Patent Grant
10167309
The present invention is directed to a chiral reagent that is used to synthesize stereocontrolled phosphorus atom-modified oligonucleotide derivatives.
JP 2005-89441 A discloses a method for producing a derivative of nucleotides called an oxazaphospholidine method. However, the isolate yield of the monomers is low and the method requires special capping agents that are not commercially available. Further obtained monomers are chemically unstable. Furthermore, the isolate yields of oligonucleotide derivatives are not high. It is thought that the low yield of oligonucleotide derivatives is caused by the degradation reactions under the de-protection steps.
WO2010/064146 pamphlet discloses a method for producing a derivative of nucleotides. The method disclosed therein requires special capping agents that are not commercially available. Furthermore, the isolate yields of oligonucleotide derivatives are not high. The low yield is thought to be caused by the degradation reactions under the de-protection steps. This tendency becomes strongly apparent when the length of oligonucleotide derivatives becomes long.
WO2012/039448 pamphlet discloses Asymmetric auxiliary group which is used to produce stereocontrolled phosphorus atom-modified oligonucleotide derivatives.
The first Aspect of the Invention relates to a chiral reagent or a salt thereof. The chiral reagent has following chemical formula (I).
In the formula (I), G1 and G2 are independently a hydrogen atom, a nitro group (—NO2), a halogen atom, a cyano group (—CN), a group of formula (II), (III) or (V), or both G1 and G2 taken together to form a group of formula (IV).
In the formula (II), G21 to G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group.
In the formula (III), G31 to G33 are independently C1-4 alkyl group, C6-14 aryl group C1-4 alkoxy group, C7-14 aralkyl group, C1-4 alkyl C6-14 aryl group, C1-4 alkoxy C6-14 aryl group, or C6-14 aryl C1-4 alkyl group.
In the formula (IV), G41 to G46 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group.
In the formula (V), G51 to G53 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, C1-3 alkyl group or C1-3 alkyloxy group.
G3 and G4 are independently a hydrogen atom, C1-3 alkyl group, C6-14 aryl group, or both G3 and G4 taken together to form a heteroatom-containing ring that has 3 to 16 carbon atoms, together with the NH moiety in formula (I).
A preferred embodiment is that the chiral reagent has following chemical formula (I′).
In the formula (I′), G1 and G2 are same as above. Namely, G1 and G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II) or (III), or both G1 and G2 taken together to form a group of formula (IV).
A preferred embodiment is that the chiral reagent has chemical formula (I′) and each of G1 and G2 is a group of formula (II), wherein G21 to G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and each of G1 and G2 is a group of formula (II) and each of G21 to G23 is a hydrogen atom
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (II), and G21 to G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (II), each of G21 and G22 is a hydrogen atom and G23 is a nitro group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom and G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group, C6-14 aryl group, C7-14 aralkyl group, C1-4 alkyl C6-14 aryl group, C1-4 alkoxy C6-14 aryl group, or C6-14 aryl C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom and G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group, C6 aryl group, C7-10 aralkyl group, C1-4 alkyl C6 aryl group, C1-4 alkoxy C6 aryl group, or C6 aryl C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group or C6 aryl group. Examples of C1-4 alkyl group are methyl group, ethyl group, n-propyl group, iso-propyl group, n-buthyl group and tert-buthyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (III), and G31 and G33 are C6 aryl group and G32 is C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 and G2 taken together to form a group of formula (IV), and G41 to G46 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 and G2 taken together to form a group of formula (IV), wherein each of G41 to G46 is a hydrogen atom.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom and G2 is a group of formula (V). Further each of G51 to G53 is independently a hydrogen atom, a nitro group, a methyl group, or a methoxy group. More preferred embodiment is that G1 is a hydrogen atom and G2 is a group of formula (V), wherein each of G51 and G53 is a hydrogen atom and G53 is a 4-methyl group.
A preferred embodiment is that the chiral reagent is selected from one of III-a, III-b, V-a, VII-a, VII-b, IX-a, IX-b, XI-a, XIII-a and XIII-b:
The second aspect of the invention relates to a nucleoside 3′-phosphoramidite derivative which is represented by formula (Va) or (Vb).
In the formula (Va) and (Vb), G1 to G4 are same as above, G5 is a protective group of the hydroxyl group, and Bs is a group selected from the groups represented by following formula (VI) to (XI) or derivatives thereof.
Examples of Bs are an adenine, a thymine, a cytosine, a guanine, an uracil, a 5-methylcytosine or derivative thereof.
R2 is hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRb, wherein Rb is a blocking moiety.
Y1 is O, NRd, S, or Se.
Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Rc)2, or —HP(O)(Rc).
Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+, Li+, or K+.
Y2 is O, NRd, or S.
R3 is a group represented by —CH2—, —(CH2)2—, —CH2NH—, or —CH2N(CH3)—.
Examples of G5 are trityl, 4-monomethoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 9-phenylxanthin-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthin-9-yl (MOX).
A preferred embodiment of the second aspect is that the nucleoside 3′-phosphoramidite derivative is represented by formula (Va′) or (Vb′).
In the formula (Va′) and (Vb′), G1, G2, G5, Bs, R2, and R3 are same as above.
The third aspect of the invention relates to a method for synthesis of a stereocontrolled phosphorus atom-modified oligonucleotide derivative.
First step is a step of reacting a molecule comprising an achiral H-phosphonate moiety, the first activating reagent and a chiral reagent or a salt thereof to form a monomer. The chiral reagent has chemical formula (I) or (I′) and the monomer may be represented by formula (Va), (Vb), (Va′), or (Vb′). The monomer reacts with the second activating reagent and a nucleoside to form a condensed intermediate. Next step is a step of converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety.
Based on the present method, it is possible to use stable and commercially available materials as starting materials. It is possible to produce stereocontrolled phosphorus atom-modified oligonucleotide derivatives using an achiral starting material.
As shown in a working example, the method of the present invention does not cause degradations under de-protection steps. Further the method does not require special capping agents to produce phosphorus atom-modified oligonucleotide derivatives.
The fourth aspect of the invention relates to a method for synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives using a chiral monomer.
The first step is reacting a nucleoside 3′-phosphoramidite derivative which is represented by formula (Va), (Vb), (Va′), or (Vb′) with the second activating reagent and a nucleoside to form a condensed intermediate. The second step is converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety.
All publications and patent applications disclosed herein in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The term “nucleic acid” encompasses poly- or oligo-ribonucleotides (RNA) and poly- or oligo-deoxyribonucleotides (DNA); RNA or DNA derived from N-glycosides or C-glycosides of nucleobases and/or modified nucleobases; nucleic acids derived from sugars and/or modified sugars; and nucleic acids derived from phosphate bridges and/or modified phosphorus-atom bridges. The term encompasses nucleic acids containing any combinations of nucleobases, modified nucleobases, sugars, modified sugars, phosphate bridges or modified phosphorus atom bridges. Examples include, and are not limited to, nucleic acids containing ribose moieties, the nucleic acids containing deoxyribose moieties, nucleic acids containing both ribose and deoxyribose moieties, nucleic acids containing ribose and modified ribose moieties. The prefix poly- refers to a nucleic acid containing about 1 to about 10,000 nucleotide monomer units and wherein the prefix oligo- refers to a nucleic acid containing about 1 to about 200 nucleotide monomer units.
The term “nucleobase” refers to the parts of nucleic acids that are involved in the hydrogen-bonding that binds one nucleic acid strand to another complementary strand in a sequence specific manner. The most common naturally-occurring nucleobases are adenine (A), guanine (G), uracil (U), cytosine (C), 5-methylcytosine, and thymine (T).
The term “modified nucleobase” refers to a moiety that can replace a nucleobase. The modified nucleobase mimics the spatial arrangement, electronic properties, or some other physicochemical property of the nucleobase and retains the property of hydrogen-bonding that binds one nucleic acid strand to another in a sequence specific manner. A modified nucleobase can pair with all of the five naturally occurring bases (uracil, thymine, adenine, cytosine, or guanine) without substantially affecting the melting behaviour, recognition by intracellular enzymes or activity of the oligonucleotide duplex.
The term “nucleoside” refers to a moiety wherein a nucleobase or a modified nucleobase is covalently bound to a sugar or modified sugar.
The term “sugar” refers to a monosaccharide in closed and/or open form. Sugars include, but are not limited to, ribose, deoxyribose, pentofuranose, pentopyranose, and hexopyranose moieties.
The term “modified sugar” refers to a moiety that can replace a sugar. The modified sugar mimics the spatial arrangement, electronic properties, or some other physicochemical property of a sugar.
The term “nucleotide” refers to a moiety wherein a nucleobase or a modified nucleobase is covalently linked to a sugar or modified sugar, and the sugar or modified sugar is covalently linked to a phosphate group or a modified phosphorus-atom moiety.
The term “chiral reagent” refers to a compound that is chiral or enantiopure and can be used for asymmetric induction in nucleic acid synthesis.
The term “chiral ligand” or “chiral auxiliary” refers to a moiety that is chiral or enantiopure and controls the stereochemical outcome of a reaction.
In a condensation reaction, the term “activating reagent” refers to a reagent that activates a less reactive site and renders it more susceptible to attack by a nucleophile.
The term “blocking moiety” refers to a group that transiently masks the reactivity of a functional group. The functional group can be subsequently unmasked by removal of the blocking moiety.
The terms “boronating agents”, “sulfur electrophiles”, “selenium electrophiles” refer to compounds that are useful in the modifying step used to introduce BH3, S, and Se groups, respectively, for modification at the phosphorus atom.
The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.
The term “solid support” refers to any support which enables synthetic mass production of nucleic acids and can be reutilized at need. As used herein, the term refers to a polymer that is insoluble in the media employed in the reaction steps performed to synthesize nucleic acids, and is derivatized to comprise reactive groups.
The term “linking moiety” refers to any moiety optionally positioned between the terminal nucleoside and the solid support or between the terminal nucleoside and another nucleoside, nucleotide, or nucleic acid.
As used herein, “treatment” or “treating,” or “palliating” or “ameliorating” are used interchangeably herein. These terms refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder. For prophylactic benefit, the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.
A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl moiety may be a saturated alkyl group (which means that it does not contain any units of unsaturation, e.g. carbon-carbon double bonds or carbon-carbon triple bonds) or the alkyl moiety may be an unsaturated alkyl group (which means that it contains at least one unit of unsaturation). The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or include a cyclic portion. The point of attachment of an alkyl is at a carbon atom that is not part of a ring.
The “alkyl” moiety may have 1 to 10 carbon atoms (whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). Alkyl includes both branched and straight chain alkyl groups. The alkyl group of the compounds described herein may be designated as “C1-C6 alkyl” or similar designations. By way of example only, “C1-C6 alkyl” indicates that there are one, two, three, four, five, or six carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, allyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, and the like. In one aspect, an alkyl is a C1-C6 alkyl.
C1-3 alkyl group means straight or branched alkyl group that has 1 to 3 carbon atoms. Examples of C1-3 alkyl group are methyl, ethyl, propyl and isopropyl. C1-4 alkyl group means straight or branched alkyl group that has 1 to 4 carbon atoms. Examples of C1-4 alkyl group are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl.
As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl rings are formed by five, six, seven, eight, nine, or more than nine carbon atoms. Aryl groups are a substituted or unsubstituted. In one aspect, an aryl is a phenyl or a naphthalenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). In one aspect, an aryl is a C6-C10 aryl.
C6-14 aryl group means aryl group that has 6 to 14 carbon atoms. The examples of C6-14 aryl group are phenyl, biphenyl, naphthyl, anthracyl, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, and tetrahydronaphthyl.
The term “aralkyl” refers to an alkyl group substituted with an aryl group. Suitable aralkyl groups include benzyl, picolyl, and the like, all of which may be optionally substituted.
An “acyl moiety” refers to an alkyl(C═O), aryl(C═O), or aralkyl(C═O) group. An acyl moiety can have an intervening moiety (Y) that is oxy, amino, thio, or seleno between the carbonyl and the hydrocarbon group. For example, an acyl group can be alkyl-Y—(C═O), aryl-Y—(C═O) or aralkyl-Y—(C═O).
“Alkenyl” groups are straight chain, branch chain, and cyclic hydrocarbon groups containing at least one carbon-carbon double bond. Alkenyl groups can be substituted.
“Alkynyl” groups are straight chain, branch chain, and cyclic hydrocarbon groups containing at least one carbon-carbon triple bond. Alkynyl groups can be substituted.
An “alkoxy” group refers to an alklyl group linked to oxygen i.e. (alkyl)-O— group, where alkyl is as defined herein. Examples include methoxy (—OCH3) or ethoxy (—OCH2CH3) groups.
An “alkenyloxy” group refers to an alkenyl group linked to oxygen i.e. (alkenyl)-O— group, where alkenyl is as defined herein.
An “alkynyloxy” group refers to an alkynyl group linked to oxygen i.e. (alkynyl)-O— group, where alkynyl is as defined herein.
An “aryloxy” group refers to an aryl group linked to oxygen i.e. (aryl)-O— group, where the aryl is as defined herein. An example includes phenoxy (—OC6H5) group.
The term “alkylseleno” refers to an alkyl group having a substituted seleno group attached thereto i.e. (alkyl)-Se— group, wherein alkyl is defined herein.
The term “alkenylseleno” refers to an alkenyl group having a substituted seleno group attached thereto i.e. (alkenyl)-Se— group, wherein alkenyl is defined herein.
The term “alkynylseleno” refers to an alkynyl group having a substituted seleno group attached thereto i.e. (alkynyl)-Se— group, wherein alkenyl is defined herein.
The term “alkylthio” refers to an alkyl group attached to a bridging sulfur atom i.e. (alkyl)-S— group, wherein alkyl is defined herein. For example, an alkylthio is a methylthio and the like.
The term “alkenylthio” refers to an alkenyl group attached to a bridging sulfur atom i.e. (alkenyl)-S— group, wherein alkenyl is defined herein.
The term “alkynylthio” refers to an alkynyl group attached to a bridging sulfur atom i.e. (alkynyl)-S— group, wherein alkenyl is defined herein.
The term “alkylamino” refers to an amino group substituted with at least one alkyl group i.e. —NH(alkyl) or —N(alkyl)2, wherein alkyl is defined herein.
The term “alkenylamino” refers to an amino group substituted with at least one alkenyl group i.e. —NH(alkenyl) or —N(alkenyl)2, wherein alkenyl is defined herein.
The term “alkynylamino” refers to an amino group substituted with at least one alkynyl group i.e. —NH(alkynyl) or —N(alkynyl)2, wherein alkynyl is defined herein.
The term “halogen” is intended to include fluorine, chlorine, bromine and iodine.
A “fluorescent group” refers to a molecule that, when excited with light having a selected wavelength, emits light of a different wavelength. Fluorescent groups include, but are not limited to, indole groups, fluorescein, tetramethylrhodamine, Texas Red, BODIPY, 5-[(2-aminoethyl)amino]napthalene-1-sulfonic acid (EDANS), coumarin and Lucifer yellow.
An “ammonium ion” is a positively charged polyatomic cation of the chemical formula NH4+.
An “alkylammonium ion” is an ammonium ion that has at least one of its hydrogen atoms replaced by an alkyl group, wherein alkyl is defined herein. Examples include triethylammonium ion, N,N-diisopropylethylammonium ion.
An “iminium ion” has the general structure R2C═NR2+. The R groups refer to alkyl, alkenyl, alkynyl, aryl groups as defined herein. A “heteroaromatic iminium ion” refers to an imminium ion where the nitrogen and its attached R groups form a heteroaromatic ring. A “heterocyclic iminium ion” refers to an imminium ion where the nitrogen and its attached R groups form a heterocyclic ring.
The terms “amino” or “amine” refers to a —N(Rh)2 radical group, where each Rh is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a —N(Rh)2 group has two Rh other than hydrogen they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, —N(Rh)2 is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. Any one or more of the hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl are optionally substituted by one or more substituents which independently are alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilyl, —ORi, —SRi, —OC(O)Ri, —N(Ri)2, —C(O)Ri, —C(O)ORi, —OC(O)N(Ri)2, —C(O)N(Ri)2, —N(Ri)C(O)OR, —N(Ri)C(O)Ri, —N(R)C(O)N(Ri)2, N(Ri)C(NRi)N(Ri)2, —N(Ri)S(O)tRi (where t is 1 or 2), —S(O), or —S(O)tN(Ri)2 (where t is 1 or 2), where each Ri is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl.
“Carbamate” as used herein, refers to a moiety attached to an amino group which has the formula —C(O)OR where R is alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl. Examples include but are not limited to Boc (tert-butyl-OC(O)—), CBz (benzyl-OC(O)—), Teoc (Me3SiCH2CH2OC(O)—), alloc (allyl-OC(O)—), or Fmoc (9-fluorenylmethyl-OC(O)—) group.
“Substituted silyl” as used herein, refers to a moiety which has the formula R3Si—. Examples include, but are not limited to, TBDMS (tert-butyldimethylsilyl), TBDPS (tert-butyldiphenylsilyl) or TMS (trimethylsilyl) group.
The term “thiol” refers to —SH groups, and include substituted thiol groups i.e. —SRJ groups, wherein RJ are each independently a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl aralkyl, heterocyclyl or heterocyclylalkyl group as defined herein.
The first aspect of the invention relates to a chiral reagent or a salt thereof. The chiral reagent has following chemical formula (I). The term “chiral reagent” is a chemical composition which is used to produce stereocontrolled phosphorus atom-modified nucleotide or oligonucleotide derivatives. The chiral reagent reacts with a nucleotide to form a chiral intermediate.
In the formula (I), G1 and G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group (—CN), a group of formula (II), (III) or (V), or both G1 and G2 taken together to form a group of formula (IV).
In the formula (II), G21 to G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group. Preferred examples of G21 to G23 are a hydrogen atom.
In the formula (III), G31 to G33 are independently C1-4 alkyl group, C6-14 aryl group C1-4 alkoxy group, C7-14 aralkyl group, C1-4 alkyl C6-14 aryl group, C1-4 alkoxy C6-14 aryl group, or C6-14 aryl C1-4 alkyl group. Examples of C1-4 alkyl C6-14 aryl group are methylphenyl group, and ethylphenyl group. Examples of C1-4 alkoxy C6-14 aryl group are a methoxyphenyl group and an ethoxyphenyl group. Examples of C6-14 aryl C1-4 alkyl groups are a benzyl group and a phenylethyl group. Preferred examples of G31 to G33 are independently a methyl group and a phenyl group.
In the formula (IV), G41 to G46 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group. Preferred examples of G41 to G46 are a hydrogen atom.
In the formula (V), G51 to G53 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, C1-3 alkyl group or C1-3 alkyloxy group.
G3 and G4 are independently a hydrogen atom, C1-3 alkyl group, C6-14 aryl group, or both G3 and G4 taken together to form a heteroatom-containing ring that has 3 to 16 carbon atoms. Preferred examples of G3 and G4 are that taken together to form a heteroatom-containing ring that has 3 to 16 carbon atoms with NH moiety in the formula (I).
A preferred embodiment is that the chiral reagent has following chemical formula (I′).
In the formula (I′), G1 and G2 are same as above and G1 and G2 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group, a group of formula (II) or (III), or both G1 and G2 taken together to form a group of formula (IV).
A preferred embodiment is that the chiral reagent has chemical formula (I′) and each of G1 and G2 is a group of formula (II), wherein G21 to G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and each of G1 and G2 is a group of formula (II) and each of G21 to G23 is a hydrogen atom.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (II), and G21 to G23 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (II), each of G21 and G22 is a hydrogen atom and G23 is a nitro group (—NO2).
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom and G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group, C6-14 aryl group, C7-14 aralkyl group, C1-4 alkyl C6-14 aryl group, C1-4 alkoxy C6-14 aryl group, or C6-14 aryl C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom and G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group, C6 aryl group, C7-10 aralkyl group, C1-4 alkyl C6 aryl group, C1-4 alkoxy C6 aryl group, or C6 aryl C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group or C6 aryl group (a phenyl group). Examples of C1-4 alkyl group are methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group and tert-butyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (III), and G31 to G33 are independently C1-4 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom, G2 is a group of formula (III), and G31 and G33 are C6 aryl group (a phenyl group) and G32 is C1-2 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 and G2 taken together to form a group of formula (IV), and G41 to G46 are independently a hydrogen atom, a nitro group, a halogen atom, a cyano group or C1-3 alkyl group.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 and G2 taken together to form a group of formula (IV), wherein each of G41 to G46 is a hydrogen atom.
A preferred embodiment is that the chiral reagent has chemical formula (I′) and G1 is a hydrogen atom and G2 is a group of formula (V). Further each of G51 to G53 is independently a hydrogen atom, a nitro group, a methyl group, or a methoxy group. More preferred embodiment is that G1 is a hydrogen atom and G2 is a group of formula (V), wherein each of G51 and G53 is a hydrogen atom and G53 is a 4-methyl group.
A preferred embodiment is that the chiral reagent is selected from one of III-a, III-b, V-a, VII-a, VII-b, IX-a, IX-b, XI-a, XIII-a and XIII-b:
The chiral reagent reacts with a nucleic acid or modified nucleic acid to be an asymmetric auxiliary group. A nucleoside 3′-phosphoramidite derivative, which is an intermediate of manufacturing a stereocontrolled phosphorus atom-modified oligonucleotide derivative, is obtained by chiral reagent reacting with a nucleic acid or modified nucleic acid.
The second aspect of the invention relates to a nucleoside 3′-phosphoramidite derivative which is represented by formula (Va) or (Vb). The compounds of formula (Va) and (Vb) are known as monomers that are used in synthesizing oligonucleotide derivatives. These compounds are also known as oxazaphospholidine monomers. The sugar moieties of the compounds represented by formula (Vb) are known as BNA and LNA (when R3 is a methylene group).
In the formula (Va) and (Vb), G1 to G4 are same as above, G5 is a protective group of the hydroxyl group, and Bs is a group selected from the groups represented by formula (VI) to (XI) or derivatives thereof.
Examples of Bs are an adenine, a thymine, a cytosine, a guanine, an uracil, a 5-methylcytosine, or derivative thereof.
R2 is hydrogen, —OH, —SH, —NRdRd, —N3, halogen, alkyl, alkenyl, alkynyl, alkyl-Y1—, alkenyl-Y1—, alkynyl-Y1—, aryl-Y1—, heteroaryl-Y1—, —ORb, or —SRb, wherein Rb is a blocking moiety.
Y1 is O, NRd, S, or Se.
Rd is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, acyl, substituted silyl, carbamate, —P(O)(Re)2, or —HP(O)(Re).
Re is independently hydrogen, alkyl, aryl, alkenyl, alkynyl, alkyl-Y2—, alkenyl-Y2—, alkynyl-Y2—, aryl-Y2—, or heteroaryl-Y2—, or a cation which is Na+, Li+, or K+.
Y2 is O, NRd, or S.
Preferred examples of alkyl are C1-10 alkyl group, preferred examples of alkenyl are C2-10 alkenyl, preferred examples of alkynyl are C2-10 alkynyl, preferred examples of aryl are C6-14 aryl, and preferred examples of heteroaryl are C6-14 heteroaryl.
R3 is a group represented by —CH2—, —(CH2)2—, —CH2NH—, or —CH2N(CH3)—.
Examples of G5 the trityl, 4-monomethoxytrityl, 4,4′-dimethoxytrityl, 4,4′,4″-trimethoxytrityl, 9-phenylxanthin-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthin-9-yl (MOX).
Bs is an adenine, a thymine, a cytosine, a guanine, or derivative thereof. Bs is a nucleobase or a modified nucleobase. The examples of the derivatives are that disclosed in JP 2005-89441 A and are represented as follows.
In the above formula, each of R8 to R10 is independently C1-10 alkyl, C6-C10 aryl, C6-C10 aralkyl, or C6-C10 aryloxyalkyl. Preferred examples of R8 are methyl, isopropyl, phenyl, benzyl, and phenoxymethyl. Preferred examples of R9 and R10 are C1-4 alkyl group.
A preferred embodiment of the second aspect is that the nucleoside 3′-phosphoramidite derivative is represented by formula (Va′) or (Vb′).
In the formula (Va′) and (Vb′), G1, G2, G5, Bs, R2, and R3 are same as above. The nucleoside 3′-phosphoramidite derivative is a chiral monomer which is used to produce stereocontrolled phosphorus atom-modified nucleotides and oligonucleotide derivatives.
Preferred examples of the nucleoside 3′-phosphoramidite derivatives are represented by the formula 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a, 16b, 17a, 17b, 18a, 18b, 19a, 19b, 20a, 20b, 21a, 21b, 22a, 22b, 23a, 23b, or 24a. These formulas are described at the Experimental section.
DMTr represents a 4,4′-dimethoxytrityl group and TOM represents a triisopropylsiloxymethyl group.
The examples of using the nucleoside 3′-phosphoramidite derivative are disclosed in, e.g., JP 2005-89441 A. By repeating steps of condensation and de-protection, it is possible to lengthen the chain of oligonucleotide derivatives as disclosed therein.
Formula of such an oligonucleotide derivative is shown in formula (X).
In the formula (X), X represents sulfide (═S), C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C6-C10 aryl, C6-C10 aralkyl, or C6-C10 aryloxialkyl. Preferably, X represents sulfide (═S). “n” is an integer that represents 1 to 150, 1 to 100, 1 to 50, or 1 to 30. “n” may be preferably 2 to 100, preferably 10 to 100, preferably 10 to 50, and more preferably 15 to 30.
The third aspect of the invention relates to a method for synthesis of a stereocontrolled phosphorus atom-modified oligonucleotide derivative. First step is a step of reacting a molecule comprising an achiral H-phosphonate moiety, the first activating reagent and a chiral reagent or a salt thereof to form a monomer. The chiral reagent has chemical formula (I) or (I′) and the monomer may be represented by formula (Va), (Vb), (Va′), or (Vb′). The monomer reacts with the second activating reagent and a nucleoside to form a condensed intermediate. Next step is a step of converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety. The method basically based on disclosure of WO 2010/064146 pamphlet. Namely, fundamental steps are disclosed as route A and route B therein. In the method the chiral reagent of the present invention is used.
First Scheme Relates to Synthesis of Chiral Oligos.
Activation Step
An achiral H-phosphonate moiety is treated with the first activating reagent to form the first intermediate. In one embodiment, the first activating reagent is added to the reaction mixture during the condensation step. Use of the first activating reagent is dependent on reaction conditions such as solvents that are used for the reaction. Examples of the first activating reagent are phosgene, trichloromethyl chloroformate, bis(trichloromethyl)carbonate (BTC), oxalyl chloride, Ph3PCl2, (PhO)3PCl2, N,N′-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BopCl), 1,3-dimethyl-2-(3-nitro-1,2,4-triazol-1-yl)-2-pyrrolidin-1-yl-1,3,2-diazaphospholidinium hexafluorophosphate (MNTP), or 3-nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP).
The example of achiral H-phosphonate moiety is a compound shown in the above Scheme. DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene. H+DBU may be, for example, ammonium ion, alkylammonium ion, heteroaromatic iminium ion, or heterocyclic iminium ion, any of which is primary, secondary, tertiary or quaternary, or a monovalent metal ion.
Reacting with Chiral Reagent
After the first activation step, the activated achiral H-phosphonate moiety reacts with a chiral reagent, which is represented by formula (I) or (I′), to form a chiral intermediate of formula (Va), (Vb), (Va′), or (Vb′).
Stereospecific Condensation Step
A chiral intermediate of Formula Va ((Vb), (Va′), or (Vb′)) is treated with the second activating reagent and a nucleoside to form a condensed intermediate. The nucleoside may be solidified. Examples of the second activating reagent are 4,5-dicyanoimidazole (DCI), 4,5-dichloroimidazole, 1-phenylimidazolium triflate (PhIMT), benzimidazolium triflate (BIT), benztriazole, 3-nitro-1,2,4-triazole (NT), tetrazole, 5-ethylthiotetrazole (ETT), 5-benzylthiotetrazole (BTT), 5-(4-nitrophenyl)tetrazole, N-cyanomethylpyrrolidinium triflate (CMPT), N-cyanomethylpiperidinium triflate, N-cyanomethyldimethylammonium triflate. A chiral intermediate of Formula Va ((Vb), (Va′), or (Vb′)) may be isolated as a monomer. Usually, the chiral intermediate of Va ((Vb), (Va′), or (Vb′)) is not isolated and undergoes a reaction in the same pot with a nucleoside or modified nucleoside to provide a chiral phosphite compound, a condensed intermediate. In other embodiments, when the method is performed via solid phase synthesis, the solid support comprising the compound is filtered away from side products, impurities, and/or reagents.
Capping Step
If the final nucleic acid is larger than a dimer, the unreacted —OH moiety is capped with a blocking group and the chiral auxiliary in the compound may also be capped with a blocking group to form a capped condensed intermediate. If the final nucleic acid is a dimer, then the capping step is not necessary.
Modifying Step
The compound is modified by reaction with an electrophile. The capped condensed intermediate may be executed modifying step. In some embodiments of the method, the modifying step is performed using a sulfur electrophile, a selenium electrophile or a boronating agent. The preferred examples of modifying steps are step of oxidation and sulfurization.
In some embodiments of the method, the sulfur electrophile is a
compound having one of the following formulas:
S8,
Z1—S—S—Z2, or
Z1—S—V—Z2. (Formula B)
Z1 and Z2 are
independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl,
aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or
thiocarbonyl, or Z1
and Z2 are taken together to form a 3 to 8 membered alicyclic or
heterocyclic ring, which may be substituted or unsubstituted; V is SO2, O, or NRf;
and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl.
In some embodiments of the method, the sulfur electrophile is a compound of following Formula A, B, C, D, E, or F:
In some embodiments of the method, the selenium electrophile is a compound having one of the following formulas:
Se,
Z3—Se—Se—Z4, or
Z3—Se—V—Z4 (Formula G)
Z3 and Z4 are independently alkyl, aminoalkyl, cycloalkyl, heterocyclic, cycloalkylalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxy, aryloxy, heteroaryloxy, acyl, amide, imide, or thiocarbonyl, or Z3 and Z4 are taken together to form a 3 to 8 membered alicyclic or heterocyclic ring, which may be substituted or unsubstituted; V is SO2, S, O, or NRf; and Rf is hydrogen, alkyl, alkenyl, alkynyl, or aryl.
In some embodiments of the method, the selenium electrophile is a compound of Formula G, H, I, J, K, or L.
In some embodiments of the method, the boronating agent is borane-N,N-diisopropylethylamine (BH3 DIPEA), borane-pyridine (BH3 Py), borane-2-chloropyridine (BH3 CPy), borane-aniline (BH3 An), borane-tetrahydrofurane (BH3 THF), or borane-dimethylsulfide (BH3 Me2S).
In some embodiments of the method, the modifying step is oxidation step. Oxidation step is disclosed in, e.g., JP 2010-265304 A and WO2010/064146.
Chain Elongation Cycle and De-Protection Step
The capped condensed intermediate is deblocked to remove the blocking group at the 5′-end of the growing nucleic acid chain to provide a compound. The compound is optionally allowed to re-enter the chain elongation cycle to form a condensed intermediate, a capped condensed intermediate, a modified capped condensed intermediate, and a 5′-deprotected modified capped intermediate. Following at least one round of chain elongation cycle, the 5′-deprotected modified capped intermediate is further deblocked by removal of the chiral auxiliary ligand and other protecting groups, e.g., nucleobase, modified nucleobase, sugar and modified sugar protecting groups, to provide a nucleic acid. In other embodiments, the nucleoside comprising a 5′-OH moiety is an intermediate from a previous chain elongation cycle as described herein. In yet other embodiments, the nucleoside comprising a 5′-OH moiety is an intermediate obtained from another known nucleic acid synthetic method. In embodiments where a solid support is used, the phosphorus-atom modified nucleic acid is then cleaved from the solid support. In certain embodiments, the nucleic acids is left attached on the solid support for purification purposes and then cleaved from the solid support following purification.
Based on the present method, it is possible to use stable and commercially available materials as starting materials. It is possible to produce stereocontrolled phosphorus atom-modified oligonucleotide derivatives using an achiral starting material.
As shown in a working example, the method of the present invention does not cause degradations under the de-protection steps. Further the method does not require special capping agents to produce phosphorus atom-modified oligonucleotide derivatives.
The fourth aspect of the invention relates to a method for the synthesis of stereocontrolled phosphorus atom-modified oligonucleotide derivatives using a chiral monomer. The first step is reacting a nucleoside 3′-phosphoramidite derivative which is represented by formula (Va), (Vb), (Va′), or (Vb′) with the second activating reagent and a nucleoside to form a condensed intermediate. The second step is converting the condensed intermediate to the nucleic acid comprising a chiral X-phosphonate moiety.
Second Scheme relates to synthesis of Chiral Oligos using a monomer of Formula Va ((Vb), (Va′), or (Vb′)). The second Scheme based on the method disclosed in JP 2005-89441 A.
The detailed conditions of the above scheme are similar to that of the first scheme. The starting material of formula Va (Vb), especially of formula Va′ (or Vb′), is chemically stable. As shown in a working example, the method of the present invention does not cause degradations under the de-protection steps. Further the method does not require special capping agents to produce phosphorus atom-modified oligonucleotide derivatives.
Mechanism for the removal of auxiliaries is shown as follows:
In the above scheme, Nu stands for Nucleophile. The above mechanism is thought to be different from the previous mechanism for the removal of auxiliaries.
Compound I-a was synthesized from L-proline according to the procedure described in the literature (Guga, P. Curr. Top. Med. Chem. 2007, 7, 695-713.).
Compound I-b was synthesized from D-proline in a similar manner to compound I-a.
To a solution of methyldiphenylsilylmethyl magnesium chloride in THF prepared from chloromethyldiphenylmethylsilane (4.02 g, 16.3 mmol) and magnesium (402 mg, 16.3 mmol) in THF (14 mL) was added I-a (2.79 g, 8.14 mmol) in THF (30 mL) solution with ice cooling. After stirring for 1.5 h with ice cooling, the mixture warmed to room temperature and continued stirring for 30 min. Saturated aqueous NH4Cl (100 mL) was added to the reaction mixture at 0 degrees C., and extraction was performed with diethylether (100 mL) for three times. The combined extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel afforded II-a as a colorless foam (3.91 g, 87%).
1H NMR (300 MHz, CDCl3) d 7.48-7.08 (25H, m), 4.33-4.23 (1H, m), 3.16-2.89 (3H, m), 2.84 (1H, brs), 1.70-1.54 (1H, m), 1.35 (1H, dd, J=14.7, 6.3 Hz), 1.10 (1H, dd, J=14.7, 8.1 Hz), 1.18-1.05 (1H, m), 1.04-0.90 (1H, m), 0.34 (3H, s), −0.17-−0.36 (1H, m).
II-a (3.91 g, 7.06 mmol) was dissolved in 3% DCA in DCM (70 mL), and stirred for 10 min at room temperature. To the mixture, 1M NaOH (200 mL) was added, and extraction was performed with DCM (100 mL) for three times. The combined extract was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel afforded III-a as a light yellow oil (1.99 g, 90%).
1H NMR (300 MHz, CDCl3) d 7.57-7.52 (5H, m), 7.38-7.33 (5H, m), 3.77 (1H, ddd, J=8.9, 5.4, 3.5 Hz), 3.01 (1H, dt, J=7.4, 3.6 Hz), 2.97-2.79 (2H, m), 2.27 (2H, brs), 1.76-1.53 (4H, m), 1.38 (1H, dd, J=15.0, 9.0 Hz), 1.24 (1H, dd, J=15.0, 5.4 Hz), 0.65 (3H, s); 13C NMR (100.4 MHz, CDCl3) d 137.4, 137.1, 134.6, 134.5, 129.1, 127.8, 69.5, 64.1, 47.0, 25.8, 24.0, 19.6, −3.4. MALDI TOF-MS m/z Calcd for C19H26NOSi [M+H]+ 312.18, found 312.06.
Compound II-b was obtained by using I-b instead of I-a in a similar manner to compound II-a.
1H NMR (300 MHz, CDCl3) d 7.48-7.12 (25H, m), 4.33-4.24 (1H, m), 3.16-2.89 (3H, m), 2.86 (1H, brs), 1.69-1.52 (1H, m), 1.35 (1H, dd, J=14.4, 6.0 Hz), 1.10 (1H, dd, J=14.4, 8.4 Hz), 1.18-1.05 (1H, m), 1.03-0.89 (1H, m), 0.33 (3H, s), −0.19-−0.39 (1H, m); 13C NMR (75.5 MHz, CDCl3) d 144.5, 137.5, 136.8, 134.6, 134.3, 129.8, 129.0, 127.8, 127.7, 127.4, 126.1, 77.9, 71.7, 65.1, 53.5, 25.0, 24.8, 19.6, −4.0. MALDI TOF-MS m/z Calcd for C38H40NOSi [M+H]+ 554.29, found 554.09.
Compound III-b was obtained by using II-b instead of II-a in a similar manner to compound III-a.
1H NMR (300 MHz, CDCl3) d 7.58-7.52 (5H, m), 7.38-7.33 (5H, m), 3.78 (1H, ddd, J=9.0, 5.1, 3.6 Hz), 3.00 (1H, dt, J=7.4, 3.3 Hz), 2.97-2.78 (2H, m), 2.19 (2H, brs), 1.76-1.53 (4H, m), 1.38 (1H, dd, J=14.6, 9.0 Hz), 1.24 (1H, dd, J=14.6, 5.1 Hz), 0.66 (3H, s); 13C NMR (75.5 MHz, CDCl3) d 137.5, 137.1, 134.5, 134.4, 129.0, 127.7, 69.2, 64.2, 46.9, 25.8, 24.0, 19.7, −3.4. MALDI TOF-MS m/z Calcd for C19H26NOSi [M+H]+ 312.18, found 312.09.
Compound IV-a was obtained by using “chloromethyltrimethylsilane” instead of “chloromethyldiphenylmethylsilane” in a similar manner to compound II-a.
