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 1, 3, 32, 37-38, 45, 52, 66, 69, 151-168 are pending.
Status of the Application
Applicant’s response and amendment filed 26 November 2025 are acknowledged and entered.
Applicant has amended Claims 1, 3, 32, 37-38, 45, 52, 66, 69, 151-166 and 168. Applicant has cancelled Claim 6.
Response to Amendment
Applicant has amended the claims to overcome the 112(b) rejections. The 112(b) rejections are withdrawn.
Applicant has amended the claims to overcome the 103 rejections; the 103 rejections are not withdrawn.
The NSDP rejection over copending App. No. 18918355 is withdrawn. The other NSDP rejections are maintained.
Claims 1, 3, 32, 37-38, 45, 52, 66, 68, 151-168 are examined.
Arguments applicable to newly applied rejections are addressed below. Arguments that are no longer relevant are not addressed.
Rejections not reiterated here are withdrawn.
103 REJECTIONS MAINTAINED BUT UPDATED AS NECESSITATED BY AMENDMENT
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 3, 32, 37-38, 69, 151-154, 158, 163-164, and 166-167 are rejected under 35 U.S.C. 103 as being unpatentable over WO276 (of record); Sledz (and Williams. 2005. RNA interference in biology and disease. Blood 106[3]:787-794; “Sledz”, of record); Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708, “Foster”, of record), and Chernikov (et al. 2019. Current Development of siRNA Bioconjugates: From Research to the Clinic. Frontiers Pharmacol. 10:444; “Chernikov”, of record). This rejection has been updated in response to the 26 November 2025 claim amendments.
WO276 is drawn to compounds that inhibit DGAT2 expression which (PDF p. 4 L7-9) may improve NAFLD/NASH, as well as the metabolic profile of patients with lipodystrophy syndromes by reducing triglycerides, improving insulin sensitivity, and decreasing hepatic steatosis. [Note: all WO doc page references are to the PDF page #.]
Regarding the dsRNA, sense/AS strands, 5’/3’ends of Claim 1: WO276 discloses (p. 61 L3-16) antisense compounds [that] are double stranded, comprising two oligomeric compounds that form a duplex and (p. 9 L4-6) “double-stranded antisense compound” means an antisense compound comprising two oligomeric compounds that are complementary to each other and form a duplex. The passage (p. 61 L3-16) discloses embodiments wherein the double stranded (ds) antisense compounds (AS; or together, dsRNA) can comprise one or more conjugate groups, in which one single nt is modified and in which each nt is (i.e., all nts are) modified. The dsRNAs are made of nt so they inherently possess a 5’end and a 3’end. In addition, WO276 teaches (p. 60 L10-26) adding or deleting nt to or from the 5’end and/or the 3’end, which further indicates that each component strand of the dsRNAs has a 3’end and a 5’end. WO276 discloses (p. 34 L 14-15) the compound or oligonucleotide can be at least 85%...or 100% complementary to a nucleic acid encoding DGAT2.
Regarding the strand lengths and strand complementarity of Claims 1 and 153-154: WO276 teaches (p. 62. L10-20)
In certain embodiments, the first strand of the double-stranded compound is an siRNA guide strand and the second strand of the double-stranded compound is an siRNA passenger strand. In certain embodiments, the second strand of the double-stranded compound is complementary to the first strand. In certain embodiments, each strand of the double-stranded compound consists of 16… or 23 linked nucleosides. In certain embodiments, the first or second strand of the double-stranded compound can comprise a conjugate group.
Artisans know that “guide strand” and “passenger strand” are, respectively, synonyms for “antisense strand” and “sense strand”. Therefore these passages of WO276 clearly envision double-stranded RNAi compounds and read on instant Claim 1’s limitation a dsRNA molecule comprising a sense strand and an antisense strand, wherein the dsRNA is a small interfering dsRNA… They also teach limitation 2 of Claims 45 and 162A (i.e., a portion of the antisense strand is complementary to a portion of the sense strand).
Regarding the GalNAc of Claim 1: WO276 discloses (p. 34 L24-29) linking the modified nt to a GalNAc conjugate at either the 3’end or the 5’end. WO276 teaches (p. 62 L1-18) dsRNAs wherein either strand can comprise a conjugate group. Together, those ¶ teach the GalNAc may be conjugated to the 3’ end of the sense strand (a limitation of Claim 1).
Regarding complementarity to specific contiguous nt of specific sequences of Claim 3, the WO276 sequences discussed/shown below comprise complementarity to at least 13 contiguous nt of the claimed DGAT2 nucleic acid sequences of any one of SEQ ID NO 7.
Regarding the strand lengths of Claim 1, WO276 discloses (p. 59 L15) an antisense compound—which, p. 6 L16-20 includes dsRNA—that is 10-30 subunits long or compounds (p. 60 L2-7) of various lengths that include 15-25 nt long.
Regarding the sequences of Claims 1 and 168: WO276 discloses (p. 16 L5-26) the antisense compounds should target a DGAT2 nucleic acid sequence within SEQ ID NO 1, which comprises a region from base 1510 to 1528 that is 100% identical to claimed SEQ ID NO 7, as shown by the sequence alignment below:
RESULT 1
US-15-741-996-1
Query Match 100.0%; Score 19; DB 1; Length 2485;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TGTGGGTTATTTAAAAGAA 19 SEQ ID NO 7
|||||||||||||||||||
Db 1510 TGTGGGTTATTTAAAAGAA 1528 WO276 SEQ ID NO 1
WO276 teaches (p. 16 ¶4-6) using sequences that are at least 8-12 contiguous nt of SEQ ID NOs 16-4679. That encompasses claimed SEQ ID NO 7 as discussed in the next ¶.
Further regarding the sequences complementary to 10 contiguous nt of SEQ ID NO 7 of Claims 1 and 168, WO276 teaches SEQ ID NOs 136-137 that are each 100% complementary to claimed SEQ ID NO 7. Each of those WO276 sequences is a 20-mer and 100% complementary to claimed SEQ ID NO 7. Alignments of SEQ ID NOs 136-137 to claimed SEQ ID NO 7 are shown here:
RESULT 2
BDM82397/c
ID BDM82397 standard; DNA; 20 BP.
XX
AC BDM82397;
XX
DT 09-MAR-2017 (first entry)
XX
DE Human DGAT2 gene antisense oligo, SEQ:136.
