DETAILED ACTION
Applicant’s amendment and Arguments/Remarks received on 09 July 2025 have been entered. Claims 1, 12, 13, 49-52, 55-57, 59, 61, 66-68, 74, 113, 140, 143, 144, 149, and 160-163 were previously pending in the application. New claim 164 have been added by Applicant. Claims 1, 12, 13, 49-52, 55-57, 59, 61, 66-68, 74, 113, 140, 143, 144, 149, and 160-164 are currently pending in the application.
Election of the following species was previously in effect in the instant application:
Cas9 amino acid mutations: I322A, S409I, E427G, R654L, R753G, R1114G, D1135N, V1139A, and D1180G;
PAM sequence: AAA
Effector domain: cytidine deaminase of SEQ ID NO: 53;
Fusion protein sequence: SEQ ID NO: 122.
Applicant has withdrawn the election of species for the species of 1)-4) in view of the generic claim, independent claim 1 as currently amended, being in condition for allowance.
Claims 66-68 and 162 were previously withdrawn from consideration as being directed to a nonelected species and have now been rejoined for examination on the merits. Claims 1, 12-13, 49-52, 55-57, 59, 61, 66-68, 74, 113, 140, 143-144, 149, 160-164 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Information Disclosure Statement
The information disclosure statement filed 09 July 2025 has been considered by the Examiner. Note that Applicant has provided a size fee assertion under 37 C.F.R. 1.17, indicating that this information disclosure statement does not cause the cumulative number of items of information cited in instant application to exceed any item threshold, and as such, no fee is required.
Claim Objections
The objection to previously presented claim 61 for 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if rewritten in independent form including all of the limitations of the base claim and any intervening claims is withdrawn in view of independent claim 1 being in condition for allowance.
Claim Rejections - 35 USC § 112(b)
The rejection of amended claims 160 and 163 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “wherein the amino acid sequence of the Cas9 protein further comprises two or more additional mutations selected from the group” of listed mutations in claim 160 and “wherein the amino acid sequence of the Cas9 protein further comprises the mutations” as listed in new claim 163, is withdrawn in view of Applicant’s amendments to the claims such that amended claim 1 no longer recites wherein the amino acid sequence of the Cas9 protein further comprises one or more additional mutations; claim 160 has been amended to remove the mutations specifically recited in amended claim 1; and claim 163 has been amended to specify that the amino acid sequence of the Cas9 protein comprises a list of mutations including the mutations specifically recited in claim 1 and additional specifically recited mutations.
Claim Rejections - 35 USC § 112(a)
The rejection of amended, previously presented, and original claims 1-3, 12-13, 49-52, 55-57, 59, 74, 113, 140, 143-144, 149, and 160-161 under 35 U.S.C. 112(a) because the specification, while being enabling for:
a mutant Cas9 protein which exhibits an increased activity on a target sequence that does not comprise the canonical PAM (5’-NGG-3’) at its 3’ end as compared to a wildtype SpCas9, wherein the mutant Cas9 comprises at least the mutations:
A10T, I322V, S409I, E427G, G715C, D1135N, D1180G, K1211R, E1219V, Q1221H, H1264Y, A1320V, and R1333K, or
A10T, I322V, S409I, E427G, G715C, R1114G, D1135N, D1180G, K1211R, E1219V, Q1221H, A1320V, and R1333K;
a mutant Cas9 protein which exhibits an activity on a target sequence having a 3’ end that is not directly adjacent to the canonical PAM sequence (5’-NGG-3’) that is at least 5-fold increased as compared to the activity of a wildtype SpCas9 Cas9 protein, wherein the mutant Cas9 protein comprises at least the mutations:
A10T, I322V, S409I, E427G, G715C, D1135N, D1180G, K1211R, E1219V, Q1221H, H1264Y, A1320V, and R1333K, or
A10T, I322V, S409I, E427G, G715C, R1114G, D1135N, D1180G, K1211R, E1219V, Q1221H, A1320V, and R1333K;
a mutant Cas9 protein which exhibits an increased activity on a target sequence comprising a 5’-NRNH-3’ PAM sequence at its 3’ end compared to a wildtype SpCas9, wherein each N is independently any nucleotide, R is A or G, and H is A, C, or T, and wherein the mutant Cas9 protein comprises at least the mutations:
A10T, I322V, S409I, E427G, G715C, D1135N, D1180G, K1211R, E1219V, Q1221H, H1264Y, A1320V, and R1333K, or
A10T, I322V, S409I, E427G, G715C, R1114G, D1135N, D1180G, K1211R, E1219V, Q1221H, A1320V, and R1333K;
