WO2015010135A2 - Compositions for modulating tau expression - Google Patents

Compositions for modulating tau expression Download PDF

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Publication number
WO2015010135A2
WO2015010135A2 PCT/US2014/047486 US2014047486W WO2015010135A2 WO 2015010135 A2 WO2015010135 A2 WO 2015010135A2 US 2014047486 W US2014047486 W US 2014047486W WO 2015010135 A2 WO2015010135 A2 WO 2015010135A2
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WO
WIPO (PCT)
Prior art keywords
compound
soooossssssssssooss
modified
seq
tau
Prior art date
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Ceased
Application number
PCT/US2014/047486
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English (en)
French (fr)
Other versions
WO2015010135A3 (en
Inventor
Holly Kordasiewicz
Eric E. Swayze
Susan M. Freier
Huynh-Hoa Bui
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Ionis Pharmaceuticals Inc
Original Assignee
Isis Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to CN201480040726.6A priority Critical patent/CN108064227B/zh
Priority to EP21166766.2A priority patent/EP3910060A1/en
Priority to JP2016527154A priority patent/JP6684707B2/ja
Priority to MX2016000782A priority patent/MX379535B/es
Priority to CN202510791742.9A priority patent/CN120796262A/zh
Priority to IL302146A priority patent/IL302146A/en
Priority to PL14826839T priority patent/PL3022217T3/pl
Priority to SM20210371T priority patent/SMT202100371T1/it
Priority to CA2918600A priority patent/CA2918600C/en
Priority to KR1020237013823A priority patent/KR20230062658A/ko
Priority to HK16111947.3A priority patent/HK1223626B/en
Priority to US14/906,047 priority patent/US9683235B2/en
Priority to KR1020167003896A priority patent/KR102273926B1/ko
Priority to DK14826839.4T priority patent/DK3022217T3/da
Priority to KR1020257018963A priority patent/KR20250091306A/ko
Priority to BR112016000654-2A priority patent/BR112016000654B1/pt
Priority to RS20210805A priority patent/RS62054B1/sr
Priority to KR1020247016358A priority patent/KR20240093742A/ko
Priority to KR1020217020564A priority patent/KR102424991B1/ko
Priority to AU2014290395A priority patent/AU2014290395B2/en
Priority to CN202110665888.0A priority patent/CN113667667B/zh
Application filed by Isis Pharmaceuticals Inc filed Critical Isis Pharmaceuticals Inc
Priority to IL279572A priority patent/IL279572B2/en
Priority to ES14826839T priority patent/ES2871533T3/es
Priority to LTEP14826839.4T priority patent/LT3022217T/lt
Priority to NZ715828A priority patent/NZ715828A/en
Priority to KR1020227025324A priority patent/KR102526525B1/ko
Priority to HRP20211051TT priority patent/HRP20211051T1/hr
Priority to EP14826839.4A priority patent/EP3022217B1/en
Priority to RU2016104824A priority patent/RU2735551C2/ru
Priority to SI201431848T priority patent/SI3022217T1/sl
Publication of WO2015010135A2 publication Critical patent/WO2015010135A2/en
Publication of WO2015010135A3 publication Critical patent/WO2015010135A3/en
Priority to IL243609A priority patent/IL243609B/en
Anticipated expiration legal-status Critical
Priority to US15/593,173 priority patent/US10793856B2/en
Priority to IL260378A priority patent/IL260378B/en
Priority to US16/986,770 priority patent/US11591595B2/en
Priority to AU2020250262A priority patent/AU2020250262B2/en
Priority to CY20211100565T priority patent/CY1124292T1/el
Priority to US18/155,945 priority patent/US12091662B2/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/711—Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • C07H21/02—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids with ribosyl as saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/10—Type of nucleic acid
    • C12N2310/11—Antisense
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/31—Chemical structure of the backbone
    • C12N2310/315—Phosphorothioates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/321—2'-O-R Modification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/33—Chemical structure of the base
    • C12N2310/334—Modified C
    • C12N2310/3341—5-Methylcytosine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/341—Gapmers, i.e. of the type ===---===
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/345—Spatial arrangement of the modifications having at least two different backbone modifications
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/34—Spatial arrangement of the modifications
    • C12N2310/346—Spatial arrangement of the modifications having a combination of backbone and sugar modifications
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/352—Nature of the modification linked to the nucleic acid via a carbon atom
    • C12N2310/3525—MOE, methoxyethoxy

