The present invention relates to a preparation for stimulating or enhancing an immune system comprising one or more agents that stimulate T-lymphocytes in vivo. Such a preparation can be sued in the prophylaxis and/or treatment of a medical condition. The invention further relates to a preparation for use in a pharmaceutical or food product and to a preparation for medical use.

The invention relates to a preparation for stimulating the immune system. The invention further relates to a method of treating and/or preventing a medical condition by administration of said preparation to a human or an animal and to a method to manufacture a product for use in prophylaxis and/or treatment of a medical condition.
The immune system in animals, including humans, plays an important role in prevention and treatment of many disorders/diseases, such as infections by foreign bodies such as bacteria, viruses, parasites, toxins or proteins, but also in the prevention and treatment of various forms of cancer. Viruses or bacteria may for example cause infections in the respiratory tract, or cause systemic infections (e.g. herpes virus). Infections may also be associated with other diseases such as an infection by a cytomegalo-virus (CMV) in an AIDS patient or an infection by pneumococcen sp in a cancer patient. Such an infection is also referred to as a secondary infection.
In clinical practice, large groups of hospital patients or other persons suffering from an underdeveloped (e.g. neonates) or compromised (e.g. cancer or transplantation patients treated with chemotherapeutics or part of the elderly population) immune function, suffer at one point in time from (primary or secondary) infections, which may increase the period of hospital stay or the duration of an illness in general. An underdeveloped or compromised immune function of patients may require aggressive treatment with antibiotics, which even can lead to life-threatening situations.
In daily life, also xe2x80x9chealthyxe2x80x9d persons are frequently infected by a foreign entity such as a virus and/or a bacterium, leading to symptoms such as bad wound healing, pain, fever or general malaise. Commonly known examples thereof are various infections of the respiratory tract, including the throat, and such infections frequently occur in particular after stress (e.g. due to bad weather, heavy exercise or emotional stress).
The functioning of the immune system is inter alia related to various chemical substances that are produced in vivo or obtained by nutrition. Administration of such substances in order to support the immune function can help prevention and/or treatment of many diseases. In addition various substances such as antioxidants, are known to play a beneficial role in the prevention and treatment of diseases. Antioxidants may prevent damage of healthy cells by radicals, formed by the immune system, that are directed against infecting moieties (infectants).
The presence of chlorogenic acid in an antioxidant composition is reported in U.S. Pat. No. 5,788,971. In this publication, sunflower seed extract containing chlorogenic acid and green tea leaf extract containing EGCG is said to be able to scavenge free radicals, which may be useful in the treatment of inflammatory disorders.
European patent application 0/906/761 also mentions chlorogenic as a possible antioxidant.
In JP 60243016 an anti-influenza tablet is described containing 3,5-dicaffeoylqluinic acid obtained by subjecting a methanol extract of a Helianthus annus seed to counter-current distribution.
In WO 99/34812 a composition comprising baicalin, chlorogenic acid and forsythiaside is reported to have antiviral, antibacterial or immuno-modulating properties. According to this publication said composition is capable of increasing the natural killer cell (NK cell) activity and the interferon-xcex1 production of peripheral blood cell lymphocytes in vitro. It remains unclear from this publication what the contribution of chlorogenic acid is in a composition mentioned in this publication.
With respect to prevention of diseases, there is a limited value to administering substances which may give protection to the subject in a general way. It is however also possible to stimulate the immune system more specifically, such as by vaccination of an animal and human to give protection against a particular disease. Vaccination aims to present an innocuous yet antigenic form of an infectious organism or its toxin(s), for establishing protective immunity. So called T-lymphocytes play an important role in this process. By vaccination the immune system can very specifically be stimulated to become active against a particular antigen. Large vaccination programs, are currently applied, both to animals and to humans, against a wide variety of diseases. This vaccination may cause discomfort to a subject that is vaccinated, and sometimes has limited success.
The present invention seeks to provide a preparation to stimulate or to enhance the immune system of animals or humans to be more effective. Surprisingly it has been found that a preparation comprising one or more agents that stimulate T-lymphocytes proliferation in vivo have the desired effect.
Accordingly the invention relates to a preparation for stimulating or enhancing an immune system comprising one or more agents that stimulate T-lymphocytes in vivo.
Highly suitable agents that stimulate T-lymphocytes in vivo have been found to be chlorogenic acid (1-caffeoylquinic acid) or a functional analog thereof. Preferred examples of chlorogenic acid and functional analogs thereof may be represented by formula 1:
wherein xe2x80x9caxe2x80x9d represents either a single bond or a double bond and R1 is only present in case xe2x80x9caxe2x80x9d represents a single bond, and wherein at least one of the functional groups R1-R4, preferably at least R4, represents a functional group represented by formula 2 (further referred to as subst. II)
and the remaining of said functional groups R1-R4 are independently chosen from the group formed by xe2x80x94OH, and other substituentsxe2x80x94like caffeic acid moiety analogsxe2x80x94that are abundant in a material of a vegetable nature and can be split off by the intestinal flora. It is to be noted that the compound of formula 1 has the 1xcex1, 3xcex1, 4xcex1, 5xcex2-hydroxy configuration.
Preferred functional analogs of chlorogenic acid in a preparation according to the invention are 4-caffeoylquinic acid, neochlorogenic acid (3-caffeoylquinic acid), dicaffeoyl quinic acids wherein the 1 and 5 positions are substituted (1,5-dicaffeoylquinic acid), isochlorogenic acids (i.e. dicaffeoyl quinic acids substituted on 3 and 4 positions, 3 and 5 positions or 3, 4 and 5 position (3,4,5 tricaffeoyl quinic acid)), kryptochlorogenic acid (4-O-caffeoylquinic acid, cynarin (1,3-O-caffeoylquinic acid), 1,3,4,5-O-tetracaffeoylquinic acid and caffeoylshikimic acids, in particular 5-O-caffeoylshikimic acid. With reference to formula 1, these analogs have the following chemical structures:
Chlorogenic acid and functional analogs thereof will be referred to herein as CA-compounds.
A CA-compound in a preparation according to the invention may be of synthetic origin, or of natural origin Chlorogenic acid and derivatives thereof can be synthesized by applying one of the methods known in the art, such as the method described by Panizzi et al. (Gazz.Chim.Ital, 86, 913, (1956)). Alternative sources for chlorogenic acid and its derivatives are inter alia Vaccinium myrtillus extracts, potato extracts (pressing juice) and sunflower extracts.
The preparation may comprise plant material in raw form. This may be advantageous, in particular to lower the cost-price of preparation. A CA-compound in the preparation is preferably of natural origin, e.g. as an extract of one or more plants. The extracts (or raw material) can for example be taken from plants like Echinacea sp., green coffee bean, green cacao bean, hawthorn, green tea, elder tree, artichoke (Cynara scolymus), guerana, butterbur. Pheonix spp, Butia capitata, Dandelion, various members of the dicotylus plants, in particular members of the Compositae, as well as Arnica montana and Birch tree or combinations thereof. Several suitable extraction methods are known in the art. A highly preferred extraction method typically comprises crushing of the plant material, blending the crushed material with a polar, preferably aqueous, solvent, filtering the slurry of crushed material and polar solvent and purifying the filtrate. Several purification methods like one-sep or multi-step liquid-liquid extraction, solid-phase extraction, chromatography and the like are known from the state of the art. A possible extraction method is disclosed in WO 99/34812.
The T-lymphocyte stimulating properties of CA-compounds may give an important boost to the activity of the immune systems. The term xe2x80x9cT-lymphocytesxe2x80x9d is commonly used to describe a family of leucocytes originating from lymphoid progenitors that have differentiated in the thymus and descended cells thereof. Cytotoxic lymphocytes may develop from precursors which are activated by antigen plus major histocompatibility complex class I (MHC class I) and are expanded and mature by the action of interleukin-2 and ill-defined maturation factors produced by helper T-lymphocytes. [ref Ivan Roitt, Essential Immunology, 7th Ed., (1991) Blackwell Scientific Publications, Oxford, UK]. T-lymphocytes have several crucial functions in the immune system. They are responsible for the recognition of an entity which is foreign to the body (an antigen) and they are involved in the development of a specific immune response in order to eliminate an antigen. Such an antigen may be a pathogen originating from outside the body, like a bacterium, a virus or parasite, but it may also be a neoplastic somatic cell that has obtained a neo-antigenic structure. A protein or peptide structure such as a prion, a vaccine or a toxin as well as other non-cell structures can also be antigenic. Once an antigen has entered the body, it is taken up, processed and presented by so called antigen presenting cells, i.e. dendritic cells, to precursor T-lymphocytes. Subsequently, those T-lymphocytes that recognize the antigen need to proliferate in order to mount a significant immune response. Activated (helper) T-lymphocytes are required to support the formation of specific antibodies by B-lymphocytes, which predominantly clear foreign entities from the body.
In addition the helper T-lymphocytes (T-helper cells) support the formation of cytotoxic T-lymphocytes, which are inter ala able to eliminate virus-infected cells or neoplastic cells which are developed in several forms of cancer. Cytotoxic T-lymphocytes may also play a role in the defense against a parasite and they are able to release interferon-gamma. Interferon-gamma may contribute to making cells surrounding an infected cell resistant to viral spread.
