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 .
DETAILED ACTION
Claims 1-18 are pending and under examination.
Election/Restrictions
Applicant’s species election without traverse of the both the deletion of a BRCT domain and an NLS domain, and SEQ ID NO:1, in the reply filed on 12/29/2025 is acknowledged.
Claim Rejections - 35 USC § 112(b)
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.
Claims 4 and 12 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.
Claims 4 and 12 recite TdT variants comprising an N-terminal deletion of amino acid residues 1-129, wherein numbering of the amino acid positions is determined by alignment with the sequence of SEQ ID NO:1. It is unclear if the claim means that the TdT variant comprises residues 130-510 of SEQ ID NO:1, or if the claim encompasses any TdT homolog comprising a deletion in the residues that align with 1-129 of SEQ ID NO:1. Therefore, the scope of the claim is unclear and one of ordinary skill in the art would not understand what is required.
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 1-18 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claims 1-8 are drawn to a method of synthesizing a polynucleotide using terminal deoxynucleotidyl transferase (TdT) variants comprising a deletion of a BRCT domain, an NLS domain, or both. Claim 7 limits the TdT variant to an amino acid sequence that is at least 90% identical to any of SEQ ID NOs:1, 11, 12, or 13. Claim 8 limits the variant to an amino acid sequence that is at least 90% identical to SEQ ID NO:1. Claim 9 is drawn to a method of adding a 3’-O-blocked nucleoside triphosphate to a nucleic acid using a TdT variant comprising a deletion of a BRCT domain, an NLS domain, or both. Claim 15 limits the TdT variant to an amino acid sequence that is at least 90% identical to any of SEQ ID NOs:1, 11, 12, or 13. Claim 16 limits the variant to an amino acid sequence that is at least 90% identical to SEQ ID NO:1
MPEP 2163.05 II states “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that ‘only describe[d] one type of structurally similar antibodies’ that ‘are not representative of the full variety or scope of the genus.’). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure "indicates that the patentee has invented species sufficient to constitute the gen[us].’”
The instant specification discloses the specificity of SEQ ID NO:3, which is the wild type TdT enzyme comprising a deletion of amino acid residues 1-129, and the variants shown in Table 5 (Example 5), and discloses DNA synthesizing ability without a template of a TdT variant comprising R336N, R454A, and E457G substitution mutations (Example 6). The specification does not disclose the entire genus of TdT variants that are capable of: synthesizing a polynucleotide without a template, or adding a 3’O-blocked nucleoside triphosphate to a nucleic acid. The specification does not disclose all variants with up to 10% divergence from SEQ ID NO:1 that are capable of: synthesizing a polynucleotide without a template, or adding a 3’O-blocked nucleoside triphosphate to a nucleic acid. The specification does not disclose what structural properties are required for the enzyme to maintain its activity or disclose which regions of SEQ ID NO:1, the wild type TdT sequence, are the active site residue(s) required for conserving the claimed enzyme activity. Therefore, the disclosed species are not representative of the entire genus of claimed TdT variants.
Efcavitch et al., (WO 2016/064880 A1) teaches modified terminal deoxynucleotidyl transferase (TdT) enzymes that can be used for de novo polynucleotide synthesis without the use of a template (p. 1, Field of the Invention; Summary). Repasky et al., (Mutational Analysis of Terminal Deoxynucleotidyltransferase-Mediated N-Nucleotide Addition in V(D)J Recombination. J Immunol. 2004 May 1;172(9):5478-88; cited in the IDS filed 12/29/2025) teaches a TdT mutant that excludes the putative nuclear localization signal (NLS) and the BRCT domain but retains catalytic activity (p. 5479, col. 1, para. 4; Figure 6). However, neither Efcavitch nor Repasky disclose all possible TdT variants that are capable of synthesizing a polynucleotide by adding nucleotides to the 3’hydroxyl terminus of a nucleic acid.
In summary, neither the instant specification, nor the prior art, discloses a structure-function relationship between conserved amino acid residues in the claimed enzyme structure and the claimed enzyme activity. One of ordinary skill in the art cannot reasonably predict all residues of SEQ ID NOs:1, 11, 12, or 13 that may be modified to generate a functional TdT capable of adding nucleotides to the 3’hydroxyl terminus of a nucleic acid. Based on the instant disclosure, those skilled in the art would not conclude that the applicant was in possession of all claimed variants.
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.
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 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Efcavitch et al., (WO 2016/064880 A1; IDS 10/29/2024) in view of Repasky et al., (Mutational Analysis of Terminal Deoxynucleotidyltransferase-Mediated N-Nucleotide Addition in V(D)J Recombination. J Immunol. 2004 May 1;172(9):5478-88; IDS 12/29/2025).
Regarding claim 1, Efcavitch teaches modified terminal deoxynucleotidyl transferase (TdT) enzymes that can be used for de novo polynucleotide synthesis without the use of a template (p. 1, Field of the Invention; Summary). Efavitch teaches that the method for synthesizing a polynucleotide comprises providing a nucleic acid having an unprotected 3’-hydroxyl group, and reacting the nucleic acid with a nucleoside 5’ triphosphate comprising a removable 3’O’-blocking moiety in the presence of a modified TdT enzyme (claim 24). Efcavitch teaches that once the 3’-O-blocked dNTP analogs are added and the nucleotide is extended, the reactants can be recycled and the 3’-O-blocking group will be removed, allowing the cycle to start anew (p. 4, para. 2), i.e., deblocking and repeating.
