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1. 发明授权

US08461311B2 TRAIL trimers, methods and uses therefor 有权
标题翻译： TRAIL三聚体，方法和用途
公开(公告)号：US08461311B2
公开(公告)日：2013-06-11
申请号：US13155577
申请日：2011-06-08
申请人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
发明人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
IPC分类号： C07K14/52 , C07K14/47 , C07K16/46
CPC分类号： C07K14/4747 , C07K14/52
摘要： Disclosed are TNF-related apoptosis-inducing ligand (TRAIL) trimers (TR3) and nucleic acids encoding covalently linked TRAIL trimers. A TRAIL trimer can have greater stability compared to native TRAIL, and can retain the native killing ability of TRAIL. Target specificity of a TR3 can be shown by blocking its activity with soluble death receptor 5 (DR5-Fc). Also disclosed are modified TRAIL trimers and nucleic. acids encoding them. These modifications include additional functional domains, such as antibody fragments (scFvs). A TR3 comprising an additional functional domain can allow for cell-specific delivery of the TR3. The inventors disclose TR3-decorated RBCs that target cell killing in a model of pancreatic cancer.
摘要翻译：公开了TNF相关凋亡诱导配体（TRAIL）三聚体（TR3）和编码共价连接的TRAIL三聚体的核酸。与天然TRAIL相比，TRAIL三聚体可以具有更高的稳定性，并且可以保留TRAIL的天然杀伤能力。可通过用可溶性死亡受体5（DR5-Fc）阻断其活性来显示TR3的靶特异性。还公开了修饰的TRAIL三聚体和核酸。编码它们的酸。这些修饰包括额外的功能域，例如抗体片段（scFv）。包含附加功能域的TR3可以允许TR3的细胞特异性递送。本发明人公开了在胰腺癌模型中靶向细胞杀伤的TR3装饰的RBC。

2. 发明申请

US20110300629A1 TRAIL trimers, methods and uses therefor 有权
标题翻译： TRAIL三聚体，方法和用途
公开(公告)号：US20110300629A1
公开(公告)日：2011-12-08
申请号：US13155577
申请日：2011-06-08
申请人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
发明人： William G. Hawkins , Dirk Spitzer , Richard S. Hotchkiss
IPC分类号： C12N5/09 , C07H21/00 , C07K19/00 , C12N15/63 , C07K14/52
CPC分类号： C07K14/4747 , C07K14/52
摘要： Disclosed are TNF-related apoptosis-inducing ligand (TRAIL) trimers (TR3) and nucleic acids encoding covalently linked TRAIL trimers. A TRAIL trimer can have greater stability compared to native TRAIL, and can retain the native killing ability of TRAIL. Target specificity of a TR3 can be shown by blocking its activity with soluble death receptor 5 (DR5-Fc). Also disclosed are modified TRAIL trimers and nucleic acids encoding them. These modifications include additional functional domains, such as antibody fragments (scFvs). A TR3 comprising an additional functional domain can allow for cell-specific delivery of the TR3. In some configurations, a modification such as the addition of a functional domain can be stoichiometrically controlled. In some configurations, a modification can be inconsequential with regard to the bioactivity of TRAIL. In various embodiments, a TR3, including a modified TR3, can be a cancer-selective drug. In some configurations, a TR3 that comprises an additional biologically active moiety such as a functional domain of a protein can have fewer off-target toxicities compared to TRAIL alone. In some configurations, a TR3 that comprises an additional biologically active moiety such as a functional domain of a protein can have enhanced killing capacities compared to the moiety alone. In some aspects, TR3 activity can be targeted to an RBC membrane. The inventors disclose TR3-decorated RBCs that target cell killing in a model of pancreatic cancer.
摘要翻译：公开了TNF相关凋亡诱导配体（TRAIL）三聚体（TR3）和编码共价连接的TRAIL三聚体的核酸。与天然TRAIL相比，TRAIL三聚体可以具有更高的稳定性，并且可以保留TRAIL的天然杀伤能力。可通过用可溶性死亡受体5（DR5-Fc）阻断其活性来显示TR3的靶特异性。还公开了修饰的TRAIL三聚体和编码它们的核酸。这些修饰包括额外的功能域，例如抗体片段（scFv）。包含附加功能域的TR3可以允许TR3的细胞特异性递送。在一些配置中，可以化学计量地控制诸如添加功能域的修饰。在一些配置中，关于TRAIL的生物活性，修饰可能是无关紧要的。在各种实施方案中，包括修饰的TR3的TR3可以是癌症选择性药物。在一些配置中，与单独的TRAIL相比，包含另外的生物活性部分如蛋白质的功能结构域的TR3可以具有较少的靶外毒性。在一些构型中，与单独的部分相比，包含另外的生物活性部分如蛋白质的功能结构域的TR3可以具有增强的杀伤能力。在一些方面，TR3活性可以靶向RBC膜。本发明人公开了在胰腺癌模型中靶向细胞杀伤的TR3装饰的RBC。

