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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 11, 2026 has been entered.
Applicants previously canceled claim 13. Applicants make no amendments, but add new claim 22. Claims 1-12 and 14-22 are pending in this application, and are under examination.
Any objection or rejection of record in the previous Office and Advisory Actions, mailed November 19, 2025 and March 2, 2026, respectively, which is not addressed in this action has been withdrawn in light of Applicants’ amendments and/or arguments.
Claim Interpretation
It is noted that Applicants define the term substantially complementary as including at least 80% complementary to at least 99% or 100% complementary. In addition, Applicants define the term “portion” as including at least 1 to at least 250 nucleotides in length.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 1-11 and 13-20 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Liu et al. (Liu I, U.S. Patent No. 11,447,770, issued September 20, 2022).
Regarding claim 1, Liu I discloses a prime editing guide (pegRNA) comprising a spacer domain, a gRNA core domain, a nucleic acid synthesis template domain (RTT), and a primer binding site (column 16, line 35 to column 17, line 21 and Figure 1M). Liu I discloses that the edit template comprises a sequence that has one or more nucleotide changes compared to a second strand (column 16, line 35 to column 17, line 21 and Figure 1M). Liu I discloses that the pegRNA may comprise a homology arm (column 16, line 35 to column 17, line 21 and Figure 1M). Liu I discloses that the pegRNA can be circularized (column 556, lines 1-4). Liu I discloses that the pegRNA can be split into two portions, which together form the gRNA core domain (column 561, lines 50-63). Liu I discloses a linker that can be located between the primer binding site and the spacer domain, and can have a secondary structure (column 4, line 63 to column 5, line 7, column 17, line 27 to column 18, line 13, and Figures 3A-3C).
Regarding claim 2, Liu I discloses that the pegRNA can be circularized (column 556, lines 1-4).
Regarding claims 3-5, Liu I discloses that the order of the pegRNA, from 5’ to 3’, is spacer, gRNA core domain, nucleic acid synthesis template domain, and the primer binding site (column 16, line 35 to column 17, line 21 and Figure 1M). Liu I discloses the presence of two litigation sites, where the integration of the edit is inserted via flap equilibration (Figure 1M).
Regarding claim 6, Liu I discloses that the pegRNA can be an RNA:DNA chimera (column 63, lines 1-22).
Regarding claim 7, Liu I discloses that the synthesis template domain is a template for an RNA-dependent polymerase or a DNA-dependent polymerase (column 63, lines 1-44).
Regarding claim 8, Liu I discloses that the nucleotide changes can be a single nucleotide substitution, a deletion, or an insertion (column 10, lines 28-37).
Regarding claim 9, Liu I discloses that the nucleotide change can be a G to T, a G to A, a G to C, a T to G, a T to A, a T to C, a C to G, a C to T, a C to A, an A to T, an A to G, or an A to C substitution (column 10, lines 28-37). Liu discloses that the change can convert a G:C basepair to a T:A basepair, a G:C basepair to an A:T basepair, a G:C basepair to a C:G basepair, a T:A basepair to a G:C basepair, a T:A basepair to an A:T basepair, a T:A basepair to a C:G basepair, a C:G basepair to a G:C basepair, a C:G basepair to a T:A basepair, a C:G basepair to an A:T basepair, an A:T basepair to a T:A basepair, an A:T basepair to a G:C basepair, or an A:T basepair to a C:G basepair (column 10, lines 38-47). Liu discloses that an insertion can be at least 1 nucleotide (column 10, lines 48-56). Liu discloses that a deletion can be of at least 1 nucleotide (column 10, lines 57-65).
Regarding claim 10, Liu I discloses that the nucleic acid synthesis template domain comprises a sequence complementary to a sequence downstream of a nick region in a second strand of a double-stranded target nucleic acid (column 3, line 17 to column 5, line 42 and column 9, lines 34-54).
Regarding claim 11, Liu I discloses that the spacer has a sequence complementary to a first strand of the target nucleic acid or that the spacer can have mismatches with the target nucleic acid (column 15, lines 28-39, column 25, lines 40-44, and Figure 31).
Regarding claim 14, Liu I discloses that the napDNAbp can be an RNA guided DNA-binding protein such as a CRISPR-Cas enzyme, an Argonaute protein, or a retrotransposon (column 3, lines 17-35, column 4, lines 40-48, column 81, line 40 to column 84, line 22, and column 137, line 33 to column 140, line 22).
