Apparatus, methods and computer program products are disclosed that allows a thread-unaware routine that accesses an operation-dependent temporary data structure to be shared by multiple threads in a multi-threaded computing environment. The programmer for an operation provides three routinesxe2x80x94a pre-processing routine, a operation routine, and a post-processing routine. The pre-processing routine allocates the operation-dependent temporary data structure. The operation routine accesses the operation-dependent temporary data structure to perform its operation for each thread that invokes the operation routine. The post-processing routine deallocates the operation-dependent temporary data structure when it is no longer needed.

1. Field of the Invention
This invention relates to the field of multithreaded processing techniques. Specifically, this invention is a method, apparatus, and computer program product for the execution of a thread-unaware routine that implements an operation and accesses an operation-dependent temporary data structure in a multithreaded computing environment.
Many computing environments are multi-threaded. Such environments simplify the development of programs that have multiple simultaneous independent sequences of control in both single- and multi-processor systems. One difficulty with developing such programs is that multiple threads may simultaneously execute a routine that uses an operation-dependent temporary data structure to perform an operation. The prior art routine coordinates the creation of the operation-dependent temporary data structure among the threads that invoke the routine. The prior art routine also monitors and controls the execution of the threads that access to the temporary data structure. This explicit thread control within the routine increases the complexity of the routine, limits the number of simultaneous threads that invoke the routine, and increases the routine""s overhead.
One use of multiple threads, is to partition a problem domain and then to assign each partition to a thread for processing. For example, this technique can be used by an image processing program to partition the image data of an image (each partition being termed a tile) and operating on each tile by its assigned thread. In this example, each thread invokes a routine that uses the same operation-dependent temporary data structure to process its assigned tile. The result of processing all the tiles is the same as if the complete image data was processed by a single thread except that the multiple threads allow concurrent processing. An example of such an operation in the image processing problem domain is graphically represented as shown in FIG. 1. One problem in the prior art is that as each thread invokes the routine, the routine must determine which thread has invoked it and if the operation-dependent temporary data structure has already been allocated for that thread.
FIG. 1 illustrates a xe2x80x98LUT image processing operation and dataxe2x80x99 graph, indicated by general reference character 100. The xe2x80x98LUT image processing operation and dataxe2x80x99 graph 100 is a directed acyclic graph (DAG) representing an operation performed on a source image 101 and resulting in a destination image 103. In this example the operation is a xe2x80x98LUT image processing operationxe2x80x99 105 that uses a xe2x80x98lookup tablexe2x80x99 107. The xe2x80x98lookup tablexe2x80x99 107 is an operation-dependent temporary data structure. The xe2x80x98lookup tablexe2x80x99 107 is temporary in that the xe2x80x98LUT image processing operationxe2x80x99 105 creates the table in memory (from other data accessible to the operation) to optimize performance of the LUT operation. Once the LUT operation is completed, the xe2x80x98lookup tablexe2x80x99 107 can be deleted. The xe2x80x98LUT image processing operationxe2x80x99 105 can be thread-aware to allow concurrent processing of tiles in the source image 101. To perform the same operation on each tile, each execution accesses the same operation-dependent temporary data structure. The xe2x80x98LUT image processing operationxe2x80x99 105 is thread aware in that it detects its first invocation by a thread and creates the operation-dependent temporary data structure. The xe2x80x98LUT image processing operationxe2x80x99 105 also detects subsequent thread invocations and uses the previously created operation-dependent temporary data structure. If the xe2x80x98LUT image processing operationxe2x80x99 105 routine is also called to process another image while the source image 101 is being processed it generally must create another operation-dependent temporary data structure for that image. Thus, to allow multiple images to be processed, the xe2x80x98LUT image processing operationxe2x80x99 105 must also have the capability to associate the appropriate operation-dependent temporary data structure with each thread. Thus, during execution of the routine by each thread, the routine must account for, and manipulate, the threads used to parallelize its execution; and associate the operation-dependent temporary data structure with the thread. These overheads reduce the routine""s performance. One skilled in the art will understand that temporary data structures can also be used by other graphical or non-graphical operations.
Another drawback of using thread-aware routines which access operation-dependent temporary data structures is that including the thread-aware programmed logic complicates the routine""s programming. For example, detecting when all threads have completed processing (so as to be able to determine when to delete the operation-dependent temporary data structure) increases the routine""s complexity. In addition, the number of threads supported by the routine limits the number of threads available to parallelize execution of the operation.
For these reasons, it would be advantageous to provide a mechanism that enables a thread-unaware routine (that accesses an operation-dependent temporary data structure to perform its operation) to be executed by a plurality of threads.
The present invention provides an apparatus, method and computer program product for invoking a thread-unaware routine in a multi-threaded environment. A thread-unaware routine is a routine that does not contain programmed logic to manage or manipulate threads in preparation for an access to operation-dependent temporary data structure used by the routine. One aspect of the invention includes a computer controlled method for invoking an operation routine from within a multi-threaded computing environment. The operation routine implements an operation and accesses an operation-dependent temporary data structure. The operation routine is executed by a plurality of threads. The computer controlled method invokes a pre-process routine that prepares the operation-dependent temporary data structure. The computer controlled method also invokes the operation routine by one or more of the plurality of threads to perform the operation using the operation-dependent temporary data structure. The operation routine is thread-unaware.
Another aspect of the invention includes an apparatus for invoking an operation routine from within a multi-threaded computing environment. The apparatus has a central processing unit (CPU) and a memory coupled to the CPU. The operation routine implements an operation, accesses an operation-dependent temporary data structure and is executed by a plurality of threads. The apparatus includes a pre-process invocation mechanism that is configured to invoke a pre-process routine. The pre-process routine prepares the operation-dependent temporary data structure for access by the operation routine. The apparatus also includes an operation invocation mechanism that is configured to invoke the operation routine by one or more of the plurality of threads to perform the operation using the operation-dependent temporary data structure allocated by the pre-process invocation mechanism. The operation routine is thread-unaware.
Yet a further aspect of the invention is a computer program product that includes computer readable code, embedded in a computer usable storage medium, for causing a computer to invoke an operation routine. The operation routine implements an operation and accesses an operation-dependent temporary data structure, from within a multi-threaded computing environment. The operation routine is executed by a plurality of threads. When executed on a computer, the computer readable code causes a computer to effect a pre-process invocation mechanism and an operation invocation mechanism. Each of these mechanisms have the same functions as the corresponding mechanisms for the previously described apparatus.
These and other features of the invention will become apparent when the following detailed description is read in combination with the accompanying figures.

Method, apparatus and computer program product for invoking a thread-unaware routine that uses an operation-dependent temporary data structure


In order to compensate for performance degradation caused by inferior low-cost analog radio component tolerances of an analog radio, a future system architecture (FSA) wireless communication transceiver employs numerous digital signal processing (DSP) techniques to compensate for deficiencies of such analog components so that modern specifications may be relaxed. Automatic gain control (AGC) functions are provided in the digital domain, so as to provide enhanced phase and amplitude compensation, as well as many other radio frequency (RF) parameters.

Existing wireless system architectural configurations impose stringent constraints on the system designer with regards to receiving and transmitting communication signals. Moreover, such configurations often provide low reliability communication links, high operating costs, and an undesirably low level of integration with other system components.
In the radio frequency (RF) section of a conventional low-cost wireless transceiver configured with analog components, a considerable level of distortion occurs when RF signals are processed. Such distortions include filter amplitude and phase nonlinearities, phase and amplitude imbalance, power amplifier nonlinearities, carrier leakage or the like. Higher cost components with better distortion characteristics that enhance signal quality may be overlooked during the design phase in order to reduce the cost of the end-product.
In addition, variations in the channel loss and dynamic range of incoming signals of a wireless communication system must be compensated for in an efficient manner without subjecting the signals to undue distortion or interference.
Because the costs of components that process RF analog signals are higher than the components that use (DSP), it is desired to provide a digital baseband (DBB) system, including a low cost receiver and transmitter with low noise and minimal power requirements, that utilizes DSP techniques as much as is practicable.

Compensating for analog radio component impairments to relax specifications


A device (20, 301–306, 501–503, 566, 700) for playing “spotting type” games. In one embodiment, the device includes an elongate member (24) having visible thereon two sets (36, 40) of indicia (44, 48), wherein the indicia in each set are spaced apart along the length of the member and the sets are spaced apart around the circumference of the member. A spotter 28 having an indicator 92 is movable along the member to allow the user to move the indicator to ones of the indicia as needed to play the game. A game may be played by reading one of the indicia, spotting an item corresponding to the indicia and then moving the spotter so that the indicator indicates that indicia.

