DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1, 2, and 4-10 are pending in the application.
Applicant’s amendment to the claims, filed September 19, 2025, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Applicant’s amendment to the specification, filed September 19, 2025, is acknowledged.
Applicant’s remarks filed September 19, 2025 in response to the non-final rejection mailed March 24, 2025 are acknowledged.
Rejections previously applied to claim 3 are withdrawn in view of applicant’s amendment to cancel claim 3.
Restriction/Election
In response to a requirement for restriction/election mailed October 9, 2024, applicant elected without traverse species (D), Virion infectivity factor (Vif), in the reply filed March 10, 2025.
Claim 5 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected species, there being no allowable generic or linking claim.
In view of applicant’s amendment to claim 7, deaminase is no longer a species of DNA modifying enzyme-binding module. Claims 7 and 8 are rejoined and are being examined on the merits.
Claims 1, 2, 4, and 6-10 are being examined on the merits with claims 1 and 6 being examined only to the extent the claims read on the elected subject matter.
Specification/Informalities
The objection to the specification for an embedded hyperlink is withdrawn in view of applicant’s amendment to the specification.
Claim Interpretation
As amended, claim 1 is drawn to (in relevant part) a complex comprising
a nucleic acid sequence-recognizing module specifically binding to a target nucleotide sequence in a DNA and
a DNA modifying enzyme-binding module bonded to each other,
wherein the nucleic acid sequence-recognizing module is a CRISPR-Cas system,
wherein at least one DNA cleavage ability of Cas is inactivated, and
wherein the DNA modifying enzyme-binding module is Virion infectivity factor (Vif) and fragments thereof that bind to the DNA modifying enzyme.
The recitation of “a CRISPR-Cas system” is interpreted as meaning a Cas endonuclease and a guide RNA complementary to a target sequence in a DNA.
The recitation of “wherein at least one DNA cleavage ability of Cas is inactivated” is interpreted as meaning that the Cas endonuclease of the CRISPR-Cas system has modification(s) to abolish double stranded DNA cleavage activity while maintaining single stranded DNA cleavage activity (nickase activity) or has modification(s) to abolish double stranded DNA cleavage activity and single stranded DNA cleavage activity. Regardless of the modification(s), given that claim 1 recites “a nucleic acid sequence-recognizing module specifically binding to a target nucleotide sequence in a DNA,” the recited Cas maintains specific binding activity to a target nucleotide sequence in a DNA.
Regarding the recitation of “Virion infectivity factor (Vif)…and fragments thereof that bind to the DNA modifying enzyme,” according to the instant specification (p. 17, paragraph [0032]), “[e]xamples of the protein that binds to a DNA modifying enzyme include, but are not limited to, Vif (Virion Infectivity Factor)…These proteins may be altered (altered protein is sometimes referred to as a ‘variant’ of protein)…For example, when Vif is used…it is preferable to apply alteration that causes lack of bindability to proteins other than APOBEC3. Examples of such alteration include deletion of several (e.g., 11, 10, 9, 8, 7 etc.) amino acids in the N terminal of Vif protein (refseq No. AAF20197) and substitution of the 145th leucine residue with other amino acid residue (e.g., alanine residue) and the like, but they are not limited to these alterations…The above-mentioned protein fragment is not particularly limited as long as it has a binding region to the DNA modifying enzyme” (underline added for emphasis). According to MPEP 2111, “[d]uring patent examination, the pending claims must be ‘given their broadest reasonable interpretation consistent with the specification’" and in light of the specification’s broad description of “Vif” as being an “altered protein” or “variant” with unlimited alterations, the recitation of “Vif” in claims 1 and 6 is interpreted as encompassing a protein having any amino acid sequence, wherein the protein binds to a DNA modifying enzyme.
Claim Rejections - 35 USC § 112(a)
The rejection of claims 1, 2, 4, 6, 9, and 10 under 35 U.S.C. 112(a) because the specification does not reasonably provide enablement for all complexes as encompassed by the claims is withdrawn in view of the instant amendment to claim 1 to delete the phrase “wherein the complex converts one or more nucleotides in the targeted site to other one or more nucleotides or deletes one or more nucleotides, or inserts one or more nucleotides into the targeted site.”
