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 .
DETAILED ACTION
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on December 8, 2025. Pursuant to amendment filed on December 8, 2025, claims 1-3 and 8-10 are currently amended. Claims 4-6 have been canceled. Claim 12 is newly added.
Therefore, claims 1-3 and 7-12 are currently under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/CN2020/088887 filed May 07, 2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. CN201910375061.9, filed on May 07, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The certified English translation of the Foreign Priority document was received May 20, 2025. Applicant has not complied with one or more conditions for receiving the priority of the earlier filing date as follows: The certified English translation of the Foreign Priority disclosure fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. Specifically, the instant claims 1-3 and 7-12 are drawn to an APOBEC3A comprising an amino acid sequence of SEQ ID NO:7 introduced by the amendment filed December 8, 2025 represents new matter, See certified translation pg. 20.
The later-filed application must be an application for a patent for an invention that is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
Should the applicant disagree, the applicant is encouraged to point out with particularity by page and line number where such support might exist in the intervening document. In order to properly claim priority, the support for each of the claim limitations must exist in each of the intervening documents.
Thus, the earliest possible priority for the instant application is May 7, 2020.
Withdrawn- Specification Objection
The objection to the specification abstract has been withdrawn.
Withdrawn- Claim Rejections- 35 USC§ 112(a)
In view of Applicants’ amendment to the instant application’s claim set, the rejections under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement have been withdrawn.
Withdrawn- Claim Rejections - 35 USC § 112(b)
In view of Applicants’ amendment to claims 3, 9, and 10, removing the recitations of “such as”, “preferably”, and “for example”, the rejection of claims 3, 9, and 10 under 35 U.S.C. 112(b) has been withdrawn.
Withdrawn- Claim Rejections - 35 USC § 103
In view of Applicants amendment to the instant claims requiring new limitations, such as SEQ ID NO: 2 or SEQ ID NO: 7, the rejection under 35 U.S.C. 103 to claims 1-6 and 8-11 as being unpatentable over Lande et al. (US 2021/0322577 A1, filed Mar. 3, 2017) in view of Komor et al. (Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016), see IDS), Liu et al. (US 11,542,496 B2, filed Mar. 10, 2017; hereinafter Presidents and Fellows of Harvard), Liu et al. (US 12,043,852 B2, citation is to prior publication WO 2017/070633), Kwon et al. (US 7,723,093 B2, filed Jun. 26, 2007), and further in view of McCutchen-Maloney (US 6,365,355 B1, filed Aug. 29, 2000) has been withdrawn. Applicants’ arguments are moot in view of the withdrawn rejection. A response to Applicant’s arguments pertinent to a new or remaining rejection can be found below.
Claim objections
Claims 1 and 2 are objected to because of the following informalities: abbreviations such as APOBEC3A should be spelled out at the first encounter in the claims for clarity.
Claim 3 is objected to because of the following informalities: abbreviations such as spCas9 should be spelled out at the first encounter in the claims for clarity.
Claim 7 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
New Claim Rejections - 35 USC § 103
Claims 1-3 and 8-12 are newly rejected under 35 U.S.C. 103 as being unpatentable over Lande et al. (US 2021/0322577 A1, filed Mar. 3, 2017) in view of Komor et al. (Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 533, 420–424 (2016), see IDS), Liu et al. (US 11,542,496 B2, filed Mar. 10, 2017; hereinafter Presidents and Fellows of Harvard), Chen (US 11,884,947 B2, prior published August 29, 2019, WO 2019/161783), Liu et al. (US 12,043,852 B2, citation is to prior publication WO 2017/070633), Kwon et al. (US 7,723,093 B2, filed Jun. 26, 2007), and further in view of McCutchen-Maloney (US 6,365,355 B1, filed Aug. 29, 2000). This is a new rejection necessitated by amendment of the claims in the response filed December 8, 2025.
