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 preliminary amendment filed on December 30, 2025 is acknowledged. Claims 1, 2, and 20 have been canceled. Claims 3-19 and 21-31 were amended. Claims 3-19 and 21-31 are pending.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-28) and species: SEQ ID NO: 79 in the reply filed on December 30, 2025 is acknowledged.
Claims 29-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 December 30, 2025.
Claims 18 and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 30, 2025.
Claims 3-17 and 21-28 are examined on the merits herein.
Priority
PNG
media_image1.png
30
398
media_image1.png
Greyscale
Information Disclosure Statement
The information disclosure statement (IDS) submitted on July 18, 2023, November 7, 2023, and December 30, 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings were received on March 29, 2023.
The drawings are objected to because FIGS. 1, 3A, and 3B are blurry. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 is indefinite because it is unclear whether or not the parenthetical phrases recited in the claim are a limitation of the claim. Specifically, “(PMO, PPMO, PMO-X)”, “(PNA)”, and “(PMOPlus)”.
Improper Markush Grouping
Claims 3, 18, and 19 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of SEQ ID NOS: 1-93 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the alternatives listed in the claims lack any common structure or obvious common function. As evidenced by the instant specification on pages 50-53 in Tables 5 and 6, SEQ ID NOS: 1-93 do not have a common function because some of the sequences do not have splicing modulation activity. Although the elected species of SEQ ID NO: 79 has a high level of splicing activity, the claims as currently written encompasses sequences that have no splicing modulation activity.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 3-14, 21, 22, and 24-28 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 2022/0186217) in view of Aznarez et al. (US 11,096,956).
Regarding claims 3-10, 12-14, and 24-27, Zhang et al. teaches an oligonucleotide or an oligonucleotide composition capable of mediating skipping of an exon, e.g., exon 51, of the DMD gene [0005]. Zhang et al. teaches SEQ ID NO: 394 (designated as Db) which has a match to instant SEQ ID NO: 79 (designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 18; DB 1; Length 20;
Best Local Similarity 72.2%;
Matches 13; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTAAGTTCTGTCCAAGC 18
||:|||::|:|:||||||
Db 1 GGUAAGUUCUGUCCAAGC 18
Zhang et al. also teaches that chemical modifications (e.g., modifications of sugar, base, and/or internucleotidic linkages, and patterns thereof) can have a significant impact on oligonucleotide properties, e.g., exon skipping (e.g., of exon 51 of DMD), toxicities, stability, protein binding characteristics, etc. [0004].
Regarding claim 11, Zhang et al. teaches DMD oligonucleotides comprising one or more modified base moieties [0228].
Regarding claims 21 and 22, Zhang et al. teaches SEQ ID NO: 394 which is 20 nucleotides in length.
Regarding claim 28, Zhang et al. teaches a pharmaceutical composition comprising a DMD oligonucleotide or a DMD oligonucleotide composition of the present disclosure and a pharmaceutically acceptable carrier [0091].
However, Zhang et al. does not teach chemical modification of the sugar moiety of each of the nucleotides of the antisense oligonucleotide (claim 3) wherein each nucleotide is 2’-MOE (claims 4 and 24) or wherein each nucleotide is 2’-OMe (claims 7 and 26).
Zhang et al. also does not teach wherein the chemical modification of 1, 2, 3, or 4 sugar moieties is a locked nucleic acid and the nucleotides not comprising a LNA is 2’-MOE (claim 5) or the nucleotides not comprising a LNA is 2’-OMe (claim 8).
Zhang et al. also does not teach wherein each of the two 5’ terminal nucleotides and each of the two 3’ terminal nucleotides is a LNA and the nucleotides not comprising a LNA is 2’-MOE (claims 6 and 25) or the nucleotides not comprising a LNA is 2’-OMe (claims 9 and 27).
Zhang et al. also does not teach wherein the chemical modification of the sugar moiety of one or more nucleotides is a PNA (claim 10).
Zhang et al. also does not teach wherein all cytosine bases are replaced with 5-methylcytosine bases (claims 12, 24, 25, 26, and 27) or wherein all thymine bases are replaced with uracil bases (claim 13). Zhang et al. also does not teach a fully phosphorothioate backbone (claims 14, 24, 25, 26, and 27).
