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 10/31/2025. Claims 1 and 3-20 are currently pending. Applicant canceled claim 2 in the amendments filed on 10/31/2025. No claims are withdrawn from prosecution as being drawn to non-elected subject matter. Accordingly, claims 1 and 3-20 are examined herein.
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.
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 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.
The following rejection has been modified to address the amendments to claim 1, received 10/31/2025. Please see the underlined portions.
Claims 1, 3-12, 14-15 and 18-20 are rejected under 35 U.S.C. § 103 as being unpatentable over WIPO Patent Publication 2014/192310 A1 to Yokota (applicant’s submission on the IDS of 07/12/2022; published 2014-12-04; hereinafter ‘Yokota’).
Regarding claim 1, Yokota teaches a nucleic acid complex comprising a first nucleic acid strand (DNA/LNA gapmer) and a second nucleic acid strand (RNA), wherein said first nucleic acid strand: (1) is capable of hybridizing to at least a part of a target transcriptional product; (2) has an antisense effect on the target transcriptional product and (3) is a gapmer comprising: a central region comprising at least four contiguous deoxyribonucleosides; and a 5' wing region and a 3' wing region each comprising a non-natural nucleoside (LNA), on the 5' end side and the 3' end side of the central region, respectively, said second nucleic acid strand comprises at least one first exposed region and at least one protected region, said first exposed region consists of one sugar-unmodified ribonucleoside or two or three contiguous sugar-unmodified ribonucleosides linked by an internucleoside bond, which is or are complementary to a part of said first nucleic acid strand, said protected region consists of one of (a) a deoxyribonucleoside; (b) a sugar-modified nucleoside; and/or (c) a nucleoside having a modified internucleoside bond on the 3' side, or two or more of said (a) to (c) linked by an internucleoside bond, and said first nucleic acid strand is annealed to said second nucleic acid strand (please see Fig. 4, reproduced and annotated below for convenience):
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Please note in particular constructs E and F in Fig. 4. The top strands of both constructs are gapmers with at least four (actually eight) contiguous DNA molecules flanked by non-natural nucleosides (LNA) at the 5’ and 3’ ends. These are analogous to the instantly recited first nucleic acid strand. It is noted that the Applicant regards the term “exposed region” to mean, “a sugar-unmodified central region (also herein referred to as "first exposed region")” (in para [0009]). Per that definition, the bottom strands of E and F have an exposed region of unmodified 2-3 contiguous sugar-unmodified RNA molecules linked by internucleoside bonds, and that region is complementary to part of the top strand. Both bottom strands also have a protected region comprising a sugar-modified nucleoside (2’-OMe RNA, white boxes) linked by modified (phosphorothioate, black circles) or unmodified (phosphodiester, white circles) internucleoside bonds. The top and bottom (first and second) strands, as required by the claim, are annealed.
Regarding the functional language of claim 1, Applicant defines “antisense effect” as follows (in para [0016]):
The "antisense effect" means the modulation of expression of a target transcriptional product, which results from hybridization of the target transcriptional product (RNA sense strand) with a strand (e.g., DNA strand) that is complementary to a partial sequence of a transcriptional product or the like and is designed to produce an antisense effect.
Consistent with the above definition, Yokota evidences that antisense oligonucleotides comprising DNA (e.g., gapmers) are capable of hybridizing to a target transcriptional product (mRNA of the target gene) and having an antisense effect on that product (inhibiting, i.e. modulating, gene expression) via recruitment of RNase H:
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Yokota also teaches that the second strand (i.e., top strand in Fig. 4, as shown in Fig. 3), “may itself be an antisense oligonucleotide.” (para [0015], p. 5).
The difference between the above teachings and the amended claims is that Fig. 4 of Yokota does not teach wherein the first strand is from 16 to 22 bases in length and the second strand is from 13 to 22 bases in length.
However, Yokota teaches that the length of the first and second strands may be optimized in a range of up to 100 bases for the first strand (analogous to the instantly claimed second strand) and anywhere from 10 to 35 bases for the second strand (analogous to the instantly claimed first strand).