Many people enjoy games. However, relatively few games are suitable for use in virtually any setting, e.g., travel, sightseeing, home, running errands around town, and neighborhood play, among many others. For example, traveling in an automobile can be boring and tedious, particularly to children. Parents often try to find ways to keep their children occupied and entertained in order to keep everyone in the automobile happy. Parents often prefer simple games, such as license plate spotting, "I spy" and other spotting games, that do not necessarily require any type of device for recording the items spotted and can be played for free. Children, on the other hand, often tend to prefer games that are played with various devices, e.g., boards, cards, and electronic devices, that they can handle. However, problems with such games are that they often require too much set up time, are too difficult to operate in an automobile or are too expensive. What is needed, therefore, are game devices that are desirable to the players, particularly children, but are simple to play and inexpensive. Such devices would tend to make both the parents and their children happy.


Release sheets that can be used to manufacture artificial leather, paneling, and other products, as well as methods of making such release sheets are described. In general, the release sheets include a substrate and a release coating. The release coating is formed on the substrate by applying a crosslinkable material, such as an acrylic functional material, then crosslinking the material. An example of a release coating is the crosslinked reaction product of an acrylic functional material and a Michael donor. The release sheets have surfaces that can be replicated with high fidelity using a casting material, such as a urethane casting material.

A number of processes exist in which a polymeric film or sheet material is formed on or against a release sheet, and then separated from the release sheet after cooling or curing. Curing the polymeric film or sheet material (when necessary) can be accomplished by heat, by peroxide catalyst, or by radiation (e.g., ultraviolet radiation or electron beam radiation). The release sheet provides a surface from which the set polymeric film or sheet material can be separated, and also imparts a desired surface finish to the set polymeric film or sheet material. For example, a desired textured surface can be provided on the polymeric film or sheet material by forming the polymeric film or sheet material on or against a release sheet having a textured surface that is a mirror image of the desired textured surface. One example of making a set polymeric film or sheet material includes providing a release sheet having a desired surface effect, such as high gloss or texturing, and then casting a reactive urethane resin onto the provided release sheet. Typically, the reactive urethane resin is formed by mixing one or more diisocyanates and one or more polyol components, along with any other additives such as crosslinkers and accelerators (if desired). Upon mixing, the components begin to react. After mixing, the reactive urethane resin is applied to the release sheet where it sets, forming the set polymeric film or sheet material.
Release sheets can be made by applying a coating of an electron beam radiation curable material to one surface of a web substrate; pressing the coated side of the substrate against a replicative surface having a desired surface effect; irradiating the coating with electron beam radiation to cure the coating; and stripping the substrate from the replicative surface with the cured coating adhered to the substrate. The replicative surface can be a metal roll with a pattern engraved in its surface if a textured release sheet surface is desired, or a highly polished surface having a low surface roughness, if a high gloss release sheet surface is desired.

Release sheets and methods of making the same


The invention relates to a vehicle active suspension system. There is a need for an active suspension system which can alert an operator to certain conditions. The suspension system includes an actuator for moving a second vehicle part relative to a first vehicle part. The suspension system also includes sensors and a control unit. A vehicle operator is located in or on the second part. The sensors sense vehicle parameters and transmit parameter signals to the control unit. In response to the parameter sensors, the control unit causes the actuator to move the second part in such a manner that the movement alerts the operator to the existence of a condition, such as a critical or non-optimal operating state of the utility vehicle or of an implement coupled to the vehicle.

Active suspension systems are used on utility vehicles, such as tractors, harvesting machines, combine harvesters, forage harvesters, self-propelled sprayers, as well as industrial utility vehicles, such as construction vehicles, bulldozers, graders, backhoe excavators, loader vehicles, tipper trucks, cranes and telescopic loaders. Active suspension systems are suspension and damping systems, by means of which movements between a first part and a second part of the vehicle are cushioned and/or dampened. Such systems are known from the prior art, in particular with a seat suspension system of the applicant, which is disclosed in EP 1 186 467 B1. Such active suspension systems are also used in chassis of vehicles—generally large executive cars. A known axle suspension system is described in EP 0 913 280 A1. Such systems exclusively serve to cushion the driver relative to vibrations of the vehicle and/or of the first part and/or to counteract said movements. As a result, comfort is increased during the operation of the vehicle. Such cushioning, however, may lead to a false evaluation of critical driving conditions, as identifiable, tactile feedback between the vehicle and the operator due to the active suspension system no longer being present or the effect of said active suspension system being considerably reduced.
During the operation of a utility vehicle, assistance is provided to the operator visually, or optionally acoustically, by warning display elements. In this connection, warning lights are primarily provided which indicate a critical state of the utility vehicle, for example that of the excessive temperature of the engine oil or the coolant above an upper threshold value. The detection by an operator of such warning signs may be interfered with by external influences, such as light, noise and/or field of vision.


The present invention relates to compositions that comprise an anti-S1P monoclonal antibody, antibody fragment, or derivative in a carrier, particularly a buffered, hypertonic aqueous solution, as well as to kits containing such compositions, and methods for using such compositions for treatment of diseases and conditions associated with S1P.

