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 .
Status of the Application
1. Claims 1, 3, 6-7, 9-17, 31-32, and 56 are pending and subject to examination on the merits.
Priority
2. Acknowledgment is made for the Applicant’s claim for domestic priority based on the US provisional application PRO 63/169,725 filed 01 April 2021.
Specification
3. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, an instance of browser executable code is still present at paragraph 0082, line 12. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Withdrawn Objections/Rejections
4. The objection to the drawings for illegible figures has been withdrawn, since the drawings have been resubmitted in a clear and legible format.
5. The objection to the specification for the lack of italicized scientific names of various species is withdrawn, since the tables have been resubmitted with italicization.
6. The objection to claim 12 for not providing a definition for HNH has been withdrawn, since the abbreviation has been defined in the claim as “histidine-asparagine-histidine.”
7. The objection to claim 14 for the use of improper Markush language is withdrawn, since the claim was amended to recite “wherein the Cas protein is a Cas protein selected from the group consisting of…”
8. The 35 U.S.C. 112(b) indefiniteness rejection of claim 3 is withdrawn, since the claim was amended to delete “about.”
9. The 35 U.S.C. 112(b) indefiniteness rejection of claim 17 is withdrawn, since the claim was amended to delete “about.”
10. The 35 U.S.C. 112(b) indefiniteness rejection of claim 10 is withdrawn, since the claim was amended to end in a period.
11. The 35 U.S.C. 101 rejection of claims 1-7 and 31 for being directed to a judicial exception (natural phenomenon) without additional elements that integrate the judicial exception into practical practice is withdrawn, since claim 1 was amended to recite “wherein the DNA binding domain comprises a CRISPR associated (Cas) protein.”
12. The 35 U.S.C. 102 anticipation rejection of claims 1, 3, and 31 as being anticipated by Fluegel and Pfrepper (Fluegel and Pfrepper, 2003, Curr. Top. Microbiol. Immunol.—cited previously) is withdrawn, since claim 1 has been amended to delete SEQ ID NO: 261.
13. The 35 U.S.C. 102 anticipation rejection of claims 1, 3, and 31 as being anticipated by Rua et al (Rua et al., 2012, J. Virol.—cited previously) is withdrawn, since claim 1 has been amended to delete SEQ ID NO: 270.
14. The 35 U.S.C. 102 anticipation rejection of claims 1, 3, 6, and 31 as being anticipated by Ashton et al., who submitted the sequence to GenBank/EMBL/DDBJ databases in January 2019, since claim 1 has been amended to include a CRISPR associated protein as the DNA binding element (previously claim 8).
15. The 35 U.S.C. 102 anticipation rejection of claims 1, 3, 7, and 31 as being anticipated by Kuroda et al (Kuroda et al., 2001, Lancet—cited previously), since claim 1 has been amended to include a CRISPR associated protein as the DNA binding element (previously claim 8).
16. The 35 U.S.C. 103 obviousness rejection of claims 1, 3, 9-17, 31-32, and 56 over Liu et al (Liu et al, 2020, WO 2020/191153—cited on the IDS dated 01 November 2023) and Scharenberg et al. (Scharenberg et al., 2019, US 10,378,026 B2—cited previously) as evidenced by “NCBI Blast Protein Sequence” (“NCBI Blast Protein Sequence,” 2005, downloaded as a PDF on 24 November 2025 from < https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE_TYPE=BlastSearch&BLAST_SPEC=GlobalAln > --cited previously), and Huang et al (Huang et al., 2020, US10822606 B2—cited previously) has been withdrawn, since the claims have been modified to include the claim limitations of previous claim 8 into claim 1 and claims 2 and 4 were cancelled.
Maintained and New Rejections/Objections—necessitated by amendments
Claim Objections
17. Claim 32 is objected to because of the following informalities: periods in claims are not permitted except at the end of the claim and when used for abbreviations (See MPEP 608.01(m)). Thus, it is suggested to replace, for example, “a.” with “(a)” or “a)”, etc. and “i.” with “(i)” or “i)”, etc. It is noted, the preferred format for sequence identifiers is “SEQ ID NO:” – see MPEP 2422.01 and 37 C.F.R. 1821(c) and (d). The claim recites “SEQ ID NO.:” and should be amended to “SEQ ID NO:”
Appropriate corrections are required.
FOR SEQ ID NO: - – See MPEP 2422.01 and 37 C.F.R. 1.821(c) and (d)
Claim Rejections - 35 USC § 112(b)
18. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
19. Claim 31 is 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.
20. Claim 31 is indefinite because Applicants cannot restrict or specify to the office how the sequence alignment is determined according to the applicant’s algorithms. Therefore, Examiner considers said requirement of sequence alignment and percent identity determination according to “Needleman-Wunsch alignment” as indefinite. The office determines the percent sequence identity according to the rules set forth by the office, which Is the Smith Waterman algorithm with Gap costs set according to the STIC library of the office. Please see the sequence search results in the supplemental contents files, where these specific search parameters may be viewed. Examiner suggests canceling the claim.
Claim Rejections - 35 USC § 103
21. 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.
