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 of 06/09/2026, including a substitute specification, substitute sequence listing, and replacement drawings, has been received and entered into the application file.
Claims 1, 6, 10, 12, 14, and 15 were amended in the claim set filed 06/09/2026.
Claims 3-5, 7-9, and 16-20 were canceled in the claim set filed 06/09/2026.
Claims 146-156 were added in the claim set filed 06/09/2026.
Accordingly, claims 1, 2, 6, 10-15, and 146-156 are pending and under consideration.
Information Disclosure Statement
Receipt of an information disclosure statement on 06/09/2026 is acknowledged. The signed and initialed PTO-1449 has been mailed with this action.
Status of Prior Objections/Rejections
RE: Drawings
►The drawings were previously objected to for various informalities.
The replacement drawings received 06/09/2026 have obviated most, but not all, of the objections of record. Those objections not repeated below are hereby withdrawn.
RE: Nucleotide and/or Amino Acid Sequence Disclosures
The sequence listing validated on 06/15/2026 is hereby accepted. The instant application complies with sequence listing requirements.
RE: Specification
►The disclosure was previously objected to for various informalities.
The substitute specification filed 06/11/2026 has obviated the basis of the objections of record. The objections of record are hereby withdrawn.
RE: Claim Objections
►Claim 1-20 were previously objected to for various informalities.
The cancellation of claims 3-5, 7-9, and 16-20 renders the objections thereof moot.
The amendments to the instant claim set have obviated the basis of the objections of record. The objections of record are hereby withdrawn.
RE: Claim Rejections - 35 USC § 112(a)
►Claims 1-20 were previously rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The cancellation of claims 3-5, 7-9, and 16-20 renders the rejection thereof moot.
The amendments to the instant claim set have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn. However, the amendments to the instant claim set have necessitated new grounds of rejection, which are set forth in detail below.
RE: Claim Rejections - 35 USC § 112(b)
►Claim 6 was previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The amendments to instant claims 1 and 6 have obviated the basis of the rejection of record. The rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 102
►Claims 1-3 and 14-20 were previously rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by WO 2018/049168 A1 (hereinafter Smith; as cited in the IDS filed 06/23/2023), as evidenced by Jiang and Doudna, 2017 (hereinafter Jiang).
The cancellation of claims 3 and 16-20 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Smith does not teach pegRNAs that comprise all the features of a pegRNA as described in the present Application.
In response, this is found persuasive. The Examiner agrees that Smith does not teach pegRNAs that comprise all the features of a pegRNA as described in the present Application. Accordingly, the rejection of record is hereby withdrawn.
RE: Claim Rejections - 35 USC § 103
►Claims 1-3 and 14-20 were previously rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/049168 A1 (hereinafter Smith; as cited in the IDS filed 06/23/2023) in view of Nahar et al., 2018 (hereinafter Nahar; as cited in the IDS filed 06/23/2023), as evidenced by Jiang and Doudna, 2017 (hereinafter Jiang).
The cancellation of claims 3 and 16-20 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Smith in view of Nahar (as evidenced by Jiang) does not teach pegRNAs that comprise all the features of a pegRNA as described in the present Application.
In response, this is found persuasive. The Examiner agrees that Smith in view of Nahar (as evidenced by Jiang) does not teach pegRNAs the comprise all the features of a pegRNA as described in the present Application. Accordingly, the rejection of record is hereby withdrawn.
However, new grounds of rejection necessitated by amendment are set forth below.
►Claim 1-3, 9, 10, 12, and 14-20 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/049168 A1 (hereinafter Smith; as cited in the IDS filed 06/23/2023) in view of WO 2016/183402 A2 (hereinafter Rinn; as cited in the IDS filed 06/23/2023), as evidenced by Jiang and Doudna, 2017 (hereinafter Jiang).
The cancellation of claims 3, 9, and 16-20 renders the rejection thereof moot.
Applicant has traversed the rejection of record, asserting that Smith in view of Rinn (as evidenced by Jiang) does not teach pegRNAs that comprise all the features of a pegRNA as described in the present Application.
In response, this is found persuasive. The Examiner agrees that Smith in view of Rinn (as evidenced by Jiang) does not teach pegRNAs that comprise all the features of a pegRNA as described in the present Application. Accordingly, the rejection of record is hereby withdrawn.
However, new grounds of rejection necessitated by amendment are set forth below.
