The present invention relates to a process of enriching one target compound from a liquid, which process comprises at least one step of isolation performed by differentially partitioning between two aqueous phases. In the present invention the phases are formed by adding a thermally responsive, self-associating (i.e. clouding) hydrophilic polymer, and if needed some additional salts, to an aqueous biotechnical solution (such as a fermentation sample or bioseparation process stream) under thermal and other conditions where the solution separates into a one polymer, two-phase system with one phase enriched in the polymer. The target compound is to be found in the phase not enriched in the polymer, while a significant though varying percentage of contaminants may differentially partition to the phase interface or the polymer enriched phase. With minor or no modification the target containing phase solution can be further processed via standard unit operations such as precipitation, chromatography, and filtration to further purify target and remove any residual polymer.

The biotechnical revolution, including development of modern biopharmaceuticals and mapping of the human genome, has been made possible due to development of separation methods such as chromatography and electrophoresis. Such methods can be used in small scale as well as in large scale, and are known as flexible methods, being useful for a variety of substances including biological substances. However, they are demanding both technically and in terms of equipment. In addition, scaling of some processes such as preparative electrophoresis results in a need for more complicated equipment due to nonlinear scaling of heating and cooling requirements. Such complications also hinder modelling of such methods and their optimisation via (small volume, microtiter) high throughput screening methods.
Partitioning between the phases in aqueous polymer phase systems is an alternative method, which has been studied since the 1950's but whose commercial application has been severely restrained by lack of economically feasible (inexpensive) phase systems offering good capacity (target solubility). Together with separation methods such as flocculation, crystallization and size exclusion; partitioning is considered a classic separation technique. It is related to differentially distributing a target and other substances between two phases. The term "partitioning" can refer to (a) liquid-solid partition such as in classic capture chromatography, (b) partitioning between two or more liquid phases (biphasic and multiphase system, respectively), (c) partitioning between a mobile liquid phase and another liquid phase immobilized at the surface of a solid phase support, and (d) partitioning of particles between a liquid phase and the phase interface between two phases. For the purposes of this patent application, partition and partitioning refer to situations such as b, c or d i.e. partitioning between liquid phases. In this definition target capacity is not as much a function of (solid) phase surface area as much as liquid phase volumes. As a result capacities can be very high (see below). Partition is typically expressed as a coefficient (K) related to the concentration in one phase versus another and for solutes K generally follows the Brønsted equation. Thus K is expected to vary exponentially with various types of interactions such as electrostatic and/or hydrophobic interactions, and also to be sensitive to solute size i.e. the area of interaction with liquid phases. In the case of interfacial partition, where particles may be held at a liquid-liquid phase interface by interfacial tension, K is expected to vary exponentially with interfacial tension, as well as phase compositional factors.
Classic liquid-liquid two-phase systems are organic and aqueous two phase systems which normally have significant polarity differences between the phases, as well as significant interfacial tension. Such systems are not very useful for biologicals, such as proteins or cells, as they tend to be denatured by significantly apolar solutions and shear damage related to mixing of phase systems with significant interfacial tension. More useful for biologicals are low tension, aqueous polymer two phase-systems. It is well recognized that the latter may contain some added organic solvents, e.g. ethanol, or other organic additives added to enhance target solubility, reduce liquid phase polarity, reduce foaming, act as bactericidal agents, etc.
Polymer two-phase systems can be formed by mixing certain hydrophilic and typically neutral polymers in aqueous solution. These include dextran (polyglucose) and poly(ethylene glycol) (PEG); as well as polysucrose (such as Ficoll™) and PEG; or linear polyacrylamide and PEG. Typical concentrations of each polymer are 5 to 10% w/w. At such concentrations, entropic and other forces tend to drive the formation of two phases both of which are typically greater than 90% (w/w) water but show subtle differences in polarity, hydrogen bond character, freezing point, etc. The phases are typically enriched in one polymer and have low interfacial tension. Phase density differences drive the phases to separate by gravity or centrifugation. In the biotechnical field, one advantage of the PEG and Dextran type of two-phase system is that target proteins may partition in favour of the PEG-enriched, less dense, upper phase while cell debris and some contaminants may partition (or sediment) to the interface or complementary lower phase.
Independent of the challenging of adding and then removing two polymers from a bioprocess stream the major drawback to dextran and PEG and similar two-polymer phase systems is the cost of the polymers. This is especially true for the dextran, a natural bioproduct which must itself be purified for use in bioprocess phase systems. In an effort to reduce such costs scientists have investigated two paths. The first is to replace dextran with starch or other less expensive polymers. However such polymers often are less pure, less controlled in MW, form more viscous phases and come with their own unique challenges (Josefine Persson, Dana C. Andersen, Philip M. Lester, Biotechnology and Bioengineering, vol. 90, (2005) 442-451). The other approach has been to work with two phase systems formed by combining relatively high concentrations of PEG (10% w/w) and salts such as potassium sulphate (3% w/w). In regard to protein partition in such systems see Andrews, Nielsen, Asenjo, 1996. and Azevedo et al., 2007 (discussed in more detail below) while for recent review related to plasmid partition see F. Rahimpour, F. Feyzi, S. Maghsoudi, R. Hatti-Kaul, Biotechnology and Bioengineering, 95, 627-637, 2006.) Unfortunately the increased PEG and salt concentrations create challenges which negatively impact process costs. These include viscous phases, salt reagent costs, salt disposal and equipment corrosion challenges, as well as target solubility issues which relate to capacity. For example antibody capacity in these systems is often 1 g/L which means (clarified) fermentation broth containing expressed antibody at 10 g/L would have to be diluted ten fold prior to partitioning. It also means that if the phase systems cost five dollars a liter to formulate then they add at least five dollars a gram to the cost of goods. Such dilution and related increases in process volumes, process times and costs are prohibitive.
Some hydrophilic polymers exhibit inverse thermal solubility such that as temperature is raised above a certain cloud temperature (Tc) which is related to a polymer's lower critical solubility temperature (LCST), they self associate and start to form a unique polymer rich phase. Common literature offers several examples of such polymers including copolymer or block copolymers formed with mixtures of ethylene oxide (EO) and propylene oxide (PO) monomeric groups, so called EOPO polymers, polysaccharides modified with EO, PO or similar groups (e.g. ethylhydroxyethylcellulose or EHEC), or polymers formed using N-isopropylacrylamide (NIPAAM). Whereas the Tc for PEG (polymerised EO) in dilute buffered solution is around 100° C., and thus unsuitable for most biotechnical applications, the Tc for EOPO and NIPAAM polymers is often in more biotechnically useful range of 20 to 40° C., depending on solution salt composition and other factors. In addition to thermoresponsive polymers some hydrophilic polymers exhibit pH dependent self association (e.g. WO 2004/082801 A1). WO 2004/020629 (Tjerneld) relates to the use of the EOPO polymers' reverse thermal solubility to further facilitate the separation of plasmids already partitioned in a two polymer phase system. At room temperature the two-polymer, two phase system formed with EOPO and dextran polymers forms in same manner as PEG and dextran system. The less dense EOPO-enriched upper phase is isolated from the EOPO and dextran polymer aqueous two-phase system. The temperature of the EOPO-enriched phase is then raised to approximately 37° C. (i.e. above Tc) so that the upper phase undergoes further phase separation into a water-enriched phase and a self-associated EOPO polymer-enriched phase. Advantageously, the water-enriched phase should contain the desired target. In general, these kinds of EOPO and dextran systems offer advantages in terms of phase polymer component recycling and design of efficient two-stage partition separation process. However, a drawback is again the cost involved in system formulation using the biologically derived and costly dextran polymer. Less expensive polymers such as starch polymers may replace dextran in such systems (Persson et al, 2005) but there are still challenges associated with having to add then remove two polymers from the process stream.
In the above literature examples, as in the general literature, phase systems are used to purify targets from clarified feed formed by subjecting phase fermentation broth containing intact or lysed cells and cell debris to centrifugation.
In the biotechnical field, aqueous polymer two phase systems, formed with two polymers or with one polymer in presence of significant added salt are of general interest. This is because they are easily utilised in small as well as larger scale separations, without loss of efficiencies or dramatic changes in costs when scaling up to the larger volumes. Also, any standard separation approach, such as charge-based, hydrophobicity-based, affinity-based, or size-based separation, can be performed within a polymer two phase system. In general many undesired components, such as cell debris, endotoxins, nucleic acids, virus, will tend to appreciably partition to the lower (dextran-rich or salt rich, respectively) phase in a PEG and dextran, or a PEG and salt two phase system. Thus, if a system can be found which provides for good target partition into the upper (PEG-rich) phase an effective primary separation and target concentration can be obtained. However four major hurdles will still remain in terms of capacity (i.e. solubility), phase component cost, phase component removal, and effect of phase components on other (downstream) unit operations and equipment. The latter particularly inhibits easy incorporation of some phase systems, as upstream unit operations, in existing standard processes.
In efforts to overcome drawbacks related to interfacing in standard chromatographic and/or filtration processing, and to overcome the limitations of a single theoretical partition step per unit operation, liquid-liquid partitioning two phase systems such as PEG-dextran or PEG-salt have been adapted to chromatographic uses by immobilising one phase on a chromatographic or other solid support capable of preferentially wetting that phase. The complementary phase is then pumped through the column offering repeated opportunities for equilibration between the mobile and stationary phase. This was commercially exploited by W. Müller et al. at E. Merck, Darmstadt in the 1980's (U.S. Pat. No. 4,756,834).
Various combinations of the above approaches and other phase forming polymers are possible. U.S. Pat. No. 5,093,254 (Giuliano et al) relates to an aqueous two-phase protein partitioning system which employs polyvinylpyrrolidone (PVP) as the upper phase and maltodextrin as the lower phase and provides a low-cost system for protein partitioning. The system can also be employed with certain derivatives of chlorotriazine dyes, which bind in a noncovalent manner to the PVP and serve as a ligand for the proteins to be separated. It is stated that an advantage of this system is its cost-efficiency, as the dyes can easily be bound to the polymeric phase, without having to carry out the chromatographic and solvent extractions necessary to form the covalent bond in the PEG and hydroxypropyl starch system of the prior art.
Many modern biopharmaceuticals are based on monoclonal antibodies (typically IgG forms) or related antibody fragments (Fabs) or derivatives of antibodies. Use of phase systems for purification of antibodies has been studied for over thirty years, if one includes studies of plasma protein partitioning in dextran and PEG and related two polymer biphasic systems. Studies directed towards feasibility of large scale processing of antibodies by partitioning, using more cost effective PEG-salt and other systems have been in the literature for over a decade.
B. A. Andrews, S. Nielsen and J. A. Asenjo (Partitioning and purification of monoclonal antibodies in aqueous two-phase systems, Bioseparation 6, (1996) 306-313) investigated systems and used factorial design to find some they consider optimal for antibody partitioning such as 7% w/w PEG 1450, 14% NaPhosphate and 12% NaCl. Such systems gave antibody partition K (ratio of protein concentration in upper phase over lower phase) values of 100. They used serum albumin, transferin and some other proteins to represent process feed stream contaminants and demonstrated differential partition to that shown for antibodies. In addition they attempted small scale processing of a monoclonal antibody sample from hybridoma cell culture. As with Persson et al. 2005 and Azevedo et al., 2007, they worked with centrifuge clarified (cell free) sample solutions. In the experiments with hybridoma produced antibody sample they noted that K values obtained with pure protein samples appeared compromised by sample solution complexity. However they were able to achieve good partition of antibody into one phase, and show ability to enhance purity using multiple extractions, including those where the target molecule is partitioned into complementary phase using a system with lower NaCl.
