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 .
Priority
Applicant’s claim to priority from US Provisional Application No. 63/298,019 filed 01/10/2022 is hereby acknowledged.
Application Status
This Office Action is in response to Amendments and Remarks filed 06/22/2026.
Amendments to claims filed 06/22/2026 are hereby acknowledged. Claims 1, 45, 68 and 187 are currently amended. Claims 2-44, 46-67, 69-186 and 194 are cancelled. Claims 195-203 are newly added.
Claims 1, 45, 68, 187-193 and 195-203 are currently pending and under consideration in this office action.
Any objection or rejection not reiterated herein has been overcome by amendments and is therefore withdrawn.
Applicant’s amendments and arguments have been thoroughly reviewed but are not persuasive to place all the claims in condition for allowance for the reasons that follows.
The following rejections are new and necessitated by Applicant’s amendments:
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 45 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 45 depends from Claim 1, which requires that the dsRNA molecule comprises about 75-80% 2’-O-methyl nucleotide content. Claim 45 requires that both the antisense strand and the sense strand comprise alternating 2’-methoxy-ribonucleotides and 2’-Fluoro-ribonucleotides. This means that the dsRNA comprises at most 50% of 2’-O-methyl nucleotide content. Claim 45 fails to include all the limitation of the claim it depends on.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or non-obviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 45, 68, 187-192, 195-198 and 203 are rejected under 35 U.S.C. §103 as being unpatentable over Freier (Freier, S.M. et al. US 11,129,844 B2, published September 28, 2021; cited previously) in view of Bertrand (Bertrand, J-R. et al. "Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo". Biochemical and Biophysical Research Communications, Vol. 296 (2002), pp: 1000-1004; cited previously), Kraynack (Kraynack, B.A. et al. “Small interfering RNAs containing full 2’-O-methylribonucleotide-modified sense strands display Argonaute2/eIF2C2-dependent activity”. RNA, Vol. 12 (2006), pp: 163-176), Rodrigues (Rodrigues, D.C. et al. “Regulation, diversity and function of MECP2 exon and 3’UTR isoforms”. Human Molecular Genetics, Vol. 29, No. R1 (2020), pp: R90-R100) and Khvorova’899 (Khvorova, A. et al. WO 2020/033899 A1; published February 13, 2020).
Regarding claim 1, Freier teaches antisense oligonucleotides that target a MECP2 nucleic acid sequences that are set forth in GENBANK Accession No. NT_167198.1 truncated from nucleotides 4203000 and taught as SEQ ID NO: 1 (see column 17, lines 40-45).
Freier teaches antisense oligonucleotides that are complementary to the hotspots nucleic acid sequence of MECP2 mRNA ( column 36, lines 45-50), and specifically an oligonucleotide comprising SEQ ID NO: 5 of instant Application, i.e. SEQ ID NO: 171 of Freier, an oligonucleotide with 20 nucleobases in length complementary to nucleotides (nt) of SEQ ID NO: 1 of Freier from nt 69324 to nt 69343 in the last taught hotspot region 69072-69351 of SEQ ID NO: 1 (see Table 2, column 52, and column 201; hotspot regions: see column 36, lines 45-55).
A search result and an alignment of SEQ ID NO: 5 (Qy) with SEQ ID NO: 171 of Freier (Db) is shown below:
RESULT 3
US-16-535-888-171/c
(NOTE: this sequence has 1 duplicate in the database searched.
See complete list at the end of this report)
Sequence 171, US/16535888
Patent No. 11129844
GENERAL INFORMATION
APPLICANT: Ionis Pharmaceuticals, Inc.
