DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10 December 2025 has been entered.
Application Status
This action is written in response to applicant’s correspondence received 9 June 2025. Claims 42, 49, 51, 53-54, 57, 59, 96, 98-100, 102, and 106-111 are pending. Claim 42 is amended. Claims 107-111 are newly added. Claims 97, 101, and 103-105 are canceled. Accordingly, claims 42, 49, 51, 53, 57, 59, 96, 98-100, 102, and 106-111 are currently under examination.
Applicant’s amendments, filed 9 June 2025, have been fully considered and are deemed persuasive. Accordingly, the previously pending 35 USC § 112(b) and 103 rejections of record have been withdrawn. However, Applicant’s arguments with respect to the previously cited Liu, Pearl, Rai, Hu, Robert, Fujita, and Kuluev references are not found persuasive (see “Response to Argument” section below).
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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 42, 49, 96, and 107-110 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706).
Regarding claim 42, Liu is drawn to a methods of using a fusion protein system that is capable of inducing a cytosine into a guanine change in a target nucleic acid (Abstract). Liu teaches that the fusion protein system comprises a Cas9 nucleic acid programmable DNA binding protein (i.e., a CRISPR-Cas effector protein comprising a Cas9 polypeptide), a uracil DNA glycosylase domain (i.e., a “UDG” domain), and a cytidine deaminase ([0003]). Liu teaches that the programmable DNA binding protein may be a nuclease active or inactive Cas9 that utilizes a guide nucleic acid to target a nucleic acid of interest ([0071]). Liu teaches that the cytidine deaminase may be an APOBEC deaminase ([00176]). Liu teaches that the fusion protein can modify a cytosine of a target nucleic acid into a guanine via the excision of uracil from the target nucleic acid molecule mediated by the UDG (i.e., the UDG domain is recruited to the target nucleic acid) ([0002], [0006]; see Figure 1 for schematic illustration of C to G base editing).
Liu does not teach or suggest a method wherein the uracil DNA glycosylase domain is a uracil N-glycosylase (Claim 42). Liu does not teach or suggest a method where the residence time of the CRISPR-Cas protein at a target nucleic acid is reduced (Claim 42). Liu does not teach or suggest that the target nucleic acid is in a plant cell (Claim 42).
However, one of ordinary skill in the art would have considered the teachings of Pearl, Wu, and Kuluev as the references are common fields of endeavor art pertaining to the use of uracil glycosylases and CRISPR-Cas effector proteins.
Pearl is drawn to a study concerned with structure and function of glycosylases in the uracil-DNA glycosylase superfamily (Abstract). Pearl teaches that uracil-DNA N-glycosylase is within the uracil-DNA glycosylase superfamily (i.e., uracil-DNA N-glycosylase is a UDG) and is able to excise uracil from ssDNA and from dsDNA in both G:U and A:U base-pairs (pg. 177).
Wu is drawn towards a review study concerned with how CRISPR protein guide RNAs can be engineered in order to reduce off-target effects (Abstract). Wu teaches that it was known in the art that long-term expression of CRISPR by viral vectors may exacerbate off-target effects (pg. 526). Wu teaches that it was known in the art that designing a self-restricted CRISPR/Cas9 system that comprises nucleic acids encoding a gRNA that targets and allows for cleavage of a target sequence, a gRNA targeting a nucleic acid sequence encoding Cas9, and a nucleic acid encoding Cas9 was well-known in the art (pg. 526-527; see Fig. 4D). Wu teaches that utilizing a self-restricted CRISPR/Cas9 system restricts both the copies and the residence time of CRISPR within cells (i.e., such that the residence time of the CRISPR-Cas effector protein at a target nucleic acid is reduced) results in greatly increased specificity of the system for genome editing and minimized off-target effects (pg. 526-527; see Fig. 4D).