Definitions

  • Alzheimer's disease One of the early indicators that Tau may be important in neurodegenerative syndromes was the recognition that Tau is a key component of neurofibrillary inclusions in Alzheimer's disease.
  • neurofibrillary inclusions are aggregates of hyperphosphorylated Tau protein.
  • amyloid beta containing plaques neurofibrillary inclusions are a hallmark of Alzheimer's disease and correlate
  • Antisense oligonucleotide means a single-stranded oligonucleotide having a nucleobase sequence that permits hybridization to a corresponding segment of a target nucleic acid.
  • Certain embodiments provide methods for the treatment, prevention, or amelioration of diseases, disorders, and conditions associated with Tau in an individual in need thereof. Also contemplated are methods for the preparation of a medicament for the treatment, prevention, or amelioration of a disease, disorder, or condition associated with Tau.
  • Tau associated diseases, disorders, and conditions include neurodegenerative diseases.
  • tau associated diseases include Tauopathies,
  • Certain embodiments provide compounds, comprising a modified oligonucleotide consisting of 12 to 30 linked nucleosides and comprising a nucleobase sequence comprising at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleobases complementary to an equal length portion of nucleobases 135783-135929 of SEQ ID NO: 1.
  • an antisense compound targeted to a Tau nucleic acid is 12 to 30 subunits in length. In certain embodiments, an antisense compound targeted to Tau nucleic acid is 12 to 25 subunits in length. In certain embodiments, an antisense compound targeted to Tau nucleic acid is 12 to 22 subunits in length. In certain embodiments, an antisense compound targeted to Tau nucleic acid is 14 to 20 subunits in length. In certain embodiments, an antisense compound targeted to Tau nucleic acid is 15 to 25 subunits in length. In certain embodiments, an antisense compound targeted to Tau nucleic acid is 18 to 22 subunits in length. In certain embodiments, an antisense compound targeted to Tau nucleic acid is 19 to 21 subunits in length.
  • gapmers provided herein include, for example 20-mers having a motif of 5-
  • hybridization occurs between an antisense compound disclosed herein and a Tau nucleic acid.
  • the most common mechanism of hybridization involves hydrogen bonding (e.g., Watson- Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding) between complementary nucleobases of the nucleic acid molecules.
  • an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity.
  • the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases.
  • the antisense compounds are complementary to at least an 11 nucleobase portion of a target segment. In certain embodiments, the antisense compounds, are complementary to at least a 12 nucleobase portion of a target segment. In certain embodiments, the antisense compounds, are complementary to at least a 13 nucleobase portion of a target segment. In certain embodiments, the antisense compounds, are complementary to at least a 14 nucleobase portion of a target segment. In certain embodiments, the antisense compounds, are complementary to at least a 15 nucleobase portion of a target segment. Also contemplated are antisense compounds that are complementary to at least a 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more nucleobase portion of a target segment, or a range defined by any two of these values.
  • Modifications to antisense compounds encompass substitutions or changes to internucleoside linkages, sugar moieties, or nucleobases. Modified antisense compounds are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target, increased stability in the presence of nucleases, or increased inhibitory activity. Chemically modified nucleosides may also be employed to increase the binding affinity of a shortened or truncated antisense oligonucleotide for its target nucleic acid. Consequently, comparable results can often be obtained with shorter antisense compounds that have such chemically modified nucleosides. Modified Internucleoside Linkages