Andrews et al. also noted what remains the main drawback to PEG salt system protein partitioning in general, and antibody partitioning in particular, which (due to the high salt concentrations) is low protein solubility (often 1 g/L). If one considers that antibodies and other recombinant proteins may be expressed at levels of 10 g/L or higher use of such systems early in separation process would entail a 10-fold increase in process volume with a several fold increase in processing scales, costs and times. In addition to these costs would be those related to salt components including salt removal and possible corrosion of pumps and other metal equipment. A decade later Azevedo et al. (Ana M. Azevedo, Paula A. J. Rosa, I. Filipa Ferreira, M. Raquel Aires-Barros, Optimisation of aqueous two-phase extraction of human antibodies, Journal of Biotechnology 132 (2007) 209-217) extended efforts to find PEG and salt systems suitable for industrial scale process of antibodies. Their optimisation methods found systems similar to those of Andrews et al. (i.e. 12% PEG 6000, 10% NaPhosphate pH 6, 15% NaCl) which when used to partially purify Mab from a concentrated (and clarified) Chinese Hampster Ovary (CHO) cell culture supernatant with total yield of 88% and from hybridoma culture supernatant with a total yield of 90%. However their target protein concentrations were still approximately 1 g/L.
More recently Aires-Barros et al (I. Filipa Ferreira, Ana M. Azevedo, Paula A. J. Rosa, M. Raquel Aires-Barros, Purification of human immunoglobulin G by thermoseparating aqueous two-phase systems, Journal of Chromatography A, 1195 (2008) 94-100) have investigated two polymer thermoseparating phase systems for antibody partitioning in systems containing UCON® EOPO 50/50 copolymers of MW 2000 to 5100 (Dow Chemical). They studied partitioning of IgG from clarified CHO culture supernatant (Ab at 0.1 g/L) between the phases in 8% w/w UCON and 5% dextran T500 systems and to enhance antibody partition into the upper (EOPO polymer-rich) phase they added 20% w/w triethylene glycol-diglutaric acid (TEG-COOH) and 10 mM NaPhosphate pH 8. Clarified supernatant could be added to systems at 50% (to achieve above final polymer and TEG-COOH concentrations). In some experiments polyclonal IgG (Gammanorm™, Octapharma AG) was added to increase target protein to approximately 1 g/L. A two step (two polymer two phase partition followed by thermoseparation of the upper phase into polymer-rich and water rich phases, see above) partition process yielded 85% of antibody (which is relatively low for a commercially attractive process) at 88% purity (which may have been aided by adding in GammaNorm). Tc occurred at approximately 50° C. which required applied heating of the phase system in the second step extraction. While these systems offer lower salt concentration they also require significant TEG-COOH as in its absence recovery yield of IgG in the top UCON-rich phase (of UCON and Dextran phase system) was lower than 50% (i.e. K<1).
In general thermoseparating phases have normally been used together with dextran (see Aires-Barros et al, above) or similar polysaccharide (Persson et al. above) in a two step process. Thus selectivity over target and contaminant protein (as well as second polymer) occurs in the first partition step, followed by use of temperature induced phase separation (of typically EOPO polymer rich phase) to isolate target and polymer into target containing aqueous phase floating on top of a self-associated polymer rich denser phase. In regard to the use of thermoseparating phases on their own (i.e. one polymer but lower salt concentration) systems the general wisdom has been that they tend to not be useful as they offer little selectivity and should be used in systems with other polymers. A distinguished international research group was led to conclude "the water EOPO system is therefore only suitable for partitioning of hydrophobic molecules (such as denatured proteins or tryptophan-rich peptides) or for solution concentration by selective water removal (similar arguments hold for the micellar two-phase systems)" (Hans-Olof Johansson, Gunnar Karlström, Folke Tjerneld, Charles A. Haynes, J. Chromatography B, 711 (1998) 3-17). In regard to such applications the effect of various salts and other additives on phase separation of another EOPO polymer (Breox 50 A 1000 a random copolymer consisting of 50% ethylene oxide and 50% propylene oxide, molecular mass number average 3900, Specialty Chemicals, Southhampton, UK). were studied by Cunha et al. (Maria Teresa Cunha, Folke Tjerneld, Joaquim M. S. Cabral, Maria Raquel Aires-Barros, Journal of Chromatography B, 711 (1998) 53-60).
Teixeira et al. (Martinha Pereira, You-Ting Wu, Armando Venancio, José Teixeira, Biochemical Engineering Journal 15 (2003) 131-138) investigated the partitioning of endo-polygalacturonase (endo-PG) in systems composed of UCON 50-HB in two-polymer systems together with polyvinylalcohol, or hydroxypropylstarch or with relatively high concentrations of ammonium sulfate. The latter system required heating to effect formation of two phases but was the most promising in terms of reagent cost and ability for reagents to be added to culture (again clarified) supernatant prior so that 70% of the final system consisted of clarified culture broth. The UCON polymer could be recycled in a three step process in which endo-PEG was concentrated ten times and 95% of enzyme activity was recovered. In regard to this work two observations are note worthy. First the 5% minimum ammonium salt concentration (50 g/L or approx. 0.38M) necessary to effect formation of two phases is still significant and required 10% UCON. Raising temperature to 40° C. only decreased these values to 3% (0.23 M) salt and 5% polymer. So the system still contained significant added salt. Secondly at temperatures above 30 degrees Texeira et al noted phase inversion in their systems so that the top, polymer poor, less-dense phase at room temperature became the bottom phase. Such effects while interesting, could pose problems in regard to large scale processing particularly in systems containing cells and cell debris which would tend to sediment. In addition to the above noted thermoseparating phase systems there are a wide range of thermoseparated micellular systems involving hydrophobically modified EOPO and similar polymers (for discussion see H.-O. Johansson et al, 1998 above). Many patents related to the above two polymer thermoseparating aqueous phase systems are currently held by G.E. Healthcare, a General Electric company.
The ability of PEG and salt two-phase systems to partition cells and cell debris to interface, and therefore for possible use of phase partitioning to effect partial clarification, has been known for some time. Köhler et al. formed 7.5% w/w PEG 1500 and 14% potassium phosphate two-phase systems directly in a bioreactor and used them to purify a recombinant protein in E. coli (Kristina Köhler, Björn Nilsson, Andres Veide, Recovery of extracellular human insulin-like growth factor-I and II as a fusion protein from Escherichia coli culture broth by aqueous two-phase extraction, Bioseparation, 3 (1992-1993) 241-250) noting approximately 90% of cells were not in the target containing phase. However batch centrifugation was still used in the process to effect complete phase separation and was advocated, in continuous centrifugation mode, for larger scale applications. Such polymer-high salt systems have much greater interfacial tension than polymer-polymer systems formed at lower salt concentration and may be expected to function to effect some clarification due to their relatively high interfacial tension. However they would supposedly still be limited in terms of capacity (target solubility) due to the high salt concentrations required. Köhler et al. noted that biomass added to system affected some partition results. Since most studies related to finding optimized systems for recombinant protein (esp. antibodies) processing have been done using clarified feed the systems found may not be optimal or even function for clarified feed. That is why several examples of unclarified feed were used in the present work.
It can be seen from the above discussion that two phase partitioning holds much promise as method for primary processing (clarification and target partial purification) of various substances such as proteins including biopharmaceuticals from complex feeds streams however to date certain challenges have not been overcome. These include cost of reagents (polymer and salts, or two polymers), capacity issues related to needed dilution of target containing process streams, possible need to add various affinity substances (e.g. TEG-COOH) to increase target partition, removal of phase system forming substances prior to or during further downstream processing steps, and modifying target containing phases to allow for further downstream processing. From the point of simplicity thermoresponsive polymer and water systems (which do not involve micelle formation or use of special hydrophobically modified thermoresponsive polymers) may be the most attractive as they are typically neutral and in some cases biocompatible. So too residual polyethoxy and other polymers in target containing phase may not only be seen as relatively inert substances. They may confer some advantages for a. further processing by multistep partitioning, b. spray drying of target containing solution (e.g. Jessica Elversson, Anna Millqvist-Fureby, Aqueous two-phase systems as a formulation concept for spray-dried protein, International Journal of Pharmaceutics 294 (2005) 73-87) and, due to their well known antifreeze and antioxidant properties, c. low temperature intermediate storage of target containing phase solution prior to further processing. However established wisdom and experience has been that their formation required relatively high polymer and salt concentrations and the phases formed offered little selectivity, required fairly high salt concentrations and might not work to effect clarification.
For many years biopharmaceutical fermentation, purification and polishing/formulation have been seen as separate process areas. A major reason for this was they often involved different unit operations and volume scales. Both of these were related to the concentration of target substance and inversely the process volumes handled in different processing stages. Thus fermentation at perhaps 1 mg/mL, purification by affinity or ion exchange raising the concentration to perhaps 30 mg/mL with polishing followed by formulation steps taking the target to 100 in liquid (mg/mL) or solid (mg/g) form. As a result initial processing steps might involve process volumes 100× larger than formulation steps. These distinctions are blurring now that antibodies and other biopharmaceuticals can reach 30 mg/mL in fermentation feed and early ion exchange or other purification steps achieve 100 mg/L. Formulation often involves combining protein or other biopharmaceutical with excipients such as polymers including Dextrans™, poly(ethylene glycol)s or Polysorbates™ (polyethoxylated sorbitan and laurate) and various commercially available copolymers or block copolymers of oxyethylene or oxypropylene such as Tergitols™ or Pluronics™. Excipients can be charged including use of other proteins (i.e. charged amphipathic biopolymers) such as albumin. Excipients stabilize the biopharmaceutical during storage, maintain high concentrations without inducing aggregation, and allowing for rapid dissolving and uptake in the body. Some polymeric or other excipients may also enhance not only the delivery but the pharmacological properties of drugs via for example adjuvant action. Given the above it is natural that any partition, precipitation or other unit operation method which localizes antibodies or other target proteins in solution, or insoluble complex, with biocompatible polymers should be of interest not only in regard to purification but also formulation, storage, delivery and efficacy of biopharmaceuticals. Especially as polymers such as those noted above are often found in antibody and other pharmacological formulations. One key point is that any commercially viable method must be able to handle complex feeds which include proteins or other targets at relatively high concentrations (e.g. >10 g/L), and process them without significant (i.e. >2×) dilution. The above considerations hold not only for recombinant protein, nucleic acid and other biopharmaceuticals but also for vaccines, and other biotherapeutics and bioparticles.
Vaccines, and especially viral vaccines pose a set of interesting processing challenges illustrated by the processing of influenza vaccines. Much flu vaccine is produced in eggs. This offers the interesting challenge of removing ovalbumin protein and other contaminants from the viral targets. This is often done via sucrose density gradient centrifugation. However modern processing is going more and more over to processing of viral vaccines in cells (typically MDCK or Vero kidney cell lines) grown either in suspension culture or adherent culture where the cells grow attached to colloidal carriers. In both cases the cultured cells are infected with virus, which propagate to the point where the cells either lyse naturally or are readily lysed by various chemical or physical treatment. In both cases the end results is a complex feed which contains various larger (>1 micron) particles, cell debris, intact virus (which is the target to be purified) and virus related debris such as cell membrane fragments containing viral proteins. Following use of centrifugal or other methods to remove cells and related debris, sucrose density gradients may be employed to separate the viral related fractions into intact and debris fractions. Such methods are of course decades old technology and there have been attempts to employ newer separation methods such as aqueous polymer two phase partitioning or column chromatography. Most work involving partitioning of viruses was done over ten years ago and has been reviewed by Lena Hammar (Lena Hammar, Concentration of Biomaterials: Virus Concentration and Viral Protein Isolation, Chapter 62, pp. 627-658, in Methods in Enzymology, Volume 228, Aqueous Two-Phase Systems, H. Walter and G. Johansson, Eds., Academic Press, New York, 1994) where she noted that "Extraction in aqueous polymer systems remains an attractive option when virus purification from large volumes is involved and in dealing with labile viruses". Hammar and related references provide many examples of partitioning of a wide variety of different viruses of medical significance. The labile nature of viruses generally dictate that two polymer (typically PEG and dextran) phase systems, which offer lower interfacial tensions than single polymer and high salt (e.g. PEG and sodium phosphate) systems were used. Naturally fractionation of virus using such systems suffers many of the same drawbacks which are related to processing antibodies or other macromolecular targets via partitioning. This includes cost of two polymers, and addition of a separate partitioning step to a process. Some vaccine processes recovery of viral product after centrifugal clarification followed by sucrose density gradient fractionation can be as low as 20%. An inexpensive partition system which offered as good or better recovery while replacing one or both of the clarification and density gradient steps is desirable, especially if it could be performed in disposable bag format, rather than in fixed line centrifuges. Commercial viability of partition processing of viral vaccines must also rest on new inexpensive systems which offer excellent selectivity. Such a goal is achieved in this application.

