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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/26/2026 has been entered.
Applicant’s amendment of claim 1, 33, 39, in the paper of 1/26/2026, is acknowledged. Applicants' arguments filed on 1/26/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 32, 33, 34, 39, 40, 41, 47, 50, 52, 54, 59, 61, 62, 66, 71, 72, 73, 75, 77, 83, 89, 90, 96, 97, 99, 100, are still at issue and are present for examination.
Election/Restriction
Applicant’s election of Group I, claims 1, 3, 4, 6, 9 , 10, 13, 14, 16, 17, 21, 23, 26, 97, 99 and 100, drawn to a system for modifying nucleotides in an RNA target comprising a dead Cpfl or Cpfl nickase protein in the reply filed on 7/15/2022 is acknowledged.
Applicant’s election of each of the following species:
The species are as follows:
Species Group 1: D908 of claim 6;
Species Group 2: Acidaminococcus sp, in claim 9;
Species Group 3: the linker (GGGGS)3 in claim 10
Species Group 4: the adapter sequences MS2 in claim 10;.
Species Group 5: the nuclear export signals or nuclear localization signal HIV RevNES of claim 13;
Species Group 6: the adenine deaminase proteins hADAR2d in claim 16;
Species Group 7: the adenine deaminase protein mutation E488Q in claim 16;
Species Group 8: the adenine deaminase protein huADAR in claim 21;
Species Group 9: the cytidine deaminase protein from rat in claim 26 and
Species Group 10: the APOBEC1 and W90 mutation in claim 26;
in the paper filed on 7/15/2022 is acknowledged.
Applicants confirmation of the telephonic election of the species of:
Species Group 11: the invention of 1) adenine deaminases, claims 3, 4, 16, 17, 21, 23, in the paper of 6/8/2023 is acknowledged.
Claims 32-34, 39-41, 47, 50, 52, 54, 59, 61, 62, 66, 71-73, 75, 77, 83, 89, 90, 96 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.
Claim Objections
Claim 6 is objected to because of the following informalities:
Claim 6 recites “human ADAR-D” and claim 1 from which claim 6 depends recites “hADAR2”. It is suggested that applicants maintain consistency throughout the specification, especially throughout the claims.
Claim 6 recites “S486” twice.
Claim 34 recites “optionally wherein said cell is a eukaryotic cell, wherein said cell is an animal cell, wherein said cell is a human cell, wherein said cell is a plant cell”, which is missing a conjunction such as “or” between “human cell” and “wherein”. It is suggested that a proper conjunction be used.
Appropriate 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, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 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.
Previously claim 1 (claims 4, 6, 9 , 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 dependent on) was rejected in reference to position E488 and S370 . Previously claim 1 (claims 4, 6, 9 , 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 dependent on) was indefinite in the recitation of “wherein the mutated hADAR2 protein comprises at least the mutations at positions E488 and S370 relative to amino acid sequence positions 1388-2034 of wild-type human ADAR2-D (SEQ ID NO: 359),”. The recitation was indefinite in the reference to the mutation positions E488 and S370 relative to amino acid sequence positions 1388-2034 of wild-type human ADAR2-D.
In response applicants have amended the recitation to “wherein the mutated hADAR2 protein or catalytic domain thereof comprises at least the mutations at positions E488 and S370, wherein said positions are numbered according to the hADAR2d catalytic domain sequence present in SEQ ID NO: 359” and traverse the rejection on the basis that applicants submit that this amendment unambiguously establishes SEQ ID NO: 359 as the definitive reference sequence for identifying positions E488 and S370, thereby resolving any alleged indefiniteness.
Applicants amendment of the claim and applicants complete argument is acknowledged and is found persuasive in overcoming the above previous rejection. It is noted that throughout applicants rather lengthy argument supporting applicants position, applicant did not state which positions of reference sequence SEQ ID NO:359 correspond to positions E488 and S370 of the hADAR2d catalytic domain present in SEQ ID NO: 359. Based upon applicants arguments and the applicants specification, position S370 corresponds to position 1730 of SEQ ID NO:359 and position E488 corresponds to position 1848 of SEQ ID NO:359.
