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 .
Application Status
This action is written in response to applicant’s correspondence received 07/31/2026. Claims 1-13, 15-27, and 48-52 are currently pending. Claim 20 and 23-25 are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1-13, 15-19, 21-22, 26-27, and 48-52 are examined herein. The restriction requirement mailed 06/04/2026 is still deemed proper. Applicant elected the invention of Group I and species of a dTdTdT linker with traverse in the reply filed 07/31/2026.
Election/Restrictions
Applicant's election with traverse of the invention of Group I and species of a dTdTdT linker in the reply filed on 07/31/2026 is acknowledged. The traversal is on the ground(s) that, “the examiner has not shown that a serious burden would be required to examine Groups I-IV together”, citing MPEP 803. Respectfully, this is not found persuasive because this application is a national stage filing of an international application. Restriction in such applications is based on lack of unity practice and the provisions of MPEP 800 do not apply. Further, Applicant argues that, “Groups I-IV claims share a special technical feature that distinguishes the claims of those groups over the prior art cited by the examiner”, and “the nucleic acid composition recited in independent claim 1 can be distinguished over the multimeric oligonucleotide disclosed in Brown, at least because Brown does not teach or suggest that each of the first dsRNA and second dsRNA (or single-stranded nucleic acid) has to independently comprise a conjugated lipophilic moiety”. However, in view of the newly cited reference applied in the prior art rejections under 35 U.S.C. 103 below, the technical feature does not make a contribution over the prior art.
The requirement is still deemed proper and is therefore made FINAL.
Claims 20 and 23-25 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 07/31/2026.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
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 1-13, 15-19, 21-22, 26-27, and 48-52 are rejected under 35 U.S.C. 103 as being unpatentable over WIPO Publication 2017/015109 A1 to Jadhav (of record, cited on an IDS, hereinafter ‘Jadhav’) in view of WIPO Publication 2019/217459 A1 to Nair (cited on an IDS, hereinafter ‘Nair’).
Regarding claim 1, Jadhav teaches a multi-targeted dsRNA molecule which is a nucleic acid composition for modulating one or more target RNAs comprising one or more distinct target RNA sequences, the nucleic acid composition comprising a first double-stranded RNA (dsRNA) molecule and a second dsRNA molecule, wherein the first dsRNA molecule and the second dsRNA molecule are connected together by a linker (dTdTdT) and do not overlap with each other:
[0004] …the multi- targeted molecules comprise at least two nucleic acid based effector molecules, wherein said at least two nucleic acid based effector molecules are covalently or non-covalently linked to each other. Without limitations, any nucleic acid based effector molecule capable of modulating gene expression of a target can be comprised in the multi-targeted molecules disclosed herein.
[0008] …Without limitations, each effector molecule in the multi-targeted molecule can be directed to the same target gene, different target genes, different positions with the same target gene, or different transcripts of the same target gene.
FIG. 15:
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Jadhav further teaches that the multimeric dsRNAs (multi-targeted molecules) “can independently modulate gene expression of their respective target nucleic acids by at least 50% (e.g., 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more) relative to their modulation of gene expression when not part of a multi-targeted molecule” (para [0009]).
Jadhav does not teach that the composition modulates genes in the CNS, or that the first dsRNA comprises at least one conjugated lipophilic moiety, the single-stranded nucleic acid agent or second dsRNA molecule comprises at least one conjugated lipophilic moiety.
Nair teaches double-stranded oligonucleotides (iRNA agents, see paras [0002]-[0006]) for delivery to the CNS, thereby modulating genes in the nervous system (Id.).
Nair further teaches conjugating lipophilic moieties to internal positions in least one strand of the dsRNA construct:
[0183] In one embodiment, one or more lipophilic moieties are conjugated to one or more of the following internal positions: positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5’end of each strand.
