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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/17/2025 has been entered.
Further, since the claims are not amended with the rejection of the examined claims maintained, and the Remarks make similar arguments as the previous action(s), the action is made final.
Election/Restriction
Claims 1-29, 32-36, and 38-44 are pending. Claims 32-36 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-29, 38-44 and the species of 2’-methoxy RNA, beta-D-oxy LNA, phosphodiester linkage, antisense oligonucleotide (ASO) are considered here.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55. Priority to EP 18186679.9, filed on 07/31/2018, is acknowledged. All examined claims enjoy the priority of ‘679.9 filing.
Claim Rejections - 35 USC § 103
Rejection of the examined claims is maintained, see below.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-25, 27-29, 38-41, 43 are rejected under 35 U.S.C. 103 as being unpatentable over Hossbach et al. (US20170319614, pub. 11/9/2017, referred as Hossbach, of record) and Olesiak et al. (2009, Organic and Biomolecular Chemistry, 7, 2162-2169, referred as Olesiak), and as evidenced by Grunweller and Hartmann (2007, Biodrugs, 21, 235-243, referred as Grunweller) for claims 6, 8, 9, 12, 18, 19, 20, 21, 23, 24, 25 and 39; and as evidenced by Frey (1985, Science, 228, 541-545) for cl. 16.
Regarding instant claims 1-5 and 12, 17, Hossbach discloses antisense oligonucleotides (ASOs) targeting TGF-R (transforming growth factor-receptor). Although Hossbach discloses (—S—P(S)(S−)—) for internucleotide linkage (par. 397) between either a DNA or RNA nucleotide block (par. 387-390), represented by -X”-P(=X’)(X) at 3’ end of a formula B1 nucleotide (par. 387-389) and with S- conjugated to hydrogen (par. 391-394, see below), Hossbach focuses on oligonucleotides, specifically gapmers, with phosphorothioate internucleotide linkages (PS-INL) or phosphorodithioate internucleotide linkages (PS2-INL) and provides exemplary embodiments with PS2-INLs in Tables 4-9 (see par. 581, —O—P(S)(S−)—O—). Hossbach discloses that phosphorothioate/phosphorodithioate INLs is preferred for improved nuclease resistance and for ease in manufacture while maintaining RNase H degradation compatibility (par. 563). Thus the exemplary embodiments of the PS2-INL are the non-bridging sulfur types or PS2-INL. A few that are tested (237i, 209an, 263i, 276j, 289p) shows inhibition of expression of target protein (see Table 27, relevant to instant cl. 1-5, 12, 17).
Hossbach does not disclose specific examples of, i.e. enabled, phosphorotrithioate INLs (PS3-INLs) with the bridging sulfur at the 5’ end.
Olesiak discloses making a phosphorodithioates with one non-bridging sulfur group and one bridging sulfur at the 5’ of the phosphate internucleotide linkage (in the art, the bridging sulfur are termed phosphorothiolates, thus a 3’-S-phosphorothiolate or 5’-S-phosphorothiolate, see pg. 2164, see excerpt from scheme 1 below of a 5’-S-phosphorothiolate). Olesiak tested the stability of 5’-S-phosphorodithioate INL by incubating modified dinucleotides in snake venom phosphodiesterase (svPDE) and nuclease P1 (nP1) (both are 5’-exonucleases, pg. 2164) and demonstrated that treatment with 1 to 10 ug/ml of the 5’-exonucleases did not lead to hydrolytic degradation of substrates for 16 h at 37oC, while there was complete degradation of unmodified dinucleotides (pg. 2164, relevant to instant cl. 1-5, 12). Olesiak also note that the “observed resistance of 5’-S-phosphorodithioate internucleotide linkage to degradation by nucleolytic enzymes is similar to that described for oligonucleotide phosphorodithioates with both non-bridging oxygen atoms replaced by sulfur” (pg. 2164). Similar testing with spleen phosphodiesterase, a typical 3’-exonuclease, led the authors to conclude that the Sp diastereomer (SLOW isomer) being digested easier than the Rp diastereomer (FAST isomer) of the dinucleotide with modified phosphorodithioates (see pg. 2164, 2165). A single non-bridging sulfur group creates a diastereomer (a chiral group) with either a Rp or Sp isomers, and the authors hypothesized that one chiral group (the Sp) was more sensitive to 3’ exonuclease than the other (pg. 2164).
From Scheme 1 on pg. 2163 of Olesiak.
