Pentavalent Phosphorus Compound Utilized Patents (Class 536/25.33)
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Patent number: 6653458Abstract: Modified oligonucleotides containing at least one 2′,5′-internucleotide linkage are provided. The oligonucleotides of the invention may also bear additional substituents at the 2′- and 3′-positions.Type: GrantFiled: November 8, 1999Date of Patent: November 25, 2003Assignee: ISIS Pharmaceuticals, Inc.Inventors: Muthiah Manoharan, Phillip Dan Cook, Charles J. Guinosso
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Patent number: 6649751Abstract: Provided is a method for purification and synthesis of RNA molecules that have at least one chemical modification.Type: GrantFiled: May 28, 2002Date of Patent: November 18, 2003Assignee: Sirna Therapeutics, Inc.Inventors: Nassim Usman, Francine Wincott, David Sweedler, Leonid Beigelman, Lech W. Dudycz, Susan Grimm, Anthony DiRenzo, Danuta Tracz
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Patent number: 6646118Abstract: The present invention relates to a support system for solid phase synthesis of oligomers, such as oligonucleotides, wherein the starting compound is bound to the support via a disiloxyl linkage. Furthermore, the invention relates to a method for synthesis of oligonucleotides on a solid support. The support system comprises a stable disiloxyl linkage providing high nucleoside loadings to the support and the method allows convenient non-laborious oligomer synthesis.Type: GrantFiled: March 25, 2002Date of Patent: November 11, 2003Assignee: Quiatech ABInventors: Marek Kwiatkowski, Mats Nilsson, Ulf Landegren
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Patent number: 6642373Abstract: The present invention relates to improved methods for the preparation of nucleoside phosphoramidites and oligonucleotides. In one aspect, the methods of the invention are used to prepare phosphitylating reagents using pyridinium salts as activators. In a further aspect, the methods of the invention are used to prepare internucleoside linkages using activators which include at least one pyridinium salt and at least one substituted imidazole. In a further aspect, methods are provided preparation of internucleoside linkages between nucleosides having 2′-substituents using imidazolium or benzimidazolium salts as an activator. In a further aspect, methods are provided preparation of internucleoside linkages between nucleosides having bioreversible protecting group that confers enhanced chemical and biophysical properties, without exocyclic amine protection, using imidazolium or benzimidazolium salts as an activator.Type: GrantFiled: December 12, 2002Date of Patent: November 4, 2003Assignee: ISIS Pharmaceuticals, Inc.Inventors: Muthia Manoharan, Vasulinga T. Ravikumar
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Patent number: 6630581Abstract: The invention provides a method for synthesizing oligonucleotides using carbonate protection of hydroxyl groups and nucleophilic deprotection reagents. The deprotection reagents irreversibly cleave the carbonate protecting groups while simultaneously oxidizing the internucleotide phosphite triester linkage, and can be used in aqueous solution at neutral to mildly basic pH. The method eliminates the need for separate deprotection and oxidation steps, and, since the use of acid to remove protecting groups is unnecessary, acid-induced depurination is avoided. Fluorescent or other readily detectable carbonate protecting groups can be used, enabling monitoring of individual reaction steps during oligonucleotide synthesis. The invention is particularly useful in the highly parallel, microscale synthesis of oligonucleotides. Reagents and kits for carrying out the aforementioned method are provided as well.Type: GrantFiled: January 8, 2001Date of Patent: October 7, 2003Assignee: Agilent Technologies, Inc.Inventors: Douglas J. Dellinger, Marvin H. Caruthers, Jason R. Betley
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Patent number: 6610842Abstract: Synthetic processes are provided wherein oligomers are prepared using phosphoramidite compositions. Oligomers having phosphodiester, phosphorothioate, phosphorodithioate covalent linkages are prepared that can include other covalent linkages. Also provided are compositions useful in such processes.Type: GrantFiled: May 6, 1999Date of Patent: August 26, 2003Assignee: ISIS Pharmaceuticals, Inc.Inventors: Vasulinga T. Ravikumar, Daniel C. Capaldi, Douglas L. Cole