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Nair further teaches that the conjugated siRNA was capable of modulating the activity or expression of one or more target RNAs in a CNS tissue (e.g., cerebellum) of the subject by at least 15% relative to an appropriate control (unconjugated siRNA):
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It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the multi-targeted dsRNA molecule for modulating multiple target genes, as taught by Jadhav, by conjugating each dsRNA (i.e., effector molecule) to a lipophilic moiety, as taught by Nair. The ordinary artisan would have been motivated to do so based on Nair’s teachings that conjugated siRNA achieved better silencing relative to unconjugated siRNA. The ordinary artisan would also have had a reasonable expectation that Nair’s conjugation strategy could have successfully been applied to each dsRNA of Jadhav’s multimeric constructs based on Jadhav’s teachings that the multi-targeted molecules were more effective to individual effector molecules. In other words, linking two siRNAs did not interfere with their individual silencing ability. Based on that, the ordinary artisan would have predicted, with a reasonable expectation of success, that each siRNA could have been modified in the same ways without interfering with their silencing ability. The ordinary artisan further would have had a reasonable expectation that conjugation of a lipophilic moiety to each of the dsRNAs would have resulted in a 15% decrease in target gene expression relative to a non-conjugated control, based on Nair’s teachings that these outcomes were achieved with individual siRNAs having a lipophilic conjugate, and on Jadhav’s that the multimeric siRNAs were at least as, if not more, effective than separate siRNAs such as Nair’s.
Regarding claim 2, Jadhav teaches the first and second dsRNAs connected by a linker, as described above.
Regarding claim 3, Nair teaches wherein at least one lipophilic moiety comprises a saturated or unsaturated C4-C30 hydrocarbon chain (e.g., Uhd):
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Regarding claim 4, Nair teaches wherein the lipophilic moiety comprises a C16 chain (see above).
Regarding claim 5, Jadhav teaches wherein the sense strand of the first dsRNA molecule is covalently linked to the sense strand of the second dsRNA molecule (i.e., via a dTdTdT linker; see above).
Regarding claims 6 and 7, Nair teaches wherein one or more of the first and second dsRNA molecules, if present, comprises a lipophilic moiety conjugated independently to positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5'-end of each strand as position 1:
[0031] In one embodiment, one or more lipophilic moieties are conjugated to one or more of the following internal positions: positions 5, 6, 7, 15, and 17 on the sense strand, and positions 15 and 17 on the antisense strand, counting from the 5’end of each strand.
Regarding claims 8 and 9, Nair teaches wherein one or more of the first and second dsRNA molecules, if present, comprises a sense strand of 19-30 nucleotides in length and an antisense strand of 19-30 nucleotides in length, or more specifically 21-25 nucleotides in length:
[0354] In a particular embodiment, the dsRNA agents of the present invention comprise:
(a) a sense strand having:
a length of 21 nucleotides
…
and
(b) an antisense strand having:
(i) a length of 23 nucleotides;
Further regarding claims 8 and 9, Jadhav also teaches that sense strand of the multi-targeted dsRNAs are 21 nucleotides long, and the antisense are 23:
[0130] …the sense strand has 21 nucleotides, and the antisense strand has 23 nucleotides.
Regarding claims 10 and 11, Nair teaches wherein each dsRNA molecule of the nucleic acid composition comprises at least 2'-O-methyl modified nucleotide, a 2'-fluoro modified nucleotide, and a nucleotide that includes a vinyl phosphonate, and further comprises between two and eight phosphorothioate or methylphosphonate internucleotide linkages.
[0354] In a particular embodiment, the dsRNA agents of the present invention comprise: (a) a sense strand having:
(i) a length of 21 nucleotides;
…
(iii) 2’-F modifications at positions 1, 3, 5, 7, 9 to 11, 13, 17, 19, and 21, and 2’-OMe modifications at positions 2, 4, 6, 8, 12, 14 to 16, 18, and 20 (counting from the 5’ end);
and
(b) an antisense strand having:
(i) a length of 23 nucleotides;
(ii) 2’-OMe modifications at positions 1, 3, 5, 9, 11 to 13, 15, 17, 19, 21, and 23, and 2’F modifications at positions 2, 4, 6 to 8, 10, 14, 16, 18, 20, and 22 (counting from the 5’ end); and
(iii) phosphorothioate internucleotide linkages between nucleotide positions 21 and 22, and between nucleotide positions 22 and 23 (counting from the 5’ end);
Regarding claim 12, Applicant defines “substantially all” as follows:
[0782] As used herein, "substantially all of the nucleotides are modified" refers to
effector molecules or multi-targeted molecules that are largely but not wholly modified and can include not more than 5, 4, 3, 2, or 1 unmodified nucleotides.