  • Examples of chemically modified sugars include 2'-F-5 '-methyl substituted nucleoside (see PCT International Application WO 2008/101157 Published on 8/21/08 for other disclosed 5',2'-bis substituted nucleosides) or replacement of the ribosyl ring oxygen atom with S with further substitution at the 2'-position (see published U.S. Patent Application US2005-0130923, published on June 16, 2005) or alternatively 5'-substitution of a BNA (see PCT International Application WO 2007/134181 Published on 11/22/07 wherein LNA is substituted with for example a 5'-methyl or a 5'-vinyl group).
  • the modified THP nucleosides of Formula VII are provided wherein q b q 2 , q3, q4, q 5 , q6 and q 7 are each H. In certain embodiments, at least one of qi, q 2 , q 3 , q 4 , q 5 , q 6 and q 7 is other than H. In certain embodiments, at least one of qi, q 2 , q 3 , q 4 , q 5 , q 6 and q 7 is methyl. In certain embodiments, THP nucleosides of Formula VII are provided wherein one of Ri and R 2 is fluoro. In certain embodiments, Ri is fluoro and R 2 is H; R t is methoxy and R 2 is H, and Ri is H and R 2 is methoxyethoxy.
  • 2'-modified or “2 '-substituted” refers to a nucleoside comprising a sugar comprising a substituent at the 2' position other than H or OH.
  • 2'-F refers to a nucleoside comprising a sugar comprising a fluoro group at the 2' position.
  • compositions comprising antisense compounds encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other oligonucleotide which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of antisense compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts.
  • the effects of antisense compounds on the level, activity or expression of Tau nucleic acids can be tested in vitro in a variety of cell types.
  • Cell types used for such analyses are available from commerical vendors (e.g. American Type Culture Collection, Manassus, VA; Zen-Bio, Inc., Research Triangle Park, NC; Clonetics Corporation, Walkersville, MD) and are cultured according to the vendor's instructions using commercially available reagents (e.g. Invitrogen Life Technologies, Carlsbad, CA).
  • Illustrative cell types include, but are not limited to, HepG2 cells, Hep3B cells, and primary hepatocytes.
  • Cells may be treated with antisense oligonucleotides when the cells reach approximately 60-80% confluency in culture.
  • Example 1 Antisense inhibition of human Tau in HepG2 cells by MOE gapmers
  • Example 2 Dose-dependent antisense inhibition of human tau in HepG2 cells by 5-10-5 MOE gapmers
  • Start site indicates the 5 '-most nucleoside to which the gapmer is targeted in the human gene sequence.
  • “Stop site” indicates the 3 '-most nucleoside to which the gapmer is targeted human gene sequence.
  • Each gapmer listed in the Tables below is targeted to either the human Tau genomic sequence, designated herein as SEQ ID NO: 1 (GENBANK
  • Additional antisense oligonucleotides were designed targeting a Tau nucleic acid and were tested for their effects on Tau mRNA in vitro.
  • Cultured SH-SY5Y cells were plated at a density of 20,000 cells per well and were transfected using electroporation with 6,000 nM antisense oligonucleotide. After a treatment period of approximately 24 hours, RNA was isolated from the cells and Tau mRNA levels were measured by quantitative real-time PCR. Human primer probe set RTS3104 was used to measure mRNA levels. Tau mRNA levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented as percent inhibition of tau, relative to untreated control cells.