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One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified the PS2-INL of Hossbach in view of Olesiak and arrive at the claimed invention with a reasonable expectation of success. Based on the success of using PS2-INLs containing oligonucleotides to degrade the target transcript and disclosure of (—S—P(S)(S−)—) by Hossbach, and success of Olesiak to protect oligonucleotides from both 5’- and 3’-exonucleases by incorporating both a bridging and non-bridging sulfur in a phosphorodithioate-INL, a skilled artisan would expect reasonable success by incorporating a bridging sulfur-INL of Olesiak into phosphorodithioate represented by non-bridging sulfates of Hossbach to protect INLs from degradation from 3’-and 5’-exonucleases. Thus, cl. 1-25, 27-29, 38-41, 43 are obvious.
Regarding instant cl. 6, 8, 9, 12, 18, 19, 20, 23, 24, 39, Hossbach discloses various exemplary embodiments of β-D-oxy LNA modified antisense gapmer oligonucleotides (represented by “b1” in Tables 4-9 par. 571) with phosphorodithioate linkages (represented by ss in Tables 4-9, par. 581, relevant to instant cl. 6, 12, 19, 20, 39). Hossbach demonstrates β-D-oxy LNA gapmers inhibit their respective target genes (see par. 878-885, see, e.g., Fig. 4-5). Fig. 4 represents a beta-d-oxy LNA gapmer (relevant to instant cl. 8, 9, 19, 20, 23) of 16 nt. with 3 LNA units at 5’ end and 4 LNA units at 3’ end with a central 9 nt. of DNA, thus each LNA flanking region is adjacent to central DNA region (relevant to instant cl. 24) with each INL as a phosphorothioate linkage (PS-INL) and a modified 5-methylcytosine (par. 878, 879, Fig. 4, relevant to instant cl. 18); and also discloses similar gapmers with phosphorodithioate INL (see Table 4, e.g. SEQ ID NO: 235h). Fig. 5 shows inhibition of target gene pSmad2 (par. 879). Phosphorothioate, phosphorodithioates or phosphodiester INLs are compatible for RNAse H mediated cleavage (par. 421, relevant to instant cl. 24).
As evidenced by Grunweller, B-D-oxy-LNA, synonymous with LNA, freezes the sugar in the C3’-endo conformation typical of A-helical RNA duplexes, which increases their melting temperature by several degrees per introduced LNA residue (pg. 236) and thus is a stable duplex complex than an unmodified duplex.
Regarding instant cl. 13, Hossbach demonstrates gapmers with both phosphorothioate INL and phosphodiester INL (see Table 4, par. 809); and Hossbach discloses various scenarios for the use of phosphodiester INL; e.g. in a A-B-C gapmer, where A and C are modified with nucleotide analogues and thus regions A and C are protected from endonuclease degradation, then phosphodiester linkages suffice (par. 562).
Regarding instant cl. 14, Hossbach discloses gapmers with phosphorothioate INL (PS-INL) to protect the oligonucleotide from nuclease degradation while still enabling RNAse H degradation of target transcript following hybridization of gapmer to a region within the target transcript (par. 563, see Fig. 4 with all PS-INL).
Regarding instant cl. 21, 22, 25, Hossbach discloses PS2-INL gapmers throughout the gapmer, in the flank region or in the gap region or throughout the oligomer (see, for e.g., SEQ ID NO: 143j on par. 809, with each INL is PS2-INL, relevant to cl. 21, 22, 25). As evidenced by Grunweller, LNA gapmers with central DNA gap are sensitive to nucleases in the central DNA gap area (pg. 236, relevant to instant cl. 21 and 25)). One of the ordinary skill in the art would have been motivated to combine the prior arts of Hossbach discloses phosphorothioate/phosphorodithioate INL protect against nuclease degradation and phosphorodithioate with a linking sulfur moiety protect against nuclease degradation taught by Olesiak to design a phosphorotrithioate to protect the nuclease sensitive central DNA area.
Regarding instant cl. 15, 40, MPEP recognizes that making duplicate of a product would be obvious, thus having an oligomer with two or more PS3-INL would be obvious.
Regarding instant claims 7, 10, 11, 38, 41, Hossbach discloses a gapmer with a 5 nt. modified with 2’ methoxyethyl (2MOE) as flanking wings with phosphorothioate INL (par. 909, ref. 3) and shows approximately 30% inhibition of target mRNA by gymnotic uptake of the gapmer in vitro (i.e. without transfection agent) (see par. 979, Table 16a, Ref. 3).
Regarding instant claim 27, 43, Hossbach discloses a pharmaceutically acceptable salt of ASO and, depending on the charged molecule, the salt form maybe sodium or potassium (par. 376).
Regarding instant claim 28, Hossbach discloses ASO chemically linked moiety for cellular distribution or cellular uptake purposes, including lipid moieties (par. 831).
Regarding instant claim 29, Hossbach discloses an oral nontoxic pharmaceutically acceptable inert carrier to combine with ASO (par. 822).