1H NMR (300 MHz, CDCl3) d 7.58-7.51 (5H, m), 7.31-7.14 (10H, m), 4.13 (1H, dt, J=7.5, 3.0 Hz), 3.39-3.31 (1H, m), 3.20-2.99 (2H, m), 2.84 (1H, s), 1.74-1.57 (1H, m), 1.29-1.10 (2H, m), 0.74 (1H, dd, J=14.4, 7.2 Hz), 0.46 (1H, dd, J=14.4, 7.2 Hz), −0.15 (9H, s). MALDI TOF-MS m/z Calcd for C28H36NOSi [M+H]+ 430.26, found 430.09.
Compound V-a was obtained by using IV-a instead of II-a in a similar manner to compound III-a.
1H NMR (300 MHz, CDCl3) d 3.76 (1H, ddd, J=8.8, 5.7, 3.3 Hz), 3.08 (1H, dt, J=7.8, 3.3 Hz), 3.02-2.87 (2H, m), 2.48 (2H, brs), 1.81-1.58 (4H, m), 0.83 (1H, dd, J=14.7, 8.7 Hz), 0.68 (1H, dd, J=14.7, 6.0 Hz), 0.05 (9H, s); 13C NMR (75.5 MHz, CDCl3) d 69.6, 64.3, 46.9, 25.8, 23.9, 22.0, −0.8. MALDI TOF-MS m/z Calcd for C9H22NOSi [M+H]+ 188.15, found 188.00.
To a solution of diphenylmethane (6.7 mL, 40 mmol) in anhydrous THF (36 mL), n-BuLi (1.67M solution of Hexane, 24 mL, 40 mmol) was added dropwise at room temperature and stirred for 1 h. To the mixture, I-a (3.41 g, 10 mmol), which was dried by repeated coevaporations with toluene, in anhydrous THF (40 mL) was slowly added at 0 degrees C., and continued stirring for 45 min. A saturated NH4Cl aqueous solution (100 mL) and Et2O (100 mL) were then added, and the organic layer was separated and the aqueous layer was extracted with Et2O (2×100 mL). The organic layer were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford VI-a (1.41 g, 28%) as white foam.
1H NMR (300 MHz, CDCl3) d 7.45-7.01 (23H, m), 6.67-6.61 (2H, m), 4.80 (1H, d, J=10.8 Hz), 3.63 (1H, d, J=10.8 Hz), 3.36-3.27 (1H, m), 3.23-3.09 (1H, m), 3.02-2.89 (1H, m), 2.66 (1H, s), 1.90-1.75 (1H, m), 1.32-1.04 (2H, m), 0-−0.18 (1H, m).
Compound VII-a was obtained by using VI-a instead of II-a in a similar manner to compound III-a.
1H NMR (300 MHz, CDCl3) d 7.44-7.38 (2H, m), 7.33-7.14 (8H, m), 4.46 (1H, dd, J=9.9, 3.3 Hz), 3.91 (1H, d, J=9.9 Hz), 3.02-2.88 (2H, m), 2.81-2.69 (1H, m), 2.52 (2H, brs), 1.88-1.56 (4H, m); 13C NMR (75.5 MHz, CDCl3) d 142.3, 142.0, 128.6, 128.5, 128.4, 128.2, 126.5, 126.4, 73.5, 60.1, 55.8, 46.6, 25.8, 23.4. MALDI TOF-MS m/z Calcd for C18H22NO [M+H]+ 268.17, found 268.06.
Compound VI-b was obtained by using I-b instead of I-a in a similar manner to compound VI-a.
1H NMR (300 MHz, CDCl3) d 7.44-7.37 (6H, m), 7.30-7.01 (17H, m), 6.66-6.61 (2H, m), 4.80 (1H, d, J=10.8 Hz), 3.63 (1H, d, J=10.8 Hz), 3.36-3.28 (1H, m), 3.22-3.09 (1H, m), 3.01-2.89 (1H, m), 2.66 (1H, s), 1.90-1.75 (1H, m), 1.29-1.04 (2H, m), 0.00-−0.19 (1H, m); 13C NMR (75.5 MHz, CDCl3) d 144.2, 142.9, 141.6, 130.0, 128.5, 128.4, 127.9, 127.8, 127.4, 126.4, 126.2, 77.9, 75.9, 61.9, 55.4, 53.4, 24.7, 24.5. MALDI TOF-MS m/z Calcd for C37H36NO [M+H]+ 510.28, found 510.11.
Compound VII-b was obtained by using VI-b instead of VI-a in a similar manner to compound VII-a.
1H NMR (300 MHz, CDCl3) d 7.45-7.14 (10H, m), 4.45 (1H, dd, J=9.9, 3.3 Hz), 3.91 (1H, d, J=9.9 Hz), 3.00-2.89 (2H, m), 2.82-2.71 (1H, m), 2.40 (2H, brs), 1.87-1.55 (4H, m); 13C NMR (75.5 MHz, CDCl3) d 142.3, 142.0, 128.5, 128.3, 128.1, 126.3, 126.2, 73.4, 60.1, 55.9, 46.5, 25.8, 23.5. MALDI TOF-MS m/z Calcd for C18H22NO [M+H]+ 268.17, found 268.03.
Compound VIII-a was obtained by using “4-nitrobenzylchloride” instead of “diphenylmethane” in a similar manner to compound VI-a.
1H NMR (300 MHz, CDCl3) d 8.09-8.03 (2H, m), 7.49-7.43 (6H, m), 7.28-7.09 (11H, m), 4.23 (1H, ddd, J=8.3, 5.6, 3.0 Hz), 3.43-3.33 (1H, m), 3.23-3.11 (1H, m), 3.07-2.96 (1H, m), 2.83 (1H, brs), 2.74 (1H, dd, J=13.8, 8.4 Hz), 2.49 (1H, dd, J=13.8, 5.1 Hz), 1.83-1.67 (1H, m), 1.41-1.17 (2H, m), 0.27-0.08 (1H, m); 13C NMR (75.5 MHz, CDCl3) d 147.3, 146.3, 144.3, 129.8, 129.6, 127.5, 126.3, 123.4, 77.9, 74.8, 63.5, 53.2, 39.5, 25.0, 24.9. MALDI TOF-MS m/z Calcd for C31H31N2O3 [M+H]+ 479.23, found 479.08.
Compound IX-a was obtained by using VIII-a instead of VI-a in a similar manner to compound VII-a.
1H NMR (300 MHz, CDCl3) d 8.15 (2H, d, J=8.7 Hz), 7.42 (2H, d, J=8.7 Hz), 3.86-3.79 (1H, m), 3.16-3.07 (1H, m), 2.99-2.68 (6H, m), 1.84-1.68 (4H, m); 13C NMR (75.5 MHz, CDCl3) d 147.4, 146.2, 129.9, 123.2, 72.4, 62.0, 46.6, 40.4, 25.7, 24.4. MALDI TOF-MS m/z Calcd for C12H17N2O3 [M+H]+ 237.12, found 237.01.
Compound VIII-b was obtained by using I-b instead of I-a in a similar manner to compound VIII-a.
1H NMR (300 MHz, CDCl3) d 8.09-8.04 (2H, m), 7.49-7.43 (6H, m), 7.28-7.09 (11H, m), 4.22 (1H, ddd, J=8.4, 5.6, 3.0 Hz), 3.43-3.33 (1H, m), 3.24-3.10 (1H, m), 3.08-2.94 (1H, m), 2.81 (1H, brs), 2.75 (1H, dd, J=14.0, 8.1 Hz), 2.49 (1H, dd, J=14.0, 5.1 Hz), 1.81-1.67 (1H, m), 1.40-1.16 (2H, m), 0.26-0.09 (1H, m); 13C NMR (75.5 MHz, CDCl3) d 147.3, 144.3, 129.8, 129.6, 129.4, 126.3, 123.5, 77.9, 74.8, 63.5, 53.2, 39.5, 25.0, 24.9. MALDI TOF-MS m/z Calcd for C31H31N2O3 [M+H]+ 479.23, found 479.08.
Compound IX-b was obtained by using VIII-b instead of VIII-a in a similar manner to compound IX-a.
1H NMR (300 MHz, CDCl3) d 8.19-8.13 (2H, m), 7.45-7.39 (2H, m), 3.83 (1H, ddd, J=7.7, 5.4, 3.9 Hz), 3.14 (1H, dt, J=7.7, 3.9 Hz), 3.01-2.87 (2H, m), 2.83 (1H, d, J=3.3 Hz), 2.81 (1H, s), 2.62 (2H, brs), 1.79-1.72 (4H, m); 13C NMR (75.5 MHz, CDCl3) d 147.3, 146.5, 130.0, 123.5, 72.7, 61.7, 46.7, 40.1, 25.8, 24.2. MALDI TOF-MS m/z Calcd for C12H17N2O3 [M+H]+ 237.12, found 237.02.
Compound X-a was obtained by using “fluorene” instead of “diphenylmethane” in a similar manner to compound VI-a.
1H NMR (300 MHz, CDCl3) d 7.70 (1H, d, J=7.5 Hz), 7.66 (1H, d, J=7.8 Hz), 7.55 (2H, d, J=7.5 Hz), 7.44-7.09 (18H, m), 6.87-6.62 (1H, m), 4.55-4.48 (1H, m), 4.06 (1H, d, J=7.5 Hz), 3.43-3.34 (1H, m), 3.18-3.06 (1H, m), 2.98-2.88 (1H, m), 2.85 (1H, brs), 1.42-1.24 (1H, m), 1.18-1.04 (1H, m), 0.53-0.39 (1H, m), −0.02-−0.20 (1H, m); MALDI TOF-MS m/z Calcd for C37H34NO [M+H]+ 508.26, found 508.12.
Compound XI-a was obtained by using X-a instead of II-a in a similar manner to compound III-a.
1H NMR (300 MHz, CDCl3) d 7.76 (2H, d, J=7.5 Hz), 7.68 (2H, t, J=8.0 Hz), 7.43-7.35 (2H, m), 7.34-7.25 (2H, m), 4.28 (1H, d, J=6.3 Hz), 4.03 (1H, dd, J=6.5, 4.2 Hz), 3.19-3.11 (1H, m), 2.97-2.88 (1H, m), 2.86-2.76 (1H, m), 2.02 (2H, brs), 1.77-1.53 (3H, m), 1.38-1.23 (1H, m); MALDI TOF-MS m/z Calcd for C18H20NO [M+H]+ 266.15, found 266.04.
Compound XII-a was obtained by using “chloromethyl p-tolyl sulfone” instead of “chloromethyldiphenylmethylsilane” in a similar manner to compound II-a.
1H NMR (600 MHz, CDCl3) d 7.66 (2H, d, J=8.4 Hz), 7.48-7.44 (6H, m), 7.35 (2H, d, J=7.2 Hz), 7.21-7.13 (9H, m), 4.39-4.36 (1H, m), 3.33 (1H, s), 3.24-3.20 (1H, m), 3.19-3.10 (2H, m), 2.98-2.92 (2H, m), 2.49 (3H, s), 1.55-1.49 (1H, m), 1.33-1.26 (1H, m), 1.12-1.04 (1H, m), 0.22-0.14 (1H, m); 13C NMR (150.9 MHz, CDCl3) d 144.6, 144.5, 136.3, 129.9, 129.5, 128.1, 127.5, 126.2, 78.0, 69.1, 63.9, 60.2, 52.6, 25.5, 24.7, 21.7.
Compound XIII-a was obtained by using XII-a instead of II-a in a similar manner to compound III-a.
1H NMR (600 MHz, CDCl3) d 7.82 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz), 4.01 (1H, ddd, J=12.0, 5.1, 3.0 Hz), 3.32 (1H, dd, J=14.4, 3.0 Hz), 3.25 (1H, dd, J=14.4, 9.0 Hz), 3.16 (1H, dt, J=7.8, 5.1 Hz), 2.90-2.82 (2H, m), 2.46 (3H, s), 2.04 (2H, brs), 1.78-1.63 (3H, m), 1.62-1.55 (1H, m); 13C NMR (150.9 MHz, CDCl3) d 144.5, 136.7, 129.7, 127.7, 67.4, 61.8, 60.1, 46.7, 25.7, 21.4. MALDI TOF-MS m/z Calcd for C13H20NO3S [M+H]+ 270.12, found 270.04.
Compound XII-b was obtained by using I-b instead of I-a in a similar manner to compound XII-a.
1H NMR (600 MHz, CDCl3) d 7.66 (2H, d, J=8.4 Hz), 7.47-7.44 (6H, m), 7.35 (2H, d, J=7.8 Hz), 7.21-7.13 (9H, m), 4.37 (1H, dt, J=8.6, 2.4 Hz), 3.33 (1H, s), 3.23-3.20 (1H, m), 3.19-3.12 (2H, m), 2.98-2.92 (2H, m), 2.49 (3H, s), 1.56-1.49 (1H, m), 1.32-1.26 (1H, m), 1.11-1.03 (1H, m), 0.23-0.15 (1H, m); 13C NMR (150.9 MHz, CDCl3) d 144.6, 144.5, 136.3, 129.9, 129.6, 128.1, 127.6, 126.2, 78.0, 69.1, 63.9, 60.2, 52.6, 25.5, 24.7, 21.7.
Compound XIII-b was obtained by using XII-b instead of XII-a in a similar manner to compound XIII-a.
1H NMR (600 MHz, CDCl3) d 7.82 (2H, d, J=8.4 Hz), 7.37 (2H, d, J=8.4 Hz), 4.01 (1H, ddd, J=9.0, 5.1, 3.0 Hz), 3.32 (1H, dd, J=14.4, 3.0 Hz), 3.25 (1H, dd, J=14.4, 9.0 Hz), 3.17 (1H, dt, J=7.2, 5.1 Hz), 2.89-2.83 (2H, m), 2.46 (3H, s), 2.04 (2H, brs), 1.79-1.64 (3H, m), 1.62-1.55 (1H, m); 13C NMR (150.9 MHz, CDCl3) d 144.8, 136.6, 129.8, 127.9, 67.7, 61.8, 60.1, 46.8, 25.9, 25.8, 21.6. MALDI TOF-MS m/z Calcd for C13H20NO3S [M+H]+ 270.12, found 270.05.
III-a (560 mg, 1.80 mmol) were dried by repeated coevaporations with dry toluene and dissolved in dry diethylether (0.90 mL) under argon. N-Methylmorpholine (400 mL, 3.60 mmol) was added to the solution, and the resultant solution was added dropwise to a solution of PCl3 (160 mL, 1.80 mmol) in dry diethylether (0.90 mL) at 0 degrees C. under argon with stirring. The mixture was then allowed to warm to room temperature and stirred for 30 min. The resultant N-methylmorpholine hydrochloride was removed by filtration under nitrogen, and the filtrate was concentrated to dryness under reduced pressure to afford crude 2-chloro-1,3,2-oxazaphospholidine derivative. The crude materials were dissolved in freshly distilled THF (3.6 mL) to make 0.5 M solutions, which were used to synthesize the nucleoside 3′-O-oxazaphospholidines without further purification.
5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine (636 mg, 0.84 mmol) was dried by repeated coevaporations with dry toluene, and dissolved in freshly distilled THF (2.5 mL) under argon. Et3N (0.58 mL, 4.2 mmol) was added, and the mixture was cooled to −78 degrees C. A 0.5 M solution of the corresponding crude 2-chloro-1,3,2-oxazaphospholidine derivative in freshly distilled THF (3.6 mL, 1.80 mmol) was added dropwise via a syringe, and the mixture was stirred for 15 min at room temperature. A saturated NaHCO3 aqueous solution (70 mL) and CHCl3 (70 mL) were then added, and the organic layer was separated and washed with saturated NaHCO3 aqueous solutions (2×70 mL). The combined aqueous layers were back-extracted with CHCl3 (70 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford 3a (829 mg, 90%) as a white foam.
1H NMR (300 MHz, CDCl3) d 8.77 (1H, brs), 7.99 (1H, s), 7.54-6.98 (24H, m), 6.81-6.73 (4H, m), 6.35 (1H, dd, J=8.0, 6.3 Hz), 4.89-4.73 (4H, m), 4.68 (2H, brs), 4.05-3.98 (1H, m), 3.75 (6H, s), 3.62-3.46 (1H, m), 3.41-3.20 (3H, m), 3.18-3.04 (1H, m), 3.08 (2H, t, J=6.6 Hz), 2.58-2.36 (2H, m), 1.94-1.59 (2H, m), 1.56 (1H, dd, J=15.0, 8.7 Hz), 1.43 (1H, dd, J=15.0, 5.7 Hz), 1.33-1.16 (2H, m), 0.62 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 153.5 (1P, s).
Compound 3b was obtained by using III-b instead of III-a in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.80 (1H, brs), 7.96 (1H, s), 7.54-6.96 (24H, m), 6.79-6.71 (4H, m), 6.19 (1H, t, J=6.6 Hz), 4.90-4.73 (4H, m), 4.66 (2H, brs), 4.16-4.08 (1H, m), 3.76 (6H, s), 3.60-3.36 (2H, m), 3.29 (1H, d, J=3.9 Hz), 3.27-3.12 (2H, m), 3.09 (2H, t, J=6.6 Hz), 2.59-2.46 (1H, m), 2.07-1.97 (1H, m), 1.94-1.41 (5H, m), 1.36-1.18 (1H, m), 0.65 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.1 (1P, s).
Compound 1a was obtained by using “5′-O-(DMTr)-6-N-(benzoyl)adenosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (600 MHz, CDCl3) d 8.71 (1H, s), 8.12 (1H, s), 8.04 (2H, d, J=7.8 Hz), 7.62-7.15 (23H, m), 6.80-6.75 (4H, m), 6.37 (1H, dd, J=7.8, 6.0 Hz), 4.94-4.88 (1H, m), 4.80 (1H, ddd, J=12.0, 6.0, 5.4 Hz), 4.07-4.04 (1H, m), 3.76 (6H, s), 3.58-3.49 (1H, m), 3.41-3.34 (1H, m), 3.33 (1H, dd, J=10.8, 4.8 Hz), 3.25 (1H, dd, J=10.8, 4.8 Hz), 3.13-3.06 (1H, m), 2.66-2.58 (1H, m), 2.40-2.35 (1H, m), 1.91-1.84 (1H, m), 1.73-1.66 (1H, m), 1.56 (1H, dd, J=15.0, 9.0 Hz), 1.44 (1H, dd, J=15.0, 5.4 Hz), 1.47-1.41 (1H, m), 1.30-1.23 (1H, m), 0.63 (3H, s); 31P NMR (243.0 MHz, CDCl3) d 151.8 (1P, s).
Compound 1b was obtained by using III-b instead of III-a in a similar manner to compound 1a.
1H NMR (300 MHz, CDCl3) d 9.06 (1H, brs), 8.76 (1H, s), 8.12 (1H, s), 8.07-7.99 (2H, m), 7.64-7.14 (22H, m), 6.83-6.75 (4H, m), 6.25 (1H, t, J=6.6 Hz), 4.86-4.75 (2H, m), 4.20-4.15 (1H, m), 3.77 (6H, s), 3.61-3.38 (2H, m), 3.36 (1H, dd, J=10.2, 4.2 Hz), 3.27 (1H, dd, J=10.2, 4.2 Hz), 3.27-3.13 (1H, m), 2.71-2.59 (1H, m), 2.12-2.01 (1H, m), 1.94-1.42 (5H, m), 1.36-1.20 (1H, m), 0.67 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.3 (1P, s).
Compound 2a was obtained by using “5′-O-(DMTr)-4-N-(isobutyryl)cytidine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.33 (1H, brs), 8.17 (1H, d, J=7.5 Hz), 7.52-7.22 (19H, m), 7.07 (1H, d, J=7.5 Hz), 6.88-6.81 (4H, m), 6.20 (1H, t, J=6.2 Hz), 4.81-4.64 (2H, m), 3.93-3.87 (1H, m), 3.79 (6H, s), 3.59-3.43 (1H, m), 3.39-3.29 (3H, m), 3.16-3.02 (1H, m), 2.69-2.52 (2H, m), 2.12-2.00 (1H, m), 1.91-1.50 (3H, m), 1.47-1.32 (2H, m), 1.27-1.16 (7H, m), 0.60 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 154.8 (1P, s).
Compound 2b was obtained by using III-b instead of III-a in a similar manner to compound 2a.
1H NMR (300 MHz, CDCl3) d 8.33 (1H, d, J=7.5 Hz), 8.23 (1H, brs), 7.57-7.22 (19H, m), 7.12 (1H, d, J=7.5 Hz), 6.88-6.81 (4H, m), 6.15 (1H, dd, J=6.6, 4.2 Hz), 4.82-4.63 (2H, m), 4.03-3.97 (1H, m), 3.80 (6H, s), 3.55-3.26 (4H, m), 3.19-3.05 (1H, m), 2.59 (1H, quintet, J=6.9 Hz), 2.39-2.27 (1H, m), 2.21-2.10 (1H, m), 1.90-1.56 (3H, m), 1.50-1.32 (2H, m), 1.26-1.17 (7H, m), 0.66 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.2 (1P, s).
Compound 4a was obtained by using “5′-O-(DMTr)thymidine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.58-7.23 (21H, m), 6.86-6.79 (4H, m), 6.35 (1H, dd, J=8.1, 5.7 Hz), 4.79-4.67 (2H, m), 3.83-3.78 (1H, m), 3.78 (6H, s), 3.59-3.43 (1H, m), 3.34 (1H, dd, J=10.5, 2.4 Hz), 3.35-3.24 (1H, m), 3.20 (1H, dd, J=10.5, 2.4 Hz), 3.16-3.02 (1H, m), 2.36-2.26 (1H, m), 2.15-2.02 (1H, m), 1.92-1.77 (1H, m), 1.74-1.59 (1H, m), 1.52 (1H, dd, J=14.7, 9.0 Hz), 1.40 (3H, s), 1.45-1.15 (3H, m), 0.60 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 153.7 (1P, s).
Compound 4b was obtained by using III-b instead of III-a in a similar manner to compound 4a.
1H NMR (300 MHz, CDCl3) d 8.46 (1H, brs), 7.59-7.20 (20H, m), 6.86-6.79 (4H, m), 6.26 (1H, t, J=6.8 Hz), 4.78-4.65 (2H, m), 4.01-3.95 (1H, m), 3.78 (6H, s), 3.55-3.40 (1H, m), 3.42 (1H, dd, J=10.5, 2.7 Hz), 3.40-3.28 (1H, m), 3.22 (1H, dd, J=10.5, 3.0 Hz), 3.19-3.06 (1H, m), 2.16-1.95 (2H, m), 1.90-1.54 (3H, m), 1.49-1.35 (1H, m), 1.43 (3H, s), 1.34-1.17 (2H, m), 0.67 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 156.2 (1P, s).
Compound 5a was obtained by using “5′-O-(DMTr)-2′-O-methyl-6-N-(benzoyl)adenosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.66 (1H, s), 8.13 (1H, s), 8.03 (2H, d, J=7.2 Hz), 7.64-7.16 (23H, m), 6.79 (4H, d, J=8.7 Hz), 6.08 (1H, d, J=6.3 Hz), 4.91-4.81 (1H, m), 4.77-4.69 (1H, m), 4.64-4.57 (1H, m), 4.15-4.10 (1H, m), 3.76 (6H, s), 3.60-3.23 (4H, m), 3.35 (3H, s), 3.14-3.00 (1H, m), 1.90-1.19 (6H, m), 0.62 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.8 (1P, s).
Compound 5b was obtained by using III-b instead of III-a in a similar manner to compound 5a.
1H NMR (300 MHz, CDCl3) d 9.12 (1H, brs), 8.73 (1H, s), 8.24 (1H, s), 8.07-8.01 (2H, m), 7.62-7.17 (22H, m), 6.83-6.77 (4H, m), 6.12 (1H, d, J=4.8 Hz), 4.84-4.73 (2H, m), 4.43 (1H, t, J=4.8 Hz), 4.25-4.19 (1H, m), 3.77 (6H, s), 3.55-3.20 (4H, m), 3.28 (3H, s), 3.16-3.03 (1H, m), 1.90-1.17 (6H, m), 0.65 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.0 (1P, s).
Compound 6a was obtained by using “5′-O-(DMTr)-2′-O-methyl-4-N-(isobutyryl)cytidine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.49 (1H, d, J=7.2 Hz), 7.58-7.20 (19H, m), 6.96 (1H, d, J=7.2 Hz), 6.90-6.82 (4H, m), 5.98 (1H, s), 4.84 (1H, dd, J=13.1, 7.5 Hz), 4.59 (1H, dt, J=8.3, 4.5 Hz), 4.19-4.13 (1H, m), 3.79 (6H, s), 3.78-3.72 (1H, m), 3.63-3.40 (3H, m), 3.55 (3H, s), 3.36-3.24 (1H, m), 3.09-2.95 (1H, m), 2.59 (1H, septet, J=6.9 Hz), 1.85-1.53 (5H, m), 1.48-1.37 (1H, m), 1.24-1.17 (6H, m), 0.59 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.2 (1P, s).
Compound 6b was obtained by using III-b instead of III-a in a similar manner to compound 6a.
1H NMR (300 MHz, CDCl3) d 8.62 (1H, d, J=7.5 Hz), 7.57-7.23 (19H, m), 7.02 (1H, d, J=7.5 Hz), 6.89-6.81 (4H, m), 5.92 (1H, s), 4.90 (1H, dt, J=9.0, 5.7 Hz), 4.61 (1H, dt, J=8.7, 4.8 Hz), 4.25-4.17 (1H, m), 3.81 (6H, s), 3.67 (1H, d, J=4.5 Hz), 3.62-3.25 (4H, m), 3.38 (3H, s), 3.16-3.02 (1H, m), 2.58 (1H, septet, J=6.9 Hz), 1.87-1.40 (6H, m), 1.26-1.14 (6H, m), 0.64 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 158.2 (1P, s).
Compound 7a was obtained by using “5′-O-(DMTr)-2′-O-methyl-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.67 (1H, brs), 8.01 (1H, s), 7.56-7.16 (24H, m), 6.83-6.74 (4H, m), 6.08 (1H, d, J=6.9 Hz), 4.85-4.76 (1H, m), 4.84 (2H, t, J=6.6 Hz), 4.65-4.56 (1H, m), 4.59 (2H, brs), 4.48 (1H, dd, J=6.6, 5.1 Hz), 4.09-4.05 (1H, m), 3.75 (6H, s), 3.60-3.42 (2H, m), 3.40-3.26 (2H, m), 3.35 (3H, s), 3.18-3.05 (1H, m), 3.08 (2H, t, J=6.6 Hz), 1.89-1.49 (3H, m), 1.48-1.16 (3H, m), 0.59 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 156.9 (1P, s).
Compound 7b was obtained by using III-b instead of III-a in a similar manner to compound 7a.
1H NMR (300 MHz, CDCl3) d 8.74 (1H, brs), 8.09 (1H, s), 7.56-6.94 (24H, m), 6.84-6.71 (4H, m), 6.09 (1H, d, J=4.8 Hz), 4.83-4.70 (2H, m), 4.83 (2H, t, J=6.6 Hz), 4.63 (2H, brs), 4.35 (1H, t, J=5.0 Hz), 4.23-4.16 (1H, m), 3.75 (6H, s), 3.58-3.19 (4H, m), 3.32 (3H, s), 3.16-3.04 (1H, m), 3.07 (2H, t, J=6.6 Hz), 1.90-1.55 (3H, m), 1.48-1.15 (3H, m), 0.64 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 154.6 (1P, s).
Compound 8a was obtained by using “5′-O-(DMTr)-2′-O-(methyl)uridine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.91 (1H, d, J=7.8 Hz), 7.58-7.20 (19H, m), 6.88-6.80 (4H, m), 5.96 (1H, d, J=3.3 Hz), 5.19 (1H, d, J=7.8 Hz), 4.88-4.78 (1H, m), 4.66-4.57 (1H, m), 4.03-3.95 (1H, m), 3.90-3.74 (1H, m), 3.78 (6H, s), 3.77-3.71 (1H, m), 3.58-3.29 (2H, m), 3.45 (3H, s), 3.13-2.82 (2H, m), 1.88-1.53 (3H, m), 1.49-1.16 (3H, m), 0.60 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.3 (1P, s).
Compound 8b was obtained by using III-b instead of III-a in a similar manner to compound 8a.
1H NMR (300 MHz, CDCl3) d 8.10 (1H, d, J=8.4 Hz), 7.58-7.20 (19H, m), 6.87-6.79 (4H, m), 5.89 (1H, d, J=1.5 Hz), 5.21 (1H, d, J=8.4 Hz), 4.92-4.82 (1H, m), 4.73-4.63 (1H, m), 4.15-4.08 (1H, m), 3.89-3.73 (1H, m), 3.78 (6H, s), 3.66-3.62 (1H, m), 3.57-3.27 (2H, m), 3.30 (3H, s), 3.17-2.82 (2H, m), 1.89-1.55 (3H, m), 1.55-1.40 (1H, m), 1.35-1.15 (2H, m), 0.66 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.5 (1P, s).
Compound 9a was obtained by using “5′-O-(DMTr)-2′-deoxy-2′-fluoro-6-N-(benzoyl)adenosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.64 (1H, s), 8.14 (1H, s), 8.06-8.01 (2H, m), 7.63-7.07 (23H, m), 6.78-6.70 (4H, m), 6.12 (1H, dd, J=18.0, 2.4 Hz), 5.24-5.01 (2H, min), 4.94-4.84 (1H, m), 4.17-4.06 (1H, m), 3.73 (6H, s), 3.55-3.40 (3H, m), 3.30-3.22 (1H, m), 3.03-2.88 (1H, m), 1.92-1.19 (6H, m), 0.62 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 150.5 (1P, d, J=7.7 Hz).
Compound 9b was obtained by using III-b instead of III-a in a similar manner to compound 9a.
1H NMR (300 MHz, CDCl3) d 9.07 (1H, brs), 8.80 (1H, s), 8.24 (1H, s), 8.08-8.01 (2H, m), 7.66-7.15 (22H, m), 6.81-6.75 (4H, m), 6.14 (1H, dd, J=18.0, 1.8 Hz), 5.16-4.91 (3H, m), 4.28-4.21 (1H, m), 3.76 (6H, s), 3.57-3.11 (5H, m), 1.82-1.16 (6H, m), 0.65 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.8 (1P, d, J=5.6 Hz).
Compound 10a was obtained by using “5′-O-(DMTr)-2′-deoxy-2′-fluoro-4-N-(isobutyryl)cytidine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.66 (1H, brs), 8.41 (1H, d, J=7.5 Hz), 7.55-7.20 (19H, m), 7.01 (1H, d, J=7.5 Hz), 6.89-6.81 (4H, m), 6.06 (1H, d, J=15.9 Hz), 4.85 (1H, dd, J=51.4, 3.9 Hz), 4.84 (1H, dd, J=12.9, 7.5 Hz), 4.77-4.59 (1H, m), 4.15-4.08 (1H, m), 3.79 (6H, s), 3.63-3.29 (4H, m), 3.10-2.96 (1H, m), 2.65 (1H, septet, J=6.9 Hz), 1.85-1.53 (3H, m), 1.48-1.17 (3H, m), 1.21 (3H, d, J=4.8 Hz), 1.19 (3H, d, J=4.8 Hz), 0.59 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.5 (1P, d, J=6.6 Hz).
Compound 10b was obtained by using III-b instead of III-a in a similar manner to compound 10a.
1H NMR (300 MHz, CDCl3) d 8.53 (1H, d, J=7.5 Hz), 7.57-7.23 (20H, m), 7.10 (1H, d, J=7.5 Hz), 6.89-6.81 (4H, m), 6.10 (1H, d, J=15.9 Hz), 5.00-4.92 (1H, m), 4.84 (1H, dd, J=51.5, 3.3 Hz), 4.75-4.58 (1H, m), 4.24 (1H, d, J=9.3 Hz), 3.81 (6H, s), 3.65-3.39 (3H, m), 3.32-3.06 (2H, m), 2.59 (1H, septet, J=6.9 Hz), 1.88-1.53 (4H, m), 1.49-1.34 (2H, m), 1.27-1.18 (6H, m), 0.65 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 159.0 (1P, d, J=4.4).
Compound 11a was obtained by using “5′-O-(DMTr)-2′-deoxy-2′-fluoro-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.74 (1H, brs), 8.03 (1H, s), 7.55-6.94 (24H, m), 6.80-6.69 (4H, m), 6.21 (1H, dd, J=14.9, 3.6 Hz), 5.34 (1H, dt, J=52.3, 3.6 Hz), 5.01-4.75 (2H, m), 4.84 (1H, t, J=6.6 Hz), 4.62 (2H, brs), 4.15-4.07 (1H, m), 3.73 (6H, s), 3.59-3.29 (4H, m), 3.15-3.00 (1H, m), 3.07 (2H, t, J=6.6 Hz), 1.90-1.49 (3H, m), 1.47-1.12 (3H, m), 0.58 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.6 (1P, d, J=10.9 Hz).
Compound 11b was obtained by using III-b instead of III-a in a similar manner to compound 11a.
1H NMR (300 MHz, CDCl3) d 8.81 (1H, brs), 8.06 (1H, s), 7.55-6.95 (24H, m), 6.77-6.69 (4H, m), 6.06 (1H, d, J=17.1 Hz), 5.24-5.08 (1H, m), 5.04-4.80 (2H, m), 4.87 (1H, t, J=6.6 Hz), 4.62 (2H, brs), 4.25-4.19 (1H, m), 3.73 (6H, s), 3.58-3.02 (5H, m), 3.10 (2H, t, J=6.6 Hz), 1.90-1.56 (3H, m), 1.50-1.15 (3H, m), 0.63 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 158.0 (1P, d, J=4.4 Hz).
Compound 12a was obtained by using “5′-O-(DMTr)-2′-deoxy-2′-fluorouridine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.85 (1H, d, J=8.1 Hz), 7.58-7.20 (19H, m), 6.87-6.79 (4H, m), 5.98 (1H, d, J=16.5 Hz), 5.23 (1H, d, J=8.1 Hz), 4.86-4.61 (3H, m), 3.99 (1H, d, J=6.9 Hz), 3.76 (6H, d, J=3.0 Hz), 3.56-3.34 (4H, m), 3.10-2.96 (1H, m), 1.88-1.74 (1H, m), 1.72-1.52 (2H, m), 1.48-1.16 (3H, m), 0.61 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 154.3 (1P, d, J=8.9 Hz).
Compound 12b was obtained by using III-b instead of III-a in a similar manner to compound 12a.
1H NMR (300 MHz, CDCl3) d 8.01 (1H, d, J=8.4 Hz), 7.58-7.20 (19H, m), 6.87-6.79 (4H, m), 6.03 (1H, d, J=16.2 Hz), 5.29 (1H, d, J=8.4 Hz), 4.96 (1H, dd, J=13.1, 7.5 Hz), 4.80-4.54 (2H, m), 4.15 (1H, d, J=9.0 Hz), 3.78 (6H, s), 3.61-3.39 (3H, m), 3.37-3.25 (1H, m), 3.23-3.09 (1H, m), 1.91-1.56 (3H, m), 1.51-1.13 (3H, m), 0.66 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 158.9 (1P, d, J=4.4 Hz).
Compound 13a was obtained by using “5′-O-(DMTr)-2′-O-TOM-6-N-(acetyl)adenosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.82 (1H, brs), 8.49 (1H, s), 8.10 (1H, s), 7.58-7.17 (19H, m), 6.83-6.73 (4H, m), 6.11 (1H, d, J=6.6 Hz), 5.15 (1H, dd, J=6.6, 5.4 Hz), 4.98-4.77 (4H, m), 4.18-4.11 (1H, m), 3.76 (6H, s), 3.59-3.25 (4H, m), 3.16-3.02 (1H, m), 2.62 (3H, s), 1.91-1.53 (3H, m), 1.49-1.18 (3H, m), 0.96-0.80 (3H, m), 0.90 (18H, s), 0.62 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 156.7 (1P, s).
Compound 13b was obtained by using III-b instead of III-a in a similar manner to compound 13a.
1H NMR (300 MHz, CDCl3) d 8.56 (1H, brs), 8.55 (1H, s), 8.13 (1H, s), 7.57-7.17 (19H, m), 6.82-6.73 (4H, m), 6.16 (1H, d, J=5.7 Hz), 5.06 (1H, t, J=5.6 Hz), 4.93 (1H, d, J=5.1 Hz), 4.83 (1H, d, J=5.1 Hz), 4.81-4.69 (2H, m), 4.27-4.19 (1H, m), 3.76 (6H, s), 3.55-3.40 (2H, m), 3.33-3.16 (2H, m), 3.12-2.97 (1H, m), 2.63 (3H, s), 1.88-1.52 (3H, m), 1.45-1.16 (3H, m), 0.91-0.79 (3H, m), 0.86 (18H, s), 0.64 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 154.8 (1P, s).
Compound 14a was obtained by using “5′-O-(DMTr)-2′-O-TOM-4-N-(acetyl)cytidine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 10.04 (1H, brs), 8.30 (1H, d, J=7.5 Hz), 7.51-7.21 (19H, m), 6.99 (1H, d, J=7.5 Hz), 6.89-6.81 (4H, m), 6.12 (1H, d, J=3.3 Hz), 5.07 (1H, d, J=4.8 Hz), 5.05 (1H, d, J=4.8 Hz), 4.84-4.75 (1H, m), 4.62-4.52 (1H, m), 4.31-4.25 (1H, m), 4.08-4.01 (1H, m), 3.78 (6H, d, J=3.0 Hz), 3.55-3.23 (4H, m), 3.10-2.96 (1H, m), 2.24 (3H, s), 1.84-1.49 (3H, m), 1.46-0.96 (24H, m), 0.58 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 156.5 (1P, s).
Compound 14b was obtained by using III-b instead of III-a in a similar manner to compound 14a.
1H NMR (300 MHz, CDCl3) d 10.19 (1H, brs), 8.46 (1H, d, J=7.5 Hz), 7.54-7.23 (19H, m), 7.01 (1H, d, J=7.5 Hz), 6.88-6.79 (4H, m), 6.19 (1H, d, J=1.8 Hz), 5.11 (1H, d, J=4.8 Hz), 5.07 (1H, d, J=4.8 Hz), 4.81-4.71 (1H, m), 4.60-4.51 (1H, m), 4.26-4.18 (2H, m), 3.79 (6H, s), 3.63-3.55 (1H, m), 3.48-3.28 (2H, m), 3.21-2.94 (2H, m), 2.26 (3H, s), 1.81-1.49 (3H, m), 1.43-0.96 (24H, m), 0.62 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 156.4 (1P, s).