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Patent number: 6610841Abstract: This invention relates to nucleotide-based prodrugs and their drug-delivery applications. The nucleotide-based prodrugs of the present invention comprise a drug component covalently attached via junctional ester bond(s) to one or more nucleotide components. Release and activation of the drug component of a nucleotide-based prodrug arises from hydrolysis of the junctional ester bond joining the nucleotide component to the drug component. The active drug component may be a nucleoside analog, a nucleic acid ligand, or a non-nucleoside drug. The nucleotide component provides a means of targeting and/or anchoring the nucleotide-based prodrug to the desired tissue compartment and/or a mechanism of sustained release of the active drug, thereby providing for a more effective drug delivery system with reduced toxicity.Type: GrantFiled: December 18, 1997Date of Patent: August 26, 2003Assignee: Gilead Sciences, Inc.Inventor: Stephen Warren
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Patent number: 6586219Abstract: The present invention relates to compositions and methods for increasing the yields of polynucleotide synthetic reactions. In particular, it relates to an improved reaction mixture for use in in vitro RNA trancription and in various other enzymatic reactions in which a polynucleotide is synthesized. The reaction mixture uses high concentrations of total nucleotides, in the order of 12 mM to 40 mM, i.e. levels that were previously thought to be inhibitory. Other useful modifications are also disclosed.Type: GrantFiled: September 28, 2001Date of Patent: July 1, 2003Assignee: Ambion, Inc.Inventors: Susan Milburn, Marianna Goldrick, Matthew Winkler
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Patent number: 6586218Abstract: The present invention relates to compositions and methods for increasing the yields of polynucleotide synthetic reactions. In particular, it relates to an improved reaction mixture for use in in vitro RNA trancription and in various other enzymatic reactions in which a polynucleotide is synthesised. The reaction mixture uses high concentrations of total nucleotides, in the order of 12 mM to 40 mM, i.e. levels that were previously thought to be inhibitory. Other useful modifications are also disclosed.Type: GrantFiled: September 28, 2001Date of Patent: July 1, 2003Assignee: Ambion, Inc.Inventors: Susan C. Milburn, Marianna Goldrick, Matthew Winkler
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Patent number: 6566515Abstract: Novel compounds are provided which are useful as linking groups in chemical synthesis, preferably in the solid phase synthesis of oligonucleotides and polypeptides. These compounds are generally photolabile and comprise protecting groups which can be removed by photolysis to unmask a reactive group. The protecting group has the general formula Ar—C(R1)(R2)—O—C(O)— wherein: Ar is an optionally substituted fused polycyclic aryl or heteroaromatic group or a vinylogous derivative thereof; R1 and R2 are independently H, optionally substituted alkyl, alkenyl or alkynyl, optionally substituted aryl or optionally substituted heteroaromatic, or a vinylogous derivative of the foregoing; and X is a leaving group, a chemical fragment linked to Ar—C(R1)(R2)—O—C(O)— via a heteroatom, or a solid support; provided that when Ar is 1-pyrenyl and R1 and R2 are H, X is not linked to Ar—C(R1)(R2)—O—C(O)— via a nitrogen atom.Type: GrantFiled: March 14, 2000Date of Patent: May 20, 2003Assignee: Affymetrix, Inc.Inventors: Glenn H. McGall, Ngo Q. Nam, Richard P. Rava
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Publication number: 20030088088Abstract: Synthetic processes are provided wherein oligomeric compounds are prepared having phosphodiester, phosphorothioate, phosphorodithioate, or other covalent linkages. The oligomers have substantially reduced exocyclic adducts deriving from acrylonitrile or related contaminants.Type: ApplicationFiled: August 30, 2002Publication date: May 8, 2003Inventors: Vasulinga T. Ravikumar, Muthiah Manoharan, Daniel C. Capaldi, Achim Krotz, Douglas L. Cole, Andrei Guzaev
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Patent number: 6555693Abstract: Charged compounds are provided that comprise one or more regions of localized positive charge, compositions comprising such compounds, methods of synthesizing such compounds, methods of screening such compounds to identify those having anti-infective activity, and methods of using such compounds to prevent or inhibit infections. These compounds, and compositions containing them, have multiple applications, including use in human and animal medicine and in agriculture.Type: GrantFiled: March 14, 2001Date of Patent: April 29, 2003Assignee: Genesoft, Inc.Inventors: Yigong Ge, Matthew J. Taylor, Eldon E. Baird, Heinz E. Moser, Roland W. Bürli
