DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
This action is written in response to applicant’s correspondence received 08/06/2025. Claims 1,4-5,7-15,18,20,22-23 and 25-36 are currently pending.
Any rejection or objection not reiterated herein has been overcome by amendment. Applicant’s amendments and arguments have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/06/2025 was filed after the mailing date of the non-final office action on 02/10/2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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, 4-5, 7-15, 18, 20, 22-23 and 25-36 are rejected under 35 U.S.C. 103 as being unpatentable over Sheehan (Sheehan et al. Biochemical properties of phosphonoacetate and thiophosphonoacetate oligodeoxyribonucleotides. Nucleic Acids Research. 31(14):4109-18 (2003); of record, applicant’s submission) in view of WIPO Publication 2013/022966 A1 to Oestergaard (hereinafter ‘Oestergaard’; of record, applicant’s submission).
Regarding claim 1, Sheehan teaches a single stranded antisense gapmer comprising at least one dinucleoside of formula (I) and A is oxygen or sulfur (see Figure 1, which shows the same chemical structure).
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Sheehan teaches wherein one of A1 and A2 is a DNA nucleotide, wherein the oligonucleotide comprises a contiguous nucleotide sequence of formula 5’-F-F-F’-3-, wherein G is a region of 5 to 18 nucleoside capable of recruiting RNase H (i.e., DNA nucleosides), and G is flanked by 1-7 nucleosides. Please see Table 1. The broadest reasonable interpretation of the nucleosides present in the F and F’ regions encompasses any (sugar modified) nucleoside, including DNA and RNA, such that Sheehan’s ODNs are encompassed by the claim.
Sheehan provides a teaching, suggestion or motivation to use internucleoside linkages of formula I (phosphonoacetate or thiophosphonoacetate) in antisense oligonucleotides because they were found to be, “nuclease resistant, capable of stimulating RNase H activity and, as neutral esters, to be taken up by cells via passive diffusion.” (p. 4110), and that the capped oligonucleotides, “stimulated RNase H1 catalysis at a rate faster than with unmodifed DNA (Fig. 7, Table 3).” (p. 4117).
Sheehan does not teach wherein regions F and F’ comprise 1-7 sugar modified nucleosides, including the nucleosides immediately flanking region G.
Oestergaard teaches wherein “each modified nucleoside in the 5' and 3 -regions comprises a modified sugar moiety.” (p. 8 ln 3; claim 23). Please see also Table 1 on p. 48, which shows various gapmer nucleoside motifs.
Regarding claim 4, Oestergaard teaches that the sugar modified nucleosides are 2’ modified (“the 5’ and 3’-regions comprise one or more 2’-modified nucleosides”; p. 8 ln 7-8; claims 23-25).
Regarding claim 5, Oestergaard teaches wherein the 2’ sugar modified nucleoside is a LNA nucleoside:
As used herein, "locked nucleic acid nucleoside" or "LNA" means a nucleoside comprising a bicyclic sugar moiety comprising a 4'-CH2-O-2'bridge. (p. 17 ln 21-22)
23. The gapped oligomeric compound of any of claims 1 to 22 wherein each modified nucleoside in the 5' and 3'-regions comprises a modified sugar moiety.
24. The gapped oligomeric compound of claim 23 wherein each modified nucleoside in the 5' and 3'-regions is, independently, a bicyclic nucleoside comprising a bicyclic furanosyl sugar moiety or a modified nucleoside comprising a furanosyl sugar moiety having at least one substituent group.
29. The gapped oligomeric compound of claim 24 comprising one or more bicyclic nucleosides that each have a bridging group between the 4' and 2' carbon atoms of the furanosyl ring independently selected from 4'-(CH2)-O-2', 4'-(CH2)-S-2', 4'-(CH2)2-O-2', 4'-CH(CH3)-O-2', 4'-CH( CH2OCH3)-O-2', 4'-C(CH3)2-O-2', 41-CH2-N(OCH3)-2', 4'-CH2-O-N(CH3)-2', 4'-CH2-NCH3-O-2',
Regarding claim 7, Hossbach teaches wherein the LNA is beta D-oxy LNA (see above).
Please see also the figure on p. 31, formula (B).
Regarding claim 7, Oestergaard teaches wherein the LNA is beta-D-oxy LNA (p. 31, formula (B)).
