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 amendment of claim 1, 6, 34, 39, in the paper of 6/17/2026, is acknowledged. Applicants' arguments filed on 6/17/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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Claims 32-34, 39-41, 47, 50, 52, 54, 59, 61, 62, 66, 71-73, 75, 77, 83, 89, 90, 96 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention.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 Rejections - 35 USC § 112
The rejection of 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 is withdrawn based upon applicants amendment of the claims and applicants arguments presented in the papers of 6/17/2026.
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 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 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.
Applicants Response
Applicants traverse the rejection on the basis of applicants summary of the position of the office in making the rejection and applicants submitted statutory guidelines for an Obvious type double-patenting analysis.
Applicants further submit that the office has mischaracterized Liu and lack of prior art teaching.
Applicants submit that the Office alleges that Liu teaches "dead Cpfl linked to an adenine nucleotide deaminase comprising a mutation such as the APOBEC3G variant." (Office Action at 10.) Applicants submit that this characterization is incorrect, as applicants submit that APOBEC3G is a cytidine deaminase. Applicants submit that because the rejection rests on a characterization of Liu that the reference does not support, it fails to establish a prima facie case of obviousness-type double patenting.
Applicants submit that the deficiency is compounded with respect to dependent claim 4, which recites specific inactivating mutations at D908 or E993 of AsCpfl (RuvC domain) and R1226 of AsCpfl (Nuc domain). Applicants submit that the Office expressly acknowledges that Liu does not teach what the specific mutation is that renders Cpfl inactive, yet provides no secondary reference or other basis to supply this limitation. Applicants submit that an express concession that the reference does not teach a required claim limitation, unaccompanied by any reasoning to bridge that gap from another source, cannot sustain a prima facie case. MPEP § 804, II.B.2; MPEP § 2143.
Applicants submit that the rejection also fails to address a material limitation of claim 1. Applicants submit that Claim 1(b) requires guide molecules comprising a guide sequence that hybridizes to a target RNA sequence and is designed to form a complex with the catalytically inactive Cpfl protein for RNA editing. Applicants submit that this is not a substrate-location requirement; it is a structural and functional design requirement specific to RNA targeting. Applicants submit that the '636 Patent reference claims recite only "a targeting domain," which is generic and substrate-agnostic. Applicants submit that Liu's guide sequences are designed for DNA targeting, not RNA targeting. Applicants submit that the Office's response to this limitation is that the target of Liu's guide sequences "while not a part of the claimed composition occurs within a cell." (Office Action at 10.) Applicants submit that whether a target substrate is located within a cell is irrelevant to whether the guide molecules are designed to hybridize to RNA and form an RNA-targeting complex with Cpfl.
Applicants amendment of the claims and applicants complete 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.
In response to applicants submission that Liu does not teach a "dead Cpfl linked to an adenine nucleotide deaminase comprising a mutation such as the APOBEC3G variant.", this is acknowledged as Liu teaches a “dead Cpfl linked to an nucleotide deaminase comprising a mutation such as the APOBEC3G variant”. While applicants are correct in what Liu teaches, this does not change the basis of the rejection. Liu teaches a dead Cpfl linked to an cytosine nucleotide deaminase comprising a mutation such as the APOBEC3G variant. As stated previously one of ordinary skill in the art would have beem motivated to substitute the cytidine deaminase variants taught by U.S. Patent No. 12,221,636 in the compositions and methods taught by Liu et al. thus resulting in the claimed compositions.
In response to applicants submission that the deficiency is compounded with respect to dependent claim 4, which recites specific inactivating mutations at D908 or E993 of AsCpfl (RuvC domain) and R1226 of AsCpfl (Nuc domain) this is not found persuasive on the basis that claim 4 to which applicants refer is limited to alternative catalytically inactive Cpfl or Cpfl nickase and depends from claim 1 which is drawn to “a catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability”. Clearly the dCpfl as well as the Cpfl taught by Liu et al. comprise a ”fragment thereof which retains RNA binding activity”.
