The instant invention comprises a process of preparing a composition comprising directed sequence polymer (DSP) mixtures that act as epitopes and useful as vaccines, such DSP synthesized according to a set of rules regarding the identity and the frequency of occurrence of amino acids that substitute a base or native amino acid of a known epitope. The resulting composition is a mixture of related peptides for therapeutic use as a vaccine, preferably for infectious agents that are immune evasive.

The infection of a host by an infectious pathogen is a complex event comprising a series of coordinated events in which the pathogen attempts to evade both the host's innate and adaptive immune systems. In their attempts to replicate and survive, the invading pathogens cause damage to the host. The destruction generally takes the form of cell death, either from pathogen entry into the cell or from endo/exo-toxins produced by the pathogen, as well as the induction of host cellular responses that have the ability to cause further tissue damage, scarring or hypersensitivity. Although between 1938 and 1952, the decline in infectious disease-related mortalities decreased 8.2% per year (Armstrong, G L et al., JAMA 1999, 281:61-6), the death rates due to infectious disease have been increasing since the 1980s. A study performed at the National Center for Infectious Diseases demonstrated that the death rate due to infectious diseases as the underlying cause of death increased 58% from 1980 to 1992. In 1992, 64 of every 1,000 deaths were attributable to infectious disease (Pinner, R W et al., JAMA 1996, 275:3).
The mechanisms of infectious diseases comprise two distinct but interconnected aspects: (1) the various organisms attempting to invade a host, each different class of infectious agents having distinct means by which they attempt to evade the host's immune system, and (2) the host's immune response to the invading pathogen. Humans have warded off infectious diseases in both of these aspects, in the first aspect, by preventing the access of infectious agents (e.g. by sanitary habits) and in the second aspect, by assisting and boosting the immune system by, for example, vaccination.
The Fight Against Infectious Disease
Immunization programs in the effort to control infectious diseases, such as small-pox, polio, measles, mumps, rubella, influenza caused by Haemophilus influenza (flu), pertussis, tetanus, and diphtheria, used centuries old technology to safely create an immune response in a host prior to pathogenic infection by the live organism. These vaccination protocols called for the introduction to the host of an inactive or very weak form of the actual pathogen, and in so doing an active immune response was created.
To make vaccination more effective, advances in eliciting stronger immune responses have been made with the development of antigen/epitope non-specific treatments that boost immune activity, such as the adjuvant alum (see Vaccine Adjuvants and Delivery Systems, edited by Manmohan Singh 2007 Wiley & Sons ISBN: 978-0-471-73907-4, incorporated by reference herein, for an extensive review of vaccine adjuvants), as well as development of immunogens based on the understanding of the genetic basis of these pathogens (GenBank, a database managed by the National Center for Biotechnology Information, now has over 85 billion base pairs in its database. Searching based on pathogen is widely used (http://www.ncbi.nlm.nih.gov/Genbank/). The latter has opened up the possibility of utilizing discrete sequences of proteins derived from the pathogen as immunizing agents in the context of cell-mediated (T cell via MHC class I and/or II), but not humoral (Bcell/antibody-mediated immunity). These peptide-based vaccines are specific to epitopes (also called antigenic determinants) that are the precise moieties within antigenic materials to interact with immune system components, intended to boost immune reactivity, and are administered using methods designed to excite immune function. One major limitation of the epitope/peptide-based approach is the variability with which the human MHC class I and II receptors bind the peptides.
While improvements to the techniques have been made in the form of differing types of inactivation of pathogen or in the use of adjuvants to enhance immunogenicity, there remain infectious diseases that are generally refractory to traditional vaccine therapies. In the context of influenza vaccines specific for a particular strain of the virus, clinical efficacy rates range near 40% when there is not a match with the circulating strain (Ben-Yedidia, T and Arnon, R, Expert Rev. Vaccine 2007, 6:939-948).
A need remains in the development of vaccines that can handle the infectious agents such as human immunodeficiency virus (HIV), cytomegalovirus, and severe acute respiratory syndrome coronavirus, as well as bacteria such as Pseudomonas aeruginosa, Neisseria gonorrhea, or Mycobacterium tuberculosis or parasitic diseases such as malaria or hookworm disease. In the context of influenza, the current licensed vaccines are produced in eggs, and make use of half-century old technology (Ben-Yedidia 2007, above).
These infectious agents, bacteria, and parasitic diseases are harder to treat using the inactive pathogen vaccine approach because of the organism's ability to evade host detection. The HIV or the flu virus has the ability to alter its immune profile multiple times in the amount of time less than a calendar year, progressively marginalizing the effectiveness of immunity gained by previous infection and/or even the most recently created vaccine.
In particular, flu viruses, which can easily spread widely and ubiquitously throughout the world, have a large adverse effect on the human population, affecting 10-20% of the total world-wide population (Ben-Yedidia 2007, above). Flu viruses are categorized into three types, A, B, and C. Influenza C rarely infects humans, but influenza A viruses infect various species and B viruses are specific to humans. A and B can be highly virulent. The human immune system attacks flu viruses by targeting their surface proteins hemagglutinin (HA) and neuraminidase (NA). As such, subtypes of flu viruses are categorized as combination of HA type and NA type. HA is a tri-valent viral glycoprotein with two subunits H1 and H2. The virus uses the H1 portion to gain entry to host cells by binding to α2-6 linked sialosides (human), or 2-3 linked sialosides (avian) (Stevens, J et al., J. Mol. Biol. 2008, 381:1382-1394). The secondary and tertiary structures of HA have been solved (Wilson, I A et al., Nature 1981, 289:366-73). Currently there are 15 known subtypes of HA and 9 known subtypes of NA.
The difficulty for the human body to effectively counter influenza infection lies in the fact that the HA protein mutates quickly, allowing the viruses to evade the host organism's immune system. The average rate of amino acid substitutions is 3.6 per year (Smith, D J et al., Science 2004, 305:371-6). Once a mutation occurs in a given epitope region of influenza HA, a second mutation does not immediately occur in that epitope region resulting in a linear profile of temporal appearance of mutation sequence clusters in HA (Plotkin, J B et al., Proc. Nat. Acad. Sci. USA 2002, 99:6263-68). The H1 subunit of HA has been shown to have five main antigenic epitopes. In these regions the amount of mutation is significantly higher than in other regions of the protein.
It is important to understand the metes and bounds of the immunity induced in a host by immunization with a single strain of influenza; how said host responds to another strain dictates the selection of the next vaccine strain. The mutations in the influenza HA protein are subdivided into two groups, antigenic drift and antigenic shift. Antigenic drift is a phenomenon where the protein sequence of HA changes, resulting in immune evasion and improved ability of the virus to enter and replicate in a host cell. Drift measurement metrics have evolved and include the Hamming and Miyata metrics (Miyata, T et al., J. Mol. Evol. 1979, 12:219-36; Henikoff, S et al., Proc. Nat. Acad. Sci. USA 1992, 89:10915-19). Antigenic drift causes the seasonal flu surge that is usually not lethal to otherwise healthy people with normal immune system, but it still affects 10-20% of the world's human population, with up to 5 million cases of serious illness and half million deaths, according to the World Health Organization (WHO). Using the Hamming metric, investigators have suggested that no viral cluster (drifted sequences) has members that last longer than seven years, due to new dominant clusters that replace one another on average every 2-5 years. Other investigators have characterized the inter-pandemic evolution of influenza as intervals of immunologically neutral sequence evolution without significant antigenic alteration. During this time of stasis, there is a slow extinction of coexisting virus lineages that is contrasted with rapid and dramatic excess of amino acid replacements in the variable, or epitopic regions of HA, resulting in the ascension of the new dominant strain at the expense of the earlier variants (Wolf Y I et al., Biology Direct 2006, 34:1-19). These investigators determined that in periods of slow extinction (drift), the ratio of the number of amino acid replacements in the variable, or epitopic regions to the non-variable regions was 9:8, whereas periods of rapid extinction (shift) saw a ratio of 23:1 (Wolf, 2006, above). Thus one means to define a cluster of variants is those currently existing strains that have a ratio smaller than 9:8 of amino acid changes between epitopic and non-epitopic regions.
Antigenic shift, on the other hand, is a major change, requiring four or more amino acid changes across two or more antigenic sites (Plotkin, 2002 above). Such antigenic shift causes an increase in pathology and mortality in humans because of their immunological naiveté to the new strain. In the past, the fast expansions of Spanish flu or Hong Kong flu were deadly. Recently a threat of the H5N1 strain, the "bird flu" more fully described below, turning into a human pandemic strain is emerging.
The modern world has combated influenza epidemics by attempting to predict the next prevalent viral subtype and vaccinating people against it. In 1952, the WHO established the Influenza Program to assist fight against influenza epidemic, and coordinates a network of over 100 influenza surveillance centers all over the world. The centers characterize the antigenic properties of the isolated viruses using a test known as the hemagglutination inhibition (HI) assay, which measures the ability of the virus to agglutinate red blood cells, and the capability of antisera against related strains to inhibit such agglutination. The results of the HI assay is measured in units called antigenic distances, each of which unit corresponding to a twofold dilution of anti-sera in the assay (Smith, 2004, above). Thus a subsequent means to identify a cluster of variants is those currently existing strains having less than a twofold dilution of anti-sera in the HI assay.