Regarding claims 1 and 2, Lande teaches technologies for modulating gene expression comprising, the polypeptide comprising a CRISPR nuclease (claim 8, [0164], and Example 12), and an AP lyase (claim 8, [0008], [0065], and [0108]), along with a guide RNA ([0021], [0085], [0261]). Regarding the targeting of a guide RNA being capable of targeting the polypeptide to the target sequence in the genome of the cell, the prior art recognizes the ability of CRISPR/Cas9 guide RNA precision targeting (claims 1-32).
While Lande teaches where the gene editing system utilizes a deaminase (claims 3, 8, and 26), the teachings of Lande do not expressly teach the components of a cytosine deaminase and species of N-glycosylase, uracil-DNA glycosylase (UDG).
However, Komor teaches the development of a base editing system for genome editing that enables the direct, irreversible conversion of one target DNA base into another in a programmable manner, without requiring dsDNA backbone cleavage or a donor template. Komor teaches engineered fusions of CRISPR/Cas9 and a cytidine deaminase enzyme that retain the ability to be programmed with a guide RNA, do not induce dsDNA breaks, and mediate the direct conversion of cytidine to uridine, thereby effecting substitution more efficiently and permanently (Abstract). Specifically, Komor teaches,
“The deamination of cytosine (C) is catalysed by cytidine deaminases and results in uracil (U), which has the base-pairing properties of thymine (T). Most known cytidine deaminases operate on RNA, and the few examples that are known to accept DNA require single-stranded (ss) DNA. Recent studies on the dCas9–target DNA complex reveal that at least nine nucleotides (nt) of the displaced DNA strand are unpaired upon formation of the Cas9–guide RNA–DNA ‘R-loop’ complex. Indeed, in the structure of the Cas9 R-loop complex, the first 11 nt of the protospacer on the displaced DNA strand are disordered, suggesting that their movement is not highly restricted11. It has also been speculated that Cas9 nickase-induced mutations at cytosines in the non-template strand might arise from their accessibility by cellular cytosine deaminase enzymes (pg. 420, column 2, para. 2).”
Furthermore, the ordinary artisan would have recognized the inclusion of N-glycosylase, specifically the species uracil DNA N-glycosylase (UNG/UDG) in CRISPR-Cas systems was recognized in the prior art, further in view of Presidents and Fellows of Harvard.
Presidents and Fellows of Harvard teaches cytosine-to-guanine base editors in which a programable DNA-binding protein such as Cas9 is fused to a cytidine deaminase and a base excision repair enzyme such as uracil DNA glycosylase. Presidents and Fellows of Harvard teaches incorporating UDG/UNG enables removal of the uracil intermediate created by cytidine deamination, producing an abasic site that is processed through downstream repair pathways to yield C-G conversions, thereby enabling base editing beyond simple C-to-T transitions (Abstract; Fig. 2 and 4; column 1 para. 5 through column 2, para. 2; claim 1).
Before the effective filing date, a person of ordinary skill in the art would have found it obvious to combine Lande’s teachings on optimization of domain orientation, linkers, and localization to improve editing efficiency and fidelity, Komor’s teachings establishing cytosine base editors by fusing a Cas9 nickase to a cytidine deaminase for C-T editing, and Presidents and Fellows of Harvard teachings of adding uracil DNA glycosylase (UNG/UDG) to the same modular architecture to process deaminated cytosines into abasic sites and thereby expanding the editing outcome spectrum. Each reference teaches a predictable, incremental modification of the same CRISPR-deaminase platform, and a person of ordinary skill would have had clear motivation and a reasonable expectation of success in incorporating UDG into an optimized CBE design to broaden editing outputs while retaining Cas9 targeting.