3. 发明申请

US20130302270A1 TUMOR TARGETED TNF-RELATED APOPTOSIS INDUCING LIGAND FUSION POLYPEPTIDE, METHODS AND USES THEREFOR 有权
标题翻译：肿瘤靶向性TNF相关性炎症诱导配体融合多肽，其方法及其用途
公开(公告)号：US20130302270A1
公开(公告)日：2013-11-14
申请号：US13892238
申请日：2013-05-10
申请人： Dirk Spitzer , William G. Hawkins
发明人： Dirk Spitzer , William G. Hawkins
IPC分类号： C07K14/47
CPC分类号： C07K14/705 , A61K38/00 , A61K38/17 , A61K38/1761 , A61K38/1764 , A61K38/177 , A61K38/191 , C07K14/4747 , C07K14/4748 , C07K14/525 , C07K14/70575 , C07K2319/00 , C07K2319/21 , C07K2319/33 , C07K2319/43 , C07K2319/74 , C12N15/62 , C12N15/63 , C12N15/70 , C12N15/74 , C12N15/79
摘要： Fusion polypeptides comprising a TRAIL trimer and a targeting domain are disclosed. The targeting domain can be, in some embodiments, a sequence that binds MUC16, which is prevalent on some tumor cells such as pancreatic and ovarian tumor cells. A sequence that binds MUC 16 can be mesothelin or a MUC16-binding fragment thereof, such as amino acids 1-64 of mesothelin. A fusion polypeptide of the present teachings can induce apoptosis in a target cell such as a MUC16-expressing cancer cell. Also disclosed are nucleic acids encoding the fusion polypeptides, and methods of use of the fusion polypeptides and nucleic acids.
摘要翻译：公开了包含TRAIL三聚体和靶向结构域的融合多肽。在一些实施方案中，靶向结构域可以是结合MUC16的序列，其在一些肿瘤细胞如胰腺和卵巢肿瘤细胞上是普遍存在的。结合MUC16的序列可以是间皮素或其MUC16结合片段，例如间皮素的第1-64位氨基酸。本教导的融合多肽可以在靶细胞例如表达MUC16的癌细胞中诱导凋亡。还公开了编码融合多肽的核酸，以及融合多肽和核酸的使用方法。

4. 发明授权

US11952410B2 Mesothelin-targeted trail trimer 有权
公开(公告)号：US11952410B2
公开(公告)日：2024-04-09
申请号：US16610433
申请日：2018-05-02
申请人： Dirk M. Spitzer , William G. Hawkins
发明人： Dirk M. Spitzer , William G. Hawkins
IPC分类号： C07K14/705 , A61K38/00 , A61P35/00 , C07K16/30
CPC分类号： C07K14/70575 , A61P35/00 , C07K16/30 , A61K38/00 , C07K2317/567 , C07K2317/622 , C07K2317/76 , C07K2319/30
摘要： The present disclosure provides constructs that comprise (a) a TNF-related apoptosis-inducing ligand (TRAIL) trimer comprising three consecutive extracellular TRAIL domains fused together in a head-to-tail configuration; (b) an epitope binding agent, and (c) optionally one or more additional components, wherein the epitope binding agent competitively inhibits binding of P4-TR3 or HN1-TR3 to cell surface human mesothelin. Constructs of the present disclosure induce apoptosis in cells expressing human mesothelin and a death receptor (DR4 or DR5) on the cell's surface.

