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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 6/9/2026 has been entered.
Applicant’s amendment of claims 1-16, 18 and 22, in the paper of 6/9/2026, is acknowledged. Applicants' arguments filed on 6/9/2026, have been fully considered and are deemed to be persuasive to overcome some of the rejections previously applied. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. Claims 1-16, 18, 20 and 22 are still at issue and are present for examination.
Election/Restrictions
Applicant's election without traverse of the invention of Group 1, claims 1-18, 20 and 22, to a modified terminal deoxynucleotidyl transferase (TdT) enzyme, in the paper of 8/7/2025, is acknowledged. Applicant's election without traverse of the following species : Species Group 1: Polu; Species Group 2: E385N; Species Group 3: M152T; Species Group 4: giɭ 768 Bos taurus; .Species Group 5: 3’-aminooxy, in the paper of 8/7/2025, is acknowledged.
Claims 3, 4, 6, 7, 9-15, 18 and 20 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Specification
The disclosure is objected to because of the following informalities:
Applicants specification is objected to because applicants specification comprises Nucleotide and/or Amino Acids Disclosures Requiring a "Sequence Listing".
Applicants attention is directed to 37 CFR 1.821(a) which presents a definition for "nucleotide and/or amino acid sequences." This definition sets forth limits, in terms of numbers of amino acids and/or numbers of nucleotides, at or above which compliance with the sequence rules is required. Nucleotide and/or amino acid sequences as used in 37 CFR 1.821 through 37 CFR 1.825 are interpreted to mean an unbranched sequence of four or more amino acids or an unbranched sequence of ten or more nucleotides.
It is noted that previously applicants specification was objected to because it contained a number of sequences that were not associated with proper sequence identifiers (see office action dated 8/22/2025). In response applicants amended their specification to include sequence identifiers with the sequences in applicants specification. It is noted that the response of 11/21/2025 applicants amended the specification by adding text of “SEQ ID NO: 5”, “SEQ ID NO: 6”, “SEQ ID NO: 7” and “SEQ ID NO: 8”, however it is noted that applicants sequence listing submitted with applicants filing on 1/23/2023 only contains 4 sequences ( SEQ ID NO:1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4. While applicants amended the specification to include additional sequence identifiers, they have not added the sequences to the applicants sequence listing as required.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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, 2, 5, 8, 16 and 22 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 claim(s) contains 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
This rejection was stated in the previous office action as it applied to previous claims 1, 2, 5, 8, 16, 17 and 22. In response applicants have amended the claims and traverse the rejection as it applies to the newly amended claims.
Applicants submit that they have amended independent claim 1 to clarify both the structural requirements of the claimed modified TdT enzyme (e.g., defines the sequence changes in the modified TdT enzyme based on the corresponding residues in the wild-type TdT (SEQ ID NO: 1) or a specific truncated version thereof (SEQ ID NO: 6)), and the functional requirement of the same (e.g., "retains TdT activity").
Applicants submit that TdT enzymes are well-known in the art and the structural domains for TdT function are also well-known. Applicants submit that TdT belongs to the X family of DNA polymerases, and X-ray crystallography data reveals that its tertiary structural core mimics the classic "right-hand" configuration common to polymerases, consisting of an 8 kDa N-terminal domain and a 31 kDa catalytic core divided into fingers, palm, and thumb subdomains (Mutt and Sowdhamini (2016) PLoS ONE 11(6): e0157286. https://doi.org/10.1371/journal.pone.0157286).
Applicants submit that the specification has provided a multi-sequence alignment in FIG. 2 to further illustrate the conserved regions and less conserved regions in several TdT enzymes with respect to SEQ ID NO: 1. Applicants submit that the species included a wide range from other fish (Pundamilia Nyererei - Victorian cichlid, an African freshwater fish native to Lake Victoria), to domestic livestock animals such as cattle (Bos taurus), to wild boar (Sus scrofa), to rodents (such as house mice Mus musculus and chinchilla (Chinchilla lanigera), to marsupial (such as opossum (Monodelphis domestica) and Tasmanian devil (Sarcophilus harrisii)), to bat (Myotis brandtii), and to primates (such as the northern greater galago (Otolemur garnettii) and Bonobos (Pan paniscus)). Applicants submit that the alignment clearly shows regions that are highly conserved from fish to primate, while also showing regions much less conserved even between two species of fish.