Efcavitch does not teach that the TdT variant comprises a deletion in a BRCT domain or an NLS domain.
However, Repasky teaches a TdT mutant that excludes the putative nuclear localization signal (NLS) and the BRCT domain but retains catalytic activity (p. 5479, col. 1, para. 4; Figure 6).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to substitute the TdT variant of Repasky for the TdT variant of Efcavitch. One of ordinary skill in the art would have had a reasonable expectation of success because substituting known enzyme variants for those of similar function is well within the knowledge of one of ordinary skill, and the results are reasonably predictable.
Regarding claims 2 and 3, Repasky teaches that the BRCT and the NLS domains are removed (p. 5479, col. 1, para. 4; Figure 6).
Regarding claim 4, which is interpreted as requiring that the TdT variant is SEQ ID NO:1 with residues 1-129 removed, Efcavitch teaches murine TdT (SEQ ID NO:9), which shares 100% sequence identity to instant SEQ ID NO:1 (see alignment below). Repasky teaches the deletion of residues 1-129 or murine TdT (p. 5479, col. 1, para. 4; Figure 6). Therefore, it would have been obvious to one of ordinary skill in the art to remove residues 1-129 of SEQ ID NO:9 of Efcavitch, based on the teachings of Repasky.
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Regarding claim 5, Repasky teaches that the TdT variant that excludes the NLS and BRCT is murine (Figure 6).
Regarding claim 6, Efcavitch teaches a wild type TdT sequence (SEQ ID NO:9) with 100% sequence identity to instant SEQ ID NO:1 (see alignment above).
Regarding claims 7 and 8, Repasky teaches the removal of residues 1-129 of murine TdT, the sequence of which is shown in SEQ ID NO:9 of Efcavitch. SEQ ID NO:9 lacking residues 1-129 shares 100%
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sequence identity with residues 130-510 of instant SEQ ID NO:1 (see alignment below).
Regarding claim 9, Efavitch teaches a method comprising providing a nucleic acid having an unprotected 3’-hydroxyl group, and reacting the nucleic acid with a nucleoside 5’ triphosphate comprising a removable 3’O’-blocking moiety in the presence of a modified TdT enzyme (claim 24). Efcavitch teaches that the 3’-O-blocked dNTP analogs are added to the nucleotide (p. 4, para. 2).
Efcavitch does not teach that the TdT variant comprises a deletion in a BRCT domain or an NLS domain.
However, Repasky teaches a TdT mutant that excludes the putative nuclear localization signal (NLS) and the BRCT domain but retains catalytic activity (p. 5479, col. 1, para. 4; Figure 6).
It would have been obvious to one of ordinary skill in the art, prior to the effective filing date of the claimed invention, to substitute the TdT variant of Repasky for the TdT variant of Efcavitch. One of ordinary skill in the art would have had a reasonable expectation of success because substituting known enzyme variants for those of similar function is well within the knowledge of one of ordinary skill, and the results are reasonably predictable.
Regarding claims 10 and 11, Repasky teaches that the BRCT and the NLS domains are removed (p. 5479, col. 1, para. 4; Figure 6).
Regarding claim 12, which is interpreted as requiring that the TdT variant is SEQ ID NO:1 with residues 1-129 removed, Efcavitch teaches murine TdT (SEQ ID NO:9), which shares 100% sequence identity to instant SEQ ID NO:1 (see alignment below). Repasky teaches the deletion of residues 1-129 or murine TdT (p. 5479, col. 1, para. 4; Figure 6). Therefore, it would have been obvious to one of ordinary skill in the art to remove residues 1-129 of SEQ ID NO:9 of Efcavitch, based on the teachings of Repasky.
Regarding claim 13, Repasky teaches that the TdT variant that excludes the NLS and BRCT is murine (Figure 6).
Regarding claim 14, Efcavitch teaches a wild type TdT sequence (SEQ ID NO:9) with 100% sequence identity to instant SEQ ID NO:1 (see alignment below).
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Regarding claims 15 and 16, Repasky teaches the removal of residues 1-129 of murine TdT, the sequence of which is shown in SEQ ID NO:9 of Efcavitch. SEQ ID NO:9 lacking residues 1-129 shares 100% sequence identity with residues 130-510 of instant SEQ ID NO:1 (see alignment below).
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Claims 17 and 18 are intended use claims. According to MPEP 2111.02 II, a composition comprising the TdT variant of modified Efcavitch and a 3’O-blocked nucleoside triphosphate is considered to meet the limitations of instant claims 17 and 18. Efcavitch teaches a composition comprising a TdT variant and a nucleotide triphosphate having a removable 3’O-blocking moiety (claim 23), while Repasky teaches a TdT variant lacking a BRCT domain and an NLS domain (p. 5479, col. 1, para. 4; Figure 6).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RACHEL EMILY MARTIN whose telephone number is (703)756-1416. The examiner can normally be reached M-Th 8:30-16:00, F 8:30-10:00 EST.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/RACHEL EMILY MARTIN/Examiner, Art Unit 1657