Compound 15a was obtained by using “5′-O-(DMTr)-2′-O-TOM-2-N-(acetyl)guanosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.70 (1H, s), 7.63-7.13 (21H, m), 6.84-6.76 (4H, m), 5.77 (1H, d, J=8.4 Hz), 5.41-5.33 (1H, m), 4.90 (2H, s), 4.78-4.68 (2H, m), 3.86 (1H, brs), 3.75 (3H, s), 3.74 (3H, s), 3.56-3.41 (2H, m), 3.32-2.90 (3H, m), 1.92-1.10 (9H, m), 0.97-0.87 (21H, m), 0.52 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 158.1 (1P, s).
Compound 15b was obtained by using III-b instead of III-a in a similar manner to compound 15a.
1H NMR (300 MHz, CDCl3) d 7.77 (1H, s), 7.56-7.15 (21H, m), 6.82-6.75 (4H, m), 5.86 (1H, d, J=7.5 Hz), 5.26-5.17 (1H, m), 4.95 (1H, d, J=5.4 Hz), 4.85 (1H, d, J=5.4 Hz), 4.78-4.71 (1H, m), 4.59-4.49 (1H, m), 4.10-4.05 (1H, m), 3.74 (6H, s), 3.52-3.37 (2H, m), 3.30-3.18 (1H, m), 3.11-2.85 (2H, m), 1.85-1.15 (9H, m), 0.93-0.84 (21H, m), 0.62 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 152.3 (1P, s).
Compound 16a was obtained by using “5′-O-(DMTr)-2′-O-TOM-uridine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.76 (1H, d, J=8.1 Hz), 7.55-7.18 (20H, m), 6.88-6.80 (4H, m), 6.11 (1H, d, J=6.0 Hz), 5.32 (1H, d, J=8.1 Hz), 4.99 (1H, d, J=5.1 Hz), 4.93 (1H, d, J=5.1 Hz), 4.84-4.75 (1H, m), 4.54-4.46 (1H, m), 4.38 (1H, t, J=5.7 Hz), 3.87-3.83 (1H, m), 3.78 (3H, s), 3.77 (3H, s), 3.56-3.42 (1H, m), 3.39-3.28 (1H, m), 3.36 (1H, dd, J=11.0, 2.7 Hz), 3.25 (1H, dd, J=11.0, 2.7 Hz), 3.16-3.03 (1H, m), 1.88-1.12 (6H, m), 1.08-0.97 (21H, m), 0.59 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 156.6 (1P, s).
Compound 16b was obtained by using III-b instead of III-a in a similar manner to compound 16a.
1H NMR (600 MHz, CDCl3) d 7.87 (1H, d, J=7.8 Hz), 7.52-7.48 (4H, m), 7.38-7.21 (16H, m), 6.83-6.79 (4H, m), 6.14 (1H, d, J=4.8 Hz), 5.33 (1H, d, J=7.8 Hz), 4.99 (1H, d, J=5.4 Hz), 4.89 (1H, d, J=5.4 Hz), 4.67 (1H, dd, J=13.8, 7.2 Hz), 4.52 (1H, dt, J=10.4, 4.8 Hz), 4.31 (1H, t, J=4.8 Hz), 4.06-4.03 (1H, m), 3.78 (3H, s), 3.77 (3H, s), 3.47 (1H, dd, J=10.4, 2.4 Hz), 3.47-3.39 (1H, m), 3.22-3.17 (2H, m), 3.00 (1H, ddd, J=19.5, 10.4, 4.8 Hz), 1.82-1.74 (1H, m), 1.68-1.58 (1H, m), 1.56 (1H, dd, J=14.4, 8.4 Hz), 1.38 (1H, dd, J=14.4, 7.2 Hz), 1.31-1.25 (1H, m), 1.26-1.17 (1H, m), 1.08-0.98 (21H, m), 0.63 (3H, s); 31P NMR (243.0 MHz, CDCl3) d 154.3 (1P, s).
Compound 17a was obtained by using “5′-O-(DMTr)-2′-O,4′-C-methylene-6-N-(benzoyl)adenosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 9.10 (1H, brs), 8.76 (1H, s), 8.32 (1H, s), 8.04 (2H, d, J=7.2 Hz), 7.64-7.18 (22H, m), 6.84 (4H, d, J=8.7 Hz), 6.10 (1H, s), 4.76 (1H, d J=6.9 Hz), 4.58 (1H, s), 4.61-4.51 (1H, m), 3.91 (1H, d, J=7.8 Hz), 3.77 (1H, d, J=7.8 Hz), 3.75 (6H, s), 3.50 (1H, s), 3.47-3.33 (1H, m), 3.31-3.19 (1H, m), 3.03-2.88 (1H, m), 1.84-1.09 (6H, m), 0.51 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 152.9 (1P, s).
Compound 17b was obtained by using III-b instead of III-a in a similar manner to compound 17a.
1H NMR (300 MHz, CDCl3) d 8.81 (1H, s), 8.30 (1H, s), 8.07-8.00 (2H, m), 7.64-7.17 (22H, m), 6.86-6.79 (4H, m), 6.12 (1H, s), 4.81-4.72 (1H, m), 4.62 (1H, d J=7.2 Hz), 4.57 (1H, s), 3.94 (1H, d, J=7.8 Hz), 3.89 (1H, d, J=7.8 Hz), 3.77 (6H, s), 3.48 (2H, s), 3.46-3.32 (1H, m), 3.24-3.13 (1H, m), 3.10-2.97 (1H, m), 1.84-1.49 (3H, m), 1.42-1.09 (3H, m), 0.58 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.3 (1P, s).
Compound 18a was obtained by using “5′-O-(DMTr)-2′-O,4′-C-methylene-4-N-(isobutyryl)-5-methylcytidine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.88 (1H, brs), 7.58-7.18 (20H, m), 6.88-6.80 (4H, m), 5.65 (1H, s), 4.69-4.60 (1H, m), 4.52 (1H, d, J=6.6 Hz), 4.49 (1H, s), 3.81-3.74 (1H, m), 3.75 (3H, s), 3.73 (3H, s), 3.64 (1H, d, J=8.1 Hz), 3.56 (1H, d, J=11.1 Hz), 3.53 (1H, d, J=8.1 Hz), 3.46 (1H, d, J=11.1 Hz), 3.56-3.40 (1H, m), 3.32-3.20 (1H, m), 3.14-3.00 (1H, m), 1.85-1.12 (6H, m), 1.60 (3H, s), 1.19 (6H, d, J=6.9 Hz), 0.55 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.9 (1P, s).
Compound 18b was obtained by using III-b instead of III-a in a similar manner to compound 18a.
1H NMR (300 MHz, CDCl3) d 7.86 (1H, brs), 7.56-7.19 (20H, m), 6.88-6.79 (4H, m), 5.69 (1H, s), 4.86-4.76 (1H, m), 4.46 (1H, s), 4.45 (1H, d, J=7.5 Hz), 3.80-3.75 (1H, m), 3.79 (6H, s), 3.74 (1H, d, J=8.1 Hz), 3.69 (1H, d, J=8.1 Hz), 3.51 (1H, d, J=11.1 Hz), 3.44-3.30 (1H, m), 3.39 (1H, d, J=11.1 Hz), 3.29-3.17 (1H, m), 3.11-2.97 (1H, m), 1.86-1.52 (3H, m), 1.64 (3H, s), 1.45-1.10 (3H, m), 1.21 (6H, d, J=6.6 Hz), 0.62 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 158.2 (1P, s).
Compound 19a was obtained by using “5′-O-(DMTr)-2′-O,4′-C-methylene-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 8.71 (1H, brs), 8.16 (1H, s), 7.50-7.17 (21H, m), 7.09-7.01 (3H, m), 6.86-6.79 (4H, m), 6.03 (1H, s), 4.84 (2H, t, J=6.6 Hz), 4.72 (2H, s), 4.68 (1H, d, J=7.2 Hz), 4.55-4.46 (1H, m), 4.50 (1H, s), 3.90 (1H, d, J=7.8 Hz), 3.77 (1H, d, J=7.8 Hz), 3.75 (6H, s), 3.51 (1H, d, J=10.8 Hz), 3.47 (1H, d, J=10.8 Hz), 3.45-3.21 (2H, m), 3.08 (2H, t, J=6.6 Hz), 3.03-2.89 (1H, m), 1.80-1.08 (6H, m), 0.47 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 153.2 (1P, s).
Compound 19b was obtained by using III-b instead of III-a in a similar manner to compound 19a.
1H NMR (300 MHz, CDCl3) d 8.86 (1H, brs), 8.13 (1H, s), 7.55-7.17 (21H, m), 7.08-6.98 (3H, m), 6.95-6.78 (4H, m), 6.01 (1H, s), 4.86 (2H, t, J=6.6 Hz), 4.82-4.73 (1H, m), 4.70 (2H, s), 4.64 (1H, d, J=7.5 Hz), 4.49 (1H, s), 3.94 (1H, d, J=7.8 Hz), 3.89 (1H, d, J=7.8 Hz), 3.77 (6H, s), 3.46 (2H, s), 3.45-3.30 (1H, m), 3.24-3.12 (1H, m), 3.09 (2H, t, J=6.6 Hz), 3.09-2.96 (1H, m), 1.81-1.50 (3H, m), 1.41-1.06 (3H, m), 0.58 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.4 (1P, s).
Compound 20a was obtained by using “5′-O-(DMTr)-2′-0,4′-C-methylene-5-methyluridine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.71 (1H, d, J=0.9 Hz), 7.50-7.17 (20H, m), 6.87-6.80 (4H, m), 5.61 (1H, s), 4.69-4.60 (1H, m), 4.55 (1H, d, J=6.9 Hz), 4.41 (1H, s), 3.74 (3H, s), 3.73 (3H, s), 3.64 (1H, d, J=7.8 Hz), 3.55 (1H, d, J=7.8 Hz), 3.53 (1H, d, J=10.8 Hz), 3.46 (1H, d, J=10.8 Hz), 3.56-3.42 (1H, m), 3.35-3.24 (1H, m), 3.13-3.00 (1H, m), 1.85-1.45 (3H, m), 1.55 (3H, d, J=0.9 Hz), 1.41-1.12 (3H, m), 0.56 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.1 (1P, s).
Compound 20b was obtained by using III-b instead of III-a in a similar manner to compound 20a.
1H NMR (300 MHz, CDCl3) d 7.69 (1H, s), 7.56-7.19 (20H, m), 6.88-6.79 (4H, m), 5.66 (1H, s), 4.87-4.77 (1H, m), 4.47 (1H, d, J=7.8 Hz), 4.40 (1H, s), 3.78 (6H, s), 3.74 (1H, d, J=7.8 Hz), 3.68 (1H, d, J=7.8 Hz), 3.50 (1H, d, J=10.8 Hz), 3.46-3.32 (1H, m), 3.39 (1H, d, J=10.8 Hz), 3.30-3.19 (1H, m), 3.12-2.98 (1H, m), 1.85-1.56 (3H, m), 1.59 (3H, s), 1.46-1.12 (3H, m), 0.63 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 158.1 (1P, s).
Compound 21a was obtained by using “5′-O-(DMTr)-2′-O-methoxyethyl-5-methyluridine” instead of “5′-O-(DMTr)-2-N-(phenoxyacetyl)-6-O-(cyanoethyl)guanosine” in a similar manner to compound 3a.
1H NMR (300 MHz, CDCl3) d 7.62-7.18 (21H, m), 6.84 (4H, d, J=8.7 Hz), 6.07 (1H, d, J=5.7 Hz), 4.86-4.76 (1H, m), 4.63-4.54 (1H, m), 4.20 (1H, t, J=5.4 Hz), 3.95-3.89 (1H, m), 3.78 (6H, s), 3.78-3.71 (2H, m), 3.60-3.48 (2H, m), 3.44-3.02 (5H, m), 3.31 (3H, s), 1.88-1.15 (6H, m), 1.35 (3H, s), 0.58 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 156.3 (1P, s).
Compound 21b was obtained by using III-b instead of III-a in a similar manner to compound 21a.
1H NMR (300 MHz, CDCl3) d 7.71 (1H, d, J=1.2 Hz), 7.55-7.22 (20H, m), 6.86-6.78 (4H, m), 5.99 (1H, d, J=3.9 Hz), 4.78-4.62 (2H, m), 4.13-4.08 (1H, m), 4.07-4.02 (1H, m), 3.77 (6H, s), 3.77-3.70 (1H, m), 3.65-3.56 (1H, m), 3.52-3.36 (4H, m), 3.33-3.14 (2H, m), 3.29 (3H, s), 3.08-2.94 (1H, m), 1.86-1.72 (1H, m), 1.71-1.55 (2H, m), 1.30 (3H, d, J=1.2 Hz), 1.47-1.16 (3H, m) 0.64 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 155.6 (1P, s).
Compound 22a was obtained by using VII-a instead of III-a in a similar manner to compound 4a.
1H NMR (300 MHz, CDCl3) d 7.57 (1H, d, J=0.9 Hz), 7.37-6.94 (20H, m), 6.87-6.78 (4H, m), 6.48 (1H, dd, J=8.6, 5.7 Hz), 5.42 (1H, dd, J=11.0, 5.1 Hz), 4.81-4.71 (1H, m), 4.02 (1H, d, J=11.0 Hz), 3.83 (1H, d, J=2.1 Hz), 3.79 (6H, s), 3.61-3.41 (2H, m), 3.24-3.09 (1H, m), 3.16 (1H, dd, J=10.8, 2.4 Hz), 3.02 (1H, dd, J=10.8, 2.4 Hz), 2.54-2.44 (1H, m), 2.34-2.22 (1H, m), 1.94-1.79 (1H, m), 1.74-1.56 (1H, m), 1.38 (3H, s), 1.38-1.28 (2H, m); 31P NMR (121.5 MHz, CDCl3) d 160.9 (1P, s).
Compound 22b was obtained by using VII-b instead of VII-a in a similar manner to compound 22a.
1H NMR (300 MHz, CDCl3) d 7.57 (1H, d, J=1.5 Hz), 7.43-7.11 (20H, m), 6.85-6.78 (4H, m), 6.48 (1H, dd, J=7.5, 5.7 Hz), 5.58 (1H, dd, J=11.4, 5.1 Hz), 4.82-4.73 (1H, m), 4.17-4.02 (2H, m), 3.78 (6H, s), 3.56-3.40 (3H, m), 3.32 (1H, dd, J=10.7, 2.4 Hz), 3.22-3.07 (1H, m), 2.26-2.04 (2H, m), 1.95-1.81 (1H, m), 1.74-1.56 (1H, m), 1.40 (3H, d, J=1.5 Hz), 1.44-1.34 (2H, m); 31P NMR (121.5 MHz, CDCl3) d 162.2 (1P, s).
Compound 23a was obtained by using IX-a instead of III-a in a similar manner to compound 4a.
1H NMR (300 MHz, CDCl3) d 9.22 (1H, brs), 8.05-7.99 (2H, m), 7.52 (1H, d, J=1.2 Hz), 7.41-7.19 (11H, m), 6.87-6.79 (4H, m), 6.37 (1H, dd, J=8.4, 5.7 Hz), 4.88-4.75 (2H, m), 3.86-3.80 (1H, m), 3.79 (6H, s), 3.64-3.49 (2H, m), 3.27-3.12 (3H, m), 2.97 (2H, d, J=6.6 Hz), 2.51-2.41 (1H, m), 2.33-2.20 (1H, m), 2.03-1.75 (2H, m), 1.72-1.59 (1H, m), 1.46-1.36 (1H, m), 1.40 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 157.5 (1P, s).
Compound 23b was obtained by using IX-b instead of IX-a in a similar manner to compound 23a.
1H NMR (300 MHz, CDCl3) d 8.67 (1H, brs), 8.18-8.11 (2H, m), 7.57 (1H, d, J=1.2 Hz), 7.47-7.22 (11H, m), 6.86-6.79 (4H, m), 6.29 (1H, t, J=6.6 Hz), 4.87 (1H, dt, J=7.5, 5.7 Hz), 4.80-4.72 (1H, m), 4.11-4.05 (1H, m), 3.79 (6H, s), 3.67-3.47 (2H, m), 3.43 (1H, dd, J=10.8, 2.7 Hz), 3.27 (1H, dd, J=10.8, 2.4 Hz), 3.25-3.13 (1H, m), 3.07-2.99 (2H, m), 2.19-2.12 (2H, m), 2.03-1.62 (3H, m), 1.46-1.30 (1H, m), 1.41 (3H, s); 31P NMR (121.5 MHz, CDCl3) d 158.1 (1P, s).
Compound 24a was obtained by using XIII-a instead of III-a in a similar manner to compound 4a.
1H NMR (600 MHz, CDCl3) d 7.76 (2H, d, J=9.0 Hz), 7.62 (1H, d, J=1.2 Hz), 7.40 (2H, d, J=7.2 Hz), 7.32-7.23 (10H, m), 6.85 (4H, d, J=8.4 Hz), 6.41 (1H, dd, J=8.4, 5.4 Hz), 4.94 (1H, dd, J=12.3, 5.4 Hz), 4.84-4.79 (1H, m), 4.03-4.01 (1H, m), 3.79 (6H, s), 3.59-3.53 (1H, m), 3.52-3.44 (2H, m), 3.41 (1H, dd, J=14.7, 7.2 Hz), 3.37-3.30 (2H, m), 3.13 (1H, ddd, J=19.3, 10.3, 4.1 Hz), 2.50-2.44 (1H, m), 2.39 (3H, s), 2.35-2.29 (1H, m), 1.91-1.72 (2H, m), 1.64-1.59 (1H, m), 1.40 (3H, s), 1.12-1.05 (1H, m); 31P NMR (243.0 MHz, CDCl3) d 154.2 (1P, s).
General Procedure for the Synthesis of Chiral-Oligos:
The automated solid-phase synthesis of chiral-oligos were performed according to the cycles shown in Table 1. After the synthesis, the resin was treated with a 25% NH3 aqueous solution (1 mL) for 12 h at 55 degrees C. The mixture was cooled to room temperature and the resin was removed by membrane filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in H2O (3 mL) and analyzed by RP-UPLC-MS with a linear gradient of acetonitrile (0-50%/30 min) in 0.1 M triethylammonium acetate buffer (pH 7.0) at 50 degrees C. at a rate of 0.3 mL/min.
The above Compound 25, which represents a conventional monomer, was used to produce oligos.
Analysis
The monomers of the working examples were chemically stable. The isolate yield of the monomers were more than 80%, which was higher that of conventional method.
We synthesized oligonucleotide derivatives using the chiral reagents of the above working examples based on the second general procedure and monomers of the above working examples based on the first general procedure. As shown in
| Number | Name | Date | Kind |
|---|---|---|---|
| 2878264 | Lunsford | Mar 1959 | A |
| 3135766 | Gould | Jun 1964 | A |
| 3484473 | Buckman et al. | Dec 1969 | A |
| 3687808 | Merigan et al. | Aug 1972 | A |
| 3745162 | Helsley | Jul 1973 | A |
| 4022791 | Welch, Jr. | May 1977 | A |
| 4113869 | Gardner | Sep 1978 | A |
| 4415732 | Caruthers et al. | Nov 1983 | A |
| 4458066 | Caruthers et al. | Jul 1984 | A |
| 4500707 | Caruthers et al. | Feb 1985 | A |
| 4542142 | Martel et al. | Sep 1985 | A |
| 4659774 | Webb et al. | Apr 1987 | A |
| 4663328 | Lafon | May 1987 | A |
| 4666777 | Caruthers et al. | May 1987 | A |
| 4725677 | Koster et al. | Feb 1988 | A |
| 4735949 | Domagala et al. | Apr 1988 | A |
| 4840956 | Domagala et al. | Jun 1989 | A |
| 4845205 | Huynh Dinh et al. | Jul 1989 | A |
| 4923901 | Koester et al. | May 1990 | A |
| 4943629 | DeVries et al. | Jul 1990 | A |
| 4945158 | DeVries et al. | Jul 1990 | A |
| 4973679 | Caruthers et al. | Nov 1990 | A |
| 4981957 | Lebleu et al. | Jan 1991 | A |
| 5047524 | Andrus et al. | Sep 1991 | A |
| 5118800 | Smith et al. | Jun 1992 | A |
| 5130302 | Spielvogel et al. | Jul 1992 | A |
| 5132418 | Caruthers et al. | Jul 1992 | A |
| 5134066 | Rogers et al. | Jul 1992 | A |
| 5138045 | Cook et al. | Aug 1992 | A |
| 5141813 | Nelson | Aug 1992 | A |
| 5151510 | Stec et al. | Sep 1992 | A |
| 5175273 | Bischofberger et al. | Dec 1992 | A |
| 5200553 | Nudelman et al. | Apr 1993 | A |
| 5212295 | Cook | May 1993 | A |
| 5223618 | Cook et al. | Jun 1993 | A |
| 5262530 | Andrus et al. | Nov 1993 | A |
| 5292875 | Stec et al. | Mar 1994 | A |
| 5319080 | Leumann | Jun 1994 | A |
| 5359044 | Cook et al. | Oct 1994 | A |
| 5367066 | Urdea et al. | Nov 1994 | A |
| 5378825 | Cook et al. | Jan 1995 | A |
| 5386023 | Sanghvi et al. | Jan 1995 | A |
| 5432272 | Benner | Jul 1995 | A |
| 5457187 | Gmeiner et al. | Oct 1995 | A |
| 5457191 | Cook et al. | Oct 1995 | A |
| 5459255 | Cook et al. | Oct 1995 | A |
| 5484908 | Froehler et al. | Jan 1996 | A |
| 5489677 | Sanghvi et al. | Feb 1996 | A |
| 5502177 | Matteucci et al. | Mar 1996 | A |
| 5506212 | Hoke et al. | Apr 1996 | A |
| 5512668 | Stec et al. | Apr 1996 | A |
| 5521302 | Cook | May 1996 | A |
| 5525711 | Hawkins et al. | Jun 1996 | A |
| 5541307 | Cook et al. | Jul 1996 | A |
| 5552540 | Haralambidis | Sep 1996 | A |
| 5565488 | Braunlich et al. | Oct 1996 | A |
| 5576302 | Cook et al. | Nov 1996 | A |
| 5587361 | Cook et al. | Dec 1996 | A |
| 5587469 | Cook et al. | Dec 1996 | A |
| 5594121 | Froehler et al. | Jan 1997 | A |
| 5596091 | Switzer | Jan 1997 | A |
| 5599797 | Cook et al. | Feb 1997 | A |
| 5602240 | De Mesmaeker et al. | Feb 1997 | A |
| 5607923 | Cook et al. | Mar 1997 | A |
| 5608046 | Cook et al. | Mar 1997 | A |
| 5610289 | Cook et al. | Mar 1997 | A |
| 5614617 | Cook et al. | Mar 1997 | A |
| 5618704 | Sanghvi et al. | Apr 1997 | A |
| 5620963 | Cook et al. | Apr 1997 | A |
| 5622989 | Br aunlich et al. | Apr 1997 | A |
| 5623070 | Cook et al. | Apr 1997 | A |
| 5635488 | Cook et al. | Jun 1997 | A |
| 5643889 | Suhadolnik et al. | Jul 1997 | A |
| 5643989 | Van De Grampel et al. | Jul 1997 | A |
| 5646267 | Stec et al. | Jul 1997 | A |
| 5654284 | Cook et al. | Aug 1997 | A |
| 5661134 | Cook et al. | Aug 1997 | A |
| 5677437 | Teng et al. | Oct 1997 | A |
| 5681940 | Wang et al. | Oct 1997 | A |
| 5681941 | Cook et al. | Oct 1997 | A |
| 5688941 | Cook et al. | Nov 1997 | A |
| 5708161 | Reese | Jan 1998 | A |
| 5712378 | Wang | Jan 1998 | A |
| 5734041 | Just et al. | Mar 1998 | A |
| 5750692 | Cook et al. | May 1998 | A |
| 5777092 | Cook et al. | Jul 1998 | A |
| 5783682 | Cook et al. | Jul 1998 | A |
| 5792844 | Sanghvi et al. | Aug 1998 | A |
| 5795765 | Izu et al. | Aug 1998 | A |
| 5808023 | Sanghvi et al. | Sep 1998 | A |
| 5824503 | Kurome et al. | Oct 1998 | A |
| 5834607 | Manoharan et al. | Nov 1998 | A |
| 5846466 | Abe et al. | Dec 1998 | A |
| 5851840 | Sluka et al. | Dec 1998 | A |
| 5852188 | Cook | Dec 1998 | A |
| 5856465 | Stec et al. | Jan 1999 | A |
| 5883237 | Stec et al. | Mar 1999 | A |
| 5892024 | Chaturvedula et al. | Apr 1999 | A |
| 5898031 | Crooke | Apr 1999 | A |
| 5908772 | Mitta et al. | Jun 1999 | A |
| 5914396 | Cook et al. | Jun 1999 | A |
| 5932450 | Dattagupta et al. | Aug 1999 | A |
| 5936080 | Stec et al. | Aug 1999 | A |
| 5965721 | Cook et al. | Oct 1999 | A |
| 5969118 | Sanghvi et al. | Oct 1999 | A |
| 5976855 | Svendsen et al. | Nov 1999 | A |
| 5998148 | Bennett et al. | Dec 1999 | A |
| 5998602 | Torrence et al. | Dec 1999 | A |
| 5998603 | Cook et al. | Dec 1999 | A |
| 6004813 | Serlupi-Crescenzi et al. | Dec 1999 | A |
| 6005107 | Nguyen-Ba et al. | Dec 1999 | A |
| 6015886 | Dale et al. | Jan 2000 | A |
| 6015887 | Teng | Jan 2000 | A |
| 6017700 | Horn et al. | Jan 2000 | A |
| 6025482 | Cook et al. | Feb 2000 | A |
| 6031092 | Just et al. | Feb 2000 | A |
| 6056973 | Allen et al. | May 2000 | A |
| 6057371 | Glennon | May 2000 | A |
| 6066500 | Bennett et al. | May 2000 | A |
| 6080543 | Engel et al. | Jun 2000 | A |
| 6087482 | Teng et al. | Jul 2000 | A |
| 6107094 | Crooke | Aug 2000 | A |
| 6121433 | Cook et al. | Sep 2000 | A |
| 6124445 | Imbach et al. | Sep 2000 | A |
| 6127540 | Nguyen-Ba et al. | Oct 2000 | A |
| 6133438 | Cook et al. | Oct 2000 | A |
| 6140096 | Kofod et al. | Oct 2000 | A |
| 6146829 | Cook et al. | Nov 2000 | A |
| 6147200 | Manoharan et al. | Nov 2000 | A |
| 6159728 | Stockley et al. | Dec 2000 | A |
| 6160109 | Just et al. | Dec 2000 | A |
| 6166197 | Cook et al. | Dec 2000 | A |
| 6172209 | Manoharan et al. | Jan 2001 | B1 |
| 6191266 | Wang | Feb 2001 | B1 |
| 6194576 | Nguyen-Ba et al. | Feb 2001 | B1 |
| 6207646 | Krieg et al. | Mar 2001 | B1 |
| 6214551 | Sanghvi et al. | Apr 2001 | B1 |
| 6214805 | Torrence et al. | Apr 2001 | B1 |
| 6222025 | Cook et al. | Apr 2001 | B1 |
| 6232463 | Cook et al. | May 2001 | B1 |
| 6235887 | Froehler et al. | May 2001 | B1 |
| 6239116 | Krieg et al. | May 2001 | B1 |
| 6239265 | Cook | May 2001 | B1 |
| 6242589 | Cook et al. | Jun 2001 | B1 |
| 6248519 | Engel et al. | Jun 2001 | B1 |
| 6265172 | St. Clair et al. | Jul 2001 | B1 |
| 6270968 | Dalbøge et al. | Aug 2001 | B1 |
| 6271004 | Warthoe | Aug 2001 | B1 |
| 6271357 | Cook et al. | Aug 2001 | B1 |
| 6300069 | Missel et al. | Oct 2001 | B1 |
| 6306627 | Decker | Oct 2001 | B1 |
| 6316024 | Allen et al. | Nov 2001 | B1 |
| 6316626 | Swayze et al. | Nov 2001 | B1 |
| 6320040 | Cook et al. | Nov 2001 | B1 |
| 6322985 | Kashi et al. | Nov 2001 | B1 |
| 6326199 | Cook et al. | Dec 2001 | B1 |
| 6339066 | Bennett et al. | Jan 2002 | B1 |
| 6344356 | Stemmer | Feb 2002 | B1 |
| 6369209 | Manoharan et al. | Apr 2002 | B1 |
| 6369237 | Verdine et al. | Apr 2002 | B1 |
| 6372492 | Bennett et al. | Apr 2002 | B1 |
| 6380368 | Froehler et al. | Apr 2002 | B1 |
| 6383808 | Monia et al. | May 2002 | B1 |
| 6407223 | Stec et al. | Jun 2002 | B1 |
| 6440739 | Bennett et al. | Aug 2002 | B1 |
| 6440943 | Cook et al. | Aug 2002 | B1 |
| 6444656 | Nguyen-Ba et al. | Sep 2002 | B1 |
| 6451524 | Ecker | Sep 2002 | B1 |
| 6455308 | Freier | Sep 2002 | B1 |
| 6468983 | Silverman et al. | Oct 2002 | B2 |
| 6495677 | Ramasamy et al. | Dec 2002 | B1 |
| 6500945 | Cook | Dec 2002 | B2 |
| 6506594 | Barany et al. | Jan 2003 | B1 |
| 6506894 | Reese et al. | Jan 2003 | B1 |
| 6528262 | Gilad et al. | Mar 2003 | B1 |
| 6528640 | Beigelman et al. | Mar 2003 | B1 |
| 6538126 | Cho et al. | Mar 2003 | B1 |
| 6559279 | Manoharan et al. | May 2003 | B1 |
| 6562960 | Baxter et al. | May 2003 | B1 |
| 6582936 | Serafini et al. | Jun 2003 | B1 |
| 6608186 | Miculka et al. | Aug 2003 | B1 |
| 6610837 | Guzaev et al. | Aug 2003 | B1 |
| 6613873 | Buchardt et al. | Sep 2003 | B1 |
| 6617438 | Beigelman et al. | Sep 2003 | B1 |
| 6632600 | Short | Oct 2003 | B1 |
| 6639022 | Michels et al. | Oct 2003 | B2 |
| 6639062 | Manoharan et al. | Oct 2003 | B2 |
| 6649750 | Capaldi et al. | Nov 2003 | B1 |
| 6670461 | Wengel et al. | Dec 2003 | B1 |
| 6682889 | Wang et al. | Jan 2004 | B1 |
| 6699979 | Cook | Mar 2004 | B2 |
| 6737520 | Manoharan et al. | May 2004 | B2 |
| 6762281 | Manoharan et al. | Jul 2004 | B2 |
| 6767739 | Crooke et al. | Jul 2004 | B2 |
| 6809195 | Sanghvi et al. | Oct 2004 | B1 |
| 6811975 | Cook et al. | Nov 2004 | B2 |
| 6815542 | Hong et al. | Nov 2004 | B2 |
| 6861518 | Just et al. | Mar 2005 | B2 |
| 6867294 | Sanghvi et al. | Mar 2005 | B1 |
| 6900301 | Cook et al. | May 2005 | B2 |
| 6933146 | Helliwell et al. | Aug 2005 | B2 |
| 6933288 | Migawa et al. | Aug 2005 | B2 |
| 6936432 | Gopalan et al. | Aug 2005 | B2 |
| 6943240 | Bauer et al. | Sep 2005 | B2 |
| 6949520 | Hartmann et al. | Sep 2005 | B1 |
| 6977245 | Klinman et al. | Dec 2005 | B2 |
| 6995259 | Vargeese et al. | Feb 2006 | B1 |
| 7015315 | Cook et al. | Mar 2006 | B1 |
| 7018793 | Short | Mar 2006 | B1 |
| 7019127 | Reese et al. | Mar 2006 | B2 |
| 7022833 | Reese | Apr 2006 | B2 |
| 7030230 | Ross et al. | Apr 2006 | B2 |
| 7045610 | Dempcy et al. | May 2006 | B2 |
| 7049122 | Chang et al. | May 2006 | B2 |
| 7067497 | Hanecak et al. | Jun 2006 | B2 |
| 7101993 | Cook et al. | Sep 2006 | B1 |
| 7119184 | Manoharan et al. | Oct 2006 | B2 |
| RE39464 | Cook et al. | Jan 2007 | E |
| 7160920 | Garvey et al. | Jan 2007 | B2 |
| 7205399 | Vargeese et al. | Apr 2007 | B1 |
| 7214491 | Yadav et al. | May 2007 | B2 |
| 7227014 | Crooke et al. | Jun 2007 | B2 |
| 7238795 | Seela et al. | Jul 2007 | B2 |
| 7247621 | Hong et al. | Jul 2007 | B2 |
| 7259150 | Crooke et al. | Aug 2007 | B2 |
| 7264932 | Latham et al. | Sep 2007 | B2 |
| 7268119 | Cook et al. | Sep 2007 | B2 |
| 7271156 | Krieg et al. | Sep 2007 | B2 |
| 7285658 | Cook et al. | Oct 2007 | B2 |
| 7288376 | Sarma et al. | Oct 2007 | B2 |
| 7303895 | O'Regan et al. | Dec 2007 | B1 |
| 7304081 | Yao et al. | Dec 2007 | B2 |
| 7354909 | Klinman et al. | Apr 2008 | B2 |
| 7381527 | Sarma et al. | Jun 2008 | B2 |
| 7399845 | Seth et al. | Jul 2008 | B2 |
| 7407943 | Crooke et al. | Aug 2008 | B2 |
| 7407965 | Chen et al. | Aug 2008 | B2 |
| 7410975 | Lipford et al. | Aug 2008 | B2 |
| 7414116 | Milton et al. | Aug 2008 | B2 |
| 7425545 | Crooke et al. | Sep 2008 | B2 |
| 7427672 | Imanishi et al. | Sep 2008 | B2 |
| 7429565 | Boojamra et al. | Sep 2008 | B2 |
| 7432249 | Crooke | Oct 2008 | B2 |
| 7432250 | Crooke | Oct 2008 | B2 |
| 7432261 | Cannizzaro et al. | Oct 2008 | B2 |
| 7452901 | Boojamra et al. | Nov 2008 | B2 |
| 7470724 | Cannizzaro et al. | Dec 2008 | B2 |
| 7495088 | Brakel et al. | Feb 2009 | B1 |
| 7501091 | Munoz et al. | Mar 2009 | B2 |
| 7507808 | Dobie | Mar 2009 | B2 |
| 7507811 | Khvorova et al. | Mar 2009 | B2 |
| 7511131 | Crooke et al. | Mar 2009 | B2 |
| 7517520 | Manolova et al. | Apr 2009 | B2 |
| 7534879 | van Deutekom | May 2009 | B2 |
| 7537767 | Bachmann et al. | May 2009 | B2 |
| 7547684 | Seth et al. | Jun 2009 | B2 |
| 7585847 | Bratzler et al. | Sep 2009 | B2 |
| 7598031 | Liew | Oct 2009 | B2 |
| 7598227 | Crooke et al. | Oct 2009 | B2 |
| 7598230 | Cook et al. | Oct 2009 | B2 |
| 7608594 | Blagg et al. | Oct 2009 | B2 |
| 7622451 | Blagg et al. | Nov 2009 | B2 |
| 7629321 | Crooke | Dec 2009 | B2 |
| 7645747 | Boojamra et al. | Jan 2010 | B2 |
| 7662558 | Liew | Feb 2010 | B2 |
| 7666854 | Seth et al. | Feb 2010 | B2 |
| 7666888 | Bartberger et al. | Feb 2010 | B2 |
| 7683036 | Esau et al. | Mar 2010 | B2 |
| 7695902 | Crooke | Apr 2010 | B2 |
| 7696345 | Allerson et al. | Apr 2010 | B2 |
| 7713941 | Cook et al. | May 2010 | B2 |
| 7718623 | Kitagawa et al. | May 2010 | B2 |
| 7723508 | Crooke et al. | May 2010 | B2 |
| 7732590 | Bhanot et al. | Jun 2010 | B2 |
| 7732660 | Helliwell et al. | Jun 2010 | B2 |
| 7741305 | Crooke et al. | Jun 2010 | B2 |
| 7741457 | Seth et al. | Jun 2010 | B2 |
| 7749700 | Baird et al. | Jul 2010 | B2 |
| 7750131 | Seth et al. | Jul 2010 | B2 |
| 7750141 | Crooke et al. | Jul 2010 | B2 |
| 7750731 | Poulsen et al. | Jul 2010 | B2 |
| 7759318 | Perera et al. | Jul 2010 | B1 |
| 7776344 | Hartmann et al. | Aug 2010 | B2 |
| 7776874 | Yao et al. | Aug 2010 | B2 |
| 7777023 | Vargeese et al. | Aug 2010 | B2 |
| 7803930 | Crooke et al. | Sep 2010 | B2 |
| 7807653 | Cook et al. | Oct 2010 | B2 |
| 7807816 | Wilton et al. | Oct 2010 | B2 |
| 7811998 | Blagg et al. | Oct 2010 | B2 |
| 7812003 | Safe et al. | Oct 2010 | B2 |
| 7838287 | Goldsmith et al. | Nov 2010 | B2 |
| 7863252 | Crooke et al. | Jan 2011 | B2 |
| 7884086 | Bennett et al. | Feb 2011 | B2 |
| 7884117 | Zhang et al. | Feb 2011 | B2 |
| 7888324 | Crooke et al. | Feb 2011 | B2 |
| 7893039 | Swayze et al. | Feb 2011 | B2 |
| 7919472 | Monia et al. | Apr 2011 | B2 |
| 7947658 | Aronin et al. | May 2011 | B2 |
| 7951934 | Freier | May 2011 | B2 |
| 7960353 | Blagg | Jun 2011 | B2 |
| 7960541 | Wilton et al. | Jun 2011 | B2 |
| 7973015 | van Ommen et al. | Jul 2011 | B2 |
| 8003619 | Hartmann et al. | Aug 2011 | B2 |
| 8008011 | Schmutz et al. | Aug 2011 | B2 |
| 8008459 | Goldsmith et al. | Aug 2011 | B2 |
| 8022083 | Boojamra et al. | Sep 2011 | B2 |
| 8039235 | Lin et al. | Oct 2011 | B2 |
| 8057997 | Seela et al. | Nov 2011 | B2 |
| 8058288 | Yao et al. | Nov 2011 | B2 |
| 8067173 | Liew | Nov 2011 | B2 |
| 8076303 | Iyer et al. | Dec 2011 | B2 |
| 8084437 | Freier et al. | Dec 2011 | B2 |
| 8084600 | Natt et al. | Dec 2011 | B2 |
| 8088582 | Sampath et al. | Jan 2012 | B2 |
| 8093222 | Freier et al. | Jan 2012 | B2 |
| 8093225 | Mamet | Jan 2012 | B2 |
| 8101348 | Tuschl et al. | Jan 2012 | B2 |
| 8101358 | Liew | Jan 2012 | B2 |
| 8101585 | Yu et al. | Jan 2012 | B2 |
| 8101743 | Brown-Driver et al. | Jan 2012 | B2 |
| 8106025 | Bennett et al. | Jan 2012 | B2 |
| 8110358 | Liew | Feb 2012 | B2 |
| 8110558 | Bennett et al. | Feb 2012 | B2 |
| 8114597 | Liew | Feb 2012 | B2 |
| 8124745 | Allerson et al. | Feb 2012 | B2 |
| 8133674 | Liew | Mar 2012 | B2 |
| 8133675 | Liew | Mar 2012 | B2 |
| 8133876 | Bennett et al. | Mar 2012 | B2 |
| 8138328 | Crooke et al. | Mar 2012 | B2 |
| 8143230 | Bhanot et al. | Mar 2012 | B2 |
| 8148072 | Liew | Apr 2012 | B2 |
| 8158598 | Bhanot et al. | Apr 2012 | B2 |
| 8163707 | Qiu et al. | Apr 2012 | B2 |
| 8178506 | Lollo et al. | May 2012 | B2 |
| 8188059 | Bhanot et al. | May 2012 | B2 |
| 8206923 | Garza Gonzalez et al. | Jun 2012 | B2 |
| 8207263 | Popot et al. | Jun 2012 | B2 |
| 8212011 | Blagg | Jul 2012 | B2 |
| 8212012 | Blagg | Jul 2012 | B2 |
| 8226759 | Shin et al. | Jul 2012 | B2 |
| 8232384 | Wilton et al. | Jul 2012 | B2 |
| 8257922 | Liew | Sep 2012 | B2 |
| 8258289 | Bhanot et al. | Sep 2012 | B2 |
| 8350022 | Meier et al. | Jan 2013 | B2 |
| 8361977 | Baker et al. | Jan 2013 | B2 |
| 8383660 | Chang et al. | Feb 2013 | B2 |
| 8410070 | Miller et al. | Apr 2013 | B2 |
| 8415465 | Freier | Apr 2013 | B2 |
| 8431693 | Manoharan et al. | Apr 2013 | B2 |
| 8450474 | Wilton et al. | May 2013 | B2 |
| 8455634 | Wilton et al. | Jun 2013 | B2 |
| 8455635 | Wilton et al. | Jun 2013 | B2 |
| 8455636 | Wilton et al. | Jun 2013 | B2 |
| 8470987 | Wada et al. | Jun 2013 | B2 |
| 8476423 | Wilton et al. | Jul 2013 | B2 |
| 8481710 | Davidson et al. | Jul 2013 | B2 |
| 8486907 | Wilton et al. | Jul 2013 | B2 |
| 8501414 | Danzer et al. | Aug 2013 | B2 |
| 8524880 | Wilton et al. | Sep 2013 | B2 |
| 8557549 | Chang et al. | Oct 2013 | B2 |
| 8557844 | Platt et al. | Oct 2013 | B2 |
| 8592566 | Iwamura et al. | Nov 2013 | B2 |
| 8632963 | Shah et al. | Jan 2014 | B2 |
| 8633206 | Promo et al. | Jan 2014 | B2 |
| 8647742 | Dendukuri et al. | Feb 2014 | B2 |
| 8648186 | Monteleone | Feb 2014 | B2 |
| 8653254 | Umemoto et al. | Feb 2014 | B2 |
| 8669058 | Liew | Mar 2014 | B2 |
| 8674044 | Popot et al. | Mar 2014 | B2 |
| 8679750 | Hayden et al. | Mar 2014 | B2 |
| 8680063 | Aronin et al. | Mar 2014 | B2 |
| 8729036 | Zamore et al. | May 2014 | B2 |
| 8735417 | Altman et al. | May 2014 | B2 |
| 8750507 | Roosta et al. | Jun 2014 | B2 |
| 8754107 | George et al. | Jun 2014 | B2 |
| 8759507 | Van Deutekom | Jun 2014 | B2 |
| 8802659 | Thomas et al. | Aug 2014 | B2 |
| 8809516 | Manoharan et al. | Aug 2014 | B2 |
| 8815817 | Hessel et al. | Aug 2014 | B2 |
| 8822671 | Shimizu et al. | Sep 2014 | B2 |
| 8859755 | Wada et al. | Oct 2014 | B2 |
| 8865146 | Fukuhara et al. | Oct 2014 | B2 |
| 8871785 | Boojamra et al. | Oct 2014 | B2 |
| 8877435 | Helliwell et al. | Nov 2014 | B2 |
| 8883752 | Swayze et al. | Nov 2014 | B2 |
| 8883969 | Ide et al. | Nov 2014 | B2 |
| 8927513 | Manoharan et al. | Jan 2015 | B2 |
| 8952145 | Freier | Feb 2015 | B2 |
| 8957040 | Bennett et al. | Feb 2015 | B2 |
| 8957042 | Safe et al. | Feb 2015 | B2 |
| 8975389 | Manoharan et al. | Mar 2015 | B2 |
| 8980853 | Bennett et al. | Mar 2015 | B2 |
| 8987222 | Aronin et al. | Mar 2015 | B2 |
| 8987435 | Swayze et al. | Mar 2015 | B2 |
| 8993738 | Prakash et al. | Mar 2015 | B2 |
| 9006198 | Bennett et al. | Apr 2015 | B2 |
| 9018368 | Wilton et al. | Apr 2015 | B2 |
| 9024007 | Wilton et al. | May 2015 | B2 |
| 9035040 | Wilton et al. | May 2015 | B2 |
| 9040674 | Benson et al. | May 2015 | B2 |
| 9057066 | Hung et al. | Jun 2015 | B2 |
| 9120774 | Blagg et al. | Sep 2015 | B2 |
| 9121020 | Feinstein et al. | Sep 2015 | B2 |
| 9126927 | Yao et al. | Sep 2015 | B2 |
| 9127033 | Prakash et al. | Sep 2015 | B2 |
| 9127123 | Livingston et al. | Sep 2015 | B2 |
| 9132289 | Kawai | Sep 2015 | B2 |
| 9139604 | Boojamra et al. | Sep 2015 | B2 |
| 9175286 | Wilton et al. | Nov 2015 | B2 |
| 9186367 | Thomas et al. | Nov 2015 | B2 |
| 9249416 | Wilton et al. | Feb 2016 | B2 |
| 9260716 | Davidson et al. | Feb 2016 | B2 |
| 9273315 | Hung et al. | Mar 2016 | B2 |
| 9284344 | Kim et al. | Mar 2016 | B2 |
| 9308252 | Suckow et al. | Apr 2016 | B2 |
| 9321799 | Prakash et al. | Apr 2016 | B2 |
| 9353372 | Freier | May 2016 | B2 |