In order to be effective it is crucial that the specific T-helper cells are abundant in sufficient numbers or proliferate to reach sufficient numbers, as soon as possible after the appearance or arising of an antigen in the body. It has been found that a preparation according to the invention can be used to increase the proliferation of antigen-specific T-lymphocytes, such as T-helper cells and cytotoxic T-lymphocytes. A preparation may also promote differentiation of cells to become functional T-lymphocytes.
A preparation according to the present invention may also stimulate T-helper cells to develop particular cytokines which support other types of lymphocytes. Examples of such lymphocyte supporting cytokines are interleukin-2 (IL-2), interleukin-6 (IL-6) and interferon-gamma (IFN-xcex3).
The general nature of the immune stimulating properties of preparations according to the invention enables it employment in a broad field of applications. The person skilled in the art will recognize that the type of foreign entity is not essential. Some examples of viruses against which a preparation according to the invention stimulates the immune system are DNA viruses, like Pox-viridae, Herpes-viridae (e.g. herpes, simplex, varicella zoster virus, CMV), Adenoviridae, Papavoviridae, Hepadnaviridae, Parvoviridae, RNA viruses like Reo-viridae, Picorna-viridae (e.g. Polio-virus, Echo-virus, Entero-virus, Rhino-virus), Toga-virdae, Flavi-viridae, Corona-viridae, Rhabdo-viridae, Paramyxo-viridae (e.g. parainfluenza, Mumps, measles and RS virus), Orthomixo-viridae, Filo-viridae, Bunya-viridae, Arena-viridae, Calici-viridae, and Retroviridae. According to the invention also Papilloma, influenza, HIV, HTLV, Corona and Eppstein Barr can be prevented or treated.
Bacterial infections that can be prevented or treated by using a preparation according to the invention include those that can occur as a secondary infection after a virus infection (for example after a common cold) or during another disease. The preparation can be used to stimulate lymfocytes against all kinds of bacteria. Some examples are pneumococcus sp, Staphylococcus aureus and bacteria that enter the blood circulation e.g in situations of gut leakage, sepsis and the like.
Some examples of parasites against which the invention can be directed are protozoan and metazoan parasites, including but not limited to Leishmania donovani, Trypanosoma cruzi, Toxoplasma gondii, Plasmodium sp., Theilaria parva and Schistosomas sp.
As already indicated, a preparation according to the invention stimulates or induces T-lymphocytes in a general way. It has been found that the preparation is particularly suitable for use before, during and after situations in which the immune system is highly challenged in order to increase the resistance of a patient or a xe2x80x9chealthyxe2x80x9d person. Such situations may be surgery, heavy physical exercise, exposure to bad weather conditions, sore throat, coughing, fever, general malaise and the like.
The present preparation is however not only effective in the prophylaxis and/or treatment of infection by one or more antigens, but the immune system may also be stimulated to deal with a neoplastic cell which may develop in several forms of cancer. Thus the invention can help to decrease tumor growth, optionally in combination with prevention or treatment of occasional infections that may occur during or after cancer therapy, such as radiation- or chemotherapy. Accordingly the invention relates to a preparation for stimulating T-lymphocytes for use in treatment and/or prophylaxis of cancer, infection by a parasite, a toxin, a virus, and/or a bacterium, to a method for stimulating T-lymphocytes by administration of said preparation and to a method which is part of a prophylactic or treatment protocol for cancer. Such a protocol includes, but is not limited to, a vaccination protocol with autologous tumor cells, tumor antigen autologous dendritic cells or other immunotherapeutic protocols used in the treatment of different cancers. In addition to a general stimulation of T-lymphocytes, it has surprisingly been found that in an embodiment of the invention, further comprising an innocuous yet antigenic form of an infectious organism and/or a toxin thereof, chlorogenic acid and/or a functional analog thereof may also act as an adjuvant, i.e. chlorogenic acid and/or a functional analog thereof may stimulate the specific immune response, directed by T-lymphocytes, against said infectious organism and/or said toxin. Besides a more general effect that a CA-compound may have on the immune system, as an adjuvant, a CA-compound may enable an antigen to be presented more effectively to a T-lymphocyte, or even to be transported into a T-lymphocyte and possibly to activate that particular T-lymphocyte. Thus the CA-compound may enable or enhance the induction of an immune response against the particular pathogenic antigen, against which the vaccine is directed. Thus T-lymphocyte stimulation by a CA-compound allows the use of a preparation according the present invention to be used in a vaccine. Accordingly, an embodiment of the invention is a vaccine comprising chlorogenic acid and/or a functional analog thereof as adjuvant.
The use of a chlorogenic acid or a functional analog thereof as adjuvant is another embodiment of the invention. It may be used in a vaccine for immunization of a subject or a population. The vaccine may further comprise one or more additives, such as those that will be discussed below. The method of vaccination may be orally or subcutaneously or by another method known in the art. In a preferred embodiment the vaccine is administered orally.
For various reasons, a preparation according to the invention may comprise a one or more other active substances or additives. It has been found that a stimulation of T-lymphocytes can further be enhanced if a preparation according to the invention further comprises a particular type of cytokine or an agent that is capable of inducing such type of cytokine. The presence of such a compound may lead to a quicker and/or larger immune response, which may be particularly desirable when fast recovery of a patient is wanted e.g. due to his bad condition, or for economical reasons. A larger response is also useful in case one aims to prevent the use of antibiotics, e.g. because development of tolerance of a micro-organism against an antibiotic is feared.
The additional effect of a cytokine inducing agent in combination with a CA-compound also allows inclusion of lower amounts of said CA-compound in a preparation without decrease in effectiveness. This reduction can lead to a reduced cost-price and improved organoleptic properties of preparations according to the invention.
Interferon-gamma is a preferred cytokine in relation to this invention and accordingly a cytokine inducing agent in a preparation should preferably be capable of inducing the production of interferon-gamma. It is to be noted that preparations intended for oral administration will generally not contain interferon-gamma itself, but rather an agent capable of inducing the production of interferon-gamma, as it may be digested in the gastro-intestinal tract. In preparations for other types of administration, such as vaccines, interferon-gamma itself may be used. Preferred examples of interferon-gamma inducing agents are specific polysaccharides, zinc salts and N-acetyl cysteine. Suitable zinc sources can for example be any edible food-grade zinc salt, such as an inorganic salt like zinc carbonate, zinc sulfate, zinc oxide, zinc chloride etc. Examples of suitable polysaccharides are arabinogalactans from Baptisa tinctoria, Echinacea species, Larix occidentalis, Angelica acutiloba or other polysaccharides that can be isolated from Echinacea species, Thuja occidentalis and Panax ginseng. Polysaccharides from fungi, in particular from Flammulina velupites may also be used.
Polysaccharides that can enhance the cellular immune response are thought to induce interferon production as well, e.g. polysaccharides from Arnica montana cell cultures (stimulating TNFxcex1 release in macrophages), Plantago spp (increasing NK cell activity), Achyrocline satureioides, Aconitum officinalis, Angelica acutiloba, Aristolochia officinalis, Astralagus gummerifa, A. membranaceus, A. mongholicus, Avena sativa, Bambusa vulgaris, Baptisia tinctoria, Bryonia dioica, Calendula officinalis, Carthamus tinctorius, Chamomilla recutita, Echinacea angustifolia, E. pallida, E. purpurea, Eleutherococcus senticosus, Eupatorium cannabinum, Silene vulgaris, Thuja occidentalis, Triticum sativum, Vincetoxicum officinalis, Viscum album.
Naturally a preparation according to the invention may also comprise several cytokine inducing agents, including the ones mentioned above.
A preparation according to the invention for use in the treatment of cancer may also comprise one or more compounds with an anti-tumor activity. Examples of such compounds include polysaccharides which demonstrate anti-tumor activity in vivo. These are thought to act via a similar pathway as the polysaccharides stimulating interferon production such as mentioned above. In general they also have an immunostimulating activity. Examples are polysaccharides (in particular xcex2-1,3-glucans and/or xcex2-1,4-glucans) from the mushrooms, Lentinus edodes (lentinan), Schizophyllum commune (schizophyllan), Phytophtora parasytica, Grifola frondosa, Sclerotinia clerotiorum, Ganoderma lucidum, Coriolus versicolor (krestin) and the like, or from the plants Morinda citrifolia fruit or Viscum album and the like.
The anti-carcinogenic effect of xcex2-1,3-glucans is shown in U.S. Pat. No. 4,454,286, for example for xcex2-1,3-glucans from Schizophyllum commune, Auricularia spp and lentinan from Lentinus edodes. Methods for isolating polysaccharides such as arabinogalactans from a larch tree are disclosed in U.S. Pat. Nos. 2,073,616 and 4,950,751.
U.S. Pat. No. 5,096,708 shows the induction of T-helper cells by thuja polysaccharides and the antiviral effect against retroviruses in vitro.
A preferred preparation according to the present invention, comprises chlorogenic acid and/or a functional analog thereof and N-acetylcystein, for medical use. Surprisingly such a preparation shows a particularly well synergistic effect in medical use. Not only is NAC capable of inducing interferon-gamma, but it is also a scavenger of hydrogen peroxide and may inhibit activation of NF-xcexaB and (rhinovirus mediated) IL-8 release. Furthermore NAC may enhance the glutathion status, which may be important for providing protection against oxygen radical related damage. Preferably the weight to weight ratio of chlorogenic acid and/or a functional analog thereof (CA-compound) to N-acetylcystein (NAC) is about 0.005-4 CA-compound/NAC, more preferably 0.02-1 CA-compound/NAC and most preferably 0.045-0.5 CA-compound/NAC.
