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<SOH> BACKGROUND OF THE INVENTION <EOH>ras-GTPase-Activating Protein SH3-Domain-binding Proteins (G3BPs) are a family of proteins which comprise SH3 domain-binding motifs which have been shown to specifically bind the ras-GTPase-activating protein, rasGAP 120 (Parker et al., 1996; Kennedy et al, 1997). Furthermore, this family of proteins have been shown to be RNA-binding proteins (Kennedy et al., 1997) that may have an RNAase activity on c-myc transcripts (Gallouzi et al., 1998). Both the ras-GAP signalling pathway and c-myc have been implicated in oncogenic activity (Bos, 1989; Facchini and Penn, 1998). The evidence presented suggests that the G3BP family of proteins are members of a novel signal transduction mechanism that utilises components of previously described pathways to regulate mRNA stability and through these pathways may regulate oncogenic signals or factors. These activities may be modulated through their SH3 domain-binding activity (Parker et al., 1996), their RNAase activity (Gallouzi et al., 1998) or their helicase activity (Costa et al., 1999). G3BPs have recently been shown to be upregulated at the transcriptional level in some cancers (Guitard et al., 2001). rasGAP 120 is an important regulator of signal transduction (Pomerance et al., 1996) as it sits at the nexus of positive and negative control of the oncogene ras. rasGAP 120 itself stimulates the hydrolysis of GTP bound ras (reviewed in Tocque et al., 1997) and thereby regulates the activity of ras. The amino-terminus of rasGAP 120 comprises a Scr homology (SH3) domain (Tocque et al. 1997) which has been implicated in an effector-like activity (Duchesne et al., 1993). Human G3BP-1 was first identified by its co-immunoprecipitation with rasGAP 120 using an antibody raised to the carboxy-terminal domain of rasGAP 120 (Parker et al., 1996). G3BP was the first protein shown to bind the rasGAP 120 SH3 domain, however, other rasGAP 120 SH3 binding proteins have since been reported, including a 14 kDa protein (Hu and Settleman 1997) and the huntingtin protein (Liu et al., 1997). Genetic studies in Drosophila support a role for G3BP in ras signaling (Pazman et al., 2000). The inventors previously cloned and sequenced mouse G3BP-2 as part of a general screening for RNA Recognition motif (RRM)-containing proteins (Kennedy et al., 1997). Primary sequence analysis of G3BPs also indicated that they contain an RNA Recognition Motif (RRM) (Nagai et al., 1995), an RGG domain (Burd and Dreyfuss 1994; Siomi and Dreyfuss 1997) and a Nuclear Transport Factor 2-like (NTF2-like) domain (Suyama et al., 2000). The proposed structure of the RRM in G3BP has been reported elsewhere (Kennedy et al. 1997). The G3BPs also contain acid-rich and RGG domains which are often considered auxiliary domains for RRM-type RNA-binding proteins (Burd and Dreyfuss 1994; Siomi and Dreyfuss 1997). These structural motifs are consistent with a recent finding that G3BP-1 is implicated in RNA metabolism by acting in vitro as a cleavage factor for c-myc transcripts (Gallouzi et al. 1998). NTF2 polypeptide is involved in nuclear transport of polypeptides and appears to be facilitated by binding RanGDP in the cytoplasm. Once NTF2/RanGDP is bound to a cargo the complex is imported to the nucleus where it is released and the Ran nucleotide exchange factor, RCC1, converts RanGDP to RanGTP. This signals export of NTF2 to the cytoplasm where RanGTP is hydrolysed by Ran GTPase activating protein (RanGAP) and the system is reset (reviewed in Macara 1999). The NTF2-like domain of G3BP-2 may target G3BP-2 to the nuclear envelope, although a mechanism for this activity is unclear (Prigent et al., 2000). RNA processing is an integral part of cellular metabolism controlled through pre-mRNA splicing, RNA transport and RNA stability (Dreyfuss et al., 1996). Regulation of RNA metabolism has been shown to play an important role in development. Recently there has been increased interest in the control of mRNA translation mediated by RNA-binding proteins, in particular the role of these proteins in 5′ UTR interactions that influence elongation factors (Svitkin et al., 1996) as well as 3′ interactions involving translational activity (Dreyfuss et al. 1996) and degradation (Gallouzi et al., 1998). It is important to characterise the mechanisms that allow RNA-binding proteins to respond to environmental and developmental signals through transduction cascades in order to understand their role in human diseases. SH3 domains were initially characterised in signal transduction proteins such as Src, Fyn and Grb as well as rasGAP 120 . Typically these domains interact with proline rich motifs with a minimum consensus of PxxP (Urquhart et al., 2000 and papers cited therin). It has also been shown that the acidic and PxxP domains, and not the RNA-binding domain nor the NTF2-like domain of G3BP-2, are sufficient to mediate binding to IκBα (Prigent et al; 2000). Primary sequence analysis of alternatively spliced homologues of human G3BP-2a and G3BP-2b reveals that they respectively comprise five and six minimal potential SH3 domain-binding motifs (Lee et al., 1996). As G3BP-2a and G3BP-2b comprise PxxP sequences, it was predicted that these proline-rich motifs would bind with SH3 domains of polypeptides. Major advances have been achieved in the early diagnosis (screening mammography) and treatment (adjuvant therapy) of breast cancer and this has translated into a significant reduction in the mortality generated by this disease (Chlebowski, 2002). However, breast cancer still accounts for 26% of the cancers diagnosed in Australia in 1999, and in 1996 there were 9,556 new cases diagnosed with 2,619 deaths ((AIHW), 1999). An additional important input into the better management of the disease has been the characterization of genetic predisposing markers BRCA1 and 2 (reviewed in (Nathanson et al., 2001)), allowing the prediction of a proportion (10%) of women at risk to develop breast cancer. Considering the reduced adjuvant therapeutic options currently available (Pritchard et al., 2002) and the risks involved with their use, novel strategies are urgently needed that could prevent the development of the disease at early stages of the disease and/or in those with higher genetic risk. |
<SOH> SUMMARY OF THE INVENTION <EOH>Although G3BPs have been shown to bind the SH3 domain of GAP 120 the inventors were surprised to discover that this binding is mediated through the N-terminal NTF2-like domain of G3BP and not facilitated by a proline-rich motif (PxxP) contained within G3BP-2 as the prior art would suggest. The smallest G3BP truncated protein that was capable of binding to the SH3 domain of rasGAP 120 did not contain any of the predicted PxxP motifs normally associated with SH3 binding. The unexpected results clearly showed that the N-terminal NTF2-like domain of G3BP is responsible for the binding interactions with N-terminal rasGAP 120 . This finding has led to novel uses of G3BP, in particular the NTF2-like domain thereof, as described herein for identifying and producing potential reagents for diagnosing, treating or preventing breast cancer. In a first aspect, the invention provides an isolated G3BP-2 protein fragment comprising an NTF2-like domain, said isolated G3BP2 protein fragment capable of binding another protein by way of said NTF2-like domain. Preferably, the G3BP-2 protein comprises G3BP-2a and/or G3BP-2b proteins. Preferably, the another protein is selected from the group consisting of: ran nuclear pore polypeptide, ubiquitin hydrolase and GAP 120 . More preferably, the ubiquitin hydrolase is ODE1. The NTF2-like domain preferably is encoded by amino acid residues 1 to 146 as set forth in SEQ ID NO: 22. In a second aspect the invention provides an isolated protein complex comprising a G3BP-2 protein having an NTF2-like domain and another protein bound to the NTF2-like domain, selected from the group consisting of: ran nuclear pore polypeptide, ubiquitin hydrolase and GAP 120 . In a third aspect, the invention provides an isolated G3BP-2 protein, inclusive of a fragment, homolog, variant or derivative thereof capable of eliciting an immune response in an animal. Preferably, the animal is human. Preferably, the G3BP-2 fragment is selected from the group consisting of: (i) KLPNFGFW; [SEQ ID NO:1] (ii) IMFRGEVRL; [SEQ ID NO:2] and (iii) SATPPPAEPASLPQEPPKPRV [SEQ ID NO:3] In a fourth aspect, the invention provides an isolated G3BP-2 protein fragment selected from the group consisting of: (a) KLPNFGFW; [SEQ ID NO:1] (b) IMFRGEVRL; [SEQ ID NO:2] and (c) SATPPPAEPASLPQEPPKPRV [SEQ ID NO:3] In a fifth aspect, the invention provides an isolated nucleic acid encoding a protein of the first aspect, inclusive of fragments, homologs, variants and derivatives thereof, each capable of binding another protein by way of said NTF2-like domain. In one form, the isolated nucleic acid encodes a protein comprising the NTF2-like domain comprising an amino acid sequence as set forth in SEQ ID NO: 22, said NTF2-like domain being encoded by amino acid residues 1 to 146, wherein amino acid residue 1 is the first methionine (M). In another form, the isolated nucleic acid comprises a nucleotide sequence set forth in SEQ ID NO: 23. In a sixth aspect, the invention provides an isolated nucleic acid encoding a G3BP-2 protein fragment of the fourth aspect. In a seventh aspect, the invention provides an expression vector comprising a nucleic acid of any one of the abovementioned aspects. In an eighth aspect, the invention relates to use of an antagonist to prevent or disrupt binding between G3BP-2 and another protein. In one form, the antagonist of the eighth aspect prevents or disrupts binding between a NTF2-like domain of G3BP-2 and said another protein. In another form, the antagonist is a mimetic of the NTF2-like domain of G3BP-2. In yet another form, the antagonist binds to the NTF2-like domain. The antagonist may be a protein. In one form, the protein comprises an Src homology 3 (SH3) domain. Preferably, the protein comprises an amino acid sequence as set forth in SEQ ID NO: 6. The antagonist may be a non-peptide compound. In a ninth aspect, the invention provides an isolated antigen presenting cell which has been in contact with a G3BP-2 protein, fragment, homolog, variant or derivative thereof, wherein contact includes pulsing or loading the antigen presenting cell with G3BP-2 protein, fragment, homolog, variant or derivative thereof. In a tenth aspect, the invention provides an isolated antigen presenting cell which has been transfected with a nucleic acid encoding G3BP-2 protein, inclusive of fragments, homologs, variants and derivatives thereof. The isolated antigen presenting cell of the ninth and tenth aspects is preferably a dendritic cell. The G3BP-2 protein, inclusive of a fragment, a homolog, a variant and a derivative thereof of the ninth and tenth aspects preferably comprises an amino acid sequence as set forth in SEQ ID NO: 5. The G3BP-2 fragment of the ninth and tenth aspects preferably comprises an amino acid sequence selected from the group consisting of: KLPNFGFVV [SEQ ID NO: 1] and IMFRGEVRL [SEQ ID NO: 2]. In an eleventh aspect, the invention provides an isolated lymphocyte cell that is G3BP-2 antigen specific. Preferably, the isolated lymphocyte cell is a cytotoxic T-lymphocyte. Preferably, the lymphocyte cell is G3BP-2 antigen specific for a protein, inclusive of fragments, homologs, variants and derivatives thereof, comprising an amino acid sequence as set forth in SEQ ID NO: 5. Preferably, the G3BP-2 protein fragment comprises an amino acid sequence as set forth in SEQ ID NO: 1 or SEQ ID NO: 2. In a twelfth aspect, the invention provides a pharmaceutical composition comprising at least one active, wherein the active is selected from the group consisting of: a protein, a nucleic acid or an isolated cell of any one of the above aspects. In a thirteenth aspect, the invention provides a method for preventing or treating breast cancer in a mammal including the step of administering to said mammal a pharmaceutical composition comprising at least one active, wherein the active is selected from the group consisting of: a protein, a nucleic acid, a mimetic of the NTF2-like domain of G3BP-2, an antagonist that prevents or disrupts binding between a NTF2-like domain of G3BP-2 and another protein or isolated cell of any one of the above-mentioned aspects. Preferably the mammal is human. In a fourteenth aspect, the invention provides a method for modulating cell proliferation including the step of administering to an animal or isolated cell, an active which prevents or disrupts binding between G3BP-2 and another protein. Preferably the animal is human. In a fifteenth aspect, the invention provides a method for isolating a molecule that binds G3BP-2, including the step of determining if one or more candidates in a sample bind to the NTF2-like domain of G3BP-2. In one form, the molecule is an antagonist. The antagonist may be a protein or a non-protein molecule. In a sixteenth aspect, the invention provides a method for diagnosing breast cancer in a mammal including the steps of comparing G3BP-2 protein expression in a test sample obtained from the mammal with G3BP-2 in a reference sample, wherein if the expression of G3BP-2 in the test sample is different than the reference sample, the mammal is diagnosed with an increased likelihood of having breast cancer. G3BP-2 protein expression may be detected using an antibody. The antibody may bind to a G3BP-2 protein, inclusive of a fragment, a homolog, a variant and a derivative thereof, comprising an amino acid sequence as set forth in SEQ ID NO: 5. In one form, the antibody binds to a G3BP-2 protein fragment comprising an amino acid sequence SATPPPAEPASLPQEPPKPRV [SEQ ID NO: 3]. The G3BP-2 fragment may comprise a NTF2-like domain. Preferably, the mammal is human. In a seventeenth aspect, the invention provides a method for diagnosing breast cancer in a mammal including the step of detecting a G3BP-2 nucleic acid or fragment thereof in a test sample obtained from the mammal. Preferably, the test sample is breast tissue. Preferably, the mammal is human. In an eighteenth aspect, the invention provides a method of immunising a mammal against breast cancer, including the step of administering to said mammal an immunogenic agent comprising at least one active selected from the group consisting of: (1) a G3BP-2 protein; (2) a fragment, a homolog, a variant or a derivative of (1); (3) a G3BP-2 nucleic acid; (4) a fragment, a homolog, a variant or a derivative of (3); (5) an isolated antigen presenting cell that has been contacted with (1) or (2); and (6) an isolated antigen presenting cell that has been transfected with a nucleic acid of (3) or (4). The immunisation may be preventative or as a treatment for an animal with breast cancer. The G3BP-2 protein fragment is preferably selected from the group consisting of: KLPNFGFVV [SEQ ID NO: 1] and IMFRGEVRL [SEQ ID NO: 2]. The antigen presenting cell is preferably a dendritic cell. Preferably, the mammal is human. The isolated protein and nucleic acid, and methods according to the aforementioned aspects of the invention are useful in therapeutic or prophylactic treatments of breast cancer and diagnosis thereof. As will be described in more detail hereinafter, disruption of interactions between G3BP-2 and another protein or endogenous binding partner may inhibit tumour proliferation. |
Methods and device for interfacing communication between devices on different networks |
The invention concerns a 1. Method for interfacing communication between a first device on a first network and a second device on a second network, the networks being connected by an interface device, the method being carried out by the interface device and being characterized by the steps of: detecting a first message on the first network, said first message being generated by the first device, said first message being relevant for the second device; translating the first message into a format compatible with the second device; sending a second message to the second device on the second network, the second message informing the second device that the first message has been detected; upon reception of a request from the second device, transmitting the translated first message. The invention also concerns a device for implementing the method. |
1. Method for interfacing communication between a first device on a first network and a second device on a second network, the networks being connected by an interface device, the method being carried out by the interface device and comprising the steps of: detecting a first message on the first network, said first message being generated by the first device, said first message being relevant for the second device; translating the first message into a format compatible with the second device; sending a second message to the second device on the second network, the second message informing the second device that the first message has been detected; upon reception of a request from the second device, transmitting the translated first message. 2. Method according to claim 1, wherein the interface device further carries out the steps of providing at least one applet, wherein said applet is adapted to receive the second message and to generate the request; and transmitting the applet to the second device. 3. Method according to claim 2, further comprising the step of including the at least one applet into at least one html page, and transmitting the at least one page to the second device. 4. Method according to claim 3, wherein the step of translating the first message comprises the steps of updating at least one relevant object of the html page with parameters contained in the first message. 5. Method according to claim 2, further comprising the step of: retrieving user interface elements of the first device; translating the user interface elements into a format compatible for control of the first device through the second device; including the translated user interface elements into the html page. 6. Method according to claim 5, wherein the step of translating the first message comprises updating at least one translated user interface element, based on parameters comprised in the first message. 7. Method according to claim 3, wherein the html page comprises at least one java object and/or at least one html object. 8. Method according to claim 3, wherein the step of sending the second message to the second device comprises performing a remote method invocation call to the applet, the remote method of the applet being such as to trigger an appropriate request from the second device to the interface device for transmission of the translated first message. 9. Method according to claim 8, wherein the request comprises one of the following: an HTML GET message, a remote method invocation call to the interface device. 10. Method according to claim 2, wherein the applet is adapted to regularly poll a predetermined port of the interface device for determining whether a translated message is available at the interface device. 11. Method according to claim 1, wherein the request for transmission of the translated first message comprises one of the following: a request to transmit an update of part of an html page; or a request to transmit an update of an entire html page; or a request to transmit an update of a java object or an HTML object. 12. Method according to claim 1, the first network is a HAVi network. 13. Method according to claim 1, wherein the second network is an Internet Protocol based network. 14. Method according to claim 1, wherein the first network is an Internet Protocol based network and the step of receiving the first message comprises receiving said message on a predetermined port from an applet in the first device. 15. Method according to claim 1, wherein the first network is an Internet Protocol based network and the step of receiving the first message comprises receiving said message through a remote method invocation call performed by an applet in the first device. 16. Device for interfacing communication between a first device on a first network and a second device on a second network, said device comprising means for detecting a first message on the first network, said first message being generated by the first device, said first message being relevant for the second device; means for translating the first message into a format compatible with the second device; means for sending a second message to the second device on the second network, the second message informing the second device that the first message has been detected and upon reception of a request from the second device, transmitting the translated first message. 17. Device according to claim 16, further comprising memory for storing user interface element representations for user interface elements of devices of the first network for control by devices of the second network and vice-versa, and means for translating the user interface elements of the first device according to the representations, for transmission of the translated elements to the second device, wherein the translation means are adapted to translating actions performed on one device or notifications generated by one device to a format compatible with the other device. 18. Method for interfacing communication between a first device on a first network and a second device on a second network, the networks being connected by an interface device, the method being carried out by the interface device and comprising the steps of: detecting a first message on the first network, said first message being generated by the first device, said first message being relevant for the second device; translating the first message into a format compatible with the second device; transmitting the translated message to the second device, wherein the first and second networks are IP and HAVi networks or vice-versa, and wherein the message is a notification or an action. 19. Method according to claim 18, wherein the exchange of a notification or action between the interface device and a device on an IP based network is carried out through a remote method invocation call. 20. Method according to claim 19, wherein the transmission of a notification from the interface device to the second device on an IP based network includes having the second device regularly poll a fixed port of the interface device acting as a server. |
Data processing system for implementing a financial market |
The disclosure relates to the field of banking and finance, and in particular relates to the implementation of a novel mechanism for providing pricing for financial products or transactions. There is provided a computer based data processing system for implementing a financial market, which permits customers to obtain prices for financial products from a range of banks, with some of which the customer has no normal trading relationship, in order to obtain optimum liquidity prices for the products. |