Separation method using single polymer phase systems


A plasma process utilizing an electron cyclotron resonance (ECR) phenomenon caused by generating a magnetic field either parallel or perpendicular to, or both parallel and perpendicular to, a microwave propagation direction, characterized in that an ion beam is made to converge by applying a pulse voltage to a rotating magnetic field, a pulse voltage is applied to deflection plates, and an accelerating pulse voltage is further applied to a plasma.

1. Field of the Invention
This invention relates to a high precision ECR plasma process for etching and coating.
2. Description of the Prior Art
The conventional ECR plasma process employs electron cyclotron resonance due to a constant magnetic field of 0.0875 T in the plasma state that can be used for etching and coating.
In the conventional ECR plasma process which uses a constant magnetic field, a rapid ion rotation current is set up so that the ions scatter. The .theta. offset angle of an ion beam in a substrate therefore increases as shown in FIG. 3 so that anisotropic patterning becomes difficult. Further, as a result of continuous irradiation, hollow cavities are formed by vapor and the substrate is heated over a large part of its area so that it is difficult to achieve high patterning precision.


A system and method for generating loans is provided. The system and method of the present disclosure are generally designed to encourage previous and current customers of a financial institution to use the services provided by the financial institution as well as attract new customers to the financial institution. The system generally comprises a computing entity, a processor operably connected to said computing entity via a network, a server operably connected to the processor via the network, and a non-transitory computer-readable medium having instructions stored thereon, wherein said instructions include multiple user interfaces. The user interfaces allow customers to research vehicles in which they may buy. The system also provides users with information about vehicle financing as well as providing financial institutions with information they may use to promote their services.

Online competition in the auto loan industry has become particularly fierce, and traditional financial institutions, such as credit unions and banks, are having a tough time competing against well-funded, focused, mass marketing organizations in this area since it has moved more online. This is particularly devastating to Credit Unions, which often times provide better financing, protection product terms, and product cost than these more focused organizations. By being unable to effectively compete in the online auto loan marketplace, both financial institutions and consumers lose out. Financial institutions lose because they are having a more difficult time than ever before retaining current customers and obtaining new customers. Consumers lose by paying higher costs when purchasing and financing vehicles. Further, because financial institutions are purchasing car loans to make their balance sheets look better, they are missing out on one of their primary goals, which is to enhance the financial well-being of their customers.
A typical consumer today will spend ten or more hours online researching prior to buying a vehicle. During this research, consumers are bombarded with auto loan and finance options, and many of these finance options come with instantaneous approval. If financial institutions could take advantage of this trend of online vehicle research, they might be able to obtain new customers who may otherwise go somewhere else for their auto loans. Additionally, an advantage financial institutions should be able to take advantage of is that they often possess the contact information of current customers and previous customers. However, many financial institutions do not have a system in place that would allow them to take advantage of this information in a way that encourages current and previous customers to use the vehicle research, pricing, and financing services the financial institutions provide. Because of this, financial institutions are failing to take advantage of a valuable resource that could generate new income by encouraging both current customers and potential new customers to take advantage of the financial institution's services.
Therefore, there is a need in the art for a system and method that encourages previous and current customers to use the services provided by a financial institution as well as attracting new customers to the financial institution.