In the United States, the Vaccines and Related Biological Products Advisory Committee of the Division of Viral Products ("the Vaccines Committee") at the Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration defines the most relevant strains for the production of vaccines using the HI assay. When the antigenic distance is greater than two, the Vaccines Committee will update the variant for the upcoming season (Smith, 2004, above). For the Northern Hemisphere's 2008-9 season, for example, the Vaccines Committee recommended H1N1 A/Brisbane/59/2007 and H3N2 A/Brisbane/10/2007 for Influenza A and B/Florida/4/2006 for Influenza B for the seasonal production of licensed vaccines (inactivated or attenuated viruses).
The choice of the Vaccines Committee of which is the appropriate strain for the upcoming season's vaccine production and distribution is based in large part on antigenicity. Quantitative measurements of antigenic data include numerical taxonomy or its equivalent (Papaud, A, Poisson A, J Mar Res 1986, 44:385; Mecking S, Warner J, Geophys Res 1999, 104:11087), the method of Lapedes and Farber (Wallace D W R, Ocean Circulation and Climate Academic Press San Diego, Calif. 2001 pp 489-521) which uses ordinal multidimensional scaling in the interpretation of binding data so that an antigenic map, or the distance between an antigen and antiserum can be visualized. A refinement of the Lapedes and Farber method (Smith D J, 2004, above; Sabine C L et al., Global Biogeochem Cycles 16:1083, 2002) positions/overlays the antigens and the antisera on a map.
An alternate approach of defining clusters is differentiation by the organization of genetic (DNA) data into phylogenetic trees. The international surveillance programs are responsible for the majority of the sequencing performed in order to identify serologically novel influenza strains (Layne S P, Emerg. Infect. Dis. 12:562-68, 2006). Investigators have reported that the meaningful antigenic changes that occurred in an H3N2 subtype influenza virus during the period between 1983 ad 1997 were found predominantly in the internal and not external branches of the tree (Bush, R M et al. Mol Biol Evol 1999, 16:1457-65). Thus a further subsequent means to identify a cluster of variants is the branching organization of those currently existing strains obtained using genetic data.
There are various types of vaccines available for human use: DNA-based, cellular, live pathogen, attenuated or inactivated pathogen-based, recombinant protein and peptides. There are currently five inactivated seasonal vaccines for human use (Fluzone®, Fluvirin®, Fluarix®, FluLaval®, and Afluria®), and one live attenuated (FluMist®). Peptide based vaccines can be either recombinant or synthetic. Since 1993 there have been over 1,000 peptide based vaccines in pre-clinical research, over 100 in Phase I human clinical trials, a small few in Phase II, and none passing Phase III (Hans, D et al., Medicinal Chemistry 2006, 2:627-46).
The candidate viral subtypes for annual flu vaccine update do not include the mainly avian infective H5N1, which have historically infected poultry. However, investigators at Scripps Research Institute and others have identified the Egret/Egypt/1162/NAMRU-3/06 as a variant having likely human infective potential (Stevens, 2008, above). In fact, reports of the H5N1 viruses infecting humans are increasing. Because of the lack of exposure to related sub-strains, an H5N1 infection in a human often has severe effects. The recently emerging ability of the virus to infect humans is thought to be attributable to the conversion from a SAα2-3Gal to SAα2-6Gal receptor recognition by the virus. Investigators have found that H5N1 virus that infected humans is capable of recognizing both types of receptors (Yamada, S et al., Nature 2006, 444:378-82).
Although helpful to an extent in preventing the disease, the success of the WHO's Influenza Program is limited for several reasons. One such reason is the limited number of surveillance locations and a small sampling size compared to the occurrence of influenza infection (in 2004-2005, about 6000 samples, or 1 sample per 100,000 cases). Another drawback is the time it takes to prepare vaccines once such candidate antigenic subtypes have been selected (Layne, Emerging Infectious Disease 2004, 12(4): 562-568). Added to the difficulties is the above-mentioned antigenic drift and shift. New strains may appear at any time.
Another complicating phenomenon is broadening of the immune response via the process of epitope spreading, where a host's immune system over time changes target of the immune attack to nearby epitopes (N. Suciu-Foca et al., Immunol. Rev. 1998, 164:241). Thus, the inability to modulate the relevant antigenic determinants over time renders simple vaccines ineffective in a short time.
Therefore, a new method for developing and preparing vaccines that are effective under these circumstances are needed.
Strategy for Creating Active Peptides
In recent years, vaccines based on synthetic peptide epitopes rather than whole antigenic molecules have been explored and developed, in the hope of more refined targeting and ease of achieving consistent quality, as well as the safety of being non-infectious. The results are mixed. As a practical matter, it is time- and resource-intensive to identify one peptide or a set of a limited number of peptides that would be effective as a vaccine. In addition, because of the infectious agents' immune evasion strategies briefly described above, peptide epitope-based vaccines have not overcome the shortcomings of traditional vaccines. Investigators have attempted to make use of conserved epitopes within the virus. These regions do not mutate, and thus represent an approach for the generation of broad-spectrum, peptide-based vaccines (Ben-Yedidia, 2007, above). These approaches using short peptides; however, the invoked immunity is T cell-based, requires adjuvant or carrier proteins (flagella) and lacks the proven pathogen fighting ability of preexisting antibodies (Zinkernagel, R M, Nobel Lecture Dec. 8, 1996).
The development and exploitation of combinatorial chemistry (CC) has propelled drug discovery. Drug discovery can be generalized into two major steps, lead generation and lead optimization. Oftentimes, a lead compound is identified that has some of the desired characteristics of a commercially viable therapeutic, but has shortcomings such as a low specific activity, toxicity, instability, etc. Thus, once a lead is identified, practitioners attempt to optimize the lead compound by testing other related compounds with similar structures. CC allows practitioners to create and quickly screen a library made of a vast number of candidates, to identify those with a specific activity against a target of interest.
For peptide based drugs, the goal is to define a single, or a limited set of peptides which demonstrate a particular activity. The art of CC as applied to the synthesis of peptide libraries, too, has advanced, producing highly reliable and pure mixtures of peptides of great diversity. The process of identifying the single or limited set of peptides that were responsible for the observed activity from such diverse libraries, called deconvolution, is schematically represented in FIG. 1A.
Drug discovery based on CC are powerful, but deconvolution can be difficult and time- and cost-intensive. Thus, to simplify deconvolution and make the process more efficient, practitioners have spent great efforts to create suitable synthesis methods. Examples of the resulting evolution of subtypes of combinatorial methods include: multiple synthesis, iterative synthesis, positional scanning, and one-compound-one-bead post assay identification design. They are briefly described below to show the state of the art and how peptide epitopes were successfully identified.
"Multiple synthesis" provides for any method whereby distinct compounds are synthesized simultaneously to create a library of isolated compounds. The identity of these compounds would be known from the rules of the synthesis. An example is found in H. M. Greysen et al., Proc. Nat. Acad. Sci. USA, 1984, 81:3998, where the investigators identified GDLQVL (SEQ ID NO: 20), out of 108 overlapping peptides, as the epitope recognized by an antibody raised against VPI protein of foot-and-mouth disease virus.
"Iterative synthesis/screening" involves methods of peptide synthesis which facilitates the determination of the peptide sequences as deconvolution is performed. This is done by synthesizing pools of peptides, each pool consisting of peptides with the two amino terminal residues defined and known to the investigators. These peptides can be shown as O1O2XXXX, wherein O1 and O2 are the defined residues and X is randomly selected. When a pool that contains a peptide that binds to a target is identified, the two amino terminal residues are known. The next step was to do the same for position three, by synthesizing peptides that can be shown as F F2O3XXX, wherein 03 is a fixed residue. Subsequent residues are determined in a similar manner. An example of iterative synthesis can be seen in R. A. Houghten et al., Nature 1991, 354:84-86, wherein the investigators honed in on the sequence DVPDYA (SEQ ID NO: 21) as the core epitope after identifying YPYDVPDYASLRS (SEQ ID NO: 22) using an ELISA type assay format.
"Positional scanning" is a synthesis method producing complex mixtures of peptides that allows for the determination of the activity of each individual peptide. Based on the screening results, the derived peptide can then be separately synthesized for optimization. As seen in C. Pinilla et al., Biochem J. 1994, 301:847-853, positional scanning libraries were used to identify decapeptides which bound the same YPYDVPDYASLRS-binding antibody (SEQ ID NO: 22). In this case ten different libraries each containing 20 pools with a defined amino acid at each of the ten positions in the peptide. Fifteen peptides were identified.
Each of the above methods were also employed to identify enzyme substrates (J. H. Till et al., J. Biol. Chem. 1994, 269:7423-7428, J. Wu et al, Biochemistry 1994, 33:14825-14833, W. Tegge et al., Biochemistry 1995, 34:10569-10577) or enzyme inhibitors (M. Bastos et al., Proc. Nat. Acad. Sci. USA 1995, 92:6738-6742, Meldal et al., Proc. Nat. Acad. Sci. USA 1994, 91:3314-3318, R. A. Owens et al., Biomed Biophys. Res. Commun. 1994, 181:402-408, J. Eichler et al., Pept. Res. 1994, 7:300-7).