1. A computer based data processing system for implementing a financial market, which system comprises; a hub data processing system for administering a financial market in financial products provided to customers by a plurality of banks, means for permitting access by customers to the financial market by data communication with the hub, a plurality of satellite data processing systems in data communication with the hub, each satellite unit being associated with a bank providing: credit approval for transactions, margins for transactions, and liquidity quotes for financial products to be the subject of the transactions, thereby permitting access of the financial products of the banks to the financial market, and wherein the hub is provided with software which implements the following features, a database of bank identifiers, each identifier being associated with a satellite bank, a database of financial product identifiers, each of which financial products is offered by at least one, but preferably all, of the banks, a database of customer identifiers, permitting identification of a customer accessing the hub, each customer identifier being associated with one or more relationship bank identifiers which identify the bank or banks with which a customer has a prearranged trading relationship and with whom the customer can therefore trade, a database of liquidity provider identifiers, permitting identification of banks which are providers of liquidity quotes, each identifier being associated with one or more financial product identifiers which identify the financial product for which the liquidity provider can provide liquidity quotes and transactions, means for initiating a request for a quote for executing a transaction involving one or more of the financial products, means for communicating a liquidity price quote request for the transaction to each of the liquidity providers offering that financial product, means for logging each liquidity price quote for the requested financial transaction returned to the hub by each of the liquidity providers, means for communicating a margin price request for the financial transaction to each of the relationship banks, means for logging a margin price quote returned to the hub by each of the relationship banks, means for calculating an array of composite quotes, each quote comprising the sum of (1) a liquidity price provided by one of the liquidity providers and (2) a margin quote provided by one of the relationship banks, means for permitting selection by the user of a preferred composite quote from the array of quotes in order to generate an order command for executing the transaction at the selected composite price, means for instructing execution of the transaction which will either be between (a) the relationship bank and the customer on the one hand, or (b) the liquidity provider bank, the relationship bank and the customer on the other hand, depending upon the particular composite quote chosen and whether the liquidity provider is also a relationship bank, thereby permitting the customer to have access to liquidity prices from banks other than those with which it has a trading relationship. means for communicating to the customer that the transaction has been executed. 2. A system as claimed in claim 1 wherein the means for initiating a quote comprises means for logging a quote communicated to the hub by the customer. 3. A system as claimed in claim 1 wherein the means for initiating a quote comprises means for the automatic and periodic provision of a quote or quotes to a customer on the basis of a set of one or more financial products for which that customer has selected for real-time quoting. 4. A system as claimed in claim 1 wherein the software provides means for requesting credit approval for the transaction for which a quote has been requested, or made, from the relationship bank or banks. 5. A system as claimed in claim 4 wherein the software includes means for logging an credit approval/disapproval communication, and in the event of a disapproval communication the relationship bank concerned is excluded from the set of relationship banks providing margin quotes for that transaction. 6. A system as claimed in claim 1 wherein the means permitting access of the customers to data communication with the hub is an Internet link. 7. A system as claimed in claim 6 wherein the hub provides a website for presentation of information and receipt of trading instructions from customers. 8. A system as claimed in claim 1 wherein the hub system is provided with software which permits a direct trading mode, in which the system only shows to a customer liquidity price/margin composite prices which are derived from one or more relationship banks for that customer and not from non-relationship liquidity providers. 9. A system as claimed claim 1 wherein the hub system is provided with software which ensures that a customer is provided with a best price which comprises a composite of the best liquidity price provided by all of the liquidity providers, plus the lowest margin provided by a relationship bank. 10. A system as claimed in claim 9 wherein the customer is also provided with a comparison price list, which is a sub-optimal price on comparison with the best price. 11. A system as claimed in claim 10 wherein the comparison price list comprises a combination of the worst relationship bank margin and the worst liquidity price. 12. A system as claimed in claim 10 wherein the comparison price list comprises a composite of a liquidity price provided by a non-relationship bank and the worst margin of the relationship banks 13. A system as claimed in claim 1 wherein the financial products are one or more of: Money Market Loans, Money Market Deposits, Foreign Exchange Spot, Foreign Exchange forwards, Foreign Exchange swaps, Foreign Exchange Non-deliverable forward, Foreign Exchange options, Certificates of deposit, Commercial Paper, Interest Rate Derivatives, Fixed-Income Issuance, Secondary Fixed-Income. |
Novel genetic products from ashbya gossypii, associated with the structure of the cell wall or the cytoskeleton |
The invention relates to novel polynucleotides from Ashbya gossypii; to oligonucleotides hybridizing therewith; to expression cassettes and vectors which comprise these polynucleotides; to microorganisms transformed therewith; to polypeptides encoded by these polynucleotides; and to the use of the novel polypeptides and polynucleotides as targets for modulating the properties of the cell wall or of the cytoskeleton and, in particular, improving vitamin B2 production in microorganisms of the genus Ashbya. |
1. An isolated polynucleotide that can be isolated from Ashbya gossypii and that codes for a protein associated with construction of a cell wall or a cytoskeleton of an organism. 2. The polynucleotide of claim 1, which has a structural or functional property of a protein selected from the group consisting of a cell wall protein, a serine-threonine protein a GTPase-activating protein, a protein that has resistance to over expression of actin or contributes to such resistance, a Nuf1p-like protein, a calponin-homologous protein, a protein that is essential for pseudohyphal development, and a protein that interacts with actin. 3. The polynucleotide of claim 1, comprising: the nucleic acid sequence of SEQ ID NO: 1, 8, 12, 17, 21, 26, 30 or 36 a sequence complementary thereto; or a sequence derived from said nucleic acid sequence or said sequence complementary thereto through degeneracy of the genetic code. 4. The polynucleotide of claim 1, which comprises a nucleic acid that contains the sequence of SEQ ID NO: 4, 10, 15, 19, 23, 28, 34 or 38, or a fragment thereof. 5. An oligonucleotide that hybridizes to the polynucleotide of claim 1. 6. An isolated polynucleotide that hybridizes to the oligonucleotide of claim 5, and codes for a gene product derived from a microorganism of the genus Ashbya or a functional equivalent thereof. 7. An isolated polypeptide is encoded by the polynucleotide of claim 1 or a fragment thereof. 8. An expression cassette comprising the polynucleotide of claim 1 operatively linked to at least one regulatory sequence. 9. A recombinant vector comprising at least one expression cassette of claim 8. 10. A prokaryotic or eukaryotic host cell transformed with at least one vector of claim 9. 11. The host cell of claim 10, wherein functional expression of said protein is modulated. 12. A The host cell of claim 10, which is a microorganism of the genus Ashbya. 13. A method for microbiological production of vitamin B2 or a precursor or derivative thereof comprising expressing the polynucleotide of claim 1 in a microorganism. 14. A method for recombinant production of the polypeptide of claim 7 comprising expressing said polynucleotide in a microorganism. 15. A method for detecting an effector target for modulating microbiological production of vitamin B2 or a precursor or derivative thereof comprising treating a microorganism capable of the microbiological production of said vitamin B2 or the precursor or derivative thereof with an effector that interacts with a target wherein said target comprises the polypeptide of claim 7 or a nucleic acid that encodes said polypeptide and detecting said effector target. 16. A method for modulating microbiological production of vitamin B2 or a precursor or derivative thereof comprising treating a microorganism capable of the microbiological production of said vitamin B2 or the precursor or derivative thereof with an effector that interacts with a target wherein said target comprises the polypeptide of claim 7 or a nucleic acid that encodes said polypeptide. 17. An isolated effector selected from the group consisting of: antibodies or antigen-binding fragments thereof that bind to the polypeptide of claim 7; polypeptide ligands that are different from said antibodies or antigen-binding fragments and that interact with said polypeptide; low molecular weight effectors that modulate a biological activity of said polypeptide; antisense nucleic acid sequences, catalytic RNA molecules and ribozymes which interact with a nucleic acid sequence that encodes said polypeptide; and combinations and mixtures thereof. 18. A method for microbiological production of vitamin B2 or a precursor or derivative thereof comprising: culturing the host cell of claim 10 under conditions favoring the production of vitamin B2 or the precursor or derivative thereof; and isolating a desired product. 19. The method of claim 18, wherein the host cell is treated with an effector before or during culturing. 20. The method of claim 18, wherein the host cell is a microorganism of the genus Ashbya. 21. A method for modulating production of vitamin B2 or a precursor or derivative thereof in a microorganism of the genus Ashbya comprising treating said microorganism with the polynucleotide of claim 1. 22. A method for modulating production of vitamin B2 or a precursor or derivative thereof in a microorganism of the genus Ashbya comprising treating said microorganism with the polypeptide of claim 7. 23. A method for modulating construction of a cell wall or cytoskeleton of a microorganism of the genus Ashbya comprising culturing said microorganism for microbiological production of vitamin B2 or a precursor or derivative thereof with the polynucleotide of claim 1 or with a polypeptide encoded by said polynucleotide. 24. The host of claim 12, which has a modified cell wall or cytoskeleton construction as compared with a non-transformed cell, wherein said modified cell wall or cytoskeleton construction provides for an increased production of vitamin B2 or a precursor or derivative thereof. 25. The polynucleotide of claim 1, wherein the organism is A. gossypii, S. cerevisiae, or C. maltosa. 26. The polynucleotide of claim 1, wherein the protein is associated with a developmental-specific or environmentally-related change to morphology of the organism. 27. The polynucleotide of claim 2, wherein the protein is derived from a microorganism of A. gossypii, S. cerevisiae, or C. maltosa. 28. The oligonucleotide of claim 5, wherein hybridization is under stringent conditions. 29. The polynucleotide of claim 6, wherein hybridization is under stringent conditions. 30. An isolated polypeptide or fragment thereof encoded by the polynucleotide of claim 6. 31. An isolated polypeptide or fragment thereof which has an amino acid sequence that comprises at least ten consecutive amino acid residues of SEQ ID NO: 2, 3, 5, 6, 7, 9, 11, 13, 14, 16, 18, 20, 22, 24, 25, 27, 29, 31, 32, 33, 35, 37 or 39, or a functional equivalent thereof. 32. The polypeptide of claim 31, which has an activity comparable with a protein selected from the group consisting of a cell wall protein, a serine-threonine protein, a GTPase-activating protein, a protein that has resistance to over expression of actin or contributes to such resistance, a Nuf1p-like protein, a calponin-homologous protein, a protein that is essential for pseudohyphal development, and a protein that interacts with actin. 33. The polypeptide of claim 32, wherein the protein is derived from a microorganism of A. gossypii, S. cerevisiae, or C. maliosa. 34. The host cell of claim 10, wherein biological activity of said protein is reduced or increased. 35. The method of claim 11, wherein modulating comprises an increase or decrease in the functional expression of said protein. 36. The method of claim 13, wherein expressing said polypeptide results in an improved production of vitamin B2 or a precursor or derivative thereof by said microorganism. 37. The method of claim 36, wherein the improved production comprises an increased yield, production or efficiency of production by said microorganism. 38. The method of claim 15, wherein detecting validates said effector target. 39. The method of claim 15, wherein the effector binds to said target. 40. The method of claim 15, further comprising isolating said target. 41. The method of claim 19, wherein the effector is selected from the group consisting of: antibodies or antigen-binding fragments thereof that bind to a polypeptide associated with construction of a cell wall or a cytoskeleton of an organism; polypeptide ligands that are different from said antibodies or antigen-binding fragments and that interact with said polypeptide; low molecular weight effectors that modulate a biological activity of said polypeptide; antisense nucleic acid sequences, catalytic RNA molecules and ribozymes which interact with a nucleic acid sequence that encodes said polypeptide; and combinations and mixtures thereof. 42. The method of claim 21, wherein modulating comprises an increase in rate or amount of the vitamin B2 or the precursor or derivative thereof produced by said microorganism. 43. The method of claim 22, wherein modulating comprises an increase in rate or amount of the vitamin B2 or the precursor or derivative thereof produced by said microorganism. 44. A recombinant cell with a modified cell wall or cytoskeleton construction that provides for an increased production of vitamin B2 or a precursor or derivative thereof as compared with a non-recombinant cell. 45. The recombinant cell of claim 44, which is A. gossypii, S. cerevisiae, or C. maltosa. |
Novel metabolism-associated gene products from ashbya gossypii |
The present invention relates to novel polynucleotides from Ashbya gossypii; to oligonucleotides hybridizing therewith; to expression cassettes and vectors which comprise these polynudeotides; to microorganisms transformed therewith; to polypeptides encoded by these polynucleotides; and to the use of the novel polypeptides and polynucleotides as targets for modulating the metabolic reactions and, in particular, improving vitamin B2 production in microorganisms of the genus Ashbya. |
1. An isolated polynucleotide that can be isolated from Ashbya gossypii and that codes for a protein associated with metabolism of an organism. 2. The polynucleotide of claim 1, which has a structural or functional property of a protein selected from the group consisting of C1-tetrahydrofolate synthase, argininosuccinate synthase, phosphoribosylaminoimidazole succinocarboxamide synthase, fumarate reductase, phosphoenolpyruvate carboxykinase, uroporphyrinogen decarboxylase, siroheme synthase, uroporphyrinogen III synthase, phosphoglycerate kinase, proteinase B inhibitor 2 and cysteine synthase. 3. The polynucleotide of claim 1, comprising: the nucleic acid sequence of SEQ ID NO: 1, 6, 12, 16, 20, 24, 28, 32, 36, 40 or 44; a sequence complementary thereto; or a sequence derived from said nucleic acid sequence or said sequence complementary thereto through degeneracy of the genetic code. 4. The polynucleotide of claim 1, which comprises a nucleic acid containing the sequence of SEQ ID NO: 4, 9, 14, 18, 22, 26, 30, 34, 38, 42 or 47, or a fragment thereof. 5. An oligonucleotide that hybridizes to the polynucleotide of claim 1. 6. An isolated polynucleotide that hybridizes to the oligonucleotide of claim 5, and codes for a gene product derived from a microorganism of the genus Ashbya or a functional equivalent thereof. 7. An isolated polypeptide encoded by the polynucleotide of claim 1 or a fragment thereof. 8. An expression cassette comprising the polynucleotide of claim 1 operatively linked to at least one regulatory sequence. 9. A recombinant vector comprising at least one expression cassette of claim 8. 10. A prokaryotic or eukaryotic host cell transformed with at least one vector of claim 9. 11. The host cell of claim 10, wherein functional expression of said protein is modulated. 12. A The host cell of claim 10, which is a microorganism of the genus Ashbya. 13. A method for microbiological production of vitamin B2 or a precursor or derivative thereof comprising expressing the polynucleotide of claim 1 in a microorganism. 14. A method for recombinant production of the polypeptide of claim 7 comprising expressing said polynucleotide in a microorganism. 15. A method for detecting an effector target for modulating microbiological production of vitamin B2 or a precursor or derivative thereof comprising treating a microorganism capable of the microbiological production of said vitamin B2 or the precursor or derivative thereof with an effector that interacts with a target wherein said target comprises the polypeptide of claim 7 or a nucleic acid that encodes said polypeptide and detecting said effector target. 16. A method for modulating microbiological production of vitamin B2 or a precursor or derivative thereof comprising treating a microorganism capable of the microbiological production of said vitamin B2 or the precursor or derivative thereof with an effector that interacts with a target wherein said target comprises the polypeptide of claim 7 or a nucleic acid that encodes said polypeptide. 17. An isolated effector selected from the group consisting of: antibodies or antigen-binding fragments thereof that bind to the polypeptide of claim 7; polypeptide ligands that are different from said antibodies or antigen-binding fragments and that interact with the polypeptide; low molecular weight effectors that modulate a biological activity of a said polypeptide; antisense nucleic acid sequences, catalytic RNA molecules and ribozymes which interact with a nucleic acid sequence that encodes said polypeptide; and combinations and mixtures thereof. 18. A method for microbiological production of vitamin B2 or a precursor or derivative thereof comprising: culturing the host cell of claim 10 under conditions favoring the production of vitamin B2 or the precursor or derivative thereof; and isolating a desired product. 19. The method of claim 18, wherein the host cell is treated with an effector before or during culturing. 20. The method of claim 18, wherein the host cell is a microorganism of the genus Ashbya. 21. A method for modulating production of vitamin B2 or a precursor or derivative thereof in a microorganism of the genus Ashbya comprising treating said microorganism with the polynucleotide of claim 1. 22. A method for modulating production of vitamin B2 or a precursor or derivative thereof in a microorganism of the genus Ashbya comprising treating said microorganism with the polypeptide of claim 7 and hereby modulating production as desired. 23. A method for modulating a metabolic function of a microorganism of the genus Ashbya comprising culturing said microorganism for microbiological production of vitamin B2 or a precursor or derivative thereof with the polynucleotide of claim 1 or with a polypeptide encoded by said polynucleotide. 24. The host cell of claim 12, which has an improved metabolic regulation or modified metabolic function as compared with an untransformed microorganism, wherein said improved metabolic regulation or modified metabolic function provides for an increased production of vitamin B2 or a precursor or derivative thereof. 25. The polynucleotide of claim 1, wherein the organism is A. gossypii, S. cerevisiae or A. nidulans. 26. The polynucleotide of claim 1, wherein the protein is associated with synthesis or regulation of metabolic enzymes of the organism. 27. The polynucleotide of claim 2, wherein the protein is derived from a microorganism of A. gossypii, S. cerevisiae or A. nidulans. 28. The oligonucleotide of claim 5, wherein hybridization is under stringent conditions. 29. The polynucleotide of claim 6, wherein hybridization is under stringent conditions. 30. An isolated polypeptide or fragment thereof encoded by the polynucleotide of claim 6. 31. An isolated polypeptide or fragment thereof which has an amino acid sequence that comprises at least ten consecutive amino acid residues of SEQ ID NO:2, 3, 5, 7, 8, 10, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, 39, 41, 43, 45, 46 or 48; or a functional equivalent thereof. 32. The polypeptide of claim 31, which has an activity comparable with a protein selected from the group consisting of C1-tetrahydrofolate synthase, argininosuccinate synthasephosphoribosylaminoimidazole succinocarboxamide synthase, fumarate reductase, phosphoenolpyruvate carboxykinase, uroporphyrinogen decarboxylase, siroheme synthase, uroporphyrinogen III synthase, phosphoglycerate kinase, proteinase B inhibitor 2 and cysteine synthase. 33. The polypeptide of claim 32, wherein the protein is derived from a microorganism of A. gossypii, S. cerevisiae, or A. nidulans. 34. The host cell of claim 10, wherein biological activity of said protein is reduced or increased. 35. The method of claim 11, wherein modulating comprises an increase or decrease in the functional expression of said protein. 36. The method of claim 13, wherein expressing said polypeptide results in an improved production of vitamin B2 or a precursor or derivative thereof by said microorganism. 37. The method of claim 36, wherein the improved production comprises an increased yield, production or efficiency of production by said microorganism. 38. The method of claim 15, wherein detecting validates said effector target. 39. The method of claim 15, where the effector binds to said target. 40. The method of claim 15, further comprising isolating said target. 41. The method of claim 19, wherein the effector is selected from the group consisting of: antibodies or antigen-binding fragments thereof that bind to a polypeptide associated with A. gossypii metabolism; polypeptide ligands that are different from said antibodies or antigen-binding fragments and that interact with said polypeptide; low molecular weight effectors that modulate a biological activity of said polypeptide; antisense nucleic acid sequences, catalytic RNA molecules and ribozymes which interact with a nucleic acid sequence that encodes said polypeptide; and combinations and mixtures thereof. 42. The method of claim 21, wherein modulating comprises an increase in rate or amount of the vitamin B2 or the precursor or derivative thereof produced by said microorganism. 43. The method of claim 22, wherein modulating comprises an increase in rate or amount of the vitamin B2 or the precursor or derivative thereof produced by said microorganism. 44. A recombinant cell with an improved metabolic regulation or modified metabolic function that provides for an increased production of vitamin B2, or a precursor or derivative thereof, as compared with a non-recombinant cell. 45. The recombinant cell of claim 37, which is A. gossypii, S. cerevisiae or A. nidulans. |
Method for manucfacturing an optical device having a cavity |
A method of manufacturing an optical device, by forming a cavity (5) of a desired shape in an optical substrate (3) comprising the steps of irradiating, with radiation from a laser source (1), a mask (2) whose surface is patterned in accordance with the desired shape of the cavity (5); and projecting the radiation transmitted through the mask (2) onto the substrate (3) such that substrate material is ablated from an area thereof exposed to the radiation, thereby forming the required cavity (5) in such a way that at least one sidewall of the cavity has a desired inclination relative to a chosen axis. |
