Deprotection Step Patents (Class 536/25.31)
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Patent number: 8431693Abstract: The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups.Type: GrantFiled: February 28, 2011Date of Patent: April 30, 2013Assignee: Alnylam Pharmaceuticals, Inc.Inventors: Muthiah Manoharan, Michael F. Jung, Kallanthottathil G. Rajeev, Rajendra K. Pandey, Gang Wang
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Publication number: 20130085272Abstract: A procedure for using thermolabile groups to protect a hydroxyl function, above all in nucleosides, nucleotides, oligomers, nucleic acids during the reactions of organic synthesis. Various new compounds that can be used to implement the procedure. The way of using thermolabile groups to protect hydroxyl functions consists in a primary, secondary and tertiary hydroxyl group converting into a groups during the reaction between a compound and a compound whose hydroxyl group is to be blocked. The blocking reaction is carried out by means of widely known methods appropriate for that purpose in the presence of a chemically basic catalyst. The obtained product has its hydroxyl group blocked. Then the compound with the group blocked can be used for the purposes of various chemical processes. After their completion, the hydroxyl group is unblocked by dissolving it in a solvent at a temperature of 50-95° C.Type: ApplicationFiled: June 1, 2011Publication date: April 4, 2013Applicant: INSTYTUT CHEMII BIOORGANICZNEJ POLSKIEJ AKADEMII NAUKInventor: Marcin Krzysztof Chmielewski
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Publication number: 20130030166Abstract: Minor groove binder phosphoramidites having unique structures have been synthesized according to particular methods. These minor groove binder phosphoramidites are useful in the preparation of oligonucleotide conjugates, particularly those for use as probes and primers.Type: ApplicationFiled: July 24, 2012Publication date: January 31, 2013Inventors: Alexei Vorobiev, Eugeny A. Lukhtanov
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Patent number: 8344132Abstract: Methods for the preparation of the ? isomer of a 9-deazapurine derivatives using benzyl protecting groups as the protecting groups for the 2 and 3 hydroxyl groups in ribose are provided.Type: GrantFiled: June 21, 2006Date of Patent: January 1, 2013Assignee: BioCryst Pharmaceticals, Inc.Inventors: Pooran Chand, Minwan Wu, Pravin L. Kotian, V. Satish Kumar, Tsu-Hsing Lin
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Patent number: 8318860Abstract: The invention relates to a method for the fluid-phase synthesis of a polymer formed from n monomers.Type: GrantFiled: September 17, 2008Date of Patent: November 27, 2012Inventors: Christian Wolfrum, Wolfgang Prinz
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Publication number: 20120296074Abstract: The problem of the present invention is provision of a method of producing an n+p-mer oligonucleotide efficiently in a high yield, which includes use of, as a starting material, an n-mer oligonucleotide wherein the 3?-terminal hydroxyl group is protected, and the 5?-terminal hydroxyl group is protected by a temporary protecting group, and continuously performing, in a solution, (1) a deprotection step of the 5?-terminal hydroxyl group, (2) a 5?-terminal elongation step by the addition of a p-mer oligonucleotide wherein the 3?-position is phosphoramidited, and (3) an oxidation step or a sulfurization step of a phosphite triester moiety. It has been found that the above-mentioned problem can be solved by adding a particular cation scavenger during the deprotection step, applying a neutralization treatment after completion of the deprotection reaction, and using a particular oxidizing agent or sulfurizing agent in the oxidation step or sulfurization step.Type: ApplicationFiled: May 17, 2012Publication date: November 22, 2012Applicant: AJINOMOTO CO., INC.Inventors: Kunihiro HIRAI, Satoshi KATAYAMA
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Publication number: 20120289691Abstract: A method of deprotecting a solid support bound polynucleotide includes the step of contacting the polynucleotide with a composition comprising a diamine under conditions sufficient to deprotect the 2?-protected ribonucleotide residue. The solid support bound polynucleotide has at least one 2?-protected ribonucleotide residue, which has the following structure: wherein BP is a protected or unprotected heterocycle; R12 is a protecting group selected from a hydrocarbyl, a substituted hydrocarbyl, an aryl, and a substituted aryl; X is O or S; and PG is a thionocarbamate protecting group.Type: ApplicationFiled: June 22, 2012Publication date: November 15, 2012Applicant: AGILENT TECHNOLOGIES, INC.Inventors: Douglas J. Dellinger, Joel Myerson, Agnieszka Sierzchala, Geraldine F. Dellinger, Zoltan Timar