New/Maintained Grounds of Objection/Rejection
Drawings
The drawings are objected to because:
With regard to Figure 12, the replacement drawings filed 06/09/2026 indicate that several SEQ ID NO are depicted therein. However, the sequences listed in Figure 12 are not all consistent with the associated SEQ ID NOs in the sequence listing. SEQ ID NO: 787 of Figure 12 is not consistent with SEQI D NO: 787 of the substitute sequence listing filed 06/09/2026. It would be remedial to update either the listed sequences or the listed sequence identifiers such that the listed sequences are consistent with the listed sequence identifiers.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 146, 148, and 154 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 146 and 148 are drawn to a set of evopreQ1-1 sequences, wherein said sequences are defined by having at least 80% sequence identity to recited sequence identifiers. Claim 154 is drawn to a set of linker sequences, wherein said sequences are defined by having at least 80% sequence identity to recited sequence identifiers. The rejected claims thus comprise a set of sequences that encompass a large number of variable residues, all variations of which must function as evopreQ1-1 or linker sequences.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification describes sequence identifiers corresponding to evopreQ1-1 sequences (SEQ ID NOs: 215-221; paragraph [0018]; Table 6) and linker sequences (SEQ ID NOs: 225-236; paragraphs [0022] and [0597]). No description is provided of evopreQ1-1 sequences or linker sequences comprising at least 80% sequence identity to the instantly recited sequence identifiers.
Even if one accepts that the examples described in the specification meet the claim limitations of the rejected claims with regard to structure and function, the examples are only representative of evopreQ1-1 sequences and linker sequences comprising the instantly recited sequence identifiers. The results are not necessarily predictive of evopreQ1-1 sequences or linker sequences comprising at least 80% sequence identity to the instantly recited sequence identifiers.
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As previously set forth and as shown in the alignment below, evopreq1 sequences are known to exhibit variable levels of sequence identity. Furthermore, linker sequences are known to be quite variable. As disclosed in the instant specification, linkers may be long or short and function only to link two molecules or moieties (paragraphs [0601] and [0602]). Thus, they encompass a wide range of variable sequences, as is reflected in the alignment below.
As shown in the alignment above, the instantly recited evopreQ1-1 and linker sequences include sequences with less than 80% sequence identity to each other. The instant specification is silent as to the essentiality of any particular sub-sequence or other general principles for designing functional nucleotide sequences sharing at least 80% identity to the instantly claimed sequences. Thus, it is impossible for one to extrapolate from the few examples described herein those evopreQ1-1 sequences or linker sequences that would necessarily meet the structural/functional characteristics of the rejected claims.
The prior art does not appear to offset the deficiencies of the instant specification in that it does not describe a set of evopreQ1-1 sequences or linker sequences comprising at least 80% sequence identity to the instantly recited sequence identifiers that are capable of functioning as claimed in the instantly claimed system. As is known to those of ordinary skill in the art, the prior art teaches that sequence conservation is a hallmark indicator of functionality, and that as conservation decreases, functionality comes into question, as sequences subject to transient or lower constraints cannot be distinguished easily from neutrally evolving, non-functional sequences (Ponting, 2017: abstract; of record). Thus, based on the disclosure and state of the art, it is not clear to someone of ordinary skill in the art whether a sequence with less than or at least 80% sequence identity across the entirety of said sequence would necessarily meet the structural/functional characteristics of the rejected claims.
Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 146,148, and 154.
Claim Rejections - 35 USC § 103
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, 10, 12, 14, 15, 153, 155, and 156 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/049168 A1 (hereinafter Smith; as cited in the IDS filed 06/23/2023; of record) in view of WO 2022/032085 A1 (hereinafter Cheng; effectively filed 08/07/2020), Roth et al., 2007 (hereinafter Roth), WO 2016/183402 A2 (hereinafter Rinn; as cited in the IDS filed 06/23/2023; of record), and WO 2020/028857 A1 (hereinafter Subramanian).
With regard to amended instant claim 1, which recites “a prime editing guide RNA (pegRNA) comprising:
a guide RNA and at least one nucleic acid extension arm comprising a DNA synthesis template and a primer binding site,
wherein the extension arm comprises a nucleic acid moiety attached thereto comprising a prequeosin1-1 riboswitch aptamer (evopreQ1-1),” as previously set forth, Smith discloses compositions and methods for high-efficiency genome editing, including the utility of retron-guide RNA cassettes (abstract; Figure 1). As shown in Figure 1, the retron-guide RNA cassette of Smith comprises a guide RNA linked to an extension arm comprising: a DNA synthesis template that also serves as a self-primer for synthesis by a reverse transcriptase, thereby yielding donor DNA sequence for insertion into the genome (paragraphs [0021 ], [0024], [0122], and [0133]; figure 1), which reads on the instantly claimed pegRNA comprising a guide RNA and at least one nucleic acid extension arm comprising a DNA synthesis template and a primer binding site. However, Smith is silent as to the instantly claimed evopreQ1-1 of the extension arm.