System and method for vehicle loan lead generation


The invention provides a transmission apparatus (100) for transmission of electrical signals between a line driver (205), which is connected to a transmission line (201), and a switching center (301), having an analog feedback device (101) for coarse setting of a line voltage level (210) on the transmission line (201), and a digital feedback device (102), which is coupled to the analog feedback device (101) and has a feedback filter device (118), designed such that a filter input signal (404) can be converted to a filter output signal (405) at a rate which is lower than the sampling rate (fa) of an analog/digital converter (104).

The invention relates specifically to a transmission apparatus for transmission of electrical signals between a line driver, which is connected to a transmission line, and a switching center, having:
a) an analog feedback device for coarse setting of a line voltage level on the transmission line as a function of a line current which is detected in the line driver; and
b) a digital feedback device, which has a feedback filter device for fine setting of an amplitude and phase relationship between the line voltage level and the line current.
FIG. 3 shows a coding/decoding unit (Codec) based on the prior art. The coding/decoding unit is connected via a filter F2 to a line driver (SLIC=Subscriber Line Interface Circuit). The line driver is connected via a further filter F1 to a transmission line L, which is represented in FIG. 3 by a (generally complex) resistor. The line driver contains a power amplifier and a current sensor device for detection of the current which is flowing in the line. The coding/decoding unit Codec is required, inter alia, in order to set a country-specific input impedance.
Normally, this is done by means of programmable analog and digital feedback loops AS, DS1 and DS2. The coding/decoding unit (CODEC) illustrated in FIG. 3 comprises an analog circuit part and a digital circuit part, which are isolated from one another by an analog/digital converter ADC and/or a digital/analog converter DAC. As illustrated, the analog part contains an analog feedback loop AS, while the digital part contains two digital feedback loops DS1 and DS2.
The signal which is emitted from the current sensor is supplied via the filter F2 to a pre-filter PREFI for the coding/decoding unit. The signal which is emitted from the pre-filter PREFI is supplied on the one hand to the analog/digital converter ADC and on the other hand is fed back in an analog feedback loop AS, and is supplied to a summation device "+". The analog feedback loop AS makes it possible to set a line voltage level on the transmission line as a function of a line current which is detected in the line driver.
The digital feedback loops DS1 and DS2 which are provided in the digital part of the coding/decoding unit are used for fine setting of an exact amplitude and phase relationship between the line voltage level and the line current. The feedback loop DS1 feeds a signal, which is output between two decimation units D1 and D2, back to a summation unit which is arranged between two interpolation units I1 and I2.
The feedback loop DS2 feeds the output signal from the decimation unit D2 back to the input of the interpolation unit I1 by superimposing the signal to be transmitted on the feedback signal in a summation unit "+". The signal which is emitted from the second interpolation unit I2 is converted in the digital/analog converter DAC to an analog signal and is supplied to a post-filter unit POFI. The signal which is emitted from the post-filter unit POFI has the analog feedback signal that is produced by the analog feedback loop superimposed on it. This means that the conventional circuit arrangement illustrated in FIG. 3 can be used to provide both a line voltage level and a phase relationship between the voltage and the current, that is to say complex line impedance matching.
The conventional circuit arrangement illustrated in FIG. 3 for setting a complex line impedance has significant disadvantages, however. The first feedback loop DS1 contained in the digital part has to operate at a high sampling rate, since the feedback signal is in fact extracted after the decimation by the first decimation device D1. This means that this digital feedback loop has to be designed for a high signal and sampling rate. A further disadvantage is that the digital feedback loop DS1 comprises a recursive filter unit, which is less flexible than a non-recursive filter unit.
A further disadvantage is that it is difficult to reduce the number of coefficients in a recursive filter unit which is arranged as shown in FIG. 3. A recursive filter unit is disadvantageously less flexible than a non-recursive filter unit.
One major disadvantage of the conventional circuit arrangement illustrated in FIG. 3 is that two digital feedback loops must be provided in the digital circuit part, in addition to the analog feedback loop in the analog circuit part. This considerably increases the circuit complexity, and disadvantageously leads to an increase in cost.

Transmission apparatus with variable impedance matching


A multiple-user graphical programming and analysis environment is disclosed that includes graphically represented code objects, graphically represented inter-code object connections, application programs, and a graphical white board area. Each code object may be created by a user, and accessible by other users in an asynchronous fashion, in accordance with the security privileges of the other users. Each inter-code object connection represents data transfer between a pair of code objects. Each application program is made up of one or more chains of the code objects, interconnected via the inter-code object connections. The code objects are definable and movable within the graphical white board area, and the inter-code object connections are creatable within this area. The application programs are executable within the graphical white board area. The code objects, as well as the environment itself, may be developed in an architecture-independent and Internet web browsing program-independent computer programming technology, such as Java.

Computer programs have become generally recognized as good analytical tools and decision aids for a number of different problem sets. Typically, once a problem set is identified, a computer program that can act as an analytical tool or a decision aid within the problem set is coded from scratch. Specifications for the program may be drafted, and then a computer programmer or a team of programmers may be called in to develop the program in accordance with the specifications.
Such computer program development can, however, be time-consuming, costly, and inconvenient. For certain problem sets, a quickly developed analytical tool or decision aid may be desired. The time and cost necessary to draft specifications and retain one or more computer programmers to develop a custom program may be too great, such that the program is ultimately never developed. End users who are not computer programmers especially may decide that, although computer programs to assist their analyses or decisions within problem sets may be desirable, the cost and expense in obtaining them are not worth the benefits that such programs can provide.
For these and other reasons, therefore, there is a need for the present invention.

Multiple-user graphical programming and analysis environment

The United States of America as represented by the Secretary of the Navy


A maintenance apparatus includes a flexible carriage configured to anchor between adjacent airfoils of a turbine assembly. The maintenance apparatus includes a maintenance tool operably coupled with the flexible carriage. The maintenance tool is configured to one or more of generate image data representative of one or more surfaces of the turbine assembly or repair the one or more surfaces of the turbine assembly. The maintenance apparatus comprises one or more motors operably coupled with the maintenance tool and configured to move the maintenance tool relative to the flexible carriage.

Turbines for aircraft engines as well as gas and steam powered turbines for industrial applications comprise at least one rotor carrying multiple stages of airfoils (henceforth referred to as blades), which rotate with respect to the turbine case. In turn, a turbine case carries multiple stages of airfoils (henceforth referred to as guide vanes), such that the turbine consists of alternating stages of blades and guide vanes. To reduce leakage of air, steam, or combustion gas over the tips of the blades, shrouds can be disposed on the radially inner surfaces of the stator so as to form a ring seal around the blade tips. To limit air, steam, combustion gas, or the like from entering the rotor cavities or wheel spaces, blades have platforms and guides vanes have inner sidewalls. Similarly, guide vanes have outer sidewalls to limit radially outward leakage. Together, the blades, guide vanes and shrouds define the primary flowpath inside the turbine.
During use, the turbine components can experience degradation. Currently, periodic inspections, such as borescope inspections, are performed in order to assess the condition of the turbine in-between service intervals. Examples of damage that can be observed during inspection include wear (e.g., from incursion of blade tips into the shrouds, particle-induced erosion, water droplet induced erosion, wear due to sliding contact between stationary components), impact (e.g., spallation of thermal barrier coating (TBC) or environmental barrier coating (EBC) from turbine-section components, leading edge burring/bending of compressor blades), cracking (e.g., thermal fatigue, low-cycle fatigue, high-cycle fatigue, creep rupture), edge-of-contact damage between stationary parts, oxidation or hot corrosion of high-temperature metallic sections, static seal degradation, and creep deformation (e.g., of guide vane sidewalls/airfoils, blade platforms, and tip shrouds).
During service intervals, the turbines are at least partially disassembled to allow repair and/or replacement of damaged components. Currently, damaged components of turbine engines are primarily repaired at overhaul or component repair facilities, with only limited intervention conducted in the field. The processes used to repair compressor and turbine flowpath components may include surface cleaning so as to remove accumulated dirt and oxidation products, stripping and restoration of coated surfaces, crack repair, section replacement, aero contouring and smoothing, and the like. Although the cost of the repair operations is typically lower than the component replacement cost, waiting for planned outages may run some fraction of components beyond their repair limits and may even lead to unplanned outages caused by the failure of the most heavily distressed component. Consequently, conventional systems and methods of maintaining turbines using periodic inspections and factory-based component repair methods may not be optimal.
To address the above described problems, there have been disclosed in situ methods of repairing a damaged component, such as an abradable coating (e.g., U.S. Pat. Nos. 7,509,735, 8,563,080, U.S. Patent Application Publication No. 2015/0174837). However, these prior disclosures are focused on borescope-type access using small-diameter, tethered tools. These tools are severely limited for the purpose of maintenance because they are constrained in size and can access only limited locations within the gas turbine engine. Furthermore, even if a damaged area can be reached, the orientation of the tool to a damaged area may be disadvantageous for performance of an inspection or repair task. The size restrictions imposed by borescope access port diameter limit the capability of inspection and repair tools, and the access path may cause jamming or severing of the tether. Accordingly, the present invention seeks to provide a novel system of maintaining turbine assemblies that overcomes the above-mentioned limitations by using a remotely controlled maintenance apparatus that is inserted in the machine via alternate routes, such as axially through the turbine, and may be operated with or without a tether.

