DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. The Amendment filed on June 22, 2026, has been received and entered.
Claim Disposition
3. Claims 1-14 are pending and are under examination.
Claim objection
4. Claims 1-14 are objected to for the following informalities:
For clarity it is suggested that claim 1 is amended to read, “A terminal deoxynucleotidyl transferase (TdT) variant comprising an amino acid sequence at least 90% identical to SEQ ID NO: 2, wherein the amino acid sequence comprises at least one amino acid substitution at a position selected from the group consisting of positions 23, 262, 264[[,] and 298, or an amino acid sequence at least 90% identical to SEQ ID NO: 8, wherein the amino acid sequence comprises at least one amino acid replacement with a replacing amino acid at a position selected from the group consisting of positions 4, 243, 245[[,]] and 279, and wherein the TdT variant produces DNA strand or RNA strand with less misincorporations during DNA synthesis.
For clarity and precision of claim language it is suggested that claims 2-10 and 12-13 are amended to “of” in lieu of “according to” (i.e. “The TdT variant of claim 1….”).
For clarity it is suggested that claim 12 is amended to recite, “The kit of claim 11, further comprising two additional TdT variants…..”.
For clarity it suggested that claim 13 is amended to read, “The kit of claim 12, wherein the two TdT variants comprises:
an amino acid sequence at least…… or an amino acid sequence at least 90% identical to SEQ ID NO:9….”.
For clarity it is suggested that claim 14 is amended to read, “A method for synthesizing a polynucleotide, [[the method]] comprising :…… (a)…….(b) elongated fragment, [[and]] (c) deblocking…… and (d) repeating…….”.
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.
5. Claims 1-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AlA), 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claimed invention as amended is directed to “a TdT variant, kit and method which comprises an amino acid at least 90% identical to SEQ ID NO: 2 with at least one amino acid substitutions at 4 positions or at least 90% identical to SEQ ID NO: 8 with at least one amino acid replacement at 4 positions (among other structures), see claims 1, 10 and 13-14 in its entirety. The claimed invention is not adequately described because it encompasses a large variable genus of structures and variants and at least 90% sequence identity to for example SEQ ID NO: 2 or 8 with no functional language. The instant specification discloses that, “…there is a need for new template-free polymerases variants to limit or prevent the number of substitutions or deletions during the DNA synthesis and thus achieve a satisfying DNA quality synthesis” (page 2).
Further, at paragraph [0011] on page 3 of the specification it is disclosed that “to address this need, the inventors has developed new TdT variants and surprisingly discovered that more active TdT variants produce DNA strand or RNA strand with less misincorporations such as deletions, insertions or substitutions, particularly during DNA synthesis. Note that no correlation is made between structure and function and with the claim language not limited to four substitutions or replacements. The claimed invention encompasses a product thereof which is overly broad. The claimed invention is not adequately described and is not commensurate in scope with the disclosure in the specification. The specification fails to provide a representative number of species for the claimed genus to show that applicant was in possession of the claimed genus. A representative number of species means that the species, which are adequately described, are representative of the entire genus.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by
functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. Vas-Cath Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), states that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed" (See page 1117). The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed" (See Vas-Cath at page 1116). The skilled artisan cannot envision the detailed chemical structure of the encompassed genus, and therefore, conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993).
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed.
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.
6. 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.
7. Claim(s) 1-2, 4-5, 9-12 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/116270 (of record in the application) and alternatively WO 2021/122539 (of record in the application) and in view of WO 2021/170524 (of record in the application).
The claimed invention as amended is directed to “a TdT variant, kit and method which comprises an amino acid at least 90% identical to SEQ ID NO: 2 with at least one amino acid substitutions at 4 positions or at least 90% identical to SEQ ID NO: 8 with at least one amino acid replacement at 4 positions (among other structures), see claims 1, 10 and 14 in its entirety. The primary reference and the secondary reference are considered equally as the state of the art and disclose the subject of claim 1 by teaching
a chimeric variant of TdT (the primary reference, SEQ ID NO: 81; secondary reference, SEQ ID NO:49) having 98.4% identity with the sequence SEQ ID NO: 2 (or SEQ ID NO:8) of the application and comprising the amino acid substitutions N246D (or N227D) and E252L (or E233L), T264R (or T245L), H279R (or H260R), K336N (or K317N) and E371W (or E352W), the position being numbered with reference to sequence SEQ ID NO: 2 (or SEQ ID NO:8). The TdT variant of claim 1 differs from the TdT variants of primary/secondary references in that it has at one amino acid substitutions at positions selected from the group consisting of positions 23, 262, 264 and 298 (or 4, 243, 245 and 279), the position being numbered with reference to sequence SEQ ID NO: 2 (or SEQ ID NO: 8). According to the application (see for example paragraph 3 on page 2), the technical effect associated with at least two or three amino acid substitutions at
positions selected from the group consisting of positions 23, 262, 264 and 298
(or 4, 243, 245 and 279) is a variant having the ability to produce DNA strands
with less misincorporations such as deletions, insertions or substitutions.