XX
[truncated to save space]
Query Match 100.0%; Score 19; DB 56; Length 20;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TGTGGGTTATTTAAAAGAA 19 SEQ ID NO 7
|||||||||||||||||||
Db 19 TGTGGGTTATTTAAAAGAA 1 WO276 SEQ ID NO 136
RESULT 3
BDM82398/c
ID BDM82398 standard; DNA; 20 BP.
XX
AC BDM82398;
XX
DT 09-MAR-2017 (first entry)
XX
DE Human DGAT2 gene antisense oligo, SEQ:137.
XX
[truncated to save space]
Query Match 100.0%; Score 19; DB 56; Length 20;
Best Local Similarity 100.0%;
Matches 19; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TGTGGGTTATTTAAAAGAA 19 SEQ ID NO 7
|||||||||||||||||||
Db 20 TGTGGGTTATTTAAAAGAA 2 WO276 SEQ ID NO 137
Therefore those sequences read on limitations (i.e., nucleic acid sequences and AS strand lengths) of Claims 1, 3, 151-154.
Regarding the mismatches of Claim 151: WO276 SEQ ID NOs 136 and 137 comprise no more than 3 mismatches to SEQ ID NO 7. WO276 discloses (p. 8 L2-3) complementary oligonucleotides and/or nucleic acids … may include one or more nucleobase mismatches. More than one mismatch encompasses up to 3 mismatches. WO276 teaches (p . 67 ¶2-3) antisense compounds that are up to 20 nt long and comprise no more than 4, no more than 3, no more than 2, or no more than 1 noncomplementary nucleobases relative to a target, which means no more than 3 or no more than 4 mismatches.
Regarding the full complementarity to claimed SEQ ID NOs of Claim 152, the alignments shown above demonstrate that WO276 SEQ ID NOs 136/137 comprise full complementarity to claimed SEQ ID NO 7. Therefore WO276’s SEQ ID NOs 136-137 read on the limitation of Claim 152 requiring full complementarity to claimed SEQ ID NO 7.
Regarding the at least one modified or specifically PS-modified linkage of Claims 32 and 158: WO276 teaches (p. 31 L25-30) embodiments where the modified oligo comprises at least one modified linkage such as a PS linkage.
Regarding the PS linkages joining nts at positions 1-2 from the 3’end of the sense strand and 1-2 from the 5’end of the AS strand of Claim 66: WO276 teaches (p. 79 ¶1) …each internucleoside linking group… is a phosphorothioate linkage. WO276 teaches (p. 69 L30-35) each internucleoside linkage…is a phosphorothioate linkage. That encompasses a fully phosphorothioated dsRNA in which all positions (including 1 and 2 from the 3’ end of the sense strand or antisense strand and 1 and 2 from the 5’ end of the antisense strand or sense strand) are connected to adjacent ribonucleotides via phosphorothioate linkages; therefore WO276 teaches the limitations of Claim 66.
Regarding the pharmaceutical composition and carrier of Claim 69: WO276 teaches (p. 88 L 20-26) a pharmaceutical composition comprising a pharmaceutical carrier.
Regarding the overhang of Claims 155-157: WO276 discloses (p. 60 L14-26) “certain” embodiments wherein the dsRNA may be shortened or truncated. For example… A shortened or truncated AS targeted to an DGAT2 nucleic acid may have two subunits deleted from the 5’ end… When two or more additional subunits are present, the added subunits may be adjacent to each other. Such end truncation/addition can be interpreted as an up-to-2-subunit overhang. A “shortened” sequence can be interpreted as, among other possibilities, a double-stranded region whose length = nt length - 2 nt. Acceptable sequence lengths were provided in WO276 p. 59 L15 as described above. Such a double-stranded region could be as short as 13- or as long as 23 nt long. Therefore WO276 teaches the up-to-2-nt overhang of instant Claims 155-157.
Regarding Claim 159: WO276 discloses (p. 71 L20-34) 5’ substituent groups including 5’-vinyl.
Regarding the cleavable linker that links the GalNAc to the sense strand of Claim 163: WO276 discloses (p. 82 ¶2-3) cleavable moieties attached to either the 3’- or 5’-terminal nt by a phosphate internucleoside linkage and in certain embodiments, the cleavable moiety is a phosphate linkage between an oligonucleotide and a conjugate linker or conjugate group. As discussed above, WO276 teaches the GalNAc may be conjugated to the 3’ end of the sense strand. A figure on p. 86 shows the cleavable moiety is a phosphodiester linkage and that it is attached to a GalNAc:
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Regarding the ethylene glycol linker of Claim 164 (i.e., the dsRNA of claim 1, wherein the [GalNAc] functional moiety is linked to the sense strand by a linker… that is an ethylene glycol linker…): WO276 discloses (p. 34 L24-29) linking the modified nt to a GalNAc conjugate. That ¶ teaches the GalNAc may be conjugated to the 5’ end or the 3’ end. WO276 teaches (p. 81 full ¶1-3) conjugate linkers that attach the conjugate to the oligo. Those ¶ teach the linker can be an ethylene glycol chain, which is a limitation of Claim 164. Those ¶ teach conjugating the GalNAc to the 3’end of the sense strand, which is a limitation of Claims 1 and 168.
Regarding the sense strand comprising at least 50% 2’OMe mods of Claim 166: WO276 teaches that (pp. 61-62 L26-17) :
a ds compound comprises (i) a first strand comprising a nucleobase sequence complementary to the site on DGAT2 to which any of SEQ ID NOs: 16-4679 is targeted, and (ii) a second strand…the ds compound comprises one or more modified nts in which the 2' position in the sugar contains a…2’-F…or…2’-OMe)…[which can be] arranged in an alternating pattern for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 contiguous nucleobases…In certain embodiments, the ds compound comprises one or more [non-natural] linkages [such as] phosphorothioate.
A dsRNA wherein the strands comprise or either strand comprises an alternating pattern of 2’-F and 2’-OMe would have been a dsRNA wherein the dsRNA or sense strand comprises at least 50% 2’-OMe modifications.
