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 .
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are pending.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 13 March 2026 has been entered.
Status of the Application
Applicant’s response and amendment filed 13 March 2026 are acknowledged and entered.
Applicant has amended Claims 119, 126, 156-158, and 164-165. Applicant has cancelled Claims 142, 151, 154, 160, 166, and 168. Applicant has added Claim 170.
Response to Amendment
The objections to the claims are withdrawn.
The 112(b) rejections are withdrawn.
The 103 rejection is maintained and updated in response to the claim amendments.
The NSDP rejections are maintained.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are examined.
Arguments applicable to newly applied rejections to amended or newly presented claims are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn in light of Applicant’s amendments and/or arguments.
Claim Objections
Claim 119 is objected to for minor informalities: The claim should follow a consistent indentation scheme. The claim will be better if it is organized as follows:
A branched oligonucleotide compound capable of mediating RNA silencing in a cell, comprising two or more double-stranded nucleic acids connected to one another, wherein:
each double-stranded nucleic acid comprises an antisense strand and a sense strand, wherein:
each antisense strand comprises a 5' end, a 3' end, and a length of at least 20 nucleotides; and
each sense strand is complementary to the antisense strand and comprises a 5' end, a 3' end, and a length of at least 15 nucleotides;
wherein at least one antisense strand comprises:
greater than 50% 2'-O-methyl modified nucleotides and less than 85% 2'-O-methyl modified nucleotides,
one or more nucleotides at positions 1-7 from the 3' end connected to adjacent nucleotides via phosphorothioate linkages; and
the nucleotide at position 5 from the 5' end comprises a 2'-fluoro modification.
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:
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 119-120, 125-126, 155-159, 163-165, and 169-170 are rejected under 35 U.S.C. 103 as being unpatentable over International Patent Application Publication No. WO 2017/132669, published 03 August 2017 (“WO669”, of record), and further in view of Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record). This rejection is modified in response to the claim amendments.
WO669 is drawn to branched oligonucleotides that (¶3) achieve unexpectedly high efficacy, uptake, and tissue distribution. ¶81 teaches that the compositions described herein allow efficient, stable delivery of siRNA in order to promote potent silencing of therapeutic target genes.
Regarding Claim 119: WO669 teaches (¶15-16; Table 1) branched compounds that comprise two or more RNA duplexes that are connected to each other, wherein the duplex comprises a sense strand and an AS strand. WO669 teaches (¶11) each strand has a 5’end and a 3’end. WO669 shows examples of strands (¶18-23; e.g., Fig. 1) wherein the sense strand comprises 15 nt and the AS strand comprises 20 nt. Those ¶ and Fig. show the sense and AS strands are complementary to each other. WO669 teaches (¶18, ¶86, ¶97) each nt can be modified and the strands can be more than 50% modified, entirely modified, or any amount between 50-100% modified. WO669 teaches (¶201-204) at least 50-95% of internal nt may be modified and such modifications include 2’-OMe and 2’-F. That § (specifically ¶201) indicates each strand can comprise 15, 20, or 22 nt.
Regarding Claims 119 and 155: WO669 teaches (¶12) one or more nt at positions 1-7 from the 3’end are connected via PS linkages.
Regarding Claims 119 and 164-165: WO669 teaches (¶9) each strand comprises at least 15 or at least 20 contiguous nt. Since WO669 teaches (¶201-204) at least 50-95% of internal nt may be modified and such modifications include 2’-OMe and 2’-F, that indicates each strand can comprise 15, 20, or 22 nt (among other variations).
Regarding Claim 120, those teachings apply to any dsRNA within the branched compound and, therefore, to any AS strand.
Regarding Claims 125 and 157: WO669 teaches (¶6) the two or more nucleic acids are connected by a linker, spacer, or branching point and (¶11) an embodiment wherein each nucleic acid is double-stranded (ds) and each ds nucleic acid is independently connected to a linker, spacer, or branching point at the 3’end or 5’end of the sense or antisense strand (i.e., Claim 157). WO669 teaches (¶14) that each linker is independently selected from an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, and combinations thereof; any carbon or oxygen atom of the linker is optionally replaced with a nitrogen atom, bears a 5 hydroxyl substituent, or bears an oxo substituent (i.e., Claims 125).
Regarding Claim 126; WO669 shows (¶19-20; Fig. 1, ¶34) the pt at position 20 from the 5’end of at least one AS strand comprises a 2’-F modification.
Regarding Claim 156, WO669 teaches (¶12) nts at positions 1 and 2 from the 5’end of the sense and antisense strands can be connected to adjacent nts via PS linkages. Therefore WO669 teaches limitations of Claim 156.
Regarding Claims 158 and 159, WO669 teaches (¶13, ¶95) an embodiment wherein the branched oligo comprises a hydrophobic moiety [that] is attached to one or more terminal 5’ positions of the branched oligonucleotide compound (a limitation of Claim 158). WO669 teaches (same ¶) the hydrophobic moiety comprises an alkyl or alkenyl moiety … a vitamin or cholesterol derivative, … a lipophilic amino acid or a combination thereof (limitations of Claim 159).
Regarding Claim 163, WO669 teaches (¶157) RNA molecules comprising ribonts that have been chemically modified from 2’-OH groups to 2’-OMe groups are metabolically stabilized. WO669 teaches (¶83) embodiments in which at least 40% of the nt bases are chemically modified or all of the nts are modified. WO669 teaches (¶97) each nucleic acid can comprise one or more chemically modified nts, and that more than 50%, more than 80%, more than 90%, and more than 95% of each nucleic acid can comprise chemically-modified nts. WO669 teaches (¶116) an embodiment wherein the sense strand comprises a total of 20-mer, in which each nt on the sense strand comprises either any RNA base (i.e., A, C, G, or U) or a chemically modified derivative thereof. From those teachings, it is clear that WO669 envisioned compounds wherein at least one strand comprised at least 80% 2’-OMe modifications.
WO669 teaches (¶194) chemical modifications serve many benefits, including: enhancing target discrimination, stability of the agent (e.g., to prevent degradation), and target efficiency; promoting cellular uptake; improving efficacy in binding (e.g., to the targets) and patient tolerance to the agent; and/or reducing toxicity.
Regarding Claim 169: WO669 teaches (¶43) treating mouse primary cortical neurons with dibranched oligos and show the compounds reduce HTT mRNA expression compared to untreated control. That indicates that it is known in the art to use branched dsRNA to mediate silencing in a neuronal cell.
Regarding Claim 170: WO669 teaches (¶137) overhangs of at least 3 nt; those teachings don’t limit the overhang to either the 3’ or 5’end so an artisan would understand the teaching broadly allows an overhang on either or both ends. WO669 shows (¶21-22) dsRNA comprising overhangs of at least 3 nt at one end when the sense and AS strands align.
