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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 07/29/2026 has been entered.
Election/Restriction
Claims 1-18, 21-23, 27-29, 32-36, and 38-41, 43-44 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 Claims 32-36 stand withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 1-18, 21-23, 27-29, 38-41, and 43-44 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 Objections
Claim 12 is objected to because of the following informalities: the claim recites “nucleoside nucleosides” in line 2. Appropriate correction is required.
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 1-18, 21-23, 27-29, 38-41, and 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, 21, 23, and 39; and as evidenced by Frey (1985, Science, 228, 541-545) for cl. 16.
Regarding instant claims 1-5, 8-9, 12, 17, and 21-23 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). Fig. 4 represents a beta-d-oxy LNA gapmer of 16 nt. with 3 LNA units at 5’ end and 4 LNA units at 3’ end with a central 9 nt. of DNA, and each LNA flanking region is adjacent to central DNA region (relevant to instant cl. 1, 8, 9, 23). 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).
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)).
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 effective 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. Further, a skilled artisan would have been motivated to introduce a phosphorotrithioate within the gap region to protect the nuclease-sensitive central DNA area.
Thus, cl. 1-5, 8-9, 12, 17, and 21-23 are obvious.
Regarding instant cl. 6, 18, 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, 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 illustrates a gapmer with a modified 5-methylcytosine (par. 878, 879, Fig. 4, relevant to instant cl. 18). Fig. 5 shows inhibition of target gene pSmad2 (par. 879).
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. 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 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 1-18, 21-23, 27-29, 38-41, and 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 effective 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 07/28/2026 (“the Remarks”) have been fully considered but they are not persuasive.
The Remarks argue the following:
The Applicant submits Papargyri et al. (a 2019 reference) to make several points of why a skilled artisan would not have arrived at the claimed invention.
The Remarks indicate that each prior art, individually (Hossbach, Olesiak, Grunweller, Frey), fails to disclose the claimed invention (pg. 8-10) and “claim 1 is nonobvious over Hossbach, Olesiak, Grunweller, and Frey, either alone or in combination” (pg. 10). And same argument is made for cl. 44, i.e. Prakash fails to cure the deficiencies of Hossbach and Olesiak (pg. 11).
The arguments are not persuasive.
The Papargyri is a post-filing reference (12/18/2019) and its teaching cannot be used by a skilled artisan to support a stance for a filing after its effective filing date.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Here, the action is making an obvious rejection. The Remarks do not provide further argument against obviousness except that the claimed invention is not obvious.
The examined claims remain rejected under 103.
Conclusion
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/KEYUR A VYAS/ Examiner, Art Unit 1637 /Soren Harward/Primary Examiner, TC 1600
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