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 February 11, 2026 are acknowledged. Claims 1-26, 28-30, 32, 33, 36, and 38-44 have been canceled. Claims 27, 31, and 52-57 were amended. Claims 27, 31, 34, 35, 37, and 45-59 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 27, 29, 31, and 45-58) in the reply filed on June 26, 2025 is acknowledged.
Claims 34, 35, and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 June 26, 2025.
Newly added claim 59 is drawn to the composition of claim 27; therefore, claim 59 will be examined with Applicant’s election of Group I.
Claims 27, 31, and 45-59 are examined on the merits herein.
Priority
This application claims priority to PCT/US20/29957 filed on April 24, 2020 which claims priority to U.S. provisional application 62/905,323, filed on September 24, 2019 and U.S. provisional application 62/838,701, filed on April 25, 2019.
Withdrawn Objections
In view of Applicant’s amendments and response, the objection to the abstract is withdrawn.
Withdrawn Rejections
In view of Applicant’s amendments and response, the 35 U.S.C 112(b), 35 U.S.C 112(a) written description, and 35 U.S.C. 103 rejections are withdrawn.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on February 11, 2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claim 55 is objected to because of the following informality:
Claim 55 recites in part “comprises charged internucleotidic linkages” and should recite “comprises internucleotidic linkages”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 31 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 31 recites the composition of claim 27 wherein 30-100% of all oligonucleotides within the composition that share the common base sequence are oligonucleotides of the plurality. Claim 27 requires oligonucleotides of the plurality to share a common base sequence; therefore, claim 31 does not further limit the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Response to Arguments
Applicant's arguments filed February 11, 2026 have been fully considered but they are not persuasive.
Applicant asserts the following:
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These arguments are not found persuasive. Contrary to Applicant’s assertions, claim 27 as currently written recites wherein the composition is enriched and still requires oligonucleotides of the plurality to share a common base sequence; therefore, claim 31 does not further limit the claim upon which it depends.
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.
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 27, 31, and 45-58 are rejected under 35 U.S.C. 103 as being unpatentable over Butler et al. (WO 2014/012081; reference cited by Applicant) as evidenced by Rigo et al. (WO 2014/062686; reference previously cited by the Examiner) in view of Van Diepen et al. (US 2019/0256847) and Stetsenko et al. (US 2017/0362270).
Regarding claims 27, 31, and 58, Butler et al. teaches chirally controlled compositions comprising a plurality of oligonucleotides of the same type, wherein each type is defined by: 1) base sequence; 2) pattern of backbone linkages; 3) pattern of backbone chiral centers; and 4) pattern of backbone P-modifications [00217]. In some embodiments, all such provided oligonucleotides are of the same type, i.e., all have the same base sequence, pattern of backbone linkages (i.e., pattern of internucleotidic linkage types, for example, phosphate, phosphorothioate, etc), pattern of backbone chiral centers (i.e. pattern of linkage phosphorus stereochemistry (Rp/Sp)), and pattern of backbone phosphorus modifications (e.g., pattern of "-XLR1" groups in formula I) [00511]. Further, in certain embodiments, multiple chiral phosphorothioate linkages are introduced inside a fully ribose-modified RNA oligonucleotide having corresponding desired ribose 2’-chemical modification such as 2’-deoxy-2’-fluoro (2’-F) [00370]. Butler et al. also teaches that methods of the invention provide chirally controlled oligonucleotide compositions that are enriched in a particular oligonucleotide type [00996].
Regarding claims 45-57, Butler et al. teaches that a chirally controlled oligonucleotide is a gapmer [00242]. Rigo et al. teaches a single-stranded antisense oligonucleotide comprising a gap segment consisting of linked deoxynucleosides, a 5 ' wing segment consisting of linked nucleosides, and a 3 ' wing segment consisting of linked nucleosides wherein the gap segment is positioned immediately adjacent to and between the 5' wing segment and the 3' wing segment and wherein each nucleoside of each wing segment comprises a modified sugar and each nucleoside of each wing segment comprises a 2’-O-methoxyethyl sugar and each internucleoside linkage is a phosphorothioate linkage [pages 14-15]. Rigo et al. also teaches that in certain embodiments, the 2’-modified sugar moiety comprises a 2’-O-methyl group [page 14]. Further, Rigo et al. teaches various gapmer motifs including 5-10-5 [page 20].