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Patent number: 6548652Abstract: Derivatized oligonucleotides (ODNs) are coupled to a solid support in improved yield resulting in a high density of coupled oligonucleotide per surface unit of the support, through a Schiff base type bond formed between an NH2 group attached either to the solid support or to the ODN and an aromatic aldehyde attached to the other of the solid support and the ODN. The preferred solid support-ODN conjugate is formed between semicarbazide groups attached to a glass surface and an aromatic aldehyde attached at either 3′, or 5′ end of an ODN or to an intermediate nucleotide of the ODN.Type: GrantFiled: February 9, 2001Date of Patent: April 15, 2003Assignee: Epoch Biosciences, Inc.Inventors: Eugeny Alexander Lukhtanov, Mikhail A. Podyminogin, Joel Hedgpeth
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Patent number: 6545162Abstract: The present invention describes a novel method for the solid phase synthesis of polyamides containing imidazole and pyrrole carboxamides. The polyamides are prepared on a solid support from aromatic carboxylic acids and aromatic amines with high stepwise coupling yields (>99%), providing milligram quantities of highly pure polyamides. The present invention also describes the synthesis of analogs of the natural products Netropsin and Distamycin A, two antiviral antibiotics. The present invention also describes a novel method for the solid phase synthesis of imidazole and pyrrole carboxamide polyamide-oligonucleotide conjugates. This methodology will greatly increase both the complexity and quantity of minor-groove binding polyamides and minor-groove binding polyamide-oligonucleotide conjugates which can be synthesized and tested.Type: GrantFiled: July 22, 1999Date of Patent: April 8, 2003Assignee: California Institute of TechnologyInventors: Peter B. Dervan, Eldon E Baird
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Patent number: 6538128Abstract: The invention provides improved processes for oligonucleotide synthesis utilizing arenes as solvents for detritylation of oligonucleotides.Type: GrantFiled: March 22, 1999Date of Patent: March 25, 2003Assignee: Avecia Biotechnology, Inc.Inventors: Guangrong Zhang, Jin-Yan Tang
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Patent number: 6531589Abstract: The invention provides new methods for synthesizing oligonucleotides that allow for deprotection of the oligonucleotides under more mild conditions than existing methods. The invention further provides a nucleoside base protecting group that is stable under oligonucleotide synthesis conditions, but which can be removed under more mild conditions than existing protecting groups, as well as nucleoside synthons having such base protecting groups.Type: GrantFiled: February 8, 1996Date of Patent: March 11, 2003Assignee: Hybridon, Inc.Inventors: Radhakrishnan P. Iyer, Theresa Devlin, Ivan Habus, Dong Yu, Sudhir Agrawal, Nan-Hui Ho
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Patent number: 6500945Abstract: Sequence-specific oligonucleotides are provided having substantially pure chiral Sp phosphorothioate, chiral Rp phosphorothioate, chiral Sp alkylphosphonate, chiral Rp alkylphosphonate, chiral Sp phosphoamidate, chiral Rp phosphoamidate, chiral Sp phosphotriester, and chiral Rp phosphotriester linkages. The novel oligonucleotides are prepared via a stereospecific SN2 nucleophilic attack of a phosphodiester, phosphorothioate, phosphoramidate, phosphotriester or alkylphosphonate anion on the 3′ position of a xylonucleotide. The reaction proceeds via inversion at the 3′ position of the xylo reactant species, resulting in the incorporation of phosphodiester, phosphorothioate, phosphoramidate, phosphotriester or alkylphosphonate linked ribofuranosyl sugar moieties into the oligonucleotide.Type: GrantFiled: February 16, 2001Date of Patent: December 31, 2002Assignee: ISIS Pharmaceuticals, Inc.Inventor: Phillip Dan Cook
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Patent number: 6489466Abstract: Immobilized nucleotide primers of this invention include a modified nucleotide tethered to a support substrate through a linking group. In particular, the modified nucleotide is constructed such that the C-5′ end of the nucleotide is tetherable to the linking group and the protected C-3′ end is available for further controlled modification, e.g., addition of other nucleotides in specific sequences to the immobilized nucleotide primer. Additionally, the linking group is of sufficient length to allow the immobilized nucleotide primer to be used to synthesize and screen arrays of oligonucleotides, e.g., enzymatic C-3′ primer extension.Type: GrantFiled: January 26, 2001Date of Patent: December 3, 2002Assignee: Linden Technologies, Inc.Inventors: Yih Huang, Tai-Nang Huang, Ming Shen