As powerful and clear-cut the identification of a specific peptide may be, as a therapeutic, such identified peptide may only be a lead peptide that is not itself useful. The identified peptide epitope may be ignored by the immune system if it resembles a self protein or possibly exacerbate the very condition that the therapy aims to relieve. However, by designing peptides of similar sequence, one may create, based on such peptide, epitope reactive analogs that would act as modifiers of the immune responses and/or as excitors of an immunogenicity response.
One such approach is creation of altered peptide ligands (APL). This approach is schematically represented in FIG. 1B. An APL is defined as an analog peptide which contains a small, number of amino acid changes from a starting sequence such as that of a native immunogenic peptide ligand. While recognition of the native response may induce an antagonist-like reaction, an APL might also induce a partial agonist response, or induce a state of anergy in the reactive T cell population. In discussing APL in the context of allograft rejection therapy, Fairchild et al., Curr. Topics Peptide Protein Res. 2004, 6:237-44, note that an APL acting as an antagonist for one TCR, may become an agonist for another, complicating the rational design of an APL. Compounding the obstacle of the development of APL is the difficulty in translating a response developed in an animal system into human.
An illustrative example is an APL based on an epitope of myelin basic protein, MBP83-99 (ENPVVHEFKNIVTPRTP (SEQ ID NO: 23)), which is reported to be a target of autoimmune response causing multiple sclerosis. APLs were made by replacing the bold and underlined amino acid residues "E", "N", "E" and "K," resulting in identification of a single peptide having the amino acid residue sequence AKPVVHLFANIVTPRTP (SEQ ID NO: 24) that appeared to have the desired activity of neutralizing antibodies against MBP83-99, Kim et al. Clinical Immunology, 2002, 104:105-114. The peptide was placed into limited human trials, which reportedly resulted in the long term immune reactivity against the peptide, but the treatment has been deemed clinically ineffective by evaluation using MRI. Thus an APL, once identified, can be used as a therapeutic agent; however, its effectiveness may be limited in terms of clinical efficacy.
Evasive Targets
In the context of developing vaccines in the prevention of infectious disease, the invading pathogens have acquired by natural selection the ability to quickly create variability in the relevant immunogenic epitope. Examples of viral mutants generating escape variants that avoid immune detection have been reported for Hepatitis B, influenza, and HIV (Tabor, E, Journal of Med. Virol., 2006, 78:S43-S47; Daniels, R S et al., EMBO Journal 1987, 6:1459-65; D'Costa, S et al., AIDS Res Hum Retroviruses 2001, 17:1205-9). This variation progressively dampens the utility of single-epitope vaccines.
Thus, investigators have attempted to overcome this limitation by introducing variance by creating a mixture of immunity-inducing epitopes to be used as vaccines. Furthermore, it has previously been shown that mixtures of related peptides may be therapeutically more effective than a single peptide. Lustgarten et al., J. Immunol. 2006, 176: 1796-1805; Quandt et al., Molec. Immunol. 2003, 40: 1075-1087. The effectiveness of a peptide mixture as opposed to a single peptide is the likelihood of interaction with the broadening of the relevant epitopes via evolution-induced variation. Therefore, to increase and maintain the longer-term effectiveness, these previous treatment modalities have been modified. For example, a therapeutic composition based on an APL may include multiple peptides created by the APL method in combination with the original peptide, or other APLs. Fairchild et al., Curr. Topics Peptide & Protein Res. 2004, 6:237-44. Each APL would have a defined sequence, but the composition may be a mixture of APLs with more than one sequence. A reverse example involving conceptually similar altered peptide ligands involves an inventor's attempt to reduce the amount of variation created by pathogens to avoid immune recognition (viral alteration of immunogenic epitopes over time, e.g., the creation of altered peptide ligands), by using the very changes created by the pathogen in an epitope sequence to create a limited diversity pool of peptides potentially useful in vaccinations (U.S. Pat. No. 7,118,874). In this invention, distinct hyper-Variable region sequences from HCV or influenza virus were compared. The amino acid changes having a frequency greater than 12% were incorporated into a mixture of between 2 and 64 different peptides.
However, a simple mixture of several soluble peptide epitopes faced certain manufacturing issue of soluble peptide mixtures, such as difficulties in delivering a consistent ratio and quantity of each of the peptides in the mixture.
Peptide dendrimers were conceived to overcome some of these shortcomings of soluble peptide mixtures, and also by providing other perceived advantages. This approach is schematically represented in FIG. 1C. The design of dendrimers intends to mimic two traits of naturally occurring biological structures: a globular structure and polyvalency to amplify the ligand:substrate interaction. Beyond these commonalities, dendrimers are chemically and structurally diverse, with reports of a wide range of sizes, from 2 kDa to greater than 100 kDa. Dendrimers are described in two comprehensive reviews (P. Niederhafner et al., J. Peptide Sci. 2005 December; 11(12):757-788; K. Sadler and J. P. Tam, Rev. Mol. Biotechnol. 2002, 90:195-229), and their applications in additional literature (D. Zanini and R. Roy, J. Org. Chem. 1998, 63:3468-3491; J. Haensler and F. C. Szoka, Bioconjug Chem. 1993, 4:372-379; Tam, James P et al., J. Exp. Med. 1990, 171:299-306).
Despite attempts and a certain amount of success in utilizing dendrimers and some improvements in synthesis and purification strategies, a high cost of manufacturing and the subsequent analytical development precludes this technology from being further currently developed commercially.
All of the above strategies, while recognizing the advantage of variations in the therapeutic peptide compositions, derive from the concept that there is one or more defined peptide sequences evoking a defined immunological response. These strategies have attempted to multiply and diversify modulatory peptides via the introduction of defined, single changes performed one at a time.
An entirely different approach which has evolved alongside the defined sequence peptide immunotherapy approach is the use of random epitope polymers. Random sequence polymers (RSP) can be described as a random order mixture of amino acid copolymers comprising two or more amino acid residues in various ratios, forming copolymers by random sequence bonding, preferably through peptide bonds, of these amino acid residues, which mixture is useful for invoking or attenuating certain immunological reactions when administered to a mammal. Because of the extensive diversity of the sequence mixture, a large number of therapeutically effective peptide sequences are likely included in the mixture. In addition, because of the additional peptides which may at any given time not be therapeutically effective, but may emerge as effective as the epitope shifting and spreading occurs, the therapeutic composition may remain effective over a time of dosing regimen. This approach is schematically represented in FIG. 1D.
Copolymer-1 (also known as Copaxone®, glatiramer acetate, COP-1, or YEAK random copolymer) is an FDA approved, commercially available therapeutic used for the treatment of multiple sclerosis comprising random copolymers of Y, E, A, and K. Random copolymers are described in International PCT Publication Nos. WO 00/05250, WO 00/05249; WO 02/59143, WO 0027417, WO 96/32119, WO/2005/085323, in U.S. Patent Publication Nos. 2004/003888, 2002/005546, 2003/0004099, 2003/0064915 and 2002/0037848, in U.S. Pat. Nos. 6,514,938, 5,800,808 and 5,858,964. It is one of the few therapeutics for multiple sclerosis that continues to be effective over time.
Attempts continue to build on the success of COP-1 by creating other RSPs and related peptide compositions. WO/2005/074579 (the '579 publication) describes complex peptide mixtures of various amino acid composition. The disclosure also contains diversity-constraining mechanisms of defining amino acids at certain positions rather than being chosen by the random nature of the synthesis rules. Another such attempt is the work originated by Strominger et al. (WO/2003/029276) and developed further by Rasmussen et al. (US 2006/0194725) wherein they created RSP consisting of the amino acids Y, F, A, and K with different amino acid ratios and a shorter average length than COP-1 Alanine content was increased based on Maurer (Pinchuck and Maurer, J. Exp Med 122(4), 673-9, 1965), which described how an EAK polymer with higher alanine content (10-60 mole percent) produced "better antigens"; Rasmussen et al. in fact demonstrated that a YFAK input ratio of 1:1:1:1 was not effective in eliciting a recall response as compared to a YFAK preparation with an input ratio of 1:1:10:6.
WO/2005/032482 (the '482 publication) describes another approach, which is to build degenerate peptide sequences based on motifs, exemplified by [EYYK]. The motifs are used as is, or can be altered by amino acid substitutions (defined on page 10-11 of the '482 publication). A significant difference from COP-1 is that it lacks alanine. Much of the invention hinges on the presence of a D-amino acid at the amino terminal of the motif.
Tracing back steps to the defined peptide search, there have also been attempts to identify the active peptide(s) within the RSP mixture. The drawback of this technology lies in the very nature of the attempt to determine discrete substitutes for the randomness that COP-1 encompasses.
Effective as the random sequence polymer approach may be, even the improvements have not resolved the drawback and limitation of COP-1, which is, for example, the undefined nature of what is effective in each motif and the possibility of containing a large proportion of truly inactive peptides, lowering the concentration of the active components, or worse, adversely stimulating the immune system. Additionally, these compounds are difficult to manufacture and to obtain consistency from lot-to-lot.
All these approaches have not overcome the shortcomings of previously existing systems, and need remains for a composition and a method to create such composition that would serve effectively as a vaccine by eliciting beneficial immune responses consistently and over time toward pathogens, for which existing vaccine compositions have failed to be effective.

