Trivalent Phosphorus Compound Utilized Patents (Class 536/25.34)
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Publication number: 20120142763Abstract: This disclosure relates to nucleic acid constructs modified to have a reduced net anionic charge. The constructs comprise phosphotriester and/or phosphothioate protecting groups. The disclosure also provides methods of making and using such constructs.Type: ApplicationFiled: June 1, 2010Publication date: June 7, 2012Applicant: THE REGENTS OF THE UNIVERSITY OF CALIFORNIAInventors: Steven F. Dowdy, Bryan R. Meade, Khirud Gogoi
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Patent number: 8193337Abstract: A process for the preparation of an oligonucleotide having at least one phosphate internucleotide linkage I provided. The process comprises the steps of: a) forming a nascent oligonucleotide comprising a phosphorus (III) internucleotide linkage; and b) oxidation of the nascent oligonucleotide with aqueous iodine solution thereby to form a phosphorus (V) internucleotide linkage; wherein the oxidation is carried out in the presence of a base, the conjugate acid of said base having a pKa higher than the pKa of the conjugate acid of pyridine. Preferably the base is N-methylimidazole.Type: GrantFiled: July 14, 2008Date of Patent: June 5, 2012Assignee: Avecia Biotechnology, Inc.Inventor: Nanda D. Sinha
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Publication number: 20120095201Abstract: Provided herein is a method for replacing the allyl group in a compound of formula R—O-allyl, R2N(allyl), RNH(allyl), RN(allyl)2 or R—S-allyl with a hydrogen, using a transition metal and one or more phosphine ligands.Type: ApplicationFiled: October 25, 2011Publication date: April 19, 2012Applicant: ILLUMINA CAMBRIDGE LIMITEDInventors: John MILTON, Xiaolin Wu, Mark Smith, Joseph Brennan, Colin Barnes, Xiaohai Liu, Silke Ruediger
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Patent number: 8124756Abstract: A method for preparing amino linker oligonucleotides is provided. More specifically, a method of preparing 5?-amino-linker oligonucleotides comprising the steps of: introducing an amino linker having a protecting group into the 5? terminus of an oligonucleotide; and removing the protecting group from the amino linker oligonucleotide by contacting with acetic acid and 2,2,2-trifluoroethanol is provided. The amino protecting group is efficiently removed from the amino linker oligonucleotides, and thereby achieving a high yield of the amino linker oligonucleotides.Type: GrantFiled: September 15, 2009Date of Patent: February 28, 2012Assignees: Postech Academy-Industry Foundation, PoscoInventors: Jung-Hwan Lee, Hyun-Gu Kang, Sung-Ho Ryu, Jong-In Kim, Sun-Hak Lee, Hye-Jung Lee, Eun-Jung Jang
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Patent number: 8039612Abstract: According to the present invention, there is provided a process for making an oligonucleotide or a phosphorothioate oligonucleotide. The process has the following steps: (a) providing an amount of a blocked nucleotide; (b) deblocking the blocked nucleotide to form an unblocked nucleotide; (c) activating the deblocked nucleotide; (d) coupling the deblocked nucleotide with a phosphoramidite to form a phosphite oligomer; (e) capping any uncoupled deblocked nucleotide via reaction with an amount of acetic anhydride and an amount of N-methylimidazole that is substantially free of 1,3,5-trimethylhexahydro-1,3,5-triazine; (f) oxidizing the phosphite oligomer to form the oligonucleotide or sulfurizing the phosphite oligomer to form a phosphorothioate oligonucleotide; and (g) optionally repeating steps (b) through (f). There is also a process for capping a nucleotide.Type: GrantFiled: October 10, 2008Date of Patent: October 18, 2011Assignee: Honeywell International, Inc.Inventors: Sandra Lorenz, Jim Przybytek, Karel Snoble
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Nucleoside derivative, modified oligonucleotide, method for their synthesis and applications thereof
Patent number: 8026348Abstract: Compositions and methods of preparing carboranes and metallacarboranes, which can be used as a new type of electrochemically active label for biological compounds, are disclosed. Nucleic acid derivatives labelled with carborane or metallacarborane can be detected by electrochemical methods and can find several practical applications, such as materials for nanoconstruction, in DNA array technology or for the construction of biosensors, especially electrochemical biosensors. Other applications can include use as modified primers in amplification of RNA and DNA, antisense drugs, boron carriers for BNCT, radiopharmaceuticals bearing a range of isotopes useful in different types of radiotherapy, molecular probes, elements of biosensors, materials for nanotechnology and others.Type: GrantFiled: April 30, 2004Date of Patent: September 27, 2011Inventors: Zbigniew J. Lesnikowski, Agnieszka Olejniczak -
