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 2, 4, 6, 8, 10, 13, 15, 17, 19 and 21, amendment of claims 1, 5, in the paper of 5/4/2026, is acknowledged. Applicants' arguments filed on 5/4/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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 1, 3, 5, 7, 9, 11, 12, 14, 16, 18, 20 and 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.
Claims 12, 14, 16, 18, 20, 22 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claim Objections
Claims 1 is objected to because of the following informalities:
Claims 1 recites a number of amino acid residues (i.e. 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q) in the format of a number followed by a letter. This is inconsistent with applicants previous reciting of amino acid residues (i.e. N717, Y794, N725, K789, V675, L723, R721, S792, N626, and N801). It is suggested that applicants maintain consistency in referencing amino acid residues.
Appropriate correction and/or comment is required.
Specification
The disclosure is objected to because of the following informalities:
It is acknowledged that applicants have corrected the previously noted issues with the “Summary” section (pages 2 and 3).
Applicants specification was previously 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.
It is noted that it appears as if applicants were attempting to make changes to the above page 27 mistake, however, applicants did not make any changes to the above page 27 mistake:(see page 27 of applicants marked up copy of specification submitted 5/4/2026):
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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 1, 3, 5, 7, 9, 11 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.
Claim 1 (claims 3, 5, 7, 9, 11 dependent on) is indefinite in the newly added recitation “wherein the one or more mutated amino acid residues of SEQ ID NO: 2 are selected from the group comprising 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q” in that many of the listed amino acid residues to not occur in SEQ ID NO:2. For example residues 133S, 134I, 135Y, 136S, 141Q, and 142Q do not exist in SEQ ID NO:2.
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.
Claims 1, 3, 5, 7, 9, 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.
This rejection was stated in the previous office action as it applied to previous claims 1-11. In response applicants have amended the claims and state that they have made the appropriate corrections and request withdrawal of the rejection.
Applicants amendment of the claims and applicants traversal is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
Newly amended claims 1, 3, 5, 7, 9, 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 80% or more 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, and further wherein the one or more mutated amino acid residues of SEQ ID NO: 2 are selected from the group comprising 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q. 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.
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.
NEW REJECTION:
Claims 1, 3, 5, 7, 9, 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.
Claims 1, 3, 5, 7, 9, 11 are further rejected under this statute because applicants newly amended recitation “and further wherein the one or more mutated amino acid residues of SEQ ID NO: 2 are selected from the group comprising 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q” is not supported by applicants specification at the time of filing and is thus considered new matter (see also above rejection under 112(b)).
Newly amended claims 1, 3, 5, 7, 9, 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 80% or more 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, and further wherein the one or more mutated amino acid residues of SEQ ID NO: 2 are selected from the group comprising 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q. 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 rejection was stated in the previous office action as it applied to previous claims 1-11. In response applicants have amended the claims and state that they have made the appropriate corrections and request withdrawal of the rejection.
Applicants amendment of the claims and applicants traversal is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
Claim(s) 1, 3, 5, 7, 9, 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 80% or more 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, and further wherein the one or more mutated amino acid residues of SEQ ID NO: 2 are selected from the group comprising 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q. 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 80% or more 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, and further wherein the one or more mutated amino acid residues of SEQ ID NO: 2 are selected from the group comprising 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q, 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 80% or more 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, and further wherein the one or more mutated amino acid residues of SEQ ID NO: 2 are selected from the group comprising 18V, 60Q, 64R, 65G, 66L, 67L, 129K, 133S, 134I, 135Y, 136S, 141Q, and 142Q. 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
The rejection of claim(s) 1-3, 5, 7 and 9 under 35 U.S.C. 102(a)(2) as being anticipated by Sung-Hycok (US 2023/0332120) is withdrawn based upon applicants amendment of the claims in the paper of 5/4/2026.
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). 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 RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached 6-3 EST Mon-Fri.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached at (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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rgh
6/12/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
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