1-38. cancel 39. A method for use in manufacturing an optical device which method comprises the steps of: forming a cavity of a desired shape in an optical substrate by irradiating, with radiation from a laser source, a mask whose surface is patterned in accordance with the desired shape of the cavity; and projecting the radiation transmitted through the mask onto the substrate such that the substrate material is ablated from an area thereof exposed to the radiation, thereby forming the required cavity, in such a way that at least one sidewall of the cavity has a desired inclination relative to a chosen axis. 40. A method as claimed in claim 39, wherein the fluence of the laser radiation projected onto the substrate is controlled so as to produce the desired inclination of the or each side wall. 41. A method as claimed in claim 40, wherein the laser is controlled to emit pulsed radiation at a fluence of 8 J/cm2. 42. A method as claimed in claim 40, wherein the laser is controlled to emit pulsed radiation at a fluence greater than 8 J/cm2. 43. A method as claimed in claim 39, wherein the focus of the ablating radiation projected onto the substrate is selected and/or adjusted such that the desired inclination of the or each sidewall is achieved. 44. A method as claimed in claim 43, wherein the position of the optical substrate relative to the ablating radiation is modulated, by moving the optical substrate up or down relative to the ablating radiation. 45. A method as claimed in claim 39, wherein the radiation that is used to irradiate the mask subjected to demagnification prior to being projected onto the substrate. 46. A method as claimed in claim 45, wherein the demagnification ratio is chosen to ensure that the energy density of the ablating laser radiation is greater in magnitude than the ablation threshold of the substrate material. 47. A method as claimed in claim 39, wherein the optical substrate is in the form of an optical fibre. 48. A method as claimed in claim 47, wherein the optical fibre is made of plastics material. 49. A method as claimed in claim 39, wherein the optical substrate comprises silica. 50. A method as claimed in claim 39, wherein the optical substrate comprises sapphire. 51. A method as claimed in claim 39, wherein the optical substrate comprises material that is suitable for optical applications. 52. A method as claimed in claim 51, wherein the material is chalcogenide or ceramic. 53. A method as claimed in claim 39, wherein the cavity is formed in a bulk optical substrate and is suitable for use in optical circuits. 54. A method as claimed in claim 39, wherein the cavity formed is suitable for use as a Fabry-Perot etalon. 55. A method as claimed in claim 39, wherein the cavity formed is suitable for use in a Mach Zehnder device. 56. A method as claimed in claim 39, wherein the cavity formed is suitable for use in waveguiding structures. 57. A method as claimed in claim 39, wherein, after forming the cavity, material having selected characteristics is inserted into the cavity to form an optode that is sensitive to external perturbation, the sensitivity of the said optode being determined by the characteristics of the material inserted into the cavity. 58. A method as claimed in claim 57, wherein the inserted material reacts to the presence of a chemical compound. 59. A method as claimed in claim 57, wherein the inserted material reacts to a change in pH level. 60. A method as claimed in claim 57, wherein the inserted material reacts to a change in temperature. 61. A method as claimed in claim 57, wherein the inserted material reacts to light. 62. A method as claimed in claim 39, wherein the laser is an excimer laser that is controlled to emit radiation of excimer wavelength. 63. A method as claimed in claim 39, wherein the laser is controlled to emit radiation of 157 nm wavelength. 64. A method as claimed in claim 39, wherein the laser is controlled to emit radiation of 193 nm wavelength. 65. A method as claimed in claim 39, wherein the laser is controlled to emit radiation of 248 nm wavelength. 66. A method as claimed in claim 39, wherein the laser is controlled to emit pulsed radiation between 193 nm and 248 nm wavelengths. 67. A method as claimed in claim 39, wherein the laser is a deep UV laser that is controlled to emit radiation of deep UV wavelengths. 68. An apparatus for manufacturing an optical device by forming a cavity of a desired shape in an optical substrate, which apparatus comprises a mask whose surface is patterned in accordance with the desired shape of the cavity and means for projecting radiation from a laser source onto a substrate through the mask, the means for projecting operable in such a way that substrate material is ablated from an area thereof exposed to in such a way that at least one sidewall of the cavity has a desired inclination relative to a chosen axis. 69. An apparatus as claimed in claim 68, wherein a condenser lens is used to demagnify the laser radiation that is used to irradiate the mask. 70. An apparatus as claimed in claim 68, wherein the demagnification ratio is chosen to ensure that the energy density of the ablating laser radiation is greater in magnitude than the ablation threshold of the substrate material. 71. An apparatus as claimed in claim 68, wherein the means for projecting includes a doublet that focuses the radiation transmitted through the mask onto the optical substrate. 72. An apparatus as claimed in claim 68, wherein the means for projecting includes a mirror that projects the radiation transmitted through the mask onto the doublet. 73. An apparatus as claimed in claim 68, wherein the substrate is mounted on a micropositioner. 74. An apparatus as claimed in claim 73, wherein the micropositioner allows positioning of the substrate relative to the radiation. |
1-(2,5'-Anhydro-lyxofuranosyl) thymines for the synthesis of radiomarked fluoro-3 deoxynucleotides |
What is described are compounds wherein R represents Br, I or R1—SO3, where R1 is an unsubstituted or substituted C1-C5-alkyl group, or an unsubstituted or substituted phenyl group; X is O or NR″, where R″ is a usual protective group for N; and R′ represents hydrogen, a halogen, such as F, Cl, and Br, a substituted or unsubstituted C1-C7-alkyl group, such as methyl and ethyl, a substituted or unsubstituted C2-C7-alkenyl group, or a substituted or unsubstituted C2-C7-alkynyl group. |
1. A compound of the following formula wherein R represents Br, I or R1—SO3, wherein R1 is an unsubstituted or substituted C1-C5-alkyl group, or an unsubstituted or substituted phenyl group; X is O or NR″, wherein R″ is a usual protective group for N; and R′ represents hydrogen, halogen, a respectively substituted or unsubstituted C1-C7-alkyl group, a respectively substituted or unsubstituted C2-C7-alkenyl group, or a respectively substituted or unsubstituted C2-C7-alkynyl group. 2. The compound of claim 1, wherein the substituent on the substituted C1-C5-alkyl group is an electron-withdrawing group. 3. The compound of claim 1, wherein the substituent on the substituted phenyl group is C1-C5-alkyl or an electron-withdrawing group. 4. The compound of claim 1, wherein R1—SO3 comprises methane sulfonyl, 4-nitrophenylsulfonyl or p-toluene sulfonyl or trifluoromethane sulfonyl. 5. The compound of claim 1, wherein the compound is 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuranosyl)-thymine, 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuonosyl)-uridine or 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuranosyl)-cytidine. 6. A method for producing the compound of claim 1 comprising the step of introducing a radical R into a second compound having the following formula wherein R is Br, I, or a R1—SO3 group where R1 is an unsubstituted or substituted C1-C5-alkyl group or an unsubstituted or substituted phenyl group; X is O or a NR″ group, where R″ is a usual protective group for N; and R′ is hydrogen, a halogen, a substituted or unsubstituted C1-C7-alkyl group, a substituted or unsubstituted C2-C7-alkenyl group, or a substituted or unsubstituted C2-C7-alkynyl. 7-8. (canceled) 9. The compound of claim 2, wherein the R1—SO3 group comprises methane sulfonyl, 4-nitrophenylsulfonyl, p-toluene sulfonyl, or trifluoromethane sulfonyl. 10. The compound of claim 3, wherein the R1—SO3 group comprises methane sulfonyl, 4-nitrophenylsulfonyl, p-toluene sulfonyl, or trifluoromethane sulfonyl. 11. The compound of claim 2 wherein the compound is selected from the group consisting of 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuranosyl)-thymine, 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuonosyl)-uridine, and 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuranosyl)-cytidine. 12. The compound of claim 9 wherein the compound is selected from the group consisting of 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuranosyl)-thymine, 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuonosyl)-uridine, and 1-(3′-O-mesyl-2,5′-anhydro-β-D-lyxofuranosyl)-cytidine. 13. The method of claim 6 wherein the substituted C1-C5-alkyl group comprises an electron withdrawing group. 14. The method of claim 13 wherein the R1—SO3 group comprises methane sulfonyl, 4-nitrophenylsulfonyl, p-toluene sulfonyl, or trifluoromethane sulfonyl. 15. The method of claim 6 wherein the substituted phenyl group comprises a C1-C5-alkyl group or an electron withdrawing group. 16. The method of claim 6 wherein the introducing step comprises the reaction of the second compound with a third compound having the formula R1—SO2Hal where R1 is an unsubstituted or substituted C1-C5-alkyl group or an unsubstituted or substituted phenyl group; and Hal is a halogen. 17. The method of claim 6 wherein Hal is chloride. 18. A method of making 3′-[18F] fluoro-3′-deoxythymidine comprising the step of inserting a nucleophile at the 3′ position of the compound of claim 1. 19. The method of claim 18 wherein the nucleophile is 18F. |
<SOH> SUMMARY OF THE INVENTION <EOH>In the first aspect, this invention features a compound of the following formula: wherein R represents Br, I or R 1 —SO 3 , wherein R 1 is an unsubstituted or substituted C 1 -C 5 -alkyl group, or an unsubstituted or substituted phenyl group; X is O or NR″, wherein R″ is a usual protective group for N; and R′ represents hydrogen, halogen, such as F, Cl or Br, a respectively substituted or unsubstituted C 1 -C 7 -alkyl group, a respectively substituted or unsubstituted C 2 -C 7 -alkenyl group, or a respectively substituted or unsubstituted C 2 -C 7 -alkynyl group. In the second aspect, this invention features a method for producing the compound of claim 1 comprising the step of introducing a radical R into a second compound having the following formula: wherein R is Br, I, or a R 1 —SO 3 group where R 1 is an unsubstituted or substituted C 1 -C 5 -alkyl group or an unsubstituted or substituted phenyl group; X is O or a NR″ group, where R″ is a usual protective group for N; and R′ is hydrogen, a halogen, a substituted or unsubstituted C 1 -C 7 -alkyl group, a substituted or unsubstituted C 2 -C 7 -alkenyl group, or a substituted or unsubstituted C 2 -C 7 -alkynyl. In the third aspect, this invention features a method of making 3′-[ 18 F] fluoro-3′-deoxythymidine comprising the step of inserting a nucleophile at the 3′ position of the compound of claim 1 . detailed-description description="Detailed Description" end="lead"? |
Stacked chip assembly with stiffening layer |
A microelectronic subassembly 210 includes a substrate 215 having a top surface 216 and at least one peripheral region 219, a microelectronic element 201 mounted over the substrate 215, a plurality of leads 218, 222 electrically connected to the microelectronic element 201 having outer ends overlying the at least one peripheral region 219 of the substrate 215, and vertical conductors 208 electrically connected with the outer ends of the leads. The subassembly includes an encapsulant layer 204 provided over the top surface 216 of the substrate 215 and around the microelectronic element 201 and the vertical conductors 208 for stiffening the substrate 215 at the at least one peripheral region 219 of the substrate for facilitating handling and testing of the subassembly. |
1. A microelectronic subassembly comprising: a substrate having a top surface and at least one peripheral region; a microelectronic element mounted over the substrate; a plurality of leads electrically connected to the microelectronic element having outer ends overlying the at least one peripheral region of the substrate; vertical conductors electrically connected with the outer ends of the leads; an encapsulant layer provided over the top surface of the substrate and around the microelectronic element and the vertical conductors for stiffening the substrate at the at least one peripheral region of the substrate. 2. The subassembly as claimed in claim 1, wherein the substrate is flexible. 3. The subassembly as claimed in claim 2, wherein the flexible substrate comprises a dielectric material. 4. The subassembly as claimed in claim 2, wherein the flexible substrate comprises a polymeric material. 5. The subassembly as claimed in claim 1, wherein the microelectronic element is a semiconductor chip having a front face with contacts and a back face remote therefrom. 6. The subassembly as claimed in claim 5, wherein the front face of the semiconductor chip faces the top surface of the substrate and the leads are connected to the chip contacts. 7. The subassembly as claimed in claim 5, wherein the back face of the semiconductor chip faces the top surface of the substrate, and wherein the subassembly further comprises conductive wires having first ends connected to the chip contacts and second ends connected to the leads. 8. The subassembly as claimed in claim 1, further comprising a compliant layer disposed between the microelectronic element and the substrate so as to permit relative movement of the microelectronic element and the substrate during thermal cycling of the subassembly. 9. The subassembly as claimed in claim 8, wherein the compliant layer comprises a plurality of compliant pads spaced from one another, the spaced compliant pads defining channels therebetween. 10. The subassembly as claimed in claim 9, wherein the stiffening encapsulant layer is disposed in the channels between the compliant pads. 11. The subassembly as claimed in claim 1, wherein the stiffening encapsulant layer is selected from the group consisting of flexibilized epoxies, silicone elastomers, glass sheet, glass-filled epoxy, ceramic materials and plastic. 12. The subassembly as claimed in claim 1, wherein the substrate comprises a plurality of dielectric layers, and wherein a plurality of layers of conductive traces extend through the substrate. 13. The subassembly as claimed in claim 1, wherein the substrate includes a conductive metal layer adapted to function as a power plane. 14. The subassembly as claimed in claim 1, wherein the substrate includes a conductive metal layer adapted to function as a ground plane. 15. A microelectronic subassembly comprising: a substrate having a top surface, a bottom surface and at least one peripheral region; a microelectronic element mounted over the top surface of the substrate; a plurality of leads electrically connected to the microelectronic element having outer ends overlying the at least one peripheral region of the substrate; vertical conductors electrically connected with the outer ends of the leads; an encapsulant layer provided over one of the surfaces of the substrate and around the vertical conductors for stiffening the at least one peripheral region of the substrate. 16. The subassembly as claimed in claim 15, wherein the vertical conductors are disposed over the bottom surface of the substrate. 17. A microelectronic assembly including a plurality of microelectronic subassemblies, each the subassembly comprising: a substrate having at least one peripheral region; a microelectronic element mounted over the substrate; a plurality of leads electrically connected to the microelectronic element having outer ends overlying the at least one peripheral region of the substrate; vertical conductors electrically connected with the outer ends of the leads; an encapsulant layer provided over a surface of the substrate and around the vertical conductors for stiffening the substrate at the at least one peripheral region of the substrate, wherein the microelectronic subassemblies are stacked one atop another and electrically interconnected through the vertical conductors. 18. The microelectronic assembly as claimed in claim 17, wherein the substrates are flexible dielectric substrates. 19. The microelectronic assembly as claimed in claim 17, wherein the vertical conductors form interconnections between leads of different subassemblies. 20. The microelectronic assembly as claimed in claim 17, wherein the vertical conductors comprise metallic masses. 21. The microelectronic assembly as claimed in claim 20, wherein each the substrate has a central region aligned with the microelectronic element mounted to such flexible substrate and a plurality of peripheral regions extending outwardly at a plurality of edges of each such substrate. 22. The microelectronic assembly as claimed in claim 17, wherein the microelectronic element is a semiconductor chip having a front face with contacts and a back face remote therefrom. 23. The microelectronic assembly as claimed in claim 22, wherein the front face of the semiconductor chip faces a top surface of the substrate and the leads are connected to the chip contacts. 24. The microelectronic assembly as claimed in claim 22, wherein the back face of the semiconductor chip faces a top surface of the substrate and wherein the subassembly further comprises conductive wires having first ends connected to the chip contacts and second ends connected to the leads. 25. The microelectronic assembly as claimed in claim 17, further comprising a compliant layer disposed between the microelectronic element and the substrate so as to permit relative movement of the microelectronic element and the substrate during thermal cycling of the subassembly. 26. The microelectronic assembly as claimed in claim 25, wherein the compliant layer comprises a plurality of compliant pads spaced from one another for defining channels therebetween. 27. The microelectronic assembly as claimed in claim 26, wherein the stiffening encapsulant layer is disposed in the channels between the compliant pads. 28. The microelectronic assembly as claimed in claim 17, wherein the stiffening encapsulant layer is provided around outer edges of the microelectronic element. |
<SOH> BACKGROUND ART <EOH>In certain preferred embodiments of commonly assigned U.S. Pat. No. 5,861,666, the disclosure of which is hereby incorporated by reference herein, a stacked microelectronic assembly includes a plurality of chip and interposer subassemblies. Each subassembly has a circuitized interposer and a semiconductor chip, one face of which confronts a surface of the interposer. Each interposer has at least one peripheral region projecting laterally beyond an edge of the chip mounted to the interposer. Each interposer also includes a plurality of leads electrically connected to contacts on the chip face that extend to the peripheral region of the interposer. The subassemblies are stacked one atop another in a generally vertical configuration so that the chips overlie one another and so that the projecting portions of the interposers overlie one another. The subassemblies are electrically connected one to another by vertical conductors extending alongside the chips and interconnecting the leads of the various interposers at their peripheral regions. FIG. 1A shows a microelectronic assembly 100 disclosed in U.S. Pat. No. 5,861,666 made from a number N of prefabricated subassemblies, comprising N−1 subassemblies 110 and base subassembly 120 . Subassembly 110 comprises a semiconductor chip 101 having opposed surfaces 102 and 103 , one surface having exposed electrical contacts (not shown), and an interposer 115 having a first surface 116 and a second surface 117 . Interposer 115 is preferably a flexible sheet-like element. Chip 101 is mounted on first surface 116 of interposer 115 and the contacts are electrically connected to conductors (not shown) on a surface of interposer 115 . Fan-out connectors 111 , such as high-melting temperature solder balls, are affixed to the second surface 117 of the interposer 115 (the side opposite chip 101 ). In each subassembly 110 , the electrical connections between chip 101 and interposer 115 are encapsulated in a material 104 such as an epoxy or elastomer, which fills the gaps between chip 101 and surface 116 and partially surrounds the chip. The base subassembly 120 comprises an encapsulated microelectronic element 101 , encapsulant 104 and interposer 125 similar to those described above for subassembly 110 . A plurality of joining units 121 are affixed to second surface 127 (the side opposite from microelectronic element 101 ) of interposer 125 . Base subassembly 120 is adapted to serve as the bottom-most unit of stack 100 and may be affixed directly to an external element such as a printed circuit board or a second microelectronic assembly. When subassemblies 110 and 120 are stacked, fan-out connectors 111 electrically interconnect the subassemblies within the stack, thereby acting as vertical conductors. To allow stacking, fan-out connectors 111 of each subassembly 110 must be positioned outside of the region of interposer 115 of the next lower subassembly occupied by chip 101 and encapsulant 104 . Typically, this requirement results in fan-out connectors 111 of each subassembly 110 being disposed in a peripheral region of interposer 115 which is not covered by encapsulant 104 on first surface 116 . This peripheral region, therefore, remains quite flexible, which may lead to difficulties in handling the subassemblies and in bonding the fan-out connectors when the subassemblies are stacked. The subassemblies can be made more rigid by dispensing additional encapsulant as shown in FIG. 2A . Increasing the area covered by encapsulant reduces the area available for the fan-out connectors, thereby decreasing the number of rows of connectors that may be used and resulting in poor utilization of the interposer. The problems arising from excessive flexing of the peripheral regions are even more pronounced where multiple rows of fan-out connectors or joining units are employed ( FIG. 2B ) and where a differently sized die is used in the upper subassemblies ( FIG. 2C ). In spite of the advances set forth in U.S. Pat. No. 5,861,666, there remains a need for a stackable microelectronic subassembly that is easily handled and tested during making of a stacked microelectronic assembly. There also remains a need for a stackable microelectronic subassembly having a stiffening layer for stiffening peripheral regions of the subassembly. The present invention addresses these needs. |
<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with certain preferred embodiments of the present invention, a microelectronic subassembly includes a substrate, such as a flexible dielectric substrate, having a top surface and at least one peripheral region, a microelectronic element mounted over the substrate, and a plurality of leads electrically connected to the microelectronic element having outer ends overlying the at least one peripheral region of the substrate. The subassembly also desirably includes vertical conductors, such as solder balls, electrically connected with the outer ends of the leads, and an encapsulant layer provided over the top surface of the substrate and around the microelectronic element and the vertical conductors for stiffening the substrate at the at least one peripheral region of the substrate. In certain embodiments, the substrate may be a flexible substrate made of a polymeric material. In certain preferred embodiments, the microelectronic element is a semiconductor chip having a front face with contacts and a back face remote therefrom. The semiconductor chip may be assembled with the substrate so that the front face of the semiconductor chip faces the top surface of the substrate with the leads connected to the chip contacts. In other preferred embodiments, the semiconductor chip may be assembled with the substrate so that the back face of the semiconductor chip confronts the top surface of the substrate and the front face faces away from the substrate. In this particular embodiment, the subassembly may include conductive wires having first ends connected to the chip contacts and second ends connected to the leads. The subassembly also preferably includes a compliant layer disposed between the microelectronic element and the substrate so as to permit relative movement of the microelectronic element and the substrate during thermal cycling of the subassembly. The compliant layer may include a plurality of compliant pads spaced from one another for defining channels or gaps therebetween. The stiffening encapsulant layer may be disposed in the channels between the compliant pads. The stiffening encapsulant layer is preferably selected from the group consisting of flexibilized epoxies, silicone elastomers, glass sheet, glass-filled epoxies, ceramic materials and plastics. Although the present invention is not limited by any particular theory of operation, it is believed that providing a stiffening layer that surrounds the vertical conductors in the peripheral region of the substrate will enhance handling and testability of the subassembly by providing sufficient stiffness in the peripheral region of the subassembly. Absent the stiffener layer, the peripheral region of the substrate may flex, bend or flop to an undesirable degree during testing and handling. In certain preferred embodiments, the substrate includes a plurality of dielectric layers, and a plurality of layers of conductive traces extending through the substrate. The substrate may also include a conductive metal layer adapted to function as a power plane. In yet other preferred embodiments, the substrate may also include a conductive metal layer adapted to function as a ground plane. In other preferred embodiments of the present invention, a microelectronic subassembly includes a substrate having a top surface, a bottom surface and at least one peripheral region, a microelectronic element mounted over the top surface of the substrate, and a plurality of leads electrically connected to the microelectronic element, the leads having outer ends overlying the at least one peripheral region of the substrate. The microelectronic subassembly also preferably includes vertical conductors electrically connected with the outer ends of the leads, and an encapsulant layer provided over one of the surfaces of the substrate and around the vertical conductors for stiffening the at least one peripheral region of the substrate. In certain preferred embodiments, the vertical conductors are disposed over the bottom surface of the substrate and the stiffening encapsulant layer is provided over the bottom surface of the substrate and around the vertical conductors. In yet further preferred embodiments of the present invention, a microelectronic assembly includes a plurality of microelectronic subassemblies, each subassembly having a substrate with at least one peripheral region, a microelectronic element mounted over the substrate, a plurality of leads electrically connected to the microelectronic element having outer ends overlying the at least one peripheral region of the substrate, vertical conductors electrically connected with the outer ends of the leads, and an encapsulant layer provided over a surface of the substrate and around the vertical conductors for stiffening the substrate at the least one peripheral region of the substrate. The microelectronic subassemblies are stacked one atop another and electrically interconnected through the vertical conductors. The vertical conductors preferably form electrical interconnections between leads of different subassemblies. The vertical conductors preferably include metallic masses, such as solder balls. The microelectronic elements of the assembly may vary in size. In certain preferred embodiments, each of the substrates has a central region aligned with the microelectronic element mounted thereto and a plurality of peripheral regions extending outwardly at a plurality of edges of the substrate. These and other preferred embodiments of the present invention will be described in more detail below. |