The rejection of claims 1, 2, 4, 6, 9, and 10 under 35 U.S.C. 112(a) as failing to comply with the written description requirement is withdrawn in view of the instant amendment to claim 1 to delete the phrase “wherein the complex converts one or more nucleotides in the targeted site to other one or more nucleotides or deletes one or more nucleotides, or inserts one or more nucleotides into the targeted site.”
Claim Rejections - 35 USC § 102
The rejection of claims 1, 2, 4, 6, and 10 under 35 U.S.C. 102(a)(1) as being anticipated by Nishida et al. (WO 2015/13554 A1; cited on the IDS filed on December 14, 2023; hereafter “Nishida”) is withdrawn in favor of the new rejection set forth below, which includes the evidentiary reference Salter et al. (Trends Biochem. Sci. 41:578-594, 2016; cited on the attached Form PTO-892; hereafter “Salter”) to address the limitations of rejoined claim 8.
Claims 1, 2, 4, 6-8, and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nishida et al. (WO 2015/13554 A1; cited on the IDS filed on December 14, 2023; hereafter “Nishida”) as evidenced by Salter. Reference is made to US 2017/0073670 A1 (cited on the IDS filed on December 14, 2023) as an English-language translation of Nishida.
Regarding claims 1 and 6, claim 20 of US 2017/0073670 A1 recites a nucleic acid-modifying enzyme complex wherein a nucleic acid sequence-recognizing module that specifically binds to a target nucleotide sequence in a given double stranded DNA and a nucleic acid base converting enzyme are bonded and the nucleic acid sequence-recognizing module is a CRISPR-Cas system wherein at least one DNA cleavage ability of Cas is inactivated, which complex converts one or more nucleotides in the targeted site to other one or more nucleotides or deletes one or more nucleotides, or inserts one or more nucleotides into said targeted site, without cleaving at least one strand of said double stranded DNA in the targeted site.
US 2017/0073670 A1 teaches the nucleic acid sequence-recognizing module can be provided as a fusion to a protein binding domain such as SH3 domain, PDZ domain, GK domain, GB domain and the like and a binding partner thereof may be fused with a nucleic acid base converting enzyme and provided as a protein complex via an interaction of the domain and a binding partner thereof (paragraph [0046]). Given the specification’s broad description of “Vif,” the protein binding domain at paragraph [0046] of US 2017/0073670 A1 is interpreted as being encompassed by “Vif” in claims 1 and 6.
US 2017/0073670 A1 teaches the CRISPR-Cas system recognizes the object double stranded DNA sequence by a guide RNA complementary to the target nucleotide sequence (paragraph [0093]). US 2017/0073670 A1 teaches the nucleic acid sequence-recognizing module of the present invention using CRISPR-mutant Cas is provided as a complex of an RNA molecule consisting of a guide RNA complementary to the target nucleotide sequence and tracrRNA necessary for recruiting mutant Cas protein, and a mutant Cas protein (paragraph [0096]).
Regarding claim 2, claim 21 of US 2017/0073670 A1 recites a nucleic acid encoding the nucleic acid-modifying enzyme complex according to claim 20.
Regarding claim 4, US 2017/0073670 A1 teaches the CRISPR-Cas system recognizes the object double stranded DNA sequence by a guide RNA complementary to the target nucleotide sequence (paragraph [0093]). US 2017/0073670 A1 teaches the nucleic acid sequence-recognizing module of the present invention using CRISPR-mutant Cas is provided as a complex of an RNA molecule consisting of a guide RNA complementary to the target nucleotide sequence and tracrRNA necessary for recruiting mutant Cas protein, and a mutant Cas protein (paragraph [0096]). US 2017/0073670 A1 teaches the Cas protein to be used in the present invention is not particularly limited as long as it belongs to the CRISPR system, and preferred is Cas9 (paragraph [0097]).
Regarding claim 7, claim 25 of US 2017/0073670 A1 recites the nucleic acid base converting enzyme is a deaminase.
Regarding claim 8, US 2017/0073670 A1 teaches the deaminase is activation-induced cytidine deaminase, i.e., AID (paragraph [0039]). US 2017/0073670 A1 does not teach AID is an APOBEC, however, evidentiary reference Salter is cited in accordance with MPEP 2131.01.III to show that AID is an APOBEC (p. 578, middle).
