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 on 11/11/2025. Claims 1, 2, 5, 7-10, 13-16, 19, and 21-27 are pending. Claims 1, 2, 8, 10, 13, and 27 have been amended. Claims 3-4, 6, 11-12, 17-18, 20, and 28-33 have been cancelled. All pending claims are currently under examination.
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. This Office Action is Final.
Claim Rejections - 35 USC § 103 – Maintained/Updated in View of Amendments
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.
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 1-2, 5, 7-10, 13-16, 19, and 21-27 are rejected under 35 U.S.C. 103 as being unpatentable over Jin (WO 2018/129129 A1, published 7/12/2018) in view of Komor (Komor AC et al. Nature. 2016 May 19;533(7603):420-4) and Wang (Wang L et al. 2017 Oct;27(10):1289-1292).
Regarding claim 1, Jin is a patent document which teaches targeted gene editing and methods of use (Title, Abstract, and throughout). Jin teaches a system comprising (i) a sequence-targeting component or a polynucleotide encoding the same, comprising a sequence targeting protein, (ii) an RNA scaffold comprising (a) a first nucleic acid-targeting motif comprising a first guide RNA sequence that is complementary to a target nucleic acid sequence in a nucleic acid, (b) a CRISPR/”RNA” motif capable of binding to the sequence-targeting protein, and (c) a recruiting RNA motif, and (iii) a first effector fusion protein, comprising (a) a first RNA binding domain capable of binding to the first recruiting RNA motif, (b) a first linker, and (c) a first effector domain, where the first effector domain has an enzymatic activity for DNA/RNA modification, where the activity maybe cytidine or adenosine deamination (claims 1 and 13 of Jin). Furthermore, Jin also teaches that uracil DNA glycosylase inhibitor peptide UGI can be used in their systems, with the beneficial effect of further enhancing nucleotide conversion efficiency (page 10 final paragraph). Jin teaches that UGI can be fused with elements of the system (page 10, final paragraph, see also page 40, which discusses the benefits of incorporating UGI within the systems to enhance conversion efficiency).
Jin, while teaching the above elements of claim 1, and UGI, also that UGI has benefits in such systems and can be part of a fusion protein, does not specifically teach that UGI is fused with the sequence-targeting protein.
Komor is a research article which focuses on programmable editing of a target base in genomic DNA (Title, Abstract, and throughout). Thus, Jin and Komor directly overlap in subject matter, field of endeavor, and design objectives. Furthermore, Komor teaches the fusion of UGI to base editors, where such fusion results in enhanced gene conversion efficiencies (see page 421, right column, third and fourth paragraphs into page 422, left column, first two paragraphs). Komor teaches that the conjugation of UGI with base editors increases the efficiency of base editing in human cells (page 422, left column, first paragraph).
Furthermore, Wang is a research article which similarly teaches the enhancement of base editing by the co-expression of UGI and fusion of UGI with dCas9 in base editing systems (Title, Abstract, and throughout). Wang also teaches that such expression of UGI has beneficial implications in base editing efficiencies and accuracy (e.g., page 1289, right column in its entirety). Thus, per Komor and Wang, the art was replete with knowledge concerning the introduction and fusion of UGI into base editing systems and provide sufficient motivation to a practitioner to fuse UGI with such base editing systems.
It would have been obvious to a person of ordinary skill in the art before the time of filing of the claimed invention to modify the base editing systems of Jin, where Jin already teaches the benefits of UGI in such systems, to include the fusion of UGI with the elements of Jin, because Komor teaches that this is a known technique and furthermore teaches that there are known benefits to such UGI-fusion strategies in base editing systems. Furthermore, the results are predictable, as the use of UGI fusions (Komor) and UGI in general base editing systems (Wang) has been reduced to practice multiple times in the art (Komor/Wang).
Regarding claim 2, given that Jin, Komor, and Wang all teach the benefits of UGI, the inclusion of multiple UGIs is obvious given the obvious benefits of the inclusion of UGIs in the systems of Jin. Furthermore, Wang teaches that additional UGI activity is required to further improve efficiency and fidelity of base editing systems, and therefore provides a direct motivation to include additional UGIs (page 1289 of Wang, right column, final paragraph).