Regarding claim 15, Liu I discloses that the nucleic acid modifying enzyme can be a polymerase, such as reverse transcriptase (column 8, lines 21-67).
Regarding claim 16, Liu I discloses a prime editing system that comprises a pegRNA, a napDNAbp, and a nucleic acid modifying enzyme (column 8, lines 21-67).
Regarding claim 17, Liu I discloses a composition comprising the pegRNA and a napDNAbp (column 8, lines 30-67 and column 622, lines 55-63).
Regarding claim 18, Liu I discloses cells that contain the pegRNA (column 624, lines 18-61).
Regarding claim 19, Liu I discloses that the cells can be a mismatch repair competent cell (column 602, lines 22-43).
Regarding claim 20, Liu I discloses that the prime editing system can be used to effect one or more changes in the nucleotide sequence of a target nucleic acid, comprising contacting a double-stranded target nucleic acid with the prime editing system (abstract and column 9, line 34 to column 10, line 20).
Regarding claim 21, Liu I discloses that the pegRNA, from 5’ to 3’, is spacer, gRNA core domain, nucleic acid synthesis template domain, and the primer binding site (column 16, line 35 to column 17, line 21 and Figure 1M).
Regarding claim 22, Liu I discloses that the linking domain can comprise a variety of secondary structures, including a hairpin structure (columns 17-18).
Liu I discloses each and every limitation of claims 1-11 and 43-22 and therefore Liu I anticipates claim 1-11 and 14-22.
Alternatively, Liu I discloses the pegRNA, as discussed above. Liu I discloses that the peg RNA can have secondary structures, including a hairpin (columns 17-18). Liu discloses that the pegRNA can have different ordering of elements and that the pegRNA can have a hairpin structure (columns 17-18).
While Liu I does disclose a linker sequence in the pegRNA and that the pegRNA can have a hairpin secondary structure, it would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that Liu I’s pegRNA, which has a linker structure, can have a hairpin secondary structure in that linker. Because Liu I discloses that the elements of the pegRNA can have variations, and because Liu I clearly discloses that the pegRNA can have secondary structures, including hairpins, one of ordinary skill in the art would have been able to provide a pegRNA having a linker having a hairpin structure with a predictable and reasonable expectation of success.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (Liu I, U.S. Patent No. 11,447,770, issued September 20, 2022), as applied to claims 1-11 and 13-20 above, and in view of Liu et al. (Liu II, U.S. Patent Application Publication No. 2023/0357766, published November 9, 2023, filed March 23, 2023, and claiming priority to PCT Patent Application No. PCT/US2021/052097 and U.S. Provisional Patent Application Nos. 63/231,231; 63/182,633; 63/091,272; and 63/083,067; filed September 24, 2021; August 9, 2021; April 30, 2021; October 13, 2020; and September 24, 2020, respectively, and cited in the Information Disclosure Statement filed May 5, 2025).
Liu I discloses prime editing RNAs (pegRNAs), nucleic acid programmable DNA binding proteins (napDNAbps), and methods of editing nucleic acid sequences, as discussed above.
Liu I fails to disclose or suggest that the gRNA core domain has at least 80% identity with SEQ ID NO: 1 or SEQ ID NO: 572.
Liu II discloses prime editing guide RNAs (pegRNAs that can be used to edit a genome using prime editor complexes (abstract). Liu II discloses that modified pegRNAs can increase prime editing efficiency, pegRNA half-life in vivo, and increase lifespan in a cell (abstract). Liu II discloses gRNA core domain sequences that are at least 80% identical, and 100% identical over at least a portion of the gRNA core domain that have the sequences of SEQ ID NO: 1 and SEQ ID NO: 572 (Appendix I, SEQ ID NO: 545 and Appendix II, SEQ ID NO: 891). Liu II discloses a linker that can be located between the primer binding site and (paragraph [0064], and Figures 3A-3C). Liu II also discloses that the pegRNA can include a linker sequence, as well as having structural elements including hairpins (paragraph [0290]).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to use Liu II’s gRNA core domain sequences in the pegRNAs of Liu I and in methods of prime editing of nucleic acid target sequences of both Liu I and Liu II because both Liu I and Liu II are directed to pegRNAs, prime editing systems, and methods of editing target nucleic acid sequences in cells. One of ordinary skill in the art would have been motivated to use Liu II’s sequences in the pegRNAs and prime editing systems and methods in order to increase editing efficiency, in vivo half-life, and pegRNA lifespans in cells.