Claim 1 (claims 4, 6, 9 , 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 dependent on) is indefinite in that the newly added recitation “the mutations at positions E488 and S370” lack antecedent basis and are thus indefinite. While it is recognized that applicants are referring to a mutated hADAR2 protein or catalytic domain thereof, it remains that there is a lack of proper antecedent basis for “the mutations at positions E488 and S370”. It is suggested that this rejection could be overcome with an amendment such as “a mutation at positions E488 and S370”.
Claim 6 is indefinite in the recitation “based on amino acid sequence positions of human ADAR2-D, and mutations in a homologous ADAR protein” as claim 1 from which claim 6 depends references hADAR2d amino acid positions according to the hADAR2d catalytic domain sequence present in SEQ ID NO: 359. It is unclear and confusing to reference amino acid positions of the same protein using two different references. It is suggested that applicants maintain consistency in referencing amino acid positions in the claims.
Claim 17 recites the limitation "the one or more guide sequences”" in claim 16. There is insufficient antecedent basis for this limitation in the claim.
Appropriate amendment and/or comment is requested.
Claim Rejections - 35 USC § 102
The previous rejection of claim(s) 1, 6, 9, 10, 13, 14, 97, 99 and 100 under 35 U.S.C. 102(a)(1) as being anticipated by The Broad Institute Inc., (WO 2017/189308) was withdrawn based upon applicants filing of a Declaration under 37 CFR 1.1.30 stating that the subject matter relied upon in WO 2017/189308 is applicants own work and not that of another or others.
The rejection of claim(s) 1, 3, 4, 9, 10, 13, 14, 21, 97, 99 and 100 under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Liu et al. (WO 2017/070632) as evidenced by Nishikura (Annu Rev Biochem. Vol 79, pp 321-349, 2012) is withdrawn based upon applicants amendment of the claims in the paper of 11/29/2024.
Claim Rejections - 35 USC § 103
The rejection of claim(s) 3, 4, 16, 17, 21, 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over The Broad Institute Inc., (WO 2017/189308) as applied to claims 1, 6, 9, 10, 13, 14, 97, 99 and 100 above, and further in view of Cox et al. Science Vol 358, No. 6366, pp 1019-1027, Nov 2017) is withdrawn based upon applicants filing of a Declaration under 37 CFR 1.1.30 stating that the subject matter relied upon in WO 2017/189308, thus removing it from availability as art, is applicants own work and not that of another or others.
The rejection of claim(s) 1, 3, 4, 9, 10, 13, 14, 16, 17, 21, 23, 26, 97, 99, 100 under 35 U.S.C. 103 as being unpatentable over Liu et al. (WO 2017/070632) and Cox et al. (Science Vol 358, No. 6366, pp 1019-1027, Nov 2017) is withdrawn based upon applicants amendment of the claims and the arguments presented in the paper of 5/5/2025.
The rejection of claim(s) 1, 3, 4, 9, 10, 13, 14, 16, 17, 21, 23, 26, 97, 99, 100 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (WO 2017/070632) and Zhang et al. (US 2021/0009972) is withdrawn based upon applicants statement in the paper of 1/26/2026, that US 2021/0009972 and the instant application are assigned and/or obligated to be assigned to one or more parties to a joint research agreement, namely The Broad Institute, Inc., President and Fellows of Harvard College, and Massachusetts Institute of Technology.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An terminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 12,221,636 in view of Liu et al. (WO 2017/070632).
