A facsimile machine scans one document page which is a mixture of an elaborative image and a normal image, and transmits the elaborative image portion in a fine mode and the normal image portion in a standard mode, so as to save a transmission time, maintaining the quality of the image. To this end, a previous line is compared with a current line to detect a dot number difference. If the dot number difference is not greater than a predetermined value, a command code is transmitted to a called facsimile machine to print the same image data as that of the previous line. Otherwise, if the dot number difference is greater than the predetermined value, the scanning data is coded by the existing coding method and transmitted to the called facsimile machine. In this way, it may be possible to save the data transmission time.

1. Field of the Invention
The present invention relates to a technique for controlling a resolution in an image processing system, and more particularly a technique for automatically controlling a resolution of a document to be transmitted and/or copied.
2. Description of the Related Art
In general, a facsimile has a resolution control function which includes a standard mode, a fine mode, and a super fine mode. If a user selects one of the above mentioned resolution modes by using an operating panel in order to control a resolution of the document to be transmitted, a controller (e.g., central processing unit) recognizes the selected resolution mode and transmits corresponding mode information according to a protocol to a called facsimile prior to transmitting actual image data. Thereafter, the facsimile transmits the document image based on the selected mode information. At this moment, the user should check every new page as to whether or not the resolution mode should be changed, thereby causing inconveniences. Once the resolution mode is selected for a page, the whole page will be transmitted with the same resolution.
The standard mode is to scan the document every other line (where one line is 1/7.7 mm) and code the scanned image to transmit to the called facsimile. Then, the called facsimile prints one line with the received image and prints a next line with the same image. The fine mode is to scan the document line by line and code the scanned image to transmit to the called facsimile. Then, the called facsimile prints the received images line by line. Further, the super fine mode is to scan the document every half line (where a half line is 1/15.4 mm) and code the scanned image to transmit to the called facsimile. The transmitted image is printed at the called facsimile every half line. Thus, in the light of the vertical lines, the resolution with respect to one line becomes 1/3.85 mm in the standard mode, 1/7.7 mm in the fine mode, and 1/15.4 mm in the super fine mode. For the convenience of explanation, it is assumed that one line is 1/7.7 mm throughout the specification.
As can be clearly appreciated from the above descriptions, the standard mode has a fast transmission speed but a low resolution. On the contrary, the fine mode and the super fine mode have a high resolution, but they have the disadvantage of the low transmission speed. Conventionally, when scanning a document in a facsimile, the user should determine an elaboration of the document by the naked eye, and select the resolution mode accordingly.
Therefore, in the case where the document is a mixture of the elaborative image and the normal image, several problems may be caused unavoidably. Namely, it takes a long time to transmit the document in the fine or super fine mode continuously, which results into an expensive communication fee. On the contrary, if the user transmits the document in the standard mode in order to reduce the transmission time, a quality of the image will be degraded. Furthermore, in the case where the facsimile is erroneously set to the standard mode for a document that should have been set to the fine or super fine mode, the user might retransmit document due to the degradation of the image.
The following patents each disclose features in common with the present invention but do not teach or suggest the specifically recited features of the present invention: U.S. Pat. No. 5,337,159 to Iida et al., entitled Image Data Smoothing Method, U.S. Pat. No. 5,274,462 to Satoh, entitled Image Input And Output Method, U.S. Pat. No. 4,028,731 to Arps et al., entitled Apparatus For Compression Coding Using Cross-Array Correlation Between Two-Dimensional Matrices Derived From Two-Valued Digital Images, U.S. Pat. No. 4,070,694 to Sakamoto et al., entitled Picture Image Information Band Compression And Transmission System, U.S. Pat. No. 4,115,815 to Nakagome et al., entitled Facsimile Signal Coding Method, U.S. Pat. No. 4,191,974 to Ono et al., entitled Facsimile Encoding Communication System, U.S. Pat. No. 3,974,325 to Wilmer, entitled Interpolator For Facsimile Bandwidth Compression, U.S. Pat. No. 4,193,092 to Stoffel, entitled Image Interpolation System, U.S. Pat. No. 4,291,339 to Ogawa et al., entitled Facsimile Transceiver, U.S. Pat. No. 4,396,952 to Tisue et al., entitled Facsimile Transmission Apparatus, and U.S. Pat. No. 4,571,632 to Schaphorst et al., entitled Alternate Line Interpolation Method And Apparatus.

Technique for automatically controlling resolution


An example processing system may comprise: a lower stack bound register configured to store a first memory address, the first memory address identifying a lower bound of a memory addressable via a stack segment; an upper stack bound register configured to store a second memory address, the second memory address identifying an upper bound of the memory addressable via the stack segment; and a stack bounds checking logic configured to detect unauthorized stack pivoting, by comparing a memory address being accessed via the stack segment with at least one of the first memory address and the second memory address.

Stack pivoting is often exploited in return-oriented programming (ROP) attacks. ROP is a method of hijacking the execution flow of the current process by exploiting return instruction which, in many processor architectures, retrieves from the top of the stack the address of the next executable instruction within the calling routine. Thus, by modifying the return address on the stack, an attacker can divert the execution flow of the current process to an arbitrary memory location.
Having hijacked the execution flow, the attacker can, for example, initialize the arguments and perform a library function call. This technique is known as "return-into-library." In another example, the attacker can locate within the code segment several instruction sequences to be executed. This approach is known as "borrowed code chunks technique."

Systems and methods for preventing unauthorized stack pivoting


Materials capable of delivering stabilized free radicals to targeted treatment sites. The materials comprise semi-crystalline, hydrolytically degradable polymers that are subjected to ionizing radiation to create stabilized free radicals therein. Upon exposure to oxygen containing aqueous media, the materials generate reactive oxidative species which are useful in biological processes.

Sterilization of medical devices may be provided by several means. Two common means are ethylene oxide sterilization (EO) and sterilization by exposure to ionizing radiation. However, exposure of certain polymers and organic materials, common in the production of medical devices, to ionizing radiation has been shown to cause some level of degradation to the polymer or organic material. The extent to which a polymer or organic material degrades is believed to be related to the dose of ionizing radiation absorbed. Thus, where a device is constructed of polymeric or organic materials, the applied radiation dose should be high enough to sterilize the device while concurrently being as low as possible in order to minimize the amount of device degradation that occurs. Where used for permanent and absorbable polymers and copolymers, typical, final packaged device sterilization is achieved with a dose of approximately 25 kGy.
Additionally, certain polymers, when exposed to ionizing radiation, undergo chain scission which may result in the formation of free radical(s) along the affected polymer chain. Free radicals of this type are generally known to exist in polymers for only brief periods of time after generation. The high energy of free radicals makes them unstable, rapidly reacting or recombining whenever possible. If the free radical combines with another free radical, and those free radicals are on differing polymer chains, crosslinking occurs and effectively increases molecular weight. If the free radical formed on the irradiated polymer chain combines with another element such as, but not limited to, oxygen, it may result in a degradation reaction and possibly a decrease in overall polymer molecular weight. In either case, the free radical reaction rate is typically very fast once the necessary conditions exist. Where the free radicals react with an oxygen molecule, reactive oxidative species (ROS) may be generated.
ROS are chemically reactive and biologically active oxygen-containing species such as superoxide, hydrogen peroxide, singlet oxygen, hydroxyl radical, hypochlorite, peroxynitrite, and perhydroxy radical, and combinations thereof. Further, ROS are highly reactive due to the presence of unpaired valence shell electrons.
In biology, ROS serve critical functions involving the immune response. For example, superoxide is naturally generated during "the respiratory burst" by activated neutrophils during phagocytosis of a microbe and is the mechanism used by the engulfing polymorphonuclear leukocytes (PMNs) in order to destroy bacteria. In light of this, current antibacterial drug therapies use ROS, particularly hydroxyl radicals, as the mechanism for bactericidal action (Kohanski et al., Cell, 130, 797-810 (2007)).
ROS are also active in cell signaling, including but not limited to stimulating cell proliferation, differentiation, migration, apoptosis, and angiogenesis (Klebanoff. Annals Internal Medicine, 93, 480-9 (1980)) (Turrens, Jrl Physiol, 552 (2), 335-44 (2003)) (Veal et al., Molecular Cell, 26, 1-14 (2007)). In particular, it has been shown that ROS even at relatively low concentrations (micro- to nanomolar) act as key cell signaling molecules to regulate a variety of biological processes such as angiogenesis, cell proliferation, and cell migration (Veal et al., Mol Cell.; 26(1): 1-14 (2007)) (D'Autrraux et al., Nature Reviews Molecular Cell Biology, 8, 813-824 (2007)). ROS have also been shown to be influential in platelet activation (Krotz et al., Arterioscler Throm Vase Biol; 24: 1988-96 (2004)). Involvement in these biological processes places ROS in the critical role of regulating numerous physiologic and pathologic states, including but not limited to some cancers, cardiovascular disease, chronic wounds, aging and neurodegeneration. For instance, use of ROS in clinical therapy has been demonstrated in photodynamic therapy (PDT) for cancer treatment (Dolmans et al., Nature Reviews Cancer, 3, 380-7 (2003)).
Higher level of ROS is known to inhibit cell proliferation and even induce cell apoptosis. Thus, one application of such ROS generation materials is to make medical devices, e.g. stent and balloons, to treat stenosis and restenosis in humoral ducts, including blood vessel, bile duct, esophagus and colon.
A stenosis is an abnormal narrowing in blood vessels or other ducts that is caused by uncontrolled proliferation and deposition of cells, extracellular matrix, lipids and other cellular contents. Thus, materials that release high levels of ROS can be used to inhibit such cellular proliferation and resolve the stenosis through the induction of apoptosis.
Restenosis refers to the recurrence of stenosis that follows the interventions that treat the original stenosis. Restenosis usually pertains to blood vessel that has become narrowed; received treatment to clear the blockage and subsequently become re-narrowed. Restenosis can occur following interventions such as percutaneous transluminal coronary angioplasty and stent treatments. These cardiovascular interventions induce unwanted proliferation of vascular smooth muscle cells (neointimal hyperplasia), which eventually leads to the re-narrowing of blood vessels. To prevent restenosis, drug-eluting stent (DES) was introduced into clinical cardiology at the beginning of the 2000s. Antiproliferative drugs, such as paclitaxel (an anti-cancer drug) and sirolimus (an immuno-suppressive drug), were coated on the surface of cardiovascular stent and released locally to the blood vessel wall. These drugs effectively inhibit vascular smooth muscle cell proliferation, and thus prevent in-stent neointimal hyperplasia and consequently restenosis.
It has been demonstrated that high level of ROS, particularly hydrogen peroxide, can effectively inhibit the proliferation of smooth muscle cells (Deshpande, N. N., et al., Mechanism of hydrogen peroxide-induced cell cycle arrest in vascular smooth muscle. Antioxid Redox Signal, 2002. 4(5): p. 845-54) and other cells (Li, M., et al., Hydrogen peroxide induces G2 cell cycle arrest and inhibits cell proliferation in osteoblasts. Anat Rec (Hoboken), 2009. 292(8): p. 1107-13) & (Chen, Q. and B. N. Ames, Senescence-like growth arrest induced by hydrogen peroxide in human diploid fibroblast F65 cells. Proc Natl Acad Sci USA, 1994. 91(10): p. 4130-4). ROS generating materials thus can be used to make medical devices, such as stent and balloons, which once deployed can locally deliver high level of ROS to prevent/treat restenosis.
To date, the benefits of ROS have been limited due to the short nature of their existence and difficulties in providing them at therapeutic levels and durations to desired treatment sites. It has surprisingly been found that stabilized free radicals can be formed in certain polymers and such free radicals can, in turn, generate ROS when exposed to an oxygen containing aqueous environment. Given the biological relevance of ROS, materials, devices and methods that enable the extended generation of ROS at a treatment site would be advantageous in the medical field and are contemplated herein.