Aznarez et al. teaches that any component of an antisense oligonucleotide (ASO) (e.g., a nucleobase, sugar moiety, backbone) may be modified in order to achieve desired properties or activities of the ASO or reduce undesired properties or activities of the ASO. In some embodiments, the ASO comprises 2′MOE modifications and a phosphorothioate backbone. In some embodiments, the ASO comprises a peptide nucleic acid (PNA) [column 119, first full paragraph]. Further, Aznarez et al. teaches that ASOs comprised of 2’-O-(2-methoxyethyl) (MOE) phosphorothioate-modified nucleotides have significantly enhanced resistance to nuclease degradation and increased bioavailability [column 119, second full paragraph]. Aznarez et al. also teaches that in some examples each monomer of the ASO is modified in the same way, for example each linkage of the backbone of the ASO comprises a phosphorothioate linkage or each ribose sugar moiety comprises a 2′O-methyl modification [column 118, last paragraph]. In some embodiments, the antisense oligomer comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2′-O-methyl, a 2′-Fluoro, or a 2′-O-methoxyethyl moiety. Further, in some embodiments, each sugar moiety is a modified sugar moiety [column 6, first paragraph]. Aznarez et al. also teaches that the nucleobase of an ASO may be any naturally occurring, unmodified nucleobase such as adenine, guanine, cytosine, thymine and uracil, or any synthetic or modified nucleobase (e.g., 5-methylcytosine or 5,6-dihydrouracil) such that it is capable of hydrogen bonding with a nucleobase present on a target pre-mRNA [column 116, second full paragraph].
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 Zhang et al. using the design principles taught by Aznarez et al. because it would have amounted to applying known design principles to yield predictable results. Although Aznarez et al. does not explicitly teach that each nucleotide of the AON is 2’-O-methoxyethyl (2’-MOE) or incorporating two LNAs and the specific position of the LNAs, it would have been obvious to try because Aznarez et al. taught that any component of an antisense oligonucleotide (ASO) (e.g., a nucleobase, sugar moiety, backbone) may be modified in order to achieve desired properties or activities of the ASO or reduce undesired properties or activities of the ASO. Further, Aznarez et al. taught uniform modification of the antisense oligonucleotide, an antisense oligomer may comprise a 2′-O-methoxyethyl moiety, and an antisense oligomer may comprise a locked nucleic acid. One of ordinary skill in the art would have been motivated to modify each nucleotide of the antisense oligonucleotide of Zhang et al. with 2’-MOE or 2’-OMe, modify each linkage of the backbone to comprise a phosphorothioate linkage, incorporate a PNA, incorporate a LNA with 2’-MOE or 2’-OMe, and/or replace all cytosine with 5-methylcytosine to enhance binding affinity to a target sequence on a pre-mRNA transcript, reduce binding to any non-target sequence, reduce degradation by cellular nucleases (i.e., RNase H), improve uptake of the ASO into a cell and/or into the nucleus of a cell, alter the pharmacokinetics or pharmacodynamics of the ASO, and modulate the half-life of the ASO as taught by Aznarez et al. [column 119, first full paragraph].
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 2022/0186217) and Aznarez et al. (US 11,096,956) as applied to claims 3-14, 21, 22, and 24-28 above, and further in view of Schnell et al. (US 9,238,042).
Regarding claims 15-17, the teachings of Zhang et al. and Aznarez et al. are discussed above.
However, Zhang et al. and Aznarez et al. do not teach an antisense oligonucleotide comprising a triethylene glycol (TEG) or a hexaethylene glycol (HEG) at the 5’ terminus or 3’ terminus of the antisense oligonucleotide.
Schnell et al. teaches that a siRNA modulating agent may be modified to stabilize one or more 3’- or 5’- terminus of an siRNA agent, e.g., against exonucleases, or to favor the antisense siRNA agent to enter into RISC. Schnell et al. also teaches that modifications can include triethylene glycol or hexaethylene glycol [column 34, last paragraph bridging to column 35].
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 Zhang et al. and Aznarez et al. by incorporating a TEG or HEG at the 5’ or 3’ terminus. One of ordinary skill in the art would have been motivated to do so because Schnell et al. taught that TEG or HEG at the 5’ or 3’ terminus of an antisense oligonucleotide can stabilize the antisense oligonucleotide against exonucleases.
Claim 23 is rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (US 2022/0186217) and Aznarez et al. (US 11,096,956) as applied to claims 3-14, 21, 22, and 24-28 above, and further in view of Madocsai et al. (Molecular Therapy 2005).
Regarding claim 23, the teachings of Zhang et al. and Aznarez et al. are discussed above.
However, Zhang et al. and Aznarez et al. do not teach an antisense oligonucleotide that is 18 nucleotides in length.