22. Claims 1, 3, 6-7, 9-17, 31-32, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (Liu et al, 2020, WO 2020/191153—cited on the IDS dated 01 November 2023), Ashton et al., who submitted the sequence (SEQ ID NO: 16) to GenBank/EMBL/DDBJ databases in January 2019—cited previously, Kuroda et al (Kuroda et al., 2001, Lancet—cited previously), as evidenced by “SEQ ID NO: 18 Alignment” (“SEQ ID NO: 18 Alignment, 2026, downloaded 04 August 2026 from < https://blast.ncbi.nlm.nih.gov/Blast.cgi#alnHdr_Query_645049> and provided as a PDF herein), Liu et al. 2 (Liu et al., 2, 2020, WO2020041751-A1—cited herein), and Huang et al (Huang et al., 2020, US10822606 B2—cited previously). Regarding claim 1, drawn to a prime editing composition comprising: a) DNA binding domain, wherein the DNA binding domain comprises a CRISPR associated (Cas) protein and b) a DNA polymerase domain with at least 86% identity (claim 3) to a sequence selected from the group consisting of SEQ ID NOs: 16 and 18 (claims 6 and 7), Liu et al teaches compositions for conducting prime editing of a target DNA molecule that enables the incorporation of a nucleotide change and/or targeted mutagenesis, where said composition is a fusion protein comprising a nucleic acid programmable DNA binding protein (napDNAbp) and a polymerase, which is guided by a prime editor RNA (abstract), wherein said polymerase may be a RNA-dependent DNA polymerase, such as a reverse transcriptase or a DNA-dependent DNA polymerase, such as a Pol I, Pol II, or Pol III prokayrotic polymerase (paragraph 0451). Regarding the DNA binding domain comprising a CRISPR associated (Cas) protein, specifically a Type II Cas9 (claims 9-10) nickase (claim 11), Liu et al. teaches the prime editing composition comprising a DNA binding domain, which can include a Cas9 nickase (paragraphs 0010 and 0068). Regarding claim 12, drawn to the prime editing composition of claim 11, comprising a Cas9 protein with a mutation in the HNH domain, Liu et al. teaches a prime editor comprising a fusion protein having a polymerase and a napDNAbp (e.g. a SpCas9 having a deactivating mutation in an HNH nuclease domain (paragraph 0096, Fig. 1J). Regarding claims 13-15, drawn to the prime editing composition of claim 1, wherein the Cas protein is a Type V Cas12b, Liu et al., teaches that the prime editors described may also comprise Cas9 equivalents, including Cas12a and Cas12b1, which are the result of convergent evolution (paragraph 0338). Regarding claim 32, drawn to a prime editing composition that comprises a fusion protein comprising a DNA binding domain and a DNA polymerization domain connected via peptide linker, wherein the linker has at least 80% sequence identity to SEQ ID NO: 279. Liu et al. teaches the prime editing composition comprising the domains linked with a peptide linker; i.e. the napDNAbp domain linked via peptide linker to the polymerase domain (RT domain) (paragraph 0423). Regarding claim 32, drawn to the utilization of a linker sequence with at least 85% sequence identity to SEQ ID NO: 278, Liu et al. teaches the utilization of linker sequences (paragraph 0060).
Liu et al. does not teach the DNA polymerase domain being at least 86% sequence identity to SEQ ID NOs: 16 and 18 (claims 6 and 7). Liu et al. does not teach the specific use of Needleman-Wunsch alignment of two protein sequences with Gap costs set to Existence: 11 Extension: 1 for the sequence (claim 31). Additionally, Liu et al. does not teach a specific linker comprising a linker sequence having at least 85% sequence identity to SEQ ID NO: 278 (claim 32). Last, Liu et al. does not teach the DNA binding domain comprising a sequence with at least 80% identity to SEQ ID NO: 1011 (claim 56).
Regarding claims 1, 3, and 6, drawn to the DNA polymerase domain being at least 85% or 86% sequence identity to SEQ ID NOs: 16, Ashton et al. teaches a Reverse Transferase DNA polymerase domain from shotgun sequencing data from Salmonella enterica, that shares 100% identity to SEQ ID NO: 16. (See Supplemental File: 20251112_104604_us-18-478-179-16.rup; Result 1).
Regarding claims 1, 3, and 7 drawn to the DNA polymerase domain being at least 85% or 86% sequence identity to SEQ ID NOs: 18, Kuroda et al. teach an RNA directed DNA Polymerase from whole genome sequencing of methicillin resistant Staphylococcus aureus that shares 100% identity to SEQ ID NO: 18. (See Supplemental File: 20251112_104604_us-18-478-179-18.rup; Result 1).
