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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 17, 2026 has been entered.
Application Status and Restriction/Election
Applicant’s remarks and amendments to the claims filed February 17, 2026 are acknowledged. Claims 1 and 20 were amended, and claims 16, 18, and 20 were cancelled. Claims 1-2, 4-6, and 14-15, 17, 19, and 21-26 are pending.
Claims 25-26 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention. Claims 1-2, 4-6, and 14-15, 17, 19, and 21-24 are under examination herein.
Applicant’s remarks and amendments to the claims have been thoroughly reviewed, but are not persuasive to place the claims in condition for allowance for the reasons that follow. Any rejection or objection not reiterated herein has been overcome by amendment.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed provisional application, Application No. 63/186,342, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Specifically, Application No. 63/186,342, while disclosing instant SEQ ID NOs: 1-114 and 147-156 (Table 1), does not disclose instant SEQ ID NOs: 115-146. The first disclosure of SEQ ID NOs: 115-146 is in the instant application, filed May 10, 2022. Since all claims under examination encompass SEQ ID NO: 144, and this sequence was not disclosed in Application No. 63/186,342, the claims have an effective filing date of May 10, 2022 (i.e., the filing date of the instant application).
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 – Lenk in view of Monia, GenBank, and Freier
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.
Claims 1-2, 4, 6, 14-15, 17, 19, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Lenk (Lenk et al., 2020, Annals of Neurology, 87(3): p. 339-346; of record), in view of Monia (Monia et al., US 2011/0207797 A1, published 25 August 2011; of record), GenBank (Accession: NM_014191.4, available 18 April 2019; of record), and Freier (Freier and Watt, 2007, “Basic Principles of Antisense Drug Discovery,” Chapter 5, Antisense Drug Technology, pg. 117-141; of record). The rejections that follow are maintained from the prior action.
Regarding claims 1-2, and 4, Lenk teaches a composition comprising an oligonucleotide (“Scn8a ASO”) that hybridizes to a segment of an RNA encoding Nav1.6 (“Scn8a transcript”)(“ASO in phosphate-buffered saline (PBS)”, pg. 341, Intracerebroventricular Administration of ASOs). Lenk teaches the oligonucleotide knocks down expression of Nav1.6 mRNA and prevents translation of the RNA into the sodium channel protein (Fig. 1A-C, 2E)(pg. 340, Antisense Oligonucleotides; Fig. 1). Lenk teaches the oligonucleotide functions via RNase H cleavage (“Antisense oligonucleotides (ASOs) hybridize by Watson-Crick base pairing to mRNAs, leading to degradation by ribonuclease H, inhibition of translation, or altered splicing,” pg. 340, left col.). Lenk teaches the oligonucleotide is 20-nts in length, and has a 5-10-5 gapmer structure comprising a central DNA segment flanked by 2’-O-methoxyethyl (MOE) modified RNA wings (“ASOs are 20 base pair (bp) gapmers with 5 2’-O-methoxyethyl-modified nucleotides at each end and 10 DNA nucleotides in the center”, pg. 340, Antisense Oligonucleotides).
Regarding claim 14, Lenk teaches the composition exhibits a dose-dependent knockdown of Nav1.6 mRNA when delivered to cells in vitro (“relative transcript level in cultured neurons”, Fig. 1B).
Regarding claim 22, Lenk teaches the oligonucleotide knocks down expression of an SCN8A transcript to an amount about 50-90% compared to an un-treated control (“untreated wildtype” v. “Scn8a ASO”, Fig. 1C).
Lenk teaches the oligonucleotide prolong survivals and remedies symptoms in mice models of SCN8A encephalopathy (Fig. 2-4). Lenk teaches that they provide “the first preclinical evidence that therapeutic reduction of Scn8A transcript could delay the onset of spontaneous convulsive seizures in patients with SCN8A encephalopathy” (pg. 345, right col.). Lenk states that clinical application of their findings “will also require prevention of deleterious effects associated with more extensive reduction of SCN8A expression” (pg. 345, right col.). Lenk indicates that oligonucleotide treatments that reduce SCN8A expression to approximately 50% of wild-type expression will prevent seizures, with only mild side effects (pg. 345, left col.). Lenk states that reduction of brain transcripts to below 5% is lethal, and reduction to 10% results in adverse side effects, e.g., dystonia, muscle wasting, and reduced body weight (pg. 345, left col.).
