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
Applicant's amendments and remarks filed on May 4, 2026 are acknowledged. Claims 3, 7-10, 13, 14, 16, 18, 24-36, 40, and 41 have been canceled. Claims 1, 2, 5, 6, 37, 43, and 45 were amended. Claims 1, 2, 4-6, 11, 12, 15, 17, 19-23, 37-39, and 42-48 are pending.
Election/Restrictions
Applicant's election with traverse of Group I (claims 1, 2, 4-6, 11, 12, 15, 17, 19-23, 37-39, and 41-47) in the reply filed on December 22, 2025 is acknowledged. Applicant’s remarks filed on May 4, 2026 assert that Yamamoto et al. does not teach or suggest the common technical feature shared by Group I and II because claim 1 has been amended so that the sciRNA comprises (a), (b), and (c).
The technical feature of the sciRNA of claim 1 linking groups I and II is not a special technical feature because the shared technical feature is taught by Yamamoto et al. (reference of record) in view of Sehgal et al. (reference of record) and Parmar et al. (reference of record). See the 35 U.S.C. 103 rejection section below. Thus, groups I and II lack unity. The requirement is still deemed proper and is therefore made FINAL.
Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on December 22, 2025.
Claims 1, 2, 4-6, 11, 12, 15, 17, 19-23, 37-39, and 42-47 are examined on the merits herein.
Priority
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Withdrawn Objections
In view of Applicant’s amendments and response, the objection to the drawings is withdrawn.
In view of Applicant’s amendments and response, the objections to the specification are withdrawn.
In view of Applicant’s amendments and response, the claim objections are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b) rejections are withdrawn.
Drawings
The drawings were received on May 4, 2026. These drawings are found acceptable by the examiner.
Claim Objections
Claim 37 is objected to because of the following informality:
To improve the grammar of the claim, claim 37 should recite “forms a circular structure” (emphasis added).
Appropriate correction is required.
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:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. 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.
Claims 1, 2, 4-6, 11, 12, 15, 17, 19-23, 37-39, and 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. (EP 3617314; reference cited by Applicant) in view of Sehgal et al. (US 9,574,192) and Parmar et al. (Chembiochem 2016).
Regarding claims 1, 23, and 42-45, Yamamoto et al. teaches an oligonucleotide derivative or a salt thereof comprising a circular oligonucleotide and a linear oligonucleotide, wherein the circular oligonucleotide and the linear oligonucleotide have base sequences complementary to each other, and form a complex via a hydrogen bond between the complementary base sequences [abstract]. Specifically, the invention relates to an oligonucleotide derivative or a salt thereof which exhibits improved resistance to degradation by an enzyme in vivo [0001]. Yamamoto et al. also teaches that an object of the invention is to provide a novel oligonucleotide derivative having resistance to nuclease and having strong knock-down activity [0009]. Yamamoto et al. teaches the oligonucleotide derivative or a salt thereof comprising at least one 2’-modified nucleotide [0010]. Further, nuclease resistance can be improved or stabilized, affinity for a complementary strand nucleic acid can be enhanced, and/or cell permeability can be enhanced through the use of nucleotide derivatives such as a nucleotide modified at its sugar moiety, a nucleotide modified at its phosphodiester bond, or a nucleotide modified at its base [0019-0020]. Yamamoto et al. teaches that a targeting compound may be added to an appropriate site of the circular oligonucleotide and/or the linear oligonucleotide [0129].
Regarding claim 2, Yamamoto et al. teaches that when the circular oligonucleotide comprises a sense strand, the linear nucleotide more preferably comprises an antisense strand [0036].
Regarding claims 4-6, Yamamoto et al. teaches that the oligonucleotide of the circular oligonucleotide has a base sequence having a base length of 15 to 80, more preferably a base length of 15 to 30 [0050]. Yamamoto et al. also teaches that the antisense strand is complementary to a partial base sequence of mRNA of a target gene and the sense strand is complementary to the antisense strand [0040]. Further, the linear oligonucleotide has a base sequence having a base length of 19 to 25 [0053].
