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
Applicant’s response, including remarks and amendments to the claims, specification, abstract, and drawings, filed February 24, 2026 is acknowledged. Claims 1-6, 9-11, 13, 16-17 were amended, claims 7-8, 12, and 14-15 were cancelled, and claim 18 was newly introduced. Claims 1-6, 9-11, 13, and 16-18 are pending and under examination herein.
Priority
Acknowledgement is made of Applicant’s claim for priority to Application No. EP21211372.4. The certified copy of Application No. EP21211372.4 has been received. Claims 1-6, 9-11, 13, and 16-18 find support in Application No. EP21211372.4, and therefore, the effective filing date of the claims under examination is November 30, 2021.
With respect to claim 18 specifically, the skilled artisan would understand that the invention encompasses chemically modified oligonucleotides which “do[] not comprise stereopure phosphorothioate linkages.” This phrase would be interpreted by the skilled artisan as an oligonucleotide in which the stereochemistry of the phosphorothioate linkages is not controlled. The specification describes oligonucleotides in which the stereochemistry of the phosphorothioate linkages is not controlled (see Tables throughout specification). Support for the limitations of claim 18 is, therefore, implicitly provided, based on the knowledge of the skilled artisan.
Withdrawn Rejections
Applicant’s remarks and amendments have been thoroughly reviewed. Applicant’s amendments to the claims are sufficient to overcome the § 112(b) rejections raised in the prior action, which are withdrawn, accordingly. Applicant’s amendments to claim 1 are sufficient to overcome the § 102 rejections raised over Boudet. Boudet teaches that linkages b and c are phosphorothioate linkages, and does not teach the structural limitations required of nucleotide Nu +1, or the length and symmetry with respect to the central base triplet, as required of the instant claims. The amendments to claim 1 are also sufficient to overcome the § 103 rejections raised over Boudet in view of Merkle, in the manner presented in the previous action. Each of the aforementioned rejections are withdrawn, accordingly.
Applicant’s remarks and amendments have been thoroughly considered. The response is not sufficient to place the claims in condition for allowance for the reasons that follow. Any objection or rejection not reiterated hereinafter has been overcome by amendment.
Notice to Joint Inventors
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 Rejections - 35 USC § 103 – Merkle in view of Boudet
Claims 1-6, 9-11, 13, and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record) in view of Boudet (Boudet, US 2021/0230590 A1, published 29 July 2021; of record). The rejections that follow are new, and necessitated by Applicant’s amendments to the claims.
Regarding claims 1-6, and 16-17, Merkle teaches a chemically modified oligonucleotide for use in site-directed A-to-I editing of a target RNA inside a cell with an endogenous ADAR (“v117.25,” pg. 64, Table 7). See Fig. A below. Merkle’s oligonucleotide has a length within the recited range of 30 to 60 nucleotides (i.e., 59 nucleotides). Merkle’s oligonucleotide comprises a core sequence comprising a central base triplet (underlined in Fig. A), wherein the central nucleotide of the central base triplet is opposite the target adenosine in the target RNA (“The C opposite the target A is highlighted in bold,” pg. 64, Table 7), wherein nucleotide Nu +1 of the central base triplet carries an 2’-deoxy-inosine (“I,” pg. 64, Table 7). The terms “5’ flanking sequence” and “3’ flanking sequence” are interpreted as referring to any 19 or more consecutive nucleotides 5’ of, or 4 or more consecutive nucleotides 3’ of, the central base triplet. As shown in Fig. A below, the triplet is flanked at the 5’ end by a sequence that is at least 19 nucleotides, and flanked at the 3’ end by a sequence that is at least 4 nucleotides, wherein the 5’ flanking sequence is longer than the 3’ flanking sequence. Merkle teaches the editing efficiency of the oligonucleotide with endogenous ADAR, and thus, Merkle’s oligonucleotide must inherently be capable of binding a target sequence in a RNA (Figs. 20-21, pg. 62-65).
FIGURE A. “v117.25” of Table 7 (pg. 64).
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As shown in Fig. A above, Merkle’s oligonucleotide comprises phosphorothioate linkages (*) at linkages a and j, and phosphate linkages at least at linkages b, c, h and i. Merkle does not, however, teach that linkages a, d, and e are also phosphorothioate linkages (claims 1-2, 4, and 16), and that linkages f and/or g are also phosphorothioate linkages (claims 3, 5-6, and 17).