This deficiency is cured by Cheng and Roth. Cheng discloses methods and compositions for integrating large sequences into a selected target DNA sequence via prime editing (abstract). Said compositions include pegRNAs (page 1, lines 19-25), wherein the primer binding sequence of the pegRNA may comprise a modification or sequence that provides for an additional desirable feature, for example a riboswitch sequence or an aptamer sequence which allows for regulated stability and/or regulated accessibility by proteins and protein complexes (page 29, lines 20-30). Those of ordinary skill in the art would therefore be motivated by the disclosure of Cheng to test the functionality of various riboswitch or aptamer sequences in pegRNAs. Per the instant specification, evopreQ1-1 is the same as prequeosine1-1 riboswitch aptamer (paragraph [0237]). Roth discloses that the prequeosine1-1 riboswitch contains an unusually small aptamer domain (abstract). Those of ordinary skill in the art are aware that small domain structures are less likely to interfere with structure and therefore function. Thus, one of ordinary skill in the art would have been motivated to select the small riboswitch aptamer disclosed in Roth as the riboswitch aptamer sequence disclosed to facilitate regulated pegRNA stability and/or regulated pegRNA accessibility by proteins and protein complexes, as disclosed in Cheng. Thus, it is considered that Smith, Cheng, and Roth collectively disclose each and every limitation of amended instant claim 1.
With regard to claim 2, which recites “the nucleic acid moiety [of the pegRNA of claim 1] is attached to the 3’ end of the extension arm,” as set forth above, Smith, Cheng, and Roth collectively disclose each and every limitation of amended instant claim 1. Furthermore, the retron-guide RNA cassettes of Smith (set forth above) comprise inverted repeat sequences (i.e. hairpins) located at the 5’ or 3’ end of the retron (i.e. the extension arm) (paragraphs [0007], [0008], [0010], [0065], and [0122]). Therefore, Smith establishes that the extension arm of the pegRNA may be further extended at either the 5’ or 3’ end, as instantly claimed. Thus, it is considered that Smith discloses each and every additional limitation of instant claim 2.
With regard to amended instant claim 10, which recites “the nucleic acid moiety [of the pegRNA of claim 1] is attached to the extension arm by a linker,” as set forth above, Smith, Cheng, and Roth collectively disclose each and every limitation of amended instant claim 1. Furthermore, as previously set forth, Rinn discloses CRISPR/Cas systems where guide RNAs are connected to one or more selected RNA sequences (such as a ribozyme; as in Cheng) via a linker for delivery to a target nucleic acid sequence (abstract; page 2, paragraph 2-page 3, paragraph 1). Accordingly, the disclosure of Rinn establishes that guide RNAs (of which pegRNAs are a species) may be extended by attaching a linker thereto. Thus, it is considered that Rinn discloses each and every additional limitation of amended instant claim 10.
With regard to amended instant claim 12, which recites "the linker [of the pegRNA of claim 10] is at least 3 nucleotides in length, and wherein the linker is no longer than 50 nucleotides," as set forth above, Rinn discloses CRISPR/Cas systems where guide RNAs are connected to one or more selected RNA sequences (such as a ribozyme; as in Cheng) via a linker for delivery to a target nucleic acid sequence (abstract; page 2, paragraph 2-page 3, paragraph 1 ). The linkers of Rinn are disclosed to be between 4 and 6 nucleotides (page 17, paragraph 3), which falls within the instantly claimed range. Accordingly, Rinn discloses that linkers may be used to connect additional species to guide RNAs. Thus, it is considered that Rinn discloses each and every additional limitation of amended instant claim 12.
With regard to amended instant claim 14, which recites "the extension arm [of the pegRNA of claim 1] is positioned at the 3' end of the guide RNA," as set forth above, Smith, Cheng, and Roth collectively disclose each and every limitation of amended instant claim 1. Smith further discloses that the gRNA coding region of the cassette may be located 3' or 5' of the retron (i.e. extension sequence) (paragraph [0102]; claims 8 and 9). Thus, it is considered that Smith discloses each and every additional limitation of amended instant claim 14.
With regard to amended instant claim 15, which recites “the guide RNA [of the pegRNA of claim 1] comprises a gRNA core capable of interacting with a nucleic acid programmable DNA binding protein (napDNAbp) selected from the group consisting of Cas9, Cas12a (Cpf1)…and Argonaute,” Smith further discloses that the retron-guide RNA cassettes taught therein are compatible with Cas9 nucleases, directing said Cas9 nuclease to make a double-strand DNA cut at a desired genomic location and facilitating insertion of a donor DNA sequence (paragraphs [0048], [0127], and [0136]). Furthermore, Cheng discloses that the pegRNAs taught therein comprise sequence that interacts with/binds to/forms a complex with a Cas9 enzyme (page 11, lines 24-30), as instantly claimed. Thus, it is considered that Smith and Cheng each disclose each and every additional limitation of amended instant claim 15.