| 9382540 | Prakash et al. | Jul 2016 | B2 |
| 9382575 | Eom et al. | Jul 2016 | B2 |
| 9394333 | Wada et al. | Jul 2016 | B2 |
| 9422555 | Wilton et al. | Aug 2016 | B2 |
| 9428541 | Platt et al. | Aug 2016 | B2 |
| 9441229 | Wilton et al. | Sep 2016 | B2 |
| 9447415 | Wilton et al. | Sep 2016 | B2 |
| 9453228 | Kandimalla et al. | Sep 2016 | B2 |
| 9476044 | Tuschl et al. | Oct 2016 | B2 |
| 9480740 | Reed et al. | Nov 2016 | B2 |
| 9481704 | Clarke | Nov 2016 | B2 |
| 9572824 | Thomas et al. | Feb 2017 | B2 |
| 9598458 | Shimizu et al. | Mar 2017 | B2 |
| 9605019 | Verdine et al. | Mar 2017 | B2 |
| 9605262 | Wilton et al. | Mar 2017 | B2 |
| 9605263 | Rigo | Mar 2017 | B2 |
| 9611472 | Zamore et al. | Apr 2017 | B2 |
| 9617547 | Gemba | Apr 2017 | B2 |
| 9695211 | Wada et al. | Jul 2017 | B2 |
| 9725474 | Murata et al. | Aug 2017 | B2 |
| 9738895 | Swayze et al. | Aug 2017 | B2 |
| 9744183 | Verdine et al. | Aug 2017 | B2 |
| 9809616 | Amblard et al. | Nov 2017 | B2 |
| 9827258 | Thomas et al. | Nov 2017 | B2 |
| 9885082 | Hrdlicka | Feb 2018 | B2 |
| 9896688 | Chang et al. | Feb 2018 | B2 |
| 9982257 | Butler et al. | May 2018 | B2 |
| 20010055761 | Kanemoto et al. | Dec 2001 | A1 |
| 20020013792 | Imielinski et al. | Jan 2002 | A1 |
| 20020082227 | Henry | Jun 2002 | A1 |
| 20020137921 | Cook | Sep 2002 | A1 |
| 20020183502 | Mesmaeker et al. | Dec 2002 | A1 |
| 20030045705 | Cook et al. | Mar 2003 | A1 |
| 20030049662 | Monia et al. | Mar 2003 | A1 |
| 20030050261 | Krieg et al. | Mar 2003 | A1 |
| 20030159938 | Hradil | Aug 2003 | A1 |
| 20030198982 | Seela et al. | Oct 2003 | A1 |
| 20030232978 | Seeberger et al. | Dec 2003 | A1 |
| 20030235845 | van Ommen et al. | Dec 2003 | A1 |
| 20040002596 | Hong et al. | Jan 2004 | A1 |
| 20040023901 | Cook et al. | Feb 2004 | A1 |
| 20040023921 | Hong et al. | Feb 2004 | A1 |
| 20040059104 | Cook et al. | Mar 2004 | A1 |
| 20040063647 | Johnson | Apr 2004 | A1 |
| 20040149587 | Hradil | Aug 2004 | A1 |
| 20040203145 | Zamore et al. | Oct 2004 | A1 |
| 20040213780 | Krainc | Oct 2004 | A1 |
| 20050042646 | Davidson et al. | Feb 2005 | A1 |
| 20050059619 | Krieg et al. | Mar 2005 | A1 |
| 20050096284 | McSwiggen | May 2005 | A1 |
| 20050159375 | Srivastava et al. | Jul 2005 | A1 |
| 20050169888 | Hartmann et al. | Aug 2005 | A1 |
| 20050176045 | Fedorov et al. | Aug 2005 | A1 |
| 20050203044 | Zinnen | Sep 2005 | A1 |
| 20050215513 | Boojamra et al. | Sep 2005 | A1 |
| 20050227947 | Chen et al. | Oct 2005 | A1 |
| 20050239102 | Verdine et al. | Oct 2005 | A1 |
| 20050261237 | Boojamra et al. | Nov 2005 | A1 |
| 20050277133 | McSwiggen | Dec 2005 | A1 |
| 20050277609 | Krieg et al. | Dec 2005 | A1 |
| 20060003962 | Ahluwalia et al. | Jan 2006 | A1 |
| 20060035858 | Geary et al. | Feb 2006 | A1 |
| 20060035866 | Cannizzaro et al. | Feb 2006 | A1 |
| 20060041115 | Ravikumar | Feb 2006 | A1 |
| 20060063730 | Monia et al. | Mar 2006 | A1 |
| 20060079478 | Boojamra et al. | Apr 2006 | A1 |
| 20060099616 | van Ommen et al. | May 2006 | A1 |
| 20060147952 | van Ommen et al. | Jul 2006 | A1 |
| 20060166910 | Tuschl et al. | Jul 2006 | A1 |
| 20060199776 | Blagg et al. | Sep 2006 | A1 |
| 20060199788 | Cannizzaro et al. | Sep 2006 | A1 |
| 20060211644 | Krieg et al. | Sep 2006 | A1 |
| 20060257912 | Kaemmerer et al. | Nov 2006 | A1 |
| 20060264404 | Boojamra et al. | Nov 2006 | A1 |
| 20070027116 | Cho et al. | Feb 2007 | A1 |
| 20070099851 | Linn | May 2007 | A1 |
| 20070099860 | Sah et al. | May 2007 | A1 |
| 20070123484 | Bhat et al. | May 2007 | A1 |
| 20070135363 | Cook et al. | Jun 2007 | A1 |
| 20070149462 | Iyer et al. | Jun 2007 | A1 |
| 20070161547 | Bhat et al. | Jul 2007 | A1 |
| 20070161590 | Van Bilsen et al. | Jul 2007 | A1 |
| 20070196852 | Heindl et al. | Aug 2007 | A1 |
| 20070249589 | Aebi et al. | Oct 2007 | A1 |
| 20070259832 | Cook et al. | Nov 2007 | A1 |
| 20070265224 | Cook et al. | Nov 2007 | A1 |
| 20070270452 | Blagg et al. | Nov 2007 | A1 |
| 20070282097 | Ohgi et al. | Dec 2007 | A1 |
| 20070287831 | Seth et al. | Dec 2007 | A1 |
| 20070299027 | Hung et al. | Dec 2007 | A1 |
| 20080015158 | Ichiro et al. | Jan 2008 | A1 |
| 20080015162 | Bhanot et al. | Jan 2008 | A1 |
| 20080039418 | Freier | Feb 2008 | A1 |
| 20080045473 | Uhlmann et al. | Feb 2008 | A1 |
| 20080064867 | Leuck et al. | Mar 2008 | A1 |
| 20080119426 | Dale | May 2008 | A1 |
| 20080200409 | Wilson et al. | Aug 2008 | A1 |
| 20080200423 | Cook et al. | Aug 2008 | A1 |
| 20080209581 | van Ommen et al. | Aug 2008 | A1 |
| 20080221055 | Sah et al. | Sep 2008 | A1 |
| 20080221303 | Katzhendler et al. | Sep 2008 | A1 |
| 20080249291 | Kwon et al. | Oct 2008 | A1 |
| 20080274989 | Davidson et al. | Nov 2008 | A1 |
| 20090012120 | Borhan et al. | Jan 2009 | A1 |
| 20090023675 | McSwiggen et al. | Jan 2009 | A1 |
| 20090053148 | Kandimalla et al. | Feb 2009 | A1 |
| 20090053205 | Kandimalla et al. | Feb 2009 | A1 |
| 20090060898 | Kandimalla et al. | Mar 2009 | A1 |
| 20090062224 | Kim et al. | Mar 2009 | A1 |
| 20090076246 | van Deutekom | Mar 2009 | A1 |
| 20090093425 | Dowdy et al. | Apr 2009 | A1 |
| 20090131372 | Chen et al. | May 2009 | A1 |
| 20090162316 | Verdine et al. | Jun 2009 | A1 |
| 20090163709 | Blagg | Jun 2009 | A1 |
| 20090186410 | Aronin et al. | Jul 2009 | A1 |
| 20090187014 | Blagg | Jul 2009 | A1 |
| 20090227543 | Cannizzaro et al. | Sep 2009 | A1 |
| 20090228998 | van Ommen et al. | Sep 2009 | A1 |
| 20090247488 | Cannizzaro et al. | Oct 2009 | A1 |
| 20090263413 | Iwamura et al. | Oct 2009 | A1 |
| 20090275535 | Boojamra et al. | Nov 2009 | A1 |
| 20090306176 | Schlingensiepen et al. | Dec 2009 | A1 |
| 20100008937 | Peer et al. | Jan 2010 | A1 |
| 20100008981 | Kaemmerer et al. | Jan 2010 | A1 |
| 20100022467 | Boojamra et al. | Jan 2010 | A1 |
| 20100022620 | Crispin et al. | Jan 2010 | A1 |
| 20100038543 | Toda et al. | Feb 2010 | A1 |
| 20100048882 | Blagg et al. | Feb 2010 | A1 |
| 20100069472 | Hung et al. | Mar 2010 | A1 |
| 20100074889 | Qiu et al. | Mar 2010 | A1 |
| 20100105630 | Blagg | Apr 2010 | A1 |
| 20100120900 | van Bilsen et al. | May 2010 | A1 |
| 20100186626 | Shin et al. | Jul 2010 | A1 |
| 20100203002 | Fukuhara et al. | Aug 2010 | A1 |
| 20100204162 | Platt et al. | Aug 2010 | A1 |
| 20100215642 | Lan et al. | Aug 2010 | A1 |
| 20100273999 | Jung et al. | Oct 2010 | A1 |
| 20100299768 | Perrin et al. | Nov 2010 | A1 |
| 20100311684 | Cook et al. | Dec 2010 | A1 |
| 20100325746 | Kaemmerer et al. | Dec 2010 | A9 |
| 20110009477 | Yu et al. | Jan 2011 | A1 |
| 20110015253 | Wilton et al. | Jan 2011 | A1 |
| 20110015258 | Wilton et al. | Jan 2011 | A1 |
| 20110021365 | Seela et al. | Jan 2011 | A1 |
| 20110039334 | Bennett et al. | Feb 2011 | A1 |
| 20110046203 | Wilton et al. | Feb 2011 | A1 |
| 20110071101 | Boojamra et al. | Mar 2011 | A1 |
| 20110105587 | Fishcher et al. | May 2011 | A1 |
| 20110111491 | Davidson et al. | May 2011 | A1 |
| 20110136765 | Promo et al. | Jun 2011 | A1 |
| 20110178284 | Wada et al. | Jul 2011 | A1 |
| 20110201599 | Bahceci et al. | Aug 2011 | A1 |
| 20110212520 | Davidson et al. | Sep 2011 | A1 |
| 20110213010 | Hayden et al. | Sep 2011 | A1 |
| 20110257251 | Gude-Rodriguez et al. | Oct 2011 | A1 |
| 20110263686 | Wilton et al. | Oct 2011 | A1 |
| 20110269814 | Manoharan et al. | Nov 2011 | A1 |
| 20110269821 | Swayze et al. | Nov 2011 | A1 |
| 20110288053 | Boojamra et al. | Nov 2011 | A1 |
| 20110294124 | Wada et al. | Dec 2011 | A1 |
| 20110294869 | Petersen | Dec 2011 | A1 |
| 20110306652 | Freier | Dec 2011 | A1 |
| 20110312086 | Van Deutekom | Dec 2011 | A1 |
| 20120022144 | Wilton et al. | Jan 2012 | A1 |
| 20120022145 | Wilton et al. | Jan 2012 | A1 |
| 20120029057 | Wilton et al. | Feb 2012 | A1 |
| 20120029058 | Wilton et al. | Feb 2012 | A1 |
| 20120029059 | Wilton et al. | Feb 2012 | A1 |
| 20120029060 | Wilton et al. | Feb 2012 | A1 |
| 20120041050 | Wilton et al. | Feb 2012 | A1 |
| 20120059045 | Prakash et al. | Mar 2012 | A1 |
| 20120064137 | Kawai | Mar 2012 | A1 |
| 20120095076 | Sah et al. | Apr 2012 | A1 |
| 20120108800 | Murata et al. | May 2012 | A1 |
| 20120136039 | Aronin et al. | May 2012 | A1 |
| 20120156138 | Smith | Jun 2012 | A1 |
| 20120157511 | Manoharan et al. | Jun 2012 | A1 |
| 20120190649 | Thomas et al. | Jul 2012 | A1 |
| 20120208864 | Bhanot et al. | Aug 2012 | A1 |
| 20120214865 | Bennett et al. | Aug 2012 | A1 |
| 20120216823 | Fukuhara et al. | Aug 2012 | A1 |
| 20120246747 | Tuschl et al. | Sep 2012 | A1 |
| 20120252745 | Blagg et al. | Oct 2012 | A1 |
| 20120252879 | Hung et al. | Oct 2012 | A1 |
| 20120276037 | Suzuki et al. | Nov 2012 | A1 |
| 20120308609 | Gibbon et al. | Dec 2012 | A1 |
| 20120316224 | Verdine et al. | Dec 2012 | A1 |
| 20130005794 | Kaemmerer et al. | Jan 2013 | A1 |
| 20130046008 | Bennett et al. | Feb 2013 | A1 |
| 20130072671 | Van Deutekom | Mar 2013 | A1 |
| 20130084576 | Prakash et al. | Apr 2013 | A1 |
| 20130116310 | Wilton et al. | May 2013 | A1 |
| 20130116420 | Prakash et al. | May 2013 | A1 |
| 20130156845 | Manoharan et al. | Jun 2013 | A1 |
| 20130178612 | Wada et al. | Jul 2013 | A1 |
| 20130184450 | Wada et al. | Jul 2013 | A1 |
| 20130189782 | Hung et al. | Jul 2013 | A1 |
| 20130197061 | Hohjoh et al. | Aug 2013 | A1 |
| 20130217755 | Wilton et al. | Aug 2013 | A1 |
| 20130236536 | Phiasivongsa et al. | Sep 2013 | A1 |
| 20130243725 | Clarke | Sep 2013 | A1 |
| 20130253033 | Wilton et al. | Sep 2013 | A1 |
| 20130253178 | Shimizu et al. | Sep 2013 | A1 |
| 20130253180 | Wilton et al. | Sep 2013 | A1 |
| 20130274313 | Wilton et al. | Oct 2013 | A1 |
| 20130281684 | Freier | Oct 2013 | A1 |
| 20130302806 | Van Deutekom | Nov 2013 | A1 |
| 20130316969 | Boojamra et al. | Nov 2013 | A1 |
| 20130323836 | Manoharan et al. | Dec 2013 | A1 |
| 20130331438 | Wilton et al. | Dec 2013 | A1 |
| 20140080769 | Platt et al. | Mar 2014 | A1 |
| 20140080896 | Nelson et al. | Mar 2014 | A1 |
| 20140080898 | Wilton et al. | Mar 2014 | A1 |
| 20140107330 | Freier et al. | Apr 2014 | A1 |
| 20140120088 | Carpentier | May 2014 | A1 |
| 20140142160 | Lee et al. | May 2014 | A1 |
| 20140155587 | Wilton et al. | Jun 2014 | A1 |
| 20140163213 | Debelak et al. | Jun 2014 | A1 |
| 20140194610 | Verdine et al. | Jul 2014 | A1 |
| 20140213635 | Van Deutekom | Jul 2014 | A1 |
| 20140220573 | Hrdlicka | Aug 2014 | A1 |
| 20140221395 | Dhanoa | Aug 2014 | A1 |
| 20140235566 | Amblard et al. | Aug 2014 | A1 |
| 20140243515 | Wilton et al. | Aug 2014 | A1 |
| 20140243516 | Wilton et al. | Aug 2014 | A1 |
| 20140255936 | Rademakers et al. | Sep 2014 | A1 |
| 20140256578 | Hayden et al. | Sep 2014 | A1 |
| 20140275212 | van Deutekom | Sep 2014 | A1 |
| 20140303238 | Linsley et al. | Oct 2014 | A1 |
| 20140309190 | Thomas et al. | Oct 2014 | A1 |
| 20140309283 | Wilton et al. | Oct 2014 | A1 |
| 20140309284 | Wilton et al. | Oct 2014 | A1 |
| 20140309285 | Wilton et al. | Oct 2014 | A1 |
| 20140316121 | Prakash et al. | Oct 2014 | A1 |
| 20140323707 | Seth et al. | Oct 2014 | A1 |
| 20140350076 | van Deutekom | Nov 2014 | A1 |
| 20140357698 | Van Deutekom et al. | Dec 2014 | A1 |
| 20140357855 | Van Deutekom et al. | Dec 2014 | A1 |
| 20140373188 | Zamore et al. | Dec 2014 | A1 |
| 20140378527 | van Deutekom | Dec 2014 | A1 |
| 20150025039 | Boojamra et al. | Jan 2015 | A1 |
| 20150051369 | Seth et al. | Feb 2015 | A1 |
| 20150057330 | Wilton et al. | Feb 2015 | A1 |
| 20150080457 | Manoharan et al. | Mar 2015 | A1 |
| 20150080563 | van Deutekom | Mar 2015 | A2 |
| 20150096064 | Tuschl et al. | Apr 2015 | A1 |
| 20150126725 | Swayze et al. | May 2015 | A1 |
| 20150148404 | de Visser et al. | May 2015 | A1 |
| 20150159163 | Prakash et al. | Jun 2015 | A1 |
| 20150166999 | Gemba | Jun 2015 | A1 |
| 20150167006 | Swayze et al. | Jun 2015 | A1 |
| 20150197540 | Shimizu et al. | Jul 2015 | A1 |
| 20150211006 | Butler et al. | Jul 2015 | A1 |
| 20150218559 | Van Deutekom et al. | Aug 2015 | A1 |
| 20150259679 | Bennett et al. | Sep 2015 | A1 |
| 20150267197 | Bennett et al. | Sep 2015 | A1 |
| 20150275208 | Oestergaard et al. | Oct 2015 | A1 |
| 20150291636 | Atamanyuk et al. | Oct 2015 | A1 |
| 20150292015 | Bennett et al. | Oct 2015 | A1 |
| 20150307877 | Freier | Oct 2015 | A1 |
| 20150315594 | Prakash et al. | Nov 2015 | A1 |
| 20150322434 | van Deutekom | Nov 2015 | A1 |
| 20150329859 | Bennett et al. | Nov 2015 | A1 |
| 20150335708 | Froelich et al. | Nov 2015 | A1 |
| 20150353931 | Wilton et al. | Dec 2015 | A1 |
| 20150361424 | van Deutekom | Dec 2015 | A1 |
| 20150376615 | Wilton et al. | Dec 2015 | A1 |
| 20150376616 | Wilton et al. | Dec 2015 | A1 |
| 20150376624 | Gryaznov et al. | Dec 2015 | A1 |
| 20150376625 | Oestergaard et al. | Dec 2015 | A1 |
| 20160002281 | Mayes et al. | Jan 2016 | A1 |
| 20160002631 | Wilton et al. | Jan 2016 | A1 |
| 20160002632 | Wilton et al. | Jan 2016 | A1 |
| 20160002635 | Wilton et al. | Jan 2016 | A1 |
| 20160017327 | Rudnicki et al. | Jan 2016 | A1 |
| 20160024496 | Bennett et al. | Jan 2016 | A1 |
| 20160040161 | Packard et al. | Feb 2016 | A1 |
| 20160046939 | Prakash et al. | Feb 2016 | A1 |
| 20160050929 | Benfatti et al. | Feb 2016 | A1 |
| 20160050930 | Benfatti et al. | Feb 2016 | A1 |
| 20160053256 | Hung et al. | Feb 2016 | A1 |
| 20160068837 | Chang et al. | Mar 2016 | A1 |
| 20160076033 | Torii et al. | Mar 2016 | A1 |
| 20160108396 | Jensen et al. | Apr 2016 | A1 |
| 20160122761 | Prakash et al. | May 2016 | A1 |
| 20160128928 | Fukuhara et al. | May 2016 | A1 |
| 20160129023 | Thomas et al. | May 2016 | A1 |
| 20160138022 | Kandimalla et al. | May 2016 | A1 |
| 20160159846 | Prakash et al. | Jun 2016 | A1 |
| 20160168570 | Van Deutekom et al. | Jun 2016 | A1 |
| 20160186175 | Seth et al. | Jun 2016 | A1 |
| 20160186178 | Radovic-Moreno et al. | Jun 2016 | A1 |
| 20160186185 | Prakash et al. | Jun 2016 | A1 |
| 20160194349 | Prakash et al. | Jul 2016 | A1 |
| 20160194636 | Van Deutekom et al. | Jul 2016 | A1 |
| 20160214974 | Schaetzer et al. | Jul 2016 | A1 |
| 20160230172 | Rigo | Aug 2016 | A1 |
| 20160237108 | Fraley et al. | Aug 2016 | A1 |
| 20160237432 | Bennett et al. | Aug 2016 | A1 |
| 20160251653 | Davidson et al. | Sep 2016 | A1 |
| 20160251655 | Freier et al. | Sep 2016 | A1 |
| 20160251658 | Van Deutekom et al. | Sep 2016 | A1 |
| 20160264964 | Cancilla et al. | Sep 2016 | A1 |
| 20160312217 | Hung et al. | Oct 2016 | A1 |
| 20160331835 | Gemba et al. | Nov 2016 | A1 |
| 20160331836 | Gemba et al. | Nov 2016 | A1 |
| 20160333349 | Gemba et al. | Nov 2016 | A1 |
| 20160347780 | Wada et al. | Dec 2016 | A1 |
| 20160347784 | Verdine et al. | Dec 2016 | A1 |
| 20160355810 | Van Deutekom | Dec 2016 | A1 |
| 20160369273 | Freier | Dec 2016 | A1 |
| 20170009233 | Wilton et al. | Jan 2017 | A1 |
| 20170009234 | Wilton et al. | Jan 2017 | A1 |
| 20170029457 | Verdine et al. | Feb 2017 | A1 |
| 20170037399 | Meena et al. | Feb 2017 | A1 |
| 20170044526 | Wan et al. | Feb 2017 | A1 |
| 20170067050 | Tuschl et al. | Mar 2017 | A1 |
| 20170114086 | Clarke | Apr 2017 | A1 |
| 20170114340 | Mueller et al. | Apr 2017 | A1 |
| 20170130224 | Oestergaard et al. | May 2017 | A1 |
| 20170197903 | Hoashi | Jul 2017 | A1 |
| 20170239280 | Thomas et al. | Aug 2017 | A1 |
| 20170275621 | Butler et al. | Sep 2017 | A1 |
| 20170327824 | Oestergaard et al. | Nov 2017 | A1 |
| 20170349897 | Rigo | Dec 2017 | A1 |
| 20180111958 | Wada et al. | Apr 2018 | A1 |
| Number | Date | Country |
|---|---|---|
| 102675386 | Sep 2012 | CN |
| 1144279 | Feb 1963 | DE |
| 01934150 | Jan 1970 | DE |
| 133885 | Jan 1979 | DE |
| 008940 | Oct 2007 | EA |
| 0 002 322 | Jun 1979 | EP |
| 192521 | Aug 1986 | EP |
| 269258 | Jun 1988 | EP |
| 0506242 | Sep 1992 | EP |
| 0531447 | Mar 1993 | EP |
| 0604409 | Jul 1994 | EP |
| 0655088 | May 1995 | EP |
| 0779893 | Jun 1997 | EP |
| 0831854 | Apr 1998 | EP |
| 0973945 | Jan 2000 | EP |
| 1097162 | May 2001 | EP |
| 1100807 | May 2001 | EP |
| 1185305 | Mar 2002 | EP |
| 1244682 | Oct 2002 | EP |
| 1311526 | May 2003 | EP |
| 1418179 | May 2004 | EP |
| 1499627 | Jan 2005 | EP |
| 1539188 | Jun 2005 | EP |
| 1556077 | Jul 2005 | EP |
| 1560840 | Aug 2005 | EP |
| 1562971 | Aug 2005 | EP |
| 1670810 | Jun 2006 | EP |
| 1670896 | Jun 2006 | EP |
| 1795536 | Jun 2007 | EP |
| 1957507 | Aug 2008 | EP |
| 1984381 | Oct 2008 | EP |
| 2021472 | Feb 2009 | EP |
| 2062980 | May 2009 | EP |
| 2066684 | Jun 2009 | EP |
| 2149571 | Feb 2010 | EP |
| 2161038 | Mar 2010 | EP |
| 2170917 | Apr 2010 | EP |
| 2173760 | Apr 2010 | EP |
| 2176280 | Apr 2010 | EP |
| 2282744 | Feb 2011 | EP |
| 2285819 | Feb 2011 | EP |
| 2316967 | May 2011 | EP |
| 2360166 | Aug 2011 | EP |
| 1 866 319 | Nov 2011 | EP |
| 2399588 | Dec 2011 | EP |
| 2422819 | Feb 2012 | EP |
| 2428227 | Mar 2012 | EP |
| 2458005 | May 2012 | EP |
| 2462153 | Jun 2012 | EP |
| 2479182 | Jul 2012 | EP |
| 1606407 | Dec 2013 | EP |
| 14193887.8 | Nov 2014 | EP |
| 14198167.0 | Dec 2014 | EP |
| 15182401.8 | Aug 2015 | EP |
| 15191074.2 | Oct 2015 | EP |
| 15191075.9 | Oct 2015 | EP |
| 15191076.7 | Oct 2015 | EP |
| 2982758 | Feb 2016 | EP |
| 2125852 | Apr 2016 | EP |
| 2370451 | Nov 2016 | EP |
| 2 534 262 | Dec 2016 | EP |
| 1448437 | Sep 1976 | GB |
| 2016273 | Sep 1979 | GB |
| 3072345 | Jul 2000 | JP |
| 2003238586 | Aug 2003 | JP |
| 2009-190983 | Aug 2009 | JP |
| 4348044 | Oct 2009 | JP |
| 04348077 | Oct 2009 | JP |
| 2010241836 | Oct 2010 | JP |
| 2010265304 | Nov 2010 | JP |
| A03-074398 | Mar 2011 | JP |
| 2011088935 | May 2011 | JP |
| 2011-526931 | Oct 2011 | JP |
| 2011225598 | Nov 2011 | JP |
| WO-9110671 | Jul 1991 | WO |
| WO-9116331 | Oct 1991 | WO |
| WO-9117755 | Nov 1991 | WO |
| WO-9203452 | Mar 1992 | WO |
| WO-9220822 | Nov 1992 | WO |
| WO-9220823 | Nov 1992 | WO |
| WO-9308296 | Apr 1993 | WO |
| WO-9417093 | Aug 1994 | WO |
| WO-9422886 | Oct 1994 | WO |
| WO-9422888 | Oct 1994 | WO |
| WO-9422890 | Oct 1994 | WO |
| WO-9602555 | Feb 1996 | WO |
| WO-9607392 | Mar 1996 | WO |
| WO-9614329 | May 1996 | WO |
| WO-9619572 | Jun 1996 | WO |
| WO-9636627 | Nov 1996 | WO |
| WO-9637504 | Nov 1996 | WO |
| WO-9639413 | Dec 1996 | WO |
| WO-9706183 | Feb 1997 | WO |
| WO-9709443 | Mar 1997 | WO |
| WO-9714710 | Apr 1997 | WO |
| WO-9747637 | Dec 1997 | WO |
| WO-9802582 | Jan 1998 | WO |
| WO-9803542 | Jan 1998 | WO |
| WO-9807734 | Feb 1998 | WO |
| WO-98016535 | Apr 1998 | WO |
| WO-9818810 | May 1998 | WO |
| WO-9839334 | Sep 1998 | WO |
| WO-9846794 | Oct 1998 | WO |
| WO-9853801 | Dec 1998 | WO |
| WO-9900377 | Jan 1999 | WO |
| WO-9905160 | Feb 1999 | WO |
| WO-9912034 | Mar 1999 | WO |
| WO-9956755 | Nov 1999 | WO |
| WO-9958118 | Nov 1999 | WO |
| WO-0000499 | Jan 2000 | WO |
| WO-0004034 | Jan 2000 | WO |
| WO-0006588 | Feb 2000 | WO |
| WO-0009159 | Feb 2000 | WO |
| WO-0023444 | Apr 2000 | WO |
| WO-0031110 | Jun 2000 | WO |
| WO-0037658 | Jun 2000 | WO |
| WO-0055179 | Sep 2000 | WO |
| WO-0058329 | Oct 2000 | WO |
| WO-0076554 | Dec 2000 | WO |
| WO-0102415 | Jan 2001 | WO |
| WO-01022990 | Apr 2001 | WO |
| WO-0127126 | Apr 2001 | WO |
| WO-0140515 | Jun 2001 | WO |
| WO-0149701 | Jul 2001 | WO |
| WO-0164702 | Sep 2001 | WO |
| WO-2001068663 | Sep 2001 | WO |
| WO-0181303 | Nov 2001 | WO |
| WO-0185751 | Nov 2001 | WO |
| WO-0188198 | Nov 2001 | WO |
| WO-0212263 | Feb 2002 | WO |
| WO-0214340 | Feb 2002 | WO |
| WO-0215410 | Feb 2002 | WO |
| WO-0220544 | Mar 2002 | WO |
| WO-0222635 | Mar 2002 | WO |
| WO-0224906 | Mar 2002 | WO |
| WO-0232450 | Apr 2002 | WO |
| WO-0257425 | Jul 2002 | WO |
| WO-2002051716 | Jul 2002 | WO |
| WO-0297134 | Dec 2002 | WO |
| WO-02099317 | Dec 2002 | WO |
| WO-03002065 | Jan 2003 | WO |
| WO-03004602 | Jan 2003 | WO |
| WO-03011887 | Feb 2003 | WO |
| WO-03012057 | Feb 2003 | WO |
| WO-03014306 | Feb 2003 | WO |
| WO-03014307 | Feb 2003 | WO |
| WO-03018600 | Mar 2003 | WO |
| WO-03066633 | Aug 2003 | WO |
| WO-2003071001 | Aug 2003 | WO |
| WO-2003072757 | Sep 2003 | WO |
| WO-2003073989 | Sep 2003 | WO |
| WO-03097662 | Nov 2003 | WO |
| WO-03099840 | Dec 2003 | WO |
| WO-03100017 | Dec 2003 | WO |
| WO-03106477 | Dec 2003 | WO |
| WO-2004000351 | Dec 2003 | WO |
| WO-2004003228 | Jan 2004 | WO |
| WO-2004007718 | Jan 2004 | WO |
| WO-2004014312 | Feb 2004 | WO |
| WO-2004014933 | Feb 2004 | WO |
| WO-2004016805 | Feb 2004 | WO |
| WO-2004010956 | Feb 2004 | WO |
| WO-2004024919 | Mar 2004 | WO |
| WO-2004039829 | May 2004 | WO |
| WO-2004041889 | May 2004 | WO |
| WO-2004044134 | May 2004 | WO |
| WO-2004044136 | May 2004 | WO |
| WO-2004044141 | May 2004 | WO |
| WO-2004044181 | May 2004 | WO |
| WO-2004048522 | Jun 2004 | WO |
| WO-2004055162 | Jul 2004 | WO |
| WO-2004080466 | Sep 2004 | WO |
| WO-2004083432 | Sep 2004 | WO |
| WO-2004083446 | Sep 2004 | WO |
| WO-2004085454 | Oct 2004 | WO |
| WO-2004096233 | Nov 2004 | WO |
| WO-2004096235 | Nov 2004 | WO |
| WO-2004096286 | Nov 2004 | WO |
| WO-2004093783 | Nov 2004 | WO |
| WO-2005002626 | Jan 2005 | WO |
| WO-2005000201 | Jan 2005 | WO |
| WO-2005005599 | Jan 2005 | WO |
| WO-2005014609 | Feb 2005 | WO |
| WO-2005013901 | Feb 2005 | WO |
| WO-2005019236 | Mar 2005 | WO |
| WO-2005019237 | Mar 2005 | WO |
| WO-2005021568 | Mar 2005 | WO |
| WO-2005023828 | Mar 2005 | WO |
| WO-2005028494 | Mar 2005 | WO |
| WO-2005019418 | Mar 2005 | WO |
| WO-2005023825 | Mar 2005 | WO |
| WO-2005023995 | Mar 2005 | WO |
| WO-2005039630 | May 2005 | WO |
| WO-2005042018 | May 2005 | WO |
| WO-2005042716 | May 2005 | WO |
| WO-2005040180 | May 2005 | WO |
| WO-2005063976 | Jul 2005 | WO |
| WO-2005070859 | Aug 2005 | WO |
| WO-2005085272 | Sep 2005 | WO |
| WO-2005092909 | Oct 2005 | WO |
| WO-2006000057 | Jan 2006 | WO |
| WO-2006020676 | Feb 2006 | WO |
| WO-2006022323 | Mar 2006 | WO |
| WO-2006029258 | Mar 2006 | WO |
| WO-2006031267 | Mar 2006 | WO |
| WO-2006031461 | Mar 2006 | WO |
| WO-2006044531 | Apr 2006 | WO |
| WO-2006049454 | May 2006 | WO |
| WO-2006050501 | May 2006 | WO |
| WO-2006053861 | May 2006 | WO |
| WO-2006065751 | Jun 2006 | WO |
| WO-2006066260 | Jun 2006 | WO |
| WO-2006070284 | Jul 2006 | WO |
| WO-2006080596 | Aug 2006 | WO |
| WO-2006091915 | Aug 2006 | WO |
| WO-2006117400 | Nov 2006 | WO |
| WO-2006121960 | Nov 2006 | WO |
| WO-2007002904 | Jan 2007 | WO |
| WO-2007005941 | Jan 2007 | WO |
| WO-2007027775 | Mar 2007 | WO |
| WO-2007041045 | Apr 2007 | WO |
| WO-2007051045 | May 2007 | WO |
| WO-2007059041 | May 2007 | WO |
| WO-2007064291 | Jun 2007 | WO |
| WO-2007070598 | Jun 2007 | WO |
| WO-2007064954 | Jun 2007 | WO |
| WO-2007089584 | Aug 2007 | WO |
| WO-2007089611 | Aug 2007 | WO |
| WO-2007090071 | Aug 2007 | WO |
| WO-2007095316 | Aug 2007 | WO |
| WO-2007131232 | Nov 2007 | WO |
| WO-2007131237 | Nov 2007 | WO |
| WO-2007131238 | Nov 2007 | WO |
| WO-2007134014 | Nov 2007 | WO |
| WO-2007136988 | Nov 2007 | WO |
| WO-2007139190 | Dec 2007 | WO |
| WO-2007143315 | Dec 2007 | WO |
| WO-2007143316 | Dec 2007 | WO |
| WO-2007143317 | Dec 2007 | WO |
| WO-2007146511 | Dec 2007 | WO |
| WO-2008005562 | Jan 2008 | WO |
| WO-2008008476 | Jan 2008 | WO |
| WO-2008021136 | Feb 2008 | WO |
| WO-2008017081 | Feb 2008 | WO |
| WO-2008049085 | Apr 2008 | WO |
| WO-2008051763 | May 2008 | WO |
| WO-2008068638 | Jun 2008 | WO |
| WO-2008073959 | Jun 2008 | WO |
| WO-2008066776 | Jun 2008 | WO |
| WO-2008098104 | Aug 2008 | WO |
| WO-2008118883 | Oct 2008 | WO |
| WO-2008139262 | Nov 2008 | WO |
| WO-2008148801 | Dec 2008 | WO |
| WO-2008151833 | Dec 2008 | WO |
| WO-2009001097 | Dec 2008 | WO |
| WO-2009007855 | Jan 2009 | WO |
| WO-2009014237 | Jan 2009 | WO |
| WO-2009046141 | Apr 2009 | WO |
| WO-2009086264 | Jul 2009 | WO |
| WO-2009089659 | Jul 2009 | WO |
| WO-2009089689 | Jul 2009 | WO |
| WO-2009098197 | Aug 2009 | WO |
| WO-2009117589 | Sep 2009 | WO |
| WO-2009124238 | Oct 2009 | WO |
| WO-2009135322 | Nov 2009 | WO |
| WO-2009143387 | Nov 2009 | WO |
| WO-2009143390 | Nov 2009 | WO |
| WO-2009143391 | Nov 2009 | WO |
| WO-2009143463 | Nov 2009 | WO |
| WO-2009146123 | Dec 2009 | WO |
| WO-2009148605 | Dec 2009 | WO |
| WO-2010003133 | Jan 2010 | WO |
| WO-2010030858 | Mar 2010 | WO |
| WO-2010039543 | Apr 2010 | WO |
| WO-2010042636 | Apr 2010 | WO |
| WO-2010048549 | Apr 2010 | WO |
| WO-2010048585 | Apr 2010 | WO |
| WO-2010036696 | Apr 2010 | WO |
| WO-2010036698 | Apr 2010 | WO |
| WO-2010048552 | Apr 2010 | WO |
| WO-2010064146 | Jun 2010 | WO |
| WO-2010072831 | Jul 2010 | WO |
| WO-2010080953 | Jul 2010 | WO |
| WO-2010096650 | Aug 2010 | WO |
| WO-2010091301 | Aug 2010 | WO |
| WO-2010107838 | Sep 2010 | WO |
| WO-2010113937 | Oct 2010 | WO |
| WO-2010118263 | Oct 2010 | WO |
| WO-2010120262 | Oct 2010 | WO |
| WO-2010129853 | Nov 2010 | WO |
| WO-2010141471 | Dec 2010 | WO |
| WO-2010146784 | Dec 2010 | WO |
| WO-2010150789 | Dec 2010 | WO |
| WO-2011005761 | Jan 2011 | WO |
| WO-2011005764 | Jan 2011 | WO |
| WO-2011005860 | Jan 2011 | WO |
| WO-2011010706 | Jan 2011 | WO |
| WO-2011015572 | Feb 2011 | WO |
| WO-2011015573 | Feb 2011 | WO |
| WO-2011017521 | Feb 2011 | WO |
| WO-2011017561 | Feb 2011 | WO |
| WO-2011034072 | Mar 2011 | WO |
| WO-2011038288 | Mar 2011 | WO |
| WO-2011045702 | Apr 2011 | WO |
| WO-2011062210 | May 2011 | WO |
| WO-2011064974 | Jun 2011 | WO |
| WO-2011085271 | Jul 2011 | WO |
| WO-2011097643 | Aug 2011 | WO |
| WO-2011097644 | Aug 2011 | WO |
| WO-2011108682 | Sep 2011 | WO |
| WO-2011133871 | Oct 2011 | WO |
| WO-2011127175 | Oct 2011 | WO |
| WO-2011127307 | Oct 2011 | WO |
| WO-2011139699 | Nov 2011 | WO |
| WO-2011139911 | Nov 2011 | WO |
| WO-2011135396 | Nov 2011 | WO |
| WO-2012030683 | Mar 2012 | WO |
| WO-2012039448 | Mar 2012 | WO |
| WO-2012073857 | Jun 2012 | WO |
| WO-2012092367 | Jul 2012 | WO |
| WO-2012109395 | Aug 2012 | WO |
| WO-2012151324 | Nov 2012 | WO |
| WO-2013012758 | Jan 2013 | WO |
| WO-2013013068 | Jan 2013 | WO |
| WO-2013022984 | Feb 2013 | WO |
| WO-2013022990 | Feb 2013 | WO |
| WO-2013022966 | Feb 2013 | WO |
| WO-2013022967 | Feb 2013 | WO |
| WO-2013033223 | Mar 2013 | WO |
| WO-2013030588 | Mar 2013 | WO |
| WO-2013089283 | Jun 2013 | WO |
| WO-2013138236 | Sep 2013 | WO |
| WO-2014010250 | Jan 2014 | WO |
| WO-2014010718 | Jan 2014 | WO |
| WO-2014012081 | Jan 2014 | WO |
| WO-2014025805 | Feb 2014 | WO |
| WO-2014028739 | Feb 2014 | WO |
| WO-2014059356 | Apr 2014 | WO |
| WO-2014062686 | Apr 2014 | WO |
| WO-2014062691 | Apr 2014 | WO |
| WO-2014062736 | Apr 2014 | WO |
| WO-2014067904 | May 2014 | WO |
| WO-2014069520 | May 2014 | WO |
| WO-2014076195 | May 2014 | WO |
| WO-2014076196 | May 2014 | WO |
| WO-2014080004 | May 2014 | WO |
| WO-2014070771 | May 2014 | WO |
| WO-2014099941 | Jun 2014 | WO |
| WO-2014118267 | Aug 2014 | WO |
| WO-2014118272 | Aug 2014 | WO |
| WO-2014130607 | Aug 2014 | WO |
| WO-2014132671 | Sep 2014 | WO |
| WO-2014154486 | Oct 2014 | WO |
| WO-2014154488 | Oct 2014 | WO |
| WO-2014179626 | Nov 2014 | WO |
| WO-2014188001 | Nov 2014 | WO |
| WO-2014192310 | Dec 2014 | WO |
| WO-2014203518 | Dec 2014 | WO |
| WO-2014205451 | Dec 2014 | WO |
| WO-2014207232 | Dec 2014 | WO |
| WO-2015010135 | Jan 2015 | WO |
| WO-2015017675 | Feb 2015 | WO |
| WO-2015032617 | Mar 2015 | WO |
| WO-2015051169 | Apr 2015 | WO |
| WO-2015051214 | Apr 2015 | WO |
| WO-2015051366 | Apr 2015 | WO |
| WO-2015054676 | Apr 2015 | WO |
| WO-2015057727 | Apr 2015 | WO |
| WO-2015057738 | Apr 2015 | WO |
| WO-2015070212 | May 2015 | WO |
| WO-2015071388 | May 2015 | WO |
| WO-2015089511 | Jun 2015 | WO |
| WO-2015107425 | Jul 2015 | WO |
| WO-2015108046 | Jul 2015 | WO |
| WO-2015108047 | Jul 2015 | WO |
| WO-2015108048 | Jul 2015 | WO |
| WO-2015143078 | Sep 2015 | WO |
| WO-2015168172 | Nov 2015 | WO |
| WO-2015168589 | Nov 2015 | WO |
| WO-2015171932 | Nov 2015 | WO |
| WO-2015179525 | Nov 2015 | WO |
| WO-2016011226 | Jan 2016 | WO |
| WO-2016020399 | Feb 2016 | WO |
| WO-2016021683 | Feb 2016 | WO |
| WO-2016027168 | Feb 2016 | WO |
| WO-2016037191 | Mar 2016 | WO |
| WO-2016079181 | May 2016 | WO |
| WO-2016079183 | May 2016 | WO |
| WO-2016096938 | Jun 2016 | WO |
| WO-2016102664 | Jun 2016 | WO |
| WO-2016112132 | Jul 2016 | WO |
| WO-2016126995 | Aug 2016 | WO |
| WO-2016127000 | Aug 2016 | WO |
| WO-2016127002 | Aug 2016 | WO |
| WO-2016130589 | Aug 2016 | WO |
| WO-2016130806 | Aug 2016 | WO |
| WO-2016138017 | Sep 2016 | WO |
| WO-2016141236 | Sep 2016 | WO |
| WO-2016145142 | Sep 2016 | WO |
| WO-2016154096 | Sep 2016 | WO |
| WO-2016161374 | Oct 2016 | WO |
| WO-2016164896 | Oct 2016 | WO |
| WO-2016167780 | Oct 2016 | WO |
| WO-2016168592 | Oct 2016 | WO |
| WO-2016209862 | Dec 2016 | WO |
| WO-2017004261 | Jan 2017 | WO |
| WO-2017011276 | Jan 2017 | WO |
| WO-2017011286 | Jan 2017 | WO |
| WO-2017015109 | Jan 2017 | WO |
| WO-2017015555 | Jan 2017 | WO |
| WO-2017019660 | Feb 2017 | WO |
| WO-2017023660 | Feb 2017 | WO |
| WO-2017032726 | Mar 2017 | WO |
| WO-2017035340 | Mar 2017 | WO |
| WO-2017040078 | Mar 2017 | WO |
| WO-2017055423 | Apr 2017 | WO |
| WO-2017059411 | Apr 2017 | WO |
| WO-2017059446 | Apr 2017 | WO |
| WO-2017062862 | Apr 2017 | WO |
| WO-2017067970 | Apr 2017 | WO |
| WO-2017068087 | Apr 2017 | WO |
| WO-2017079291 | May 2017 | WO |
| WO-2017081223 | May 2017 | WO |
| WO-2017157672 | Sep 2017 | WO |
| WO-2017157899 | Sep 2017 | WO |
| WO-2017160741 | Sep 2017 | WO |
| WO-2017165489 | Sep 2017 | WO |
| WO-2017178656 | Oct 2017 | WO |
| WO-2017180835 | Oct 2017 | WO |
| WO-2017192679 | Nov 2017 | WO |
| WO-2017194498 | Nov 2017 | WO |
| WO-2017194664 | Nov 2017 | WO |
| WO-2017198775 | Nov 2017 | WO |
| WO-2017210647 | Dec 2017 | WO |
| WO-2017221883 | Dec 2017 | WO |
| WO-2018022473 | Feb 2018 | WO |
| WO-2018067973 | Apr 2018 | WO |
| WO-2018098264 | May 2018 | WO |
| Entry |
|---|