Lenk does not teach that the oligonucleotide:
has a central DNA segment 12 nucleotides in length, flanked by wings comprising four consecutive 2’-MOE modified nucleobases;
comprises a plurality of phosphorothioate linkages;
comprises all cytosine bases substituted with 5-methylcytosine; and
has a sequence identical to one of the SEQ ID NOs recited in claim 1.
Regarding (I-III), Monia teaches “gap-widened” oligonucleotides which have “an improved therapeutic index as compared to a corresponding antisense oligonucleotide having a 5-10-5 MOE gapmer antisense oligonucleotide with the same sequence” ([0005]). Monia teaches the gap-widened oligonucleotides comprise a central DNA segment of at least 11 nucleotides, wing regions comprising 2-MOE modified nucleobases, wherein all linkages are phosphorothioate linkages, and all cytosines throughout the oligonucleotide are 5-methylcytosine ([0005]; see oligonucleotides used throughout Examples). Monia teaches gap-widened oligonucleotides in which a central DNA segment 12 nucleotides in length is flanked on either side by wings comprising four consecutive 2’-MOE modified nucleobases (“4-12-4,” [0018]; Examples 10-13). Monia demonstrates use of 4-12-4 2’-MOE gapmers in vivo (Examples 10-12). Monia concludes that the 4-12-4 2’-MOE gapmers function dose-dependently (Example 13, Table 15c), and are more potent (i.e., requiring less oligonucleotide to reach the same level of knockdown) than 5-10-5 2’-MOE gapmers of the same sequence (Example 10, Table 11c; Example 13, Table 16).
Regarding (IV), Monia teaches that the oligonucleotides are designed to be fully complementary to their target RNA ([0100]; [0102]; Table 19). Monia also teaches a method to identify gap-widened oligonucleotides with an improved therapeutic index comprising I) screening a plurality of oligonucleotides targeting a human RNA and having a single wing-gap-wing motif, II) identifying a parent oligonucleotide having a potent in vitro activity, III) synthesizing a plurality of gap-widened oligonucleotides having the sequence of the parent oligonucleotide, and IV) testing the gap-widened oligonucleotides in a plurality of animals ([0007]-[0018]). Monia points the skilled artisan to specific gap-widened structures: 2-16-2, 3-14-3, or 4-12-4 ([0015]; [0018]).
Monia does not teach the RNA sequence encoding Nav1.6 mRNA (i.e., SCN8A mRNA). However, GenBank teaches the sequence of human SCN8A mRNA to which each of the SEQ ID NOs recited in instant claim 1 are 100% complementary. See alignment of record between SEQ ID NOs: 1-156 and NM_014191.4 in the office action appendix dated 4 January 2024 (38 pages).
None of Lenk, Monia, or GenBank teach the level of predictability of Monia’s method. However, Freier teaches that although “hit rates” vary by target, typically about 1/3 of tested ASOs reduce target mRNA below 40% control; 12% reduce target mRNA to below 25% control; and 7% reduce to below 20% control (section 5.2.8, pg. 127). Freier teaches that “it is advantageous to find the most potent drug because therapeutic doses will be smaller, ultimately improving therapeutic index and reducing manufacturing costs” (section 5.2.8, pg. 127). Freier teaches that screening methods are well-known, and that the “the incremental cost of screening more compounds is small” (section 5.2.8, pg. 127).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have prepared a plurality of oligonucleotides fully complementary to the human SCN8A mRNA disclosed by GenBank, and subsequently, prepared a plurality of oligonucleotides with a gap-widened structure taught by Monia (i.e., 4-12-4), in which all linkages are phosphorothioate, and all cytosines comprise a 5-methyl modification. It would have amounted to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
Lenk teaches a oligonucleotide 20-nts in length and complementary to an SCN8A mRNA which knocks down expression of SCN8A mRNA, prevents translation of Nav1.6, and provides a therapeutic effect in mice models of SCN8A encephalopathy. Lenk teaches that clinical application of their findings will require prevention of deleterious effects associated with more extensive reduction of SCN8A expression (pg. 345, right col.). Lenk states that reduction of brain transcripts to 10% results in adverse side effects, and below 5% is lethal (pg. 345, left col.). Lenk indicates that oligonucleotide treatments that reduce SCN8A expression to approximately 50% of wild-type expression will prevent seizures, with only mild side effects (pg. 345, left col.). Thus, it was known in the art before the effective filing date that the knockdown levels of an SCN8A mRNA-targeting oligonucleotide would need to be within an optimal range for therapeutic effects in vivo. Together with Monia and Freier, there is substantial motivation and guidance to prepare a plurality of oligonucleotides 100% complementary to human SCN8A mRNA, identify oligonucleotides with optimal knockdown levels, and prepare 4-12-4 gap-widened oligonucleotides which would be expected to have improved therapeutic indices relative to 5-10-5 gapmers.