System and method for maintenance of a turbine assembly


An extrusion die may include a first die component and a second die component configured to mate with one another. The first die component may have a first body with a rim extending axially therefrom and at least one first channel through which a material is flowable, where the rim may define a recess. The second die component may have a second body with a platform extending axially therefrom and at least one second channel through which the material is flowable. The recess of the first die component may be configured to receive the platform. The rim of the first die component may include at least one protrusion extending radially into the recess, and the platform may include at least one notch complementary to the at least one protrusion to form a concordant step register for positioning the first die component and the second die component with respect to each other.

Extrusion dies, such as those used for extruding aluminum parts, generally may include multiple components assembled together during the extrusion process to define the shape of the extruded part. The components must be pieced together with the proper respective orientations in order for the part to have the correct shape. Currently, extrusion dies incorporate locating holes in one or more components, and complementary dowels, pins, or the like, in one or more other components. However, the locating holes generally require extra machining steps of drilling or otherwise producing the holes, and the dowels and parts are extra parts that complicate assembly of the extrusion die. Further, once the extrusion process is complete, disassembly of the extrusion die components is also complicated, often requiring workers to chisel or pry the components apart.
Accordingly, an improved extrusion die incorporating a concordant step register, a method of manufacturing said improved extrusion die, and a method of extruding a part via the improved extrusion die are presented to simplify manufacturing, assembly, and disassembly of extrusion dies, thereby reducing the costs of making extruded parts.


A method for form-based conversation system design is provided. The embodiment may include ingesting, by a processor, a plurality of forms from a given domain. The embodiment may also include extracting indicators of required input fields from the ingested plurality of forms. The embodiment may further include generating a required input list based on the extracted indicators of the required input fields to update a size of the required input list. The embodiment may also include determining transactional intents based on the required input list. The embodiments may further include generating a dialog flow that satisfies the determined transactional intents.

The present invention relates, generally, to the field of computing, and more particularly to a dialogue system.
A dialogue system is a computer system utilizing text, speech, and graphics recognition technologies to enable a user to converse with a machine. A typical dialogue system may entail an input recognizer or decoder component, a natural language understanding unit, a dialog manager, an output generator and an output renderer. Dialogue systems can support various applications in business enterprises, education and government. For example, a customer service agent may utilize a dialogue system to retrieve an appropriate answer for a customer's question raised during a call inquiry. Many enterprises utilize a dialogue system to respond to customer technical problems and to diagnose the problem with a product or device. Typically, dialogue systems are widely used by call centers to decrease human workload and are also known as interactive voice response (IVR) systems.

This patent is subject to a terminal disclaimer.

Form-based transactional conversation system design

INTERNATIONAL BUSINESS MACHINES CORPORATION


An antiviral compound comprises a dendrimer such as a polyamidoamine or polyly sine dendrimer having a plurality of terminal groups, wherein at least one of the terminal groups has an anionic- or cationic-containing moiety bonded thereto, particularly a sulfonic acid-containing, carboxylic acid-containing or trimethylammonium-containing moiety or the like.

It has been established that certain sulfonated polysaccharide compounds have antiviral activity when screened against HIV, however these compounds are relatively unstable and accordingly large amounts of these compounds are required to obtain effective antiviral effects. In addition, many of these compounds, including heparin and dextran sulfate for example, are potent anticoagulants and because of this activity they are not particularly suited for clinical use as antiviral agents.
The present invention provides a new class of antiviral agents based on a particular type of polymer referred to herein as a "dendrimer", which have substantial antiviral activity against HIV1 and HIV2, CMV and HSV, and which have substantially no anticoagulant activity. These compounds are therefore well suited for prophylactic and therapeutic use as antiviral agents in humans.


A method for controlling operation of a flotation cell, where the liquid level and the foam level in the cell are measured and controlled. The method includes measuring at least one quality characteristic of the accept leaving the cell and determining the set value(s) for the liquid level and/or the foam level on the basis of the measured quality characteristic. The method is particularly suitable for flotation of a pulp suspension, particularly in deinking flotation.

This invention relates generally to processes for aerating suspensions. More particularly, the present invention relates to processes for flotating suspensions.
It is known that operation of a flotation cell can be controlled by means of the liquid level in the flotation cell, the amount of foam overflowing, and the throughput, where the throughput is pre-defined by the required production level.
Known control systems have the disadvantage that they are relatively inflexible. In particular, it is difficult with the control systems known to achieve a favorable compromise between the quality of the accept leaving the cell on the one hand and the energy input and loss of potentially recyclable materials on the other.
DE 42 25 117 C1 presents a control system in which, among other things, the foam back-up height in the foam channel of a primary flotation cell is measured and the amount of accept leaving the primary cell controlled on the basis of this measurement, thus the back-up height in the foam channel of the primary flotation cell remains constant. According to a similar principle the proportion of backfeed to the primary cell is also controlled in the secondary cell, based on the level height in the foam channel to the secondary cell.
This process, however, also does not provide a more flexible means of controlling operation in a flotation cell.
The problems with the state-of-the-art processes also occur in flotation of pulp suspensions, particularly in deinking flotation.
Deinking flotation is a process for removing contaminants and printing ink particles from pulp suspensions, particularly those produced in waste paper treatment. In this process, hydrophobic solids, such as printing ink particles or stickies, are brought into contact with gas bubbles in a suitable flotation cell. The solids adhering to them are carried to the surface of the liquid along with the gas bubbles and can be removed there as foam. Since the pulp is hydrophilic, it is discharged together with the accept. As there is no 100% separation of fibers and ink particles or stickies, there is a direct relation here between the losses and the cleaning effect achieved.

Process for controlling operation of a flotation cell


Disclosed herein is an apparatus for applying multi-axial inertial force, the apparatus including: a lower support plate; two first support members fixed to stand up from the lower support plate; a second support member positioned to be orthogonal to inner sides of the two first support member in a stand-up direction thereof and rotatably coupled to the first support member; and a third support member stacked on the second support member and coupled to the second support member so as to be rotatable based on a rotational axis corresponding to a stacked direction. Therefore, it is possible to obtain an apparatus for applying multi-axial inertial force in which vibration excitation and rotation may be performed in multiple-axes directions using a uni-axial inertial force generator that may be vibration-excited and rotated only in a single direction.

1. Technical Field
The present invention relates to an apparatus for applying multi-axial inertial force.
2. Description of the Related Art
Recently, as a small and light inertial sensor is easily manufactured using a micro electro mechanical system (MEMS) technology, application fields of the inertial sensor have been expanded to home appliances, etc. Therefore, in accordance with the continuous development of functions of the inertial sensor, the function of the inertial sensor has been continuously developed from a uni-axial sensor capable of detecting only an inertial force for a single axis using a single sensor to a multi-axial sensor capable of detecting an inertia force for a multi-axis of two axes or more using a single sensor.
The manufactured inertial sensor is necessarily subjected to a performance test before being released as a product. Since the inertial sensor is a transducer transducing inertial force (angular velocity, acceleration) applied to the sensor into electrical signals, performance thereof may be confirmed by applying the inertial force directly to the sensor and measuring an electrical output.
However, as the function of the inertial sensor has been expanded from the single axis to the multiple axes, a direction of inertial force that should be applied to the sensor at the time of measurement should also be increased from the single axis to the multiple axes, which causes a structure or a function of an apparatus for applying inertial force to be significantly complicated.
A tri-axial ratetable according to the prior art for this has volume three times or more larger than that of a uni-axial ratetable and is significantly more expensive than the uni-axial ratetable. Particularly, a vibration exciter used for generating linear acceleration may not generate tri-axial simultaneous vibration-excitation using a single apparatus, such that the sensor to be measured should be measured while moving the apparatus for each axis.
Due to the above-mentioned reason, a time required to test the multi-axial inertial sensor becomes significantly longer than a time required to test the uni-axial inertial sensor. An increase in test time, which is directly associated with an increase in product cost, is an important factor deteriorating competitiveness of a product.
Further, in the case of a tri-axial angular velocity sensor that may detect inertial force in three-axes directions, since characteristics thereof should be evaluated with respect to all of the three-axes directions that are orthogonal to each other, an apparatus for applying tri-axial angular velocity is required. However, the apparatus for applying tri-axial angular velocity according to the prior art has volume significantly larger than that of an apparatus for applying uni-axial angular velocity. In addition, the number of components used in the apparatus for applying tri-axial angular velocity becomes three times or more as compared to the apparatus for applying uni-axial angular velocity. In the apparatus for applying tri-axial angular velocity, an expensive and significantly precise motor is required, and significantly elaborate components such as an angle encoder that may detect a rotation amount, a slip ring connecting an electrical signal to the outside of a shaft of the motor, or the like, are used. Therefore, when the number of axes increases, components as much as a multiple of the number of increased axes are required. In addition, the slip ring serves as a channel connecting a signal output from a device under test (DUT) to an external measuring device. Since the slip ring itself becomes a noise source at the time of rotation of the motor, as the number of slip rings through which the electrical signal passes increases, a noise component of the channel increases.
Further, in the case of the vibration exciter or a linear acceleration generator, it is very difficult to generate acceleration in the multiple axes using a single apparatus. Therefore, several uni-axial vibration exciters are generally fixed and used in each axis direction. In this case, in order to perform multi-axial measurement, the DUT should be moved to and mounted on several vibration exciters set according to the directions of the axes, a test time is significantly increased, and several apparatuses for applying acceleration are required for each of the directions of the axes, such that a cost required to configure a measuring system is also increased.