Regarding claim 5, Jin teaches that the effector fusion protein can comprise an NLS (page 25, third paragraph).
Regarding claims 7 and 8, Jin teaches that the sequence targeting protein is a CRISPR protein, where such protein does not have nuclease activity (page 16, third paragraph, “nuclease dead Cas9”).
Regarding claim 9, Jin teaches that the sequence targeting protein comprises the sequence of dCas9 of S. pyogenes (page 16, third paragraph).
Regarding claim 10, Jin teaches the RNA motif and RNA binding domain can be a telomerase Ku binding motif and Ku protein or an RNA-binding section thereof (e.g., claim 9 of Jin).
Regarding claim 13, Jin teaches that system components can be encoded in an isolated nucleic acid (e.g., claim 24 of Jin).
Regarding claim 14, Jin teaches an expression vector of host cell comprising the isolated nucleic acid of claim 13 (see claim 25 of Jin).
Regarding claim 15, Jin teaches a method of site-specific modification of a target DNA, comprising contacting the target nucleic acid with the recited system (claim 1 of Jin).
Regarding claim 16, Jin teaches that the method is in a cell (claim 15 of Jin).
Regarding claim 19, Jin teaches that the cell can be a bacterial cell (claim 17 of Jin).
Regarding claim 21, Jin teaches that the cell is in or derived from a human or non-human subject (claim 18 of Jin).
Regarding claim 22, Jin teaches the human or non-human subject has a genetic mutation of a gene (claim 19 of Jin).
Regarding claim 23, Jin teaches the subject has a disorder caused by the genetic mutation or is at risk of having the disorder (claim 20 of Jin).
Regarding claim 24, Jin teaches that the sit-specific modification corrects the genetic mutation or inactivates the expression of the gene (claim 21 of Jin).
Regarding claim 25, Jin teaches that the subject has a pathogen or is at risk of exposing to the pathogen (claim 22 of Jin).
Regarding claim 26, Jin teaches the site-specific modification inactivates a gene of the pathogen (claim 23 of Jin).
Regarding claim 27, Jin teaches a kit comprising the system (claim 26 of Jin). Jin teaches that the kit can comprise instructions (page 46, second paragraph).
Response to Arguments
The Applicant’s arguments filed 11/11/2025 have been reviewed but are not persuasive. As discussed above in the 103 rejection, Jin teaches each of the components of the system of claim 1, and furthermore teaches UGI molecules to be fused with the components of their system with beneficial properties (page 10 final paragraph and page 40). Thus, the components of the present system are taught by Jin, where Jin simply did not reduce to practice the fusion of the UGI protein. As discussed in the above rejection, Komor and Wang supply ample motivation to fuse the UGI with the Cas portion of the systems of Jin, and therefore supplies a reasonable motivation to modify the teachings of Jin. The results are predictable because Jin teaches the same components and the fusion of UGI has been taught and reduced to practice (Wang). The prior art therefore appears to be replete with knowledge, skill, and motivation to arrive at the present invention.
The Applicant argues that Jin teaches a system with two sequence-targeting components whereas the present claim 1 is directed to a system with one sequence-targeting component. This argument is not persuasive. The first component of claim 1 of Jin is the same as the presently recited system, with the exception that a UGI is fused with the sequence-targeting protein. This summary appears to be in agreement with the specification itself, which states that with regards to the invention disclosed by Jin (i.e., the first generation CRC):
“As disclosed herein, a new, second generation CRC base editors CRC system with increased efficacy was tested and further improved in mammalian cells. The second generation of CRC base editors including one or all of the following features. First, the Cas9 protein contains one, two, or more than two UGis; second, the Cas9-UGI protein has at least two nuclear localization signal peptides (NLS); and three, both the Cas9-UGI and the effector proteins are codon optimized,” (page 10, fourth paragraph of specification).