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Patent number: 6486313Abstract: The present invention provides alkylphosphonate dimers and oligonucleotides prepared therefrom. The invention further provides novel methods for the preparation of these alkylphosphonate dimers. Methods for the preparation of substantially diastereomerically pure alkylphosphonate dimers are also provided.Type: GrantFiled: February 18, 1999Date of Patent: November 26, 2002Assignees: ISIS Pharmaceuticals, Inc., McGill UniversityInventors: Muthiah Manoharan, George Just, Andrei Guzaev, Arlène Roland, Jianchao Wang, Michael E. Jung
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Patent number: 6479262Abstract: The present invention provides methods of preparing large polynucleotides of arbitrary sequence and in a manner that will readily lend itself to automation. The present invention provides methods of preparing a polynucleotide having at least 200 nucleotides in either a 5′ to 3′ or 3′ to 5′ direction by ligating a plurality of oligonucleotides, the assembly of which, represents the nucleotide sequence of the desired polynucleotide.Type: GrantFiled: May 16, 2000Date of Patent: November 12, 2002Assignee: Hercules, IncorporatedInventor: Simon Delagrave
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Patent number: 6479656Abstract: A process and use of at least one catalyst for phosphorylation, in particular phosphitylation, of hydroxyl groups, whereby a phosphorous compound is added to a hydroxyfunctional compound having at least one hydroxyl group. The addition yields a phosphorylated product having at least one O—P bond. The catalyst employed in the process is of the general formula (R1)nX(R2)4−n, wherein each R1 independently is hydrogen, at least one hydrocarbyl, amino, halogenated and/or silylated hydrocarbyl group, X is Si, Ge or Sn, each R2 independently is a leavening group and is F, Cl, Br, I or a sulphonate group optionally being halogen substituted and wherein n is 1, 2 or 3.Type: GrantFiled: October 16, 2000Date of Patent: November 12, 2002Assignees: Perstorp AB, Polish Academy of Science, Centre of Molecular and Macromolecular StudiesInventors: Jan Michalski, Wojciech Dabkowski, Friedrich Cramer
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Publication number: 20020165389Abstract: Methods and compositions to label oligonucleotides and analogs directly on a solid-support having the structure 1Type: ApplicationFiled: November 7, 2001Publication date: November 7, 2002Applicant: PE Corporation (NY)Inventors: Ravi S. Vinayak, Linda G. Lee, Khairuzzaman B. Mullah, Barnett B. Rosenblum
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Patent number: 6472522Abstract: Oligomers are prepared substantially free of error sequences by sequentially adding monomers to a growing chain bound to a support through a first selectably cleavable linkage, a first capture moiety and a second selectably cleavable linkage. At the completion of monomer addition, the completed oligomer is cleaved from the support to reveal the first capture moiety and purified by virtue of the presence of a second capture moiety, e.g., a terminal blocking group, and the first capture moiety. A support-bound oligomer having the structural formula (I) S—[X1]n1—SC1—CP2—[X2]n2—SC3—T1—X—T2—SC2—CP1 (I) is also provided wherein T1, T2, X1, X2, n1, n2, SC1, SC2, SC3, CP1 and CP2 are as defined herein.Type: GrantFiled: August 27, 1999Date of Patent: October 29, 2002Assignee: Bayer CorporationInventors: Thomas Horn, Michael S. Urdea
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Patent number: 6465628Abstract: Synthetic processes are provided wherein oligomeric compounds are prepared having phosphodiester, phosphorothioate, phosphorodithioate, or other covalent linkages. The oligomers have substantially reduced exocyclic adducts deriving from acrylonitrile or related contaminants.Type: GrantFiled: April 9, 1999Date of Patent: October 15, 2002Assignee: ISIS Pharmaceuticals, Inc.Inventors: Vasulinga T. Ravikumar, Muthiah Manoharan, Daniel C. Capaldi, Achim Krotz, Douglas L. Cole, Andrei Guzaev