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Patent number: 8309706Abstract: The invention provides methods for synthesizing oligonucleotides using nucleoside monomers having carbonate protected hydroxyl groups that are deprotected with ?-effect nucleophiles. The ?-effect nucleophile irreversibly cleave the carbonate protecting groups while simultaneously oxidizing the internucleotide phosphite triester linkage to a phosphodiester linkage. The procedure may be carried out 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.Type: GrantFiled: September 6, 2007Date of Patent: November 13, 2012Assignee: Agilent Technologies, Inc.Inventors: Douglas J. Dellinger, Marvin H. Caruthers, Jason R. Betley
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Patent number: 8304531Abstract: This invention relates to a process for the preparation of an (Rp)-8-substituted adenosine-3?,5?-cyclic phosphorothioic acid, or a salt or ester thereof, which comprises P-amidating 8-bromoadenosine-3?,5?-cyclic phosphoric acid, and reacting the P-amidate with a base and with carbon disulphide to yield (Rp)-8-bromoadenosine-3?,5?-cyclic phosphorothioic acid or a salt or ester thereof.Type: GrantFiled: September 17, 2007Date of Patent: November 6, 2012Assignee: Solvell ASInventors: Kjell Undheim, Mioara Andrei
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Patent number: 8299225Abstract: 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: GrantFiled: October 12, 2010Date of Patent: October 30, 2012Assignee: Fujitsu LimitedInventor: Tsuyoshi Fujihara
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Publication number: 20120253028Abstract: The invention relates to a process for deblocking substantially a blocked, detectably labeled oligonucleotide by contacting the blocked detectably labeled oligonucleotide with an effective amount of a nucleophilic amino compound under conditions that result in substantial deblocking of the oligonucleotide, thereby giving the substantially deblocked oligonucleotide.Type: ApplicationFiled: June 3, 2011Publication date: October 4, 2012Applicant: LIFE TECHNOLOGIES CORPORATIONInventors: Gulilat GEBEYEHU, Richard M. Pires
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Publication number: 20120220761Abstract: The present invention describes simple, efficient, and enzyme-free method of making oligonucleotides with 5?-triphosphate. This invention presents novel process for synthesizing triphosphate oligonucleotides using a diaryl phosphonate as reagent. The process of the present invention is amenable to large-scale, economic 5?-triphosphate oligonucleotide synthesis.Type: ApplicationFiled: December 22, 2009Publication date: August 30, 2012Applicant: ALNYLAM PHARMACEUTICALS, INC.Inventors: Ivan Zlatev, Francois Morvan, Jean-Jacques Vasseur, Francoise Debart, Muthiah Manoharan
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Publication number: 20120184724Abstract: A nucleoside monomer that is protected by a thionocarbamate protecting group and contains one or more 2H, 13C, or 15N isotopes in the ribose and/or base part is provided, as well as a method for making a polynucleotide that uses the same. Also provided is a polynucleotide synthesis method that employs a diamine to deprotect a protected polynucleotide.Type: ApplicationFiled: December 28, 2011Publication date: July 19, 2012Applicant: AGILENT TECHNOLOGIES, INC.Inventors: Agnieszka B. Sierzchala, Brian Phillip Smart, Douglas J. Dellinger, Geraldine Dellinger, Joel Myerson, Zoltan Timar
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Publication number: 20120178710Abstract: The invention provides methods for the synthesis of cyclic dinucleotides and thiophosphate analogs thereof as well as a new family of analogs of cyclic diguanosine monophosphate that includes a series of seven phosphorothioate derivatives that includes diastereomers of mono-, di-, and trithiophosphates.Type: ApplicationFiled: July 1, 2010Publication date: July 12, 2012Applicant: Rutgers, The State University of New JerseyInventors: Roger A. Jones, Barbara L. Gaffney
