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21. 发明授权

US07794936B1 Using thymidine analogs to improve replication in an expanded genetic alphabet 有权
标题翻译：使用胸苷类似物改善扩增的基因字母表中的复制
公开(公告)号：US07794936B1
公开(公告)日：2010-09-14
申请号：US11541295
申请日：2006-09-29
申请人： Steven Albert Benner , Albert Michael Sismour
发明人： Steven Albert Benner , Albert Michael Sismour
IPC分类号： C12Q1/68
CPC分类号： C12Q1/6844 , C12Q2525/117 , C12Q2521/101
摘要： This invention relates to nucleoside, nucleotide, and oligonucleotide analogs that incorporate non-standard nucleobase analogs, those that present a pattern of hydrogen bonds to a paired nucleobase analog in a complementary strand that is different from the pattern presented by adenine, guanine, cytosine, and thymine. Most specifically, this invention discloses and claims processes for amplifying nucleic acid analogs containing non-standard nucleobases using polymerase chain reactions, and combinations of non-standard nucleobases, analogs of standard nucleotides, and enzymes that perform this amplification. Most specifically, this invention is for the use of 2-thiothymidine triphosphate (2-thioTTP) instead of thymidine triphosphate in a six letter polymerase chain reaction that includes 2′-deoxyadenosine triphosphate, 2′-deoxyguanosine triphosphate, 2′-deoxycytidine triphosphate, 2′-deoxy-iso-guanosine triphosphate, and 2′-deoxy-iso-cytidine triphosphate, as well as their forms that contain side chain modifications. Because of the size and hydrogen bonding properties of the sulfur unit in 2-thioT, 2-thioT does not mispair effectively with the minor tautomer of isoG. This permits the PCR amplification of a six letter artificially expanded genetic information system, we examined the relative rates of misincorporation of 2-thioTTP and TTP opposite isoG using affinity electrophoresis with a fidelity-per-round of ca. 98%. The analogous PCR employing TTP has a fidelity-per-round of only ca. 93%. Therefore, this invention represents the first example of a six letter artificial genetic system that is amplifiable by a thermostable polymerase, and capable of Darwinian evolution.
摘要翻译：本发明涉及包含非标准核碱基类似物的核苷，核苷酸和寡核苷酸类似物，那些与互补链中的配对核碱基类似物呈现氢键图案的核苷酸，核苷酸和寡核苷酸类似物不同于腺嘌呤，鸟嘌呤，胞嘧啶，和胸腺嘧啶。最具体地，本发明公开并要求使用聚合酶链反应扩增含有非标准核碱基的核酸类似物的方法，以及非标准核碱基，标准核苷酸的类似物和进行该扩增的酶的组合。最具体地，本发明是在六字母聚合酶链反应中使用二硫代胸苷三磷酸（2-硫代TTP）代替三磷酸胸苷，其包括二脱氧腺苷三磷酸，2'-脱氧鸟苷酸三磷酸，2'-脱氧胞苷三磷酸， 2'-脱氧异鸟苷三磷酸和2'-脱氧 - 异胞苷三磷酸，以及其含有侧链修饰的形式。由于2-硫代噻硫单元的大小和氢键性质，2-硫代不能有效地与异构体的次互变异构体失配。这允许PCR扩增六个字母的人工扩增的遗传信息系统，我们使用亲和力电泳，以每秒保真度为单位检查了2-thioTTP和TTP与isoG的错配合相对速率。 98％。使用TTP的类似的PCR具有仅保留每一倍的保真度。 93％。因此，本发明代表了可通过热稳定聚合酶扩增并具有达尔文进化的六字母人造遗传系统的第一个例子。

