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 .
This action is in response to the amendment filed 08/08/2025, in which claim 1 was amended and claim 67 was canceled. Claims 1, 7, 13, 14, 21, 25, 28, 33-35, 46, 49, 50, 53, 62, 63, 89 and 90 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Response to Amendment - Claim Objections
The previous objection of claim 1 for a clerical error has been withdrawn in view of Applicant’s amendment to the claim filed 08/08/2025.
Response to Amendment - Claim Rejections - 35 USC § 112
The previous rejection of claims 1, 7, 13, 14, 21, 25, 28, 33-35, 46, 49, 50, 53, 57, 62, 63, 67, 89 and 90 under 35 U.S.C. 112(b) has been withdrawn in view of Applicant’s cancellation of the claims.
Response to Amendment - Claim Rejections - 35 USC § 101
The previous rejection of claim 67 under 35 U.S.C. 101 has been withdrawn in view of Applicant’s cancellation of the claim filed 08/08/2025.
Declaration Under 37 CFR 1.130(a)
The Declaration under 37 CFR 1.130(a) filed 08/08/2025 is insufficient to overcome the rejection of claims 1, 7, 13, 14, 21, 25, 28, 33-35, 46, 49, 50, 53, 57, 62, 63, 89 and 90 under 35 U.S.C. 103 based upon the application of the Chong et al (WO 2021/202800) reference as set forth in the last Office action because: the declaration does not provide a reasonable explanation of the presence of additional authors on the Chong reference. Although the declaration provides the inventor names that were present in Chong that were not contributors on the instant invention, the declaration does not provide an explanation of how the other inventors of Chong did not contribute to the embodiments of the invention disclosed in Chong and relied upon by the examiner. See MPEP § 717.01(a)(1).
Response to Amendment - Claim Rejections - 35 USC § 102
The previous rejection of claim 67 under 35 U.S.C. 102(a)(l) over Anzalone et al (Nature, Vol. 576, Pgs. 149-178; Dec 2019) has been withdrawn in view of Applicant’s cancellation of the claim filed on 08/08/2025.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 7, 13, 14, 21, 25, 28, 33-35, 46, 49, 50, 53, 57, 62, 63, 89 and 90 are rejected under 35 U.S.C. 103 as being unpatentable over Bonnen et al (WO 2021/092130 A1) in view of Chong et al (WO 2021/202800 A1).
Regarding claim 1 and 7, Bonnen teaches a system comprising (a) a type V CRISPR-Cas effector protein or a first nucleic acid encoding a type V CRISPR-Cas effector protein; (b) a reverse transcriptase, and (c) an extended guide nucleic acid (Page 1 bridging Page 2; Lines 31 of Page 1 to Line 2 of Page 2). Bonnen teaches a guide nucleic acid including a template for editing and a primer binding site where a region or sequence on its 5° or 3’ end that is complementary to an editing template (a reverse transcriptase template), which is an extended guide nucleic acid) (Page 45, Lines 24-28). Bonnen teaches the target nucleic acid is fully complementary to a spacer sequence in a guide RNA where the target region is located immediately adjacent to a PAM sequence on the target strand (Page 52, Lines 4-16). Bonnen teaches that the guide RNA comprises at least one spacer sequence that is complementary/hybridizes to the target DNA (e.g., protospacer) and at least one repeat sequence that corresponds to a particular CRISPR-cas effector protein (e.g., the Type V CRISPR Cas effector protein) in which it is capable of binding to (Page 44 bridging Page 45).
Bonnen does not teach that Cas12i2 comprises an amino acid sequence at least 95% identical to SEQ ID NO: 2 with the mutations D581R. 1926R and V1030G.
Chong teaches a novel engineered Type V CRISPR-Cas variant, Cas12i such as a Cas12i2 nuclease (SEQ ID NO:4) (Page 203, Lines 9-14). SEQ ID NO: 4 of Chong shows the wild-type Cas12i2 sequence with three mutations of D581R. I1926R and V1030G which is 100% identical to SEQ ID NO: 4 of the instant application, which SEQ ID NO: 4 of the instant application has been showed to be 99.6% identical to SEQ ID NO: 2 (wild-type Cas12i2 sequence) of the instant application (Page 262, Figure 1). Chong teaches the invention comprises the Cas12i2 polypeptide, an RNA guide and target nucleic acid (Page 6, Lines 18-22). Chong teaches that the PAM is a DNA sequence adjacent to a target sequence to which a binary complex comprising a polypeptide (e.g., an enzyme such as Cas12i2) and a targeting moiety (e.g., an RNA guide) binds as well as a spacer sequence specific to a target sequence such as the 5’-NAAN-3’ sequence (Page 29, Lines 22-30). Chong teaches the increased enzymatic activity of the modified sequence compared to the wild-type sequence using the mutations listed (Page 69, Paragraph 3 and 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Bonnen to include the Cas12i2 sequence with the mutations of D581R, I926R and V1030G as taught by Chong because Bonnen teaches it is within the ordinary skill in the art to create a gene editing system comprising a Cas12i2 polypeptide for targeting a target nucleic acid and Chong teaches the invention used along with the mutations to SEQ ID NO: 2, results in greater activity than the wild-type sequence.