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PCT/US2014/047486 2013-07-19 2014-07-21 Compositions for modulating tau expression Ceased WO2015010135A2 (en)

Priority Applications (37)

Application Number Priority Date Filing Date Title
CN202110665888.0A CN113667667B (zh) 2013-07-19 2014-07-21 用于调节τ蛋白表达的组合物
IL279572A IL279572B2 (en) 2013-07-19 2014-07-21 Preparations for the modulation of tau expression
MX2016000782A MX379535B (es) 2013-07-19 2014-07-21 Composiciones para modular la expresión de tau.
CN202510791742.9A CN120796262A (zh) 2013-07-19 2014-07-21 用于调节τ蛋白表达的组合物
IL302146A IL302146A (en) 2013-07-19 2014-07-21 Preparations for the modulation of tau expression
PL14826839T PL3022217T3 (pl) 2013-07-19 2014-07-21 Kompozycje do modulowania ekspresji tau
SM20210371T SMT202100371T1 (it) 2013-07-19 2014-07-21 Composizioni per modulare l'espressione di tau
CA2918600A CA2918600C (en) 2013-07-19 2014-07-21 Compositions for modulating tau expression
KR1020237013823A KR20230062658A (ko) 2013-07-19 2014-07-21 타우 발현 조절 조성물
HK16111947.3A HK1223626B (en) 2013-07-19 2014-07-21 Compositions for modulating tau expression
US14/906,047 US9683235B2 (en) 2013-07-19 2014-07-21 Compositions for modulating Tau expression
KR1020167003896A KR102273926B1 (ko) 2013-07-19 2014-07-21 타우 발현 조절 조성물
DK14826839.4T DK3022217T3 (da) 2013-07-19 2014-07-21 Sammensætninger til modulering af tau-ekspression
KR1020257018963A KR20250091306A (ko) 2013-07-19 2014-07-21 타우 발현 조절 조성물
BR112016000654-2A BR112016000654B1 (pt) 2013-07-19 2014-07-21 Oligonucleotídeo modificado, oligonucleotídeo modificado de fita única, seus usos e composição que os compreende e compostos antissenso conjugados
RS20210805A RS62054B1 (sr) 2013-07-19 2014-07-21 Kompozicije za modulaciju ekspresije tau
KR1020247016358A KR20240093742A (ko) 2013-07-19 2014-07-21 타우 발현 조절 조성물
KR1020217020564A KR102424991B1 (ko) 2013-07-19 2014-07-21 타우 발현 조절 조성물
AU2014290395A AU2014290395B2 (en) 2013-07-19 2014-07-21 Compositions for modulating Tau expression
CN201480040726.6A CN108064227B (zh) 2013-07-19 2014-07-21 用于调节τ蛋白表达的组合物
EP21166766.2A EP3910060A1 (en) 2013-07-19 2014-07-21 Compositions for modulating tau expression
JP2016527154A JP6684707B2 (ja) 2013-07-19 2014-07-21 タウ発現を調節するための組成物
ES14826839T ES2871533T3 (es) 2013-07-19 2014-07-21 Composiciones para modular la expresión de Tau
LTEP14826839.4T LT3022217T (lt) 2013-07-19 2014-07-21 Kompozicijos, skirtos tau ekspresijos moduliavimui
NZ715828A NZ715828A (en) 2013-07-19 2014-07-21 Compositions for modulating tau expression
KR1020227025324A KR102526525B1 (ko) 2013-07-19 2014-07-21 타우 발현 조절 조성물
HRP20211051TT HRP20211051T1 (hr) 2013-07-19 2014-07-21 Pripravci namijenjeni moduliranju eksprimiranja tau
EP14826839.4A EP3022217B1 (en) 2013-07-19 2014-07-21 Compositions for modulating tau expression
RU2016104824A RU2735551C2 (ru) 2013-07-19 2014-07-21 Композиции для модулирования экспрессии тау-белка
SI201431848T SI3022217T1 (sl) 2013-07-19 2014-07-21 Sestave za moduliranje izražanja TAU
IL243609A IL243609B (en) 2013-07-19 2016-01-14 Compounds and preparations for modulating tau expression
US15/593,173 US10793856B2 (en) 2013-07-19 2017-05-11 Compositions for modulating Tau expression
IL260378A IL260378B (en) 2013-07-19 2018-07-02 Preparations for the modulation of tau expression
US16/986,770 US11591595B2 (en) 2013-07-19 2020-08-06 Compositions for modulating Tau expression
AU2020250262A AU2020250262B2 (en) 2013-07-19 2020-10-08 Compositions for modulating tau expression
CY20211100565T CY1124292T1 (el) 2013-07-19 2021-06-24 Συνθεσεις για τροποποιηση της εκφρασης tau
US18/155,945 US12091662B2 (en) 2013-07-19 2023-01-18 Compositions for modulating tau expression

Applications Claiming Priority (8)

Application Number Priority Date Filing Date Title
US201361856551P 2013-07-19 2013-07-19
US61/856,551 2013-07-19
US201361879621P 2013-09-18 2013-09-18
US61/879,621 2013-09-18
US201361885371P 2013-10-01 2013-10-01
US61/885,371 2013-10-01
US201462014486P 2014-06-19 2014-06-19
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