Regarding claim 10, claim 20 of US 2017/0073670 A1 recites the complex converts one or more nucleotides in the targeted site to other one or more nucleotides or deletes one or more nucleotides, or inserts one or more nucleotides into said targeted site, without cleaving at least one strand of said double stranded DNA in the targeted site.
Therefore, Nishida anticipates claims 1, 2, 4, 6-8, and 10 as written.
RESPONSE TO REMARKS: Applicant argues Nishida does not teach or suggest the DNA modifying enzyme-binding modules specified in claim 1.
Applicant’s argument is not found persuasive. The instant specification discloses “Vif” encompasses variants with unlimited amino acid alterations (p. 17, paragraph [0032]). Given the specification’s broad description of “Vif,” the protein binding domain of Nishida (see paragraph [0046] of US 2017/0073670 A1) is interpreted as being encompassed by “Vif” in claims 1 and 6.
For these reasons, Nishida anticipates claims 1, 2, 4, 6-8, and 10.
Claim Rejections - 35 USC § 103
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Nishida in view of Komor et al. (Nature 533:420-424, 2016; cited on the IDS filed on December 14, 2023; hereafter “Komor”).
Claim 9 is drawn to the complex according to claim 1, wherein the nucleic acid sequence-recognizing module bonded to the DNA modifying enzyme-binding module further comprises a base excision repair inhibitor bonded thereto.
The relevant teachings of Nishida as applied to claim 1 are set forth above. Regarding claim 9, Nishida teaches a specific embodiment of the complex as an AID cytidine deaminase and dCas9 fused via SH3 domain and a SH3 ligand (paragraphs [0020] and [0137] and Figure 4 of US 2017/0073670 A1).
Nishida does not teach a base excision repair inhibitor.
The reference of Komor teaches that fusing a uracil DNA glycosylase inhibitor (UGI) to the C-terminus of dCas9 in a fusion of a cytidine deaminase and dCas9 had the effect of increasing the efficiency of base editing (p. 421, column 2, bottom to p. 422, column 1, top). UGI is considered to be a base excision repair inhibitor in claim 9.
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine Nishida and Komor to modify the Cas of Nishida’s complex to comprise a C-terminal UGI. One would have been motivated to and would have expected success to do this because Nishida taught a complex of dCas9 and an AID cytidine deaminase as a specific embodiment, and Komor taught fusing a UGI to the C-terminus of dCas9 had the effect of increasing the efficiency of base editing by a fusion of dCas9 with a cytidine deaminase. Therefore, the complex of claim 9 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: Applicant argues claim 9 depends from claim 1 and neither Nishida nor Komor not teaches or suggests the DNA modifying enzyme-binding modules specified in claim 1.
Applicant’s argument is not found persuasive. The instant specification discloses “Vif” encompasses variants with unlimited amino acid alterations (p. 17, paragraph [0032]) and given the specification’s broad description of “Vif,” the protein binding domain of Nishida (see paragraph [0046] of US 2017/0073670 A1) is interpreted as being encompassed by “Vif” in claims 1 and 6.
Applicant argues the fusion strategy disclosed in Komor is specific to cytidine deaminase and differs from the claimed configuration involving a distinct enzyme-binding module. According to applicant, one of ordinary skill in the art would not have had reason to incorporate the UGI of Komor into the complex of Nishida with a reasonable expectation of success.
Applicant’s argument is not found persuasive. As stated above, Nishida teaches a specific embodiment of the complex as an AID cytidine deaminase and dCas9 fused via SH3 domain and a SH3 ligand as illustrated in Nishida’s Figure 2 (reproduced below for convenience).
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Given that Nishida teaches the utility of the complex is nucleic acid base editing (paragraph [0010] of US 2017/0073670 A1) and Komor teaches fusing a UGI to the C-terminus of dCas9 in a fusion of a cytidine deaminase and dCas9 had the effect of increasing the efficiency of base editing, one would have been motivated and expected success to modify the dCas9 of Nishida’s complex to comprise a C-terminal UGI.
For these reasons, the invention of claim 9 would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the claims:
Claims 1, 2, and 4-10 are pending.
Claim 5 is withdrawn from consideration.
Claims 1, 2, 4, and 6-10 are rejected.
No claim is in condition for allowance.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/David Steadman/Primary Examiner, Art Unit 1656