5-methyl cytosine.
Univ Shangai Tech (WO 2019/042284) teach fusion proteins comprising a cytidine deaminase such as APOBEC3A and a catalytically active Cpf1. The APOBEC3A may have one or more mutations, examples including Y130F-D131E-Y132D, Y130F-D131Y-Y132D (see paragraph 0051 and 0072).
One of skill in the art before the effective filing date of the invention would have been motivated to combine the teachings and methods of Joung and Gehrke, Chen et al. and Univ Shangai Tech to create additional substitutions at positions Y130, D131 and Y132 of APOBEC3A to create additional creatine deaminases with altered properties since positions 130-132 were known determinators of enzyme specificity and activity. Included in these mutations is Y130A, as taught by Joung and Gehrke and additional substitutions such as Y132R (Arg) and Y132H (His) since like Y132D as taught by both Chen et al. and Univ Shangai Tech, Y132R and Y132H are substitutions with an amino acid with a similar hydrophilic side group (D versus R and D versus H). It would be further obvious to screen such obvious double mutants for favorable activities and use them in the methods of editing taught by both Joung and Gehrke and Chen et al.. The functional limitations of claims 95-97 are considered inherent to the obvious cytidine deaminase mutants based upon the high degree of sequence identity of the obvious cytidine deaminase mutants. The expectation of success is high based upon the high level of expertise in the art as illustrated by Joung and Gehrke, Chen et al. and Univ Shangai Tech who teach all methodology and substrates required to create the obvious mutants.
Applicants comments in the prior office action regarding the teaching of Bulliard et al., 2011, J Virol., 85(4): 1765-1776, and Shi et al., 2017, Nat Struct Mol Biol., 24(2): 131-139) regarding the activity of the Y130A mutation are acknowledged, however, not found persuasive in overcoming the teachings of Joung and Gehrke, Chen et al. and Univ Shangai Tech and those mutations that are obvious over such.
Thus, claims 68-73, 75, 76, 95-101 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chen et al. (US 2021/163913) and Univ Shangai Tech (WO 2019/042284).
Remarks
No claim is allowed.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicants are reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached on 6-3 EST Mon-Fri.
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rgh
9/1/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
Prosecution Insights