The TdT variant of claim 1 differs from the TdT variants of the primary and secondary references in that it has at least one amino acid substitution with a substitute amino acid at position 23 (or 4), the position being numbered with reference to sequence SEQ ID NO: 2 (or SEQ ID NO: 8). According to the application (see for example paragraph 3 on page 2), the technical effect associated with an amino acid substitution at position 23 (or 4) is a variant having the ability to produce DNA strands with less misincorporations such as deletions, insertions or substitutions. The technical problem that the present invention proposes to solve could therefore be considered as the provision of a TdT variant capable of producing DNA strands with less misincorporations such as deletions, insertions or substitutions.
In the application, it has only been shown that a TdT variant consisting of SEQ
ID NO: 4 and having the C23A substitution combined with the other two T264R
and I298V substitutions is characterized by a lower global deletion rate
compared with the TdT variant of SEQ ID NO: 2 (0.24% versus 0.32%, see
Example 2, Table 2) and by a better average of insertion (0.09% versus 0.11%)
and deletion (0.26% versus 0.30%) relative to the TdT variant of SEQ ID NO:2
(see Example 3, Figure 4). In other words, no comparison with the TdT variant of SEQ ID NO:76 or 44 of the primary or secondary references is provided in the application.
Furthermore, for the other TdT variants encompassed by the definition of claim
1 (i.e. for TdT variants having the C23A substitution and an amino acid
sequence at least 90% identical to SEQ ID NO: 2, or for TdT variants of SEQ ID
NO: 2 having any other type of substitution at position 23 and an amino acid
sequence at least 90% identical to SEQ ID NO:2), no data are provided.
Therefore, it is not shown in the application that all TdT variants encompassed
by the definition of claim 1 have an unexpected or surprising activity relative to
TdT variants of the primary and secondary reference. It is therefore not clear which problem is solved by making available these said variants of TdT.
Accordingly, the subject-matter of claim 1 is considered to represent an arbitrary
selection of variants of the TdT to which the person skilled in the art would
arrive without any inventive skill. It is safe to conclude therefore that the inventive activity cannot be recognized for the subject matter of claim 1 and claims 2, 4-12 and 14 dependents thereon. Moreover, with the functional equivalent language which is even broader the cited references disclosure meets the claim limitations (see the entire primary and secondary references). Further, the tertiary reference (see SEQ ID NO: 22) discloses a TdT variant comprising the amino acid sequence as set forth in SEQ ID NO: 2, wherein said amino acid sequence comprises the amino acid substitutions E144K and N246D. The common concept is therefore obvious over the tertiary reference. In addition, the primary and secondary references teach a chimeric variant of TdT (SE ID NO: 81 in the primary reference and SEQ ID NO: 49 in the secondary reference having 98.4% identity with the sequence of SEQ ID NO:2 (or SEQ ID NO: 8) that is instantly claimed and comprising the amino acid substitutions of N246D… T264R (or T245L), H279R(or H260R)….based on the numbering of SEQ ID NOs: 2 (or SEQ ID NO: 8).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to arrive at the claimed invention as a whole because the combined teaching of the references renders the claimed invention as obvious. Motivation exists to combine the teaching of the references because they ae analogous art. Moreover, the Supreme Court pointed out in KSR, “a patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art.” KSR, 127 S. Ct. at 1741. The Court thus reasoned that the analysis under 35 U.S.C. 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the “inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 1741. The Court further advised that “[a] person of ordinary skill is…a person of ordinary creativity, not an automation.” Id. at 1742. Therefore, the claimed invention was obvious to make and use at the time the invention was made and was prima facie obvious.
Art of Record
RESULT 1
US-18-010-424-68
Sequence 68, US/18010424
Patent No. 12377397
GENERAL INFORMATION
APPLICANT: DNA Script
TITLE OF INVENTION: SYSTEMS, APPARATUS AND KITS FOR ENZYMATIC POLYNUCLEOTIDE
TITLE OF INVENTION: SYNTHESIS
FILE REFERENCE: B3312PC00
CURRENT APPLICATION NUMBER: US/18/010,424
CURRENT FILING DATE: 2022-12-14
PRIOR APPLICATION NUMBER: 20 180224.6
PRIOR FILING DATE: 2020-06-16
NUMBER OF SEQ ID NOS: 71
SEQ ID NO 68
LENGTH: 361
TYPE: PRT
ORGANISM: Artificial Sequence
FEATURE:
OTHER INFORMATION: TdT-M96 without N-terminal His tag
Query Match 100.0%; Score 1841; Length 361;
Best Local Similarity 98.9%;
Matches 354; Conservative 4; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EYACQRRTTLNNYNELFTRALDXLAENDEFRENEESRDAFRRASSVLKSLPFPITSMKDT 60
||||||||||||||||||||||:|||||||||||||||||||||||||||||||||||||
Db 4 EYACQRRTTLNNYNELFTRALDILAENDEFRENEESRDAFRRASSVLKSLPFPITSMKDT 63
Qy 61 EGIPCLGDKVKRIIEEIIEDGESSEVKAVLNDERYKAFKLFTSVFGVGRKTAEKWFRMGF 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 64 EGIPCLGDKVKRIIEEIIEDGESSEVKAVLNDERYKAFKLFTSVFGVGRKTAEKWFRMGF 123
Qy 121 RTLEEIRSDKSLRFTQMQKAGFLYYEDLVSGVTRAEAEAVGVLVKEAVWAFLPDAFVTMT 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 124 RTLEEIRSDKSLRFTQMQKAGFLYYEDLVSGVTRAEAEAVGVLVKEAVWAFLPDAFVTMT 183
Qy 181 GGFRLGKKIGHDVDFLITSPGSAEDEEQLLPKVINLWEKKGLLLYYNLVESTFEKFKLPS 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 184 GGFRLGKKIGHDVDFLITSPGSAEDEEQLLPKVINLWEKKGLLLYYNLVESTFEKFKLPS 243
Qy 241 RQVDTLDHFQKCFLILKLHHQXVXSSKSNQQEGKTWKAIRVDLVMCPYENRAFALLGXTG 300
|||||||||||||||||||||:|:|||||||||||||||||||||||||||||||||:||
Db 244 RQVDTLDHFQKCFLILKLHHQRVDSSKSNQQEGKTWKAIRVDLVMCPYENRAFALLGWTG 303
Qy 301 SPQFNRDLRRYATHERKMMLDNHALYDKTKRVFLEAESEEEIFAHLGLDYIEPWERNA 358
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 304 SPQFNRDLRRYATHERKMMLDNHALYDKTKRVFLEAESEEEIFAHLGLDYIEPWERNA 361
Response to Arguments
8. Applicant’s comments have been considered in full. Withdrawn objections/rejections will not be discussed as applicants’ comments are moot. Note that rejections remain that were previously instituted but have been altered to reflect amendments made to the claims. With regard to the 112 first paragraph rejection, applicant traverses the rejection and stated to advance prosecution, claim 1 has been amended, however, the amendments were not sufficient to withdraw the rejection because not all issues raised were addressed such as the claim remains devoid of a structure-function correlation for a product with a genus claim. Applicant states that certain substitutions have different effects, however, the claim language remains broad.
Regarding the 103 rejection, applicant traverses the rejection by stating that the cited art does not teach the modifications. This argument is not persuasive as set forth above since there is disclosure in the 4 corners of the reference of mutation found in the Markush list which renders the claims invention as obvious.
Conclusion
9. No claims are presently allowable.
10. Applicant’s amendment necessitated the new/modified 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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HOPE A ROBINSON whose telephone number is (571) 272-0957. The examiner can normally be reached 9-5pm on Monday to Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert Mondesi can be reached on (408) 918-7584. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HOPE A ROBINSON/Primary Examiner, Art Unit 1652
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