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 preliminary amendment filed on December 22, 2025 is acknowledged. Claims 3, 7-10, 13, 14, 16, 18, 24-36, and 40 have been canceled. Claim 1 was amended. Claims 1, 2, 4-6, 11, 12, 15, 17, 19-23, 37-39, and 41-48 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. The traversal is on the ground(s) that Yamamoto et al. does not teach or suggest a small circular interfering RNA comprising a phosphate mimic at the 5’-end of an antisense nucleotide sequence selected from the group consisting of 5’-phosphorodithioate, 5’-vinylphosphonate, 5’-methylphosphonate, and 5’-deoxy-5’-C-malonyl. This is not found persuasive because claim 1 (reproduced below) only requires the sciRNA to comprise one or more of part (a), (b), or (c). Thus, the claim limitation is met if the sciRNA comprises part (a) or part (b) or part (c).
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Therefore, 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. and 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Claim 48 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 41-47 are examined on the merits herein.
Priority
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Information Disclosure Statement
The information disclosure statement (IDS) submitted on January 9, 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on January 9, 2023.
The drawings are objected to because 37 CFR 1.84 (u)(1) states “View numbers must be preceded by the abbreviation "FIG."”. In the current case, the view numbers for all figures are preceded by the word "Figure" instead of the abbreviation "FIG.". In addition, Figures 3A, 3B, 5A, and 5B are blurry and thus difficult to distinguish between the different lines. Further, the labels of Figure 7 are not clear.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The substitute specification filed on September 30, 2025 has been entered.
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because of the use of the word “said”. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
The disclosure is objected to because of the following informalities:
Paragraph [0074] discloses that the Z linker carbons are highlighted; however, it is difficult to distinguish what is or is not highlighted since the figure is in black and white.
The Scheme on pages 14 and 166 are both labeled as Scheme 1. Nonetheless, the flow diagram on pages 14 and 166 should be removed from the specification and added to the drawings. See 37 CFR 1.58(a) which indicates that the specification shall not contain drawings or flow diagrams.
Appropriate correction is required.
Claim Objections
Claims 41, 43, and 45 are objected to because of the following informalities:
Claim 41 recites in part “5’-vinyl phosphonate (VP)”; however, the claim should recite “5’-vinylphosphonate (5’-VP)”.
Claims 43 and 45 recite in part “position 1-5” and should recite “positions 1-5” (emphasis added).
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 2, 5, 6, 37, 38, 39, and 46 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.
The term “substantially” in claims 2 and 37 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the phrase “substantially circular” has been rendered indefinite by the use of the term “substantially”. One of skill cannot know what is or is not considered substantially circular because the term “substantially” is an undefined relative term.
Claims 38, 39, and 46 are indefinite because the claims depend from rejected claims 2 and 37 without addressing the issue in claims 2 and 37.
The term “about” in claims 5 and 6 is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Therefore, the phrase “about 20 to about 45” (claim 5) and the phrase “about 19 to about 23” (claim 6) have been rendered indefinite by the use of the term “about”. One of skill cannot know the metes and bounds of this limitation in the claim because the term “about” is an undefined relative term.
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).
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 explicitly teach wherein each of the sense and antisense strands comprise at least one nucleic acid modification and wherein all of the nucleotides of the sense strand or 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].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify at least one nucleotide of the sense and antisense strand and modify all the nucleotides in the sense or antisense strand of Yamamoto et al., and to modify all the nucleotides in the sense and/or antisense strand of Yamamoto et al. with a 2’-O-methyl or 2’-fluoro modification as taught by Sehgal et al. because Sehgal et al. teaches that all the nucleotides of the sense and antisense strand are modified and Yamamoto et al. and Sehgal et al. both teach 2’-modified nucleotides 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 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].
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Yamamoto et al. (EP 3617314; reference cited by Applicant) and Sehgal et al. (US 9,574,192) as applied to claims 1, 2, 4-6, 11, 12, 15, 17, 19-23, 37-39, and 42-47 above, and further in view of Parmar et al. (Chembiochem 2016).
Regarding claim 41, the teachings of Yamamoto et al. and Sehgal et al. are discussed above.
However, Yamamoto et al. and Sehgal et al. do not teach the antisense strand comprising 5’-vinylphosphonate (5’-VP) at the 5’-end of an antisense nucleotide sequence.
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 antisense strand of Yamamoto et al. and Sehgal et al. by incorporating a phosphate mimic at the 5’-end of the antisense strand as taught by Parmar et al. One of skill in the art would have been motivated to do so because Parmar et al. taught that incorporating 5’-(E)-vinyl-phosphonate to siRNA-GalNAc conjugates results in up to 20-fold improved in vitro potency and up to a threefold benefit in in vivo activity.
Conclusion
No claims are allowed.
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