Device for closing a container et for drawing a fluid product |
The device comprises: a piece fixed to the container, having a lateral fluid output opening and a passage allowing the entry of air; a movable piece comprising a tube having a lateral fluid output opening, the tube being movable rotationally in the fixed piece and in axial translation between a maximum pushing-in position and an extraction position where the lateral openings can be brought into coincidence by rotation of the movable piece. The movable piece comprises an internal skirt making it possible to channel the fluid towards the output opening in order to prevent leakages through the air entry passage. The fixed piece comprises means for guiding the displacement of the movable piece with respect to the fixed piece from the maximum pushing-in position to the extraction position with coincidence of the openings. |
1. A device for stoppering a container and drawing off a fluid product contained in said container, comprising: a fixed piece (2) comprising a part (4) for fixing to the container and a pouring part (5) of general cylindrical shape, continuing said fixing part (4) towards the outside of the container, the pouring part (5) being open at its two axial ends and having a lateral fluid output opening (20) and means (22) defining a passage allowing the entry of air into the device during pouring of the fluid; a movable piece (3) comprising a transverse end wall (28) from which there project in the same direction on the one hand a tube (29) of general cylindrical shape, open at its free axial end and having at least one lateral fluid output opening (32, 32′), and on the other hand an external skirt (30) making it possible to grip and operate the movable piece (3) from the outside, the tube (29) being mounted with a tight fit in the pouring part (5) of the fixed piece (2) so that the movable piece (3) is: movable rotationally in the fixed piece (2); and movable in axial translation with respect to the fixed piece (2), the fixed piece (2) and the movable piece (3) comprising first means (11, 34, 36, 37) designed for defining a first axial position of the movable piece (3) with respect to the fixed piece (2), referred to as the maximum pushing-in position, in which the lateral openings (20, 32, 32′) in the two pieces (2, 3) are offset axially so that it is not possible for them to be brought into coincidence, and second means (17,18, 33) designed for defining a second axial position of the movable piece (3) with respect to the fixed piece (2), referred to as the extraction position, in which the lateral openings (20, 32, 32′) in the two pieces (2, 3) can be brought into coincidence by rotation of the movable piece (3); characterised in that the movable piece (3) also comprises an internal skirt (31) projecting from the transverse wall (28) in the same direction as the tube (29), between said tube (29) and the external skirt (30), said internal skirt (31) having an axial length such that, when the movable piece (3) is in the extraction position, the free end of the internal skirt (31) is situated facing the pouring part (5) of the fixed piece (2), so that, during pouring of the fluid, the fluid contained in the container cannot escape through the passage allowing the entry of air but is channelled, in the annular space contained between the tube (29) and the internal skirt (31), towards the fluid output opening (20) in the fixed piece (2). 2. A device according to claim 1, characterised in that the pouring part (5) comprises a prominence (22) projecting towards the outside, substantially diametrically opposite the fluid output opening (20), said prominence (22) defining a passage allowing the entry of air into the device (1), when the movable piece (3) is in the extraction position and during pouring of the fluid. 3. A device according to claim 1, characterised in that the fixed piece (2) comprises: third means (23, 26) intended to cooperate with complementary means (38) provided on the movable piece (3), so as to limit to a reduced value the amplitude of the rotational movement of the movable piece (3) with respect to the fixed piece (2) in the two directions (R1, R2) when the movable piece (3) is in the maximum pushing-in position, and to permit the axial displacement of said movable piece (3) towards the extraction position; fourth means (23, 25, 27) intended to cooperate with complementary means (38) provided on the movable piece (3), so as to allow the movable piece (3) to be kept in the extraction position and to limit, in this position, the amplitude of the rotational movement of the movable piece (3) with respect to the fixed piece (2) between a position where the lateral openings (20, 32, 32′) in the two pieces (2, 3) coincide perfectly and a position where no area of the opening (32, 32′) in the movable piece (3) is in coincidence with an area of the opening (20) in the fixed piece (2), so that the displacement of the movable piece (3) with respect to the fixed piece (2) from the maximum pushing-in position to the extraction position with coincidence of the openings (20, 32, 32′) is guided and facilitated. 4. A device according to claim 1, characterised in that the internal skirt (31) comprises at least one rib (38, 38′) projecting towards the axis of the tube (29), and in that the fixed piece (2) comprises at least one limit stop (23) projecting towards the outside of the pouring part (5) of the fixed piece (2), the rib (38, 38′) being intended to cooperate with the limit stop (23) so as to limit the amplitude of the rotational movement of the movable piece (3) with respect to the fixed piece (2) in a first direction (R1), when the movable piece (3) is in the maximum pushing-in position or in the extraction position. 5. A device according to claim 4, characterised in that the rib (38) projecting from the internal skirt (31) extends over substantially the entire axial height of said internal skirt (31). 6. A device according to claim 4, characterised in that the tube (29) comprises two diametrically opposite fluid output openings (32, 32′), and in that the internal skirt (31) comprises at least one rib (38, 38′) situated at substantially 90° from each opening (32, 32′). 7. A device according to claim 4, characterised in that the limit stop (23) projecting from the pouring part (5) is situated towards the free end (24) of said pouring part (5), the axial height of said limit stop (23) being small compared with the axial height of the pouring part (5). 8. A device according to claim 4, characterised in that the limit stop (23) is substantially diametrically opposite the lateral fluid output opening (20). 9. A device according to claim 1, characterised in that the pouring part (5) comprises a ramp (25) which is substantially flat and orthogonal to the axis of the pouring part (5), projecting towards the outside of the pouring part (5) and extending over part of the periphery of the pouring part (5), said ramp (25) being situated towards the free end (24) of said pouring part (5), but at a distance therefrom, and being intended to prevent the movable piece (3) from being displaced from its extraction position towards its maximum pushing-in position. 10. A device according to claim 4, characterised in that the distance between the free end (24) of the pouring part (5) and the ramp (25) is substantially equal to the axial height of the limit stop (23) projecting from the pouring part (5). 11. A device according to claim 4, characterised in that a first end of the ramp (25) is situated in proximity to, but at a distance from, the limit stop (23) projecting from the pouring part (5), in a second direction (R2) opposite to the first direction (R1), so as to limit the amplitude of the rotational movement of the movable piece (3) with respect to the fixed piece (2) in said second direction (R2), when the movable piece (3) is in the maximum pushing-in position. 12. A device according to claim 11, characterised in that the ramp (25) extends from its first end in the second direction (R2) to a second end, said second end of the ramp (25) being continued by a wall (27) substantially parallel to the axis of the pouring part (5) and directed towards the free end (24) of the pouring part (5), said wall (27) being intended to cooperate with a rib (38) of the movable piece (3) so as to limit the amplitude of the rotational movement of the movable piece (3) with respect to the fixed piece (2) in the second direction (R2), when the movable piece (3) is in the extraction position. 13. A device according to claim 9, characterised in that the ramp (25) extends over substantially 90° of angle. 14. A device according to claim 4, characterised in that, when the movable piece (3) is in the maximum pushing-in position, the rib (38) is placed between the limit stop (23) projecting from the pouring part (5) of the fixed piece (2) and the first end of the ramp (25). 15. A device according to claim 4, characterised in that, when the movable piece (3) is in the extraction position, the rib (38) is situated between the limit stop (23) projecting from the pouring part (5) of the fixed piece (2)—a position in which the rib (38) is not in contact with the ramp (25) and where no area of the opening (32, 32′) in the movable piece (3) is in coincidence with an area of the opening (20) in the fixed piece (2)—and the wall (27) continuing the second end of the ramp (25)—a position in which the rib (38) is in contact with the ramp (25) and where the lateral openings (20, 32, 32′) in the two pieces (2, 3) coincide. 16. A device according to claim 1, characterised in that the fixed piece (2) comprises at least one internal flange (17) defining a groove (18) in which a flange (33) projecting towards the outside of the tube (29) of the movable piece (3) is able to be engaged, so as to keep the movable piece (3) axially in its extraction position corresponding to the second position. 17. A device according to claim 16, characterised in that the internal flange (17) extends over two diametrically opposite arcs each extending over approximately 90°. 18. A device according to claim 1, characterised in that the first means comprise a tamper-resistant band (34) which, as long as it is not torn off, connects the external skirt (30) to the fixed piece (2) and keeps the movable piece (3) in an axial maximum pushing-in position, corresponding to said first axial position, and in a defined angular position, and in that, after tearing off of said tamper-resistant band (34) and translational movement of the movable piece (3) with respect to the fixed piece (2) towards said second axial position, the second means permit a rotation of the movable piece (3) with respect to the fixed piece (2) in order to make it possible to bring the lateral openings (20, 32, 32′) in the two pieces (2, 3) selectively into coincidence with a view to the dispensing of the product. 19. A dispenser according to claim 1, characterised in that the fixed piece (2) is fixed by screws to the neck of the container, and in that the fixed piece (2) comprises, on its fixing part (4), a tamper-resistant ring (13) cooperating by latching with the neck. |
Method and device for delivery of high molecular weight substances |
A method and device for administration of a high molecular weight protein into the intradermal space. |
1. A method for directly delivering a high molecular weight substance into an intradermal space within mammalian skin comprising administering the substance through at least one hollow needle having an outlet with an exposed height between 0 and 1 mm, said outlet being inserted into the skin to a depth of between 0.3 mm and 2 mm, such that delivery of the substance occurs at a depth between 0.3 mm and 2 mm. 2. The method according to claim 1 wherein the delivered substance has improved pharmacokinetics compared to pharmacokinetics after subcutaneous injection. 3. The method of claim 1 wherein the administration is through at least one small gauge hollow needle. 4. The method of claim 1 wherein the needle has an outlet with an exposed height between 0 and 1 mm. 5. The method of claim 1 wherein injecting comprises inserting the needle to a depth which delivers the substance at least about 0.3 mm below the surface to no more than about 2 mm below the surface. 6. The method of claim 1 wherein administering comprises inserting the needle into the skin to a depth of at least about 0.3 mm and no more than about 2 mm. 7. The method of claim 2 wherein the improved pharmacokinetics is increased bioavailability of the substance. 8. The method of claim 2 wherein the improved pharmacokinetics is a decrease in Tmax. 9. The method of claim 2 wherein the improved pharmacokinetics is an increase in Cmax. 10. The method of claim 2 wherein the improved pharmacokinetics is a decrease in Tlag. 11. The method of claim 2 wherein the improved pharmacokinetics is enhanced absorption rate. 12. The method of claim 1 wherein the substance is administered over a time period of not more than ten minutes. 13. The method of claim 1 wherein the substance is administered over a time period of greater than ten minutes. 14. The method of claim 1 wherein the substance is a protein. 15. The method of claim 1 wherein the substance is administered at a rate between 1 nL/min. and 200 mL/min. 16. The method of claim 1 wherein said substance is a hormone. 17. The method of claim 14 wherein said protein is a receptor protein or antibody. 18. The method of claim 17 wherein said protein is etanercept. 19. The method of claim 14 wherein said protein is a fusion protein. 20. The method of claim 1 wherein said substance has a molecular weight of at least 40,000 kD. 21. The method of claim 20 wherein said substance has a molecular weight of at least 100,000 kD. 22. The method of claim 21 wherein said substance has a molecular weight of at least 150,000 kD. 23. The method of claim 1 wherein said substance is a nucleic acid. 24. The method of claim 1 wherein said substance is hydrophobic. 25. The method of claim 1 wherein said substance is hydrophilic. 26. The method of claim 1 wherein the needle(s) are inserted substantially perpendicularly to the skin. 27. The method of claim 1 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed. 28. A method of administering a pharmaceutical substance comprising injecting or infusing the substance intradermally through one or more microneedles having a length and outlet suitable for selectively delivering the substance into the dermis to obtain absorption of the substance in the dermis. 29. The method of claim 28 wherein absorption of the substance in the dermis produces improved systemic pharmacokinetics compared to subcutaneous administration. 30. The method of claim 29 wherein the improved pharmacokinetics is increased bioavailability. 31. The method of claim 29 wherein the improved pharmacokinetics is decreased Tmax. 32. The method of claim 29 wherein the improved pharmacokinetics is an increase in Cmax. 33. The method of claim 29 wherein the improved pharmacokinetics is a decrease in Tlag. 34. The method of claim 29 wherein the improved pharmacokinetics is an enhanced absorption rate. 35. The method of claim 28 wherein the length of the microneedle is from about 0.5 mm to about 1.7 mm. 36. The method of claim 28 wherein the microneedle is 30 gauge or narrower. 37. The method of claim 28 wherein the microneedle has an outlet of from 0 to 1 mm. 38. The method of claim 28 wherein the microneedle is configured in a delivery device which positions the microneedle perpendicular to skin surface. 39. The method of claim 28 wherein the microneedle needle is contained in an array of microneedles needles. 40. The method of claim 39 wherein the array comprises 3 microneedles. 41. The method of claim 39 wherein the array comprises 6 microneedles. 42. The method of claim 28 wherein the substance has a molecular weight of at least 40 kD. 43. The method of claim 42 wherein the substance is a protein. 44. The method of claim 43 wherein said protein is a receptor protein or antibody. 45. The method of claim 44 wherein said protein is etanercept. 46. The method of claim 28 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed. 47. A microneedle for intradermal injection of a high molecular weight pharmaceutical substance, wherein the microneedle has a length and outlet selected for its suitability for specifically delivering the substance into the dermis. 48. The microneedle according to claim 47 wherein the length of the microneedle is from about 0.5 mm to about 1.7 mm. 49. The microneedle of claim 47 which is a 30 gauge or narrower. 50. The microneedle of claim 47 which has an outlet of from 0 to 1 mm. 51. The microneedle of claim 47 which is configured in a delivery device which positions the microneedle perpendicular to skin surface. 52. The microneedle of claim 47 which is in an array of microneedles needles. 53. The microneedle of claim 52 wherein the array comprises 3 microneedles. 54. The microneedle of claim 52 wherein the array comprises 6 microneedles. 55. A method for delivering a bioactive substance to a subject comprising: contacting the skin of the subject with a device having a dermal-access means for accurately targeting the dermal space of the subject with an efficacious amount of the bioactive substance. 56. The method of claim 55 wherein the pharmacokinetics of the bioactive substance is improved relative to the pharmacokinetics of the substance when administered subcutaneously. 57. The method of claim 56 wherein the improved pharmacokinetics is an increase in bioavailability. 58. The method of claim 56 wherein the improved pharmacokinetics is a decrease in Tmax. 59. The method of claim 56 wherein the improved pharmacokinetics comprises an increase in Cmax of the substance compared to subcutaneous injection. 60. The method of claim 56 wherein the improved pharmacokinetics is a decrease in Tlag. 61. The method of claim 56 wherein the improved pharmacokinetics is an enhanced absorption rate. 62. The method of claim 55 wherein the device has a fluid driving means including a syringe, infusion pump, piezoelectric pump, electromotive pump, electromagnetic pump, or Belleville spring. 63. The method of claim 55 wherein the dermal access means comprises one or more hollow microcannula having a length of from about 0.5 to about 1.7 mm. 64. The method of claim 55 wherein said dermal access means comprises one or more hollow microcannula having an outlet with an exposed height between 0 and 1 mm. 65. The method of claim 55 wherein the substance has a molecular weight of at least 40 kD. 66. The method of claim 55 wherein the substance is or protein. 67. The method of claim 66 wherein said protein is a receptor protein or antibody. 68. The method of claim 67 wherein said protein is etanercept. 69. The method of claim 55 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed. 70. A method for delivering a high molecular weight bioactive substance to a subject comprising: contacting the skin of a subject with a device having a dermal-access means for accurately targeting the dermal space of the subject with an efficacious amount of the bioactive substance at a rate of 1 nL/min. to 200 mL/min. 71. The method of claim 70 wherein the rapid onset pharmacokinetics of the bioactive substance is substantially improved relative to subcutaneous injection. 72. The method of claim 71 wherein the bioavailability is increased. 73. The method of claim 71 wherein the pharmokinetics is a decreased Tmax. 74. The method of claim 71 wherein the pharmokinetics is an increased Cmax. 75. The method of claim 71 wherein the pharmokinetics is a decreased Tlag. 76. The method of claim 71 wherein the pharmacokinetics is an enhanced absorption rate. 77. The method of claim 70 wherein the dermal access means has one or more hollow microcannula that inserts into the skin of said subject to a depth of from about 0.5 to about 2.0 mm. 78. The method of claim 70 wherein the dermal access means has one or more hollow microcannula having an outlet with an exposed height between 0 and 1 mm. 79. The method of claim 70 wherein said substance has a molecular weight of at least 40 kD. 80. The method of claim 70 wherein said substance is a protein. 81. The method of claim 80 wherein said protein is a receptor protein or antibody. 82. The method of claim 80 wherein said protein is etanercept. 83. The method of claim 70 wherein administration is carried out under conditions such that an intradermal depot containing said substance is formed. 84. The method of claim 80 wherein said protein is a fusion protein. 85. The method of claim 70 wherein said substance has a molecular weight of at least 100,000 kD. 86. The method of claim 85 wherein said substance is a protein. 87. The method of claim 85 wherein said substance has a molecular weight of at least 150 kD. 88. The method of claim 87 wherein said substance is a protein. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The importance of efficiently and safely administering pharmaceutical substances such as diagnostic agents and drugs has long been recognized. Although an important consideration for all pharmaceutical substances, obtaining adequate bioavailability of large molecules such as proteins that have arisen out of the biotechnology industry has recently highlighted this need to obtain efficient and reproducible absorption (Cleland et al., Curr. Opin. Biotechnol. 