WO669 does not explicitly teach the AS strand comprises ≥50% but ≤85% 2’-OMe modified nt. WO669 does not explicitly teach that the nt at position 5 from the 5’end of the AS strand comprises a 2’-F modification. Those are limitations of Claim 119. WO669 does not explicitly teach that the sense strand complementary to the at least one AS strand comprises at least 80% or at least 90% 2’-OMe modified nt.
However, Foster, drawn to siRNA modifications to improve in vivo performance of siRNA, teaches (§Abstract) iterative design approach to optimize the positioning of 2’-F and 2’-OMe ribosugar modifications across both strands of a double-stranded siRNA duplex. Foster teaches (§Abstract) such optimization enhances stability without compromising intrinsic RNAi activity. Foster teaches (§Results ¶3) their analysis shows certain positions in each strand are positively impacted by 2’-F relative to 2’-OMe. Foster used iterative modification changes to improve potency and duration of siRNA. Foster teaches (§Introduction ¶2) their GalNAc-siRNA conjugates comprise 2'-OMe and 2'-F sugar modifications throughout both strands and terminal PS linkages that provide protection against nucleases. Foster teaches (§Introduction ¶3) dsRNA modifications must balance bulk (caused by bulky 2'-OMe mods) with activity; 2'-Fs are less bulky so they are used to optimize the balance. Foster used (§Introduction, final ¶, §Results ¶1-2) in silico modeling to identify an initial group of 2'-F/2'-OMe modified dsRNAs and followed that with in vitro tests and further tweaks.
Foster teaches (§Introduction ¶4) 2'-F and 2'-OMe modifications should be balanced within a dsRNA to produce the compound(s) with best performance:
Foster demonstrates it is well known in the RNAi field that modifying the position of RNA modifications can significantly enhance the nuclease stability of oligonucleotides and that sterically more demanding modifications, such as 2'-OMe, can have a greater stabilizing effect compared to less bulky modifications, such as 2’-F. If not applied judiciously, however, the steric bulk introduced by such modifications can substantially reduce RNAi activity.
Foster teaches (§Introduction ¶4-5) dsRNA comprising 2'-F are well-tolerated while 2'-OMe has better stabilizing effects but is bulkier and can reduce RNAi activity. Foster suggests (same §) refining, analyzing, and further refining dsRNA to improve dsRNA potency and duration. Foster further teaches (§Discussion ¶1) their studies show that relatively small changes in design can have a large impact on metabolic stability, thereby affecting the in vivo performance of the siRNA conjugates, (¶2) the modification patterns on the strands have to be considered in context of each other, and (¶4) in vivo performance can be enhanced without sacrificing activity by optimizing the 2'-F/2'-OMe modification pattern, specifically by including a greater than 50% reduction in 2' F content (vs. a parent strand; see Fig. 1) and concomitant increase in 2'-OMe content.
Foster shows (e.g., Figs. 1 and 2) a number of dsRNAs wherein the AS strand comprises 50-85% 2’-OMe modifications. See, e.g., DV6 and DV18. Foster also shows a number of dsRNAs wherein the sense strand comprises at least 80% 2’-OMe mods. See, e.g., DV18.
The sum teachings of Foster indicate that it is routine and conventional in the art of dsRNA design to change the proportion of 2'-F and 2'-OMe modifications in the strands of a dsRNA to find the proportion that works best for a chosen purpose.
KSR' s “obvious to try” rationale for supporting conclusion of obviousness requires the following three findings: (1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem; (2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem; (3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success.
Altogether, Foster teaches that altering the proportion of 2'-F and 2'-OMe within a dsRNA was known in the art for the benefit of optimizing stability and silencing activity. Foster explicitly teaches dsRNAs wherein the AS strand comprises ≥50% and ≤85% 2’-OMe mods and where in the sense strand comprises ≥80% 2’-OMe mods.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify WO669’s branched dsRNA with Foster’s teachings about optimizing the proportion of 2’-OMe and 2’-F modification within a dsRNA for the benefits of optimizing efficacy and stability of the siRNA and minimizing immune response and off-target effects. One would have been motivated to do so with a reasonable expectation of success because Foster teaches altering the proportions of 2’-F and 2’-OMe nts to enhance stability without comprising intrinsic RNAi activity and WO669 teaches (§Abstract) their branched dsRNA reduce immune response and off-target effects. Foster’s teachings that (§Introduction ¶4) 2’-OMe has great stabilizing effects would have motivated an artisan to maximize content of that specific modification, thereby leading them to an AS strand comprising 50-85% 2’-OMe and a sense strand comprising over 80% 2’-OMe. Foster shows dsRNA comprising that 2’-OMe composition was effective and their teachings indicate modifying 2’-OMe composition within a dsRNA was routine and customary.
Although Foster doesn’t explicitly show a 2’-F mod at position 5 from the 5’end of the AS strand, Foster’s teachings would have made it obvious to place a 2’-F or 2’-OMe modification at any position in the sense or AS strands. Furthermore, nothing in Foster teaches that placing a 2’-F at AS strand position 5 has any negative impact on silencing. In fact, Foster’s teachings (§Results ¶2-3, Fig. 1A) indicate that although a 2’-F at position 5 wasn’t found to be an extremely preferred position, a 2’-F mod at that position had a significant positive effect on target silencing. As Foster teaches (same §), the results from that analysis were considered starting points for further optimization rather than general design rules. Foster’s teachings indicate optimizing 2’-F and 2’-OMe composition within a dsRNA was routine and customary.
Since a dsRNA wherein the AS strand comprises 50-85% 2’-OMe modifications would have resulted in obvious benefits as described above, it would have been obvious to make a branched dsRNA compounds wherein each dsRNA comprises the same modifications. An artisan would have been motivated to do so for the benefits of producing a branched dsRNA compound comprising maximally efficacious dsRNAs.
Therefore the limitations of Claims 119-120, 125-126, 155-159, 163-165, and 169-170 would have been obvious in view of WO669 and Foster.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are rejected under 35 U.S.C. 103 as being unpatentable over WO669 (of record) and Foster as applied to Claims 119-120, 125-126, 155-159, 163-165, and 169-170 above, and further in view of International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). This rejection is new in view of the claim amendments.
NOTE: references to p. # in WO162 refer to the PDF p. #.
The teachings of WO669 and Foster as applicable to Claims 119-120, 125-126, 155-159, 163-165, and 169-170 have been described above.
WO669 and Foster would have made obvious branched dsRNA compounds wherein at least one AS strand comprises 50-85% 2’-OMe modified nt and wherein the nt at position 5 from the 5’end is a 2’-F modified nt.
WO669 and Foster don’t disclose, using the exact terminology, placing a 2’-F modification “at position 5” from the 5’end of the AS strand.
However, WO162 teaches that.