One would have been motivated to make such a modification in order to receive the expected benefit of increased enzymatic activity as taught by Chong.
Regarding claim 13, Bonnen teaches the nucleic acid construct of the invention is mRNA that encodes one or more introns within the encoded polynucleotide (Page 60, Lines 25-26).
Regarding claim 14, Bonnen teaches the reverse transcriptase is a MMLV-RT (e.g., Page 61, Lines 14-15).
Regarding claim 21, Bonnen teaches the Type V CRISPR-Cas effector protein domain (such as a Cas12i2) is fused to a reverse transcriptase (Page 38, Lines 13-15, Claim 15 and Claim 32).
Regarding claim 25 and 28, Bonnen does not teach the identical sequence of the direct repeat sequences.
Chong teaches the CRISPR nuclease binding sites are direct repeat sequences with SEQ ID NO: 492 being 100% identical to SEQ ID NO: 17 as well as being at least 23 nucleotides long (Page 117, Paragraph 2-3 and Table 13). Chong teaches the variant Cas12i2 polypeptide to interact with the direct repeat sequence of an RNA guide (shown in table 4) exhibits enhanced RNA guide complex formation relative to a parent polypeptide (Page 75, Paragraph 2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Bonnen to include the Cas12i2 sequence and a direct repeat sequence as taught by Chong because Bonnen teaches it is within the ordinary skill in the art to use the invention for the method of modifying a target nucleic acid and Chong teaches the invention used along a direct repeat sequence identified in the instant application as SEQ ID NO: 17 that is 100% identical to SEQ ID NO: 492.
One would have been motivated to make such a modification in order to receive the expected benefit of enhanced RNA guide complex formation as taught by Chong.
Regarding claim 33-35, Bonnen teaches the PBS can be between 1-100 nucleotides in length (Page 50, Lines 24-31). Bonnen teaches the PBS, Primer binding site, is designed to bind to the 3’end of a strand of the target nucleic acid and can bind to the target strand with complementarity to the primer on the target nucleic acid (Page 50, Lines 13-24).
Regarding claim 46, Bonnen teaches in figure 1, the gRNA and the RT on a single RNA molecule comprising the CRISPR nuclease binding site, the spacer sequence, the PBS and the template sequence (Page 93, Figure 1).
Regarding claim 49, Bonnen teaches in the 5’ to 3” direction, the extended portion (the primer binding site and RT template) is fused to the 3’ end of the CRISPR nuclease binding site with a spacer in between, such that the order would be the CRISPR nuclease binding site, the spacer, the template sequence and the PBS (Page 29, Lines 5-30).
Regarding claim 50, Bonnen teaches the single RNA molecule comprises a hairpin structure (such as a stem loop structure) or a pseudoknot-like structure at its 5” end (Page 46, lines 10-12).
Regarding claim 53, Bonnen teaches in figure 3, the gRNA and the RT on a two separate RNA molecule (Page 95, Figure 3).
Regarding claim 57 and 62, Bonnen teaches the introducing, transferring or delivering of the system into a cell for expression in the host cell (Page 22, Lines 1-23).
Bonnen does not teach the system comprising lipid nanoparticles.
Chong teaches the compositions or complexes are formulated including a carrier for delivery to cells by known methods such as a lipid nanoparticle-mediated transfer (Page 180, Paragraph 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Bonnen to formulate the system in a lipid nanoparticle for delivery to cells as taught by Chong because Bonnen teaches it is within the ordinary skill in the art to create a gene editing system comprising a Cas12i2 polypeptide for targeting a target nucleic acid delivered to a host cell and Chong teaches Cas12i2 invention for delivery using lipid nanoparticles to be delivered to cells.
One would have been motivated to make such a modification in order to receive the expected benefit of delivery to cells as taught by Chong.
Regarding claim 63, Bonnen teaches a kit comprising one or more nucleic acid constructs of the invention and/or expression cassettes and/or vectors comprising (a) a type V CRISPR-Cas effector protein; (b) a reverse transcriptase, and (c) an extended guide nucleic acid for methods of modifying a target nucleic acid (Page 60, Lines 11-20).
Regarding claim 89 and 90, Bonnen does not teach the specific sequence used in the Cas12i2 with the mutations required.