In a preferred embodiment the preparation further comprises one or more additional ingredients, such as anti-inflammatory agents, antioxidants, trace elements, minerals, vitamins, extracts of plants and the like.
Under specific conditions, as for example can occur in patients that suffer from chronically inflamed tissues, it may be advantageous to include certain anti-inflammatory components in the composition. Preferred anti-inflammatory agents areacetylsalicylic acid, apocynin, curcumin and equivalents thereof as well as mixtures of these components. As an equivalent of acetylsalicylic acid can be considered salicylic acid or salts thereof as well as extracts of plants that are sources of these compounds, such as Salix spp Functional equivalents of apocynin are considered to be related acetophenones and glycosides thereof, such as those that can be found in Picrorhiza species. Curcumin can be applied as pure synthetic component, as a functional analogxe2x80x94such as tetrahydroxy-curcuminxe2x80x94or as an extract from a plant that is rich in Curcuma species.
Effective amounts of these anti-inflammatory compounds are known in the art and are usually in the range of 5-4000 mg, and preferably 50-1000 mg per daily dose of acetylsalicylic acid, aponycin or curcumin or analogs thereof.
A preparation according to the present invention preferably comprises one or more other antioxidants, other than a CA-compound or NAC. Ascorbic acid and xcex1-tocopherol are particularly preferred examples of suitable antioxidants in the preparation. Other suitable antioxidants are for example flavenoids, catechins, proanthocyanidins or other polyphenols.
In a preferred embodiment the preparation comprises one or more trace elements, such as manganese, copper or selenium. A trace element may be added in a solution or a crystalline form, e.g. of a medical grade trace element oxide, -carbonate, -citrate, gluconate and the like. A trace element may also be added to the preparation in the form of a natural product, rich or enriched in trace elements, e.g. a yeast or a plant extract. Trace elements may have various functions. Several trace elements, including manganese, copper and selenium, are vital elements of various enzymes. Enzymes like superoxide dismutases (e.g. those that are copper-dependent) and gluthathion peroxidase (selenium dependent) can act as antioxidants. Furthermore trace element supplements may be administered in a case of a potential deficiency of a trace element in a patient e.g. as a symptom of a disease or as the result of the administration of a particular (pharmaceutical) compound, such as NAC, of which it is known that it may lead to an increase of urinary zinc excretion.
A preferred preparation comprises an extract of one or more plants, such as plant extracts from Echinacea, e.g. Echinacea purpurea, Astragalus membranaceus, Panax ginseng, artichoke and the like. These extracts may be alcoholic and/or aqueous extracts. Echinacea extract is preferably obtained from the dried pressed juice of the fresh xe2x80x9csubterraneanxe2x80x9d parts of the plant, or alternatively by an aqueous-ethanolic extract of the roots, standardized to alkylamides; Ginseng may be prepared according to any method and is preferably standardized to ginsenosides or polysaccharides; Artichoke may be prepared according to any method and is preferably standardized to caffeoyl acid derivatives.
The extracts may be dried, or mixed in a liquid and may provide various active compounds, such as polysaccharides which have been found capable of inducing release of interferons or have another function.
Particularly good results have been achieved with preparations comprising one or more compounds selected from the group formed by ginsenosides, beta glucans, e.g. xcex2-1,3-D-glucan, lipoic acids and L-carnitine and analogs thereof.
A lipoic acid, preferably alfa-lipoic acid (thioctic acid) can be included as pure synthetic compound, such as a racemate of the oxidized form. It could however also be in the form of the pure biologically active isomer in reduced form. Analogs are considered to be salts thereof as well as the lipoic acid amide. The compound is preferably administered in an amount of 1-100 mg per daily dose.
L-carnitine may be present as a synthetic compound or as acylated compound. The daily consumption of carnitine it typically in the range of 0.01-2 grams.
xcex2-glucans can be isolated from plants (e.g. barley) or micro-organisms (Sacccharomyces sp). Isolation methods are known in the art (e.g. EP 0 606 080 and WO 92-13896). The daily dose of xcex2-glucans is preferably 0.2-10 grams
A preparation may also comprise additives such as flavors, coloring agents, aroma""s, preservatives and the like. A variety of examples of such additives are known from the art.
A preparation according to the invention can be widely used for a variety reasons and to a variety of subjects of any age and of various species including humans. The concentration of a substance present in a preparation according to the invention may vary widely based upon several factors. These factors include the species to be treated (e.g. cattle, a pet or a human), the condition of the subject to be treated, the reason for administration (e.g. a particular diagnosis or prophylaxis), or the form of a preparation (e.g. a concentrated tablet, dissolved in a drink or mixed in cattle- or pet feed). In a preferred embodiment a preparation comprises one or more substances shown in Table 1, more preferably in a daily dose as indicated in Table 1. Herein xe2x80x9cdaily dosexe2x80x9d is used to describe a daily dose for a primate having a body weight 70 kg, unless stated otherwise. Methods to calculate the daily dose for other subjects will be known to the skilled professional. Once the daily dose is determined it can be calculated how much of a certain preparation needs to be administered, knowing the (approximate) fraction of active components and additives in the preparation.
In a much preferred embodiment, the preparation comprises 2-300 mg/day, and a most preferably 10-200 mg/day, of one or more CA-compounds and 50-2000 mg/day N-acetylcystein, plus optionally one or more of the other compounds in an amount as can be deducted from Table 1. Most preferably N-acetylcystein is present in a daily dose of 100-1000 mg.
Particularly preferred are also preparations comprising one or more CA-compounds, zinc and/or one or more polysaccharides in a concentration in the range shown in Table 1.
In another preferred embodiment a preparation comprises a mixture of 4-caffeoylquinic acid, 5-caffeoylquinic acid and 1,5-dicaffeoylquinic acid in a dose of 2-300 mg. A preferred distribution of CA-compounds in such a dose is 25-40 mole % 4-caffeoylquinic acid, 25-40 mole % 5-caffeoylquinic acid and 25-40 mole % 1,5-dicaffeoylquinic acid. In a more preferred preparation the distribution of CA-compounds is 30-35 mole %. for each of these three compounds.
When present, substances mentioned in Table 1, are preferably present in a preparation to match the daily recommended dose as indicated in Table 1.
It is further an advantage of the invention that the CA-compounds and other components comprised by the preparation are often natural products, which have substantially no negative side effects upon administration. This makes it possible to market the preparation as an over the counter drug, which means that it can be sold without prescription of a physician. Moreover it has surprisingly been found that it is possible to process preparations according to the invention in foodanddrinks products, which may further facilitate the accessibility of products of the invention to the public, which more an more becomes aware of the importance of health-food products as an aid to maintain one""s general health. The invention also provides in a novel foodanddrink product, by its capability to stimulate the immune system, and in particular T-lymphocytes.
For the manufacture of a product for stimulating T-lymphocytes in vivo, a preparation according to the invention may be used. The preparation may be processed by methods known from the pharmaceutical and foodanddrinks processing industries into a pharmaceutical, a drink or a food product.
In a preferred embodiment the preparation may be in a more or less solid form such as a capsule, a tablet, a lozenge, a powder, an agglomerate, a snack, a bar or a paste. The preparation may also be a solution, a liquid or a semi-liquid shaped product, such as a gel, an emulsion, a suspension, a drink (such as a lemonade, a fruit juice, a dairy drink) a pudding, an ice cream, a sauce and the like.
A preparation may be processed in a drink or food product at the factory. A drink, comprising a daily dose may for example be packed in a 250 ml package, or another volume that is suitably consumed by a subject. In another embodiment the active components are present in a bar of typically up to 25 g, which may further comprise typically at least 60% of (sweet) carbohydrates. In another embodiment, a preparation, e.g. a powder, a liquid, a suspension and the like, may be administered to a drink or food, such as a dessert or a juice, relatively shortly before oral intake. Such a preparation may for example substantially consist of active components and may in principle by administered by anyone.
The preparation may also be a complete food product, e.g. for patients on a particular (strict) diet or for cancer patients.
In a preferred method for stimulating T-lymphocytes, a preparation according to the invention is administered to a patient, in the form of a capsule, a tablet, a powder or a lozenge. In another embodiment the preparation may be administered in another form such as drops or a potion.
For the formulation of the dosage form, the above described preparation may suitably be combined with a pharmaceutically acceptable (carrier. A much preferred dosage form is the tablet, in which the preparation may be combined with usual tablet constituents such as filler-binders, lubricants and the like.
The dosage in which the preparation is to be administered will of course depend on the concentration of active ingredients of the preparation and on the severity of the medical disorder or disease that is to be treated or prevented. The person skilled in the art will be able to optimize and formulate a suitable dosage scheme based on his ordinary knowledge of the field.
Preferably the preparation is orally administered, although other administration methods known in the art may also be applied, for some embodiments.
The packaging preferably occurs to facilitate convenience of packaging, storage, transport and/or consumption, and to ensure stability of the product, using methods known in the art.
The invention will now be further elucidated by the following, non-restrictive examples.