WO162 teaches (p. 2 L1-15) dsRNA for downregulating gene expression. WO162 teaches (p. 19 L9-11) an AS that is exactly 20- or 22-mer. WO162 teaches (p. 31 15-26) the AS strand can comprise nt analogs and that such analogs include 2’-F which (p. 32 L3-4) is a preferred analog. WO162 teaches (p. 36 L10-39) an AS strand comprising entirely 2’-F and 2’-OMe modified nt can provide silencing effect.
Regarding the limitation about a 2’-F modification at position 5 from the 5’end of the AS strand, WO162 teaches (p. 36 L29-39) the AS strand can comprise a nt analog at specific positions, including positions 5 and 20.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the branched dsRNAs of WO669 and Foster with WO162’s teaching about an AS strand comprising a 2’-F nt analog at position 5 from its 5’end. One would have included the 2’-F nt analog at position 5 from the AS strand 5’end for the benefit of enhancing stability to nucleases. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 also teaches 2’-F mods are beneficial: WO162 teaches (p. 11 L3-10; p. 22 L28-31) nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO162 indicate that placing a 2’-F modified nt at position 5 from the 5’end of the AS strand was routine and conventional in the art of RNAi.
Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The motivation to combine falls under an “obvious to try” rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding (1): WO669 teaches it was routine and conventional in the art of RNAi to modify nt with 2’-F and 2’-OMe modified nt. Foster teaches it was routine and conventional to modify the proportion of 2’-F and 2’-OMe modified nt within a dsRNA because modifying the position of RNA significantly enhances the nuclease stability of oligonucleotides but too many 2’-OMe mods can substantially reduce RNAi activity. Foster teaches (§Introduction ¶4-5) refining, analyzing, and further refining dsRNA to improve dsRNA potency and duration. That indicates that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem—namely the problem of which specific positions to place which specific nt modifications—for the benefit of optimizing nuclease stability and RNAi activity.
Regarding (2): WO162 teaches placing nt analogs, including the preferred nt analog 2’-F, at AS strand position 5 from the 5’end. WO162 indicates it was routine and conventional to place nt analogs at certain disclosed positions within an AS strand. WO162 teaches AS strand comprising 20 or 22 nts. That means there was only a finite number of identified, predictable potential solutions to the recognized need or problem.
Regarding (3): Foster, WO162, and even WO669 all teach that it was routine and conventional to alter the positions of 2’-F– and 2’-OMe–modified nts within dsRNA, and that doing so was part of routine optimization for the benefits of improving compound efficacy. WO162 discloses a nt analog at exactly position 5 and Foster teaches iteratively modifying 2’-F and 2’-OMe positions within a dsRNA to find the most efficacious compounds. That indicates a person of ordinary skill could have and would have pursued the known potential solutions with a reasonable expectation of success and that doing so was routine.
Therefore all limitations of Claims 119-120, 125-126, 155-159, 163-165, and 169-170 would have been obvious in view of WO669, Foster, and WO162.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
IMPORTANT NOTES:
Since the pending claims are very broad and would have been obvious in view of the prior art, the instant claims would have been obvious in view of any patented or copending claims directed to dsRNA plus the prior art. NSDP rejections over a selection of those documents appear below. It is not possible to identify all such patents/applications (over 500 documents) in the limited time provided for examination. Applicant is notified that the instant claims are found obvious in view of the claims of any patented or copending application directed to the same subject matter (i.e., dsRNA, branched dsRNA, or dsRNA comprising a 2’-F modification or a non-2’-OMe modification at position 5 from the 5’end of the AS strand) together with the prior art.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending applications in view of WO669 (of record), Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record), and International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). These rejections are new in response to the claim amendments.
Patent No. (App. No.)
Claims
US 9012623 (13/561357)
all
US 10087441 (14/661810)
all
US 11136578 (16/106997)
all
US 8309704 (10/859321)
20-29
US 7750144 (10/912440)
11-13, 24-25, 28-36
US 8304530 (12/729892)
all
US 8309705 (12/748937)
all
US 8329892 (12/748689)
all
US 9121018 (13/654199)
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US 10604754 (14/294817)
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US 7595387 (11/019831)
all
US 7507811 (11/633306)
all
US 7511132 (11/974885
all
US 7514550 (11/903001
all
US 7576197 (12/330981
all
US 7576196 (12/287757
all
US 7579457 (11/635618
all
US 7592444 (12/378164
all
US 7595389 (11/880628
all
US 7608707 (11/633342
all
US 7642349 (12/157137
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US 7645869 (11/633383
all
US 7655788 (11/880775
all
US 7674896 (11/635329
all
US 7691997 (11/101244
all
US 769634 (11/635330
all
US 7745611 (12/459670)
all
US 7795420 (11/975152)
all
US 7803933 (12/590707
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US 7807819 (12/584705
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US 7820809 (11/083784
all
US 7893247 (12/592335
all
US 7985854 (12/806320
all
US 8008474 (12/799844
all
US 8030474 (12/384768
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US 8093370 (12/928190
all
US 7498316 (11/101162
all
US 8008271 (12/175369)
all
US 12252691 (18/807591)
all
US 12435336 (18/040302)
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US 9879266 (14/937607)
all
Any other patents with claims directed to dsRNAs
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
Each of the patented claim sets is directed to dsRNA compounds or methods of using dsRNAs to silence a target gene.
All claim sets are directed to dsRNA compounds.
Although the patented claim sets don’t necessarily teach all of the limitations of the claimed invention, those would have been obvious in view of the prior art:
WO669 teaches (¶3, ¶6, ¶9, ¶11-16; Table 1; ¶18-23; e.g., Fig. 1; ¶34, ¶43, ¶81, ¶83, ¶86, ¶95, ¶97, ¶116, ¶137, ¶157, ¶194, ¶201-204) branched dsRNA compounds connected via a linker/spacer/branching point, kinds of hydrophobic moiety, connecting the nts at positions 1-7 from the 3’end of the at least one or each AS strand via PS linkages and connecting the nt at positions 1 and 2 from the 5’end of the at least one AS strand via PS linkages, 2’-OMe and 2’-F modified nts, the neuronal cell, the overhang, the strand lengths.
Foster teaches (§Abstract, §Results ¶1-3, §Introduction ¶2-5, §Introduction, final ¶, §Results ¶1-2, §Discussion ¶1-2, §Discussion ¶4; Figs. 1 and 2) optimizing the locations/positions of 2’-F and 2’-OMe mods, including iteratively, to improve in vivo performance of siRNA.