TITLE OF INVENTION: COMPOSITIONS FOR MODULATING MECP2 EXPRESSION
FILE REFERENCE: BIOL0264WO
CURRENT APPLICATION NUMBER: US/16/535,888
CURRENT FILING DATE: 2019-08-08
PRIOR APPLICATION NUMBER: 62/127,682
PRIOR FILING DATE: 2015-03-03
NUMBER OF SEQ ID NOS: 328
SEQ ID NO 171
LENGTH: 20
TYPE: DNA
ORGANISM: Artificial sequence
FEATURE:
OTHER INFORMATION: Synthetic oligonucleotide
Query Match 100.0%; Score 16; Length 20;
Best Local Similarity 100.0%;
Matches 16; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 ACAAAGCTTCCCGATT 16
||||||||||||||||
Db 18 ACAAAGCTTCCCGATT 3
Therefore, Freier teaches an antisense strand of 20 contiguous nucleotides comprising a sequence 100% complementary to nucleotides 1 to 16 of SEQ ID NO: 5 of instant Application. The Antisense oligonucleotide is also substantially complementary to a MECP2 mRNA; the complementarity of the antisense strand is 100% over 16 contiguous nucleotides in this antisense oligonucleotide with SEQ ID NO: 171.
Freier also teaches that this specific ASO of SEQ ID NO: 171 triggers a 78% inhibition in expression of MECP2 mRNA (see Table 2, column 52).
Regarding claim 1, Freier does not teach a double stranded RNA (dsRNA) molecule.
However, Bertrand teaches comparison between antisense oligonucleotides (ASOs) with siRNAs in cell culture and in vivo (see title).
Bertrand teaches an ASO protected with two phosphorothioates in 3’ and two phosphorothioates in 5’ and a 22 base pair siRNA targeted both against the coding region of a green fluorescent protein (GFP). Bertrand teaches that the siRNA inhibition rises to 70% efficacy after 5 hours, while the ASO only rises to 50% after the same amount of time, then decreases to zero at 20hours. The siRNA efficiency keeps rising to 80% at 20hours (see Figure 3 on page 1002).
Bertrand also teaches that a double stranded RNA is more stable (75% remaining after 24hours in Hela cells lysate) than a single stranded RNA or a single stranded DNA (see Figure 6, page 1004). Bertrand’s teachings suggest that the prolonged effect of siRNA compared to the ASO’s effect, is likely due to a longer half-life of the siRNA, and to sequestration of ASO in cellular compartments away from interaction with the mRNA, and therefore maintaining it inactive (see page 1003, left column, lines 10-25).
Bertrand concludes that siRNA duplexes are very resistant to biodegradation in fetal calf serum or human plasma. Bertrand also teaches that siRNA are tools to specifically inhibit the gene expression in vivo as they are powerful agents in cell culture and are more resistant to degradation (see page 1004, right column, first paragraph).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have substituted the ASO comprising an antisense strand complementary to instant SEQ ID NO: 5, i.e., a 20 nucleobases oligonucleotide of SEQ ID NO: 171 as taught by Freier, with a double stranded RNA targeting the same region for RNA interference, as taught by Bertrand. One with ordinary skills in the art, motivated in targeting a “hotspot” for MECP2 mRNA expression inhibition using a more stable molecule, leading to a longer effect, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
The combination of Freier and Bertrand does not teach a dsRNA molecule comprising 75-80% of 2’-O-methyl nucleotide content, nor a duplex in which the strands align or anneal such that the 3’ end of the antisense extends 1, 2, 3, 4, 5, 6, 7, or 8 nucleotides further than the 5’ end of the sense strand.
However, Kraynack teaches that siRNAs duplexes containing full 2’-O-Methyl sense strands (i.e., 100% of sense strand, or at least 50% of duplexes) or full duplex modifications (100% modification on both strands) exist (see title, abstract and page 164, left column, lines 4-29).
Kraynack teaches that a full sense strand modification targeted to sites within PTEN mRNA, mediate mRNA target reduction with similar efficacy and potency as the unmodified parent siRNA (see page 164, lines 30-34).
Kraynack teaches that target reduction with fully modified 2’-O-Methyl modified sense strands is impacted by strong sequence-dependent effects as only one active site out of the four examined was able to reduce target RNA in the context of the 19-bp 3’-dTdT construct design (Figure 1) (see page 166, left column, lines 26-31; right column, lines 1-2).