Methods for designing and preparing vaccines comprising directed sequence polymer compositions via the directed expansion of epitopes


A connection between a metallic threaded fastener having a threaded portion and a part of plastic material having a bore, the threaded portion forming or tapping a counter thread into the wall of the bore, characterized in that for a predetermined number of threads, the entrance portion of the bore is provided with a circular shaped or arc shaped inclined cam surface which encircles the bore helically and which forms a step between the ends of the cam surface or the associated ends of adjacent cam surfaces, respectively.

There are various types of connections or joints comprising a metallic screw or bolt to be screwed into a plastic part. The plastic part has a bore having a diameter which, for example, approximately similar to the pitch diameter of the screw threads. The screw threads of the screw or bolt are of such a structure that they form threads within the plastic part by displacing material or by a tapping or cutting operation.
Conventional connections or joints--no matter whether the screw threads are of the single, double or multiple thread type--suffer from the drawback that the screw when being positioned upon the plastic part is oriented obliquely to the axis of the bore corresponding to the pitch angle of the threads. It is difficult to screw or thread the bolt or screw into the bore under substantial axial pressure. Furthermore there is the risk that the screw or bolt will be screwed into the bore in an oblique manner when the axis of the screw or bolt is inclined with respect to the axis of the bore. Still further, when a screw or bolt is screwed into the bore again there will be the risk that it will form additional threads in the bore so as to weaken the connection or joint.

Connection between a metallic threaded fastener and a part of plastic material


A solar cell module is discussed. The solar cell module includes a plurality of solar cells, each solar cell including a substrate and an electrode part positioned at a surface of the substrate, an interconnector electrically connecting at least one of the solar cells to another of the solar cells; and a first conductive adhesive film including a first resin and a plurality of first conductive particles dispersed in the first resin. The first conductive adhesive film is positioned between the electrode part of the at least one solar cell and the interconnector to electrically connect the electrode part of the at least one solar cell to the interconnector. A contact surface between the first conductive particles and the interconnector is an uneven surface.

1. Field of the Invention
Example embodiments of the invention relate to a solar cell module in which adjacent solar cells are electrically connected to one another using an interconnector.
2. Description of the Related Art
Solar power generation to convert light energy into electric energy using a photoelectric transformation effect has been widely used as a method for obtaining eco-friendly energy. A solar power generation system using a plurality of solar cell panels has been installed in places, such as houses due to an improvement in a photoelectric transformation efficiency of solar cells.
In a solar cell module, power produced by the solar cells may be output to the outside of the solar cell module by connecting a conductive element (for example, an interconnector) connected to an anode and a cathode of each of the solar cells, to lead wires to provide an extension of the conductive element to the outside of the solar cell module. Further, current may be output through a power supply line of a junction box by connecting the lead wires to the junction box.


One implementation provides a novel station-to-station handoff using an adaptive or directional antenna. The directional antenna generates a plurality of directional search beams to search for pilot signals from new base stations. The search beams are scanned one beam at a time to obtain the relative direction of all new base stations detected. From the detected base stations, a new base station with the strongest signal strength is selected and compared to the currently used base station. If the new base station has stronger signal strength than the current base station, then a communication handoff from the current base station to the new base station is initiated. In one feature of the present invention, two directional beams are used to communicate with the current and new base stations. Once a communication link is established with the new base station, the directional beam to the current base station is terminated.

1. Field
Various embodiments of the invention pertain to wireless communication systems. At least one embodiment of the invention pertains to a system and method of transferring communications from a first base station to a second base station from a mobile communication device using a directional antenna.
2. Background
Wireless communication networks enable communication devices to transmit and/or receive information while on the move. These wireless communication networks may be communicatively coupled to other public or private networks to enable the transfer of information to and from the mobile communication devices. Such communication networks typically include a plurality of base stations which provide wireless communication links to mobile communication devices. The base stations may be stationary (e.g., fixed to the ground) or mobile (e.g., mounted on satellites, etc.) and positioned to provide wide area coverage as the mobile communication device travels across different coverage areas.
As a mobile communication device moves around, its communication link with a base station may degrade. In this situation, the communication device switches or connects with another base station for a better quality communication link while its first link is still active. This process of establishing a communication link with another base station is referred to as a "handoff". The handoff process typically faces the problem of maintaining a reliable communication link with the wireless communication network while switching base stations. Soft handoffs and hard handoffs are two commonly used types of handoffs. A soft handoff is one where a new communication link with a new base station is established before the existing communication link is terminated. In a hard handoff, an existing communication link is typically terminated before a new communication link is established.
Some mobile communication devices may utilize a directional or adaptive antenna. Directional and/or adaptive antennas are typically used to direct signal transmissions in a desired direction. These types of antennas have many advantages over omni-directional antennas when used in modern communications systems. These advantages occur for both transmission and reception of information-bearing signals. During transmission, the directional concentration of radiated energy beam towards a receiver significantly increases the amount of received power per unit of transmitted power. This generally improves the throughput rate of the transmitter-to-receiver link and allows higher rates of information transfer. Furthermore, in interference-limited systems the concentration of power towards the intended receiver reduces the interference caused by the transmitter to the rest of the system, hence increasing its overall capacity. However, performing an efficient handoff using an adaptive or directional antenna has several challenges since directional beams make it difficult to switch between receivers (e.g., base stations) while maintaining a reliable link at the same time.

This patent is subject to a terminal disclaimer.

Communications handoff using an adaptive antenna


Systems and methods are provided for positioning a therapy device, such as an ultrasound transducer, using a tilt sensor carried by the transducer and a positioner coupled to the transducer. The positioner provides roll and pitch control as well as translating the transducer in lateral and longitudinal directions. A processor receives signals from the tilt sensor corresponding to the actual rotational orientation of the transducer and controls the positioner to adjust the orientation of the therapy device until a desired position is achieved.