WO162 teaches (p. 2 L1-15, p. 19 L9-11, p. 31 15-26, p. 32 L3-4, p. 36 L10-39, p. 36 L29-39) placing a nt analog, including a 2’-F mod, in the AS strand at position 5 from the AS strand’s 5’end.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify any dsRNA, including the dsRNA of each of the patented claim sets, with WO669’s branched dsRNA designs, Foster’s modification optimization, and WO162’s teaching about an AS strand comprising a 2’-F nt analog at position 5 from its 5’end. One would have done so for the benefit of further improving in vivo performance of the patented dsRNAs. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 teaches (p. 11 L3-10; p. 22 L28-31) 2’-F mods are beneficial: nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO669, Foster, and WO162 indicate that altering locations of modified nt within a dsRNA, including placing a 2’-F modified nt at position 5 from the 5’end of the AS strand, was routine and conventional in the art of RNAi. One would have been motivated to make any dsRNAs into branched dsRNAs because WO669 teaches branched oligonucleotides (¶3, ¶81) achieve unexpectedly high efficacy, uptake, and tissue distribution and allow efficient, stable delivery of siRNA in order to promote potent silencing of therapeutic target genes.
Therefore the instant claims would have been obvious in view of the patented claims, WO669, Foster, and WO162.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending applications in view of WO669 (of record), Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record), and International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). These rejections are new in response to the claim amendments.
Application
Claims
17532636
all
18/756700
all
18375206
all
18375235
all
18380871
all
18537392
all
18592676
all
18592943
all
18593212
all
18609299
all
18609621
all
18666191
all
18682646
all
18755993
all
18799165
all
19/055377
all
19399527
all
19243931
all
19248996
all
Any other copending applications with claims directed to dsRNAs
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
Each of the copending claim sets is directed to dsRNA compounds or methods of using dsRNAs to silence a target gene.
All claim sets are directed to dsRNA compounds.
Although the copending claim sets don’t necessarily teach all of the limitations of the claimed invention, those would have been obvious in view of the prior art:
WO669 teaches (¶3, ¶6, ¶9, ¶11-16; Table 1; ¶18-23; e.g., Fig. 1; ¶34, ¶43, ¶81, ¶83, ¶86, ¶95, ¶97, ¶116, ¶137, ¶157, ¶194, ¶201-204) branched dsRNA compounds connected via a linker/spacer/branching point, kinds of hydrophobic moiety, connecting the nts at positions 1-7 from the 3’end of the at least one or each AS strand via PS linkages and connecting the nt at positions 1 and 2 from the 5’end of the at least one AS strand via PS linkages, 2’-OMe and 2’-F modified nts, the neuronal cell, the overhang, the strand lengths.
Foster teaches (§Abstract, §Results ¶1-3, §Introduction ¶2-5, §Introduction, final ¶, §Results ¶1-2, §Discussion ¶1-2, §Discussion ¶4; Figs. 1 and 2) optimizing the locations/positions of 2’-F and 2’-OMe mods, including iteratively, to improve in vivo performance of siRNA.
WO162 teaches (p. 2 L1-15, p. 19 L9-11, p. 31 15-26, p. 32 L3-4, p. 36 L10-39, p. 36 L29-39) placing a nt analog, including a 2’-F mod, in the AS strand at position 5 from the AS strand’s 5’end.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify any dsRNA, including the dsRNA of each of the copending claim sets, with WO669’s branched dsRNA designs, Foster’s modification optimization, and WO162’s teaching about an AS strand comprising a 2’-F nt analog at position 5 from its 5’end. One would have done so for the benefit of further improving in vivo performance. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 teaches (p. 11 L3-10; p. 22 L28-31) 2’-F mods are beneficial: nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO669, Foster, and WO162 indicate that altering locations of modified nt within a dsRNA, including placing a 2’-F modified nt at position 5 from the 5’end of the AS strand, was routine and conventional in the art of RNAi. One would have been motivated to make any dsRNAs into branched dsRNAs because WO669 teaches branched oligonucleotides (¶3, ¶81) achieve unexpectedly high efficacy, uptake, and tissue distribution and allow efficient, stable delivery of siRNA in order to promote potent silencing of therapeutic target genes.
Therefore the instant claims would have been obvious in view of the copending claims, WO669, Foster, and WO162.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending applications in view of WO669 (of record), Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record), and International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). These rejections are new in response to the claim amendments.
Patent No. (App. No.)
Claims
US 12252691 (18/807591)
all
US 12435336 (18/040302)
all
US 12084662 (17/719821
all
Any other patents with claims directed to dsRNAs with a 2’-F modification or a non-2-OMe modification at AS strand position 5 from the 5’end
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
Each of the patented claim sets is directed to dsRNA compounds comprising at least one AS strand comprising a 2’-F modification at the nucleotide at position 5 from the 5’end of the AS strand, wherein the at least one AS strand comprises ≥50-85% 2’-OMe modifications, or to methods of using such dsRNAs.
All claim sets are directed to dsRNA compounds comprising a 2’-F modification at the nucleotide at position 5 from the 5’end of the AS strand, wherein the AS strand comprise ≥50-85% 2’-OMe modified nt.
Although the patented claim sets don’t necessarily teach all of the limitations of the claimed invention, those would have been obvious in view of the prior art:
WO669 teaches (¶3, ¶6, ¶9, ¶11-16; Table 1; ¶18-23; e.g., Fig. 1; ¶34, ¶43, ¶81, ¶83, ¶86, ¶95, ¶97, ¶116, ¶137, ¶157, ¶194, ¶201-204) branched dsRNA compounds connected via a linker/spacer/branching point, kinds of hydrophobic moiety, connecting the nts at positions 1-7 from the 3’end of the at least one or each AS strand via PS linkages and connecting the nt at positions 1 and 2 from the 5’end of the at least one AS strand via PS linkages, 2’-OMe and 2’-F modified nts, the neuronal cell, the overhang, the strand lengths.
Foster teaches (§Abstract, §Results ¶1-3, §Introduction ¶2-5, §Introduction, final ¶, §Results ¶1-2, §Discussion ¶1-2, §Discussion ¶4; Figs. 1 and 2) optimizing the locations/positions of 2’-F and 2’-OMe mods, including iteratively, to improve in vivo performance of siRNA.
WO162 teaches (p. 2 L1-15, p. 19 L9-11, p. 31 15-26, p. 32 L3-4, p. 36 L10-39, p. 36 L29-39) placing a nt analog, including a 2’-F mod, in the AS strand at positions 5 and/or 20 from the AS strand’s 5’end.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify any dsRNA, including the dsRNA of each of the patented claim sets, with WO669’s branched dsRNA designs, Foster’s modification optimization, and WO162’s teaching about an AS strand comprising a 2’-F nt analog at position 5 from its 5’end. One would have done so for the benefit of further improving in vivo performance of the patented dsRNAs. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 teaches (p. 11 L3-10; p. 22 L28-31) 2’-F mods are beneficial: nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO669, Foster, and WO162 indicate that altering locations of modified nt within a dsRNA, including placing a 2’-F modified nt at position 5 from the 5’end of the AS strand, was routine and conventional in the art of RNAi. One would have been motivated to make any dsRNAs into branched dsRNAs because WO669 teaches branched oligonucleotides (¶3, ¶81) achieve unexpectedly high efficacy, uptake, and tissue distribution and allow efficient, stable delivery of siRNA in order to promote potent silencing of therapeutic target genes.
