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 .
Species Election & Claim Status
Applicant’s reply filed 5/11/2026 in response to the Restriction Requirement mailed 3/12/2026 has been considered. Upon reconsideration in view of Applicant’s claim amendments, the species election requirement is withdrawn. The previously non-elected species are rejoined/reinstated for examination to the extent they are encompassed by the currently pending claims. The claims are examined on the merits as presented.
Claims 1, 5, 9, 12, 21, 29, 30, 32, 34, 37, 44, 46, 48, 51, 57, 59, 68, 70, and 94-96 are pending and under examination. Claims 2-4, 6-8, 10-11, 13-20, 22-28, 31, 33, 35-36, 38-43, 45, 47, 49-50, 52-56, 58, 60-67, 69, and 71-93 are cancelled.
Claim Rejections - 35 USC § 112 – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 5 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 5 recites that the sense strand “has a sequence set forth in any one of Tables 1-5.” The claim does not identify the particular sequence, table entry, SEQ ID NO, or duplex being claimed. Because Tables 1-5 contain numerous sequence entries and modified sequence entries, the metes and bounds of the claimed sense strand are unclear.
MPEP § 2173.02 provides that claims must set out and circumscribe the invention with a reasonable degree of clarity and particularity. MPEP § 2173.05(e) further explains that unclear claim language that creates uncertainty as to claim scope may render a claim indefinite.
Accordingly, claim 5 fails to particularly point out and distinctly claim the subject matter regarded as the invention.
Claim Rejections - 35 USC § 103
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, 5, 9, 21, 29, 30, 32, 34, 37, 44, 46, 48, 51, 57, 59, 68, 70, and 94-96 are rejected under 35 U.S.C. 103 as being unpatentable over Prakash et al. (US 9,382,540 B2, issued July 5, 2016).
Regarding claim 1, Prakash identifies ANGPTL3 as the target gene and discloses compositions and methods for reducing expression of ANGPTL3 mRNA and protein in an animal. See Prakash, Abstract, col. 3-23. Prakash discloses a DNA version of the claimed core sequence in SEQ ID NO: 423, corresponding to ISIS 544167, having the sequence 5’-ATAGAGTATAACCTTCCATT-3’. See Prakash, Table 127. The following is a sequence search alignment result from file 18554692_seq1.oligo17_szlim17_32.rni:
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193
637
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Greyscale
Prakash further reports that SEQ ID NO: 423 exhibited 71% inhibition of ANGPTL3 mRNA expression. See Prakash, Table 127, col. 500, Example 116. Prakash also teaches that RNA containing uracil in place of thymidine is considered identical to the corresponding DNA sequence for nucleobase-pairing purposes. See Prakash, col. 142-143. Accordingly, Prakash SEQ ID NO: 423 corresponds to the RNA sequence 5’-AUAGAGUAUAACCUUCCAUU-3’, which maps to the antisense-strand formula of claim 1, 5’-z1uagaguauaaccuuccz2-3’, where z1 is “a” and z2 is “auu.” Claim 1 expressly permits z1 to be “a” and z2 to be a nucleotide sequence IV of 0-15 nucleotides. Therefore, Prakash discloses a DNA version of an active ANGPTL3-targeting sequence whose RNA equivalent contains the same core sequence encompassed by claim 1.
Prakash further teaches using ANGPTL3-targeting sequences in RNAi/dsRNA/siRNA formats. Prakash discloses that antisense compounds may include RNAi compounds, double-stranded RNA compounds, siRNA compounds, and RISC-based compounds for reducing ANGPTL3 expression. See Prakash, col. 135-142, siRNA compounds. Prakash also teaches double-stranded compositions comprising an antisense strand complementary to a target nucleic acid and a sense strand hybridized to the antisense strand to form a duplex region. See Prakash, col. 135-142, siRNA compounds. Thus, Prakash identifies ANGPTL3 as the target, discloses a DNA version of a core sequence encompassed by claim 1, reports 71% inhibition for the core-containing sequence, teaches T/U interchangeability for RNA embodiments, and teaches RNAi/dsRNA/siRNA duplex agents comprising sense and antisense strands.
