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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 27 May 2026 has been entered.
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 was previously 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 Claims 48-50, 53-54, 57-58, 68, 72, and 74 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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Claims 48-50, 53-54, 57-58, 68, 72, and 74 are withdrawn, claims 2-4, 7-8, 11-12, 14-40, 42-47, 51-52, 55-56, 59-67, 69-71, 73, and 75 were previously canceled, and claims 1, 5-6, 9-10, 13, and 41 have been considered on their merits.
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., of record) 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 rejection is repeated with regard to claims 1, 5-6, 9-10, 13, and 41 for the same reasons of record as set forth in the Official action mailed 28 November 2025. A response to Applicant' s traversal follows the reiterated rejection below.
Regarding claims 1, 5-6, and 13, Cowan teaches 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 teaches 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 teaches 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 teaches 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 teaches 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 teaches 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:
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164
626
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Greyscale
Cowan teaches 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 teaches the modified transcriptional control sequence can be located within a +58 DNA hypersensitive site (DHS) or the BCL11A gene (para. [0033]). Cowan teaches different patients with hemoglobinopathy will generally require different deletion, modulation, or inactivation strategies (para. [00347]).
Cowan is silent to a base editor protein.
However, Gehrke teaches 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 teaches 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 teaches, the engineered nCas9 protein, A3A-BE3 base editor, was used to target an EGFP reporter gene in human cells using gRNA (Gehrke, p. 977).
Additionally, Liang teaches 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 discloses 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 suggests 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 in view of Liang with the RNP comprising the nucleic acid sequence, SEQ ID NO: 23,151, with at least one chemical modification to a nucleotide of Cowan 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 in view of Liang with the RNP of Cowan because Liang teaches base editing is more efficient than active Cas9.
Regarding claims 9 and 10, Cowan teaches 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 in view of Gehrke and Liang 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 filed 27 May 2026 have been fully considered but they are not persuasive.
The arguments found starting on page 6 of the remarks are directed to the sequence of Cowan being included within a vast list of sequences and the presence of the sequence does not establish a person of ordinary skill in the art would have a reason to select that particular sequence. This argument is not persuasive because Cowan is the primary reference and the starting point is the sequence. The thrust of the rejection is not pertaining to selecting the sequence, the rejection is directed to the obviousness of using the base editor with the RNP complex comprising the disclosed sequence. The sequence is not novel in light of Cowan, there is no established motivation to select the particular sequence because the sequence is what the primary reference teaches.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Applicant asserts the Office is not permitted to select Applicant’s specific guide sequence from Cowan’s disclosure without identifying some teaching, suggestion, motivation, property, etc. that would have directed a skilled artisan to that specific sequence. This is not persuasive because Cowan is the teaching.
In response to Applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case it was established, in the rejection above, it would have been obvious to one of ordinary skill in the art to utilize the base editor protein of Gehrke in view of Liang with the RNP comprising the nucleic acid sequence, SEQ ID NO: 23,151, with at least one chemical modification to a nucleotide of Cowan 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 in view of Liang with the RNP of Cowan because Liang teaches base editing is more efficient than active Cas9.
Additionally, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Conclusion
No claims are allowed.
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/N.A.H./Examiner, Art Unit 1631
/LAURA SCHUBERG/Primary Examiner, Art Unit 1631
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