Thus, applicants submit that one of skill in the art, in view of the well-known general structure of the TdT enzymes, its well-defined functional domains, and conserved vs. non-conserved regions based on sequence alignments of TdTs from a wide variety of species, would readily conclude that the claimed genus of modified TdT enzymes having both the recited structural and functional limitations is adequately represented by the numerous disclosed species in the specification.
Applicants amendment of the claims and applicants complete traversal is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
In response to applicants submission that they have amended independent claim 1 to clarify both the structural requirements of the claimed modified TdT enzyme (e.g., defines the sequence changes in the modified TdT enzyme based on the corresponding residues in the wild-type TdT (SEQ ID NO: 1) or a specific truncated version thereof (SEQ ID NO: 6)), and the functional requirement of the same (e.g., "retains TdT activity"), applicants amendment of the claims is acknowledged. It is further noted that applicants amendment of the claims continues to read on a very broad genus of modified TdT enzyme variants. (see also above comments regarding newly referenced SEQ ID NO:6 above, under the objection to applicants sequence listing).
In response to applicants submission that TdT enzymes and the structural domains for TdT function are well-known in the art, while this is appreciated applicants claims continue to read on an extremely large genus of TdT enzyme variants with limited to no structural limitations.
In spite of applicants additional submitted species and alignments, it continues that the specification only provides the representative species of that modified terminal deoxynucleotidyl transferase (TdT) enzymes comprising the amino sequence of SEQ ID NO 1, wherein said modified Tdt comprises a E385N modification relative to SEQ ID NO:1, encompassed by these claims. There is insufficient disclosure of any particular structure to function/activity relationship in the disclosed species. The specification also fails to describe additional representative species of these modified terminal deoxynucleotidyl transferase (TdT) enzymes by any identifying structural characteristics or properties, for which no predictability of structure is apparent.
Given this lack of additional representative species as encompassed by the claims, Applicants have failed to sufficiently describe the claimed invention, in such full, clear, concise, and exact terms that a skilled artisan would recognize Applicants were in possession of the claimed invention.
Applicant is referred to the revised guidelines concerning compliance with the written description requirement of U.S.C. 112, first paragraph, published in the Official Gazette and also available at www.uspto.gov.
Claim(s) 1, 2, 5, 8, 16 and 22 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for that modified terminal deoxynucleotidyl transferase (TdT) enzymes comprising the amino sequence of SEQ ID NO 1, wherein said modified Tdt comprises a E385N modification relative to SEQ ID NO:1, does not reasonably provide enablement for all possible modified terminal deoxynucleotidyl transferase (TdT) enzyme of either a wild type TdT, or a truncated version of said wild type TdT: wherein said modified TdT enzyme retains TdT activity, wherein the wild type TdT has the amino acid sequence of SEQ ID NO: 1, and the truncated version of said wild type TdT has the amino acid sequence of SEQ ID NO: 6, wherein said modified TdT enzyme differs from SEQ ID NO: 1 or 6 with amino acid modifications, and wherein the amino acid modifications comprise one or more of the amino acid changes corresponding to E385N, P422S and R442Q of SEQ ID NO: 1 The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
This rejection was stated in the previous office action as it applied to previous claims 1, 2, 5, 8, 16, 17 and 22. In response applicants have amended the claims and traverse the rejection as it applies to the newly amended claims.
Applicant continue to traverses the rejection on the basis that applicants submit that TdT is a well known enzyme discovered over 75 years ago and its structural and functional domains are well known. Applicants submit that their specification provides a multi sequence alignmen t using other TdT sequences.
Applicants amendment of the claims and applicants complete traversal is acknowledged and has been carefully considered, however, is not found persuasive for the reasons previously made of record and for those reasons repeated herein.