12: 212-219, 2001). The use of conventional needles has long provided one approach for delivering pharmaceutical substances to humans and animals by administration through the skin. Considerable effort has been made to achieve reproducible and efficacious delivery through the skin while improving the ease of injection and reducing patient apprehension and/or pain associated with conventional needles. Furthermore, certain delivery systems eliminate needles entirely, and rely upon chemical mediators or external driving forces such as iontophoretic currents or electroporation or thermal poration or sonophoresis to breach the stratum corneum, the outermost layer of the skin, and deliver substances through the surface of the skin. However, such delivery systems do not reproducibly breach the skin barriers or deliver the pharmaceutical substance to a given depth below the surface of the skin and consequently, clinical results can be variable. Thus, mechanical breach of the stratum corneum such as with needles, is believed to provide the most reproducible method of administration of substances through the surface of the skin, and to provide control and reliability in placement of administered substances. Approaches for delivering substances beneath the surface of the skin have almost exclusively involved transdermal administration, i.e. delivery of substances through the skin to a site beneath the skin. Transdermal delivery includes subcutaneous, intramuscular or intravenous routes of administration of which, intramuscular (IM) and subcutaneous (SC) injections have been the most commonly used. Anatomically, the outer surface of the body is made up of two major tissue layers, an outer epidermis and an underlying dermis, which together constitute the skin (for review, see Physiology, Biochemistry, and Molecular Biology of the Skin, Second Edition, L. A. Goldsmith, Ed., Oxford University Press, New York, 1991). The epidermis is subdivided into five layers or strata of a total thickness of between 75 and 150 μm. Beneath the epidermis lies the dermis, which contains two layers, an outermost portion referred to at the papillary dermis and a deeper layer referred to as the reticular dermis. The papillary dermis contains vast microcirculatory blood and lymphatic plexuses. In contrast, the reticular dermis is relatively acellular and avascular and made up of dense collagenous and elastic connective tissue. Beneath the epidermis and dermis is the subcutaneous tissue, also referred to as the hypodermis, which is composed of connective tissue and fatty tissue. Muscle tissue lies beneath the subcutaneous tissue. As noted above, both the subcutaneous tissue and muscle tissue have been commonly used as sites for administration of pharmaceutical substances. The dermis, however, has rarely been targeted as a site for administration of substances, and this may be due, at least in part, to the difficulty of precise needle placement into the intradermal space. Furthermore, even though the dermis, in particular, the papillary dermis has been known to have a high degree of vascularity, it has not heretofore been appreciated that one could take advantage of this high degree of vascularity to obtain an improved absorption profile for administered substances compared to subcutaneous administration. This is because small drug molecules are typically rapidly absorbed after administration into the subcutaneous tissue which has been far more easily and predictably targeted than the dermis has been. On the other hand, large molecules such as proteins are typically not well absorbed through the capillary epithelium regardless of the degree of vascularity so that one would not have expected to achieve a significant absorption advantage over subcutaneous administration by the more difficult to achieve intradermal administration even for large molecules. One approach to administration beneath the surface to the skin and into the region of the intradermal space has been routinely used in the Mantoux tuberculin test. In this procedure, a purified protein derivative is injected at a shallow angle to the skin surface using a 27 or 30 gauge needle (Flynn et al, Chest 106: 1463-5, 1994). A degree of uncertainty in placement of the injection can, however, result in some false negative test results. Moreover, the test has involved a localized injection to elicit a response at the site of injection and the Mantoux approach has not led to the use of intradermal injection for systemic administration of substances. Some groups have reported on systemic administration by what has been characterized as “intradermal” injection. In one such report, a comparison study of subcutaneous and what was described as “intradermal” injection was performed (Autret et al, Therapie 46:5-8, 1991). The pharmaceutical substance tested was calcitonin, a protein of a molecular weight of about 3600. Although it was stated that the drug was injected intradermally, the injections used a 4 mm needle pushed up to the base at an angle of 60°. This would have resulted in placement of the injectate at a depth of about 3.5 mm and into the lower portion of the reticular dermis or into the subcutaneous tissue rather than into the vascularized papillary dermis. If, in fact, this group injected into the lower portion of the reticular dermis rather than into the subcutaneous tissue, it would be expected that the substance would either be slowly absorbed in the relatively less vascular reticular dermis or diffuse into the subcutaneous region to result in what would be functionally the same as subcutaneous administration and absorption. Such actual or functional subcutaneous administration would explain the reported lack of difference between subcutaneous and what was characterized as intradermal administration, in the times at which maximum plasma concentration was reached, the concentrations at each assay time and the areas under the curves. Similarly, Bressolle et al. administered sodium ceftazidime in what was characterized as “intradermal” injection using a 4 mm needle (Bressolle et al. J. Pharm. Sci. 82:1175-1178, 1993). This would have resulted in injection to a depth of 4 mm below the skin surface to produce actual or functional subcutaneous injection, although good subcutaneous absorption would have been anticipated in this instance because sodium ceftazidime is hydrophilic and of relatively low molecular weight. Another group reported on what was described as an intradermal drug delivery device (U.S. Pat. No. 5,997,501). Injection was indicated to be at a slow rate and the injection site was intended to be in some region below the epidermis, i.e., the interface between the epidermis and the dermis or the interior of the dermis or subcutaneous tissue. This reference, however, provided no teachings that would suggest a selective administration into the dermis nor did the reference suggest any possible pharmacokinetic advantage that might result from such selective administration. To date, numerous therapeutic proteins and small molecular weight compounds have been delivered intradermally and used to effectively elicit a pharmacologically beneficial response. Most previous compounds (e.g. insulin, Neupogen, hGH, calcitonin) have been hormonal proteins not engineered receptors or antibodies. To date all administered proteins have exhibited several effects associated with ID administration, including more rapid onset of uptake and distribution (vs. SC) and in some case increased bioavailability. Little or no information is known about the behavior of high molecular weigh substances (e.g. >40 kD) when administered intradermally. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present disclosure relates to a new parenteral administration method based on directly targeting the dermal space whereby such method dramatically alters the pharmacokinetics (PK) and pharmacodynamics (PD) parameters of administered substances. By the use of direct intradermal (ID) administration means hereafter referred to as dermal-access means, for example, using microneedle-based injection and infusion systems (or other means to accurately target the intradermal space), the pharmacokinetics of many substances including drugs and diagnostic substances, especially high molecular weight proteins, can be altered when compared to traditional parental administration routes of subcutaneous and intravenous delivery. These findings are pertinent not only to microdevice-based injection means, but other delivery methods such as needleless or needle-free ballistic injection of fluids or powders into the ID space, Mantoux-type ID injection, enhanced iontophoresis through microdevices, and direct deposition of fluid, solids, or other dosing forms into the skin if such delivery means can be accurately controlled to deposit the drug dose within the intradermal space. Disclosed is a method to increase the rate of uptake for parenterally-administered drugs without necessitating IV access. One significant beneficial effect of this delivery method is providing a shorter T max . (time to achieve maximum blood concentration of the drug). Potential corollary benefits include higher maximum concentrations for a given unit dose (C max ), higher bioavailability, more rapid uptake rates, more rapid onset of pharmacodynamics or biological effects, and reduced drug depot effects. According to the present invention, improved pharmacokinetics means increased bioavailability, decreased lag time (T lag ), decreased T max , more rapid absorption rates, more rapid onset and/or increased C max for a given amount of compound administered, compared to subcutaneous, intramuscular or other non-IV parenteral means of drug delivery. Decreases in Tlag and Tmax, and more rapid absorption rates indicate faster onset for the therapeutic activity of drugs, while increased Cmax and bioavailability indicate that more drug is present in systemic circulation, and generally indicate the potential for significant reduction of doses without loss of therapeutic effect. By bioavailability is meant the total amount of a given dosage that reached the blood compartment. This is generally measured as the area under the curve in a plot of concentration vs. time. By “lag time” is meant the delay between the administration of a compound and time to measurable or detectable blood or plasma levels. T max is a value representing the time to achieve maximal blood concentration of the compound, and C max is the maximum blood concentration reached with a given dose and administration method. The time for onset is a function of T lag , T max and C max , as all of these parameters influence the time necessary to achieve a blood (or target tissue) concentration necessary to realize a biological effect. T max and C max can be determined by visual inspection of graphical results and can often provide sufficient information to compare two methods of administration of a compound. However, numerical values can be determined more precisely by analysis using kinetic models (as described below) and/or other means known to those of skill in the art. Directly targeting the dermal space as taught by the invention provides more rapid onset of effects of drugs and diagnostic substances. The inventors have found that substances can be rapidly absorbed and systemically distributed via controlled ID administration that selectively accesses the dermal vascular and lymphatic microcapillaries, thus the substances may exert their beneficial effects more rapidly than SC administration. This has special significance for drugs requiring rapid onset, such as insulin to decrease blood glucose, pain relief such as for breakthrough cancer pain, or migraine relief, or emergency rescue drugs such as adrenaline or anti-venom. Natural hormones are also released in pulsatile fashion with a rapid onset burst followed by rapid clearance. Examples include insulin that is released in response to biological stimulus, for example high glucose levels. Another example is female reproductive hormones, which are released at time intervals in pulsatile fashion. Human growth hormone is also released in normal patients in a pulsatile fashion during sleep. This benefit allows better therapy by mimicking the natural body rhythms with synthetic drug compounds. Likewise, it may better facilitate some current therapies such as blood glucose control via insulin delivery. Many current attempts at preparing “closed loop” insulin pumps are hindered by the delay period between administering the insulin and waiting for the biological effect to occur. This makes it difficult to ascertain in real-time whether sufficient insulin has been given, without overtitrating and risking hypoglycemia. The more rapid PK/PD of ID delivery eliminates much of this type of problem. Mammalian skin contains two layers, as discussed above, specifically, the epidermis and dermis. The epidermis is made up of five layers, the stratum corneum, the stratum lucidum, the stratum granulosum, the stratum spinosum and the stratum germinativum and the dermis is made up of two layers, the upper papillary dermis and the deeper reticular dermis. The thickness of the dermis and epidermis varies from individual to individual, and within an individual, at different locations on the body. For example, it has been reported that the epidermis varies in thickness from about 40 to about 90 μm and the dermis varies in thickness ranging from just below the epidermis to a depth of from less than 1 mm in some regions of the body to just under 2 to about 4 mm in other regions of the body depending upon the particular study report (Hwang et al., Ann Plastic Surg 46:327-331, 2001; Southwood, Plast. Reconstr. Surg 15:423-429, 1955; Rushmer et al., Science 154:343-348, 1966). As used herein, intradermal is intended to mean administration of a substance into the dermis in such a manner that the substance readily reaches the richly vascularized papillary dermis and is rapidly absorbed into the blood capillaries and/or lymphatic vessels to become systemically bioavailable. Such can result from placement of the substance in the upper region of the dermis, i.e. the papillary dermis or in the upper portion of the relatively less vascular reticular dermis such that the substance readily diffuses into the papillary dermis. It is believed that placement of a substance predominately at a depth of at least about 0.3 mm, more preferably, at least about 0.4 mm and most preferably at least about 0.5 mm up to a depth of no more than about 2.5 mm, more preferably, no more than about 2.0 mm and most preferably no more than about 1.7 mm will result in rapid absorption of macromolecular and/or hydrophobic substances. Placement of the substance predominately at greater depths and/or into the lower portion of the reticular dermis is believed to result in the substance being slowly absorbed in the less vascular reticular dermis or in the subcutaneous region either of which would result in reduced absorption of macromolecular and/or hydrophobic substances. The controlled delivery of a substance in this dermal space below the papillary dermis in the reticular dermis, but sufficiently above the interface between the dermis and the subcutaneous tissue, should enable an efficient (outward) migration of the substance to the (undisturbed) vascular and lymphatic microcapillary bed (in the papillary dermis), where it can be absorbed into systemic circulation via these microcapillaries without being sequestered in transit by any other cutaneous tissue compartment. Another benefit of the invention is to achieve more rapid systemic distribution and offset of drugs or diagnostic agents. This is also pertinent for many hormones that in the body are secreted in a pulsatile fashion. Many side effects are associated with having continuous circulating levels of substances administered. A very pertinent example is female reproductive hormones that actually have the opposite effect (cause infertility) when continuously present in the blood. Another benefit of the invention is to achieve higher bioavailabilities of drugs or diagnostic agents. This effect has been most dramatic for ID administration of high molecular weight substances, especially proteins. The direct benefit is that ID administration with enhanced bioavailability, allows equivalent biological effects while using less active agent. This results in direct economic benefit to the drug manufacturer and perhaps consumer, especially for expensive protein therapeutics and diagnostics. Likewise, higher bioavailability may allow reduced overall dosing and decrease the patient's side effects associated with higher dosing. Another benefit of the invention is the attainment of higher maximum concentrations of drugs or diagnostic substances. The inventors have found that substances administered ID are absorbed more rapidly, with bolus administration resulting in higher initial concentrations. This is most beneficial for substances whose efficacy is related to maximal concentration. The more rapid onset allows higher C max values to be reached with lesser amounts of the substance. Therefore, the dose can be reduced, providing an economic benefit, as well as a physiological benefit since lesser amounts of the drug or diagnostic agent has to be cleared by the body. Another benefit of the invention is no change in systemic elimination rates or intrinsic clearance mechanisms of drugs or diagnostic agents. All studies to date by the applicants have maintained the same systemic elimination rate for the substances tested as via IV or SC dosing routes. This indicates this dosing route has no change in the biological mechanism for systemic clearance. This is an advantageous from a regulatory standpoint, since degradation and clearance pathways need not be reinvestigated prior to filing for FDA approval. This is also beneficial from a pharmacokinetics standpoint, since it allows predictability of dosing regimes. Some substances may be eliminated from the body more rapidly if their clearance mechanism are concentration dependent. Since ID delivery results in higher Cmax, clearance rate may be increased, although the intrinsic mechanism remains unchanged. Another benefit of the invention is no change in pharmacodynamic mechanism or biological response mechanism. As stated above, administered drugs by the methods taught by the applicants still exert their effects by the same biological pathways that are intrinsic to other delivery means. Any pharmacodynamic changes are related only to the difference patterns of appearance, disappearance, and drug or diagnostic agent concentrations present in the biological system. Using the methods of the present invention, pharmaceutical compounds may be administered as a bolus, or by infusion. As used herein, the term “bolus” is intended to mean an amount that is delivered within a time period of less than ten (10) minutes. “Infusion” is intended to mean the delivery of a substance over a time period greater than ten (10) minutes. It is understood that bolus administration or delivery can be carried out with rate controlling means, for example a pump, or have no specific rate controlling means, for example user self-injection. Another benefit of the invention is removal of the physical or kinetic barriers invoked when drugs passes through and becomes trapped in cutaneous tissue compartments prior to systemic absorption. Elimination of such barriers leads to an extremely broad applicability to various drug classes. Many drugs administered subcutaneously exert this depot effect—that is, the drug is slowly released from the SC space, in which it is trapped, as the rate determining step prior to systemic absorption, due to affinity for or slow diffusion through the fatty adipose tissue. This depot effect results in a lower C max and longer T max , compared to ID, and can result in high inter-individual variability of absorption. This effect is also pertinent for comparison to transdermal delivery methods including passive patch technology, with or without permeation enhances, iontophoretic technology, sonopheresis, or stratum corneum ablation or disruptive methods. Transdermal patch technology relies on drug partitioning through the highly impermeable stratum corneum and epidermal barriers. Few drugs except highly lipophilic compounds can breach this barrier, and those that do, often exhibit extended offset kinetics due to tissue saturation and entrappment of the drugs. Active transdermal means, while often faster than passive transfer means, are still restricted to compound classes that can be moved by charge repulsion or other electronic or electrostatic means, or carried passively through the transient pores caused by cavitation of the tissue during application of sound waves. The stratum corneum and epidermis still provide effective means for inhibiting this transport. Stratum corneum removal by thermal or laser ablation, abrasive means or otherwise, still lacks a driving force to facilitate penetration or uptake of drugs. Direct ID administration by mechanical means overcomes the kinetic barrier properties of skin, and is not limited by the pharmaceutical or physicochemical properties of the drug or its formulation excipients. Another benefit of the invention is highly controllable dosing regimens. The applicants have determined that ID infusion studies have demonstrated dosing profiles that are highly controllable and predictable due to the rapid onset and offset kinetics of drugs or diagnostic agents delivered by this route. This allows almost absolute control over the desired dosing regimen when ID delivery is coupled with a fluid control means or other control system to regulate metering of the drug or diagnostic agent into the body. This single benefit alone is one of the principal goals of most drug or diagnostic agent delivery methods. Bolus ID substance administration as defined previously results in kinetics most similar to IV injection and is most desirable for pain relieving compounds, mealtime insulin, rescue drugs, erectile dysfunction compounds, or other drugs that require rapid onset. Also included would be combinations of substances capable of acting alone or synergistically. Extending the ID administration duration via infusion can effectively mimic SC uptake parameters, but with better predictability. This profile is particularly good for substances such as growth hormones, or analgesics. Longer duration infusion, typically at lower infusion rates can result in continuous low basal levels of drugs that is desired for anticoagulants, basal insulin, and chronic pain therapy. These kinetic profiles can be combined in multiple fashion to exhibit almost any kinetic profile desired. An example would be to pulsatile delivery of fertility hormone (LHRH) for pregnancy induction, which requires intermittent peaks every 90 minutes with total clearance between pulses. Other examples would be rapid peak onset of drugs for migraine relief, followed by lower levels for pain prophylaxis. Another benefit of the invention is reduced degradation of drugs and diagnostic agents and/or undesirable immunogenic activity. Transdermal methods using chemical enhancers or iontophoresis, or sonophoresis or electroporation or thermal poration require that a drug pass through the viable epidermal layer, which has high metabolic and immunogenic activity. Metabolic conversion of substances in the epidermis or sequestration by immunoglobulins reduces the amount of drug available for absorption. The ID administration circumvents this problem by placing the drug directly in the dermis, thus bypassing the epidermis entirely. Additional benefits of the invention may be achieved when high molecular weight substances are delivered intradermally. By “high molecular weigh substance” is meant a substance comprising a compound or compounds having molecular weight(s) of 40 kD or greater. Such compounds preferably have molecular weights between 40 kD and 300 kD, but may have molecular weights up to 500 kD, 1000 D or even 2000 kD or more. Benefits of the methods of the invention for administration of high molecular weight substances include: a) Reduced dosage (drug amount) for the patient; b) Reduced manufacturing capacity needed to obtain an equivalent number of doses; and c) More predictable dosing across the patient population. It has also been found that when such high molecular weight substances are administered according to one method of the invention, an intradermal depot of the administered substance can form. Although depot formation is often undesirable, as mentioned above, in certain instances it may provide benefits for localized therapy, pharmacokinetic control, or immunological therapy. By “intradermal depot” is meant a localized concentration of the administered substance within the dermis that is released into the surrounding tissue and the bloodstream or lymphatic systems at a reduced rate compared to that obtained by direct IV access, more dilute solutions administered SC or ID over time, or with lower molecular weight analogs of the compound administered by the same route. Such depot formation is useful in the intradermal space because, as illustrated by the present case of Enbrel, higher blood concentrations than that obtained by SC injection may be obtained over several hours, enhancing biovailability or efficacy of the drug, or both. In the case of vaccines, such ID depot formulation may enhance the uptake of vaccine by Langerhans or other dendritic cells in the skin, and may enhance direct uptake of antigen by lymphatic vessels in the intradermal space. Such effects may lead to faster seroconversion, higher antibody titers, and stronger cellular immune responses (including cytotoxic T cell and cytokine production, and cellular proliferation) as well as lowering of doses necessary for those effects compared to subcutaneous administration. Depot formation is also useful in the treatment of some localized dermal medical conditions such as skin cancers, eczema, psoriasis, warts, or moles. It could also be important for treatment of localized infections (fungal, bacterial or otherwise), and effective for longer term localized pain relief, such as that needed for orthopedic injury or nerve blocks. Depot formation would also have potential benefit for cosmetic purposes such as administration of anti-wrinkle agents. These and other benefits of the invention are achieved by directly targeting absorption by the papillary dermis and by controlled delivery of drugs, diagnostic agents, and other substances to the dermal space of skin. The inventors have found that by specifically targeting the intradermal space and controlling the rate and pattern of delivery, the pharmacokinetics exhibited by specific drugs can be unexpectedly improved, and can in many situations be varied with resulting clinical advantage. Such pharmacokinetics cannot be as readily obtained or controlled by other parenteral administration routes, except by IV access. The present invention improves the clinical utility of ID delivery of drugs, diagnostic agents, and other substances to humans or animals. The methods employ dermal-access means (for example a small gauge needle, especially microneedles), to directly target the intradermal space and to deliver substances to the intradermal space as a bolus or by infusion. It has been discovered that the placement of the dermal-access means within the dermis provides for efficacious delivery and pharmacokinetic control of active substances. The dermal-access means is so designed as to prevent leakage of the substance from the skin and improve adsorption within the intradermal space. The pharmacokinetics of hormone drugs delivered according to the methods of the invention have been found to be vastly different to the pharmacokinetics of conventional SC delivery of the drug, indicating that ID administration according to the methods of the invention will provide improved clinical results. Delivery devices that place the dermal-access means at an appropriate depth in the intradermal space and control the volume and rate of fluid delivery provide accurate delivery of the substance to the desired location without leakage. Disclosed is a method to increase the rate of uptake for parenterally-administered drugs without necessitating IV access. This effect provides a shorter T max . Potential corollary benefits include higher maximum concentrations for a given unit dose (C max ), higher bioavailability, more rapid onset of pharmacodynamics or biological effects, and reduced drug depot effects. It has also been found that by appropriate depth control of the dermal-access means within the intradermal space that the pharmacokinetics of hormone drugs delivered according to the methods of the invention can, if required, produce similar clinical results to that of conventional SC delivery of the drug. The pharmacokinetic profile for individual compounds will vary according to the chemical properties of the compounds. For example, compounds that are relatively large, having a molecular weight of at least 1000 Daltons as well as larger compounds of at least 2000 Daltons, at least 4000 Daltons, at least 10,000 Daltons and larger and/or hydrophobic compounds are expected to show the most significant changes compared to traditional parenteral methods of administration, such as intramuscular, subcutaneous or subdermal injection. It is expected that small hydrophilic substances, on the whole, will exhibit similar kinetics for ID delivery compared to other methods. |