Publication number: 20110201799Abstract: A method for preparing an oligonucleotide comprising the steps of a) providing a hydroxyl containing compound having formula (1), wherein B is a heterocyclic base, and radicals R2, R3 and R5 are as defined in the description; b) reacting said compound with a phosphitylating agent in the presence of an activator I having formula (I), wherein R=alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; R1, R2=either H or form a 5- to 6-membered ring together; X1, X2=independently either N or CH; Y=H or Si(R4)3, with R4=alkyl, cycloalkyl, aryl, aralkyl, heteroalkyl, heteroaryl; B=deprotonated acid; to prepare a phosphitylated compound; c) reacting said phosphitylated compound without isolation with a second compound having the formula (1), wherein R5, R3, R2, B are independently selected, but have the same definition as above in the presence of an activator II selected from the group of imidazole, imidazolium salts, and mixtures thereof.Type: ApplicationFiled: July 19, 2010Publication date: August 18, 2011Applicant: GIRINDUS AGInventors: Meinolf LANGE, Andreas HOHLFELD, Andreas SCHÖNBERGER, Christina KIRCHHOFF, Olaf GRÖSSEL
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Patent number: 7999098Abstract: Hydrazino, oxyamino and carbonyl-based monomers and methods for incorporation into oligonucleotides during enzymatic synthesis are provided. Modified oligonucleotides are provided that incorporate the monomers provided herein. Immobilized oligonucleotides and oligonucleotide conjugates that contain covalent hydrazone or oxime linkages are provided. Methods for preparation of surface bound oligonucleotides are provided. Methods for the preparation of oligonucleotide conjugates are also provided.Type: GrantFiled: December 11, 2006Date of Patent: August 16, 2011Assignee: Solulink Biosciences, Inc.Inventors: David A. Schwartz, Richard I. Hogrefe
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Publication number: 20110137022Abstract: A method for the analysis of oligonucleotides is provided. The method comprises: desalting a mixture of oligonucleotides under conditions such that there is substantially no separation of the mixture of oligonucleotides, and/or by on-line desalting, introducing the desalted mixture of oligonucleotides into a mass spectrometer; and quantifying one or more oligonucleotides comprised in the mixture by mass spectrometry.Type: ApplicationFiled: August 7, 2009Publication date: June 9, 2011Inventors: Dennis Paul Michaud, Paul McCormac
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Publication number: 20110092693Abstract: The present invention relates to a process for the preparation of an oligomeric compound made up of two or more individual oligomers, in which said oligomeric compound the individual oligomers are separated by a photocleavable linker, comprising the step of photoactively cleaving said linker.Type: ApplicationFiled: January 16, 2007Publication date: April 21, 2011Applicant: NOVARTIS AGInventors: Francois Jean-Charles Natt, Jurg Hunziker, Robert Haner, Simon Matthias Langenegger
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Publication number: 20110092685Abstract: To provide an excellent amidite for synthesizing modified nucleic acid, which enables a protective group therein to be removed under a moderate condition, thereby stably producing a hydroxyl group-containing modified nucleic acid, and a method for synthesizing modified nucleic acid using the amidite. Specifically, an amidite for synthesizing modified nucleic acid, expressed by General Formula (I): where X represents a base, Y represents a substituent, Z represents a protective group for protecting a hydroxyl group in the substituent, and Q represents one of a hydrogen atom, a hydroxyl group and a hydroxyl group protected by a protective group, wherein the protective group can be removed in an aprotic solvent, and when the protective group is removed, the hydroxyl group emerges in the substituent, and a method for synthesizing modified nucleic acid using the amidite.Type: ApplicationFiled: October 12, 2010Publication date: April 21, 2011Applicant: FUJITSU LIMITEDInventor: Tsuyoshi Fujihara