Chlorogenic acid and an analog thereof for immune system stimulation


Alpha-olefins are dimerized to form branched-chain feedstocks for detersive surfactants.

The present invention relates to processes for manufacturing detersive surfactants, especially those containing branched-chain hydrophobic units.
Conventional detersive surfactants comprise molecules having a water-solubilizing substituent (hydrophilic group) and an oleophilic substituent (hydrophobic group). Such surfactants typically comprise hydrophilic groups such as carboxylate, sulfate, sulfonate, amine oxide, polyoxyethylene, and the like, attached to an alkyl, alkenyl or alkaryl hydrophobe usually containing from about 10 to about 20 carbon atoms. Accordingly, the manufacturer of such surfactants must have access to a source of hydrophobe groups to which the desired hydrophile can be attached by chemical means. The earliest source of hydrophobe groups comprised the natural fats and oils, which were converted into soaps (i.e., carboxylate hydrophile) by saponification with base. Coconut oil and palm oil are still used to manufacture soap, as well as to manufacture the alkyl sulfate (xe2x80x9cASxe2x80x9d) class of surfactants. Other hydrophobes are available from petrochemicals, including alkylated benzene which is used to manufacture alkyl benzene sulfonate surfactants (xe2x80x9cLASxe2x80x9d).
The literature asserts that certain branched hydrophobes can be used to advantage in the manufacture of alkyl sulfate detersive surfactants; see, for example, U.S. Pat. No. 3,480,556 to deWitt, et al., Nov. 25, 1969. However, it has been determined that the beta-branched surfactants described in the ""556 patent are inferior with respect to certain solubility parameters, as evidenced by their Krafft temperatures. It has further been determined that surfactants having branching towards the center of carbon chain of the hydrophobe have much lower Krafft temperatures. See: xe2x80x9cThe Aqueous Phase Behavior of Surfactantsxe2x80x9d, R. G. Laughlin, Academic Press, N.Y. (1994) p. 347. Accordingly, it has now been determined that such surfactants are preferred for use especially under cool or cold water washing conditions (e.g., 20xc2x0 C.-5xc2x0 C.).
One problem associated with the manufacture of detersive surfactants having hydrophobe groups with mid- or near-mid chain branching is the lack of a ready source of such hydrophobes. By the present invention, a process is described for manufacturing such branched hydrophobes and converting them into mid- or near-mid chain branched surfactants.
The present invention encompasses a process for preparing mid- to near mid-chain branched olefins (primarily, methyl branched at or near the mid-chain region). Such materials are then used as the basic feedstock which provides the hydrophobic portion of branched-chain detersive surfactants.
The process herein is illustrated by the following reaction sequence.
1) Alpha-Olefin Dimerization
wherein R and Rxe2x80x2 may be the same or different linear alkyl, and wherein R is C3-C7, preferably C5 to C7 linear alkyl, and Rxe2x80x2 is C3-C7, preferably C5-C7 linear alkyl. For use in preparing surfactants in cleaning products such as laundry detergents, dishwashing liquids, and the like, R and Rxe2x80x2 are preferably the same or within one or two carbon atoms of each other in chain length. Some linear olefins may also result from the dimerization and these can optionally be removed using molecular sieves. Step 1 of the process herein is designed to provide branched olefins which preferably contain from about 12 to about 18 (avg.) total carbon atoms.
2) Alcohol Production
In Step 2 (Route A), the olefin mixture for Step 1 can be pre-randomized to enhance the ultimate formation of alcohols (i) and (ii) in subsequent Step 3. Alternatively (Step 2, Route B), this pre-randomization step can be deleted and the Oxo catalyst, itself, can randomize the final product among the three possible terminal positions.
The Oxo process to make alcohols is described in detail in Kirk-Othmer Encyclopedia of Chemical Technology, 4th Edition, Volume 1, pp. 903-8 (1991), Jacqueline 1. Kroschwitz, Executive Editor, Wiley-Interscience, N.Y. The catalyst for this step is, for example, cobalt-carbon monoxide-organophosphine.
The alcohol mixture of Step (2) of the present process comprises branched-chain primary alcohol compounds of the following formulae for use in Step (3), below.
It is to be understood that when CH2OH is substituted on R or Rxe2x80x2 it is primarily on their respective terminal carbons or to a lesser extent on their penultimate carbons. Desirably, minimal amounts of compounds of the formula (iii) are present in Step (3).
3) Surfactant Production
Advantageously, the present process results in no geminal branching; i.e., no xe2x80x9cquaternaryxe2x80x9d carbon substitution. Steric hindrance will block inverse addition to vinylidene carbon with cobalt-carbon monoxide-organophosphine which otherwise would form a non-biodegradable quaternary carbon. Moreover, little (less than about 3%) vicinal branching occurs. Of course, some of the overall feedstock may remain unbranched. Typically, and preferably from the standpoint of cleaning performance and biodegradability, the present process provides hydrophobes with one near-central methyl in the case of isomers i) and ii).
All percentages, ratios and proportions herein are by weight, unless otherwise specified. All documents cited herein are, in relevant part, incorporated herein by reference.
1) Olefin Dimerization:
The present invention encompasses, in a process for preparing surfactant precursor hydrophobes from dimerization of two same or near same chain length alpha-olefins to form a detergent range vinylidene olefin. These alpha olefins C5 to C10, preferably C7 to C9 are dimerized to give C10 to C20, preferably C14 to C18 vinylidene olefins which upon Oxo reaction give C11 to C21, preferably C15 to C19 alcohols. There are a number of processes for accomplishing said dimerization; see U.S. application Ser. No. 9,200,398, U.S. Pat. No. 4,658,078, U.S. Pat. No. 4,973,788; O. S. Vostrikova, A. G. Ibragimov, G. A. Tolstikov, L. M. Zelenova and U. M. Dzhemilev, Izv. Akad. Nauk SSSR, Ser. Khim. (1980), (10), 2330-2 [Chem. Abstr. 94:65032]; Jpn. Kokai Tokkyo Koho, 06228016 A2 [Chem. Abstr. 122:186930].
2) Alcohol Production
Route A
part a) The carbon-carbon double bond of the vinylidene olefin is pre-isomerized using a method such as Shell uses to isomerize alpha-olefins in their SHOP process; see Kirk-Othmer Encyclopedia of Chemical Technology, 4th Edition, Volume 17, pp. 848-50 (1996), Jacqueline I. Kroschwitz, Executive Editor, Wiley-Interscience, N. Y. and Chemical Economics Handbook, pp. 681.5030K-L, Stanford Research Institute, Menlo Park, Calif. 94025, October 1993.
part b) Oxo chemistry is used to convert the pre-isomerized vinylidene olefin (now largely internal olefin) to a primary alcohol mixture. For this an Oxo catalyst which isomerizes the double bond to alpha positions prior to carbonylation is desired as is the case using cobalt-carbonyl-phosphine catalysts in the one step process, see Kirk-Othmer Encyclopedia of Chemical Technology, 4th Edition, Volume 1, pp. 903-8 (1991). Route A, (that is including pre-isomerization) is undertaken to assure relatively high yields of alcohols i and ii versus alcohol iii. Note alcohol sulfates of i and ii are desired surfactants whereas that of iii may be deficient.