The human SCN8A mRNA taught by GenBank is 11,559bp long, and thus, there are 11,539 possible oligonucleotides which are 20nts long (the length of the oligonucleotide of Lenk) and 100% complementary to the SCN8A mRNA. Among the 11,539 possible oligonucleotides are the SEQ ID NOs recited in instant claim 1. The skilled artisan could have pursued the finite, identified solutions with a reasonable expectation of success because I) based on Freier, the skilled artisan would predict that a significant percentage of oligonucleotides 100% complementary to the SCN8A mRNA would knockdown expression within the optimal range identified by Lenk, and II) based on Monia and Freier, it was well within the capabilities of one of ordinary skill to design and order oligonucleotides which are 100% complementary to a known mRNA sequence with a known gapmer structure, deliver them to cells to determine their ability to knock down SCN8A mRNA, and order selected oligonucleotides with a known 4-12-4 gap-widened structure and test their effectivity in vivo. The skilled artisan would have been motivated to do so because I) Lenk teaches an effective gapmer to treat SCN8A encephalopathy, but suggests that clinical application of their findings will require identifying oligonucleotides which function within an optimal range in vivo, and II) Monia teaches specific gap-widened oligonucleotides, including 4-12-4 gapmer structured oligonucleotides, which would be predicted to be more potent than Lenk’s 5-10-5 gapmer, and both Freier and Monia teach that more potent oligonucleotides have greater therapeutic indices.
Regarding claim 6, the central DNA segment of a 4-12-4 gap-widened oligonucleotide rendered obvious above is at least 9 bases.
Regarding claims 15 and 17, the 4-12-4 gap-widened oligonucleotide rendered obvious above comprises only phosphorothioate linkages, which also meets the term “majority” recited in claim 17, a central DNA segment of 12 nucleosides, and modified RNA wings comprising four consecutive 2’-MOE bases.
Regarding claim 19, the obviousness of arriving at one of the recited SEQ ID NOs which hybridize to a location within the first 3700 bases of an SCN8A transcript (e.g., any of the SEQ ID NOs recited in claim 1, see Table 1 of the specification) is described above and applied here.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Lenk (Lenk et al., 2020, Annals of Neurology, 87(3): p. 339-346; of record), Monia (Monia et al., US 2011/0207797 A1, published 25 August 2011; of record), GenBank (Accession: NM_014191.4, available 18 April 2019; of record) and Freier (Freier and Watt, 2007, “Basic Principles of Antisense Drug Discovery,” Chapter 5, Antisense Drug Technology, pg. 117-141; of record) as applied to claims 1-2, 4, 6, 14-15, 17, 19, and 22 above, as evidenced by Kennedy (Kennedy et al., 2022, In: Arechavala-Gomeza, V., Garanto, A. (eds) Antisense RNA Design, Delivery, and Analysis. Methods in Molecular Biology, Vol. 2434, Chapter 24, pg. 345-353; of record). This rejection is maintained from the prior action.
The teachings of Lenk, Monia, GenBank, and Freier are described above and applied as to claims 1-2, 4, 6, 14-15, 17, 19, and 22 therein.