Chong (WO 2021) teaches an engineered Type V CRISPR-Cas variant, Cas12i such as a Cas12i2 nuclease (SEQ ID NO:4) (Page 203, Lines 9-14). SEQ ID NO: 4 of Chong shows the wild-type Cas12i2 sequence with three mutations of D581R. 1926R and V1030G which is 100% identical to SEQ ID NO: 4 of the instant application, which SEQ ID NO: 4 of the instant application has been showed to be 99.6% identical to SEQ ID NO: 2 (wild-type Cas12i2 sequence) of the instant application (Page 262, Figure 1). Chong teaches the increased enzymatic activity of the modified sequence compared to the wild-type sequence using the mutations listed (Page 69, Paragraph 3 and 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Bonnen to include the Cas12i2 sequence with the mutations of D581R, 1926R and V1030G as taught by Chong because Bonnen teaches it is within the ordinary skill in the art to use the invention to provide a system for modifying a target nucleic acid and Chong teaches the a system for editing that comprises a Cas12i2 nuclease with the mutations to SEQ ID NO: 2, which results in greater activity than the wild-type sequence.
One would have been motivated to make such a modification in order to receive the expected benefit of increased enzymatic activity as taught by Chong.
Response to Arguments - Claim Rejections - 35 USC § 103
The previous rejection of claims 1, 7, 13, 14, 21, 25, 28, 33-35, 46, 49, 50, 53, 57, 62, 63, 89 and 90 under 35 U.S.C. 103 over Bonnen et al (WO 2021/092130 Al) in view of Chong et al (WO 2021/202800 Al) has been maintained in view of Applicant’s declaration filed 08/08/2025 due to insufficient explanation as stated above with regard to the declaration.
The previous rejection of claim 67 under 35 U.S.C. 103 over Bonnen et al (WO 2021/092130 Al) and Chong et al (WO 2021/202800 Al) and further in view of Chong et al (WO 2019/178427 Al) has been withdrawn in view of Applicant’s cancellation of the claim filed on 08/08/2025.
Terminal Disclaimer
The terminal disclaimer filed on 08/08/2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of 18/565,148 has been reviewed and is accepted. The terminal disclaimer has been recorded.
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 were
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 Langi, 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 CPR l.32l(c) or l.32l(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 CPR l.32l(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory
double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be
accompanied by a reply requesting reconsideration of the prior Office action. Even where the
NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B. l.
For a reply to a non-final Office action, see 37 CPR 1.11 l(a). For a reply to final Office action,
see 37 CPR 1.113(c). A request for reconsideration while not provided for in 37 CPR 1.113(c)
may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used.
Please visit www.uspto.gov/patent/patents-forms. The actual 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 eTerminal 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/apply I appl ying-online/ eterminal-disclaimer.
Claims 1, 7, 25, 28, 89 and 90 are provisionally rejected on the ground of nonstatutory
double patenting as being unpatentable over claims 1-6, 13 and 17 of copending Application No.
17 /831,852 in view of Bonnen et al (WO 2021/092130 Al).
Claim 2 of the '852 application is drawn to "A gene editing system for genetic editing of
a transthyretin (TTR) gene, comprising (i) a Cas 12i2 polypeptide or a first nucleic acid encoding
the Cas12i2 polypeptide, wherein the Cas 12i2 polypeptide comprises an amino acid sequence at
least 95% identical to SEQ ID NO: 222 and comprises one or more mutations relative to SEQ ID
NO: 222; (ii) an RNA guide or a second nucleic acid encoding the RNA guide, wherein the RNA
guide comprises a spacer sequence specific to a target sequence within a TTR gene, the target
sequence being adjacent to a protospacer adjacent motif (PAM) comprising the motif of 5'-TTN-
3', which is located 5' to the target sequence, wherein the one or more mutations in the Casl2i2
polypeptide are at positions D581, G624, F626, P868, 1926, V1030, E1035, and/or S 1046 of
SEQ ID NO: 222." SEQ ID NO: 222 of the '852 application is identical to instant SEQ ID NO:
2. Claim 2 does not require a reverse transcriptase polypeptide or a second nucleic acid encoding
the RT polypeptide or a reverse transcription donor (RT donor RNA) or fourth nucleic acid encoding the RT donor RNA, wherein the RT donor RNA comprises a primer binding site (PBS)
and a template sequence. However, Bonnen teaches a system comprising contacting the target
nucleic acid with (a) a type V CRISPR-Cas effector protein or a first nucleic acid encoding a
type V CRISPR-Cas effector protein; (b) a reverse transcriptase, and (c) an extended guide
nucleic acid, thereby modifying the target nucleic acid (Page 1 bridging Page 2; Lines 31 of Page
1 to Line 2 of Page 2). Bonnen teaches a guide nucleic acid including a template for editing and a
primer binding site where a region or sequence on its 5' or 3' end that is complementary to an
editing template (a reverse transcriptase template), thereby recruiting the editing template to the
target nucleic acid (i.e., an extended guide nucleic acid) (Page 45, Lines 24-28). It would have
been obvious to one to combine the product of the '852 application with the products of the (WO
2021/092130 Al) reference, because both '852 and (WO 2021/092130 Al) are directed to
Cas12i2. One would have combined the products in order to achieve the benefit of providing
reagents suitable for performing prime editing. Accordingly, instant claim 1 is not patentably
distinct from claim 2 of the '852 application.