Focused ultrasonic therapy uses localized heating to destroy tumors or other tissue anomalies. Heating tissue beyond a critical temperature for a period of time causes the destruction of tissue (necrosis). Using Magnetic Resonance Imaging (MRI) guidance to guide the focal point of an ultrasonic therapy device is well known. For instance, U.S. Pat. Nos. 5,443,068, 5,275,165, and 5,247,935, each describes using an ultrasonic transducer guided by an MRI system to selectively destroy tissue.
In order to accurately position a focused ultrasonic therapy device, a positioner may be employed, which should provide repeatedly predictable control of the ultrasonic transducer. For example, tumors that are small or have irregular shapes require exact positioning of the ultrasonic transducer in order to destroy only the intended tissue while leaving the surrounding healthy tissue undamaged.
Known positioners, such as those described in U.S. Pat. Nos. 5,247,935 and 5,275,165, use hydraulic mechanisms to position an ultrasonic transducer beneath a patient. These systems have inherent reliability and accuracy problems due to the hydraulic positioners, which may experience motor backlash, degrading the accuracy of the positioner.
The need to accurately position an ultrasonic transducer for use in selective tissue necrosis presents additional problems when the transducer is used in combination with a Magnetic Resonance Imaging (MRI) guidance system. MRI systems employ large magnets for creating a homogenous magnetic field, and gradient coils for altering the magnetic field in a uniform manner in time and/or space to create magnetic field gradients. MRI systems also employ radio frequency (RF) coils for applying an RF field to the tissue that is to be imaged, causing the tissue to resonate and create an MR response signal. The MR response signal is then used to construct an image of the tissue that may be displayed, printed, and/or stored for later use and analysis. The degree of homogeneity of the magnetic field and the linearity of the magnetic field gradient over space and time are important in creating a clear undistorted image. Any interference with the RF field may reduce the quality of the image. The best and most consistent imaging typically occurs when surgical equipment or other objects do not interfere with the magnetic and RF fields created by the MRI system.
For example, equipment that is constructed from ferro-magnetic materials should not be used near an MRI system since the large magnetic fields generated by the MRI system may physically attract the magnetic equipment. Furthermore, conductive materials may disturb and distort the radio frequency electromagnetic fields necessary for resonance imaging. Other problems may occur with materials that produce eddy currents when placed in a time-varying magnetic field. The eddy currents in these materials, usually electrical conductors, may create their own magnetic field that may interfere with the fields used for magnetic resonance imaging. Therefore, materials that exhibit good conductivity, such as aluminum and copper, should not be used within a time-varying magnetic field.
For these reasons, motors of positioners used to move the transducer may be placed at a significant distance from the ultrasonic transducer and MRI system, i.e., outside the MRI imaging space. Such positioners therefore require long drive shafts and/or multiple joints, which may increase the physical footprint of the positioner. This arrangement also may cause inaccuracies in determining the actual position of the transducer due to mechanical freedom and elasticity of the transmission components extending from the motor to the ultrasonic transducer.
For example, U.S. Pat. No. 5,443,068 describes an MRI guided ultrasonic therapy system that uses threaded shafts attached to screw drives through universal joints in order to position a transducer in three orthogonal linear dimensions. The screw drives, and particularly the universal joints, used in this system compound motor backlash problems and therefore may limit the accuracy of the system. Furthermore, the motor drives may be formed from magnetic material and, therefore, are located away from the imaging space to eliminate interference with the MRI system. Therefore, this system may introduce reliability and accuracy problems explained above.
Accordingly, positioning systems for accurately positioning a therapeutic or diagnostic device, such as an ultrasound transducer, would be useful.

Positioning systems and methods for guided ultrasound therapy systems


A system and a method avoids the collision of a vehicle with animals tending to cross the road before the moving vehicle. Such system comprises a visual system directly actuating a RF emitter, or more RF emitters, emitting directional sound waves with a frequency above 25,000 Hz. Sound waves are directed frontally though with a frequency decreasing from the center of the roadway towards the road edge, so as to lead the animal to move towards the road edge.

Statistical data show that from 1984 to 1993 40,000 roads accidents took place only in Italy, in which 4,000 people were injured and 200 people died, due to animals crossing roads, especially abandoned dogs. Only in the area comprising the province of Turin, Italy, in the second half of 2001 there were 157 accidents due to wild animals crossing roads, in particular wild boars, but also roes, foxes, stags and badgers.
In general in Europe the number of accidents involving animals and vehicles, considering only large mammals, has been calculated to be of 507,000, with 100 deaths, 30,000 injured people and damages for about 1,000,000 Euro. The corresponding figure for each Italian province is of about 100 accidents every year.
Similarly alarming statistics come from the United States, especially as far as accidents involving stags are concerned. Every year there are 726,000 accidents with said animals in the United States, with subsequent damages for about 1,000,000 dollars. Always every year 29,000 people are injured and 200 people die in the United States due to this kind of accidents.
In the light of solving this problem several solutions have already been suggested, all of which propose the use of ultrasounds so as to keep the animal away from the area in which vehicles travel. Such a solution includes the so-called "wild life warning system" marketed by International Road Dynamics Inc., which achieves its objective by installing systems detecting the passage of vehicles and ultrasound emitters in stationary positions, typically in the areas where statistically animal crossing is most frequent. The sensors detect the arrival of a vehicle and thus activate ultrasound emitters, and—if necessary—light bands and/or scent emitters which frighten the animals and prevent the latter from crossing the road. The first system to be activated leads to the activation of the following ones on both road sides.
Ultrasound emission is an excellent system to make the animal get away, without simultaneously disturbing humans. Animals generally have a sound sensitive threshold that is far higher that humans. They can hear sounds having a lower intensity with respect to human ear. For instance, while the audible range for humans is of 64 to 23,000 Hz, the corresponding range for dogs is of 67–45,000 Hz, for cats of 45–64,000 Hz, for cows of 23–35,000, for sheep of 100–30,000 Hz, for rabbits of 360–42,000 Hz. Scientific researches have shown that generating sounds within the critical perceptible range a lot of animals feel so much disturbed and threatened to get away from sound source. At the same time humans are not disturbed by ultrasounds, which belong to a frequency range beyond human audible threshold. In humans the eardrum has a far lower specific resonance frequency than animals, and cannot therefore vibrate at ultrasound frequency. Human ear can perceive sounds up to a frequency of 20,000 Hz.
Considering the above, on-board devices to be installed on a vehicle have also been used to keep away animals crossing the road before said vehicle. For instance U.S. Pat. No. 5,278,537 discloses an electronic alarm system that generates ultrasounds to prevent animals from moving before the vehicle. Said device includes a simplified pilot circuit generating electric pulses in form of square waves having constant peak-to-peak tensions. The pilot circuit generates said square waves with sequentially increasing periodical wave frequencies followed by sequentially decreasing wave frequencies. A coupling transformer converts square waves into sinusoidal wave electric tensions having high peak-to-peak tensions, so that a piezoelectric transducer emits ultrasounds with periodically increasing frequencies followed by periodically decreasing frequencies, thus simulating the effect of a siren, without overheating the transducer and causing its premature breaking. The ultrasonic effect thus obtained confounds the animal and prevents the latter from suddenly crossing the road before the vehicle.

System to avoid the collision of a vehicle with animals


In a communications system where a mobile node seeks to establish contact with a server node within or outside the home network of the mobile node by first providing the general location information and the server type of the server node to a DHCP (Dynamic Host Configuration Protocol) server. The DHCP server then matches the provided information with its record in storage to arrive at an IP (Internet Protocol) address of the sought server node. The DHCP server then sends the IP address to the mobile node, thereby allowing the mobile node to directly access the server node.

