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 .
DETAILED ACTION
2. This Office Action is responsive to Applicant’s Amendment and Remarks, filed November 18, 2025. The amendment, filed November 18, 2025, is entered, wherein claims 1 – 2, 9, 26, 28, 33, 35, 40, 54, 72 – 73, and 84 are amended, claims 4 – 8, 10 – 25, 27, 29 – 32, 34, 36 – 39, 41 – 53, 55 – 71, 74 – 75, 77 – 83, 85, 87 – 88, and 90 – 122 are canceled, claims 128 – 141 are new, and claims 26, 28, 54, 76, 84, 86, 89, and 126 are withdrawn.
Claims 128 – 130 are withdrawn because they depend from claim 26, which is a withdrawn claim. Claims 131 – 132 and 138 – 141 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to non-elected invention, there being no allowable generic or linking claim.
Claims 1 – 3, 9, 33, 35, 40, 72 – 73, 123 – 125, 127, and 133 – 137 are currently examined.
Priority
3. This application is a national stage application of PCT/US2019/055870, filed October 11, 2019, which claims benefit of domestic application of 62/745,136, filed October 12, 2018.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/745,136, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The domestic application 62/745,136 does not provide support for the limitation of “H336 mutation selected from the group consisting of H336A, H336C, H336D, H336E, H336F, H336G, H336I, H336K, H336L, H336M, H336M, H336T, H336V, H336W, H336Y, H336N, H336P, H336Q, H336R, H336S, and H336W” that recited in claim 73. Thus the priority date of claim 73 is October 11, 2019.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/18/2025 was filed after the mailing date of the previous Office Action on May 19, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Objections
5. The objection of drawings in the previous Office Action, mailed May 19, 2025, is withdrawn in view of the amended figures.
The objection of disclosure for the embedded hyperlink in line 25 of page 94 in the previous Office Action, mailed May 19, 2025, is withdrawn in view of the amended specification.
The objection of claims 35 and 73 in the previous Office Action, mailed May 19, 2025, is withdrawn in view of the amended claims.
Withdrawn Rejections
6. The rejection of claims 1 – 4, 8, 24, 40, 123 – 125, and 127 in the previous Office Action, mailed May 19, 2025, under 35 U.S.C. 102(a)(1) as being anticipated by Efcavitch et al. has been considered and is withdrawn in view of the amended claim 1.
The following are new grounds of rejection necessitated by Applicant’s Amendment and Remarks, filed November 18, 2025, wherein claims 1 – 2, 9, 26, 28, 33, 35, 40, 54, 72 – 73, and 84 are amended, claims 4 – 8, 10 – 25, 27, 29 – 32, 34, 36 – 39, 41 – 53, 55 – 71, 74 – 75, 77 – 83, 85, 87 – 88, and 90 – 122 are canceled, claims 128 – 141 are new, and claims 26, 28, 54, 76, 84, 86, 89, 126, 128 – 132 and 138 – 141 are withdrawn. Previously and newly cited references have been used to establish the new grounds of rejection.
Sequence Compliance
7. REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is missing or incomplete. See item 1) a) or 1) b) above.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
The sequence disclosures are located Figure 7B and claim 137.
Required response – Applicant must provide:
A "Sequence Listing" part of the disclosure, as described above in item 1); as well as
An amendment specifically directing entry of the "Sequence Listing" part of the disclosure into the application in accordance with 1.825(b)(2);
A statement that the "Sequence Listing" includes no new matter in accordance with 1.825(b)(5); and
A statement that indicates support for the amendment in the application, as filed, as required by 37 CFR 1.825(b)(4).
If the "Sequence Listing" part of the disclosure is submitted according to item 1) a) or b) above, Applicant must also provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference paragraph, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter;
If the "Sequence Listing" part of the disclosure is submitted according to item 1) b), c), or d) above, Applicant must also provide:
A replacement CRF in accordance with 1.825(b)(6); and
Statement according to item 2) a) or b) above.
New Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 – 3, 33, 35, 40, 123 – 125, 127, and 133 – 134 are/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Efcavitch et al. (US2016/0046974A1).
a. Independent claim 1 is directed to a method for template-independent synthesis of an oligonucleotide, the method comprising: (a) providing an initiator oligonucleotide, wherein the initiator oligonucleotide is single stranded oligonucleotide; (b) providing a poly(U) polymerase; (c) combining the initiator oligonucleotide, the poly(U) polymerase, and a 3’-O-protected reversible terminator nucleotide under conditions sufficient for the addition of the 3’-O-protected reversible terminator nucleotide to the 3’ end of the initiator oligonucleotide; and (d) deprotecting the oligonucleotide formed in step (c) at the protected 3’-O-position of the 3’-O-protected reversible terminator nucleotide. Dependent claim 2 is directed to the method, wherein the method further comprising: (e) repeating steps (a) – (d) until a desired oligonucleotide sequence is obtained. Dependent claim 3 is directed to the method, wherein the method further comprising adding one or more natural or modified nucleotides to the 3’ end of the resulting oligonucleotide until a desired oligonucleotide sequence is obtained. Dependent claim 33 is directed to the method, wherein the reversible terminator nucleotide is a 3’-O-protected reversible terminator nucleotide protected at the 3’-O position with an oxygen protecting group. Dependent claim 35 is directed to the method, wherein the 3’-O-protected reversible terminator nucleotide is a 3’-O-allyl. Dependent claim 40 is directed to the method, wherein the 3’-O-protected reversible terminator nucleotide is of one of the following formulae:
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or a salt thereof, wherein Y is O; X is O; RP is an oxygen protecting group; R is hydrogen; and “Base” is a natural or non-natural nucleotide base. Dependent claim 123 is directed to the method, wherein the oligonucleotide is an RNA oligonucleotide. Dependent claim 124 is directed to the method, wherein the initiator oligonucleotide is a single-stranded RNA. Dependent claim 125 is directed to the method, wherein the oligonucleotide is a polynucleotide. Dependent claim 127 is directed to the method, wherein the oligonucleotide is a modified RNA oligonucleotide containing one or more DNA nucleotides.
Efcavitch et al. teaches an improved methods for synthesizing polynucleotides, such as DNA and RNA, using renewable initiators coupled to a solid support (Abstract). Methods of the invention are directed to template-independent synthesis of polynucleotides, including DNA and RNA (para. [0054]) by using a nucleotidyl transferase enzyme to incorporate nucleotide analogs coupled to an inhibitor by a cleavable linker (para. [0004]). De novo synthesis begins with a nucleic acid initiator that is bound to a solid support. In the presence of suitable enzyme, nucleotide analogs are added to the nucleic acid initiator in order to create an oligonucleotide. It is preferable that the nucleotide analogs include removable terminating groups that cause the enzymatic addition to stop after the addition of one nucleotide. A removable terminating group can be linked to the base portion of the nucleic acid and/or to the 3’ hydroxyl of the nucleic acid. Deblocking of the terminating group and/or the 3’ blocking group is done and it creates a new active site that is a substrate for the enzyme. With subsequent addition of a new nucleotide or nucleotide analog, the oligonucleotide is extended (para. [0005]). The invention includes an apparatus. In some embodiments, the apparatus is designed to recycle nucleotide analog solutions by recovering the solutions after nucleotide addition and reusing solutions for subsequent nucleotide addition (para. [0007]). In some embodiments, the nucleotide analog is a 3’-O-blocked nucleotide analog, wherein the 3’-O-blocking groups are typically small and easily removed, thus allowing use with engineered enzyme having modified active sites, wherein the blocking group may be an allyl group (para. [0009]). The 3’-O-blocked nucleotide analog may also be 3’-O-N3-dATP with the following structure (figure 21):
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with the circled moieties that address the limitations “X”, “Y”, RP”, “R”, and “Base” of claim 40. For synthesis of RNA polynucleotides, a nucleotidyl transferase like E. coli poly(A) polymerase can be used to catalyze the addition of ribonucleotides to the 3’ end of a ribonucleotide initiator. In other embodiments, E. coli poly(U) polymerase may be more suitable for use with the methods of the invention. These enzymes may be used with 3’unblocked reversible terminator ribonucleotide triphosphates (rNTPs) to synthesize RNA. In certain embodiments, RNA may be synthesized using 3’blocked, 2’blocked, or 2’-3’blocked rNTPs and poly(U) polymerase or poly(A) polymerase. These enzymes may have an amino acid sequence at least 99% in common with SEQ ID NO. 3 (para. [0080]). In some embodiments, the initiator is a single-stranded oligonucleotide, such as pentamer, hexamer, septamer, or octomer (para. [0094]). Furthermore, an aqueous phase DNA synthesizer is used to produce desired polynucleotides in substantial quantities to capitalize the efficiency of the disclosed methods. In one embodiment, a synthesizer will include four wells of the described NTP analog reagents, i.e., dCTP, dATP, dGTP, and dTTP, as well as TdT at concentrations sufficient to effect polynucleotide growth (para. [0097]).