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Patent number: 7923550Abstract: The present invention describes novel compounds and methods for capping reactive groups on support and during multistep synthesis. These new capping reagents are also useful for high quality synthesis on solid supports and surfaces used as microarrays, biosensors, or in general as biochips. The compounds are also useful for controlling surface density of reactive groups on a support. The compounds may also be used to modify the hydrophilic/hydrophobic characteristics of a surface or a molecule. The compounds have functional utility in various applications in the fields of genomics, proteomics, diagnostics and medicine.Type: GrantFiled: April 14, 2004Date of Patent: April 12, 2011Inventors: Xiaolian Gao, Peilin Yu
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Publication number: 20110077389Abstract: Novel CE-phosphoramidites and CPG reagents have been synthesized from a serinol backbone. These reagents are useful to introduce functional groups or directly label oligonucleotides. The versatile serinol scaffold allows for labeling at any position (5? or 3? termini, or any internal position) during automated DNA synthesis. Multiple labels or functional groups can be achieved by repetitive coupling cycles. Optimal spacer arms and protected label moieties have been specially designed. Further, the natural 3-carbon atom internucleotide phosphate distance is retained when inserted internally.Type: ApplicationFiled: September 28, 2010Publication date: March 31, 2011Applicants: Nelson Biotechnologies, Inc., Glen Research CorporationInventors: Paul S. Nelson, Hugh Mackie, Andrew Murphy
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Patent number: 7910726Abstract: The disclosure provides an excellent amidite for synthesizing a modified nucleic acid, which enables a protective group therein to be removed under a moderate condition, thereby stably producing a hydroxyl group-containing modified nucleic acid. The disclosure also provides a method for synthesizing a modified nucleic acid using the amidite. Specifically, an amidite for synthesizing the modified nucleic acid is expressed by General Formula (I): where X represents a base, Y represents a substituent, Z represents a protective group for protecting a hydroxyl group in the substituent, and Q represents one of a hydrogen atom, a hydroxyl group and a hydroxyl group protected by a protective group, wherein the protective group can be removed in an aprotic solvent, and when the protective group is removed, the hydroxyl group emerges in the substituent.Type: GrantFiled: July 29, 2008Date of Patent: March 22, 2011Assignee: Fujitsu LimitedInventor: Tsuyoshi Fujihara
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Publication number: 20110065909Abstract: A method for preparing an oligonucleotide comprising the steps of a) providing a hydroxyl containing compound having the formula (A), b) reacting said compound with a phosphitylating agent in the presence of an activator (activator I) having the formula (I) to prepare a phosphitylated compound; and c) reacting said phosphitylated compound without isolation with a second compound having the formula (A) wherein R5, R3, R2, B are independently selected, but have the same definition as above in the presence of an activator II different from activator I.Type: ApplicationFiled: July 14, 2010Publication date: March 17, 2011Applicant: Girindus AGInventors: Meinolf Lange, Andreas Schönberger, Andreas Hohlfeld, Olaf Grössel, Christina Kirchhoff, Fritz Link
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Patent number: 7893249Abstract: Method for synthesis, deprotection, and/or purification of nucleic acid molecules, such as oligonucleotides comprising one or more ribonucleotides. Such nucleic acid molecules include siRNA, dsRNA, ribozymes, antisense, and aptamers.Type: GrantFiled: December 7, 2009Date of Patent: February 22, 2011Assignee: Sirna Therapeutics, Inc.Inventors: Keith Bowman, Christopher Shaffer, Chandra Vargeese
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Patent number: 7872120Abstract: Methods for synthesizing a collection of partially identical polynucleotides are disclosed.Type: GrantFiled: August 10, 2007Date of Patent: January 18, 2011Inventor: Venkata Chalapathi Rao Koka
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Patent number: 7858772Abstract: The present invention provides methods of extending nucleic acids and purifying target nucleic acids. The methods include the use of capping reagents to effect chain termination and provide a handle for purification via fluorous affinity methods.Type: GrantFiled: December 18, 2007Date of Patent: December 28, 2010Assignee: Roche Molecular Systems, Inc.Inventors: Amar Gupta, Stephen Will