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 single stranded gapmers of WO276 with the suggestion to make them into double-stranded dsRNA compounds of WO276 for the benefit of inducing more potent sequence specific silencing. One would have been motivated to do so with a reasonable expectation of success because Sledz, drawn to a review about RNAi in biology and disease, teaches dsRNAi is more potent than single-stranded RNAi: (§Introduction ¶1) RNA interference (RNAi) was first characterized in the nematode worm C[.] elegans by Fire and colleagues, who found that double-stranded RNA (dsRNA) induced a more potent sequence-specific silencing response than single-stranded antisense RNA alone... Modifying the ssRNAs of WO276 to be double stranded using the instructions provided in WO276 would have produced most of the limitations of Claims 1, 3, 32, 66, 69, 151-154, 155-157, 163-164, and 166—aside from the limitations of Claim 1 requiring at least 70% 2-OMe modifications on the antisense strand and the non-2’-OMe modifications at recited positions—and some limitations of Claims 155-159 and 168.
WO276 does not explicitly teach that nts at positions 2, 4, 6, 14, and 16 (Claims 1, 168) and 20 (Claims 45, 162) from the 5’end of the AS strand are not 2’-O-methyl. WO276 does not teach that nts at positions 7 and 9-11 from the 3’end of the sense strand are not 2’-OMe (Claims 1, 168) or are 2’-deoxy-2’-fluoro ribonucleotides (aka 2’F, Claim 167).
WO276 does not explicitly teach that the antisense strand comprises at least 70% 2’-OMe modifications (Claims 1, 168) or 70-90% 2’-OMe modifications (Claims 37, 162B[1]); or that the sense strand comprises at least 65% 2’-OMe modifications (Claim 38), at least 70% 2’O-Me modifications (Claims 45, 162C/D), or at least 75% 2’O-Me modifications (Claim 162B).
However, Foster teaches advanced siRNA designs for further improving performance of GalNAc-siRNA conjugates. Foster teaches (§Abstract) further improving siRNA efficacy by optimizing positioning of 2’-deoxy-2’-fluoro (2’F) and 2’-O-methyl (2’OMe) ribosugar modifications in a dsRNA. 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’OMes) 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’s AS strands were 23-mer and their sense strand was 21-mer. Those are well within the size ranges taught by WO276. Foster’s starting “parent” sequences comprise an AS strand with 15/23 2’OMe nts and a sense strand with 9/21 2’OMe nts. Foster teaches (Fig. 2A, 2B) dsRNAs comprising 2’F at positions 2, 6, 14, and 16 from the 5’end of the AS strand and 80% 2’OMe. Foster teaches a variety of sequences comprising 2’F at various positions on the sense strand; those include (see Fig. 1A) 1, 3, 5, 7, 9, 11-13, 15, 17, 19, and 21, as well as others (see Figs. 2 and 3).
Foster teaches (§Results ¶3) a preference for 2’F at antisense (AS) strand positions 2, 6, and 14 from the 5’end, and at sense strand position 11 from the 5’end. 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.
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.
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. WO276 taught DGAT2-targeting sequences. WO276 also taught (p. 60 L27-34) increasing or decreasing the length of an antisense compound and that seemingly small changes in nt sequence, chemistry, and motif can make large differences in one or more of the many properties required for clinical development. Starting with any of the sequences disclosed in WO276 and changing their size and modification pattern would have produced a finite (albeit large) number of identified, predictable potential solutions to the problem of optimizing DGAT2 silencing. Foster’s work shows that a person of ordinary skill could have pursued the known potential solutions with a reasonable expectation of success. Success would have been a reasonable expectation because WO276’s Table 2 shows that at least some of sequences comprising the claimed sequences induce some amount of DGAT2 silencing and Sledz teaches that dsRNAi is more potent than single-stranded RNAi, so formulating the sequences as dsRNAs would have been expected to increase silencing efficacy.
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 dsRNAs for targeting DGAT2 of WO276 and Sledz with the Foster’s teachings about minimizing 2’F content and maximizing 2’OMe content within a dsRNA for the benefit of optimizing stability and silencing performance of the DGAT2-targeting dsRNAs. One would have been motivated to do so with a reasonable expectation of success because Foster teaches 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 and because WO276 teaches (p. 60 L27-34) increasing or decreasing the length of an antisense compound and that seemingly small changes in nt sequence, chemistry, and motif can make large differences in one or more of the many properties required for clinical development. Further demonstrating that altering the proportion of 2’F and 2’OMe was common in the art, Chernikov, drawn to a review of chemical modifications to oligos, teaches (§CHEMICAL MODIFICATIONS OF siRNA: Ribose Modifications ¶1 and 4) that varying the proportion of 2’-F and 2’-OMe for optimal results is a balancing act of toxicity and stability.
An artisan would have only had to apply some of Foster’s motifs to a WO276 sequence to arrive at the claimed invention. An artisan would have used WO276 20-mer SEQ ID NO 136 as the AS strand and applied any of Foster’s patterns to it to start before iteratively further modifying. Applying the patterns of DV6—characterized in Fig. 2A as “more active”—would have produced an AS strand with a total of four 2’F (at positions 2, 6, 14, and 16), and 80% 2’OMe. A paired 19-mer sense strand, produced by removing the last two bases of DV6 sense strand pattern, would have produced a sense strand comprising 2’F at positions 1, 3, 5, 7, and 9-11 from the 3’end of the sense strand. That is simply one variation of what the teachings of Foster would have inspired an artisan to do with a reasonable expectation of success. As discussed, Foster teaches making further modifications for the purpose of optimization and dsRNAs comprising strands of a range of lengths were known in the art; Chernikov also demonstrates such modification was routine in the art and obvious to try. It would have been obvious to try further reducing the 2’F content to produce even more DGAT2-targeting dsRNAs and improve the efficacy by altering modification pattern. Iteratively further reducing the 2’F content would have produced sense strands comprising at least 65% (Claim 38) or at least 70% 2’OMe modifications (Claims 45, 162). Therefore the claimed invention of Claims 1, 3, 32, 37-38, 69, 151-154, 158, 163-164, and 166-167 would have been obvious in view of WO276, Sledz, Foster, and Chernikov.
Claim(s) 1, 3, 32, 37-38, 45, 52, 66, 69, 151-160, and 162-167 are rejected under 35 U.S.C. 103 as being unpatentable over WO276 (of record), Sledz (of record), Foster, and Chernikov (of record) as applied to Claims 1, 3, 32, 37-38, 69, 151-154, 158, 163-164, and 166-167 above, and further in view of International Patent Application Publication No. WO 2018/031933 (published 15 February 2018; “WO933”, of record) This rejection has been updated in response to the claim amendments .
The teachings of WO276, Sledz, Foster, and Chernikov as applicable to Claim(s) 1, 3, 32, 37-38, 69, 151-154, 158, 163-164, and 166-167 have been described above.