1. Field of the Invention
The present invention relates to formulations and pharmaceutical compositions that comprise agents, particularly antibodies such as humanized monoclonal antibodies, antibody fragments, and antibody derivatives specifically reactive to sphingosine-1-phosphate (S1P) under physiological conditions. Such agents are useful in the treatment and/or prevention of various diseases or disorders.
The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein, or any publication specifically or implicitly referenced herein, is prior art, or even particularly relevant, to the presently claimed invention.
2. Background.
Bioactive Signaling Lipids
Lipids and their derivatives are now recognized as signaling mediators important in animal and human disease. Although most of the lipids of the plasma membrane play an exclusively structural role, a small proportion of them are involved in relaying extracellular stimuli to cells. "Lipid signaling" refers to any of a number of cellular signal transduction pathways that use cell membrane lipids as second messengers, as well as referring to direct interaction of lipid signaling molecules with their specific receptors. Lipid signaling pathways are activated by a variety of extracellular stimuli, ranging from growth factors to inflammatory cytokines, and regulate cell fate decisions such as apoptosis, differentiation and proliferation.
A particularly important class of bioactive signaling lipid mediators are the sphingolipids, which include molecules such as sphingomyelin, ceramide, ceramide-1-phosphate, sphingosine, sphingosylphosphoryl choline, sphinganine, sphinganine-1-phosphate (Dihydro-S1P), and sphingosine-1-phosphate (S1P). Sphingolipids and their derivatives represent a group of extracellular and intracellular signaling molecules with pleiotropic effects on important cellular processes. For a review of sphingolipid metabolism, see Liu, et al., Crit. Rev. Clin. Lab. Sci. 36:511-573, 1999. For reviews of the sphingomyelin signaling pathway, see Hannun, et al., Adv. Lipid Res. 25:27-41, 1993; Liu, et al., Crit. Rev. Clin. Lab. Sci. 36:511-573, 1999; Igarashi, J. Biochem. 122:1080-1087, 1997; Oral, et al., J. Biol. Chem. 272:4836-4842, 1997; and Spiegel et al., Biochemistry (Moscow) 63:69-83, 1998.
S1P is a mediator of cell proliferation and protects from apoptosis through the activation of survival pathways. It has been proposed that the balance between CER/SPH levels and S1P provides a rheostat mechanism that decides whether a cell is directed into the death pathway or is protected from apoptosis. The key regulatory enzyme of the rheostat mechanism is sphingosine kinase (SPHK) whose role is to convert the death-promoting bioactive signaling lipids (CER/SPH) into the growth-promoting S1P. S1P has two fates: S1P can be degraded by S1P lyase, an enzyme that cleaves S1P to phosphoethanolamine and hexadecanal, or, less common, hydrolyzed by S1P phosphatase to SPH.
The pleiotropic biological activities of S1P are mediated via a family of G protein-coupled receptors (GPCRs) originally known as Endothelial Differentiation Genes (EDG). Five GPCRs have been identified as high-affinity S1P receptors (S1PRs): S1P1/EDG-1, S1P2/EDG-5, S1P3/EDG-3, S1P4/EDG-6, and S1P5/EDG-8 only identified as late as 1998 (Lee, et al., 1998). Many responses evoked by S1P are coupled to different heterotrimeric G proteins (Gq−, Gi, G12-13) and the small GTPases of the Rho family.
In the adult, S1P is released from platelets and mast cells to create a local pulse of free S1P (sufficient enough to exceed the Kd of the S1PRs) for promoting wound healing and participating in the inflammatory response. Under normal conditions, the total S1P in the plasma is quite high (300-500 nM); however, it has been hypothesized that most of the S1P may be 'buffered' by serum proteins, particularly lipoproteins (e.g., HDL>LDL>VLDL) and albumin, so that the bio-available S1P (or the free fraction of S1P) is not sufficient to appreciably activate S1PRs. If this were not the case, inappropriate angiogenesis and inflammation would result. S1P may also have intracellular signaling activity.
Widespread expression of the cell surface S1P receptors allows S1P to influence a diverse spectrum of cellular responses, including proliferation, adhesion, contraction, motility, morphogenesis, differentiation, and survival. The regulation of various cellular processes involving S1P has particular impact on neuronal signaling, vascular tone, wound healing, immune cell trafficking, reproduction, and cardiovascular function, among others. Alterations of endogenous levels of S1P within these systems can have detrimental effects, eliciting several pathophysiological conditions, including cancer, inflammation, angiogenesis, heart disease, asthma, and autoimmune diseases.
A recent novel approach to the treatment of various diseases and disorders, including cardiovascular diseases, cerebrovascular diseases, and various cancers, involves reducing levels of biologically available S1P, either alone or in combination with other treatments. While sphingolipid-based treatment strategies that target key enzymes of the sphingolipid metabolic pathway, such as SPHK, have been proposed, interference with the lipid mediator S1P itself has not until recently been emphasized, largely because of difficulties in directly mitigating this lipid target, in particular because of the difficulty first in raising and then in detecting antibodies against the S1P target.
Recently, the generation of antibodies specific for S1P has been described. See, e.g., commonly owned, U.S. patent application Serial No. 20070148168; WO2007/053447; U.S. Pat. Nos. 6,881,546 and 6,858,383; and U.S. patent application Ser. No. 10/029,372, each of which applications and patents is hereby incorporated by reference in its entirety for all purposes. Such antibodies, which can, for example, selectively adsorb S1P from serum, act as molecular sponges to neutralize extracellular S1P. Among these antibodies is SPHINGOMAB™, a murine monoclonal antibody (mAb) developed by Lpath, Inc. and described in certain of the patents or patent applications listed above. SPHINGOMAB™ has been shown to be effective in models of human disease. In some situations, however, a humanized antibody may be preferable to a murine antibody, particularly for therapeutic uses in humans, where human-anti-mouse antibody (HAMA) response may occur. Such a response may reduce the effectiveness of the antibody by neutralizing the binding activity and/or by rapidly clearing the antibody from circulation in the body. The HAMA response can also cause toxicities with subsequent administrations of mouse antibodies. To address such concerns, a series of humanized anti-S1P monoclonal antibodies have been developed, and are described in commonly owned U.S. patent application Ser. Nos. 60/854,971 (now expired) and 11/924,890 and corresponding PCT application PCT/U.S.07/082,647, each of which applications is hereby incorporated by reference in its entirety for all purposes. These antibodies, and their S1P-binding fragments and derivatives, possess the advantages of the murine mAb in terms of efficacy in binding S1P, neutralizing S1P, and having the capacity to modulate disease states related to S1P, but with fewer or none of the potential disadvantages of the murine mAb when used in a human context. One particularly preferred example of such an antibody described in the above-referenced patent applications is referred to as LT1009 (or sonepcizumab), which antibody has exhibited greater activity than that of the parent murine monoclonal antibody in various animal models of disease. In the descriptions provided elsewhere in this document, LT1009 is used as a representative but non-limiting example of the antibodies, fragments, and derivatives amendable to inventions described herein.
3. Definitions
Before describing the instant invention in detail, several terms used in the context of the present invention will be defined. In addition to these terms, others are defined elsewhere in the specification, as necessary. Unless otherwise expressly defined herein, terms of art used in this specification will have their art-recognized meanings In the event of conflict, the present specification, including definitions, will control.
The term "therapeutic agent" means an agent to administered to effect therapy. "Therapy" refers to the prevention and/or treatment of diseases, disorders, or physical or psychological trauma. As used herein, the term "therapeutic" encompasses the fill spectrum of treatments for a disease or disorder. A "therapeutic" agent of the invention may act in a manner that is prophylactic or preventive, including those that incorporate procedures designed to target individuals that can be identified as being at risk (pharmacogenetics); or in a manner that is ameliorative or curative in nature; or may act to slow the rate or extent of the progression of at least one symptom of a disease or disorder being treated; or may act to minimize the time required, the occurrence or extent of any discomfort or pain, or physical limitations associated with recuperation from a disease, disorder or physical trauma; or may be used as an adjuvant to other therapies and treatments.
The term "treatment" or "treating" of a disease or disorder includes preventing or protecting against the disease or disorder (that is, causing the clinical symptoms not to develop or recur); inhibiting the disease or disorder (i.e., arresting or suppressing the development of clinical symptoms; and/or relieving the disease or disorder (i.e., causing the regression of clinical symptoms). As will be appreciated, it is not always possible to distinguish between "preventing" and "suppressing" a disease or disorder since the ultimate inductive event or events may be unknown or latent. Accordingly, the term "prophylaxis" will be understood to constitute a type of "treatment" that encompasses both "preventing" and "suppressing." The term "treatment" thus includes "prophylaxis".
The term "combination therapy" refers to a therapeutic regimen that involves the provision of at least two distinct therapies to achieve an indicated therapeutic effect. For example, a combination therapy may involve the administration of two or more chemically distinct active ingredients, for example, an anti-S1P antibody and another antibody specifically reactive against another target molecule. Alternatively, a combination therapy may involve the administration of an anti-S1P antibody and the administration of one or more other chemotherapeutic agents. Combination therapy may, alternatively, involve administration of an anti-S1P antibody together with the delivery of another treatment, such as radiation therapy and/or surgery. Further, a combination therapy may involve administration of an anti-S1P antibody (e.g., LT1009) together with one or more other biological agents (e.g., anti-VEGF, TGFβ, PDGF, or bFGF agent), chemotherapeutic agents, and another treatment such as radiation and/or surgery. In the context of combination therapy using two or more chemically distinct active ingredients, it is understood that the active ingredients may be administered as part of the same composition or as different compositions. When administered as separate compositions, the compositions comprising the different active ingredients may be administered at the same or different times, by the same or different routes, using the same of different dosing regimens, all as the particular context requires and as determined by the attending physician. Similarly, when one or more anti-S1P antibody species, for example, LT1009, alone or in conjunction with one or more chemotherapeutic agents, are combined with, for example, radiation and/or surgery, the drug(s) may be delivered before or after or even during surgery or radiation treatment.
