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 .
Claims 1-22 are still at issue and are present for examination.
Election/Restrictions
Applicant's election with traverse of the invention of Group 1, claims 1-11, to a method of increasing fidelity, specificity, or processivity of a Cas9 molecule, in the paper of 12/5/2025, is acknowledged.
Applicant's election with traverse of the following species:
Species Group 1: K789; .
Species Group 2: K789 and S792;
Species Group 3: K789, S792 and Y794.
Species Group 4: K789, S792, N717 and Y794;
Species Group 5: K789, S792, N717, Y794 and V675;
in the paper of 12/5/2025, is acknowledged.
Applicants traverse the restriction requirement on the basis that applicants submit that the office has not shown that a serious burden would be required to examine all of the claims. This is not found persuasive on the basis that a serious burden would be required to examine all of the claims based upon different databases that would need to be searched and considered as well as the different text searches, sequence searches, classification searches, mutation and or substitution searches that need to be considered for each of the different groups.
Applicants complete traversal is acknowledged and is not found persuasive for the reasons previously made of record and for those reasons repeated herein. This is made FINAL.
Claims 12-22 are withdrawn from further consideration by the examiner, 37
CFR 1.142(b), as being drawn to a non-elected invention.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609 A(1) states, "the list may not be incorporated into the specification but must be submitted in a separate paper."
Applicants filing of information disclosure statement on 1/18/2024 is acknowledged and has been considered.
Claim Objections
Claims 2, 4, 6, 8 and 10 are objected to because of the following informalities:
Claims 2, 4, 6, 8 and 10 each recite multiple amino acid positions that are not in numerical order. It is suggested that amino acid positions be listed in numerical order unless there is a reason for not doing so.
Appropriate correction and/or comment is required.
Specification
The disclosure is objected to because of the following informalities:
Applicants specification is objected to because throughout the “Summary” section (pages 2 and 3) the specification recites “wherein the REC3 clamp is 80% or more identical to SEQ ID NO: 1” wherein elsewhere in applicants specification (i.e. sequence listing, and page 17 lines 27-28) applicants refer to SEQ ID NO:1 as being the “full length FnCas9” and SEQ ID NO:2 as being the REC3 clamp. Thus applicants specification appears to contradict itself.
Based upon the actual amino acid sequences of SEQ ID NO:1 and SEQ ID NO:2, it appears that SEQ ID NO:1 is the full-length sequence and SEQ ID NO:2 is the smaller REC3 clamp domain.
Applicants specification is further objected to because throughout applicants specification applicants refer to amino acid residues that do not appear to correlate with the reference sequence applicants refer to. For example applicants specification states “Even more specifically, such mutations can be in residues N717, Y794, N725, K789, V675, L723, R721, S792, N626, and/or N801 of SEQ ID NO: 2 “ (page 27, lines 12-14). Applicants sequence of SEQ ID NO:2 is a 155 amino acid sequence, hence each of the referred to amino acid positions, N717, Y794, N725, K789, V675, L723, R721, S792, N626, and/or N801, cannot exist in SEQ ID NO:2. Further, many of the positions do not exist in SEQ ID NO:1, which presumably comprises SEQ ID NO:2, either.
Appropriate comment and/or correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 2, 4, 6, 8, 10 are indefinite in the reference to SEQ ID NO:2 for each of the recited amino acid residues, because SEQ ID NO:2 is 155 amino acids in length and each of the amino acid residue positions refer to positions greater than 155 (i.e. N717, Y794, N725, K789, V675, L723, R721, S792, N626, and N801). It is further noted that each of the amino acid residues do not also correspond to or line up with SEQ ID NO:1, with the exception of K789 which is present in SEQ ID NO:1.
Claims 2, 4, 6, 8, 10 are further indefinite in the reference to the amino acid residue N626 as it does not appear that position 626 falls within the clamp region of Cas9 Recognition Lobe (REC3 clamp) of SEQ ID NO: 1. This indefiniteness is based upon the definition of the REC3 clamp of SEQ ID NO:1 as corresponding to SEQ ID NO:2.
Claim 5, 7, 9 recites the limitation "amino acid residues of SEQ ID NO:1" in claim 1. There is insufficient antecedent basis for this limitation in the claim.
Appropriate correction and/or comment is required.
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.
Claim(s) 1-11 are rejected 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.