Regarding claim 5, Lenk injects the composition intracerebroventricularly, but is silent as to whether phosphate-buffered saline (PBS) is formulated for intrathecal injection.
However, Kennedy teaches that PBS is a suitable solution for intrathecal injection (“adjust to the desired concentration using sterile 1 x PBS”, pg. 347, 3.1 Preparation of Test Oligonucleotides; “load the Hamilton Syringe with a test compound”, pg. 348, 3.2 Direct Intrathecal Injection). Thus, Lenk inherently teaches that the oligonucleotide is provided in a solution formulated for intrathecal injection.
Claim Rejections - 35 USC § 103 – Lenk, Monia, GenBank, and Freier in view of Jafar-Nejad, Peng-Ho
Claims 21, and 23-24 are rejected under 35 U.S.C. 103 as being unpatentable over Lenk (Lenk et al., 2020, Annals of Neurology, 87(3): p. 339-346; of record), Monia (Monia et al., US 2011/0207797 A1, published 25 August 2011; of record), GenBank (Accession: NM_014191.4, available 18 April 2019; of record) and Freier (Freier and Watt, 2007, “Basic Principles of Antisense Drug Discovery,” Chapter 5, Antisense Drug Technology, pg. 117-141; of record) as applied to claims 1-2, 4, 6, 14-15, 17, 19, and 22 above, in further view of Jafar-Nejad (Jafar-Nejad et al., WO 2022/032060 A2, effectively filed 7 August 2020; of record) and Peng Ho (Peng Ho et al., 1998, Molecular Brain Research, 62 (1998) pg. 1-11; of record). The rejections that follow are maintained from the prior action.
The teachings of Lenk, Monia, GenBank, and Freier are described above and applied as to claims 1-2, 4, 6, 14-15, 17, 19, and 22 therein. As described therein, the prior art renders obvious a composition comprising an oligonucleotide having one of the SEQ ID NOs recited in instant claim 1, wherein the oligonucleotide is 20-nts in length and has a 4-12-4 gapmer structure comprising a central DNA segment flanked by 2’-MOE wings, wherein all cytosine bases in the oligonucleotide comprise a 5-methyl modification, and the oligonucleotide is fully phosphorothioated.
Regarding claim 24, Lenk also teaches the oligonucleotide knocks down expression of an SCN8A transcript to an amount about 50 to 70% when delivered to cells at about 1000nM concentration compared to a control (“1µM”, Fig. 1C; “using as endogenous control the Tata binding protein mRNA… Relative transcript quantity was calculated by the CT method”, pg. 341-342, Quantitative Reverse Transcription Polymerase Chain Reaction).
None of Lenk, Monia, GenBank, or Freier teach that each wing has 1-3 phosphodiester linkages, with remaining linkages being phosphorothioate (claim 21), or that the 2nd, 3rd, and 18th , or 2nd, 3rd, 4th, and 18th linkages are phosphodiester linkages, with remaining linkages being phosphorothioate (claim 23).
Jafar-Nejad teaches similar gapmer structured oligonucleotides to Lenk and Monia, which target a different sodium channel mRNA involved in encephalopathy, SCN2A mRNA (“Summary of the Invention,” pg. 2; section B(1)-(3), pg. 41-44). Jafar-Nejad teaches gapmer oligonucleotides in which each wing has 1-3 phosphodiester linkages, and the remaining linkages in the oligonucleotide are phosphorothioate (“the sugar motif of a modified oligonucleotides is a gapmer, and the internucleoside linkage motif comprises at least one phosphodiester internucleoside linkage in at least one wing, wherein the at least one phosphodiester internucleoside linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages,” “sooosssssssssooss,” section (B)(3), pg. 44; “Embodiment 62,” pg. 17; “sooossssssssssoooss,” pg. 75).
Peng Ho teaches that while phosphorothioate modifications promote stability of modified oligonucleotides, increasing evidence indicates that phosphorothioate modified oligonucleotides cause CNS-specific toxicities (pg. 1, right col.; section 3.1). Peng Ho demonstrates that phosphodiester oligonucleotides have lower efficacy, but are less toxic (section 3.3). Peng Ho teaches that relative to fully phosphorothioated oligonucleotides, “chimeric” phosphorothioate oligonucleotides, in which phosphorothioate linkages are replaced with phosphodiester linkages, have improved efficacy and no apparent toxicity (section 3.4).