Route B
This step utilizes the same Oxo catalyst on the vinylidene olefin directly without its pre-isomerization. This relies upon the catalyst to completely isomerize the carbonxe2x80x94carbon double bond of the vinylidene olefin prior to carbonylation. The object is to obtain as much i and ii relative to iii as is obtained in Route A.
Other fatty alcohol-derived surfactants can also be made, e.g., alkyl ethoxyl sulfates (AES), alkyl polyglucosides (APG), etc. Note that surfactants other than alcohol sulfates or AES may be made by oxidizing said alcohol or its aldehyde intermediate into a carboxylate (i.e., a branched-chain soap). This soap can be an excellent surfactant and/or detergent builder in and of itself. This carboxylate can also be used as a feedstock and converted to branched acyl-taurates, -isethionates, -sarcosinates, -N-methylglucamide or other acyl-derived surfactants using art-disclosed techniques.
Branched-chain surfactants of the type resulting from the present process can be used in all manner of cleaning compositions. Such compositions include, but are not limited to: granular, bar-form and liquid laundry detergents; liquid hand dishwashing compositions; liquid, gel and bar-form personal cleansing products; shampoos; dentifrices; hard surface cleaners, and the like. Such compositions can contain a variety of conventional detersive ingredients. The following listing of such ingredients is for the convenience of the formulator, and not by way of limitation of the types of ingredients which can be used with the branched-chain surfactants herein.
The branched-chain surfactants herein can be used in combination with detergency builders. Such builders include, for example, 1-10 micrometer zeolite A, polycarboxylate builders such as citrate, layered silicate builders such as xe2x80x9cSKS-6xe2x80x9d (Hoechst) and phosphate materials, especially sodium tripolyphosphate (xe2x80x9cSTPPxe2x80x9d). Most laundry detergents typically comprise at least about 1% builder, more typically from about 5% to about 80% builder or mixtures of builders.
Enzymes, such as proteases, amylases, lipases, cellulases, peroxidases, and mixtures thereof, can be employed in detergent compositions containing the branched-chain surfactants. Typical detergent compositions comprise from about 0.001% to about 5% of commercial enzymes.
Detergent compositions can also contain polymeric soil release agents (SRA""s). Such materials include, for example, anionic, cationic and non-charged monomer units, especially polyester materials. Preferred materials of this type include oligomeric terephthalate esters, sulfonated substantially linear ester oligomers comprising a backbone of terephthaloyl and oxyalkyleneoxy-repeat units and phthalolyl-derived sulfonated terminal moieties. A variety of SRA""s are described, for example, in U.S. Pat. Nos. 4,968,451; 4,711,730; 4,721,580; 4,702,857; 4,877,896; 5,415,807; and in other literature references. Such soil release materials typically comprise from about 0.01% to about 10% of finished detergent compositions.
Detergent compositions may also optionally contain bleaching compositions comprising a bleaching agent and one or more bleach activators. If present, bleaching agents such as percarbonate or perborate (especially perborate monohydrate xe2x80x9cPBIxe2x80x9d) typically are used at levels from about 1% to about 30% of finished detergent compositions. Bleach activators such as nonanoyloxy-benzene sulfonate (xe2x80x9cNOBSxe2x80x9d) and tetraacetyl ethylenediamine (xe2x80x9cTAEDxe2x80x9d), and mixtures thereof, can be used to enhance the bleaching activity of materials such as perborate and percarbonate. If present, the amount of bleach activator will typically be from about 0.1% to about 60% of a bleaching composition comprising a bleaching agentplus-bleach activator. Other bleaching agents such as the so-called xe2x80x9cphotoactivatedxe2x80x9d bleaches (see U.S. Pat. No. 4,033,718) can also be used. Sulfonated zinc phthalocyanine is an especially preferred photoactivated bleaching agent.
Detergent compositions can also contain clay soil removal/antiredeposition agents such as ethoxylated tetraethylene pentamine; see U.S. Pat. No. 4,597,898. Such materials typically comprise from about 0.01% to about 10% of fully-formulated laundry detergents.
Detergent compositions can also contain from about 0.1% to about 7% of polymeric dispersing agents, which are especially useful in the presence of zeolite and/or layered silicate builders. Such materials are known in the art (see U.S. Pat. No. 3,308,067). Such materials include acrylatelmalic-based copolymers, such as described in EP 193,360, as well as polyethylene glycol (xe2x80x9cPEGxe2x80x9d).
Detergent compositions herein can also include various brighteners, dye transfer inhibiting agents (especially polymers of N-vinylpyrrolidone and N-vinylimidazole), suds suppressors (especially silicones), chelating agents such as nitrilotriacetate, ethylenediamine disuccinate, and the like. Such materials will typically comprise from about 0.5% to about 10%, by weight, of fully-formulated cleaning compositions.
Moreover, it is to be understood that the branched-chain surfactants prepared in the manner of the present invention may be used singly in cleaning compositions or in combination with other detersive surfactants. Typically, fully-formulated cleaning compositions will contain a mixture of surfactant types in order to obtain broad-scale cleaning performance over a variety of soils and stains and under a variety of usage conditions. One advantage of the branched-chain surfactants herein is their ability to be readily formulated in combination with other known surfactant types. Nonlimiting examples of additional surfactants which may be used herein typically at levels from about 1% to about 55%, by weight, include the unsaturated sulfates such as oleyl sulfate, the C10-C18 alkyl alkoxy sulfates (xe2x80x9cAEXSxe2x80x9d; especially EO 1-7 ethoxy sulfates), C10-C18 alkyl alkoxy carboxylates (especially the EO 1-5 ethoxycarboxylates), the C10-18 glycerol ethers, the C10-C18 alkyl polyglycosides and their corresponding sulfated polyglycosides, and C12-C18 alpha-sulfonated fatty acid esters. Nonionic surfactants such as the ethoxylated C10-C18 alcohols and alkyl phenols, (e.g., C10-C18 EO (1-10) can also be used. If desired, other conventional surfactants such as the C12-C18 betaines and sulfobetaines (xe2x80x9csultainesxe2x80x9d), C10-C18 amine oxides, and the like, can also be included in the overall compositions. The C10-C18 N-alkyl polyhydroxy fatty acid amides can also be used. Typical examples include the C12-C18 N-methylglucamides. See WO 9,206,154. Other sugar-derived surfactants include the N-alkoxy polyhydroxy fatty acid amides, such as C10-C18 N-(3-methoxypropyl) glucamide. The N-propyl through N-hexyl C12-C18 glucamides can be used for low sudsing. C10-C20 conventional soaps may also be used. If high sudsing is desired, the branched-chain C10-C16 soaps may be used. C10C14 alkyl benzene sulfonates (LAS), which are often used in laundry detergent compositions, can also be used with the branched surfactants herein.