Taken together, Prakash provides a step-by-step roadmap to the claimed ANGPTL3-targeting dsRNA composition. Thus, it would have been prima facie obvious to one of ordinary skill in the art as of the effective filing date of the claimed invention to prepare a dsRNA/siRNA agent comprising an antisense strand having the RNA equivalent of Prakash SEQ ID NO: 423, or a sequence retaining the same ANGPTL3-targeting core encompassed by claim 1, together with a complementary sense strand, because Prakash expressly teaches that ANGPTL3 expression may be inhibited using RNAi/dsRNA/siRNA agents comprising sense and antisense strands. A person of ordinary skill would have had a reasonable expectation of success because Prakash identifies the same ANGPTL3 target region, discloses the DNA version of the same core sequence, and reports that SEQ ID NO: 423 exhibited 71% inhibition of ANGPTL3 mRNA expression.
Regarding claims 5 and 21, Prakash teaches dsRNA/siRNA compounds comprising an antisense strand and a complementary sense strand. See Prakash, col. 135-142, siRNA compounds. Prakash further teaches double-stranded RNAi/siRNA compositions having sense and antisense strands hybridized to form duplex regions, including duplex regions of about 15-30 nucleotides or about 15-25 nucleotides. See Prakash, col. 138 and throughout disclosure. Although Prakash may not expressly identify the specific sense strand by reference to Applicant’s Tables 1-5, absent persuasive evidence otherwise, once Prakash provides the active ANGPTL3-targeting core sequence and teaches dsRNA/siRNA duplex formation, it would have been routine and predictable to generate a complementary sense strand for hybridization with the antisense strand. It also would have been obvious to use a region of complementarity within the claimed 16-23 nucleotide range because Prakash expressly teaches duplex regions within that range as suitable for RNAi.
Regarding claim 9, Prakash teaches modified RNAi/dsRNA/siRNA agents and modified oligonucleotides containing modified nucleosides, modified sugars, 2’-F, 2’-OMe, 2’-MOE, bicyclic sugars, modified internucleoside linkages, phosphorothioate linkages, phosphodiester linkages, and modified nucleobases. See Prakash, col.135 and throughout disclosure.
Regarding claims 29 and 30, Prakash teaches modified oligonucleotides and conjugate groups, including GalNAc targeting moieties, ASGPR ligands, linkers, cleavable moieties, tethers, and ligands for hepatocyte delivery. See Prakash, col. 194. Prakash further teaches GalNAc-containing conjugates attached to siRNA sense strands, typically at the 3’ end, and also teaches conjugation at the 5’ and/or 3’ ends. See Prakash, col. 194.
Regarding claim 32, Prakash teaches terminal stabilizing or cap groups for antisense compounds, including inverted deoxy abasic caps, to protect termini from exonuclease degradation. See Prakash, col. 156-157.
Regarding claim 34, Prakash teaches dsRNA embodiments having no single-stranded regions and embodiments having one or more single-stranded regions or overhangs. See Prakash, col. 138.
Regarding claim 37, Prakash teaches pharmaceutical compositions comprising ANGPTL3 antisense/RNAi compounds and pharmaceutically acceptable carriers or diluents. See Prakash, col. 23, 156.
Regarding claims 44, 46, and 48, Prakash teaches contacting cells with ANGPTL3-targeted antisense/RNAi compounds and reducing ANGPTL3 mRNA and protein expression. See Prakash, col.125-126, Table 127, col. 500, Example 116. Prakash further teaches that the cell may be in a subject and that the ANGPTL3 inhibitor may be administered to animals, including by parenteral, subcutaneous, or intravenous administration. See Prakash, col. 41. Prakash also teaches determining ANGPTL3 mRNA and protein levels and assessing phenotypic changes including cholesterol, LDL, triglycerides, glucose, and lipid markers. See Prakash, col.140.
Regarding claim 51, Prakash teaches administering ANGPTL3 inhibitors to animals and humans to reduce ANGPTL3 expression. See Prakash, col.140.
Regarding claims 57 and 59, Prakash teaches treating ANGPTL3-related metabolic and cardiovascular diseases, including hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, dyslipidemia, diabetes, obesity, atherosclerosis, coronary artery disease, NAFLD, and NASH. See Prakash, col. 125-126. Prakash also teaches co-administration and combination therapies including glucose-lowering agents, lipid-lowering therapies, HMG-CoA reductase inhibitors/statins, PCSK9 inhibitors, and therapeutic lifestyle changes. See Prakash, col. 125-126.