Claim 3 of the '852 application depends from claim 2 and specifies, "the one or more
mutations are amino acid substitutions, which optionally is D581R, G624R, F626R, P868T,
l926R, V1030G, E1035R, S1046G, or a combination thereof." Accordingly, instant claim 7 is
not patentably distinct from the claims of the '852 application.
Claim 4 of the '852 application depends from claim 3, "(i) mutations at positions D581,
D911, 1926, and V1030, which optionally are amino acid substitutions of D581R, D911R,
1926R, and V1030G;(ii) mutations at positions D581, 1926, and V1030, which optionally are
amino acid substitutions of D581R, 1926R, and V 1030G;(iii) mutations at positions D581, 1926, V1030, and S 1046, which optionally are amino acid substitutions of D581R, l926R, V1030G, and Sl046G; (iv) mutations at positions D581, G624, F626, 1926, Vl030, El035, and Sl046, which optionally are amino acid substitutions of D581R, G624R, F626R, I926R, Vl030G,
El035R, and Sl046G; or (v) mutations at positions D581, G624, F626, P868, 1926, Vl030,
El035, and Sl046, which optionally are amino acid substitutions of D581R, G624R, F626R,
P868T, I926R, Vl030G, El035R, and Sl046G." Accordingly, instant claim 7 is not patentably
distinct from the claims of '852 application.
Claim 5 of the '852 application depends from claim 1 and specifies, "wherein the
Cas12i2 polypeptide comprises the amino acid sequence of SEQ ID NO: 223,224,225,226 or
227.", where SEQ ID NO: 224 is the same as SEQ ID NO: 4 in the instant application.
Accordingly, instant claim 1 is not patentably distinct from the claims of the '852 application.
Claim 6 of the '852 application depends from claim 1 and specifies, "which comprises
the first nucleic acid encoding the Cas12i2 polypeptide." Accordingly, instant claim 1 is not
patentably distinct from the claims of the '852 application.
Claim 13 of the '852 application depends from claim 1 and specifies, "wherein the RNA
guide comprises the spacer sequence and a direct repeat sequence, which is at least 90% identical
to any one of SEQ ID NOs: 1-10 or a fragment thereof that is at least 23- nucleotide in length."
Accordingly, instant claims 25 and 28 is not patentably distinct from the claims of the '852
application.
Claim 17 of the '852 application depends from claim 13 and specifies, "wherein the
direct repeat sequence is 5'-AGAAAUCCGUCUUUCAUUGACGG-3' (SEQ ID NO: 10).”
Accordingly, instant claims 25 and 28 is not patentably distinct from the claims of the '852
application.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 7, 25, 28, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 13 and 17 of copending Application No. 17 /832,038 in view of Bonnen et al (WO 2021/092130 Al).
Claim 2 of the '038 application is drawn to "A gene editing system for genetic editing of a hydroxyacid oxidase 1 (HAOl) gene, comprising (i) a Cas12i2 polypeptide or a first nucleic acid encoding the Cas12i2 polypeptide, wherein the Cas 12i2 polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 922 and comprises one or more mutations relative to SEQ ID NO: 922; (ii) an RNA guide or a second nucleic acid encoding the RNA guide, wherein the RNA guide comprises a spacer sequence specific to a target sequence within a TTR gene, the target sequence being adjacent to a protospacer adjacent motif (PAM) comprising the motif of 5'-TTN-3', which is located 5' to the target sequence, wherein the one or more mutations in the Casl2i2 polypeptide are at positions D581, G624, F626, P868, 1926, V1030, E1035, and/or S 1046 of SEQ ID NO: 922." SEQ ID NO: 922 of the '038 application is identical to instant SEQ ID NO: 2. Claim 2 does not require a reverse transcriptase polypeptide or a second nucleic acid encoding the RT polypeptide or a reverse transcription donor (RT donor RNA) or fourth nucleic acid encoding the RT donor RNA, wherein the RT donor RNA comprises a primer binding site (PBS) and a template sequence. However, Bonnen teaches a system comprising contacting the target nucleic acid with (a) a type V CRISPR-Cas effector protein or a first nucleic acid encoding a type V CRISPR-Cas effector protein; (b) a reverse transcriptase, and (c) an extended guide nucleic acid, thereby modifying the target nucleic acid (Page 1 bridging Page 2; Lines 31 of Page 1 to Line 2 of Page 2). Bonnen teaches a guide nucleic acid including a template for editing and a primer binding site where a region or sequence on its 5' or 3' end that is complementary to an editing template (a reverse transcriptase template), thereby recruiting the editing template to the target nucleic acid (i.e., an extended guide nucleic acid) (Page 45, Lines 24-28). It would have been obvious to one to combine the product of the '038 application with the products of the (WO 2021/092130 Al) reference, because both '038 and (WO 2021/092130 Al) are directed to Casl2i2. One would have combined the products in order to achieve the benefit of providing reagents suitable for performing prime editing.