Regarding claim 21, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted between 1-3 phosphorothioate linkages in the wings of the oligonucleotide rendered obvious above, for phosphodiester linkages in view of Jafar-Nejad and Peng Ho. It would have amounted to applying a known chemical modification design strategy, to an obvious oligonucleotide, by known means to yield predictable results. Peng Ho teaches that phosphorothioate internucleoside linkages are associated with CNS-specific toxicities, and that limiting the number of phosphorothioate linkages reduces toxicity and preserves efficacy. Jafar-Nejad teaches gapmer oligonucleotides which are similar in structure and intended use to the obvious oligonucleotide, and which have 1-3 phosphodiester linkages in each wing. Based on Jafar-Nejad and Peng Ho, it was well within the purview of the skilled artisan to design and use chimeric oligonucleotides in which selected internucleoside linkages were phosphodiester linkages. Given that the oligonucleotide rendered obvious above would be a potential therapeutic for a nervous system disease, based on the teachings of Peng Ho regarding CNS toxicity of fully phosphorothioated oligonucleotides, the skilled artisan would have been motivated to substitute 1-3 phosphorothioate linkages in the wings as taught by Jafar-Nejad, for phosphodiester linkages.
Regarding claims 23-24, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted 1-3 phosphorothioate linkages in the wings of the oligonucleotide rendered obvious above, to arrive at the linkage patterns recited in claim 23. It would have amounted to choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success.
It was known in the prior art that fully phosphorothioated oligonucleotides, while increasing oligonucleotide stability, have increased toxicity. Peng Ho demonstrates that reducing the number of phosphorothioate linkages, by replacing them with phosphodiester linkages, is a suitable strategy to reduce toxicity but maintain efficacy. Jafar-Nejad teaches oligonucleotides which are similar in structure and intended use to the obvious oligonucleotide, in which 1-3 phosphorothioate linkages in the wings are replaced with phosphodiester linkages. Jafar-Nejad teaches “the at least one phosphodiester internucleoside linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages.”
In the 4-12-4 gap-widened oligonucleotide rendered obvious above, there are 4 internucleoside linkages in each wing (between the 1st and 2nd nucleotide, 2nd and 3rd, 3rd and 4th, and 4th and 5th, wherein the 5th nucleotide is the first nucleotide in the deoxy gap; between the 16th and 17th nucleotide, wherein the 16th nucleotide is the last nucleotide in the deoxy gap, 17th and 18th, 18th and 19th, and 19th and 20th). Jafar-Nejad teaches that “the at least one phosphodiester internucleoside linkage is not a terminal internucleoside linkage,” which excludes the linkages between 1st and 2nd, and 19th and 20th nucleotides. There are, therefore, 3 remaining internucleoside linkages in each wing of the 4-12-4 gap-widened oligonucleotide which may be either a phosphodiester or phosphorothioate. Thus, there are 64 (26) possible 4-12-4 oligonucleotides in which each non-terminal internucleoside linkage in the wing is either a phosphodiester or phosphorothioate linkage. A skilled artisan could have pursued the finite, identified solutions with a reasonable expectation of success because as evidenced by Jafar-Nejad and Peng Ho, it was well within the capabilities of one of ordinary skill to design and use oligonucleotides with desired combinations of internucleoside linkages. The skilled artisan would have been motivated to pursue the solutions in an effort to balance the stability of the oligonucleotide with the potential toxic effects on the CNS in vivo described by Peng Ho.
Response to Remarks – § 103
Applicant’s arguments with respect to the § 103 rejections made in the prior action have been thoroughly considered, but are not found persuasive to overcome the rejections of record for the reasons that follow.
Applicant argues that “the amended claims are not obvious because the cited references, alone or in combination, fail to disclose all the elements of the amended claims” (pg. 5, remarks). Applicant refers to the amendments to the claims, and submits that “[t]he cited references fail to teach or suggest a composition comprising an oligonucleotide having any of the sequences recited in amended claim 1” (pg. 6, remarks). These arguments have been considered, but are not found convincing because I) they amount to mere statements of patentability, and II) the obviousness rejections above arrives at the instantly claimed compositions based on the teachings of the cited prior art as they would be understood by the skilled artisan.