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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 optimized the lengths of the first and second strands of the nucleic acid depending on the particular characteristics of the sequence (e.g., the balance of binding affinity for each base pair, the degree of complementarity, etc.) and conditions in which the nucleic acid is to be used, such as temperature of the biological sample with which the complex is to be contacted. Yokota explicitly suggests that the first and second strands of the complex should be optimized within a range of lengths which encompasses those recited in the claims. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation (In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)).
Regarding claims 3, 5 and 7, in Fig. 4, construct E, Yokota teaches wherein the second strand has only one first exposed region (claim 5) consisting of three contiguous sugar-unmodified natural ribonucleosides (RNA) linked by an internucleoside (phosphodiester) bond (claims 3, 7).
Regarding claim 4, Yokota teaches wherein the first exposed region (i.e., the regions comprising unmodified RNA) of the non-gapmer strand comprises purine bases (adenine)(annotations added by the examiner):
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Regarding claims 6 and 8, please note that because neither the claim nor specification indicate that the exposed regions must be non-contiguous, the broadest reasonable interpretation of the first and second exposed regions encompasses embodiments where the multiple exposed regions are contiguous. Under that interpretation, constructs A and B in Fig. 4 have two exposed regions consisting of four or more contiguous sugar-unmodified ribonucleosides.
Regarding claims 9-12, in any of the constructs in Fig. 4, Yokota teaches wherein at least one of the protected region, including all of the region, comprises a sugar-modified nucleoside (2’-OMe RNA) having a modified internucleoside bond on the 3’ side (see e.g., the first two or three 2’-OMe RNAs in any of the constructs of Fig. 4, which have 3’ phosphorothioate linkages). Regarding the recitation of pyrimidine bases, the same logic as applied to claim 4 applies here.
Regarding claims 14-15 and 18, Yokota teaches the nucleic acid complex wherein the second nucleic acid does not comprise a sugar-unmodified region other than the first/second exposed regions (claims 14, 18) and/or comprises a sugar-modified terminal region comprising at least one sugar-modified nucleoside at the 5’ or 3’ end (claim 15)(please see any of the constructs in Fig. 4).
Regarding claim 19, Yokota teaches the second nucleic acid strand linked to a functional moiety (tocopherol; see Fig. 4), and further teaches that the tocopherol moity has a targeted delivery function:
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Regarding claim 20, Yokota teaches a pharmaceutical composition comprising the nucleic acid agent:
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Claims 13 and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Yokota (of record, cited above), as applied to claims 1, 3-12, 14-15 and 18-20 above, in view of Iwamoto et al. (Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides. Nature Biotechnology volume 35, pages845–851 (2017), of record).
Yokota renders obvious the nucleic acid complex of claim 1, from which instantly rejected claim 13 and 16-17 depend.
Yokota does not teach wherein the exposed region(s) comprise at least one modified internucleoside bond (relevant to claim 13).
Yokota does not teach wherein the exposed region(s) comprise at least one phosphorothioate bond chirally controlled in an Rp or Sp configuration (relevant to claims 16-17).
Iwamoto et al. teach that, “Sp-configured PS linkages are stabilized relative to Rp, providing stereochemical protection from pharmacologic inactivation of the drug. Further, we elucidated a triplet stereochemical code in the stereopure ASOs, 3′-SpSpRp, that promotes target RNA cleavage by RNase H1 in vitro and provides a more durable response in mice than stereorandom ASOs.” (§Abstract)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the exposed (i.e., unprotected from RNase H) region of the nucleic acid complex, as taught by Yokota, by introducing modified and chirally controlled PS linkages, as taught by Iwamoto. As taught by Yokota and discussed in the above rejection of claim 1 under 35 U.S.C. 102, Yokota’s construct induces an antisense effect via RNase H recruitment and cleavage. One having ordinary skill would have been motivated to chirally control the PS linkages in Yokota’s construct based on Iwamoto’s teachings that this promotes RNA cleavage by RNase H1 and provides a more durable in vivo response.