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Patent number: 7855285Abstract: A process for providing regiospecific and highly stereoselective synthesis of 9-? anomeric purine nucleoside analogs is described. The introduction of the sugar moiety on to 6-(azolyl)-substituted purine bases is performed so that highly stereoselective formation of the ? anomers of only the 9 position regioisomers of the purine nucleoside analogs (either D or L enantiomers) is obtained. This regiospecific and stereoselective introduction of the sugar moiety allows the synthesis of nucleoside analogs, and in particular 2?-deoxy, 3?-deoxy, 2?-deoxy-2?-halo-arabino and 2?,3?-dideoxy-2?-halo-threo purine nucleoside analogs, in high yields without formation of the 7-positional regioisomers. Processes for providing novel 6-(azolyl)purines for the regiospecific and highly stereoselective synthesis of 9-? anomeric purine nucleoside analogs are described. The compounds are drugs or intermediates to drugs.Type: GrantFiled: June 14, 2006Date of Patent: December 21, 2010Assignee: Brigham Young UniversityInventors: Morris J. Robins, Minghong Zhong
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Publication number: 20100273999Abstract: The present invention provides a method for preparing nucleotide oligomers, including (a) coupling a nucleotide dimer or nucleotide trimer to a nucleoside attached to solid supports or to universal solid supports as a starting material; (b) sequentially coupling nucleotide monomers to the resulting structures of Step (a) to prepare a nucleotide oligomer; and (c) removing the nucleotide oligomers from the solid supports. The method of the present invention provides nucleotide oligomers having 15-20% higher purity than the conventional art. The present invention enables the efficient and inexpensive synthesis of nucleotide oligomers with high purity within a shorter period of time.Type: ApplicationFiled: May 7, 2010Publication date: October 28, 2010Applicant: SAMCHULLY PHARM. CO., LTD.Inventors: Kyeong-Eun Jung, Alexei Kayushin, Moon Hee Kim, Kyung-Il Kim, Sungwon Kim, Yumi Ji
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Patent number: 7807821Abstract: A phosphoramidite method for the synthesis of a nucleic acid oligomer without protecting the base moiety characterized in that a 3? or 5? hydroxyl group of a nucleotide is reacted with a nucleoside phosphoramidite, a cyclonucleoside phosphoramidite, a 2?-substituted nucleoside phosphoramidite, a 4?-substituted nucleoside phosphoramidite, or a 2?,4?-di-substituted nucleoside phosphoramidite to produce a phosphodiester linkage. The phosphoramidite is contacted with an activator containing both a) hydroxybenzotriazole-1-ol (HOBt), a mono-substituted HOBt, a di-substituted HOBt, or a di-substituted phenol and b) imidazole, tetrazole, benzimidazoletriflate (BIT), 4-ethylthiotetrazole, imidazolium triflate(trifluoromethane sulfonate) or 4,5-dicyanoimidazole.Type: GrantFiled: February 24, 2005Date of Patent: October 5, 2010Assignee: Japan Science and Technology AgencyInventors: Mitsuo Sekine, Kohji Seio, Akihiro Ohkubo
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Patent number: 7786293Abstract: The present invention provides a process for the sulfurization of phosphorus-containing compounds. More particularly, the process involves contacting the compound to be sulfurized with a sulfur transfer reagent as defined hereinbefore in a solvent or a mixture of solvents.Type: GrantFiled: June 16, 2006Date of Patent: August 31, 2010Assignee: Novartis AGInventors: Pierre Martin, Francois Jean Charles Natt
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Patent number: 7786294Abstract: A method of producing a polydeoxyribonucleotide molecule by reverse transcriptase polymerase chain reaction wherein the polydeoxyribonucleotide molecule has a length of greater than 5,000 base-pairs is disclosed. The method involves combining two reverse transcriptases followed by two protocols of polymerase chain reaction. This method enable the amplification of large DNAs, such as viruses, from a sample while preserving genetic diversity of the large DNA.Type: GrantFiled: May 31, 2007Date of Patent: August 31, 2010Assignee: Saint Louis UniversityInventors: Xiaofeng Fan, Adrian M. Di Bisceglie
