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1. 发明申请

WO2013158936A1 MONITORING IMMUNOGLOBULIN HEAVY CHAIN EVOLUTION IN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA 审中-公开
标题翻译：监测B细胞急性淋巴细胞白血病中的免疫球蛋白重链发生
公开(公告)号：WO2013158936A1
公开(公告)日：2013-10-24
申请号：PCT/US2013/037258
申请日：2013-04-18
申请人： SEQUENTA, INC , PEPIN, Francois , CARLTON, Victoria , KLINGER, Mark , FAHAM, Malek
发明人： PEPIN, Francois , CARLTON, Victoria , KLINGER, Mark , FAHAM, Malek
IPC分类号： C12Q1/68 , C07H21/04
CPC分类号： C12Q1/6886 , C12Q2600/156
摘要： The invention is directed to methods of monitoring B-cell lymphoid proliferative disorders, such as B-cell acute lymphoblastic leukemias, by measuring the presence, absence and/or levels of correlating, or index, clonotypes and related clonotypes that have evolved therefrom, for example, as part of the disease condition. In one aspect, such methods are implemented by generating sequencing-based clonotype profiles and determining frequencies of correlating, or index, clonotypes present, including new clonotypes that have evolved therefrom, particularly, in the case of B-cell ALL, by VH substitution. The invention also includes use of such monitoring information to modify treatment status of a patient.
摘要翻译：本发明涉及监测B细胞淋巴样增殖性疾病如B细胞急性淋巴细胞白血病的方法，其通过测量从其发展而来的克隆型和相关克隆型的存在，不存在和/或水平，以及相关的克隆型，例如，作为疾病状况的一部分。在一个方面，这样的方法通过产生基于测序的克隆型谱并确定存在的克隆型的相关或指数的频率来实现，包括从其发展的新克隆型，特别是在B细胞ALL的情况下，通过VH取代。本发明还包括使用这种监测信息来修改患者的治疗状态。

2. 发明申请

WO2013134302A1 MONITORING IMMUNE RESPONSIVENESS TO CANCER VACCINATION 审中-公开
标题翻译：监测免疫对疫苗接种的反应
公开(公告)号：WO2013134302A1
公开(公告)日：2013-09-12
申请号：PCT/US2013/029181
申请日：2013-03-05
申请人： SEQUENTA, INC. , FAHAM, Malek , KLINGER, Mark
发明人： FAHAM, Malek , KLINGER, Mark
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6881 , C12Q2600/156
摘要： The invention is direct to a method for determining a cancer patient's immune responsiveness to anti-cancer vaccination. In one aspect, for each of a plurality of vaccinations, pairs of clonotype profiles are obtained, one immediately prior to vaccination and one during the period of peak immune response, usually within two to twenty days after the vaccination. Responsiveness is correlated to successive increases in identical clonotypes within each pair of clonotype profiles in at least two successive vaccinations.
摘要翻译：本发明直接涉及确定癌症患者对抗癌疫苗接种的免疫反应性的方法。在一个方面，对于多个接种中的每一个，通常在疫苗接种后的二至二十天内获得一对克隆型谱，一个在接种前一个，一个在免疫应答峰期期间。响应性与至少两次连续接种疫苗中每对克隆型谱中相同克隆型的连续增加相关。