Liu et al. teaches reagents, methods, and kits that are useful for the targeted editing of nucleic acids, including editing a single site within the genome of a cell or subject, e.g., within the human genome (abstract). Liu et al. teach a composition for modifying nucleotides in a RNA target of interest comprising a dead Cpfl, a guide sequence that hybridizes to a RNA target sequence designed to form a complex with the dead Cpfl and a nucleotide deaminase (rAPOBEC1) linked to the dead Cpfl (see FIGURE 73 dCpflBE2, nCpfl1BE3, and supporting text, [00373]). Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a mutation such as the APOBEC3G variant ([0009]). While Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a catalytically inactive Cpf2 enzyme (dCpfl), they do not teach what the specific mutation is that renders the Cpfl inactive. Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising dCpfl is derived from Acidaminococcus sp. While Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a nucleotide deaminase linked to the N- or C- terminus of dCpfl, regardless, claim 10 and 13 are included in the rejection by virtue that it refers to the linkages in the alternative, such that the linkage taught by Liu et al. continues to read on the claim. The target of the guide sequences taught by Liu et al. while not a part of the claimed composition occurs within a cell. Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising adenosine deaminase of human. Regardless, claim 21 is included in the rejection by virtue that it refers to the linkages in the alternative, such that the linkage taught by Liu et al. continues to read on the claim. Lui et al. further teach cells comprising the above taught compositions and non-human animals and plants comprising said cells.
Claims 1-9 of U.S. Patent No. 12,221,636, drawn to an engineered composition for site directed base editing comprising: a) a targeting domain; and b) an adenosine deaminase or catalytic domain thereof, wherein the adenosine deaminase is modified to convert activity to a cytidine deaminase, wherein the adenosine deaminase or catalytic domain thereof comprises one or more mutations selected from P462A, N597I, or both of a human ADAR2 or mutations corresponding thereto in a homologue, ortholog, or variant thereof, wherein the adenosine deaminase further comprises one or more mutations at one or more positions selected from E396, C451, V351, R455, T375, K376, S486, Q488, R510, K594, R348, G593, S397, H443, L444, Y445, F442, E438, T448, A353, V355, T339, P539, V525 and I520 of a human ADAR2 or in positions corresponding thereto in a homologue, ortholog, or variant thereof; at one or more positions selected from E488, V351, S486, T375, and S370 of a human ADAR2 or in positions corresponding thereto in a homologue, ortholog, or variant thereof, or selected from E488Q, V351G, S486A, T375S, and S370C of a human ADAR2 or mutations corresponding thereto in a homologue, ortholog, or variant thereof make obvious in view of Liu et al. instant claims 1, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 drawn to an engineered, non-naturally occurring composition for modifying nucleotides in a target RNA of interest, comprising: a) a catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability; b) one or more guide molecules each comprising a guide sequence that hybridizes to target RNA sequence in the target RNA of interest and designed to form a complex with the catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability; and c) an adenosine deaminase protein or catalytic domain thereof, wherein said adenosine deaminase protein or catalytic domain thereof is covalently or non-covalently linked to said dead catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability, wherein the adenosine deaminase protein comprises a mutated human ADAR2 (hADAR2) protein or catalytic domain thereof having cytidine deamination activity, wherein the mutated hADAR2 protein or catalytic domain thereof comprises at least the mutations at positions E488 and S370, wherein said positions are numbered according to the hADAR2d catalytic domain sequence present in SEQ ID NO: 359, on the basis that one of skill in the art before the effective filing date would have been motivated to substitute the dead Cpfl taught by Liu et al. for the targeting domain in the engineered composition for site directed base editing of claims 1-9 of U.S. Patent No. 12,221,636.
Claims 1, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 5 and 6 of copending Application No. 16/756,134 in view of Liu et al. (WO 2017/070632).
Liu et al. teaches reagents, methods, and kits that are useful for the targeted editing of nucleic acids, including editing a single site within the genome of a cell or subject, e.g., within the human genome (abstract). Liu et al. teach a composition for modifying nucleotides in a RNA target of interest comprising a dead Cpfl, a guide sequence that hybridizes to a RNA target sequence designed to form a complex with the dead Cpfl and a nucleotide deaminase (rAPOBEC1) linked to the dead Cpfl (see FIGURE 73 dCpflBE2, nCpfl1BE3, and supporting text, [00373]). Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a mutation such as the APOBEC3G variant ([0009]). While Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a catalytically inactive Cpf2 enzyme (dCpfl), they do not teach what the specific mutation is that renders the Cpfl inactive. Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising dCpfl is derived from Acidaminococcus sp. While Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a nucleotide deaminase linked to the N- or C- terminus of dCpfl, regardless, claim 10 and 13 are included in the rejection by virtue that it refers to the linkages in the alternative, such that the linkage taught by Liu et al. continues to read on the claim. The target of the guide sequences taught by Liu et al. while not a part of the claimed composition occurs within a cell. Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising adenosine deaminase of human. Regardless, claim 21 is included in the rejection by virtue that it refers to the linkages in the alternative, such that the linkage taught by Liu et al. continues to read on the claim. Lui et al. further teach cells comprising the above taught compositions and non-human animals and plants comprising said cells.