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Patent number: 7777013Abstract: Labeled nucleotide analogs used in place of naturally occurring nucleoside triphosphates or other analogs in template directed nucleic acid synthesis reactions and other nucleic acid reactions, and various analyses based thereon, including DNA sequencing, single base identification, hybridization assays and others.Type: GrantFiled: May 15, 2008Date of Patent: August 17, 2010Assignee: Pacific Biosciences of California, Inc.Inventors: Yue Xu, Jeffrey Wegener, Arek Bibillo
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Publication number: 20100197902Abstract: A nucleic acid synthesizing dimer amidite including two nucleoside compounds, wherein the two nucleoside compounds are linked with each other via a phosphite triester bond.Type: ApplicationFiled: February 26, 2010Publication date: August 5, 2010Applicant: FUJITSU LIMITEDInventor: Tsuyoshi Fujihara
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Patent number: 7759513Abstract: The present invention discloses novel and improved nucleosidic and nucleotidic compounds that are useful in the light-directed synthesis of oligonucleotides, as well as, methods and reagents for their preparation. These compounds are characterized by novel photolabile protective groups that are attached to either the 5?- or the 3?-hydroxyl group of a nucleoside moiety. The photolabile protective group is comprised of a 2-(2-nitrophenyl)-ethyoxycarbonyl skeleton with at least one substituent on the aromatic ring that is either an aryl, an aroyl, a heteroaryl or an alkoxycarbonyl group. The present invention includes the use of the aforementioned compounds in light-directed oligonucleotide synthesis, the respective assembly of nucleic acid microarrays and their application.Type: GrantFiled: January 26, 2004Date of Patent: July 20, 2010Assignee: NIGU Chemie GmbHInventors: Sigrid Bühler, Markus Ott, Wolfgang Pfleiderer
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Patent number: 7759480Abstract: A process of manufacturing oligonucleotides includes a 5?-deblocking step in which the 5-blocking group is removed with dichloroacetic acid that is essentially free of chloral. The process is useful for making oligonucleotides that are substantially free of chloral adducts.Type: GrantFiled: January 29, 2007Date of Patent: July 20, 2010Assignee: Isis Pharmaceuticals, Inc.Inventors: Achim Krotz, Daniel C. Capaldi, Hans-Joachim Josef Gaus, Brett Turney
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Publication number: 20100174058Abstract: Oligonucleotide probes containing two labels are provided and are useful in hybridization assays. The probes can also contain a minor groove binding group.Type: ApplicationFiled: January 6, 2010Publication date: July 8, 2010Inventors: Michael W. Reed, Eugeny Alexander Lukhtanov, Alexander A. Gall, Robert O. Dempcy, Nicolaas M.J. Vermeulen
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Patent number: 7741471Abstract: The present invention provides the combination of the O-2 diphenylcarbamoyl (“DPC”) and N-6 dimethylaminomethylidene (“DMF”) protecting groups for isoguanosine nucleosides that can be utilized in oligonucleotide synthesis.Type: GrantFiled: May 26, 2005Date of Patent: June 22, 2010Assignee: EraGen Biosciences, Inc.Inventors: James R. Prudent, Christopher B. Sherrill
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Patent number: 7741472Abstract: The present invention concerns modified oligonucleotides and processes for their production wherein these oligonucleotides contain at least once the structure P?N-Acc where Acc is an electron acceptor or an electron acceptor substituted with a residue R and R is any organic substituent.Type: GrantFiled: May 16, 2008Date of Patent: June 22, 2010Assignee: Roche Diagnostics Operations, Inc.Inventors: Dieter Heindl, Dirk Kessler
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Patent number: 7723319Abstract: The present invention relates to an acyclic nucleoside phosphonate derivative which is useful as an antiviral agent (particularly, against hepatitis B virus), pharmaceutically acceptable salts, stereoisomers, and a process for the preparation thereof.Type: GrantFiled: September 9, 2009Date of Patent: May 25, 2010Assignee: LG Life Sciences Ltd.Inventors: Dong-Gyu Cho, Jae-Hong Lim, Jae-Taeg Hwang, Woo-Young Cho, Hyun-Sook Jang, Chang-Ho Lee, Tae-Saeng Choi, Chung-Mi Kim, Yong-Zu Kim, Tae-Kyun Kim, Seung-Joo Cho, Gyoung-Won Kim, Jong-Ryoo Choi, Jeong-Min Kim, Kee-Yoon Roh
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Patent number: 7723511Abstract: 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 sulfurized according to the methods of the invention with higher yields than have been previously reported.Type: GrantFiled: April 21, 2008Date of Patent: May 25, 2010Assignee: Isis Pharmaceuticals, Inc.Inventors: Douglas L. Cole, Vasulinga Ravikumar, Zacharia S. Cheruvallath