3. 发明申请

WO2013090469A1 DETECTION AND MEASUREMENT OF TISSUE-INFILTRATING LYMPHOCYTES 审中-公开
标题翻译：组织浸润淋巴细胞的检测和测量
公开(公告)号：WO2013090469A1
公开(公告)日：2013-06-20
申请号：PCT/US2012/069310
申请日：2012-12-12
申请人： SEQUENTA, INC. , FAHAM, Malek , KLINGER, Mark
发明人： FAHAM, Malek , KLINGER, Mark
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6881 , C12Q1/06 , G01N33/5091 , G01N33/5094
摘要： The present invention is drawn to methods for measuring numbers, levels, and/or ratios of cells, such as lymphocytes, infiltrated into a solid tissue, such as a tumor or a tissue affected by an autoimmune disease, and to methods for making patient prognoses based on such measurements. In one aspect, methods of the invention comprise sorting lymphocytes from an accessible tissue, such as peripheral blood, into functional subsets, such as cytotoxic T cells and regulatory T cells, and generating clonotype profiles of each subset. An inaccessible disease- affected tissue is sampled and one or more clonotype profiles are generated. From the latter clonotype profiles, levels lymphocytes in each of the functional subsets are determined in the disease-affected tissue by their clonotypes, which are identified from lymphocytes sorted into subsets from the accessible tissue.
摘要翻译：本发明涉及用于测量浸润到固体组织例如肿瘤或受自身免疫性疾病影响的组织的细胞例如淋巴细胞的数量，水平和/或比率的方法，以及用于产生患者预后的方法基于这样的测量。在一个方面，本发明的方法包括将淋巴细胞从诸如外周血的可及组织分选成功能性亚类，例如细胞毒性T细胞和调节性T细胞，以及产生每个子集的克隆型谱。对不能接近的疾病影响的组织进行采样，并产生一个或多个克隆型谱。从后一种克隆型谱中，通过其克隆型在疾病影响组织中测定每个功能亚类中的淋巴细胞水平，所述克隆型从从可及组织分类为亚群的淋巴细胞中鉴定。

4. 发明申请

WO2013090390A2 METHOD OF MEASURING IMMUNE ACTIVATION 审中-公开
标题翻译：测量免疫激活的方法
公开(公告)号：WO2013090390A2
公开(公告)日：2013-06-20
申请号：PCT/US2012/069187
申请日：2012-12-12
申请人： SEQUENTA, INC. , FAHAM, Malek , KLINGER, Mark
发明人： FAHAM, Malek , KLINGER, Mark
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6881 , C12Q2600/156
摘要： The invention is directed to a method of detecting immune activation in an individual by measuring frequencies and sizes of certain groups of related clonotypes, referred to herein as "clans," in a clonotype profile of the individual. A clan may arise from a single lymphocyte progenitor that gives rise to many related lymphocyte progeny, each possessing and/or expressing a slightly different immunoglobulin receptor due to somatic mutation(s), such as base substitutions, inversions, related rearrangements resulting in common V(D)J gene segment usage, or the like. Immune activation is correlated to frequencies and sizes of clans in a clonotype profile exceeding reference values for those features.
摘要翻译：本发明涉及通过测量个体的克隆型谱中某些相关克隆型组（本文中称为“部落”）的频率和大小来检测个体中的免疫激活的方法。一个氏族可能由单个淋巴细胞祖细胞产生，其引起许多相关的淋巴细胞后代，每个拥有和/或表达由于体细胞突变而导致的略微不同的免疫球蛋白受体，例如碱基取代，反转，相关重排导致普通V （D）J基因片段的用途等。免疫激活与克隆型分布中部族的频率和大小相关，超过这些特征的参考值。

5. 发明申请

WO2013086462A1 METHOD OF MEASURING IMMUNE ACTIVATION 审中-公开
标题翻译：测量免疫激活的方法
公开(公告)号：WO2013086462A1
公开(公告)日：2013-06-13
申请号：PCT/US2012/068631
申请日：2012-12-07
申请人： SEQUENTA, INC. , FAHAM, Malek , KLINGER, Mark
发明人： FAHAM, Malek , KLINGER, Mark
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6869 , C12Q1/6883 , C12Q2600/118
摘要： The invention is directed to methods for measuring immune activation by the level of clonotypes having the same unique regions and different isotype-determining regions. In one aspect, the method of the invention comprises forming a sequence-based clonotype profile from a sample containing B lymphocytes, wherein each clonotype of such profile comprises a unique region, such as a portion of a VDJ segment, and an isotype determining region, such as a portion of a C gene segment. Immune activation is indicated whenever the level of such clonotypes exceeds an upper bound of a reference range determined from multiple individual measurements or population measurements.
摘要翻译：本发明涉及通过具有相同独特区域和不同同种型确定区域的克隆型水平测量免疫激活的方法。一方面，本发明的方法包括从含有B淋巴细胞的样品形成基于序列的克隆型谱，其中这种分布的每个克隆型包含独特的区域，例如VDJ片段的一部分和同种型确定区，例如C基因区段的一部分。每当这种克隆型的水平超过从多个单独测量或群体测量确定的参考范围的上限时，就表示免疫活化。