The term "chemotherapeutic agent" means anti-cancer and other anti-hyperproliferative agents. Put simply, a "chemotherapeutic agent" refers to a chemical intended to destroy cells and tissues. Such agents include, but are not limited to: (1) DNA damaging agents and agents that inhibit DNA synthesis: anthracyclines (doxorubicin, donorubicin, epirubicin), alkylating agents (bendamustine, busulfan, carboplatin, carmustine, cisplatin, chlorambucil, cyclophosphamide, dacarbazine, hexamethylmelamine, ifosphamide, lomustine, mechlorethamine, melphalan, mitotane, mytomycin, pipobroman, procarbazine, streptozocin, thiotepa, and triethylenemelamine), platinum derivatives (cisplatin, carboplatin, cis diamminedichloroplatinum), telomerase and topoisomerase inhibitors (Camptosar), (2) tubulin-depolymerizing agents: taxoids (Paclitaxel, docetaxel, BAY 59-8862), (3) anti-metabolites such as capecitabine, chlorodeoxyadenosine, cytarabine (and its activated form, ara-CMP), cytosine arabinoside, dacabazine, floxuridine, fludarabine, 5-fluorouracil, 5-DFUR, gemcitibine, hydroxyurea, 6-mercaptopurine, methotrexate, pentostatin, trimetrexate, and 6-thioguanine (4) anti-angiogenics (Avastin, thalidomide, sunitinib, lenalidomide), vascular disrupting agents (flavonoids/flavones, DMXAA, combretastatin derivatives such as CA4DP, ZD6126, AVE8062A, etc.), (5) biologics such as antibodies or antibody fragments (Herceptin, Avastin, Panorex, Rituxan, Zevalin, Mylotarg, Campath, Bexar, Erbitux, Lucentis), and (6) endocrine therapy: aromatase inhibitors (4-hydroandrostendione, exemestane, aminoglutehimide, anastrozole, letozole), anti-estrogens (Tamoxifen, Toremifine, Raoxifene, Faslodex), steroids such as dexamethasone, (7) immuno-modulators: cytokines such as IFN-beta and IL2), inhibitors to integrins, other adhesion proteins and matrix metalloproteinases), (8) histone deacetylase inhibitors, (9) inhibitors of signal transduction such as inhibitors of tyrosine kinases like imatinib (Gleevec), (10) inhibitors of heat shock proteins, (11) retinoids such as all trans retinoic acid, (12) inhibitors of growth factor receptors or the growth factors themselves, (13) anti-mitotic compounds such as navelbine, Paclitaxel, taxotere, vinblastine, vincristine, vindesine, and vinorelbine, (14) anti-inflammatories such as COX inhibitors and (15) cell cycle regulators, e.g., check point regulators and telomerase inhibitors.
The present invention provides patentable compositions or formulations that comprise anti-S1P antibodies that are useful, for example, in treating or preventing hyperproliferative disorders such as cancer and cardiovascular or cerebrovascular diseases and disorders and various ocular disorders, as described in greater detail below. The term "hyperproliferative disorder" refers to diseases and disorders associated with, the uncontrolled proliferation cells, including but not limited to uncontrolled growth of organ and tissue cells resulting in cancers or neoplasia and benign tumors. Hyperproliferative disorders associated with endothelial cells can result in diseases of angiogenesis such as angiomas, endometriosis, obesity, age-related macular degeneration and various retinopathies, as well as the proliferation of endothelial cells and smooth muscle cells that cause restenosis as a consequence of stenting in the treatment of atherosclerosis. Hyperproliferative disorders involving fibroblasts (for example, fibrogenesis) include but are not limited to disorders of excessive scarring (for example, fibrosis) such as age-related macular degeneration, cardiac remodeling and failure associated with myocardial infarction, excessive wound healing such as commonly occurs as a consequence of surgery or injury, keloids, and fibroid tumors and stenting.
"Cardiovascular therapy" encompasses cardiac therapy as well as the prevention and/or treatment of other diseases associated with the cardiovascular system, such as heart disease. The term "heart disease" encompasses any type of disease, disorder, trauma or surgical treatment that involves the heart or myocardial tissue. Of particular interest are heart diseases that relate to hypoxia and/or ischemia of myocardial tissue and/or heart failure. One type of heart disease that can result from ischemia is reperfusion injury, such as can occur when anti-coagulants, thrombolytic agents, or anti-anginal medications are used in therapy, or when the cardiac vasculature is surgically opened by angioplasty or by coronary artery grafting. Another type of heart disease to which the invention is directed is coronary artery disease (CAD), which can arise from arteriosclerosis, particularly atherosclerosis, a common cause of ischemia. CAD has symptoms such as stable or unstable angina pectoris, and can lead to myocardial infarctions (MI) and sudden cardiac death. Conditions of particular interest include, but are not limited to, myocardial ischemia; acute myocardial infarction (AMI); coronary artery disease (CAD); acute coronary syndrome (ACS); cardiac cell and tissue damage that may occur during or as a consequence of pericutaneous revascularization (coronary angioplasty) with or without stenting; coronary bypass grafting (CABG) or other surgical or medical procedures or therapies that may cause ischemic or ischemic/reperfusion damage in humans; and cardiovascular trauma. The term "heart failure" encompasses acute myocardial infarction, myocarditis, a cardiomyopathy, congestive heart failure, septic shock, cardiac trauma and idiopathic heart failure. The spectrum of ischemic conditions that result in heart failure is referred to as Acute Coronary Syndrome (ACS).
The term "cardiotherapeutic agent" refers to an agent that is therapeutic to diseases and diseases caused by or associated with cardiac and myocardial diseases and disorders.
"Cerebrovascular therapy" refers to therapy directed to the prevention and/or treatment of diseases and disorders associated with cerebral ischemia and/or hypoxia. Of particular interest is cerebral ischemia and/or hypoxia resulting from global ischemia resulting from a heart disease, including without limitation heart failure.
"Monotherapy" refers to a treatment regimen based on the delivery of one therapeutically effective compound, whether administered as a single dose or several doses over time.
"Neoplasia" or "cancer" refers to abnormal and uncontrolled cell growth. A "neoplasm", or tumor or cancer, is an abnormal, unregulated, and disorganized proliferation of cell growth, and is generally referred to as cancer. A neoplasm may be benign or malignant. A neoplasm is malignant, or cancerous, if it has properties of destructive growth, invasiveness, and metastasis. Invasiveness refers to the local spread of a neoplasm by infiltration or destruction of surrounding tissue, typically breaking through the basal laminas that define the boundaries of the tissues, thereby often entering the body's circulatory system. Metastasis typically refers to the dissemination of tumor cells by lymphatics or blood vessels. Metastasis also refers to the migration of tumor cells by direct extension through serous cavities, or subarachnoid or other spaces. Through the process of metastasis, tumor cell migration to other areas of the body establishes neoplasms in areas away from the site of initial appearance.
"Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or pet animals, such as dogs, horses, cats, cows, etc. Preferably, the mammal is human.
An "anti-S1P antibody" or an "immune-derived moiety reactive against S1P" refers to any antibody or antibody-derived molecule that binds S1P. As will be understood from these definitions, antibodies or immune-derived moieties may be polyclonal or monoclonal and may be generated through any suitable technique, and/or may be isolated from an animal, including a human subject.
The term "antibody" ("Ab") or "immunoglobulin" (Ig) refers to any form of a peptide, polypeptide derived from, modeled after or encoded by, an immunoglobulin gene, or fragment thereof, that is capable of binding an antigen or epitope. See, e.g., IMMUNOBIOLOGY, Fifth Edition, C. A. Janeway, P. Travers, M., Walport, M. J. Shlomchiked., ed. Garland Publishing (2001). The term "antibody" is used herein in the broadest sense, and encompasses monoclonal, polyclonal or multispecific antibodies, minibodies, heteroconjugates, diabodies, triabodies, chimeric, antibodies, synthetic antibodies, antibody fragments, and binding agents that employ the complementarity determining regions (CDRs) of the parent antibody, or variants thereof that retain antigen binding activity. Antibodies are defined herein as retaining at least one desired activity of the parent antibody. Desired activities can include the ability to bind the antigen specifically, the ability to inhibit proleration in vitro, the ability to inhibit angiogenesis in vivo, and the ability to alter cytokine profile(s) in vitro.
Native antibodies (native immunoglobulins) are usually heterotetrameric glycoproteins of about 150,000 Daltons, typically composed of two identical light (L) chains and two identical heavy (H) chains. The heavy chain is approximately 50 kD in size, and the light chain is approximately 25 kDa. Each light chain is typically linked to a heavy chain by one covalent disulfide bond, while the number of disulfide linkages varies among the heavy chains of different immunoglobulin isotypes. Each heavy and light chain also has regularly spaced intrachain disulfide bridges. Each heavy chain has at one end a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at one end (VL) and a constant domain at its other end; the constant domain of the light chain is aligned with the first constant domain of the heavy chain, and the light-chain variable domain is aligned with the variable domain of the heavy chain. Particular amino acid residues are believed to form an interface between the light- and heavy-chain variable domains.
The light chains of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa (κ) and lambda (λ), based on the amino acid sequences of their constant domains. The ratio of the two types of light chain varies from species to species. As a way of example, the average κ to λ ratio is 20:1 in mice, whereas in humans it is 2:1 and in cattle it is 1:20.
Depending on the amino acid sequence of the constant domain of their heavy chains, immunoglobulins can be assigned to different classes. There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA, and IgA2. The heavy-chain constant domains that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively. The subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
An "antibody derivative" is an immune-derived moiety, i.e., a molecule that is derived from an antibody. This includes any antibody (Ab) or immunoglobulin (Ig), and refers to any form of a peptide, polypeptide derived from, modeled after or encoded by, an immunoglobulin gene, or a fragment of such peptide or polypeptide that is capable of binding an antigen or epitope. This comprehends, for example, antibody variants, antibody fragments, chimeric antibodies, humanized antibodies, multivalent antibodies, antibody conjugates and the like, which retain a desired level of binding activity for antigen.