| Aartsma-Rus, A. et al., Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy, Neuromuscular Disorders, 12: S71-S77 (2002). |
| Adams, S.P. et al., Hindered dialkylamino nucleoside phosphite reagents in the synthesis of two DNA 51-mers, Journal of the American Chemical Society, 105(3): 661-663 (1983). |
| Adarsh, et al., Organelle Specific Targeted Drug Delivery—A Review, International Journal of Research in Pharmaceutical and Biomedical Sciences, 2(3): 895-912 (2011). |
| Ager, D.J. The Peterson olefination reaction, Organic Reactions, 38:1-223 (2004). |
| Agrawal, S. and Kandimalla, E.R., Antisense and/or Immunostimulatory Oligonucleotide THerapeutics, Current Cancer Drug Targets, Bentham Science, 1(3): 1 page. URL: <http:www.eurekaselect.com/65067/article> [Retrieved Apr. 3, 2016]. |
| Agrawal, S. and Tang, J.Y., GEM 91—an antisense oligonucleotide phosphorothioate as a therapeutic agent for AIDS, Antisense Research and Development, 2(4):261-266 (1992). |
| Agrawal, S. et al. Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: In vitro and in vivo studies, Proc. Natl. Acad. Sci. USA, 94: 2620-2625 (1997). |
| Aldaye, F.A. et al., Assembling materials with DNA as the guide, Science, 321(5897): 1795-1799 (2008). |
| Aldrich Chemical Co. Catalog, 2007-2008 Issue, only p. 1719 supplied: see first full entry at col. 1 (S-methyl methanethiosulfonate), Milwaukee, WI. |
| Almer et al., Synthesis of Stereochemically Homogeneous Oligoribonucleoside All-Rp-Phosphorothioates by Combining H-Phosphonate Chemistry and Enzymatic Digestion, J. Chem. Soc., Chem. Commun., 1459-1460 (1994). |
| Almer, et al. A New Approach to Stereospecific Synthesis of P-chiral Phosphorothioates. Preparation of Diastereomeric Dithymidy1-(3′-5′) Phosphorothioates, Chem. Commun., (3): 290-1 (2004). |
| Almer, et al. Solid Support Synthesis of all-Rp-oligo(ribonucleoside phosphorothioate)s, Nucleic Acids Research 24(19): 3811-3820 (1996). |
| Almer, H. et al., Synthesis of Diribonucleoside Phosphorothioates via Sterospecific Sulfurization of H-Phosphonate Diesters, J. Org. Chem., 57(23): 6163-6169 (1992). |
| Altschul, S.F. et al., Basic local alignment search tool, Journal of Molecular Biology, 215(3):403-410 (1990). |
| Altschul, S.F. et al., Gapped BLAST and PSI-BLAST: a new generation of protein database search programs, Nucleic Acids Research, 25(17):3389-3402 (1997). |
| Alul, R.N. et al., Oxalyl-CPG: a labile support for synthesis of sensitive oligonucleotide, Nucleic Acids Research, 19(7):1527-1532 (1991). |
| Alvarez, K. et al., Photocleavable Protecting Groups as Nucleobase Protections Allowed the Solid-Phase Synthesis of Base-Sensitive SATE-Prooligonucleotides, Journal of Organic Chemistry, 64(17): 6319-6328(1999). |
| Amarzguioui et al., Tolerance for mutations and chemical modifications in a siRNA, Nucleic Acids Research 31(2): 589-595 (2003). |
| Arai, K. et al., Synthesis and properties of novel 2′-O-alkoxymethyl-modified nucleic acids, Bioorganic & Medicinal Chemistry Letters, 21(21): 6285-6287 (2011). |
| Aristarkhova, L.N. et al., Investigation in the field of thiosulfonic acids. 28. alkyl esters of cyclopentane- and cyclohexanethiosulfonic acids, Journal of Organic Chemistry of the USSR, 6: 2454-2458 (1970). |
| Athyros, V.G. et al., Antisense technology for the prevention or the treatment of cardiovascular disease: the next blockbuster?, Expert Opin. Investig. Drugs, 17(7): 969-72 (2008). |
| Ausin, C. et al., Assesment of heat-sensitive thiophosphate protecting groups in the development of thermolytic DNA oligonucleotide prodrugs, Tetrahedron, 66(1):68-79 (2010). |
| Bachelin et al., Structure of a Stereoregular Phosphorothioate DNA/RNA duplex, Nat. Struct. Biol., 5(4): 271-276 (1998). |
| Baek, M-S. et al., In Vitro Metabolic Stabilities and Metabolism of 2′-O-(Methoxyethyl) Partially Modified Phosphorothioate Antisense Oligonucleotides in Preincubated Rat or Human Whole Liver Homogenates, Oligonucleotides, 20(6): 309-316 (2010). |
| Ballas, Z.K. et al., Induction of NK Activity in Murine and Human Cells by CpG Motifs in Oligodeoxynucleotides and Bacterial DNA, J. Immunoll., 57: 1840-1845 (1996). |
| Barber, I. et al., The Prooligonucleotides Approach I: Esterase-Mediated Reversibility of Dithymidine S-Alkyl Phosphorothiolates to Dithymidine Phosphorothioates, Bioorganic and Medicinal Chemistry Letters, 5(6):563-568 (1995). |
| Barber, I. et al., The Prooligonucleotides Approach II: Synthesis and stability studies of chimeric oligonucleotide models, Bioorganic and Medicinal Chemistry Letters, 5(14):1441-1444 (1995). |
| Barnes, P.J. and Peterson, S. Efficacy and Safety of Inhaled Corticosteroids in Asthma, Am. Rev. Respir. Dis., 148: SI-S26 (1993). |
| Bartz, H. et al., Poly-guanosine strings improve cellular uptake and stimulatory activity of phosphodiester CpG oligonucleotides in human leukocytes, Vaccine, 23: 148-155 (2004). |
| Battistini et al., Stereoselective Synthesis of Cyclic Dinucloetide Phosphorothioates, Tetrahedron, 49(5): 1115-1132 (1993). |
| Bayever, E. et al., Systematic administration of a phosphorothioate oligonucleotide with a sequence complementary to p53 for acute myelogenous leukemia and myelodysplastic syndrome: intial results of a phase I trial, Antisense Research Development, 3(4):383-390 (1993). |
| Beal, P.A. et al., Second Structural Motif for Recognition of DNA by Oligonucleotide-Directed Triple-Helix Formation, Science, 251: 1360-1363 (1991). |
| Beaucage, S.L. and Iyer, R.P., Advances in the Synthesis of Oligonucleotides by the Phosphoramidite Approach, Tetrahedron, 48(12):2223-2311 (1992). |
| Benner, S.A. and Sismour, A.M., Synthetic biology, Nature Reviews Genetics, 6(7):533-543 (2005). |
| Berge, S.M. et al., Pharmaceutical salts, J. Pharm. Sci., 66(1):1-19 (1997). |
| Besch, R. et al, Specific Inhibition of ICAM-1 Expression Mediated by Gene Targeting with Triplex-forming Oligonucleotides, J. Biol. Chem., 277(26): 32473-32479 (2002). |
| Bisbal, C. and Silverman, R.H., Diverse functions of RNase L and implication in pathology, Biochimie, 89(6-7):789-798 (2007). |
| Block, E et al., Allium Chemistry: Synthesis and Sigmatropic Rearrangements of Alk(en)yl 1-Propenyl Disulfide S-Oxides from Cut Onion and Garlic, Journal of the Ameican Chemical Society, 118(12): 2799-2810 (1996). |
| Block, S.S. and Weidner, J.P, Vibrational Behavior and Structure of Disulfide Dioxides (Thiolsulfonates), Applied spectroscopy, 20(2): 71-73 (1966). |
| Bobkov, G.V. et al., Phosphoramidite building blocks for efficient incorporation of 2′-O-aminoethoxy(and propoxy)methyl nucleosides into oligonucleotides, Tetrahedron, 64: 6238-6251 (2008). |
| Bock, L.C. et al., Selections of single-stranded DNA molecules that bind and inhibit human thrombin, Nature, 355: 564-566 (1992). |
| Boczkovvska, M. et al., Stereodefined Phosphorothioate Analogues of DNA: Relative Thermodynamic Stability of the Model PS-DNA/DNA and PS-DNA/RNA complexes, Biochemistry, 41: 12483-12487 (2002). |
| Bode, C. et al. CpG DNA as a vaccine adjuvant, Expert Rev. Vaccines, 10(4): 499-511. |
| Bodor, N. et al., A convenient synthesis of (acyloxy)alkyl .alpha.-ethers of phenols, The Journal of Organic Chemistry, 48(26):5280-5284 (1983). |
| Bohringer, M. et al., Why Pentose and not Hexose Nucleic Acids? Part II: Oligonucleotides of 2′3′-dideoxy-β-d-glucopyranosyl (‘homo-DNA’) production, Helvetica Chimica Acta, 75:1416-1477 (1992). |
| Bologna, J. et al., Uptake and Quantification of Intracellular Concentration of Lipophilic Pro-Oligonucleotides in HeLa Cells, Antisense and Nucleic Acid Drug Development, 12(1):33-41 (2002). |
| Bonora, G.M. et al., Large scale, liquid phase synthesis of oligonucleotides by the phosphoramidite approach, Nucleic Acids Research, 21(5): 1213-1217 (1993). |
| Boudreau, R.L. et al., Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice, 17(6): 1053-1063 (2009). |
| Braasch et al., RNA Interference in Mammalian Cells by Chemically-Modified RNA, Biochemistry 42(26): 7967-7975 (2003). |
| Brill, W. et al., Thioalkylation of Nucleoside-H-Phosphonates and Its Application to Solid Phase Synthesis of Oligonucleotides, Tetrahedron Letters, 36(5):703-706 (1995). |
| Brooks, P.C. et al., Insulin-like Growth Factor Receptor Cooperates with Integrin ανβ5 to Promote Tumor Cell Dissemination in Vivo, The Journal of Clinical Investigation, 99(6):1390-1398 (1997). |
| Brown, J.W.S. and Simpson, C.G., Splice Site Selection in Plant Pre-mRNA Splicing, Ann. Rev. Plant Physiol. Plant Mol. Biol., 49: 77-95 (1998). |
| Bumcrot, D et al., RNAi therapeutics: a potential new class of pharmaceutical drugs, Nat. Chem. Biol., 2: 711-9 (2006). |
| Bundgaard, H., (C) Means to Enhance Penetration. (1) Prodrugs as a means to improve the delivery of peptide drugs, Advanced Drug Delivery Reviews, 8:1-38 (1992). |
| Bundgaard, H., Design and Application of Prodrugs, A Textbook of Drug Design and Development, Edited by Krogsgaard-Larsen, P. and Bundgaard, H., Chapter 5: 113-191 (1991). |
| Bundgaard, H., Design of Prodrugs, Elsevier, 7-9 and 21-24 (Chapter 1) (1985). |
| Bunnell. B.A. et al., Targeted Delivery of Antisense Oligonucleotides by Molecular Conjugates, Somatic Cell and Molecular Genetics, 18(6):559-569 (1992). |
| Burgers et al., Absolute configuration of the diastereomers of adenosine 5′-O-(1-thiaotriphosphate): Consequences for the stereochemistry of polymerization by DNA-dependent RNA polymerase from Escherichia coli, Proceedings of the National Academy of Sciences of the United States of America 75(10): 4798-4800 (1978). |
| Campbell J. et al., Hybrid polymer/MOF membranes for Organic Solvent Nanofiltration (OSN): Chemical modification and the quest for perfection, Journal of Membrance Science, 503: 166-176 (2016). |
| Cankurtaran, E.S. et al., Clinical Experience with Risperidone and Memantine in the Treatment of Huntington's Disease, Journal of the National Medical Association, 98(8): 1353-1355 (2006). |
| Carbone, G.M. et al., Selective inhibition of transcription of the Ets2 gene in prostate cancer cells by a triplex-forming oligonucleotide, Nucl. Acid. Res., 31: 833-843 (2003). |
| Carrillo, H., and Lipman, D.J., The multiple sequence alignment problem in biology, SIAM J. Appl. Math., 48:1073-1082 (1988). |
| CAS Registry No. 1225524-67-3; STN Entry Date May 28, 2010; α-[(2-methylphenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1225524-68-4; STN Entry Date May 28, 2010; α-[(4-methylphenyfimethyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1225545-00-5; STN Entry Date May 28, 2010; α-[(2,4,6-trimethylphenyfimethyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1225554-20-0; STN Entry Date May 28, 2010; α-[(4-ethylphenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1225594-74-0; STN Entry Date May 28, 2010; α-[(2-chloro-6-fluorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1225682-42-7; STN Entry Date May 30, 2010; α-[(4-chlorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226037-41-7; STN Entry Date May 30, 2010; α-[(3-chlorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226118-97-3; STN Entry Date May 30, 2010; α-[(3-bromophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226119-02-3; STN Entry Date May 30, 2010; α-[(4-bromophenyl)methyl]-2-Pyrradinemethanol. |
| CAS Registry No. 1226146-65-1; STN Entry Date May 30, 2010; α-[(2,4-dimethylphenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226160-20-8; STN Entry Date May 30, 2010; α-[(2,5-dimethylphenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226178-36-4; STN Entry Date May 30, 2010; α-[(2-fluorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226188-06-2; STN Entry Date May 30, 2010; α-[[4-(1-methylethyl)phenyl]methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226204-20-1; STN Entry Date May 30, 2010; α-[(3-methylphenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226231-44-2; STN Entry Date May 30, 2010; α-[(2-chlorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226352-28-8; STN Entry Date May 30, 2010; α-[(2,4-dichlorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226352-38-0; STN Entry Date May 30, 2010; α-[(3,4-dichlorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1226413-27-9; STN Entry Date May 30, 2010; α-(phenylmethyl)- 2-Pyrrolidinemethanol. |
| CAS Registry No. 1226419-15-3; STN Entry Date May 30, 2010; α-[(4-fluorophenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS Registry No. 1263282-82-1 ; STN Entry Date Feb. 21, 2011; (S)-[(diphenyl)methyl]-2-Pyrrolidinemethanol. |
| CAS RN 76-96-6, Entered STN: Nov. 16, 1984. |
| Chang, W. et al., Systematic chemical modifications of single stranded siRNAs significantly improved CTNNB1 mRNA silencing, Bioorg. Med. Chem. Lett., 1-5 (2016), http://dx.doi.org/10.1016/j.bmcl.2016.07.064. |
| Chatgilialoglu, C. and Snieckus, V., Chemical Synthesis: Gnosis to Prognosis, Kluwer Academic, 293-340 (1996). |
| Check, E., RNA interference: hitting the on switch, Nature, 448(7156): 855-858 (2007). |
| Chiu, Y. and Rana, T.M., siRNA function in RNAi: A chemical modification analysis, RNA, 9(9):1034-1048 (2003). |
| Cieslak, J. et al., Thermolytic 4-methylthio-1-butyl group for phosphate/thiophosphate protection in solid-phase synthesis of DNA oligonucleotides, Journal of Organic Chemistry, 69(7):2509-2515 (2004). |
| Clark, J.H, Flouride IOn as a Base in Organic Synthesis, Chemical Reviews, 1980 American Chemical Society 80(5): 429-452 (1980). |
| Communication Relating to the Results of the Partial International Search of PCT/IB2015/000395, Annex to Form PCT/ISA/206, 3 pages (dated Aug. 24, 2015). |
| Conway, N., The introduction of reporter groups at multiple and/or specific sites in DNA containing phosphorothioate diesters, Nucleic Acids Research, 43-44 (1989). |
| Cooney, M., et al., Site-Specific Oligonucleotide Binding Represses Transcription of the Human c-myc Gene in Vitro, Science, 241: 456-459 (1988). |
| Cosstick, R. and Eckstein, F., Synthesis of d(GC) and d(CG) Octamers Containing Alternating Phosphorothioate Linkages: Effect of the Phosphorothioate Group on the B-Z Transition, Biochemistry, 24: 3630-3638 (1985). |
| Coughlin, J.E. et al., Orally bioavailable anti-HBV dinucleotide acyloxyalkyl prodrugs, Bioorganic and Medicinal Chemistry Letters, 20(5):1783-1786 (2010). |
| Cox, J.R. and Ramsay, O.B., Mechanisms of Nucleophilic Substitution in Phosphate Esters, Chemical Reviews, 64(4): 317-352, (1964). |
| Crary, S.M. et al., Specific phosphorothioate substitutions probe the active site of Bacilus subtilis ribonuclease P, RNA, 8:933-947 (2002). |
| Crooke, S.T. and Geary, R.S. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B, Br. J. Clin. Pharmacol., 76: 269-276 (2012). |
| Crooke, S.T., Molecular mechanisms of action of antisense drugs, Biochemica et Biophysica Acta, 1489: 31-44 (1999). |
| Cullen, K.A. et al., Ambulatory surgery in the United States, 2006, National Health Statistics Reports, 11: 1-28 (Jan. 28, 2009—Revised Sep. 4, 2009). |
| Current Protocols in Nucleic Acid Chemistry, Edited by Beaucage, S.L. et al., Chapter 2: Protection of Nucleosides for Oligonucleotide Synthesis, 2.0.1.-2.16.31 (2012). |
| Davis, B.G. et al., Altering the specificity of subtilisin bacillus lentus through the introduction of positive charge at single amino acid sites, Bioorganic & Medicinal Chemistry, 7(11): 2303-2311 (1999). |
| De Koning, M.G. et al., Simple and Efficient Solution-Phase Synthesis of Oligonucleotides Using Extractive Work-Up, Organic Process Research & Developmen, 10: 1238-1245 (2006). |
| Deleavey, G.F. and Damha, M.J., Designing chemically modified oligonucleotides for targeted gene silencing. Chem. Biol., 19: 937-54 (2012). |
| Dellinger, D.J. et al., Streamlined Process for the Chemical Synthesis of RNA Using 2′-O-Thionocarbamate-Protected Nucleoside Phosphoramidites in the Solid Phase, J. Am. Chem. Soc., 133: 11540-11556 (2011). |
| Devereux, J. et al., A comprehensive set of sequence analysis programs for the VAX, Nucleic Acids Research, 12(1):387-395 (1984). |
| Dietz, G.P.H. et al., Delivery of bioactive molecules into the cell: the Trojan horse approach, Molecular and Cellular Neuroscience, 27(2): 85-131 (2004). |
| Djukanovic, R. et al., Mucosal Inflammation in Asthma, Am. Rev. Respir. Dis., 142: 434-457 (1990). |
| Documents submitted to and/or received from the United States Securities and Exchange Commission; downloaded from Edgar (Feb. 2, 2015 to Dec. 10, 2015). |
| Documents submitted to and/or received from the United States Securities and Exchange Commission; downloaded from Edgar (Dec. 17, 2015 to Oct. 4, 2016). |
| Dorman et al., Synthesis of Oligodeoxynucleotides and Oligodeoxynucleotide Analogs using Phosphoramidite Intermediates, Tetrahedron, 40(1):95-102 (1984). |
| Dua, P. et al., Patents on SELEX and therapeutic aptamers, Recent Patents on DNA & Gene Sequences, 2(3):172-186 (2008). |
| Eaton, W.A. et al., Submillisecond kinetics of protein folding, Curr. Opin. Chem. Biol., 1:10-14 (1997). |
| Eckstein, F. et al., Stereochemistry of polymerization by DNA-dependent RNA-polymerase from Escherichia coli: an investigation with a diastereomeric ATP-analogue, Proc. Natl. Acad. Sci. USA, 73: 2987-90 (1976). |
| Eckstein, F. Phosphorothioates, Essential Components of Therapeutic Oligonucleotides, Nucleic Acid Therapeutics, 1-14 (2014). |
| Eckstein, F., Oligonucleotides and Analogues A Practical Approach, IRL Press, 1-24 (1991). |
| Egli, M. et al., Crystal structure of homo-DNA and nature's choice of pentose over hexose in the genetic system, Journal of the American Chemical Society, 128(33)10847-56 (2006). |
| Egli, M. et al., Probing the Influence of Stereoelectronic Effects on the Biophysical Properties of Oligonucleotides: Comprehensive Analysis of the RNA Affinity, Nuclease Resistance, and Crystal Structure of Ten 2′-0-Ribonucleic Acid Modifications, Biochemistry, 44: 9045-9057 (2005). |
| El Harchaoui, K. et al., Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins, Am. J. Cardiovasc. Drugs, 8(4): 233-242 (2008). |
| Elbashir, S.M. et al., Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells, Nature, 411: 494-498 (2001). |
| Elbashir, S.M. et al., Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate, The EMBO Journal, 20(23): 6877-6888 (2001). |
| Ellington, A.D. and Szostak, J.W., In vitro selection of RNA molecules that bind specific ligands, Nature, 346: 818-822 (1990). |
| Engelhardt, J.A. et al., Scientific and Regulatory Policy Committee Points-to-consider Paper: Drug-induced Vascular Injury Associated with Nonsmall Molecule Therapeutics in Preclinical Development: Part 2. Antisense Oligonucleotides, Toxicologic Pathology, XX: 1-10 (2015). |
| Epton, R., Innovation and Perspectives in Solid Phase Synthesis, Peptides, Proteins and Nucleic Acids, 21:157-162 (1994). |
| Eschenmoser, A. et al., Why pentose- and not hexose-nucleic acids? Introduction to the problem, conformational analysis of oligonucleotide single strands containing 2′, 3′-dideoxyglucopyranosyl building blocks (‘homo-DNA’), and reflections on the conformation of A- and B-DNA, Helvetica Chimica Acta, 75:218-259 (1992). |
| Eschenmoser, A., Chemical etiology of nucleic acid structure, Science, 284(5423):2118-24 (1999). |
| Eschenmoser, A., Towards a Chemical Etiology of the Natural Nucleic Acids' Structure, Chemical Synthesis, Edited by Chatgilialoglu, C. and Snieckus, V., Kluwer Academic Publishers, 293-340 (1996). |
| Famulok, M. Oligonucleotide aptamers that recognize small molecules, Curr. Opin. Struct. Biol., 9: 324-329 (1999). |
| Fearon, K. et al., Phosphorothioate oligodeoxynucleotides: large-scale synthesis and analysis, impurity characterization, and the effect of phosphorus stereochemistry, Oligonucleotides as Therapeutic Agents, Ciba Found. Symp. 209: 19-31 (1997). |
| Fendrich et al., Determination of the Absolute P-configuration of a Phthalidyl└Phosphonate Thymidine-Thymidine Dimer, Nucleosides Nucleotides Nucleic Acids., 22(5-8): 1127-1129 (2003). |
| Ferreira, F. et al. Lewis acid deprotection of silyl-protected oligonucleotides and base-sensitive oligonucleotide analogues, Tetrahedron Letters, 45(33):6287-6290 (2004). |
| File Registry on STN, RN 18217-60-2, Entered STN: Nov. 16, 1984. |
| File Registry on STN, RN 871246-91-2, Entered STN: Jan. 5, 2006. |
| Fire, A. et al., Potent and specific RNA interference by double-stranded RNA in Caenorhadbditis elegans, Nature, 391: 806-811 (1998). |
| Forster, A.C. and Symons, R.H. Self-cleavage of plus and minus RNAs of a virusoid and a structural model for the active sites, Cell, 49(2): 211-220 (1987). |
| Forster, A.C. and Symons, R.N. Self-Cleavage of Virusoid RNA is performed by the Proposed 55-Nucleotide Active Site, Cell, 50: 9-16 (1987). |
| Frank-Kamenetsky, M. et al., Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA., 105(33): 11915-11920 (2008). |
| Frazier, K. et al. Potential Mechanisms of vascular toxicity in Monkeys with antisense oligonucleotides, TIDES oligo conference, 1-25 (May 15, 2014). |
| Frazier, K.S. Antisense Oligonucleotide Therapies: The Promise and the Challenges from a Toxicologic Pathologist's Perspective, Toxicology Pathology, 43: 78-89 (2015). |
| Frederiksen, J.K. et al., Separation of RNA Phosphorothioate Oligonucleotides by HPLC, Methods of Enzymology, 468:289-309 (2009). |
| Freier, S.M. et al., Improved free-energy parameters for predictions of RNA duplex stability, Proc. Nat. Acad. Sci. USA, 83: 9373-9377 (1986). |
| Froehler, B.C. et al., Synthesis of DNA via deoxynucleoside H-phosphonate intermediates, Nucleic Acids Research, 14(13): 5399-5407 (1986). |
| Fujii et al., Acylphosphonates. 5.1A new method for stereospecific generation of phosphorothioate via aroylphosphonate intermediate, Tetrahedron Letters, 27(8): 935-938 (1986). |
| Fujii et al., Acylphosphonates. 7.1 A New Method for Stereospecific and Stereoselective Generation of Dideoxyribonucleoside Phosphorothioates via the Acylphosphonate Intermediates, Tetrahedron, 43: 3395-3407 (1987). |
| Gaffney, P.R.J. et al., Liquid-Phase Synthesis of 2′-Methyl-RNA on a Homostar Support through Organic-Solvent Nanofiltration, Chem. Eur. J., 21:1-10 (2015). |
| Ganguly, A.K. et al., Structure of Halomicin B, J.C.S. Chem. Comm., 395-396 (1974). |
| Garegg, P.J. et al., Nucleoside H-Phosphonates. III. Chemical Synthesis of Oligodeoxyribonucleotides by the Hydrogenphosphonate Approach, Tetrahedron Letters, 27(34): 4051-4054 (1986). |
| Gauglitz, G.G. et al., Hypertrophic Scarring and Keloids: Pathomechanisms and Current Emerging Treatment Strategies, Mol. Med., 17(1-2): 113-125 (2011). |
| Gijsen, H.J.M et al., Development of two diastereoselective rougtes towards trans-4-aminomethyl-piperidin-3-o1 building blocks, Tetrahedron 64(10): 2456-2464 (2008). |
| Goraczmiak, R. et al., Gene silencing by synthetic U1 Adaptors, Nature Biotechnology 27(3): 257-263 (2008). |
| Gosselin, G. et al., New insights regarding the potential of the pronucleotide approach in antiviral chemotherapy, 43(1):195-208 (1996). |
| Gough, G.R. et al., Recovery and recycling of synthetic units in the construction of oligodeoxyribonucleotides on solid supports, Tetrahedron Letters, 22(42): 4177-4180 (1981). |
| Gould, W.A. et al., Pyrrolidines IX. 3-Aryl-3-pyrrolidinols, Journal of Medicinal Chemistry, 7(1): 60-67 (1964). |
| Graham, M.J. et al., Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice, J. Lipid Res., 48(4): 763-767 (2007). |
| Grajkowski, A. et al., Design and Development of Thermolytic DNA Oligonucleotide Prodrugs, Annals of the New York Academy of Sciences, 1058:26-38 (2005). |
| Grajkowski, A. et al., Solid-Phase Synthesis of Thermolytic DNA Oligonucleotides Functionalized with a Single 4-Hydroxy-1-butyl or 4-Phosphato-/Thiophosphato-1-butyl Thiophosphate Protecting Group, Journal of Organic Chemistry, 72(3): 805-815 (2007). |
| Grajkowski, A. et al., Thermolytic CpG-containing DNA oligonucleotides as potential immunotherapeutic prodrugs, Nucleic Acids Research, 33(11):3550-3560 (2005). |
| Green, L.S. et al., Inhibitory DNA Ligands to Platelet-Derived Growth Factor B-Chain, Biochemistry, 35: 14413-14424 (1996). |
| Green, L.S. et al., Nuclease-resistant nucleic acid ligands to vascular permeability factor/vascular endothelial growth factor, Chem. Biol., 2(10): 683-695 (1995). |
| Griffiths-Jones, S. et al., miRBase: microRIVA sequences, targets and gene nomenclature, Nucleic Acids Research, 34 (Database Issue): D140-D144 (2006). |
| Griffiths-Jones, S. The microRNA Registry, Nucleic Acids Research, 32 (Database Issue): D109-D111 (2004). |
| Groebke, K. et al., Why pentose and not hexose nucleic acids? Part V. Purine-purine pairing in homo-DNA: guanine, isoguanine, 2,6-diaminopurine and xanthine. Helvetica Chimica Acta. 81: 375-474 (1998). |
| Gude, L. et al., Mapping Targetable Sites on Human Telomerase RNA Pseudoknot/Template Domain Using 2′-OMe RNA-interacting Polynucleotide (RIPtide) Microarrays, J. Biol. Chem., 287(22): 18843-18853 (2012). |
| Guerciolini, R., Allele-selective Silencing of Mutant Huntingtin by Stereopure Oligonucleotides, WAVE Life Sciences, Huntington's Disease Society of America, HDSA Presentation 2016 (Jun. 3, 2016). |
| Guerlavais-Dagland, T et al., Fluoride-labile protecting groups for the synthesis of base-sensitive methyl-SATE oligonucleotide prodrugs, European Journal of Organic Chemistry, 2003(12):2327-2335 (2003). |
| Guga et al. Oxathiaphospholane Approach to the Synthesis of P-Chiral, Isotopomeric Deoxy(ribonucleoside phosphorothioate)s and Phosphates Labeled with an Oxygen Isotope. Angew Chem., 113(3): 630-633 (2001). |
| Guga et al, Unusual Thermal Stability of RNA/[RP-PS]-DNA/RNA Triplexes Containing a Homopurine DNA Strand, Biophys J. 92(7): 2507-2515 (2007). |
| Guga, P. and Stec, W.J., Synthesis of Phosphorothioate Oligonucleotides with Stereodefined Phsphorothioate Linkages, Current Protocols in Nucleic Acid Chemistry, Unit 4.17: 4.17.1-4.17.28 (2003). |
| Guga, P., P-chiral oligonucleotides in biological recognition processes, Current Topics in Medicinal Chemistry, 7:695-713 (2007). |
| Guo, M. et al., Solid-phase stereoselective synthesis of 2′-0-methyl-oligo-ribonucleoside phosphorothioates using nucleoside bicyclic oxazaphospholidines, Biorganic & Medicinal Chemistry Letters, 8(18):2539-2544 (1998). |
| Guzaev, A.P., Reactivity of 3H-1,2,4-dithiazole-3-thiones and 3H-1,2-dithiole-3-thiones as sulfurizing agents for oligonucleotide synthesis, Tetrahedron Letters, 52: 434-437 (2011). |
| Hacia, J.G. et al., Phosphorothioate oligonucleotide-directed triple helix formation, Biochemistry, 33:5367-5369 (1994). |
| Hammond, S.M. and Wood, M.J. Genetic therapies for RNA mis-splicing diseases, Trends Genet., 27: 196-205 (2011). |
| Hanagata, N., Structure-dependent immunostimulatory effect of CpG oligodeoxynucleoties and their delivery system, Int. J. Nanomedicine, 7: 2181-95 (2012). |
| Hansen et al., Azaribofuranoside Analogues as Designed Inhibitors of Purine Nucleoside Phosphorylase, Synthesis and Biological Evaluation, Acta Chemis Scandinavica 52: 1214-1222 (1998). |
| Harper, S.Q. et al., RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model, Proc. Natl. Acad. Sci. USA, 102(16): 5820-5825 (2005). |
| Hartmann, B. et al., Sequence effects on energetic and structural properties of phosphorothioate DNA: a molecular modelling study, Nucleic Acids Research, 27(16): 3342-3347 (1999). |
| Hartmann, G. et al., Delineation of a CpG Phosphorothioate Oligodeoxynucleotide for Activating Primate Immune Responses In Vitro and In Vivo, The Journal of Immunology, 164(3): 1617-1624 (2000). |
| Hau, P. et al., Results of G004, a phase lib actively controlled clinical trial with the TGF-b2 targeted compound AP 12009 for recurrent anaplastic astrocytoma, Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings (Post-Meeting Edition), 24(18, Jun. 20 Supplement): 1566 (2006). |
| Hayashi, S. et al., Studies on Antitumor Substances, Chemical & Pharmaceutical Bulletin, 12(11): 1271-1276 (1964). |
| Heger, W. et al., Embryotoxic effects of thalidomide derivatives on the non-human primate Callithrix jacchus; 3. Teratogenic potency of the EM 12 enantiomers, Arch. Toxicol., 62: 205-208 (1988). |
| Henry, A.A. and Romesberg, F.E., Beyond A, C, G and T: augmenting nature's alphabet, Current Opinion in Chemical Biology, 7(6): 727-733 (2003). |
| Henry, S.P. et al., Activation of the Alternative Pathway of Complement by a Phosphorothioate Oligonucleotide: Potential Mechanism of Action, The Journal of Pharmacology and Experimental Therapeutics, 281(2): 810-816 (1997). |
| Herbert, B-S. et al., Nonradioactive detection of telomerase activity using the telomeric repeat amplification protocol, Nat. Protoc., 1(3): 1583-1590 (2006). |
| Herdewijn, Oligonucleotide Synthesis, Methods in Molecular Biology, 288: 1-435 (2005). |
| Heuberger, B.D. and Swtzer, C., A Pre-RNA Candidate Revisited: Both Enantiomers of Flexible Nucleoside Triphosphates are DNA Polymerase Substrates, Journal of the American Chemical Society, 130(2):412-413 (2008). |
| Higuchi, T. et al., Pro-drugs as Novel Delivery Systems, ACS Symposium Series, 14 (1975). |
| Hirao, I., Unnatural base pair systems for DNA/RNA-based biotechnology, Current Opinion in Chemical Biology,10:622-627 (2006). |
| Hohjoh, H., Disease-Causing Allele-Specific Silencing by RNA Interference, Pharmaceuticals, 6: 522-535 (2013). |
| Hunziker, J. et al., Why Pentose-And Not Hexose-Nucleic Acids? Part III. Oligo(2′,3′-dideoxy-β-D-glucopyranosyl)nucleotides. (‘Homo-DNA’): Base-Pairing Properties, Helvetica Chimica Acta, 76(1):259-352 (1993). |
| Inagawa, T. et al., Inhibition of human immunodeficiency virus type 1 replication by P-stereodefined oligo(nucleoside phosphorothioate)s in a long-term infection model, FEBS Letters, 528(1-3): 48-52 (2002). |
