DETAILED ACTION
Applicant’s response filed 11/14/2025 has been received and entered into the application file. All arguments have been fully considered. Claims 1, 3-4, 6, 9, 11, 15-17, 20-23, 27, 33, 48 and 50-53 are currently pending. Claims 2, 5, 7-8, 10, 12-14, 18-19, 24-26, 28-32, 34-47 and 49 are cancelled. Claims 9, 11, 15-17, 20-23, 27 and 48 are withdrawn. Claims 1 and 33 are currently amended. Claims 50-53 are new.
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 .
REJECTIONS MAINTAINED
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.
Claim(s) 1, 3-4, 6, 33, and new claims 50-52, are rejected under 35 U.S.C. 103 as being unpatentable over Dellinger et al., (WO 2017/214460, IDS 4/20/2022, previously cited) (“Dellinger”).
The rejection has been updated in view of Applicant’s amendment submitted 11/14/2025.
Claim 1 has been amended to recite the following:
A clustered regularly interspaced short palindromic repeats (CRISPR) polynucleotide comprising a spacer sequence comprising at least one nucleotide selected from:
a CRISPR abasic restricted nucleotide (CABRNT) selected from an apurinic deoxyribose and an apyrimidinic deoxyribose, and
a CRISPR accuracy via analogs (CAVA) nucleotide selected from deoxyinosine, deoxyuridine, xanthosine C3 spacer, 5-methyl dC, 5 -hydroxybutynl-2 '-deoxyuridine, 5 -nitroindole, 5-methyl iso-deoxycytosine, iso- deoxyguanosine, and iso-deoxycytidine.
Regarding claims 1, 3-4 and 51-52, Dellinger is directed to CRISPR technology and specifically teaches CRISPR polynucleotides comprising guide RNAs with chemical modifications that provide enhanced specificity for target sequence, thus minimizing off-target effects of the gRNA:Cas nuclease complex, and the modifications encompass consecutive modifications, such as 1-24 consecutive specificity enhancing modifications (Abstract; [0005] and [0046]).
It is noted that Dellinger’s Fig. 1 illustrates a CRISPR-Cas system, wherein a complex is formed by the CRISPR polynucleotide single-guide RNA and a Cas9 protein, and the complex recognizes and binds a target polynucleotide. FIG. 1 exemplifies a 20 nt (nucleotide) guide RNA (i.e., CRISPR polynucleotide comprising a spacer sequence, see specification FIG. 8). Dellinger teaches the guide sequence is complementary to an exemplary 20-nt target sequence in a DNA target. ([0006], [0059], [0151]; FIG. 1).
Dellinger, at paragraphs [0078]—[0094] and [0111]-[0136], teaches of numerous modifications to the guide RNA that are specificity-enhancing modifications (e.g., stability-altering to resist degradation by nucleases, reduces off-target effects, optimizes melting temperature), and the modifications take place within the guide sequence or crRNA segment of the guide RNA ([0091]).
Further, although Dellinger’s FIG. 1 does not further exemplify the guide RNA sequence comprising abasic restricted nucleotides selected from an apurinic deoxyribose and an apyrimidinic deoxyribose, or selected from the recited analog nucleotides, e.g., 5-nitroindole, it is noted that Dellinger’s paragraph [0079] teaches the chemically modified guide RNA comprises any nucleotide other than the four canonical ribonucleotides (A, C, G, and U), paragraph [0080] teaches the modifications include deoxyribose nucleotides, paragraph [0082] teaches modifications encompass abasic nucleotide modifications, which reads on apurinic and apyrimidinic nucleotides, and Dellinger, at page 113 (paragraph A18), teaches the guide RNA wherein nucleotide modifications includes nucleotide analogs such as 5-nitroindole.
Thus, Dellinger does render obvious a CRISPR polynucleotide comprising a spacer sequence (guide RNA) comprising various modifications of numerous nucleotides for the purpose of specificity-enhancement and reducing off-target effects, wherein the modifications encompass deoxyribose abasic nucleotides and analog nucleotides such as 5-nitroindole, as recited in amended claim 1. That is, Dellinger teaches the limitations required by the current claims and as all limitations are found in one reference it is held that a CRISPR polynucleotide comprising a spacer sequence (guide RNA) comprising various modifications of numerous nucleotides (i.e., at least one) wherein the modifications encompass deoxyribose abasic nucleotides (apurinic and apyrimidinic), and analog nucleotides such as 5-nitroindole, is within the scope of the teachings of Dellinger, and thus renders the invention of claims 1, 3 and 4 prima facie obvious. The rationale to support this conclusion of obviousness is that the single reference provides the teachings and suggestion to modify the guide RNA (spacer) using abasic restricted nucleotides or analog nucleotides such as 5-nitroindole. Furthermore, there is no evidence on the record that shows that the claimed limitation has any greater or unexpected results than that exemplified by Dellinger.
Regarding claim 6, Dellinger teaches the polynucleotide comprises deoxyribonucleotide (DNA) bases (FIG. 1), thus meeting the limitation of claim 6.
Regarding claim 33, as set forth above Dellinger renders obvious the nucleotide modifications that include modification of canonical nucleotides, including uridine, wherein non-canonical modifications include deoxynucleotides (paragraph [0082]), thus meeting the limitation of claim 33.
Regarding claim 50, it is noted that Dellinger teaches the specificity-enhancing modifications to guide RNA include sequence comprising nucleotide analogs such as inosine ([0079]), thus meeting the limitation of claim 50.
NEW GROUND(S) OF REJECTION, NECESSITATED BY AMENDMENT
Claim(s) 53 is rejected under 35 U.S.C. 103 as being unpatentable over Dellinger, as applied to claims 1, 3-4, 6, 33 and 50-52 above, and further in view of May et al., (WO 2016/123230; PTO-892) (“May”).
The teaching of Dellinger is set forth above.
Regarding claims 53, Dellinger does not specifically teach the CRISPR polynucleotide comprises an activating region comprising a DNA, or a mixture of RNA and DNA. However, May is directed to DNA-guided CRISPR polynucleotide systems comprising DNA, RNA and mixtures thereof for use with CRISPR systems (Abstract).
May teaches that CRISPR systems comprising single polynucleotides include a targeting region comprising deoxyribonucleic acid (DNA); and an activating region comprising ribonucleic acid (RNA), wherein the activating region comprises DNA, RNA or a mixture of DNA and RNA, said activating region reduces off-target effects or increases target-specific modification (page 2 and page 6, second paragraph).
Thus, May has established it was known prior to Applicant’s filing, that activating regions of CRISPR polynucleotides can be modified to reduce off-target effects and comprises a mixture of RNA and DNA.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the activating region of CRISPR polynucleotides to comprise a mixture of RNA and DNA, thus reducing off-target effects.
The person of ordinary skill in the art would have been motivated to modify the CRISPR composition of Dellinger to include activating regions comprising a mixture of RNA and DNA, as taught by May, for the predictable result of successfully reducing off-target effects, thus meeting the limitation of claim 53.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of Dellinger and May because each of these teachings are directed at CRISPR systems comprising modifications that enhance specificity and reduce off-target effects.
Response to Remarks/Amendment
Applicant’s arguments at Remarks, page 5, asserts that the Dellinger reference does not teach nor suggest a CRISPR polynucleotide where the spacer sequence comprises at least a nucleotide recited in amended claim 1.
Applicant’s argument has been fully considered, but is not found persuasive in view of the updated rejection set forth above, specifically addressing the newly amended claims.
Conclusion
No claim is allowed. No claim is free of prior art.
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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633