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, claims 1-2, 4-6, 9-11, 14, and 41, and species election, target the BCLIIA enhancer DHS +58 (SEQ ID NO: 37-74) in the reply filed on 13 June 2025 is acknowledged. Claims 48-50, 53-54, 57-58, 68, 72, and 74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 13 June 2025.
Claim Status
Claims 48-50, 53-54, 57-58, 68, 72, and 74 are withdrawn, claims 3, 7-8, 12, 14-40, 42-47, 55-56, 59-67, 69-71, 73, and 75 were previously canceled, claims 2, 4, and 11 are newly canceled, and claims 1, 5-6, 9-10, 13, and 41 have been considered on their merits.
Removed Rejections
The claim rejections under 35 U.S.C. § 112(b) have been withdrawn due to Applicant’s
cancelling claims 2 and 11.
The claim rejections under 35 U.S.C. § 103 have been withdrawn due to Applicant’s amendments to the claims, however, a new rejection has been set forth below.
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.
Claims 1, 5-6, 9-10, 13, and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Cowan et al. (WO 2017/182881, published 26 October 2017, IDS ref.) and further in view of Gehrke et al. (Nature Biotechnology, published online 30 July 2018, of record) and Liang et al. (Protein & Cell, published 23 September 2017, of record).
This is a new rejection, necessitated by applicants’ amendments to the claims. A response to Applicant’s traversal follows the rejection below.
Regarding claims 1, 5-6, and 13, Cowan et al. teach ex vivo and in vivo methods of deleting, modulating, or inactivating a transcriptional control sequence of a BCL11A gene in a cell by genome editing for the treatment of hemoglobinopathies (Abstract). Cowan et al. teach the method can comprise introducing into the cell one or more polynucleotides encoding one or more DNA endonucleases, wherein, the polynucleotides can be modified polynucleotides, to include one or more nuclear localization signals (NLSs) (para. [0029]). Cowan et al. teach introducing to a cell guide ribonucleic acids (gRNAs), to include sgRNAs, modified sgRNAs, wherein the modified sgRNAs can comprise 2’-O-methyl-phosphorothioate (claim 6) residues at or near each of its 5’ and 3’ ends (claim 5) (para. [0030]). Cowan et al. teach the DNA endonucleases can be pre-complexed with one or more gRNA, sgRNA, or combinations thereof to form one or more ribonucleoproteins (RNPs) (para. [0030]). Cowan et al. teach SEQ ID NO: 23,151, which corresponds to instant SEQ ID NO: 56 with 100% identity (claim 1b) (see sequence results file us-17-764-413-56.rng, Result 1). Cowan et al. teach the gRNA spacer sequences for targeting within or near a BCL11A gene or other DNA sequence that encodes a regulatory element of the BCL11A gene with a CRISPR/Cas9 endonuclease have been identified, to include SEQ ID NO: 23,151 (para. [00347]). See alignments results below:
PNG
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164
626
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Greyscale
Cowan et al. teach the DNA endonucleases can be one or more Cas9 or Cpf1 endonucleases that effect one single-strand break (SSB) at a locus within or near the BCL11A gene or other DNA sequence that encodes a regulatory element of the BCL11A gene (para. [0032]). Cowan et al. teach the modified transcriptional control sequence can be located within a +58 DNA hypersensitive site (DHS) or the BCL11A gene (para. [0033]). Cowan et al. teach different patients with hemoglobinopathy will generally require different deletion, modulation, or inactivation strategies (para. [00347]).
Cowan et al. is silent to a base editor protein.
However, Gehrke et al. teach utilization of engineered CRISPR-Cas9 to direct cytidine deaminase enzymatic activity to specific genomic loci, specifically an engineered base editor 3 (BE3), eA3A-BE3 (claim 13), to correct a human β-thalassemia promoter mutation (Abstract).
Cowan et al. teach an active Cas9, however, it would have been reasonable to one of ordinary skill in the art to substitute an inactive Cas protein, such as the nCas9, because Gehrke et al. teach, the engineered nCas9 protein, A3A-BE3 base editor, was used to target an EGFP reporter gene in human cells using gRNA (Gehrke et al., p. 977).
Additionally, Liang et al. teach a method of correcting HBB -28 (A>G) mutation in primary skin fibroblast cells of a β-thalassemia patient by base editing (p. 814, 1st column).
Liang et al. disclose the combination of CRISPR/Cas9 and homology directed repair in human zygotes have low efficiency, off-target cleavage, and unintended homologous recombination are obstacles in clinical applications (p. 811, Introduction, 1st para.). Liang et al. suggest using base editors to directly repair point mutations may represent an efficient and highly specific alternative to CRISPR/Cas9 (p. 812, Introduction, 1st column).
Therefore, it would have been obvious to one of ordinary skill in the art to utilize the base editor protein of Gehrke et al. in view of Liang et al. with the RNP comprising the nucleic acid sequence, SEQ ID NO: 23,151, with at least one chemical modification to a nucleotide of Cowan et al. with a reasonable expectation of success because the sgRNA would direct the base editor in the same manner as the active Cas9. One would have been motivated to utilize the base editor of Gehrke et al. in view of Liang et al. with the RNP of Cowan et al. because Liang et al. teach base editing is more efficient than active Cas9.
Regarding claims 9 and 10, Cowan et al. teach the site-directed polypeptide can be pre-complexed with one or more genome-targeting nucleic acids, to include, guide RNA, sgRNA, or crRNA together with a tracrRNA (claim 9 and 10) (para. [00417]).
Regarding claim 41, the teachings of Cowan et al. in view of Gehrke et al. and Liang et al. read as a composition comprising the RNP complex of claim 1.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention.
Response to Traversal
Applicant’s arguments, see pp. 6-7, filed 29 October 2025, with respect to the rejection(s) of claim(s) 1, 2, 4-6, 9-11, 13, and 41 under 35 U.S.C. § 103 have been fully considered and are persuasive, because Applicant amended claim 1 to remove the previously cited sequence. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Cowan et al.
Applicant argues none of the previously cited references teach or suggest use of the specific sequences in the amended claims, therefore, Cowan et al. has been identified as teaching instant SEQ ID NO: 56. Therefore, the cited references teach and/or suggest use of the specific sequences and teach every element of the pending claims.
Conclusion
No claims are allowed.
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). Applicant is 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.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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