Regarding claims 11, 12, and 15, Yamamoto et al. teaches that a targeting compound may be added to an appropriate site of the circular oligonucleotide and/or the linear oligonucleotide. Examples of the targeting compound include cholesterol and N-acetyl-D-galactosamine [0129].
Regarding claim 17, Yamamoto et al. teaches examples of the targeting compound include cholesterol and N-acetyl-D-galactosamine. Further, the targeting compound is bonded to formula 9:
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[0129] and [0130]. Although formula 9 above shows cholesterol, Yamamoto et al. teaches that an example of the targeting compound also includes N-acetyl-D-galactosamine.
Regarding claims 19 and 20, Yamamoto et al. teaches that a targeting compound may be added to an appropriate site of the circular oligonucleotide and/or the linear oligonucleotide [0129].
Regarding claims 21 and 22, Yamamoto et al. teaches that examples of the nucleotide derivative include a nucleotide modified at its sugar moiety, a nucleotide modified at its phosphodiester bond, or a nucleotide modified at its base [0020]. An example of a 2’-modified nucleotide includes 2’-F [0022].
Regarding claims 37 and 38, Yamamoto et al. teaches that the oligonucleotide derivative or a salt thereof wherein the circular oligonucleotide is represented by Formula 1 (reproduced below):
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[page 3]. Further, wherein M is selected from the group consisting of formula 3-1 to formula 3-4 (reproduced below):
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[page 4]. Specifically, formulas 3-1 to 3-4 meets the disulfide linkage limitation of claim 38.
Regarding claim 39, Yamamoto et al. teaches formulas 3-2 and 3-3 (reproduced above) wherein n9 is 1 and Y1 is O and formula 3-4 wherein n10 is 1 and Y2 is O [page 4]. Therefore, Yamamoto et al. teaches that the cycling linking moiety contains tetrahydrofuranyl.
Regarding claim 46, Yamamoto et al. also teaches that the antisense strand is complementary to a partial base sequence of mRNA of a target gene and the sense strand is complementary to the antisense strand [0040].
Regarding claim 47, Yamamoto et al. teaches a pharmaceutical composition comprising the oligonucleotide derivative or a salt thereof [0254]. Examples of a preparation appropriate as the pharmaceutical composition include an injection. A prepared liquid formulation may be directly used in the form of an injection or the liquid formulation may be supplemented with an excipient [0259].
However, Yamamoto et al. does not teach that the antisense strand comprises a 5’-vinylphosphonate (5’-VP) at the 5’-end of an antisense nucleotide sequence (claim 1). Yamamoto et al. also does not explicitly teach that all the nucleotides in the sense strand and antisense strand are modified (claim 1) with 2’-O-methyl or 2’-fluoro (claim 23). Yamamoto et al. also does not teach that all of the nucleotides in the sense strand and antisense strand are modified with a 2’-O-methyl or 2’-fluoro modification (claim 45). Yamamoto et al. also does not teach the sciRNA comprising at least two blocks of two consecutive phosphorothioate internucleotide linkage modifications (claims 42 and 44) and the specific positions of the consecutive phosphorothioate internucleotide linkage modifications on the antisense and sense strands (claims 43 and 45). Yamamoto et al. does not explicitly teach that the carbohydrate-based ligand is conjugated at the 3’-end of the sense nucleotide sequence (claim 45).