| International Preliminary Report on Patentability for PCT/JP2013/069107, 10 pages (dated Jan. 15, 2015). |
| International Preliminary Report on Patentability and Written Opinion of the Searching Authority for PCT/JP2011/055018 (dated Oct. 11, 2012) with English Translation thereof. |
| International Preliminary Report on Patentability for Application No. PCT/JP2010/065900, 6 pages (dated Mar. 29, 2012). |
| International Preliminary Report on Patentability for Application No. PCT/JP2010/065900, 7 pages (dated Apr. 19, 2012). (English Translation). |
| International Preliminary Report on Patentability for Application No. PCT/JP2011/071559, 7 pages (dated Apr. 25, 2014). |
| International Preliminary Report on Patentability for PCT/JP2013/004303, 1 page (dated Jan. 13, 2015). |
| International Search Report for PCT/IB2009/007923, 4 pages (dated Sep. 6, 2010). |
| International Search Report for PCT/IB2015/000395, 7 pages (dated Oct. 30, 2015). |
| International Search Report for PCT/JP11/71559, 3 pages (dated Dec. 20, 2011). |
| International Search Report for PCT/JP15/50716 and English Translation, 8 pages (dated Apr. 21, 2015). |
| International Search Report for PCT/JP2010/065900, 1 page (dated Sep. 15, 2010). |
| International Search Report for PCT/JP2011/077313, 2 pages (dated Jan. 10, 2012). |
| International Search Report for PCT/JP2011/55018 (dated Mar. 29, 2011). |
| International Search Report for PCT/JP2013/004303, 3 pages (dated Aug. 13, 2013). |
| International Search Report for PCT/JP2015/050714, and English Translation, 6 pages (dated Apr. 21, 2015). |
| International Search Report for PCT/JP2015/050718 and English Translation, 8 pages (dated Apr. 21, 2015). |
| International Search Report for PCT/US2010/041068, 1 page (dated Sep. 1, 2010). |
| International Search Report for PCT/US2011/064287, 2 pages (dated Apr. 12, 2012). |
| International Search Report for PCT/US2012/046805, 2 pages (dated Sep. 19, 2012). |
| International Search Report for PCT/US2013/050407, 5 pages (dated Jan. 9, 2014). |
| International Search Report for PCT/US2016/043542, 6 pages (dated Dec. 28, 2016). |
| International Search Report for PCT/US2016/043598, 4 pages (dated Nov. 28, 2016). |
| International Search Report of PCT/JP2013/069107, 2 pages (dated Oct. 1, 2013). |
| Isis Pharmaceuticals, Intellectual Property: Capturing Value From Innovation, Isis' Annual Meeting of Stockholders and Open House, Intellectual Property Poster, 1 page (2011). Received from Internet <http://www.isispharm.com/Site_Gfx/pdf/11-AnMtg_IntellectualProperty_TAB.pdf>. |
| Isis Pharmaceuticals, Intellectual Property: Capturing Value From Innovation, Isis' Annual Meeting of Stockholders and Open House, Intellectual Property Poster, 1 page (2012). Received from Internet <http://www.isispharm.com/Site_Gfx/pdf/2012_Annual_Meeting_IP_Poster.pdf>. |
| Iwamoto et al., Stereocontrolled Synthesis of H-phosphonate DNA, Nucleic Acids Symposium Series, (50):159-60 (2006). |
| Iwamoto, N. et al., Optimization of Therapeutic Phosphorothioate Oligonucleotides by P-Chirality Control, WAVE Life Sciences, PSJ Congress: The Pharmaceutical Society of Japan, (Mar. 25, 2015-Mar. 28, 2016). |
| Iwamoto, N. et al., Stereocontrolled solid-phase synthesis of oligonucleoside H-phosphonates by an oxazaphospholidine approach, Angewandte Chemie International Edition, 48(3):496-499 (2009). |
| Iyer, R.P. et al., A novel nucleoside phosphoramidite synthon derived from 1R, 2S-ephedrine, Tetrahedron Asymmetry 6(5):1051-1054 (1995). |
| Iyer, R.P. et al., Acyloxyaryl prodrugs of oligonucleoside phosphorothioates, Bioorganic and Medicinal Chemistry Letters, 6(16):1917-1922 (1996). |
| Iyer, R.P. et al., Bioreversible oligonucleotide conjugates by site-specific derivatization, Bioorganic and Medicinal Chemistry Letters, 7:871-876 (1997). |
| Iyer, R.P. et al., Stereospecific Bio-Reversibility of Dinucleoside S-Alkyl Phosphorothiolates to Dinucleoside Phosphorothioates, Bioorganic & Medicinal Chemistry Letter, 4(20):2471-2476 (1994). |
| Iyer, R.P., et al., 3H-1,2-Benzodithiole-3-one 1,1-Dioxide as an Improved Sulfurizing Reagent in the Solid-Phase Synthesis of Oligodeoxyribonucleoside Phosphorothioates, Journal of the American Chemical Society, 112(3):1253-1254 (1990). |
| Iyer, R.P., et al., Prodrugs of Oligonucletides: The Acyloxyalkyl Esters of Oligodeoxyribonucleoside Phosphorothioates, Bioorganic Chemistry, 23:1-21 (1995). |
| Iyer, R.P., et al., Solid-phase stereoselective synthesis of oligonucleoside phosphorothioates: The nucleoside bicyclic oxazaphospholidines as novel synthons, Tetrahedron Letters, 39:2491-2494 (1998). |
| Jahns, H., et al., Stereochemical bias introduced during RNA synthesis modulates the activity of phosphorothioate siRNAs, Nat. Commun., 6: 6317 (2015). |
| Jiang, J. et al., Allele-Specific Silencing of Mutant Myh6 Transcripts in Mice Suppresses Hypertrophic Cardiomyopathy, Science, 342: 111-114 (2013). |
| Jin et al., A Stereoselective Synthesis of Dinucleotide Boranophosphate, Using Chiral Indole-Oxazaphosphorine Intermediates, Tetrahedron Letters, 39: 6433-6436 (1998). |
| Jin et al., Stereoselective Synthesis of Dithymidine Phosphorothioates Using Xylose Derivatives as Chiral Auxiliaries, J. Org. Chem., 63(11): 3647-3654 (1998). |
| Johansson et al., Studies towards synthesis of dinucleoside arylphosphonates with metal complexing properties, Nucleosides Nucleotides & Nucleic Acids, 22(5-8): 1459-61 (2003). |
| Johansson et al., Synthesis of dinucleoside pyridylphosphonates involving palladium(o)-catalysed phosphorus-carbon bond formation as a key step, Chem. Commun., 2564-2565 (2001). |
| Johansson et al., The case for configurational stability of H-phosphonate diesters in the presence of diazabicyclo[5.4.0]undec-7-ene (DBU), Bioorg Med Chem., 9(9): 2315-22 (2001). |
| Jopling, C.L. et al., Modulation of Hepatitis C Vicus RNA Abundance by a Liver-Specific MicroRNA, Science, 309: 1577-1581 (2005). |
| Joyce, G.F. et al., The case for an ancestral genetic system involving simple analogues of the nucleotide, Proceedings of the National Academy of Sciences, 84:4396-4402 (1987). |
| Joyce, G.F. The antiquity of RNA-based evolution, Nature, 418(6894): 214-221 (2002). |
| Kakeya, N. et al., Studies on Prodrugs of Cephalosporins. I. Synthesis and Biological Properties of Glycyloxybenzoyloxymethyl and Glycylaminobenzoyloxymethyl Esters of 7-[2-(2-Aminothiazol-4-yl) (Z) 2 methoxyiminoacetamido]-3-methyl-3-cephem-4-carboxylic Acid, Chem. Pharm. Bull., 32(2): 692-698 (1984). |
| Kamada, A.K. et al., Issues in the Use of Inhaled Glucocorticoids, Am. J. Respir. Crit. Care. Med., 153: 1739-1748 (1996). |
| Karwowski, B. et al., Stereocontrolled Synthesis of LNA Dinucleoside Phosphorothioate by the Oxathiaphospholane Approach, Bioorganic & Medicinal Chemistry Letters, 11: 1001-1003 (2001). |
| Kaur, H. et al., Activation of natural killer-like YT-INDY cells by oligodeoxynucleotides and binding by homologous pattern recognition proteins, Scandinavian Journal of Immunology, 62: 361-370 (2005). |
| Kawasaki, A et. al., Uniformly Modified 2′-Deoxy-2′-fluoro Phosphorothioate Oligonucleotides as Nuclease-Resistant Antisense Compounds with High Affinity and Specificity for RNA Targets, J. Med. Chem., 36: 831-841 (1993). |
| Kay, C. et al., Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-Specific Silencing in Huntington Disease Patients of European Ancestry, Molecular Therapy, Accepted Article Preview Online (Jul. 23, 2015). |
| Kay, C. et al., Huntingtin Haplotypes Provide Prioritized Target Panels for Allele-specific Silencing in Huntington Disease Patients of European Ancestry, The American Society of Gene & Cell Therapy, 1-13 (2015). |
| Kers et al., A new type of nucleotide analogue with 4-pyridylphosphonate internucleotide linkage, Tetrahedron Letters, 40(22): 4263-4266 (1999). |
| Kihara, M et al., New norepinephrine potentiators: synthesis and structure-actvity relastionships of a series of 4-phenyl-1,2,3,4-tetrahydroisoquinolin-4-ols, Chemical & Pharmaceutical Bulletin 42(1): 67-73 (1994). |
| Kim, D. et al., Immunostimulation and anti-DNA antibody production by backbone modified CpG-DNA, Biochemical and Biophysical Research Communicationes, 379: 362-367 (2009). |
| Kim, M., Beta conformation of polyglutamine track revealed by a crystal structure of Huntingtin N-terminal region with insertion of three histidine residues, Prion, 7(3): 221-228 (2013). |
| Kim, N.W. et al., Specific Association of Human Telomerase Activity with Immortal Cells and Cancer, Science, 226: 2011-2015 (1994). |
| Kim, S-H. and Cech, T.R., Three-dimensional model of the active site of the selfsplicing rRNA precursor of Tetrahymena, Proc. Natl. Acad. Sci. U S A., 84(24): 8788-8792 (1987). |
| Kim, S. et al., Liquid-Phase RNA Synthesis by Using Alkyl-Chain-Soluble Support, Chem. Eur. J., 19: 8615-8620 (2013). |
| Kiviniemi, A. et al., Solid-Supported 2′-O-Glycoconjugation of Oligonucleotides by Azidation and Click Reactions, Bioconjugate Chemistry, 22(6): 1249-1255 (2011). |
| Klose, J. et al., Preparation of 2-(2-Cyanoethyp-sulfanyl-1H-isoindole-1,3-(2H)-dione and related sulfur transfer reagents, Tetrahedron, 53(42):14411-14416 (1997). |
| Kool, E.T., Replacing the Nucleobases in DNA with Designer Molecules, Accounts of Chemical Research, 35:936-943 (2002). |
| Kordasiewicz, H.B. et al., Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis, Neuron, 74(6): 1031-1044 (2012). |
| Kozikowski, A.P. et al., Chemistry of the main group metals: A stereoselective synthesis of allyl vinyl thioethers for the thio-claisen reaction, Journal of Organometallic Chemistry, 164(3): C33-C37 (1979). |
| Koziolkewicz et al., Stability of Stereoregular Oligo-(nucleoside Phosphorothioate)s in Human Plasma: Diastereoselectiviy of Plasma 3′-Exonuclease, Antisense Nucl. Acid Drug Dev., 7:43-48 (1997). |
| Koziolkewicz et al., Stereodifferentiation-the effect of P chirality of oligo(nucleoside phosphorothioates) on the activity of bacterial RNase H, Nucl. Acids Res., 23(24): 5000-5005 (1995). |
| Koziolkiewicz, M. et al., Effect of P-chirality of oligo(deoxyribonucleoside phosphorothioate)s) on the activity of terminal deoxyribonucleotidyl transferase, FEBS Letters, 434(1-2): 77-82 (1998). |
| Kraszewski et al., Studies on Reactions of Nucleoside H-phosphonates with Bifunctional Reagents. Part 1. Reaction with amino alcohols, J. Chem. Soc., Perkin Trans., 1: 1699-1704 (1993). |
| Kremer, B. et al., A Worldwide Study of the Huntington's Disease Mutation, The New England Journal of Medicine, 330(20): 1401-1406 (1994). |
| Krieg, A.M. et al., CpG motifs in bacterial DNA trigger direct B-cell activation, Nature, 374: 546-549 (1995). |
| Krieg, A.M. et al., P-Chirality-Dependent Immune Activiation by Phosphorothioate CpG Oligodeoxynucleotides, Oligonucleotides, 13:491-499 (2003). |
| Krieg, A.M., Development of TLR9 agonists for cancer therapy, The Journal of Clinical Investigation, 117(5): 1184-1194 (2007). |
| Krueger, A.T. et al., Synthesis and properties of size-expanded DNAs: toward designed, functional genetic systems, Accounts of Chemical Research, 40:141-150 (2007). |
| Krutzfeldt, J. et al., Silencing of microRNAs in vivo with ‘antagomirs’, Nature, 438: 685-689 (2005). |
| Kungurtsev, V. et al., Solution-Phase Synthesis of Short Oligo-2′-deoxyribonucleotides by Using Clustered Nucleosides as a Soluble Support, Eur. J. Org. Chem., 6687-6693 (2013). |
| Kuramoto, Y. et al., Mannosylated cationic liposomes/CpG DNA complex for the treatment of hepatic metastasis after intravenous administration in mice, Journal of Pharmaceutical Science, 98(3): 1193-1197 (2009). |
| Kwon, H-J. et al., NF-kappaB-dependent regulation of tumor necrosis factor-alpha gene expression by CpG-oligodeoxynucleotides, Biochem. Biophys. Res. Commun., 311(1): 129-138 (2003). |
| LaPlanche, L.A. et al., Phosphorothioate-modified oligodeoxyribonucleotides. III. NMR and UV spectroscopic studies of the Rp-Rp, Sp-Sp, and Rp-Sp duplexes, [d(GGsAATI′CC)2, derived from diastereomeric 0-ethyl phosphorothioates, Nucleic Acids Research, 14(22): 9081-9093 (1986). |
| Latimer, L.J.P. et al, Synthetic repeating sequence DNAs containing phosphorothioates: nuclease sensitivity and triplex formation, Nucleic Acids Research, 17(4): 1549-1561 (1989). |
| Laurent et al., Chiral and steric effects in the efficient binding of alpha-anomeric deoxyoligonucleoside N-alkylphosphoramidates to ssDNA and RNA, Nucleic Acids Res., 27(21): 4151-9 (1999). |
| Lavergne, T. et al., A Base-Labile Group for 2′-OH Protection of Ribonucleosides: A Major Challenge for RNA Synthesis, Chem. Eur. J, 14, 9135-9138 (2008). |
| Lesnikowski et al., Studies on Stereospecific Formation of P-Chiral Internucleotide Linkage. Synthesis of (RP, RP)- and (SP, SP)- Thymidylyl (3′, 5′) Thymidylyl (3′, 5′) Thymidine DI (O,O-Phosphorothioate) Using 2-Nitrobenzyl Group as a New S-Protection, Tetrahedron Letters 30(29) 3821-3824 (1989). |
| Lesnikowski, Z. J. et al., Octa(thymidine methanephosphonates) of partially defined sterochemistry: synthesis and effect of chirality at phosphorus on binding to pentadecadeoxyriboadenylic acid, Nucleic Acids Research, 18(8): 2109-2115 (1990). |
| Levin, A.A. et al., Basic Principles of the Pharmacokinetics of Antisense Oligonucleotide Drugs, Antisense Drug Technology: Principles, Strategies, and Applications, Second Edition, Chapter 7: 183-215 (2008). |
| Li L.C., Small RNA Mediated Gene Activation, RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity, Edited by Kevin V. Morris, Chapter 13, Caister Academic Press (2008). |
| Li, L-C. et al., Small dsRNAs induce transcriptional activation in human cells, PNAS, 103(46): 17337-17342 (2006). |
| Li-Tsang, C.W. et al., Prevalence of hypertrophic scar formation and its characteristics among the Chinese population, Burns, 31: 610-616 (2005). |
| Liang, X-h. et al., Identification and characterization of intracellular proteins that bind oligonucleotides with phosphorothioate linkages, Nucleic Acids Research, 43(5): 2927-2945, Supplemental Data pp. 1-20 (2015). |
| Lima, W. et al., Single-Stranded ssRNAi Activate RNAi in Animals, Cell, 150: 883-894 (2012). |
| Lima, W.F. et al., The influence of antisense oligonucleotide-induced RNA structure on Escherichia coli RNase H1 activity, J. Biol. Chem., 272(29):18191-9 (1997). |
| Lima, W.F., et al., Human RNase H1 discriminates between subtle variations in the structure of the heteroduplex substrate, Mol. Pharmacol., 71: 83-91 (2007). |
| Limbach, P.A. et al., Summary: the modified nucleosides of RNA, Nucleic Acids Research, 22(12):2183-2196 (1994). |
| Lin et al., Synthesis and resolution of dinucleotide (TpAZT) phosphoramidates, Synthetic Commun., 33(14): 2553-2562 (2003). |
| Linton, M.F., et al., Transgenic Mice Expressing High Plasma Concentrations of Human Apolipoproteins B100 and Lipoprotein (a), J. Clin. Invest., 92: 3029-37 (1993). |
| Liu, W. et al., Increased Steady-State Mutant Huntingtin mRNA in Huntington's Disease Brain, Journal of Huntington's Disease 2: 491-500 (2013). |
| Lu, X. et al., Antisense-Mediated Inhibition of Human Immunodeficiency Virus (HIV) Replication by Use of an HIV Type 1-Based Vector Resuts in Severely Attenuated Mutants Incapable of Developing Resistance, Journal of Virology, 78(13): 7079-7088 (2004). |
| Lu, Y. and Just, G., Stereoselective synthesis of dithymidine phosphorothioates using d-xylose derived chiral auxiliaries, Tetrahedron, 57(9):1677-1687 (2001). |
| Lu, Y. et al., Stereoselective Synthesis of R(P)- and S(P)-Dithymidine Phosphorothioates via Chiral Indolooxazaphosphorine Intermediates Derived from Tryptophan This work was financially supported by Natural Science and Engineering Research Council of Canada (NSERC). We thank Nadim Saadeh and Dr. Orval Mamer, McGill University biomedical mass spectroscopy unit, for recording mass spectra, Angewandte Chemie International Edition, 39(24):4521-4524 (2000). |
| Lu, Y., Recent advances in the stereocontrolled synthesis of antisense phosphorothioates, Mini Reviews in Medicinal Chemistry, 6(3): 319-330 (2006). |
| Machine Translation of JP 2010-265304 (2010). <http://dossier1.ipdl.inpit.go.jp/AIPN/odse_top_dn.ipdl?NOOOO.7400>. |
| Machytka et al., Extension of the Applicability of &I-Values for the Configurational Assignment of Diastereomeric Phosphate-Modified Dideoxynucleotides, Nucleosides and Nucleotides, 17(12): 2311-2322 (1998). |
| Machytka et al., Synthesis and NMR characterization of diastereomeric CPSMeG derivatives, Nucleosides Nucleotides Nucleic Acids., 19(5-6): 903-15 (2000). |
| Maher III, L.J., et al., Inhibition of DNA Binding Proteins by Oligonucleotide-Directed Triple Helix Formation, Science, 245: 725-730 (1989). |
| Mann, M.J. et al., Therapeutic applications of transcription factor decoy oligonucleotides, J. Clin. Invest., 106:1071-1075 (2000). |
| Mannironi, C. et al., In Vivo Selection of Dopamine RNA Ligands, Biochemistry, 36: 9726-9734 (1997). |
| Martin, P., A New Access to 2′-O-alkylated Ribonucleosides and Properties of 2′-O-Alkylated Oligoribonucleotides, Hely. Chim. Acta., Abstract Only, 78: 486-504 (1995). |
| Martin, P., Stereoselective Synthesis of 2′-O-(2-Methoxyethyl)ribonucleosides: Neighboring-Group Participation of the Methoxyethoxy Group in the Ribosylation Step, Hely. Chim. Acta, 79: 1930-1938 (1996). |
| Masahiro, T. et al., Nematicidal and antimicrobial constituents from Allium grayi Regel and Allium fstulosum L. var. caespitosum, Agricultural and Biological Chemistry, 52(9): 2383-2385 (1988). |
| Matsuno, Y. et al., Synthetic Method for Oligonucleotide Block by Using Alkyl-Chain-Soluble Support, Org. Lett., 18: 800-803 (2016). |
| Matysiak, S et al., Acetals as New 2′-O-Protecting Functions for the Synthesis of the Oligoribonucleotides: Synthesis of Uridine Building Blocks and Evaluatino of Their Relative Acid Stability, Helvetica Chimica Acta 81: 1545-1566 (1998). |
| Maung, J. et al., Alternatives to 1-H-tetrazole in the preparation of phosphonate diesters and phosphonamidates from phosphonyl dichlorides, Tetrahedron Lett., 45: 6497-6499 (2004). |
| Mauritz, R.P. et al., Elucidation of the Hydrolytical Properties of α-Hydroxybenzylphosphonates as a New Potential Pro-Oligonucleotide Concept, Nucleosides and Nucleotides, 18(6-7):1417-1418 (1999). |
| Mauritz, R.P. et al., Synthesis of 3′,5′-Dithymidylyl-α-hydroxyphosphonate Dimer Building Blocks for Oligonucleotide Synthesis—A New Pro-oliguncleotide, Nucleosides and Nucleotides, 16(7-9):1209-1212 (1997). |
| McBride, J.L. et al., Prelinical Safety of RNAi-Mediated HTT Suppression in the Rhesus Macaque as a Potential Therapy for Huntington's Disease, Molecular Therapy, 19: 1-11 (2011). |
| Meade, M.F., et al., Efficient delivery of RNAi prodrugs containing reversible charge-neutralizing phosphotriester backbone modifications, Nat. Biotech., 32: 1256-61 (2014). |
| Medical News Today, AVI BioPharma Announces FDA Clears IND Applications for Clinical Trials of RNA Therapeutic Agents for Treatment of Ebola and Marburg Viruses, Accessed Apr. 2, 2015, 2 pages (Dec. 30, 2008). |
| Meena, Control of Human RNase H Mediated Cleavage by Stereopure Phosphorothioate Oligonucleotides, WAVE Life Sciences, TIDES Meeting (May 3-6, 2015). |
| Meena, Development of Allele Specific Antisense Oligonucleotides, WAVE Life Sciences, ACS Central Regional Meeting (CERM), Covington, KY (May 19, 2016). |
| Meena, Development of Allele Specific Antisense Oligonucleotides, WAVE Life Sciences, Tides Meeting (May 11, 2016). |
| Meena, et al., Therapeutic Implications of Controlling P-Chirality in Phosphorothioate Oligonucleotides, TIDES Poster (May 12-15, 2014). |
| Meena, Optimization of Antisense Drugs by P-Stereochemistry Control, Wave Life Sciences, OTS Annual Meeting 2014, Oligonucleotide Therapeutics Society (Oct. 12-14, 2014). |
| Merki, E. et al., Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-1 00 particles in lipoprotein(a) transgenic mice, Circulation, 118(7): 743-53 (2008). |
| Mesmaeker, A.D. Backbone modifications in oligonucleotides and peptide nucleic acid systems, Current Opinion in Structural Biology, 5: 343-355 (1995). |
| Methods in Enzymology, Edited by Widder, K. and Green, R., Drug and Enzyme Targeting, Academic Press, 112: 309-396 (1985). |
| Mignet, N. et al., Synthesis and evaluation of glucuronic acid derivatives as alkylating agents for the reversible masking of internucleoside groups of antisense oligonucleotides, Carbohydrate Research, 303:17-24 (1997). |
| Mignet, N. et al., The Prooligonucleotide Approach. V: Influence of the phosphorus atom environment on the hydrolysis of enzymolabile dinucleoside phosphotriesters, Bioorganic and Medicinal Chemistry Letters, 7(7):851-854 (1997). |
| Milkowski, J.D. et al., Thiol Protection with the Acetamidomethyl Group: S-Acetamidomethyl-l-cysteine Hydrochloride, Organic Syntheses, 6: 5 (1988). |
| Misaki, S et al., Dehydration of 2-Trifluoromethyl-3,3,3-Trifluoropropanil with Base, Journal of Flourine Chemistry 24: 531-533 (1984). |
| Molenkamp, B.G. et al., Local Administration of PF-3512676 CpG-B Instigates Tumor-Specific CD8+ T-Cell Reactivity in Melanoma Patients , Clin. Cancer Res., 14(14): 4532-4542 (2008). |
| Molina, A.G. et al., Acetylated and Methylated β-Cyclodextrins asViable Soluble Supports for the Synthesis of Short 2′-Oligodeoxyribo-nucleotides in Solution, Molecules, 17: 12102-12120 (2012). |
| Molina, A.G. et al., Assembly of Short Oligoribonucleotides from Commercially Available Building Blocks on a Tetrapodal Soluble Support, Current Organic Synthesis, 12:1-6 (2015). |
| Molina, A.G. et al., Solution phase synthesis of short oligoribonucleotides on a precipitative tetrapodal support, Beilstein Journal of Organic Chemistry, 10: 2279-2285 (2014). |
| Molina, A.G., Synthesis of Short Oligonucleotides on a Soluble Support by the Phosphoramidite Method, University of Turku, 1-66 (2015). |
| Monteys, A.M. et al., Artificial miRNAs Targeting Mutant Huntingtin Show Preferential Silencing In Vitro and In Vivo, Molecular THerapy—Nucleic Acids, 4: e234 1-11 (2015). |
| Monteys, A.M. et al., Single nucleotide seed modification restores in vivo tolerability of a toxic artificial miRNA sequence in the mouse brain, Nucleic Acids Res., 42(21): 13315-13327 (2014). |
| Morales-Rojas, H. and Kool, E.T., A porphyrin C-nucleoside incorporated into DNA, Organic Letters, 4(25):4377-4380 (2002). |
| Morcos, P.A., Achieving targeted and quantifiable alteration of mRNA splicing with Morpholino oligos, Biochem. Biophys. Res. Commun., 358(2): 521-527 (2007). |
| Morvan, F. et al., Cellular uptake and intracellular quantification of fluorescent labeled T20 Me-SATE prooligonucleotides, Nucleosides Nucleotides Nucleic Acids, 20(4-7):1165-1168 (2001). |
| Morvan, F. et al., Kinetics study of the biotransformation of an oligonucleotide prodrug in cells extract by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, Nucleosides, Nucleotides and Nucleic Acids, 20(2-4):1159-1163 (2001). |
| Morvan, F. et al., The Oligonucleotide Prodrug Approach: The Pro-Oligonucleotides, Pharmaceutical Aspects of Oligonucleotides, 79-97 (2000). |
| Moser, H. E. et al., Sequence-Specific Cleavage of Double Helical DNA by Triple Helix Formation, Science, 238: 645-650 (1987). |
| Nawrot et al., DNA Oligonucleotides Containing Stereodefned Phosphorothioate Linkages in Selected Positions, Current Protocols in Nucleic Acid Chemistry, UNIT 4.34: 4.34.1-4.34.15 (2009). |
| Nielsen, J. and Caruthers, M.H., Directed Arbuzov-type reactions of 2-cyano-1,1-dimethylethyl deoxynucleoside phosphites, J. Am. Chem. Soc., 110: 6275-6 (1988). |
| Nielsen, N.M. and Bundgaard, H. Glycolamide Esters as Biolabile Prodrugs of Carboxylic Acid Agents: Synthesis, Stability, Bioconversion, and Physicochemical Properties, Journal of Pharmaceutical Sciences, 77(4): 285-298 (1988). |
| Nieuwlandt, D. et al., In Vitro Selection of RNA Ligands to Substance P, Biochemistry, 34: 5651-5659 (1995). |
| Nilsson et al., Chemical and Stereochemical Aspects of Oxidative Coupling of H-Phosphonate and H-Phosphonothioate Diesters. Reactions with N,N-,N,O and O,O-Binucleophiles, Letters in Organic Chemistry, 2(2): 188-197 (2005). |
| Nilsson et al., Controlling Stereochemistry During Oxidative Coupling. Preparation of Rp or Sp Phosphoramidates from One P-chiral Precursor, Chem. Commun., (22): 2566-7 (2004). |
| Nilsson, J. et al., Chemoselectivity in oxidative coupling of bifunctional nucleophiles with dinucleoside H-phosphonate and dinucleoside H-phosphonothioate diesters, Nucleosides, Nucleotides & Nucleic Acids, 22(5-8):1467-1469 (2003). |
| Nowotny, M. et al., Structure of human RNase H1 complexed with an RNA/DNA hybrid: insight into HIV reverse transcription, Mol Cell, 28(2):264-76 (2007). |
| Nukaga, Y. et al., Stereocontrolled Solid-Phase Synthesis of Phosphate/Phosphorothioate (PO/PS) Chimeric Oligodeoxyribonucleotides on an Automated Synthesizer Using an Oxazaphospholidine-Phosphoramidite Method, J. Org. Chem., A-J, 10 pages (Publication Date (Web): Mar. 3, 2016). |
| Nukaga, Y. et al., Stereocontrolled Solid-Phase Synthesis of Phosphorothioate Oligoribonucleotides Using 2′-O-(2-Cyanoethoxymethyl)-nucleoside 3′-O-Oxazaphospholiidine Monomers, Journal of Organic Chemistry, 77(18):7913-7922 (2012). |
| O'Connell, D. et al., Calcium-dependent oligonucleotide antagonists specific for L-selectin, Proc. Natl. Acad. Sci. USA, 93: 5683-5887 (1996). |
| Ohgi, T. et al., A New RNA Synthetic Method with a 2′-O-(2-Cyanoethoxymethyl) Protecting Group, Organic Letters, 7(16): 3477-3480 (2005). |
| Ohkubo et al., Synthesis of oligodeoxyribonucleotides containing hydroxymethylphosphonate bonds in the phosphoramidite method and their hybridization properties, Tetrahedron Letters, 46(51): 8953-8957 (2005). |
| Oka, N. and Wada, T., Stereocontrolled synthesis of oligonucleotide analogs containing chiral internucleotidic phosphorus atoms, Chemical Society Reviews, 40(12):5829-5843 (2011). |
| Oka, N. et al., An oxazaphospholidine approach for the stereocontrolled synthesis of oligonucleoside phosphorothioates, Journal of the America Chemical Society, 125(27):8307-8317 (2003). |
| Oka, N. et al., Diastereocontrolled Synthesis of Dinucleoside Phosphorothioates Using a Novel Class of Activators, Dialkyl(cyanomethyl)ammonium Tetrafluoroborates, Journal of the American Chemical Society, 124(18):4962-4963 (2002). |
| Oka, N. et al., Solid-Phase Synthesis of Stereoregular Oligodeoxyribonucleoside Phosphorothioates Using Bicyclic Oxazaphospholidine Derivatives as Monomer Units, Journal of the American Chemical Society, 130(47):16031-16037 (2008). |
| Oka, N. et al., Stereocontrolled synthesis of dinucleoside boranophosphates by an oxazaphospholidine method, Nucleic Acids Symposium Series, (49): 131-132 (2005). |
| Oka, N. et al., Stereocontrolled synthesis of oligonucleoside phosphorothioates and PO/PS-chimeric oligonucleotides by using oxazaphospholidine derivaties, Nucleic Acids Symposium Series, 52: 335-336 (2006). |
| Oka, N. et al., Stereocontrolled Synthesis of Oligoribonucleoside Phosphorothioates by an Oxazaphospholidine Approach, Organic Letters, 11(4):967-970 (2009). |
| Ostergaard, M. et al., Rational design of antisense oligonucleotides targeting single nucleotide polymorphisms for potent and allele selective suppression of mutant Huntingtin in the CNS, Nucleic Acids Research, 41(21), 9634-9650 (2013). |
| Otting, G. et al., Why Pentose- and Not Hexose-Nucleid Acids? Part IV. ‘Homo-DNA’: 1H-, 13C-, 31P-, and 15N-NMR-Spectroscopic Investigation of ddGlc(A-A-A-A-A-T-T-T-T-T) in Aqueous Solution, Helvetica Chimica Acta, 76(8):2701-2756 (1993). |
| Padmanabhan, S. et al., Anti-HBV nucleotide prodrug analogs: Synthesis, bioreversibility, and cytotoxicity studies, Bioorganic and Medicinal Chemistry Letters, 16(15):1491-1494 (2006). |
| Pan, O-W. et al., New therapeutic opportunities for Hepatitis C based on small RNA, World J. Gastroenterol., 13(33): 4431-4436 (2007). |
| Parrish et al., Functional Anatomy of a dsRNA Trigger: Differential Requirement for the Two Trigger Strands in RNA Interference, Molecular Cell, 6:1077-1087 (2000). |
| Patil et al., Syntheses and properties of oligothymidylate analogs containing stereoregulated phosphorothioate and phosphodiester linkages in an alternating manner, Bioorganic & Medicinal Chemistry Letters, 4(22): 2663-2666 (1994). |
| Perrino, E. et al., New sulfurated derivatives of valproic acid with enhanced histone deacetylase inhibitory activity, Bioorganic & Medicinal Chemistry Letters, 18(6): 1893-1897 (2008). |
| Peyrottes, S. et al., SATE pronucleotide approaches: an overview, Mini-Reviews Medicinal Chemistry, 4(4):395-408 (2004). |
| Pfister, E.L. et al., Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients, 19(9): 774-778 (2009). |
| Pharmacology Review(s), Application No. 203568Orig1s000, Center for Drug Evaluation and Research, Food and Drug Administration, Department of Health & Human Services, 2013. |
| Pitsch, S. et al., Reliable Chemical Synthesis of Oligoribonucleotides (RNA) with 2′-O-[(Trilsopropylsilyl)oxy]methyl(2′-O-tom)-Protected Phosphoramidites, Helvetica Chimica Acta, 84: 3773-3795 (2001). |
| Poijarvi, P. et al., 2,2-Bis(ethoxycarbonyl)- and 2-(Alkylaminocarbonyl)-2-cyano-Substituted 3-(Pivaloyloxy)propyl Groups as Biodegradable Phosphate Protections of Oligonucleotides, Bioconjugate Chemistry, 16(6):1564-1571 (2005). |
| Poijarvi, P. et al., The chemical stability of S-(2-acylthioethyl) and S-acyloxymethyl protected thymidylyl-3′,5′-thymidine phosphoromonothiolates and their deacylation products in aqueous solution, Nucleosides Nucleotides and Nucleic Acids, 20(1-2):77-91 (2001). |
