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.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 30, 2026 has been entered.
The amendment filed March 30, 2026 has been entered. Claims 1 and 13 have been amended, claims 2, 9, and 16 have been cancelled, and claims 19-23 has been added. This application is a continuation application of PCT Application No. PCT/JP2025/007821, filed on March 5, 2025, which claims the benefit of U.S. Provisional Patent Application No. 63/562424, filed on March 7, 2024.
Applicant’s arguments filed March 30, 2026 were fully considered but they were not persuasive. Rejections and response to arguments as they currently apply are addressed below.
Claims 1, 3-8, 10-15, and 17-23 are pending in this application.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on April 21, 2026 has been considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities:
Claim 1 recites “wherein if Y has two or more R1….” Or “wherein if Y has two or more R3”. However, wherein m and n can only be 1, Y cannot have more than one R1 or R3. The phrases relating to two or more should be removed to avoid confusion.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 (d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 15, which depends from claim 14, and recites inter alia “m represents an integer of 1 to 20”. However, claim 14, which depends from the polynucleotide structure of claim 1, limits m to 1. Thus claim 15 expands, rather than limits, instant claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 3-8, 10-15, and 17-23 are rejected under 35 U.S.C. 103 as being unpatentable over Wang (US 2024/0277872, effectively filed May 12, 2021, cited in previous action) in view of Nelson (WO 2016/011226, IDS filed July 17, 2025), Martin (EP 0626387A1, cited in previous action), and Kandimalla (WO 2025/111430, IDS filed April 21, 2026, effectively filed November 21, 2023). The English translation of Martin has been provided by the Examiner.
Regarding claims 1, 3-8, 10-15, and 17-23: Wang teaches modified RNAs with poly(A) tails containing modified nucleotides (abstract). Wang teaches the preparation of oligonucleotide conjugated RNA comprising a synthetic nucleotide, poly(a) tail, and a chain terminating nucleotide, wherein the oligonucleotide is produced using a RNA ligase connecting the hydroxyl group bonded to the 3’carbon of a nucleoside present at a terminal of the poly(a) region with a phosphate of a synthetic oligonucleotide with adenosine as the nitrogenous base:
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(abstract). The end of the oligonucleotide can comprise the following formula:
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(right structure, second oligonucleotide, R1 is adenine R3 is thymine, n =1, pg. 3353, abstract). At least 6-8 nucleotides comprised unmodified rA nucleotides are necessary to provide a handle for ligation (i.e. m=6-8, pg. 39, para. 0450). The ligation can be performed with as few as three modified nucleotides onto the 3’ end of an mRNA containing a pre-existing poly-A tail (pg. 1, para. 0004). The InvdT group acts as a blocking group to prevent oligo self-ligation (pg. 39, para. 0450).The oligonucleotides can be connected through phosphodiester or phosphorothioate linkages (modified internucleotide linkage, pentose sugar modification, pg. 3, para. 0045). The oligonucleotides comprise a 5’ cap structure (pg. 3, paras. 0062-0065). Wang generally suggests that the technique can be utilized with other types of modified RNA nucleotides, including 2'-O-methoxy-ethyl (2'-MOE, i.e. methoxy-ethyleneoxy), and 2'-O-methylation (2'-OMe) (pg. 3, para. 0041-0044).
The preparation of these oligonucleotide meets the limitations of instant claims 1, 3-8, 10-15, and 17-23 except Wang does not explicitly teach wherein the 2’ position of InvdT is methoxy or methoxy-ethyleneoxy (R2 as instantly claimed). In other words, Wang does not teach wherein the chain terminating oligonucleotide has a methoxy or methoxy-ethyleneoxy group at the 2’ position of the pentose sugar ring. Wang does not explicitly teach an oligonucleotide solely comprising an inverted nucleotide at the end of the chain.
However, Nelson teaches an oligonucleotide with a polyA sequence with a chain terminating nucleoside wherein the poly-A tail terminates in the following structure
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(i.e. a single chain terminating inverted nucleotide, wherein the previous nucleotide is adenosine, pg. 10, para. 00071). Nelson teaches this compound is of the formula XXI
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wherein R29 or R28 can be C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl (pg. 10, 00070). This suggests that 2’ modifications have been contemplated as tolerable modifications in inverted chain terminating nucleotides. Nelson teaches an oligonucleotide with a polyA sequence with a chain terminating nucleoside wherein the chain terminating nucleosides include 2’O-methyl, F, and locked nucleic acids, suggesting that 2’O-methyl modifications are typical 2’ modifications in the art (abstract, pg. 23-24, para. 000168). Additionally, Martin teaches nucleosides and oligonucleotides with 2'-ether groups (abstract). Martin demonstrates that 2’ modification possessing the “
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” group improves stability compared to unmodified ribonucleotides (English translation, pgs. 85-86, bridging structures). Martin teaches 2’-OH oligoribonucleotide modifications of the invention (i.e. methoxy-ethyleneoxy) have increased nuclease resistance (i.e. stability) and increased cellular uptake and consequently have an improved bioavailability and activity in vivo (English translation, pg. 8, last two sentences). Kandimalla teaches stabilizing 3’-end of poly(A) tail of mRNA by incorporating inverted dA or modified nucleotides at the 3’ end comparable to that of Wang (drawings sheet 2, figures 2A-2B). Kandimalla teaches an example comprising solely an inverted chain terminating nucleotide (pg. 46, para. 00212, seq 1).
