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1. 发明授权

US08354477B2 Multi-armed, monofunctional, and hydrolytically stable derivatives of poly(ethylene glycol) and related polymers for modification of surfaces and molecules 失效
标题翻译：聚（乙二醇）多官能，单官能和水解稳定的衍生物以及用于表面和分子修饰的相关聚合物
公开(公告)号：US08354477B2
公开(公告)日：2013-01-15
申请号：US12849683
申请日：2010-08-03
申请人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
发明人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
IPC分类号： C08G65/34 , C08F283/00
CPC分类号： C08G65/48 , A61K47/60 , C08G65/329 , C12N9/96 , Y10S530/815 , Y10S530/816
摘要： Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms polya and polyb, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure where mPEGa and mPEGb have the structure CH3O—(CH2CH2O)nCH2CH2— wherein n may be the same or different for polya- and polyb- and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.
摘要翻译：描述了具有以下结构的多臂，单功能和水解稳定的聚合物，其中Z是可被激活以附着于生物活性分子如蛋白质的部分，并且其中P和Q分别表示分别连接聚合物臂polya和polyb的连接片段通过在连接片段中不存在芳环的水解稳定键而与中心碳原子C连接。 R通常是氢或甲基，但可以是包含另一聚合物臂的连接片段。具体实例是mPEG二取代的赖氨酸，其具有结构，其中mPEGa和mPEGb具有结构CH 3 O-（CH 2 CH 2 O）n CH 2 CH 2 - ，其中n可以相同或不同，用于聚-α-和polyb-，并且可以为1至约1,150，以提供分子约100至100,000的重量。

2. 发明申请

US20100298496A1 MULTI-ARMED, MONOFUNCTIONAL, AND HYDROLYTICALLY STABLE DERIVATIVES OF POLY(ETHYLENE GLYCOL) AND RELATED POLYMERS FOR MODIFICATION OF SURFACES AND MOLECULES 失效
标题翻译：聚（乙烯甘油）和相关聚合物的多臂，单功能和水解稳定性衍生物，用于修饰表面和分子
公开(公告)号：US20100298496A1
公开(公告)日：2010-11-25
申请号：US12849683
申请日：2010-08-03
申请人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
发明人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
IPC分类号： A61K47/48
CPC分类号： C08G65/48 , A61K47/60 , C08G65/329 , C12N9/96 , Y10S530/815 , Y10S530/816
摘要： Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms polya and polyb, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure where mPEGa and mPEGb have the structure CH3O—(CH2CH2O)nCH2CH2— wherein n may be the same or different for polya- and polyb- and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.
摘要翻译：描述了具有以下结构的多臂，单功能和水解稳定的聚合物，其中Z是可被激活以附着于生物活性分子如蛋白质的部分，并且其中P和Q分别表示分别连接聚合物臂polya和polyb的连接片段通过在连接片段中不存在芳环的水解稳定键而与中心碳原子C连接。 R通常是氢或甲基，但可以是包含另一聚合物臂的连接片段。具体实例是mPEG二取代的赖氨酸，其具有结构，其中mPEGa和mPEGb具有结构CH 3 O-（CH 2 CH 2 O）n CH 2 CH 2 - ，其中n可以相同或不同，用于聚-α-和polyb-并且可以为1至约1,150，以提供分子约100至100,000的重量。

3. 发明申请

US20090054590A1 Multi-armed, monofunctional, and hydrolytically stable derivatives of poly (ethylene glycol) and related polymers for modification of surfaces and molecules 失效
标题翻译：聚（乙二醇）多官能，单官能和水解稳定的衍生物以及用于表面和分子修饰的相关聚合物
公开(公告)号：US20090054590A1
公开(公告)日：2009-02-26
申请号：US12284357
申请日：2008-09-20
申请人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
发明人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
IPC分类号： C08L89/00 , C08G65/00 , C08G73/10 , C08G63/00 , C08G69/26
CPC分类号： C08G65/48 , A61K47/60 , C08G65/329 , C12N9/96 , Y10S530/815 , Y10S530/816
摘要： Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms polya and polyb, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure where mPEGa and mPEGb have the structure CH3O—(CH2CH2O)nCH2CH2— wherein n may be the same or different for polya- and polyb- and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.
摘要翻译：描述了具有以下结构的多臂，单功能和水解稳定的聚合物，其中Z是可被激活以附着于生物活性分子如蛋白质的部分，并且其中P和Q分别表示分别连接聚合物臂polya和polyb的连接片段通过在连接片段中不存在芳环的水解稳定键而与中心碳原子C连接。 R通常是氢或甲基，但可以是包含另一聚合物臂的连接片段。具体实例是mPEG二取代的赖氨酸，其具有结构，其中mPEGa和mPEGb具有结构CH 3 O-（CH 2 CH 2 O）n CH 2 CH 2 - ，其中n可以相同或不同，用于聚-α-和polyb-，并且可以为1至约1,150，以提供分子约100至100,000的重量。

