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 1-17, 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.
Information Disclosure Statement
3. The information disclosure statements (IDS) submitted on 01 November 2023, 05 January 2024, 24 March 2025, and 25 June 2025 have been considered by the examiner. See initialed and signed PTO/SB/08’s.
Drawings
4. The drawings are objected to because multiple figures are illegible: a) Fig. 6 labels are illegible, b) Fig. 8 is unclear, specifically what are the white bars?, c) Fig. 10b X-axis is illegible; there are no x-axis or y-axis lines (i.e. vertical and horizontal lines on which labels are made), d) Fig. 14 is unclear and illegible: there is no explanation of the numbering at the top of the figure (1-7), and the SEQ ID NOs listed in the “Brief Description of the Drawings” are not in the figure. 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.
Specification
5. The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on p. 18, paragraph 0082. 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.
6. The disclosure is objected to because of the following informalities: Table 1 (starting on p. 174) lists multiple genus species without italicizing them.
Appropriate correction is required.
Claim Objections
7. Claim 4 is objected to because of the following informalities: “the selected sequence is…” should be amended to “the selected sequence for the DNA polymerase domain is…” to conform with the claim language used in the other claims. Appropriate correction is required.
8. Claim 12 is objected to because of the following informalities: there is no definition of the acronym “HNH” in the claim. Appropriate correction is required.
9. Claim 14 is objected to because of the following informalities: “wherein the Cas protein is a…” should be amended to “wherein the Cas protein is a Cas protein selected from the group consisting of…” to conform to correct Markush language. Appropriate correction is required.
Claim Rejections - 35 USC § 112
10. 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.
11. Claims 3, 12, 17, and 31 are 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.
12. The term “at least about” in claims 3 and 17 is a relative term which render the claims indefinite. It is unclear if the claim is directed to “at least” 86% or more sequence identity or what “about” means in context with “at least;” i.e. is 86% is the absolute least amount of sequence identity or not. It is recommended to amend the claim to delete “about” to increase the clarity of the claim.
13. Claim 10 is indefinite because it does not end in a period; therefore, it is unclear if there are further claim limitations.
14. 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. 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.
Claim Rejections - 35 USC § 101
15. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
16. Claims 1-7 and 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a natural phenomenon) without additional elements that integrate the judicial exception into a practical application. An analysis with respect to the claims as a whole reveals that they do not include additional elements that integrate the judicial exception into a practical application. See MPEP 2106.
Analysis of subject-matter eligibility under 35 U.S.C. § 101 requires consideration of the following steps:
Step (1) whether the claim is directed to one of the four categories recited in §101 (process, machine, manufacture or composition of matter);
Step (Revised 2A - Prong 1) do the claims recite an abstract idea (mathematical concepts, mental processes or method of organizing human activity), law of nature or natural phenomenon;
Step (Revised 2A - Prong 2) do the claims recite additional elements that integrate the judicial exception into a practical application; and
Step (2B) whether the claim as a whole recites something that amounts to significantly more than the judicial exception. (See 2019 Revised Patent Subject Matter Eligibility Guidance (2019 PEG)).
Step 1: Yes; the claims are directed to a composition of matter.
Step 2A – Prong 1: Yes, the claims recite a natural phenomenon, namely, a naturally occurring DNA binding domain and a DNA polymerase domain.
Step 2A – Prong 2: No, the claims do not recite any additional elements that integrate the judicial exception into a practical application because the claim does not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements claimed with the DNA binding and polymerase domains.
Step 2B: As noted in answering that of 2A – This judicial exception is not integrated into a practical application because DNA polymerases inherently contain a DNA binding domain, where specifically it is not claimed that these domains are heterologously linked. As such, there is no distinguishable modifications to delineate the DNA polymerases recited in the claims and any naturally occurring DNA polymerases.
Claim Rejections - 35 USC § 102
17. 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.
18. 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.
19. Claims 1-4 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fluegel and Pfrepper (Fluegel and Pfrepper, 2003, Curr. Top. Microbiol. Immunol.—cited herein). Claims 1-4 and 31 are drawn to a DNA binding domain and a DNA polymerase domain, wherein the DNA polymerase domain comprises SEQ ID NO: 261. Fluegel and Pfrepper teach a reverse transcriptase comprising a DNA polymerase that shares 100% identity to SEQ ID NO: 261. (See Supplemental File: 20251112_104604_us-18-478-179-261.rup; Result 1).