WO276, Sledz, Foster, and Chernikov teach a dsRNA molecule that induces silencing of DGAT2, wherein the dsRNA comprises sense and AS strands and has a GalNAc is conjugated to the 3’end of the sense strand and wherein the AS strand is complementary to at least 10 contiguous nt of a DGAT2 nucleic acid sequence comprising SEQ ID NO2 or is complementary to any one of SEQ ID NOs 6-8, wherein the AS strand comprises at least 70% 2’OMe modified nts and wherein nts at positions 2, 6, 14, and 16 from the 5’end of the AS strand are 2’F, and wherein nts at positions 7 and 9-11 from the 3’end of the sense strand are 2’F.
WO276, Sledz, Foster, and Chernikov do not explicitly teach that the nts at positions 1-2 to 1-7 from the 3’end of the AS strand are connected via PS linkages (Claims 45, 66, and 162) or that nts at positions 1-2 from the 5’end of the sense strand are connected via PS linkages (Claims 45, 66, and 162). WO276, Sledz, Foster, and Chernikov do not teach the divalent or trivalent linkers of Claim 52 or the set of phosphodiesters/phosphodiester derivatives of Claim 165. WO276, Sledz, Foster, and Chernikov do not explicitly teach the dsRNA comprises at least one single-stranded overhang (Claim 155), or a 2- to 5-nt overhang (Claims 156-157).
WO276, Sledz, Foster, and Chernikov do not explicitly teach that the 5’vinyl phosphonate is on the AS strand (Claim 159), or that the mismatches are between the sense and AS strands (Claim 160).
However, WO933 teaches many of the claim limitations that WO276, Sledz, and Foster do not teach. WO933 is broadly drawn to conjugated oligonucleotides that are characterized by efficient and specific tissue distribution.
Regarding the PS linkages at specific positions of Claims 45 and 66 and 162: WO933 teaches (¶13) the nt of the AS strand (“first oligo”), specifically at positions 1-7 from the 3’end, are connected to adjacent nt via PS linkages; (¶13) the nt of the sense strand (“second oligo”), specifically at positions 1-2 or 1-7 from the 3’end, are connected to adjacent nt via PS linkages; and (¶12) the nt of the sense strand (“second oligo”), specifically at positions 1 and 2 from the 5’end, are connected to adjacent nt via PS linkages.
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 dsRNAs of WO276, Sledz, Foster, and Chernikov with the PS linkages at specific positions of WO933 for the benefit of increasing nuclease resistance. One would have been motivated to do so with a reasonable expectation of success because WO276 teaches producing an antisense compound comprising entirely PS linkages and because Foster teaches (§Introduction ¶2) PS linkages at termini protect against 3’ and 5’exonucleases and because WO933 teaches incorporating PS linkages at those specific positions. Therefore modifying the dsRNAs of WO276, Sledz, Foster, and Chernikov with the PS linkages at specific positions of WO933 would have produced the limitations of Claims 45 and 66 and some limitations of Claims 162 (i.e., 1 and 3 of 162A, 2 and 5 of 162B, and 1 and 4 of 162C/D).
Regarding the divalent/trivalent linkers of Claim 52: WO933 teaches (¶3) their oligo conjugates are designed to achieve unexpectedly high efficacy, uptake and tissue distribution. WO933 teaches (¶5) using a divalent or trivalent linker and a phosphodiester or phosphodiester derivative. WO933 teaches (¶61) the divalent or trivalent linker can be:
L is a divalent or trivalent linker selected from:
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Those are the same structures as what’s in instant Claim 52.
Regarding the PO/PS derivatives of Claim 165: WO933 teaches (¶9) a phosphodiester or phosphodiester derivative can be linked to a trivalent linker by any of the following structures:
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504
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Those are the same structures as what’s in instant Claim 165 and the last structure (Zc4) is simply a phosphodiester or phosphorothioate linkage.
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 dsRNAs of WO276, Sledz, Foster, and Chernikov with the divalent or trivalent linkers and/or the teachings of WO933 (i.e., the specific phosphodiester or phosphodiester derivative) to link the GalNAc functional moiety to the dsRNA for the benefit of achiev[ing] unexpectedly high efficacy, uptake and tissue distribution. One would have been motivated to do so with a reasonable expectation of success because WO933 teaches (¶3) their oligo conjugates are designed to achieve unexpectedly high efficacy, uptake and tissue distribution and because WO933 teaches (¶189-190) their conjugates are good for delivery of oligos to the liver and (¶26) for treating fatty liver. Modifying the dsRNAs of WO276, Sledz, Foster, and Chernikov with the divalent or trivalent linkers and/or the teachings of WO933 would have produced the limitations of Claims 52 and 165.
Regarding Claims 155-157: WO933 teaches (¶18) an embodiment wherein the first oligo has 3-7 more nt than the second oligo. That can be considered an overhang. WO933also teaches (¶312, 320, 347) overhangs of up to 4 nt e.g., 2 nucleotides.
Therefore it would have been obvious to an artisan of ordinary skill to modify the dsRNA of WO276, Sledz, Foster, and Chernikov with the 3-7 nt overhang—including a 5-nt overhang—of WO933 for the benefit of increasing asymmetry of the dsRNA molecule. One would have been motivated to do so with a reasonable expectation of success because doing so would have also produced an asymmetric molecule and WO933 teaches (¶336) increasing asymmetry can improve the efficiency of RNA silencing. Such techniques are known to artisans and such optimization is routine in the art. Modifying the dsRNA of WO276, Sledz, Foster, and Chernikov with the 3-7 nt overhang of WO933 would have produced a limited number of alternatives and the 5-nt overhang would have been among them, thereby producing the limitations of Claims 155-157 and an alternative limitation of Claim 158.
Regarding Claim 159: WO933 teaches (¶146) placing a vinyl phosphonate at the 5’end of the AS strand because 5’-E-VP enables sustained delivery to distant tissues (7 days post injection, PNA assay).
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 dsRNAs of WO276, Sledz, Foster, and Chernikov with the 5’ vinyl phosphonate on the AS strand of WO933 for the benefit of sustaining delivery to distant tissues. One would have been motivated to do so with a reasonable expectation of success because WO933 teaches (¶146) placing a vinyl phosphonate enables sustained delivery to distant tissues. The 20-mer described in the previous rejection would then comprise 15/20 2’OMe modifications which still comprises 75% 2’OMe-modified nts. Modifying the dsRNAs of WO276, Sledz, Foster, and Chernikov with the 5’ vinyl phosphonate on the AS strand of WO933 would have produced the limitations of Claim 159.