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Publication number: 20020137921Abstract: Sequence-specific oligonucleotides are provided having substantially pure chiral Sp phosphorothioate, chiral Rp phosphorothioate, chiral Sp alkylphosphonate, chiral Rp alkylphosphonate, chiral Sp phosphoamidate, chiral Rp phosphoamidate, chiral Sp phosphotriester, and chiral Rp phosphotriester linkages. The novel oligonucleotides are prepared via a stereospecific SN2 nucleophilic attack of a phosphodiester, phosphorothioate, phosphoramidate, phosphotriester or alkylphosphonate anion on the 3′ position of a xylonucleotide. The reaction proceeds via inversion at the 3′ position of the xylo reactant species, resulting in the incorporation of phosphodiester, phosphorothioate, phosphoramidate, phosphotriester or alkylphosphonate linked ribofuranosyl sugar moieties into the oligonucleotide.Type: ApplicationFiled: May 17, 2002Publication date: September 26, 2002Inventor: Phillip Dan Cook
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Patent number: 6451998Abstract: A method of capping a hydroxy group of a moiety, comprising coupling the moiety to a phosphor or phosphite derivative of a protected alcohol, so as to form the corresponding phosphate or phosphite between the hydroxy and phosphor or phosphite groups. The hydroxy group may be later de-capped by hydrolyzing the resulting compound to deprotect the protected alcohol and cleave the phosphate from the moiety so as to regenerate the hydroxy group of the moiety. The method has particular application to fabrication of addressable polynucleotide arrays and allows failed sequences, as well as inter-feature regions, to be left with a free hydroxy group at the ends of the molecules (failed sequences or linkers) at such locations.Type: GrantFiled: October 18, 1999Date of Patent: September 17, 2002Assignee: Agilent Technologies, Inc.Inventor: Michael G. M. Perbost
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Patent number: 6441159Abstract: Derivatized oligonucleotides (ODNs) are coupled to a solid support in improved yield resulting in a high density of coupled oligonucleotide per surface unit of the support through a Schiff base type bond formed between an NH2 group attached either to the solid support or to the ODN and an aromatic aldehyde attached to the other of the solid support and the ODN. The preferred solid support-ODN conjugate is formed between semicarbazide groups attached to a glass surface and an aromatic aldehyde attached at either 3′, or 5′ end of an ODN or to an intermediate nucleotide of the ODN.Type: GrantFiled: February 9, 2001Date of Patent: August 27, 2002Assignee: Epoch Biosciences, Inc.Inventors: Eugeny Alexander Lukhtanov, Mikhail A. Podyminogin
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Patent number: 6429309Abstract: The present invention relates to a support system for the solid phase synthesis of oligomers, such as oligonucleotide, wherein the starting compound is bound to the support via a disiloxyl linkage. Furthermore, the invention relates to a method for synthesis of oligonucleotides on a solid support. The support system comprises a stable disiloxyl linkage providing high nucleoside loadings to the support and the method allows convenient non-laborious oligomer synthesis.Type: GrantFiled: August 2, 2001Date of Patent: August 6, 2002Assignee: Quiatech ABInventors: Marek Kwiatkowski, Mats Nilsson, Ulf Landegren
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Publication number: 20020103365Abstract: The object of the present invention is a process for synthesizing solid phase nucleic acids, characterized in that a mineral or organic polymer, bound by a bivalent hydrocarbon radical to an epoxy or glycol-type group, is used as a solid support, said epoxy or glycol-type group comprising two adjacent saturated carbon atoms on which an OH and a nucleophilic group are substituted. The present invention also pertains to compounds containing an epoxy or glycol-type group as defined above, useful for example as a solid support in a process for solid support nucleic acid synthesis.Type: ApplicationFiled: May 13, 1998Publication date: August 1, 2002Inventors: LUDMILLA BARANOVA, FRANCOIS CHATELAIN, VIKTOR KUMAREV
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Patent number: 6414127Abstract: Compounds having structure (1) wherein R1 is —H a protecting group, a linker or a binding partner; and R2 and R34 are as defined in the specification. The invention also provides intermediates and methods make the structure (1) compounds, as well as methods to use the compounds as labels in diagnostic assays and to enhance binding to complementary bases.Type: GrantFiled: September 21, 1999Date of Patent: July 2, 2002Assignee: ISIS Pharmaceuticals, Inc.Inventors: Kuei-Ying Lin, Mark D. Matteucci