Therefore the instant claims would have been obvious in view of the patented claims, WO669, Foster, and WO162.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending applications in view of WO669 (of record), Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record), and International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). These rejections are new in response to the claim amendments.
App. No.
Claims
Notes
19290213
All
See Claim 108
18430581
all
See Claim 45DE
18393044
all
See Claim 45DEH
19392928
all
See Claims 48-49
19/355121
all
See Claims 64-65
19338285
all
See Claim 45DE
17391475
all
See Claim 48D
Any other copending applications with claims directed to dsRNAs with a 2’-F modification or a non-2-OMe modification at AS strand position 5 from the 5’end
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
Each of the copending claim sets is directed to dsRNA compounds comprising an AS strand comprising a 2’-F modification or non-2’-OMe modification at the nucleotide at specifically position 5 from the 5’end of the AS strand, and wherein the at least one AS strand comprises ≥50-85% 2’-OMe mods, and/or to methods of using such dsRNAs.
All claim sets are directed to dsRNA compounds comprising a 2’-F modification or non-2’-OMe modification at the nucleotide at specifically position 5 from the 5’end of the AS strand, and wherein the at least one AS strand comprises ≥50-85% 2’-OMe mods.
Although the copending claim sets don’t necessarily teach all of the limitations of the claimed invention, those would have been obvious in view of the prior art:
WO669 teaches (¶3, ¶6, ¶9, ¶11-16; Table 1; ¶18-23; e.g., Fig. 1; ¶34, ¶43, ¶81, ¶83, ¶86, ¶95, ¶97, ¶116, ¶137, ¶157, ¶194, ¶201-204) branched dsRNA compounds connected via a linker/spacer/branching point, kinds of hydrophobic moiety, connecting the nts at positions 1-7 from the 3’end of the at least one or each AS strand via PS linkages and connecting the nt at positions 1 and 2 from the 5’end of the at least one AS strand via PS linkages, 2’-OMe and 2’-F modified nts, the neuronal cell, the overhang, the strand lengths.
Foster teaches (§Abstract, §Results ¶1-3, §Introduction ¶2-5, §Introduction, final ¶, §Results ¶1-2, §Discussion ¶1-2, §Discussion ¶4; Figs. 1 and 2) optimizing the locations/positions of 2’-F and 2’-OMe mods, including iteratively, to improve in vivo performance of siRNA.
WO162 teaches (p. 2 L1-15, p. 19 L9-11, p. 31 15-26, p. 32 L3-4, p. 36 L10-39, p. 36 L29-39) placing a nt analog, including a 2’-F mod, in the AS strand at positions 5 and/or 20 from the AS strand’s 5’end.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify any dsRNA, including the dsRNA of each of the copending claim sets, with WO669’s branched dsRNA designs, Foster’s modification optimization, and WO162’s teaching about an AS strand comprising a 2’-F nt analog at position 5 from its 5’end. One would have done so for the benefit of further improving in vivo performance of the patented dsRNAs. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 teaches (p. 11 L3-10; p. 22 L28-31) 2’-F mods are beneficial: nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO669, Foster, and WO162 indicate that altering locations of modified nt within a dsRNA, including placing a 2’-F modified nt at position 5 from the 5’end of the AS strand, was routine and conventional in the art of RNAi. One would have been motivated to make any dsRNAs into branched dsRNAs because WO669 teaches branched oligonucleotides (¶3, ¶81) achieve unexpectedly high efficacy, uptake, and tissue distribution and allow efficient, stable delivery of siRNA in order to promote potent silencing of therapeutic target genes.
Therefore the instant claims would have been obvious in view of the copending claims, WO669, Foster, and WO162.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following patents in view of WO669 (of record), Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record), and International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). These rejections are new in response to the claim amendments.
Patent No (App. No.)
App. No.
Claims
US10478503
15/419,593
all
US10799591
16390712
all
US11896669
17012787
all
US12365894
17022678
all
US 12077758
17333839
all
US 12297430
17580269
all
Any other patents with claims directed to branched dsRNAs
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
Each of the patented claim sets is directed to branched dsRNA compounds or methods of using branched dsRNAs to silence a target gene.
All claim sets are directed to branched dsRNA compounds.
Although the patented claim sets don’t necessarily teach all of the limitations of the claimed invention, those would have been obvious in view of the prior art:
WO669 teaches (¶3, ¶6, ¶9, ¶11-16; Table 1; ¶18-23; e.g., Fig. 1; ¶34, ¶43, ¶81, ¶83, ¶86, ¶95, ¶97, ¶116, ¶137, ¶157, ¶194, ¶201-204) branched dsRNA compounds connected via a linker/spacer/branching point, kinds of hydrophobic moiety, connecting the nts at positions 1-7 from the 3’end of the at least one or each AS strand via PS linkages and connecting the nt at positions 1 and 2 from the 5’end of the at least one AS strand via PS linkages, 2’-OMe and 2’-F modified nts, the neuronal cell, the overhang, the strand lengths.
Foster teaches (§Abstract, §Results ¶1-3, §Introduction ¶2-5, §Introduction, final ¶, §Results ¶1-2, §Discussion ¶1-2, §Discussion ¶4; Figs. 1 and 2) optimizing the locations/positions of 2’-F and 2’-OMe mods, including iteratively, to improve in vivo performance of siRNA.
WO162 teaches (p. 2 L1-15, p. 19 L9-11, p. 31 15-26, p. 32 L3-4, p. 36 L10-39, p. 36 L29-39) placing a nt analog, including a 2’-F mod, in the AS strand at position 5 from the AS strand’s 5’end.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify any dsRNA, including the dsRNA of each of the patented claim sets, with WO669’s branched dsRNA designs, Foster’s modification optimization, and WO162’s teaching about an AS strand comprising a 2’-F nt analog at position 5 from its 5’end. One would have done so for the benefit of further improving in vivo performance. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 teaches (p. 11 L3-10; p. 22 L28-31) 2’-F mods are beneficial: nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO669, Foster, and WO162 indicate that altering locations of modified nt within a dsRNA, including placing a 2’-F modified nt at position 5 from the 5’end of the AS strand, was routine and conventional in the art of RNAi.
Therefore the instant claims would have been obvious in view of the patented claims, WO669, Foster, and WO162.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending applications in view of WO669 (of record), Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record), and International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). These rejections are new in response to the claim amendments.
Application
Claims
Notes
16833107
all
18396613
all
19243931
all
18142852
all
See Claim 87
18134167
all
See Claim 158
Any other copending applications with claims directed to branched dsRNAs
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
Each of the copending claim sets is directed to branched dsRNA compounds or methods of using branched dsRNAs to silence a target gene.
All claim sets are directed to branched dsRNA compounds.