Local digital network, methods for installing new devices and data broadcast and reception methods in such a network |
The invention relates to a local digital network comprising: at least one source device intended to broadcast data over the network; and at least one receiver device intended to receive said data. The source device uses a network active encryption key to encrypt data liable to be broadcast in the network and the receiver device contains: a network active decryption key for decrypting data encrypted using said active encryption key and at least one decryption key of the network for decrypting data encrypted with the aid of an encryption key used previously in the network. The invention also relates to the installing of new devices in such a network as well as the sending of data from a source device to a receiver device. |
1. Local digital network comprising: at least one source device intended to broadcast data over the network; and at least one receiver device intended to receive said data, wherein the source device uses a network active encryption key to encrypt data liable to be broadcast in the network; and in that the receiver device contains: a network active decryption key for decrypting data encrypted using said active encryption key and at least one decryption key of the network for decrypting data encrypted with the aid of an encryption key used previously in the network. 2. Local digital network according to claim 1, wherein the receiver device contains all the network's decryption keys used previously since the creation of the network. 3. Local digital network according to claim 1, wherein the source device Contains the network active encryption key and in that it encrypts the data liable to be broadcast in the network with said active key of the network. 4. Local digital network according to claim 1, wherein the source device contains: a first symmetric key as well as said first symmetric key encrypted with the network active encryption; in that it encrypts the data liable to be broadcast in the network with said first symmetric key and in that it is adapted for transmitting, with said encrypted data, the first symmetric key encrypted with the network active encryption key. 5. Local digital network according to claim 1, wherein the source device and the receiver device use symmetric encryption processes and in that the encryption keys and the corresponding decryption keys used in the network are identical. 6. Method for installing a new receiver device in a local digital network according to claim 1 already comprising at least one receiver device, wherein a preexisting receiver device of the network, possessing the network active decryption key and at least one decryption key used previously in the network, and having the capacity to send them in a secure manner, sends said decryption keys to the new receiver device. 7. Method for installing a new source device in a local digital network according to claim 5 already comprising at least one receiver device, wherein a preexisting receiver device of the network, possessing the network active encryption/decryption key and at least one encryption/decryption key used previously in the network and having the capacity to send them in a secure manner, sends the network active encryption/decryption key to the new source device. 8. Method for transmitting data by a source device linked to a network according to claim 5, wherein it consists in: encrypting the data with the aid of the network active encryption/decryption key; and transmitting said encrypted data as well as a fingerprint of said active key, calculated with the aid of a one-way function applied to the active key of the network. 9. Method for receiving encrypted data in a receiver device linked to a network, said data having been broadcast according to the method of claim 8, wherein, since the receiver device furthermore contains a fingerprint of each encryption/decryption key that it contains, calculated with the aid of a one-way function applied to said key, the method consists in: extracting a key fingerprint from the data received; comparing the extracted fingerprint with the fingerprints of the encryption/decryption keys contained in the receiver device; and in the case of equality between the extracted fingerprint and one of the fingerprints stored in the receiver device, decrypting the data with the key corresponding to said fingerprint. 10. Method for transmitting data by a source device linked to a network according to claim 1, wherein it consists in: (a) applying a one-way function to a first part of the data; (b) encrypting the result of the calculation performed in step (a) and a second part of the data to be protected with the aid of the network active encryption key; and (c) transmitting said data encrypted in step (b) as well as the first part of the data over the network. 11. Method for receiving data in a receiver device linked to a network, said data having been broadcast according to the method of claim 10, characterized in that wherein it consists in: (a) applying a one-way function to a first part of the nonencrypted data; (b) decrypting a second part of the data with the aid of a network decryption key contained in the receiver device, and (c) comparing the result of the decryption of a portion of the data decrypted in step (b) with the result of the calculation performed in step (a) so as, in the case of equality, to recover the remaining portion of the data decrypted in step (b); and in the case of difference, to return to step (b) to perform the decryption of the second part of the data with the aid of another network decryption key contained in the receiver device. 12. Method for transmitting data by a source device linked to a network according to claim 1, wherein it consists in: encrypting the data with the aid of the network active encryption key; and transmitting said encrypted data as well as an index corresponding to the active key of the network. 13. Method for receiving data in a receiver device linked to a network, said data having been broadcast according to the method of claim 12, wherein it consists in: extracting from the data received an index corresponding to the network encryption key used to encrypt said data; deducing a corresponding network decryption key from this index; and decrypting the data with the aid of said decryption key. |
<SOH> FIELD OF THE INVENTION <EOH>The present invention relates in a general manner to the field of local digital networks and more particularly to the field of domestic digital networks. It is more precisely concerned with protection against the copying of the digital data flowing around such networks. |
<SOH> SUMMARY OF THE INVENTION <EOH>The subject of the invention is a local digital network comprising: at least one source device intended to broadcast data over the network; and at least one receiver device intended to receive said data. According to the invention, the source device uses a network active encryption key to encrypt data liable to be broadcast in the network; and the receiver device contains a network active decryption key for decrypting data encrypted using the active encryption key and at least one other decryption key of the network for decrypting data encrypted with the aid of an encryption key used previously in the network. The local digital network may also comprise one or more of the following characteristics: the receiver device contains all the network's decryption keys used previously since the creation of the network; the source device contains the network active encryption key and it encrypts the data liable to be broadcast in the network with this active key of the network; the source device contains a first symmetric key as well as this first symmetric key encrypted with the network active encryption key; it encrypts the data liable to be broadcast in the network with the first symmetric key and it is adapted for transmitting, with the encrypted data, the first symmetric key encrypted with the network active encryption key; the source device and the receiver device use symmetric encryption methods and the encryption keys and the corresponding decryption keys used in the network are identical. The invention also relates to a method for installing a new receiver device in a local digital network as hereinabove already comprising at least one receiver device. According to this method, a preexisting receiver device of the network, possessing the network active decryption key and at least one decryption key used previously in the network and having the capacity to send them in a secure manner, sends said decryption keys to the new receiver device. Another aspect of the invention relates to a method for installing a new source device in a local digital network as hereinabove in which the source device and the receiver device use symmetric encryption methods and the encryption keys and the corresponding decryption keys used in the network are identical. According to this method, a preexisting receiver device of the network, possessing the network active encryption/decryption key and at least one encryption/decryption key used previously in the network and having the capacity to send them in a secure manner, sends the network active encryption/decryption key to the new source device. The invention also relates to a method for transmitting data by a source device linked to a network as hereinabove in which the encryption keys and the decryption keys used are identical. This method consists in encrypting the data with the aid of the network active encryption/decryption key; and in transmitting the encrypted data along with a fingerprint of the active key, the fingerprint being calculated with the aid of a one-way function applied to the active key of the network. The invention also relates to a method for receiving encrypted data in a receiver device linked to a network as mentioned above, said data having been broadcast according to the method described hereinabove and the receiver device furthermore containing a fingerprint of each encryption/decryption key that it contains, calculated with the aid of a one-way function applied to said key. The method consists in extracting a key fingerprint from the data received; in comparing the extracted fingerprint with the fingerprints of the encryption/decryption keys contained in the receiver device; and in the case of equality between the extracted fingerprint and one of the fingerprints stored in the receiver device, in decrypting the data with the key corresponding to said fingerprint. The invention also relates to another method for transmitting data by a source device linked to a network as mentioned above. This method consists in: (a) applying a one-way function to a first part of the data; (b) encrypting the result of the calculation performed in step (a) and a second part of the data to be protected with the aid of the network active encryption key; and (c) transmitting said data encrypted in step (b) as well as the first part of the data over the network. The invention also relates to a method for receiving data, broadcast according to the method above, in a receiver device linked to a network as described above. The method consists in: (a) applying a one-way function to a first part of the nonencrypted data; (b) decrypting a second part of the data with the aid of a network decryption key contained in the receiver device; and (c) comparing the result of the decryption of a portion of the data decrypted in step (b) with the result of the calculation performed in step (a) so as: in the case of equality, to recover the remaining portion of the data decrypted in step (b); and in the case of difference, to return to step (b) to perform the decryption of the second part of the data with the aid of another network decryption key contained in the receiver device. The invention furthermore relates to a third method for transmitting data by a source device linked to a network as described above. The method consists in encrypting the data with the aid of the network active encryption key; and transmitting said encrypted data as well as an index corresponding to the active key of the network. A method for receiving data, broadcast according to the method above, in a receiver device linked to a network as mentioned above, consists in extracting from the data received an index corresponding to the network encryption key used to encrypt said data; in deducing the corresponding network decryption key from this index; and in decrypting the data with the aid of the decryption key. |
Control method |
A hybrid actuation system comprises first and second actuator arrangements (10, 12) arranged to apply first and second output loads respectively to a common element (14). A control method for controlling the operation of the hybrid actuation system includes the steps of supplying first and second demand signals to the first and second actuator arrangements (10, 12) respectively to cause movement of the common element (14) into a demanded position, monitoring the first and second output loads applied by the first and second actuator arrangements (10, 12) and generating an output signal indicative of the difference between the first and second output loads. The first and second demand signals are corrected in response to the output signal to compensate for any difference between the first and second output loads, thereby to ensure the first and second output loads applied to the common element (14) are substantially identical and synchonised. |
1. A method for controlling the operation of a hybrid actuation system comprising first and second actuator arrangements (10, 12) for applying first and second output loads respectively to a common element (14), the method comprising: supplying first and second demand signals to the first and second actuator arrangements (10, 12) respectively to cause movement of the common element (14) into a demanded position, monitoring the first and second output loads applied by the first and second actuator arrangements (10, 12) and generating an output signal indicative of the difference between the first and second output loads, and correcting the first and second demand signals in response to the output signal to compensate for any difference between the first and second output loads, thereby to ensure the first and second output loads applied to the common element (14) are substantially identical and synchronised. 2. A method as claimed in claim 1, further comprising generating a load difference signal (70) representative of the difference between the first and second output loads and adjusting the first and second demand signals in response to the load difference signal. 3. A method as claimed in claim 2, comprising generating a differential fluid pressure difference signal (70) representative of the difference between the first and second output loads and adjusting the first and second demand signals in response to the differential fluid pressure difference signal. 4. A method as claimed in claim 3, further comprising: providing first and second actuator arrangements (10, 12), each comprising respective first and second control chambers (48, 59, 50, 61) and a respective piston member (52, 152) which is coupled to the common element (14) and is exposed to fluid pressure within the respective first and second control chambers (48, 59, 50, 61), controlling the fluid pressure within the respective first and second control chambers (48, 59, 50, 61) of the first and second actuator arrangements (10, 12), thereby to control the position of the respective piston member (52, 152), calculating a first difference in fluid pressure between the first and second control chambers (48, 50) of the first actuator arrangement (10) and a second difference in fluid pressure between the first and second control chambers (59, 61) of the second actuator arrangement (12), calculating the difference between said first and second differences to generate the corresponding differential fluid pressure difference signal (70), and applying a correction to at least one of the first and second demand signals supplied to the first and second actuator arrangements (1 0, 12) respectively in response to the differential fluid pressure difference signal (70). 5. A method as claimed in claim 2, wherein the step of correcting the first and second demand signals in response to the load difference signal is achieved by means of a Proportional, Integral, and Derivative (PID) feedback and control algorithm. 6. A method as claimed in claim 1, including controlling the position of the first and second actuator arrangements (10, 12) using a position control algorithm. 7. A method as claimed in claim 6, including the steps of: generating a position command signal (18) to cause movement of the common element (14) to the demanded position, calculating the difference between the position command signal (18) and an average current position of the first and second actuator arrangements (10, 12) and, using the difference to deduce the first and second demand signals required to cause movement of the first and second actuator arrangements (10, 12) into the demanded position. 8. A method as claimed in claim 1, wherein each of the first and second actuator arrangements (10, 12) has a respective dead band, the method further comprising the step of adjusting the relative timing of the first and second demand signals to compensate for differences in the dead bands of the first and second actuator arrangements (10, 12). 9. A method as claimed in claim 8, comprising synchronising the matched first and second output loads applied to the common element (14). 10. A method as claimed in claim 1, wherein said first and second demand signals have associated therewith first and second gain factors respectively, the method further comprising adjusting the first and second gain factors in the region of the dead band for the respective actuator arrangement (10, 12). 11. A hybrid actuation system comprising a first actuator arrangement for applying a first output load to a common element (14), a second actuator arrangement for applying a second output load to the common element (14), and processor means for supplying first and second demand signals to the first and second actuator arrangements (10, 12) respectively to cause movement of the common element (14) into a demanded position, for monitoring the first and second output loads applied by the first and second actuator arrangements (10, 12) and for generating an output signal indicative of the difference between the first and second output loads, and for correcting the first and second demand signals in response to the output signal to compensate for any difference between the first and second output loads, thereby to ensure the first and second output loads applied to the common element (14) are substantially identical and synchronised. 12. A hybrid actuation system as claimed in claim 11, wherein the first actuator arrangement (10) is an electro hydraulic actuator (EHA). 13. A hybrid actuation system as claimed in claim 11, wherein the first actuator arrangement (10) is an electro mechanical actuator (EMA). 14. A hybrid actuation system as claimed in claim 11, wherein the first actuator arrangement (10) is an Integrated Actuation Package. 15. A hybrid actuation system as claimed in claim 11, wherein the second actuator arrangement (12) is a servo actuator. |
Dessicant based on clay-bound zeolite process for its preparation and its use |
The invention relates to a desiccant based on clay-bound zeolite which is characterized in that it comprises hygroscopic salt and optionally further conventional additives. Preferably, it is present in the form of granules, the hygroscopic salt being arranged in the pores of the granular particles. Furthermore the invention relates to a process for the preparation of the desiccant as well as its use, in particular in insulating glass windows and spacers for insulating glass windows. |
1. Desiccant based on clay-bound zeolite which comprises hygroscopic salt and optionally further conventional additives. 2. Desiccant according to claim 1, wherein the zeolite comprises sodium-containing zeolite of the structure type A, potassium-containing zeolite of the structure type A, zeolite of the faujasite structure type or a mixture thereof. 3. Desiccant according to claim 1 or 2, wherein the zeolite comprises potassium-containing zeolite of the structure type A. 4. Desiccant according to claim 2 or 3, wherein the potassium-containing zeolite of the structure type A has a potassium content of 9 to 18 wt.-% (relative to the weight of the zeolite). 5. Desiccant according to one of claims 1 to 4, wherein the clay comprises montmorillonite, kaolinite, bentonite, smectite, attapulgite, sepiolite or a mixture thereof. 6. Desiccant according to one of claims 1 to 5, wherein the hygroscopic salt comprises magnesium chloride, calcium chloride, magnesium sulphate, sodium sulphite, magnesium polyphosphate, sodium polyphosphate, sodium carbonate, sodium sulphate or a mixture thereof. 7. Desiccant according to claim 6, wherein the hygroscopic salt is selected from magnesium chloride, magnesium sulphate and magnesium polyphosphate. 8. Desiccant according to claim 7, wherein the hygroscopic salt is magnesium sulphate. 9. Desiccant according to one of claims 1 to 8, which comprises 50 to 90 wt.-% zeolite, 5 to 40 wt.-% clay, 2 to 30 wt.-% hygroscopic salt and optionally 0 to 5 wt.-% further conventional additives. 10. Desiccant according to one of claims 1 to 9, which is present as granules and hygroscopic salt is arranged in the pores of the granular particles. 11. Desiccant according to one of claims 1 to 10, which has a water-absorption capacity (measured at 10% relative humidity and 25° C.) of 18 wt.-% or greater, more preferably 18 wt.-% to 22 wt.-%, (each relative to the weight of the desiccant), a bulk density of 800 g/l or greater, more preferably 800 to 1000 g/l, and a water-absorption capacity per volume of 160 g H2O/1 desiccant or greater, more preferably 160 to 180 g H2O/1 desiccant. 12. Process for the preparation of a desiccant according to one of claims 1 to 11, wherein a starting mixture comprising the components (a) zeolite, (b) clay, (c) hygroscopic salt and (d) optionally further conventional additives is mixed, aggregated and the product obtained by aggregation is activated, optionally after drying and/or sieving. 13. Process according to claim 12, wherein a starting mixture is aggregated by granulation using granulation liquid (wet granulation). 14. Process according to claim 13, wherein a solvent or solvent mixture, preferably water, is used as granulation liquid. 15. Process according to claim 14, wherein a solvent or suspension of part or all of the hygroscopic salt (component (c)) of the starting mixture in the solvent or solvent mixture is used as granulation liquid. 16. Process according to claim 15, wherein the starting mixture comprising the components zeolite, clay and optionally further customary additives is wet-granulated using a solution or suspension of hygroscopic salt in a solvent or solvent mixture, preferably water, and then the granules obtained are activated, optionally after the drying and/or sieving. 17. Process according to claim 16, wherein an aqueous solution of one or more hygroscopic salt(s), preferably magnesium sulphate, is used as granulation liquid. 18. Process according to claim 17, characterized in that the aqueous solution of one or more hygroscopic salt(s) has a concentration of 10 to 50 wt.-% (relative to the weight of the solution) and/or comprises a saturated aqueous solution of a one or more hygroscopic salt(s). 19. Process according to claim 18, wherein a saturated aqueous magnesium sulphate solution is used as granulation liquid. 20. Use of a desiccant according to one of claims 1 to 11 or prepared according to claims 12 to 19 in insulating glass windows, composite windows, spacers for insulating glass windows or composite windows, packed in paper or plastic bags, in stoppers of tablet tubes or in air dryers. 21. Insulating glass window or composite window, which comprises desiccant according to one of claims 1 to 11 or prepared according to one of claims 12 to 19. 22. Spacer for insulating glass windows or composite windows, which comprises desiccant according to one of claims 1 to 11 or prepared according to one of claims 12 to 19. |