However, Merkle teaches that “choosing the right modification pattern and especially including phosphorothioate linkages could in many cases more than double the editing yields” compared to oligonucleotides without such optimization (i.e., “RESTORE v1 ASOs”) (pg. 70). Merkle strongly suggests even further optimization of the chemical modification pattern to achieve “even higher stability and efficacy” (pg. 70). Merkle demonstrates that phosphorothioate linkage-comprising oligonucleotides in general are capable of directing ADAR editing, although at different efficacies (see Fig. 14 and Table 4, pg. 49-50). Based on Merkle, the skilled artisan would understand that phosphorothioate linkage-comprising oligonucleotides would be functional to promote ADAR editing, and that the positioning of phosphorothioate linkages would influence the efficacy of editing by “stabilizing against nucleases,” and positively and/or negatively influencing ADAR binding (pg. 50).
Like Merkle, Boudet teaches that while phosphorothioate linkages protect an oligonucleotide from nuclease-mediated degradation, the linkages can interfere with intermolecular hydrogen bonding between protein-RNA complexes, e.g., an ADAR and an editing oligonucleotide ([0025]). Boudet teaches that “[t]here is a constant need for improving the pharmacokinetic properties of (RNA) editing oligonucleotides (EONs) without negatively affecting editing efficiency of the target adenosine in the target RNA” ([0017]). Boudet teaches a design strategy that specifically interrogates “where in the oligonucleotide phosphorothioate linkages are tolerated and, if so, if controlling chirality in particular positions where phosphorothioate is tolerated improves the hydrogen bonding interaction between the internucleosidic linkages and those amino acid residues of the enzyme having deamination activity” ([0018]; Examples 1-2). Using ADAR2 as a model editing enzyme, Boudet substitutes phosphodiester linkages for phosphorothioate linkages (and Sp and Rp configurations thereof) in the 24 nucleotides surrounding the edited nucleotide in Idua mRNA-editing oligonucleotide, and determines optimal positions for each linkage type (Examples 1-2; Figs. 2-3). Boudet’s strategy establishes general principles for editing oligonucleotides; certain positions “prefer[] that no phosphorothioate modification should be introduced as it would hamper the EON-protein interaction,” while other positions prefer to “carry an Rp configuration… [or] an Sp configuration,” or exhibit no preference for “the two configurations… as either of the two could be introduced” ([0028]; Fig. 2-3).
Boudet teaches that their strategy “albeit modelled with ADAR2 nucleotide deaminase domain, is not limited thereto, as the teaching of the current disclosure makes that the skilled person can model the stereospecificity for any (editing) oligonucleotide towards any enzyme with nucleotide deaminase activity it interacts with” ([0027]). Boudet teaches that “[t]he skilled person is capable of using methodology in vitro as well as in vivo to determine which of the positions should or should not carry a phosphorothioate modification to obtain the most efficient RNA editing outcome” ([0028]). Boudet teaches that the outcome clearly depends on “the sequence of the EON itself and the target sequence, possibly the structure of the pre-mRNA, the enzyme with ADAR activity that appears to be use (ADAR 1 or ADAR2), the cell in which the RNA editing should occur, etc.” ([0028]). Boudet teaches that their invention “provides the tools for the skilled person to apply this method to make that determination for each possible EON that can be used for any disease that could potentially be targeted by an EON” ([0027]).
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 oligonucleotide of Merkle using the phosphorothioate design strategy of Boudet in order to arrive at an oligonucleotide with the specific phosphorothioate linkages recited in instant claims 1-6, and 16-17. It would have amounted to applying a known oligonucleotide design strategy to a known oligonucleotide, by known means to yield predictable results. Taken together, Boudet and Merkle would have illustrated to the skilled artisan that phosphorothioate linkages are critical to stabilize oligonucleotides and promote RNA editing, but that optimizing their positioning within a particular oligonucleotide is necessary to minimize disruption to the deaminating enzyme within the enzyme-oligonucleotide complex. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide because Boudet teaches their design strategy is applicable to “each possible EON that can be used for any disease that could potentially be targeted by an EON,” and as evidenced by both Boudet and Merkle, preparing editing oligonucleotides with various phosphorothioate modification patterns so as to improve editing efficiency was well within the purview of the skilled artisan. Furthermore, based on Merkle, the skilled artisan would predict that phosphorothioate linkage-comprising oligonucleotides generally are functional to promote ADAR editing. The skilled artisan also would have had a reasonable expectation that such applying the phosphorothioate design strategy would improve the editing efficiency of the oligonucleotide based on the teachings of Boudet and Merkle, which together, demonstrate the beneficial effects of phosphorothioate linkages in optimal positions. The skilled artisan would have been motivated to modify the oligonucleotide because Merkle strongly suggests further optimization of the chemical modification pattern, and the skilled artisan would recognize that the modification would result in an oligonucleotide with improved editing yield for applications of the technology, e.g., methods of treatment.