4) a mutant Cas9 protein which exhibits lower off-target activity as compared to an off-target activity of a wildtype SpCas9 protein, wherein the mutant Cas9 protein comprises at least the mutations A10T, I322V, S409I, E427G, R1114G, D1135N, V1139A, D1180G, E1219V, Q1221H, A1320V, and R1333K;
does not reasonably provide enablement for the breadth of the claim as written for a mutant Cas9 protein which exhibits an increased activity on a target sequence that does not comprise the canonical PAM (5’-NGG-3’) at its 3’ end as compared to a wildtype SpCas9, and/or wherein the Cas9 has decreased off-target activity, wherein the mutant Cas9 does not comprises at least the mutations recited above;
is withdrawn over amended, previously presented, and original claims 1-3, 50-52, 55-57, 59, 74, 113, 140, 143-144, 149, and 160-161 and maintained over previously presented claims 12-13 and 49 in view of Applicant’s amendments to the claims such that amended independent claim 1 now recites “a Cas9 protein comprising an amino acid sequence that is at least 80% identical to the amino acid sequence of a Cas9 protein as provided by SEQ ID NO: 9, wherein the amino acid sequence of the Cas9 protein comprises the mutations I322V, S409I, E427G, R1114G, D1135N, V1139A, D1180G, E1219V, Q1221H, A1320V, and R1333K relative to the amino acid sequence provided in SEQ ID NO: 9. Applicant’s amendments to independent claim 1 correspond essentially to the scope of enablement indicated in the prior action for a Cas9 protein of claim 1.
Applicant’s amendments and arguments have been fully considered for previously presented claims 12-13 and 49, but have not been found persuasive for the reasons outlined below.
Applicant amended claim 1 to conform to the enabled scope 4 presented in the previous action for a mutant Cas9 protein which exhibits lower off-target activity as compared to an off-target activity of a wildtype SpCas9 protein [page 6 ¶ 1 of prior action]. However, the amendments to independent claim 1 lack two of the mutations (e.g., G715C and K1211R) identified as necessary for enablement corresponding with scopes 1-3, which encompass 1) a mutant Cas9 protein which exhibits an increased activity on a target sequence that does not comprise the canonical PAM (i.e., 5’-NGG-3’) at its 3’ end as compared to a wildtype SpCas9 (as recited in claim 12); 2) a mutant Cas9 protein which exhibits an activity on a target sequence having a 3’ end that is not directly adjacent to the canonical PAM sequence (i.e., 5’-NGG-3’) that is at least 5-fold increased as compared to the activity of a wildtype SpCas9 protein (as recited in claim 13); and 3) a mutant Cas9 protein which exhibits an increased activity on a target sequence comprising a 5’-NRNH-3’ PAM sequence at its 3’ end compared to a wildtype SpCas9, wherein each N is independently any nucleotide, R is A or G, and H is A, C, or T (as recited in claim 49) [page 5 of prior action]. Therefore, Applicant’s amendments do not overcome the scope of enablement rejection under 35 U.S.C. 112(a) for claims 12-13 and 49.
Applicant argues that since the amendments have rendered claim 1 enabled, then all claims dependent on claim 1 directly or indirectly are also enabled. However, this is not agreed.
The amendments to claim 1 enable claim 1 for scope 4, which encompasses wherein the Cas9 protein exhibits lower off-target activity as compared to an off-target activity of a wildtype SpCas9 protein, but not for the additional functional limitations as recited in claims 12-13 and 49, corresponding to enabled scopes 1-3, which require two additional mutations for enablement: G715C and K1211R. Therefore, the enablement of claim 1 does not provide for the enablement of claims 12-13 and 49. As such, Applicant’s arguments do not overcome the scope of enablement rejection under 35 U.S.C. 112(a) for claims 12-13 and 49, and the rejection is maintained for previously presented claims 12-13 and 49.
Examiner suggests that if Applicant amends claims 12-13 and 49 to recite the inclusion of the additional mutations G715C and K1211R, the rejection under 35 U.S.C. 112(a) will be overcome.
Allowable Subject Matter
Claims 1, 50-52, 55-57, 59, 61, 66-68, 74, 113, 140, 143, 144, 149, and 160-164 are considered free of the prior of record and 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 Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
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DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634