For these reasons above, Efcavitch et al. anticipate the claimed invention.
New Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
i. Determining the scope and contents of the prior art.
ii. Ascertaining the differences between the prior art and the claims at issue.
iii. Resolving the level of ordinary skill in the pertinent art.
iv. Considering objective evidence present in the application indicating obviousness or
nonobviousness.
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.
Claim 1 – 3, 9, 33, 35, 40, 72 – 73, 123 – 125, 127, 133 – 134, and 136 – 137 are rejected under 35 U.S.C. 103 as being unpatentable over Efcavitch et al. (US2016/0046974A1) in view of Lunde et al. (Nucleic Acids Research, 2012, Vol. 40, Issue 19, page 9815 – 9824, cited in the previous Office Action). Claims 1 – 3, 33, 35, 40, 123 – 125, 127, and 133 – 134 are rejected here because they have been rejected by the primary reference under 102 above.
b. Regarding claims 1 – 3, 9, 33, 35, 40, 72 – 73, 123 – 125, 127, 133 – 134, and 136 – 137, Efcavitch et al. teaches an improved methods for synthesizing polynucleotides, such as DNA and RNA, using renewable initiators coupled to a solid support (Abstract). Methods of the invention are directed to template-independent synthesis of polynucleotides, including DNA and RNA (para. [0054]) by using a nucleotidyl transferase enzyme to incorporate nucleotide analogs coupled to an inhibitor by a cleavable linker (para. [0004]). De novo synthesis begins with a nucleic acid initiator that is bound to a solid support. In the presence of suitable enzyme, nucleotide analogs are added to the nucleic acid initiator in order to create an oligonucleotide. It is preferable that the nucleotide analogs include removable terminating groups that cause the enzymatic addition to stop after the addition of one nucleotide. A removable terminating group can be linked to the base portion of the nucleic acid and/or to the 3’ hydroxyl of the nucleic acid. Deblocking of the terminating group and/or the 3’ blocking group is done and it creates a new active site that is a substrate for the enzyme. With subsequent addition of a new nucleotide or nucleotide analog, the oligonucleotide is extended (para. [0005]). The invention includes an apparatus. In some embodiments, the apparatus is designed to recycle nucleotide analog solutions by recovering the solutions after nucleotide addition and reusing solutions for subsequent nucleotide addition (para. [0007]). In some embodiments, the nucleotide analog is a 3’-O-blocked nucleotide analog, wherein the 3’-O-blocking groups are typically small and easily removed, thus allowing use with engineered enzyme having modified active sites, wherein the blocking group may be an allyl group (para. [0009]). The 3’-O-blocked nucleotide analog may also be 3’-O-N3-dATP with the following structure (figure 21):
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with the circled moieties that address the limitations “X”, “Y”, RP”, “R”, and “Base” of claim 40. For synthesis of RNA polynucleotides, a nucleotidyl transferase like E. coli poly(A) polymerase can be used to catalyze the addition of ribonucleotides to the 3’ end of a ribonucleotide initiator. In other embodiments, E. coli poly(U) polymerase may be more suitable for use with the methods of the invention. These enzymes may be used with 3’unblocked reversible terminator ribonucleotide triphosphates (rNTPs) to synthesize RNA. In certain embodiments, RNA may be synthesized using 3’blocked, 2’blocked, or 2’-3’blocked rNTPs and poly(U) polymerase or poly(A) polymerase. These enzymes may have an amino acid sequence at least 99% in common with SEQ ID NO. 3 (para. [0080]). In some embodiments, the initiator is a single-stranded oligonucleotide, such as pentamer, hexamer, septamer, or octomer (para. [0094]). Efcavitch et al. further teach that the initiator is preferably a universal initiator for the enzyme, such as a homopolymer sequence (para. [0052]). An aqueous phase DNA synthesizer is used to produce desired polynucleotides in substantial quantities to capitalize the efficiency of the disclosed methods. In one embodiment, a synthesizer will include four wells of the described NTP analog reagents, i.e., dCTP, dATP, dGTP, and dTTP, as well as TdT at concentrations sufficient to effect polynucleotide growth (para. [0097]). Furthermore, Efcavitch et al. teach another embodiment for using non-template dependent polymerase enzymes. Protein engineering or protein evolution is used to modify the enzyme to accept 3-blocked reversible terminators with high efficiency. Modifying either single or several amino acid in the active sites of the enzyme can allow the highly-efficient incorporation of 3’-blocked reversible terminators into a support bound initiator (para. [0085]). Efcavitch et al. teaches that amino acid sequence with arginine at 336 position have enzymatic activity against 3’-O-blocked nucleotide analogs (para. [0086]).