Claims 5 and 6 of copending Application No. 16/756,134, drawn to an engineered, non-naturally occurring system suitable for modifying post-translational phosphorylation sites on a protein encoded by a target RNA, comprising:(a) a catalytically inactive (dead) Casl3 protein, or a nucleotide sequence encoding said dead Cas13 protein; (b) a nucleotide deaminase protein or catalytic domain thereof, or a nucleotide sequence encoding said nucleotide deaminase protein or catalytic domain thereof, wherein the nucleotide deaminase protein or catalytic domain thereof [[is]] has at least 98%sequence identity to a human adenosine deaminase acting on RNA 2_(hADAR2) protein or catalytic domain thereof comprising a K350I mutation; and (c) a guide molecule comprising a guide sequence designed to have a degree of complementarity with a target sequence in the target RNA at one or more codons that comprises an adenosine or cytosine and encodes an amino acid that is post-translationally modified by phosphorylation, wherein said nucleotide deaminase protein or catalytic domain thereof is covalently or non- covalently linked to said dead Casl3 protein or said guide molecule, or is adapted to link thereto when contacted with the dead Cas13 protein or the guide molecule, wherein the hADAR2 protein or catalytic domain thereof further comprises one or more mutations in amino acids E488, V351, S486, T375, S370, and N597 of an hADAR2-D amino acid sequence and/or one or more of the mutations L332I and I398V; or wherein the hADAR2 protein or catalytic domain thereof further comprises one or more mutations selected from E488Q, V351G, S486A, T375S, S370C, P462A, N5971, L3321, and I398V, make obvious in view of Liu et al. instant claims 1, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 drawn to an engineered, non-naturally occurring composition for modifying nucleotides in a target RNA of interest, comprising: a) a catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability; b) one or more guide molecules each comprising a guide sequence that hybridizes to target RNA sequence in the target RNA of interest and designed to form a complex with the catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability; and c) an adenosine deaminase protein or catalytic domain thereof, wherein said adenosine deaminase protein or catalytic domain thereof is covalently or non-covalently linked to said dead catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability, wherein the adenosine deaminase protein comprises a mutated human ADAR2 (hADAR2) protein or catalytic domain thereof having cytidine deamination activity, wherein the mutated hADAR2 protein or catalytic domain thereof comprises at least the mutations at positions E488 and S370, wherein said positions are numbered according to the hADAR2d catalytic domain sequence present in SEQ ID NO: 359, on the basis that one of skill in the art before the effective filing date would have been motivated to substitute the dead Cpfl taught by Liu et al. for the targeting domain in the engineered composition for site directed base editing of claims 5 and 6 of copending Application No. 16/756,134.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 17 of copending Application No. 17/264,340 in view of Liu et al. (WO 2017/070632).
Liu et al. teaches reagents, methods, and kits that are useful for the targeted editing of nucleic acids, including editing a single site within the genome of a cell or subject, e.g., within the human genome (abstract). Liu et al. teach a composition for modifying nucleotides in a RNA target of interest comprising a dead Cpfl, a guide sequence that hybridizes to a RNA target sequence designed to form a complex with the dead Cpfl and a nucleotide deaminase (rAPOBEC1) linked to the dead Cpfl (see FIGURE 73 dCpflBE2, nCpfl1BE3, and supporting text, [00373]). Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a mutation such as the APOBEC3G variant ([0009]). While Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a catalytically inactive Cpf2 enzyme (dCpfl), they do not teach what the specific mutation is that renders the Cpfl inactive. Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising dCpfl is derived from Acidaminococcus sp. While Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising a nucleotide deaminase linked to the N- or C- terminus of dCpfl, regardless, claim 10 and 13 are included in the rejection by virtue that it refers to the linkages in the alternative, such that the linkage taught by Liu et al. continues to read on the claim. The target of the guide sequences taught by Liu et al. while not a part of the claimed composition occurs within a cell. Liu et al. teach the above dead Cpfl linked to an adenine nucleotide deaminase comprising adenosine deaminase of human. Regardless, claim 21 is included in the rejection by virtue that it refers to the linkages in the alternative, such that the linkage taught by Liu et al. continues to read on the claim. Lui et al. further teach cells comprising the above taught compositions and non-human animals and plants comprising said cells.