Regarding instant claim 16, Hossbach also discloses phosphorothioate INL (PS-INL) and one of the inherent structure due to the electron resonance (the negative charge) that the double bonds moves around the atoms with the negative charge (i.e. both the unlinked S and O) and Frey suggests that the predominant structure is the -P(=O)S, thus regardless which is the predominant form, there is a one form with P(=S)(OH) (Frey, 1985, Science, 228, 541-545, pg. 544 for the excerpt of the structures below).
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Regarding instant claims 26 and 42:
Claims 26 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Hossbach et al. (US20170319614, pub. 11/9/2017, referred as Hossbach) and Olesiak et al. (2009, Organic and Biomolecular Chemistry, 7, 2162-2169, referred as Olesiak) as applied to claim 1-25, 27-29, 38-41, 43 above, and further in view of Grunweller and Hartmann (2007, Biodrugs, 21, 235-243, referred as Grunweller).
Disclosure of Hossbach and Olesiak regarding rejection of claim 1 is noted above.
Hossbach and Olesiak do not teach a totalmer or a mixmer or a splice-switching oligonucleotide.
Grunweller in its review article discloses that a comparison of a fully substituted 2’-O-methyl (2OMe), morpholino, LNA 14-mer and PNA oligomers, demonstrated highest levels of exon skipping were achieved with all-LNA monomer but preferred fully substituted 2OMe, i.e. a totalmer where every sugar moiety is modified, since it was more sensitive to mismatches in the target transcript (pg. 237, relevant to instant cl. 26 and 42).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified an oligonucleotide with PS3-INL of both Hossbach and Olesiak in view of Grunweller and arrive at the claimed invention with a reasonable expectation of success. Based on the success of using PS2-INLs containing oligonucleotides to degrade the target transcript and disclosure of (—S—P(S)(S−)—) by Hossbach, and success of Olesiak to protect oligonucleotides from both 5’- and 3’-exonucleases by incorporating both a bridging and non-bridging sulfur in a phosphorodithioate-INL, and teaching of Grunweller noting that a totalmer exhibited highest levels of exon skipping, a skilled artisan would expect reasonable success by incorporating a bridging sulfur-INL of Olesiak into phosphorodithioate represented by non-bridging sulfates of Hossbach to protect INLs from degradation from 3’-and 5’-exonucleases and complete 2’-ribose modification with O-methyl/LNA will allow reasonable success as an exon-skipping oligonucleotide. Thus, cl. 26 and 42 are obvious.
Regarding instant claim 44:
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over Hossbach et al. (US20170319614, pub. 11/9/2017, referred as Hossbach) and Olesiak et al. (2009, Organic and Biomolecular Chemistry, 7, 2162-2169, referred as Olesiak) as applied to claims 1-25, 27-29, 38-41, 43 above, and further in view of Prakash et al. (2016, J. Med. Chem., 59, 2718-2733, referred as Prakash).
Disclosure of Hossbach and Olesiak regarding rejection of claim1 is noted above.
Hossbach and Olesiak do not disclose a conjugate moiety attached to an oligonucleotide via a linker moiety.
Prakash compared the use of various tether moieties (i.e. linker) conjugating a N-acetyl galactosamine (GalNac) to antisense oligonucleotide for delivery of the ASO to hepatocytes (pg. 2728). Based on the study, Prakash identified an optimal tether (THA-GN3, Fig. 9) linking GalNac to an ASO for delivery to hepatocytes and is easily assembled and is shown to be 30-fold more potent in humans relative to parent ASO (pg. 2728, see Fig. 9).
One of the KSR rationale that may be used to support a conclusion of obviousness is that there is some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Therefore, it would have been prima facie obvious for one of ordinary skill in the art before the filing date of the claimed invention to have modified a ASO with a targeting moiety having a PS3-INL of Hossbach and Olesiak in view of Prakash and arrive at the claimed invention with a reasonable expectation of success. Based on the success of using PS2-INLs containing oligonucleotides to degrade the target transcript and disclosure of (—S—P(S)(S−)—) by Hossbach, and success of Olesiak to protect oligonucleotides from both 5’- and 3’-exonucleases by incorporating both a bridging and non-bridging sulfur in a phosphorodithioate-INL, and Prakash’s success of delivering oligonucleotides conjugated to GalNAc moiety via linkers to hepatocytes, a skilled artisan would reasonably expect success of delivering oligonucleotide comprising PS2-INL of Hossbach and INL with bridging sulfur of Olesiak conjugated to a GalNAc moiety via a linker of Prakash to hepatocytes. Thus, cl. 44 is obvious.