Madocsai et al. teaches that optimal splicing modulation is achieved with antisense sequences around 20 +/- 2 nucleotides in length and with a G/C content close to 50% [page 1018, left column].
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 length of the antisense oligonucleotide of Zhang et al. and Aznarez et al. to 18 nucleotides as taught by Madocsai et al. One of ordinary skill in the art would have been motivated to do so because Madocsai et al. taught that optimal splicing modulation is achieved with antisense sequences around 20 +/- 2 nucleotides in length.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3-17 and 21-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 of copending Application No. 18/179,064 (reference application) in view of Zhang et al. (US 2022/0186217), Aznarez et al. (US 11,096,956), and Schnell et al. (US 9,238,042). ‘064 SEQ ID NO: 4565 (designated as Db) has a 100% match to instant SEQ ID NO: 79 (designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTAAGTTCTGTCCAAGC 18
||||||||||||||||||
Db 1 GGTAAGTTCTGTCCAAGC 18
‘064 SEQ ID NO: 4568 (designated as Db) has a 100% match to instant SEQ ID NO: 79 (designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 100.0%;
Matches 18; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTAAGTTCTGTCCAAGC 18
||||||||||||||||||
Db 1 GGTAAGTTCTGTCCAAGC 18
PNG
media_image2.png
702
602
media_image2.png
Greyscale
PNG
media_image3.png
128
566
media_image3.png
Greyscale
However, ‘064 does not teach that each of the nucleotides of the AON is 2’-MOE or 2’-OMe. ‘064 also does not teach that the chemical modification of the sugar moiety of the nucleotides not comprising a LNA is 2’-MOE or 2’-OMe. ‘064 also does not teach that the chemical modification of the sugar moiety of one or more nucleotides of the antisense oligonucleotide is a PNA. ‘064 does not teach that all thymine bases are replaced with uracil bases. ‘064 does not teach that the AON comprises a TEG or HEG at the 5’ terminus, 3’ terminus, or at each of the 5’ terminus and 3’ terminus of the AON.
Aznarez et al. teaches that any component of an antisense oligonucleotide (ASO) (e.g., a nucleobase, sugar moiety, backbone) may be modified in order to achieve desired properties or activities of the ASO or reduce undesired properties or activities of the ASO. In some embodiments, the ASO comprises 2′MOE modifications and a phosphorothioate backbone. In some embodiments, the ASO comprises a peptide nucleic acid (PNA) [column 119, first full paragraph]. Further, Aznarez et al. teaches that ASOs comprised of 2’-O-(2-methoxyethyl) (MOE) phosphorothioate-modified nucleotides have significantly enhanced resistance to nuclease degradation and increased bioavailability [column 119, second full paragraph]. Aznarez et al. also teaches that in some examples each monomer of the ASO is modified in the same way, for example each linkage of the backbone of the ASO comprises a phosphorothioate linkage or each ribose sugar moiety comprises a 2′O-methyl modification [column 118, last paragraph]. In some embodiments, the antisense oligomer comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2′-O-methyl, a 2′-Fluoro, or a 2′-O-methoxyethyl moiety. Further, in some embodiments, each sugar moiety is a modified sugar moiety [column 6, first paragraph]. Aznarez et al. also teaches that the nucleobase of an ASO may be any naturally occurring, unmodified nucleobase such as adenine, guanine, cytosine, thymine and uracil, or any synthetic or modified nucleobase (e.g., 5-methylcytosine) such that it is capable of hydrogen bonding with a nucleobase present on a target pre-mRNA [column 116, second full paragraph].
Schnell et al. teaches that a siRNA modulating agent may be modified to stabilize one or more 3’- or 5’- terminus of an siRNA agent, e.g., against exonucleases, or to favor the antisense siRNA agent to enter into RISC. Schnell et al. also teaches that modifications can include triethylene glycol or hexaethylene glycol [column 34, last paragraph bridging to column 35].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify each nucleotide of the antisense oligonucleotide of ‘064 with 2’-OMe or 2’-MOE. Although Aznarez et al. does not explicitly teach that each nucleotide of the AON is 2’-O-methoxyethyl (2’-MOE), Aznarez et al. taught uniform modification of the antisense oligonucleotide and taught that an antisense oligomer may comprise a 2′-O-methoxyethyl moiety. One of ordinary skill in the art would have been motivated to do so because Aznarez et al. taught that ASOs comprised of 2’-O-(2-methoxyethyl) (MOE) phosphorothioate-modified nucleotides have significantly enhanced resistance to nuclease degradation and increased bioavailability. One of ordinary skill in the art would have been motivated to modify each nucleotide of the antisense oligonucleotide with 2’-OMe for resistance to endonucleases, exonucleases, and RNaseH.