Regarding the non 2’OMe nt at position 20 from the 5’end of the AS strand of Claim 162, in view of the teachings of Foster, it would have been obvious to try further reducing the 2’F content to produce even more DGAT2-targeting dsRNAs and improve the efficacy by improving modification pattern. Foster shows AS strands comprising 2’F at position 20 from the 5’end of the AS strand. Modifying the dsRNAs based on the teachings of Foster would have produced a 20-mer with 14/20 2’OMe modifications (if it also included a 5’-vinyl phosphonate) or 15/20 2’OMe (not including the 5’-vinyl phosphonate) which comprises 70% or 75% 2’OMe modified nts. Therefore further modifications of the dsRNA of WO276, Sledz, Foster, and Chernikov with the teachings of Foster and WO933 would have produced the limitations of Claim 162.
Regarding Claim 160: WO933 teaches (¶336-337) at least one mismatch between the sense and antisense strands. WO933 teaches (¶336) asymmetry between strands facilitate entry of the AS strand into RISC so the AS strand preferentially guides cleavage of the target. WO933 teaches (same ¶s) mismatches between strands are a way to enhance asymmetry.
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 dsRNAs of WO276, Sledz, Foster, and Chernikov with the teaching about mismatches between the sense and AS strands of WO933 for the benefit of increasing the asymmetry of the molecule and lessening the base pair strength between the two strands. One would have been motivated to do so with a reasonable expectation of success because WO933 teaches (¶336) such [asymmetrical] alterations facilitate entry of the AS strand of the siRNA into RISC in favor of the sense strand, such that the AS strand preferentially guides cleavage or translational repression of a target mRNA, and thus increasing or improving the efficiency of target cleavage and silencing. Modifying the dsRNAs of WO276, Sledz, Foster, and Chernikov with the teaching about asymmetrical strands of WO933 would have produced the limitations of Claim 160.
Claim(s) 1, 3, 32, 37-38, 45, 52, 66, 69, and 151-167 are rejected under 35 U.S.C. 103 as being unpatentable over WO276 (of record), Sledz (of record), Foster, and WO933 (of record) as applied to Claims 1, 3, 32, 37, 45, 52, 66, 69, 151-160, and 162-167 above, and further in view of US Patent Application Publication No. US 2019/0270995 (published 05 September 2019; “US995”). This rejection has been updated in response to the claim amendments.
WO276, Sledz, Foster, Chernikov, and WO933 teach a dsRNA molecule that induces silencing of DGAT2, wherein the dsRNA comprises sense and AS strands and has a GalNAc is conjugated to the 3’end of the sense strand and wherein the AS strand is complementary to at least 10 contiguous nt of a DGAT2 nucleic acid sequence comprising SEQ ID NO2 or is complementary to any one of SEQ ID NOs 6-8, wherein the AS strand comprises at least 70% 2’OMe modified nts and wherein nts at positions 2, 6, 14, and 16 from the 5’end of the AS strand are 2’F, and wherein nts at positions 7 and 9-11 from the 3’end of the sense strand are 2’F, wherein the AS strand comprises one or more nt mismatches between the AS and sense strands.
WO276, Sledz, Foster, Chernikov, and WO933 do not teach a mismatch between the two strands at any one of positions 2, 6, or 12 from the 5’end of the sense strand (Claim 161).
However, US995, drawn to general methods and compositions for improving siRNA functionality, teaches (¶358) incorporating to a dsRNA a mismatch at position 2 of the sense strand to destabilize its 5’end and increase molecule functionality.
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 dsRNAs comprising a mismatch between the two strands of WO276, Sledz, Foster, Chernikov, and WO933 with the teaching about a mismatch at specifically position 2 from the 5’end of the sense strand of US995 for the benefit of improving the asymmetry of the molecule and increasing its functionality. One would have been motivated to do so with a reasonable expectation of success because WO933 teaches mismatches between the 3’end of the AS strand and the 5’end of the sense strand:
(¶93) such alterations facilitate entry of the antisense strand of the siRNA… into RISC in favor of the sense strand, such that the antisense strand preferentially guides cleavage or translational repression of a target mRNA, and thus increasing or improving the efficiency of target cleavage and silencing. Preferably the asymmetry of an RNA silencing agent is enhanced by lessening the … base pair strength between the antisense strand 3' end (AS 3') and the sense strand 5' end (S '5) of said RNA silencing agent,
and because US995 teaches a mismatch at specifically position 2 of the sense strand destabilizes its 5’end and increases dsRNA functionality. Therefore, modifying the dsRNA of WO276, Sledz, Foster, Chernikov, and WO933 with mismatch at specifically position 2 from the 5’end of the sense strand of US995 would have produce the limitations of Claim 161.
Claim(s) 1, 3, 32, 37-38, 45, 52, 66, 69, and 151-168 are rejected under 35 U.S.C. 103 as being unpatentable over WO276 (of record), Sledz (of record), Foster, WO933 (of record), and US995 (of record) and as applied to Claims 1, 3, 32, 37-38, 45, 52, 66, 69, and 151-167 above, and further in view of International Publication Number WO 2021/119019 (“WO019”, published 17 June 2021 but effectively filed as US Provisional Application No. 62/945,732 on 09 December 2019, [“Pro732”]). The rejection of Claim 168 is modified in view of the claim amendments.
Although WO019 was published 17 June 2021, the content relied upon for this rejection was effectively filed in Pro732 on 09 December 2019, which is approx. 11 months before the earliest provisional document of the instant application.
The WO019 content discussed in this rejection are entitled to the priority date of 09 December 2019 and are considered prior art under 35 U.S.C. 102(a)(2).
If the issue date of the U.S. patent or publication date of the U.S. patent application publication or WIPO published application is not before the effective filing date of the claimed invention, it may be applicable as prior art under AIA 35 U.S.C. 102(a)(2) if it was "effectively filed" before the effective filing date of the claimed invention in question with respect to the subject matter relied upon to reject the claim. MPEP § 2152.01 discusses the "effective filing date" of a claimed invention. AIA 35 U.S.C. 102(d) sets forth the criteria to determine when subject matter described in a U.S. patent document was "effectively filed" for purposes of AIA 35 U.S.C. 102(a)(2).