Further regarding claim 12, Nair teaches wherein all or substantially all of the nucleotides are modified, as described above.
Regarding claim 13, Nair teaches wherein the nucleic acid composition comprises two nucleic acid dsRNA molecules, wherein the sense strand of each dsRNA molecule is 21 nucleotides in length, the antisense strand of each dsRNA molecule is 23 nucleotides in length, and the lipophilic moiety is conjugated to position 6 of the sense strand of each dsRNA molecule, while Jadhav teaches wherein the linker that connects the first dsRNA molecule and the single-stranded nucleic acid agent or second dsRNA molecule is a nucleic acid linker of three nucleotides in length that connects the sense strands of each dsRNA molecule(see above).
Regarding claims 15 and 18, Jadhav teaches wherein the linker comprises DNA/deoxyribonucleotides (dTdTdT; see above).
Regarding claims 16 and 17, Jadhav teaches wherein the linker is three nucleotides in length (see above).
Regarding claim 19, Jadhav teaches wherein the linker that connects the first dsRNA molecule and the single-stranded nucleic acid agent or second dsRNA molecule is a polynucleotide comprising one or more modifications selected from the group consisting of (at least) a 2'-O-methyl ribonucleotide modification, a 2'-fluoro-ribonucleotide modification and a locked nucleic acid (LNA) modification:
[0058] …the nucleotide-based linker connecting the effector molecules comprises at least one modification selected from the group consisting of modified intemucleoside linkage, modified nucleobase, modified sugar, and any combinations thereof. Exemplary modifications for the linker include, but are not limited to, locked nucleic acids (e.g., LNA, ENA and BNA), 2'-0-alkyl nucleosides, 2'-halo nucloesides (such as 2'-F nucleotides)
Regarding claim 21, Jadhav teaches herein said nucleic acid composition modulates gene expression of at least two target nucleic acids by at least 75% each relative to when said first dsRNA molecule and said single-stranded nucleic acid agent or second dsRNA molecule are not connected together:
[0009] the effector molecules comprised in the multi-targeted molecule described herein can independently modulate gene expression of their respective target nucleic acids by at least 50% (e.g., 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95% or more) relative to their modulation of gene expression when not part of a multi-targeted molecule.
Regarding claim 22, Jadhav teaches wherein the first dsRNA molecule modulates gene expression of a first target nucleic acid and the single-stranded nucleic acid agent or second dsRNA molecule modulates gene expression of a second nucleic acid (see above).
Regarding 26, Jadhav teaches pharmaceutical composition comprising the nucleic acid composition:
[00426] Multi -targeted molecules can be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations.
Regarding claim 27, Jadhav teaches wherein the molecule has the depicted formula, as already shown in FIG. 15, reproduced above.
Regarding claim 48, Jadhav teaches wherein the linker is represented by (nt1)(nt2)(nt3), i.e., is a three-nucleotide linker which is covalently bonded to ss1 and ss2 at each end and wherein each of the nucleotides is independent an unmodified or modified nucleotide, as already described above.
Regarding claim 49, Jadhav teaches wherein the linker is dTdTdT, as described above.
Regarding claim 50, Jadhav teaches wherein asl and as2 each comprise an independent two-nucleotide 3'-overhang:
[00144] …the dsRNA agent has a 3' overhang of 2 nucleotides in length at the 3 '-end of the antisense.
Regarding claim 51, Nair teaches wherein one or more non-terminal nucleotide positions of the first sense strand and one or more non-terminal nucleotide positions of the second sense strand independently have the following structure:
Claimed structure:
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Nair’s structure (also shown above in Example 12):
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Regarding claim 52, Nair teaches wherein the one non-terminal nucleotide position of the first sense strand is selected from the group consisting of positions 4-8, 15, and 17 of the first sense strand; and the one non-terminal nucleotide position of the second sense strand is selected from the group consisting of positions 4-8, 15, and 17 of the second sense strand,wherein the positions are independently counted starting at the 5'-termini of the first and second sense strands, respectively. Please see above regarding the recommended positions of the lipophilic conjugates.
Conclusion
No claim is allowed at this time.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached on (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMANDA M ZAHORIK/Examiner, Art Unit 1636
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