However, Butler et al. does not teach an internucleotidic linkage having the structure of
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wherein the phosphorus is of the Rp configuration. Butler et al. also does not teach that the common base sequence comprises at least 15 contiguous nucleobases of SEQ ID NO: 4. Butler et al. also does not teach that the oligonucleotides of the plurality are capable of increasing the level of skipping of a deleterious exon in an USH2A gene transcript or a gene product thereof.
Stetsenko et al. teaches
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[0062] wherein Y is selected from the 3′ end of a nucleoside, nucleoside analogue, oligonucleotide, or oligonucleotide analogue and X is selected from the 5′ end of a nucleoside, nucleoside analogue, oligonucleotide, or oligonucleotide analogue [0038] which reads on the instantly claimed structure of
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. Stetsenko et al. also teaches that substituting charge neutral or positively charged groups for natural anionic phosphate can improve cellular uptake [0021-0022]. Stetsenko et al. also teaches that phosphates and modified phosphates may be chiral and recognizes that stereochemistry encompasses both Rp and Sp configurations [0120].
Van Diepen et al. teaches antisense oligonucleotides capable of treating Usher syndrome type II and/or USH2A-associated non syndromic retina degeneration [abstract]. Van Diepen et al. teaches antisense oligonucleotides for skipping exon 13 in human USH2A pre-mRNA, wherein the AON comprises or consists of the sequence of SEQ ID NO: 6 or 7 [0017]. Van Diepen et al. SEQ ID NO: 7 (designated as Db) matches to instant SEQ ID NO: 4 (designated as Qy) as shown in the alignment below.
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Van Diepen et al. SEQ ID NO: 7 (designated as Db) matches to instant SEQ ID NO: 16 (designated as Qy) as shown in the alignment below.
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Van Diepen et al. SEQ ID NO: 6 (designated as Db) matches to instant SEQ ID NO: 13 (designated as Qy) as shown in the alignment below.
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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 substitute the oligonucleotide of Butler et al. with the oligonucleotide of Van Diepen et al. because doing so would have been no more than the simple substitution of one known element for another to obtain predictable results. One of ordinary skill in the art would have been motivated to do so because Van Diepen et al. taught antisense oligonucleotides for skipping exon 13 in human USH2A pre-mRNA wherein the antisense oligonucleotides are capable of treating Usher syndrome type II and/or USH2A-associated non syndromic retina degeneration.
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 oligonucleotide composition of Butler et al. and Van Diepen et al. with the modification of Stetsenko et al. with a reasonable expectation of success because this would have amounted to applying a known technique of internucleotide modification to a known product ready for improvement to yield predictable results. One of ordinary skill in the art would have been motivated to modify the oligonucleotide with the internucleotide linkage because Stetsenko et al. taught the instantly claimed structure of
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encompassing a Rp configuration and also taught that substituting charge neutral or positively charged groups for natural anionic phosphate can improve cellular uptake. Further, it would have been obvious to have used chirally controlled positions because Butler et al. taught that structurally optimized chirally controlled oligonucleotides exhibit certain desirable characteristics such as increased stability and improved efficacy for in vitro and/or in vivo applications [00200].
Allowable Subject Matter
Claim 59 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Table A1 discloses that SEQ ID NO: 289 is associated with oligonucleotide WV-30205 and SEQ ID NO: 223 is associated with WV-24382. Further, Table A1 discloses that SEQ ID NO: 223 is identical to SEQ ID NO: 289 except the n001 modification in SEQ ID NO: 223 is stereorandom and the n001 modification in SEQ ID NO: 289 is in the Rp configuration.
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WV-24382 (SEQ ID NO: 223) was tested for its efficacy in inducing skipping of exon 13 in an USH2A gene transcript in Y-79 cells in vitro. The oligonucleotide was tested at a concentration of 20 uM and delivered gymnotically and achieved exon skipping at 62.4% and 76.2% [00858].
WV-30205 (SEQ ID NO: 289) was tested for its efficacy in inducing skipping of exon 13 in an USH2A gene transcript in Y-79 retinoblastoma cells in vitro. The oligonucleotide was tested at various concentrations and delivered gymnotically and achieved the same or similar level of exon skipping at 10 uM which is half of the concentration of WV-24382 [00891].
In addition, Table 27 (reproduced in part below) demonstrates that increasing the concentration of WV-30205 (SEQ ID NO: 289) increases the level of exon skipping. Therefore, it is unexpected that the same or similar level of exon skipping is achieved with a chirally controlled oligonucleotide at half of the concentration of a non-chirally controlled oligonucleotide.
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Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 CHRISTINA TRAN whose telephone number is (571)270-0550. The examiner can normally be reached M-F 7:30 - 5:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571) 272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637