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Patent number: 7700706Abstract: The present invention provides solid support media for use in oligomer synthesis, methods of producing the media, and methods of using the media. In some embodiments, the processes of the invention comprise (a) providing an organic phase comprising an olefin monomer, a cross-linker, a functionalizing reagent and an initiator; and (b) contacting the organic phase with an aqueous phase under conditions of time and temperature effective to form the polymeric bead.Type: GrantFiled: December 17, 2007Date of Patent: April 20, 2010Assignee: Isis Pharmaceuticals, Inc.Inventors: Vasulinga Ravikumar, Raju K. Kumar, Kenjirou Mori, Tatsuya Konishi, Ayako Matsunawa, Takeo Matsumura, Cheiko Kitaura, Gang Zhao
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Patent number: 7700761Abstract: Provided are processes for preparing a 3?-deoxypentopyranosyl oligomers with linkers for linking biomolecules. The processes can the steps of: bonding a 4?-protected-3?-deoxypentopyranosyl nucleoside to a solid support by coupling the 2?-OH group with a CPG support or other similar support with an amide linkage; deprotecting the 4?-protected-3?-deoxypentopyranosyl nucleoside at the 4? position; deprotecting the 4?-protected-3?-deoxypentopyranosyl nucleoside at the 4? position; and conjugating a linker to the free 4? position. The resulting product can be conjugated via the linker to a biomolecule. The method can include, prior to addition of the linker, reacting the 4?-OH group of the 4?-protected-3?-deoxypentopyranosyl nucleoside that is linked to the solid support with a 4?-protected-3?-deoxypentopyranosyl nucleoside phosphoramidite in the presence of a coupling reagent, and oxidizing the reaction product. This step can be repeated one or more times to produce an oligomer of desired length.Type: GrantFiled: May 31, 2006Date of Patent: April 20, 2010Assignee: Nanogen Recognomics GmbHInventors: Christian Miculka, Thomas Wagner, Norbert Windhab
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Patent number: 7655790Abstract: Method for synthesis, deprotection, and/or purification of nucleic acid molecules, such as oligonucleotides comprising one or more ribonucleotides. Such nucleic acid molecules include siRNA, dsRNA, ribozymes, antisense, and aptamers.Type: GrantFiled: January 12, 2005Date of Patent: February 2, 2010Assignee: Sirna Therapeutics, Inc.Inventors: Chandra Vargeese, Christopher Shaffer, Keith Bowman
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Patent number: 7635772Abstract: A process for the synthesis of an oligonucleotide is provided in which an oligonucleotide is assembled on a swellable solid support using the phosphoramidite approach in the presence of an activator, wherein the activator is not tetrazole or a substituted tetrazole. Preferred activators are pyridinium, imidazolinium and benzimidazolinium salts; benzotriazole and derivatives thereof; and saccharin or a saccharin derivative. Preferred swellable solid supports comprise functionalised polystyrene, partially hydrolysed polyvinylacetate or poly(acrylamide).Type: GrantFiled: December 16, 2003Date of Patent: December 22, 2009Assignee: Avecia Biotechnology Inc.Inventor: Paul McCormac
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Publication number: 20090312534Abstract: A method is provided for efficiently removing the silicon substituent which protects the 3?-hydroxyl group and the 5?-hydroxyl group of a ribose of a ribonucleic acid derivative in which the 2?-hydroxyl group of the ribose is protected with the following substituent (I) where WG1 represents an electron withdrawing group, and the 3?-hydroxyl group and the 5?-hydroxyl group of the ribose are protected with a silyl protecting group.Type: ApplicationFiled: February 26, 2007Publication date: December 17, 2009Applicant: NIPPON SHINYAKU CO., LTD.Inventors: Hidetoshi Kitagawa, Hirofumi Masuda
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Publication number: 20090306358Abstract: The use of N-formamidino-5-amino-3H-1,2,4-dithiazole-3-thiones as novel, efficient sulfur-transfer reagents is disclosed. The sulfur transfer from these reagents to compounds containing P(III) atom, triphenylphosphine, 5?-O-DMT-thymidine 2-cyanoethyl-(N,N-diisopropyl)phosphoramidite, and 5?-O-DMT-3?-O-levulinyl dithymidilyl 2-cyanoethyl phosphite, was studied in solution by 31P NMR and HPLC. The sulfur transfer from title compounds was also studied in the solid-phase synthesis of oligonucleotide phosphorothioates by phosphoramidite methods. In this application, the efficiency of the sulfur transfer reaction for 2?-deoxyoligonucleotides was better than 99.5%. The novel sulfurizing agents are synthesized, at low cost, using simple chemical methods.Type: ApplicationFiled: June 5, 2008Publication date: December 10, 2009Inventor: Andrei P. Guzaev