Regarding claims 9 and 11, as shown in Fig A above, at least 90% of the pyrimidine nucleosides outside of the central base triplet are chemically modified at the 2’ position of the sugar moiety or are deoxyribonucleosides (see nucleosides labeled “f,” which indicate a 2’-fluoro modification), no more than 6 consecutive nucleosides are chemically modified with 2’-O-methyl at the 2’ position of the sugar moiety, and each of the three nucleosides of the central base triplet (i.e., Nu -1, Nu 0, and Nu +1) are deoxyribonucleosides (i.e., they have an H residue at the 2’ position of the ribose) (pg. 64, Table 7).
Regarding claim 10, as shown in Fig. A above, at least 50% of the nucleotides from Nu -5 to Nu +5 comprise one of 2’ fluoro, 2’-O-methyl, or 2’-H at the 2’ position of the ribose (see nucleosides labeled “f,” which indicate a 2’-fluoro modification, and underlined nucleotides, which indicate a 2’-H, pg. 64, Table 7).
Regarding claim 13, as shown in Fig. A above, Nu 0 carries a cytosine.
Regarding claim 18, as described above, the phrase “does not comprise stereopure phosphorothioate linkages” is interpreted as an oligonucleotide in which the stereochemistry of the phosphorothioate linkages is not controlled. When the stereochemistry of a phosphorothioate modified oligonucleotide is not controlled during synthesis, each phosphorothioate linkage may adopt an Rp or Sp configuration. Thus, the structure conferred by the claim is an oligonucleotide in which each phosphorothioate linkage may have an Rp or Sp configuration. This genus of oligonucleotides encompasses oligonucleotides comprising any combination of Rp and Sp phosphorothioate linkages. Merkle’s oligonucleotide comprises phosphorothioate linkages, each of which may have an Rp or Sp configuration. Accordingly, Merkle’s oligonucleotides “do not comprise stereopure phosphorothioate linkages” as interpreted herein.
Response to Remarks – Prior Art
Applicant’s remarks regarding the prior art rejections raised in the previous action have been considered. With the exception of the remarks directed to “New claim 18,” the remarks are moot, because the new grounds of rejection raised herein do not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the remarks.
The remarks directed to “New claim 18” have been considered, but are not found convincing. As described above, the phrase “does not comprise stereopure phosphorothioate linkages” is interpreted as encompassing oligonucleotides in which the stereochemistry of the phosphorothioate linkages is not controlled. The structure conferred by claim 18 is an oligonucleotide in which each phosphorothioate linkage may have an Rp or Sp configuration. Claim 18 is indistinguishable from the prior art applied above, because each phosphorothioate linkage of Merkle’s oligonucleotide may have an Rp or Sp configuration.
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.
Application No. 17/256,092
Claims 1-6, 9-11, 13, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 76 of co-pending Application No. 17/256,092 in view of Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record) and Boudet (Boudet, US 2021/0230590 A1, published 29 July 2021; of record). This is a provisional nonstatutory double patenting rejection. The rejections that follow are new, and necessitated by Applicant’s amendments to the claims.