Apparatus for applying multi-axial inertial force


An apparatus for making temporary road mats characterized by multiple layers of mutually perpendicular elongated timbers having an array of vertical intersections aligned in lateral rows. The apparatus includes a pair of assembly tables spaced along an assembly line on a work floor. Each table has an upper layout surface spaced vertically above the work floor and provides a work bay therebelow. The layout surface having indicia for orienting the discrete timbers in each layer whereby the timber may be roughly assembled. A gang drill moves in a longitudinal path along the assembly line with respect to the assembly tables. The gang drill carries a plurality of drills for sequentially drilling the lateral rows of intersections. The gang drill alternates between tables while manual assembly operations are conducted at the other table.

The present invention relates to temporary road surfaces and, in particular, to a machine for assembling temporary road mats.
Temporary road mats are used extensively to allow vehicles and equipment to reach locations not serviced by permanent roads, particularly under conditions where ground surface would not support the traffic or where the temporary nature of use does not warrant the time and expense of a permanent road. The mats are generally constructed in multiple layers of heavy wood timbers in crisscrossing layers. The mats may also be provided with interlocking joints for connecting with adjacent mats as disclosed in U.S. Pat. No. 4,462,712 to Penland; U.S. Pat. No. 5,032,037 to Phillips et al.; and U.S. Pat. No. 4,889,444 to Pouyer. Commonly, each layer is nailed to the underlying layer. The final layer is fastened with extended length nails having protruding tips that crimped over to secure the assembly as disclosed in U.S. Pat. No. 5,234,204 to Hunt. The manual assembly, even with air powered nailing guns is time consuming and tiring and prone to misalignments.
Various assembly devices have been proposed for more accurately aligning the timber layers prior to nailing. U.S. Pat. No. 4,922,598 to Pouyer discloses an assembly table having an array of alignment stops for assisting positioning the timbers prior to nailing. U.S. Pat. No. 5,234,204 to Hunt, referenced above, discloses a dual stage assembly table facilitating nailing on opposite sides of the mat. Crimped extended length nails are used on the final layer to resist a lifting of the nail heads that can damage vehicle tires.
The nailing of the timbers also precludes convenient repair and replacement of damaged timbers. Typically, the mat must be substantially disassembled to access and replace damaged members. Such limitations have been overcome by the use of bolted mat configurations. Therein, holes are drilled at the intersections of the crossed timbers for receiving threaded fasteners. The resulting construction provides a smooth upper surface free of protruding nail heads. When replacement of a member is required, only the fasteners in the affected area need to be removed to allow substitution. Notwithstanding the advantages of the bolted construction, production rates, even with fixtures and assembly tables, have been limited by the cycle times of the serially required operations.
The present invention provides an improved method for making bolted temporary road mats wherein an assembly line includes a pair of in-line, phase opposed multilevel assembly tables supplied with precut timbers from conveyor systems including a trimming station. The precut timbers are oriented into multiple layers of mutually perpendicular timbers atop the table. A mobile gang drill carrying a plurality of drill heads travels along rails at the sides of the assembly tables and sequentially drills through holes at each lateral row of timber intersections. Carriage bolts are inserted downwardly through the drilled holes as completed. At lower bays beneath the assembly tables, nuts are assembled on the bolts to provide a unitized assembly. During the drilling at the first table, another mat is assembled at the other table. Following completion at the first table the gang drill indexes to the second table and performs the drilling sequence thereat, while the bolts are fastened at the first table. The gang drill alternates between the tables, with upper and lower crews transferring between tables for continuity and efficiency.
In one aspect of the invention there is provided an improved apparatus for making temporary road mats of bolted construction characterized by multiple layers of mutually perpendicular elongated timbers having an array of vertical intersections comprised of longitudinally spaced lateral rows, wherein said apparatus comprises: a pair of assembly tables spaced along an assembly line of a work floor, each of the tables having an upper layout surface spaced vertically above the work floor and providing a work bay therebelow, said layout surface having indicia for orienting the discrete timbers in each layer whereby said timber may be roughly assembled thereon into said layers with said intersections; a gang drill assembly supported for controlled movement in a longitudinal path along said assembly line with respect to said pair of assembly tables, said gang drill assembly carrying a plurality of drill units above said layout surface aligned for drilling the lateral rows of intersection; means for aligning said drill units at said lateral rows and for downwardly moving said drill units to form through holes through said timbers at said intersections subsequent to which bolts are inserted into said through holes from above said layout surface and fasteners are connected with said bolts in said work bay, the movement of said gang drill assembly and the sequence of said drilling being alternated between said assembly tables.
Accordingly, it is an object to provide an improved temporary road mat having threaded fasteners releasably interconnecting the various components.
A further object is to provide an improved apparatus for assembling temporary road mats wherein rough timbers are feed on a conveyor system through a trimming station to provide precut timbers to a pair of spaced assembly tables for positioning into multiple crossed layer orientation and a longitudinally positionable multiple drill assembly alternately drills fastener holes in the timbers at each table.
Another object is to provide an apparatus for assembling bolted temporary road mats wherein a gang drill assembly is used to simultaneously drill lateral rows of through holes for receiving fasteners for interconnecting the mat components.

Apparatus for assembling temporary road mats


A print management system, includes a management unit to receive print manuscript data from a connected manuscript processor, and obtain status information indicating states of connected multiple output enabled printers; a status identification unit to predict whether the output enabled printers stop in the middle of a print job; and a print data generator to generate multiple types of print data whose amount of toner consumption during printing is different respectively, based on the print manuscript data. The management unit classifies the output enabled printers predicted that there is less possibility to stop in the middle of a print job as output candidate printers, and selects an output destination printer from the output candidate printers. The management unit selects one type of print data from the multiple types of print data, depending on the output destination printer, and outputs the selected print data to the output destination printer.

1. Field of the Invention
The present disclosure generally relates to a print management system, a distributed printing system, and a method for managing a distributed printing system.
2. Description of the Background Art
In the digital printing industry, in order to build a mechanism to make a profit from multi-type, small-lot printing, effective print workflows using networks such as Web2Print and online calibration have been introduced. In addition, in the digital printing industry, as the number of ordered copies is large, the most rapid printing available is required. In order to solve this problem, a so-called hybrid workflow technique involving comprehensively managing and efficiently operating multiple output devices on the output side (including those in different places, for example, different branches or at an affiliated printing company) is already known.
However, in the above-described hybrid workflow, when a print engine assigned as an output destination printer stops during operation, since any given printing job is assigned to multiple output printers not located near a server, throughput decreases and the output device owner must take emergency repairs.
In a printing system as proposed in JP-2006-155017-A, in order to process printing as rapidly as possible, a management device (server) generates and manages page description language (PDL), intermediate data (e.g., portable document format (PDF)), and raster image data from input data, and outputs the most suitable intermediate print data from among these when a print command is input. This printing system is similar to the present invention in that the management device (server) prepares processed data in advance so that the rapid printing can process. However, the problem described above remains unresolved: Once the print engine assigned as the output destination printer stops in the middle of printing, throughput is decreased and the output device owner must undertake urgent repairs.

Print management system, distributed printing system, and managing method for distributed printing system


A system and method in accordance with exemplary embodiments may include receiving a message from a location-aware mobile device associated with a user, receiving content delivery information from the user, formulating a content package at least based on the content delivery information, and sending a content message associated with the content package to the location-aware mobile device via a network.

People may regularly interact with multiple electronic devices to access, view, and/or manipulate information. For instance, one individual may use a desk top computer while at home to view information of interest made available on the Internet. The same individual may then use a mobile device to view the same information of interest while commuting from one location to another location. Even further, this individual may use a computer system, such as, a lap top computer while at a place of employment to view information of interest. Accordingly, accessing multiple electronic devices to view information of interest has become overly cumbersome and time consuming.