Response to Arguments
Applicant's arguments filed 12/17/2025 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks make the following arguments:
The Examiner has failed to show a reasonable motivation to combine or modify the prior art (pg. 8). Since Hossbach has disclosed many INLs, the Remarks question why PS2-INL was selected for further modification and that the action fails to provide an articulated reasoning (pg. 8); i.e. the action does not point out “supposed benefits” there may be by selecting PS2-INL over the many well-characterized PS-INL or PS2-INL species (pg. 8); nor indicate insufficiency/drawback of PS2-INL of Hossbach to improve upon the PS2-INL (pg. 8); or that a skilled artisan may consider PS3-INL “less favored” than the PS2-INL due to lack of experimentation (Olesiak also does not study PS3-INL), pg. 8. The action fails to provide “evidence that 5’-exonucleases are a problem for Hossbach’s ASOs that would require such modification” (pg. 9).
The action uses improper hindsight rationale: “it appears that that[sic] the Examiner is using the Applicant’s disclosure as a road map to combine references” (pg. 9).
The “proposed modification would frustrate the purpose of the prior art” (pg. 9), since Olesiak teaches that “aforementioned modification dramatically influences the avidity of these modified oligonucleotides towards complementary oligodeoxyribonucleotides, and that the strong decrease of Tm disfavours practical applications of such modification eg. in antisense strategy” (pg. 10).
There is no reasonable expectation of success in combining or modifying the prior art references to arrive at the claimed invention, since nothing in Olesiak suggests that the different PS2-INL species are anything other than alternatives to one another for use in DNA dimers and oligomers, rather than guidance on where to place a third sulfur in an INL in a gapmer ASO (pg. 11). The Remarks note “unpredictability associated with swapping out one INL species for another” and it is not a simple “plug and play” (pg. 11).
Regarding cl. 26 and 42 rejection, Grunweller fails to cure the deficiencies of Hossbach and Olesiak, and for cl. 44, Prakash fails to cure the deficiencies of Hossbach and Olesiak as well.
The arguments are not persuasive.
Addressing arguments 1 and 4, first, Examiner has addressed similar arguments in previous action of 6/17/2025, see pg. 13-15. In addition to the points raised in previous action(s), it should be noted that the obviousness rejection uses a rational basis for combination of prior art, and is a flexible approach in determining obviousness. Thus it does not need to provide specific motivations as noted by the Remarks, but Hossbach provides other, sufficient motivations. Noting that the INL of gapmer need to be nuclease resistant and RNase H compatible, Hossbach demonstrates that gapmer with PS2-INL (i.e. 2 opposite non-bridging sulfurs) is effective for RNase H degradation of target transcript. Thus, addition of one more bridging sulfur would be an ideal choice, since it is shown that two sulfurs in PS2-INL was still RNase H compatible. Further. it discloses the instant claimed INL and MPEP does not require that a disclosure needs to be mentioned a minimum number of times before it becomes a disclosure; a disclosure is a disclosure. Olesiak provides further motivation of protection against 5’-exonucleases and to synthesize phosphorodithioate with bridging sulfurs and further reducing predictability of using PS3-INL will be nuclease resistant. Thus, based on Hossbach’s demonstration of a PS2-INL and disclosing a PS3-INL a skilled artisan would reasonably expect success in adding a bridging sulfur to a PS2-INL.
Consequently, and addressing argument 2, since Hossbach mentions the claimed subject matter there is no use of improper hindsight.
Addressing argument 3, this is also discussed in prior action of 6/17/25, pg. 14, the statement quoted from Olesiak does not apply here, thus does not frustrate the purpose of Olesiak. The Remarks argue that Olesiak’s teaching of “aforementioned modification dramatically influences the avidity of these modified oligonucleotides towards complementary oligodeoxyribonucleotides, and that the strong decrease of Tm disfavours practical applications of such modification eg. in antisense strategy” (pg. 10). Olesiak is discussing “these modified oligonucleotides [oligomers with bridging-sulfurs phosphorodithioates] towards complementary oligodeoxyribonucleotides.” The target Olesiak is discussing is complementary DNA-based oligomers, the target of instant specification is mRNA (see Ex. 1-3, noting malat1 and ApoB as mRNA targets, pg. 52-54). RNase H recognizes and degrades the RNA-DNA complex following the binding of the gapmer with central DNA and mRNA transcript and not a DNA-DNA complex of Olesiak.
Regarding argument 5, since no specific argument against the prior art is noted, the rejection still stands.
Thus, rejection of examined claims is maintained.
Double Patenting
The provisional nonstatutory double patenting rejection of examined claims over copending Application No. 17/055,510 (referred as ‘510) in view of Olesiak is withdrawn. App. ‘510 is abandoned as of 12/30/2025.
Conclusion
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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/KEYUR A VYAS/ Examiner, Art Unit 1637 /Soren Harward/Primary Examiner, TC 1600