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 .
Applicant’s response filed 11/10/2025 has been received and considered entered. This is a response to amendments and arguments filed 11/10/2025.
Claims Status
Claims 1-15 is/are currently pending. Claims 1-15 is/are under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
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) 1-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Ji (WO2019027728A1), in view of Basila (2017). This rejection is amended to address new claim limitations, and maintained.
Regarding claims 1, 6, and 11, Ji teaches a two-component guide RNA (gRNA) for use in a CRISPRa SAM system (paragraph [0002]), the gRNA comprising a crRNA and a tracrRNA, wherein the crRNA hybridizes to the tracrRNA, forming a functional gRNA (claim 1) (required by claims 1, 6, and 11). Ji teaches kits comprising this two-component gRNA (claims 13-14) (required by claim 6). Ji teaches a method of transcription activation by a CRISPRa system in a cell comprising introducing into the cell the two-component gRNA (claim 35) (required by claim 11).
Regarding claims 2, 7, and 12, Ji teaches that the tracrRNA is modified with the insertion of an aptamer sequence (claim 1).
Regarding claims 3, 8, and 13, Ji teaches that the aptamer sequence is inserted between a 5’ tetraloop sequence and the loop 2 sequence (Table 1, SEQ ID NO:47). Ji also teaches that the aptamer sequence can be inserted between a portion of the loop 2 sequence and the loop 3 sequence (Fig. 1).
Regarding claims 4, 9, and 14, Ji teaches that the aptamer sequence is an MS2 stem loop (claim 2).
Regarding claims 5, 10, and 15, Ji teaches that the two-component gRNA comprises a tracrRNA of the sequence of SEQ ID NO:45 (SEQ ID NO:45 comprises a sequence 100% identical to instant SEQ ID NO:9, and thus the two-component gRNA comprises a tracrRNA sequence of instant SEQ ID NO:9; see alignment below; paragraph [0171], Table 1). SEQ ID NO:9, as appears in Table 1 of the instant specification, comprises uridines where SEQ ID NO:9 as appears in the sequence listing comprises thymidines in the same positions; thus, SEQ ID NO:45 of Ji teaches SEQ ID NO:9 as presented in the specification, comprising uridines and not thymidines.
PNG
media_image1.png
155
592
media_image1.png
Greyscale
However, SEQ ID NO:9 requires that the three 3’-terminal and three 5’-terminal nucleotides are 2’-O-methylated and comprise phosphorothioate linkages, while Ji merely teaches that the tracrRNA can comprise phosphorothioate linkages and 2’-O-methyl modifications, but does not teach the specific positions of these modifications within the tracrRNA (paragraphs [0033], [0025], [0164]).
Regarding claims 1, 5-6, 10-11, and 15, Basila teaches that MS modifications (2’-O-methyl plus phosphorothioate linkages, page 2) of the three 3’-terminal and three 5’-terminal nucleic acids of a tracrRNA and crRNA provide significantly increased stability (Figs. 2, 4; pages 2-3, 6-8).
The teachings of Basila rendered obvious to a person of ordinary skill in the art at the time of filing that any tracrRNA, including the tracrRNA taught by Ji, should be modified such that the three 3’-terminal and three 5’-terminal nucleotides are 2’-O-methylated and comprise phosphorothioate linkages, in order to improve the stability and efficacy of the tracrRNA in cells, which would prove beneficial for the efficacy of the method taught by Ji.
Response to Arguments
Applicant's arguments filed 11/10/2025 have been fully considered but they are not persuasive.
Applicant asserts that “Basila teaches MS-modification (PS + 2’-OME) specifically in the context of tracrRNA stabilization. Basila does not teach that such modifications should be introduced in the crRNA strand, nor that such modifications should be introduced symmetrically on both strands. Indeed, Basila teaches away from modification of the crRNA, as it was expected to have no effect (Basila at page 3)” (arguments, page 8). The Basila passage cited by Applicant teaches that crRNA:tracrRNA are less efficient than sgRNA, but that 2’-O-methyl + phosphorothioate modifications of crRNA improve the efficiency of crRNA:tracrRNA to 75% of the efficiency of the more-efficient sgRNA (“modified crRNAs were compared to expressed sgRNAs in HEK293T cells and were found to improve activity of the native crRNA up to 75% of the expressed sgRNA, depending on modification pattern”, Basila page 3). This teaches that 2’-OMe and phosphorothioate modifications improve gene editing efficiency of a crRNA relative to an unmodified crRNA, but do not improve the gene editing efficiency of a crRNA to a great enough degree to approximate the efficiency of an sgRNA. An artisan would therefore be motivated to so modify a crRNA in order to improve gene editing efficiency while using a crRNA:tracrRNA guide RNA instead of a single guide RNA.
Furthermore, while Applicant asserts that Basila does not teach modification of both a crRNA and a tracrRNA, pages 6-8 and Figures 2 and 4 of Basila do teach multiple modification patterns of paired crRNA and tracrRNA. Basila teaches that “2x-3xMS modifications were necessary to better stabilize the crRNA and tracrRNA” and “2x or 3xMS modifications of both 5’ and 3’ ends on crRNA and tracrRNA provided stabilization to nuclease degradation” (page 6). Fig. 2A on page 7 shows that 3xMS crRNA and 3xMS tracrRNA comprise 2’-OMe and phosphorothioate modifications at the three 3’- and 5’-terminal nucleotides of the crRNA and the tracrRNA, respectively, and these modifications are symmetrical. Therefore, Basila does teach 2’-OMe and phosphorothioate modification of both the 3’- and 5’-terminal three nucleotides of both the crRNA and tracrRNA of a guide RNA, as required by claims 1, 5-6, 10-11, and 15.
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 AFRICA M MCLEOD whose telephone number is (703)756-1907. The examiner can normally be reached Mon-Fri 9:00AM-6:00PM 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, Ram Shukla can be reached on (571) 272-0735. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
For those applications where applicant wishes to communicate with the examiner via Internet communications, e.g., email or video conferencing tools, the following is a sample authorization form which may be used by applicant:
"Recognizing that Internet communications are not secure, I hereby authorize the USPTO to communicate with the undersigned and practitioners in accordance with 37 CFR 1.33 and 37 CFR 1.34 concerning any subject matter of this application by video conferencing, instant messaging, or electronic mail. I understand that a copy of these communications will be made of record in the application file."
To facilitate processing of the internet communication authorization or withdraw of authorization, the Office strongly encourages use of Form PTO/SB/439, available at www.uspto.gov/patent/patents-forms. The form may be filed via EFS-Web using the document description Internet Communications Authorized or Internet Communications Authorization Withdrawn to facilitate processing. See MPEP 502.03(II).
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.
/AFRICA M MCLEOD/ Examiner, Art Unit 1635
/KIMBERLY CHONG/ Primary Examiner, Art Unit 1636