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 .
Applicant’s cancellation of claim 17, amendment of claims 1-16, in the paper of 11/21/2025, is acknowledged. Applicants' arguments filed on 11/21/2025, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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Claims 3, 4, 6, 7, 9-15, 18 and 20 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
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.
Applicant traverses the rejection on the basis that applicants submit that they have amended claim 1 and claims dependent therefrom to clarify that the presently claimed invention is directed to a modified TdT compared to the wild type TdT comprising SEQ ID NO: 1 (Lepisosteus oculatus TdT). Applicant further submits that the presently claimed genus of modified TdTs are adequately represented by the species disclosed in the specification.
Applicant submits as amended, present claim 1 and claims dependent therefrom require the claimed modified TdT to have distinct structural features - one or more amino acid modifications at T160, E174, C179, M183, A195, S198, D210, Q211, Q224, S245, R259, H263, L265, A273, H275, L285, A293, G303, Q304, L312, A314, C331, V335, M344, V348, R357, D368, 1369, E385, M387, D388, F390, K392, F394, K401, A404, P422, V424, E441, R442, R445, K453, N458, K464, D488. Applicant submits such residue modifications / changes are made with respect to the wild-type TdT (SEQ ID NO: 1) from Lepisosteus oculatus from which the modified TdT is derived. Applicant submits such mutants are indeed representative of the entire (much narrower) claimed genus in claim 1.
Applicant submitsf furthermore, the claimed genus of modified TdT is also characterized by common wild type sequence (SEQ ID NO: 1), which is modified.
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, 17 and 22 are directed to all 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.
In response to applicants submission that the presently claimed invention is directed to a modified TdT compared to the wild type TdT comprising SEQ ID NO: 1 (Lepisosteus oculatus TdT), this is acknowledged and herein lies part of the problem. Applicants claimed modified TdT is described in terms of it is wildtype TdT and not in terms of its own structure. Thus the genus of modified TdT’s is extremely broad. Broader than applicants have adequately described While the claimed genus of modified TdTs may include the species disclosed in the specification, it is not adequyately represented by the species.
While the residue modifications / changes are made with respect to the wild-type TdT (SEQ ID NO: 1) from Lepisosteus oculatus from which the modified TdT is derived, such does not adequately describe the breadth of the currently claimed genus of modified Tdts.
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 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 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 traverses the rejection on the basis that applicants submit that the Examiner has acknowledged that the specification is "enabling for that modified terminal deoxynucleotidyl transferase (TdT) enzymes comprising the amino acid sequence of SEQ ID NO: 1, wherein said modified TdT comprises a E385N modification relative to SEQ ID NO: 1.". Applicants submit that in the interest of advancing prosecution and without acquiescing to the asserted grounds of rejection, Applicant has amended independent claim 1 to be directed to the enabled embodiments.
Applicants newly amended claim(s) 1, 2, 5, 8, 16 and 22 are directed to all 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. The breadth of the claimed genus remains broader than that which is enabled.
The scope of the claims is not 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.
Conclusion
THIS ACTION IS MADE FINAL. 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 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
1/8/2026
/RICHARD G HUTSON/Primary Examiner, Art Unit 1652