Although the copending claim sets don’t necessarily teach all of the limitations of the claimed invention, those would have been obvious in view of the prior art:
WO669 teaches (¶3, ¶6, ¶9, ¶11-16; Table 1; ¶18-23; e.g., Fig. 1; ¶34, ¶43, ¶81, ¶83, ¶86, ¶95, ¶97, ¶116, ¶137, ¶157, ¶194, ¶201-204) branched dsRNA compounds connected via a linker/spacer/branching point, kinds of hydrophobic moiety, connecting the nts at positions 1-7 from the 3’end of the at least one or each AS strand via PS linkages and connecting the nt at positions 1 and 2 from the 5’end of the at least one AS strand via PS linkages, 2’-OMe and 2’-F modified nts, the neuronal cell, the overhang, the strand lengths.
Foster teaches (§Abstract, §Results ¶1-3, §Introduction ¶2-5, §Introduction, final ¶, §Results ¶1-2, §Discussion ¶1-2, §Discussion ¶4; Figs. 1 and 2) optimizing the locations/positions of 2’-F and 2’-OMe mods, including iteratively, to improve in vivo performance of siRNA.
WO162 teaches (p. 2 L1-15, p. 19 L9-11, p. 31 15-26, p. 32 L3-4, p. 36 L10-39, p. 36 L29-39) placing a nt analog, including a 2’-F mod, in the AS strand at position 5 from the AS strand’s 5’end.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify any dsRNA, including the dsRNA of each of the copending claim sets, with WO669’s branched dsRNA designs, Foster’s modification optimization, and WO162’s teaching about an AS strand comprising a 2’-F nt analog at position 5 from its 5’end. One would have done so for the benefit of further improving in vivo performance. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 teaches (p. 11 L3-10; p. 22 L28-31) 2’-F mods are beneficial: nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO669, Foster, and WO162 indicate that altering locations of modified nt within a dsRNA, including placing a 2’-F modified nt at position 5 from the 5’end of the AS strand, was routine and conventional in the art of RNAi.
Therefore the instant claims would have been obvious in view of the copending claims, WO669, Foster, and WO162.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 66, 97 of copending Application No. Application No. 18918355, filed on 17 October 2024 (reference application, “App355”) in view of WO669 (of record). This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
The copending App355 claims are directed to an RNA molecule comprising modification patterns recited in Table 2. The modification patterns of antisense strand P2_EG1_as and sense strand P2_EG1_s read on the instant claims because those modification patterns have a 2’-F modification at position 5 from the 5’end of the antisense strand and 50-85% 2’-OMe mods. That is shown in this excerpt of App355’s Table 2:
PNG
media_image1.png
49
650
media_image1.png
Greyscale
Therefore it is clear that both claim sets are directed to dsRNAs wherein position 5 from the 5’end of the at least one antisense strand is not a 2’-F and the at least one AS strand comprises 50-85% 2’-OMe mods.
The App355 claims do not recite that the oligos are branched or connected by a branch point but WO669 discloses that (¶3) branched oligos achieve unexpectedly high efficacy, uptake, and tissue distribution. WO669 also teaches a hydrophobic moiety attached to the branched oligo.
Regarding Claims 125, 157, and 166, WO669’s ¶6 teaches the two or more nucleic acids are connected by a linker, spacer, or branching point. ¶11 teaches an embodiment wherein each nucleic acid is double-stranded (ds) and each ds nucleic acid is independently connected to a linker, spacer, or branching point at the 3’end or 5’end of the sense or antisense strand (i.e., Claim 157). ¶14 teaches that each linker is independently selected from an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, and combinations thereof; any carbon or oxygen atom of the linker is optionally replaced with a nitrogen atom, bears a 5 hydroxyl substituent, or bears an oxo substituent (i.e., limitations of Claims 125 and 166).
Regarding Claim 156, WO669 teaches (¶12) nts at positions 1 and 2 from the 5’end of the sense and antisense strands, and at positions 1-6 or 1-7 from the 3’end can be connected to adjacent nts via PS linkages. Therefore WO669 teaches limitations of Claim 156.
Regarding Claims 158 and 159, WO669 teaches (¶13, ¶95) an embodiment wherein the branched oligo comprises a hydrophobic moiety [that] is attached to one or more terminal 5’ positions of the branched oligonucleotide compound (a limitation of Claim 158). WO669 teaches (same ¶) the hydrophobic moiety comprises an alkyl or alkenyl moiety (e.g., an alkyl or alkenyl chain, or a saturated or unsaturated fatty acid residue), a vitamin or cholesterol derivative, an aromatic moiety (e.g., phenyl or naphthyl), a lipophilic amino acid or a combination thereof (limitations of Claim 159).
Regarding Claim 163, WO669 teaches (¶157) RNA molecules comprising ribonts that have been chemically modified from 2’-OH groups to 2’-OMe groups are metabolically stabilized. WO669 teaches (¶83) embodiments in which at least 40% of the nt bases are chemically modified or all of the nts are modified. WO669 teaches (¶97) each nucleic acid can comprise one or more chemically modified nts, and that more than 50%, more than 80%, more than 90%, and more than 95% of each nucleic acid can comprise chemically-modified nts. WO669 teaches (¶116) an embodiment wherein the sense strand comprises a total of 20-mer, in which each nt on the sense strand comprises either any RNA base (i.e., A, C, G, or U) or a chemically modified derivative thereof. From those teachings, it is clear that WO669 envisioned compounds wherein at least one strand comprised at least 80% 2’-OMe modifications.
WO669 teaches (¶194) chemical modifications serve many benefits, including: enhancing target discrimination, stability of the agent (e.g., to prevent degradation), and target efficiency; promoting cellular uptake; improving efficacy in binding (e.g., to the targets) and patient tolerance to the agent; and/or reducing toxicity.
Therefore it would have been obvious to an artisan to modify the oligos of App355 Claim 66 and make them into branched oligos for the benefits of achieving unexpectedly high efficacy, uptake, and tissue distribution. One would have been motivated to do so with a reasonable expectation of success because WO669 teaches branched oligos achieve unexpectedly high efficacy, uptake, and tissue distribution. Modifying the invention of App355 Claims 66 and 97 with the teachings of WO669 would have produced the limitations of the instant claims.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7, 15-16, 1820-21, 23, 25, 28, 34-37, 40, 42-43 of copending Application No. Application No. 18197948, filed on 16 May 2022 (reference application, “App948”) in view of WO669 (of record). This rejection is maintained and updated in response to the claim amendments.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
The copending App948 claims are directed to an RNA molecule comprising modification various modifications. The modification patterns of at least antisense strand P1_b6_as, recited in Claim 34, read on the instant claims because the App948 claimed antisense strand comprises a 2’-F modification at position 5 from the 5’end and at least 50% 2’-OMe modifications:
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Therefore it is clear that both claim sets are directed to dsRNAs wherein position 5 from the 5’end of the antisense strand is a 2’-F nt and wherein the antisense strand comprises at least 50% 2’-OMes.