2154.01(a) WIPO Published Applications [R-11.2013]
[Editor Note: This MPEP section is only applicable to applications subject to examination under the first inventor to file (FITF) provisions of the AIA as set forth in 35 U.S.C. 100 (note). See MPEP § 2159 et seq. to determine whether an application is subject to examination under the FITF provisions, and MPEP § 2131-MPEP § 2138 for examination of applications subject to pre-AIA 35 U.S.C. 102.]
The WIPO publication of a PCT international application that designates the United States is an application for patent deemed published under 35 U.S.C. 122(b) for purposes of AIA 35 U.S.C. 102(a)(2) under 35 U.S.C. 374. Thus, under the AIA , WIPO publications of PCT applications that designate the United States are treated as U.S. patent application publications for prior art purposes, regardless of the international filing date, whether they are published in English, or whether the PCT international application enters the national stage in the United States. Accordingly, a U.S. patent, a U.S. patent application publication, or a WIPO published application that names another inventor and was effectively filed before the effective filing date of the claimed invention, is prior art under AIA 35 U.S.C. 102(a)(2). This differs from the treatment of a WIPO published application under pre-AIA 35 U.S.C. 102(e), where a WIPO published application is treated as a U.S. patent application publication only if the PCT application was filed on or after November 29, 2000, designated the United States, and is published under PCT Article 21(2) in the English language. See MPEP § 2136.03, subsection II.
§MPEP 2154.01
See also §MPEP 2152.01.
WO276, Sledz, Foster, Chernikov, WO933, and US995 teach a dsRNA molecule that induces silencing of DGAT2, wherein the dsRNA comprises sense and AS strands and has a GalNAc is conjugated to the 3’end of the sense strand and wherein the AS strand is complementary to at least 10 contiguous nt of a DGAT2 nucleic acid sequence comprising SEQ ID NO2 or is complementary to any one of SEQ ID NOs 6-8, wherein the AS strand comprises at least 70% 2’OMe modified nts and wherein nts at positions 2, 6, 14, and 16 from the 5’end of the AS strand are 2’F, and wherein nts at positions 7 and 9-11 from the 3’end of the sense strand are 2’F, wherein the AS strand comprises one or more nt mismatches between the AS and sense strands, and wherein the mismatches can be at specific positions.
WO276, Sledz, Foster, Chernikov, WO933, and US995 do not teach the specific GalNAc moiety recited in instant Claim 168.
However, WO019, drawn to oligonucleotides for RNAi of a different gene that is not DGAT2, teaches using that specific GalNAc moiety.
Regarding Claim 168, WO019 teaches (Table 11, starts after ¶248/Pro732 Table 4, starts after ¶170) the specific GalNAc moiety shown in instant Claim 168. An excerpt of Pro732 Table 4 (which is the same content as Table 11 in WO019) is shown here:
PNG
media_image4.png
297
684
media_image4.png
Greyscale
That indicates that the specific species of GalNAc shown above was a potential design choice available to an artisan.
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 dsRNAs of WO276, Sledz, Foster, Chernikov, WO933, and US995 with the GalNAc of WO019/Pro732 for the benefit of using the dsRNA with a species of GalNAc that was known and commonly used in the art. One would have been motivated to do so with a reasonable expectation of success because WO276, WO933, Foster, US995, and WO019/Pro732 all teaches using a GalNAc moiety with dsRNAs, and the specific GalNAc shown in WO019/Pro732 was simply a design choice an artisan would have made.
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 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 choosing any specific GalNAc moiety is not inventive since conjugating GalNAc moieties to an siRNA for optimal or better results is known in the prior art. Therefore the limitations of Claim 168 would have been obvious in view of WO276, Sledz, Foster, Chernikov, WO933, and US995, and WO019/Pro732.
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.
NSDP REJECTIONS UPDATED IN RESPONSE TO AMENDMENT
Claims 1, 6, 20, 32, 37-38, 45, 52, 66, 69, and 151-168 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-20 of U.S. Patent No. 7,709,629 (issued 04 May 2010; “US629”, of record) in view of International Patent Application Publication No. WO 2017/011276 (published 19 January 2017; “WO276”, of record); Foster (et al. 2018. Advanced siRNA Designs Further Improve In Vivo Performance of GalNAc-siRNA Conjugates. Molec. Ther. 26[3]:708, “Foster”); Chernikov (et al. 2019. Current Development of siRNA Bioconjugates: From Research to the Clinic. Frontiers Pharmacol. 10:444; “Chernikov”, of record); International Patent Application Publication No. WO 2018/031933 (published 15 February 2018; “WO933”, of record); US Patent Application Publication No. US 2019/0270995 (published 05 September 2019; “US995”, of record), and International Publication Number WO 2021/119019 (“WO019”, published 17 June 2021 but effectively filed as US Provisional Application No. 62/945,732 on 09 December 2019, [“Pro732”]). This rejection is updated in view of the claim amendments.
Although the claims at issue are not identical, they are directed to overlapping subject matter. The instant claims are directed to DGAT2-targeting dsRNA molecules that induce silencing of DGAT2, wherein the dsRNA comprises sense and AS strands and has a GalNAc is conjugated to the 3’end of the sense strand and wherein the AS strand is complementary to at least 10 contiguous nt of a DGAT2 nucleic acid sequence comprising SEQ ID NO2 or any one of SEQ ID NOs 6-8, wherein the AS strand comprises at least 70% 2’OMe modified nts and wherein nts at positions 2, 6, 14, and 16 from the 5’end of the AS strand are 2’F, and wherein nts at positions 7 and 9-11 from the 3’end of the sense strand are 2’F; and wherein the dsRNA comprise further modifications.
The US629 claims are directed to a pool of siRNAs 19-30 nt long or with or without overhang regions. The first siRNA has an antisense region that is the complement of SEQ ID NO 550 and the second siRNA has an antisense region that is the complement of any sequence from the group consisting of SEQ ID NO 438-549 and 551-568. An artisan would not know what these SEQ ID NOs are but would consult the Spec. and sequence listing and find that SEQ ID NO 529 is a 19-mer that comprises at least 10 contiguous nt of instant SEQ ID NO 2 and SEQ ID NO 7:
ALIGNMENT:
Query Match 15.8%; Score 19; Length 19;
Score over Length 100.0%;
Best Local Similarity 52.6%;
Matches 10; Conservative 9; Mismatches 0; Indels 0; Gaps 0;
Qy 54 GGGTGTCTGTGGGTTATTT 72
|||:|:|:|:|||::|:::
Db 1 GGGUGUCUGUGGGUUAUUU 19
NASEQ2_08212025_134615
Query Match 63.2%; Score 12; DB 1; Length 19;
Best Local Similarity 41.7%;
Matches 5; Conservative 7; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TGTGGGTTATTT 12 SEQ ID NO 7
:|:|||::|:::
Db 8 UGUGGGUUAUUU 19.