This patent is subject to a terminal disclaimer.

Reactive oxidative species generating materials and methods of use


A system and method to provide content and call attributes for a destination phone number using a click-to-dial connection includes accepting a query, retrieving links to a document, and searching through cached data using the query to identify relevant or destination number information. If no match is found, the method continues with accessing the document identified by the link for identifying relevant number information and creating a click-to-dial icon to link to the relevant numbers included in the relevant phone number information identified by the query. Next, a popup box for content relevant to the click-to-dial icon and a click feature on the popup box are created to retrieve call destination attributes for viewing by a user. Further, computer instructions create at least one communication connection between two communication devices after viewing call destination attributes.

Information search and retrieval services for locating relevant phone numbers and phone number information has improved with advancements in automation to some extent. Generally, information searches to find or locate a phone number have entailed a standard manual practice of looking up the number in the yellow pages and, then, dialing the number to determine if the phone number is for the correct person or entity.
Improvements to information search methods have evolved with information searches through the World Wide Web network using a search engine, such as Google or some other search engine for information on a particular individual or group of individuals regarding relevant phone numbers. However, these methods can be time-consuming and can lack the ability to match selected destination phone numbers that were responsive to the general searches performed on the network.
Thus, a method and a system are needed to provide automated information about a called relevant phone number to a user and include using a click-to-dial service to connect to the correct particular person or entity. Further, there is a need to provide improved response time and a more efficient customer care strategy for information searches and retrievals.
The present embodiments address these needs.

Providing called number characteristics to click-to-dial customers


An automated lens inspection system that images the edge and surface of an ophthalmic lens transmits light through the ophthalmic lens to a camera to create a complete digital image of the lens edge or lens surface. The digitized image(s) is(are) analyzed to detect defects or abnormalities of the ophthalmic lens. Methods of inspecting ophthalmic lenses are also disclosed.

1. Field of the Invention
The present invention relates to lens inspection systems, and more particularly, the invention relates to automated systems and methods for inspecting ophthalmic lenses by acquiring and analyzing a plurality of images of the lenses being inspected.
2. Description of Related Art
Precision and accuracy in manufacturing ophthalmic lenses, such as contact lenses, are crucial for the use of such lenses in patients. Due to the increased demand for contact lenses, the manufacturing process of contact lenses has been automated to reduce manufacturing time and increase product turnover. However, the contact lenses are susceptible to damage, abnormalities, or contamination that would make the lenses unsuitable for use in patients. Accordingly, it is desirable to provide an inspection process of the manufactured lenses to reduce, and preferably eliminate, production of defect lenses.
Examples of contact lens inspection systems are disclosed in U.S. Pat. Nos. 5,500,732; 5,574,554; 5,748,300; 5,818,573; and 5,828,446.
U.S. Pat. No. 5,574,554 discloses an automated contact lens inspection system that inspects a contact lens while the lens is still in place on a transparent lens mold. The system uses a white light source that emits collimated white light through the transparent lens mold and through the lens being inspected to a camera. The camera utilizes a lens having a viewing angle that is constant within 0.5° for a ⅔ inch CCD array camera and 0.4° for a ½ inch camera, which is important in that system for the optical detection of the edge of the contact lens. The camera acquires a single image of the contact lens and converts the image into a digital representation of the lens for further processing by a computer to detect abnormalities of the lens.
U.S. Pat. No. 5,818,573 discloses an ophthalmic lens inspection system that uses diffuse white light to illuminate an inspected lens. The lens inspection system utilizes a plurality of cameras to acquire images of the inspected lens, and each camera is provided with a light source. The cameras that image the lens edge only image a portion of the lens edge. Accordingly, in order to obtain a complete image of the ophthalmic lens edge, eight cameras perimetrically disposed around the ophthalmic lens are used. Each camera is positioned at an acute angle with respect to the plane of the lens support. Each image acquired by each of the eight cameras is separately processed to minimize computational processing power. The system of the '573 patent does not inspect lenses for defects, instead, the system of the '573 patent inspects lenses to determine whether the lens is properly centered on the inspection system.
U.S. Pat. No. 5,500,732 discloses an ophthalmic lens inspection system that utilizes non-infrared light to image a hydrated lens. The light must pass through a ground glass diffuser, an air spaced doublet collector lens, and a field lens. The numerous components required in the inspection system necessarily require precise alignment and spacing of the various optical components in order to achieve the intended results. The image processor acquires a single image from the camera and analyzes either the center of the ophthalmic lens or the edge of the ophthalmic lens.
U.S. Pat. Nos. 5,748,300 and 5,828,446 disclose an automated lens inspection system that inspects hydrated lenses using dark field illumination. The lenses are imaged in a single step thereby contributing to the continuous lens inspection cycle disclosed therein. Each dark field image of a lens may reveal the lens edge as well as any defects or abnormalities in the lens that are sufficient to cause a scattering of light so that the light is imaged by the camera.
The lens inspection systems disclosed hereinabove that acquire only a single image of the ophthalmic lenses are susceptible to high false rejection rates, which may be caused by debris within the system or on the lens, or which may be caused by "noise", such as optical noise, within the system. For example, these systems are not readily able to determine whether a potential defect near the lens edge is actually a defect of the lens, or whether it is debris on the window on which the lens is positioned. Accordingly, these systems may have high false rejection rates (e.g., rejection of lenses that were placed on a contaminated window), or may accept lenses that have small, but significant, defects near the lens edge.

Systems and methods for inspection of ophthalmic lenses


A method comprising: receiving a plurality of duplicates of a serial bit stream, wherein said serial bit stream comprises a sequence of data packets; continuously dividing each of said duplicates of said serial bit stream based on sequential time windows; with respect to each of said time windows, aligning said data packets associated with each of said duplicates of said serial bit stream, received within said time window, based, at least in part, on data packet similarity; and recreating in real time said serial bit stream by selecting at least one of said aligned data packets as representing a next data packet in said sequence of data packets.

When sending data over packetized networks, some packets may be dropped, or they may arrive corrupted. Generally, a packetized network or channel may relate to dividing content to be sent into packets or messages, sending the packets or messages and reconstructing the content, by the receiving end, based on the packets.
To overcome loss or corruption of packets, some known systems and methods send some or even all packets more than once. However, sending the same data more than once is generally a wasteful method to overcome errors. Other methods, e.g., forward error correction (FEC) enable detecting a limited number of errors and may further enable a receiver to correct some of the errors, however, such methods come with a cost of increased computation resources and sender complexity.
Both stream duplication and FEC methods associate sequence numbers or other identifiers with packets and use the identifiers to reconstruct a stream of packets according the right (or original) order or sequence. However, such methods are inadequate when packets are not numbered or sequenced.
The foregoing examples of the related art and limitations related therewith are intended to be illustrative and not exclusive. Other limitations of the related art will become apparent to those of skill in the art upon a reading of the specification and a study of the figures.

Packetized data communication over multiple unreliable channels


For phase-shifting micro lithography, a method of assigning phase to a set of shifter polygons in a mask layer separated by a set of target features includes assigning a first phase to a first shifter polygon, identifying a set of target features that touch the first shifter polygon, and assigning a second phase to all shifter polygons in the set that touch the set of target features in contact with the first shifter polygon. The set of shifter polygons and the set of target features are separated into aggregates that are spatially isolated from each other such that the phase assignment in one aggregate does not affect the phase assignments in other aggregates. In one embodiment, the first shifter polygon in each aggregate is selected by merging the set of shifter polygons and set of target features into a large polygon, marking a vertex of the large polygon, checking the vertex to make sure it only touches one shifter polygon, and selecting the single shifter polygon touching the vertex as the first shifter polygon.