22. 发明授权

US07741294B1 Non-standard nucleobases implementing the isocytidine and isoguanosine hydrogen bonding patterns 有权
标题翻译：非标准核碱基实现异细胞苷和异鸟嘌呤氢键合模式
公开(公告)号：US07741294B1
公开(公告)日：2010-06-22
申请号：US11371756
申请日：2006-03-09
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： A01N43/04 , C07H21/02 , C07H7/06
CPC分类号： C07H21/00 , C07D405/04 , C07D487/04 , C12N15/111 , C12N2310/33 , C12N2320/52
摘要： This invention provides compositions of matter that, when incorporated into an oligonucleotide, present to a complementary strand in a Watson-Crick pairing geometry a pattern of hydrogen bonds that is different from the pattern presented by adenine, guanine, cytosine, and thymine. Most specifically, this invention discloses and claims compositions of matter that present the same hydrogen bonding patterns as the isocytidine and isoguanosine nucleobases, but do not have unfavorable tautomeric forms, do not become disassociated from their sugar, and do not make major groove interactions, as much, as easily, or as strongly as isocytidine and isoguanosine.
摘要翻译：本发明提供了当组合成寡核苷酸时，在Watson-Crick配对几何中存在与腺嘌呤，鸟嘌呤，胞嘧啶和胸腺嘧啶呈现的图案不同的氢键图案。最具体地说，本发明公开并要求具有与异细胞苷和异鸟嘌呤核碱基相同的氢键形式但不具有不利的互变异构形式的物质组合物，不会与糖分离，并且不会产生大的沟槽相互作用，如非常容易或与异胞苷和异鸟嘌呤一样强烈。

23. 发明授权

US06617106B1 Methods for preparing oligonucleotides containing non-standard nucleotides 失效
标题翻译：制备含有非标准核苷酸的寡核苷酸的方法
公开(公告)号：US06617106B1
公开(公告)日：2003-09-09
申请号：US09538338
申请日：2000-03-29
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： C12Q168
CPC分类号： C07H21/00 , C12N15/102 , C12P19/34 , C12Q1/68 , Y10S977/80 , Y10S977/898 , Y10S977/915
摘要： The disclosure describes building blocks for preparing oligonucleotides carrying non-standard nucleobases that can pair with complementary non-standard nucleobases so as to fit the Watson-Crick geometry, in that the resulting base pair joins a monocyclic six membered ring pairing with a fused bicyclic heterocyclic ring system composed of a five member ring fused with a six membered ring, with the orientation of the heterocycles with respect to each other and with respect to the backbone chain analogous to that found in DNA and RNA, but with a pattern of hydrogen bonds holding the base pair together different from that found in the AT and GC base pairs (a “non-standard base pair”).
摘要翻译：本公开描述了用于制备携带非互补非标准核碱基的非标准核碱基的寡核苷酸的构建块，以便适应沃森 - 克里克几何，因为得到的碱基对与稠合的双环杂环连接单环六元环配对环系统由与六元环稠合的五元环组成，杂环相对于彼此的方向和相对于骨架链的取向类似于DNA和RNA中发现的，但具有氢键的模式碱基对与AT和GC碱基对（“非标准碱基对”）中发现的不同。