As used herein, "antibody fragment" refers to a portion of an intact antibody that includes the antigen binding site or variable regions of an intact antibody, wherein the portion can be free of the constant heavy chain domains (e.g., CH2, CH3, and CH4) of the Fc region of the intact antibody. Alternatively, portions of the constant heavy chain domains (e.g., CH2, CH3, and CH4) can be included in the "antibody fragment". Antibody fragments retain antigen-binding and include Fab, Fab′, F(ab′)2, Fd, and Fv fragments; diabodies; triabodies; single-chain antibody molecules (sc-Fv); minibodies, nanobodies, and multispecific antibodies formed from antibody fragments. Papain digestion of antibodies produces two identical antigen-binding fragments, called "Fab" fragments, each with a single antigen-binding site, and a residual "Fc" fragment, whose name reflects its ability to crystallize readily. Pepsin treatment yields an F(ab′)2 fragment that has two antigen-combining sites and is still capable of cross-linking antigen. By way of example, a Fab fragment also contains the constant domain of a light chain and the first constant domain (CH1) of a heavy chain. "Fv" is the minimum antibody fragment that contains a complete antigen-recognition and -binding site. This region consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. It is in this configuration that the three hypervariable regions of each variable domain interact to define an antigen-binding site on the surface of the VH-VL dimer. Collectively, the six hypervariable regions confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site. "Single-chain Fv" or "sFv" antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the sFv to form the desired structure for antigen binding. For a review of sFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315 (1994).
The Fab fragment also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab′ fragments differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1 domain including one or more cysteine(s) from the antibody hinge region. Fab′-SH is the designation herein for Fab′ in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab′)2 antibody fragments originally were produced as pairs of Fab′ fragments which have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
An "antibody variant," in this case generally an anti-S1P antibody variant, refers herein to a molecule which differs in amino acid sequence from a native anti-LPA antibody amino acid sequence by virtue of addition, deletion and/or substitution of one or more amino acid residue(s) in the antibody sequence and which retains at least one desired activity of the parent anti-binding antibody. Desired activities can include the ability to bind the antigen specifically, the ability to inhibit proliferation in vitro, the ability to inhibit angiogenesis in vivo, and the ability to alter cytokine profile in vitro. The amino acid change(s) in an antibody variant may be within a variable region or a constant region of a light chain and/or a heavy chain, including in the Fc region, the Fab region, the CH1 domain, the CH2 domain, the CH3 domain, and the hinge region. In one embodiment, the variant comprises one or more amino acid substitution(s) in one or more hypervariable region(s) of the parent antibody. For example, the variant may comprise at least one, e.g. from about one to about ten, and preferably from about two to about five, substitutions in one or more hypervariable regions of the parent antibody. Ordinarily, the variant will have an amino acid sequence having at least 50% amino acid sequence identity with the parent antibody heavy or light chain variable domain sequences, more preferably at least 65%, more preferably at 80%, more preferably at least 85%, more preferably at least 90%, and most preferably at least 95%. Identity or homology with respect to this sequence is defined herein as the percentage of amino acid residues in the candidate sequence that are identical with the parent antibody residues, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity. None of N-terminal, C-terminal, or internal extensions, deletions, or insertions into the antibody sequence shall be construed as affecting sequence identity or homology. The variant retains the ability to bind LPA and preferably has desired activities which are superior to those of the parent antibody. For example, the variant may have a stronger binding affinity, enhanced ability to reduce angiogenesis and/or halt tumor progression. To analyze such desired properties (for example les immunogenic, longer half-life, enhanced stability, enhanced potency), one should compare a Fab form of the variant to a Fab form of the parent antibody or a full length form of the variant to a full length form of the parent antibody, for example, since it has been found that the format of the anti-sphingolipid antibody impacts its activity in the biological activity assays disclosed herein. The variant antibody of particular interest herein can be one which displays at least about 10 fold, preferably at least about % 5, 25, 59, or more of at least one desired activity. The preferred variant is one that has superior biophysical properties as measured in vitro or superior activities biological as measured in vitro or in vivo when compared to the parent antibody.
An "anti-S1P agent" refers to any therapeutic agent that binds S1P, and includes antibodies, antibody variants, antibody-derived molecules or non-antibody-derived moieties that bind LPA and its variants.
The "parent" antibody herein is one that is encoded by an amino acid sequence used for the preparation of the variant. Preferably, the parent antibody has a human framework region and, if present, has human antibody constant region(s). For example, the parent antibody may be a humanized or human antibody.
An "isolated" antibody is one that has been identified and separated and/or recovered from a component of its natural environment. Contaminant components of its natural environment are materials that would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In preferred embodiments, the antibody will be purified (1) to greater than 95% by weight of antibody as determined by the Lowry method, and most preferably more than 99% by weight, (2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator, or (3) to homogeneity by SDS-PAGE under reducing or nonreducing conditions using Coomassie blue or, preferably, silver stain. Isolated antibody includes the antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, isolated antibody will be prepared by at least one purification step.
The word "label" when used herein refers to a detectable compound or composition that is conjugated directly or indirectly to the antibody. The label may itself be detectable by itself (e.g., radioisotope labels or fluorescent labels) or, in the case of an enzymatic label, may catalyze chemical alteration of a substrate compound or composition that is detectable.
A "patentable" composition, process, machine, or article of manufacture according to the invention means that the subject matter satisfies all statutory requirements for patentability at the time the analysis is performed. For example, with regard to novelty, non-obviousness, or the like, if later investigation reveals that one or more claims encompass one or more embodiments that would negate novelty, non-obviousness, etc., the claim(s), being limited by definition to "patentable" embodiments, specifically exclude the unpatentable embodiment(s). Also, the claims appended hereto are to be interpreted both to provide the broadest reasonable scope, as well as to preserve their validity. Furthermore, the claims are to be interpreted in a way that (1) preserves their validity and (2) provides the broadest reasonable interpretation under the circumstances, if one or more of the statutory requirements for patentability are amended or if the standards change for assessing whether a particular statutory requirement for patentability is satisfied from the time this application is filed or issues as a patent to a time the validity of one or more of the appended claims is questioned.
The term "pharmaceutically acceptable salt" refers to salts which retain the biological effectiveness and properties of the agents and compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the agents and compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of charged groups, for example, charged amino and/or carboxyl groups or groups similar thereto. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids, while pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. For a review of pharmaceutically acceptable salts (see Berge, et al. (1977) J. Pharm. Sci., vol. 66, 1-19).
A "plurality" means more than one.
The terms "separated", "purified", "isolated", and the like mean that one or more components of a sample contained in a sample-holding vessel are or have been physically removed from, or diluted in the presence of, one or more other sample components present in the vessel. Sample components that may be removed or diluted during a separating or purifying step include, chemical reaction products, unreacted chemicals, proteins, carbohydrates, lipids, and unbound molecules.
The term "species" is used herein in various contexts, e.g., a particular species of chemotherapeutic agent. In each context, the term refers to a population of chemically indistinct molecules of the sort referred in the particular context.
A "subject" or "patient" refers to an animal in need of treatment that can be effected by molecules of the invention. Animals that can be treated in accordance with the invention include vertebrates, with mammals such as bovine, canine, equine, feline, ovine, porcine, and primate (including humans and non-human primates) animals being particularly preferred examples.
A "therapeutically effective amount" (or "effective amount") refers to an amount of an active ingredient, e.g., an agent according to the invention, sufficient to effect treatment when administered to a subject or patient. Accordingly, what constitutes a therapeutically effective amount of a composition according to the invention may be readily determined by one of ordinary skill in the art. In the context of ocular therapy, a "therapeutically effective amount" is one that produces an objectively measured change in one or more parameters associated with treatment of the ocular disease or condition including an increase or decrease in the expression of one or more genes correlated with the ocular disease or condition, induction of apoptosis or other cell death pathways, clinical improvement in symptoms, a decrease in aberrant neovascularization or in inflammation, etc. Of course, the therapeutically effective amount will vary depending upon the particular subject and condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skill in the art. It will be appreciated that in the context of combination therapy, what constitutes a therapeutically effective amount of a particular active ingredient may differ from what constitutes a therapeutically effective amount of the active ingredient when administered as a monotherapy (i.e., a therapeutic regimen that employs only one chemical entity as the active ingredient).