5. 发明授权

US06315398B1 Thermal ink jet heater design 失效
标题翻译：热喷墨加热器设计
公开(公告)号：US06315398B1
公开(公告)日：2001-11-13
申请号：US07963969
申请日：1992-10-21
申请人： Cathie J. Burke , Narayan V. Desphande , William G. Hawkins , Dale R. Ims , Michael P. O'Horo , Gary A. Kneezel , Thomas A. Tellier , Ivan Rezanka
发明人： Cathie J. Burke , Narayan V. Desphande , William G. Hawkins , Dale R. Ims , Michael P. O'Horo , Gary A. Kneezel , Thomas A. Tellier , Ivan Rezanka
IPC分类号： B41J205
CPC分类号： B41J2/1604 , B41J2/14129 , B41J2/1628 , B41J2/1629 , B41J2/1631 , B41J2/1642 , B41J2/1646
摘要： The new heater element design has a pit layer which protects the overglaze passivation layer, PSG step region, portions of the Ta layer and dielectric isolation layer and junctions or regions susceptible to the cavitational pressures. Further, the inner walls of the pit layer define the effective heater area and the dopant lines define the actual heater area. In alternative embodiments, the dopant lines define the actual and effective heater areas, and an inner wall and a dopant line define the actual and effective heater areas. Further, when the new heater element designs are incorporated into printheads having full pit channel geometry and open pit channel geometry, the operating lifetime of the printhead is extended because the added protection of the pit layer prevents: 1) passivation damage and cavitational damages of the heater elements; and 2) degradation of heater robustness, hot spot formations and heater failures well into the 109 pulse range. The printhead incorporating the new heater element design can be incorporated into drop-on-demand printing systems of a carriage type or a full width type.
摘要翻译：新的加热器元件设计具有凹坑层，其保护釉面钝化层，PSG阶梯区域，Ta层和电介质隔离层的部分以及对空穴压力敏感的结或区域。此外，凹坑层的内壁限定有效的加热器面积，并且掺杂剂线限定实际的加热器面积。在替代实施例中，掺杂剂线限定实际和有效的加热器区域，并且内壁和掺杂剂线限定实际和有效的加热器区域。此外，当新的加热器元件设计结合到具有全坑通道几何形状和露天通道几何形状的打印头中时，打印头的工作寿命延长，因为凹坑层的附加保护防止：1）钝化损伤和空穴损伤加热元件; 和2）加热器鲁棒性，热点形成和加热器故障的恶化达到109脉冲范围。包含新的加热器元件设计的打印头可以结合到托架型或全宽型的按需按需打印系统中。

6. 发明授权

US5371530A Thermal ink jet printhead having a switched stand-by mode 失效
标题翻译：具有切换待机模式的热喷墨打印头
公开(公告)号：US5371530A
公开(公告)日：1994-12-06
申请号：US55891
申请日：1993-05-04
申请人： William G. Hawkins , Thomas A. Tellier
发明人： William G. Hawkins , Thomas A. Tellier
IPC分类号： B41J2/01 , B41J2/05 , B41J2/375 , B41J29/38 , G01D15/16
CPC分类号： B41J2/04515 , B41J2/04541 , B41J2/0455 , B41J2/0457 , B41J2/0458 , B41J2/375
摘要： A thermal ink jet printhead includes a switched power supply for the intermediate voltage predriver sections. The power supply is switched by a MOSFET connected between an intermediate point of a voltage divider and ground. By switching the power supply, the predriver sections are turned off, unnecessary power consumption and overheating the printhead are avoided.
摘要翻译：热喷墨打印头包括用于中间电压预驱动部分的开关电源。电源由连接在分压器的中间点和地之间的MOSFET切换。通过切换电源，预驱动部分被关闭，避免了不必要的功耗和打印头的过热。