24. 发明授权

US09334534B1 Processes replacing standard nucleotides by non-standard nucleotides and non-standard nucleotides by standard nucleotides in DNA 有权
标题翻译：用DNA中的标准核苷酸替换非标准核苷酸和非标准核苷酸的方法
公开(公告)号：US09334534B1
公开(公告)日：2016-05-10
申请号：US12653613
申请日：2009-12-16
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： C12P19/34 , C12Q1/68 , C07H21/04
CPC分类号： C12P19/34 , C07H21/04 , C12Q1/6844 , C12Q1/6869 , C12Q2525/117 , C12Q2521/101
摘要： This invention concerns non-standard nucleotides that can form non-standard Watson-Crick nucleobase pairs having geometries similar to the geometries of standard nucleotide pairs, but that are joined by a non-standard hydrogen bonding schemes. Disclosed are processes that yield oligonucleotides that are semi-complementary to a standard oligonucleotide, where the region of semi-complementarity pairs one or more standard nucleotides with a non-standard nucleotide, or vice versa. Duplexes formed from two semi-complementary oligonucleotides are also inventions disclosed. The processes extending a primer annealed to an oligonucleotide template with a polymerase in the presence of a non-standard nucleoside triphosphate and a mixture of standard nucleoside triphosphates, where the non-standard triphosphate is incorporated opposite the standard triphosphate because it has available a protonated or deprotonated form, or a minor tautomeric form, that is complementary in the Watson-Crick sense to the standard nucleotide, even though in its normal form (neither protonated or deprotonated, or as its major tautomer) it is complementary in the Watson-Crick sense to a non-standard nucleobase. Also disclosed are processes that exploit an intermediary nucleoside, one whose nucleobase is partially complementary to both a standard nucleotide and a non-standard nucleotide at two of their three hydrogen bonding units. Also disclosed are intermediary nucleotides whose hydrogen bonding patterns are changed by chemical reagents. Also disclosed are the vice versa processes and process pairs where standard nucleotides are incorporated opposite non-standard nucleotides, yielding clonable products that can be sequenced to determine where non-standard nucleotides were present in the parent template oligonucleotide.
摘要翻译：本发明涉及可以形成具有类似于标准核苷酸对的几何形状但具有非标准氢键合方案的几何形式的非标准沃森 - 克里克核碱基对的非标准核苷酸。公开了产生与标准寡核苷酸半互补的寡核苷酸的方法，其中半互补区域与一个或多个具有非标准核苷酸的标准核苷酸对应，反之亦然。由两个半互补寡核苷酸形成的双链体也是公开的发明。在非标准核苷三磷酸盐和标准核苷三磷酸盐的混合物存在下，使用聚合酶将引物退火至寡核苷酸模板的方法，其中非标准三磷酸盐与标准三磷酸盐相结合，因为其可用于质子化或即使在正常形式（既不质子化还是去质子化，或作为其主要互变异构体），它在沃森 - 克里克意思上与沃森 - 克里克意识相互补充，就是在沃森 - 克里克的意义上是互补的到非标准核碱基。还公开了利用中间核苷的方法，其核碱基与其三个氢键单元中的两个处的标准核苷酸和非标准核苷酸部分互补。还公开了通过化学试剂改变其氢键图案的中间核苷酸。还公开了相反的过程和方法对，其中标准核苷酸与非标准核苷酸相结合，产生可测序的可克隆产物以确定亲本模板寡核苷酸中存在非标准核苷酸的位置。

25. 发明授权

US08153361B1 Dynamic and combinatorial synthesis of polymerase primers 有权
标题翻译：聚合酶引物的动态和组合合成
公开(公告)号：US08153361B1
公开(公告)日：2012-04-10
申请号：US11702327
申请日：2007-02-05
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： C12Q1/68 , C12P19/34 , C07H21/00
CPC分类号： C12P19/34
摘要： This invention relates to the field of nucleic acid chemistry, more specifically to compositions of matter that are nucleic acid analogs, and processes that use them. Still more specifically, these compositions comprise two fragments of DNA-like molecules, each having one or more ends modified to carry a reactive group, where the reactive group on one fragment can form a transient covalent bond with the reactive group on the other under conditions of dynamic equilibrium to form a composite, where the composite can then bind to a target oligonucleotide, such as a DNA or RNA molecule. Most specifically, once the transient covalent bond forms, the composite serves as a primer for a template-directed polymerization using a DNA polymerase, an RNA polymerase, or a reverse transcriptase. Once incorporated, the epimerization causes the base pair to be destabilized, the duplex containing the epimerized nucleoside to likewise be destabilized, and the double strand to then disassociate. This leaves the template available to template the synthesis of another complementary oligonucleotide containing the epimerizing base.
摘要翻译：本发明涉及核酸化学领域，更具体地涉及作为核酸类似物的物质组合物以及使用它们的方法。更具体地，这些组合物包含两个DNA样分子的片段，每个片段具有一个或多个末端被修饰以携带反应性基团，其中一个片段上的反应性基团可以在条件下与另一个片段上的反应性基团形成瞬时共价键的动态平衡以形成复合物，其中复合物然后可以结合靶DNA，例如DNA或RNA分子。最具体地，一旦形成瞬时共价键，该复合物用作使用DNA聚合酶，RNA聚合酶或逆转录酶的模板定向聚合的引物。一旦并入，差向异构化导致碱基对失去稳定，含有差向异构化核苷的双链体同样地不稳定，然后双链脱离。这使模板可用于模拟含有差向异构化碱基的另一互补寡核苷酸的合成。

