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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Amendment
The amendment filed May 16, 2025 has been entered. Claims 17-19 and 22-33 were amended, claim 1 was canceled, and claims 2-16 remain cancelled. Applicant’s amendments to the claims have overcome 112 (b) rejections previously set forth in the Non-Final Office Action mailed February 20, 2025. As such, these rejections are hereby withdrawn.
Applicant’s arguments filed May 16, 2025 were fully considered and were found persuasive with respect to the 103 rejections previously set forth in the Non-Final Office Action mailed February 20, 2025. Thus these rejections are hereby withdrawn. Maintained rejections, New rejections necessitated by Applicant’s amendment, and response to arguments are addressed below.
Claims 17-33 are pending in this application.
Priority
This application is a 371 of PCT/GB2020/051181 filed May 14, 2020. Acknowledgment is made of applicant’s claim for foreign priority to Application No. GB1906772.7, filed on May 14, 2019, under 35 U.S.C. 119 (a)-(d). Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of Group II method claims and election of species (a) “O-NH2” as the 3’-O blocking group in the reply filed on November 26, 2024 is acknowledged.
Claim 1 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim, however was cancelled. Election was made without traverse in the reply filed on November 26, 2024. Claim 21 would have been withdrawn as drawn to a non-elected species, however based on the reliance of prior art that teaches the non-elected species, claim 21 was examined herein.
Thus, claims 17-33 are examined herein.
Claim Interpretation
Regarding claims 23 and 25-33, which are directed towards limiting the nucleic polymer individual amine-masked nitrogenous heterocycles. The Examiner is interpreting the “said nucleic acid polymer” to be in reference to the extended nucleic acid polymer prior to the unmasking step of instant claim 17. The Examiner additionally notes that the transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps (See MPEP 2111.03 (I)). For example the claims directed towards comprising one or two types of amine-masked heterocycles (claims 25-26), or specific amine-masked nucleotides (claims 28-33) would still be anticipated should a nucleic acid polymer in the prior art possesses more types, additional amine-masked heterocycles, or amine-masked nucleotides
New Claim Rejections - 35 USC § 112 (b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 17-33 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 17-33: Claim 17 recites inter alia “A method of nucleic acid synthesis comprising
adding extension reagents comprising a 3’-O-reversibly terminated nucleoside triphosphate having either an amine-masked nitrogenous heterocycle or nitrogenous heterocycles with free amine groups….”.
Claim 17 later goes on to recite:
“d) repeating steps a), b), and c) to extend the nucleic acid polymer by one single nucleotide in each repeat in order to produce a nucleic acid polymer having a subset of the amine groups masked in amine-masked nitrogenous heterocycles;”.
In the first step, the claim could be interpreted whereby incorporation of an amine-masked nitrogenous heterocycle is optional (i.e. the phrases “either/or”), however in later steps it appears to be a necessary part of the method. Making a previously optional limitation, non-optional leads to a lack of clarity, rendering claim 17 indefinite. Claims 18-33 which depend from claim 17 are similarly rejected. For Examination purposes the claims will be interpreted such that in at least one repeating step, an extension reagent comprising amine-masked nitrogenous heterocycles are included.
Maintained Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 17-33 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. US 11,505,815 in view of Chen (WO 2016/128731, IDS filed May 23, 2022, cited in previous action) and Iyer (Current Protocols in Nucleic Acid Chemistry, 2000, cited in previous action).
Regarding claims 17-33: The patented claims teach a method of enzymatic nucleic acid synthesis comprising:
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(claim 1).
The patented claims teach compounds of claim 1 include
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which are 3’-O-reversibly terminated nucleoside triphosphates (3’-O-NH2) and amine-masked nitrogenous heterocycles (N3, N2-amine masked guanine, N4-amine masked cytosine, or N6-amine masked adenine) (claim 2).
The patented claims do not teach the steps of providing an initiator sequence, adding TdT to the initiator sequence, removing extension reagents, or cleaving the 3’-O blocking group from the polymer.
However, Chen teaches a similar template independent nucleic acid synthesis (pg. 1, lines 1-9). The method of Chen comprises a) providing an initiator sequence;
b) adding a adding a 3'-blocked nucleotide triphosphate to said initiator sequence in the
presence of a terminal deoxynucleotidyl transferase (TdT) as defined in the first aspect of the invention;
c) removal of all reagents from the initiator sequence (i.e. extension reagents);
d) cleaving the 3’ blocking group
e) removal of the cleaving agent (pgs. 3-4, bridging para.).