Kraynack teaches that siRNA duplexes containing full 2’-O-methyl modified sense strands can be recognized by the RNAi pathway and that the anti-sense strand is loaded into the RISC complex to elicit hAgo2-dependent siRNA-mediated target reduction (see page 172, left column, “Discussion” section, third paragraph).
Kraynack also teaches that certain sites with highly active unmodified siRNAs display very limited activity (or none at all) with full 2’-O-Methyl modified duplexes (100% on both strands); Kraynack suggests that fully modified 2’-O-methyl strands may inhibit RISC loading, as there is a significant reduction in levels of hAgo2 associated with fully modified strands; Kraynack teaches that certain siRNAs can discriminate between single nucleotide changes (SNPs) in mRNA targets, and that siRNA treatment can lead to off-target silencing effects when partial complementation to unintended targets exists in either strand of the duplex. Kraynack proposes that usage of fully modified anti-sense strands will minimize or eliminate off-target gene silencing that results from this strand (see page 173, left column, last paragraph).
In sum, Kraynack’s teachings suggest that a fully modified 2’-O-methyl sense strand has the same efficacy/potency than the unmodified sense strand and increasing the 2’-O-methyl modifications number in the antisense strand might contribute to enhanced specificity in targeting, an especially important characteristic for the discriminating of targets in presence of mutant alleles.
Rodrigues teaches that MECP2 gene has a 3’UTR that is variable in length with multiple alternative poly Adenylation sites (see Figure 1). Rodrigues teaches that mutations in 3’UTR region can lead to alterations in miRNA binding sites and further deregulate the expression and level of mRNA and proteins in neurons (see Figure 2; see page R96, left column, last paragraph and right column, first paragraph).
Khvorova’899 teaches the design and use of oligonucleotides targeting single nucleotide polymorphisms (SNPs), that can enhance silencing of the expression of a mutated gene relative to the expression of the corresponding wild-type gene (see title and abstract). Khvorova’899 teaches that there are “gain-of-function disorder” characterized by gain-of-function mutation, e.g., neurodegenerative diseases (see [0142]).
Khvorova’899 teaches a dsRNA comprising a first strand of about 15-35 nucleotides that is complementary to a region of a gene comprising an allelic polymorphism, and a second strand of about 15-35 nucleotides that is complementary to at least a portion of the first strand (see [025]-[026]).
Khvorova’899 teaches that the RNAi is designed according to asymmetry design rules (see [0205]).
Khvorova’899 teaches oligonucleotides with asymmetry and overhang of 5 nucleotides (see Formula (II), [0275]; Formula (III), [0278]). Khvorova teaches overhangs on both strands (see Formulas (IV), (V), [0282], [0285]).
Khvorova’899 teaches siRNA duplexes comprising of 20 nucleotides in the antisense strand and 15 nucleotides in the sense strand (see [0335]; Tables 5-7).
Khvorova’899 teaches a “methyl rich” pattern P4 for siRNA duplexes where all but 4 nucleotides are modified with 2’-O-methyl in the antisense strand (16/20 = 80%) and all but 3 nucleotides are modified with 2’-O-methyl in the sense strand (12/15 = 80%), which leads to a siRNA duplex with 28 modified nucleotides with 2’-O-methyl (28/35= 80%). Therefore, Khvorova teaches a content of 80% of 2’-O-methyl nucleotides in the siRNA duplexes (see Figure 35; Pattern P4).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have modified the dsRNA comprising an antisense strand complementary to instant SEQ ID NO: 5, i.e., a 20 nucleobases oligonucleotide of SEQ ID NO: 171 as taught by Freier modified by Bertrand, with a chemical modification pattern as taught by Kraynack and Khvorova’899. One with ordinary skills in the art, motivated in a “hotspot” for MECP2 mRNA expression or a gain-of-function mutation within the 3’UTR of the gene for targeted inhibition using a stable molecule, leading to less off-target effect and specific allele targeting as suggested by Kraynack, Rodrigues and Khvorova’899, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claim 45, Khvorova’899 teaches Formulas III and V for a dsRNA in which the antisense strand comprises alternating 2’-methoxy-ribonucleotides and 2’-fluoro-ribonucleotides, in which nucleotides at positions 2 and 14 from the 5’ end of the antisense strand are not 2’-methoxy-ribonucleotides; a dsRNA in which the nucleotides at positions 1-2 to 1-7 from the 3’ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages, a dsRNA in which the sense strand comprises alternating 2’-methoxy-ribonucleotides and 2’-fluoro-ribonucleotides; and a dsRNA in which the nucleotides at positions 1-2 from the 5’ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages (see [0278], [0285]).