A device and method for pulling a tongue forward thereby preventing obstruction to the flow of air during sleep or an emergency.

This invention relates to a device that decreases interference of breathing during sleep. More particularly, this invention relates to a device that the user can insert into their mouth that alleviates snoring and obstructive sleep apnea.
Snoring sounds are vibrations as air passes collapsed structures caused by the relaxation of body tissues during sleep. The tissues which collapses are especially in the lingual compartment, including the tongue, the pharyngeal folds, the soft palate, the muscles of the uvula, and the palate-pharyngeal arch, the pharynx, and the larynx. Muscle tone during normal waking hours maintains the airway patent for free passage of air. Obstructive sleep apnea (OSA) and obstructive breathing (snoring) are mainly caused by the collapse of the airway, especially when the soft palate relaxes while the tongue falls to the back of the throat, both blocking the airway. In OSA, the airway becomes intermittently blocked by the tongue and other airway structures, and at times the person or animal cannot breathe at all.
Uvulopalatopharnygoplasty, adenoidectomy, tonsillectomy, orthognathic, genioglossus advancement, hyoid suspension, lingual plasty, lingual reduction, and other surgery of the mouth, pharynx, hypopharynx and tongue are used for correcting sleep disorders such as OSA or snoring. A need exists for a simple and convenient method and apparatus to obviate surgery while providing a means to bring the tongue forward.
Various devices for preventing or decreasing snoring are known in the prior art. For example, Samelson, in U.S. Pat. No. 4,304,277, discloses a device providing a rearwardly open central socket that cooperates with the forward portion of a user""s tongue in such a manner as to draw the tongue forward to increase the unobstructed dimension of the breathing passage. The tongue is held in the socket by negative pressure developed in the socket. The tongue thus held draws the body of the tongue forward thereby increasing the dimension of the air flow passage to facilitate breathing.
Karell in U.S. Pat. No. 5,792,067 discloses a means to reduce or prevent snoring and OSA by increasing muscle tone to airway structures (muscles) by applying electrical energy through strategically placed electrodes within a removable dental appliance. Karell discloses an intraoral structural support containing electrodes for making contact with intraoral mucosa. Energizing the electrodes with electrical energy causes stimulation to nerves and muscles, which in turn causes increased muscle tone and muscle contraction.
The present invention provides a method and device that can prevent snoring and OSA. The device can be adjusted and form fitted by the user, is of simple design, and may be more comfortable than the devices disclosed by the prior art.
One object of the present invention and method is to provide an anti-snore or anti-OSA device that serves to hold the tongue in a forward position, thereby drawing the remainder of the tongue forwardly to increase airway passage.
A further object of the present invention is to provide an anti-snore or anti-OSA device that provides an airway within the appliance. Also, the airway has the capability for attaching to other medical equipment such an an ambu bag or other airway means, including oxygen delivery, respiratory and CPAP systems.
A further object of the present invention is to provide an anti-snore or anti-OSA device that provides one or more electrodes for making contact to intraoral structures for increasing muscle tone by the application of energy from an energy source.
Another object of the present invention is to provide an anti-snoring or anti-OSA device which is moldable after immersion in boiling water or some other method of molding, so that it can be adapted by the user to have a comfortable and individualized fit.
And still another object of this invention and method is to provide an anti-snore device which also prevents bruxism (nocturnal tooth grinding), by bringing the tongue forward through the teeth.
And still another object is provide for a configuration allowing for unity of construction thereby having no parts which may be swallowed.
And still another object is to provide for a configuration allowing for emergency airway usage.
And still another object is to provide a simple method for keeping a tongue forward during sleep and at other times.
These and other objects and advantages of the invention will become clear from the following description of a preferred embodiment of the invention.
A device of the instant invention can be readily adapted to fit any particular user""s mouth, human or animal, for the prevention of bruxism, snoring, other obstructed breathing problems such as OSA, and may be fitted and adjusted by the user. In general, the method for reducing interference of breathing during sleep comprises the following steps: (a)making a hole in a user""s tongue; (b)molding an structural support to a user""s mouth; (c)wherein the structural support comprises a releasable fastener; (d)placing the releasable fastener through the tongue hole thereby affixing tongue to structural support, pulling tongue forward and preventing obstruction to the flow of air. The device of the instant invention utilizing this method comprises a structural support for fitting within a user""s mouth. Additionally, it comprises releasable fastener for holding the tongue in a forward position. A hole tongue may be made using various implements known in the art. The structural support may be a moldable material that contains the impressions of all or part of the upper and/or lower teeth or gums of a user. The releasable fastener may be a firm or non-firm structure passing through the tongue, as do body piercing tongue rings/posts/bars and strings. Prior to going to sleep, the user inserts the device into his or her mouth, passes the releasable fastener through the tongue, and affixes the tongue to the appliance. In this manner, the forward portion of the tongue is held firmly in position to, as example, the rear of the incisor teeth region, thereby pulling the entire tongue forward, thereby opening the airway. The releasable fastener may simply be a hook. Or it may be a pivoting bar which after passing through the tongue, pivots to become a substantially perpendicular xe2x80x9cTxe2x80x9d shape for comfortably resting under the tongue (that is, the sublingual region of the tongue). The releasable fastener may additionally have a piercer for piercing through a tongue when no previous hole was made.
Although the preferred configuration would be a one-piece device, fastener may be separate from the structural support. An example of such a configuration is one in which a hook-and-eye arrangement is utilized, wherein, for example, the structural support has the hook and the fastening means has the eye. There are many coupling systems are known to the art; for example, the structural support may contain a magnet and another magnet may be inserted through the tongue, or a screw threaded coupling may be utilized.
A simpler method for reducing interference of breathing during sleep may be to place a bar through a forward portion of a tongue so that during sleep the bar can be positioned external to a user""s teeth for keeping the tongue in a forward position.
The device may additionally have an airway and/or electrodes. U.S. Pat. No. 5,792,067 to Karell is disclosed and is incorporated herein by reference. This patent teaches a device and method and provides appropriate techniques and devices amenable to the practice of the instant invention.
The device may be configured for use in emergency situations in which case the structural support is configured as an airway with a stop. In this configuration the releasable fastener contains a sharp piercer for piercing through a tongue which has no previous hole. Also, the airway has the ability for attaching to an ambu bag and other airway devices, including oxygen delivery, respiratory and CPAP systems.