6. 发明申请

WO2013134162A2 DETERMINING PAIRED IMMUNE RECEPTOR CHAINS FROM FREQUENCY MATCHED SUBUNITS 审中-公开
标题翻译：确定来自频率匹配子载体的配对的免疫受体链
公开(公告)号：WO2013134162A2
公开(公告)日：2013-09-12
申请号：PCT/US2013/028942
申请日：2013-03-04
申请人： SEQUENTA, INC. , FAHAM, Malek , KLINGER, Mark
发明人： FAHAM, Malek , KLINGER, Mark
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6886 , C12N15/1034 , C12Q1/6883 , C12Q2600/112
摘要： The invention is directed to methods for determining nucleic acids that encode immune receptor chains originating from the same cell, that is, paired immune receptor chains. Methods of the invention comprise high-throughput sequencing of rearranged nucleic acids encoding immune receptors from one or more samples of lymphocytes. In one aspect, from a plurality of subsets of a sample, nucleic acids encoding separate chains of a pair are separately sequenced, wherein the size of the sample and the number of subsets are selected so that the distribution of lymphocytes approximates a binomial model. Paired chains are determined by identifying pairs that appear together or that are entirely absent in the subsets.
摘要翻译：本发明涉及用于测定编码源自相同细胞的免疫受体链的核酸的方法，即配对的免疫受体链。本发明的方法包括编码来自淋巴细胞的一个或多个样品的免疫受体的重排核酸的高通量测序。一方面，从样品的多个子集中，分别对编码一对分离链的核酸进行测序，其中选择样品的大小和子集的数目，使得淋巴细胞的分布近似于二项式模型。配对链通过识别出在一起或完全不存在于子集中的对确定。

7. 发明申请

WO2014026031A1 HIGH SENSITIVITY MUTATION DETECTION USING SEQUENCE TAGS 审中-公开
标题翻译：使用序列标签的高灵敏度突变检测
公开(公告)号：WO2014026031A1
公开(公告)日：2014-02-13
申请号：PCT/US2013/054189
申请日：2013-08-08
申请人： SEQUENTA, INC. , FAHAM, Malek
发明人： FAHAM, Malek
IPC分类号： C12Q1/68 , C12N15/11
CPC分类号： C12Q1/6874 , C12Q1/6827 , C12Q1/6869 , C12Q2521/501 , C12Q2523/107 , C12Q2525/185 , C12Q2525/191 , C12Q2525/307 , C12Q2531/125 , C12Q2535/122 , C12Q2565/543
摘要： The invention is directed to methods for increasing the sensitivity of high throughput sequencing, particularly for distinguishing true rare mutations from amplification, sequencing and other sample processing errors that occur in sequencing techniques. In one aspect, methods of the invention includes steps of (a) preparing templates from nucleic acids in a sample; (b) labeling by sampling the templates to form tag-template conjugates, wherein substantially every template of a tag-template conjugate has a unique sequence tag; (c) linearly amplifying the tag- template conjugates; (d) generating a plurality of sequence reads from the linearly amplified tag- template conjugates; and (e) determining a nucleotide sequence of each of the nucleic acids based on the frequencies, or numbers, of each type of nucleotide at each nucleotide position of each plurality of sequence reads having identical sequence tags.
摘要翻译：本发明涉及用于增加高通量测序的灵敏度的方法，特别是用于区分在测序技术中发生的真实罕见突变与扩增，测序和其他样品处理错误。一方面，本发明的方法包括以下步骤：（a）从样品中的核酸制备模板; （b）通过对模板进行取样以形成标签 - 模板缀合物进行标记，其中基本上标签 - 模板缀合物的每个模板具有唯一的序列标签; （c）线性扩增标签 - 模板缀合物; （d）从线性放大的标签 - 模板缀合物生成多个序列读数; 和（e）基于在具有相同序列标签的每个多个序列读取的每个核苷酸位置处的每种类型的核苷酸的频率或数量来确定每种核酸的核苷酸序列。

8. 发明申请

WO2013036459A3 SEQUENCE-BASED MEASURES OF IMMUNE RESPONSE 审中-公开
公开(公告)号：WO2013036459A3
公开(公告)日：2013-03-14
申请号：PCT/US2012/053530
申请日：2012-08-31
申请人： SEQUENTA, INC. , FAHAM, Malek , MOORHEAD, Martin , WILLIS, Thomas
发明人： FAHAM, Malek , MOORHEAD, Martin , WILLIS, Thomas
IPC分类号： C12Q1/68 , C12Q1/02
摘要： The invention is directed to methods of measuring an immune response by comparing sequence-based clonotype frequency data from successively measured clonotype profiles. In particular, the invention includes immunotherapies of cancers, such as lymphomas, that include sensitive pre- and post-vaccination sequence-based measurements of changes in a patient's immune repertoire, thereby providing a sensitive measure of the likelihood of treatment success.