Taken together, it would have been prima facie obvious to a person of ordinary skill in the art to modify the single chain terminating nucleotide of Wang by incorporating a 2’ modification such as a methoxy or methoxy-ethyleneoxy group as suggested by Nelson, Martin, and Kandimalla. A person of ordinary skill in the art would have had the motivation to do so with a reasonable expectation of success as 2’-O modifications in ribonucleotides are a known technique in the art, for the purpose of improving stability and/or cellular uptake/bioavailability. It is prima facie obvious to apply a known technique (i.e. 2’ modification) to a known product (i.e. oligonucleotide) ready for improvement to yield predictable results (i.e. improved stability or cellular uptake/bioavailability).
Response to Arguments
Applicant’s arguments filed March 30, 2026 with respect to the claims have been fully considered but they are not persuasive.
On page 9 of Applicant’s response, Applicant argues that Wang teaches including at least three modified nucleotides, and a person of ordinary skill would not have reduced the number of modified nucleotides to only one or two as required by claim 1. On page 10 of Applicant’s response, Applicant argues that the teachings of Wang suggest inclusion of both a modified region and a chain terminating nucleotide (paras. 2-3).
However, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)). Additionally, see 103 rejection above wherein Kandimalla teaches an example comprising solely an inverted chain terminating nucleotide, establishing that polynucleotides with such a singular modification are contemplated in the art (pg. 46, para. 00212). One of ordinary skill in the art would only require requisite motivation to modify this position at the 2’ position, which is taught generally by Nelson and Martin as a known practice in the art for improving stability, and a person of ordinary skill in the art would recognize the applicability to nucleotides as a whole.
On pages 10-12 of Applicant’s response (bridging para.), Applicant argues Wang does not describe the specific 2’-modified, inverted chain-terminating nucleotide of the present claims. Applicant argues even if it were the case, to improve polynucleotide stability, one of skill wouldn’t reduce the number of modified nucleotides therein to less than 3, because Wang emphasizes that inclusion of multiple modified nucleotides contribute to stability (bridging para.).
However, as discussed above, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (See MPEP 2123 (II)). Additionally, see 103 rejection above wherein Kandimalla teaches an example comprising solely an inverted chain terminating nucleotide, establishing that polynucleotides with such a singular modification are contemplated in the art (pg. 46, para. 00212). One of ordinary skill in the art would only require requisite motivation to modify this position at the 2’ position, which is taught generally by Nelson and Martin.
On page 11 of Applicant’s response (para. 2), Applicant argues that the presently claimed invention demonstrates On pages 12-13 of Applicant’s response (bridging para.), applicant argues a single inverted chain terminating nucleotide can sufficiently stabilize nucleotides and points to specific examples in tables 9 and 10 in the specification.
However, the Examiner notes that the difference between the teachings of the prior art and the presently claimed invention is the presence of the 2’ modification of the chain terminating nucleotide As discussed above, Martin demonstrates that 2’ modification possessing the “
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” group improves stability compared to unmodified ribonucleotides (English translation, pgs. 85-86, bridging structures). Martin teaches 2’-OH oligoribonucleotide modifications of the invention (i.e. methoxy-ethyleneoxy) have increased nuclease resistance (i.e. stability) and increased cellular uptake and consequently have an improved bioavailability and activity in vivo (English translation, pg. 8, last two sentences). Wherein the art generally recognizes that improved stability is a result of modified 2’ positions, the result cannot be considered to be unexpected by modifying the teachings of Wang. Additionally, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range (See MPEP 716.02 (d). While applicant has demonstrated improved stability by utilizing the 2’-methoxyethoxy modification, Applicant has not demonstrated such improvement for the full scope of 2’ modifications encompassed by the claims. For example, the instant claims include fluoro, methoxy, benzyloxy substitutions as 2’ modifications (R2). Table 9 demonstrates that OMe substitution of an inverted adenine (idA vs iOMeA) actually hurts the overall stability (pgs. 145-146, table 9). Thus, if the unexpected results were found to be persuasive, the unexpected results would not be commensurate in scope with the claims.
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 § 103 rejection is maintained for reason of record and foregoing discussion.
Conclusion
No claims are allowed in this 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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/SAMUEL L GALSTER/Examiner, Art Unit 1693
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