Method and system for providing preference based content to a location aware mobile device


A self-refresh period measurement circuit of a semiconductor device is disclosed, herein which includes a shift register configured to receive an oscillation signal that is periodically enabled after a self-refresh signal is enabled, to allow a self-refresh operation to be performed, and delay the received oscillation signal by a unit self-refresh period to output a delayed oscillation signal, a period measurement start signal generator configured to receive the self-refresh signal and the oscillation signal and generate a period measurement start signal for setting a time that the oscillation signal is enabled for the first time as a start time for measurement of a self-refresh period, and a refresh period output unit configured to receive the period measurement start signal and the delayed oscillation signal from the shift register and generate a refresh period output signal that is enabled for a period from a time that the period measurement start signal is enabled to a time that the delayed oscillation signal is enabled for the first time.

1. Field of the Disclosure
The present disclosure relates to a self-refresh period measurement circuit of a semiconductor device, and more particularly to a self-refresh period measurement circuit of a semiconductor device which is capable of measuring a more accurate self-refresh period of the semiconductor device.
2. Description of the Related Art
One of the most important matters in mobile products such as mobile phones, notebook computers, etc., is how long the products can successfully be operated with given batteries. In this regard, it is very important in mobile dynamic random access memories (DRAMs) installed in such products to reduce self-refresh current that is generated in a standby state of the DRAMs.
Functions such as a Partial Array Self Refresh (PASR) mode, Temperature Compensated Self Refresh (TCSR) mode and Deep Power Down (DPD) mode are generally installed in such mobile products to reduce self-refresh current of the products so as to reduce power consumption thereof. Among these, the PASR mode and TCSR mode are programmed and used by the user to utilize Extended Mode Register Set (EMRS) feature.
In general, the data preservation time of a device at low temperature is longer than that at high temperature. In this regard, a TCSR circuit can reduce power consumption of a DRAM by varying a self-refresh period of the DRAM with temperature in such a manner as to shorten the self-refresh period when the DRAM is used at high temperature and lengthen the self-refresh period when the DRAM is used at low temperature. In particular, in an auto TCSR circuit, a temperature setting is not performed by the user, but the temperature of a chip is sensed and the period of an oscillation signal for a refresh operation is automatically adjusted according to the sensed temperature.
In order to automatically adjust a self-refresh period of a semiconductor device such as a mobile DRAM or the like according to temperature to reduce current consumption of the semiconductor device as stated above, it is very important to measure how long the self-refresh period actually is. However, a conventional self-refresh period measurement circuit has a disadvantage in that operation characteristics thereof are unstable when measuring a self-refresh period, as will hereinafter be described in detail with reference to FIG. 1.
FIG. 1 is a timing diagram showing the waveforms of respective signals in a conventional self-refresh period measurement circuit. Here, a control signal TM_REF is a test mode signal that enables a test mode for measuring a self-refresh period. A control signal OSC_MEAS_ON is a pulse that is enabled high in level when a semiconductor device enters a self-refresh mode, to indicate that the semiconductor device has entered the self-refresh mode. The semiconductor device performs a first cycle of a self-refresh operation (also referred to hereinafter as a "first self-refresh cycle") at a time t2 that the control signal OSC_MEAS_ON is enabled. A control signal OSC is an oscillation signal that is periodically enabled after the semiconductor device enters the self-refresh mode, to allow the self-refresh operation to be periodically performed. The semiconductor device performs the self-refresh operation each time the control signal OSC makes a high level transition. The control signal OSC allows the self-refresh operation to be performed periodically beginning with a second cycle.
The self-refresh period is conventionally measured by measuring a period corresponding to the first cycle of the self-refresh operation, namely, a period between the enable time t2 of the control signal OSC_MEAS_ON and an enable time t3 of the oscillation signal OSC, as shown in FIG. 1. That is, the conventional self-refresh period measurement circuit generates a refresh period output signal REF_OSC that is enabled for the period from the time t2 that the control signal OSC_MEAS_ON is enabled to the time t3 that the oscillation signal OSC is enabled for the first time. The conventional circuit then measures the self-refresh period by counting the number of specific signals, such as clocks with a certain period, strobed for the enable period (from t2 to t3).
However, an oscillator of an auto TCSR circuit is liable to operate unstably in the first self-refresh cycle that is performed simultaneously with the self-refresh mode entry. For this reason, it is unreasonable to recognize that the measurement result of the period of the first self-refresh cycle represents an accurate self-refresh period. Nevertheless, the conventional self-refresh period measurement circuit takes, as the self-refresh period, the period in which the refresh period output signal REF_OSC is enabled, namely, the period in which the first self-refresh cycle is performed, as described above, so that it cannot measure an accurate period of the self-refresh operation, thereby causing the auto TCSR circuit not to perform the self-refresh operation appropriately for the chip temperature.

Self-refresh period measurement circuit of semiconductor device


An implantable medical device uses a sampling scheme to obtain digital representation from analog signals. The analog signals represent intracardiac activity. Generally, a detector detects the amplitude of the analog signals and generates first and second difference signals. The first difference signal is generated after detection of significant changes in the analog signal amplitude. The second difference signal is generated upon confirmation of the absence of significant changes in the analog signal amplitude over a predetermined period of time. A frequency selection is implemented to select the sampling frequency based on the first and second difference signal.

As a result of significant technological advances over the past decade, implantable medical devices (IMDs) can now be equipped with processing circuitry and memories for storing episodes of digitized physiological signals. For example, a pacemaker may be designed to perform the task of sensing, digitizing, and storing intracardiac signals for later uploading to an external device. The pacemaker need not be restricted to acquiring cardiac signals, but can also be used for obtaining, digitizing, and storing sensor signals, e.g., pressure sensor signals. Such signals are conventionally continuously sampled at a high rate in order to capture the highest anticipated or relevant frequency, such as those which occur during the actual contraction of the heart. For physiological heart signals, the importance is to be able to measure the amplitude of a signal during a contraction accurately. Typically, during cardiac contraction, the signals contain much more high frequency components compared to the situation between two contractions. This means that when the high frequencies are left out (which happens when the signal is sampled at a too low frequency), the amplitude is measured inaccurately. Examples of systems already in use which obtain and store digitized physiological signals are pacemakers, cardioverter defibrillator units and implantable hemodynamic monitors.
In IMDs, the task of digitizing data for storage and transmission to an external receiver becomes difficult because of the need to conserve data processing time and power. Generally available memory is a limitation, but even where the memory limitation is not significant, a data compression scheme is needed to save power during the data processing, telemetry communication, and the sampling process. It is known that data compression techniques can be used in order to increase the amount of signal information available for storage in available memory. See, for example, commonly assigned pending U.S. application Ser. No. 08/561,738, P-3432, "System and Method for Compressing Digitized Signals in Implantable and Battery-Powered Devices," filed Nov. 22, 1995.
Because of the limited availability of processing resources and power, compression techniques for IMDs need to focus on achieving the greatest degree of data compression within the confines of allowable information loss. Thus, some lossy compression can be utilized in IMDs, to reach higher compression ratios with limited signal distortion.


A system for reading and encoding a magnetic track (2) carried by a supporting document (1) which is displaced manually past read and write members, the magnetic track comprising a first portion (3) on which a fixed first encoded message characteristic of the supporting document is recorded, said message being encoded by means of an encoding system which conveys its own clock signal, the first portion of the track being followed by a second portion (6) in which a variable second encoded message is written each time the supporting document goes past said read and write members, wherein the read and write members comprise three magnetic heads in alignment, comprising a first head (9) which is a read head, a second head (10) which is a write head, and a third head (11) which is a read head, the write head (10) being connected to a write signal generator (12) having a first input (13) which receives data representative of said variable message to be recorded on said second portion of the magnetic track, and a second input ( 14) on which it receives a clock signal generated by an electronic circuit (15) having an input (16) on which it receives the signals from the said read third head (11), and serving to extract the clock signal from said fixed encoded message recorded on said first portion (3) of the magnetic track (2), the arrival of the clock signal (14) at the write signal generator (12) triggering said writing.

Ticket-processing machines exist for processing such ticket, said machines being equipped with motor-driven read/write apparatuses, i.e. users insert their tickets into a chute or slot, after which the tickets are driven automatically to the reader/writer and the ticket is then returned either through an outlet which is separate from the inlet, or else via the inlet itself after being reversed.
There also exist ticket-processing machines through which travellers themselves displace their tickets along a slideway so that the tickets go past a reader without the travellers letting go their tickets. Ticket machines of this type are used in single charge transport systems which do not deduct credit from a ticket, such machines containing a reader only and not containing a write head.
For writing purposes it is necessary that the linear density of bits in the magnetic coding scheme used should be independent of the speed and any variations in the speed at which a ticket moves past a write head, and this leads to complications when the ticket is displaced manually.
One known solution consists in having a second magnetic track running parallel to the first magnetic track and recording a clock signal on the second track, which solution requires an additional read head to be provided in order to read the clock signal which serves for synchronizing writing and making writing independent of the speed at which the ticket is moving.
An object of the invention is to provide a system enabling a document supporting a magnetic track to be displaced manually and in which a portion of the magnetic track carries a fixed message while another portion carries a variable message, the system not requiring the provision of an additional track with a clock signal and not requiring an additional magnetic head.
A system making use of manual displacement has several advantages. Firstly there is no need to provide a motor, thus enabling complex mechanical items to be avoided, and secondly such a system is less vulnerable to vandalism.