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 ‘064 wherein the chemical modification of the sugar moiety of one or more nucleotides is a PNA. One of ordinary skill in the art would have been motivated to do so because Aznarez et al. taught that modifying the sugar moiety of an antisense oligonucleotide enhances binding affinity to a target sequence.
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 ‘064 by incorporating a TEG or HEG at the 5’ or 3’ terminus. One of ordinary skill in the art would have been motivated to do so because Schnell et al. taught that TEG or HEG at the 5’ or 3’ terminus of an antisense oligonucleotide can stabilize the antisense oligonucleotide against exonucleases.
This is a provisional nonstatutory double patenting rejection.
Claims 3-17 and 21-28 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6-10, 15, 16, and 20-24 of copending Application No. 17/449,290 in view of Aznarez et al. (US 11,096,956). ‘290 SEQ ID NO: 22333 (designated as Db) has a 100% match to instant SEQ ID NO: 79 (designated as Qy) as shown in the alignment below.
Query Match 100.0%; Score 18; DB 1; Length 18;
Best Local Similarity 72.2%;
Matches 13; Conservative 5; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GGTAAGTTCTGTCCAAGC 18
||:|||::|:|:||||||
Db 1 GGUAAGUUCUGUCCAAGC 18
PNG
media_image4.png
630
638
media_image4.png
Greyscale
PNG
media_image5.png
226
612
media_image5.png
Greyscale
PNG
media_image6.png
150
612
media_image6.png
Greyscale
PNG
media_image7.png
370
626
media_image7.png
Greyscale
However, ‘290 does not teach that each nucleotide of the antisense oligonucleotide is 2’-OMe or 2’-MOE. ‘290 does not teach that the chemical modification of the sugar moiety of the nucleotides not comprising a LNA is 2’-OMe or 2’-MOE. ‘290 also does not teach that the chemical modification of the sugar moiety of one or more nucleotides of the antisense oligonucleotide is a PNA.
Aznarez et al. teaches that any component of an antisense oligonucleotide (ASO) (e.g., a nucleobase, sugar moiety, backbone) may be modified in order to achieve desired properties or activities of the ASO or reduce undesired properties or activities of the ASO [column 119, first full paragraph]. Further, Aznarez et al. teaches that ASOs comprised of 2’-O-(2-methoxyethyl) (MOE) phosphorothioate-modified nucleotides have significantly enhanced resistance to nuclease degradation and increased bioavailability [column 119, second full paragraph]. Aznarez et al. also teaches that in some examples each monomer of the ASO is modified in the same way, for example each linkage of the backbone of the ASO comprises a phosphorothioate linkage or each ribose sugar moiety comprises a 2′O-methyl modification [column 118, last paragraph]. In some embodiments, the antisense oligomer comprises a phosphorodiamidate morpholino, a locked nucleic acid, a peptide nucleic acid, a 2′-O-methyl, a 2′-Fluoro, or a 2′-O-methoxyethyl moiety. Further, in some embodiments, each sugar moiety is a modified sugar moiety [column 6, first paragraph].
It would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify each nucleotide of the hydroxyalkoxylated antisense oligonucleotide of ‘290 with 2’-OMe or 2’-MOE. Although Aznarez et al. does not explicitly teach that each nucleotide of the AON is 2’-O-methoxyethyl (2’-MOE), Aznarez et al. taught uniform modification of the antisense oligonucleotide and taught that an antisense oligomer may comprise a 2′-O-methoxyethyl moiety. One of ordinary skill in the art would have been motivated to do so because Aznarez et al. taught that ASOs comprised of 2’-O-(2-methoxyethyl) (MOE) phosphorothioate-modified nucleotides have significantly enhanced resistance to nuclease degradation and increased bioavailability.
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 hydroxyalkoxylated antisense oligonucleotide of ‘290 wherein the chemical modification of the sugar moiety of one or more nucleotides is a PNA. One of ordinary skill in the art would have been motivated to do so because Aznarez et al. taught that modifying the sugar moiety of an antisense oligonucleotide enhances binding affinity to a target sequence.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claims are allowed.
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.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.T./
Examiner, Art Unit 1637
/Jennifer Dunston/Supervisory Patent Examiner, Art Unit 1637