Regarding claims 68 and 70, Prakash teaches reducing ANGPTL3 protein levels and measuring ANGPTL3 protein reductions in vivo. See Prakash, col. 125-126 and throughout disclosure. Prakash also teaches modulation or reduction of lipid levels, triglycerides, cholesterol, glucose, insulin resistance, and related phenotypes after ANGPTL3-targeted treatment. See Prakash, col. 125-126 and throughout disclosure.
Regarding claims 94-96, these claims depend from claim 1 and therefore retain the same core sequence required by claim 1. Prakash SEQ ID NO: 423 discloses the DNA version of the same active ANGPTL3-targeting core with terminal flanking nucleotides and reports 71% inhibition for that core-containing sequence. See Prakash, Table 127, col. 500, Example 116. Prakash further teaches truncation, lengthening, mismatch tolerance, and terminal variation of antisense compounds while retaining activity. See Prakash, col. 128 and throughout disclosure. Absent persuasive evidence otherwise, these nucleotide sequence alternatives recited in these claims represent predictable terminal variants of the active core-containing sequence disclosed by Prakash.
Accordingly, Prakash provides a step-by-step roadmap to the claimed RNA composition by identifying ANGPTL3 as the target, disclosing a DNA version of an active ANGPTL3-targeting sequence whose RNA equivalent contains the claim 1 core sequence, reporting 71% inhibition of ANGPTL3 mRNA expression for that core-containing sequence, teaching T/U interchangeability, teaching that ANGPTL3-targeting sequences may be used in RNAi/dsRNA/siRNA agents comprising sense and antisense strands, teaching complementary duplex formation, teaching routine chemical modifications and terminal structures, teaching GalNAc-mediated hepatocyte delivery, and teaching pharmaceutical compositions and therapeutic methods for reducing ANGPTL3 expression and treating ANGPTL3-associated conditions. Thus, claims 1, 5, 9, 21, 29, 30, 32, 34, 37, 44, 46, 48, 51, 57, 59, 68, 70, and 94-96 are therefore unpatentable over Prakash.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Prakash et al. (US 9,382,540 B2, issued 7/15/2016 “Prakash”) in view of Maier et al. (WO 2016/028649 A1, published 2/25/2016 “Maier”).
Regarding claim 12, the teachings of Prakash have been outlined above. Prakash does not expressly disclose that the antisense strand comprises an E-vinylphosphonate nucleotide at its 5’ end, as required by claim 12.
Maier discloses modified double-stranded RNA agents comprising a sense strand and an antisense strand for inhibiting target gene expression. See Maier, Abstract, pg. 2-9. Maier teaches that the dsRNA agent may comprise a phosphorus-containing group at the 5’ end of the antisense strand, including a 5’-vinylphosphonate group. Maier further teaches that the 5’-vinylphosphonate may be a 5’-E-vinylphosphonate isomer, a 5’-Z-vinylphosphonate isomer, or mixtures thereof. See Maier, Abstract, pg. 9-10. Maier specifically teaches embodiments in which the dsRNA agent comprises a 5’-vinylphosphonate at the 5’ end of the antisense strand and a targeting ligand, such as a GalNAc/ASGPR ligand, on the sense strand. See Maier, Examples 5-6. Maier also teaches that 5’-trans-vinylphosphonate, i.e., 5’-E-vinylphosphonate, mimics a natural phosphate, improves Ago2/RISC loading, and improves in vivo activity of chemically modified siRNAs. See Maier, Examples 5-6.
It would have prima facie been obvious to one of ordinary skill in the art as of the effective filing date to modify the ANGPTL3-targeting dsRNA agent taught or suggested by Prakash to include a 5’-E-vinylphosphonate modification on the antisense strand, as taught by Maier, because Maier teaches that such 5’-vinylphosphonate modifications are useful in dsRNA/siRNA agents to mimic the natural 5’ phosphate, promote Ago2/RISC loading, improve metabolic stability, and improve in vivo RNAi activity. A person of ordinary skill would have had a reasonable expectation of success because both Prakash and Maier concern modified dsRNA/siRNA agents for inhibiting target gene expression, and Maier teaches the 5’-E-vinylphosphonate antisense-strand modification as a generally applicable improvement to chemically modified siRNA agents.
Conclusion
No claims are allowed.
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/CHRISTOPHER M BABIC/ Supervisory Patent Examiner, Art Unit 1633
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