This patent is subject to a terminal disclaimer.

Pharmaceutical compositions for binding sphingosine-1-phosphate


An apparatus and method for repairing broken, compromised, damaged or cracked conduits is provided. Conduits such as pipes and tubing may bear fluid flows therethrough. Often these conduits are damaged or compromised and begin leaking fluid. A clamp is provided that holds expandable metal securely about the outer circumference of the conduit. The expandable metal may react with any leaking fluid, such as water, thereby expanding and sealing the crack or otherwise seals the compromised conduit in a permanent manner.

Conduits such as pipes or tubing may develop cracks or flaws that leads to loss of fluids that may be carried by the conduit. Often traditional methods for addressing such compromised conduits that are in service and bearing fluid transport often involve significant downtime of the service, significant time to repair, difficulty in accessing the compromised conduit for repair by traditional means, or may involve only temporary repair.


A system and method is disclosed for enabling individualized software functions in a device. In accordance with one embodiment of the present invention software is distributed as omnibus installations containing various software modules that are initially turned off. The user gains access to the turned off modules by requesting a certificate from a system provider. The system provider creates and transmits a certificate containing the information required to enable the desired module. The device can then use the certificate to access the desired software.

With the advent of digital video broadcasting (DVB) many new services and/or capabilities are becoming available, and will continue to become available, to DVB users. Naturally, most of these new features will be provided via software modules running on the user's DVB receiver. However, due to variations in hardware, the number of possible modules, the numerous possible combinations of installed modules, and intermittent upgrades, the number of possible software combinations that could run on an individual receiver are limitless. While this limitless variety is desired and anticipated by DVB user's, because it allows them to have enhanced services individually tailored. It has the potential to cause increased costs, reduced reliability, and increased maintenance difficulties, because the growing variety will create increased system management complexity.
Ensuring that users' DVB systems operate easily and reliably is of special concern to party responsible for the DVB system, e.g. cable companies, because they are ultimately responsible for the condition of the user's equipment and the whole of the DVB system. This, for example, is in contrast to personal computers where individual users are responsible for the maintenance and operation of their systems. Accordingly, a cost effective, reliable, and easily maintained system for providing users with the varied and personalized services they desire is needed.

System and method for activating individualized software modules in a digital broadcast environment


A material for forming silica-base coated insulation films used to form interlayer insulation films of multi-layer interconnection in VLSIs is provided. A material for forming a silica-base coated insulation film, obtained from (a) an alkoxysilane and/or a partially hydrolyzed product thereof, (b) a fluorine-containing alkoxysilane and/or (e) an alkylalkoxysilane, (c) an alkoxide of a metal other than Si and/or a derivative thereof and (d) an organic solvent. The material for forming silica-base coated insulation films according to the present invention has a storage stability and also enables thick-layer formation. Silica-base insulation films obtained are transparent and uniform films and are those in which no defects such as cracks or pinholes are seen, also having a superior oxygen plasma resistance.

In recent years, VLSIs have been rapidly made higher in packaging density and more highly integrated, and there is a demand for more multi-layered aluminum wiring and for decreasing minimum working line width as its wiring patterns are made finer. Accordingly, multi-layer wiring interlayer insulation films used in such LSIs are required to be formed by a smoothing technique which fills wiring gaps without vacancies and also makes their surfaces smooth.
As interlayer insulation films that are required to be made smooth, films (SOG films) formed by what is called the spin-on-glass method (SOG method) are conventionally employed in which a coating solution obtained by hydrolyzing an alkoxysilane and an alkylalkoxysilane in an organic solvent such as alcohol in the presence of water and a catalyst is applied by spin coating, followed by heating to cause coatings to cure. In particular, organic SOG films are mainly used in which the side chain of an organic component (an alkyl group such as methyl) is bonded to the backbone chain of a siloxane bond, i.e., an organic component (an alkyl group such as methyl) is left in the film, which can prevent cracks from occurring and improve smoothing properties to enable thick-layer formation.
The SOG films have advantages such that they cause less volume shrinkage, show a hydrophobicity and have a low dielectric constant. However, when dry etching is carried out using oxygen plasma during the course of the fabrication of an LSI in order to strip a photosensitive resist used to form contact holes that connect aluminum wiring provided at the lower layer and upper layer of the insulation film, this oxygen plasma causes alkyl groups in the film to be released, thus causing cracks. Accordingly, the insulation film is basically formed not in a single layer structure but in a three-layer structure so that the organic SOG film is not laid bare to the surface at the time of oxygen plasma processing, i.e., (i) an SiO.sub.2 film serving as a base for SOG film coating is formed by plasma-assisted CVD, (ii) the organic SOG film is formed thereon by coating and etchback-treated and (iii)another SiO.sub.2 film serving as an upper coat is formed by plasma-assisted CVD.
FIG. 1 illustrates an example of a process for producing a semiconductor device by the use of such an organic SOG film.
In FIG. 1, reference numeral 11 denotes a semiconductor chip substrate on which circuit electronic components such as a transistor, a diode, a resistor and a capacitor that constitute an electronic circuit are formed; 12, a first aluminum wiring formed on the semiconductor chip substrate; 13, the SiO.sub.2 film serving as a base for coating the organic SOG film, formed by plasma-assisted CVD; and 14, the organic SOG film [FIG. 1 (a)]. Etchback treatment is carried out to subject the whole surface of the organic SOG film 14 to oxygen plasma processing to make the plasma CVD SiO.sub.2 film laid bare at the part corresponding to the aluminum wiring 12 [FIG. 1 (b)]. Over the entire surface having been subjected to etchback treatment, another SiO.sub.2 film 15 serving as an upper coat is formed by plasma-assisted CVD, and a stated etching resist 16 is formed thereon [FIG. 1 (c)]. The plasma CVD SiO.sub.2 film at the part corresponding to the aluminum wiring 12, not covered with the etching resist 16, is removed by etching to make the aluminum wiring 12 exposed, and the etching resist is removed [FIG. 1 (d)]. Then, a second aluminum wiring 17 connected with the first aluminum wiring 12 is formed [FIG. 1 (e)]. Thus a semiconductor device is produced.
However, as the VLSIs are made higher in packaging density and more highly integrated, the space between aluminum wirings becomes so fine that the formation of the plasma CVD SiO.sub.2 film serving as a base for SOG coating makes the fine space between aluminum wirings still finer in the conventional three-layer structure, and hence an SOG coating solution can be caused to flow into the aluminum wiring space only with difficulty, resulting in a defective state of burying the organic SOG film. For this reason, with a decrease in minimum working line width, which decreases as the aluminum wiring becomes finer, it has become difficult to form the interlayer insulation film in the conventional three-layer structure. Accordingly, it is desirable to provide an SOG film having a good oxygen plasma resistance and enabling formation of the interlayer insulation film even in a single-layer structure.
In order to shorten the semiconductor device fabrication process, aiming at a cost reduction, there is a demand for non-etchback type SOG films that necessitate no etchback treatment. Accordingly, taking as a basis an inorganic SOG film (a film basically containing no organic component) having a good ashing resistance, it has been studied to add fine SiO.sub.2 particles, to use B-O and Mg-O bonds in combination or to introduce an Si-N skeleton, but no positive results have been forthcoming.

Material for forming silica-base coated insulation film, process for producing the material, silica-base insulation film, semiconductor device, and process for producing the device


A method of forming a treated granulized zeolite product includes applying a cationic surfactant to a granulized zeolite material, such that an amount applied to the granulized zeolite material covers at least 20 percent of the ECEC sites of the granulized zeolite material, granulizing a zeolite material to produce the granulized zeolite material, the zeolite material having a d50 in a range of 300 to 30 micron size.

1. Field of the Present Application
The present application relates to improved filtration of fluids.
2. Description of Related Art
Water filtration processes have been developed over the history of mankind to enhance clarity and to remove impurities from mediums, such as recreation and potable water. For example, water transported by aqueducts built by Roman engineers for the purposes of filling city fountains for drinking and bathing were passed through beds of sand to clarify the water.


A water solvent extraction degreasing method capable of reducing degreasing time without consideration of abrupt decomposition/vaporization and swelling caused by heat. An organic binder is removed from a molded product that is produced by a powder material mixed with the organic binder and this organic binder contains at least one water-soluble organic compound and at least one water-insoluble thermoplastic resin. The degreasing step of this method includes a water solvent extraction step for extracting the water-soluble organic compound from the organic binder contained in the molded product, using water as a solvent.