The two claim sets are directed to overlapping subject matter because they are both directed to DGAT2-targeting dsRNAs and require the same sequences. The US629 claims do not teach modifications at certain positions or a GalNAc moiety.
WO276 teaches (p. 34 L24-29, p. 62 L1-18) a GalNAc conjugate at the 3’end including of the sense strand and (p. 81 full ¶1-3) various modifications, (p. 59 L15, p. 60 L2-7) lengths, (p. 34 L 14-15) complementarities. Foster (§Abstract, §Introduction ¶2, §Introduction ¶3, §Introduction, final ¶, §Results ¶1-2, Figs. 1,2A, 2B; §Results ¶3), Chernikov (§CHEMICAL MODIFICATIONS OF siRNA: Ribose Modifications ¶1 and 4), WO933 (¶3, ¶5, ¶9, ¶12-13, ¶26, ¶61, ¶146, ¶189-190, ¶312, ¶320, ¶336-337, ¶347), and US995 (¶358) teach modifying oligos with various percentages of modifications and at various positions and other modifications to optimize the dsRNAs. WO019 teaches (Table 11, starts right after ¶248/Pro732 Table 4, starts after ¶170) the specific GalNAc moiety shown in instant Claim 168 which indicates that the specific species of GalNAc shown above was a potential design choice available to an artisan.
Therefore it would have been obvious to an artisan to modify the dsRNAs of US629 claims with the teachings of WO276, Foster, Chernikov, WO933, US995, and WO019 for the benefit of optimizing the dsRNAs. Doing so would have produced the instant claims.
Claims 1, 20, 32, 37-38, 45, 52, 66, 69, and 151-168 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-20 of U.S. Patent No. 8,247,169 (issued 21 August 2012, “US169”, of record) in view of WO276, Foster, Chernikov, WO933, US995, and WO019/Pro732. This rejection is updated.
Although the claims at issue are not identical, they are directed to overlapping subject matter. The instant claims are directed to DGAT2-targeting dsRNA molecules that induce silencing of DGAT2, wherein the dsRNA comprises sense and AS strands and has a GalNAc is conjugated to the 3’end of the sense strand and wherein the AS strand is complementary to at least 10 contiguous nt of a DGAT2 nucleic acid sequence comprising SEQ ID NO2 or any one of SEQ ID NOs 6-8, wherein the AS strand comprises at least 70% 2’OMe modified nts and wherein nts at positions 2, 6, 14, and 16 from the 5’end of the AS strand are 2’F, and wherein nts at positions 7 and 9-11 from the 3’end of the sense strand are 2’F; and wherein the dsRNA comprise further modifications.
The US169 claims are directed to a pool of siRNAs 19-30 nt long or with or without overhang regions. The first siRNA has an antisense region that is the complement of SEQ ID NO 450 and the second siRNA has an antisense region that is the complement of any sequence from the group consisting of SEQ ID NO 438-449, 451-549, and 551-568. An artisan would not know what these SEQ ID NOs are but would consult the Spec. and sequence listing and find that SEQ ID NO 529 is a 19-mer that comprises at least 10 contiguous nt of instant SEQ ID NO 2 and SEQ ID NO 7:
ALIGNMENT:
Query Match 15.8%; Score 19; Length 19;
Score over Length 100.0%;
Best Local Similarity 52.6%;
Matches 10; Conservative 9; Mismatches 0; Indels 0; Gaps 0;
Qy 54 GGGTGTCTGTGGGTTATTT 72
|||:|:|:|:|||::|:::
Db 1 GGGUGUCUGUGGGUUAUUU 19
NASEQ2_08212025_134615
Query Match 63.2%; Score 12; DB 1; Length 19;
Best Local Similarity 41.7%;
Matches 5; Conservative 7; Mismatches 0; Indels 0; Gaps 0;
Qy 1 TGTGGGTTATTT 12 SEQ ID NO 7
:|:|||::|:::
Db 8 UGUGGGUUAUUU 19.
The two claim sets are directed to overlapping subject matter because they are both directed to DGAT2-targeting dsRNAs and require the same sequences.
The US169 claims do not teach the claimed specific modifications, including specifically modified positions, or a GalNAc moiety.
WO276 teaches (p. 34 L24-29, p. 62 L1-18) a GalNAc conjugate at the 3’end including of the sense strand and (p. 81 full ¶1-3) various modifications, (p. 59 L15, p. 60 L2-7) lengths, (p. 34 L 14-15) complementarities. Foster (§Abstract, §Introduction ¶2, §Introduction ¶3, §Introduction, final ¶, §Results ¶1-2, Figs. 1,2A, 2B; §Results ¶3), Chernikov (§CHEMICAL MODIFICATIONS OF siRNA: Ribose Modifications ¶1 and 4), WO933 (¶3, ¶5, ¶9, ¶12-13, ¶26, ¶61, ¶146, ¶189-190, ¶312, ¶320, ¶336-337, ¶347), and US995 (¶358) teach modifying oligos with various percentages of modifications and at various positions and other modifications to optimize the dsRNAs. WO019 teaches (Table 11, starts right after ¶248/Pro732 Table 4, starts after ¶170) the specific GalNAc moiety shown in instant Claim 168 which indicates that the specific species of GalNAc shown above was a potential design choice available to an artisan.
Therefore it would have been obvious to an artisan to modify the dsRNAs of US169 claims with the teachings of WO276, Foster, Chernikov, WO933, US995, and WO019 for the benefit of optimizing the dsRNAs. Doing so would have produced the instant claims.
Claims 1, 20, 32, 37-38, 45, 52, 66, 69, and 151-168 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 11, 15, 19-20, 40, 42, 46, 59, 66, 69-71, 83, 91, and 94-96 of copending Application No. 18666191 (reference application; “App191”) in view of Foster, WO933, US995, and WO019/Pro732. This rejection has been updated.