7. 发明授权

US5010355A Ink jet printhead having ionic passivation of electrical circuitry 失效
标题翻译：喷墨打印头具有电路的离子钝化
公开(公告)号：US5010355A
公开(公告)日：1991-04-23
申请号：US456431
申请日：1989-12-26
申请人： William G. Hawkins , Cathie J. Burke , Daniel O. Roll , Pamela J. Hartman , Diane Atkinson
发明人： William G. Hawkins , Cathie J. Burke , Daniel O. Roll , Pamela J. Hartman , Diane Atkinson
IPC分类号： B41J2/05 , B41J2/16 , H01L23/29 , H01L23/31
CPC分类号： B41J2/14129 , B41J2/1604 , B41J2/1628 , B41J2/1629 , B41J2/1631 , B41J2/1632 , B41J2/1646 , H01L23/291 , H01L23/3157 , B41J2202/13 , H01L2924/0002
摘要： An improved ink jet printhead is disclosed of the type having a plurality of parallel ink flow channels which terminate with an ink droplet emitting nozzle, a heating element with a cavitational protective layer thereover located in each channel, and MOS electronic circuitry monolithically integrated within the printhead for applying electrical pulses to the heating elements. The pulsed heating elements produce bubbles momentarily on the protective layer of the heating elements which expel ink droplets from the nozzles. The improvement is obtained by providing multi-layer ionic passivation of the MOS electronic circuitry which is exposable to the ink. This is accomplished through the deposition of a multi-layered, thin film insulative coating thereon consisting of a first layer of doped or undoped silicon dioxide having a thickness of 200 .ANG. to 2 .mu.m followed by a second layer of plasma nitride having a thickness of 1000 .ANG. to 3 .mu.m. The silicon nitride is etched from the protective layers of the heating elements and electrical contact pads for external connection to electrical power so that the first layer of silicon oxide is exposed, followed by etching of the silicon oxide to remove it from the protective layer and contact pads. Thus, the MOS circuitry is protected from mobile ions in the ink while the cost effective fabrication of a printhead is maintained. In an alternate embodiment, the multi-layered ionic passivation comprises three thin film layers comprising polyimide interfacing with the ink, followed by silicon nitride, and doped or undoped silicon dioxide directly interfacing with the metallization.

8. 发明授权

US4985710A Buttable subunits for pagewidth "Roofshooter" printheads 失效
标题翻译：页面宽度“Roofshooter”打印头的Buttable子单元
公开(公告)号：US4985710A
公开(公告)日：1991-01-15
申请号：US442641
申请日：1989-11-29
申请人： Donald J. Drake , William G. Hawkins
发明人： Donald J. Drake , William G. Hawkins
IPC分类号： B41J2/05 , B41J2/155 , B41J2/16
CPC分类号： B41J2/1623 , B41J2/155 , B41J2/1603 , B41J2/1626 , B41J2/1632 , Y10T156/1052
摘要： A "roofshooter" pagewidth printhead for use in a thermal ink jet printing device is fabricated by forming a plurality of subunits, each being produced by bonding a heater substrate having an architecture including an array of heater elements and an etched ink feed slot to a secondary substrate having a series of spaced feed hole openings to form a combined substrate in which said series of spaced feed hole openings communicates with said ink feed slot, and dicing said combined substrates through said ink feed slot to form a subunit. An array of butted subunits having a length equal to one pagewidth is formed by butting one of said subunits against an adjacent subunit. The array of butted subunits is bonded to a pagewidth support substrate. The secondary substrate provides an integral support structure for maintaining the alignment of the heater plate which, if diced through the feed hole without the secondary substrate, would separate into individual pieces, thereby complicating the alignment and assembly process.