Furthermore, Lande explicitly teaches embodiments where gene editing system utilizes effector activity to alter a target site through a substitution, addition, or deletion of one or more nucleotides, including N-glycosylase and AP-lypase and the DNA targeting moiety can be a nucleic acid including DNA and RNA ([Claim 8], [0008], [0065], and [0108-0109]). The ordinary artisan would have recognized that Uracil DNA N-glycosylase (UNG/UDG) is species of the genus N-glycosylases, and N-glycosylase is an enzyme that removes damaged or inappropriate bases from DNA by cleaving the N-glycosylic bond, which is the bond between a base and the sugar-phosphate backbone. This critical step was known to initiate the process of base excision repair (BER), a fundamental DNA repair pathway that protects the genome from damage and maintains its stability. Hence, Lande teaches the incorporation of the genus, and the species were taught by Presidents and Fellows of Harvard for parallel purposes.
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Regarding the limitation that the gene editing system comprise the cytosine deaminase is an APOBEC3A comprising an amino acid sequence of SEQ ID NO:2, the ordinary artisan would have recognized the inclusion of Human apolipoprotein B mRNA editing enzyme catalytic subunit 3A, or APOBEC3A, and Cas9 nucleases were standard for designing fusion proteins for base editing, in view of Chen, and found it obvious to simply substitute the known element for another to obtain the predictable result of producing a gene editing system. Chen teaches fusion proteins for base editing, including APOBEC3A and Cas9, including fusion protein 1 and dCas12a-hA3A-BE containing SEQ ID NO: 16 and SEQ ID NO: 40, with 100% identity to instant SEQ ID NO: 2 (Abstract; claims 1, 3, and 4; column 2, lines 57-59; column 19-20, bridging para.; Table 2).
Furthermore, regarding the inclusion of the APOBEC3A cytosine deaminase, Presidents and Fellows of Harvard teaches the cytidine deaminase domain is an APOBEC3A deaminase (column 79, lines 59-60), and where the fusion protein includes an APOBEC3A deaminase (column 93-93, bridging para.). Likewise, Liu teaches strategies, systems, reagents, methods, and kits that are useful for engineering Cas9 and Cas9 variants that have increased activity on target sequences (abstract), wherein the effector domain is a deaminase which is an APOBEC3A deaminase (column 14, lines 44-45 and column 46, lines 60-61). Thus, prior to the effective filing date, the ordinary artisan would have found it prima facie obvious to simply substitute the APOBEC3A deaminase, as taught by Chen, for the deaminase taught by Lande, Komor, Presidents and Fellows of Harvard and Liu and to obtain the predictable result of generating a gene editing system.
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Regarding the limitation that the UDG comprises the amino acid sequence shown in SEQ ID NO: 3, Kwon teaches the uracil-DNA glycosylase comprising the amino acid sequence shown in SEQ ID NO: 3 (SEQ ID NO: 28).
Prior to the effective filing date, the ordinary artisan would have found it obvious to simply substitute the UDG, as taught by Kwon, for the UDG taught by the combined teachings of Lande and Komor, to obtain the predictable result of generating a gene editing system.
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Regarding the limitation that the AP lyase comprises the amino acid sequence shown in SEQ ID NO.4 claim 6, McCutchen-Maloney teaches chimeric proteins having both DNA mutation binding activity and nuclease activity are synthesized by recombinant technology, wherein the endonuclease III recognizes primarily apurinic (abasic) sites system included apurinic (column 2, lines 58-62; column 6, lines 46-47 column 9, lines 34-39).
A person of ordinary skill in the art would recognize that another name for AP lyase is DNA-(apurinic or apyrimidinic site) lyase, also referred to as DNA-(apurinic or apyrimidinic site) 5'-phosphomonoester-lyase (systematic name), DNA AP lyase, or UV endonuclease. The ordinary artisan would have found it obvious to simply substitute the known Escherechia coli UVr C nuclease SEQ ID NO: 27, as taught by McCutchen-Maloney, for the AP lyase as taught by the combined teachings of Lande and Komor, to obtain the predictable result of generating a gene editing system. Furthermore, since the Escherechia coli UVr C nuclease and the AP lyase of the instant application are 100% homologous, the ordinary artisan would have found similar catalytic activity of the genetic system imparted by the nuclease activity of this component. It is prima facie obvious for the ordinary artisan to simply substitute one known element for another to obtain predictable results.