The obviousness of combining the references Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 is described above.
Regarding claim 68, Freier teaches a pharmaceutical composition for inhibiting
expression of MECP2 gene in an organism, comprising the antisense nucleic acid and a pharmaceutically acceptable carrier ( see columns 30 (lines 66-67) and 31 (lines 6-29).
Bertrand teaches replacing an ASO with a siRNA duplex to be delivered to nude
mice using a formulation (vectorized) comprising 30 ng Cytofectin™ GSV (see page 1001, right column, “Animal experiments” section).
Khvorova’899 teaches compositions comprising a dsRNA agent and a pharmaceutically acceptable carrier (see [036], [0307], [0346]; page 111, claim 45).
The obviousness of combining the references Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 is described above.
Regarding claim 187, Freier teaches an antisense strand molecule of SEQ ID NO: 171 that comprises three (3) 5-methylcytosines, 13 phosphorothioate internucleotide linkages, ten (10) 2’-methoxyethyl modified nucleosides and ten (10) 2’-deoxynucleosides (see Table 2, columns 51-52). Freier also teaches that the internucleotide linkages include, but are not limited to, phosphodiesters, phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates (see column 22, lines 4-9). Freier teaches modified sugar moieties that can be C1-C12 alkyl groups as well (see column 22, line 32).
Khvorova’899 teaches a 5’ stabilizing moiety selected from the group consisting of phosphate, vinyl phosphonate (see [023], [092], [0125]; page 114, claim 65; Figures 11, 28A, 28B).
The obviousness of combining the references Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 is described above.
Regarding claims 188, 189 and 190, Freier teaches linking covalently the antisense compound with “lipid moieties that enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides” (see column 31, lines 35-38). Freier teaches that the conjugates can include cholesterol ( i.e. a steroid and hydrophobic moiety), phospholipids, biotin, phenazine, folate (i.e., a vitamin), phenanthridine, coumarins and dyes (see column 31, lines 38-42).
Khvorova’899 teaches functional moieties that can be DHAg2, DHA, GalNAc and cholesterol (see [0260]). Khvorova’899 teaches that conjugates moieties can be any length alkyl chain, a vitamin, a ligand, a peptide, or a bioactive conjugate, e.g., a glycosphingolipid, a polyunsaturated fatty acid, a secosteroid, a steroid hormone, a steroid lipid, or the like (see [093]). Khvorova’899 teaches that the oligonucleotides can be conjugated with hydrophobic moieties (see {0233]-[0237], [0262]; see Figures 37, 38).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Freier modified with Bertrand and obtained a dsRNA as taught by Bertrand. It would have been obvious to one with ordinary skills in the art to have modified and conjugated an hydrophobic moiety, such as cholesterol, to the 5’ end and/or 3’ end of the antisense strand of the resulting dsRNA, and/or the 5’ end and/or 3’ end of the sense strand of the dsRNA, as taught by Freier and Khvorova’899. One with ordinary skills in the art, motivated in obtaining a dsRNA compound that has enhanced activity, cellular distribution and/or cellular uptake could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claims 191 and 192, Khvorova’899 teaches linkers for attaching oligonucleotides to functional/bioactive moieties such as DHAg2, DHA, GalNAc and cholesterol (see [0260]). Khvorova’899 also teaches linking branched oligonucleotides via linkers that can be selected from an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphonate, a phosphoramidate, an ester, an amide, a triazole, and combinations thereof (see [0263]).