| Poijarvi, P. et al., Towards Nucleotide Prodrugs Derived from 2,2-Bis(hydroxymethyl)malonate and Its Congeners: Hydrolytic Cleavage of 2-Cyano-2-(hydroxymethyl)-3-methoxy-3-oxopropyl and 3-(Alkylamino)-2-cyano-2-(hydroxymethyl)-3-oxopropyl Protections from the Internucleosidic Phosphodiester and Phosphorothioate Linkages, Helvetica Chimica Acta, 85(7):1869-1876 (2002). |
| Poijarvi, P. et al., Towards Oligonucleotide Pro-Drugs: 2,2-Bis(ethoxycarbonyl) and 2-(Alkylaminocarbonyl)-2-cyano Substituted 3-(Pivaloyloxy)Propyl Groups as Biodegradable Protecting Groups for Internucleosidic Phosphoromonothioate Linkages, Letters in Organic Chemistry, 1(2):183-188 (2004). |
| Poijarvi, P., Prodrug Approaches of Nucleotides and Oligonucleotides, Current Medicinal Chemistry, 13(28):3441-3465 (2006). |
| Pon, R. T., Solid-Phase Supports for Oligonucleotide Synthesis, Current Protocols in Nucleic Acid Chemistry, 3.1.1-3.1.28 (2000). |
| Pontiggia, R. et al., 2-C-Methyluridine modified hammerhead riboxyme against the estrogen receptor, Bioorganic & Medicinal Chemistry Letters, 20: 2806-2808 (2010). |
| Pontiggia, R. et al., DNAzymes and ribozymes carrying 2′-C-methyl nucleotides, Nucleic Acids Sumposium Series, 52: 521-522 (2008). |
| Potter et al, Stereospecificity of nucleases towards phosphorothioate-substituted RNA: stereochemistry of transcription by T7 RNA polymerase, Nucleinc Acids Research, 15(10): 4145-4162 (1987). |
| Potter, B.V.L. et al., Synthesis and Configurational Analysis of Dinucleoside Phosphate Isotopically Chiral at Phosphorus. Stereochmical Course of Penicillium citrum Nuclease P1 Reaction, Biochemistry, 22: 1369-1377 (1983). |
| Prakash, T.P. et al., 2′-O-[2-(Methylthio )ethyl]-Modified Oligonucleotide: An Analogue of 2′-O-[2-(Methoxy)-ethyl]-Modified Oligonucleotide with Improved Protein Binding Properties and High Binding Affinity to Target RNA, Biochemistry, 41: 11642-11646 (2002). |
| Prhavc, M. et al., 2′-O-[2-[2-(N,N-Dimethylamino)ethoxy]ethyl] Modified Oligonucleotides: Symbiosis of Charge Interaction Factors and Stereoelectronic Effects, Organic Letters, 5(12): 2017-2020 (2003). |
| Puri, N. et al, Targeted Gene Knockout by 2′-O-Aminoethyl Modified Triplex Forming Oligonucleotides, J. Biol. Chem., 276: 26991-26998 (2001). |
| Puri, N. et al., The Synthesis and Reactivity of New 2-(N,N-Diisoprophylamino)-3-Methylsulfonyl-1,3,2-Benzoxazaphospholes. The Utility of the 5-Chloro analogue in the One-Pot Synthesis of Oligothiophosphates: [ApsppA, ApspppA, ppp5′A2′ps5′A, m7GpsppA, Apspppp, Apspp], Tetrahedron 51(10): 2991-3014 (1995). |
| Perez, B. et al., Antisense Mediated Splicing Modulation for Inherited Metabolic Diseases: Challenges for Delivery, Nucleic Acid Therapies, 24(1): 48-56 (2014). |
| Ravikumar, V.T. et al., Unylinker: An Efficient and Scaleable Synthesis of Oligonucleotides Utilizing a Universal Linker Molecule: A Novel Approach to Enhance the Purity of Drugs, Org. Process Res. Dev., 12(3): 399-410 (2008). |
| Reese, C.B. and Yan, H., Solution phase synthesis of ISIS 2922 (Vitravene) by the modified H-phophane approach, J. Chem. Soc., Perkin Trans. I, 2619-2633 (2002). |
| Regan, J.F. et al., A Rapid Molecular Approach for Chromosomal Phasing, PLOS ONE, 1-15 (2015). |
| Reither, S. and Jeltsch, A., Specificity of DNA triple helix formation analyzed by a FRET assay, BMC Biochemistry, 3: 9 pages (2002). |
| Revankar, G. R. and Rao, T.S., DNA with Altered Bases, DNA and Aspects of Molecular Biology, Comprehensive Natural Products Chemistry, 7.09: 313-339 (1999). |
| Robinson, D.S. et al., Predominant TH2-Like Bronchoalveolar T-Lymphocyte Population in Atopic Asthma, The New England Journal of Medicine, 326: 298-304 (1992). |
| Rossetti, G., Structural aspects of the Huntingtin protein investigated by biocomputing methods, Thesis, RWTH Aachen University, Forschungszentrum Juelich, 173 pages (2011). |
| Rozners, E. et al., Evaluation of 2′-hydroxyl protection in RNA-synthesis using the H-phosphonate approad, Nucleic Acids Research, 22(1): 94-99 (1994). |
| Sakatsume, O. et al., Solid Phase Synthesis of Oligoribonucleotides by the Phosphoramidite Approach Using 2′-O-1-(2-Chloroethoxy)Ethyl Protection, Tetrahedron, 47(41): 8717-8728 (1991). |
| Saneyoshi, H. et al., A General Method for the Synthesis of 2′-0-Cyanoethylated Oligoribonucleotides Having Promising Hybridization Affinity for DNA and RNA and Enhanced Nuclease Resistance, The Journal of Organic Chemistry, 70(25): 10453-10460 (2005). |
| Schmitz, C. et al., Synthesis of P-Stereogenic Phosphoramidite and Phosphorodiamidite Ligands and Their Application in Asymmetric Catalysis, Eur. J. Org. Chem., 6205-6230 (2015). |
| Schoning, K.-U. et al., Chemical Etiology of Nucleic Acid Structure: The α-Threofuranosyl-(3′->2′) Oligonucleotide System, Science, 290(5495):1347-1351 (2000). |
| Schultz, C., Prodrugs of Biologically Active Phospate Esters, Bioorganic and Medicinal Chemistry, 11(6):885-898 (2003). |
| Schulz, W.G. and Cai, S.L., Synthetic Genetics, Chemical and Engineering News, 5 (2012). |
| Scrimgeour, E.M. Huntington Disease (Chorea) in the Middle East, SQU. Med. J., 9(1): 16-23 (2009). |
| Seela et al, Diastereomerically pure Rp and Sp dinucleoside H-phosphonates. The stereochemical course of their conversion into P-methylphosphonates, phosphorothioates and [18O] chiral phosphates, Journal of Organic Chemistry, 56(12): 3861-3869 (1991). |
| Seidman, M.M. and Glazer, P.T. The potential for gene repair via triple helix formation, The Journal of Clinical Investigation, 112(4): 487-494 (2003). |
| Senn, J.J. et al., Non-CpG-Containing Antisense 2-Methoxyethyl Oligonucleotides Activate a Proinflammatory Response Independent of Toll-Like Receptor 9 or Myeloid DifferentiationFactor 88, The Journal of Pharmacology and Experimental Therapeutics, 314: 972-979 (2005). |
| Sergueeva et al., Synthesis of Dithymidine Boranophosphates via Stereospecific Boronation of H-phosphonate Diesters and Assignment of their Configuration, Tetrahedron Letters, 40: 2041-2044 (1999). |
| Seth, P., and Olson, R., Nucleic Acid Therapeutics—Making Sense of Antisesnse, 2016 Drug Design and Delivery Symposium, ACS Webinar, 1-36 (Jul. 26, 2016). |
| Seth, P.P. et al., An Exocyclic Methylene Group Acts as a Bioisostere of the 2′Oxygen Atom in LNA, J. Am. Chem. Soc, 132(42): 14942-14950 (2010). |
| Sharma, V.K. et al. Antisense oligonucleotides: modifications and clinical trials, Med. Chem. Commun., 5: 1454-71 (2014). |
| She, X. et al., Synergy between Anti-Endoglin (CD105) Monoclonal Antibodies and TGF-β in Suppression of Growth of Human Endothelial Cells, Int. J. Cancer, 108: 251-257 (2004). |
| Sheehan, J.P. and Phan, T.M. Phosphorothioate Oligonucleotides Inhibit the Intrinsic Tenase Complex by an Allosteric Mechanism, Biochemistry, 40: 4980-4989 (2001). |
| Sierzchala et al., Oxathiaphospholane Method of Stereocontrolled Synthesis of Diribonucleoside 3′, 5′-Phosphorotioates, Journal of Organic Chemistry 61(19): 6713-6716 (1996). |
| Silverman, R.H., A scientific journey through the 2-5A/RNase L system, Cytokine Growth Factor Reviews, 18(5-6):381-388 (2007). |
| Singhrao, S.K. et al., Increased Complement Biosynthesis by Microglia and Complement Activation on Neurons in Huntington's Disease, Experimental Neurology, 159: 362-376 (1999). |
| Skotte, N.H. et al., Allele-specific suppression of mutant huntingtin using antisense oligonucleotides: providing a therapeutic option for all Huntington disease patients, PLoS One, 9(9): e107434 1-18 (2014). |
| Small, L.D. et al.,Comparison of Some Properties of Thiolsulfonates and Thiolsulfinates, Journal of the American Chemical Society, 71(10): 3565-3566 (1949). |
| Smith, A. et al., The murine haemopexin receptor, Biochem. J., 276: 417-425 (1991). |
| Sobkowski, et al. Stereochemistry of internucleotide bond formation by the H?phosphonate method. 1. Synthesis and 31P NMR analysis of 16 diribonulceoside (3′-5′)-H-phosphonates and the corresponding phosphorothioates, Nucleosides Nucleotides Nucleic Acids, 24(10-12): 1469-84 (2005). |
| Sonveaux, E., Protecting Groups in Oligonucleotide Synthesis, Protocols for Oligonucleotide Conjugates, Methods in Molecular Biology, Edited by Agrawal, S., Humana Press, 26:1-71 (1994). |
| Spinelli, N. et al., Use of Allylic Protecting Groups for the Synthesis of Base-Sensitive Prooligonucleotides, European Journal of Organic Chemistry, 49-56 (2002). |
| Sproat, B.S., RNA Synthesis Using 2′-0-(Teri-Butyldimethylsilyl) Protection, Methods in Molecular Biology, 288: 17-31 (2005). |
| Stawinski et al., Nucleoside H-phosphonates. 14. Synthesis of nucleoside phosphoroselenoates and phosphorothioselenoates via stereospecific selenization of the corresponding H-phosphonate and H-phosphonothioate diesters with the aid of new selenium-transfer reagent, 3H-1,2-benzothiaseleno1-3-one, J. Org. Chem., 59(1): 130-136 (1994). |
| Stawinski et al., Stereospecific oxidation and oxidative coupling of H-phosphonate and H-phosphonothioate diesters, Tetrahedron Letters, 33(22):3185-3188 (1992). |
| Stawinski, J. and Stromberg, R. Di- and Oligonucleotide Synthesis Using H-Phosphonate Chemistry, Methods in Molecular Biology, 288: 81-100 (2005). |
| Stawinski, J. and Thelin, M., 3-H-2,1-benzoxathiol-3-one 1-oxide—A New Reagent for Stereospecific Oxidation of Nucleoside H-Phosphonothioate Diesters, Tetrahedron Letters, 33(22): 3189-3192 (1992). |
| Stawinski, J. and Thelin, M., 3H-1,2-benzothiaseleno1-3-one. A new selenizing reagent for nucleoside H-phosphonate and H-phosphonothioate diesters, Tetrahedron Letters, 33(47): 7255-7258 (1992). |
| Stec et al., Deoxyribonucleoside 3′-O-(2-Thio- and 2-Oxo-“spiro”-4,4 pentamethylene-1,3,2-oxathiaphospholane)s:? Monomers for Stereocontrolled Synthesis of Oligo(deoxyribonucleoside phosphorothioate)s and Chimeric PS/PO Oligonucleotides, J. Am. Chem. Soc., 120(29): 7156-7167 (1998). |
| Stec et al., Stereocontrolled Synthesis of Oligo (nucleoside phosphorothioate)s , Angew. Chem. Int. Ed. Engl., 33:709-722 (1994). |
| Stec et al., Stereospecific Synthesis of P-Chiral Analogs of Oligonucleotides, Methods in Molecular Biology, 20: 285-313 (1993). |
| Stec, Oligo(nucleoside Phosphorothioate)s: The Quest of P-Chirality, in Phosphorus, Sulfur, and Silicon, 177(6): 1775-1778 (2002). |
| Stec, W.J. and Zon, G., Stereochemical Studies of the Formation of Chiral Internucleotide Linkages by Phosphormadite COupling in the Synthesis of Oligodeocyribonucleotides, Tetrahedron Letters, 25(46): 5279-5282 (1984). |
| Stec, W.J. et al., Automated Solid-Phase Synthesis, Separation, and Stereochemistry of Phosphorothioate Analogues of Oligodeocyribonucleotides, J. Am. Chem. Soc., 106: 6077-6079 (1984). |
| Stec, W.J. et al., Diastereomers of Nucleoside 3′-O-(2-Thio-1,3,2-oxathia(selena)phospholanes): Building Blocks for Stereocontrolled Synthesis of Oligo(nucleoside phosphorothioate)s, Journal of the American Chemical Society, 117(49):12019-12029 (1995). |
| Stec, W.J. et al., Novel route to oligo(deoxyribonucleoside phosphorothioates). Stereocontrolled synthesis of P-chiral oligo(deoxyribonucleoside phosphorothioates), Nucleic Acids Research, 19(21):5883-5686 (1991). |
| Stec, W.J. et al., Stereodependent inhibition of plasminogen activator inhibitor type 1 by phosphorothioate oligonucleotides: proof of sequence specificity in cell culture and in vivo rat experiments, Antisense Nucleic Acid Drug Dev., 7(6):567-73 (1997). |
| Stein, C.A. and Cheng, Y.C., Antisense oligonucleotides as therapeutic agents—is the bullet really magical?, Science, 261(5124):1004-12 (1993). |
| Sureshbabu, V.V. et al., Synthesis of tetrazole analogues of amino acids using Fmoc chemistry: isolation of amino free tetrazoles and their incorporation into peptides, Tetrahedron Letters, 48(39): 7038-7041 (2007). |
| Suska, A. et al., Antisense oligonucleotides: Stereocontrolled synthesis of phosphorothioate oligonucleotides, Pure and Applied Chemistry, 65(4):707-714 (1993). |
| Swayze, E.E. and Bhat, B., The medicinal chemistry of oligonucleotides, Crooke, S.T. (ed) Antisense Drug Technology: Principles, Strategies, and Applications, CRC Press, Boca Raton, FL: 143-82 (2007). |
| Swayze, E.E. et al., Antisense oligonucleotides containing locked nucleic acid improve potency but cause significant hepatotoxicity in animals, Nucleic Acids Research, 35(20: 687-700 (2007). |
| Takahashi, D. et al., Novel diphenylmethyl-Derived Amide Protecting Group for Efficient Liquid-Phase Peptide Synthesis: AJIPHASE, Org. Lett, 14(17): 4514-4517 (2012). |
| Takeno, H. et al., Selection of an RNA Molecule that Specifically Inhibits the Protease Activity of Subtilisin, J. Biochem., 125: 1115-1119 (1999). |
| Tam, Journal of Hematotherapy & Stem Cell Research, 12: 467-471 (2003). |
| Tamura et al., Preparation of Stereoregulated Antisense Oligodeoxyribonucleoside Phoshorothioate and Interaction with its Complementary DNA and RNA, Nucleosides & Nucleotides,17(1-3): 269-282 (1998). |
| Tang, J. et al., Enzymatic Synthesis of Stereoregular (All Rp) Oligonucleotide Phosphorothioate and Its Properties, Nucleosides Nucleotides, 14(3-5):985-990 (1995). |
| Tawarada, R. et al., Mechanistic studies on oxidative condensation of a thymidine 3′-H-phosphonate derivative with 3′-O-acetylthymidine, Archive for Organic Chemistry, (3):264-273 (2009). |
| Thayer, J.R. et al., Separation of oligonucleotide phosphorothioate distereoisomers by pellicular anion-exchange chromatography, Journal of Chromatography A, 1218: 802-808 (2011). |
| Tomoskozi et al., Stereospecific conversion of H-phosphonates into phosphoramidates. The use of vicinal carbon-phosphorus couplings for configurational determination of phosphorus, Tetrahedron, 51(24): 6797-6804 (1995). |
| Tosquellas, G. et al., First synthesis of alternating SATE-phosphotriester/phosphodiester prooligonucleotides on solid support, Bioorganic and Medicinal Chemistry Letters, 8(20): 2913-2918 (1998). |
| Tosquellas, G. et al., Prooligonucleotides exhibit less serum-protein binding than phosphodiester and phosphorothioate oligonucleotides, Nucleosides, Nucleotides and Nucleic Acids, 19(5-6):995-1003 (2000). |
| Tosquellas, G. et al., The pro-oligonucleotide approach: solid phase synthesis and preliminary evaluation of model pro-dodecathymidylates, Nucleic Acids Research, 26(9):2069-2074 (1998). |
| Tosquellas, G. et al., The Prooligonucleotide Approach III: Synthesis and bioreversibility of a chimeric phosphorodithioate prooligonucleotide, Bioorganic and Medicinal Chemistry Letters, 6(4):457-462 (1996). |
| Tosquellas, G. et al., The Prooligonucleotide Approach IV : Synthesis of chimeric prooligonucleotides with 6 enzymolabile masking groups and unexpected desulfurization side reaction, Bioorganic and Medicinal Chemistry Letters, 7(3):263-268 (1997). |
| Tsai, C.H. et al., Enzymatic synthesis of DNA on glycerol nucleic acid templates without stable duplex formation between product and template, Proceedings of the National Academy of Science, 104(37):14598-14603 (2007). |
| Tuerk, C. and Gold, L., Systematic Evolution of Ligans by Exponential Enrichment: RNA Ligands to Bacteriophage T4 DNA Polymerase, Science, 249: 505-510 (1990). |
| Turner, D.H. et al, Improved Parameters for Prediction of RNA Structure, Cold Spring Harbor Symposia on Quantitative Biology, LII: 123-133 (1987). |
| Turner, D.H. et al., Free Energy Increments for Hydrogen Bonds in Nucleic Acid Base Pairs, J. Am. Chem. Soc., 109: 3783-3785 (1987). |
| U.S. Food and Drug Administration, Development of New Stereoisomeric Drugs, 8 pages (May 1, 1992). URL: http://www.fda.gov/Drugs/GuidanceCompfianceRegulatoryInformation/Guidances/ucm122883.htm [Retrieved Jun. 15, 2016]. |
| Umemoto, T et al., Oligoribonucleotide Synthesis by the use of 1-(2-cyanoethoxy)ethyl (CEE) as a 2′-hydroxy protecting group, Tetrahedron Letters 45: 9529-9531 (2004). |
| Uphoff, K.W. et al., In vitro selection of aptamers: the death of pure reason, Curr. Opin. Struct. Biol., 6: 281-288 (1996). |
| Usman, N et al., Automated Chemical Synthesis of Long Oligoribonucleotides Using 2′-O-Siylylated Ribonucleoside 3′-O-Phosphoramidites on a Controlled-Pore Glass Support, J. Am. Chem. Soc. 109(25): 7845-7854 (1987). |
| Uznanski, B. et al., Stereochemistry of base-catalyzed ring opening of 1,3,2-oxathiaphospholanes. Absolute configuration of 2-{N-[(RC)-1-(.alpha.-naphthyl)ethyl]amino}-2-thiono-1,3,2-oxathiaphospholanes and O,S-dimethyl N-[(Rc)-1-(.alpha.-naphthyl)ethyl]phosphoramidothioates, Journal of the American Chemical Society, 114(26):10197-10202 (1992). |
| Van Der Veken, P. et al., Irreversible inhibition of dipeptidyl peptidase 8 by dipeptide-derived diaryl phosphonates, Journal of Medicinal Chemistry, 50(23): 5568-5570 (2007). |
| Vasquez, K.M. et al., Chromosomal mutations induced by triplex-forming oligonucleotides in mammalian cells, Nucl. Acids Res. 27(4): 1176-1181 (1999). |
| Verma, S. and Eckstein, F., Modified Oligonucleotides: Synthesis and Strategy for Users, Annu. Rev. Biochem., 67: 99-134 (1998). |
| Vermeulen, A. et al., Double-Stranded Regions Are Essential Design Components of Potent Inhibitors of RISC Function, RNA, 13: 723-730 (2007). |
| Vives, E. et al., Lipophilic pro-oligonucleotides are rapidly and efficiently internalized in HeLa cells, Nucleic Acids Research, 27(20):4071-4076 (1999). |
| Vlassov, V.V. et al., Transport of oligonucleotides across natural and model membranes, Biochimica et Biophysica Acta, 1197: 95-108 (1994). |
| Vu, H. and Hirschbein, B.L., Internucleotide Phosphite Sulfurization With Tetraethylthiuram Disulfide. Phosphorothioate Oligonucleotide Synthesis via Phosphoramidite Chemistry, Tetrahedron Letters, 32(26):3005-3008 (1991). |
| Vuyisich, M. and Beal, P.A., Regulation of the RNA-dependent protein kinase by triple helix formation, Nuc, Acids Res., 28(12): 2369-74 (2000). |
| Wada et al., Stereocontrolled Synthesis of Phosphorothioate RNA by the Oxazaphospholidine Approach, Nucleic Acids Symp. Ser., 48: 57-58 (2004). |
| Wada, T. et al., Chemical synthesis and properties of stereoregulated phosphorothioate RNAs, Nucleic Acids Symposium Series, 51:119-120 (2007). |
| Wada, T. et al., Stereocontrolled synthesis of phosphorothioate DNA by an oxazaphospholidine approach, Nucleic Acids Research Supplement, 3:109-110 (2003). |
| Wada, Takeshi, Chapter I Development of nucleic acid medicines, 3.3 Chemical synthesis of phosphorous atom-modified nucleic acids, CMC Publication., Fronteir of Development of Nucleic Acid Medicine: 67-75 (2009). |
| Wagner, C.R. et al., Pronucleotides: toward the in vivo delivery of antiviral and anticancer nucleotides, Medicinal Research Reviews, 20(6):417-451 (2000). |
| Walker, J.R. et al., Structure of the Ku heterodimer bound to DNA and its implications for double-strand break repair, Nature, 412: 607-614 (2001). |
| Wan et al., Synthesis of Second Generation Antisense Oligonucleotides Containing Chiral Phosphorothioate Linkages and Evaluation of their Biophysical Properties and Biological Activity, 10th Annual Meeting of the Oligonucleotide Therapeutics Society, abstract received by Applicant Oct. 7, 2014, poster setup prior to presentation (first known to Applicant late Oct. 12, 2014, PST), poster presentation Oct. 13, 2014. |
| Wan, W.B. and Seth, P.P., The Medicinal Chemistry of Therapeutic Oligonucleotides, J. Med. Chem., 59: 9645-9667 (2016). |
| Wan, W.B. et al., Synthesis, biophysical properties and biological activity of second generation antisense oligonucleoties containing chiral phosphorothioate linkages, Nucleic Acid Research, 42: 13456-13468 (2014). |
| Wang H, et al., Therapeutic gene silencing delivered by a chemically modified siRNA against mutant SOD 1 slows ALS progression, The Journal of Biological Chemistry, 283(23):15845-15852 (2008). |
| Wang, J.-C. et al., A stereoselective synthesis of dinucleotide phosphorothioate triesters through a chiral indol-oxazaphosphorine intermediate, Tetrahedron Letters, 38(5):705-708 (1997). |
| Warby, S.C. et al., CAG expansion in the Huntington disease gene is associated with a specific and targetable predisposing haplogroup, Am. J. Hum. Genet., 84(3): 351-366 (2009). |
| WaVe Life Sciences Poster, Therapeutic Implications of Controlling P-Chirality in Phosphorothioate Oligonucleotides, TIDES, San Diego (May 3-6, 2014). |
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| WAVE Life Sciences Press Release, WAVE Life Sciences Raises $66 Million in Series B Financing, 3 pages (Aug. 18, 2015). |
| WAVE Life Sciences Press Release, WAVE Life Sciences Receives Orphan Drug Designation from FDA for its Lead Candidate Designed to Treat Huntington's Disease, 5 pages (Jun. 21, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences Reports First Quarter 2016 Financial Results and Provides Business Update, 9 pages (May 16, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences Reports Fourth Quarter and Full Year 2015 Financial Results and Provides Business Update, 10 pages (Mar. 30, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences Reports Second Quarter 2016 Financial Results and Provides Business Update, 10 pages (Aug. 15, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences to Advance Next-Generation Nucleic Acid Therapies to Address Unmet Need in Duchenne Muscular Dystrophy, 6 pages (May 9, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences to Present at the Deutsche Bank 41st Annual Health Care Conference, 2 pages (Apr. 29, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences to Present at the Jefferies 2016 Healthcare Conference, 2 pages (Jun. 1, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences to Present at the JMP Securities Life Sciences Conference, 2 pages (Jun. 15, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences to Present at the LEERINK Partner 5th Annual Global Healthcare Conference, 2 pages (Feb. 3, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences to Present at the Leerink Partners Rare Disease & Immuno-Oncology Roundtable, 2 pages (Sep. 14, 2016). |
| WAVE Life Sciences Press Release, WAVE Life Sciences to Present at the SunTrust Robinson Humphrey 2016 Orphan Drug Day Conference, 2 pages (Feb. 16, 2016). |
| Weidner, J.P. et al., Alkyl and Aryl Thiolsulfonates, Journal of Medicinal Chemistry, 7(5): 671-673 (1964). |
| Weiser, T.G., et al., An estimation of the global volume of surgery: a modeling strategy based on available data, Lancet, 372(9633): 139-144 (2008). |
| Welz et al., 5-(Benzylmercapto)-1H-tetrazole as activator for 2′-O-TBDMS phosphoramidite building blocks in RNA synthesis, Tetrahedron Letters, 43: 795-797 (2002). |
| Wengel, J., Synthesis of 3′-C- and 4′-C-Branched Oligodeoxynucleotides and the Development of Locked Nucleic Acid (LNA), Ace. Chem. Res., 32: 301-310 (1999). |
| Widdison, W. C. et al., Semisynthetic Maytansine analogues for the targeted treatment of cancer, Journal of Medicinal Chemistry, 49(14): 4392-4408 (2006). |
| Wild, E. et al., Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients, The Journal of Clinical Investigation, 125(5): 1979-1986 (2015). |
| Wilk, A. and Stec, W.J., Analysis of oligo(deoxynucleoside phosphorothioate)s and their diastereomeric composition, Nucleic Acids Research, 23(3):530-534 (1995). |
| Wilk, A. et al., Deoxyribonucleoside Cyclic N-Acylphosphoramidites as a New Class of Monomers for the Stereocontrolled Synthesis of Oligothymidylyl- and Oligodeoxycytidylyl-Phosphorothioates, Journal of the American Chemical Society, 122(10): 2149-2156 (2000). |
| Wong, Chui Ming, Synthesis of anisomycin. Part I. The stereospecific synthesis of N-benzoyl-2-(p-methoxybenzyl)-3-hydroxy-4-carboxamido pyrrolidine and the absolute configuration of anisomycin, Canadian journal of Chemistry 46: 1101-1104 (1968). |
| Wright, P. et al., Large scale synthesis of oligonucleotides via phosphoramidite nucleosides and a high-loaded polystyrene support, Tetrahedron Letters, 34(21):3373-3736 (1993). |
| Written Opinion for PCT/IB2009/007923, 8 pages (dated Sep. 6, 2010). |
| Written Opinion for PCT/IB2015/000395, 10 pages (dated Oct. 30, 2015). |
| Written Opinion for PCT/JP11/55018, 3 pages (dated Mar. 29, 2011). |
| Written Opinion for PCT/JP11/71559, 6 pages (dated Dec. 20, 2011). |
| Written Opinion for PCT/JP15/50716 and English Translation, 11 pages (dated Apr. 21, 2015). |
| Written Opinion for PCT/JP2010/065900, 5 pages (dated Sep. 15, 2010). |
| Written Opinion for PCT/JP2013/004303, 6 pages (dated Aug. 13, 2013). |
| Written Opinion for PCT/JP2015/050714, and English Translation, 11 pages (dated Apr. 21, 2015). |
| Written Opinion for PCT/JP2015/050718 and English Translation, 6 pages ( dated Apr. 21, 2015). |
| Written Opinion for PCT/US2010/041068, 11 pages, (dated Sep. 1, 2010). |
| Written Opinion for PCT/US2011/064287, 14 pages (dated Apr. 12, 2012). |
| Written Opinion for PCT/US2012/046805, 9 pages (dated Sep. 19, 2012). |
| Written Opinion for PCT/US2013/050407, 12 pages (dated Jan. 9, 2014). |
| Written Opinion for PCT/US2016/043542, 14 pages (dated Dec. 28, 2016). |
| Written Opinion for PCT/US2016/043598, 10 pages (dated Nov. 28, 2016). |
| Wu, X. et al., Synthesis of 5′-C- and 2′-O-(Bromoalkyfl-Substituted Ribonucleoside Phosphoramidites for the Post-synthetic Functionalization of Oligonucleotides on Solid Support, Helvetica Chimica Acta, 83: 1127-1144 (2000). |
| Xiang, Y. et al., Effects of RNase L mutations associated with prostate cancer on apoptosis induced by 2′,5′-oligoadenylates, Cancer Research, 63(20):6795-6801 (2003). |
| Xiong, H.Y. et al., The human splicing code reveals new insights into the genetic determinants of disease, Science, 347(6218): 144 1254806-1-1254806-8 (2015). |
| Xu, D. and Esko, J.D., Demystifying Heparan Sulfate-Protein Interactions, Annu. Rev. Biochem., 83: 129-157 (2014). |
| Xu, L. et al., Cyclic ADP-ribose analogues containing the methylenebisphosphonate linkage: effect of pyrophosphate modifications on Ca2+ release activity, J. Med. Chem., 48(12): 4177-4181 (2005). |
| Yamada, O. et al., Diastereoselective Synthesis of 3,4-Dimethoxy-7-morphinanone: A Potential Route to Morphine, Organic Letters, 2(18): 2785-2788 (2000). |
| Yamakage, S-i. et al., 1-(2-Chloroethoxy)Ethyl Group for the Protection of 2′-Hydroxyl Group in the Synthesis of Oligoribonucleotides, Tetrahedron Letters, 30(46): 6361-6364 (1989). |
| Yamamoto, S. et al., Unique Palindromic Sequences in Synthetic Oligonucleotides are Required to Induce INF and Augment INF-Mediated Natural Killer Activity, J. Immunol., 148(12): 4072-4076 (1992). |
| Yamato, K. et al., Enhanced specificity of HPV16 E6E7 siRNA by RNA-DNA chimera modification, Cancer Gene Therapy, 18: 587-597 (2011). |
| Yanai, H. et al., Suppression of immune responses by nonimmunogenic oligodeoxynucleotides with high affinity for high-mobility group box proteins (HMGBs), PNAS Early Edition, 1-6 (2011). |
| Yu, D. et al., Accessible 5′-end of CpGcontaining phosphorothioate oligodeoxynucleotides is essential for immunostimulatory activity, Bioorganic & Medicinal Chemistry Letters, 10: 2585-2588 (2000). |
| Yu, D. et al., Single-Stranded RNAs Use RNAi to Potently and Allele-Selectively Inhibit Mutant Huntingtin Expression, Cell, 150: 895-908 (2012). |
| Yu, D. et al., Stereo-Enriched Phosphorothioate Oligodeoxynucleotides: Synthesis, Biophysical and Biological Properties, Bioorganic & Medicinal Chemitry, 8: 275-284 (2000). |
| Yu, R.Z. et al., Cross-species comparison of in vivo PK/PD relationships for second-generation antisense oligonucleotides targeting apolipoprotein B-100, Biochem. Pharmacol., 77: 910-919 (2009). |
| Yu, S. et al., A One-Pot Formal [4 + 2] Cycloaddition Approach to Substituted Piperidines, Indolizidines, and Quinolizidines. Total Synthesis of Indolizidine (-)-209I, Journal of Organic Chemicals, 70:7364-7370 (2005). |
| Zhang, J. et al., Optimization of Exon Skipping Therapies for Duchenne Muscular Dystrophy, Wave Life Sciences, PPMD: Parent Project Muscular Dystrophy Meeting, Orlando, FL (Jul. 25, 2016). |
| Zhang, L. et al., A simple glycol nucleic acid, Journal of the American Chemical Society,127(12):4174-4175 (2005). |
| Zhang, R.S. et al., Synthesis of two mirror image 4-helix junctions derived from glycerol nucleic acid, Journal of the American Chemical Society, 130(18):5846-5847 (2008). |
| Zhao, J. et al., Genome-wide Identification of Polycomb-Associated RNAs by RIP-seq, Molecular Cell, 40: 939-953 (2010). |
| Zlatev et al., Phosphoramidate dinucleosides as hepatitis C virus polymerase inhibitors, J Med Chem., 51(18): 5745-57 (2008). |
| Zon, Automated synthesis of phosphorus-sulfur analogs of nucleic acids-25 years on: potential therapeutic agents and proven utility in biotechnology, New J. Chem., 34(5): 795-804 (2010). |
| Zon, G and Stec, W.J., Phosphorothioate oligonucleotides, Oligonucleotides and Analogues: A Practical Approach, 87-108 (1991). |
| Aaronson, J.G. et al., Rapid HATU-Mediated Solution Phase siRNA Conjugation, Bioconjugate. Chem., 22: 1723-1728 (2011). |
| Aartsma-Rus, A. et al., Antisense-Induced Multiexon Skipping for Duchenne Muscular Dystrophy Makes More Sense, Am. J. Hum. Genet., 74:83-92 (2004). |
| Aartsma-Rus, A. et al., Therapeutic antisense-induced exon skipping in cultured muscle cells from six different DMD patients, Human Molecular Genetics, 12(8):907-914 (2003). |
| ALS Association, The ALS Association and the Packard Center Partner to Develop Animal Model Systems for Most Common Cause of Familial ALS, 4 pages (Mar. 1, 2012). URL: http://www.alsa.org/news/archive/new-animal-model-systems.html [Retrieved Dec. 14, 2017]. |