Co-pending claim 76 recites “An artificial nucleic acid for site-directed editing of a target RNA in a human cell, the artificial nucleic acid comprising a targeting sequence, which comprises a nucleic acid sequence complementary to a target sequence in the target RNA, wherein the artificial nucleic acid is capable of recruiting an adenosine deaminase acting on dsRNA (ADAR),wherein the targeting sequence comprises at least one nucleotide comprising a chemical modification at the 2' position, and at least one modified phosphate group; and wherein at least one of the two nucleotides positioned 5' or 3' of the position corresponding to a nucleotide to be edited in the target sequence comprises a substituent at the 2' carbon atom wherein the substituent is selected from the group consisting of a halogen, an alkoxy group, a hydrogen, an aryloxy group, an amino group and an aminoalkoxy group,” wherein the target RNA is a SERPINA1 transcript.
Co-pending claim 76 recites a chemically modified oligonucleotide for site-directed A-to-I editing of a SERPINA1 transcript, wherein the oligonucleotide comprises at least one nucleotide with a 2’- modification, and at least one modified phosphate group, and wherein the two nucleotides positioned at N -1 and N +1 may have a hydrogen, i.e., and thereby be deoxyribonucleosides.
The co-pending claim is generic with respect to the length of the oligonucleotide and flanking sequences, presence of phosphodiester or phosphorothioate linkages at specific internucleoside linkages relative to the N 0 positioned nucleotide, structure of the Nu +1 and Nu 0 nucleotide, and composition of 2’-modifications.
Regarding claims 1-6, 9-11, 13, and 16-18, the teachings of Merkle and Boudet are described above. Merkle provides chemically modified oligonucleotides for site-directed A-to-I editing of a SERPINA1 transcript inside a cell with endogenous ADAR (pg. 64, Table 7). Merkle’s oligonucleotide v117.25 comprises an optimized length and flanking sequence which meets the limitations of the instant claims, optimized 2’-modifications throughout which meet the limitations of the instant claims, as well as the structures required of the Nu +1 nucleotide and central base triplet of the instant claims (see section 3.5, “RESTORE v2,” pg. 44-64). As described above, Merkle and Boudet also render obvious an oligonucleotide comprising phosphorothioate linkages at the instantly claimed positions.
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 generic SERPINA1-targeting co-pending oligonucleotide using the teachings of Merkle and Boudet in order to arrive at an oligonucleotide recited in instant claims 1-6, 9-11, 13, and 16-18. It would have amounted to applying known SERPINA1-targeting oligonucleotide design features to a generic SERPINA1-targeting oligonucleotide, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide to arrive at the invention of instant claims 1-6, 9-11, 13, and 16-18, because as evidenced by both Merkle and Boudet, preparing editing oligonucleotides with the instantly claimed features was well within the purview of the skilled artisan. The skilled artisan would have had a reasonable expectation that applying the teachings of Merkle and Boudet would improve the editing efficiency based on the teachings of Merkle and Boudet. The skilled artisan would have been motivated to modify the oligonucleotide in an effort to improve editing yield for applications of the technology, e.g., methods of treatment.
Application No. 18/565,733
Claims 1-6, 9-11, 13, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 24 of co-pending Application No. 18/565,733 in view of Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record) and Boudet (Boudet, US 2021/0230590 A1, published 29 July 2021; of record). This is a provisional nonstatutory double patenting rejection. The rejections that follow are new, and necessitated by Applicant’s amendments to the claims.
Co-pending claim 24 recites “A chemically modified oligoribonucleotide for use in site-directed A-to-I editing of a target RNA inside a cell with endogenous ADAR, comprising a sequence with a length from 25 to 80 nucleotides, capable of binding to a target sequence in the target RNA, comprising a Central Base Triplet (CBT) of 3 nucleotides with the central nucleotide opposite to the target adenosine in the target RNA which is to be edited to an inosine, characterized in that a) at least 90% of the pyrimidine nucleosides outside the CBT are chemically modified, either at the 2' position of the sugar moiety, or are deoxyribonucleosides, or a combination thereof, b) no more than 6 consecutive nucleosides are chemically modified with 2'-O-methyl at the 2' position of the sugar moiety, and c) at least two of the three nucleosides of the CBT are chemically modified at the 2' position of the sugar moiety, or are deoxyribonucleosides, or a combination thereof, wherein at least 30% of the linkages between the nucleosides are phosphorothioate (PS) linkages,” wherein the oligonucleotide is for use in treatment or prevention of “alpha1-antitrypsin deficiency by targeting the common E342K mutation in human SERPINA1.”