In semiconductor manufacture, micro lithography is used in the formation of integrated circuits on a semiconductor wafer. During a lithographic process, a form of radiant energy, such as ultraviolet light, is passed through a photo mask or a reticle and onto the semiconductor wafer. "Light" is not limited to the visible spectrum. The photo mask contains opaque and transparent regions formed in a predetermined pattern. A grating pattern, for example, can be used to define parallel spaced conducting lines on a semiconductor wafer. The ultraviolet light exposes the mask pattern on a layer of resist formed on the wafer. The resist is then developed to remove either the exposed portions of resist for a positive resist or the unexposed portions of resist for a negative resist. The patterned resist can then be used for subsequent semiconductor fabrication processes such as ion implantation or etching.
As microcircuit densities have increased, the size of the features of semiconductor devices has decreased to the sub-micron level. These sub-micron features may include the width and spacing of metal conducting lines or the size of various geometric features of active semiconductor devices. The requirement of sub-micron features in semiconductor manufacture has necessitated the development of improved lithographic processes and systems. One such improved lithographic process is known as phase shift lithography.
Recently, different techniques have been developed in the art for fabricating different types of phase shifting photo masks. One type of phase shifting mask, named after a pioneer researcher in the field, M. D. Levenson, is known in the art as a "Levenson" or "strong" phase shifting mask. This type of mask is also referred to as an "alternating aperture" phase shifting mask because every other aperture contains a phase shifter. The term "strong" refers to the use of non-attenuated or full strength phase shifting illumination.
This type of mask is typically formed on a transparent quartz substrate. An opaque layer, formed of a material such as chromium, is deposited on the quartz substrate and etched with openings in a desired pattern. Phase shifting areas on the mask are formed by depositing a phase shifting material over the opaque layer and into every other opening in the opaque layer. The phase shifting areas may also be formed by etching a pocket or trench in the transparent substrate. The target features for phase shift lithography are the opaque regions. Each opaque target feature is bordered by a transparent, i.e. non phase shifting, opening on one side and a phase shifting opening on the other side. The transparent openings and the phase shifting openings are referred to as shifter polygons.
With phase shift lithography, the interference of light rays is used to improve the resolution and depth of focus of an image projected onto a target. In "strong" phase shift lithography, the phase of an exposure light at the object is controlled such that adjacent bright areas are formed preferably 180 degrees out of phase with one another. Dark regions are thus produced between the bright areas by destructive interference even when diffraction without phase shifting would otherwise cause these areas to be exposed away. This technique improves total resolution at the object and allows resolutions as fine as 0.1 μm or finer to occur.
In general, a strong phase shifting photo mask is constructed with a repetitive pattern having three distinct layers or areas. An opaque layer provides areas that allow no light transmission. A transparent layer provides areas which allow close to 100% of light to pass through. A phase shift layer provides areas which allow close to 100% of light to pass through but phase shifted 180 degrees from the light passing through the transparent areas. The transparent areas and phase shift areas are situated such that light rays diffracted are canceled out in a darkened area therebetween. This creates the pattern of dark and bright areas which can be used to clearly delineate features of a pattern defined by the opaque layer of the mask on a photopatterned semiconductor wafer.
In order to generate a phase shift lithography mask, target features in a given circuit design, or features that are small enough to require phase shift lithography, are identified. Next, shifter polygons meeting dimensional criteria dictated by mask-making constraints and optical performance are created on either side of each target feature. Then, the shifter polygons are "colored," that is, assigned one of two color designations, so that each target feature is sandwiched between shifter polygons of opposing colors. The two colors correspond to the phase shifted and non phase shifted apertures.
An electronic representation of such a mask can be generated using a design rule check (DRC) tool of a layout verification software tool. Examples of such a layout verification tool include (1) HERCULES software available from Avant! Corporation, 46871 Bayside Parkway, Fremont, Calif. 94538, Tel 510.413.8000, (2) VAMPIRE software available from Cadence Design Systems, Inc, 555 River Oaks Parkway, San Jose, Calif. 95134, Tel 408.943.1234, and (3) CALIBRE software available from Mentor Graphics Corporation, 8005 SW Boeckman Road, Wilsonville, Oreg., 97070, Tel 503.685.7000.
The phase-shift mask is created in the DRC tool by applying several logical (such as not, and, or, and xor) and sizing operations to a representation of the circuit design to form output layers, such as a layer of target features, a layer of shifter polygons that pass light of phase 0°, and a layer of shifter polygons that pass light of phase 180°. The output layers correspond to features created on one or more masks. For simplicity, assigning shifter polygons to a particular output layer is referred to as assigning phase to a polygon or phase mapping a polygon.
In selective phase shift masks, target features are selected by applying a set of dimensional measurements to select only features with a specified width, i.e. smaller than the resolution of conventional optical lithography. The shifter polygons are created by applying sizing and logical operations using the input pattern as a starting point.
Once the shifter polygons are created, one needs to assign phases to the shifter polygons. Assigning phase by hand is burdensome particularly for random logic. Typical computer methods require first sorting the shifter polygons into runs of shifter polygons oriented in the same direction. A "run" refers to a horizontal "run" of shifter polygons separated by target features, such that the run unambiguously alters between a shifter polygon and a target feature. Phase is then assigned by traversing the run in the direction of the run and assigning phase to the shifter polygons by alternating between phase and phase 180. If two shifter polygons are not separated by a target feature, they are not interrelated. Such methods are limited. They work for a run in which the target features extend in the same predetermined direction such that traversing all of the shifter polygons in the run requires moving in only one direction. Such methods also require the data to first be sorted into runs. Sorting therefore adds an extra data processing step. Furthermore, in complex configurations where the target features contain branches or loops, it may not be possible to map the pattern by this technique alone. Therefore, it is desirable to develop more versatile computer methods for phase assignment of shifter polygons in a phase shift lithography mask.

Graph based phase shift lithography mapping method and apparatus


A battery contact apparatus has one fixed contact formed on a printed circuit board and a displaced movable contact. At least one battery is insertable into the space between the contacts. The movable contact biases the battery toward the fixed contact to provide a complete electrical circuit.

A variety of cost sensitive products incorporate one or more batteries. These include toys, thermostats, various types of audio or video players, calculators, or various types of sensors.
In known products contact pairs can be affixed by soldering. At times double spring contacts have been used to assure contact with the battery(s). Flashlights have long used a compressible spring as one contact to a string of batteries. The other contact is usually on a base of the electric light.
There is a continuing need to reduce product cost and complexity. It would be desirable to be able to do so while at the same time providing ease of insertion and reliable contact to the battery(s) required by the product.


In a data base system including a data base section for memorizing a plurality of data blocks and a buffer memory for memorizing a selected one of the data blocks as a buffered data block. The data base section includes a first memory unit for a first selected one of the data blocks as a first data block. Supplied with a search request signal which specifies a specific data block, a control unit transfers the first data block to the buffer memory when the specific data block is not present in the buffer memory but is present in the first memory unit. When the specific data block is also not present in the first memory unit, a reading unit reads the specific data block from the data base section and transfers the specific data block to the first memory unit under control of the control section. A copying unit transfers the specific data block to the buffer memory also under control of the control unit. Furthermore, the specific data block may be renewed into a renewal data block which is memorized in the buffer memory. The copying unit transfers the renewal data block to a second memory unit under control of the control unit. The control unit exchanges the specific data block for the renewal data block. Thereafter, the renewal and the specific data blocks are stored in the first and the second memory units, respectively.

This invention relates to a data base system having a buffer memory section which memorizes selected ones of data blocks transferred from a data base section.
A data base system of the type described comprises data base section for memorizing a plurality of data blocks to be searched, a processing section, and a buffer memory section between the data base section and the processing section. The buffer memory section is for temporarily memorizing selected ones of the data blocks as buffered data blocks. In addition, the processing section comprises a processing unit operable in accordance with a plurality of processing programs. At any rate, each of the processing programs runs on the processing unit.
Let a specific one of the data blocks be searched by a specific one of the processing programs through the processing unit to be received by the specific processing program. In this event, the specific processing program produces a request data block search signal which specifies the specific data block so that the processing unit accesses the data base section to deliver the specific data block to the buffer memory section. After delivery of the specific data block to the buffer memory section, the specific data block is often renewed into a renewal data block by the processing unit. The processing unit makes a data base history file store the specific data block as a history data. Furthermore, the processing unit sends the renewal data block to the buffer memory section and thereafter to the data base section on renewal of the specific data block into the renewal data block.
Under the circumstances, it is assumed that a fault occurs in the data base system during a search operation of the specific data block. In this case, the specific data block should be restored because an error might be included in the specific data block. Specifically, the processing unit accesses the data base history file to read the history data from the data base history file and sends the history data to the data base section in order to restore the specific data block in the data base section.
However, it is difficult to quickly restore the specific data block in the data base section in the conventional data base system because the history data must be read from the data base history file before transfer of the specific data block to the data base section. In addition, a processing ability of the processing unit is lowered because the processing unit inevitably refers to the data history file during each restoring operation.

Data base system capable of quickly restoring a data block in a data section when a fault occurs during operation


Disclosed is a fixing roller which comprises a core 16, a porous material layer 22 disposed in surrounding relation to an outer peripheral surface of the core 16, and a thin-walled metal sleeve 26 covering an outer peripheral surface of the porous material layer 22. The porous material layer 22 comprises a closed cell-type silicone elastomer. The present invention provides a fixing roller capable of ensuring enhanced durability and maintaining a usable state over long periods under the condition of being actually driven and rotated.