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Patent number: 6410675Abstract: Provided are functionalized silicon compounds and methods for their synthesis and use. The functionalized silicon compounds include at least one activated silicon group and at least one derivatizable functional group. Exemplary derivatizable functional groups include hydroxyl, amino, carboxyl and thiol, as well as modified forms thereof, such as activated or protected forms. The functionalized silicon compounds may be covalently attached to surfaces to form functionalized surfaces which may be used in a wide range of different applications. In one embodiment, the silicon compounds are attached to the surface of a substrate comprising silica, such as a glass substrate, to provide a functionalized surface on the substrate, to which molecules, including polypeptides and nucleic acids, may be attached.Type: GrantFiled: April 11, 2001Date of Patent: June 25, 2002Assignee: Affymetrix, Inc.Inventors: Glenn McGall, Jonathan Eric Forman
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Patent number: 6407223Abstract: The process of the instant invention is drawn to the synthesis of modified P-chiral nucleotide analogues in the form of pure diastereomers possessing preselected configuration at the P-atom. Oligonucleotides prepared by the method of the invention containing P-chiral compounds have enhanced hybridization and transporting properties.Type: GrantFiled: October 14, 1999Date of Patent: June 18, 2002Assignee: Polska Akademia Nauk Cenirum Badan Molekularnych i MakromlekularnychInventors: Wojciech J. Stec, Lucyna A. Woźniak, Arkadiusz Chworoś, Jaroslaw Pyzowski
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Patent number: 6399831Abstract: The present invention is directed to a method of synthesizing sulfurized oligonucleotide analogs by reacting an oligonucleotide analog containing a phosphorous(III) linkage with a dithiocarbonic acid diester polysulfide having the formula to produce a sulfurized oligonucleotide analog. The diester polysulfide reagent is useful in solution and solid phase oligonucleotide analog synthesis.Type: GrantFiled: December 1, 1999Date of Patent: June 4, 2002Assignee: ISIS Pharmaceuticals, Inc.Inventors: Zacharia S. Cheruvallath, Vasulinga T. Ravikumar, Douglas L. Cole, Daniel C. Capaldi
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Patent number: 6384209Abstract: The invention relates to the chemical synthesis of oligonucleotides and to chemical entities useful in such synthesis. More particularly, the invention relates to sulfurization of the internucleoside linkages of oligonucleotides. The invention provides new sulfur transfer reagents and processes for their use in sulfurizing oligonucleotides. The sulfur transfer reagents according to the invention are inexpensive to make, stable in storage and highly efficient in sulfurization.Type: GrantFiled: November 26, 1997Date of Patent: May 7, 2002Assignee: Avecia Biotechnology, Inc.Inventors: Jin-Yan Tang, Zhaoda Zhang
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Patent number: 6380378Abstract: Novel nucleotide compounds represented by the formula (I) wherein R1 represents a protective group or a PEG bearing organic group; R2, R2′, R2″, R3, R3′ and R3″ each represents a hydrogen atom or an alkyl, cycloalkyl, aryl or aralkyl group which may contain a hetero-atom; B1, B2, B3 and B4 each represents a base, if necessary, protected by a protective group common in nucleotide chemistry or by a PEG bearing organic group; X, X′ and X″ each represents an oxygen atom or a sulfur atom; Y represents an azolyl group, a mono- or di-alkylamino group or a saturated nitrogenous heterocyclic ring; A1, A2, A3 and A4 each represents a hydrogen atom, a hydroxyl group, an alkoxy group or a trialkylsilyloxy group; and m and n each represents 0 or an integer of 1 to 100.Type: GrantFiled: December 23, 1999Date of Patent: April 30, 2002Assignee: Toagosei Company, Ltd.Inventors: Akinori Kitamura, Yoji Horie, Takayoshi Uchida, Tadao Yoshida
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Patent number: 6353098Abstract: A process for deprotecting RNA alkylsilyl groups comprising, contacting the groups with a solution of anhydrous triethylamine-hydrogen fluoride (aHF-TEA) in triethylamine and N-methylpyrrolidine at between 60° C.-70° C. for 0.25-24 h.Type: GrantFiled: June 17, 1998Date of Patent: March 5, 2002Assignee: Ribozyme Pharmaceuticals, Inc.Inventors: Nassim Usman, Francine Wincott
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Patent number: 6346614Abstract: The invention provides hybrid oligonucleotides having phosphorothioate or phosphorodithioate internucleotide linkages, and both deoxyribonucleosides and ribonucleosides or 2′-substituted ribonucleosides. Such hybrid oligonucleotides have superior properties of duplex formation with RNA, nuclease resistance, and RNase H activation.Type: GrantFiled: March 14, 2000Date of Patent: February 12, 2002Assignee: Hybridon, Inc.Inventors: Valeri Metelev, Sudhir Agrawal