Thus, aside from routine modifications of systems in biotechnology applications (i.e., codon optimization and the attachment of NLS sequences, both of which are routine in the art), the present invention as stated by the specification and recited in the claims differs in that the Cas9 protein is fused with a UGI (above). Note that the recited system is recited to “comprise” the elements recited in claim 1; thus, the additional elements recited in claim 1 of Jin are not excluded from being incorporated into the scope of the invention. Thus, the present invention is not limited to a one sequence-targeting system, as the invention is recited to “comprise” the elements recited in the claims. The teachings of Jin therefore read on the present invention. Indeed, the Applicant argues that “the system of claim 1 does not encompass the cis double nicking approach described by Jin,” however, claim 1 uses open-ended claim language which can allow for additional elements such as those taught by Jin. Furthermore, Jin “encompasses” claim 1, where the present invention can simply be viewed as a modification to the first component of the system of Jin by the addition of a UGI.
Furthermore, the prior art of Komor and Wang teaches motivation to modify the first component of the system of Jin, as fusion of the UGI to such proteins as Cas9 is known to have beneficial results for such systems. Thus, Jin can also benefit from the fusion of UGI to the elements of their system, as Jin themselves teach as well as Wang.
The Applicant argues that Jin teaches away from the use of UGIs. This argument is not persuasive. Firstly, Jin directly teaches the use of UGIs to be used with their systems in fusion proteins, and therefore does not teach away from using such molecules. Secondly, the mere fact that Jin recites that the CRC system was more efficient than a system comprising a UGI does not teach away from applying the beneficial teachings of a UGI, as the incorporation of such a molecule could improve the results even further given the motivational knowledge known in the art. Jin and the art therefore do not teach away from using UGIs in the system.
Regarding the teachings of Wang, Wang teaches that:
“Uracil DNA glycosylase inhibitor (UGI) domain was fused to nCas9 in BE3 to prevent the transformation of U into AP site. To test the importance of UGI in base editing, we first removed the fused UGI in BE3. Consistent with our hypothesis mentioned above, the UGI-deleted BE3 was less competent in base editing. Compared to BE3, BE3-ΔUGI induced higher unwanted indel frequencies and lower desired C-to-T editing,” (page 1289, right column, first paragraph).
Thus, Wang does not teach away from fusing UGIs to Cas9, as such a fusion was known to have obvious benefits. The Applicant’s arguments that the addition of additional trans UGIs may improve the system even more is not persuasive because Wang teaches that fusion of UGI to Cas9 alone is itself beneficial. The fact that additional trans UGI may improve the system even more is therefore irrelevant to the clear motivational teaching of Wang regarding UGI fusion proteins, as Wang clearly teaches that such a fusion is superior to a Cas9 without the fusion of UGI (above, page 1289, right column, first paragraph). It is therefore not correct to assert that Wang does not suggest the fusion of UGI to the Cas component, as Wang clearly teaches a motivation to do so (above).
The Applicant’s argument of unexpected results is not persuasive. The Applicant argues that it is an unexpected result that the system is simpler. This argument is not persuasive, if simply for the fact that even if it were argued that such a statement were true, 1) the recited invention does not preclude and in fact allows for additional sequence-targeting components and 2) the art provides substantial motivation to incorporate a UGI into such systems. Therefore, given that the art teaches such a strong motivation, any additional benefits which would flow naturally from the suggestions in the art can not be the basis for patentability. Wang has already taught such UGI fusions and their benefits, and discovery of an additional property is not grounds for patentability. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
The Applicant argues features of the RNA scaffold render the scaffolds with more flexibility. This argument is not persuasive, as the scaffolds of Jin and the present application appear to recite the same features, and therefore comprise the same flexibility and properties.
Additionally, the Applicant argues that the system maintains smaller fusion proteins, and directs the argument to page 13, lines 10-14. However, this section, as reproduced by the Applicant, is discussing the first generation CRC application (see page 13, second paragraph). Thus, with regards to Applicant’s third point surrounding unexpected results, the Applicant appears to be referencing features and components of the first generation CRC (i.e., the reference Jin). The argument is therefore not persuasive, as such features appear from the specification to be directed at features of Jin, and not features of the present invention or how the present invention differs from Jin.
Conclusion
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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/D.C.R./Examiner, Art Unit 1635
/KIMBERLY CHONG/Primary Examiner, Art Unit 1636