1. Field of the Invention
The present invention relates to a fixing roller which includes a porous material layer covering an outer peripheral surface of a core and a thin-walled metal sleeve covering an outer peripheral surface of the porous material layer
2. Description of the Related Art
In an image forming apparatus, such as a copying machine, a printer or a facsimile machine, as a fixing device for heating/pressing/fixing on a target object (a transfer member, a photosensitive sheet, a dielectric-coated sheet, etc.) unfixed toner image formed/supported, in conformity to intended image information, on the target object in a transfer manner (indirect manner) or a direct manner through an appropriate imaging process mechanism, such as an electrophotographic process, an electrostatic recording process or a magnetic recording process, there has been widely known a so-called two-roller type device arrangement comprising a thermal-fixing roller and a pressing roller.
In connection with this type of fixing roller, as disclosed in Japanese Patent Laid-Open Publication No. 2004-53924 (Patent Publication 1), the assigner of his application provided "a fixing roller production method comprising: a first step of preparing a porous body which comprises a core and a porous material layer formed to have at least closed cells and disposed in surrounding relation to an outer peripheral surface of the core, and machining the porous body to have an outer diameter equal to or greater than an inner diameter of a thin-walled metal; a second step of applying an adhesive onto at least one of an outer peripheral surface of the porous body and an inner peripheral surface of the thin-walled metal sleeve; a third step of containing the porous body and the thin-walled metal sleeve in a pressurized container to apply pressure thereon in such a manner as to allow the porous body to have an outer diameter less than an inner diameter of the thin-walled metal sleeve; a fourth step of, within the pressurized container, inserting the porous body into the thin-walled metal sleeve to form a sleeve body; a fifth step of taking the sleeve body from the pressurized container to cause expansion of the porous body so as to allow an outer peripheral surface of the porous body to be brought in close contact with an inner surface of the thin-walled metal sleeve; and a sixth step of solidifying the adhesive to bond the porous body and the thin-walled metal sleeve together.". This method would produce a fixing roller capable of maintaining a usable state over a long period of time under the condition of being actually driven and rotated.
In the technique disclosed in the Patent Publication 1, a foamed silicone rubber sponge (hereinafter refereed to simply as "silicone sponge") is used as an elastic layer. The silicone sponge has problems specific thereto, such as unevenness in cell size and indetermination in cell shape. Thus, in a fixing roller produced by the method disclosed in the Patent Publication 1, a region deformed by an action of an external force has the risk of occurrence of cell collapse. If cell collapse occurs, the durability of the fixing roller will deteriorate. Thus, there is a strong need for solving this problem.


An electrical connector has a body with a number of probes. Each probe has a spring biased pin with a contact tip, and includes a sleeve receiving the pin. Each sleeve has a first end connected to an incoming conductor, a second end connected to the body and from which the pin protrudes, and an intermediate portion suspended out of contact with the body. The sleeve may be spaced apart from adjacent sleeves, and suspended in air except at their ends. The probes may each be connected to coaxial cables, with alternating probes connected in alternating fashion to coaxial cable shields and signal conductors.

Certain high speed electronic cable terminals employ arrays of spring pins to contact pads or lands of a circuit board or integrated circuit under test, or to contact connections of an electronic device for a permanent connection. The spring pins are straight, elongated pins received in cylindrical sleeves, and which are axially biased by spring pressure to an extended position. All pins extend in the same direction, with all the pin tips in a common plane. Contact is made by aligning the terminal with the device being probed or contacted, and applying axial pressure to ensure contact by each pin with a minimum pressure. The range of motion of each pin accommodates contour variations in the device being contacted, and slight variations in the position of each pin.
For applications in which very high frequency signals are to be transmitted, the cable to which the terminal is connected may be formed of coaxial wires, each shielded to provide consistent performance and to prevent cross talk and other electronic interference. A terminal housing having a metal shield layer encloses the sleeves retaining the pins. One such particularly effective device is shown in U.S. Pat. No. 6,575,772 to Soubh, the disclosure of which is incorporated herein by reference. This prior art connector has proven effective at providing a high impedance/high frequency probe assembly with relatively small probe spacing. It is believed to be useful for frequencies as high as 5 GHz. However, while effective, this limitation prevents usage for higher frequency applications.
Other prior art embodiments have sought to provide a high-speed connector with a metal block having sleeved spring pins inserted and protruding beyond the periphery of the block. While adequate for some applications, these suffer from certain performance variations between different connectors. Signals are carried through sleeves that are insulated from the block, and ground signals are carried through sleeves that are connected to the block. The ohmic connection between a ground pin sleeve and the block normally occurs near the periphery of the block, because the sleeve has a slightly wider portion at its end adjacent to the aperture from which the spring pin emerges. Thus, a ground signal is conducted from the pin tip, down the length of the pin to the spring at the opposite end of the pin, which bears on the sleeve. The ground signal then passes along the sleeve in the reverse direction until it reaches the point of contact where the sleeve bulges and is press-fit within the block, after which the ground signal is conducted through the block in the original direction. However, if the pin makes contact with the sleeve near the sleeve aperture, or if the sleeve makes contact with the block well away from the aperture, the ground signal path is substantially shortened, avoiding the zigzagging path described above in the nominal case. This possibility can lead to inconsistent performance between ground conductors, impairing results.

Cable terminal with air-enhanced contact pins


A user equipment device (UE) determines a beam coherence interval metric, which is a measure of stability of a beam pair over time based on a set of beam coherence intervals measured by the UE. The beam pair comprises a receive beam of the UE and a transmit beam of a base station transmitting to the UE. A beam coherence interval comprises a time duration within which a quality of a signal received on the UE receive beam remains within one of a plurality of signal quality bins. The UE also determines a hysteresis value based on the beam coherence interval metric and uses the hysteresis value to decide to switch from an active receive beam to a different receive beam that has a signal quality higher than the active receive beam by at least the hysteresis value. Alternatively, the base station determines and sends the UE the hysteresis value.

The 5G (5th generation) mobile telecommunications system is able to span a wide variety of deployment scenarios (e.g., Rural, Urban Macro, Dense Urban, Indoor, etc.) in a flexible and scalable manner. In particular, TDD (time division duplex) air interfaces such as New Radio (NR) allow for symbol-level switching and potential configurability that in turn allow for features to support three primary aspects of 5G air interfaces, namely enhanced Mobile BroadBand (eMBB), massive Machine Type Communications (mMTC) and Ultra-Reliable and Low Latency Communications (URLLC). The air interfaces may support extremely high frequencies, including in the millimeter wave (mmWave) spectrum.
The propagation characteristics of mmWave signals are such that the base station (e.g., gNB) and the mobile device both need to employ beamforming using phased array antenna panels to accomplish sufficient coverage. Unlike traditional cellular systems, many handoffs, or switches, will be performed even within a cell, only these handoffs are between beams. Herein lies a difference between 4G cellular and 5G mmWave communications: beam management. Beam management is a method for handling intracell and intercell beam handoffs. It is expected that the base station will support more than 64 beams and the mobile device up to 128 beams per phased array antenna panel, for example.
Efficient handling of handoffs between beams is important because useful communications beams have a finite lifetime. For example, under rotational channels, such as a person turning, there may be a need for frequent beam handoffs, whereas when the channel is relatively static, beam handoffs may be very infrequently needed.

Cellular system utilizing beam coherence interval metric


A lamp assembly includes a lamp and a lamp driving device. The lamp includes a body and first and second electrodes. The body converts invisible ray generated by a discharge into visible ray, and the electrodes are disposed on the body. The lamp driving device provides the first and second electrodes with first and second driving voltages, respectively, to generate the discharge. The first driving voltage is less than a first critical voltage at which a corona discharge occurs at the first and second electrodes. When the first electrode is electrically connected to a ground, the first critical voltage may be about 1,200 volts. When the second driving voltage has an inverted phase with respect to the first driving voltage, the first critical voltage is about 2,400 volts. An ozone gas may not be generated at the first and second electrodes to prevent the damage of the electrodes.

1. Field of the Invention
The present invention relates to a lamp assembly, a back light assembly having the lamp assembly, and a display device having the back light assembly.
2. Description of the Related Art
Generally, a display device converts an electric signal, which is generated in an information-processing device, into an image.
A liquid crystal display device (LCD), one of the typical display devices, displays the image using liquid crystal (LC). The LCD includes a light generating module and a liquid crystal control module for displaying the image.
The light generating module generates a light so as to display the image, and the liquid crystal control module controls the LC so as to adjust the transmittance of the light.
Additionally, the light generating module may includes a cold cathode fluorescent lamp (CCFL) in order to generate the light. The CCFL is classified into an internal electrode fluorescent lamp (IEFL) and an external electrode fluorescent lamp (EEFL) in accordance with the position of the electrode(s) of the CCFL lamp. A pair of the electrodes of the IEFL is positioned in a lamp body of the IEFL. A pair of the electrodes of the EEFL is positioned on a lamp body of the EEFL.
Recently, according as a length of an LCD panel measured in a diagonal line increases, the EEFL is used for the LCD. Additionally, the EEFLs are parallel driven and have reduced power consumption.
However, in case of the EEFL, a corona discharge often occurs between the electrodes of the EEFL and the air because the electrodes are disposed on the lamp body, so that harmful gas such as ozone gas is generated around the electrodes due to the corona discharge. Additionally, the corona discharge may cause a fatal damage of the electrodes of the EEFL and most of the parts of the LCD device are corroded by the ozone gas generated around the electrodes of the EEFL, and the ozone gas also may be harmful to a human body.