Method and device for holding a tongue in a forward position


A clock smoothing circuit generates a smoothed clock signal from a gapped clock signal having unevenly spaced pulses separated by gaps that result from the removal of data bits and from a reference clock signal having evenly spaced pulses that create a predetermined reference frequency. A smoothing element is coupled to the input elements to receive the gapped clock signal and the reference clock signal. In one embodiment, the smoothing element generates a smoothed clock signal having one pulse for each of the pulses in the gapped clock signal and having a frequency that is greater than one-half of the predetermined reference frequency. Each pulse in the smoothed clock signal is synchronized with a pulse in the reference clock signal. In another embodiment, the smoothing element includes an accumulator that counts the pulses of the reference clock signal, a modulo signal that resets the accumulator to a particular reset value when a predetermined number of pulses M is reached, and an output element that produces one pulse of the smoothed clock signal for each pulse of the reference clock signal on which the modulo element does not reset the accumulator.

The invention relates to producing smoothed clock and data signals from gapped clock and data signals.
In many modern communication systems, timing information, in the form of clock signals, plays a critical role in system performance. In these applications, the clock signals are used to drive circuitry such as mixers and sampling circuits for which consistency in the sampling instant is an important performance parameter. Minimizing timing errors requires minimizing the noise introduced during the distribution and buffering of clock signals in the system.
Some communication devices, such as cable modems, derive clock signals from timestamps embedded in data streams. In addition to timestamps, these data streams usually include error correction and synchronization information to ensure integrity and synchronization. In processing the data stream, the cable modem removes the error correction and synchronization bits, leaving a reference clock that is gapped or jittered where the error correction and other information were located. In general, these communication systems must smooth the reference clock for accurate data recovery.
Many systems use phase-locked loops (PLLs), or other similar circuits, to smooth the reference clock and the incoming data signal. A PLL uses a voltage-controlled oscillator (VCO) to produce an output frequency that is proportional to the voltage at the PLL output. As a result, PLLs require signal feedback and filtering. A PLL also requires careful attention to all sources of noise in the system and overall interaction of system components to minimize timing errors. Therefore, attaining high performance levels with PLLs may contribute considerable expense and complexity to the systems in which PLLs are used.
Direct digital synthesizers (DDSs) also are used to produce clock signals by accumulating phase changes at one clock frequency to generate highly accurate waveforms at a lower frequency. The DDS allows high resolution frequency and phase control, producing frequency steps on the order of mHz and phase increments on the order of nHz. To produce a particular frequency, an associated phase increment value is loaded into an input frequency register. The generated frequency and the DDS reference frequency are related to the phase increment value by the following equation:
Fgen=N/2kxc2x7Fref
k=number of bits in phase accumulator
N=phase increment value
A desired frequency is generated by programming the phase change within the bit resolution of the phase accumulator. However, a conventional k-bit DDS has a resolution limited by the number of bits, k. Furthermore, sampling theory limits the generated frequency to no more than one-half the frequency of the incoming reference clock (the Nyquist rate).
The inventors have developed a clock and data smoothing technique that allows generation of a clock of virtually any frequency up to the frequency of a reference clock. This technique is capable of generating exact frequencies and thus does not require approximations that normally involve the monitoring of feedback. Elimination of feedback obviates the need for a PLL circuit in many cases. This, in turn, allows the use of lower cost materials and fewer gate elements than are required for standard DDS clocks. This clock and data smoothing technique provides fully deterministic and pre-calculated phase errors of a given ratio N/M.
In addition, this technique produces a smooth clock up to the reference frequency, with a timing jitter less than the period of the reference clock. This technique also eliminates the need to maintain jitter statistics, acquisition times, and bandwidth for statistical performance analysis.
In one aspect, the invention involves the generation of a smoothed clock signal from a gapped clock signal having unevenly spaced pulses separated by gaps that result from the removal of data bits and from a reference clock signal having evenly spaced pulses that create a predetermined reference frequency. The smoothed clock signal includes one pulse for each of the pulses in the gapped clock signal and has a frequency that is greater than one-half of the predetermined reference frequency. Each pulse in the smoothed clock signal is synchronized with a pulse in the reference clock signal.
In some embodiments, the smoothed clock signal has a frequency equal to (Mxe2x88x92N)/M of the predetermined reference frequency, where M represents the total number of pulses of the reference clock signal during a period of predetermined length, and where N equals the total number of these pulses that coincide with the gaps in the gapped clock signal. In other embodiments, an accumulator counts the pulses of the reference clock signal, and a modulo element resets the accumulator to a particular reset value when a predetermined number of pulses is reached. An output element produces one pulse of the smoothed clock signal for each pulse of the reference clock signal on which the modulo element does not reset the accumulator.
In another aspect of the invention, the smoothed clock signal is generated from the gapped clock signal and the reference clock signal by using an accumulator to count the pulses of the reference clock signal and by resetting the accumulator to a particular reset value when a predetermined number of pulses M is reached. One pulse of the smoothed clock signal is produced for each pulse of the reference clock signal on which the accumulator is not reset.
In some embodiments, the particular reset value equals a number of counted pulses minus the predetermined number. In other embodiments, resetting the accumulator involves comparing a number of counted pulses to the predetermined number N and asserting a modulo signal when the number of counted pulses reaches the predetermined number M. An output element produces a pulse of the smoothed clock signal at each pulse of the reference clock signal when enabled. The output element is disabled when the modulo signal is asserted. In other embodiments, the accumulator increments by a predetermined number N at each pulse of the reference clock signal, such that N/M equals a proportion of the gapped clock signal that is consumed by the gaps.
In another aspect, the invention features a system for use in removing jitter from a signal having gaps that result from the removal of error correction and synchronization information. The system includes a reference signal having a plurality of periodic pulses and a counting mechanism configured to count the periodic pulses in the reference signal by incrementing a count value by a first predetermined number. A reset mechanism resets the count value to a particular reset value when the count reaches a second predetermined number such that the ratio of the second predetermined number to the first predetermined number represents the ratio of the total amount of information in the input signal before removal of the error correction and synchronization information to the amount of error correction and synchronization information removed from the input signal. A pulse generating mechanism generates an output signal pulse on each pulse of the reference signal for which the count value has not reached the second predetermined number and leaves a gap in the output signal on pulses for which the reset mechanism resets the count value, where each pulse of the output signal is synchronized with one of the pulses of the reference signal.

Producing smoothed clock and data signals from gapped clock and data signals


A combination of a radio frequency identification transponder (RFID Tag) and to a magnetic electronic article surveillance (EAS) device is disclosed.