Smokeless porous carbon production method and its production system |
A smokeless porous carbon production method and its production system in which porous carbon is produced by heat treating a large amount of material, e.g. wood or bamboo, efficiently in a short time with thermal energy generated by combusting combustible gas produced by heating the material, without combusting the material completely by regulating inflow of air. The smokeless porous carbon production system comprises a sequential carbonization chamber (12) for heating a material M, e.g. wood or bamboo, charged in from a material charging opening from below to carbonize the material sequentially and to generate combustible gas, a high heat treatment chamber (13) disposed below the sequential carbonization chamber continuously thereto, a residual gas combustion chamber (16) communicating with the high heat treatment chamber through a lower opening, an exhaust pipe (17) disposed continuously to the residual gas combustion chamber while being directed upward, and means for taking out an intermediate carbide subjected to high heat treatment in the high heat treatment chamber to the outside of a furnace, wherein air regulation openings (15) for taking in an appropriate amount of outer air are provided in the outer walls of the high heat treatment chamber and the residual gas combustion chamber. |
1. (Cancelled) 2. A smokeless porous carbon production method as claimed in claim 15, wherein dioxin and visible soot and smoke are prevented from being discharged outside the system by completely combusting the combustible gas while the treatment temperature during the continuous operation at the high heat treatment step is maintained at 1200-1400° C. and wherein the intermediate carbide is made intensely porous by the high heat treatment. 3. A smokeless porous carbon production system comprising: a sequential carbonization chamber for heating a material charged in from a material charging opening from below to carbonize the material sequentially and to generate combustible gas; a high heat treatment chamber disposed below the sequential carbonization chamber continuously thereto; a residual gas combustion chamber communicating with the high heat treatment chamber through a lower opening; an exhaust pipe disposed continuously to the residual gas combustion chamber while being directed upward; and means for taking out an intermediate carbide subjected to high heat treatment in the high heat treatment chamber to the outside of a furnace, wherein air regulation openings for taking in an appropriate amount of air are provided in outer walls of the high heat treatment chamber and the residual gas combustion chamber. 4. A smokeless porous carbon production system as claimed in claim 3, wherein with exhaust gas discharged from the exhaust pipe, a negative pressure condition prevails in the furnace and an appropriate amount of air is taken in from the air regulation openings so that gas comprising the combustible gas is caused to flow through the sequential carbonization chamber, the residual gas combustion chamber and the exhaust pipe continuously in this order and then into the atmosphere. 5. A smokeless porous carbon production system as claimed in claim 3, further comprising a cyclone communicating with a downstream end of the exhaust pipe and wherein the combustible gas generated in the sequential carbonization chamber proceeds downward and is completely combusted in the high heat treatment chamber and the residual gas combustion chamber, so that the generation of dioxin and visible soot and smoke is suppressed as much as possible, whereby clean exhaust gas is discharged outside from the exhaust pipe via the cyclone. 6. A smokeless porous carbon production system as claimed in claim 3, further comprising a smoke sensor and a smoke consuming blower installed within the exhaust pipe, and wherein an amount of air to be taken in the furnace is increasably regulated so as to completely combust the exhaust gas by interlocking the air regulation openings or the smoke consuming blower with movement of the smoke sensor when visible soot and smoke are generated, so that the visible soot and smoke are prevented from being discharged outside from the exhaust pipe. 7. A smokeless porous carbon production system as claimed in claim 3, further comprising stroking levers and wherein the sequential carbonization chamber is arranged so that an upper side thereof is wide and tapered toward a lower side thereof; a side wall of the high heat treatment chamber coupled to the lowermost portion of the sequential carbonization chamber is formed perpendicularly; and the material or the initial carbide is stroked by causing the stroking levers to appear or disappear, the stroking levers being slidably provided horizontally near a lower portion of the sequential carbonization chamber, whereby to allow the contents to readily drop by their own weight. 8. A smokeless porous carbon production system as claimed in claim 3, wherein high heat receiving portions are comprised of heat resistant material and the system further comprises a cooling water tank mounted to a wall portion of the furnace and means for circulating cooling water so as to insulate the exterior of the system against high heat within the furnace. 9. A smokeless porous carbon production system as claimed in claim 3, further comprising a burner with an air blower, directed toward the inside of the residual gas combustion chamber and wherein the burner is operated first when operation of the system is started so as to cause the flow of gas accompanied with an ascending air current and operation of the system is started by setting fire to the material within the high heat treatment chamber. 10. A smokeless porous carbon production system as claimed in claim 3, further comprising a fire grate, a conveying means, a carbon receiving chamber and a guide chute for guiding the intermediate carbide to a carbon container via the fire grate, the guide chute being situated below the high heat treatment chamber and wherein the intermediate carbide successively drops by its own weight onto the guide chute; and the intermediate carbide fallen onto the guide chute is moved by the conveying means so as to contain the intermediate carbide in the carbon receiving container. 11. A smokeless porous carbon production system as claimed in claim 10, wherein the conveying means is a vibrating conveyor or a screw-type conveyor. 12. A smokeless porous carbon production system as claimed in claim 10, further comprising cooling means and wherein the whole or part of the guide chute is covered with the cooling means so as to rapidly cool the intermediate carbide. 13. A smokeless porous carbon production system as claimed in claim 10, further comprising a storage chamber for the carbon container and an open-and close cover for sealing an opening in the earth in which the carbon container is situated wherein the carbon container is embedded in the earth and the carbon container can be taken in and out of the earth via the open-and-close cover. 14. A smokeless porous carbon production system as claimed in claim 13, further comprising a second open-and-close cover, the carbon container having the second open-and-close cover and the second cover being capable of opening and closing for sealing the carbon container and wherein the second open-and-close cover is left open while the porous carbon is being fed into the carbon container with the open-and-close cover of the carbon container storage chamber closed and when the porous carbon is completely accommodated in the carbon container, the open-and-close cover of the carbon container is closed whereby to take out the carbon container by opening the open-and-close cover of the carbon container storage chamber. 15. A smokeless porous carbon production method for producing porous carbon by subjecting a material to high heat treatment, comprising a series of steps including: a gasifying carbonizing step to form an initial carbide by heating the material by regulating inflow of air to generate combustible gas and simultaneously carbonizing the material sequentially; a high heat treatment step to form an intermediate carbide by combusting the combustible gas generated at the gasifying carbonizing step by regulating inflow of air without taking a separating recovering step and then subjecting the initial carbide to high temperature heat treatment; and a step to take out the intermediate carbide subjected to the high heat treatment to the outside of a furnace, wherein the combustible gas generated at the gasifying carbonizing step over the series of steps above is completely combusted at the high heat treatment step and wherein part of the thermal energy thus generated is used as a heat source for heating the material at the gasifying-carbonizing step, so that the continous operation of a smokeless porous carbon production system is made possible by using only the energy within the system after the operation is started. 16. A smokeless porous carbon production method as claimed in claim 15, wherein the material comprises at least one of wood and bamboo. 17. A smokeless porous carbon production system as claimed in claim 3, wherein the sequential carbonization chamber is for heating a material comprising at least one of wood and bamboo. |
<SOH> BACKGROUND ART <EOH>There are two kinds of charcoal: black charcoal and white charcoal. The black charcoal is produced by carbonizing Japanese oaks such as nara and kunugi in a charcoal kiln at 400-700° C. before being cooled in the kiln, whereas the white charcoal, especially Kinokuni bichoutan (charcoal), is produced by carbonizing Quercus Phillyraeoides (a kind of beech) in a charcoal kiln at 800-1000° C. before being rapidly cooling outside the kiln. The charcoal kiln above is a kind of kiln in which material is heated in the absence of air and the smoke produced during the combustion of wood is discharged directly outside. The smoke is a product resulting from the thermal decomposition of cellulose accounting for 75% of the ingredients of the wood and of lignin accounting for 20-25% thereof. On the other hand, though most of the wood-based waste materials such as waste building material are disposed of by incineration, dioxin is generated by directly combusting the waste wood-based material because chlorine synthetic resin may be intermingles with the waste material. Consequently. there arise a problem of atmospheric pollution when the combustible gas is discharged and another problem of disposing the ashes produced by incineration. In the conventional carbon production method above, moreover, it takes several days combusting the wood completely after the construction of the kiln is started and also takes a great deal of labor and time; the problem is that the production method is not fit for short-term mass production. Further, a combustion furnace for directly combusting a material by a natural draft accompanied by partially gasified combustion is disclosed in JP-A-11-63445. As shown in FIG. 7 , the combustion furnace described in JP-A-11-63445 mainly comprises an accumulated gas gasification chamber 51 having an upper opening, a first combustion chamber 52 , a second combustion chamber 56 and an exhaust pipe 58 . The combustion furnace attended with gasification combustion is provided with the accumulated gas gasification chamber 51 communicating with the first combustion chamber 52 having an ignition door 53 and a first air damper 54 in the lower portion in order to store an incineration material 59 and to convert part of the material 59 into combustible gas, and the second combustion chamber 56 communicating with the first combustion chamber 52 via a fire grate 55 and having the exhaust pipe 58 in the upper portion and a second air damper 57 in the lower portion. Although the combustion furnace above is capable of completely combusting the material so as to prevent the generation of a cloud of dust as well as an offensive smell, this system is basically different from a smokeless porous carbon production system according to the invention in that the former is characterized by completely combusting a material so as to reduce the material to ashes, whereas the latter is intended for porous carbon production. In other words, the material charging opening of the combustion furnace above is open and the material 59 is completely combusted and reduced to ashes because a large amount of air is introduced into the furnace from the charging opening and the dampers for combusting purposes. Moreover, the combustion furnace has no equipment for use in cooling or radiating heat of a carbide to be taken outside when the nature of an incinerator is considered. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a perspective view of an exemplary smokeless porous carbon production system embodying the invention. FIG. 2 is a partial sectional view of the exemplary smokeless porous carbon production system according to the embodiment of the invention. FIG. 3 is a partial sectional view of the exemplary smokeless porous carbon production system according to the embodiment of the invention. FIG. 4 is a partial sectional view of the exemplary smokeless porous carbon production system according to the embodiment of the invention. FIG. 5 is a rear view of the exemplary smokeless porous carbon production system with a smoke sensor and a smoke consuming blower additionally installed according to the embodiment of the invention. FIG. 6 is a diagram illustrating the exemplary smokeless porous carbon production system wherein a guide chute is provided with a cooling means. FIG. 7 is a diagram illustrating an incinerator under the conventional system. detailed-description description="Detailed Description" end="lead"? |
Method and installation for laser beam cutting using a multiple-focus objective and a convergent/divergent nozzle |
A method and installation which provides for cutting a material with a laser beam using at least a multiple-focus optical means, such as a lens or the like, for focusing the laser beam in several separate focusing points in combination with a convergent/divergent nozzle through which passes the laser beam and also through which flows a gas stream assisting the laser beam. |
1-10. (canceled) 11. A method of cutting a material by a laser beam comprising: a) introducing a workpiece to be cut, comprised of said material, said workpiece comprising an upper surface and a lower surface; b) employing at least one multiple-focus optical means to focus the laser beam on to at least two separate focal points, said optical means comprising splitting said laser beam into a central sub-beam and a peripheral sub-beam, said central sub-beam being focused upon a second focal point and said peripheral sub-beam being focused upon a first focal point; c) designing said optical means to position said first focal point approximately upon said upper surface of said workpiece, and to position said second focal point approximately upon the lower surface of said workpiece; and d) employing a convergent/divergent nozzle through which said laser travels coincident with and a stream of laser-beam assistance gas. 12. The method as claimed in claim 11, wherein said first focal point is in the thickness of the workpiece in a region close to said upper surface. 13. The method as claimed in claim 11, wherein said second focal point is in the thickness of the workpiece in a region close to said lower surface. 14. The method as claimed in claim 11, wherein said multiple-focus optical means is selected from the group consisting of lenses, mirrors, and combinations thereof. 15. The method as claimed in claim 11, wherein said optical means is a bifocal lens or a combination of several lenses. 16. The method as claimed in claim 11, wherein said assistance gas is selected from the group consisting of oxygen, nitrogen, argon, helium, hydrogen, carbon dioxide, and mixtures thereof. 17. The method as claimed in claim 11, wherein said workpiece is comprised of material selected from the group consisting of non-alloy steel, low-alloy steel, stainless steel, clad steel, aluminum, and aluminum alloy. 18. The method as claimed in claim 11, wherein the thickness of said workpiece is between 0.8 mm and 20 mm. 19. The method as claimed in claim 18, wherein the thickness of said workpiece is between 2 and 12 mm. 20. The method as claimed in claim 11, wherein the workpiece to be cut is selected from the group consisting of plates, sheets, and tubes. 21. The method as claimed in claim 11, wherein said laser-beam assistance gas is at a pressure of 0.5 to 30 bar. 22. The method as claimed in claim 21, wherein said laser-beam assistance gas is at a pressure of 1 to 28 bar. 23. An apparatus for cutting a material by a laser beam comprising: a) a laser beam; b) a laser beam assistance gas; c) a multiple-focus optical means, said multiple-focus optical means having at least two focal points, said focal points comprising a first focal point and a second focal point, said multiple-focus optical means splitting said laser beam into a central sub-beam and a peripheral sub-beam; d) a workpiece to be cut, said workpiece comprising an upper surface and a lower surface, said workpiece positioned such that said first focal point is approximately on said upper surface, and said second focal point is approximately on said lower surface; and e) a convergent/divergent nozzle, said nozzle positioned such that said laser-beam assistance gas, said central sub-beam and said peripheral sub-beam pass through said nozzle and contact said workpiece. 24. An apparatus as claimed in claim 23, wherein said multiple-focus optical means is selected from the group consisting of lenses, mirrors, and combinations thereof. 25. An apparatus as claimed in claim 23, wherein said optical means is a bifocal lens or a combination of several lenses. 26. An apparatus as claimed in claim 23, wherein said assistance gas is selected from the group consisting of oxygen, nitrogen, argon, helium, hydrogen, carbon dioxide and mixtures thereof. 27. An apparatus as claimed in claim 23, wherein said workpiece is comprised of material selected from the group consisting of non-alloy steel, low-alloy steel, stainless steel, clad steel, aluminum, and aluminum alloy. 28. An apparatus as claimed in claim 23, wherein the thickness of said workpiece is between 0.8 mm and 20 mm. 29. An apparatus as claimed in claim 28, wherein the thickness of said workpiece is between 2 and 12 mm. 30. An apparatus as claimed in claim 23, wherein the workpiece to be cut is selected from the group consisting of plates, sheets and tubes. 31. An apparatus as claimed in claim 23, wherein said laser-beam assistance gas is at a pressure of 0.5 to 30 bar. 32. An apparatus as claimed in claim 31, wherein said laser-beam assistance gas is at a pressure of 1 to 28 bar. |
Combustion chamber intermediate part for a gas turbine |
This invention relates to a gas turbine having a combustion chamber arrangement and a turbine chamber connected downstream of said combustion chamber arrangement, wherein the combustion chamber arrangement includes a plurality of individual combustion chambers formed by input areas and transition areas converging in an annular gap leading to the turbine chamber and wherein the longitudinal axes of the individual combustion chambers are placed at an angle relative to an engine axis that is defined by the axial extension of the turbine chamber. In order to improve said gas turbine by visibly reducing the thermal and mechanical loads of the individual combustion chambers in the transition area so that cooling requirements can be lowered in said area, the transition area of at least one individual combustion chamber into the turbine chamber is deflected in the direction of the engine axis and substantially in the input area of the turbine chamber. |
1. A combustion chamber, comprising: a turbine chamber connected downstream of the combustion chamber; and a plurality of individual combustion chambers each formed by a plurality of input sections and a plurality of transition sections converging in an annular gap leading to the turbine chamber, wherein a longitudinal axis of the individual combustion chambers is placed at an angle relative to an engine axis that is defined by an axial alignment of the turbine chamber. 2. The combustion chamber according to claim 1, wherein the transition section of at least one individual combustion chamber has an internal wall located closer to a turbine shaft than an external wall, whereby the internal and external walls of the individual combustion chamber are essentially straight or curve in the direction of the engine axis. 3. The combustion chamber according to claim 2, wherein the external wall of the transition section runs essentially in a straight line. 4. The combustion chamber according to claim 3, wherein the internal wall of the transition section runs in a curve with a radius. 5. The combustion chamber according to claim 1, wherein a plurality of blades is arranged in the turbine chamber with a plurality of fixed blade platforms aligned essentially parallel to the engine axis, with at least one fixed blade platform in an input area of the turbine chamber running at an angle in the direction of the combustion chamber longitudinal axis. 6. The combustion chamber according to claim 5, wherein at least one fixed blade platform in the input area of the turbine chamber is extended in the direction of the individual combustion chambers. 7. The combustion chamber according to claim 6, wherein a plurality of internal fixed blade platforms are located close to the turbine shaft and a plurality of external fixed blade platforms are located further from the turbine shaft are arranged in the turbine chamber and that in the input area of the turbine chamber at least one internal and/or at least one external fixed blade platform is angled in the direction of the combustion chamber longitudinal axis and/or extended in the direction of the individual combustion chambers. 8. The combustion chamber according to claim 1, wherein a cross-sectional area of the individual combustion chamber is essentially constant in the direction of the gas flow. 9. The combustion chamber according to claim 1, wherein the transition sections of all the individual combustion chambers and all corresponding input areas of the turbine chambers are embodied so that deflection of the gas flow from the individual combustion chambers to the turbine chamber in the direction of the engine axis takes place essentially in the input areas of the turbine chamber. 10. The combustion chamber as claimed in claim 1, wherein the transition section of at least one individual combustion chamber and the corresponding input area of the turbine chambers are embodied so that the gas flow running from at least one individual combustion chamber into the turbine chamber is deflected in the direction of the engine axis substantially in the input area of the turbine chamber. |