Claim(s) 1-11 are directed to all possible methods of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp is a mere 80% identical to SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule. The specification, however, only provides the representative species of those methods of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp comprises the amino acid sequence of SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule, encompassed by these claims. There is no disclosure of any particular structure to function/activity relationship in the disclosed species. The specification also fails to describe additional representative species of these enzymes by any identifying structural characteristics or properties, for which no predictability of structure is apparent.
Regarding the level of skill and knowledge in the art of amino acid mutation, the reference of Singh et al. (Curr. Protein Pept. Sci. 18:1-11, 2017; cited on the attached Form PTO-892) reviews various protein engineering methods and discloses that despite the availability of an ever-growing database of protein structures and highly sophisticated computational algorithms, protein engineering is still limited by the incomplete understanding of protein functions, folding, flexibility, and conformational changes (see p. 7, column 1, top). Also, the unpredictability associated with amino acid mutations is exemplified by the reference of Zhang et al. (Structure 26:1474-1485, 2018; cited on the attached Form PTO-892), which discloses that even a mutation of a surface residue that was predicted to be benign caused significant structural changes and unexpected effects on the function of a polypeptide (p. 1475, column 1).
Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim(s) 1-11 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for those methods of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp comprises the amino acid sequence of SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule, does not reasonably provide enablement for all possible methods of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp is a mere 80% identical to SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule. 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.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands (858 F.2d 731, 8 USPQ 2nd 1400 (Fed. Cir. 1988)) as follows: (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claim(s).
Claim(s) 1-11 are so broad as to encompass all possible methods of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp is a mere 80% identical to SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule. The scope of the claims is not commensurate with the enablement provided by the disclosure with regard to the extremely large number of methods and cas9 molecules broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the cas9 molecules of the methods encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to that method of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp comprises the amino acid sequence of SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass any possible methods of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp is a mere 80% identical to SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule, because the specification does not establish: (A) those Cas9 molecules which may be modified effecting the fidelity, specificity, and/or speed of processivity; (B) the general tolerance of enzymes of the Cas9 molecules to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of an Cas9 molecule with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required Cas9 activities including fidelity, specificity, and/or speed of processivity activities and the fact that the relationship between the sequence of a polypeptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see, Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; and Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those methods of the claimed genus.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any methods of increasing fidelity, specificity, and/or speed of processivity in a functional Cas9 molecule, the method comprising mutating one or more amino acid residues within a clamp region of Cas9 Recognition Lobe (REC3 clamp), wherein the REC3 clamp is a mere 80% identical to SEQ ID NO: 2, and further wherein the one or more mutations increase fidelity, specificity, and/or speed of processivity of the Cas9 molecule. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those methods and Cas9 molecules having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
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) 1-3, 5, 7 and 9 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Sung-Hycok (US 2023/0332120).
Sung-Hycok (US 2023/0332120) teach a method of increasing the specificity of a Cas9 protein comprising modifying at least one amino acid residue of the Cas9 protein, wherein the at least one amino acid residue is capable of interacting with a backbone phosphate of a DNA sequence and wherein the at least one amino acid residue which is modified is K786 relative to SEQ ID NO:1 of Sung-Hycok (US 2023/0332120 which is equivalent to K789 of instant SEQ ID NO:1) (see claims 58 and 59 and supporting text). Sung-Hycok (US 2023/0332120) further teach the above methods wherein an additional residue is modified at position R721 relative to SEQ ID NO:1 of Sung-Hycok (US 2023/0332120). Sung-Hycok (US 2023/0332120) further teach the above methods wherein an additional residue is modified at position K785 relative to SEQ ID NO:1 of Sung-Hycok (US 2023/0332120). Sung-Hycok (US 2023/0332120) further teach the above methods wherein an additional residue is modified at position R807 relative to SEQ ID NO:1 of Sung-Hycok (US 2023/0332120). Sung-Hycok (US 2023/0332120) further teach the above methods wherein an additional residue is modified at position K808 relative to SEQ ID NO:1 of Sung-Hycok (US 2023/0332120). It is noted that amino acid sequence of SEQ ID NO:1 of Sung-Hycok (US 2023/0332120) and instant SEQ ID NO:1 are greater than 99% identical and that their numbering is slightly off by the addition of 3 nucleotides at the 5’ end of instant SEQ ID NO:1. Additionally SEQ ID NO:1 of Sung-Hycok (US 2023/0332120) comprises a REC3 clamp region which has 100% sequence identity to instant SEQ ID NO:2.
Thus, claim(s) 1-3, 5, 7 and 9 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Sung-Hycok (US 2023/0332120).
Remarks
No claim is allowed.
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 6-3 EST Mon-Fri.
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rgh
2/4/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652