Kuluev is drawn to a review study of the progression of CRISPR/Cas editing in plants (Abstract). Kuluev teaches that CRISPR/Cas genome editing of plants (i.e., within plant cells) is realized in three basic variants, including knockout mutations as indels, insertion of alien DNA fragments, and base editing via deamination of nitrogenous bases by corresponding deaminases cross-linked with catalytically inactive nucleases (Abstract). Kuluev teaches that CRISPR guide RNAs corresponding to chosen targets in plant cells can be designed using various computer programs (pg. 695). Kuluev teaches that CRISPR/Cas editing via deamination and C to T base transformation via the use of guide RNAs that targets a Pro190 codon within an acetolactate synthase gene of watermelon resulted in the resistance of transformants to the tribenuron herbicide (pg. 696).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the UDG described by Liu for a uracil-DNA N-glycosylase, as described by Pearl, modify the CRISPR/Cas9 fusion system of Liu such that a gRNA targeting the nucleic acid sequence that encodes the Cas9 was utilized in order to reduce the residence time of the Cas9 at a target nucleic acid, as described by Wu, and substitute the target guide nucleic acid sequence and cell of Liu for a guide nucleic acid target sequence that targets a nucleic acid present in a plant cell, as described by Kuluev. A person of ordinary skill in the art would have been motivated to do so in order to reduce the off-target effects of the Cas9 that were well-known in the art to be derived from high residence time of the Cas9 nuclease in cells. A person of ordinary skill in the art would have had a reasonable expectation of success in substituting the UDG and guide RNA target sequence of Liu for a uracil-DNA N-glycosylase, as described by Pearl, and a guide RNA target sequence that targets a nucleic acid within a plant cell, as described by Kuluev, because Liu teaches the use of a genus of UDGs which, as described by Pearl, includes uracil-DNA N-glycosylases and both Liu and Kuluev teach the use of CRISPR systems that can successfully target and edit nucleic acids of interest via the use of different designed guide RNA sequences. A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the method of Liu such that a gRNA targeting the nucleic acid sequence that encodes the Cas9 was utilized in order to reduce the residence time of the Cas9 at a target nucleic acid, as described by Wu, because both Liu and Wu teach the use of functional CRISPR systems that utilize guide RNAs to successfully target and cleave nucleic acid sequences of interest and Wu further teaches that utilizing a self-restricted CRISPR/Cas9 system was well-known in the art.
Regarding claim 49, Liu teaches that the system achieves C to G base editing through the generation of an abasic site followed by replacement of the base opposite the abasic site via a polymerase (i.e., the polymerase utilizes the abasic site as a template) ([0002]-[0003]). Liu teaches that the system recruits a polymerase through the use of a nucleic acid polymerase domain ([0005]). Liu teaches that the term “nucleic acid polymerase domain” includes a DNA polymerase ([0069]).
Regarding claim 96, Liu teaches that the cytidine deaminase can be an APOBEC deaminase ([00176]).
Regarding claims 107-109, Liu teaches that the APOBEC deaminase can be an APOBEC1 or APOBEC3A deaminase ([00176]).
Regarding claim 110, Liu teaches that the cytosine deaminase may be a pmCDA1 deaminase (i.e., a CDA1 deaminase) ([00176]).
Claims 51 and 98 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706) as applied to claims 42, 49, 96, and 107-110 above, and in further view of Rai (Journal of medicinal chemistry 55.7 (2012): 3101-3112).
Regarding claims 51 and 98, Liu in view of Pearl, Wu, and Kuluev renders obvious claims 42, 49, 96, and 107-110 as described above.
Liu further teaches that the system may be utilized to target various cancers ([00241]) including cancers associated with point mutations ([00246]).
Liu does not specifically teach a method comprising inhibiting APE1 (i.e., AP endonuclease I) (Claim 51) or contacting the target nucleic acid with an APE1 inhibitor (Claim 98).
However, one of ordinary skill in the art would have considered the teachings of Rai as both references are drawn to the repair of bases that have been modified.