However, Efcavitch et al.do not teach that the poly(U) polymerase is a mutated Schizosaccharomyces pombes poly(U) polymerase and do not teach the mutated Schizosaccharomyces pombes poly(U) polymerase comprises an H336R mutation.
Lunde et al. teach that many metabolic pathways depend on nucleotidyl transferases to catalyze the template-independent addition of nucleotide monophosphates (NMP) at the 3’-end of RNA targets. These non-template-encoded nucleotides provide an additional layer of control in determining the fate of these RNA (page 9815, Left Col., para. 1). The best studied members of these polymerase, the poly(A) polymerases (PAPs), add poly (A) tails to the 3’-ends of RNA. In addition to the PAPs, poly(U) polymerases (PUPs) are identified to have catalytic effect on the addition of poly(U) tails to 3’-end of RNAs (page 9815, Right Col., para. 1). One of the first described PUPs is Schizosaccharomyces pombe Cid1. Cid1 is initially identified as a PAP with residual PUP activity. However, later work demonstrates that Cid1 is specific for poly(U) incorporation in vitro and in vivo, thus reclassifying it as a PUP. This was followed by the discovery that Cid1 plays a role in the degradation of polyadenylated mRNAs and its poly(U) activity forms the basis of a novel mRNA decay pathway in fission yeast that may be conserved in higher eukaryotes (page 9815, Right Col., para. 3). A feature that appears to be unique to Cid1 family proteins is their ability to be PUPs, PAPs, or potentially both depending on their context (page 9815, Right Col., para. 4). Moreover, Lunde et al. created the variant of Cid1, Cid1 (H336N) is found to have a significantly decreased apparent KM for ATP and the rate of catalysis has improved (page 9823, Left Col, para. 1).
It would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to substitute the E. coli PUP as taught by Efcavitch et al. with S. pombe PUP in view of Lunde et al. because Efcavitch et al. teach that E. coli PUP is used for template-independent synthesis of polynucleotide and Lunde et al. teach that S. pombe PUP is used for the same purpose. It would have been obvious to substitute enzymes that are used for the same purpose. One would have been motivated to substitute the E. coli poly(U) polymerase as taught by Efcavitch et al. with S. pombe poly(U) polymerase in view of Lunde et al. because Cid1 family proteins has the ability to be PUPs, PAPs, or potentially both depending on the context. It would have been obvious to use S. pombe PUP that comprises SEQ ID NO:3 because Efcavitch et al. suggests the same sequence for E. coli PUP. Such combination yield predictable results. Moreover, it would have been obvious for one of ordinary skill in the art to modify S. pombe PUP with the SEQ ID NO:3 to a mutated S. pombe PUP having H336R because Efcavitch et al. teach that mutating the polymerase will increase the reaction efficiency, especially, with arginine at 336 position. One would have been motivated to such modification because of the increased efficiency and enzymatic effects. For the initiator oligonucleotide, Efcavitch et al. disclose that the initiator is an RNA and a homopolymer. These disclosure imply that the initiator is expected to be the combination, which is an RNA homopolymer. The combination reads on the limitations “poly-rU”, “poly-rC”, “poly-rG”, and “poly-rA” of claim 135. Therefore, one of the skills in the art would have had a reasonable expectation of success to substitute the E.coli poly(U) polymerase as taught by Efcavitch et al. with S. pombe poly(U) polymerase and further substitute with mutated S. pombe poly(U) polymerase, such as one comprising H336R in view of Lunde et al. because Efcavitch et al. teach the template-independent synthesis of RNA oligonucleotide with SEQ ID NO: 3 of E.coli poly(U) polymerase and the benefits of modifying the amino acid to arginine at the 336 position and Lunde et al. teach that S. pombe poly(U) polymerase is known to be used as an enzyme for template-independent synthesis of polynucleotide.