It will be understood that steps (b) to (e) of the method may be repeated multiple times to
produce a DNA or RNA strand of a desired length (i.e. adding single nucleotides, pg. 13, lines 21-22). The 3' -blocked nucleotide triphosphate is blocked by either a 3'-O-methyl, 3'-azido, 3'-O-azidomethyl, 3'-aminoxy or 3'-O-allyl group (i.e. 3’-O-NH2 or 3’-O-CH2N3, pg. 14, lines 25-26). In an alternative embodiment, the initiator sequence contains at least one uridine (pg. 17, line 7). Treatment with uracil-DNA glycosylase (UDG) generates an abasic site (pg. 17, lines 7-8). Treatment on an appropriate substrate with an apurinic/apyrimidinic (AP) site endonuclease will extract the nucleic acid strand (pg. 17, lines 8-10). Additionally, Iyer teaches in the synthesis of oligonucleotides, persistent as well as transient protection of amino, imido, and hydroxy groups of nucleosides are employed (pg. 1, col. 1, para. 3). Appropriate protecting groups are utilized in order to achieve high efficiency by directing the reaction to the desired site of the nucleoside (i.e. avoiding side reactions, pg. 1, col. 1, para. 1). Persistent protecting groups, such as the exocyclic amino groups of nucleobases are those that remain on the nucleoside throughout chain assembly and are only removed at the end of synthesis (i.e. release of amino group, pg. 1, cols. 1-2, bridging para.).
Taken together, it would have prima facie obvious to a person of ordinary skill in the art to modify the patented claims by incorporating the steps the steps of providing an initiator sequence, adding TdT to the initiator sequence, removing extension reagents, and cleaving the 3’-O blocking group from the polymer into the nucleic acid synthesis as taught by Chen. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success in that both the patented claims and Chen are directed towards methods of non-templated nucleic acid synthesis using 3’-O reversibly terminated nucleoside triphosphates, and the use of amine-masked nucleosides is a known method to improve nucleic acid synthesis efficiency as taught by Iyer.
Response to Arguments
Applicant’s arguments filed May 16, 2025 with respect to the 103 rejections have been fully considered and are found persuasive.
On pages 7 of Applicant’s response (para. 3), Applicant argues the instant application is directed towards a method using enzymatic synthesis rather than chemical synthesis as disclosed by Iyer. On page 7 of Applicant’s response (paras. 6-7), Applicant argues that the inventors have found that having one or more of the amino groups on the base heterocyclic groups masked with protecting groups helps to prevent secondary structure in the extended strand. In short, Applicant is arguing an unexpected result from utilizing amine-masking groups. On page 8 of Applicant’s response (para. 5)., Applicant argues that Chens disclosure of compound 4 is not equivalent to a masked-amine nucleoside. Applicant argues there is no evidence of any such modified NTP or dNTP can be TDT substrates useful for the claimed invention. On page 9 of Applicant’s response (paras. 1-3), Applicant argues a person of ordinary skill would have had no clue as to whether the Iyer protecting groups can be used in TdT-mediated nucleic acid synthesis. Applicant argues that the protecting groups of Iyer are meant to protect in chemical synthesis, thereby improving efficiencies. Applicant argues Iyer reference masks all of the amino groups, Iyer does not suggest the benefits of masking only a subset of the free amino groups, as Iyer is unable to use nucleotides without exocyclic amino protection. In short, Applicant argues Iyers protection groups related to chemical synthesis are not related to Chens enzymatic synthesis, and does not teach protecting a subset of nucleotides in the synthesis.
The Examiner finds the argument pertaining to the application of nucleoside-N-protecting groups commonly used in chemical synthesis of nucleic acid polymers non-applicable to the instant application directed towards enzymatic synthesis of nucleic acid polymers to be persuasive. A person of ordinary skill in the art would lack the motivation to do so because there is no teaching in the prior art that protecting these groups would benefit the synthesis in any way. A person of ordinary skill in the art would not have a reasonable expectation of success in incorporating protecting groups into nucleosides to be connected enzymatically as enzymatic syntheses differ greatly compared to chemical syntheses. Thus, the 103 rejections have been withdrawn.
However, see above indefinite issues raised with the present amendment. Additionally the double patenting rejections are maintained as they are directed towards enzymatic syntheses with the instantly claimed protecting group functionalities. An appropriately filed terminal disclaimer could overcome the double patenting rejections.
Applicant’s reply is considered to be a bona fide attempt at a response and is being accepted as a complete response. The 35 USC § 112(b) and double patenting rejections are maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this action.
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 SAMUEL L GALSTER whose telephone number is (571)270-0933. The examiner can normally be reached Monday - Friday 8:00 AM - 5:00 PM.
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/S.L.G./Examiner, Art Unit 1693
/ERIC OLSON/Primary Examiner, Art Unit 1693