Accordingly, instant claim 1 is not patentably distinct from claim 2 of the '038 application.
Claim 3 of the '038 application depends from claim 2 and specifies, "the one or more mutations are amino acid substitutions, which optionally is D581R, G624R, F626R, P868T, l926R, V1030G, E1035R, S1046G, or a combination thereof." Accordingly, instant claim 7 is not patentably distinct from the claims of the '038 application.
Claim 4 of the '038 application depends from claim 3, "(i) mutations at positions D581,
D911, 1926, and V1030, which optionally are amino acid substitutions of D581R, D911R, 1926R, and V1030G;(ii) mutations at positions D581, 1926, and V1030, which optionally are amino acid substitutions of D58lR, 1926R, and V 1030G;(iii) mutations at positions D581, 1926, V1030, and S 1046, which optionally are amino acid substitutions of D581R, l926R, V1030G, and S1046G; (iv) mutations at positions D581, G624, F626, 1926, V1030, E1035, and S1046, which optionally are amino acid substitutions of D58 lR, G624R, F626R, l926R, V1030G, E1035R, and S1046G; or (v) mutations at positions D581, G624, F626, P868, 1926, V1030, E1035, and S1046, which optionally are amino acid substitutions of D581R, G624R, F626R, P868T, l926R, V1030G, E1035R, and Sl046G."
Accordingly, instant claim 7 is not patentably distinct from the claims of '038 application. Claim 5 of the '038 application depends from claim 1 and specifies, "wherein the Casl2i2 polypeptide comprises the amino acid sequence of SEQ ID NO: 923, 924, 925, 926 or 927.", where SEQ ID NO: 924 is the same as SEQ ID NO: 4 in the instant application.
Accordingly, instant claim 1 is not patentably distinct from the claims of the '038 application.
Claim 6 of the '038 application depends from claim 1 and specifies, "which comprises the first nucleic acid encoding the Cas12i2 polypeptide." Accordingly, instant claim 1 is not patentably distinct from the claims of the '038 application.
Claim 13 of the '038 application depends from claim 1 and specifies, "wherein the RNA guide comprises the spacer sequence and a direct repeat sequence, which is at least 90% identical to any one of SEQ ID NOs: 1-10 or a fragment thereof that is at least 23- nucleotide in length."
Accordingly, instant claims 25 and 28 is not patentably distinct from the claims of the '038 application.
Claim 17 of the '038 application depends from claim 13 and specifies, "wherein the direct repeat sequence is 5'-AGAAAUCCGUCUUUCAUUGACGG-3' (SEQ ID NO: 10).”
Accordingly, instant claims 25 and 28 is not patentably distinct from the claims of the '038 application.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 7, 25, 28, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 13 and 17 of copending Application No. 17/832,114 in view of Bonnen et al (WO 2021/092130 Al).
Claim 2 of the' 114 application is drawn to "A gene editing system for genetic editing of a lactate dehydrogenase A (LDHA) gene, comprising (i) a Cas12i2 polypeptide or a first nucleic acid encoding the Casl2i2 polypeptide, wherein the Cas 12i2 polypeptide comprises an amino acid sequence at least 95% identical to SEQ ID NO: 1166 and comprises one or more mutations relative to SEQ ID NO: 1166; (ii) an RNA guide or a second nucleic acid encoding the RNA guide, wherein the RNA guide comprises a spacer sequence specific to a target sequence within a TTR gene, the target sequence being adjacent to a protospacer adjacent motif (PAM) comprising the motif of 5'-TTN-3', which is located 5' to the target sequence, wherein the one or more mutations in the Casl2i2 polypeptide are at positions D581, G624, F626, P868, 1926, V1030, E1035, and/or S 1046 of SEQ ID NO: 1166." SEQ ID NO: 1166 of the '114 application is identical to instant SEQ ID NO: 2. Claim 2 does not require a reverse transcriptase polypeptide or a second nucleic acid encoding the RT polypeptide or a reverse transcription donor (RT donor RNA) or fourth nucleic acid encoding the RT donor RNA, wherein the RT donor RNA comprises a primer binding site (PBS) and a template sequence. However, Bonnen teaches a system comprising contacting the target nucleic acid with (a) a type V CRISPR-Cas effector protein or a first nucleic acid encoding a type V CRISPR-Cas effector protein; (b) a reverse transcriptase, and (c) an extended guide nucleic acid, thereby modifying the target nucleic acid (Page 1 bridging Page 2; Lines 31 of Page 1 to Line 2 of Page 2). Bonnen teaches a guide nucleic acid including a template for editing and a primer binding site where a region or sequence on its 5' or 3' end that is complementary to an editing template (a reverse transcriptase template), thereby recruiting the editing template to the target nucleic acid (i.e., an extended guide nucleic acid) (Page 45, Lines 24-28). It would have been obvious to one to combine the product of the '114 application with the products of the (WO 2021/092130 Al) reference, because both' 114 and (WO 2021/092130 Al) are directed to Cas12i2. One would have combined the products in order to achieve the benefit of providing reagents suitable for performing prime editing.