| Anthony, K. et al., Exon Skipping Quantification by Quantitative Reverse-Transcription Polymerase Chain Reaction in Duchenne Muscular Dystrophy Patients Treated with the Antisense Oligomer Eteplirsen, Human Gene Therapy Methods, 23: 336-345 (2012). |
| Birts, C.N. et a., Transcription of Click-Linked DNA un Human Cells, Angew. Chem. Int. Ed., 53:2362-2365 (2014). |
| Blade, H. et al., Modular Synthesis of Constrained Ethyl (cEt) Purine and Pyrimidine Nucleosides, J. Org. Chem., 80: 5337-5343 (2015). |
| Burgers, P. M. J. et al., Stereochemistry of Hydrolysis by Snake Venom Phosphodiesterase, J. Biol. Chem., 254(16): 7476-7478 (1979). |
| Burgers, P.M.J. and Eckstein, F., A Study of the Mechanism of DNA Polymerase I from Escherichia coli with Diastereomeric Phosphorothioate Analogs of Deoxyadenosine Triphosphate, J. Biol. Chem., 254(15): 6889-6893 (1979). |
| Burgers, P.M.J. and Eckstein, F., Diastereomers of 5′-O-adenosyl 3′-O-uridyl phosphorothioate: chemical synthesis and enzymatic properties, Biochemistry, 18: 592-596 (1979). |
| CAS Registry File RN 121563-98-2; Chemical Abstracts Accession No. 1989:450484, 2 pages (2018). |
| CAS Registry No. 1223431-57-9, Chemical Abstracts Accession No. 2000:10625, 2 pages (2018). |
| Chak, L-L, and Okamura, K., Argonaute-dependent small RNAs derived from single- stranded, non-structured precursors, Frontiers in Genetics, 5(172): 1-15 (2014). |
| Chan, J.H.P. et al., Antisense Oligonucleotides: From Design to Therapeutic Application, Clinical and Experimental Pharmacology and Physiology, 33: 544-540 (2006). |
| Chappell, C. et al., Involvement of human polynucleotide kinase in double-strand break repair by non-homologous end joining, The EMBO Journal, 21(11): 2827-2832 (2002). |
| Cheloufi, S. et al., A Dicer-independent miRNA biogenesis pathway that requires Ago catalysis, Nature, 465(7298): 584-589 (2010). |
| Chen, B. and Bartlett, M., A One-Step Solid Phase Extraction Method for Bioanalysis of a Phosphorothioate Oligonucleotide and Its 3′ n-1 Metabolite from Rat Plasma by uHPLC- MS/MS, The AAPS Journal, 14(4): 772-780 (2012). |
| Chmielewski, M.K. And Markiewicz, W.T., Novel Method of Synthesis of 5″-Phosphate 2′-O-ribosyl-ribonucleosides and Their 3′-Phosphoramidites, Molecules, 18:14780-14796 (2013). |
| Cieslak, J. et al., 31P NMR Study of the Desulfurization of Oligonucleoside Phosphorothioates Effected by “Aged” Trichloroacetic Acid Solutions, J. Org. Chem., 70: 3303-3306 (2005). |
| Crooke, S.T., Antisense Strategies, Current Molecular Medicine, 4: 465-487 (2004). |
| Crooke, S.T., Progress in Antisense Technology , Annu. Rev. Med., 55: 61-95 (2004). |
| Dejesus-Hernandez, M. et al., Expanded GGGGCC hexanucleotide repeat in non-coding region of C9ORF72 causes chromosome 9p-linked frontotemporal dementia and amyotrophic lateral sclerosis, Neuron, 72(2): 245-256 (2011). |
| Dias, N. and Stein, C.A., Antisense Oligonucleotides: Basic Concepts and Mechanisms, Molecular Cancer Therapeutics, 1: 347-355 (2002). |
| Dikfidan, A. et al., RNA Specificity and Regulation of Catalysis in the Eukaryotic Polynucleotide Kinase Clp1, Molecular Cell, 54: 975-986 (2014). |
| Documents submitted to and/or received from the United States Securities and Exchange Commission; downloaded from EDGAR (Nov. 9, 2016 to May 10, 2017). |
| Donnelly, C.J. et al., M1415. Development of C9orf72 ALS Biomarkers and Therapeutics, Annals of Neurology, 72 (suppl 16): S67-S68 (2012). |
| Donnelly, C.J. et al., RNA Toxicity from the ALS/FTD C90RF72 Expansion Is Mitigated by antisense Intervention, Neuron, 80:415-428 (2013). |
| Efimov, V.A. et al., Rapid synthesis of long-chain deoxyribooligonucleotides by the N-methylimidazolide phosphotriester method, Nucleic Acids Research, 11(23): 8369-8387 (1983). |
| Egholm, M. et al., PNA hybridizes to complementary oligonucleotides obeying the Watson-Crick hydrogen-bonding rules, Nature, 365, 566-568 (1993). |
| El-Sagheer, A.H. and Brown, T., Efficient RNA synthesis by in vitro transcription of a triazole-modified DNA template, Chem. Commun., 47(44):12057-12058 (2011). |
| El-Sagheer, A.H. and Brown, T., New strategy for the synthesis of chemically modified RNA constructs exemplified by hairpin and hammerhead ribozymes, PNAS, 107(35):15329-15334 (2010). |
| El-Sagheer, A.H. et al., Biocompatible artificial DNA linker that is read through by DNA polymerases and is functional in Escherichia coli, PNAS, 108(28):11338-11343 (2011). |
| Erler, W. et al., Patient Advisory Board Meeting, WAVE Life Sciences, London, 46 pages (Mar. 2, 2017). |
| Erler, W., Stereopure Exon 51-Skipping Oligonucleotide as a Potential Disease-Modifying Therapy for Duchenne Muscular Dystrophy, WAVE Life Sciences, 10 pages (2017). |
| Ewles, M. et al, Quantification of oligonucleotides by LC-MS/MS: the challenges of quantifying a phosphorothioate oligonucleotide and multiple metabolites, Bioanalysis, 6(4), 447-464 (2014). |
| Exiqon, Locked Nucleic Acid (LNA), Custom Oligonucleotides for RNA and DNA Research, 16 pages (Aug. 2009). |
| Freschauf, G., Identification of Small Molecule Inhibitors of the Human DNA Repair Enzyme Polynucleotide Kinase/Phosphatase, Master of Science in Experimental Oncology Thesis, University of Alberta, 155 pages (2011). |
| Gallier, F. et al., 5′,6′-Nucleoside Phosphonate Analogues Architecture: Synthesis and Comparative Evaluation towards Metabolic Enzymes, Chem Med Chem, 6: 1094-1106 (2011). |
| Giacometti, R.D. et al., Design, synthesis, and duplex-stabilizing properties of conformationally constrained tricyclic analogues of LNA, Org. Biomol. Chem., 14: 2034-2040 (2016). |
| Gryaznov, S. and, Chen, J.-K., Oligodeoxyribonucleotide N3′4P5′ Phosphoramidates: Synthesis and Hybridization Properties, J. Am. Chem. Soc., 116: 3143-3144 (1994). |
| Hagedorn, P.H. et al., Locked nucleic acid: modality, diversity, and drug discovery, Drug Discovery, 1-14 (Oct. 2017). |
| Haringsma, H.J. et al., mRNA knockdown by single strand RNA is improved by chemical modifications, Nucleic Acids Research, 40(9): 4125-4136 (2012). |
| Heemskerk, H.A. et al., In vivo comparison of 2′-O-methyl phosphorothioate and morpholino antisense oligonucleotides for Duchenne muscular dystrophy exon skipping, The Journal of Gene Medicine, 11:257-266 (2009). |
| Hendrix, C. et al., 1′,5′-Anhydrohexitol Oligonucleotides: Synthesis, Base Pairing and Recognition by Regular Oligodeoxyribonucleotides and Oligoribonucleotides, Chem. Eur. J., 3(1): 110-120 (1997). |
| Hirama, T. et al., PCR-Based Rapid Identification System Using Bridged Nucleic Acids for Detection of Clarithromycin-Resistant Mycobacterium avium-M. intracellulare Complex Isolates, Journal of Clinical Microbiology, 54(3): 699-704 (2016). |
| Hirose, M. et al., MDM4 expression as an indicator of TP53 reactivation by combined targeting of MDM2 and MDM4 in cancer cells without TP53 mutation, Oncoscience, 1(12): (2014). |
| Hu, J. et al., Allele-Selective Inhibition of Huntingtin Expression by Switching to an miRNA-like RNAi Mechanism, Chemistry & Biology 17: 1183-1188 (2010). |
| Hu, J. et al., Exploring the Effect of Sequence Length and Composition on Allele-Selective Inhibition of Human Huntingtin Expression by Single-Stranded Silencing RNAs, Nucleic Acid Therapeutics, 24(3): 199-209 (2014). |
| Hu, J. et al., Recognition of c9orf72 Mutant RNA by Single-Stranded Silencing RNAs, Nucleic Acid Therapeutics, 8 (2016). Supplementary Figure, 1 page. |
| Hyrup., B. and Nielsen, P.E., Peptide Nucleic Acids (PNA): Synthesis, Properties and Potential Applications, Bioorg. Med. Chem., 4(1): 5-23 (1996). |
| International Search Report for PCT/US2016/056123, 5 pages (dated Mar. 17, 2017). |
| International Search Report for PCT/US2017/022135, 3 pages (dated Jun. 6, 2017). |
| International Search Report for PCT/US2017/030753, 6 pages (dated Sep. 26, 2017). |
| International Search Report for PCT/US2017/030777, 5 pages (dated Oct. 2, 2017). |
| International Search Report for PCT/US2017/035837, 4 pages (dated Aug. 24, 2017). |
| International Search Report for PCT/US2017/043431, ISA/US, 5 pages (dated Dec. 21, 2017). |
| International Search Report for PCT/US2017/045218, 3 pages (dated Sep. 27, 2017). |
| International Search Report for PCT/US2017/055601, ISR/US, 6 pages (dated Feb. 15, 2018). |
| International Search Report for PCT/US2017/062996, 4 pages (dated Mar. 9, 2018). |
| Ionis Pharmaceuticals, Inc., Ionis Pharmaceuticals Licenses IONIS-HTT Rx to Partner Following Successful Phase 1/2a Study in Patients with Huntington's Disease, Press Release, 2 pages (Dec. 11, 2017). |
| Isis Pharmaceuticals, Inc. 2014 Annual Report, Improving Patients' Lives by Treating Disease Through Targeting RNA, 192 pages (2014). |
| Isis Pharmaceuticals, Inc. v. Santaris Pharma a/S Corp., Order Denying Defendants' Motion for Summary Judgment Without Prejudice, Case No. 11cv02214 BTM (KSC), United States District Court, S.D. California, 5 pages (Sep. 19, 2012). |
| Iwamoto, N. et al., Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides, Nature Biotechnology, Life Sciences Reporting Summary, 6 pages (2017). |
| Iwamoto, N. et al., Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides, Nature Biotechnology, pp. 1-9 (2017). |
| Iwamoto, N. et al., Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides, Nature Biotechnology, Supplementary Methods, Supplementary Tables 1-4, and Supplementary Note, 23 pages (2017). |
| Iwamoto, N. et al., Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides, Nature Biotechnology, Supplementary Text and Figures 1-9, 13 pages (2017). |
| Iwamoto, N. et al., Control of phosphorothioate stereochemistry substantially increases the efficacy of antisense oligonucleotides, Nature Biotechnology, with Supplemental Data, 19 pages (2017). |
| Jepsen, J.S. et al., LNA-Antisense Rivals Sirna for Gene Silencing, Current Opinion in Drug Discovery and Development, 7(2): 188-194 (2004). |
| Jepsen, J.S. et al., Locked Nucleic Acid: A Potent Nucleic Acid Analog in Therapeutics and Biotechnology, Oligonucleotides,14: 130-146 (2004). |
| Jones, R.J. et al., Synthesis and binding properties of pyrimidine oligodeoxynucleoside analogs containing neutral phosphodiester replacements: The Formacetal and 3′-Thioformacetal Internucleoside Linkages, J. Org. Chem., 58: 2983-2991 (1993). |
| Kashida, H. et al., Acyclic artificial nucleic acids with phosphodiester bonds exhibit unique functions, Polymer Journal, 1-6 (2016). |
| Kay, C. et al., Personalized gene silencing therapeutics for Huntington disease, Clinical Genetics, 1-8 (2014). |
| Kim, S-K. et al., Bridged Nucleic Acids (BNAs) as Molecular Tools, J Biochem Mol Biol Res., 1(3): 67-71 (2015). |
| Koch, T., A New Dimension in LNA Therapeutics, Roche Innovation Center, Copenhagen, Denmark, Presentation, 39 pages (May 3, 2017). |
| Koizumi, M. et al., Triplex formation with 2′-O,4′-C-ethylene-bridged nucleic acids (ENA) having C3′-endo conformation at physiological pH, Nuc. Acids Res., 31(12): 3267-3273 (2003). |
| Koseoglu, M. et al., Effects of hemolysis interference on routine biochemistry parameters. Biochemia Medica., 21(1): 79-85 (2011). Retrieved May 18, 2017, URL: <http://www.biochemia-medica.com/2011/21/79>. |
| Koshkin, A.A. et al., LNA (Locked Nucleic Acids): Synthesis of the Adenine, Cytosine, Guanine, 5-Methylcytosine, Thymine and Uracil Bicyclonucleoside Monomers, Oligomerisation, and Unprecedented Nucleic Acid Recognition, Tetrahedron 54: 3607-3630 (1998). |
| Kretschmer-Kazemi Far, R. and Sczakiel, G., The activity of siRNA in mammalian cells is related to structural target accessibility: a comparison with antisense oligonucleotides, Nucleic Acids Research, 31(15):4417-4424 (2003). |
| Krieg, A.M., Therapeutic potential of Toll-like receptor 9 activation, Nature Reviews, 471-484 (2006). |
| Krishna, H. et al., Alkynyl Phosphonate DNA: A Versatile “Click”able Backbone for DNA-Based Biological Applications, J. Am. Chem. Soc., 134: 11618?11631 (2012). |
| Krotz, A.H. et al., Phosphorothioate Oligonucleotides with Low Phosphate Diester Content: Greater than 99.9% Sulfurization Efficiency with “Aged” Solutions of Phenylacetyl Disulfide (PADS), Organic Process Research & Development, 8: 852-858 (2004). |
| Kumar, R. et al., The First Analogues of LNA (Locked Nucleic Acids): Phosphorothioate-LNA and 2′-THIO-LNA, Bioo. Med. Chem. Let., 8: 2219-2222 (1998). |
| Lahiri, N., Shooting the messenger with single-stranded RNA gene silencing, edited by Wild, E., HDBuzz, 7 pages (Sep. 24, 2012). Retrieved Oct. 7, 2015. URL: http://en.hdbuzz.net/099. |
| Lauritsen, A. et al., Methylphosphonate LNA: A Locked Nucleic Acid with a Methylphosphonate Linkage, Bioo. Med. Chem. Lett., 13: 253-256 (2003). |
| Lauritsen, A. et al., Oligodeoxynucleotides containing amide-linked LNA-type dinucleotides: synthesis and high-affinity nucleic acid hybridization, Chem. Comm., 5: 530-531 (2002). |
| Lee, K-W et al., CG sequence- and phosphorothioate backbone modification-dependent activation of the NF-κB-responsive gene expression by CpG-oligodeoxynucleotides in human RPMI 8226 B cells, Molecular Immonulogy, 41: 955-964 (2004). |
| Lee, K.-W. et al., CG sequence- and phosphorothioate backbone modification-dependent activation of the NF-κB-responsive gene expression by CpG-oligodeoxynucleotides in human RPMI 8226 B cells, Molecular Immunology, 41: 955-964 (2004). |
| Leviten, M., Wave's Purity Progress, Biocentury, 1-6 (Sep. 28, 2017). |
| Li, M. et al., Synthesis and cellular activity of stereochemically-pure 2′-O-(2-methoxyethyl)-phosphorothioate oligonucleotides, Chem. Commun., 53: 541-544 (2017). |
| Liu, J. et al., Modulation of Splicing by Single-Stranded Silencing RNAs, Nucleic Acid Therapeutics, 25(3): 113-120 (2015). |
| Liu, S. et al., Evaluation of protective effect of multi-epitope DNA vaccine encoding six antigen segments of Toxoplasma gondii in mice Parasitol Res, 105:267-274 (2009). |
| Lopez, C. et al., Inhibition of AAC(6′)-Ib-Mediated Resistance to Amikacin in Acinetobacter baumannii by an Antisense Peptide-Conjugated 2′,4′- Bridged Nucleic Acid-NC-DNA Hybrid Oligomer, Antimicrobial Agents and Chemotherapy, 59(9): 5798-5803 (2015). |
| Madsen, A., Antisense Against C90RF72, MDA/ALS News Magazine, 2 pages (Jul. 1, 2012). URL: http://alsn.mda.org/article/antisense-against-c90rf72 [Retrieved Dec. 14, 2017]. |
| Martinez, J. et al., Single-Stranded Antisense siRNAs Guide Target RNA Cleavage in RNAi, Cell, 110: 563-574 (2002). |
| Martinez, J.M.L. et al, NMR Characterization of Hydrate and Aldehyde Forms of Imidazole-2-carboxaldehyde and Derivatives, Journal of Organic Chemistry, 75: 3208-3213 (2010). |
| Martinez-Montero, S. et al., Locked 2′-Deoxy-2′,4′-Difluororibo Modified Nucleic Acids: Thermal Stability, Structural Studies, and siRNA Activity, ACS Chem. Biol., 10: 2016-2023 (2015). |
| Matranga, C. et al., Passenger-Strand Cleavage Facilitates Assembly of siRNA into Ago2-Containing RNAi Enzyme Complexes, Cell, 123: 607-620 (2005). Supplemental Data, 6 pages. |
| Matsui, M. et al., Argonaute 2-dependent Regulation of Gene Expression by Single-stranded miRNA Mimics, Molecular Therapy, 10 pages (2016). |
| Matsui, M. et al., Transcriptional Silencing by Single-Stranded RNAs Targeting a Noncoding RNA That Overlaps a Gene Promoter, ACS Chem. Biol., 8: 122-126 (2013). |
| Meena, et al., Discovery and Early Clinical Development of the First Allele-Specific Stereopure ASO Drug Candidate with Disease-Modifying Potential for the Treatment of Huntington's Disease, Wave Life Sciences, Poster, 1 page (2016). |
| Mesmaeker, A.D. et al. Amides as a New Type of Backbone Modification in Oligonucleotides, Angew. Chem., Int. Ed. Engl., 33: 226-229 (1994). |
| Midturi, J. et al., Spectrum of Pulmonary Toxicity Associated with the Use of Interferon Therapy for Hepatitis C: Case Report and Review of the Literature, Clinical Infectious Diseases, 39(11): 1724-1729 (2004). |
| Morita , K. et al., 2′-O,4′-C-Ethylene-bridged nucleic acids (ENA) with nuclease-resistance and high affnity for RNA, Nucl. Acids Res., Supp. 1: 241-242 (2001). |
| Morita , K. et al., 20-O,40-C-Ethylene-Bridged Nucleic Acids (ENA): Highly Nuclease-Resistant and Thermodynamically Stable Oligonucleotides for Antisense Drug, Bioo. Med. Chem. Lett., 12: 73-76 (2002). |
| Morita, K. et al., Synthesis and properties of 2′-O,4′-C-Ethylene-bridged nucleic acids (ENA) as effective antisense oligonucleotides, Bioorganic & Medicinal Chemistry, 11(10): 2211-2226 (2003). |
| Nencka, R. et al., Novel Conformationally Locked Nucleosides and Nucleotides, Collection Symposoim Series, 14: 119-122 (2014). |
| Nielsen, P.E. and Haaima, G., Peptide nucleic acid (PNA). A DNA mimic with a pseudopeptide backbone, Chem. Soc. Rev., 73-78 (1997). |
| Nielsen, P.E. et al., Sequence-Selective Recognition of DNA by Strand Displacement with a Thymine-Substituted Polyamide, Science, 254(5037): 1497-1500 (1991). |
| Nielsen, P.E. et al., Synthesis of 29-O,39-C-linked bicyclic nucleosides and bicyclic Oligonucleotides, J. Chem. Soc. Perkins Trans., 1: 3423-3433 (1997). |
| Nishina, K. et al., DNA/RNA heteroduplex oligonucleotide for highly efficient gene silencing, Nature Communications, 6:7969, pp. 1-13 (2015). |
| Obika et al. Stability and structural features of the duplexes containing nucleoside analogues with a fixed N-type conformation, 2′-O,4′-C-methyleneribonucleosides, Tetrahedron Lett. 39: 5401-5404 (1998). |
| Obika, S. et al., Synthesis of 2′-O,4′-C-Methyleneuridine and -cytidine. Novel Bicyclic Nucleosides Having a Fixed C a ,-endo Sugar Puckering, Tetrahedron Lett., 38(50): 8735-8 (1997). |
| Onizuka, K. et al., Short Interfering RNA Guide Strand Modifiers from Computational Screening, J. Am. Chem. Soc., 135: 17069-17077 (2013). |
| Osawa, T. et al., Synthesis and Properties of the 5-Methyluridine Derivative of 3,4-Dihydro-2H-pyran-Bridged Nucleic Acid (DpNA), J. Org. Chem., 80: 10474-10481 (2015). |
| Ostergaard, M.E. et al., Efficient Synthesis and Biological Evaluation of 5?-GaINAc Conjugated Antisense Oligonucleotides, Bioconjugate. Chem., 26: 1452-1455 (2015). |
| Pallan, P.S. et al., Structure and nuclease resistance of 20,40-constrained 20-O-methoxyethyl (cMOE) and 20-O-ethyl (cEt) modified DNAs, Chem. Comm., 48: 8195-8197 (2012). |
| Panzara, M. et al., Duchenne Muscular Dystrophy Advisory Board Meeting, WAVE Life Sciences, 70 pages (Mar. 3, 2017). |
| Parmer, R. et al., 5′-(E)-Vinylphosphonate: A Stable Phosphate Mimic Can Improve the RNAi Activity of siRNA-GaINAc Conjugates, Chem. Bio. Chem., 17: 1-6 (2016). |
| Pedersen, L. et al, A Kinetic Model Explains Why Shorter and Less Affine Enzyme-recruiting Oligonucleotides Can Be More Potent, Mol Ther Nucleic Acids, 3: e149 1-8 (2014). |
| Pendergraff, H.M. et al., Single-Stranded Silencing RNAs: Hit Rate and Chemical Modification, Nucleic Acid Therapeutics, 1-7 (2016). |
| Petersen, M. and Wengel, J., LNA: a versatile tool for therapeutics and genomics, Trends in Biotechnology, 21(2): 74-81 (2003). |
| Pontarollo, R.A. et al., Monocytes are required for optimum in vitro stimulation of bovine peripheral blood mononuclear cells by non-methylated CpG motifs, Veterinary Immunology and Immunopathology, 84(1-2): 43-59 (2002). |
| Prakash, T.P. et al., Identification of metabolically stable 5-phosphate analogs that support single-stranded siRNA activity, Nucleic Acids Research, 43(6): 2993-3011 (2015). Supplementary Data, 80 pages. |
| Prakash, T.P. et al., Lipid Nanoparticles Improve Activity of Single-Stranded siRNA and Gapmer Antisense Oligonucleotides in Animals, ACS Chem. Biol., 5 pages (2013), DOI: 10.1021/cb4001316. |
| Prakash, T.P. et al., Synergistic effect of phosphorothioate, 50-vinylphosphonate and GaINAc modifications for enhancing activity of synthetic siRNA, Bioorg. Med. Chem. Lett., 26: 2817-2820 (2016). |
| Prakash, T.P. et al., Targeted delivery of antisense oligonucleotides to hepatocytes using triantennary N-acetyl galactosamine improves potency 10-fold in mice, Nucleic Acids Res., 42(13): 8796-807 (2014). |
| Pubchem, Substance Record for SID 174316404, Available Date: Mar. 31, 2014 (retrieved on Feb. 26, 2018). Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/174316404>. |
| Pubchem, Substance Record for SID 174316700, Available Date: Mar. 31, 2014 (retrieved on Feb. 26, 2018). Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/174316700>. |
| Pubchem, Substance Record for SID 174316999, Available Date: Mar. 31, 2014 {retrieved on Feb. 26, 2018). Retrieved from the Internet: <URL: https://pubchem.ncbi.nlm.nih.gov/substance/174316999>. |
| Rajwanshi, V.K. et al., LNA stereoisomers: xylo-LNA (b-d-xylo configured locked nucleic acid) and a-l-LNA (a-l-ribo configured locked nucleic acid), Chem. Commun., 1395-1396 (1999). |
| Ravn, J. et al., Stereodefined LNA Phosphorthioate Oligonucleotides, Roche Pharma Research and Early Development, RTR Research, Roche Innovation Center Copenhagen, RNA & Oligonucleotide Therapeutics Meeting, Poster, 1 page (Mar. 29-Apr. 1, 2017). |
| Renton, A.E. et al., A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD, Neuron 72, 257-268 (Oct. 20, 2011). |
| Saetrom, P., Predicting the efficacy of short oligonucleotides in antisense and RNAi experiments with boosted genetic programming, Bioinformatics, 20(17): 3055-3063 (2004). |
| Sanhueza, C.A. et al., Efficient Liver Targeting by Polyvalent Display of a Compact Ligand for the Asialoglycoprotein Receptor, J. Am. Chem. Soc., 9 pages (2016). |
| Schirle, N. T. and Macrae, I.J., The Crystal Structure of Human Argonaute2, Science, 336(6084): 1037-1040 (2012). |
| Schirle, N.T. et al., Structural analysis of human Argonaute-2 bound to a modified siRNA guide, J. Am. Chem. Soc., 1-6 (2016). |
| Schirle, N.T. et al., Structural Basis for microRNA Targeting, Science, 346(6209): 608-613 (2014). |
| Schirle, N.T. et al., Water-mediated recognition of t1-adenosine anchors Argonaute2 to microRNA targets, eLife, 4: e07646 1-16 (2015). |
| Schultz, R.G. and Gryaznov, S.M., Oligo-24-fluoro-24-deoxynucleotide N34_P54 phosphoramidates: synthesis and properties, Nucleic Acids Res., 24(15): 2966-2973 (1996). |
| Seth, P.P. et al., Configuration of the 50-Methyl Group Modulates the Biophysical and Biological Properties of Locked Nucleic Acid (LNA) Oligonucleotides, J. Med. Chem., 53: 8309-8318 (2010). |
| Seth, P.P. et al., Design, Synthesis and Evaluation of Constrained Methoxyethyl, (cMOE) and Constrained Ethyl (cEt) Nucleoside Analogs, Nucleic Acids Symposium Series, 52(1), 553-554 (2008). |
| Seth, P.P. et al., Short Antisense Oligonucleotides with Novel 2′-4′ Conformationaly Restricted Nucleoside Analogues Show Improved Potency without Increased Toxicity in Animals, J. Med. Chem., 52: 10-13 (2009). |
| Seth, P.P. et al., Structural requirements for hybridization at the 50-position are different in a-L-LNA as compared to b-D-LNA, Bioo. Med. Chem. Lett., 22: 296-299 (2012). |
| Seth, P.P. et al., Structure Activity Relationships of α-l-LNA Modified, Phosphorothioate Gapmer Antisense Oligonucleotides in Animals, Mol. Ther-Nuc. Acids., 1: e47 1-8 (2012). |
| Seth, P.P. et al., Synthesis and Biophysical Evaluation of 2′,4′-Constrained 2′O-Methoxyethyl and 2′,4′-Constrained 2′O-Ethyl Nucleic Acid Analogues, J. Org. Chem., 75: 1569-1581 (2010). |
| Sha, S.J. and Boxer, A., Treatment implications of C9ORF72, Alzheimer's Research & Therapy, 4(46): 7 pages (2012). |
| Shivalingam, A. et al., Molecular Requirements of High-Fidelity Replication-Competent DNA Backbones for Orthogonal Chemical Ligation, J. Am. Chem. Soc., 139(4):1575-1583 (2017). |
| Simon-Sanchez, J. et al., the clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions, Brain, 135: 723-735 (2012). |
| Singh, P.P. et al., Universality of LNA-mediated high-affinity nucleic acid recognition, Chem. Comm., 1247-1248 (1998). |
| Singh, S.K. et al., Synthesis of 2′-Amino-LNA: A Novel Conformationally Restricted High-Affinity Oligonucleotide Analogue with a Handle, J. Org. Chem., 63: 10035-10039 (1998). |
| Singh, S.K. et al., Synthesis of Novel Bicyclo[2.2.1] Ribonucleosides: 2′-Amino- and 2′-Thio-LNA Monomeric Nucleosides, J. Org. Chem., 63: 6078-6079 (1998). |
| Sobkowski, M. et al., Recent Advances in H-Phosphonate Chemistry. Part 1. H-Phosphonate Esters: Synthesis and Basic Reactions, Top Curr Chem, 361:137-177 (2014). |
| Sorensen, M.D., Functionalized LNA (locked nucleic acid): high-affinity hybridization of oligonucleotides containing N-acylated and N-alkylated 2′-amino-LNA monomers, Chem. Comm., 2130-2131 (2003). |
| Stout, A.K. et al., Inhibition of wound healing in mice by local interferon a/b injection, Int J Exp Pathol, 74 (1): 79-85 (1993). |
| Surono, A. et al., Chimeric RNA/Ethylene Bridged Nucleic Acids Promote Dystrophin Expression in Myocytes of Duchenne Muscular Dystrophy by Inducing Skipping of the Nonsense Mutation-Encoding Econ, Human Gene Therapy, 15:749-757 (2004). |
| Suter, S.R. et al., Structure-Guided Control of siRNA Off Target Effects, J. Am. Chem. Soc., 1-9 (2016). |
| Takahashi, T. et al., Interactions between the non-seed region of siRNA and RNA-binding RLC/RISC proteins, Ago and TRBP, in mammalian cells, Nucleic Acids Research, 42(8): 5256-5269 (2014). |
| Takeshima, Y. et al., Oligonucleotides against a splicing enhancer sequence led to dystrophin production in muscle cells from a Duchenne muscular dystrophy patient, Brain & Development, 23:788-790 (2001). |
| Ts'O, P.O. et al., an Approach to Chemotherapy Based on Base Sequence Information and Nucleic Acid Chemistry, Ann. N. Y. Acad. Sci., 507: 220-241 (1988). |
| Tulic, M.K. et al Amb a 1-immunostimulatory oligodeoxynucleotide conjugate immunotherapy decreases the nasal inflammatory response, J. Allergy Clin. Immunol., 235-241 (2004). |
| Van Aerschot, A. et al., 1,5-Anhydrohexitol Nucleic Acids, a New Promising Antisense Construc, Angew. Chem. Int. Ed. Engl., 34: 1338-1339 (1995). |
| Van Deutekom, J.C.T. et al., Antisense-induced exon skipping restores dystrophin expression in DMD patient derived muscle cells, Human Molecular Genetics, 10(15):1547-1554 (2001). |
| Vasseur, J-J. et al., Oligonucleosides: Synthesis of a Novel Methylhydroxylamine-Linked Nucleoside Dimer and Its Incorporation into Antisense Sequences, J. Am. Chem. Soc., 114: 4006-4007 (1992). |
| Veedu, R.N. et al., Novel Applications of Locked Nucleic Acids, Nucleic Acids Symposium Series, 51: 29-30 (2007). |
| Verhagen et al., A Conformationally locked Aminomethyl C-Glycoside and Studies on Its N-Pyren-1-ylcarbonyl Derivative Inserted into Oligodeoxynucleotides, European Journal of Organic Chemistry, 2538-2548 (2006). |
| Wang, Y. et al., Structure of an argonaute silencing complex with a seed-containing guide DNA and target RNA duplex, Nature, 456(7224): 921-926 (2008). |
| Watts, J.K. and Corey, D.R., Gene silencing by siRNAs and antisense oligonucleotides in the laboratory and the clinic, J. Pathol. 226(2): 365-79 (2012). |
| Weiner, G. J. et al., Immunostimulatory oligodeoxynucleotides containing the CpG motif are effective as immune adjuvants in tumor antigen immunization, 94(20): 10833-10837 (1997). |
| Weinfeld, M., et al., Influence of nucleic acid base aromaticity on substrate reactivity with enzymes acting on single-stranded DNA, Nucleic Acids Res., 21(3): 621-626 (1993). |
| Whittaker, B. et al., Stereoselective synthesis of highly functionalised P-stereogenic nucleosides via palladium-catalysed P-C cross-coupling reactions, Tetrahedron Letters, 49: 6984-6987 (2008). |
| Woolf, T.M. et al., Specificity of antisense oligonucleotides in vivo, Prov. Natl. Aca. Sci. USA, 89: 7305-7309 (1992). |
| Written Opinion for PCT/US2016/056123, 15 pages (dated Mar. 17, 2017). |
| Written Opinion for PCT/US2017/022135, 11 pages (dated Jun. 6, 2017). |
| Written Opinion for PCT/US2017/030753, 13 pages (dated Sep. 26, 2017). |
| Written Opinion for PCT/US2017/030777, 10 pages (dated Oct. 2, 2017). |
| Written Opinion for PCT/US2017/035837, 15 pages (dated Aug. 24, 2017). |
| Written Opinion for PCT/US2017/043431, ISA/US, 38 pages (dated Dec. 21, 2017). |
| Written Opinion for PCT/US2017/045218, 11 pages (dated Sep. 27, 2017). |
| Written Opinion for PCT/US2017/055601, ISR/US, 16 pages (dated Feb. 15, 2018). |
| Written Opinion for PCT/US2017/062996, 9 pages (dated Mar. 9, 2018). |
| Xu, Y. et al., Functional comparison of single- and double-stranded siRNAs in mammalian cells, Biochemical and Biophysical Research Communications, 316: 680-687 (2004). |
| Yasuda, K. et al., CpG motif-independent activation of TLR9 upon endosomal translocation of “natural” phosphodiester DNA, European Journal of Immunology, 431-436 (2006). |
| Ye, S. et al., An efficient procedure for genotyping single nucleotide polymorphisms, Nucleic Acids Research, 29(17): e88 1-8 (2001). |
| Zhang, Y. et al., Structural Isosteres of Phosphate Groups in the Protein Data Bank, J. Chem. Inf. Model, 1-18 (2017). |
| Zhang, Y., Investigating phosphate structural replacements through computational and experimental approaches, Academic Dissertain, University of Helsinki, 119 pages (2014). |
| Zhong, Z. et al., WAVE Life Sciences: Developing Stereopure Nucleic Acid Therapies for the Treatment of Genetic Neurological Diseases, World CNS Summit 2017, Boston, MA, WAVE Life Sciences, Poster, 1 page (Feb. 20-22, 2017). |
| Zlatev, I. et al., 5′-C-Malonyl RNA: Small Interfering RNAs Modified with 5′-Monophosphate Bioisostere Demonstrate Gene Silencing Activity, ACS Chem. Biol., 8 pages (2015). |
| Number | Date | Country | |
|---|---|---|---|
| 20170029445 A1 | Feb 2017 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61671652 | Jul 2012 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 14414604 | US | |
| Child | 15294602 | US |
