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
The Response of 4 June 2026 has been entered.
Claims 1-4, 7-12 and 15-18 are pending and are examined with respect to the elected species of SEQ ID NO:1 and deletion of a BRCT domain and an NLS domain.
Any rejection not reiterated herein has been withdrawn.
Response to Arguments
Applicant's arguments filed 4 June 2026 have been fully considered but they are not persuasive.
Applicant argues that Fig. 3 shows activity of a representative number of truncated variants to support the claimed genus. This is not persuasive because the instant specification states that wild-type polymerases (including TdT) do not have the ability to incorporate 3’O-modified nucleotides due to steric hindrance and that such functionality is only conferred by specific mutations such as those enlarging the catalytic pocket (Published Spec. US20240124855, [0007], [0011]). Efcavitch et al. (WO2016/064880) also teaches that natural TdT lacks the ability to incorporate 3’O-modified nucleotides (p. 5, last ¶). The results of Fig. 3 are consistent with these teachings, showing that wild-type truncated TdT does not incorporate the 3’O-modified nucleotide (Fig. 3, top, under wt) whereas variants comprising specific substitutions are capable of such incorporation (Fig. 3, under DSX). As such, one of ordinary skill in the art would consider Applicant to be in possession of the specific variants described in the specification and combinations thereof, but not of all possible truncated variants allowing for incorporation of 3’O-modified nucleotides.
Applicant further argues that SEQ IDs 11-13 are readily alignable with SEQ ID 1, and thus one of ordinary skill in the art could determine the corresponding substitutions/truncations in human, chicken and dog TdTs from the mouse variants described in the specification. Applicant’s argument is persuasive with respect to SEQ IDs 11-13 and specific variants thereof corresponding to those described for mouse TdT, but it is not persuasive with respect to the claimed genus as a whole for the reasons set forth above.
With respect to the 103 rejection, Applicant argues that wild-type TdTs were not known in the art to have the ability to incorporate 3’O-modified nucleotides, and Repasky merely teaches that N-terminal truncation to delete the NLS/BRCT domains retains general catalytic activity rather than the ability to incorporate 3’O-modified nucleotides. This is not persuasive because Efcavitch teaches modified TdT variants (e.g., with modifications to GGFRR or TGSR motifs) that have the ability to incorporate 3’O-modified nucleotides, and Repasky teaches that N-terminal truncation of mouse TdT to delete the NLS/BRCT domains retains catalytic activity. Moreover, Efcavitch further teaches N-terminal truncations of bovine TdT variants with deleted NLS/BRCT domains that are capable of incorporating 3’O-modified nucleotides (e.g., Efcavitch, claims 2-5), and further teaches that “variety of other proteins may be explored to identify a candidate suitable for the use with 3'-O-blocked dNTP analogs, including human and murine TdT” (p. 9, 1st full ¶). The mouse TdT of instant SEQ ID 1 has >80% identity to the bovine TdT of Efcavitch (see attached alignment), and one of ordinary skill could have readily determined the corresponding substitutions/truncation points in the mouse sequence (as argued by Applicant with respect to the written description rejection). Efcavitch further cites and incorporates by reference US7494797 (cited in IDS of 29 Oct. 2024) (Efcavitch, p. 12, 1st ¶), which teaches that N-terminally truncated TdT has significantly enhanced catalytic activity (col. 2, line 24 to col. 3, line 67). Thus, one of ordinary skill in the art would have been motivated to use a N-terminally truncated version of the variants taught by Efcavitch to increase catalytic activity.
Applicant further argues that there would have been no reasonable expectation of success in using a TdT variant of Efcavitch that is truncated as taught by Repasky to incorporate 3’O-modified nucleotides. Applicant cites portions of Repasky teaching that the truncated TdT showed decreased activity in a VDJ recombination assay. This is not persuasive because Repasky teaches that the NLS and BRCT domains have non-catalytic protein-protein binding functions involved in recruiting TdT to the VDJ recombination complex (e.g., under Discussion). Thus, one of ordinary skill in the art would not have regarded the NLS and BRCT domains to have functions important for in vitro incorporation of 3’O-modified nucleotides as taught by Efcavitch and recited in the instant claims. Moreover, Efcavitch teaches N-terminally truncated bovine TdTs capable of incorporating 3’O-modified nucleotides, and the high degree of sequence homology between bovine and mouse TdTs would have provided a reasonable expectation of success in using corresponding mouse TdT variants in the same manner.