In response to applicants submission that the rejection fails to address a material limitation of claim 1, that requires guide molecules comprising a guide sequence that hybridizes to a target RNA sequence and is designed to form a complex with the catalytically inactive Cpfl protein for RNA editing, this is not found persuasive as stated previously and above, Liu et al. clearly teach the presence and use of a guide sequence that hybridizes to a RNA target sequence designed to form a complex with the dead Cpfl (see Tables 2 and 3 and supporting text of Liu et al.)
In response to applicants submission that that Liu's guide sequences are designed for DNA targeting, not RNA targeting, this is not found persuasive as regardless of what the guide sequence is designated for, it remains that the guide sequence hybridizes to a target RNA sequence in the target RNA of interest and is designed to form a complex with the catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability.
Thus the rejection is maintained for the reasons previously made of record and for those reasons repeated herein.
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 1 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.
Applicants Response
Applicants traverse the rejection as above on the basis of applicants summary of the position of the office in making the rejection and applicants submitted statutory guidelines for an Obvious type double-patenting analysis.
It is further noted that applicants traverse the rejection as the above rejection on the basis that Liu does not teach what specific mutation renders Cpfl inactive. As in the response to the above rejection this specific line of argument with regard to the “specific mutations that render Cpfl inactive” is not persuasive for the reasons stated above.
Applicants submit that the office failed to resolve the differences between the reference claims and the pending claims, and Liu Does not Remedy them.
Applicants submit that first, the reference claims specifically recite a catalytically inactive dead Cas 13 protein as the CRISPR effector. Applicants submit that the pending claims require a catalytically inactive Cpfl (Cas12a) protein. Applicants submit that Cas13 and Cpfl are structurally and functionally distinct proteins from different CRISPR effector families; they differ in guide RNA requirements, PAM preferences, target substrate architecture, and the structural features required to achieve RNA base editing. T
Applicants submit that the Office's theory requires substituting Liu's dead Cpfl for the dead Cas13 recited in the reference claims, but provides no analysis of these structural and functional differences, no articulated reason why a PHOSITA would make that substitution, and no basis for a reasonable expectation of success. Applicants submit that replacing the foundational effector protein and redesigning the guide molecule architecture around it is a reconstruction of a different invention, not an obvious variation of the reference claims.
Applicants submit that second, the reference claims require the hADAR2 protein or catalytic domain to comprise a K350I mutation. Applicants submit that the pending claims do not recite K350I, and instead require mutations at positions E488 and S370 of hADAR2d. Applicants submit that the Office does not identify any teaching or suggestion in Liu directed to the K350I mutation or to the specific Cpfl inactivating mutations, and does not explain how Liu bridges the differences between the hADAR2 mutation profiles of the reference claims and the pending claims.
Applicants submit that the rejection fails for the same reasons identified in section I above.
Applicants submit that APOBEC3G is a cytidine deaminase with no adenosine deaminase activity, and neither APOBEC3G nor rAPOBECI supports the proposition that Liu teaches an adenine nucleotide deaminase. Applicants submit that the Office's treatment of the guide molecule RNA-targeting limitation -- that the target occurs within a cell -- is equally non-responsive here, as it addresses substrate location rather than the structural and functional requirement that the guide sequence be designed to hybridize to RNA and form an RNA-targeting complex with Cpfl..
Applicants amendment of the claims and applicants complete 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.
In response to applicants arguments directed to the teaching of Liu et al. which have been repeated from the above rejection, these are not found persuasive for the reasons stated above.
In response to applicants submission that the reference claims specifically recite a catalytically inactive dead Cas 13 protein as the CRISPR effector, this is acknowledged. As stated above, the claims are drawn to “a catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability”. Clearly the dCpfl as well as the Cpfl taught by Liu et al. comprise a ”fragment thereof which retains RNA binding activity”.
In response to applicants submission that the Office's theory requires substituting Liu's dead Cpfl for the dead Cas13 recited in the reference claims, but provides no analysis of these structural and functional differences, no articulated reason why a PHOSITA would make that substitution, and no basis for a reasonable expectation of success as stated previously and above, Liu discloses that dCfl and other Cas effectors (i.e. Cas9) can be used interchangeably.
In response to applicants submission that the reference claims require the hADAR2 protein or catalytic domain to comprise a K350I mutation, this is acknowledged, however, does not affedct the rejection based upon the shared E488 and S370 mutations.