Accordingly, instant claim 1 is not patentably distinct from claim 2 of the' 114 application.
Claim 3 of the '114 application depends from claim 2 and specifies, "the one or more mutations are amino acid substitutions, which optionally is D581R, G624R, F626R, P868T, I926R, V1030G, E1035R, S1046G, or a combination thereof." Accordingly, instant claim 7 is not patentably distinct from the claims of the '114 application.
Claim 4 of the' 114 application depends from claim 3, "(i) mutations at positions D581, D911, 1926, and V1030, which optionally are amino acid substitutions of D581R, D911R, 1926R, and V1030G;(ii) mutations at positions D581, 1926, and V1030, which optionally are amino acid substitutions of D581R, 1926R, and V 1030G;(iii) mutations at positions D581, 1926, V1030, and S 1046, which optionally are amino acid substitutions of D581R, I926R, V1030G, and S1046G; (iv) mutations at positions D581, G624, F626, 1926, V1030, E1035, and S1046, which optionally are amino acid substitutions of D581R, G624R, F626R, I926R, V1030G, E1035R, and S1046G; or (v) mutations at positions D581, G624, F626, P868, 1926, V1030, E1035, and S1046, which optionally are amino acid substitutions of D581R, G624R, F626R, P868T, I926R, V1030G, E1035R, and Sl046G." Accordingly, instant claim 7 is not patentably distinct from the claims of ' 114 application.
Claim 5 of the '114 application depends from claim 1 and specifies, "wherein the Cas12i2 polypeptide comprises the amino acid sequence of SEQ ID NO: 1167, 1168, 1169, 1170, or 1171.", where SEQ ID NO: 1168 is the same as SEQ ID NO: 4 in the instant application. Accordingly, instant claim 1 is not patentably distinct from the claims of the' 114 application. Claim 6 of the '114 application depends from claim 1 and specifies, "which comprises the first nucleic acid encoding the Casl2i2 polypeptide." Accordingly, instant claim 1 is not patentably distinct from the claims of the' 114 application.
Claim 13 of the '114 application depends from claim 1 and specifies, "wherein the RNA guide comprises the spacer sequence and a direct repeat sequence, which is at least 90% identical to any one of SEQ ID NOs: 1-10 or a fragment thereof that is at least 23- nucleotide in length."
Accordingly, instant claims 25 and 28 is not patentably distinct from the claims of the '114 application.
Claim 17 of the '114 application depends from claim 13 and specifies, "wherein the direct repeat sequence is 5'-AGAAAUCCGUCUUUCAUUGACGG-3' (SEQ ID NO: 10)."
Accordingly, instant claims 25 and 28 is not patentably distinct from the claims of the '114 application.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 7, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10-15 of copending Application No. 17/931,027 in view of Bonnen et al (WO 2021/092130 Al).