Co-pending claim 24 recites a chemically modified oligonucleotide for site-directed A-to-I editing of SERPINA1 RNA, wherein the oligonucleotide length substantially overlaps with the length range recited in instant claim 1, and wherein the 2’-modifications meet the limitations recited in instant claim 9.
The co-pending claim is generic with respect to the length of the flanking sequences, presence of phosphodiester or phosphorothioate linkages at specific internucleoside linkages relative to the N 0 positioned nucleotide, and structure of the Nu +1 and Nu 0 nucleotides. The remaining co-pending claims, however, encompass oligonucleotides meeting the limitations of several instant claims (see co-pending claims 8, 12-14, and 17).
Regarding claims 1-6, 9-11, 13, and 16-18, the teachings of Merkle and Boudet are described above. Merkle provides chemically modified oligonucleotides for site-directed A-to-I editing of a SERPINA1 transcript inside a cell with an endogenous ADAR (pg. 64, Table 7). Merkle’s oligonucleotide v117.25 comprises an optimized length and “flanking” sequence which meets the limitations of the instant claims, optimized 2’-modifications throughout which meet the limitations of the instant claims, as well as the structures required of the Nu +1 nucleotide and central base triplet of the instant claims (see section 3.5, “RESTORE v2,” pg. 44-64). As described above, Merkle and Boudet also render obvious an oligonucleotide comprising phosphorothioate linkages at the instantly claimed positions.
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 generic SERPINA1-targeting co-pending oligonucleotide using the teachings of Merkle and Boudet in order to arrive at an oligonucleotide recited in instant claims 1-6, 9-11, 13, and 16-18. It would have amounted to applying known SERPINA1-targeting oligonucleotide design features to a generic SERPINA1-targeting oligonucleotide, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide to arrive at the invention of instant claims 1-6, 9-11, 13, and 16-18, because as evidenced by both Merkle and Boudet, preparing editing oligonucleotides with the instantly claimed features was well within the purview of the skilled artisan. The skilled artisan would have had a reasonable expectation that applying the teachings of Merkle and Boudet would improve the editing efficiency based on the teachings of Merkle and Boudet. The skilled artisan would have been motivated to modify the oligonucleotide in an effort to improve editing yield for applications of the technology, e.g., methods of treatment.
Application No. 18/565,415
Claims 1-6, 9-11, 13, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 41 of co-pending Application No. 18/565,415 in view of Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record) and Boudet (Boudet, US 2021/0230590 A1, published 29 July 2021; of record). This is a provisional nonstatutory double patenting rejection. The rejections that follow are new, and necessitated by Applicant’s amendments to the claims.
Co-pending claim 41 recites a chemically modified oligonucleotide for site-directed A-to-I editing of a SERPINA1 E342K mutation.
Co-pending claim 41 depends from claims which meet several limitations of instant claim 1 (see co-pending claim 6). The claim is generic with respect to the flanking sequences, presence of phosphorothioate linkages at each of the specific internucleoside linkages relative to the N 0 positioned nucleotide (although it is noted that linkages d, e, and optionally f, are phosphorothioate linkages based on co-pending claim 26), and structure of the Nu +1 and Nu 0 nucleotides. The claim also depends from claims which meet the limitations of instant claims 2 (see co-pending claim 15) and 3 (see co-pending claim 26), limitations (b) and (c) of claim 9 (see co-pending claims 1 and 11), claims 10-11 (see co-pending claims 2-3, and 29), and claim 18 (see co-pending claim 23).
Regarding claims 1-6, 9-11, 13, and 16-18, the teachings of Merkle and Boudet are described above. Merkle provides chemically modified oligonucleotides for site-directed A-to-I editing of a SERPINA1 transcript inside a cell with an endogenous ADAR (pg. 64, Table 7). Merkle’s oligonucleotide v117.25 comprises an optimized length and “flanking” sequence which meets the limitations of the instant claims, optimized 2’-modifications throughout which meet the limitations of the instant claims, as well as the structures required of the Nu +1 nucleotide and central base triplet of the instant claims (see section 3.5, “RESTORE v2,” pg. 44-64). As described above, Merkle and Boudet also render obvious an oligonucleotide comprising phosphorothioate linkages at the instantly claimed positions.