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Patent number: 6337393Abstract: A method for reducing evaporation of a liquid reagent solution during solid phase, micro-scale chemical synthesis of a molecule comprising sub-units on an open environment solid support surface. The method includes the steps of providing an open solid support surface including at least one binding site which is functionalized with a reactive chemical moiety; and depositing a substantially controlled and minute volume of liquid reagent solution onto the support surface, and in contact with the binding site. The reagent solution includes reactants contained in at least one relatively high boiling point solvent, in contrast to standard organic solvents for such reagents. Application of a high boiling point solvent substantially reduces evaporation of the reagent solution in the open environment during synthesis on the solid support while enabling the maintenance of a substantially high reaction yield.Type: GrantFiled: September 14, 2000Date of Patent: January 8, 2002Assignee: Protogene Laboratories, Inc.Inventors: Thomas M. Brennan, Albrecht W. Frauendorf
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Patent number: 6329346Abstract: Oligodeoxyribonucleotides in which at least two 2′-deoxy-&bgr;-D-erythro-pentofuranosyl groups are replaced by 2′-deoxy-&bgr;-D-threo-pentofuranosyl groups at both the 5′ end and 3′ end, and oligodeoxyribonucleotides in which at least 20% of the 2′-deoxy-&bgr;-D-erythro-pentofuranosyl groups in consecutive nucleotide building blocks are replaced by 2′-deoxy-&bgr;-D-threo-pentofuranosyl groups and which are composed of 6 to 100 nucleotide building blocks, are suitable for the inhibition of the expression of viral genes and oncogenes by the antisense principle and can be used for the production of pharmaceutical agents with antiviral activity.Type: GrantFiled: December 16, 1997Date of Patent: December 11, 2001Assignee: Roche Diagnostics GmbHInventors: Klasu Muhlegger, Herbert Von Der Eltz, Frank Seela, Helmut Rosemeyer
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Patent number: 6320041Abstract: The present invention provides a variety of compositions that comprise an activated carboxylic ester moiety on one end of an alkyl tether and a nucleic acid binding moiety on the other end for use as crosslinking reagents in conjugation reactions of nucleotides with solid support matrixes, organic molecules, reporter groups or other biomolecules.Type: GrantFiled: April 13, 2001Date of Patent: November 20, 2001Assignee: Trilink Biotechnologies, Inc.Inventors: Richard I. Hogrefe, Morteza M. Vaghefi
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Patent number: 6313284Abstract: A method of preparing an immobilized oligonucleotide having a free 3′-end comprises the steps of: i) preparing an oligonucleotide attached in a first position to a solid support via its 3′-end and having a free 5′-end; ii) binding said oligonucleotide in a second position remote from the 3′-end to the solid support; and iii) selectively releasing the 3′-end of the oligonucleotide from the solid support to obtain the oligonucleotide attached to the support in said second position in a reversed orientation with a free 3′-end.Type: GrantFiled: November 12, 1999Date of Patent: November 6, 2001Inventors: Marek Kwiatkowski, Ulf Landegren, Mats Nilsson
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Patent number: 6306598Abstract: The present invention relates to methods and compositions for the direct detection of analytes and membrane conformational changes through the detection of color changes in biopolymeric materials. In particular, the present invention provide for the direct colorimetric detection of analytes using nucleic acid ligands at surfaces of polydiacetylene liposomes and related molecular layer systems.Type: GrantFiled: June 21, 1999Date of Patent: October 23, 2001Assignee: Regents of the University of CaliforniaInventors: Deborah H. Charych, Ulrich Jonas
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Patent number: 6294659Abstract: The present invention relates, in general, to a nucleoside base and, in particular, to a universal, photocleavable nucleoside base. The invention further relates to oligonucleotides comprising such a base.Type: GrantFiled: July 15, 1999Date of Patent: September 25, 2001Assignee: Duke UniversityInventors: Michael C. Pirrung, Xiadong Zhao