Claim 17 of copending Application No. 17/264,340 drawn to an engineered, non-naturally occurring system for modifying nucleotides in a target nucleic acid, comprising:a) a dead CRISPR-Cas or CRISPR-Cas nickase protein, or a nucleotide sequence encoding said dead CRISPR-Cas or CRISPR-Cas nickase protein, optionally wherein the CRISPR-Cas or CRISPR-Cas nickase protein is Cas9, Casl2, Cas13, Cas 14, CasX, or CasY, optionally wherein the dead CRISPR-Cas or CRISPR-Cas nickase protein is Casl3b, Casl3b-tl, Casl3b-t2, or Casl3b-t3, optionally wherein the dead CRISPR-Cas protein is less than 1000 amino acids, less than 950, less than 900, less than 850, less than 800, or less than 750 amino acids in size; b) a guide molecule comprising a guide sequence that hybridizes to a target sequence and designed to form a complex with the dead CRISPR-Cas or CRISPR-Cas nickase protein; and c) [[an]] the adenosine deaminase protein having cytidine deaminase activity and comprising an amino acid sequence having at least 95% sequence identity to a human adenosine deaminase that act on RNA 2 (hADAR2) protein, a homologous hADAR2 protein of the same species, or an ortholog of hADAR2 protein of a different species and consisting of no more than 40 mutations, wherein the no more than 40 mutations comprise of E488Q and D619G and one or more mutations selected from the group consisting of:V351G, S486A, T375S, S370C, P462A, N5971, L3321, 1398V, K3501, M383L, S661T, S582T, V440I, S495N, and K418E, wherein the amino acid numbering corresponds to the hADAR2 protein or a corresponding position in the homologous hADAR2 or orthologous hADAR2, or a nucleotide sequence encoding said adenosine deaminase protein or catalytic domain thereof, wherein said adenosine deaminase protein or catalytic domain thereof is covalently or non- covalently linked to said dead CRISPR-Cas or CRISPR-Cas nickase protein or said guide molecule is adapted to link thereof after delivery, make obvious in view of Liu et al. instant claims 1, 4, 6, 9, 10, 13, 14, 16, 17, 23, 26, 97, 99 and 100 drawn to an engineered, non-naturally occurring composition for modifying nucleotides in a target RNA of interest, comprising: a) a catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability; b) one or more guide molecules each comprising a guide sequence that hybridizes to target RNA sequence in the target RNA of interest and designed to form a complex with the catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability; and c) an adenosine deaminase protein or catalytic domain thereof, wherein said adenosine deaminase protein or catalytic domain thereof is covalently or non-covalently linked to said dead catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability, wherein the adenosine deaminase protein comprises a mutated human ADAR2 (hADAR2) protein or catalytic domain thereof having cytidine deamination activity, wherein the mutated hADAR2 protein or catalytic domain thereof comprises at least the mutations at positions E488 and S370, wherein said positions are numbered according to the hADAR2d catalytic domain sequence present in SEQ ID NO: 359, on the basis that one of skill in the art before the effective filing date would have been motivated to substitute the dead Cpfl taught by Liu et al. for the targeting domain in the engineered composition for site directed base editing of claims 17 of copending Application No. 17/264,340.
This is a provisional nonstatutory double patenting rejection.
Remarks
No claim is allowed.
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rgh
3/13/2026
/RICHARD G HUTSON/Primary Examner, Art Unit 1652