System for reading and encoding a magnetic track carried by a manually-displaced supporting document

Societe Anonyme dite: Compagnie Generale d'Automatise CGA HBS


There is provided an apparatus and method for inspecting a semiconductor package. The apparatus includes at least one 3D camera positioned at a first angle relative to a normal axis of the semiconductor package; and a light source configured to provide illumination for the at least one 3D camera, the light source being directed at the semiconductor package. The method includes casting a shadow of a bonded wire onto the semiconductor package; obtaining a 3D image of the semiconductor package; determining a distance S of the shadow and the bonded wire in the image; and obtaining a wire loop height H of the bonded wire.

Die and wire bonding is the most common interconnect technology employed in the electronic packaging industry. In recent years, new packaging trends have led to, for example, increases in the number of interconnections, circuit miniaturization, increased speed of assembly, reduced cost per interconnection and the like.
It should be noted that interconnection quality affects the quality of an end product. As the number of interconnections increases, the probability of producing a defective component also increases. Given that die and wire bonding typically occurs at a downstream stage of a semiconductor production process, the cost of a defective product due to a bad interconnect is high relative to a defective product which is detected at an early stage of the production process. It is currently possible to measure a height of bonded wires. This is also known as loop height. It is also possible to carry out inspection for the quality of the die/wire bonding as well as the integrity of die/wire/substrate after the bonding process.
Typical inspection methods for wire bonding (especially in the wire profile area) are usually carried out either manually (for example, visual check with a microscope, contact inspection and the like) or in a semi-automated manner. Such inspection methods are unfortunately slow, labour intensive, costly, and also prone to suffer physical damage due to contact and/or electrostatic damage. Moreover, manual inspection methods (for example, visual inspection with/without use of a sensor) are flawed due to human limitations, and are highly subjective and dependent on a human inspector.
Hence, there is clearly a need for improvements pertaining to inspection methods for wire bonding.

Apparatus and method for inspecting a semiconductor package


A current sourcing and sinking circuit for driving a charge pump for a voltage-controlled oscillator includes two similar subcircuits, each of which is capable of simultaneously sourcing and sinking output currents. Both subcircuits have identical, corresponding CMOSFET components with two open drain outputs, one of which is a current sourcing output port and the other of which is a current sinking output port. In one subcircuit the current sourcing output port is used while the current sinking output port is terminated drain-to-source with a short circuit. In the other subcircuit the current sinking output port is used while the current sourcing output port is terminated drain-to-source with a short circuit. The similarity of the two subcircuits provides a balanced current sourcing and sinking circuit topology, resulting in substantially equal source and sink current amplitudes and current sourcing and sinking activation timing.

Charge pump circuits are normally employed in phase locked loop circuits and selectively provide current to a loop filter or receive current from the filter. Such current generation and reception causes a voltage controlled oscillator to produce an output signal having a desired frequency.
Specifically, charge pump circuits receive an error signal corresponding to a phase difference between a reference signal and the output signal. The error signal specifies frequency modifications necessary to make the frequency of the output signal substantially identical to the reference signal frequency.
If the output frequency is to be increased, the charge pump circuit selectively sources or increases the amount of current generated to the loop filter. Alternatively, if the frequency is to be decreased, the charge pump sinks or receives a certain amount of current from the loop filter. In many instances, current is both sourced and sunk in order to make desired frequency modifications. Such current sourcing and sinking respectively increases and decreases the potential or voltage of the loop filter which is applied to the voltage controlled oscillator. These voltage modifications cause the oscillator to vary the frequency of the output signal in the desired manner.
While many conventional charge pump circuits adequately and desirably modify the output signal frequency, they also suffer from many drawbacks. For example, it is not uncommon for a given charge pump to have non-identical current generating and sinking circuits and to therefore generate and absorb non-identical amounts of current. Such disparity causes these charge pumps to incorrectly modify the output signal frequency.
Moreover, these unique current generating and sinking circuits usually have unequal activation time intervals with respect to the time at which a correction signal was received. Such activation disparity increases the time necessary to produce an output signal having a desired frequency and increases phase noise and spurious frequency generation. Many conventional charge pump circuits also utilize elements which consume relatively large amounts of power and have current amplitudes which vary in proportion to variations in one or more voltage supplies. This further adds to the overall unreliability of these devices.
To understand prior charge pump operation reference is now made to FIG. 1, where there is shown a phase correction signal generator 10 made in accordance with the teachings of the prior art. As shown, generator 10 includes a typical loop filter 25 which is connected to a voltage controlled oscillator 41. Generator 10 also includes a phase comparator 12 which receives a reference signal 14 and the output signal 16 generated by the voltage controlled oscillator 41. Comparator 12 compares the phase of signal 14 with the phase of signal 16 and, in response thereto, outputs frequency correction signals 20 and 22.
Signals 20 and 22 are input to charge pump circuit 24 and are respectively effective, when they are in a first logical state (i.e. logically high), to cause pump 24 to absorb or sink current from filter 25 and to cause pump 24 to output or source current to filter 25. When current is concomitantly sourced and sunk, signal 18 is generated by charge pump 24 and causes signals 20 and 22 to be of a second and opposite logical state (i.e. logically low), thereby preventing further current sinking or sourcing.
To illustrate some of the previously-described difficulties associated with prior charge pump circuits, reference is now made to FIG. 2 where there is shown a charge pump circuit 24' made in accordance with the teachings of the prior art. As shown, circuit 24' includes a cascaded arrangement of inverters 26, 28, and 30 which cooperatively receive and invert signal 22 and apply the inverted signal to the gate of a typical PMOS field effect transistor 33.
Circuit 24' further includes a second cascaded arrangement of inverters 31 and 32 which receive signal 20 and apply signal 20 to the gate of NMOS transistor 34. The respective source terminals of transistors 32 and 34 are coupled to a voltage source 36 and to electrical ground 38. Transistors 32 and 34 are mutually coupled at their respective drain terminals. These coupled drain terminals provide the output signal 40' which is coupled to the loop filter.
In operation, as will be known to those of ordinary skill in the art, signal 22, when logically high, activates transistor 33. Such transistor activation causes current to flow from the voltage source 36 through tile drain of transistor 33 and onto bus 40'. Signal 20, when logically high, activates transistor 34. Such transistor activation provides a current path from bus 40' to electrical ground 38. Concomitant deactivation of transistors 33 and 34 (i.e. when signals 20 and 22 are each logically low) places bus 40' in a tri or high impedance state and prevents current from either sourced or sunk.
As will be appreciated, inverters 26, 28, and 32 cooperate with transistor 33 to selectively generate current to bus 40' while inverters 30 and 32 cooperate with transistor 34 to provide a "current sink" circuit. Since these circuits are dissimilar (i.e. each having a different number of circuit elements 26, 28, 30 and 31, 32), they activate respective transistors 33 and 34 at different time intervals after receipt of respective signals 22, 20. These different activation time intervals are caused by the cumulative delay differences between the respective first phase comparator output signal reception element (i.e. 26 or 30) and the respective target transistor (i.e. 33 or 34). These delay disparities result in many of the previously-discussed difficulties.
Moreover, since transistors 33 and 34 are normally operated in a low impedance output state it is difficult, due to transistor fabrication constraints, to match such dissimilar N-type and P-type transistors. Such matching difficulties in combination with variations in the current output from the voltage source causes unequal current source and sink amplitudes. It should be apparent to those of ordinary skill in the art that such amplitude differences will degrade charge pump performance.
Referring now to FIG. 3, there is shown a second prior art charge pump circuit 24" which differs from circuit 24' by the use of bipolar transistors 35 and 37 and respective biasing resistors 39, 41, 42, and 43 in place of transistors 33 and 34. Specifically, resistors 42 and 43 are respectively coupled to the base and emitter of transistors 35 and 37. Resistors 41 and 39 are respectively coupled to inverters 30' and 32' and to resistors 42 and 43.
The operation of circuit 24" is substantially similar to that of circuit 24' in that logically high signals 22 and 20 respectively cause current to flow from the collector of transistors 35 and 37, thereby selectively sourcing and sinking current. When signals 22 and 20 are logically low, resistor pairs 41, 42 and 39, 43 respectively provide a path which applies the potential of source 36' to the base of transistor 35 and discharges current from the base of transistor 37 to ground, thereby preventing substantially any current from being sourced or sunk.
While circuit 24" adequately and selectively sources and sinks current it suffers from the same drawbacks as previously described with respect to circuit 24'. Moreover, it should be appreciated that circuits 24' and 24" have been described without reference to the manner in which signal 18 (shown and previously described with reference to FIG. 1) is generated. Such description is not necessary to adequately illustrate the various deficiencies associated with these prior charge pump circuits.
Therefore, there is a need to provide a charge pump circuit having substantially identical source and sink current amplitudes, substantially identical source and sink activation time intervals, relatively low static power utilization, and having currents that are relatively insensitive to variations in voltage supply output current.

Current sourcing and sinking circuit for driving a VCO charge pump