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Patent number: 6294664Abstract: Synthetic processes are provided for the solution phase synthesis of oligonucleotides, especially phosphorothioate oligonucleotides, and intermediate compounds useful in the processes. Intermediates having structure (I) are prepared in accordance with preferred embodiments.Type: GrantFiled: January 17, 1997Date of Patent: September 25, 2001Assignee: Isis Pharmaceuticals, Inc.Inventors: Vasulinga Ravikumar, Douglas L. Cole
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Patent number: 6291669Abstract: The present invention relates to a support system for solid phase synthesis of oligomers, such as oligonucleotides, wherein the starting compound is bound to the support via a disiloxyl linkage. Furthermore, the invention relates to a method for synthesis of oligonucleotides on a solid support. The support system comprises a stable disiloxyl linkage providing high nucleoside loadings to the support and the method allows convenient non-laborious oligomer synthesis.Type: GrantFiled: July 19, 1999Date of Patent: September 18, 2001Inventors: Marek Kwiatkowski, Mats Nilsson, Ulf Landegren
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Patent number: 6274725Abstract: The present invention relates to improved methods for the preparation of nucleoside phosphoramidites and oligonucleotides. In one aspect, the methods of the invention are used to prepare phosphitylating reagents using pyridinium salts as activators. In a further aspect, the methods of the invention are used to prepare internucleoside linkages using activators which include at least one pyridinium salt and at least one substituted imidazole. In a further aspect, methods are provided preparation of internucleoside linkages between nucleosides having 2′-substituents using imidazolium or benzimidazolium salts as an activator. In a further aspect, methods are provided preparation of internucleoside linkages between nucleosides having bioreversible protecting group that confers enhanced chemical and biophysical properties, without exocyclic amine protection, using imidazolium or benzimidazolium salts as an activator.Type: GrantFiled: October 23, 1998Date of Patent: August 14, 2001Assignee: Isis Pharmaceuticals, Inc.Inventors: Yogesh Sanghvi, Muthiah Manoharan
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Patent number: 6274724Abstract: In one embodiment, the invention provides a polymer comprising imidazole ring units having nitrogen at the 1 and 3 positions of the ring; a carbon at each of the 2, 4 and 5 positions of the ring; and radical substituents G1 and G2 carried at the 4 and 5 positions. G1 and G2 are each independently selected from cyano, substituents derived from cyano, and substituents which replace cyano. The polymers formed by at least two of the cyclic imidazole units. In another embodiment, the invention provides new imidazole compounds usable as monomers to form the polymers. In still another embodiment, the invention provides a method for using the polymers as a coupling/activator for synthon synthesis.Type: GrantFiled: June 10, 1999Date of Patent: August 14, 2001Assignee: The Regents of the University of MichiganInventors: Paul G. Rasmussen, Sarah E. Reybuck, David M. Johnson, Richard G. Lawton
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Patent number: 6262251Abstract: This invention discloses an improved method for the sequential solution phase synthesis of oligonucleotides. The method lends itself to automation and is ideally suited for large scale manufacture of oligonucleotides with high efficiency.Type: GrantFiled: April 6, 1998Date of Patent: July 17, 2001Assignee: Proligo LLCInventors: Wolfgang Pieken, Danny McGee, Alecia Settle, Yansheng Zhai, Jianping Huang
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Patent number: 6248877Abstract: Methods for preparing organic compounds, such as oligonucleotides, on solid supports are described. Libraries of the compounds and methods of using the compounds are also disclosed.Type: GrantFiled: April 6, 1999Date of Patent: June 19, 2001Assignee: Biolink PartnersInventors: Alex G. Bonner, Lawrence S. Udell
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Patent number: 6242591Abstract: Methods for the formation of sulfurized oligonucleotides are provided. The methods allow for the formation of phosphorothioate linkages in the oligonucleotides or derivatives, without the need for complex solvent mixtures and repeated washing or solvent changes. Oligonucleotides having from about 8, and up to about 50, nucleotides can be sulfuiized according to the methods of the invention with higher yields than have been previously reported.Type: GrantFiled: January 11, 2000Date of Patent: June 5, 2001Assignee: Isis Pharmaceuticals, Inc.Inventors: Douglas L. Cole, Vasulinga T. Ravikumar, Zacharia S. Cheruvallath