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Patent number: 8212020Abstract: This invention relates to the field of nucleic acid chemistry, more specifically to the field of compositions of matter that comprise triphosphates of modified 2?-deoxynucleosides and oligonucleotides that are formed when these are appended to the 3?-end of a primer, wherein said modifications comprise NH2 moiety attached to their 3?-hydroxyl group and a fluorescent species in a form of a tag affixed to the nucleobase via a linker that can be cleaved. Such compositions and their associated processes enable and improve the sequencing of oligonucleotides using a strategy of cyclic reversible termination, as outlined in U.S. Pat. No. 6,664,079. Most specifically, the invention concerns compositions of matter that are 5?-triphosphates of ribo- and 2?-deoxyribonucleosides carrying detectable tags and oligonucleotides that might be derived from them.Type: GrantFiled: March 23, 2009Date of Patent: July 3, 2012Inventors: Steven Albert Benner, Daniel Hutter, Nicole Aurora Leal, Fei Chen
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Patent number: 8202985Abstract: Nucleotide monomers, polynucleotides, methods of making each, and methods of deprotecting each, are disclosed. An embodiment of the nucleotide monomer, among others, includes a nucleotide monomer having a heterobase protecting group selected from structures I through III as described herein. An embodiment of the polynucleotide, among others, includes a plurality of nucleotide moieties having a heterobase protecting group selected from one of structures I through III as described herein.Type: GrantFiled: March 23, 2006Date of Patent: June 19, 2012Assignees: Agilent Technologies, Inc., The Regents of the University of ColoradoInventors: Douglas J. Dellinger, Zoltan Timar, Agnieszka Sierzchala, Geraldino Dellinger, Marvin H. Caruthers
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Patent number: 8193336Abstract: A method and apparatus are provided for performing light-directed reactions in spatially addressable channels within a plurality of channels. One aspect of the invention employs photoactivatable reagents in solutions disposed into spatially addressable flow streams to control the parallel synthesis of molecules immobilized within the channels. The reagents may be photoactivated within a subset of channels at the site of immobilized substrate molecules or at a light-addressable site upstream from the substrate molecules. The method and apparatus of the invention find particularly utility in the synthesis of biopolymer arrays, e.g., oligonucleotides, peptides and carbohydrates, and in the combinatorial synthesis of small molecule arrays for drug discovery.Type: GrantFiled: June 19, 2009Date of Patent: June 5, 2012Inventor: Robert S. Foote
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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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Patent number: 8158774Abstract: The present invention relates to a simple, economical method for introducing substituent (I) at the 2?-hydroxyl group of the ribose of a ribonucleic acid derivative whose 3?-hydroxyl group and 5?-hydroxyl group are protected with a silicon protecting group, wherein WG1 represents an electron-withdrawing group: The invention also relates to a method for producing a ribonucleic acid derivative of formula (3), comprising the reaction of a ribonucleic acid derivative of formula (1) with a monothioacetal compound of formula (2) to produce the ribonucleic acid derivative of formula (3), using iodine as the reagent for halogenating the sulfur atom of the monothioacetal compound of formula (2) in the presence of an acid: In formulae (1), (2), and (3), Bz represents a nucleobase which may or may not have a protecting group; WG1 represents an electron-withdrawing group; R3 represents alkyl or aryl; and A represents a silicon substituent.Type: GrantFiled: August 1, 2007Date of Patent: April 17, 2012Assignee: Nippon Shinyaku Co., Ltd.Inventors: Hidetoshi Kitagawa, Kouichi Uetake
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Patent number: 8158775Abstract: The present invention provides a method for removing a 2-cyanoethoxymethyl (CEM) group, which substitutes the 2?-hydroxyl group of each ribose of an oligonucleic acid derivative, with good reproducibility and high efficiency. The present invention further provides a method for producing an oligonucleic acid derivative represented by the following general formula (11), characterized by using a sulfoxide-based solvent or an amide-based solvent or a mixture thereof as a reaction solvent in the step of removing a protecting group, which protects the 2?-hydroxyl group of each ribose of an oligonucleic acid derivative represented by the following general formula (10) by allowing TBAF to act on the oligonucleic acid derivative.Type: GrantFiled: February 26, 2007Date of Patent: April 17, 2012Assignee: Nippon Shinyaku Co., Ltd.Inventor: Yoshinobu Shiba
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Publication number: 20120070825Abstract: Disclosed are compounds of formula (I), a derivative, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. Also disclosed are methods of preparing compound of formula (I), a derivative, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer. Further disclosed are methods of conducting drug discovery and research comprises applying the compound of formula (I), a derivative, or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or said tautomer in an investigation.Type: ApplicationFiled: May 20, 2010Publication date: March 22, 2012Applicant: Sena Research, Inc.Inventor: Zhen Huang
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Patent number: 8138330Abstract: The present invention discloses novel methods for the synthesis of oligonucleotides with nucleoside phosphoramidites on solid supports. The methods comprise the stepwise chain assembly of oligonucleotides on supports with 5?-acyl phosphoramidites. The synthesis cycles consist of a front end deprotection step which is conducted with a solution of a primary amine or a phenolate, a phosphoramidite coupling step with a 5?-acyl nucleoside phosphoramidite in the presence of an activator, a phosphite oxidation step and an optional capping step. The novel methods improve the quality of synthetic oligonucleotides due to the irreversibility of the front end deprotection step, which prevents the formation of deletion sequences, and due to the avoidance of acidic reagents in the synthesis cycles, which prevent the formation of depurination side products.Type: GrantFiled: September 11, 2007Date of Patent: March 20, 2012Assignee: Sigma-Aldrich Co. LLCInventors: Michael Leuck, Andreas Wolter, Alfred Stumpe
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Publication number: 20120010396Abstract: The present invention provides a method for producing a porous resin bead containing an aromatic vinyl compound-hydroxystyrene-di(meth)acrylate copolymer, the method including: dissolving a monomer mixture containing an aromatic vinyl compound, an acyloxystyrene and a di(meth)acrylate compound, and a polymerization initiator in an organic solvent to obtain a solution containing the monomer mixture and the polymerization initiator; suspending the solution in water in the presence of a dispersion stabilizer; performing a suspension copolymerization to thereby obtain an aromatic vinyl compound-acyloxystyrene-di(meth)acrylate compound copolymer; and hydrolyzing an acyloxy group of the acyloxystyrene monomer component in the copolymer. The porous resin bead produced by the method of the present invention can be suitably used, for example, as a support for solid phase synthesis.Type: ApplicationFiled: September 19, 2011Publication date: January 12, 2012Applicant: NITTO DENKO CORPORATIONInventors: Kenjiro MORI, Tatsuya KONISHI, Eri MAETA
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Patent number: 8093372Abstract: The invention relates to a process for deblocking substantially a blocked, detectably labeled oligonucleotide by contacting the blocked detectably labeled oligonucleotide with an effective amount of a nucleophilic amino compound under conditions that result in substantial deblocking of the oligonucleotide, thereby giving the substantially deblocked oligonucleotide.Type: GrantFiled: February 13, 2003Date of Patent: January 10, 2012Assignee: Life Technologies CorporationInventors: Gulilat Gebeyehu, Richard M Pires
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Patent number: 8071755Abstract: The invention provides for nucleotide analogs and methods of using the same, e.g., for sequencing nucleic acids.Type: GrantFiled: April 4, 2008Date of Patent: December 6, 2011Assignee: Helicos Biosciences CorporationInventors: J. William Efcavitch, Suhaib Siddiqi, Philip R. Buzby, Judith Mitchell, Edyta Krzymanska-Olejnik, Subramanian Marappan, Xiaopeng Bai, Atanu Roy, Mirna Jarosz, Jayson Bowers
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Publication number: 20110294213Abstract: Oligonucleotides with a novel sugar-phosphate backbone containing at least one 2?-arabino-fluoronucleoside and an internucleoside 3?-NH—P(?O)(OR)—O-5? linkage, where R is a positively charged counter ion or hydrogen, and methods of synthesizing and using the inventive oligonucleotides are provided. The inventive phosphoramidate 2?-aribino-fluorooligonucleotides have a high RNA binding affinity to complementary nucleic acids and are base and acid stable.Type: ApplicationFiled: July 27, 2011Publication date: December 1, 2011Inventors: Sergei Gryaznov, Ronald G. Schultz
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Publication number: 20110294122Abstract: Methods for preparation of 2?,3?-dideoxynucleotides support structures, such as 2?,3?-dideoxyguanosine, 2?,3?-dideoxyadenosine, and 3?-deoxythymidine support structures are disclosed. Various methods of using such structures are also provided, such as their use for automated DNA synthesis and pyrophosphorolysis activated polymerization.Type: ApplicationFiled: May 26, 2011Publication date: December 1, 2011Applicant: Life Technologies CorporationInventors: Zhaochun Ma, Khairuzzaman Bashar Mullah, Robert Eason
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Patent number: 8063198Abstract: The present invention relates to processes and reagents for oligonucleotide synthesis and purification. One aspect of the present invention relates to compounds useful for activating phosphoramidites in oligonucleotide synthesis. Another aspect of the present invention relates to a method of preparing oligonucleotides via the phosphoramidite method using an activator of the invention. Another aspect of the present invention relates to sulfur-transfer agents. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to a method of preparing a phosphorothioate by treating a phosphite with a sulfur-transfer reagent of the invention. In a preferred embodiment, the sulfur-transfer agent is a 3-amino-1,2,4-dithiazolidine-5-one. Another aspect of the present invention relates to compounds that scavenge acrylonitrile produced during the deprotection of phosphate groups bearing ethylnitrile protecting groups.Type: GrantFiled: March 18, 2008Date of Patent: November 22, 2011Assignee: Alnylam Pharmaceuticals, Inc.Inventors: Muthiah Manoharan, Michael E. Jung, Kallanthottathil G. Rajeev, Rajendra K. Pandey, Gang Wang
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Patent number: 8063199Abstract: A method is disclosed for isolating both free and protein-associated DNA from bodily fluids, such as urine, saliva, serum, tears, sweat, cerebral spinal fluid, and plasma. The method comprises as a first step concentrating and isolating both the free DNA and the proteins present in the bodily fluid. The proteins are then digested in order to release the formerly protein-associated DNA from the isolated proteins. Lastly, the free and formerly protein-associated DNA can be isolated and purified.Type: GrantFiled: January 15, 2007Date of Patent: November 22, 2011Assignee: Norgen Biotek Corp.Inventor: Yousef Haj-Ahmad
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Publication number: 20110282044Abstract: The present invention describes simple, efficient, and enzyme-free method of making oligonucleotide phosphate derivatives. This invention presents novel process using automated synthesizer for synthesizing oligonucleotide phosphate derivatives using a diaryl phosphonate as reagent.Type: ApplicationFiled: July 30, 2010Publication date: November 17, 2011Applicant: ALNYLAM PHARMACEUTICALSInventors: Muthiah MANOHARAN, Ivan ZLATEV
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Patent number: 8039611Abstract: Provided is a ribonucleoside derivative represented by General Formula (I): (wherein R1 represents a hydrogen atom or the like, R2 represents a hydrogen atom or the like, R3 represents a methyl group or the like, and B represents a nucleic acid base residue optionally having a protecting group or a modifying group). An RNA containing this ribonucleoside derivative shows excellent hybridization ability and resistance to nuclease.Type: GrantFiled: March 8, 2007Date of Patent: October 18, 2011Assignee: Tokyo Institute of TechnologyInventors: Mitsuo Sekine, Takeshi Yamada, Hisao Saneyoshi, Kohji Seio
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Patent number: 8034923Abstract: Processes are disclosed that use 3?-reversibly terminated nucleoside triphosphates to analyze DNA for purposes other than sequencing using cyclic reversible termination. These processes are based on the unexpected ability of terminal transferase to accept these triphosphates as substrates, the unexpected ability of polymerases to add reversibly and irreversibly terminated triphosphates in competition with each other, the development of cleavage conditions to remove the terminating group rapidly, in high yield, and without substantial damage to the terminated oligonucleotide product, and the ability of reversibly terminated primer extension products to capture groups. The presently preferred embodiments of the disclosed processes use a triphosphate having its 3?-OH group blocked as a 3?-ONH2 group, which can be removed in buffered NaNO2 and use variants of Taq DNA polymerase, including one that has a replacement (L616A).Type: GrantFiled: March 27, 2009Date of Patent: October 11, 2011Inventors: Steven Albert Benner, Daniel Hutter, Nicole Aurora Leal, Fei Chen
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Publication number: 20110245460Abstract: According to the present invention, there is provided a process for the preparation of a first compound selected from peptides, oligonucleotides and peptide nucleic acids. The process comprises synthesising the first compound and then separating the first compound formed in step (i) from a second compound, which is a reaction by-product of the synthesis of the first compound and/or an excess of a reagent used for the synthesis of a first compound by a process of diafiltration. The membrane used for the diafiltration process is stable in organic solvents and provides a rejection for the first compound which is greater than the rejection for the second compound.Type: ApplicationFiled: August 7, 2009Publication date: October 6, 2011Applicant: IMPERIAL INNOVATIONS LIMITEDInventors: Andrew Guy Livingston, Ludmila Georgieva Peeva, Sheyung Wang Jerry So, Renato Campos Vasconceles, Robin John Leatherbarrow, Edward William Tate, Piers Robert James Gaffney
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Patent number: 8030459Abstract: The present invention relates to biodegradable biocompatible polyketals, methods for their preparation, and methods for creating animals by administration of biodegradable biocompatible polyketals. In one aspect, a method for forming the biodegradable biocompatible polyketals comprises combining a glycol-specific oxidizing agent with a polysaccharide to form an aldehyde intermediate, which is combined with a reducing agent to form the biodegradable biocompatible polyketal. The resultant biodegradable biocompatible polyketals can be chemically modified to incorporate additional hydrophilic moieties. A method for treating animals includes the administration of the biodegradable biocompatible polyketal in which biologically active compounds or diagnostic labels can be disposed. The present invention also relates to chiral polyketals, methods for their preparation, and methods for use in chromatographic applications, specifically in chiral separations.Type: GrantFiled: July 18, 2003Date of Patent: October 4, 2011Assignee: The General Hospital CorporationInventors: Mikhail I. Papisov, Alexander Yurkovetskiy
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Publication number: 20110237786Abstract: A method for preparing oligonucleotide comprising reacting the compound of Formula (1) with the compound of Formula (2) in a liquid reaction medium under the condition of condensation reaction to obtain the compound of formula (3). In the method according to the present invention, the functional groups are protected by suitable protective groups to only expose the 5?-OH of the compound of Formula (1) (OH-component) and the 3?-phosphate of the compound of Formula (2) (P-component) which are to be connected, so that the condensation reaction is carried out in a liquid reaction medium to bond the OH-component and P-component to obtain DNA or RNA short chain. The method of the present invention does not need a solid phase column and can be carried out in a liquid reaction medium. Thus, oligonucleotides can be synthesized on a large scale.Type: ApplicationFiled: September 22, 2009Publication date: September 29, 2011Applicant: SUZHOU RIBO LIFE SCIENCE CO., LTDInventors: Zhen Xi, Jinyu Huang, Junbin Zhang
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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 -
Patent number: 7999087Abstract: Nucleoside monomers, nucleic acids, e.g., oligonucleotides and polynucleotides, methods of making each, methods of deprotecting each, and the like are disclosed herein. Aspects of the invention include 2? silyl containing thiocarbonate protecting groups. Corresponding compositions and methods are provided.Type: GrantFiled: November 15, 2007Date of Patent: August 16, 2011Assignee: Agilent Technologies, Inc.Inventors: Douglas J. Dellinger, Agnieska Sierzchala, Marvin H. Caruthers, Geraldine F. Dellinger
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Publication number: 20110087014Abstract: A process for manufacturing an oligonucleotide which comprises removing ?-eliminating phosphorus-protecting groups, in particular ?-cyanoethyl protective groups from a protected oligonucleotide, wherein said removing comprises contacting the protected oligonucleotide with an amine solution in a solvent which preferably does not consist of pyridine, wherein the conjugate acid of the amine has preferably a pKa of greater than 11.5, and wherein the concentration of the amine in the solution is less than 0.5 mole/liters.Type: ApplicationFiled: April 24, 2009Publication date: April 14, 2011Applicant: GIRINDUS AMERICA, INC.Inventors: Tadeusz Krzysztof Wyrzykiewicz, Hagen Cramer, Huihe Zhu, Kevin James Finn
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Publication number: 20110082288Abstract: This invention provides a novel method for purifying synthetic oligomers comprising capping, polymerizing and separating any failure sequences produced during oligomer synthesis. Either the failure sequence or the full-length oligomer may be polymerized. Optionally, small molecule impurities may also be incorporated into the polymerized material. The invention provides novel capping agents having a polymerizable functional group. The invention also provides kits comprising at least one composition of the present invention.Type: ApplicationFiled: December 13, 2010Publication date: April 7, 2011Applicant: MICHIGAN TECHNOLOGICAL UNIVERSITYInventor: Shiyue Fang
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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: 7872121Abstract: Nitrogen-protecting groups are removed from the exocyclic nucleobase portion of a 2?-O protected nucleotide or 2?-halo nucleotide by contacting the nucleotide with an inorganic base. Typical is the removal of t-butylphenoxyacetyl protecting groups from the nucleobase portion of a 2?-O protected nucleotide on which the 2?-O protecting group is t-butyldimethylsilyl, removal or deprotection being accomplished by contact with a potassium carbonate solution.Type: GrantFiled: April 15, 2005Date of Patent: January 18, 2011Assignee: Avecia Biotechnology, Inc.Inventors: Nanda Dulal Sinha, Satya Kuchimanchi
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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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Patent number: 7846660Abstract: The present invention is a method for synthesizing microarrays having different oligonucleotides present within one feature area of the array. The method utilizes the techniques common to microarray synthesis, but limits the duration in which selected feature areas on the array are initially dosed with light so as to only deprotect a calculated ratio of the compounds forming the array's binding layer. The compounds initially deprotected are capped with a non-photosensitive protecting group, such as di-methoxy-trityl, to inhibit their involvement in the synthesis of a first group of DNA strands built onto the array. Once the first group of DNA strands have been synthesized, the original deprotected group may then be further processed to build one or more groups of DNA strands in the same feature area as the first group of DNA strands. The present invention also includes microarrays manufactured using the method.Type: GrantFiled: November 27, 2006Date of Patent: December 7, 2010Assignee: Roche Nimblegen, Inc.Inventors: Thomas Albert, Jason Norton, Roland Green
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Patent number: 7820810Abstract: The present invention provides an improved process for the synthesis of 2?-O-substituted purine nucleosides. The process includes anhydro or thioanhydro ring opening of a selected 8,2?-cyclopurine nucleoside with a weak nucleophile in the presence of a Lewis acid ester, followed by reduction to afford the desired 2?-O-substituted purine nucleoside.Type: GrantFiled: March 19, 2008Date of Patent: October 26, 2010Assignee: Isis Pharmaceuticals, Inc.Inventor: Vasulinga Ravikumar
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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: 7795423Abstract: The present invention provides a new labeling reagent for preparing modified oligonucleotides and processes for their production wherein these oligonucleotides contain at least once the structure P?N—SO2-benzole-L-M-X, characterized in that L is either —(CH2)n- or polyethylene glycol, M is selected from a group consisting of —NH—, —O—, —S—, and —COO—, and X is either a protecting group or a detectable unit. L is preferably either —(CH2)n- or polyethylene glycol.Type: GrantFiled: May 20, 2008Date of Patent: September 14, 2010Assignee: Roche Diagnostics Operations, Inc.Inventor: Dieter Heindl
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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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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