Rai is drawn to a study concerning the generation of novel apurinic or apyrimidinic (i.e., AP) endonuclease 1 inhibitors (Abstract). Rai teaches that overexpression of APE1 and enhanced AP endonuclease activity have been linked to increased resistance of tumor cells to treatment with monofunctional alkylators, implicating inhibition of APE1 as a valid strategy for cancer therapy (Abstract). Rai further teaches the use and comparison of two novel compounds, compounds 3 and 52 (see pg. 3102-3104 for synthesis schematic), that can be utilized to inhibit APE1 and teaches that analysis of the properties of compounds 52 and 3 in mice revealed that compound 52 has a better general cytotoxicity profile, higher exposure levels, and a more favorable t(1/2) in plasma when compared to compound 3 (pg. 3109). Rai further teaches that, for tumors outside the brain cavity a compound like 52, which does not efficiently cross the blood brain barrier, would be useful in avoiding potential complications associated the brain (pg. 3109).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Liu in view of Pearl, Wu, and Kuluev in such a manner as to inhibit APE1 through the use of an APE1 inhibitor, as described by Rai. A person of ordinary skill in the art would have been motivated to do so in order to inhibit an endonuclease known to contribute to increased resistance of tumor cells to various treatment methods. A person of ordinary skill in the art would have had a reasonable expectation of success because Liu in view of Pearl, Wu, and Kuluev teaches that the fusion protein system may be utilized to target and treat various cancers and Rai taches that inhibiting APE1 was a known to complement cancer therapies.
Claim 53 is rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706) as applied to claims 42, 49, 96, and 107-110 above, and in further view of Hu (Cell & bioscience 8.1 (2018): 1-15).
Regarding claim 53, Liu in view of Pearl, Wu, and Kuluev renders obvious claims 42, 49, 96, and 107-110 as described above.
Liu in view of Pearl, Wu, and Kuluev does not teach or suggest a method wherein the target nucleic acid is contacted with a DNA ligase IV inhibitor (Claim 53).
However, one of ordinary skill in the art would have considered the teaching of Hu as both references are analogous prior art pertaining to the use of CRISPR/Cas9 systems.
Hu is drawn to a study concerning the combination of a DNA ligase IV inhibitor with a CRISPR/Cas9 system and teaches that the combination can markedly improve CRISPR/Cas9-HDR (i.e., homology-directed repair) (pg. 1; see conclusion). Hu teaches that administration of a DNA ligase IV inhibitor can aid in increasing the efficiency of HDR-mediated repair as the inhibitor blocks the NHEJ pathway (pg. 9). Hu teaches that improving the efficiency of HDR in CRISPR/Cas systems is imperative because HDR is essential for targeted gene editing (pg. 9).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Liu in view of Pearl, Wu, and Kuluev in such a manner as to allow for the contacting of the target nucleic acid with a DNA ligase IV inhibitor, as described by Hu. A person of ordinary skill in the art would have been motivated to do so in order to improve the ability for the CRISPR/Cas system to utilize HDR (i.e., a process essential for targeted genome editing). A person of ordinary skill in the art would have had a reasonable expectation of success because both Hu and Liu in view of Pearl, Wu, and Kuluev teach the use of functional CRISPR/Cas systems that can successfully target and edit target nucleic acid sequences in cells and Hu further teaches that administering a DNA ligase IV inhibitor is complementary to CRISPR/Cas-mediated editing of target nucleic acids.
Claim 54 is rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706) as applied to claims 42, 49, 96, and 107-110 above, and in further view of Robert (Genome medicine 7 (2015): 1-11).
Regarding claim 54, Liu in view of Pearl, Wu, and Kuluev renders obvious claims 42, 49, 96, and 107-110 as described above.
Liu in view of Pearl, Wu, and Kuluev does not teach or suggest a method wherein the target nucleic acid is contacted with a DNA-PKcs inhibitor (Claim 54).
However, one of ordinary skill in the art would have considered the teaching of Robert as both references are analogous prior art pertaining to the use of CRISPR/Cas9 systems.
