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 .
The TrackOne Request, filed July 17, 2025, was granted August 19, 2025. Therefore, this application is accorded special status.
Claims 1-19 are pending in this application, and are under examination.
Information Disclosure Statement
The Information Disclosure Statements filed August 19, 2025 (11) have 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.
Claims 1-3 and 5-19 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (U.S. Patent No. 11,447,770, issued September 20, 2022, filed March 31, 2021, and claiming priority to PCT Patent Application No. PCT/US2020/023712 and U.S. Provisional Patent Application Nos. 62/991,069; 63/100,548; 62/994,231; 62/974,537; 62/931,195; 62/973,558; 62/913,553; 62/922,654; 62/889,996; 62/858,958; and 62/820,813; filed March 19, 2020; March 17, 2020; March 17, 2020; December 5, 2019; December 5, 2019; November 5, 2019; October 10, 2019; October 10, 2019; August 21, 2019; August 21, 2019; June 7, 2019; and March 19, 2019, respectively, and cited in the Information Disclosure Statement filed August 19, 2025) in view of Bohls et al. (119 Virus Research 187-194 (2006)).
Regarding claim 1, Liu discloses method for prime editing of a target DNA molecule (abstract). Liu discloses fusion protein comprising a reverse transcriptase fused to a Cas9 nickase domain and nucleic acids encoding the fusion protein (column 3, lines 25-30, column 8, lines 49-60, column 12, line 64 to column 13, line 5, column 57, lines 12-15 and column 273, lines 5-31). Liu discloses that the reverse transcriptase domain is fused to the C-terminal of the Cas9 domain (column 13, lines 14-21 and column 58, lines 63-67). Liu discloses that the Cas9 domain can be a nickase domain (column 14, lines 47-49 and column 23, lines 8-17). Liu discloses that the reverse transcriptase can be a wide variety of reverse transcriptases (column 184, lines 16-43). Liu discloses a guide RNA that binds to a target and the fusion protein, which can be used as a template, a heterologous object sequence, and a 3’ target homology zone (Figures 1A-1M).
Regarding claims 2-3, Liu discloses that the nickase can be an SpyCas9 (S. pyogenes) N863A nickase (column 83, lines 56-64).
Regarding claims 5-7, Liu discloses that the Cas9 can be an NmeCas9, an StCas9 (StlCas9) or an SaCas9 (SauCas9) (columns 103 and 134).
Regarding claims 8-9, Liu discloses a linker, which may be between 2 and 40 amino acids in length between the reverse transcriptase domain and the Cas9 nickase domain (column 5, line 65 to column 6, line 10, column 20, lines 61-66, and Figure 3G).
Regarding claims 10-12, Liu discloses that the fusion protein may include a nuclear localization sequence (NLS) at either the C-terminus of the fusion protein or the N-terminus of the Cas9 nickase domain (column 57, lines 16-29, column 58, lines 63-67, and column 236, line 55 to column 237, line 12).
Regarding claim 13, Liu discloses that the NLS can be a bipartite NLS or a monopartite NLS (column 237, lines 1-7 and column 237, line 64 to column 238, line 6)
Regarding claim 14, Liu discloses that a linker can be positioned between or flanked by two groups molecules or other moieties, which is interpreted as a linker can be situated between the NLS and the Cas9 nickase domain (column 233, lines 40-60 and column 238, lines 20-47).
Regarding claim 15, Liu discloses that the fusion protein has at least 50% activity compared to an unfused Cas9 nickase molecule (column 163).
Regarding claim 16, Liu discloses that the method can be carried out using the nucleic acid encoding the fusion protein (column 519, line 27 to column 521, line 67).
Regarding claim 17, Liu discloses that the nucleic acid can be an mRNA (column 519, line 27 to column 521, line 67).
Regarding claim 18, Liu discloses that the sequence binding the fusion protein can be a gRNA scaffold (column 553, line 58 to column 554, line 10).
Regarding claim 19, Liu discloses that the fusion protein or nucleic acid can be delivered using lipid nanoparticles (column 518, lines 45-61).
Liu fails to disclose or suggest the sequence of the reverse transcriptase.
Bohls discloses that Attwater’s prairie chicken can be infected by reticuloendotheliosis viruses, (abstract). Bohls discloses a reverse transcriptase having a sequence that has 98.9 % identity with instant SEQ ID NO: 3138 (Appendix I).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute Bohl’s reverse transcriptase for Liu’s reverse transcriptase because, as disclosed by Liu, a wide variety of reverse transcriptases can be incorporated into a fusion protein with a Cas9 nickase. As such, one of ordinary skill in the art would have been able to substitute Bohl’s known reverse transcriptase for use in Liu’s editing method with a predictable and reasonable expectation of success.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Liu in view of Bohls, as applied to claims 1-3 and 5-19 above, and further in view of Vyas et al. (U.S. Patent Application Publication No. 2017/0166928, published June 15, 2017, and cited in the Information Disclosure Statement filed August 19, 2025).