Regarding claim 3, the combined teachings of Lande, Komor, Presidents and Fellows of Harvard, Chen, Liu, Kwon, McCutchen-Maloney render claim 1 obvious. Additionally, Lande (claim 8) and Komor (abstract) teach wherein the CRISPR nuclease is a Cas9 nuclease. Streptococcus pyogenes, or spCas9 is a widely used nuclease in the CRISPR-Cas9 genome editing system also taught by Chen (column 18, para. 1).
Regarding claims 8-11, the combined teachings of Lande, Komor, Presidents and Fellows of Harvard, Chen, Liu, Kwon, McCutchen-Maloney render claim 1 obvious. Additionally, Lande teaches the production of a genetically modified cell produced using the taught system (claim 24), including in plant and crop cells, such as Arabidopsis ([0158], Examples 9-11). Lande additionally teaches deletions of consecutive nucleotides in the target sequence ([0028]; [0037]; [0108]; Fig. 8). With respect to the kit (claim 11), the instruction for use only represents matter that is not related to the claimed composition, and it is not patentably significant (see MPEP 2111.05 I).
Response to Applicants' arguments as they apply to the rejection of claims 1-6 and 8-12 under 35 USC§ 103
Applicant's arguments filed December 8, 2025, have been fully considered but they are not persuasive.
At pages 7-9 of the remarks filed December 8, 2025, Applicants essentially argue the following:
The crux of the Applicants’ argument is that the references are deficient because neither teaches every component claimed and there is no motivation to combine or reasonable expectation of success, with respect to the cited combination.
This argument is not persuasive because, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). When considering the prior art, before the effective filing date, the ordinary artisan would have found it prima facie obvious to produce and apply the gene editing system presently claimed by simply substituting known elements for those claimed. The Examiner respectfully submits that patents are relevant as prior art for all they contain. "The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain." In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). With that, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, even nonpreferred embodiments. See MPEP § 2123: Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989); Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
For example, applicant argues that the teachings of Presidents and Fellows of Harvard are not applicable because they are addressed to humans and unpredictability across all species has already been evidenced in the record. However, the application of known CRISPR components to plant cells is a routine adaption and such application is taught, see Lande, which also teaches applicability for the human cell ([0076], [0102], [0108], and [0172]). Applicant is reminded the Court commented that "[r]esponding to concerns about uncertainty in the prior art influencing the purported success of the claimed combination, this Court [in O'Farrell] stated: “[o]bviousness does not require absolute predictability of success ... all that is required is a reasonable expectation of success."' Kubin, 561 F.3d at 1360 (citing In re O'Farrell, 853 F.2d at 903-904).
Additionally, in response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, multiple the prior art clearly teaches gene editing systems comprised of the claimed components, such as the CRISPR Cas9 nuclease, APOBEC3A, and UDG, as already presented. Applicant has not demonstrated that the cited references, when properly considered as a whole, fail to render the claimed invention obvious to one of ordinary skill in the art. The applicant analyzes the cited references in isolation. As set forth in the rejection, Lande teaches a modular CRISPR-based DNA modification architecture that expressly contemplates the use of deaminases, DNA glycosylases, and AP lyases as modification domains. Komor further established the fusion of CRISPR nucleases with cytidine deaminases for targeted DNA modification, and Presidents and Fellows of Harvard additionally teaches the inclusion of uracil DNA glycosylase to process deaminated cytosines into abasic sites, expanding editing outcomes. Thus, the ordinary artisan would have been motivated to combine these teachings to achieve alternative editing outcomes, including deletions, using known DNA repair pathways.
Conclusion
Claims 1-3 and 8-12 are rejected.
Claim 7 objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOEL D LEVIN whose telephone number is (571)270-0616. The examiner can normally be reached Fulltime Teleworker.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633