The obviousness of combining the references Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 is described above.
Regarding claim 195, Khvorova’899 teaches the following pattern of modification in a dsRNA in Figure 35 ([0109]):
PNG
media_image1.png
60
522
media_image1.png
Greyscale
Therefore, Khvorova’899 teaches a dsRNA wherein the antisense strand comprises 75% 2’-O-methyl modifications (15 nt in 20 nt total), and a 5’ vinyl cap, and wherein the nucleotides at positions 2, 6, 14 and 16 from the 5’ end of the antisense strand are 2’-fluoro-ribonucleotides; and the nucleotides at position 1-2 to 1-7 from the 3’ end of the antisense strand are connected to each other via phosphorothioate internucleotide linkages; and the nucleotides at positions 7, 9, 10 and 11 from the 3’ end of the sense strand are 2’-fluoro-ribonucleotides; and the nucleotides at positions 1-2 from the 5’ end of the sense strand are connected to each other via phosphorothioate internucleotide linkages (see Figure 35).
Khvorova’899 also teaches that in Figure 30, the VP (vinyl phosphonate) modified linkage has an effect of target/non-target discrimination of SNP (single nucleotide polymorphism)-selective siRNAs (see [0104]).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teachings of Freier modified with Bertrand and Khvorova’899 and obtained a dsRNA that is modified specifically with a 5’ vinyl phosphonate linkage and with the modification pattern as shown in P5 in Figure 35 as taught by Khvorova’899. It would have been obvious to one with ordinary skills in the art to have modified using one of the 5 patterns, or all of the modifications patterns, as taught by Khvorova’899, as these are shown as efficient in reducing off-target events. One with ordinary skills in the art, motivated in obtaining a dsRNA compound that has enhanced activity, enhanced on-target effect, and enhanced stability could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Regarding claims 196, 197 and 198, Freier teaches linking covalently the antisense compound with “lipid moieties that enhance the activity, cellular distribution or cellular uptake of the resulting antisense oligonucleotides” (see column 31, lines 35-38). Freier teaches that the conjugates can include cholesterol ( i.e. a steroid and hydrophobic moiety), phospholipids, biotin, phenazine, folate (i.e., a vitamin), phenanthridine, coumarins and dyes (see column 31, lines 38-42).
Khvorova’899 teaches functional moieties that can be DHAg2, DHA, GalNAc and cholesterol (see [0260]). Khvorova’899 teaches that conjugates moieties can be any length alkyl chain, a vitamin, a ligand, a peptide, or a bioactive conjugate, e.g., a glycosphingolipid, a polyunsaturated fatty acid, a secosteroid, a steroid hormone, a steroid lipid, or the like (see [093]). Khvorova’899 teaches that the oligonucleotides can be conjugated with hydrophobic moieties (see [0233]-[0237], [0262]; see Figures 37, 38). Khvorova’899 teaches that the hydrophobic moiety can be an omega-3 fatty acid (see [0237]). Khvorova’899 teaches that the oligonucleotides may comprise conjugated bioactive ligands that enhance cellular specificity and promote membrane association, internalization, and serum protein binding (see [0260]).
Khvorova’899 teaches that to enhance stability in serum, the 3’residues may be stabilized against degradation using ligands that is a lipid or lipid-based molecule (see [0208], [0229], [0260]; Figure 37). Khvorova’899 teaches that the lipophilic moiety is attaches to the 3’ end of the sense strand (see [0222]).
The obviousness of combining the references Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 is described above.
Regarding claim 203, Freier teaches intrathecal administration of the antisense compound (see claim 4; column, 8, lines 7-14; column 13, lines 19-21). Freier teaches a pharmaceutically acceptable carrier (see column 8, lines 26-33; column 12, lines 16-19; column 30, lines 66-67; column 31, lines 1-29).