26. 发明申请

US20110124053A1 POLYMERASE INCORPORATION OF NON-STANDARD NUCLEOTIDES 有权
标题翻译：聚合物纳入非标准核素
公开(公告)号：US20110124053A1
公开(公告)日：2011-05-26
申请号：US12999138
申请日：2009-06-16
申请人： Steven Albert Benner , Fei Chen , Zunyi Yang
发明人： Steven Albert Benner , Fei Chen , Zunyi Yang
IPC分类号： C12P19/34
CPC分类号： C12Q1/6853 , C12P19/34 , C12Q1/686 , C12Q2521/101 , C12Q2525/117 , C12Q2525/191
摘要： The disclosed invention teaches processes to amplify oligonucleotides by contacting templates and primers with DNA polymerases and triphosphates of non-standard nucleotides, which form nucleobase pairs fitting the standard Watson-Crick geometry, but joined by hydrogen bonding patterns different from those that join standard A:T and G:C pairs. Thus, this invention relates to nucleotide analogs and their derivatives that, when incorporated into DNA and RNA, expand the number of replicatable nucleotides beyond the four found in standard DNA and RNA. The invention further relates to polymerases that incorporate those non-standard nucleotide analogs into oligonucleotide products using the corresponding triphosphate derivatives, and more specifically, polymerases and non-standard nucleoside triphosphates that support the polymerase chain reaction (PCR), including PCR where the products contain more than one non-standard nucleotide unit. Examples are provides that show this process using 6-amino-5-nitro-3-(1′-beta-D-2′-deoxyribofuranosyl)-2(1H)-pyridone to implement the non-standard “small” donor-donor-acceptor (pyDDA) hydrogen bonding pattern, and 2-amino-8-(r-beta-D-2′-deoxyribofuranosyl)-imidazo[1,2-α]-1,3,5-triazin-4(8H)-one to implement the “large” acceptor-acceptor-donor (puADD) pattern.
摘要翻译：所公开的发明教导了通过使模板和引物与DNA聚合酶和非标准核苷酸的三磷酸接触来扩增寡核苷酸的过程，其形成适合标准Watson-Crick几何形状的核碱基对，但是通过与加入标准A： T和G：C对。因此，本发明涉及核苷酸类似物及其衍生物，其在掺入DNA和RNA时扩大超出标准DNA和RNA中发现的四种可重复核苷酸的数量。本发明还涉及使用相应的三磷酸衍生物，更具体地，支持聚合酶链式反应（PCR）的聚合酶和非标准核苷三磷酸（包括产物含有的PCR）的寡核苷酸产物，将这些非标准核苷酸类似物结合到聚合酶中的聚合酶多个非标准核苷酸单位。提供了使用6-氨基-5-硝基-3-（1'-β-D-2'-脱氧三呋喃糖基）-2（1H） - 吡啶酮来实施非标准“小”供体 - 供体 - 受体（pyDDA）氢键图案和2-氨基-8-（r-β-D-2'-脱氧三呋喃糖基） - 咪唑并[1,2-α] -1,3,5-三嗪-4（8H） - 实施“大”受体 - 受体 - 供体（puADD）模式。

27. 发明授权

US06377893B1 Application of protein structure predictions 失效
公开(公告)号：US06377893B1
公开(公告)日：2002-04-23
申请号：US08914375
申请日：1997-08-19
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： G06G748
CPC分类号： G01N33/6803
摘要： A method for making a model for the folded structure of a set of proteins from an evolutionary analysis of a set of aligned homologous protein sequences was claimed in Ser. No. 07/857,224. The instant application concerns methods for using these models. The first method is used to confirm or deny a hypothesis that two proteins are homologous, and is comprised of comparing a predicted structure model for one family of proteins with a predicted structure model for a second family of proteins, or an experimental structure for the second family, and deducing the presence or absence of homology based on the presence or absence of structural similarity flanking key residue motifs in the polypeptide sequence. The second method identifies mutations during the divergent evolution of a protein sequence that are potentially adaptive by identifying episodes during the divergent evolution of a family of proteins where there is a high absolute rate of amino acid substitution, or a high ratio of non-silent substitutions to non-silent substitutions. Amino acids that are changing during this episode are likely to be adaptive. The third is a method for identifying specific in vitro properties of the protein that are likely to play a physiological role in vivo in an organism. This methods involves synthesizing in the laboratory proteins having the reconstructed amino acid sequences of a protein before and after a period of rapid sequence evolution that characterizes adaptive substitution, measuring the in vitro properties of the protein before the episode of rapid sequence evolution, and then measuring the in vivo properties of the protein after the episode of rapid sequence evolution. The in vitro behaviors that remained unchanged through this episode are not likely to have adaptive significance physiologically. The in vitro behaviors that changed through this episode are likely to have adaptive significance physiologically. The fourth concerns method for organizing genome sized sequence databases.