In response to applicants submission that the rejection fails for the same reasons identified in section I above, this is not found persuasive for the reasons stated above under section I.
Thus the rejection is maintained for the reasons previously made of record and for those reasons repeated herein.
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.
Applicants Response
Applicants traverse the rejection as the above rejections on the basis of applicants summary of the position of the office in making the rejection and applicants submitted statutory guidelines for an Obvious type double-patenting analysis.
It is further noted that applicants traverse the rejection as the above rejection on the basis that Liu does not teach what specific mutation renders Cpfl inactive. As in the response to the above rejection this specific line of argument with regard to the “specific mutations that render Cpfl inactive” is not persuasive for the reasons stated above.
Applicants submit that the office failed to resolve the differences between the reference claims and the pending claims, and Liu Does not Remedy them.
Applicants submit that first, the reference claims specifically recite a catalytically inactive dead Cas 13 protein as the CRISPR effector. Applicants submit that the pending claims require a catalytically inactive Cpfl (Cas12a) protein. Applicants submit that Cas13 and Cpfl are structurally and functionally distinct proteins from different CRISPR effector families; they differ in guide RNA requirements, PAM preferences, target substrate architecture, and the structural features required to achieve RNA base editing. T
Applicants submit that the Office's theory requires substituting Liu's dead Cpfl for the dead Cas13 recited in the reference claims, but provides no analysis of these structural and functional differences, no articulated reason why a PHOSITA would make that substitution, and no basis for a reasonable expectation of success. Applicants submit that replacing the foundational effector protein and redesigning the guide molecule architecture around it is a reconstruction of a different invention, not an obvious variation of the reference claims.
Applicants submit that second, the reference claims require the hADAR2 protein or catalytic domain to comprise a K350I mutation. Applicants submit that the pending claims do not recite K350I, and instead require mutations at positions E488 and S370 of hADAR2d. Applicants submit that the Office does not identify any teaching or suggestion in Liu directed to the K350I mutation or to the specific Cpfl inactivating mutations, and does not explain how Liu bridges the differences between the hADAR2 mutation profiles of the reference claims and the pending claims.
Applicants submit that the rejection fails for the same reasons identified in section I above.
Applicants submit that APOBEC3G is a cytidine deaminase with no adenosine deaminase activity, and neither APOBEC3G nor rAPOBECI supports the proposition that Liu teaches an adenine nucleotide deaminase. Applicants submit that the Office's treatment of the guide molecule RNA-targeting limitation -- that the target occurs within a cell -- is equally non-responsive here, as it addresses substrate location rather than the structural and functional requirement that the guide sequence be designed to hybridize to RNA and form an RNA-targeting complex with Cpfl..
Applicants amendment of the claims and applicants complete 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.
In response to applicants arguments directed to the teaching of Liu et al. which have been repeated from the above rejection, these are not found persuasive for the reasons stated above.
In response to applicants submission that the reference claims specifically recite a catalytically inactive dead Cas 13 protein as the CRISPR effector, this is acknowledged. As stated above, the claims are drawn to “a catalytically inactive Cpfl or Cpfl nickase protein, or fragment thereof which retains RNA binding ability”. Clearly the dCpfl as well as the Cpfl taught by Liu et al. comprise a ”fragment thereof which retains RNA binding activity”.
In response to applicants submission that the Office's theory requires substituting Liu's dead Cpfl for the dead Cas13 recited in the reference claims, but provides no analysis of these structural and functional differences, no articulated reason why a PHOSITA would make that substitution, and no basis for a reasonable expectation of success as stated previously and above, Liu discloses that dCfl and other Cas effectors (i.e. Cas9) can be used interchangeably.
In response to applicants submission that the reference claims require the hADAR2 protein or catalytic domain to comprise a K350I mutation, this is acknowledged, however, does not affedct the rejection based upon the shared E488 and S370 mutations.
In response to applicants submission that the rejection fails for the same reasons identified in section I above, this is not found persuasive for the reasons stated above under section !.
Thus the rejection is maintained for the reasons previously made of record and for those reasons repeated herein.
Remarks
No claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 on 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 on (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
rgh
7/28/2026
/RICHARD G HUTSON/Primary Examner, Art Unit 1652
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