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 .
DETAILED ACTION
Applicant’s amendments and remarks filed on June 22, 2026 are acknowledged. Claims 9, 12, 32, 33, 36, 47, 49, and 50 have been canceled. Claims 30 and 31 were amended. Claims 1-8, 10, 11, 13-31, 34, 35, 37-46, and 48 are pending.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 20, 2026 has been entered.
Election/Restrictions
Applicant’s election without traverse of Group II (claims 30-48) in the reply filed on July 14, 2025 is acknowledged.
Claims 1-8, 10, 11, and 13-29 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 14, 2025.
Claims 30, 31, 34, 35, 37-46, and 48 are examined on the merits herein.
Priority
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Withdrawn Objections
In view of Applicant’s amendments and response, the objections to the abstract and claim 31 are withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C. 103 rejection is withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 21, 2026 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 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.
Claims 30, 31, 34, 35, 37-46, and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Bennett et al. (US 2014/0005374) in view of Shen et al. (Bioorganic & Medicinal Chemistry 1998).
Regarding claims 30, 31, 34, 35, and 37, Bennett et al. teaches a chimeric oligomeric compound targeted to a selected mRNA comprising a modified sugar moiety at the 5'-most nucleoside; a modified sugar moiety at the 3'-most nucleoside; internal nucleosides comprising 2, 3, 4 or 5 separate regions of 2'-deoxyribonucleosides; and at least one nucleoside with a modified sugar moiety separating each region of 2'-deoxyribonucleosides capable of modulating splicing of a selected target mRNA in cells or tissues by contacting the cells or tissues with the chimeric oligomeric compound [0017]. Bennett et al. defines "targeting" or "targeted to" as a process of designing an oligomeric compound such that the compound hybridizes with a selected nucleic acid molecule or region of a nucleic acid molecule [0032]. Bennett et al. teaches that the sugar modifications are selected from the group consisting of 2'-O-methoxyethyl, 2'-fluoro, and locked nucleic acid [0018]. Further, the chimeric oligomeric compounds are 13 to 30 nucleobases in length [0018]. Bennett et al. also teaches that despite regions of "DNA-like" chemistry, the chimeric oligomeric compounds are capable of modulating target mRNA splicing without target degradation [0023].
Regarding claims 38-40, Bennett et al. teaches that introns (or intervening sequences) are regions of a primary transcript (or the DNA encoding it) that are not included in the coding sequence of the mature mRNA and exons are regions of a primary transcript that remain in the mature mRNA when it reaches the cytoplasm. Bennett et al. also teaches that the unspliced RNA (or pre-mRNA) has an exon/intron junction at the 5' end of an intron and an intron/exon junction at the 3' end of an intron [0004].
Regarding claim 41, Bennett et al. teaches that pharmaceutical compositions and formulations which include antisense compounds may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated [0109].
Regarding claims 42-44, Bennett et al. teaches that modified internucleoside linkages, compared to natural phosphodiester linkages, can be used to alter, typically increase, nuclease resistance of the antisense compound. Bennett et al. also teaches that representative phosphorus containing internucleoside linkages include phosphorothioates [0079]. Although Bennett et al. does not explicitly teach wherein at least half or all of the internucleotide linkages are phosphorothioate, it would have been obvious to try because there are a finite number of nucleotides in the antisense oligonucleotide and Bennett et al. taught that modified internucleoside linkages can be used to alter, typically increase, nuclease resistance of the antisense compound.
Regarding claim 45, Bennett et al. teaches that oligomeric compounds can be single stranded with sufficient self-complementarity to allow for hybridization [0048].
Regarding claim 46, Bennett et al. teaches that "specifically hybridizable" and "complementary" are terms which are used to indicate a sufficient degree of precise pairing or complementarity over a sufficient number of nucleobases such that stable and specific binding occurs between the antisense compound and a target nucleic acid. Bennett et al. also teaches that most preferably compounds contain no more than 5% or no mismatches [0070].
Regarding claim 48, Bennett et al. teaches that the compounds can be utilized in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier [0103].
However, Bennett et al. does not teach wherein the consecutive deoxyribonucleotides are at the 5’ end of the antisense oligonucleotide or wherein the consecutive deoxyribonucleotides are at the 3’ end of the antisense oligonucleotide; and wherein the remaining nucleotides are 2’-substituted non-ionic or constrained sugar nucleotides or combinations thereof.
Shen et al. teaches that all phosphorothioate mixed-backbone oligonucleotides (MBOs) composed of deoxyribonucleotide and 2’-O-methylribonucleotide segments were studied for their target binding affinity, specificity, and RNase H activation properties. The 2’-O-methylribonucleotide segment, which does not activate RNase H, serves as a high affinity target-binding domain and the deoxyribonucleotide (DNA) segment, which binds to the target with a lower affinity than the former domain, serves as an RNase H-activation or target-cleaving domain. Shen et al. designed and synthesized a series of 18-mer MBOs with the DNA segment varying from a stretch of two to eight deoxyribonucleotides in the middle, at the 5’-end, or at the 3’-end of the MBOs to understand the influence of the size and position of the DNA segment of MBOs on RNase H-mediated cleavage of the RNA target. Shen et al. taught that the minimum substrate cleavage site and cleavage efficiency of RNase H are influenced by the position of the DNA segment in the MBO sequence and RNA cleavage efficiency decreases as the position of the DNA segment of the MBO RNA heteroduplex is changed from the 3’-end to the middle and to the 5’-end of the target strand [abstract]. Specifically, MBOs containing four or more DNA residues in the M-construct or five or more DNA residues in the 3P-construct supported RNase H cleavage of the matched targets under the experimental conditions. The MBOs containing four or more DNA residues in the 5P-construct also activated RNase H for target cleavage, in contrast to an earlier report [page 1699, right column]. As shown in Figure 5 (reproduced below), RT-3P4 containing four 3’ DNA residues and RT5P-3P5 containing five 3’ DNA residues are not cleaved.
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It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the antisense oligonucleotide of Bennett et al. wherein the consecutive deoxyribonucleotides are at the 5’ end of the antisense oligonucleotide or at the 3’ end of the antisense oligonucleotide because Bennett et al. taught a chimeric oligomeric compound targeted to a selected mRNA comprising a modified sugar moiety at the 5'-most nucleoside; a modified sugar moiety at the 3'-most nucleoside; internal nucleosides comprising 2, 3, 4 or 5 separate regions of 2'-deoxyribonucleosides; and at least one nucleoside with a modified sugar moiety separating each region of 2'-deoxyribonucleosides capable of modulating splicing of a selected target mRNA in cells or tissues by contacting the cells or tissues with the chimeric oligomeric compound, Shen et al. designed and synthesized a series of 18-mer mixed-backbone oligonucleotides (MBOs) with the DNA segment varying from a stretch of two to eight deoxyribonucleotides in the middle, at the 5’-end, or at the 3’-end of the MBOs to understand the influence of the size and position of the DNA segment of MBOs on RNase H-mediated cleavage of the RNA target, and Shen et al. taught that the minimum substrate cleavage site and cleavage efficiency of RNase H are influenced by the position of the DNA segment in the MBO sequence and RNA cleavage efficiency decreases as the position of the DNA segment of the MBO RNA heteroduplex is changed from the 3’-end to the middle and to the 5’-end of the target strand [abstract]. One of ordinary skill in the art would have made such a modification because it would have amounted to combining known prior art elements to yield predictable results.
Conclusion
No claims are allowed.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637