Regarding claim 31, drawn to the prime editing composition of claim 1, where the sequence identities are determined by the Needleman-Wunsch alignment of two protein sequences with Gap Costs set to Existence: 11 Extension: 1, Kuroda et al. teach an RNA directed DNA Polymerase from whole genome sequencing of methicillin resistant Staphylococcus aureus that shares 100% identity to SEQ ID NO: 18, as evidenced by “NCBI Blast Alignment” utilizing the parameters of the claim limitation (“NCBI Blast Alignment,” 2026). For the sake of compact prosecution, this claim limitation was examined in accordance to what the applicant has filed. However, as noted in the above indefinite rejection, the office is not obligated to perform sequence searches based on the Applicant’s algorithms or parameters. The office determines the percent sequence identity according to the rules set forth by the office, which Is the Smith Waterman algorithm with Gap costs set according to the STIC library of the office. Please see the sequence search results in the supplemental contents files, where these specific search parameters may be viewed.
Regarding claim 32, drawn to the utilization of a linker sequence with at least 85% sequence identity to SEQ ID NO: 278, Liu et al. 2 teaches SEQ ID NO: 104, which is a fusion protein construction related linker for a CRISPR/Cas9 protein complex with 97% sequence identity to SEQ ID NO: 278 (See Supplemental File: 20251112_104604_us-18-478-179-278.rag; result 2).
Regarding claim 56, drawn to a prime editing composition comprising a DNA binding domain with at least 80% identity to SEQ ID NO: 1101, Huang et al. teaches a Cas9 sequence with at least 80% identity to SEQ ID NO: 6, which is 100% identical to SEQ ID NO: 1101 of the instant claim (Column 10, lines 50-53) (See Supplemental File: 20251112_104604_us-18-478-179-1011.rai, Result 2).
Therefore, it 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 combine the teachings of Liu et al., Ashton et al., Kuroda et al., Lui et al. 2, and Huang et al. to utilize a fusion protein to accomplish prime editing of the genome by utilizing a Cas nickase to initiate a single strand break and a subsequent DNA polymerase domain with 86% or greater sequence identity to integrate nucleotides to the site to introduce mutations or mitigate mutations in the DNA strand. One would be motivated to combine these teachings to arrive at the instant claims to utilize the system in gene therapy as taught by Liu et al. There would be a reasonable expectation of success, yielding no surprising results when combining the teachings of Liu et al. with those of Ashton et al., Kuroda et al., Lui et al. 2, and Huang et al., since Liu et al. teaches fusion proteins consisting of Cas protein domains and DNA polymerase domains for the utilization in prime editing.
Applicant’s Arguments and Examiner’s Rebuttal:
The applicant traverses the previous indefiniteness rejection of claim 31 and the previous obviousness rejection of claims 1, 3, 9-17, 31-32, and 56 over Liu et al (Liu et al, 2020, WO 2020/191153—cited on the IDS dated 01 November 2023) and Scharenberg et al. (Scharenberg et al., 2019, US 10,378,026 B2—cited previously) as evidenced by “NCBI Blast Protein Sequence” (“NCBI Blast Protein Sequence,” 2005, downloaded as a PDF on 24 November 2025 from < https://blast.ncbi.nlm.nih.gov/Blast.cgi?PAGE_TYPE=BlastSearch&BLAST_SPEC=GlobalAln > --cited previously), and Huang et al (Huang et al., 2020, US10822606 B2—cited previously). The claims were amended to cancel claims 2, 4, and 8; where the claim limitations of claim 8 were integrated into claim 1.
First, the applicant traverses the indefiniteness rejection of claim 31 because the applicant argues that they are able to set an algorithm or parameters because the office cites no rule, precedent, or any section of the MPEP to indicate otherwise. Additionally, the Applicant argues that they require the same parameters as NCBI’s BLAST for global alignment, which would be understood by a person of ordinary skill in the arts. The examiner acknowledges that there is no rule, precedent, or MPEP section; however, the USPTO utilizes internal tools provided by STIC (See STIC algorithmic information of the Supplementary Files as discussed above). Additionally, regarding the Applicant’s use of NCBI’s BLAST parameters, the examiner contends that much like conventional accession numbers given to deposited sequences, algorithms may change over time to improve different functionalities, typically speed and accuracy. To this end, the applicant cites that the NCBI BLAST tool utilizes the same parameters required by the claim; however, even NCBI BLAST has utilized many different iterations of its algorithms over time (See Altschul, 2014, “BLAST Algorithm”—cited herein).
The Applicant traverses the previous obviousness rejection since the DNA polymerase domain sequences were amended to SEQ ID NOs: 16 and 18. The examiner has withdrawn the previous rejection due to these claim amendments and added the rejection above. Additionally, the applicant points out that the examiner neglected to fully explain the rejection of claim 32. The examiner apologizes and thanks the applicant for amending claim 32 to be dependent upon claim 1, thus keeping the interest of compact prosecution in this case. Claim 32 has been included in the above rejection.
Last the applicant argues that the newly amended claims recite claim limitations that were previously not rejected under the obviousness rejection of record. In light of these amendments, the Examiner has withdrawn that rejection and replaced it with the rejection above including all of these claim limitations.
The examiner does not find the arguments presented by the Applicant persuasive, and for these reasons, the rejections of record above apply.
Conclusion
23. All claims are rejected.
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 CIARA A MCKNIGHT whose telephone number is (703)756-4791. The examiner can normally be reached M-F 8:00am-4:30pm.
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, Manjunath Rao can be reached on (571) 272-0939. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656
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