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 .
Notice of Pre-AIA or AIA Status
This action is written in response to applicant’s correspondence received 9 January 2026. Claims 1-10, 15-16, 25, 27-28, 33, 35, and 37 are currently pending. Claims 1-10, 15-16, and 33 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 25, 27-28, 35, and 37 are examined herein. The restriction requirement mailed 11 June 2025 is still deemed proper. Applicant's elected Group III, claims 25, 27-28, and 35-37, with traverse in the reply filed 5 September 2025.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant' s amendments 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 § 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) 25, 27-28, 35, and 37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kelso (PG Pub No: WO 2020/154714 A2, claiming priority to US 62/797,122 (i.e., “the ‘122 application”) in view of Clouaire ("A snapshot on the cis chromatin response to DNA double-strand breaks." Trends in Genetics 35.5 (May 2019): 330-345), Zheng ("Profiling single-guide RNA specificity reveals a mismatch sensitive core sequence." Scientific reports 7.1 (2017): 40638), Ordoukhanian ("Design and synthesis of a versatile photocleavable DNA building block. Application to phototriggered hybridization." Journal of the American Chemical Society 117.37 (1995): 9570-9571), and Dahlman ("Orthogonal gene knockout and activation with a catalytically active Cas9 nuclease." Nature biotechnology 33.11 (2015): 1159-1161) as evidenced by Jiang (Annual review of biophysics 46 (2017): 505-529).
Regarding claim 25, Kelso is drawn towards an invention concerned with systems and method for modulating CRISPR activity (Abstract; [001] of the ‘122 application). Kelso teaches the use of a CRISPR RNP that comprises a CRISPR-Cas9 effector protein and a CRISPR guide RNA (i.e., a gene editing agent) within a cell and exposing the cell to a cleaving agent that can cleave a linker ([0003], [0005], [0008]; [001], [004], and [0010]-[0011] of the ‘122 application). Kelso teaches that the Cas9 gRNA may comprise a cleavable linker that is 3’ of the 5’ most nucleotide in the guide sequence ([0005]; [007] of the ‘122 application). Kelso teaches that the cleavable linker may comprise a photo liable linker that is cleavable by ultraviolet radiation (i.e., a cleaving agent) ([0005]; (007] of the ‘122 application). Kelso teaches that the gRNA may be cleaved by electromagnetic radiation that can be a particular wavelength of light in the visible spectrum ([0190]-[0191]; [124]-[125] of the ‘122 application). Kelso teaches that when a photocleavable linker is present at bases 21, 24, and 50 of the Cas9 gRNA such that, upon exposure to electromagnetic radiation, the sgRNA is cleaved and the CRISPR system is deactivated and does not cleave target DNA ([0032], see FIGs. 5-6; [205], see FIGs. 5A-5B of the ‘122 application).
While Kelso does teach that the photocleavable linker may be present at base 21 of the guide RNA, Kelso does not teach that the photocleavable linker may be present within bases 1-20 of the guide RNA that are complementary to a target sequence (Claim 25).
Regarding the motivation for the inclusion of a photocleavable linker in the crRNA, Clouaire is directed towards a review concerned with how the repair of DNA double-stranded breaks operates within chromatin (Abstract). Clouaire teaches that a variety of double-strand break inducing methods have been developed, including utilizing CRISPR/Cas9 to induce double-stranded breaks in target DNA (pg. 332). Clouaire teaches that the main disadvantage of these methods stems from the ability of nuclease to recut properly repaired sites, impairing efficient kinetic deconvolution of repair reactions (pg. 332). Clouaire teaches that, because of the nuclease’s ability to recut properly repaired sites, a cell population that has been introduced to the nuclease results a mixture of cells comprising a plurality of events ranging from early cleavage to late repair, which may impede the efficient detection of transient events (pg. 332).
Regarding the presence of the photocleavable linker in the crRNA within the sequence complementary to the target, it was already known to include a photocleavable in a double stranded hybrid structure in a sequence complementary to a target as shown by Ordoukhanian. Ordoukhanian teaches the use of a versatile photocleavable DNA building block (i.e., a photocleavable linker molecule that can be utilized as a DNA base pair) that can be placed within an oligonucleotide sequence and cleaved when the oligomer is subjected to light (i.e., electromagnetic radiation) that has a wavelength of 254, 302, or 366 nm (pg. 9570-9571). Ordoukhanian teaches that the photocleavable building block does not bind to base pairs and creates a mismatch when utilized in a dsDNA construct (pg. 9571; see Figure 2).
It was known that mismatches present within bases 1-20 of a guide RNA that is complementary to a target nucleic acid and present within a double-stranded hybrid structure were tolerated by Cas9 as shown by Zheng. Zheng teaches that, using a luciferase activation assay, off-target cleavage activity of sgRNA was systematically investigated on single nucleotide-mismatched targets (Abstract). Zheng teaches that Cas9 guide RNA sequences are tolerance to single mismatches present at positions at, or before, the 15th nucleotide of the sgRNA target sequence (i.e., the crRNA sequence of Cas9) as measured by the nucleotide’s distance to a PAM sequence (pg. 3-4; see Figure 3).
Further, it was known that a crRNA whose sequence that was complementary to a target was truncated would result in an inactive guide RNA as shown by Dahlman. Dahlman teaches that Cas9 utilizes an sgRNA sequence (i.e., a gRNA sequence) that comprises a 20 bp RNA targeting sequence in order to direct the Cas9 to a target nucleic acid of interest and induce indels in a target cell (pg. 1159-1160; see Figure 1). Dahlman teaches that when the RNA targeting sequence is less than 15 nucleotides in length, the Cas9 molecule is unable to induce indels at a target nucleic acid of interest (pg. 1160; see Figure 1).