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Patent number: 7585970Abstract: A method for synthesizing a polynucleotide is disclosed. The method comprises providing a functionalized support comprising a triaryl methyl linker bound to the solid support through a substitution on one of the aryl groups, a nucleotide chain bound to the central methyl carbon of the triaryl methyl group and a nucleoside with a reactive site hydroxyl. The method further provides contacting that functionalized support with a precursor having a hydroxyl protecting group and a phosphorous derivative reactive group to produce internucleotide linkage. The resulting compound is then treated to both remove the hydroxyl protecting group on the precursor, and to oxidize the internucleotide bond.Type: GrantFiled: August 30, 2003Date of Patent: September 8, 2009Assignee: Agilent Technologies, Inc.Inventors: Douglas J Dellinger, Geraldine F Dellinger, John S Hargreaves
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Patent number: 7579459Abstract: The present invention relates to improved methods for the preparation of nucleic acids. More particularly, conventional solid supports used for nucleic acid synthesis are derivatized with activators having pKas within the 4 to 7 range. Preferentially, CPG-based solid supports are reacted with trialkoxysilanes containing an activator moiety such as pyridine. During each deblocking step of the nucleic acid synthesis cycle, bound pyridiniums are generated, yielding a weak acidic medium spreads throughout the solid support. The bound activators efficiently activate the phosphoramidite reagents towards coupling with 5?-hydroxynucleosides bound to the solid supports, thus eliminating or supplementing external deliveries of activator during the coupling steps.Type: GrantFiled: December 12, 2005Date of Patent: August 25, 2009Inventors: Nam Q. Ngo, Laurent Jaquinod
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Publication number: 20090203897Abstract: A method of synthesizing oligonucleotides is claimed. The method utilizes a synthesis column incorporating a filter-like porous polymer cartridge which contains derivatized Controlled Pore Glass (CPG) or cross-linked Polystyrene (PS) directly embedded into the polymer cartridge. Small-scale synthesis of oligonucleotides of a predetermined sequence may be accomplished by introducing reagents of the phosphoramidite method into the synthesis column. These reagents flow through the cartridge allowing the reaction sequence to take place on the derivatized CPG or PS incorporated within the polymer cartridge.Type: ApplicationFiled: February 8, 2008Publication date: August 13, 2009Applicant: Operon Biotechnologies, Inc.Inventors: Lance Larka, Philipp Wenter, Patrick A. Weiss
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Patent number: 7524950Abstract: Inkjet printhead solvents and methods of forming an addressable nucleotide array are disclosed.Type: GrantFiled: April 29, 2005Date of Patent: April 28, 2009Assignee: Agilent Technologies, Inc.Inventors: Douglas J. Dellinger, Eric LeProust, Bill Peck, Marvin H. Caruthers, Peter Cogan
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Patent number: 7511125Abstract: 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: August 19, 2004Date of Patent: March 31, 2009Assignee: CarlsbadInventors: Kuei-Ying Lin, Mark D. Matteucci
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Publication number: 20090069262Abstract: The invention relates to oligonucleotide-oligocation molecules AiBjH that can be synthetized via automated phosphoramidite chemistry having oligonucleotides moieties Ai and oligocations moieties Bj, wherein. Ai is an i-mer oligonucleotide residue, with i=5 to 50, where nucleotide A is an oligomer with naturally or non naturally occurring nucleobases and/or pentafuranosyl groups and/or native phosphodiester bonds, for example selected from the group comprising deoxyribo, ribo, locked (LNA) nucleotides as well as their chemical modifications or substitutions such as phosphorothioate, 2?-fluoro, 2?-O-alkyl, or a marker group such as a fluorescent agent, Bj is a j-mer organic oligocation moiety, with j=1 to 50, where B is selected from the group comprising .—HPO3—R1—(X—R2n)n1—X—R3—O—, where R1, R2n and R3, identical or different, are lower alkylene, X is NH or NC(NH2)2, n varies from 1 to 5 and n1=2 to 20, .Type: ApplicationFiled: December 14, 2006Publication date: March 12, 2009Inventors: Jean-Paul Behr, Mitsuharu Kotera, Benedicte Pons, Emilie Voirin, Jean-Serge Remy