Sehgal et al. teaches compositions comprising double stranded iRNA agents targeting Serpina1 for inhibiting expression of Serpina1 [column 2, second full paragraph]. Sehgal et al. teaches that all of the nucleotides of the sense strand and all of the nucleotides of the antisense strand are modified nucleotides [column 2, fifth full paragraph]. Further, the modifications on the nucleotides are 2′-O-methyl or 2′-fluoro modifications [column 4, lines 63-64]. Sehgal et al. also teaches that an RNAi agent may further comprise at least one phosphorothioate or methylphosphonate internucleotide linkage. The phosphorothioate or methylphosphonate internucleotide linkage modification may occur on any nucleotide of the sense strand or antisense strand or both strands in any position of the strand. Further, Sehgal et al. teaches that the internucleotide linkage modification may occur on every nucleotide on the sense strand and/or antisense strand; each internucleotide linkage modification may occur in an alternating pattern on the sense strand and/or antisense strand; or the sense strand or antisense strand may contain both internucleotide linkage modifications in an alternating pattern [column 34, fourth full paragraph]. Sehgal et al. also teaches that the ligand is one or more GalNAc derivatives attached through a bivalent or trivalent branched linker. The ligand is shown below and attached to the 3’ end of the sense strand
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[column 4, last paragraph and column 5, first paragraph].
Parmar et al. teaches that the presence of 5’-phosphate (5’-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Further, Parmar et al. teaches that incorporating 5’-(E)-vinylphosphonate (5’-VP), a metabolically stable phosphate mimic, to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability [abstract].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the sciRNA of Yamamoto et al. wherein the antisense strand comprises a 5’-VP at the 5’-end of an antisense nucleotide sequence and all the nucleotides in the sense strand and antisense strand of Yamamoto et al. are modified with a 2’-O-methyl or 2’-fluoro modification because Yamamoto et al. taught an oligonucleotide derivative or a salt thereof comprising a circular oligonucleotide and a linear oligonucleotide and the use of nucleotide derivatives such as a nucleotide modified at its sugar moiety, a nucleotide modified at its phosphodiester bond, or a nucleotide modified at its base to improve nuclease resistance, enhance affinity for a complementary strand, and enhance cell permeability, Sehgal et al. taught that all the nucleotides of the sense and antisense strand are modified, Yamamoto et al. and Sehgal et al. both taught 2’-modified nucleotides, and Parmar et al. taught incorporating 5’-(E)-vinylphosphonate (5’-VP) to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify two consecutive internucleotide linkages with phosphorothioate and to modify two consecutive internucleotide linkages with phosphorothioate at specific positions of the antisense and sense strands of Yamamoto et al. because Yamamoto et al. and Sehgal et al. both teach modification of the phosphodiester bond with phosphorothioate and thus it would have amounted to a simple substitution of one known element for another to obtain predictable results. One of skill in the art would have been motivated to do so because Yamamoto et al. taught that nuclease resistance can be improved or stabilized and affinity for a complementary strand nucleic acid can be enhanced and for the purposes of inhibiting target gene expression as taught by Sehgal et al.
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to conjugate a carbohydrate-based ligand at the 3’-end of the sense nucleotide sequence of Yamamoto et al. because Yamamoto et al. and Sehgal et al. both teach conjugation of N-acetyl-D-galactosamine and thus it would have amounted to applying known design principles to yield predictable results. One of skill in the art would have been motivated to do so for the purposes of directing the sciRNA of Yamamoto et al. to a site of interest as taught by Sehgal et al. [column 22, last paragraph].
Response to Arguments
Applicant's arguments filed May 4, 2026 have been fully considered but they are not persuasive.
Applicant asserts the following:
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These arguments are not found persuasive. Parmar et al. taught that the presence of 5’-phosphate (5’-P) is reported to be critical for efficient RISC loading of the antisense strand (AS) by anchoring it to the mid-domain of the Argonaute2 (Ago2) protein. Further, Parmar et al. taught that incorporating 5’-(E)-vinylphosphonate (5’-VP), a metabolically stable phosphate mimic, to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity by promoting Ago2 loading and enhancing metabolic stability [abstract]. Therefore, it is not surprising or unexpected that Applicant observed an increase in potency when introducing the 5’-VP modification. In addition, in an assertion of unexpected results, one must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). See MPEP 716.02(e). Specifically, Applicant did not compare the instantly claimed sciRNA to the sciRNA of the closest prior art.
Conclusion
No claims are 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 CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
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