I. Field
The present invention generally relates to packet data communications, and more particularly, to identifying server locations during packet data communications.
II. Background
Interconnecting of networks globally allows information to be swiftly accessed irrespective of geographical distances. FIG. 1 shows a simplified schematic drawing of the global connection of networks, commonly referred to as the Internet signified by the reference numeral 20. The Internet 20 is in essence many networks with different levels of hierarchy linked together. The Internet 20 is operated under the TCP/IP (Transmission Control Protocol/Internet Protocol) promulgated by the IETF (Internet Engineering Task Force). The TCP/IP can be found in RFC (Request For Comments) 703 and RFC 791 published by the IETF.
Connected to the Internet 20 are various individual networks, sometimes called LANs (Local Area Networks) or WANs (Wide Area Networks) depending on the network sizes. Shown in FIG. 1 are some of such networks 22, 24, 26 and 28 tied to the Internet 20.
Within each of the networks 22, 24, 26 and 28, there can be various pieces of equipment connected to and in communication with each other. Examples are computers, printers, and servers, to name just a few. Each piece of equipment has a unique hardware address, commonly called the MAC (Media Access Control) address. The piece of equipment with the MAC address is sometimes called a node. When the node communicates beyond its own network via the Internet 20, an IP address needs to be assigned to the node.
The assignment of the IP address can be manual or automatic. The manual assignment of the IP address can be performed by a network administrator, for example. More often, the IP address is automatically assigned by a server called the DHCP (Dynamic Host Control Protocol) server residing inside in the node's network.
Returning now to FIG. 1, as an example, suppose a node 30 in the network 22 attempts to send a data packet to another node 32 in the network 28. Under the TCP/IP, each data packet needs to have a source address and a destination address. In this case, the source address is address of the node 30 in the network 22. The destination address is the address of the node 32 in the network 28.
As another example, when the node 30 in the network 22 tries to retrieve information from the node 34 in another network 24, such as in a web hosting session in which the node 34 serves as a web host, the node 30 must provide a proper IP address of the node 34 in the network 24 for such a session.
Advent in wireless technologies allows nodes to be detached from their originally registered network to another network. For instance, referring back to FIG. 1, the node 30, instead of permanently wired to the network 22, can be a wireless device, such as a PDA (Personal Device Assistant), a cellular phone, or a mobile computer. The wireless node 30 can travel beyond the boundary of its home network 22. Thus, for instance, the node 30 may roam away from its home network 22 to a foreign network 26. Under such scenario, the original IP address assigned to the node 30 would no longer be applicable to the node 30. As such, data packets sent to the node 30 may not be reachable to the node 30.
The MIP (Mobile Internet Protocol) set forth by the IETF is intended to address the node mobility problems. In accordance with the RFC 2002 published by the IETF, the node 30 is assigned a "care-of address," abbreviated as CoA (Care-of Address). Under the RFC 2002, there are two types of CoA, namely, the FA CoA (Foreign Agent Care-of Address) and the CCoA (Co-Located Care of Address). The FA CoA is in essence the address of a FA (Foreign Agent) (not shown), which is a designated server in the foreign network where the node 30 is located at. The CCoA is an individual but temporary address assigned to the node 30 by the foreign network. In any case, anytime the node 30 is in a foreign territory, the node 30 must register the CoA, be it the FA CoA or the CCoA, with its home network 22, so that the home network 22 always knows the whereabouts of the node 30. After registration, the CoA is stored in the routing table maintained by a designated server, called the HA (Home Agent) (not shown), of the home network 22.
Take an example for illustration. Suppose the node 30 roams into the foreign network 26. Upon receipt of the advertisement from the foreign network 26, the node knows the FA address of the foreign network 26. The node 30 then registers the FA CoA with the home network 22. When the node 30 in the foreign network 26 sends out a data packet to the node 34 in the network 24, knowing the address of the node 34 in the network 24, the data packet can be sent straightforwardly. However, the reverse traffic may not be so straightforward.
In the reverse data route, when the node 34 in the network 24 attempts to send a data packet to the node 30, now in the foreign network 26, as mentioned above, in conformance with the TCP/IP, both the source and the destination addresses must be specified in the data packet. In this case, the source address is the IP address of the node 34 in the network 24. As for the destination address, the node 34 only knows the IP address of the node 30 assigned by its home network 22, called the HoA (Home assigned Address), not the FA CoA of the node 30. Thus, the destination address will be set at the HoA of the node 30. Nevertheless, since the FA CoA of the node 30 is stored in the routing table HA of the home network 22, when the data packet reaches the home network 22, the HA of the network 22 encapsulates the received data packet with the stored FA CoA and resend it to the node 30 in the foreign network 26. The encapsulated FA CoA serves as the destination address of the resent data packet. Once the foreign network 26 receives the rerouted data packet, the foreign network 26 merely strips away the encapsulated FA CoA and delivers the original packet to the mobile node 30.
Operating in such manner, a virtual data tunnel is said to be established between the node 34 in the network 24 and the node 30 roaming in the foreign network 26, all intended to be transparent to the users. This is despite the fact that in reality, the virtual tunnel actually involves three-way data communications.
Heretofore, while the node 30 is roaming, it is difficult and very often impossible for the node 30 to locate other nodes in other networks, even though the node 30 knows exactly the type of data it wants to access. Returning to the example immediately above, the node 30 in the foreign network 26 can send data packets to the node 34 in the network 24 because the node 30 knows the IP address of the node 34 well in advance. In reality, this is not always the case. Suppose, the node 30 merely knows the type of information to be accessed. The node 30 may even know the address of the network 24 which has a server holding information to be accessed. However, the node 30 does not know the exact IP address of the server node 34 and is consequently handicapped in reaching the node 34.
There is thus a need to provide a roaming node with ways to conveniently access server information located in different networks.

Method and apparatus for obtaining server information in a wireless network


Devices and methods for releasably securing components of a device having a sliding sleeve arrangement to prevent premature actuation due to vibration. In a currently preferred embodiment, standard elastomeric O-rings are used as shear members. The O-ring shear members reside within spaces formed between two slidable sleeve members. The O-rings are sheared cross-sectionally to allow the sleeve members to move axially with respect to one another. An exemplary coiled tubing shear release joint is described that incorporates a shear disconnect assembly which uses elastomeric O-rings as shear members. Multiple O-ring seals can be used as shear members to increase the shear value of the device. The use of O-rings as shear members helps prevent premature sliding of sleeve components in response to high vibration. Because the O-rings are resilient, they absorb vibration and do not shear during vibration, the connection between the two sleeve components will not be released prematurely.

1. Field of the Invention
The invention relates generally to the use of O-ring seals, typically formed from elastomer, as shear members. In particular aspects, the invention relates to devices that utilize O-rings as shear members to resist the movement of an axially sliding sleeve.
2. Description of the Related Art
There is a variety of tools and devices used within a wellbore that incorporate sliding sleeves, or arrangements where one tubular member is slidably moved with respect to another tubular member to accomplish some function, such as actuation of a valve or a releasable disconnect. Traditionally, shear pins or other frangible members have been used to releasably secure these components together until it is desired to cause them to slide.
However, the use of frangible members to hold sleeve components together is problematic where the components are subject to high vibration. Vibration can rupture a frangible pin, thereby prematurely releasing the connection that holds the sleeve members together. This results in an undesired activation of the tool. One example of a tool that is normally subjected to high vibration during use is a coiled tubing shear release joint. These tools are used to provide a selective separation point in a continuous length of coiled tubing. The release joint may be activated by shearing of a shearable member, such as a frangible shear pin, to allow separation of release joint components. However, substantial vibration occurs during normal operation of coiled tubing production, and this vibration might cause the shear pin to fail prematurely, thus undesirably activating the release joint.
The present invention addresses the problems of the prior art.

Sliding sleeve devices and methods using O-ring seals as shear members


A semiconductor device including an insulating layer, a patterned conductive layer on the insulating layer, a semiconductor layer on the patterned conductive layer, and a reactive layer formed by reacting the patterned conductive layer with growth nuclei on the patterned conductive layer between the patterned conductive layer and the semiconductor layer, the growth nuclei containing any of elements in group IIIb, group IVb, group Va and group VIIb that does not constitute the conductive film and the insulating film on the surface of the conductive film.