9. 发明授权

US4899181A Large monolithic thermal ink jet printhead 失效
标题翻译：大型单片热喷墨打印头
公开(公告)号：US4899181A
公开(公告)日：1990-02-06
申请号：US303620
申请日：1989-01-30
申请人： William G. Hawkins , Donald J. Drake
发明人： William G. Hawkins , Donald J. Drake
IPC分类号： B41J2/05 , B41J2/16
CPC分类号： B41J2/1642 , B41J2/1604 , B41J2/1623 , B41J2/1628 , B41J2/1629 , B41J2/1631 , B41J2/1632 , B41J2/1635
摘要： An improved thermal ink jet printhead and method of fabrication thereof is disclosed of the type formed by the mating and bonding of first and second substrates. The first substrate is silicon with {100} crystal plane surfaces and has anisotropically etched in one surface thereof a linear series of separate through recesses and a plurality of parallel, elongated ink channels grooves. The second substrate has a plurality of heating elements and addressing electrodes patterned on one surface thereof. The through recesses serve as a segmented ink reservoir with each segment having an ink inlet, and the elongated ink channel grooves having one end adjacent the segmented reservoir and the opposite end open to serve as ink droplet emitting nozzles. Each segment of the segmented reservoir is isolated from each other by dividing walls. The dividing walls strengthen the printhead, and the separate through recesses reduce the effects of angular misalignment between mask and first substrate crystal planes. In the preferred embodiment, a thick film insulative layer is sandwiched between the first and second substrates and patterned to form recesses therein to provide the means for placing the segmented reservoir into communication with the ink channel grooves. To produce a multicolor printing printhead, the thick film layer is patterned to form a linear series of recesses, each substantially equal in length to an associated one of the reservoir segments, so that each reservoir segment may have a different colored ink supplied thereto that cannot mix with the ink of the other reservoir segments.
摘要翻译：公开了一种改进的热喷墨打印头及其制造方法，其通过第一和第二基板的配合和结合而形成。第一衬底是具有{100}晶面表面的硅，并且在其一个表面中具有各向异性蚀刻线性系列的分离的通孔和多个平行的细长的墨水槽。第二基板具有在其一个表面上图案化的多个加热元件和寻址电极。贯通凹部用作分段墨水储存器，每个分段具有墨水入口，并且细长的墨水通道凹槽具有与分段的储存器相邻的一端，并且相对的端部打开以用作墨滴喷射。分段储存器的每个段通过分隔壁彼此隔离。分隔壁加强了打印头，并且单独的通孔减少了掩模和第一基板晶体平面之间的角度偏移的影响。在优选实施例中，厚膜绝缘层被夹在第一和第二基板之间并被图案化以在其中形成凹槽，以提供用于将分段的储存器放置成与墨水通道槽连通的装置。为了生产多色打印打印头，将厚膜层图案化以形成线性系列的凹槽，每个凹槽的长度与相关联的储存器段之间的长度基本上相等，使得每个储存器段可以具有供给其的不同颜色的墨水，不能与其他水库段的油墨混合。

10. 发明授权

US4863560A Fabrication of silicon structures by single side, multiple step etching process 失效
标题翻译：通过单面，多步蚀刻工艺制造硅结构
公开(公告)号：US4863560A
公开(公告)日：1989-09-05
申请号：US234994
申请日：1988-08-22
申请人： William G. Hawkins
发明人： William G. Hawkins
IPC分类号： B41J2/05 , B41J2/16 , B81B1/00 , C30B29/06 , G02B6/36 , H01L21/302 , H01L21/306 , H01L21/3065 , H01L21/308
CPC分类号： B81C1/00126 , B41J2/1601 , B41J2/1626 , B41J2/1631 , H01L21/30608 , H01L21/3081 , H01L21/3085 , B81B2201/052 , B81B2203/0338 , G02B6/3644 , G02B6/3692
摘要： Three dimensional silicon structures are fabricated from (100) silicon wafers by a single side, multiple step ODE etching process. All etching masks are formed one on top of the other prior to the initiation of etching, with the coarsest mask formed last and used first. Once the coarse anisotropic etching is completed, the coarse mask is removed and the finer anisotropic etching is done. The preferred embodiment is described using a thermal ink jet channel plate as the three dimensional structure, where coarse etching step provides the reservoir and the fine etching step provides the ink channels.

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