Lamp assembly, back light assembly having the same, display device having the same, and method of driving lamps


An electronic interactive communication system and method is disclosed. Software controls and a control manager resides on a unit that communicates with a central location. The central location transmits information to the unit. The information, or data, may reside in a database at the central location. A number of different units receive data from the central location's transmission source to update or manipulate data already on the units. The system exchanges data from the units to the central location using a narrow bandwidth. The unit includes a transceiver and a processor. The unit also includes a display to display the data to the user after the received data has been associated with the stored data. For example, received data is overlaid on a map being displayed on the unit.

1. Field of Invention
The present invention relates to an electronic interactive communication system, and more particularly, to a system with improved control and optimally distributed interactive communication functionality between various device units.
2. Discussion of the Related Art
Various communication technologies, such as an e-mail technology that enables people to transmit and receive information to/from each other, are commercially known. Palm-size and/or portable communication devices that incorporate these technologies have become popular due to their portability and power. In the conventional technology, such communication devices are capable of transmitting and/or receiving communication messages and downloading and/or uploading information from other sources. The communication devices can download substantial data on the screen. For example, a portable Global Position System ("GPS") produces signals for a navigation system to allow directional navigation.
Conventional portable communication devices either store data in a database of the device or receive data from another device, such as a server. In use, the device shows the data in a display so that the user can manipulate the data. A Blackberry™ handheld portable communication system is an example. These devices, however, provide static data not updated in real-time because it may require an increased bandwidth for transmitting the data. Due to the limit of usage of the bandwidth, the conventional communication device may not transmit and receive the data in real time.

Electronic interactive communication system and the method therefor


An X-ray generation apparatus has an anticathode which includes a high thermal conductive substrate and a target for generating X-rays by irradiation with electrons. The target penetrates the high heat conductive substrate. Improved cooling efficiency and durability of the anticathode is obtained as well as miniaturization and simplification of the X-ray generation apparatus is achieved.

1. Field of the Invention
The present invention relates to an X-ray generation apparatus, specifically, one which makes it possible to generate high X-ray output by use of a smaller apparatus than the conventional size apparatus.
The ordinary method, which generates X-rays using irradiation of accelerated electrons to a target, adapted an X-ray generation apparatus. However, when electrons, which are accelerated by some tens of thousands voltage, collide with the target, only 1% of the accelerated electron energy changes to X-ray energy and the remaining 99% is consumed by Joule's heat. It is essential to investigate how to effectively radiate one hundred times the thermal energy incidental to X-ray generation from the target, in order to obtain a high output X-ray generation apparatus. The range of X-ray strength generated by an apparatus depends on the target material and cooling ability. The generated X-ray energy can be increased by increasing electron irradiation energy within a range of the target not melted by irradiation of accelerated electrons.
Therefore, metal materials which have high thermal conductivity and high melting temperatures are mainly used as the X-ray target, and the thermal energy is radiated by water cooling. Furthermore, in order to obtain high strength X-rays, a method by which the target is cooled while rotating has been developed. In this method, a portion of the target which is irradiated by electrons and emits X-rays, rotates one after another, the temperature of the target does not increase, and higher X-ray energy can be obtained compared with a fixed type target.
2. Description of the Prior Art
A diamond containing target, in which the diamond is embedded in a copper substrate by powder sintering, is used and the target is cooled and rotated in an X-ray generation apparatus shown in Tokkai-Sho 57 (1982)-38548. However, it has been pointed out that as the size of such X-ray apparatus increases, it is imperative to prevent vibration when rotating the target. Furthermore, there are problems with decreased efficiency of the electron beam when the electron beam irradiates both copper and diamond.
An X-ray generation apparatus, in which an electron beam irradiates in the direction of a heat resistant single crystal axis, emits X-rays in the direction of the single crystal axis and a cooling means of the single crystal is prepared, as shown in Tokkai-Hei 2 (1990)-309596. However, the target is cooled insufficiently because the electron irradiating portion of the target is cooled through the peripheral portion of the single crystal.
An anticathode for X-ray generation which is made from a 2-layer structure of high heat conductive inorganic material and thin metal film, is shown in Tokkai-Hei 5 (1993)-343193. Effective cooling is expected when the back portion of the high heat conductive inorganic material is cooled as shown in this prior art. However, when the target is adapted for an X-ray generation apparatus and is cooled at the peripheral portion (as shown in Tokkai-Hei 2-309596), the target does not have sufficient cooling ability because a considerable amount of thermal energy diffuses along the thin metal film for which heat conduction is rather high. The other problem is exfoliation of the thin metal film. A method of synthesizing diamond from the gaseous phase is disclosed in U.S. Pat. No. 4,767,608 issued Aug. 30, 1988, and in U.S. Pat. No. 4,434,188 issued Feb. 28, 1994.
Spitsyn, U.S. Pat. No. 5,148,462, discloses a diamond substrate having a linear-shaped target made from a groove filled with target material. The linear shape target lacks the advantages of the target in the present invention made from a hole filled with target material of high cooling efficiency. Specifically, when the direction of the electron beam coincides with the direction of the penetration of the target, as in the hole configuration of the claimed invention, the electron beam reaches the inner portion of the target and the absorption ratio of the electron beam increases. The increased absorption results in an increased X-ray output.
Further, Spitsyn's device has a surface coating on the electron impinging side of the device, while the metal film or electric conductive diamond layer of the present invention is located on the side of the substrate that is not impinged with electrons (i.e. the back surface). Spitsyn's invention does not contemplate adding a layer to the back surface as in the present invention. Although Spitsyn discloses a surface coating, this coating is on the electron impinging side, and it generates some X-rays in the surface coating. The metal film or the electric conducting diamond layer, in combination with the hole configuration in the present invention, prevents X-ray formation in this layer.
The use of cooling holders is known in the art. Cooling an anticathode using such known holder merely cools the peripheral portion of the anticathode. The holder, therefore, inefficiently cools the entire anticathode because the cooling means is not proximate the target, which is the source of heat generation when electrons collide with the target. The present invention includes a much more efficient way to cool the targets. Cooling passages formed inside the anticathode itself surround the target, not merely the peripheral portion of the anticathode. Thus, more efficient cooling of the anticathode is possible. In an apparatus such as Spitsyn, it would be difficult to employ such cooling passages or tubes inside the anticathode because the groove-type target of Spitsyn would interfere with a practical pathway to pass coolant. It would be economically impractical to increase the size of an expensive diamond substrate simply to accommodate the configuration of a groove-type structure such as the one in Spitsyn. Using a hole configuration as in the present invention, the diamond substrate can remain smaller, and thus less expensive, and at the same time contain an efficient internal cooling means.


A physical layout of a symmetric FET is described which provides symmetry in voltages coupled to structures of the FET so to reduce OFF state asymmetry in capacitances generated by the structures when the FET is used as a switch. According to one aspect, the symmetric FET is divided into two halves that are electrically coupled in parallel. Gate structures of the two half FETs are arranged in the middle region of the layout, each gate structure having gate fingers that project towards opposite directions. Interdigitated source and drain structures run along the gate fingers and include crossover structures that cross source and drain structures in the middle region of the layout. The gate structures share a body contact region that is arranged in the middle of the layout between the two gate structures.

A field effect transistor (FET) employs a gate-modulated conductive channel between a source region and a drain region. A person skilled in the art would know of various types of FETs, including insulated gate FETs (IGFETs), of which the most common type are metal-oxide-semiconductor FETs (MOSFETs). MOSFETs having n-type or p-type channel conductivity are referred to as an "NMOSFET" or "PMOSFET", respectively.
FIG. 1A is a schematic diagram of a conventional prior art FET 100A, shown with an optional body diode (102). Shown are the source S, drain D, and gate G. Also shown is body connection B to the body or substrate on which the FET is fabricated. As is well known in the art, when a voltage is applied between the gate G and source S terminals of a FET, a generated electric field penetrates through a gate oxide layer to the transistor body B. As one example, for an enhancement mode MOSFET device, a positive bias voltage applied to the gate G creates a conductive channel in the channel region of the MOSFET body through which current passes between the source S and drain D. As another example, for a depletion mode MOSFET device, a conductive channel is present with a zero bias voltage applied to the gate G; varying the voltage applied to the gate G modulates the conductivity of the channel and thereby controls the current flow between the source S and drain D. As it is well known to a person skilled in the art, another common use of a FET is as a simple switch having an "ON" state and an "OFF" state, where in the ON state, a signal passes through the FET between the drain D and source S, and in the OFF state, the signal is blocked (isolated) from passing between the drain D and source S.
As described in the above referenced U.S. Pat. No. 7,910,993 B2, the disclosure of which is incorporated herein by reference in its entirety, when used in certain circuit implementations, conventional MOSFETs may operate under an "accumulated charge" regime and thereby exhibit undesirable non-linear characteristics that adversely impact circuit performance. For example, the accumulated charge can adversely affect the linearity of OFF state silicon-on-insulator (SOI) and silicon-on-sapphire (SOS) MOSFETs, and more specifically, accumulated charge can adversely affect the linearity of capacitances that contribute to the drain-to-source capacitance (Cds) of a MOSFET. In other words, the capacitance in the OFF state, referred to as COFF, where COFF is equal to drain-to-source capacitance Cds in the OFF state, may vary as a function of a voltage across the drain and source terminals of the MOSFET. Such variation of the OFF state capacitance COFF can in turn adversely affect harmonic distortion, intermodulation distortion, and other performance characteristics of circuits using such MOSFET, such as, for example, RF switch circuits using stacked MOSFETs. As described in U.S. Pat. No. 7,910,993 B2 referenced above, one way of controlling or removing accumulated charge in such MOSFET is by coupling the body B to the gate G of the MOSFET through a diode (102), as shown in FIG. 1.
However, while this solution significantly reduces harmonic distortion and intermodulation distortion in MOSFETs and circuits using such MOSFETs, such as, for example, RF switch circuits using stacked MOSFETs, adding the diode (102) to the MOSFETs may not (completely) eliminate harmonic distortion. As discussed in the above referenced U.S. Pat. No. 9,461,037 B2, whose disclosure is incorporated herein by reference in its entirety, such residual harmonic distortion may be attributed to asymmetry between a drain-to-body capacitance Cdb, and a source-to-body capacitance Csb, of the MOSFET in the OFF state. As further described in such patent, FET devices with an odd number of gate fingers have lower capacitance asymmetry for Csb and Cdb, and accordingly better harmonic characteristics. In other words, it is suggested that symmetry in structures of the MOSFET can reduce capacitance asymmetry for Csb and Cdb, and therefore reduce second order harmonic distortion. Proposed solutions by the above referenced U.S. Pat. No. 9,461,037 B2 include provision of structures that form compensating capacitance to reduce the capacitance asymmetry for Csb and Cdb, and/or provision of a compensating voltage source across the drain and source terminals of the MOSFET that can affect the capacitance values for Csb and/or Cdb, and therefore reduce the capacitance asymmetry.
The teachings according to the present disclosure address asymmetry in OFF state capacitances of FETs, which can adversely affect second order harmonic characteristics of the FETs, by first recognizing that such capacitances are nonlinear and may be affected by variation in voltages coupled to structures forming the capacitances, and second, forming the FETs with semiconductor structures that can provide symmetry in voltages coupled to the structures that form the capacitances. Such teachings can be effective in reducing second order harmonic distortion in a single FET operating as a switch, as well as in a switch using stacked FETs. Furthermore, the teachings according to the present disclosure can be used in conjunction with the above solutions or separate from such solutions.