1. Field of the Invention
The present invention relates to a method of preventing deterioration of film quality of a transparent conductive film, a semiconductor device and the method of manufacturing a semiconductor device.
2. Description of the Related Art
A portable information processor is indispensable for performing electronic data processing (EDP) on an individual level, and a liquid crystal display unit is used as man-machine interface required for realizing EDP. It is desired for an image display unit to realize display of high density and high color rendering capable of performing more advanced information processing of image processing or the like at a low cost.
An active matrix type liquid crystal display unit has a construction in which switching elements are connected to all of a plurality of display units called picture elements, thus making high grade display possible. A semiconductor element such as a diode and a transistor is used as the switching element.
The characteristic of the switching element is required to be excellent since it is one of the primary factors for determining the number of gradation and the display capacity of the liquid crystal display unit. Further, since these switching elements are manufactured through a complicated process accompanied by fine processing, the process thereof controls simplification of the process for the whole liquid crystal display unit.
As a means for simplifying the manufacturing process of the switching element, it is being considered to form a new pattern on the pattern already formed on a substrate in the self align manner. There is a technique for growing a thin film selectively only on a conductive pattern as one of processes adopting such a line of thinking of self alignment.
Since it is possible in selective growth to form a layer selectively only on a thin film applied with patterning on a substrate, a photolithography process becomes unnecessary. Further, since it is possible to grow still another thin film continuously without breaking vacuum after the selective forming process, contamination on interlayer interfaces is little, and the switching element characteristic is improved.
Now, in a plurality of selective growth techniques that have been heretofore developed, a chemical vapor deposition (CVD) method is utilized so as to achieve selective growth by the difference in chemical property of layer surfaces.
The CVD method is used frequently as a growth method of a semiconductor or a metal, but the growth rate is not controlled normally under such a condition that reflects the chemical disposition of the layer surface. Therefore, selective deposition of a film does not appear normally. However, it has become possible to perform selective growth by reducing a deposition rate by diluting growth gas with another gas or by having the chemical disposition of the layer surface reflected by bringing etching and deposition close to an equilibrium state.
As a technique of selective growth of silicon, there is an epitaxial lateral overgrowth (ELO) method disclosed in Japanese Patent Provisional Publication No. SHO58-120595 for instance. This is a method of expanding a margin of a selective growth of silicon by repeating deposition and etching of layers alternately for a substrate having a region where silicon is grown and a region where silicon is difficult to be grown.
It has been disclosed in U.S. Pat. No. 5,242,530 that this technique is also applicable to a plasma CVD method widely used in the manufacture of a solar cell and an active matrix type liquid crystal display unit.
The feature of these techniques is to repeat etching and deposition alternately by utilizing a slight difference in a silicon growth rate produced by the difference between materials forming the layers.
However, as the chemical state of the surface of the layer depends on the layer constituting material, growth had to be performed under a condition of a very narrow margin in order to achieve selective silicon growth between materials having closely resembling chemical dispositions.
Accordingly, when the film forming rate is increased in order to shorten the process period of time, it gets out of the condition of selective growth. Thus, such a problem that the film forming process has to be performed for a long period of time by slowing down the film forming rate for performing selective growth has been caused.
It is inevitable to increase the percentage of etching occupying in the total process period of time for surely removing the silicon film deposited in disused parts in order to make selective growth uniform in an active matrix having a large area. As a result, the effective film deposition period of time is reduced and the total selective growth process period of time gets longer, thus producing a main cause of deteriorating the productivity.
Further, it depends on the material constituting the surface of the layer where the film is grown whether silicon is grown or not. Furthermore, the state of the layer surface is also changed by contamination and natural oxidation. Therefore, when the technique of selective growth is examined practically from a viewpoint of a manufacturing process, it has more or less lacked practicability.
For example, ITO shows a disposition of a electrically degenerated semiconductor and functions as an electrode, but resembles in a chemical disposition to silicon oxide that is an oxide such as quartz and glass constituting the substrate since ITO is an oxide, and there is little difference in the processes that silicon is grown on ITO and the substrate. Further, the reducing gas used when silicon is grown selectively on the surface of the transparent conductive film deteriorates the surface of the transparent conductive film.
Accordingly, it is difficult to perform selective growth on either one of two films having resembling chemical dispositions. Practically, according to the examination of the present inventor, it has been found that the reproducibility of selective growth is poor, and such results are brought about that non-selective deposition of silicon films is produced frequently and the silicon film is deposited on the quartz substrate only.

Method of preventing deterioration of film quality of transparent conductive film a semiconductor device


Techniques comprising obtaining, using a sensor unit coupled to a power line in a power distribution system, at least one measurement of at least one inertial property of the power line; and detecting at least one condition of the power line at least in part by analyzing the at least one measurement. A sensor unit configured to be coupled to a power line in a power distribution system, the sensor unit comprising an inertial sensor configured to collect at least one measurement of at least one inertial property of the power line.

Power lines are widely used in many settings. They form an important part of the power distribution system, carrying power from generation facilities all the way to the locations where it is used. The distribution system may include many types of power lines, with high voltage lines used closer to the generation facilities and medium and lower voltage lines closer to the locations where the power is used.
Many of the lines run "overhead," meaning that the lines are attached to towers or poles to elevate the lines above the ground. High voltage lines are generally routed through open spaces, but the medium and low voltage lines, which are closer to the homes and businesses that use the power, are more likely to run over roads and near trees or other objects.
A power company may spend significant amounts of money repairing and maintaining these power lines. Environmental conditions, for example, may damage the lines. For example, ice and snow build up on a power line may load the line to the point that it stretches and breaks. Wind can also be a contributing factor to breakage or wear of a power line. Wind can directly cause damage to a line or can cause tree limbs or other obstacles to come in contact with the line, thus damaging it.
Further, power lines can experience damage or wear through overloading. When large amounts of current flow through a power line, the line may heat up, causing the line to stretch. Too much stretching may, in turn, lead to breakage of the line and, as such, create a dangerous scenario for people and property under an overhead line and lead to breakage of the line.
Accordingly, a power company may devote significant personnel and financial resources to checking power lines for the presence of these conditions and addressing the resulting issues.


A method for manufacturing glass and gold slabs for mosaics, comprising the steps of: applying a fluid or semifluid suspension that contains gold to a glass sheet of suitable thickness; heating the sheet and the suspension so as to obtain a film-like coating of the sheet according to the intended extension and contour; protecting the film-like covering with a thin layer of molten glass; and heating the sandwich of layers so as to obtain a single sheet composed of the glass of suitable thickness, the gold coating and the thin glass layer.

The present invention relates to a method for manufacturing glass and gold slabs for mosaics.
Even nowadays, the method for manufacturing glass and gold slabs for preparing gold mosaics is still a substantially skill-intensive manual process, and owing to its high costs it is performed by master glassmakers to produce mosaic compositions of particular artistic value.
The method consists in forming, by blowing, globes of thin glass which are then split so as to form convex square pieces. These square pieces are then deposited on a flat iron scoop with their concave side facing downward and a gold leaf is applied thereto by means of a wet process.
The scoop is then transferred into a furnace, where the heat flattens the square piece. Molten glass is then poured onto the gold leaf in an amount sufficient to form a considerably thick layer. A slab is thus obtained in which the gold leaf is perfectly embedded.
The tesserae for composing the mosaic are then cut from the slab. The tesserae are applied by interposing a suitable binding agent between the surface to be covered (wall, floor, ceiling) and the thicker layer of glass, so that the exposed face is the one covered by the thin layer of glass.
The conventional method for manufacturing gold mosaic tesserae entails some considerable drawbacks, which consist in the limited size of the slabs that can be obtained, also because it is very difficult to maintain the integrity of the surface of the gold leaf for sizes greater than approximately 10.times.10 cm. Another drawback of the prior art is the fact that the gold leaf, being extremely fragile, can be applied only manually and therefore entails considerable labor costs.

Method for manufacturing glass and gold slabs for mosaics


A candidate output element configured to output recognition target commodities as candidates of a recognized commodity in a descending order of the similarity degrees calculated by the similarity degree calculation element, a distance measurement element configured to measure the distance from the image capturing section to a commodity photographed by the image capturing section, and a changing element configured to change the number of candidates of a recognized commodity output by the candidate output element according to the distance measured by the distance measurement element.

There is a technology in which the appearance feature amount of a commodity (object) is extracted from the image data of the commodity photographed by an image capturing section and a similarity degree is calculated by comparing the extracted feature amount with the feature amount data of a reference image previously registered in a recognition dictionary file to recognize the category of the commodity according to the calculated similarity degree. Such a technology for recognizing the commodity contained in the image is called as a general object recognition. As to the technology of the general object recognition, various recognition technologies are described in the following document.
Keiji Yanai "Present situation and future of general object recognition", Journal of Information Processing Society, Vol. 48, No. SIG16 [ Search on Heisei 22 August 10], Internet <URL: http://mm.cs.uec.ac.jp/IPSJ-TCVIM-Yanai.pdf>
In addition, the technology carrying out the general object recognition by performing an area-division on the image for each object is described in the following document.
Jamie Shotton etc., "Semantic Texton Forests for Image Categorization and Segmentation", [Search on Heisei 22 August 10], Internet <URL: http://citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.14 5.3036&rep=repl&type=pdf>
In recent years, for example, there is a proposal in which the general object recognition technology is applied to a recognition apparatus for recognizing a commodity purchased by a customer, especially, a commodity without a barcode, such as, vegetables, fruits and the like in a checkout system (POS system) of a retail store. However, in a case in which an operator (shop clerk or customer) holds a commodity to be recognized towards an image capturing section, the distance from the image capturing section to the held commodity is not always kept constant. On the other hand, as the number of pixels of the image capturing section is fixed, the resolution of the captured image is varied depending on the distance between the image capturing section and the commodity.
As a result, the similarity degree between the appearance feature amount of the commodity extracted from the captured image and the feature amount data of a reference image is decreased due to the difference in resolution of the captured image and the reference image, which may lead to a low recognition rate.

Commodity recognition apparatus and commodity recognition method


A suspension member is coupled to a front side attachment portion and a rear side attachment portion of a front side member. A stabilizer bracket is secured to the section of the front side member between a front end portion of the front side member and the front side attachment portion. A reinforcement member that projects outward in the vehicle width direction relative to the front end portion is bonded to a vehicle width direction outside side wall portion of the front end portion. The reinforcement member makes the vehicle front and rear direction yield strength of the front side member higher at the front end portion than at the section between the front side attachment portion and the rear side attachment portion.