4. 发明授权

US5932462A Multiarmed, monofunctional, polymer for coupling to molecules and surfaces 失效
标题翻译：用于偶联到分子和表面的多臂单功能聚合物
公开(公告)号：US5932462A
公开(公告)日：1999-08-03
申请号：US443383
申请日：1995-05-17
申请人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
发明人： J. Milton Harris , Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
IPC分类号： A61K47/48 , C08G65/329 , C12N9/96 , A01N63/00 , C07K17/00 , C12N11/06
CPC分类号： C08G65/48 , A61K47/48215 , C08G65/329 , C12N9/96 , Y10S530/815 , Y10S530/816
摘要： Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure ##STR1## wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms poly.sub.a and poly.sub.b, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings and ester groups in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure ##STR2## where mPEG.sub.a and mPEG.sub.b have the structure CH.sub.3 O--(CH.sub.2 CH.sub.2 O).sub.n CH.sub.2 CH.sub.2 -- wherein n may be the same or different for mPEG.sub.a and mPEG.sub.b and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000. The mPEG disubstituted lysine can be purified from a reaction mixture by chromatography in water, including gel filtration chromatography and ion exchange chromatography because the carboxyl group is ionizable. Impurities are removed, including unreacted mPEG and mPEG monosubstituted lysine, to provide the polymer in pure form. Ion exchange chromatography permits fractionation of a greater amount of polymer per run.
摘要翻译：描述了具有以下结构的多臂，单功能和水解稳定的聚合物，其中Z是可被激活以附着于生物活性分子如蛋白质的部分，并且其中P和Q分别表示分别连接聚合物臂polya和polyb的连接片段，通过在不存在芳环和通过连接片段中的酯基的水解稳定键连接到中心碳原子。 R通常是氢或甲基，但可以是包含另一聚合物臂的连接片段。具体实例是具有mPEGa和mPEGb具有CH 3 O-（CH 2 CH 2 O）n CH 2 CH 2结构的结构的mPEG二取代的赖氨酸，其中n可以相同或不同于mPEGa和mPEGb，并且可以为1至约1,150，以提供从约100到100,000。可以通过色谱法在水中从反应混合物中纯化mPEG二取代的赖氨酸，包括凝胶过滤色谱和离子交换色谱法，因为羧基是可离子化的。除去杂质，包括未反应的mPEG和mPEG单取代的赖氨酸，以提供纯的形式的聚合物。离子交换色谱法允许每次运行更大量的聚合物分级。

5. 发明授权

US06869932B2 Site-specific preparation of polyethlene glycol-GRF conjugates 有权
标题翻译：聚乙二醇-GRF共轭物的位点特异性制备
公开(公告)号：US06869932B2
公开(公告)日：2005-03-22
申请号：US10299790
申请日：2002-11-20
申请人： Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
发明人： Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
IPC分类号： A61K8/00 , G01N33/566 , A61K38/04 , A61K47/48 , A61P5/06 , G01N33/74 , A61K38/25 , C07K17/08
CPC分类号： A61K47/60
摘要： A method is described for the site-specific preparation of hGRF-PEG conjugates containing one or more PEG units (per mole of hGRF) covalently bound to Lys12 and/or Lys21 and/or Nα, characterized in that the conjugation reaction between the hGRF peptide and activated PEG is carried out in solution and the desired hGRF-PEG conjugate can be purified by chromatography. The conjugates prepared by this method, as well as their use in the treatment, prevention or diagnosis of growth hormone deficiency, are also an object of the present invention.
摘要翻译：描述了含有共价结合至Lys 12和/或Lys 21和/或Nalpha的一个或多个PEG单元（每摩尔hGRF）的hGRF-PEG缀合物的位点特异性制备的方法，其特征在于， hGRF肽和活化的PEG之间的缀合反应在溶液中进行，并且可以通过色谱法纯化所需的hGRF-PEG缀合物。通过该方法制备的缀合物及其在治疗，预防或诊断生长激素缺乏中的用途也是本发明的目的。