The App948 claims do not recite that the oligos are branched or connected by a branch point but WO669 discloses that (¶3) branched oligos achieve unexpectedly high efficacy, uptake, and tissue distribution. WO669 also teaches a hydrophobic moiety attached to the branched oligo.
Regarding Claims 125, 157, and 166, WO669’s ¶6 teaches the two or more nucleic acids are connected by a linker, spacer, or branching point. ¶11 teaches an embodiment wherein each nucleic acid is double-stranded (ds) and each ds nucleic acid is independently connected to a linker, spacer, or branching point at the 3’end or 5’end of the sense or antisense strand (i.e., Claim 157). ¶14 teaches that each linker is independently selected from an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, and combinations thereof; any carbon or oxygen atom of the linker is optionally replaced with a nitrogen atom, bears a 5 hydroxyl substituent, or bears an oxo substituent (i.e., limitations of Claims 125 and 166).
Regarding Claim 156, WO669 teaches (¶12) nts at positions 1 and 2 from the 5’end of the sense and antisense strands, and at positions 1-6 or 1-7 from the 3’end can be connected to adjacent nts via PS linkages. Therefore WO669 teaches limitations of Claim 156.
Regarding Claims 158 and 159, WO669 teaches (¶13, ¶95) an embodiment wherein the branched oligo comprises a hydrophobic moiety [that] is attached to one or more terminal 5’ positions of the branched oligonucleotide compound (a limitation of Claim 158). WO669 teaches (same ¶) the hydrophobic moiety comprises an alkyl or alkenyl moiety (e.g., an alkyl or alkenyl chain, or a saturated or unsaturated fatty acid residue), a vitamin or cholesterol derivative, an aromatic moiety (e.g., phenyl or naphthyl), a lipophilic amino acid or a combination thereof (limitations of Claim 159).
Regarding Claim 163, WO669 teaches (¶157) RNA molecules comprising ribonts that have been chemically modified from 2’-OH groups to 2’-OMe groups are metabolically stabilized. WO669 teaches (¶83) embodiments in which at least 40% of the nt bases are chemically modified or all of the nts are modified. WO669 teaches (¶97) each nucleic acid can comprise one or more chemically modified nts, and that more than 50%, more than 80%, more than 90%, and more than 95% of each nucleic acid can comprise chemically-modified nts. WO669 teaches (¶116) an embodiment wherein the sense strand comprises a total of 20-mer, in which each nt on the sense strand comprises either any RNA base (i.e., A, C, G, or U) or a chemically modified derivative thereof. From those teachings, it is clear that WO669 envisioned compounds wherein at least one strand comprised at least 80% 2’-OMe modifications.
WO669 teaches (¶194) chemical modifications serve many benefits, including: enhancing target discrimination, stability of the agent (e.g., to prevent degradation), and target efficiency; promoting cellular uptake; improving efficacy in binding (e.g., to the targets) and patient tolerance to the agent; and/or reducing toxicity. WO669 teaches (¶187) using their compounds to silence a gene in neurons.
Therefore it would have been obvious to an artisan to modify the oligos of the App948 claims and make them into branched oligos for the benefits of achieving unexpectedly high efficacy, uptake, and tissue distribution. One would have been motivated to do so with a reasonable expectation of success because WO669 teaches branched oligos achieve unexpectedly high efficacy, uptake, and tissue distribution. Modifying the invention of the App948 claims with the teachings of WO669 would have produced the limitations of the instant claims.
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the following claims of the following copending applications in view of WO669 (of record), , Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708-717, “Foster”, of record) and International Patent Application Publication No. WO 2007/107162, published 27 September 2007 (“WO162”). This rejection is new.
Application
Abbrev.
Claims
Notes
18666191
App191
all
See Claims 59BC and 96
18120030
App030
All
See Claims 45DE and 87
18094695
App695
All
See Claims 45D and 194
Any other copending applications (provisional rejection) or patents (nonprovisional rejection) with claims directed to branched dsRNAs wherein at least one dsRNA has a 2’-F modification or a non-2’-OMe modification at AS strand position 5 from the 5’end
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims recite branched oligonucleotides for RNA silencing, comprising two or more dsRNAs, wherein at least one AS strand comprises 50-85% 2’-OMe nts, wherein position 5 (and sometimes position 20) from the 5’end of the AS strand must contain a 2’-F modification, wherein the nt at positions 1-7 from the 3’end of the at least one AS strand (or each AS strands) are connected via PS linkages, wherein the AS strand must be at least 20-mer and the sense strand must be at least 15-mer; wherein the at least two dsRNAs are connected by a linker, and comprise PS linkages at certain positions, other modifications (including wherein the nt at position 2 from the 5’end of the at least one AS strand comprises a 2’-F mod, 2’-H mod, or 2’-OH moiety), and a 3-nt overhang at one of or both ends when the sense and AS strands align.
The copending claims are directed to dsRNA compounds that can comprise (App191 Claim 96; App030 Claim87; App695 Claim 194) branched dsRNA compounds comprising two dsRNAs linked by a linker, and dsRNA compounds wherein (App191 Claim 59BC; App030 Claim 45DE; App695 Claim 45DE) at least one AS strand comprises at least 70-75% 2’-OMe modified nts and comprises non-2-OMe nt at positions 4, 5, 6, and 14 from the 5’end of the AS strand.
Both claim sets are directed to branched dsRNA compounds wherein at least one AS strand comprises at least ≥50-85% 2’-OMe modified nts and comprises a non-2-OMe nt at position 5 from the 5’end of the AS strand; both claim sets recite connecting the nts at positions 1-7 from the 3’end of the at least one or each AS strand via PS linkages and connecting the nt at positions 1 and 2 from the 5’end of the at least one AS strand via PS linkages.
Although the copending claims don’t necessarily teach all of the limitations of the claimed invention, those would have been obvious in view of the prior art:
WO669 teaches (¶3, ¶6, ¶9, ¶11-16; Table 1; ¶18-23; e.g., Fig. 1; ¶34, ¶43, ¶81, ¶83, ¶86, ¶95, ¶97, ¶116, ¶137, ¶157, ¶194, ¶201-204) branched dsRNA compounds connected via a linker/spacer/branching point, kinds of hydrophobic moiety, 2’-OMe and 2’-F modified nts, the neuronal cell, the overhang, the strand lengths.
Foster teaches (§Abstract, §Results ¶1-3, §Introduction ¶2-5, §Introduction, final ¶, §Results ¶1-2, §Discussion ¶1-2, §Discussion ¶4; Figs. 1 and 2) optimizing the locations/positions of 2’-F and 2’-OMe mods, including iteratively, to improve in vivo performance of siRNA.