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets are directed to overlapping subject matter:
The instant claims recite DGAT2-targeting dsRNA molecules that induce silencing of DGAT2, wherein the dsRNA comprises sense and AS strands and has a GalNAc is conjugated to the 3’end of the sense strand and wherein the AS strand is complementary to at least 10 contiguous nt of a DGAT2 nucleic acid sequence comprising SEQ ID NO2 or any one of SEQ ID NOs 6-8, wherein the AS strand comprises at least 70% 2’OMe modified nts and wherein nts at positions 2, 6, 14, and 16 from the 5’end of the AS strand are 2’F, and wherein nts at positions 7 and 9-11 from the 3’end of the sense strand are 2’F; and wherein the dsRNA comprise further modifications.
The App191 claims are directed to a combination of oligos comprising a DGAT2-targeting oligo and a second oligo that targets a second gene that can be FASN. The App191 oligos comprise a sequence substantially complementary to SEQ ID NOs 2 and 6-8 and those are all identical to instant SEQ ID NOS 2 and 6-8 (compare App191 Spec. pp. 116-117 with the instant SEQ Listing). Further, the App191 claims recite the same modifications at the same positions as the instant claims (see Claim 59E).
The App191 claims don’t recite any required 2’F at any position, mismatches, or the specific GalNAc moiety recited in instant Claim 168.
However, Foster (§Abstract, §Introduction ¶2, §Introduction ¶3, §Introduction, final ¶, §Results ¶1-2, Figs. 1,2A, 2B; §Results ¶3), WO933 (¶3, ¶5, ¶9, ¶12-13, ¶26, ¶61, ¶146, ¶189-190, ¶312, ¶320, ¶336-337, ¶347), and US995 (¶358) teach modifying oligos with various percentages of modifications and at various positions and other modifications to optimize the dsRNAs. WO019 teaches (Table 11, starts right after ¶248/Pro732 Table 4, starts after ¶170) the specific GalNAc moiety shown in instant Claim 168 which indicates that the specific species of GalNAc shown above was a potential design choice available to an artisan.
Therefore it would have been obvious to an artisan to modify the dsRNAs of App191 claims with the teachings of Foster, WO933, US995, and WO019 for the benefit of optimizing the dsRNAs. Doing so would have produced the instant claims. It would not be possible to use the invention of App191 without the instant claims. Alternatively, an artisan would have been motivated to use the DGAT2-targeting dsRNAs alone because single dsRNAs would have been cheaper to produce than double dsRNAs.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Arguments applicable to newly applied rejections are addressed below. Arguments that are no longer relevant are not addressed.
Applicant's arguments filed 26 November 2025 have been fully considered but they are not persuasive.
103
Applicant argues that (pp. 12-15) there is no case of obviousness because an artisan wouldn’t have had any reason to select WO276’s SEQ ID NOs 136-137 as a basis for modification. That is not found persuasive because an artisan would have chosen any of the sequences in WO276 shown to inhibit DGAT2 expression and Table 2 shows that both WO276’s SEQ ID NOs 136-137 were shown be inhibit some amount of DGAT2 expression. As discussed in the interview held in December 2025, the instant claims are compound claims and the claimed compounds are disclosed in the prior art, so patentability hinges on unexpected results.
Applicant also argues (starting full ¶2 on p. 14) unexpected results obtained using a dsRNA comprising SEQ ID NO 7. While the unexpected results showing the compound comprising SEQ ID NO 7 are compelling, ultimately the arguments aren’t persuasive because the claims recite a broader range of sequences than just SEQ ID NO 7—the claims recite an AS strand that comprises a sequence complementary to at least 10 contiguous nt of SEQ ID NO 7. If Applicant were to amend the claims to recite the exact sense and AS strands comprising GalNAc-1473 (i.e., the compound comprising SEQ ID NO 7 which provides unexpected results), patentability would be determined based on those claims. However, as stated, the claims are broader than just that GalNAc-1473 compound, so the claims are deemed obvious for what they currently recite.
As stated in the previous Office Action: Applicant’s arguments about unexpectedly good results, namely the long persistence of the 1473 compound (which targets SEQ ID NO 7) that knocks down DGAT2 expression for 12 weeks after a single subcutaneous injection and significantly improved liver-related phenotypes, are more compelling. However, those results show effects from a single compound comprising specific sense and AS strands. Meanwhile, the claims broadly encompass a large number of compounds that comprise complementarity to only 10 contiguous nt of the target. The rejection explains that those dsRNAs would have been obvious in view of the cited prior art. Applicant hasn’t shown that a representative number of those provide the same unexpectedly good results.
Applicant’s arguments about these unexpected results would be much more persuasive if the claims recited only the compound that causes the unexpectedly positive results, or if they show similar outcomes occur from a representative number of compounds encompassed by the claims. Currently the claims read broadly on many dsRNAs that would have been obvious in view of the prior art of record, and a representative number of those have not been shown to induce the unexpectedly good outcomes. Therefore the 103 rejection is maintained.
NSDP
Applicant’s arguments against the NSDP rejections are similar to those against the 103: the arguments allege there would have been no reason to use the claimed compound as a starting point for optimization. In the arguments labeled §I and II in Remarks, Applicant argues that an artisan wouldn’t have had any reason to select the patented SEQ ID NO 529 as a basis for modification. That is not found persuasive because an artisan would have chosen any of the sequences in the patented claims. Any of those sequences would have been considered of interest since they are claimed. Furthermore, the art of WO276 shows that both WO276’s SEQ ID NOs 136-137 were shown be inhibit some amount of DGAT2 expression. As discussed in the interview held in December 2025, the instant claims are compound claims and the claimed compounds are disclosed in the prior art, so patentability hinges on unexpected results. Applicant’s arguments about in vivo efficacy aren’t persuasive because, based on the cited art, an artisan would have applied known modifications to improve in vivo efficacy. As discussed regarding the unexpectedly good results, those results show effects from a single compound comprising specific sense and AS strands. Meanwhile, the claims broadly encompass numerous compounds that would have been obvious in view of the cited prior art—the claims recite an AS strand that comprises a sequence complementary to at least 10 contiguous nt of SEQ ID NO 7. Applicant hasn’t shown that a representative number of compounds encompassed by the claims provide the same unexpectedly good results.
In §III, Applicant hasn’t made any arguments but asks that the rejections be held in abeyance, so the rejections are maintained for the time being.
In §IV, Applicant argues against the rejection over App355 but that rejection has been withdrawn upon reconsideration and in view of the amended claims and arguments.
The NSDP rejections over US629, US169, and App191 are maintained for those reasons.
Conclusion
Claims 1, 3, 32, 37-38, 45, 52, 66, 69, 151-168 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to 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