20. Claims 1-3, 5 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rua et al (Rua et al., 2012, J. Virol.—cited herein). Claims 1-3, 5, and 31 are drawn to a DNA binding domain and a DNA polymerase domain, wherein the DNA polymerase domain comprises SEQ ID NO: 270. Rua et al. teach a reverse transcriptase that shares 100% identity to SEQ ID NO: 270. (See Supplemental File: 20251112_104604_us-18-478-179-270.rup; Result 1).
21. Claims 1-3, 6 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ashton et al., who submitted the sequence to GenBank/EMBL/DDBJ databases in January 2019 (Supplemental File: 20251112_104604_us-18-478-179-16.rup). Claims 1-3, 6, and 31 are drawn to a DNA binding domain and a DNA polymerase domain, wherein the DNA polymerase domain comprises SEQ ID NO: 270. Rua et al. teach a reverse transcriptase that shares 100% identity to SEQ ID NO: 270. (See Supplemental File: 20251112_104604_us-18-478-179-16.rup; Result 1).
22. Claims 1-3, 7 and 31 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kuroda et al (Kuroda et al., 2001, Lancet—cited herein). Claims 1-3, 7, and 31 are drawn to a DNA binding domain and a DNA polymerase domain, wherein the DNA polymerase domain comprises SEQ ID NO: 18. al. Kuroda et al. teach a reverse transcriptase from the whole genome sequencing of meticillin-resistant Staphylococcus aureus shares 100% identity to SEQ ID NO: 18. (See Supplemental File: 20251112_104604_us-18-478-179-18.rup; Result 1).
.
Claim Rejections - 35 UASC § 103
23. 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.
24. Claims 1-4, 8-17, 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) and Scharenberg et al. (Scharenberg et al., 2019, US 10,378,026 B2—cited herein) 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 herein), and Huang et al (Huang et al., 2020, US10822606 B2—cited herein). Regarding claims 1-4, drawn to a prime editing composition comprising: a) DNA binding domain 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: 261 and 270 (claims 2 and 4), 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). Regarding claims 8-11, drawn to the prime editing composition of claim 1, wherein the DNA binding domain comprises 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 8, 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).
Liu et al. does not teach the DNA polymerase domain being at least 86% sequence identity to SEQ ID NOs: 261 and 270 (claims 1-3) or DNA polymerase domain being SEQ ID NO: 261 (claim 4). 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 linker comprising SEQ ID NO: 279 (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 1-4, drawn to the DNA polymerase domain being at least 85% or 86% sequence identity to SEQ ID NOs: 261 and 270, Scharenberg et al. teaches the transfer of transgene into cells by the safe and efficient transfer of RNA encoding foamy components for therapeutic interest and/or gene therapy (abstract). Specifically, Scharenberg teaches that SEQ ID NOs: 13-20, which encode Pol proteins for the introduction of the RNA components into the genome (Column 6, lines 6-9), where SEQ ID NO: 20 shares 100% identity with SEQ ID NO: 261 of the instant claims (Supplemental file: 20251112_104604_us-18-478-179-261.rai, Result 1) and SEQ ID NO: 16 shares 91.1% identity with SEQ ID NO: 270 of the instant claims (Supplemental file: 20251112_104604_us-18-478-179-270.rai, 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, Scharenberg teaches that SEQ ID NO: 20 shares 100% identity utilizing this alignment tool, as evidenced by “NCBI Blast Alignment.” Utilizing the parameters of the claim limitation, SEQ ID NO: 20 is 100% identical to SEQ ID NO: 270 (“NCBI Blast Alignment,” 2025, p. 3-5). 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 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., Scharenberg et al., 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 Scharenberg et al. 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.
Conclusion
24. All claims are rejected..
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.
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/CIARA A MCKNIGHT/Examiner, Art Unit 1656
/MANJUNATH N RAO/Supervisory Patent Examiner, Art Unit 1656