1. Field of the Invention
The present invention relates to an identification tag and more particularly to an identification tag having a large number of bits of information, where the identification tag has an electronic article surveillance function which is difficult to defeat.
2. Description of the Related Art
Radio frequency identification transponders (RFID Tags) have been developed in the last years to take advantage of the fall in semiconductor logic and memory prices. Such tags are available having a single silicon chip attached to a wire or patch antenna. Such tags, however, may be shielded from the high frequency RF used to communicate with the tags. The anti-theft properties of the RFID tags are suspect.
Magnetic electronic article surveillance (EAS) tags are much less easily shielded from the low frequency magnetic detection fields. Such EAS tags as described below, however, have possibilities of storing only a few bits of information.
Some conventional magnetic EAS tags have employed the Barkhausen jump effect. Generally, the Barkhausen effect is characterized by a tendency for magnetization induced in a magnetic material to change in discrete steps as an external magnetic field is increased or decreased. (The material is said to be a non linear magnetic material if the magnetisation of the material is not proportional to the external magnetic field.) A large temporal flux change, d.phi../dt, occurs when such a step takes place, and a sizable voltage may be induced in a sensing or pickup coil.
For example, U.S. Pat. No. 5,181,020 describes a thin-film magnetic tag having a magnetic thin film formed on a polymer substrate and a method for producing the same. The thin film exhibits a large Barkhausen discontinuity without intentional application of external torsional or tensile stress on use. A particular disclosed use is as a marker or tag for use in an article surveillance system wherein articles may be identified by interrogating the tagged article in a cyclic magnetic field of a predetermined frequency in a surveillance area and detecting a harmonic wave of the magnetic field generated by the tag in the surveillance area. This conventional system is only a single bit element using a single Barkhausen layer with no ability to develop a code to distinguish items.
U.S. Pat. No. 5,313,192 describes another single bit tag which relies on the Barkhausen effect. The tag of this invention is selected to include a first component comprised of a soft magnetic material which constitutes the bulk of the tag. A second component comprised of a semi-hard or hard magnetic material is integral with the first component. The tag is conditioned such that the second component has activating and deactivating states for placing the tag in active and deactivated states, respectively. Such conditioning includes subjecting the composite tag to predetermined magnetic fields during thermal processing stages. By switching the second component between its activating and deactivating states the tag can be switched between its active and deactived states. A reusable tag with desired step changes in flux which is capable of deactivation and reactivation is thereby realized.
U.S. Pat. No. 4,980,670 describes a one bit magnetic tag formed from a magnetic material having domains with a pinned wall configuration. The resulting hysteresis characteristic for that material is such that upon subjecting the material to an applied alternating magnetic field, the magnetic flux of the material undergoes a regenerative step change in flux (Barkhausen jump) at a threshold value when the field increases to the threshold value from substantially zero and undergoes a gradual change in flux when the field decreases from the threshold value to substantially zero. For increasing values of applied field below the threshold, there is substantially no change in the magnetic flux of the material. The tag may be deactivated by preventing the domain walls from returning to their pinned condition by, for example, application of a field of sufficiently high frequency and/or amplitude.
U.S. Pat. No. 4,940,966 describes the use of a plurality of magnetic elements in predetermined associations (e.g. with predetermined numbers of magnetic elements and with predetermined spacings between said elements), for identifying or locating preselected categories of articles. When the articles are caused to move relative to a predetermined interrogating magnetic field, each particular association of magnetic elements gives rise to a magnetic signature whereby the article or category of article carrying each of the predetermined associations can be recognized and/or located.
U.S. Pat. No. 4,660,025 describes a marker for use in an electronic surveillance system. The marker, which can be in the form of a wire or strip of magnetic amorphous metal, is characterized by having retained stress and a magnetic hysteresis loop with a large Barkhausen discontinuity. When the marker is exposed to an external magnetic field whose field strength, in the direction opposing the instantaneous magnetic polarization of the marker, exceeds a predetermined threshold value, a regenerative reversal of the magnetic polarization of the marker occurs and results in the generation of a harmonically rich pulse that is readily detected and easily distinguished.
U.S. Pat. No. 5,175,419 describes a method for interrogating an identification tag comprised of a plurality of magnetic, thin wires or thin bands which have highly rectangular hysteresis curves and different coercive forces. The wires or bands are preferably of amorphous material, but means for obtaining the highly rectangular hysteresis curves and different coercive forces are not taught; nor is the concept taught of using a time varying magnetic field superimposed on a ramp field for interrogation.
U.S. Pat. No. 5,729,201 describes an inexpensive multibit magnetic tag is described which uses an array of amorphous wires in conjunction with a magnetic bias field. The tag is interrogated by the use of a ramped field or an ac field or a combination of the two. The magnetic bias is supplied either by coating each wire with a hard magnetic material which is magnetized or by using magnetized hard magnetic wires or foil strips in proximity to the amorphous wires. Each wire switches at a different value of the external interrogation field due to the differences in the magnetic bias field acting on each wire.
The above identified U.S. patents are hereby incorporated by reference.
3. Related Applications and Issued Patents
Related U.S. patents assigned to the assignee of the present invention include: 5,528,222; 5,550,547; 5,552,778; 5,554,974; 5,538,803; 5,563,583; 5,565,847; 5,606,323; 5,521,601; 5,635,693; 5,673,037; 5,682,143; 5,680,106; 5,729,201; and 5,729,607. U.S. patent applications assigned to the assignee of the present invention include: Ser. No. 08/303,965 filed Sep. 9, 1994 entitled RF Group Select Protocol, by Cesar et al.; Ser. No. 08/621,784, filed on Mar. 25, 1996 entitled "Thin Radio Frequency Transponder with Lead Frame" by Brady et al. (pending); Ser. No. 08/626,820, Filed: Apr. 3, 1996, entitled "Method of Transporting RF Power to Energize Radio Frequency Transponders", by Heinrich et al.; application submitted Aug. 9, 1996 entitled RFID System with Broadcast Capability by Cesar et al.; application submitted Jul. 29, 1996 entitled RFID transponder with Electronic Circuitry Enabling and Disabling Capability, by Heinrich et al.; Ser. No. 08/592,250; Ser. No. 08/496,838; Ser. No. 08/496,838; Ser. No. 08/909,719; Ser. No. 08/621,784,660,249; Ser. No. 08/660,261; Ser. No. 08/790,640; Ser. No. 08/790,639; and Ser. No. 08/681,742. The above identified U.S. patents and U.S. patent applications are hereby incorporated by reference.

Combination radio frequency transponder (RF Tag) and magnetic electronic article surveillance (EAS) material


In response to a query including a proposed trademark and or more search parameters, a system receives search results, each including at least one ascertainable text-based property and a numeric score indicative of a measure of similarity between the search result and the proposed trademark. To generate an interactive graphical representation of the search results, the system (i) generates a reference indicator for the proposed trademark at a reference location in the interactive graphical representation, (ii) determines, for each of the search results, a first offset along a first axis and a second offset along a second axis relative to the reference location using the numeric score and the at least one ascertainable text-based property of a respective search result, and (iii) generates, for each of the search results, a search result indicator in the interactive graphical representation, in accordance with the determined first and second offsets.

The background description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the present disclosure.
The trademark legal clearance and protection industry is currently suffering greatly from "information overload" due to the increase in the amount of information available in the clearance process as a result of technology changes over last few decades. These changes have happened steadily, and the industry has been slow to respond to the change in the amount of information due to a strong culture of tradition in the legal industry.
Information overload is characterized by difficulties a person may encounter when trying to understand complex issues or make a decision due to the presence of too much information. Studies show that decision makers have a limited cognitive processing capacity, and when facing an information overload, there is a higher chance that decision quality will be adversely impacted. The impact of information overload on the trademark legal clearance and protection industry is significant. The industry is struggling to find a balance between risk mitigation and loss of productivity due to increased information in the trademark clearance process.
While the information continues to grow significantly, no new tools are being implemented to curate and present the information so that it may be effectively processed. Current best practices and methods of trademark clearance can no longer support the large data sizes now occurring in the trademark clearance process due to the primitive means for presenting search results. Further, practitioners are struggling to arrive at confident risk analysis decisions and communicate their findings to brand owners due to the challenges of processing such large amounts of cluttered information. Trademark data has grown too large to be effectively analyzed under the current method of performing a clearance search.
The existing systems typically implement serial data review techniques (spreadsheets, lists, full records, etc.), which is daunting for a large set of search results. More particularly, these presentation techniques generally require that the user traverse numerous generations of screens to collect all the necessary information. Moreover, the existing systems do not allow the user to simultaneously review multiple, mutually independent factors when reviewing results during trademark clearance.

System and method for displaying search results for a trademark query in an interactive graphical representation