Symmetric FET for RF nonlinearity improvement


One embodiment provides a composition comprising a) a compound of formula I:

The invasive growth of cancer cells into bone tissues often results in severe pain syndromes and may ultimately result in death. Ionizing radiation has been used to achieve a reduction in pain. In particular, external radiation therapy has been applied in cases where bone pain is restricted to focal areas. For disseminated bone metastases, however, a treatment which focuses the radiation dose to bone tissue and particularly to bone metastases is desirable.
Prior to therapy it is necessary to obtain reliable diagnostic information and to this end several approaches have been tried. An approach that has been the subject of a number of patents, for example, U.S. Pat. No. 3,974,268 to Subramanian et al., involves the use of a technetium-99m diphosphonate complex as a skeletal imaging agent. This approach utilizes a diphosphonate as both the bone-seeking agent and the complexing agent for the radionuclide. Such an approach has at least three major disadvantages. First, by involving the bone-seeking agent in the complexation of the metal radionuclide, the ability of the agent to direct, or "target," the radionuclide to the desired site may be diminished. Second, because diphosphonate salts or chelates are known to form polymers, a preparation of diphosphonates and radionuclides typically includes multiple forms of diphosphonate-radionuclide complexes which have differing charge and uptake properties. Third, the complex formed between a diphosphonate and a radionuclide is not of optimal stability which may necessitate purification of the diphosphonate complex prior to use. Further, even a purified diphosphonate complex may lose the radionuclide during its use.
U.S. Pat. No. 4,853,209, is directed to the use of Sm-153, Gd-159, or Ho-166 complexed with a ligand selected from ethylenediaminetetramethylene-phosphonic acid (EDTMP), diethylenetriamine-pentamethylenephosphonic acid (DTPMP), hydroxyethylethylenediamine-trimethylenephosphonic acid (HEEDTMP), nitrilotrimethylenephosphonic acid (NTMP), and tris(2-aminoethyl)aminehexamethylenephosphonic acid (TTHMP), to suppress bone marrow growth.
U.S. Pat. No. 4,882,142, is directed to a method for the suppression of bone marrow and to a composition for use in the method. The method comprises administering a bone marrow suppressing amount of at least one composition comprised of a radionuclide Sm-153, Gd-159, or Ho-166, complexed with 1,4,7,10-tetraazacyclododecanemethylenephosphonic acid as the macrocyclic chelating moiety.
U.S. Pat. No. 5,059,412 is directed to compositions comprising a particle emitting radionuclide complexed with a macrocyclic aminophosphonic acid, wherein the nitrogen and phosphorous are interconnected by an alkylene group.
U.S. Pat. Nos. 5,202,109 and 5,089,249 are directed to conjugates formed from calcified tissue targeting agents and radiolabeled compounds. One conjugate comprises a chelate and a targeting agent that is capable of associating with calcified tissue, wherein the chelate contains at least one nitrogen atom or at least one sulfur atom, or a combination thereof.
In spite of the above disclosures, a continuing need exists for therapeutic and diagnostic agents that are useful for bone marrow suppression, cancer therapy, treating bone pain, and as diagnostic agents. Preferred agents may possess improved stability, improved uptake in bone, or improved retention in bone.

Therapeutic and diagnostic compounds, compositions, and methods

Abstract: wherein R1, X and n have any of the values described in the specification, or a pharmaceutically acceptable salt thereof; b) a radionuclide; and c) a radioprotectant.


Anti-CD3 binding domains and antibodies comprising them, including multispecific antibodies, with, inter alia, desirable T-cell activation and (re)directed target cell killing potency and developability, profiles are provided, as well as methods for their identification, isolation, and generation, and methods for their preparation and use. Reagents for identifying, isolating, selecting, generating and characterizing CD3 binding domains and antibodies comprising them are also provided.