Response to Arguments
Applicant's arguments filed 10/31/2025 have been fully considered but they are not persuasive for the reasons that follow.
In the remarks of 10/31/2025, Applicant argues that, “the presently amended complex as amended differs from the configuration illustrated in Fig. 4, panels E and F in Yokota”, on the basis that, “the first strand, which corresponds to the second strand of the present claims, is 29 bases in length, and the second strand, which corresponds to the first strand of the present claims, is 13 bases in length”. The amended claim recites a range of 16-22 bases for the first strand and 13-22 bases for the second strand. Respectfully, this is not persuasive because, as discussed above in the modified rejection, Yokota teaches that both strands may be optimized within a certain range of lengths which encompass those recited in the claims.
Applicant also argues that, “it is the first nucleic acid strand that comprises a therapeutic oligonucleotide region” (i.e., an antisense region). Respectfully, this argument is not persuasive because, as discussed above in the modified rejection, Yokota teaches that the second strand may also be antisense.
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.
The following rejections have been modified to address the amendments to the claims received 10/31/2025. Please see the underlined portions.
Claims 1, 4-12 and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 10,337,006 in view of Yokota (of record, cited above). Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, where the first strand hybridizes to a transcription target and comprises at least 4 consecutive DNA nucleotides that have an antisense effect (are recognized by RNAse H), one or more nucleotide analogs in the 5’ and 3’ regions, and a second nucleic acid strand with at least 4 consecutive RNA nucleotides that can be cleaved by RNAse H (exposed region) and modified nucleotide analogs located 5’ and 3’ of the exposed region (protected region), wherein the second strand comprises a moiety with a targeted delivery function (tocopherol). While amended claim 1 recites certain ranges of lengths for the first and second strands, Yokota teaches that the length of both strands may be optimized within ranges encompassed by both sets of claims, as discussed in the above rejection of claims 1, 3-12, 14-15 and 18-20 above.
Claims 1, 4-12 and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of U.S. Patent No. 10,329,567 in view of Yokota. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, where the first strand hybridizes to a transcription target and comprises at least 4 consecutive DNA nucleotides that have an antisense effect (are recognized by RNAse H), one or more nucleotide analogs in the 5’ and 3’ regions, and a second nucleic acid strand with at least 4 consecutive RNA nucleotides that can be cleaved by RNAse H (exposed region) and modified nucleotide analogs located 5’ and 3’ of the exposed region (protected region), wherein the second strand comprises a moiety with a targeted delivery function. The dependent patented claims further recite species of modifications, conjugated moieties, and the lengths of the nucleic acids. While amended claim 1 recites certain ranges of lengths for the first and second strands, Yokota teaches that the length of both strands may be optimized within ranges encompassed by both sets of claims, as discussed in the above rejection of claims 1, 3-12, 14-15 and 18-20 above.
Claims 1, 4-12 and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 7-14 of U.S. Patent No. 11,034,955 in view of Yokota. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, where the first strand hybridizes to a transcription target and comprises at least 4 consecutive DNA nucleotides that have an antisense effect (are recognized by RNAse H), one or more nucleotide analogs in the 5’ and 3’ regions, and a second nucleic acid strand with at least 4 consecutive RNA nucleotides that can be cleaved by RNAse H (exposed region) and modified nucleotide analogs located 5’ and 3’ of the exposed region (protected region), wherein the second strand comprises a moiety with a targeted delivery function. The dependent patented claims further recite species of modifications, conjugated moieties, and the lengths of the nucleic acids. While amended claim 1 recites certain ranges of lengths for the first and second strands, Yokota teaches that the length of both strands may be optimized within ranges encompassed by both sets of claims, as discussed in the above rejection of claims 1, 3-12, 14-15 and 18-20 above.