Claim 1 of the '027 application is drawn to "A Cas12i fusion protein comprising: i) a Cas12i polypeptide comprising an alteration relative to the amino acid sequence of SEQ ID NO: 2, wherein the alteration is selected from the group comprising D581R, D911R, I926R, V1030G, S1046G, G624R, F626R, E1035R, and P868T.[[, ]]wherein the Cas12i[[2]] polypeptide comprises at least 90% identity to the amino acid sequence of SEQ ID NO: 2, and wherein the Cas12i polypeptide has reduced nuclease activity or is a nuclease dead Cas12i polypeptide; and ii) a heterologous sequence comprising a deaminase domain." SEQ ID NO: 2 of the '027 application is identical to instant SEQ ID NO: 2. Claim 1 does not require a reverse transcriptase polypeptide or a second nucleic acid encoding the RT polypeptide or a reverse transcription donor (RT donor RNA) or fourth nucleic acid encoding the RT donor RNA, wherein the RT donor RNA comprises a primer binding site (PBS) and a template sequence. However, Bonnen teaches a system comprising contacting the target nucleic acid with (a) a type V CRISPR-Cas effector protein or a first nucleic acid encoding a type V CRISPR-Cas effector protein; (b) a reverse transcriptase, and (c) an extended guide nucleic acid, thereby modifying the target nucleic acid (Page 1 bridging Page 2; Lines 31 of Page 1 to Line 2 of Page 2). Bonnen teaches a guide nucleic acid including a template for editing and a primer binding site where a region or sequence on its 5' or 3' end that is complementary to an editing template (a reverse transcriptase template), thereby recruiting the editing template to the target nucleic acid (i.e., an extended guide nucleic acid) (Page 45, Lines 24-28). It would have been obvious to one to combine the product of the '027 application with the products of the (WO 2021/092130 Al) reference, because both '027 and (WO 2021/092130 Al) are directed to Cas12i2. One would have combined the products in order to achieve the benefit of providing reagents suitable for performing prime editing. Accordingly, instant claim 1 is not patentably distinct from claim 1 of the '027 application.
Claim 10 of the '027 application depends from claim 1 and specifies, "which comprises a plurality of alterations relative to SEQ ID NO: 2, wherein the plurality of alterations comprises one or more of D581R, D911R, I926R, V1030G, E1035R, and S 1046G." Accordingly, instant claims 1, 7, 89 and 90 are not patentably distinct from the claims of the '027 application.
Claim 11 of the '027 application depends from claim 1 and specifies, "which comprises a plurality of alterations relative to SEQ ID NO: 2, wherein the plurality of alterations comprises one or more of D581R, I926R and Vl030G." Accordingly, instant claims 1, 7, 89 and 90 are not patentably distinct from the claims of the '027 application.
Claim 12 of the '027 application depends from claim 1 and specifies, "which comprises a plurality of alterations relative to SEQ ID NO: 2, wherein the plurality of alterations comprises one or more of D581R, I926R, V1030G and S 1046G." Accordingly, instant claims 1, 7, 89 and 90 are not patentably distinct from the claims of the '027 application.
Claim 13 of the '027 application depends from claim 1 and specifies, "which comprises a plurality of alterations relative to SEQ ID NO: 2, wherein the plurality of alterations comprises one or more of D581R, G624R, F626R, I926R, V1030G, E1035R, and S 1046G." Accordingly, instant claims 1, 7, 89 and 90 are not patentably distinct from the claims of the '027 application.
Claim 14 of the '027 application depends from claim 1 and specifies, "which comprises a plurality of alterations relative to SEQ ID NO: 2, wherein the plurality of alterations comprises one or more of D581R, G624R, F626R, P868T, I926R, V1030G, E1035R, and S 1046G."
Accordingly, instant claims 1, 7, 89 and 90 are not patentably distinct from the claims of the '027 application.
Claim 15 of the '027 application depends from claim 1 and specifies, "wherein the Cas12i polypeptide comprises at least 95% or 99% identity to the amino acid sequence of SEQ ID NO: 2." Accordingly, instant claims 1, 7, 89 and 90 are not patentably distinct from the claims of the '027 application.
This is a provisional nonstatutory double patenting rejection.
Claims 1, 7, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 18/688,176 in view of Bonnen et al (WO 2021/092130 Al).
Claims 1-5 of the ‘176 application is drawn to “A method of making a modified T cell, the method comprising introducing into a T cell:(a) a variant Cas12i polypeptide or a nucleic acid encoding the variant Cas12i polypeptide, (b) a first RNA guide or a nucleic acid encoding the first RNA guide, and(c) an exogenous nucleic acid for integration into the genome of the T cell, the method comprising:(a) disrupting a gene in the genome of a T cell using a variant Casl12i polypeptide and a first RNA guide, and(b) introducing an exogenous nucleic acid into the genome of the T cell, wherein the variant Cas12i polypeptide is a variant Cas12i2 polypeptide, wherein the variant Cas12i polypeptide comprises a sequence having at least 90% identity to a sequence of any one of SEQ ID NOs: 3-7, wherein the variant Cas12i polypeptide comprises a sequence of any one of SEQ ID NOs: 3-7.” SEQ ID NO: 2 of the "176 application is identical to instant SEQ ID NO: 2 and SEQ ID NO: 4 of the “176 application is identical to instant SEQ ID NO: 4. SEQ ID NO: 4, in both applications, is 99.6% identical to SEQ ID NO: 2, in both applications, with SEQ ID NO: 4 having three mutations at positions D581, 1926 and V1030. Claims 1-5 do not require a reverse transcriptase polypeptide or a second nucleic acid encoding the RT polypeptide or a reverse transcription donor (RT donor RNA) or fourth nucleic acid encoding the RT donor RNA, wherein the RT donor RNA comprises a primer binding site (PBS) and a template sequence. However, Bonnen teaches a system comprising contacting the target nucleic acid with (a) a type V CRISPR-Cas effector protein or a first nucleic acid encoding a type V CRISPR-Cas effector protein; (b) a reverse transcriptase, and (c) an extended guide nucleic acid, thereby modifying the target nucleic acid (Page 1 bridging Page 2; Lines 31 of Page 1 to Line 2 of Page 2). Bonnen teaches a guide nucleic acid including a template for editing and a primer binding site where a region or sequence on its 5° or 3’ end that is complementary to an editing template (a reverse transcriptase template), thereby recruiting the editing template to the target nucleic acid (i.e., an extended guide nucleic acid) (Page 45, Lines 24-28).