Generally, metal powder injection molding for producing sintered products is composed of the sequential steps of (i) injection molding in which a binder is added to a metal powder material to provide pressure-moldability thereto and then the mixture is formed into a molded form; (ii) degreasing for removing the binder from the molded form; and (iii) sintering of the degreased, molded form. Such metal powder injection molding has advantages over other methods such as the metal powder press molding process in that products of intricate shapes can be produced through a single process and that less post-treatments are required. These characteristics are not only suited for the production of small-sized metal parts and but also economically advantageous.
Powder injection molding however presents a disadvantage. That is, since this technique uses large amounts of binder for providing hydrostatic pressure moldability, collapsing, blistering and cracking are more likely to occur in the resultant, molded products particularly in the steps of degreasing and sintering compared to other ordinary powder metallurgical processes. In order to prevent such collapsing, blistering and cracking, removal of the binder has to be proceeded slowly in the degreasing step, so that it usually takes two or three days to perform the degreasing step, although the time required for it principally depends on the shape and thickness of molded products to be produced. Collapsing, blistering, cracking and the prolonged degreasing step are the outstanding problems for powder injection molding.
There have been proposed several techniques to eliminate various defects as mentioned above during removal of a binder from injection-molded products. One example of such techniques is disclosed in Japanese Patent Publication No. 61-48563 (1986) in which degreasing is carried out with a turbulent flow of inert gas blown to injection-molded products and part of binder components dissolved in a porous form is absorbed. Japanese Patent Publication No. 62-33282 (1987) discloses a degreasing method for maintaining the pressure in the atmosphere for injection-molded products to be no less than the vapor pressure of the thermoplastic binder.
However, it is practically difficult to keep the interior of a degreasing furnace in a uniform turbulent condition. Even if temperature can be kept uniform, the binder removing speed on the side of an injection-molded product exposed to blown air differs from that on the side opposite to the exposed side, with the result that the degree of degreasing undesirably varies within a single piece of injection molded product. When a setter is used for effective arrangement of injection molded products in a degreasing furnace, non-uniform degreasing is often seen in areas contacting the setter or areas from which a turbulent flow of air is shut out. Such non-uniformity is remarkable particularly when a plurality of injection molded products are processed in a binder removal furnace, resulting in variations in the degree of degreasing between the injection molded products. For the above reason, it is practically infeasible to produce sound degreased products free from defects such as deformation due to the inherent weight of the products themselves, blister and cracks.
It is also contemplated in the above publication that a thermoplastic binder composed of binder components of different melting points is used and these components are allowed to sequentially, gradually flow out from the injection molded products in the form of liquid to be absorbed by a porous absorber so that the removal of the binder can be promoted while preventing occurrence of blistering and cracking. However, this method is rather impractical in consideration of the problems that (i) molded products tend to fail in withstanding their own weight during the degreasing step, resulting in collapse and that (ii) the progress of degreasing varies within a molded product similarly to the above case when the binder absorber is disposed in partial contact with the molded product, and as there are some requirements for arranging a plurality of molded products within a degreasing furnace, it is difficult to carry out stable degreasing to obtain a number of acceptable molded products free from deformation due to their own weight, blister and cracks.
There have been made proposals for overcoming the defects of the heat degreasing methods such as described above and the prolonged degreasing process. For instance, U.K. Patent No. 1516079 discloses that a molded product is formed with use of a binder composed of (i) a water-soluble polymer such as polyethylene glycol, polypropylene glycol and polyvinyl alcohol and (ii) a water-insoluble polymer such as polystyrene and polyethylene, and that the water-soluble polymer is preferentially extracted using water as a solvent and then the remaining polymer is removed for example by heating. One example disclosed in the above U.K. patent is such that a molded product produced with a binder comprising three components (i) polyethylene glycol (water-soluble polymer), (ii) polystyrene (to be extracted using methylene chloride as a solvent) and (iii) polyethylene (a strength component to be removed by heating) is first heated to a temperature equal to the melting point of polyethylene glycol or more. The water-soluble polymer is extracted using water as a solvent and then, the polystyrene polymer is extracted with methylene chloride. Thereafter, the molded product is further heated thereby finally removing the strength component, i.e., polyethylene from the molded product.
In this example, polyethylene that imparts strength to a molded product and can be extracted by a solvent is used in addition to polyethylene glycol because polyethylene glycol is poor in strength and use of it in large amounts weakens a molded product. This involves two solvent-extraction steps (one step is carried out with water and the other is with methylene chloride) and as a result, degreasing time cannot be satisfactorily reduced. Furthermore, use of an organic solvent such as methylene chloride is unavoidable which leaves financial problems as well as environmental problems to workers.
According to the above method, since water solvent extraction is performed by use of vapor heated to about 100.degree. C. after the molded product is heated to a temperature equal to the melting point of polyethylene glycol or more, the molded product swells as the binder captures water. In addition, since polyethylene glycol has the properties of a water-soluble binding agent, the aqueous solution containing a high percentage of polyethylene glycol dissolved therein exhibits high viscosity and this disallows quick, uniform removal of polyethylene glycol from the entire surface of the molded product so that "sagging" similar to a sweating phenomenon is likely to occur. These defects lead to occurrence of cracking and deformation in the heat degreasing step which follows the water solvent extraction.
Techniques substantially identical to U.K. Patent No. 1516079 are disclosed in Japanese Patent Publication Laid-Open Nos. 2-101101 (1990), 2-182803 (1990), 2-182804 (1990) and 2-305903 (1990). As the water-soluble polymer typically used in powder molding which corresponds to polyethylene glycol, polypropylene glycol and polyvinyl alcohol of U.K. Patent No. 1516079, these publications use polyethylene glycol such as described in Powder Molding Hand Book (issued by The Nikkan Kogyo Shinbun Ltd. on Feb. 1987), macromolecular polyethylene oxides, methyl cellulose, carboxyl methyl cellulose (CMC), polyacrylamide and polyvinyl ether. They use a water-insoluble polymer such as polyethylene and polystyrene, like U.K. Patent No. 1516079.
More specifically, according to the above publications, a polyethylene oxide that is a high-molecular water-soluble polymer is used as a binder component in order to compensate for the weakness of the above-mentioned water soluble polymer, i.e., polyethylene glycol. After part or all of the polyethylene oxide is removed by water solvent extraction, most of the remaining polyethylene binder is removed by heating. Thermoplastic polyethylene oxides are, however, known to be poor in thermal stability. For example, when a binder containing a polyethylene oxide is mixed with a metal powder (SUS430c) by heating at 150.degree. C., decomposition of the polyethylene oxide continuously takes place because of shear heat generated during mixing, so that stable mixing torque cannot be ensured. According to the result of a thermal analysis conducted on a binder which has been mixed with a powder material and kneaded until the mixture comparatively stabilizes, the temperature of the mixture drops from the average melting point (i.e., about 70.degree. C.) of polyethylene oxides to about 54.degree. C. that is equal to the melting point of polyethylene glycol. It can be assumed from this fact that most of the polyethylene oxide is changed to lower-molecular polyethylene glycol.
As described above, the methods of the above publications have difficulty in obtaining stable flowability in the mixed material and return row material and suffer from deterioration in the strength of the binder which is resulted from the decomposition of a polyethylene oxide. There are other problems which limit the shape of molded products to be produced, these problems including: variations in the weight of molded products caused by the unstable flowability of material; variations in dimensional accuracy after sintering; damage to products when taken out of molds owing to the decreased strength of the binder; and cracking of molded products during the step for cooling the inside of molds. Furthermore, the corners of molded parts are susceptible to collapse during the water solvent extraction because of the resistance of flowing water being gently agitated. During the water solvent extraction, molded products slightly swell throughout the entire area and swelling is considerable especially at their parting line sections. This is a fatal defect for some molded parts. Another problem is that the effects of raised temperature for increasing the rate of extraction cannot be expected, because the temperature of water in the water solvent extraction should be kept at about 50.degree. C. or less in order to prevent "sagging" similar to a sweating phenomenon.