Responses to Applicant’s Remarks:
Applicant’s Remarks, filed November 18, 2025, have been fully considered and are found to be not persuasive.
Regarding the rejection, Applicant argues that Efcavitch et al. (hereinafter ‘973A1 to avoid confusion with the newly cited reference) do not disclose 3’-modified reversible terminator. Applicant argues that ‘973A1 would not have provided motivation for a person of ordinary skill in the art to use poly(U) polymerase to incorporate a 3’-O-protected reversible terminator nucleotide with a reasonable expectation of success and it is discouraged by other publications. Applicant argues that Wu et al. fails to remedy the deficiencies because it does not mention poly(U) polymerase. The examiner acknowledges the arguments. However, the current rejection is based on Efcavitch et al. alone or in combination with Lunde et al. Efcavitch et al. alone already teach the method for template-independent synthesis of a polynucleotide with mixing initiator oligonucleotide that may be single-stranded, poly(U) polymerase, and 3’-O-blocked reversible terminator nucleotide. Efcavitch et al. suggests the use of SEQ ID NO:3 as well as the potential benefits of modifying poly(U) polymerase at the 336 position. Lunde et al. teach that Cid1 has been used for the same purpose. It would have been obvious to substitute and modify Cid1 because the substitution and modification will yield predictable and possibly improved results.
Regarding the unexpected results, Efcavitch et al. teach each and every limitation of the claimed invention. Any result or property that naturally flows from the disclosed method is considered to be inherently disclosed. Therefore, the unexpected results do not overcome the rejection as the results is also anticipated.
New 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.
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Claims 1, 3, 9, 33, 40, 72, 123 – 125, and 134 – 135 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 31, 34 – 36, 39, 41, 53 – 54 of copending Application No. 18/869,037 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘037 anticipate the claimed invention.
a. Independent claim 1 is directed to a method for template-independent synthesis of an oligonucleotide, the method comprising: (a) providing an initiator oligonucleotide, wherein the initiator oligonucleotide is single stranded oligonucleotide; (b) providing a poly(U) polymerase; (c) combining the initiator oligonucleotide, the poly(U) polymerase, and a 3’-O-protected reversible terminator nucleotide under conditions sufficient for the addition of the 3’-O-protected reversible terminator nucleotide to the 3’ end of the initiator oligonucleotide; and (d) deprotecting the oligonucleotide formed in step (c) at the protected 3’-O-position of the 3’-O-protected reversible terminator nucleotide. Dependent claim 3 is directed to the method, wherein the method further comprising adding one or more natural or modified nucleotides to the 3’ end of the resulting oligonucleotide until a desired oligonucleotide sequence is obtained. Dependent claim 9 is directed to the method, wherein the poly(U) polymerase is a mutated S. pombe poly(U) polymerase. Dependent claim 33 is directed to the method, wherein the reversible terminator nucleotide is a 3’-O-protected reversible terminator nucleotide protected at the 3’-O position with an oxygen protecting group. Dependent claim 40 is directed to the method, wherein the 3’-O-protected reversible terminator nucleotide is of one of the following formulae:
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120
259
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or a salt thereof, wherein Y is O; X is O; RP is an oxygen protecting group; and “Base” is a natural or non-natural nucleotide base. Dependent claim 72 is directed to the method, wherein the poly(U) polymerase is a mutated S. pombe poly(U) polymerase. Dependent claim 123 is directed to the method, wherein the oligonucleotide is an RNA oligonucleotide. Dependent claim 124 is directed to the method, wherein the initiator oligonucleotide is a single-stranded RNA. Dependent claim 125 is directed to the method, wherein the oligonucleotide is a polynucleotide. Dependent claim 134 is directed to the method, wherein the initiator oligonucleotide is 5 – 20 nucleotides in length. Dependent claim 135 is directed to the method, wherein the initiator oligonucleotide is poly-rC.