It would have been obvious to one to combine the product of the ‘176 application with the products of the (WO 2021/092130 Al) reference, because both ‘176 and (WO 2021/092130 A1) are directed to Cas12i2. One would have combined the products in order to achieve the benefit of providing reagents suitable for performing prime editing. Accordingly, instant claim 1 is not patentably distinct from claims 1-5 of the “176 application.
This is a provisional nonstatutory double patenting rejection.
Response to Amendments - Double Patenting
The previous rejection of claims 1, 7, 25, 28, 89 and 90 under provisional nonstatutory double patenting as being unpatentable over claims 1-6, 13 and 17 of copending Application No. 17 /831,852 in view of Bonnen et al (WO 2021/092130 Al) has been maintained in view of Applicant’s arguments filed on 08/08/2025 as Applicant’s arguments were considered but not found persuasive. Applicant’s arguments were not found to be persuasive because the NSDP rejection is not the only rejection remaining in the application at this time.
The previous rejection of claims 1, 7, 25, 28, 89 and 90 under provisional nonstatutory double patenting as being unpatentable over claims 1-6, 13 and 17 of copending Application No. 17/832,114 in view of Bonnen et al (WO 2021/092130 Al) has been maintained in view of Applicant’s arguments filed on 08/08/2025 as Applicant’s arguments were considered but not found persuasive. Applicant’s arguments were not found to be persuasive because the NSDP rejection is not the only rejection remaining in the application at this time.
The previous rejection of claims 1, 7, 89 and 90 under provisional nonstatutory double patenting as being unpatentable over claims 1 and 10-15 of copending Application No. 17/931,027 in view of Bonnen et al (WO 2021/092130 Al) has been maintained in view of Applicant’s arguments filed on 08/08/2025 as Applicant’s arguments were considered but not found persuasive. Applicant’s arguments were not found to be persuasive because the NSDP rejection is not the only rejection remaining in the application at this time.
The previous rejection of claims 1, 7, 89 and 90 under provisional nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 18/688,176 in view of Bonnen et al (WO 2021/092130 Al) has been maintained in view of Applicant’s arguments filed on 08/08/2025 as Applicant’s arguments were considered but not found persuasive. Applicant’s arguments were not found to be persuasive because the NSDP rejection is not the only rejection remaining in the application at this time.
The previous rejection of Claims 1, 7, 25, 28, 89 and 90 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 13 and 17 of copending Application No. 17/885,876 in view of Bonnen et al (WO 2021/092130 Al) has been withdrawn in view of the abandonment of Application No. 17/885,876.
The previous rejection of Claims 1, 7, 13, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims claims 1-3, 8, 17 and 409 of copending Application No. 17/916,270 in view of Bonnen et al (WO 2021/092130 A1) has been withdrawn in view of the Applicant’s arguments filed on 08/08/2025.
The previous rejection of Claims 1, 7, 13, 25, 28, 57, 62, 63, 67, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 66, 71-73, 75-77, 79, 81-83 and 85-87 of copending Application No. 18/052,791 in view of Bonnen et al (WO 2021/092130 A1) has been withdrawn in view of the Applicant’s arguments filed on 08/08/2025.
The previous rejection of Claims 1, 7, 13, 25, 28, 57, 62, 63, 67, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 66, 67, 70-73, 75-77, 79, 81- 83 and 85-87 of copending Application No. 18/052,801 in view of Bonnen et al (WO 2021/092130 A1) has been withdrawn in view of the Applicant’s arguments filed on 08/08/2025.
The previous rejection of Claims 1, 7, 89 and 90 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 50-52 and 58 of copending Application No. 18/262,086 in view of Bonnen et al (WO 2021/092130 A1) has been withdrawn in view of the Applicant’s arguments filed on 08/08/2025.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637