Applicants newly amended claim(s) 1, 2, 5, 8, 16 and 22 are directed to all possible modified terminal deoxynucleotidyl transferase (TdT) enzyme of either a wild type TdT, or a truncated version of said wild type TdT: wherein said modified TdT enzyme
The scope of the claims continues to not be commensurate with the enablement provided by the disclosure with regard to the extremely large number of modified terminal deoxynucleotidyl transferase (TdT) enzymes broadly encompassed by the claims. The claims rejected under this section of U.S.C. 112, first paragraph, place minimal structural limits on the modified terminal deoxynucleotidyl transferase (TdT) enzymes encompassed by the claims. Since the amino acid sequence of a protein determines its structural and functional properties, predictability of which changes can be tolerated in a protein's amino acid sequence and obtain the desired activity requires a knowledge of and guidance with regard to which amino acids in the protein's sequence, if any, are tolerant of modification and which are conserved (i.e. expectedly intolerant to modification), and detailed knowledge of the ways in which the proteins' structure relates to its function. However, in this case the disclosure is limited to that modified terminal deoxynucleotidyl transferase (TdT) enzymes comprising the amino sequence of SEQ ID NO 1, wherein said modified Tdt comprises a E385N modification relative to SEQ ID NO:1.
While recombinant and mutagenesis techniques are known, it is not routine in the art to screen for multiple substitutions or multiple modifications, as encompassed by the instant claims, and the positions within a protein's sequence where amino acid modifications can be made with a reasonable expectation of success in obtaining the desired activity/utility are limited in any protein and the result of such modifications is unpredictable. In addition, one skilled in the art would expect any tolerance to modification for a given protein to diminish with each further and additional modification, e.g. multiple substitutions.
The specification does not support the broad scope of the claims which encompass any possible modified terminal deoxynucleotidyl transferase (TdT) enzymes of a wild type TdT, or a truncated version of said modified TdT that retains TdT activity, wherein the wild type TdT has the amino acid sequence SEQ ID NO: 1, and wherein said modified TdT or said truncated version thereof differs from said wild type TdT with amino acid modifications, wherein the amino acid modifications comprise one or more of the amino acid changes E385N, P422S and R442Q of the sequence of SEQ ID NO: 1, because the specification does not establish: (A) regions of the terminal deoxynucleotidyl transferase (TdT) enzymes which may be modified effecting the terminal deoxynucleotidyl transferase (TdT) activity; (B) the general tolerance of terminal deoxynucleotidyl transferase (TdT) enzymes to modification and extent of such tolerance; (C) a rational and predictable scheme for modifying any amino acid residue of an terminal deoxynucleotidyl transferase (TdT) enzyme with an expectation of obtaining the desired biological function; and (D) the specification provides insufficient guidance as to which of the essentially infinite possible choices is likely to be successful. Because of this lack of guidance, the extended experimentation that would be required to determine which substitutions would be acceptable to retain the required terminal deoxynucleotidyl transferase (TdT) activity and the fact that the relationship between the sequence of a peptide and its tertiary structure (i.e. its activity) are not well understood and are not predictable (e.g., see Ngo et al. in The Protein Folding Problem and Tertiary Structure Prediction, 1994, Merz et al. (ed.), Birkhauser, Boston, MA, pp. 433 and 492-495; Franceus et al., J. Ind. Microbiol. Biotechnol. Vol 44, pp 687-695, 2017), it would require undue experimentation for one skilled in the art to arrive at the majority of those modified terminal deoxynucleotidyl transferase (TdT) enzymes of the claimed genus.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claims broadly including any modified terminal deoxynucleotidyl transferase (TdT) enzymes of a wild type TdT, or a truncated version of said modified TdT that retains TdT activity, wherein the wild type TdT has the amino acid sequence SEQ ID NO: 1, and wherein said modified TdT or said truncated version thereof differs from said wild type TdT with amino acid modifications, wherein the amino acid modifications comprise one or more of the amino acid changes E385N, P422S and R442Q of the sequence of SEQ ID NO: 1. The scope of the claims must bear a reasonable correlation with the scope of enablement (In re Fisher, 166 USPQ 19 24 (CCPA 1970)). Without sufficient guidance, determination of those modified terminal deoxynucleotidyl transferase (TdT) enzymes having the desired biological characteristics is unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue. See In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988).
Closest Prior Art:
Peterson et al. (Journal of Biological Chemistry, Vol 260, No. 19, pp 10495-10502, Sept. 1985) teach the expression of human terminal deoxynucleotidyl transferase in E. coli, wherein the amino acid sequence of the expressed human terminal deoxynucleotidyl transferase comprises a E385D modification when compared to the wild type sequence of SEQ ID NO:1.
Remarks
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RICHARD G HUTSON whose telephone number is (571)272-0930. The examiner can normally be reached on 6-3 EST Mon-Fri.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (571) 272-0956. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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rgh
7/27/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652
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