<SOH> BACKGROUND OF INVENTION <EOH>Such gas turbines are known from prior art. With a burner located upstream of the individual combustion chambers of the combustion chamber arrangement, a mixture of fuel and oxygenated combustion gas is ignited and burns in the individual combustion chambers of the combustion chamber arrangement. The hot gases produced by the combustion of the mixture of combustion gas and fuel expand and are accelerated in the direction of the turbine chamber downstream of the combustion chamber arrangement. The individual combustion chambers are formed from an input section of generally cylindrical form and a transition section in which the hot gas flow with a circular cross-section changes to a hot gas flow with a annular segment shaped cross-section, so that at the end of the plurality of individual combustion chambers a hot gas flow with an overall annular cross-section is formed. This enters the turbine chamber where it meets an arrangement of fixed blades and moving blades, and causes the latter to move. With this principle, rotation of a turbine shaft connected to the moving blades is achieved, which can be used for various purposes such as power generation or jet propulsion. For design reasons the individual combustion chambers of the combustion chamber arrangement are placed at an angle relative to an engine axis that is defined by the axial alignment of the turbine chamber. Because of this angle the hot gas flows, which initially run along the axis of the individual combustion chamber, are deflected in the direction of the engine axis. Such an arrangement of an individual combustion chamber with a transition to the turbine chamber of a gas turbine has been published in U.S. Pat. No. 4,719,748. In the arrangement presented there, the hot gas flow generated in a cylindrical input section of the individual combustion chambers are deflected via a transition section in the direction of a turbine chamber, whereby the annular input gap leading to the turbine chamber is essentially aligned coaxially with the engine axis. Deflection of the hot gas flow from the axis of the individual combustion chamber at an angle to the engine axis towards a direction parallel to the engine axis takes place in this arrangement in the transition section of the individual combustion chambers. For this purpose the internal walls in the direction of the turbine shaft and the external walls of the transition sections away from the turbine shaft are embodied with appropriate baffles which force the hot gas flow from the direction of flow parallel to the combustion chamber axis to a direction of flow parallel to the engine axis. One problem with this procedure is that in the area of the baffles embodied with comparatively small radii the hot gas flow hits the walls of the individual combustion chambers in the input area, exposing them to increased mechanical and thermal loads. This leads to a steep temperature rise in the individual combustion chambers in the transition section, which in turn calls for increased cooling. In the above-mentioned U.S. Pat. No. 4,719,748 this is taken into account by baffle cooling in the area of the transition section, which necessitates a pressure drop. The pressure drops required to cool such an embodied transition section of the individual combustion chambers and the quantities of additional cooling gas required reduce the overall efficiency of the turbine and are therefore seen as disadvantageous. In addition, the cooling arrangement shown in U.S. Pat. No. 4,719,748 for the individual combustion chambers calls for higher design costs as the chambers have to be provided with a double-shell casing along their entire length. |
<SOH> SUMMARY OF INVENTION <EOH>On the basis of this prior art, the object of the invention is to create a gas turbine in which the thermal and mechanical loads of the individual combustion chambers are significantly reduced in the transition section so that cooling requirements can be lowered in this area. In order to achieve this object it is proposed with the present invention that the transition section of at least one individual combustion chamber and a corresponding input area of the turbine chamber be embodied in such a way that the gas flow running from at least one individual combustion chamber into the turbine chamber is deflected in the direction of the engine axis substantially in the input area of the turbine chamber. Because deflection of the hot gas flow in the direction of the engine axis due to the embodiment of the transition section of the individual combustion chamber and the input area of the turbine chamber in accordance with the present invention no longer takes place almost entirely in the transition section of the individual combustion chamber but is substantially relocated to the input area of the turbine chamber, the turbine elements located in the input area of the turbine chamber, in particular the fixed blades, are exposed to the mechanical and thermal loads associated with the deflection. These elements, which are embodied as cast elements to withstand the thermal stresses already present, can dissipate the additional thermal loads resulting from the deflection of the gas flow much better however than the reshaped transition sections of the combustion chambers. Thanks to the essentially linear hot gas flow in the area of the transition section, these are relieved of thermal loads to such an extent that cooling requirements in this area can be significantly reduced. Compared with prior art, material stresses on the individual combustion chamber in the transition section are therefore reduced, which has a positive effect overall on the durability and service life of this component. The fact that there is no longer any need to expend a great deal of time, money and effort on cooling the transition section of the individual combustion chamber means that the chamber is easier to design and that designers have much greater freedom. In a beneficial embodiment of the invention, the transition section of at least one individual combustion chamber has an internal wall located closer to a turbine shaft and an external wall located further away from the turbine shaft, whereby the internal and external walls of the individual combustion chamber are essentially straight or curve gently in the direction of the engine axis. A gentle curve in the direction of the engine axis means a curve with a large radius, with the hot gas flow being deflected in a wide arc, so that thermal load peaks can be avoided in these areas. With the internal and externals walls of the transition section running essentially in a straight line there are no additional thermal or mechanical loads due to the deflection of the gas flow. In a possible embodiment of the invention the external wall of the transition section of the individual combustion chamber runs essentially in a straight line, whereas the internal wall is gently curved, in other words it has a large radius. In accordance with a further beneficial feature of the invention, fixed blades are arranged in the turbine chamber with fixed blade platforms aligned essentially parallel to the engine axis, with at least one fixed blade platform in the input area of the turbine chamber running at an angle in the direction of the combustion chamber longitudinal axis. In this way, the fixed blade platforms running at an angle or in a curve deflect the hot gas flow and absorb the additional thermal and mechanical loads resulting from deflection. Since the fixed blades are castings, as mentioned above, and as such have excellent thermal conductivity, additional thermal loads arising at this point because of the deflection of the hot gas flow can be easily dissipated and absorbed with comparatively simple cooling measures. In accordance with a further beneficial embodiment of the invention, the fixed blade platforms in the input area can be lengthened in the direction of the individual combustion chambers to further relieve the load on the transition section of the individual combustion chamber. In this way the hot gas flow can hit the lengthened sections of the fixed blade platforms very early and be deflected in the direction of the engine axis by these elements. With such a fixed blade platform in the input area of the turbine chamber, lengthened in the direction of the individual combustion chamber the radius in which deflection of the hot gas flow takes place can also be increased and the thermal and mechanical loads arising from deflection can be distributed over a larger area. In a further embodiment of the gas turbine in accordance with the invention, fixed blade platforms are provided in the turbine chamber in the form of internal and external fixed blade platforms, with the internal fixed blade platforms arranged close to the turbine shaft and the external platforms further away. To deflect the hot gas flow at least one internal and/or at least one external fixed blade platform can be angled to the engine axis and/or extended. The thermal and mechanical loads on the individual combustion chamber in the transition section are further reduced if, in accordance with a further beneficial embodiment of the invention, the cross-sectional area of the individual combustion chamber is essentially constant in the direction of the gas flow. By avoiding reductions in the cross-sectional area in the direction of the hot gas flow, the additional thermal and mechanical loads on the individual combustion chamber walls in the area of the transition section resulting from narrowing of the cross-section are further reduced. For a gas turbine, all the individual combustion chambers and corresponding input areas are preferably embodied with one or more of the features described above. |
System for electronic payment and monitoring of fees |
A system for the payment and monitoring of fees which includes a personal device carried by a user and a monitoring device which communicates with the personal device to confirm/ascertain that the personal device has been activated to deduct the required fee. |
1. A system for the payment and monitoring of fees which includes a personal device carried by a user and activatable by the user for deduction of a payable fee by electronic payment means for a particular location, the personal device having a wireless communication means for communication with a monitoring device which communicates with the personal device to confirm/ascertain that the personal device has been activated and has or is deducting the required fee, the monitoring and/or the personal device includes a location-recording unit so that deduction of the fee is identified as being for the particular location. 2. A system as claimed in claim 1 wherein the location recording unit is a global positioning system (GPS). 3. A system as claimed in claim 1 where the monitoring device includes a coded wire tag reader or a bar code reader so that it can determine the particular location where the personal device is located by reading the coded wire or barcode located at the particular location. 4. A system as claimed in claim 1 where the monitoring device includes a key pad so that the unique number identifying the particular location can be entered by the monitoring device user to determine where the personal device is located. 5. A system as claimed in claim 1 which includes a monitoring device able to record and recall the particular location at which a personal device is/was located and is able to determine the length of time elapsed since the personal device was previously recorded as being at a particular location. 6. A system as claimed in claim 1 which includes a monitoring device which is programmable to calculate the correct rate of pre-paid credit deduction for a particular location. 7. A system as claimed in claim 6 which includes a monitoring device which can automatically compare the rate of pre-paid credit deduction being deducted by a personal device to the correct rate of deduction programmed into the monitoring device for a particular location, and automatically advise the monitoring device user whether the personal device is deducting the pre-paid credit at the correct rate for the particular location. 8. A system as claimed in claim 1 that includes a monitoring device that can automatically advise the monitoring device user, through an audible or visual signal, that the personal device it is communicating with, is operating correctly. 9. A system according to claim 8 wherein the monitoring device is able to advise the monitoring device user whether pre-paid credits are being deducted at the correct rate for the particular location the personal device is located at. 10. A system as claimed in claim 1 which includes a smart card containing a pre-paid credit and a programmed unique location code which enables a personal device user to use a particular smart card in a particular location for which they are authorized and where they are authorized to deduct pre-paid credits at a rate different to other categories of personal device users such that when the personal device communicates with the monitoring device, which has been programmed to expect a particular rate the information from the smart card causes the monitoring device to indicate to the monitoring device user that the rate was correct for that combination of personal device, smart card type and particular location. 11. A system as claimed in claim 10 wherein the user has two or more smart cards, from different organisations, the selection of the organisation to pay being made by the user by inserting the appropriate card into the personal device before it is activated. 12. A system as claimed in claim 1 wherein the personal device has input means so that the user can input the rate at which the fee is to be paid, the monitoring device being adapted to determine that the correct rate has been entered. 13. A system as claimed in claim 1 wherein the personal device is mountable in a vehicle for use in payment of parking fees. 14. A system as claimed in claim 1 wherein the personal device is a hand held portable device for use in payment of public transport and/or other fees. 15. A system as claimed in claim 1 wherein a single monitoring device is mounted at a location for monitoring all personal devices utilizing a particular service at that location. 16. A system as claimed in claim 1 wherein the monitoring device is a hand held device carried by monitoring persons who patrol and service an area or location where the system is used. 17. A system as claimed in claim 1 wherein the personal device is battery or solar power operated and contains electronic capability to process the transaction. 18. A system as claimed in claim 17 wherein a flexible connection to the motor vehicle cigarette lighter and/or battery can be used to charge the internal battery and/or run the personal device. 19. A system as claimed in claim 1 wherein a clip allows the personal device to be mounted on the steering wheel of a car or handle bars of a motorbike. 20. A system as claimed in claim 1 wherein a keypad of the personal device has a display showing the amount, or value of credits left on the card, numeric keys 0 to 9 which are used by the user to input a required charge and start and stop keys. 21. A system as claimed in claim 20 wherein the keypad has a set key used to power on the device to enable setting to begin and a stand-by key that places the device in stand-by mode to minimize power usage over prolonged periods of non-use. 22. A system as claimed in claim 21 wherein the keypad has keys which are used respectively to activate a delay start and early stopping when fees are payable for only a portion of the day. 23. A system as claimed in claim 22 wherein the keypad has a display which shows the minutes/hours to delay starting and/or stopping of the personal device. 24. A system for the collection and monitoring of fees known as road user charges in which a personal device activatable by a user for deduction of a payable fee by electronic payment means, the personal device having a wireless communication means for communication with a monitoring device which communicates with the personal device to confirm/ascertain that the personal device has been activated to deduct the required fee, the personal device being either linked electronically to a vehicle's odometer or to an internal GPS device to measure distance traveled. 25. A system as claimed in claim 24 wherein the personal device is permanently mounted in the vehicle. 26. A system as claimed in claim 24 wherein the user can activate the personal device when traveling on roads subject to a user charge, entering the appropriate rate for the vehicle. 27. A system as claimed in claim 26 wherein the personal device can deduct the appropriate amount from the prepaid card based on the distance traveled. 28. A system as claimed in claim 24 wherein the monitoring device can be hand held, mounted beside the road or located strategically to cover large areas, and is adapted to receive transmissions from the personal device. 29. A system as claimed in claim 28 wherein the monitoring device records that the personal device was activated and deducting an amount from the prepaid card. 30. A system as claimed in claim 29 wherein different rates of charge are possible for different classes of vehicle and the monitoring device is pre-programmed to match the correct rate of deduction for a specific personal device. 31. A system as claimed in claim 29 wherein several different rates of charge are possible and the personal device transmits information to the monitoring device to enable it to calculate the correct rate of deduction. 32. A system as claimed in claim 28 wherein an enforcement agency at a roadside can physically or visually check that the rate of deduction is correct for the vehicle and circumstances. 33. A system for the collection and monitoring of a fee known as an entrance fee or entrance tax, which includes a personal device carried by a user and activatable by the user for deduction of a payable fee by electronic payment means, the personal device having a wireless communication means with an external device which communicates with the personal device to confirm/ascertain that the personal device has been activated and has or is deducting the required fee, the monitoring and/or the personal device includes a location-recording unit so that deduction of a fee is made when the user passes the external device at a particular location. 34. A system as described in claim 33 wherein the personal device communicates with the external device to confirm to the external device that the personal device is operating correctly and has deducted the nominated number of pre-paid credits from a smart card. |
<SOH> BACKGROUND TO THE INVENTION <EOH>One of the problems with levying a charge for indulging in common place activities, such as parking a vehicle, is the effort and overhead involved in collecting the fee and monitoring compliance. This is particularly so in the case of vehicle parking as in many instances it operates on a quasi-honesty system, i.e. payment points are stationed adjacent, or in the location of, vehicle parks and rely on persons using those parks to voluntarily pay a charge. Compliance is monitored by regular or random spot checks by parking wardens and additional fines levied for non compliance. The salary cost of the wardens constitutes a considerable added running cost The disadvantage with such systems is the cost of the fee collection infrastructure, for example parking meters or coupon machines. These machines need regular attention to keep them in working order as well as to empty collected money. An additional overhead is the cost of policing compliance. To overcome these problems pre-paid coupons are commonly used. Vehicle users can purchase a book of coupons. A coupon is removed from the book and knockouts or removable panels are manipulated to indicate the date and time of use. The coupon is displayed in the vehicle window. This system does not overcome the high cost involved in monitoring compliance, and further it is not uncommon for persons to attempt to reuse old coupons. Another situation where a charge is levied for a common place occurrence is toll roads where it is known to make an automatic deduction of road tolls and city entrance taxes. It is recognized that significant savings might be made by local authorities, such as parking and roading agencies, through efficiencies in fee collection and enforcement. It is an object of the present invention to provide a system for simplifying fee collection and monitoring for chargeable activities. It is a further object of the present invention to provide a system that ameliorates, or at least overcomes, some of the disadvantages with the prior art, or at least to provide the public with a useful alternative choice. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the invention there is provided a system for the payment and monitoring of fees which includes a personal device carried by a user and activatable by the user for deduction of a payable fee by electronic payment means, the personal device having a wireless communication means for communication with a monitoring device which communicates with the personal device to confirm/ascertain that the personal device has been activated to deduct the required fee. Preferably the electronic payment means is a smart card, or similar, inserted into the personal device. The invention envisages that preferably, although not exclusively, a user purchases/obtains a smart card, or similar, from an organisation to whom a fee is payable, the smart card containing pre-paid credits, preferably in monetary value or the equivalent of monetary value, which can be deducted from the smart card, or similar, by the personal device on activation by the user. The user can have two or more smart cards, or similar, from different organisations, the selection of the organisation to pay being made by the user by inserting the appropriate card into the personal device before it is activated. Preferably, the personal device has input means so that the user can input the rate at which the fee is to be paid, the monitoring device being adapted to determine that the correct rate has been entered. In one particular embodiment the personal device is mountable in a vehicle for use in payment of parking fees. In an alternative embodiment the personal device is a hand held portable device for use in payment of public transport and/or other fees. In further aspects of the invention there is provided a personal device and, separately, a monitoring device for use in the system for the payment and monitoring of fees. The monitoring and/or the personal device can include a global positioning system (GPS) location-recording unit. Preferably a single monitoring device is mounted at a location for monitoring all personal devices utilising a particular service at that location. Alternatively, the monitoring device can be a hand held device carried by monitoring persons who patrol and service an area or location where the system is used. In another embodiment the invention can be used for the collection and monitoring of fees known as road user charges in which case a personal device can either be linked electronically to a vehicle's odometer or to an internal GPS device to measure distance travelled. The personal device can in this case be permanently mounted in the vehicle. The user can activate the personal device when travelling on roads subject to a user charge, entering the appropriate rate for the vehicle. The personal device can deduct the appropriate amount from the prepaid card based on the distance travelled. In said another embodiment the monitoring device can be hand held, mounted beside the road or located strategically to cover large areas, and can receive transmissions from the personal device(s). The monitoring device can record that the personal device was activated and deducting an amount from the prepaid card. Where different rates of charge were possible for say, different classes of vehicle, the monitoring device can be pre-programmed to match the correct rate of deduction for a specific personal device. Where several different rates of charge are possible (for example, different rates for laden or unladen vehicles) the personal device can transmit for example the weight of the vehicle thus enabling the monitoring device to calculate the correct rate of deduction. Alternatively, enforcement agencies at the roadside can physically or visually check that the rate of deduction is correct for the vehicle and circumstances. Further aspects of the invention will become apparent from the following descriptions which are given by way of example only. |
Apparatus for supplying an oxygen-containing gas to a fuel cell system |
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