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 .
Allowable Subject Matter
The Amendments and Remarks filed 01 July 2026 in response to the Office Action dated 22 April 2026 are acknowledged and have been entered. Claims 1, 4, 6, 9 and 11 are amended and claims 2-3 have been cancelled. Claims 1 and 4-18 are pending and being examined on the merits.
Any rejection or objection not reiterated herein has been overcome by applicants claim amendments.
Priority
This application is a CON of PCT/CN2025/096995 filed 05/23/2025. Acknowledgment is made of applicant's claim for foreign priority based on applications CN202510611056.9 and CN202410661837.4 filed in China on 5/13/2025 and 5/24/2024, respectively. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e). Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1 and 5-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a system or method that comprises a fusion protein comprising a Cas12 protein as listed in Tables 5-6 with editing efficiency, does not reasonably provide enablement for any Cas12 protein having at least 95% sequence identity to an amino acid sequence shown in SEQ ID NO: 18. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. This is a new rejection necessitated by applicant’s claim amendments.
Nature of the Invention
The claims are directed to a method or a system that comprises a Cas12 protein having at least 95% sequence identity to an amino acid sequence shown in SEQ ID NO: 18. Enablement of the claims turns on whether one of ordinary skill in the art can make and use any Cas12 protein having at least 95% sequence identity to an amino acid sequence shown in SEQ ID NO: 18 as in a CRISPR system which produces a function or in a method for detecting, binding, or cleaving a target nucleic acid.
State of the Art
Zhang (Zhang et al. Genome Biology (2023) 24:102) sought to conduct a de novo screen to identify mutations in LbCas12a that improve intrinsic enzymatic activity [pg. 3, last sentence]. Zhang teaches measuring cleavage activity of over 9000 point mutations with high reproducibility [pg. 4, first paragraph; Fig. 1C]. Zhang teaches that nearly all synonymous mutations (847) displayed no significant enrichment, as their scores tightly clustered around 0; and that there were 1977 point mutants with phenotype scores (i.e., natural logarithm of relative enrichment) greater than zero over three biological replicates [pg. 4, first paragraph; Table S1]. Therefore Zhang teaches that not all point mutation in LbCas12a has cleavage activity. Zhang also teaches that certain mutation at N527, G532 and K538 are detrimental to DNA cleavage in E. coli [pg. 4, paragraph 2-3; Fig. 1D].
Swarts (Swarts et al., 2017, Molecular Cell 66, 221–233) attempts to elucidate the molecular basis of both nuclease activities for Cas12a [abstract]. Swarts teaches that in the FnCas12a protein, the RuvC (E1006Q) and Nuc (R1218A0 domains impair DNA cleavage [pg. 222, col. 2, para 2]. Swarts teach that alanine substitution of Q704 or replacement of residues Thr698–Ser702 in FnCas12a with the sequence Ala-Gly3 substantially reduced DNA cleavage activity, suggesting that these residues contribute to R-loop formation by stabilizing the displaced conformation of the nontarget DNA strand [pg. 227, col. 1. Para 1; Fig. 3E].
Thereby the prior teaches that not only will certain mutation in Cas12a affect activity, some till affect conformational formation and stability, which in turns affect cleavage activity.
Breadth of the claims
The claims of the instant specification recite “the Cas12 protein comprises an amino acid sequence having at least 95% sequence identity to an amino acid sequence shown in SEQ ID NO: 18”. This recitation broadly encompass any two or more amino acids of SEQ ID NO: 18 Cas12 protein or multiple amino acid mutated SEQ ID NO: 18 Cas12 protein, as long at the mutated protein retains Cas12 protein. SEQ ID NO: 18 consists of 891 amino acids. A protein having at least 95% identity may differ by as many as 44 amino acid substitutions while remaining withing the scope of the claims. Even considering substitutions alone, the claims encompass thousands possible amino acid sequences representing different protein variants.
Guidance of the Specification
The specification discloses Cas12 proteins in Table 1. The specification discloses that SEQ ID NO: 18 is a Cas protein identified by C12-334 and the editing efficiency of mutants of the C12-334 proteins (Tabl1 1, 5 and 6). The specification does not teach all the possible mutated C12-334 Cas12 proteins that retain 95% sequence identity to an amino acid sequence shown in SEQ ID NO: 18. Furthermore, the specification does not identity which combinations of mutations among the vast number encompassed by the claims retain the claimed functional properties of forming a complex with a guide polynucleotide, interacts with a scaffold sequence, specifically bind a target nucleic acid, and retain Cas12 activity. Instead, the specification only provides data for only a comparatively small subset of possible variants.
Experimentation Required
In order to practice the claimed invention, an immense amount of experimentation would be required. To practice the invention as broadly claimed, it would be necessary for one of ordinary skill in the art to systematically test all possible mutation combinations for all species of Cas12 while retaining 95% sequence identity to an amino acid sequence shown in SEQ ID NO: 18. However, such experimentation would be highly unpredictable in view of the prior art. Accordingly, practicing the invention as broadly claimed would require a massive amount of highly unpredictable experimentation.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
Response to Arguments
Applicant's arguments filed 07/01/2026 regarding the rejection under 35 U.S.C. § 112(a) have been fully considered but they are not persuasive. Applicant argues that amending claim 1 to require a Cas12 protein having 95% sequence identity to SEQ ID NO: 18, together with requiring that the Cas12 protein form a complex with a guide polynucleotide comprising a scaffold and further requiring one or more mutations corresponding to positions in SEQ ID NO: 18, limits the claims to a scope commensurate with the disclosure. Applicant further argues that the specification discloses numerous mutated forms of SEQ ID NO: 18 and therefore enables the amended claims.
Although Applicant has narrowed the claims from proteins having at least 90% sequence identity to having at least 95% sequence identity, the amended claims continue to encompass an extraordinary broad genus of engineered Cas12 proteins. SEQ ID NO:18 consists of 891 amino acids. A protein having at least 95% identity may differ from SEQ ID NO: 18 by as many as 44 amino acid substitutions while remaining withing the scope of the claims. Even considering the substitutions alone, the amended claims encompass many possible protein sequences, representing approximately 1.47x10131 distinct variants; not to include insertions, deletions, or other sequence modifications.
Applicants also argue that the amended functional limitations significantly narrow the scope of the claims. While these limitation may narrow the claimed subject matter, they do not reduce the amount of experimentation required to identify proteins meeting those functional requirements.
Applicants also argue that the specification teaches a large number of mutated forms of SEQ ID NO: 18. While the office agrees, the issue is not whether or not disclosed embodiments are enabled, but whether the disclosure enables the full scope of the claimed genus. The presently claimed genus remains may of orders of magnitude broader than the embodiments actually exemplified, and the specification does not disclose sufficient representative species or common structural principles that would allow one of ordinary skill to predict which members of the claimed genus will retain the required functional properties without undue experimentation.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter: A sequence that is 95% identical to SEQ ID NO: 18 is free of the art. Therefore, the rejections under 35 U.S.C. § 102 and 103 has been withdrawn.
Claim 4 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.
Conclusion
No claims 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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