Robert is drawn to a study concerning the successful compatibility of DNA-PKcs inhibition in conjunction with a CRISPR/Cas9 editing system (pg. 7 and see Fig. 1). Robert teaches that DNA-PKcs is a key player in NHEJ (i.e., non-homologous DNA end joining) and its inhibition can lead to increased rates of HDR (Claim 54) (pg. 1 see abstract). Robert also teaches that DNA-PKcs inhibitors can also be used to stimulate HDR by oligonucleotide donor templates while suppressing NHEJ events (pg. 6).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Liu in view of Pearl, Wu, and Kuluev in such a manner as to allow the target nucleic acid to be contacted with a DNA-PKcs inhibitor, as described by Robert. A person of ordinary skill in the art would have been motivated to do so in order to improve the ability for the CRISPR/Cas system to utilize HDR (i.e., a process essential for targeted genome editing). A person of ordinary skill in the art would have had a reasonable expectation of success because both Robert and Liu in view of Pearl, Wu, and Kuluev teach the use of functional CRISPR/Cas systems that can successfully target and edit target nucleic acid sequences in cells and Robert further teaches that administering a DNA-PKcs inhibitor is complementary to CRISPR/Cas-mediated editing of target nucleic acids.
Claims 57 and 99-100 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706) as applied to claims 42, 49, 96, and 107-110 above, and further in view of Fujita (International Journal of Molecular Sciences 16.10 (2015): 23143-23164).
Regarding claim 57 and 99-100, Liu in view of Pearl, Wu, and Kuluev renders obvious claims 42, 49, 96, and 107-110 as described above.
Liu in view of Pearl, Wu, and Kuluev does not teach or suggest a method wherein an exogenous polymerase is fused to the CRISPR/Cas effector protein (Claim 57). Liu in view of Pearl, Wu, and Kuluev does not teach or suggest a method wherein the target nucleic acid is contacted with an exogenous polymerase (Claim 99) via the recruitment of the polymerase to the CRISPR/Cas effector protein (Claim 100).
However, one of ordinary skill in the art would have considered the teachings of Fujita as both references are analogous prior art pertaining to the use of CRISPR/Cas systems.
Fujita is drawn to a study concerning the application of CRISPR/Cas systems in various biological activities such as transcriptional activation or repression (Abstract). Fujita teaches that it was known in the art that CRISPR/Cas9 nucleases can be fused to an RNA polymerase in order to promote transcription in a target gene via the recruitment of the RNA polymerase to the target gene via the CRISPR/Cas9 nuclease (pg. 23147).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Liu in view of Pearl, Wu, and Kuluev in such a manner as to fuse an exogenous polymerase to the CRISPR/Cas effector protein that contacts a target nucleic acid, as described by Fujita. A person of ordinary skill in the art would have been motivated to do so in order to allow for the promotion of transcription in a target gene. A person of ordinary skill in the art would have had a reasonable expectation of success because both Fujita and Liu in view of Pearl, Wu, and Kuluev teach the use of functional CRISPR/Cas systems that can utilize a guide RNA to recruit an effector protein to a target nucleic acid of interest.
Claims 59 and 102 are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706) as applied to claims 42, 49, 96, and 107-110 above, and further in view of Huang (Genome biology 18 (2017): 1-11).
Regarding claims 59 and 102, Liu in view of Pearl, Wu, and Kuluev renders obvious claims 42, 49, 96, and 107-110 as described above.
Liu in view of Pearl, Wu, and Kuluev does not teach or suggest a method wherein the CRISPR-Cas effector protein comprises a peptide tag (Claim 59). Liu in view of Pearl, Wu, and Kuluev does not teach or suggest a method wherein the cytosine deaminase comprises a peptide tag (Claim 102).
However, one of ordinary skill in the art would have considered the teachings of Huang as both references are analogous prior art pertaining to the use of CRISPR systems to edit target genomes.