As evidenced by Jiang, the sgRNA of Cas9 comprises a tracrRNA and a crRNA (Abstract). Jiang teaches that Cas9 sgRNAs comprise a tracrRNA that is bound to the Cas9 molecule and the crRNA is an RNA sequence that guides the Cas9 to a target nucleic acid of interest (pg. 507-510; see Figures 1-2).
Thus, as evidenced by Jiang, a person of ordinary skill in the art would have recognized that the Cas9 sgRNA of Dahlman comprises a tracrRNA that binds to the Cas9 molecule and the “RNA targeting sequence” of Dahlman is directed towards a Cas9 crRNA.
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 position of the photocleavable linker of Kelso such that the photocleavable linker comprised a photocleavable 2-nitrobenzyl linker at, or before, the 15th nucleotide of the crRNA sequence in order to render the Cas9 inoperable following exposure of the system to electromagnetic radiation because it would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results.
With regard to the position of the photocleavable linker to inactivate the Cas9 guide RNA, because Kelso already teaches incorporating a photocleavable linker in the crRNA for inactivating the guide RNA, then one of ordinary skill in the art would have considered any of the locations of the crRNA available for locating this photocleavable linker that would have similarly resulted in an inactive guide RNA after cleavage. Further, because Dahlman teaches that guide RNAs with truncated sequences complementary to their target were inactive, it would have been predictable that a photocleavable linker located within the crRNA sequence complementary to the target that was cleaved would have resulted in an inactive guide RNA. And because Clouaire teaches that it is advantageous to deactivate a Cas9 following repair at a target site, one would have been motivated to do so.
With regard to the use of the photocleavable linker of Ordoukhanian within the sequence complementary to the target, the modification would have merely amounted to a simple substitution of one known photocleavable linker for another. Because the photocleavable linkers of Kelso and Ordoukhanian were used in similar double-stranded hybrid structures that could be cleaved by exposure to electromagnetic radiation, it would have been predictable to have used the photocleavable linker of Ordoukhanian as the photocleavable linker within the crRNA of Kelso. Further, because Zhang teaches that there are positions within the crRNA guide sequence that are tolerant to mismatches, it would have been predictable that guide RNA would have remained functional despite the presence of the photocleavable linker.
Regarding claim 27, Ordoukhanian teaches that the photocleavable linker can be cleaved with a wavelength of 366 nm (i.e., about 365 nm) (pg. 9571).
Regarding claims 28 and 37, Ordoukhanian teaches that the photocleavable linker comprises a benzene ring with a nitro group at position 2 of the ring (i.e., a 2-nitrobenzyl moiety) (pg. 9570; see Scheme 1).
Regarding claim 35, Zheng teaches that Cas9 crRNA sequences were tolerant to mismatches at positions at, or before, the 15th nucleotide as measured by distance to the PAM (i.e., between 10-20 nucleotides distal to the PAM) (pg. 3-4; see Figure 3).
Response to Arguments
Applicant's arguments filed 9 January 2026 have been fully considered but they are not persuasive.
Applicant alleges that Kelso does not disclose a photocleavable linker within the crRNA, but only at the 3’ of the 5’ most nucleotide of the guide sequence and that Kelso is silent with respect to including a photocleavable linker within the sequence complementary to the target within the crRNA (pg. 8).
This argument is not found persuasive because, as discussed above in the pending rejection under 35 USC 103 over claim 25, Kelso does teach that the crRNA can comprise a photocleavable linker at position 21. Further, a person of ordinary skill in the art would have been motivated to modify the location of the photocleavable linker of Kelso such that it was at, or before, the 15th nucleotide of the guide sequence in order to prevent the Cas9 molecule from recutting properly repaired sites in the target DNA molecule, as described by Clouaire and discussed above in the currently pending 35 USC 103 rejections of record.
A person of ordinary skill in the art would have had a reasonable expectation of success because arriving at the claimed invention would have merely amounted to a simple combination of prior art elements according to known methods to yield predictable results.
With regard to the position of the photocleavable linker to inactivate the Cas9 guide RNA, because Kelso already teaches incorporating a photocleavable linker in the crRNA for inactivating the guide RNA, then one of ordinary skill in the art could have considered any of the locations of the crRNA available for locating this photocleavable linker that would have similarly resulted in an inactive guide RNA after cleavage. Further, because Dahlman teaches that guide RNAs with truncated sequences complementary to their target were inactive, it would have been predictable that a photocleavable linker located within the crRNA sequence complementary to the target that was cleaved would have resulted in an inactive guide RNA. And because Clouaire teaches that it is advantageous to deactivate a Cas9 following repair at a target site, one would have been motivated to do so.
With regard to the use of the photocleavable linker of Ordoukhanian within the sequence complementary to the target, the modification would have merely amounted to a simple substitution of one known photocleavable linker for another. Because the photocleavable linkers of Kelso and Ordoukhanian were used in similar double-stranded hybrid structures that could be cleaved by exposure to electromagnetic radiation, it would have been predictable to have used the photocleavable linker of Ordoukhanian as the photocleavable linker within the crRNA of Kelso. Further, because Zhang teaches that there are positions within the crRNA guide sequence that are tolerant to mismatches, it would have been predictable that guide RNA would have remained functional despite the presence of the photocleavable linker.
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.
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).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KYLE T REGA/Examiner, Art Unit 1636
/NEIL P HAMMELL/Supervisory Patent Examiner, Art Unit 1636