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 .
Application Status
This action is written in response to applicant’s correspondence received 21 April 2026. Claims 34-37 and 40-42 are currently pending. Accordingly, claims 34-37 and 40-42 are examined herein.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 34-37 and 40-42 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Liu (PG Pub No. WO 2018/165629 A1, published 13 September 2018, effectively filed 9 March 2018) as evidenced by Krusong (Journal of Biological Chemistry 281.8 (2006): 4983-4992). This rejection is maintained.
Regarding claim 34, 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 napDNAbp selected from a Cas9 nucleic acid programmable DNA binding protein (i.e., a CRISPR-Cas effector enzyme comprising a Cas9 polypeptide), a cytidine deaminase, and a uracil binding protein (i.e., termed “UBP) ([0005]). Liu teaches the use of a guide RNA that is capable of guiding the Cas9 to a specific DNA sequence that is complementary to the guide RNA ([0071]). 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., Liu teaches that the fusion protein may be utilized in a method for single base substitution) ([0002], [0006], [0009]; see Figures 1 and 4 for schematic illustration of C to G base editing). Liu teaches that the fusion protein may comprise the structure NH2-[UBP]-[cytidine deaminase]-[napDNAbp]-COOH ([00222]). Liu teaches that the napDNAbp may be a Cas9 nickase ([0071]). Liu teaches that the cytidine deaminase may be an APOBEC1 (see Claim 56). Liu teaches that the UBP may be a uracil DNA glycosylase ([0063]).
Accordingly, per MPEP 2131.02, one of ordinary skill in the art would have at once envisaged the claimed fusion protein because the classes of possible species of napDNAbp, cytidine deaminases, and UBP are sufficiently limited and their function well described, as discussed above. Liu teaches that the napDNAbp may be selected from “Cas9 (e.g., dCas9 and nCas9), CasX, CasY, Cpf1, C2c1, C2c2, C2C3, and Argonaute” ([0071]). Liu teaches that the species of cytidine deaminases may be an APOBEC1, APOBEC2, APOBEC3A, APOBEC3B, APOBEC3C, APOBEC3D, APOBEC3F, APOBEC3G, or an APOBEC3H deaminase (see Claim 56). Further, Liu teaches that the possible species of UBP is a UDG, UdgX, UdgX*, UdgX_On, or a SMUG1 ([00166]).
Therefore, the general structure of Liu does not describe an infinite number of compounds. Rather, Liu teaches a generic formula embracing a limited number of possible compounds that are closely related to each other in structure. Further, Liu teaches that the properties possessed by the species, and their mechanisms by which the species could be utilized in a method of C-to-G base editing, were well-known. Accordingly, one of ordinary skill in the art would have at once envisaged the claimed fusion protein from the disclosure of Liu.
As evidenced by Krusong (Journal of Biological Chemistry 281.8 (2006): 4983-4992), a comparative study concerned with the study of uracil DNA glycosylases, uracil DNA glycosylase is the primary enzyme responsible for the removal of uracil from DNA that functions via the cleavage of an N-glycosidic bond between the uracil and a deoxyribose backbone, leaving an apyrimidinic (AP) site (pg. 4983).
Thus, as evidenced by Krusong, a person of ordinary skill in the art would recognize that the uracil DNA glycosylase of Liu has the claimed function of catalyzing the cleavage of an N-glycosidic bond of uracil.
Regarding claim 35, Liu teaches that the fusion protein may comprise an NLS ([00235]).
Regarding claim 36, Liu teaches that the Cas9 nickase may be a Streptococcus pyogenes nickase ([00143]).
Reading claim 37, Liu teaches that the Cas9 nickase may have an inactive RuvC nuclease domain that is not able to cleave the targeted strand of DNA ([0085]).
Regarding claim 40, Liu teaches that the cytidine deaminase may be an APOBEC1 ([00176]).
Regarding claim 41, Liu teaches the use of nucleotide sequences encoding the fusion protein and guide RNA that can be present within a kit and delivered to a target cell of interest [00267], [00269]).
Regarding claim 42, Liu teaches that the UBP, cytidine deaminase, and napDNAbp may be fused via the use of linkers between each element ([00223]).
Response to Arguments
Applicant's arguments filed 21 April 2026 have been fully considered but they are not persuasive.
Applicant alleges that Liu fails to disclose a fusion protein having the following order: N terminus-[uracil DNA glycosylase]-[APOBEC]-[Cas9 nickase]-C terminus (Remarks; pg. 7). Applicant alleges that Liu does not anticipate the claimed fusion protein because the reference only discloses a general arrangement of a fusion protein comprising the following structure: NH2-[UBP]-[cytidine deaminase]-[napDNAbp]-COOH (Remarks; pg. 7). Applicant alleges that Liu does not anticipate the claimed invention because Liu’s experimental examples are limited to a fusion protein having the structure N-terminus-[cytidine deaminase]-[Cas9]-[UDG]-C-terminus (Remarks; pg. 7). Applicant alleges that Liu does not teach or suggest that the recited configuration is capable of inducing substitution of a cytosine with a base other than cytosine (Remarks; pg. 9).
These arguments are not found persuasive because although Liu teaches that the general structure of the fusion protein may be NH2-[UBP]-[cytidine deaminase]-[napDNAbp]-COOH, Liu further discloses the claimed species present within each of the categories of UBP, cytidine deaminases, and napDNAbp. As discussed above, Liu teaches that the UBP may be a uracil DNA glycosylase ([0063]), that the cytidine deaminase may be an APOBEC1 ([00176]), and that the napDNAbp may be a Cas9 nickase ([0071]). Accordingly, Liu anticipates the claimed species in the claimed configuration because Liu explicitly teaches that the claimed species may be present within the general motifs of the fusion protein comprising NH2-[UBP]-[cytidine deaminase]-[napDNAbp]-COOH.
Further, as discussed above, Liu teaches methods of using the fusion proteins described in the disclosure for the deamination of a target cytosine nucleobase in order to induce C-to-G base editing. Liu, as shown in Figures 1 and 4, teaches that the APOBEC and nickase allow for the deamination of a target cytosine into a uracil, followed by the generation of an abasic site through the use of a UDG domain, in order to allow for a polymerase to replace G opposite the abasic site with a C (i.e., induce a substitution of a single cytosine with a single guanine). Accordingly, Liu teaches that the claimed fusion protein can be utilized in a method for single base substitution and teaches the mechanisms by which the claimed fusion protein would function in a method of C-to-G base editing. The mere fact that Liu does not contain a working example of using the claimed configuration in a method for single base substitution does not detract from the teachings present in Liu teaching the claimed configuration, disclosures of the specific claimed species within the configuration, explicit disclosures of methods of using the fusion proteins in the disclosure for C-to-G base editing, and disclosures of the mechanisms by which the C-to-G base editing takes place.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636
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