6. 发明授权

US07317002B2 Site-specific preparation of polyethylene glycol-GRF conjugates 有权
标题翻译：聚乙二醇-GRF共轭物的位点特异性制备
公开(公告)号：US07317002B2
公开(公告)日：2008-01-08
申请号：US11011617
申请日：2004-12-15
申请人： Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
发明人： Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
IPC分类号： A61K38/25 , A61K47/48 , C07K17/08
CPC分类号： A61K47/60
摘要： A method is described for the site-specific preparation of hGRF-PEG conjugates containing one or more PEG units (per mole of hGRF) covalently bound to Lys12 and/or Lys21 and/or Nα, characterized in that the conjugation reaction between the hGRF peptide and activated PEG is carried out in solution and the desired hGRF-PEG conjugate can be purified by chromatography. The conjugates prepared by this method, as well as their use in the treatment, prevention of diagnosis of growth hormone deficiency, are also an object of the present invention.
摘要翻译：描述了用于特异性地制备含有共价结合到Lys 12和/或Lys 21的一个或多个PEG单元（每摩尔hGRF）的hGRF-PEG缀合物的位点特异性制备的方法 >和/或Nαα，其特征在于hGRF肽和活化的PEG之间的缀合反应在溶液中进行，并且所需的hGRF-PEG缀合物可以通过色谱法纯化。通过该方法制备的缀合物及其在治疗中的用途，预防生长激素缺乏的诊断也是本发明的目的。

7. 发明授权

US06528485B1 Site-specific preparation of polyethylene glycol-grf conjugates 有权
标题翻译：聚乙二醇-grf共轭物的位点特异性制备
公开(公告)号：US06528485B1
公开(公告)日：2003-03-04
申请号：US09587460
申请日：2000-06-05
申请人： Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
发明人： Francesco Maria Veronese , Paolo Caliceti , Oddone Schiavon
IPC分类号： A61K3825
CPC分类号： A61K47/60
摘要： Described are various human growth hormone releasing factor-PEG conjugates as well as their pharmaceutical use.
摘要翻译：描述了各种人生长激素释放因子-PEG缀合物及其药物用途。

8. 发明授权

US07786221B2 Multi-armed, monofunctional, and hydrolytically stable derivatives of poly (ethylene glycol) and related polymers for modification of surfaces and molecules 有权
标题翻译：聚（乙二醇）多官能，单官能和水解稳定的衍生物以及用于表面和分子修饰的相关聚合物
公开(公告)号：US07786221B2
公开(公告)日：2010-08-31
申请号：US12284357
申请日：2008-09-18
申请人： J. Milton Harris , Francesco Maria Veronese , Paola Caliceti , Oddone Schiavon
发明人： J. Milton Harris , Francesco Maria Veronese , Paola Caliceti , Oddone Schiavon
IPC分类号： C08G65/34 , C08F283/00 , A61K31/40
CPC分类号： C08G65/48 , A61K47/60 , C08G65/329 , C12N9/96 , Y10S530/815 , Y10S530/816
摘要： Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms polya and polyb, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure where mPEGa and mPEGb have the structure CH3O—(CH2CH2O)nCH2CH2— wherein n may be the same or different for polya- and polyb- and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.
摘要翻译：描述了具有以下结构的多臂，单功能和水解稳定的聚合物，其中Z是可被激活以附着于生物活性分子如蛋白质的部分，并且其中P和Q分别表示分别连接聚合物臂polya和polyb的连接片段通过在连接片段中不存在芳环的水解稳定键而与中心碳原子C连接。 R通常是氢或甲基，但可以是包含另一聚合物臂的连接片段。具体实例是mPEG二取代的赖氨酸，其具有结构，其中mPEGa和mPEGb具有结构CH 3 O-（CH 2 CH 2 O）n CH 2 CH 2 - ，其中n可以相同或不同，用于聚-α-和polyb-并且可以为1至约1,150，以提供分子约100至100,000的重量。