Liu and Bohls disclose and suggest a method of modifying a target site in genomic DNA of a cell, as discussed above.
Liu and Bohls fail to disclose the sequence of the Cas9 nickase, which may be the same as SEQ ID NO: 3269.
Vayas discloses a Cas9 that can genetically modify eukaryotic cells (abstract). Vayas discloses that the Cas9 can be a nickase, that can include an amino acid substitution at position 863 (paragraph [0052]). Vayas discloses a nickase having the sequence of SEQ ID NO: 5, which is identical to instant SEQ ID NO: 3269 (SEQ ID NO: 5) (Appendix II).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute Vayas’ Cas9 nickase for the Cas9 nickase claimed and disclosed by Liu and Bohls because, as disclosed by Liu, a wide variety of Cas9 nickases can be incorporated into a fusion protein with a reverse transcriptase. As such, one of ordinary skill in the art would be able to substitute Vayas’ known Cas9 nickase for the different Cas9 nickase disclosed and suggested by Liu and Bohls with a predictable and reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 8-9, and 18-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 110-113, 115-116, 121, 129, and 131 of copending Application No. 17/929,116 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘116 application claims a fusion protein comprising a reverse transcriptase domain and a Cas nickase domain, and a method of modifying a target site in genomic DNA by contacting the cell with the fusion protein system, and the instant application claims a method of using such a fusion protein for modifying a target site in the genomic DNA of a cell (claim 1). The ‘116 application claims that the reverse transcriptase has a sequence selected from those listed in Table 30 or Table 44, which the instant application claims that the sequence has the sequence of SEQ ID NO: 3138 (claim 1), which is listed in Table 44. The ‘116 application claims that the DNA binding domain is a CRISPR/Cas nickase domain (claim 1). The ‘116 application claims a linker positioned between the RT domain and the Cas9 nickase (DBD domain) (claim 8). The ‘116 application claims that the linker is between 2 and 40 amino acids in length (claim 9). The ‘116 application claims that the sequence that binds the fusion protein is a gRNA scaffold (claim 18). The ‘116 application claims that the fusion protein, or nucleic acid encoding the fusion protein is formulated in a lipid nanoparticle (claim 19).
Therefore, the claims of the ‘116 application and the instant application are not deemed to be patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 2-3 and 5-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 110-113, 115-116, 121, 129, and 131 of copending Application No. 17/929,116 (reference application) in view of Liu et al. (U.S. Patent No. 11,447,770, issued September 20, 2022, filed March 31, 2021, and claiming priority to PCT Patent Application No. PCT/US2020/023712 and U.S. Provisional Patent Application Nos. 62/991,069; 63/100,548; 62/994,231; 62/974,537; 62/931,195; 62/973,558; 62/913,553; 62/922,654; 62/889,996; 62/858,958; and 62/820,813; filed March 19, 2020; March 17, 2020; March 17, 2020; December 5, 2019; December 5, 2019; November 5, 2019; October 10, 2019; October 10, 2019; August 21, 2019; August 21, 2019; June 7, 2019; and March 19, 2019, respectively, and cited in the Information Disclosure Statement filed August 19, 2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘116 application claims a fusion protein comprising a reverse transcriptase domain and a Cas nickase domain, as well as the method of modifying a target site in a cell’s genomic DNA, as discussed above.
The ‘116 application fails to explicitly claim additional characteristics and sequences of the fusion protein. The ‘116 application does not claim that the CRISPR/Cas domain is a Cas9 domain.
Regarding claim 1, Liu discloses compositions for prime editing of a target DNA molecule (abstract). Liu discloses fusion protein comprising a reverse transcriptase fused to a Cas9 nickase domain and nucleic acids, which are interpreted to included mRNA, encoding the fusion protein (column 3, lines 25-30, column 8, lines 49-60, column 12, line 64 to column 13, line 5, and column 57, lines 12-15). Liu discloses that the reverse transcriptase domain is fused to the C-terminal of the Cas9 domain (column 13, lines 14-21 and column 58, lines 63-67). Liu discloses that the Cas9 domain can be a nickase domain (column 14, lines 47-49 and column 23, lines 8-17). Liu discloses that the reverse transcriptase can be a wide variety of reverse transcriptases (column 184, lines 16-43).
Regarding claims 2-3, Liu discloses that the nickase can be an SpyCas9 (S. pyogenes) N863A nickase (column 83, lines 56-64).
Regarding claims 5-7, Liu discloses that the Cas9 can be an NmeCas9, an StCas9 (StlCas9) or an SaCas9 (SauCas9) (columns 103 and 134).
Regarding claims 8-9, Liu discloses a linker, which may be between 2 and 40 amino acids in length between the reverse transcriptase domain and the Cas9 nickase domain (column 5, line 65 to column 6, line 10, column 20, lines 61-66, and Figure 3G).