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Patent number: 7501505Abstract: A process for the synthesis of oligonucleotides using phosphoramidite chemistry is provided. The process employs as activator a 1,1-dioxo-1,2-dihydro-1?6-benzo[d]isothiazol-3-one, preferably in the presence of an organic base.Type: GrantFiled: July 1, 2002Date of Patent: March 10, 2009Assignee: Avecia Biotechnology, Inc.Inventors: Nanda Sinha, William Edward Zedalis, Gregory Keith Miranda
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Publication number: 20090047712Abstract: The present invention provides phosphoramidite linkers that are useful for the production of synthesizing two or more oligonucleotides in tandem. The inventive linkers have the following desirable properties: (i) enhanced stability to alkali conditions versus the linkers previously published, (ii) cleave to produce 5? and 3? ends that are fully biologically compatible, (iii) cleave completely under conditions that are already used in cleavage/deprotection processes so they are fully compatible with conditions that are common in laboratories and do not require additives that necessitate further purification after cleavage, (iv) integrate easily onto commercially available synthesizers because they are compatible with standard coupling chemistry, and (v) are compatible with DNA, RNA, forward, reverse, and synthesis chemistries. In addition, the inventive linkers may be coupled to a solid support. Thus, the inventive linkers provide a significant advancement in the state of the art.Type: ApplicationFiled: August 15, 2007Publication date: February 19, 2009Inventors: Keith Anderson, Michael Jensen, Ronald W. Davis
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Publication number: 20090005550Abstract: The present invention concerns modified oligonucleotides and processes for their production wherein these oligonucleotides contain at least once the structure P?N-Acc where Acc is an electron acceptor or an electron acceptor substituted with a residue R and R is any organic substituent.Type: ApplicationFiled: May 16, 2008Publication date: January 1, 2009Inventors: Dieter Heindl, Dirk Kessler
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Patent number: 7439350Abstract: Nucleotide analogs characterized by the presence of an amidate linked amino acid or an ester linked group which is bonded to the phosphorus atom of phosphonate nucleotide analogs are disclosed. The analogs comprise a phosphoamidate or ester bond that is hydrolyzed in vivo to yield a corresponding phosphonate nucleotide analog. Methods and intermediates for their synthesis and use are described.Type: GrantFiled: June 29, 2004Date of Patent: October 21, 2008Assignee: Gilead Sciences, Inc.Inventors: Norbert W. Bischofberger, Robert J. Jones, Murty N. Arimilli, Kuei-Ying Lin, Michael S. Louie, Lawrence R. McGee, Ernest J. Prisbe, William A. Lee, Kenneth C. Cundy
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Patent number: 7435810Abstract: A method of fabricating polynucleotide arrays includes dissolving a nucleotide monomer, oligonucleotide, or polynucleotide in a solvent containing ionic liquid and depositing the resulting solution on an array substrate. The method has particular application to fabrication of an addressable array of polynucleotides on a substrate that carries substrate bound moieties each with a hydroxyl group. The process may be repeated at specific locations on the array to elongate the polynucleotide deposited on the array.Type: GrantFiled: December 22, 2004Date of Patent: October 14, 2008Assignee: Agilent Technologies, Inc.Inventors: Joel Myerson, Michel G M Perbost, Douglas J Dellinger, Geraldine F Dellinger
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Patent number: 7427678Abstract: This invention discloses a novel method for immobilizing molecules to a support. Specifically, this invention discloses a method of immobilizing derivatized biomolecules, such as oligonucleotides, using cycloaddition reactions, such as the Diels-Alder reaction. Included in this invention are the novel immobilized biomolecules that can be prepared according to the method of this invention.Type: GrantFiled: May 1, 2001Date of Patent: September 23, 2008Assignee: Sigma-Aldrich Co.Inventors: Wolfgang Pieken, Andreas Wolter, David P. Sebesta, Michael Leuck, Hallie A. Latham-Timmons, John Pilon, Gregory M. Husar