In patent document 1, there is disclosed a vehicle body front portion structure equipped with a front side frame, which extends in the vehicle front and rear direction, and a sub frame, which is coupled to the front side frame at a front side coupling portion and a rear side coupling portion spaced apart from one another in the vehicle front and rear direction.
In the vehicle body front portion structure disclosed in patent document 1, the front side frame comprises a front side deformation portion on the vehicle front side of the sub frame, a central side deformation portion between the front side coupling portion and the rear side coupling portion coupled to the sub frame, and a rear side deformation portion on the vehicle rear side of the rear side coupling portion. The vehicle front and rear direction yield strength of the front side frame is set in such a way as to become higher in the order of the front side deformation portion, the central side deformation portion, and the rear side deformation portion.
According to this vehicle body front portion structure, the amount of deformation of the front side frame in a case where the vehicle has become involved in a frontal crash or an offset crash becomes smaller heading toward the vehicle rear side, so the effect exerted on the cabin by the frontal crash or the offset crash can be reduced.


A plasma etching apparatus comprising a susceptor for holding a semiconductive wafer, a cooling jacket having a coolant of a large cooling capacity and capable of quickly cooling said susceptor to an intended low temperature, a process chamber enclosing the susceptor and the cooling jacket, a gas discharging mechanism for evacuating the process chamber, an insulating member interposed between the susceptor and the cooling jacket, a gas supply device for supplying gas to an O-ring holding groove arranged on the interface regions of the susceptor, the insulating member and the cooling section and a pressure control mechanism for controlling the pressure of the supplied gas.

1. Field of the Invention
This invention relates to a plasma etching apparatus for performing an etching process on semiconductor wafers in high temperature plasma and, more particularly, it relates to a cooling mechanism for protecting semiconductor wafers from being damaged by heat during an etching process.
2. Description of the Related Art
In a dry etching process such as plasma etching, semiconductor wafer tend to be damaged as they are overheated by radiant heat of plasma. In a magnetron plasma etching apparatus, for instance, the accuracy of etching can become significantly low as the photo-resist on a wafer is damaged by heat. Particularly when wafers are anisotropically etched, the side walls of the etching portion that are etched can lose steepness to come to show a gentle slope and adversely affect the anisotropy produced by etching.
When the damage by heat is remarkable, the mask being used for etching can be totally lost before the intended etching process is over. A solution to avoid this problem may be the use of a thick resist layer. However, a thick resist layer causes a decrease in the accuracy of printing the mask pattern to the wafer.
A photoresist can sometimes be carbonized by radiant heat of high temperature plasma in an etching process. When such is the case, the carbonized photoresist is hard to remove from the wafer. In view of this problem, the temperature of wafers in plasma should be kept as low as possible.
In conventional plasma etching apparatus, each susceptor is cooled by a lower cooling jacket in order to indirectly cool wafers and avoid damage to wafers by radiant heat.
Currently, wafers are cooled in a range of from -60 to -100.degree. C., further more the cooling temperature will be lowered to below -150.degree. C. with the technological development at hand. The most ideal coolant to be used for cooling wafers to this low temperature will be liquid nitrogen in view of heat transfer loss at various sections and members of the cooling system.
The optimum temperature for cooling wafers is dependent on the conditions where the etching process is conducted. In conventional, systems overcooled wafers are heated by a temperature control device, so that the wafer is controlled to obtain various predetermined cooling temperatures.
However, since the cooling capacity of a cooling jacket using liquid nitrogen is normally made very large, the temperature of wafers cannot necessarily be properly controlled to quickly come to an intended level particularly when the temperature control device has a small heating capacity. A temperature control device comprising a large capacity heater, on the other hand, increases high electric energy consumption and running cost.


A magnetized material is affixed to an exterior of a drill housing of a portable power drill or a battery pack used for providing power to the portable power drill. The magnetized material is employed to retain magnetic objects. The magnetized material can be provided in a planar sheet or upon a three-dimensionally shaped form. In a sheet configuration, the magnetized object retention panel is defined by a magnetized surface and an opposite, attachment surface. A series of grooves can be formed within the magnetized material enabling conformation of the sheet to a non-planar surface on the drill or battery pack. The three-dimensionally shaped form can be provided as a channel having at least one channel sidewall extending generally perpendicular from an edge of a channel basewall terminating at a base surface. Inclusion of a pair of sidewalls provides a planar supporting surface for standing the drill upright.

Drills are used for any of a variety of applications, including forming or enlarging holes through objects, forming countersinks, installing or securing threaded fasteners, or any other process utilizing a rotational motion. Because of the flexibility of the drill, there are many scenarios where the drill is used for multiple functions during the same time frame. It is common to need different objects to complete the task at hand. One example would be a process of drilling pilot holes and installing a series of screws, where the individual would need a drill bit, a driver bit, and the series of screws. The problem is retaining the drill bit, the driver bit, and the series of screws throughout the various steps required for completing the task. One known method would be to retain the objects in a pocket. This takes additional time to retrieve the objects from within the pocket. Sharp objects, such as screws, can be uncomfortable, or even cause injury to the individual, thus creating an undesirable scenario.
Another, even less desirable scenario, is to temporarily hold the objects in one's mouth. This solution introduces additional potential health risks including illness from ingesting bacteria or other contaminants residing on the surface of the objects or injury from swallowing the objects.
Some portable drills include a retention element having specifically shaped receptacles for temporarily retaining tools, such as screw driver bits, a driver bit extension, and the like. This solution is limited in that the retention element is designed to hold a specific object having a specific shape and size. This solution fails to provide accommodations for retaining a broader selection of tools including drill bits, nut drivers, and the like; fasteners, such as screws, bolts, nuts, washers, and the like; and other objects that might be used during completion of a task.
Accordingly, there remains a need in the art for a device that can temporarily retain objects while completing a task that employs a power tool, such as a portable power drill.

Magnetized drill accessory for retention of objects


A product for cleaning stains. In one embodiment, the product may include a piece of material and a volume of carbonated water, both sealed within a container. When a stain is encountered, the container may be opened and the piece of material that has been wetted by the carbonated water may be used to clean the stain.

1. Field of Invention
The invention relates to products for cleaning stains.
2. Related Art
Products for cleaning stains, such as sheets of material (commonly called wipes, napkins or towelettes) impregnated with chemical cleaning solutions, are sometimes sold in individual containers or packets. If a stain is experienced, a consumer can open a packet, remove the material, and use it to blot the stain.
Many consumers prefer to clean stains with a liquid containing gas bubbles, such as carbonated water, which is known to be a good stain remover and does not include potentially odorous and/or irritating chemicals that may leave residue or rings after use. Cleaning stains with carbonated water, however, can be inconvenient. A source of carbonated water (e.g., a bottle or fountain) must be located, and the carbonated water must be brought to the location of the stain and delivered in an appropriate volume. It is not uncommon to accidentally pour a larger than desired volume of carbonated water on a stain, resulting, for instance, in a soaked garment or handbag. Using carbonated water to remove stains can also be dangerous if a glass bottle is used. Glass can shatter, for example, by falling off a table in a restaurant.


Improved latching connectors that can be used to connect a fluid system, such as manufacturing, test, or processing equipment, to an external system, for example charging, evacuation and/or testing equipment. In one embodiment, the connector includes elements by which to protect connector seals from being exposed to fluid being transferred, thereby lengthening the lifetime and reliability of the connector. In another embodiment, the male connector portion and the female connector portion are both valved in a normally closed position. The connector is designed to achieve connection of the male portion to the female portion, and sealing between the male portion and the female portion, prior to the valves in each connector portion being opened and fluid flowing through the connector. The latching connector includes a pressure locking sleeve that, once the connector is under pressure, locks the connector to prevent accidental disconnection.

Quick connect latching connectors are often used to connect a fluid system such as manufacturing, test, or processing equipment to an external system, for example charging, evacuation and/or testing equipment. Once the connection is made and any valves are opened, fluid can flow through the connector either into the fluid system or from the fluid system depending on the processing operation being performed.
In order to maximize efficiency and safety, it is important that the connector provide fast and reliable connection and reliable seals to prevent fluid leakage. In certain implementations, it is important that the seals of the connector be protected from exposure to the fluid flowing therethrough. For example, in a medical oxygen environment, exposure of the seals to oxygen can lead to deterioration of the seals and contamination of the oxygen.
In addition, in certain implementations, it is generally desirable to achieve connection of the systems and sealing of the connector prior to any fluid being allowed to flow in order to prevent fluid leakage from the connector.