Applicant’s remarks on pgs. 6-7 analyze each of the cited references separately, i.e., identifying alleged differences between each cited reference and the instantly claimed composition. Examiner has acknowledged the differences between the primary reference, Lenk, and the instantly claimed composition in paragraph 8 of the prior action and above. Lenk was not cited for teaching the specific sequences or 4-12-4 gapmer structure, Monia was not cited for the specific SCN8A-targeting sequences recited in the claims, and neither GenBank nor Freier were cited for teaching an SCN8A-targeting oligonucleotide. In order to arrive at the instantly claimed composition, Examiner has applied Lenk with respect to the SCN8A-targeting oligonucleotide and basic gapmer structure applied thereto, Monia with respect to the 4-12-4 structure of the oligonucleotide, GenBank with respect to the sequence of the oligonucleotide, and Freier to support the predictability of, and motivation to use, Monia’s screening method to arrive at the instantly claimed oligonucleotides. Applicant’s remarks about the alleged deficiencies of each of the references separately is not convincing, because the obviousness rejection above is based on the combination of references, and no singular reference is cited as, or required to, teach each feature of the instantly claimed composition in order to render the composition obvious.
Applicant also submits that Monia’s disclosure is not relevant to any CNS target, e.g., SCN8A as in the instant claims, because “Monia’s entire disclosure is directed to liver targets” (pg. 6 of remarks). Applicant alleges that “[t]he pharmacokinetics and pharmacodynamics of oligonucleotides in the CNS differ from the liver,” and that “uptake in hepatocytes proceeds through receptor-mediated endocytosis pathways that are absent in neurons” (pg. 6, remarks). First, the claims under examination are directed to a composition comprising an antisense oligonucleotide which has neither a required target mRNA, level of target mRNA inhibition, or a therapeutic outcome. Applicant’s remarks rely on matter which is not claimed. Nevertheless, Applicant’s remarks will be addressed hereinafter.
Examiner acknowledges that Monia’s in vivo data is based on liver targets. However, the skilled artisan would not have interpreted Monia’s teachings regarding the improved features of gap-widened oligonucleotides as applying exclusively to liver targets because I) Monia does not explicitly state that the features do not apply to other targets, and II) Monia’s statements regarding the improved features are general (e.g., “The gap-widened antisense oligonucleotide of the present invention have been shown to have an improved therapeutic index as compared to a corresponding antisense oligonucleotide having a 5-10-5 MOE ga[p]mer antisense oligonucleotide with the same sequence…,” [0005]). The skilled artisan would have also been familiar with Siwkowski (Monia et al., 2007, Optimization of Second-Generation Antisense Drugs: Going Beyond Generation 2.0,” Ch. 17, 2nd edition, pgs. 487-506), which is cited herein solely to respond to Applicant’s arguments, which provides a mechanism to explain the improved features of gap-widened oligonucleotides (“2’ modifications in the gapmer wings were found to inhibit RNase H activity directly, suggesting that gapmers with shorter wings would serve as better substrates for RNase H relative to oligonucleotides with longer wing… these findings, suggested that ASO potency might be improved by optimizing deoxy gap length and wing content when utilizing an RNase H mechanism of action,” pg. 491-492). The skilled artisan would have recognized that this mechanistic explanation applies to gapmer-based oligonucleotides in general, regardless of the target. The skilled artisan would also have known that uptake of an oligonucleotide by neurons does, indeed, proceed primarily through receptor-mediated endocytosis. See Geary (Geary et al., 2015, Advanced Drug Delivery Reviews, 87 (2015), pg. 46-51), which is cited herein solely to respond to Applicant’s remarks, and which provides that “[t]he great majority of intracellular oligonucleotide distribution systemically or in the CNS occurs rapidly in just a few hours following administration and is facilitated by rapid endocytotic uptake mechanisms” (Abstract; pg. 47-49; Conclusion). Applicant has not presented evidence to support the claims that the skilled artisan would have doubted the general applicability of widening the gap of an RNase H-based antisense oligonucleotide to improve therapeutic efficacy, or predicted that such an oligonucleotide would been non-functional in CNS tissue based on the prior art.