Huang is drawn towards a study concerned with DNA epigenome editing using a CRISPR/Cas9 SunTag system (Abstract). Huang teaches that the SunTag system is utilized with a CRISPR-associated Cas effector protein it entails the fusion of the CRISPR-associated Cas effector protein to a SunTag epitope and the fusion of a heterologous protein of interest to a single-chain variable fragment (i.e., an scFv affinity peptide tag) such that the heterologous protein is recruited to the CRISPR-associated Cas effector protein and targeted to a target nucleic acid of interest (pg. 2-3; see Fig. 1). Huang teaches that the SunTag system is well-known in the art and that the heterologous protein of interest is not solely limited to the heterologous protein DNMT3A utilized in the study (pg. 2).
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the CRISPR/Cas effector protein of Liu in view of Pearl, Wu, and Kuluev such that the effector protein comprised a SunTag epitope and the cytosine deaminase comprised an scFv affinity peptide tag, as described by Huang. A person of ordinary skill would have been motivated to do so in order to recruit a cytosine deaminase to a target nucleic acid through the use of a well-known SunTag system. A person of ordinary skill in the art would have had a reasonable expectation of success because both Huang and Liu in view of Pearl, Wu, and Kuluev teach the use of a CRISPR/Cas system that can recruit a heterologous protein to a target nucleic acid of interest.
Claim(s) 106 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706) as applied to claims 42, 49, 96, and 107-110 above, and further in view of Stoner (PG Pub No. WO 2019/222545 A1, published 21 November 2019).
Regarding claim 106, Liu in view of Pearl, Wu, and Kuluev renders obvious claims 42, 49, 96, and 107-110 as described above.
Liu in view of Pearl, Wu, and Kuluev does not teach or suggest that the guide nucleic acid has less than 90% complementarity to the target nucleic acid (Claim 106).
However, one of ordinary skill in the art would have considered the teachings of Stoner as both references are common fields of endeavor pertaining to the use of Cas9 guide RNAs.
Stoner is drawn towards a study concerned with methods for designing guide RNAs for hybridizing to a genomic region of interest (Abstract; [0005]). Stoner teaches the use of a CRISPR/Cas system, including Cas9, that can utilize a guide RNA to target a genomic region of interest ([0070]-[0072]). Stoner teaches that the guide RNAs may be 17-42 nucleotides in length and comprise 1-5 mismatches relative to a target genomic sequence (i.e., Stoner teaches the use of a Cas9 guide RNA that has less than 90% complementarity to a target nucleic acid) and can selectively hybridize to the genomic region of interest ([0007]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the Cas9 guide RNA rendered obvious by Liu in view of Pearl, Wu, and Kuluev for a Cas9 guide RNA that less than 90% complementarity to the target nucleic acid, as described by Stoner. A person of ordinary skill in the art would have had a reasonable expectation of success because both Stoner and Liu in view of Pearl, Wu, and Kuluev teach the use of functional Cas9 guide RNAs that can direct the Cas9 to a target nucleic acid of interest.
Claim(s) 111 is/are rejected under 35 U.S.C. 103 as being unpatentable over Liu (PG. Pub No. WO 2018/165629 A1) in view of Pearl (Mutation Research/DNA Repair 460.3-4 (2000): 165-181), Wu (Journal of Genetics and Genomics 46.11 (2019): 523-529), and Kuluev (Russian Journal of Plant Physiology 66 (2019): 694-706) as applied to claims 42, 49, 96, and 107-110 above, and further in view of “Liu ‘828” (PG Pub No. US 2018/0312828 A1).
Regarding claim 111, Liu in view of Pearl, Wu, and Kuluev renders obvious claims 42, 49, 96, and 107-110 as described above.
Liu in view of Pearl, Wu, and Kuluev does not teach or suggest the use of a cytosine deaminase that has a sequence having at least 95% identity to the claimed SEQ ID NO: 40 (Claim 111).
However, one of ordinary skill in the art would have considered the teachings of Liu ‘828 as both references are common fields of endeavor pertaining to the use of cytosine deaminases in methods of base editing.