Regarding claims 8 and 9, Sheehan teaches that the oligonucleotide comprises phosphorothioate linkages (e.g., the central portion of S ACE-cap in Table 1).
Regarding claim 10, Sheehan teaches between 1-15 dinucleosides of formula (I) (e.g., S-ACE Cap in Table 1,which has 8 total).
Regarding claim 11, while Sheehan teaches phosphorothioate bonds, Sheehan does not teach the formula. Instead, Oestergaard teaches the formula and confirms that it is -P(=S) or -P(=O2-) (p. 37 ln 22).
Regarding claim 12, Oestergaard teaches the oligonucleotide comprising both DNA, RNA and sugar modified nucleosides (see above).
Regarding claim 13, Oestergaard teaches wherein one or more nucleoside is a nucleobase modified nucleoside (see Table 1 and p. 48 ln 13-14, which indicates that each A maybe a modified nucleobase).
Regarding claim 14, Sheehan teaches wherein at least one dinucleoside is in the flanking region or is between the gap region and the flanking region (Table 1, S-ACE Gap).
Regarding claim 15, Oestergaard teaches wherein the gapmer is a LNA gapmer, a mixed wing gapmer, or a 2’ substituted gapmer (see above).
Regarding claim 18, Oestergaard teaches wherein all the 2’ sugar modified nucleosides in the flanking region are LNA (see above) or they are independently selected from 2’-MOE, 2’-F and LNA (p. 48 ln 7-14).
Regarding claim 20, Oestergaard teaches wherein the flanking regions comprise a mix of LNA and non-LNA 2’ sugar modified nucleosides (see above).
Regarding claim 22, Sheehan (Table 1) and Oestergaard (Table 1 p. 48) both teach wherein the gap region comprises 5-16 contiguous DNA nucleosides.
Regarding claim 23, Sheehan and Oestergaard both teach wherein the flanking regions are 1-8 nucleosides in length and/or comprise 1-4 LNA nucleosides (see above).
Regarding claims 25-26, Oestergaard teaches wherein the LNA is beta-D-oxy LNA (see above).
Regarding claim 27, both Sheehan (18 nt in S-ACE Cap) and Oestergaard (maximum 21 nt) teach wherein the entire oligonucleotide is 10-30 nt in length.
Regarding claim 28, Oestergaard teaches wherein the oligonucleotide comprises formula 5’-D’-F-G-F’-F’’-3’ (see e.g. motif ABBDDDDDDDDDBBA in Table 1). The claim does not define what region D’ and D’’ are, but the broadest reasonable interpretation of the claim encompasses any motif wherein the flanking region has mixed nucleosides such as a mix of LNA and other 2’ modifications.
Regarding claims 29-31, Sheehan teaches wherein each flanking region has 1-7 dinucleosides, positioned in region F’ (see above).
Regarding claim 32, Sheehan teaches wherein the RNaseH is RNAse H1 (p. 4116, bottom right).
Regarding claims 33-36, Oestergaard teaches a pharmaceutical composition comprising an oligonucleotide, a pharmaceutically acceptable salt and/or a conjugate which is either inert or active (p. 70 ln 1-3, ln 15-17, ln 20-21; p. 19 ln 13-17).
It would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have combined the gapmer oligonucleotide comprising formula (I) internucleoside linkages in the flanking regions, as taught by Sheehan, with the modifications and modification patterns as taught be Oestergaard. Sheehan teaches gapmer antisense oligonucleotides which have been modified by thiophosphonoacetate linkages to improve nuclease resistance and cellular uptake. Oestergaard teaches gapmer antisense oligonucleotides which have also been modified by thiophosphonate linkages, and adds a variety of motifs which may be applied to the oligonucleotides as taught by Sheehan to further enhance properties such as nuclease resistance or hybridization affinity. Thus in regard to the limitations of the claims, where the prior art teaches a variety of routine modifications and motifs, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp for optimization of the oligonucleotide of Sheehan for stable, effective antisense inhibition of a target transcript via RNase H. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense to provide routine optimization.
Conclusion
Applicant's submission of an information disclosure statement under 37 CFR 1.97(c) with the timing fee set forth in 37 CFR 1.17(p) on 08/06/2025 prompted the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 609.04(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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMANDA M ZAHORIK whose telephone number is (703)756-1433. The examiner can normally be reached M-F 8:00-16:00 EST.
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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636