With regard to new claim 153, which recites “the linker [of the pegRNA of claim 10] lacks four consecutive uridines,” as set forth above, Rinn discloses CRISPR/Cas systems where guide RNAs are connected to one or more selected RNA sequences (such as a ribozyme; as in Cheng) via a linker for delivery to a target nucleic acid sequence (abstract; page 2, paragraph 2-page 3, paragraph 1). Accordingly, the disclosure of Rinn establishes that guide RNAs (of which pegRNAs are a species) may be extended by attaching a linker thereto. However, Rinn does not disclose that the linkers taught therein lack four consecutive uridines. This deficiency is cured by Subramanian. Subramanian discloses linkers suitable for attaching payloads to oligonucleotides (paragraphs [0032] and [0034]). Suitable linkers disclosed therein include poly-dT linkers and abasic linkers, neither of which comprise uridine residues (paragraph [000265]), as instantly claimed. Thus, it is considered that Subramanian discloses each and every additional limitation of instant claim 153.
With regard to new claim 155, which recites “the linker [of the pegRNA of claim 1] is 4-32 nucleotides in length,” as set forth above, as set forth above, Rinn discloses CRISPR/Cas systems where guide RNAs are connected to one or more selected RNA sequences (such as a ribozyme; as in Cheng) via a linker for delivery to a target nucleic acid sequence (abstract; page 2, paragraph 2-page 3, paragraph 1 ). The linkers of Rinn are disclosed to be between 4 and 6 nucleotides (page 17, paragraph 3), which falls within the instantly claimed range. Accordingly, Rinn discloses that linkers may be used to connect additional species to guide RNAs. Thus, it is considered that Rinn discloses each and every additional limitation of instant claim 155.
With regard to new claim 156, which recites “the nucleic acid extension arm [of the pegRNA of claim 1] is RNA,” as set forth above, Smith, Cheng, and Roth collectively disclose each and every limitation of amended instant claim 1. Furthermore, as set forth above, Smith discloses compositions and methods for high-efficiency genome editing, including the utility of retron-guide RNA cassettes (abstract; Figure 1). As shown in Figure 1, the retron-guide RNA cassette of Smith comprises a guide RNA linked to an extension arm comprising: a DNA synthesis template that also serves as a self-primer for synthesis by a reverse transcriptase, thereby yielding donor DNA sequence for insertion into the genome (paragraphs [0021 ], [0024], [0122], and [0133]; figure 1), which reads on the instantly claimed pegRNA comprising a guide RNA and at least one nucleic acid extension arm comprising a DNA synthesis template and a primer binding site. Additionally, the retron of Smith encodes an RNA molecule that, when reverse transcribed, results in a multicopy single-stranded DNA molecule that comprises both RNA and DNA (paragraph [0009]; claims 4 and 5). Thus, it is considered that Smith discloses each and every additional limitation of instant claim 156.
Allowable Subject Matter
Claims 6, 11, 13, 147, and 149-152 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter:
As Applicant has asserted in the reply filed 06/09/2026, the previously cited art does not teach or suggest the instantly claimed pegRNA structure/system, wherein said pegRNA comprises an extension arm comprising a prequeosin1-1 riboswitch aptamer attached thereto with the instantly claimed sequences. A thorough search of both the patent and non-patent literature did not return any sequence matches to instant SEQ ID NOs: 215-221 corresponding to a prequeosin1-1 riboswitch aptamer sequences prior to the effective filing date of the instant application. Additionally, the instantly claimed linker sequences (SEQ ID NOs: 225-236) were not fairly taught or disclosed in the prior art as linker sequences prior to the effective filing date of the instant application. Additionally, the prior art is silent as to the use of ViennaRNA for optimizing pegRNA structure and function.
Accordingly, claims 6, 11, 13, 147, and 149-152 stand objected to as being dependent upon a rejected base claim.
Conclusion
Claims 1-2, 10, 12, 14-15, 148-149, and 153-156 are rejected.
Claims 6, 11, 13, 147, and 149-152 are objected to.
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 Sarah E Allen whose telephone number is (571)272-0408. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at 571-272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARAH E ALLEN/ Examiner, Art Unit 1637
/J. E. ANGELL/ Primary Examiner, Art Unit 1637
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