Claim Rejections - 35 USC § 112(a) (written description)
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.
Claims 1-4, 7-12 and 15-18 are rejected under 35 U.S.C. 112(a) 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 1-4, 7-12 and 15-18 are drawn to a method of synthesizing a polynucleotide and/or adding a 3’-O-blocked nucleoside triphosphate using terminal deoxynucleotidyl transferase (TdT) variants comprising a deletion of a BRCT domain, an NLS domain, or both, wherein the TdT variant comprises an amino acid sequence that is at least 90% or 95% identical to any of SEQ ID NOs: 1, 11, 12, or 13. SEQ IDs 1, 11, 12 and 13 are greater than 500 amino acids in length, and the claims thus encompass a large genus of potential variants including substitutions of any kind at any point along the sequence.
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 instant specification discloses modified TdT variants capable of incorporating 3’O-blocked nucleosides, wherein the variants comprise one or more mutations from a list of specific substitutions at specific residues (Table 1). The specification states that the wild-type enzymes cannot incorporate 3’O-modified nucleosides, and that specific modifications are required to alleviate the steric hindrance associated with such modified nucleosides (Published Spec. US20240124855, [0007]-[0011]). The specification does not disclose the entire genus of TdT variants that are capable of: synthesizing a polynucleotide without a template and/or adding a 3’O-blocked nucleoside triphosphate to a nucleic acid, and does not describe a representative number of species representative of the claimed genus. The specification also fails to provide guidance that would allow one of ordinary skill in the art to identify additional members of the genus, such as a structure-function relationship indicating which residues are responsible for the claimed functionality.
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). The variants of Efcavitch are modified at many of the same residues described in the instant specification; e.g., the GGFRR and TGSR motifs identified as sites of modification correspond to residues 332-336 and 451-454 of SEQ ID 1 (see attached alignment of Efcavitch SEQ ID 1 vs instant SEQ ID 1; cf. Spec., Table 1). Efcavitch further teaches N-terminally truncated variants comprising deleted NLS and BRCT domains (Tables 3, 5, 7), and 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 capable of synthesizing a polynucleotide and/or incorporating 3’O-modified nucleotides.
In summary, neither the instant specification, nor the prior art, discloses sufficient variants and/or other information that would allow one of ordinary skill in the art to identify species representative of the claimed genus. Thus, 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 1-4, 7-12 and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over Efcavitch et al., (WO2016/064880 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 claims 1 and 9, 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). Efcavitch 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.
Regarding the recitation in claims 1, 7-9, 15 and 16 that the TdT variant is derived from a wild-type TdT of SEQ ID 1 and is at least 90% or 95% identical to SEQ ID 1, Efcavitch teaches that the modified TdT can be derived from a mouse TdT sequence (SEQ ID NO:9; see also, p. 9, 1st full ¶) with 100% sequence identity to instant SEQ ID NO:1. The modified TdT variants of Efcavitch comprise modifications to one or more residues in the GGFRR or TGSR motifs (9 out of 510 residues) (claim 24), and would thus have at least 95% identity to SEQ ID 1.
Claims 1-4, 7-12 and 15-18 differ from Efcavitch in that: the TdT variant comprises a deletion in a BRCT domain and an NLS domain (claims 1-3, 10, 11; elected species = both BRCT and NLS domain are deleted); and the TdT variant comprises a deletion of residues corresponding to 1-129 of SEQ ID 1 (claims 4, 12).
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 (such that the modified TdT of Efcavitch comprises deleted NLS and BRCT domains). 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 4 and 12, Repasky teaches the deletion of residues 1-129 of 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 the variant of Efcavitch based on SEQ ID NO:9, based on the teachings of Repasky.
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
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 ROBERT J YAMASAKI whose telephone number is (571)270-5467. The examiner can normally be reached M-F 930-6 PST.
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/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
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