9. 发明授权

US07419600B2 Method for purifying a branched water-soluble polymer 失效
标题翻译：纯化支链水溶性聚合物的方法
公开(公告)号：US07419600B2
公开(公告)日：2008-09-02
申请号：US10634970
申请日：2003-08-05
申请人： J. Milton Harris , Francesco Maria Veronese , Paola Caliceti , Oddone Schiavon
发明人： J. Milton Harris , Francesco Maria Veronese , Paola Caliceti , Oddone Schiavon
IPC分类号： B01D15/36 , A61K38/43 , C12N11/08 , C12N11/06 , C12N9/96 , C07K17/06 , C07K17/08
CPC分类号： C08G65/48 , A61K47/60 , C08G65/329 , C12N9/96 , Y10S530/815 , Y10S530/816
摘要： Multi-armed, monofunctional, and hydrolytically stable polymers are described having the structure wherein Z is a moiety that can be activated for attachment to biologically active molecules such as proteins and wherein P and Q represent linkage fragments that join polymer arms polya and polyb, respectively, to central carbon atom, C, by hydrolytically stable linkages in the absence of aromatic rings in the linkage fragments. R typically is hydrogen or methyl, but can be a linkage fragment that includes another polymer arm. A specific example is an mPEG disubstituted lysine having the structure where mPEGa and mPEGb have the structure CH3O—(CH2CH2O)nCH2CH2— wherein n may be the same or different for polya- and polyb- and can be from 1 to about 1,150 to provide molecular weights of from about 100 to 100,000.
摘要翻译：描述了具有以下结构的多臂，单功能和水解稳定的聚合物，其中Z是可被激活以附着于生物活性分子如蛋白质的部分，并且其中P和Q表示连接聚合物臂的连接片段分别通过在连接片段中不存在芳环的水解稳定键，与中心碳原子C分别形成。 R通常是氢或甲基，但可以是包含另一聚合物臂的连接片段。具体实例是具有以下结构的mPEG二取代赖氨酸，其中mPEG a和mPEG b具有结构CH 3 O-（CH 3） CH 2 CH 2 CH 2其中n可以相同或不同，或者可以相同或不同，对于聚<！ - SIPO - >和 - 和多个b - 不同，并且可以为1至约1,150，以提供约100至100,000的分子量。

10. 发明申请

US20100069579A1 Activated Polyoxazolines and Compositions Comprising the Same 有权
标题翻译：活性聚唑啉及其组合物
公开(公告)号：US20100069579A1
公开(公告)日：2010-03-18
申请号：US12529001
申请日：2008-02-28
申请人： J. Milton Harris , Michael David Bentley , Kunsang Yoon , Zhihao Fang , Francesco Maria Veronese
发明人： J. Milton Harris , Michael David Bentley , Kunsang Yoon , Zhihao Fang , Francesco Maria Veronese
IPC分类号： C08G73/00
CPC分类号： A61K31/787 , A61K47/60 , C07D207/452 , C07D207/46 , C07D401/12 , C08G73/0233 , C08L79/02
摘要： The present disclosure provides terminally activated monofunctional POZ derivatives having a range of functional active groups allowing conjugation of the monofunctional POZ derivatives to a variety of target molecules under a wide range of reaction conditions to produce a hydrolytically stable target molecule-POZ conjugate. Furthermore, the present disclosure provides novel methods of synthesis for the disclosed terminally activated monofunctional POZ derivatives and hydrolytically stable target molecule-POZ conjugates created using the disclosed terminally activated monofunctional POZ derivatives.
摘要翻译：本公开提供具有一定范围的官能活性基团的末端活化单官能POZ衍生物，其允许在宽范围的反应条件下将单官能POZ衍生物缀合到多种靶分子以产生水解稳定的靶分子-POZ缀合物。此外，本公开提供了所公开的末端活化单官能POZ衍生物和使用所公开的末端活化单官能POZ衍生物产生的水解稳定的靶分子-POZ共轭物的合成新方法。

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