Khvorova’899 teaches pharmaceutically acceptable carrier for the antisense compound (see [036], [0307], [0346], claim 45). Khvorova’899 teaches intrathecal administration (see [0326], [0345]-[0346], [0357]).
The obviousness of combining the references Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 is described above.
Claim 193 is rejected under 35 U.S.C. §103 as being unpatentable over Freier (Freier, S.M. et al. US 11,129,844 B2, published September 28, 2021; cited previously) in view of Bertrand (Bertrand, J-R. et al. "Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo". Biochemical and Biophysical Research Communications, Vol. 296 (2002), pp: 1000-1004; cited previously), Kraynack (Kraynack, B.A. et al. “Small interfering RNAs containing full 2’-O-methylribonucleotide-modified sense strands display Argonaute2/eIF2C2-dependent activity”. RNA, Vol. 12 (2006), pp: 163-176), Rodrigues (Rodrigues, D.C. et al. “Regulation, diversity and function of MECP2 exon and 3’UTR isoforms”. Human Molecular Genetics, Vol. 29, No. R1 (2020), pp: R90-R100) and Khvorova’899 (Khvorova, A. et al. WO 2020/033899 A1; published February 13, 2020), as applied to claims 1 and 188-191 above, and in further view of Khvorova’669 (Khvorova, A. et al. WO 2017/132669 A1, published August 3, 2017; cited on IDS filed 06/062024; cited previously).
The rejections of claims 1, and 188-191 are described above. The combination of Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 renders the elements of claims 1 and 188-191 obvious.
Regarding claim 193, the combination of Freier, Bertrand, Kraynack, Rodrigues and Khvorova’899 does not render obvious a functional moiety linked to the 5’ end and/or 3’ end of the antisense strand, and/or the 5’ end and/or 3’ end of the sense strand by a linker that has the formula Zc4.
However, Khvorova’669 teaches “branched oligonucleotide compound comprising two or more nucleic acids, the nucleic acids connected to one another by one or more moieties selected from a linker, a spacer and a branching point” (see [006]).
Khvorova’669 teaches that each linker can be an ethylene glycol chain, an alkyl chain, a peptide, RNA, DNA, a phosphate, a phosphonate, a phosphoramidate, an ester (i.e. a phosphodiester), an amide, a triazole, and combinations thereof” (see [014]).
Khvorova’669 also teaches a linker having a phosphate radical (i.e., formula Zc4 of instant Application , wherein X is a “O” (i.e., phosphodiester linkage), or a “S” (i.e., phosphorothioate linkage) attached to an ethylene glycol chain (see Figure 17; and see [024]-[025]).
Therefore, it would have been obvious to one with ordinary skills in the art before the effective filing date of the claimed invention to have combined the teaching of Freier modified with Bertrand, Kraynack, Rodrigues and Khvorova’899, with the teachings of Khvorova’669 and attached a linker taught by Khvorova’669 to the dsRNA. One with ordinary skills in the art, motivated in combining two or more antisense oligonucleotides and avoiding off-target effects and increasing specificity, could have performed this modification with a reasonable expectation of success and arrived at the claimed invention.
Claim Objections
Claim 199 is objected to as being dependent upon a rejected base claim but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Allowable Subject Matter
Claims 200, 201 and 202 are allowed.
The following is a statement of reasons for the indication of allowable subject matter:
An dsRNA oligonucleotide comprising an antisense strand comprising 20 contiguous nucleotides of SEQ ID NO: 8 appears to be free from prior art.
Conclusion
Claim 199 is objected to.
Claims 1, 45, 68, 187-193, 195-198 and 203 are rejected.
Claims 200-202 are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA G DACE DENITO whose telephone number is (703)756-4752. The examiner can normally be reached Monday-Friday, 8:30-5:00EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/A.D./Examiner, Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
Prosecution Insights