According to the above publications, the mechanism of the extraction is such that the water-soluble polymer at the surface of a molded product is first dissolved and diffused in water and at the same time, water penetrates into the molded product through the voids in which the dissolved water-soluble polymer has existed. The water-soluble polymer present in the vicinity of the void passages in the molded product is dissolved into the penetrating water and the water-soluble polymer thus dissolved then scatters in water that exists outside the molded product. The extraction rate for the water-soluble polymer in this process is discussed in connection with the relationship between the elementary process (I) where the rate of the movement/diffusion of the water-soluble polymer within the void passages of the molded product is controlled and the elementary process (II) where the difference in the concentration of the water-soluble polymer dissolved in the solvent between at the surface of the molded product and at the area remote from the above surface and the rate of the diffusion of the water-soluble polymer into the water solvent are controlled. It is known that polyethylene oxides, which are regarded as suitable water-soluble polymers in the publications, have good properties as high-viscosity water-soluble binding agents, and for instance, they are completely gelled in a 1 wt % aqueous solution at room temperature. For the reasons of (i) the properties of polyethylene oxides, (ii) the fact that the water-soluble polymer is dissolved at a high ratio in the vicinity of the surface of the molded product as illustrated in FIG. 8 of Japanese Patent Publication Laid-Open No. 2-182803 (1990) and (iii) the fact that the concentration of the polymer in the aqueous solution within the void passages of the molded product is thought to be at least equal to the concentration of the polymer at the surface of the molded product although this is not clearly stated in the publications, the water-soluble polymer moves and diffuses slowly during the elementary processes (I) and (II), resulting in a failure in archiving a satisfactory water solvent extraction rate. Known techniques for solving this problem are (i) a concentration controlling means is provided to keep the concentration of the polymer in the aqueous solution low; (ii) a sufficient amount of water is kept; and (iii) fluidization, agitation and vibration are imparted to the aqueous solution. The principle and system of extraction and lixiviation for wet refining are concretely described in "A New Metallurgical Course" New Version Refining Part (Chapter V: Non-Ferrous Metal Refining). This literature quantitatively explains the effect of agitation in the description relating to rates. Also, it is well known that highly viscous aqueous solutions containing a binding agent dissolved therein have such an inherent characteristic that their viscosity is decreased by agitation and fluidization. However, it should be noted that these promoting techniques are merely supplementary, because they leave much to solve. For instance, uniform extraction cannot be achieved even by agitation in molded products of some configurations particularly in their bores, groove bottoms and narrow drill holes. In cases where a plurality of molded products undergo multiple processes, there arises a problem in the arrangement of molded products. Further, rigorous agitation cannot be applied to light-weight molded products and to parts whose shapes are too unstable when they are placed in a furnace for degreasing. Therefore, there have been strong demands for the development of a binder composed of water-soluble substances that are capable of restricting the viscosity of an aqueous solution and it is desirable to use such a binder in combination with the above-described supplementary techniques in the degreasing process.
Of the above supplementary techniques, the fluidization of a water solvent can be attained by (i) splaying a water solvent on a molded product with a nozzle (Japanese Patent Publication Laid-Open No. 2-182803 (1990)); (ii) use of a conveying pump (Japanese Patent Publication Laid-Open No. 2-182804 (1990)); or (iii) use of ultrasonic waves (Japanese Patent Publication Laid-Open No. 2-182804 (1990)). These means are however rather infeasible in cases where a number of molded products are processed at the same time. In fact, it is very difficult in practical operation to set a number of molded products in relation to a nozzle and to bring a number of molded products in uniform contact with water fluidized by means of a conveying pump or ultrasonic waves. Further, these means cannot cope with the case where a plurality of kinds of molded products different in extraction time are continuously processed within the same water solvent extraction vessel.
Another method is disclosed in U.S. Pat. No. 4,197,118 in which a component, e.g., liquid oil is extracted with an organic solvent such as methylene chloride. This method, however, raises serious questions of safety and environmental problems. Further, the strength property of molded products is considerably degraded by use of a liquid oil so that molded products are susceptible to damage when taken out of molds, which limits the shape of molded products to be produced like other methods described earlier.
There are several problems in degreasing of an injection-molded product formed from metal powder. One of the problems is the amount of carbon remaining in the resultant degreased product which relates to the thermal decomposition of a binder. Another problem is cracking caused by the oxidation of the metal powder when degreasing is performed under an oxidation atmosphere. A further significant problem is variations in the sintering density of a sintered product. This is caused by a failure in adequately adjusting the components or carbon content of the sintered product. Some measures are reported to solve these problems, which are: (i) A choice of a suitable binder for injection molding; (ii) degreasing and composition adjustment carried out in an atmosphere of an N.sub.2, Ar or H.sub.2 gas; and (iii) adjustment of atmospheric gas during sintering. These methods are disclosed in Japanese Patent Publication Laid-Open Nos. 5-331503 (1993), 6-200303 (1994) and 6-73406 (1994).
As obvious from Japanese Patent Publication Laid-Open No. 7-305101, it is known that when degreasing is carried out under an atmosphere of an N.sub.2 gas that is inactive for metal powder, the carbon content of sintered iron products considerably differs according to the maximum temperature in completion of degreasing as well as the composition of the binder used. In any cases, it is difficult to adjust the residual carbon content in an atmosphere of an inert N.sub.2 gas or Ar gas. It is reported that when removal of a binder is carried out in the atmosphere, thermal decomposition of a thermoplastic binder is more accelerated with increasing temperature from 200.degree. C., compared to the case of thermal decomposition degreasing under an N.sub.2 gas atmosphere, but degreasing speed drops in the region after temperature reaches 250.degree. C. because of formation of residual carbon, and that the formation of residual carbon creates internal stress, making the molded product more liable to cracking. It is also reported that if a metal powder susceptible to oxidation is used, an oxide is newly created on the surface of the metal, with the result that the molded product is expanded during degreasing and therefore more likely to crack.
Further, when degreasing is carried out in the atmosphere, the residual carbon content becomes substantially zero or oxygen remains as an oxide, or the amount of carbon originally contained in the metal powder decreases. Therefore, a troublesome adjustment is involved, that is, the carbon content of the sintered product has to be adjusted by carefully selecting the type of a powder to be used, the type of a binder to be used, compounding ratio, degreasing conditions and others.
Miura et.al. has proposed a method for adjusting the residual carbon content by carrying out degreasing in an atmosphere of an N.sub.2 gas mixed with a H.sub.2 gas at a high ratio.
It is also contemplated from the difference in the residual carbon content between the case of degreasing in an atmosphere of an N.sub.2 gas and the case of degreasing in the atmosphere that the carbon content can be adjusted by mixing a flow of inert gas such as N.sub.2 with air or oxygen. The details of one example of the above method are reported by "JOURNAL OF THE JAPAN SOCIETY OF Powder and Powder Metallurgy" (Vol.40, No.4,388). This method controls the carbon content by adding hydrogen to N.sub.2 gas. According to this method, when degreasing is carried out at a temperature of 400.degree. C. (this temperature is a very common degreasing condition), a large amount of hydrogen is required to be added to N.sub.2 gas for controlling the carbon content, so that handling of hydrogen enriched gas to be taken out of the furnace is very dangerous. In consequence, it becomes necessary to control the evaporated and removed binder and employ a security system for preventing explosion. Another disadvantage is that the effect of H.sub.2 gas for controlling the carbon content is small.
The method disclosed in Japanese Patent Publication Laid-Open No. 6-200303 suffers from similar problems.
In the method in which air or oxygen is directly added as disclosed in Japanese Patent Publication Laid-Open No. 5-331503, the carbon content of the degreased product is controlled by the direct reaction (this reaction is described by the following formula) between oxygen and carbon which starts to remain in the degreased product. The principle of this method differs from that of the above-described method in which hydrogen is utilized, and it is anticipated that with this method, the residual carbon content can be more effectively controlled compared to the hydrogen addition method. EQU C(S)+(1/2)O.sub.2 (G)=CO(G)(S): solid, (G): gas! EQU G=-26,700-20.75TT: absolute temperature K!
In reality, the direct oxidation reaction between oxygen and carbon is a violent exothermic reaction and particularly when oxygen is added into an inert gas such as N.sub.2 in a slight amount, the reaction of oxygen proceeds more violently according to Le Chatelier's low. Therefore, when degreasing a number of molded products, this method has difficulty in controlling the carbon contents of a number of molded products so as to be uniform and cannot avoid the possibility of occurrence of cracks in molded products which are directly exposed to the introduced gas because of the excessive oxidation reaction. This is the case with the degreasing technique disclosed in Japanese Patent Publication Laid-Open No. 6-192706 (1994) wherein degreasing is performed under an atmosphere of oxygen-enriched air.
The present invention has been made taking the foregoing drawbacks into account, and one of the objects of the invention is therefore to provide a water solvent extraction degreasing method for removing a powder-injection-molding binder that is capable of reducing degreasing time without consideration of abrupt decomposition/vaporization and expansion caused by heat.
Another object of the invention is to provide a degreasing method comprising a water solvent extraction step for extracting a powder-injection-molding binder that is capable of reducing degreasing time while ensuring the shape retention of molded products during the degreasing step.
Another object of the invention is to provide a degreasing method comprising a step for economically, quickly and uniformly performing water solvent extraction on parts of various shapes with a simple system, such parts being formed from a stable, powder-injection-molding binder free from swelling and hydrolysis caused by water and aqueous solution components which are capable of restricting the viscosity of an aqueous solution extracted using water as a solvent.
Still another object of the invention is to provide a degreasing method for degreasing a powder-injection-molding binder that is excellent in strength and toughness in order to reduce injection molding and degreasing defects.
A further object of the invention is to provide a degreasing method in which the amount of residual carbon is adjusted during degreasing, whereby occurrence of defects in degreasing can be prevented and the amount of residual carbon in the resultant sintered product can be controlled.

Water solvent extraction degreasing method and molded products produced therewith