Claims 1, 4-12 and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4-37 of U.S. Patent No. 12,344,841 in view of Yokota. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims are drawn to a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, where the first strand hybridizes to a transcription target and comprises at least 4 consecutive DNA nucleotides that have an antisense effect (are recognized by RNAse H), one or more nucleotide analogs in the 5’ and 3’ regions, and a second nucleic acid strand with at least 4 consecutive RNA nucleotides that can be cleaved by RNAse H (exposed region) and modified nucleotide analogs located 5’ and 3’ of the exposed region (protected region), wherein the second strand comprises a moiety with a targeted delivery function. The dependent patented claims further recite species of modifications, conjugated moieties, and the lengths of the nucleic acids. While amended claim 1 recites certain ranges of lengths for the first and second strands, Yokota teaches that the length of both strands may be optimized within ranges encompassed by both sets of claims, as discussed in the above rejection of claims 1, 3-12, 14-15 and 18-20 above.
The following rejection is in view of the decision of the Court of Appeals for the Federal Circuit in Pfizer Inc, v Teva pharmaceuticals USA Inc., 86 USPQ2d 1001, at page 1008 (March 2008), which indicates that there is no patentable distinction between claims to a product and a method of using that product disclosed in the specification of the application and that the preclusion of such a double patenting rejection under 35 USC 121 does not apply where the present application is other than a divisional application of the patent application containing such patentably indistinct claims.
Claims 1, 4-12 and 18-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 9,816,089 in view of Yokota. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, where the first strand hybridizes to a transcription target and comprises at least 4 consecutive DNA nucleotides that have an antisense effect (are recognized by RNAse H), one or more nucleotide analogs in the 5’ and 3’ regions, and a second nucleic acid strand with at least 4 consecutive RNA nucleotides that can be cleaved by RNAse H (exposed region) and modified nucleotide analogs located 5’ and 3’ of the exposed region (protected region), wherein the second strand comprises a moiety with a targeted delivery function. The dependent patented claims further recite species of modifications, conjugated moieties, and the lengths of the nucleic acids. While amended claim 1 recites certain ranges of lengths for the first and second strands, Yokota teaches that the length of both strands may be optimized within ranges encompassed by both sets of claims, as discussed in the above rejection of claims 1, 3-12, 14-15 and 18-20 above.
Regarding the copending claims limited only to compositions comprising the recited oligonucleotides, the patented method claims are considered obvious over these claims in view of the findings of the court in Sun Pharmaceutical Industries, Ltd. v. Eli Lilly & Co., No. 10-1105 (Fed. Cir. July 28, 2010) in which the court indicated that obviousness-type double patenting encompasses any use for a compound where that use is disclosed in the specification of an earlier patent claiming the compound and is later claimed as a method of using that compound. Thus the invention as a whole was prima facie obvious.
Claims 1, 4-12 and 18-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of copending Application No. 18/392,869 in view of Yokota. Although the claims at issue are not identical, they are not patentably distinct from each other because both sets of claims recite a double-stranded nucleic acid complex comprising a first nucleic acid strand annealed to a second nucleic acid strand, where the first strand hybridizes to a transcription target and comprises at least 4 consecutive DNA nucleotides that have an antisense effect (are recognized by RNAse H), one or more nucleotide analogs in the 5’ and 3’ regions, and a second nucleic acid strand with at least 4 consecutive RNA nucleotides that can be cleaved by RNAse H (exposed region) and modified nucleotide analogs located 5’ and 3’ of the exposed region (protected region), wherein the second strand comprises a moiety with a targeted delivery function. The dependent copending claims further recite species of modifications, conjugated moieties, and the lengths of the nucleic acids. While amended claim 1 recites certain ranges of lengths for the first and second strands, Yokota teaches that the length of both strands may be optimized within ranges encompassed by both sets of claims, as discussed in the above rejection of claims 1, 3-12, 14-15 and 18-20 above.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
Applicant’s arguments with respect to the above rejections have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
No claims are allowed at this time.
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.
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/A.M.Z./Examiner, Art Unit 1636
/BRIAN WHITEMAN/Primary Examiner, Art Unit 1636