Regarding claims 10-12, Liu discloses that the fusion protein may include a nuclear localization sequence (NLS) at either the C-terminus of the fusion protein or the N-terminus of the Cas9 nickase domain (column 57, lines 16-29, column 58, lines 63-67, and column 236, line 55 to column 237, line 12).
Regarding claim 13, Liu discloses that the NLS can be a bipartite NLS or a monopartite NLS (column 237, lines 1-7 and column 237, line 64 to column 238, line 6)
Regarding claim 14, Liu discloses that a linker can be positioned between or flanked by two groups molecules or other moieties, which is interpreted as a linker can be situated between the NLS and the Cas9 nickase domain (column 233, lines 40-60 and column 238, lines 20-47).
Regarding claim 15, Liu discloses that the fusion protein has at least 50% activity compared to an unfused Cas9 nickase molecule (column 163).
Regarding claim 16, Liu discloses that the method can be carried out using the nucleic acid encoding the fusion protein (column 519, line 27 to column 521, line 67).
Regarding claim 17, Liu discloses that the nucleic acid can be an mRNA (column 519, line 27 to column 521, line 67).
Regarding claim 18, Liu discloses that the sequence binding the fusion protein can be a gRNA scaffold (column 553, line 58 to column 554, line 10).
Regarding claim 19, Liu discloses that the fusion protein or nucleic acid can be delivered using lipid nanoparticles (column 518, lines 45-61).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute ‘116 application’s additional components and sequences with Liu’s fusion protein because, as disclosed by Liu, a wide variety of reverse transcriptases can be incorporated into a fusion protein with a Cas9 nickase. As such, one of ordinary skill in the art would be able to substitute one known fusion protein for a different fusion protein comprising the same components with a predictable and reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 4 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 110-113, 115-116, 121, 129, and 131 of copending Application No. 17/969,116 (reference application) in view of Liu et al. (U.S. Patent No. 11,447,770, issued September 20, 2022, filed March 31, 2021, and claiming priority to PCT Patent Application No. PCT/US2020/023712 and U.S. Provisional Patent Application Nos. 62/991,069; 63/100,548; 62/994,231; 62/974,537; 62/931,195; 62/973,558; 62/913,553; 62/922,654; 62/889,996; 62/858,958; and 62/820,813; filed March 19, 2020; March 17, 2020; March 17, 2020; December 5, 2019; December 5, 2019; November 5, 2019; October 10, 2019; October 10, 2019; August 21, 2019; August 21, 2019; June 7, 2019; and March 19, 2019, and cited in the Information Disclosure Statement filed August 19, 2025), as applied to claims 1-3, 5-15, and 17-21 above, and further in view of Vyas et al. (U.S. Patent Application Publication No. 2017/0166928, published June 15, 2017, and cited in the Information Disclosure Statement filed August 19, 2025).
Although the claims at issue are not identical, they are not patentably distinct from each other because the ‘116 application and Liu claim and discloses a fusion protein comprising a reverse transcriptase and a Cas9 nickase, as discussed above.
The ‘116 application and Liu fail to claim the sequence of the Cas9 nickase, which may be the same as SEQ ID NO: 3269. The ‘116 application and Liu fail to claim that the sequence of the fusion protein is instant SEQ ID NO: 3651.
Vayas discloses a Cas9 that can genetically modify eukaryotic cells (abstract). Vayas discloses that the Cas9 can be a nickase, that can include an amino acid substitution at position 863 (paragraph [0052]). Vayas discloses a nickase having the sequence of SEQ ID NO: 5, which is identical to instant SEQ ID NO: 3269 (SEQ ID NO: 5) (Appendix I).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention to substitute Vayas’ Cas9 nickase for the Cas9 nickase claimed and disclosed by the ‘116 application and Liu because, as disclosed by Liu, a wide variety of Cas9 nickases can be incorporated into a fusion protein with a reverse transcriptase. As such, one of ordinary skill in the art would be able to substitute one known Cas9 nickase for a different Cas9 nickase with a predictable and reasonable expectation of success.
It would also have been obvious to one with ordinary skill in the art, having the ‘116 application, Liu, and Vayas in front of them, which disclose each of the components of the fusion protein, including components having the same sequences as the reverse transcriptase of the ‘116 application, the nickase of Vayas to prepare the fusion protein having the sequence of instant SEQ ID NO: 3561 in order to employ the fusion protein in methods of modifying a target site in a cell’s genomic DNA. Because each of the components of the ‘116 application, Liu, and Vayas were well known, and were known to be able to form a fusion protein for modifying genomic DNA, one of ordinary skill in the art would have had a predictable and reasonable expectation of success in creating the fusion protein having the sequence of instant SEQ ID NO: 3561, and to use the fusion protein in a method of modifying a target site in genomic DNA.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
/DANIEL M SULLIVAN/Director, Art Unit 1600