Liu ‘828 is drawn towards an invention concerned with methods of editing a target nucleic acid through the use of fusion proteins (Abstract). Liu ‘828 teaches the use of a fusion protein comprising a napDNAbp (i.e., a Cas9 CRISPR protein ([0008])) that is fused to an APOBEC ([0016]). Liu ‘828 teaches the use of an rAPOBEC1 comprising 100% sequence identity to the claimed SEQ ID NO: 40 ([0599]; see SEQ ID NO: 737 in attached sequence alignment).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute the APOBEC deaminase rendered obvious by Liu in view of Pearl, Wu, and Kuluev for an rAPOBEC1 deaminase having 100% identity to the claimed SEQ ID NOI: 40, as described by Liu ‘828. A person of ordinary skill in the art would have had a reasonable expectation of success because both Liu ‘828 and Liu in view of Pearl, Wu, and Kuluev teach the use of a CRISPR protein fused to an APOBEC deaminase.
Response to Arguments
Applicant's argument, filed 10 December 2025, have been fully considered but are not deemed persuasive for the following reasons.
Applicant alleges that the combination of Liu, Pearl, and Kuluev fails to teach or suggest a method of modifying a target nucleic acid as claimed in instant claim 1. Applicant alleges that, as conceded in the action, Liu does not teach or suggest the use of a uracil N-glycosylase in a plant cell, wherein the residence time of the CRISPR effector is reduced. Applicant alleges that Pearl is silent with regard to a CRISPR effector, a guide nucleic acid, and a deaminase. Applicant alleges that Wu does not teach a reduction in residence time of the CRISPR system at a target nucleic acid or the use of a deaminase or glycosylase. Applicant alleges that the Kuluev does not teach or suggest the use of a glycosylase, nor the reduction of the residence time of the CRISPR effector.
These arguments are not found persuasive because, as an initial mater, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d413, 208 USPQ871 (CCPA 1981); In re Merck & Co., 800 F.2d1091, 231 USPQ375 (Fed. Cir. 1986). In the instant rejection of record, Liu is relied upon for teaching a method comprising the claimed contacting of a target nucleic acid with a CRISPR-Cas effector protein, a guide nucleic acid, a cytosine deaminase, and a uracil glycosylase domain. Pearl teaches that uracil N-glycosylases are known glycosylase domains. Wu teaches that there are advantages for reducing the residence time of a CRISPR system at a target nucleic acid of interest. Kuluev teaches that utilizing CRISPR systems within plant cells was well-known in the art. Thus, it is in the combination of Liu, Pearl, Wu, and Kuluev that a person of ordinary skill in the art arrives at the claimed invention.
Applicant alleges that there is no motivation to substitute the uracil glycosylase domain of Liu for the uracil N-glycosylase of Pearl.
This argument is not found persuasive because, as noted at MPEP 2141, rationales that can support a conclusion of obviousness under 35 U.S.C. 103 can include simple substitution of one known element for another or [emphasis added] some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Accordingly, MPEP 2141 teaches that utilizing the simple substitution rationale does not require the recitation of an explicit motivation to combine references nor does the 35 U.S.C. 103 rejections of record recite a motivation statement with regard to pending claim 42 and the simple substitution of the uracil glycosylase domains.
Applicant alleges that Wu does not teach or suggest the reduction of residence time at a target nucleic acid; rather, Wu teaches the reduction of residence time of the CRISPR system within cells.
This argument is not found persuasive because the reduction of the residence time of the CRISPR system of Liu within cell necessarily results in a reduced residence time at a target nucleic acid of interest when compared to CRISPR systems that did not have their residence time reduced at all.
Applicant alleges that Kuluev is not applicable prior art because Kuluev teaches the modification of a cytosine to an adenine or guanine in a plant cell via the use of a CRISPR system.
This argument is not found persuasive because Kuluev was not relied upon for the teaching of the modification of the target nucleic acid. Kuluev was relied upon for teaching the use of a CRISPR system within a plant cell.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE T REGA whose telephone number is (571)272-2073. The examiner can normally be reached M-R 8:30-4:30, every other F 8:30-4:30 (EDT/EST).
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636