9. 发明申请

WO2013155119A1 DETECTION AND QUANTITATION OF SAMPLE CONTAMINATION IN IMMUNE REPERTOIRE ANALYSIS 审中-公开
标题翻译：免疫样品分析中样品污染的检测和定量
公开(公告)号：WO2013155119A1
公开(公告)日：2013-10-17
申请号：PCT/US2013/035857
申请日：2013-04-09
申请人： SEQUENTA, INC. , ASBURY, Thomas , CARLTON, Victoria , FAHAM, Malek , MACEVICZ, Stephen , MOORHEAD, Martin , WILLIS, Thomas , ZHENG, Jianbiao
发明人： ASBURY, Thomas , CARLTON, Victoria , FAHAM, Malek , MACEVICZ, Stephen , MOORHEAD, Martin , WILLIS, Thomas , ZHENG, Jianbiao
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6848 , G06F19/00 , C12Q2525/161 , C12Q2535/122
摘要： The invention is directed to methods for detecting and quantifying nucleic acid contamination in a tissue sample of an individual containing T cells and/or B cells, which is used for generating a sequence-based clonotype profile. In one aspect, the invention is implemented by measuring the presence and/or level of an endogenous or exogenous nucleic acid tag by which nucleic acid from an intended individual can be distinguished from that of unintended individuals. Endogenous tags include genetic identity markers, such as short tandem repeats, rare clonotypes or the like, and exogenous tags include sequence tags employed to determine clonotype sequences from sequence reads.
摘要翻译：本发明涉及用于检测和定量含有T细胞和/或B细胞的个体的组织样品中的核酸污染物的方法，其用于产生基于序列的克隆型谱。在一个方面，本发明通过测量内源或外源核酸标签的存在和/或水平来实现，通过该核酸标签，来自预期个体的核酸可以与非预期个体的核酸区别。内源性标签包括遗传同一性标记，例如短串联重复，罕见克隆型等，外源标签包括用于从序列读数确定克隆型序列的序列标签。

10. 发明申请

WO2013085855A1 CLONOTYPES AS BIOMETRIC SPECIMEN TAGS 审中-公开
标题翻译： CLONOTYPES作为生物标本标签
公开(公告)号：WO2013085855A1
公开(公告)日：2013-06-13
申请号：PCT/US2012/067656
申请日：2012-12-03
申请人： SEQUENTA, INC. , FAHAM, Malek , WILLIS, Thomas
发明人： FAHAM, Malek , WILLIS, Thomas
IPC分类号： C12Q1/68 , C12Q1/04 , G01N1/28
CPC分类号： C12Q1/6874 , C12Q1/04 , C12Q1/6869 , C12Q1/6888 , C12Q2537/143 , C12Q2563/185
摘要： The invention is directed to methods for biometrically identifying or distinguishing biological specimens, such as patient specimens, as being from the same or different individuals by analysis of specimen clonotypes. The invention provides a direct or backup method for determining or confirming specimen identities. In one aspect, a method of the invention includes generating a first clonotype profile from a first specimen and forming therefrom an identifier set of clonotypes, which serves as a molecular fingerprint of the first specimen. Other specimens are determined to be from the same source individual or from a different source individual by generating clonotype profiles from such specimens and determining the presence or absence in such profiles of clonotypes of the identifier set of the first specimen.
摘要翻译：本发明涉及通过分析样品克隆型将生物样本（例如患者标本）生物测定识别或区分为来自相同或不同个体的方法。本发明提供了用于确定或确认样本身份的直接或备用方法。在一个方面，本发明的方法包括从第一样本产生第一克隆型谱，并由其形成克隆型的标识符集合，其用作第一标本的分子指纹。通过从这些样品中产生克隆型谱并确定在第一样品的标识符集合的克隆型的这种分布的存在或不存在，确定其它样品来自相同的来源个体或来自不同的来源个体。

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