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 generic SERPINA1-targeting co-pending oligonucleotide using the teachings of Merkle and Boudet in order to arrive at an oligonucleotide recited in instant claims 1-6, 9-11, 13, and 16-18. It would have amounted to applying known SERPINA1-targeting oligonucleotide design features to a generic SERPINA1-targeting oligonucleotide, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide to arrive at the invention of instant claims 1-6, 9-11, 13, and 16-18, because as evidenced by both Merkle and Boudet, preparing editing oligonucleotides with the instantly claimed features was well within the purview of the skilled artisan. The skilled artisan would have had a reasonable expectation that applying the teachings of Merkle and Boudet would improve the editing efficiency based on the teachings of Merkle and Boudet. The skilled artisan would have been motivated to modify the oligonucleotide in an effort to improve editing yield for applications of the technology, e.g., methods of treatment.
Application No. 19/223,597
Claims 1-6, 9-11, 13, and 16-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 45-60 of co-pending Application No. 19/223,597 in view of Merkle (Merkle, Tobias., “Engineering Antisense Oligonucleotides for Site-directed RNA Editing with Endogenous ADAR,” Eberhard Karls Universitat Tubingen, “Dissertation_Tobias_Merkle.pdf” of 22.6 MB available 21 June 2021 as evidenced by the WayBack Machine; of record) and Boudet (Boudet, US 2021/0230590 A1, published 29 July 2021; of record). This is a provisional nonstatutory double patenting rejection. The rejections that follow are new, and necessitated by Applicant’s amendments to the claims.
Co-pending claim 45 recites a chemically modified oligonucleotide for site-directed A-to-I editing of a SERPINA1 mRNA wherein the oligonucleotide length and flanking sequence lengths substantially overlap with the length range recited in instant claim 1, wherein the phosphorothioate linkages meet the limitations of instant claims 1, 3, and 16-17, the 2’-modifications meet the limitations of (c) in instant claim 9, as well as instant claim 10, the structure of nucleotide Nu 0 meets the limitations of instant claim 13, and the stereopurity limitations meet instant claim 18.
The co-pending claim is generic with respect to which of the linkages are phosphate linkages, the structure of the Nu +1 nucleotide, and the remaining phosphorothioate linkages required of the instant claims.
Regarding claims 1-6, 9-11, 13, and 16-18, the teachings of Merkle and Boudet are described above. Merkle provides chemically modified oligonucleotides for site-directed A-to-I editing of a SERPINA1 transcript inside a cell with an endogenous ADAR (pg. 64, Table 7). Merkle’s oligonucleotide v117.25 comprises an optimized length and “flanking” sequence which meets the limitations of the instant claims, optimized 2’-modifications throughout which meet the limitations of the instant claims, as well as the structures required of the Nu +1 nucleotide and central base triplet of the instant claims (see section 3.5, “RESTORE v2,” pg. 44-64). As described above, Merkle and Boudet also render obvious an oligonucleotide comprising phosphorothioate linkages at the instantly claimed positions.
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 generic SERPINA1-targeting co-pending oligonucleotide using the teachings of Merkle and Boudet in order to arrive at an oligonucleotide recited in instant claims 1-6, 9-11, 13, and 16-18. It would have amounted to applying known SERPINA1-targeting oligonucleotide design features to a generic SERPINA1-targeting oligonucleotide, by known means to yield predictable results. The skilled artisan would have had a reasonable expectation of success in modifying the oligonucleotide to arrive at the invention of instant claims 1-6, 9-11, 13, and 16-18, because as evidenced by both Merkle and Boudet, preparing editing oligonucleotides with the instantly claimed features was well within the purview of the skilled artisan. The skilled artisan would have had a reasonable expectation that applying the teachings of Merkle and Boudet would improve the editing efficiency based on the teachings of Merkle and Boudet. The skilled artisan would have been motivated to modify the oligonucleotide in an effort to improve editing yield for applications of the technology, e.g., methods of treatment.
Response to Remarks – Nonstatutory Double Patenting
Applicant’s remarks regarding the provisional nonstatutory double patenting rejections raised in the previous action have been considered, but are not found persuasive. The instant claims remain indistinct from the co-pending claims in view of the prior art cited above, no terminal disclaimers have been filed, and the nonstatutory double patenting rejections are not the only remaining rejections in the application. The nonstatutory double patenting rejections remain outstanding, accordingly.
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.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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