All references cited herein, including without limitation patents, patent applications, and non-patent references and publications referenced throughout are hereby expressly incorporated by reference in their entireties for all purposes.
The body's immune system serves as a defense against infection, injury and cancer. Two separate but interrelated systems, humoral and cellular immune systems, work together to protect the body. The humoral system is mediated by soluble factors, named antibodies, which neutralize products recognized as being foreign by the body. In contrast, the cellular system involves cells, such as T cells and macrophages, which remove and neutralize foreign invaders.
The activation of T cells is important for the stimulation of immune responses. T cells exhibit immunological specificity and direct most of the cellular immune responses. Although T cells do not secrete antibodies, they are required for the secretion of antibodies by B lymphocytes. T cell activation requires the participation of a number of cell surface molecules, such as the T cell receptor complex, and CD4 or CD8 molecules. The antigen-specific T cell receptor (TcR) is composed of a disulfide-linked heterodimer, membrane glycoprotein with chains, alpha and beta (α and β), or gamma and delta (γ and δ). The TcR is non-covalently linked with a complex of invariant proteins, designated CD3.
The TcR confers antigen specificity and the CD3 structures transduce activation signals to T cells. The CD3 complex contains four subunits. They can contain two zeta subunits, one epsilon subunit and either a gamma or a delta subunit. Antigen binding leads to the cross-linking and activation of the TCR complex. T-cell receptor signaling leads to T-cell activation and IL-2 production and other cytokines in a complex process.
The ligand of the TcR is the MHC-peptide complex on the surface of target cells such as virus-infected cells. After the recognition of the MHC-peptide on the target cell, T cells can have a cytotoxic or an apoptotic effect on the target cell. Especially cytotoxic T cells (CD8 positive T cells) can have advantageous effects by directly removing virus-infected cells. This arm of the cellular immune response is particularly advantageous and is important for fighting virus infections and eliminating tumor cells.
Activation of the cytotoxic T cell may occur via direct binding of the CD3 antigen without the recognition of the MHC-peptide complex by the TcR. This alternative activation route can be achieved with anti-CD3 antibodies. Non-human monoclonal antibodies have been developed against some of the CD3 chains (subunits), as exemplified by the murine antibodies OKT3, SP34, UCHT1 or 64.1. (See e.g., June, et al., J. Immunol. 136:3945-3952 (1986); Yang, et al., J. Immunol. 137:1097-1100 (1986); and Hayward, et al., Immunol. 64:87-92 (1988)). Other CD3 antibodies are disclosed, for example, in U.S. Pat. Nos. 5,585,097; 5,929,212; 5,968,509; 6,706,265; 6,750,325; 7,381,803; 7,728,114. Bispecific antibodies with CD3 binding specificity are disclosed, for example, in U.S. Pat. Nos. 7,262,276; 7,635,472; and 7,862,813.
Many of these anti-CD3 antibodies bind the epsilon chain which leads to the development of highly activated T cells. Cancer immunotherapy with ordinary monoclonal antibodies does not typically activate T-lymphocytes sufficiently so as to elicit meaningful, targeted, pharmacologic activity towards the target cell type or tissue.
The recent development and use of multispecific antibodies, such as bispecific antibodies (bsAbs), to redirect effector T cells for the targeted killing of tumor cells has shown considerable promise both pre-clinically and clinically (see, e.g., Topp et al, 2012, Blood 120:5185-87; Bargou et al, 2008, Science 321:974-77). Many of the bispecific antibodies developed to date contain a first binding site specific to CD3 for T-cell recruitment and activation, and a second binding site for a targeted disease-associated antigen, such as CD19 (Bassan, 2012, Blood 120:5094-95). The bispecific antibody is thought to bring CD3+ T cells into direct contact with targeted disease cells and induce cell-mediated cytotoxicity (Bassan, 2012). Anti-CD3×anti-CD19 bispecific antibodies have been reported to produce a complete and durable molecular remission at very low concentrations in approximately 70% of adult patients with MRD+ ALL (Topp et al, 2012, Blood 120:5185-87). Bispecific antibodies recognizing gliomas and the CD3 epitope on T cells have been successfully used in treating brain tumors in human patients (Nitta, et al. Lancet 1990; 355:368-371). In addition, CD3×CD20 bispecific antibodies have been produced for clinical testing (US2015/0166661 and US2017/0202194), as well as CD3×CLL-1 (US2016/0368994).
Leukocyte redirecting bsAbs are not limited to T cells. The bispecific killer engagers (BiKEs) comprising scFvs against the NK cell antigen CD16 and a tumor-associated antigen (e.g., CD19, CD22, CD33) have also shown potent anti-cancer activity (e.g., Miller, Hematology Soc Hematol Educ Program 2013:247-53). Other alternatives include trispecific killer engagers (TriKEs), such as anti-CD16×anti-CD19×anti-CD22 (Miller, 2013; Gleason et al, 2012, Mol Cancer Ther 11:2674-84). An anti-CD 16×anti-CD33 BiKE was used to treat AML and myelodysplastic syndrome (Miller, 2013; Wiernik et al, 2013, Clin Cancer Res 19:3844-55). In refractory AML, a CD16×CD33 BiTE led to potent tumor cell killing and cytokine production by NK cells. Inhibition of ADAM 17 enhanced the CD16×CD33 BiKE response (Miller, 2013). Other trispecific, trivalent constructs, for example against CD16/CD19/HLA-DR, have been reported (Schubert et al, 2012, mAbs 4:45-56).
Numerous methods to produce bispecific antibodies are known (see, e.g. U.S. Pat. No. 7,405,320). Bispecific antibodies can be produced by the quadroma method, which involves the fusion of two different hybridomas, each producing a monoclonal antibody recognizing a different antigenic site (Milstein and Cuello, Nature 1983; 305:537-540). The fused hybridomas are capable of synthesizing two different heavy chains and two different light chains, which can associate randomly to give a heterogeneous population of 10 different antibody structures of which only one of them, amounting to ⅛ of the total antibody molecules, will be bispecific, and therefore must be further purified from the other forms. Fused hybridomas are often less stable cytogenetically than the parent hybridomas, making the generation of a production cell line more problematic.
Another method for producing bispecific antibodies uses heterobifunctional cross-linkers to chemically tether two different monoclonal antibodies, so that the resulting hybrid conjugate will bind to two different targets (Staerz, et al. Nature 1985; 314:628-631; Perez, et al. Nature 1985; 316:354-356). Bispecific antibodies generated by this approach are essentially heteroconjugates of two IgG molecules, which diffuse slowly into tissues and are rapidly removed from the circulation. Bispecific antibodies can also be produced by reduction of each of two parental monoclonal antibodies to the respective half molecules, which are then mixed and allowed to reoxidize to obtain the hybrid structure (Staerz and Bevan. Proc Natl Acad Sci USA 1986; 83: 1453-1457). An alternative approach involves chemically cross-linking two or three separately purified Fab′ fragments using appropriate linkers. All these chemical methods are undesirable for commercial development due to high manufacturing cost, laborious production process, extensive purification steps, low yields (<20%), and heterogeneous products.
Discrete VH and VL domains of antibodies produced by recombinant DNA technology may pair with each other to form a dimer (recombinant Fv fragment) with binding capability (U.S. Pat. No. 4,642,334). However, such non-covalently associated molecules are not sufficiently stable under physiological conditions to be of practical use. Cognate VH and VL domains can be joined with a peptide linker of appropriate composition and length (usually consisting of more than 12 amino acid residues) to form a single-chain Fv (scFv) with binding activity. Methods of manufacturing scFv-based agents of multivalency and multispecificity by varying the linker length were disclosed in U.S. Pat. Nos. 5,844,094, 5,837,242 and WO 98/44001. Common problems that have been frequently associated with generating scFv-based agents of multivalency and multispecificity are low expression levels, heterogeneous products, instability in solution leading to aggregates, instability in serum, and impaired affinity.
Several bispecific antibodies targeting CD3 and CD19 are in various stages of development and/or have been approved as therapeutics. An scFv-based bispecific antibody construct, known as BITE® (Bispecific T-cell Engager), employs a single polypeptide containing 2 antigen-binding specificities, each contributed by a cognate VH and VL, linked in tandem via a flexible linker (see, e.g., Nagorsen et al, 2009, Leukemia & Lymphoma 50:886-91; Amann et al, 2009, J Immunother 32:453-64; Baeuerle and Reinhardt, 2009, Cancer Res 69:4941-44). Another bispecific antibody called DART® (Dual-Affinity Re-Targeting) utilizes a disulfide-stabilized diabody design (see, e.g., Moore et al., 2011, Blood 117:4542-51; Veri et al, 2010, Arthritis Rheum 62: 1933-43). Both BITE® and DART® exhibit fast blood clearance due to their small size (˜55 kDa), which requires frequent administration to maintain therapeutic levels of the bispecific antibodies.
SCORPION Therapeutics (Emergent Biosolutions, Inc., Seattle, Wash.) is a platform technology combining two antigen-binding domains in a single chain protein. One binding domain is on the C-terminus and a second binding domain on the N-terminus of an effector domain base on immunoglobulin Fc regions.
Tetravalent and bispecific antibody-like proteins are DVD-Igs which are engineered from two monoclonal antibodies (Wu, C. et al., Nature Biotechnology, 25, p 1290-1297, 2007). To construct the DVD-Ig molecule, the V domains of the two mAbs are fused in tandem by a short linker (TVAAP) (SEQ ID NO: 6714) with the variable domain of the first antibody light (VL) chain at the N terminus, followed by the other antibodies VL and Ck to form the DVD-Ig protein light chain. Similarly, the variable regions of the heavy (VH) chain of the two mAbs are fused in tandem by a short linker (ASTKGP) (SEQ ID NO: 6715) with the first antibody at the N terminus, followed by the other antibody and the heavy chain constant domains to form the DVD-Ig protein heavy chain (VH1/VL1). All light chain and heavy chain constant domains are preserved in the DVD-Ig design, as they are critical for the formation of a disulfide-linked full IgG-like molecule. Cotransfection of mammalian cells with expression vectors encoding the DVD-Ig light chain and heavy chain leads to the secretion of a single species of an IgG-like molecule with molecular weight of approximately 200 kDa. This molecule has now four binding sites, 2 from each mAb.
Bispecific antibodies have shown considerable benefits over monospecific antibodies for the treatment and the detection of cancer. Broad commercial application of bispecific antibodies has been hampered by the lack of efficient/low-cost production methods, the lack of stability of bispecific polypeptides and the lack of long half-lives in humans. A large variety of methods have been developed over the last decades to produce bispecific monoclonal antibodies (BsMAB).
However, although many candidate clinical and therapeutic antibodies have been found in early discovery efforts which display exquisite selectivity and high potency towards numerous targets of interest, a large proportion of these antibodies have nonetheless subsequently been discovered through downstream development and clinical efficacy activities to suffer from undesirable characteristics such as: promiscuity of binding, polyspecific binding (also termed herein and throughout, "polyspecificity"), off-target binding; nonspecific binding; poor expression levels or profiles in eukaryotic host cells, such as mammalian host cells and yeast cells; poor chemical and physical properties, such as poor stability during storage (e.g., poor/low "shelf-life" stability), poor (low) solubility, poor (high) viscosity, propensity to aggregate, and the like; and poor clinical and biophysical profiles, such as poor pharmacokinetic profiles, poor pharmacodynamic profiles, fast or poor in vivo clearance rates, short circulation half-life, and the like; thereby requiring the termination of further therapeutic development of such candidate antibodies. Additionally, it has been observed that antibodies derived from display technologies represent a historical minority of all clinical and marketed antibodies, a trend which is believed by many to be due, at least in part, to promiscuity of binding, poor PK profiles, and poor CMC characteristics—liabilities which are further postulated to be largely due to a lack of suitable means and methods by which undevelopable antibodies may be detected and/or counter-selected against when screening for antibodies using display technologies (see, e.g., Meninger 2012; available at hyper-text transfer protocol: proteins-congress.com/wordpress/wp-content/uploads/2012/01/Trends-in-Therapeutic-Monoclonal-Antibody-Discovery-Technology.pdf).
The art has developed certain techniques and assays to assess many of the aforementioned developability characteristics for discovered antibodies in the context of downstream development activities ("post-discovery antibodies"), such as CIC, SIC, BVP-ELISA, TMA, and other assays; however, such assays are typically not amenable to their incorporation into high-throughput early polypeptide and antibody discovery platforms, such as antibody display platforms. Furthermore, assessment of these attributes typically requires milligram to gram quantities of protein, thus often imposing a de facto limitation on the number of leads that can be pragmatically considered for development, and consequently reducing the likelihood of program success. Consequently, significant resources are often expended attempting to fix poorly behaving lead candidates with few backups available in later stages of development.
In recognition of this bottleneck, considerable efforts have been made to develop assays with lower material requirements and to bring developability assessments further upstream in the development process (Esfandiary et al., 2013, Protein Eng Des Sel 26 (10): 663-670, 2013; Sathish et al., 2013, Nat Rev Drug Discov. 12(4):306-24). A number of such assays are directed at predicting antibody solubility and aggregation behavior of identified, lead candidates. Self-interaction chromatography (SIC) and cross-interaction chromatography (CIC) are column based, low-to-medium throughput assays that correlate with and thus predict antibody solubility at relatively low concentration (Ahamed et al., 2005, J Biol Chem 280(37):32090-100; Jacobs et al., Pharm Res 27:65-71, 2010; Spencer et al., Mabs 4(3)319-325, 2012). A longer retention time on such SIC or CIC columns suggests interaction with antibodies coupled to the column, and is correlated to poor solubility (Jacobs et al., 2010). Sule and co-workers reported a medium throughput gold nanoparticle assay to predict solubility at very low concentration and further broadened the assay scope to be compatible with complex cell culture media (Sule et al., Biophys J 101(7):1749-1757, 2011; Mol Pharmaceutics 10(4):1322-1331, 2013).
As mentioned above, polyspecificity is a highly undesirable property that has been linked to poor antibody pharmacokinetics (Wu et al., J Mol Biol 368:652-665, 2007; Hötzel et al., 2012, MAbs 4(6):753-760). Certain polyspecificity assays have been reported in the art to serve as medium-throughput substitutes for broad panel tissue immunohistochemistry. Wardemann and colleagues have reported an enzyme-linked immunosorbent assay (ELISA) method using LPS, Insulin, dsDNA, and ssDNA to study polyreactivity in natural antibody repertoires over the course of B-cell maturation (Wardemann et al., 2003, Science 301(5638):1374-7). Protein biochips in which a diverse set of proteins are spotted onto an array for high-throughput ELISAs are another type of screening tool. A chip with ˜400 different human proteins from Protagen (Dortmund, Germany) has been reported to compare favorably with IHC staining analysis (Lueking et al., 2008, Bio Techniques 45(4):Pi-Pv), as well as a measure of off-target binding of clinically approved TNF-alpha inhibitors (Feyen et al., Anal Bioanal Chem 391:1713-1720, 2008). More recently, Frese et al. reported on a 384-well assay that measures polyreactivity to 32 test proteins, termed Protein Panel Profiling or 3P (Frese et al., 2013, MAbs 5:2, 279-287). Using this assay, the authors showed that FDA-approved therapeutic antibodies show a highly specific profile to the 32 test proteins and apply it to screen candidates from a phage selection process. These particular polyreactivity profiling assays have not yet been correlated with downstream development issues such as solubility, expression, and stability. A recent advance in this area was reported by Hötzel et al. 2012 MAbs 4(6):753-760), in which a baculovirus particle (BVP) ELISA was shown to predict faster antibody non-target mediated clearance in vivo, while traditional biophysical properties such as Size Exclusion Chromatography retention time, Hydrophobic Interaction Chromatography elution time, Fv charge, and pI did not (Hötzel, et al., 2012 MAbs 4(6):753-760). Recently, reagents, methods, and means to assess, predict, select and enrich for developable therapeutic antibodies, and ultimately to generate and obtain developable antibodies, for example from antibody libraries, were disclosed (see, e.g., WO2014/179363).
While the CD3-targeting approach has shown considerable promise, a common side effect of certain T-cell immunostimulatory therapies is the associated production of cytokines, often leading to toxic cytokine release syndrome (CRS), also known as cytokine storm or cytokine release crisis. Because the anti-CD3 binding domain of the bispecific antibody engages all T cells, the high cytokine-producing CD4+ T cell subset is recruited. Moreover, the CD4+ T cell subset includes regulatory T cells, whose recruitment and expansion can potentially lead to immune suppression and have a negative impact on long-term tumor suppression.
Cell proliferative disorders, such as cancer, are characterized by the uncontrolled growth of cell subpopulations. They are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 12 million new cancer cases diagnosed and 7 million cancer deaths occurring each year. The National Cancer Institute estimates that greater than half a million Americans will die of cancer in 2013, accounting for nearly one out of every four deaths in the country. As the elderly population has grown, the incidence of cancer has concurrently risen, as the probability of developing cancer is more than two-fold higher after the age of seventy. Cancer care thus represents a significant and ever-increasing societal burden. There is, therefore a need for the provision for CD3 binding domains, and antibodies comprising them (including multispecific antibodies), which display desirable developability and/or CRS risk profiles and are safe and efficacious in, for example, binding specifically to CD3 expressed on T-cells, activating T-cells, (re)-directing the activated T-cells to kill target cells, and doing this with diminished risk of eliciting cytokine release syndrome (also known as cytokine storm or cytokine release crisis).

