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 .
Election/Restrictions
Applicant’s election without traverse of Group II, claims 26-29, 31, 34, 38-45, 48-50 in the reply filed on 12/01/2025 is acknowledged. Election of species of SEQ ID NO: 41 from claim 26 of subsections (ii), (v), (viii), (ix), (xv) is acknowledged.
Claims 2-6, 8, 10, 12, 15, 17-18, 20-22, 24, 53, 55, 57, 59, 61, 62, 64, 66-68, and 73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/01/2025.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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) 26-29, 31, 34, 49-50 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aznarez et al (WO 2019/040923, 28 February 2019, cited from IDS) and in further view of Prakash et al (Journal of Medicinal Chemistry, 2016, 59: 2718-2733).
Aznarez teach single-stranded antisense oligonucleotides including one of SEQ ID NO: 231 (see paragraph [0003], Table 5b on page 107), which is 100% identical to instant SEQ ID NO: 41:
SEQ ID NO: 41 1 AGTTGGAGCAAGATTATC 18
||::|||||||||::|:|
SEQ ID NO: 231 1 AGUUGGAGCAAGAUUAUC 18
Further Aznarez teach that each monomer of oligonucleotide can be 2’ MOE and phosphorothioate modified, making such oligonucleotides more resistant to nuclease degradation (see paragraph [00133]). Aznarez teach that oligonucleotides can comprise phosphodiester bonds and 5-methyl cytosines (see paragraphs [00125-00126]). Aznarez teach pharmaceutical compositions comprising antisense oligonucleotides and pharmaceutically acceptable carriers such as PBS, phosphate buffered salt (see paragraphs [00145-00146]).
Aznarez do not teach that the oligonucleotide comprises modifications of phosphodiester and phosphorothioate bonds as in instant sequences (ii) or (v) of instant SEQ ID NO: 41 as shown in claim 26, or further comprise conjugate moiety comprising three GalNAc ligands attached by single bond to 5’ end of antisense oligonucleotide.
Prakash teach that replacing some phosphorothioate bonds in antisense oligonucleotides with phosphodiester bonds is beneficial because it decreases toxicity of the oligonucleotide (see first column on page 2724). Prakash further teach conjugation of antisense oligonucleotides to GalNAc cluster comprising three GalNAc ligands attached by single bond to 5’ end of antisense oligonucleotide to improve oligonucleotide delivery (see Abstract, page 2718, Figure 1).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to modify antisense oligonucleotide of Aznarez by including some phosphodiester modifications among phosphorothioate modfications as taught by Prakash and conjugate such antisense oligonucleotide to GalNAc cluster as taught by Prakash, arriving at instant invention. One of the ordinary skill in the art would be motivated to do so to reduce toxicity of resulting antisense oligonucleotides and to improve their delivery to liver as taught by Prakash.
Claim(s) 38-45 and 48 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aznarez et al (WO 2019/040923, 28 February 2019, cited from IDS) and in further view of Rigo et al (WO 2018/014041, January 2018) and Butler et al (US 2015/0211006, July 2015).
Teachings of Aznarez are discussed above. Aznarez further teach sodium and potassium salts of antisense oligonucleotides (see paragraph [00146]).
Aznarez do not teach modifications 2’-O-(N-methyl acetamide) modifications of nucleotides as in oligonucleotides of SEQ ID NO: 41 of claims 38-40 or chirally enriched population of such oligonucleotides with phosphorothioate linkage in (Sp) or (Rp) configuration or all phosphorothioate linkages stereorandom.
Rigo teach that modified antisense oligonucleotides comprising 2’-O-(N-methyl acetamide) modifications have enhanced cellular uptake and pharmacologic activity (see lines 10-15 on page 2) and provide examples of antisense oligonucleotides fully modified with 2’-O-(N-methyl acetamide) modifications (see Table on page 29).
Butler teach that properties of antisense oligonucleotides such as binding affinity and stability to nucleases are affected by stereochemical configuration of phosphorus atom in phosphorothioate bond, therefore it is beneficial to provide chirally controlled oligonucleotides exhibiting desirable characteristics (see paragraph [0206]). Butler teach oligonucleotides comprising phosphorothioate linkages in (Sp) or (Rp) configuration for some or all linkages (see paragraphs [0107, 0127]) and oligonucleotides having particular, independently selected stereochemical configuration at each linkage (see paragraph [0124]). Butler teach stereorandom oligonucleotides (see paragraph [0602]).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to modify antisense oligonucleotide of Aznarez by including 2’-O-(N-methyl acetamide) modifications as taught by Rigo and create plurality of such oligonucleotides having particular, independently selected stereochemical configuration at each linkage as taught by Butler, arriving at instant compounds of claims 38-45 and 48. One of the ordinary skill in the art would be motivated to do so to enhance cellular uptake and pharmacologic activity of antisense oligonucleotide as taught by Rigo or to further improve properties of antisense oligonucleotides using chiral control as taught by Butler.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EKATERINA POLIAKOVA whose telephone number is (571)270-5257. The examiner can normally be reached Mon-Fri 8-5.
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/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
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