WO162 teaches (p. 2 L1-15, p. 19 L9-11, p. 31 15-26, p. 32 L3-4, p. 36 L10-39, p. 36 L29-39) placing a nt analog, including a 2’-F mod, in the AS strand at position 5 from the AS strand’s 5’end.
Therefore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the dsRNA of each of the copending claims, with WO669’s nt modifications on the dsRNA within branched dsRNAs, Foster’s modification optimization, and WO162’s teaching about an AS strand comprising nt analog (that can be a 2’-F) at specifically position 5 from its 5’end. One would have done so for the benefit of further improving in vivo performance. One would have been motivated to do so with a reasonable expectation of success because Foster teaches optimizing the proportion of 2’-F mods within a dsRNA and because WO162 teaches (p. 11 L3-10; p. 22 L28-31) 2’-F mods are beneficial: nt analogs increase serum stability and prolong target knockdown including in vivo. Furthermore, the teachings of WO669, Foster, and WO162 indicate that altering locations of modified nt within a dsRNA, including placing a 2’-F modified nt at position 5 from the 5’end of the AS strand, was routine and conventional in the art of RNAi.
Therefore the instant claims would have been obvious in view of the copending claims, WO669, Foster, and WO162.
Response to Arguments
Applicant’s arguments filed 13 March 2026 have been fully considered but they are not persuasive. Arguments that are no longer relevant are not addressed.
Objections
Claim 119 is objected to for minor informalities.
103
Applicant argues against the 103 rejections on pp. 7-11.
Applicant argues that the limitation that the nucleotide [nt] at position 5 from the 5’end of the at least one antisense [AS] strand comprises a 2’-fluoro [2’-F] modification is not taught or suggested by the prior art. Applicant argues that all of Foster’s AS strands comprise a 2’-OMe mod at position 5 from the 5’end. Applicant argues that WO669 teaches AS strands comprising a 2’-OMe mod at position 5 from the 5’end.
Those arguments are not persuasive. Even though Foster doesn’t explicitly teach an AS strand comprising a 2’-F mod at position 5 from the 5’end, that modification would have been obvious to try in view of both or either of Foster and newly applied art, WO162. In fact, Foster’s teachings (§Results ¶2-3, Fig. 1A) indicate that although a 2’-F at position 5 wasn’t found to be an extremely preferred position, a 2’-F mod at that position had a significant positive effect on target silencing. As Foster teaches (same §), the results from that analysis were considered starting points for further optimization rather than general design rules.
Obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). The motivation to combine falls under an “obvious to try” rationale; see MPEP 2143(I)(E):
To reject a claim based on this rationale, Office personnel must resolve the Graham factual inquiries. Then, Office personnel must articulate the following:
(1) a finding that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem;
(2) a finding that there had been a finite number of identified, predictable potential solutions to the recognized need or problem;
(3) a finding that one of ordinary skill in the art could have pursued the known potential solutions with a reasonable expectation of success; and
(4) whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness.
The rationale to support a conclusion that the claim would have been obvious is that "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense.
Regarding (1): WO669 teaches it was routine and conventional in the art of RNAi to modify nt with 2’-F and 2’-OMe modified nt. Foster teaches it was routine and conventional to modify the proportion of 2’-F and 2’-OMe modified nt within a dsRNA because modifying the position of RNA significantly enhances the nuclease stability of oligonucleotides but too many 2’-OMe mods can substantially reduce RNAi activity. Foster teaches (§Introduction ¶4-5) refining, analyzing, and further refining dsRNA to improve dsRNA potency and duration. That indicates that at the relevant time, there had been a recognized problem or need in the art, which may include a design need or market pressure to solve a problem—namely the problem of which specific positions to place which specific nt modifications—for the benefit of optimizing nuclease stability and RNAi activity.
Regarding (2): WO162 teaches placing nt analogs, including the preferred nt analog 2’-F, at AS strand position 5 from the 5’end. WO162 indicates it was routine and conventional to place nt analogs at certain disclosed positions within an AS strand. WO162 teaches AS strand comprising 20 or 22 nts. That means there was only a finite number of identified, predictable potential solutions to the recognized need or problem.
Regarding (3): Foster, WO162, and even WO669 all teach that it was routine and conventional to alter the positions of 2’-F– and 2’-OMe–modified nts within dsRNA, and that doing so was part of routine optimization for the benefits of improving compound efficacy. WO162 discloses a nt analog at exactly position 5 and Foster teaches iteratively modifying 2’-F and 2’-OMe positions within a dsRNA to find the most efficacious compounds. That indicates a person of ordinary skill could have and would have pursued the known potential solutions with a reasonable expectation of success, and such optimization was routine.
Furthermore (and as evidenced by Foster), everything within the instant claims is merely a variation of what was known in the prior art. As noted in In re Aller, 105 USPQ 233 at 235, more particularly, where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05 provides: It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions (In re Williams, 36 F.2d 436, 438 (CCPA 1929).
Here, the focus is that the general conditions are known in the prior art and changes in form or, possibly, substitution of equivalents, over the prior art that does the same thing as what is known in the prior art is not patentable. Substitution of equivalents in terms of the instant claims means identifying optimal locations and proportions of modifications—including PS linkage, 2’-F, and 2’-OMe nt modifications—because varying the locations and proportions of these modifications in a dsRNA for optimal or better results was well-known in the prior art. Indeed, the art of Foster demonstrates that modifying the location and proportion of 2’-F and 2’-OMe nt modifications was routine in the art.
Applicant should provide evidence that the claimed invention produces outcomes more impressive than what can be expected based on the modifications known in the prior art.
NSDP
Applicant disagrees with the NSDP rejections because the copending applications are alleged to have later filing dates than the claimed invention. That is not found persuasive because MPEP 804 instructs that a provision NSDP rejection be maintained until allowable subject matter is indicated. That is not yet the case.
Also note that since the pending claims are very broad and would have been obvious in view of the prior art, the instant claims would have been obvious in view of any patented or copending claims directed to dsRNA plus the cited prior art. NSDP rejections over a selection of those documents appear above. It is not possible to identify all such patents/applications (over 500 documents) in the limited time provided for examination. Applicant is notified that the instant claims are found obvious in view of the claims of any patented or copending application directed to the same subject matter (i.e., dsRNA, branched dsRNA, or dsRNA comprising a 2’-F modification or a non-2’-OMe modification at position 5 from the 5’end of the AS strand) together with the prior art.
Conclusion
Claims 119-120, 125-126, 155-159, 163-165, and 169-170 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to RUTHIE S ARIETI whose telephone number is (571)272-1293. The examiner can normally be reached M-Th 8:30AM-4PM, alternate Fridays 8:30AM-4PM (ET).
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RUTHIE S ARIETI
Examiner (Ruth.Arieti@uspto.gov)
Art Unit 1635
/RUTH SOPHIA ARIETI/Examiner, Art Unit 1635
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights