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 .
The Response of 11 Dec. 2025 has been entered.
Claims 1-5 and 11-28 are currently pending. Claims 12, 16-18 and 22-25 are withdrawn.
Claims 1-5, 11, 13-15, 19-21 and 26-28 are considered here with respect to the elected species of a base protecting moiety on the 3’O-blocked nucleoside as the elongation condition that prevents hydrogen bonding or base stacking; deoxyguanosine with an acetyl group on the 2’-nitrogen as the 3’O-blocked nucleoside; and DMSO as the denaturation agent.
Any rejection not reiterated herein has been withdrawn.
Response to Arguments
Applicant's arguments filed 11 Dec. 2025 have been fully considered but they are not persuasive.
Applicant argues that the results in the Declaration of Horgan showing increased rates of synthesis for polynucleotides containing secondary structure, including G-quadruplexes. Applicant points to Example 2 of the specification showing enhanced (dG)10 homopoymer comprising acetylated N2 nitrogens (Applicant also cites results for methoxyacetyl and phenoxyacetyl base-protecting moieties, but the current examination is limited to the elected species of N2-acetyl). This is not persuasive because Arlow teaches that modified guanosine with the N2-acetyl base-protecting group can "prevent base pairing or the formation of undesirable secondary structure during synthesis" and that "[s]imilar modifications were shown to significantly enhance the rate of dGTP homopolymer synthesis using TdT" (Arlow, [0142]). The above cited paragraph of Arlow cites Lefler et al., Journal of Biological Chemistry 244.3 (1969): 594-601, which shows the same effect asserted by Applicant of increased TdT synthesis rates of polyG when using N2-acetylated bases (Lefler, Fig. 1).
Applicant further argues that the Declaration of Horgan shows increased synthesis rates of hairpin-forming polynucleotides. This is not persuasive because Arlow teaches that the modified bases prevent secondary structure, which would include hairpins. Moreover, any unexpected results relating to hairpin-forming DNA would not be commensurate in scope with the instant claims, which are not limited to such DNA/structures.
Applicant's remaining arguments have been fully considered but they are moot in view of the new grounds of rejection below.
Claim Rejections - 35 USC § 112(a) (new matter)
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 19-21 are rejected under 35 U.S.C. 112(a) 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.
Claims 19-21 have been amended to recite that the base-protecting moiety is selected from a group of 3'O-linked groups (claim 19), or is an azidomethyl (claim 20) or amine (claim 21). The instant specification discloses the claimed groups as 3'O-blocking groups rather than base protecting groups (e.g., Published Spec. US20220403435, [0007], [0031], [0034]-[0037]). The base-protecting groups are described at e.g., [0039]-[0043] of the specification and comprise distinct moieties. Claims 19-21 thus comprise new matter.
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.
Claims 1-5, 11, 13-14 and 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over US20190112627 to Arlow et al. (previously cited), as evidenced by (in the case of claims 26-27) Kankia, Origins of Life and Evolution of Biospheres 51.3 (2021): 273-286.
Regarding claims 1-5 and 28, Arlow teaches a method for synthesis of a polynucleotide having a predetermined/desired sequence, comprising: (a) providing an initiator oligonucleotide having a free 3'-hydroxyl; and (b) repeating until the polynucleotide is synthesized cycles of (i) under elongation conditions, contacting the initiator or an elongated fragment thereof with a 3'-O-blocked nucleoside triphosphate (3’O-NTP) and a terminal deoxynucleotidyl transferase (TdT) so that the initiator or fragment thereof is elongated by incorporation of the 3'-O-NTP, and(ii) deblocking the 3'-O-blocked elongated fragment to form an elongated fragment having free 3'-hydroxyls, until the polynucleotide is formed (entire doc, including [0053]-[0054]; [0061]-[0067]; [0071]-[0077]; [0129]-[0130]; [0142]). Arlow teaches that the 3’O-NTPs can further comprise a removable moiety that inhibits base-pairing and 3'-secondary structure formation (i.e. hydrogen bonding) ([0142]). The moiety can be an acetyl group attached to the exocyclic amine N2 position of guanosine ([0142]).
Regarding claim 11, Arlow teaches that the N2-acetyl base-protecting group can be removed via ammonia treatment (i.e. is base labile) ([0135], [0138], [0142])
Regarding claim 13, Arlow teaches that the method can comprise a step of removing the N2-acetyl base-protecting group ([0135], [0138], [0142]).
Regarding claim 14, Arlow teaches that the initiator can be bound to a solid support ([0064]; [0146]).
Regarding claim 26-27, Arlow teaches that modified guanosine with the N2-acetyl base-protecting group can "prevent base pairing or the formation of undesirable secondary structure during synthesis" and that "[s]imilar modifications were shown to significantly enhance the rate of dGTP homopolymer synthesis using TdT" ([0142]). It would have thus been obvious to carry out the method of Arlow to synthesize a polynucleotide having a polyG tract (e.g., a polyG homopolymer) using the modified guanosine to inhibit any secondary structure formation (which would include G-quadruplex formation). Kankia evidences that polyG homopolymers can form G-quadruplex secondary structures that have H-bonding involving the exocyclic (N2) nitrogen of guanosine (Kankia, under Properties of G3N Quadruplex; Fig. 1), and thus the modified guanosine of Arlow would disrupt any such quadruplex secondary structure.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Arlow, as applied to claims 1-5, 11, 13-14 and 26-28, in view of US20190275492 to Efcavitch et al. (referred to herein as “US20190275492”) (previously cited).
Claim 15 differs from Arlow, as applied to claims 1-5, 11, 13-14 and 26-28, in that: the initiator comprises a base-cleavable nucleoside and the base protecting moiety is base labile, and the method comprises a step of removing the base protecting moiety and the base-cleavable nucleoside in the same reaction.
US20190275492 teaches reusable initiators that can be used in methods for template-independent polynucleotide synthesis of the general type taught by Arlow, wherein the initiator is bound to a solid substrate and includes a base-cleavable nucleoside linkage that allows the synthesized polynucleotide to be released from the initiator/support ([0004]-[0006]; [0101]-[0106]). The cleavage conditions can comprise treatment with ammonia (NH4OH) ([0101]-[0102]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to use the method of Arlow for template-independent synthesis of a polynucleotide using a modified 3’O-NTP having a NH4OH-labile acetyl base protecting moiety wherein the initiator has a cleavable nucleoside linkage that can be used to release the completed polynucleotide from the solid support via a NH4OH-labile bond as taught by US20190275492 such that the cleavable linkage and the base protecting moiety are cleaved at the same time because it would have been obvious to combine prior art elements according to known methods to yield predictable results. One of ordinary skill would have been motivated to use a NH4OH-labile bond as taught by US20190275492 on the initiator in the method of Arlow and to cleave the initiator linkage and the base protecting moiety at the same time because doing so would allow for a more efficient method with less steps. Using an NH4OH-labile bond taught by US20190275492 for the initiator in the method of Arlow and cleaving the initiator linkage and the base protecting moiety at the same time would have led to predictable results with a reasonable expectation of success because Arlow teaches use of an acetyl base protecting group which can be cleaved by treatment with NH4OH and US20190275492 teaches initiator linkages for use in the same type of template-independent synthesis methods that can be cleaved under the same conditions.
Conclusion
No claim is allowed.
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