Anti-CD3-binding domains and antibodies comprising them, and methods for their generation and use


After the input of a subscriber (TLN1) of the first terminal (EG1), a connection to a temporarily available voice memory (SPS) is signalized by the same, and subsequently a voice message (spn) and at least one piece of retrieval information (ai) identifying the second terminal (EG2) is transmitted and stored at that location. Subsequently, the connection is terminated and the second terminal (EG2) is informed of the presence of a retrievable voice message (spn) in the voice memory (SPS) via the voice memory (SPS) by means of the at least one piece of retrieval information (ai), and the voice message (spn) can be retrieved from the second terminal (EG2) by means of the transmitted retrieval information (ai), or is transmitted to the second terminal (EG2) by the voice memory (SPS). In this manner voice messages (spn) can be stored for terminals (EG2) and retrieved by the same, regardless of whether one or no voice memories—such as an answering machine—is associated with these terminals (EG2).

In communication networks such as PSTNs or packet-oriented intranet or Internet, a voice memory device can be permanently associated with a terminal. This is done so that a voice message can be left even when the terminal and its associated subscriber cannot be reached. In this configuration, the voice memory—also known as an answering machine—is placed on standby by the subscriber. When a voice memory associated with a terminal is on standby, a call to that terminal activates the voice memory or switches on the answering machine at the subscriber's location, either immediately or after a few rings. After playing a greeting to the calling terminal, the voice memory is placed into a mode in which it can receive and store voice messages from the calling terminal. This type of voice memory can either be assigned to an individual terminal or used in a communication network in such a way that the voice memory is associated with a particular terminal.
If no voice memory is associated with a called terminal, it is currently not possible to transfer a voice message to the called terminal if the called subscriber cannot be reached. In order to inform the called subscriber of the desire to make a connection or exchange voice information, provided that the communication network permits it, an "automatic callback" or "message waiting callback" command feature can be activated. For both of these command features, when the called subscriber is available at his terminal, either a callback to the calling terminal is initiated automatically, provided that the called subscriber's terminal is active, or information is displayed for him indicating that he should call the calling subscriber back. However, a callback resulting from either of these command features can fail again if the subscriber at the terminal that made the original call is not available or cannot be reached. It is currently not possible with either of these command features to transmit a voice message to the called subscriber.

Method, terminal and voice memory for storing voice messages in a communication network


A shunt valve for treatment of glaucoma in the form of a hollow tubular body insertable into a hole formed in the sclera and provided with retaining shoulders that hold the tubular body in place against fore and aft movement. The valve is carried on and transported by a tool at the front end of which projects a cutting member. The cutting member is driven from an energy source under the control of an operator to form a hole in the sclera after which the valve is displaced axially from the tool along a straight line into the hole coaxially thereof. A porous inflatable balloon can be carried by the valve or installed therein subsequent to the implantation of the valve in the sclera to control drainage through the valve. Medicaments and the like can be supplied with the inflatable balloon. The cutting member can be a rototrephine or a laser cutter.

Glaucoma is a general term applicable to diseases of the eye in which the intraocular pressure in the eye increases to a level which can cause damage to the structures within the eye. If the pressure increases suddenly as in acute angle closure glaucoma, surgical intervention is immediately required to reduce the intraocular pressure and prevent permanent damage to the eye structure. When the pressure increase is gradual as in open angle and neovascular glaucoma, one mode of treatment for reducing the pressure involves treatment with medication, for example, by a topical application to the eye and/or by oral administration. In more severe cases when the pressure resists control by medication, more aggressive intervention involves the installation of a shunt valve which connects the anterior chamber to the subconjunctival space. This promotes drainage or the fluid from the anterior chamber so that the pressure in the eye can be relieved.
In one embodiment of a shunt valve, referred to as a standard length "Krupin" glaucoma valve implant, the implant comprises an open plastic tube which is placed into the anterior chamber, an elastic tube fixed to the plastic tube and plastic side arms extending laterally of the plastic tube for fixation of the implant. The elastic tube has a closed distal end with vertical and horizontal slits forming unidirectional and pressure sensitive valve openings. The distant end of the elastic tube remains outside the eye. In order to install the implant it is necessary to make an external conjunctival incision and to form scleral and conjunctival flaps. The implant is placed in the bed of the scleral flap. The plastic tube must be cut to length during surgery so that the open end of the plastic tube will not contact the iris or cornea. The implant is sutured in place using the side arms as anchor points in order to prevent anterior--posterior movement. The scleral flap is closed by suturing and the conjunctiva is also closed by suturing.
In another embodiment, known as the long "Krupin" glaucoma implant, the valve end of the elastic tube is first sutured within the groove of an elastic band and the band is sutured against the sclera. A notch is formed in the elastic band through which the elastic tube extends for connection to the plastic tube. The elastic tube is sutured to the sclera. The elastic band with the elastic tube therein extends beneath both horizontal rectus muscles. As in the first described embodiment, the plastic tube is placed in the scleral bed and penetrates into the anterior chamber. Sutures are necessary to fixate the plastic tube to the sclera and to close the scleral flap and the conjunctiva. The end of the elastic tube with the valve slits remains within the subconjunctival space.
In another embodiment, known as a Molteno implant, an open silicone rubber tube extends 2 to 4 mm into the anterior chamber and the tube is attached to and opens onto the upper surface of a thin acrylic episcleral plate 13 mm in diameter. The edge of the plate has a thickened rim that is perforated to permit attachment of the tube. The plate is sutured to the sclera. As in the other embodiments, scleral and conjunctival flaps are formed. The tube is sutured to the sclera at the posterior edge of the scleral flaps.
All of the above embodiments and variations thereof have numerous disadvantages and relatively low success rates. They all involve substantial trauma to the eye and require great surgical skill. The eye is exposed to long periods of surgery and considerable manipulation of tissue. The implants themselves are complex and require careful installation to prevent leakage, damage to the lens or iris, dissection of muscle tissue as well as blockage of flow through the tube passages. Frequently, it is necessary to perform corrective surgery to overcome complications due to the implant surgery.

Shunt valve and therapeutic delivery system for treatment of glaucoma and methods and apparatus for its installation