Applicant also alleges that Monia’s data describes a “disconnect” between in vitro screening and in vivo gap-widened performance. Applicant alleges that Monia’s data supports that “in vitro activity does not predict in vivo activity for gap-widened gapmers” (pg. 7, remarks). Examiner acknowledges that Monia teaches that “there is a lack of correlation between the in vitro potency and the in vivo potency of the gap-widened antisense oligonucleotides described herein” ([0005]). The skilled artisan would have known that in vitro and in vivo efficacies of antisense oligonucleotides do not always correlate, e.g., depending on the target and tissue (Freier, pg. 138). This is a known feature of antisense oligonucleotide technology, which would likely have motivated the skilled artisan to prepare and screen antisense oligonucleotides so as to arrive at the instantly claimed composition, rather than have deterred the skilled artisan from doing so. Applicant has not presented any evidence that Monia’s observation, when considered by the skilled artisan familiar with antisense oligonucleotide technology, would have deterred the skilled artisan from preparing SCN8A-targeting antisense oligonucleotides 100% complementary to the known SCN8A target sequence in view of Lenk, and applying a known, potency improving gapmer structure thereto in view of Monia, so as to develop oligonucleotides for use in Lenk’s methods. Applicant also cites on pg. 7, that Freier teaches that computational methods for predicting antisense activity yield “disappointing” results, and have not “resulted in identification of leads with greater potency than those identified by more traditional screens.” The skilled artisan would have been well aware of the “disappointing” results of computational methods to identify antisense oligonucleotides for a particular application. Freier’s teachings, rather than teaching away from preparing and screening SCN8A-targeting antisense oligonucleotides, would have provided further motivation to prepare and screen SCN8A-targeting oligonucleotides with known design features. It is not evident how Freier’s teachings regarding computational methods, lends unpredictability in arriving at the instantly claimed compositions based on the prior art.
Applicant’s remarks bridging pgs. 7-8 regarding the alleged unpredictability of arriving at the instantly claimed oligonucleotide based on the number of possibilities have already been addressed in paragraph 29 of the prior action. These remarks are unconvincing for the reasons cited therein, which are applied here.
Applicant’s remarks on pg. 8 regarding the alleged unpredictability of arriving at the instantly claimed oligonucleotides based on Freier have already been addressed in paragraph 28 of the prior action. These remarks are unconvincing for the reasons cited therein, which are applied here. Applicant also alleges that “A skilled artisan could not have used Freier’s 5-10-5 in vitro hit rates to predict which sequences would be effective as 4-12-4 gapmers in the CNS.” Examiner notes that no such claim has been made in the prior actions or above. Freier has been cited, in the prior action and above, to demonstrate that the skilled artisan would have expected that a significant number of the oligonucleotides prepared would have been functional at levels of knockdown relevant to the methods taught by Lenk, that preparing and screening oligonucleotides was well within the purview of the skilled artisan, and that improving potency was an outcome the prior art recognized as desirable for methods such as Lenk’s.
Applicant’s remarks regarding the alleged unexpected effectivity and selectivity of the claimed oligonucleotides has also been considered. The claims have been amended so as to recite a narrower range of SEQ ID NOs, but the claims are still not commensurate with the data proffered to support Applicant’s alleged unexpected results. The claims are not “limited to fifteen specific sequences” as Applicant’s alleges, or to the specific antisense oligonucleotides which Applicant refers to support the alleged unexpected results. The claims are directed to a composition comprising any one of a genus of oligonucleotides comprising one of the recited SEQ ID NOs, with any gapmer structure, and any number and configuration of chemical modifications.
Taken together, Applicant’s remarks are not sufficient to overcome the rejections raised in the prior action, which are maintained herein.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JENNA L PERSONS whose telephone number is (703)756-1334. The examiner can normally be reached M-F: 9-5pm.
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/JENNA L PERSONS/Examiner, Art Unit 1637
/Soren Harward/Primary Examiner, TC 1600
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