Response to Amendments and Arguments
Regarding the rejection under 35 U.S.C. §§ 102(a)(1) and 102(a)(2), Applicants’ arguments have been fully considered, but are not deemed to be persuasive.
Applicants assert that Liu I’s pegRNA does not have a linker, located between the primer binding site and the spacer domain, and which has a secondary structure. Applicants point to Figures 3B-3C, and assert that these figures show that the linker has no secondary structure. However, these Figures show the components of the pegRNA. And Figure 3A shows the position of the linker. While Applicants point solely to Figures 3B and 3C, the disclosure of the patent does discuss these specific Figures, but also notes that the pegRNA can have different ordering of elements and that the pegRNA can have a hairpin structure. The disclosure of Liu is therefore deemed to clearly disclose that the linker of the pegRNA can have a secondary structure, such as a hairpin. That the linker can have a secondary structure is discussed at columns 17-18, which state that the pegRNA can comprise secondary structures, which include hairpin secondary structures. In addition, Liu I states, at column 17, that the structural elements of the pegRNA can show variations in the arrangement of the elements.
Indeed, and contrary to Applicants’ assertion, Liu I does disclose pegRNAs that have a linker domain located between the spacer domain and the primer binding site, as discussed above. And the linker domain can have a secondary structure, including hairpins. See, e.g., Figures 3A-3C and columns 17-18. In addition, Liu I does fairly disclose the structure of the pegRNA as having a spacer domain, a gRNA core domain, a nucleic acid synthesis template domain, a primer binding site, and the linking domain.
In addition, the rejection is now includes an alternative rejection under 35 U.S.C. 103, as discussed above. Because Liu I discloses that the elements of the pegRNA can have variations, and because Liu I clearly discloses that the pegRNA can have secondary structures, including hairpins, one of ordinary skill in the art would have been able to provide a pegRNA having a linker having a hairpin structure with a predictable and reasonable expectation of success.
Because Liu I does disclose each and every limitation of claims 1-11 and 14-22, Liu I is still deemed to anticipate claims 1-11 and 14-22, and in the alternative, render obvious claims 1-22 and 14-22..
Regarding the rejection under 35 U.S.C. § 103, Applicants arguments have been fully considered, but are not deemed to be persuasive.
As above, Applicants’ assert that neither Liu I nor Liu II provides a pegRNA comprising a linker domain located between the primer binding site and the spacer domain.
However, as discussed above, Liu II also discloses pegRNAs that have a linker domain located between the spacer domain and the primer binding site, as discussed above. And the linker domain can have a secondary structure. See, e.g., Figures 3A-3C and paragraph [0290]. In addition, Liu II also discloses the structure of the pegRNA as having a spacer domain, a gRNA core domain, a nucleic acid synthesis template domain, a primer binding site, and the linking domain. Liu II is also cited for disclosing gRNA core domain sequences, which are at least 80% identical, and 100% identical over at least a portion of the gRNA core domain that have the sequences of SEQ ID NO: 1 and SEQ ID NO: 572 (Appendix I, SEQ ID NO: 545 and Appendix II, SEQ ID NO: 891). For all these reasons, and those listed above Liu I in view of Liu II is deemed to render claim 12 obvious.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Anzalone et al. (40 Nature Biotechnology 731-740 (2022), and cited in the Information Disclosure Statement filed May 5, 2025) disclose prime editing pegRNAs and prime editing systems and methods for targeted deletion, replacement, integration, or inversion of genomic sequences (abstract). Anzalone et al. disclose twin prime editing, which is useful for editing double-stranded DNA sequences (Figure 1).
Nelson et al. (40 Nature Biotechnology 402-410 (2022), and cited in the Information Disclosure Statement filed May 5, 2025) disclose prime editing of target nucleic acids which provides for installation of any combination of point mutations, small insertions, or small deletions in cells (abstract). Nelson et al. disclose prime editing systems that include pegRNAs, a reverse transcriptase template, and a primer binding site (abstract). Nelson et al. disclose engineered pegRNAs that improve prime editing efficiency and stability and prevent degradation (abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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.
NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights