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51. 发明申请

US20070026393A1 Detection of variations in the dna methylation profile 审中-公开
标题翻译：检测dna甲基化谱中的变异
公开(公告)号：US20070026393A1
公开(公告)日：2007-02-01
申请号：US10240970
申请日：2001-04-06
申请人： Kurt Berlin , Christian Piepenbrock , Alexander Olek
发明人： Kurt Berlin , Christian Piepenbrock , Alexander Olek
IPC分类号： C12Q1/68 , C07H21/04
CPC分类号： C07K14/82 , C07K14/4703 , C12Q1/6883 , C12Q2600/154
摘要： The invention describes a set of oligonucleotides as probes for the detection of relevant variations of DNA methylation in a target group of genes, the use thereof for the detection of gene variants with respect to DNA methylation, a medical device which uses a set of oligonucleotides, a method for investigating the methylation state of an individual as well as a method for creating a model for evaluating the probability of occurrence of a health problem of an individual. Such disorders can be: undesired drug interactions cancer diseases CNS malfunctions, damage or disease symptoms of aggression or behavioral disturbances clinical, psychological and social consequences of brain lesions psychotic disturbances and personality disorders dementia and/or associated syndromes cardiovascular disorder, malfunction and damage malfunction, damage or disorder of the gastrointestinal tract malfunction, damage or disorder of the respiratory system lesion, inflammation, infection, immunity and/or convalescence malfunction, damage or disease of the body as an abnormality in the development process malfunction, damage or disorder of the skin, the muscles, the connective tissue or the bones endocrine and metabolic malfunction, damage or disorder headaches or sexual malfunction.
摘要翻译：本发明描述了一组寡核苷酸作为用于检测靶基因组中DNA甲基化的相关变异的探针，其用于检测关于DNA甲基化的基因变体的用途，使用一组寡核苷酸的医疗装置，用于研究个体的甲基化状态的方法以及用于创建用于评估个体的健康问题的发生概率的模型的方法。这种疾病可以是：不期望的药物相互作用癌症疾病中枢神经系统疾病，侵袭或行为障碍的损伤或疾病症状临床，脑损伤的心理和社会后果精神障碍和人格障碍痴呆和/或相关综合征心血管疾病，故障和损伤故障，胃肠道的损伤或紊乱，呼吸系统病变的损伤或紊乱，炎症，感染，免疫和/或康复失败，身体的损伤或疾病，作为发育过程失败的异常，皮肤的损伤或障碍，肌肉，结缔组织或骨骼内分泌和代谢功能障碍，损伤或障碍性头痛或性功能障碍。

52. 发明申请

US20060263779A1 Method for the detection of cytosine methylation patterns with high sensitivity 审中-公开
标题翻译：高灵敏度检测胞嘧啶甲基化模式的方法
公开(公告)号：US20060263779A1
公开(公告)日：2006-11-23
申请号：US10544161
申请日：2004-01-30
申请人： Kurt Berlin
发明人： Kurt Berlin
IPC分类号： C12Q1/68 , C12P19/34
CPC分类号： C12Q1/6827 , C12Q1/686 , C12Q2527/137 , C12Q2523/125 , C12Q2535/125 , C12Q2525/185
摘要： The present invention concerns a method for the detection of cytosine methylation in DNA samples, in which the following steps are conducted: a genomic DNA sample which comprises target DNA and background DNA is chemically treated such that all unmethylated cytosine bases are converted to uracil, while the 5-methylcytosine bases remain unchanged; the chemically treated DNA sample is amplified with the use of at least 2 primer oligonucleotides as well as a polymerase and a nucleotide mixture, the composition of which leads to a preference for the target DNA over the background DNA as the template; and the methylation state in the target DNA is concluded from the presence of an amplificate or its quantity.
摘要翻译：本发明涉及检测DNA样品中胞嘧啶甲基化的方法，其中进行以下步骤：将包含靶DNA和背景DNA的基因组DNA样品进行化学处理，使得所有未甲基化胞嘧啶碱基转化成尿嘧啶，同时 5-甲基胞嘧啶碱基保持不变; 使用至少2个引物寡核苷酸以及聚合酶和核苷酸混合物扩增化学处理的DNA样品，其组合导致在背景DNA上作为模板的靶DNA优先选择; 并且目标DNA中的甲基化状态从扩增子或其量的存在得出。

53. 发明申请

US20060166201A1 Method for the detection of nucleic acid sequences by means of crackable probe molecules 审中-公开
标题翻译：通过可裂解的探针分子检测核酸序列的方法
公开(公告)号：US20060166201A1
公开(公告)日：2006-07-27
申请号：US10526277
申请日：2003-09-01
申请人： Philipp Schatz , Matthias Schuster , Kurt Berlin
发明人： Philipp Schatz , Matthias Schuster , Kurt Berlin
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6816 , C12Q2563/167
摘要： The present invention describes a method for the detection of nucleic acid sequences, which is characterized in that the following steps are conducted: a) at least one nucleic acid is bound to a solid phase; b) probe molecules are hybridized to the nucleic acids in a sequence-specific manner, whereby the probe molecules are provided with a cleavable bond and a mass label, which is specific for the probe molecule; c) removal of the unhybridized probe molecules; d) contacting of the hybridized probe molecules with a matrix, which cleaves said cleavable bonds and at the same time serves as the matrix in a MALDI mass spectrometer; e) detection of the mass label at those positions where the nucleic acid was bound.
摘要翻译：本发明描述了用于检测核酸序列的方法，其特征在于进行以下步骤：a）至少一种核酸与固相结合; b）探针分子以序列特异性方式与核酸杂交，由此提供探针分子具有可切割键和对于探针分子是特异性的质量标记; c）去除未杂交的探针分子; d）将杂交的探针分子与基质接触，所述基质切割所述可切割键，并同时用作MALDI质谱仪中的基质; e）在核酸结合的那些位置检测质量标签。

54. 发明申请

US20060136142A1 Systems, methods and computer program products for guiding selection of a therapeutic treatment regimen based on the methylation status of the DNA 审中-公开
标题翻译：基于DNA的甲基化状态指导治疗方案选择的系统，方法和计算机程序产品
公开(公告)号：US20060136142A1
公开(公告)日：2006-06-22
申请号：US10774052
申请日：2004-02-06
申请人： Kurt Berlin , Alexander Olek , Christian Piepenbrock
发明人： Kurt Berlin , Alexander Olek , Christian Piepenbrock
IPC分类号： G06F19/00
CPC分类号： G06Q50/24 , G16B20/00 , Y02A90/22 , Y02A90/26
摘要： Systems, methods and computer program products for guiding selection of a therapeutic treatment regimen or a preventive therapeutic treatment regimen are disclosed. The method comprises (A) providing to a computing device comprising a first knowledge base comprising information about a plurality of different methylation statuses at selected sites of the DNA in cells with a known disease or medical condition and/or healthy cells, a second knowledge base comprising a plurality of expert rules for evaluating and selecting a type of disease or medical condition based on the methylation status at selected sites of the DNA of a patient, (B) generating in said computing device a ranked listing of diseases or medical conditions based on the information about the methylation status at selected sites of the DNA of the patient, the first knowledge base and the second knowledge base.
摘要翻译：公开了用于指导选择治疗方案或预防性治疗方案的系统，方法和计算机程序产品。该方法包括（A）提供给包括第一知识库的计算设备，所述第一知识库包括关于具有已知疾病或医学状况和/或健康细胞的细胞中所述DNA的选定位点处的多个不同甲基化状态的信息，和第二知识库包括用于基于患者的DNA的选定位点处的甲基化状态来评估和选择疾病或医学状况的多种专家规则，（B）在所述计算设备中产生基于以下的疾病或医疗状况的排名列表：关于患者DNA选定位点甲基化状态的信息，第一知识库和第二知识库。

55. 发明授权

US07008770B1 Method for the controlled implementation of complex PCR amplifications 失效
标题翻译：用于控制实施复杂PCR扩增的方法
公开(公告)号：US07008770B1
公开(公告)日：2006-03-07
申请号：US10130094
申请日：2000-11-12
申请人： Kurt Berlin
发明人： Kurt Berlin
IPC分类号： C12Q1/68 , C07H21/04
CPC分类号： C12Q1/6827 , C12Q1/6837 , C12Q2600/16 , C12Q2537/143
摘要： A method is described for controllably conducting complex PCR amplifications, wherein at least the following steps are conducted: a) PCR amplification with at least 50 primers of a first type (type 1) of different sequence, which are complementary to one of the strands of a random DNA sample, and also with a primer or a library of primers of a second type (type 2), which is complementary to the other strand of the DNA sample used, wherein the type 2 primers contain a first label (label 1); b) hybridizing of the amplified products to an oligomer array, which comprises oligonucleotides that hybridize to the primers utilized in the PCR reaction or to oligonucleotides that are complementary to these; or hybridizing of the amplified products to an oligomer array, which contains oligomers complementary to the primers utilized in the PCR reaction; c) length determination of the amplified products bound to the array by a second label (label 2) which can be correlated with the length of the respective DNA fragment, and which is different from the first label (label 1) in step a) and d) quantification of the signals originating from label 1 and label 2 at each site of the oligonucleotide array relevant for the analysis.
摘要翻译：描述了可控地进行复合PCR扩增的方法，其中进行至少以下步骤：a）使用至少50个不同序列的第一类型（类型1）的引物进行PCR扩增，所述引物与随机DNA样品，以及与所使用的DNA样品的另一条链互补的第二类型（类型2）的引物或引物文库，其中所述2型引物含有第一标记（标记1） ; b）将扩增产物与寡聚体阵列杂交，所述寡聚体阵列包含与PCR反应中使用的引物杂交的寡核苷酸或与其互补的寡核苷酸; 或将扩增产物杂交到寡聚体阵列，其含有与PCR反应中使用的引物互补的寡聚物; c）通过第二标记（标号2）测定与阵列结合的扩增产物的长度，其可以与各个DNA片段的长度相关，并且与步骤a）中的第一标记（标号1）不同， d）定量与分析相关的寡核苷酸阵列的每个位置处的来自标记1和标记2的信号。

56. 发明授权

US10731215B2 Method for determining the presence or absence of methylation in a sample 有权
公开(公告)号：US10731215B2
公开(公告)日：2020-08-04
申请号：US11910887
申请日：2006-04-17
申请人： Matthias Ballhause , Kurt Berlin , Theo De Vos , Dimo Dietrich , Volker Liebenberg , Catherine Lofton-Day , Joe Lograsso , Jennifer Maas , Fabian Model , Matthias Schuster , Andrew Z. Sledziewski , Reimo Tetzner
发明人： Matthias Ballhause , Kurt Berlin , Theo De Vos , Dimo Dietrich , Volker Liebenberg , Catherine Lofton-Day , Joe Lograsso , Jennifer Maas , Fabian Model , Matthias Schuster , Andrew Z. Sledziewski , Reimo Tetzner
IPC分类号： C12Q1/68 , C12Q1/6883 , C12N15/10 , C12Q1/6806 , C07H21/04
摘要： Aspects of the present invention relate to compositions and methods for providing DNA fragments from a remote sample. In particular aspects a remote sample comprising DNA is provided, DNA is isolated from the remote sample, and the isolated DNA is treated in a way which allows differentiation of methylated and unmethylated cytosine. Additional, particular embodiments provide compositions and methods for methylation analysis of DNA derived from a remote sample. Other aspects provide for compositions and methods of whole genome amplification of bisulfite treated DNA. Other aspects provide methods for determining the presence or absence of methylation of at least one cytosine, or a series of cytosines in cis, in human DNA of a blood sample, a plasma sample, a serum sample or a urine sample from a human individual.

57. 发明授权

US07932027B2 Method for determining the methylation pattern of a polynucleic acid 有权
标题翻译：确定多核酸甲基化模式的方法
公开(公告)号：US07932027B2
公开(公告)日：2011-04-26
申请号：US11355417
申请日：2006-02-16
申请人： Anne Fassbender , Ralf Lesche , Juergen Distler , Christian Piepenbrock , Tamas Rujan , Kurt Berlin , Thomas Koenig
发明人： Anne Fassbender , Ralf Lesche , Juergen Distler , Christian Piepenbrock , Tamas Rujan , Kurt Berlin , Thomas Koenig
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6827 , C12Q2531/113 , C12Q2525/191 , C12Q2521/331
摘要： Particular aspects relate to a method for determining the methylation pattern of a polynucleic acid, comprising: a) preparing a solution comprising a mixture of fragments of the polynucleic acid; b) coupling the fragments with a substance being detectable with a detection method; c) contacting a solution comprising the fragments of b) with a DNA microarray having a plurality of different immobilized oligonucleotides, each comprising at least one methylation site, at respectively assigned different locations thereon, the contacting under conditions affording hybridization of fragments with correlated immobilized oligonucleotides under defined stringency, and wherein the immobilized oligonucleotides have a length of less than 200 bases; d) optionally performing a a washing step; and e) detecting, using the physical detection method, such immobilized nucleic acids to which solution fragments are hybridized and/or to which solution fragments are not hybridized.
摘要翻译：具体方面涉及确定多核酸的甲基化模式的方法，其包括：a）制备包含所述多核酸的片段的混合物的溶液; b）将片段与可用检测方法检测的物质偶联; c）使包含b）的片段的溶液与分别具有多个不同的固定化寡核苷酸的DNA微阵列接触，所述多个不同的固定化寡核苷酸分别包含至少一个甲基化位点，分别在其上指定了不同的位置，在提供相关的固定化寡核苷酸的片段杂交的条件下进行接触在限定的严格性下，并且其中所述固定的寡核苷酸具有小于200个碱基的长度; d）任选地执行洗涤步骤; 以及e）使用所述物理检测方法检测将所述固定化的核酸与所述溶液片段杂交并且/或所述溶液片段未杂交的固定化核酸。

58. 发明授权

US07756643B2 Method for determining the biological effect and/or activity of at least one drug, chemical substances and/or pharmaceutical composition based on their effect on the methylation status of DNA 失效
标题翻译：基于它们对DNA的甲基化状态的影响来确定至少一种药物，化学物质和/或药物组合物的生物学效应和/或活性的方法
公开(公告)号：US07756643B2
公开(公告)日：2010-07-13
申请号：US10087898
申请日：2002-03-01
申请人： Alexander Olek , Kurt Berlin
发明人： Alexander Olek , Kurt Berlin
IPC分类号： G01N33/48 , G06G7/48
CPC分类号： C12Q1/6827 , C12Q1/6837 , Y02A90/26 , C12Q2523/125 , C12Q2535/125
摘要： This invention is related to methods, systems and computer program products for determining the biological effect and/or activity of drugs, chemical substances and/or pharmaceutical compositions using their effect on DNA-methylation as a marker for their biological effect(s). The invention is further related to the use of the inventive methods, systems and computer program products in obtaining new biologically active compounds which can be used as so-called “lead”-compounds for new and effective medicaments and treatment strategies of, in particular, human diseases.
摘要翻译：本发明涉及用于确定药物，化学物质和/或药物组合物的生物效应和/或活性的方法，系统和计算机程序产品，其使用它们对DNA甲基化的作用作为其生物学效应的标记。本发明进一步涉及本发明的方法，系统和计算机程序产品在获得新的生物活性化合物中的用途，所述新的生物活性化合物可用作新的和有效的药物的所谓“铅”化合物和治疗策略，人类疾病

59. 发明申请

US20090208941A1 Method for investigating cytosine methylations in dna 审中-公开
标题翻译：在dna中调查胞嘧啶甲基化的方法
公开(公告)号：US20090208941A1
公开(公告)日：2009-08-20
申请号：US11989081
申请日：2006-07-19
申请人： Kurt Berlin , Matthias Schuster , Philipp Schatz
发明人： Kurt Berlin , Matthias Schuster , Philipp Schatz
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6827
摘要： A method for sensitive and specific detection of cytosine methylation is described wherein the DNA to be analyzed is subjected to initial enrichment. More specifically, said enrichment can be effected in a methylation-specific, sequence-specific or origin-specific fashion. Thereafter, the enriched DNA is converted in a methylation-specific fashion. The converted DNA can be analyzed using various methods, particularly real-time PCR methods.
摘要翻译：描述了用于敏感和特异性检测胞嘧啶甲基化的方法，其中待分析的DNA经受初始富集。更具体地，所述富集可以以甲基化特异性，序列特异性或起始特异性方式实现。此后，富集的DNA以甲基化特异性方式转化。可以使用各种方法，特别是实时PCR方法分析转化的DNA。

60. 发明申请

US20080220418A1 Method For Providing Dna Fragments Derived From An Archived Sample 有权
标题翻译：提供从存档样本派生的Dna片段的方法
公开(公告)号：US20080220418A1
公开(公告)日：2008-09-11
申请号：US11664367
申请日：2005-09-30
申请人： Matthias Ballhause , Kurt Berlin , Dimo Dietrich , Antje Lukas , Matthias Schuster , Ute Wagner , Reinhold Wasserkort , Heike Ziebarth
发明人： Matthias Ballhause , Kurt Berlin , Dimo Dietrich , Antje Lukas , Matthias Schuster , Ute Wagner , Reinhold Wasserkort , Heike Ziebarth
IPC分类号： C12Q1/68 , C07H1/00 , C12P19/34
CPC分类号： C12Q1/6806 , C12N15/1003 , C12Q1/6858 , C12Q1/686 , C12Q2523/125 , C12Q2527/137 , C12Q2527/149 , C12Q2531/107
摘要： Aspects of the present invention relate to compositions and methods for providing DNA fragments from an archived sample (e.g., paraffin-embedded and/or fixed-tissue biopsies, etc). Particular aspects provide methods whereby high yields of DNA are isolated as well as a substantial portion of the DNA consists of long DNA fragments, and where the isolated genomic DNA is free of associated or cross-linked contaminants like proteins, peptides, amino acids or RNA. The methods are facile, cost-effective, an are characterized by high reproducibility and reliability. Particular aspects provide methods for providing DNA fragments derived from an archived sample, wherein the yield of DNA before, for example, an amplification step is at least 20%, and amplicons up to a length of about 1,000 base pairs are amplifiable.
摘要翻译：本发明的方面涉及从归档样品（例如石蜡包埋和/或固定组织活组织检查等）提供DNA片段的组合物和方法。具体方面提供了分离DNA的高产率以及大部分DNA由长DNA片段组成并且分离的基因组DNA不含相关或交联的污染物如蛋白质，肽，氨基酸或RNA的方法。这些方法是容易的，具有成本效益的，其特征在于重现性和可靠性高。特定方面提供用于提供衍生自归档样品的DNA片段的方法，其中在例如扩增步骤之前的DNA的产量为至少20％，并且可扩增至约1000个碱基对的扩增子。

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