‘037 teaches a method for template-independent synthesis of an RNA oligonucleotide, wherein the method comprises (a) providing an initiator oligonucleotide, wherein the initiator oligonucleotide is single-stranded RNA; (b) providing a polymerase; (c) combining the initiator oligonucleotide, the polymerase, and an NTP under conditions sufficient for the addition of the NTP to the 3’ end of the initiator oligonucleotide (claim 34). The NTP comprises a 3’-reversible terminator group and the method further comprises (d) deprotecting the 3’-reversible terminator group at the 3’end of the oligonucleotide formed in step (c) (claim 35). The method further comprises (e) incorporating one or more nucleoside triphosphates to the 3’end of the RNA oligonucleotide formed in step (d) (claim 36). The polymerase is a mutated poly(U) polymerase (claim 39), wherein the mutated poly(U) polymerase is a mutated S. pombe poly(U) polymerase (claim 41). The initiator oligonucleotide has a length of 5 – 20 nucleotides (claim 53), wherein the initiator oligonucleotide is poly-rC (claim 54). The NTP has a structure of (claim 31):
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274
351
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.
For these reasons above, ‘037 anticipates the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1 – 3, 33, 40, 123 – 125, and 134 – 135 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 – 2, 5 – 6, and 8 of copending Application No. 18/285,014 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘014 anticipates the claimed invention.
b. Independent claim 1 is directed to a method for template-independent synthesis of an oligonucleotide, the method comprising: (a) providing an initiator oligonucleotide, wherein the initiator oligonucleotide is single stranded oligonucleotide; (b) providing a poly(U) polymerase; (c) combining the initiator oligonucleotide, the poly(U) polymerase, and a 3’-O-protected reversible terminator nucleotide under conditions sufficient for the addition of the 3’-O-protected reversible terminator nucleotide to the 3’ end of the initiator oligonucleotide; and (d) deprotecting the oligonucleotide formed in step (c) at the protected 3’-O-position of the 3’-O-protected reversible terminator nucleotide. Dependent claim 2 is directed to the method, wherein the method further comprising: (e) repeating steps (a) – (d) until a desired oligonucleotide sequence is obtained. Dependent claim 3 is directed to the method, wherein the method further comprising adding one or more natural or modified nucleotides to the 3’ end of the resulting oligonucleotide until a desired oligonucleotide sequence is obtained. Dependent claim 33 is directed to the method, wherein the reversible terminator nucleotide is a 3’-O-protected reversible terminator nucleotide protected at the 3’-O position with an oxygen protecting group. Dependent claim 40 is directed to the method, wherein the 3’-O-protected reversible terminator nucleotide is of one of the following formulae:
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114
255
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or a salt thereof, wherein Y is O; X is O; RP is an oxygen protecting group; R is hydrogen; and “Base” is a natural or non-natural nucleotide base. Dependent claim 123 is directed to the method, wherein the oligonucleotide is an RNA oligonucleotide. Dependent claim 124 is directed to the method, wherein the initiator oligonucleotide is a single-stranded RNA. Dependent claim 125 is directed to the method, wherein the oligonucleotide is a polynucleotide. Dependent claim 134 is directed to the method, wherein the initiator oligonucleotide is 5 – 20 nucleotides in length. Dependent claim 135 is directed to the method, wherein the initiator oligonucleotide is poly-rC.
‘014 teaches a method of synthesizing a polynucleotide, the method comprises (a) providing, attached to a synthesis support, initiators with a free 3’-hydroxyl and (b) repeating in a reaction mixture including the synthesis support, until the polynucleotide is formed, cycles of (i) contacting under elongation conditions the initiators having free 3’-O-hydroxyls with a 3’-O-blocked nucleoside triphosphate and a template-independent polymerase so that the initiator are elongated by incorporation of a 3’-O-blocked nucleoside triphosphate to form 3’-O-blocked elongated fragments, and (ii) deblocking the elongated fragments (claim 1). The initiators comprise polyC oligonucleotides (claim 2). The polynucleotide is an RNA and the template-independent polymerase is a poly(U) polymerase (claim 5). The 3’-O-blocked nucleoside triphosphate is a 3’-O-azidomethyl ribonucleoside triphosphate (claim 6). The length of the polyC oligonucleotide is in the range of from 2 to 20 nucleotides (claim 8).
For these reasons above, ‘014 anticipates the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is found to be allowable.
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.
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/H.Y.L./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693