28. 发明授权

US6140496A Precursors for deoxyribonucleotides containing non-standard nucleosides 失效
标题翻译：含有非标准核苷的脱氧核糖核苷酸的前体
公开(公告)号：US6140496A
公开(公告)日：2000-10-31
申请号：US775401
申请日：1996-12-31
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： C07H21/00 , C12N15/10 , C12P19/34 , C12Q1/68 , C07H19/00
CPC分类号： C07H21/00 , C12N15/102 , C12P19/34 , C12Q1/68 , Y10S977/80 , Y10S977/898 , Y10S977/915
摘要： The disclosure describes building blocks for preparing oligonucleotides carrying non-standard nucleobases that can pair with complementary non-standard nucleobases so as to fit the Watson-Crick geometry, in that the resulting base pair joins a monocyclic six membered ring pairing with a fused bicyclic heterocyclic ring system composed of a five member ring fused with a six member ring, with the orientation of the heterocycles with respect to each other and with respect to the backbone chain analogous to that found in DNA and RNA, but with a pattern of hydrogen bonds holding the base pair together different from that found in the AT and GC base pairs (a "non-standard base pair").
摘要翻译：本公开描述了用于制备携带非互补非标准核碱基的非标准核碱基的寡核苷酸的构建块，以便适应沃森 - 克里克几何，因为得到的碱基对与稠合的双环杂环连接单环六元环配对环系统由与六元环稠合的五元环组成，杂环相对于彼此和相对于骨架链的取向类似于DNA和RNA中发现的，但具有氢键的模式，碱基对与AT和GC碱基对（“非标准碱基对”）中发现的不同。

29. 发明授权

US6001983A Oligonucleotides with non-standard bases and methods for preparing same 失效
标题翻译：具有非标准碱基的寡核苷酸及其制备方法
公开(公告)号：US6001983A
公开(公告)日：1999-12-14
申请号：US375132
申请日：1995-01-17
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： C07H21/00 , C12N15/10 , C12P19/34 , C07H1/00
CPC分类号： C07H21/00 , C12N15/102 , C12P19/34
摘要： The disclosure describes new compositions of matter that are analogs of DNA and RNA containing heterocyclic bases that can form base pairs that fit the Watson-Crick geometry in that they involve a monocyclic six membered ring pairing with a fused bicyclic heterocyclic ring system composed of a five member ring fused with a six membered ring, with the orientation of the heterocycles with respect to each other and with respect to the backbone chain analogous to that found in DNA and RNA, but where these base pairs are joined by a pattern of hydrogen bonds different from that found in the AT and GC base pairs (a "non-standard base pair").
摘要翻译：本公开描述了作为包含杂环碱基的DNA和RNA的类似物的新组合物，其可以形成适合沃森 - 克里克几何的碱基对，因为它们涉及与五元组成的稠合双环杂环体系的单环六元环配对与六元环稠合的成员环，其杂环相对于彼此的方向和相对于骨架链的取向类似于在DNA和RNA中发现的那些，但是其中这些碱基对通过不同的氢键的图案连接来自于AT和GC碱基对（“非标准碱基对”）。

30. 发明授权

US5958702A Receptor-assisted combinatorial chemistry 失效
标题翻译：受体辅助组合化学
公开(公告)号：US5958702A
公开(公告)日：1999-09-28
申请号：US386521
申请日：1995-02-06
申请人： Steven Albert Benner
发明人： Steven Albert Benner
IPC分类号： C07B61/00 , G01N33/543 , G01N33/53 , A61K38/00
CPC分类号： G01N33/54306 , C40B40/00
摘要： This invention provides a method for preparing molecules that bind to a preselected receptor, whereby the receptor itself acts as an agent for either joining two ligand fragments to form a composite, tight binding ligand, or selects a composite ligand from a mixture in solution where ligand fragments are being joined and unjoined reversibly under equilibrium conditions.
摘要翻译：本发明提供了一种制备结合预选受体的分子的方法，其中受体本身作为连接两个配体片段以形成复合物，紧密结合配体或从溶液中的混合物中选择复合配体的试剂，其中配体碎片在平衡条件下可逆地连接和不连接。

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