Sulfur Containing Reactant Patents (Class 530/408)
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Patent number: 6627460Abstract: A novel preparative methodology yields water-soluble, cross-linked conjugates and conjugate complexes that confer an improved sensitivity in immunochemical assays, particularly in the context of lateral flow devices and in determinations of the presence or absence of small amounts of active components present in a liquid sample.Type: GrantFiled: April 5, 2001Date of Patent: September 30, 2003Assignee: Amdex A/SInventors: Allan Otto Fog Lihme, Christopher John Stanley
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Patent number: 6624142Abstract: The invention is directed primarily to compounds of Formula I: wherein: R1 is a polymeric residue; L1 is a bifunctional linking group; Y1 and Y2 are independently O, S or NR7; R2-7 are independently selected from the group consisting of hydrogen, C1-6 alkyls, C3-12 branched alkyls, C3-8 cycloalkyls, C1-6 substituted alkyls, C3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C1-6 heteroalkyls, substituted C1-6 heteroalkyls, C1-6 alkoxy, phenoxy and C1-6 heteroalkoxy; D is a moiety that is a leaving group or a residue of a compound to be delivered into a cell; Z is selected from the group consisting of: a moiety that is actively transported into a target cell, a hydrophobic moiety, and combinations thereof; Ar is a moiety which when included in Formula (I) forms a multi-substituted aromatic hydrocarbon or a multi-substituted heterocyclic group; and (y) is a positive integer greater than or equal to 1. Methods of making and using the same are also disclosed.Type: GrantFiled: May 9, 2001Date of Patent: September 23, 2003Assignee: Enzon, Inc.Inventors: Richard B. Greenwald, Hong Zhao
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Patent number: 6617306Abstract: A carrier for in vivo delivery of a therapeutic agent comprising a thiol group is provided, wherein the therapeutic agent is conjugated to the carrier via a biodegradable disulfide bond. Since extracellular fluids in vivo do not provide the appropriate environment to efficiently reduce a disulfide bond, while cellular cytosol does provide an appropriate environment, the agent will remain substantially coupled to the carrier while circulating through the body until the carrier crosses a cell membrane. As a result, the therapeutic agent is protected from degradation and renal clearance, and the potential for the therapeutic agent to elicit an immune response is limited.Type: GrantFiled: March 8, 2001Date of Patent: September 9, 2003Assignees: Rutgers, The State University of New Jersey, University of Medicine and Dentistry of New JerseyInventors: Stanley Stein, Michael J. Leibowitz, Patrick J. Sinko
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Patent number: 6602507Abstract: Synthetic polypeptides from the conserved exposed region of streptococcal M protein are useful to prepare vaccines for oral or intranasal administration which will protect against streptococcal infection.Type: GrantFiled: January 6, 1995Date of Patent: August 5, 2003Assignee: The Rockefeller UniversityInventor: Vincent A. Fischetti
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Patent number: 6582928Abstract: The invention provides heterobifunctional cross-linking reagents and methods of using the cross-linking reagents. The cross-linking reagents of the invention combine a nucleophilic hydrazide residue with an electrophilic maleimide residue allowing coupling of aldehydes to free thiols. In the methods of the invention, human immunodeficiency virus (HIV) infected cells can be detected using conjugates that include CD4 molecules conjugated to detectable markers via the disclosed cross-linking reagents.Type: GrantFiled: March 2, 2000Date of Patent: June 24, 2003Assignee: Genentech, Inc.Inventors: Avi J. Ashkenazi, Steven M. Chamow, Timothy P. Kogan
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Patent number: 6576746Abstract: A method of producing a diagnostic or therapeutic conjugate of a protein, polypeptide or peptide containing at least one disulfide bond which is necessary to maintain its biological activity, and bearing at least one thiol-containing moiety linked thereto through a hydrazone or hydrazine linkage, is effected by contacting said protein, polypeptide or peptide with a thiol-reactive diagnostic or therapeutic agent, either preformed or generated in situ, to form a stable diagnostic or therapeutic conjugate of the protein, polypeptide or peptide without substantial cleavage of the disulfide bond. Diagnostic and therapeutic conjugates produced using the foregoing method, as well as kits for carrying out the method are provided.Type: GrantFiled: October 13, 1999Date of Patent: June 10, 2003Assignee: Immunomedics, Inc.Inventors: William J. McBride, Gary L. Griffiths
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Publication number: 20030083475Abstract: The present disclosure provides an effective method for the refolding of denatured proteins in solution so that properly folded, biologically active protein in solution is recovered in high yield. The refolding takes place at pressures between about 0.25 kbar to about 3.5 kbar, advantageously at about 1.5 kbar to about 3 kbar. Typically a chaotropic agent is present at a concentration which is not effective for denaturing protein at atmospheric pressure, and optionally, oxidation-reduction reagents can be incorporated in the refolding solution so that native intramolecular disulfide bonds can be formed where that is desired. The method is applicable to substantially all proteins, especially after solubilization and/or denaturation of insoluble protein aggregates, inclusion bodies, or abnormal oligomeric (soluble) aggregates.Type: ApplicationFiled: November 12, 2002Publication date: May 1, 2003Applicant: University Technology CorporationInventors: Theodore W. Randolph, John F. Carpenter, Richard St. John
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Patent number: 6528292Abstract: Molded articles formed of polystyrene or other polymers containing an aromatic moiety can be derivatized on the surface of the article by subjecting the molded article to a chemical reaction wherein the reaction media utilizes tetramethylsulfone as the reactant solvent and a suitable substituent group which is substituted on to the aromatic moiety of the polystyrene or other polymer by electrophilic substitution. By choosing the substituent group to further include a leaving group, further substitution of the primary substituent can be effected normally by nucleophilic substitution reaction. In this way, biologically important molecules can be attached to a polystyrene or other aromatic containing polymer without effecting certain properties of the molded article such as its optical or spectroscopic clarity.Type: GrantFiled: June 6, 1995Date of Patent: March 4, 2003Assignee: Aventis Pharmaceuticals Holdings Inc.Inventor: Brian R. Clark
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Patent number: 6512098Abstract: The present invention relates to a chemically modified mutant protein including a cysteine residue substituted for a residue other than cysteine in a precursor protein, the substituted cysteine residue being subsequently modified by reacting the cysteine residue with a glycosylated thiosulfonate. Also, a method of producing the chemically modified mutant protein is provided. The present invention also relates to a glycosylated methanethiosulfonate. Another aspect of the present invention is a method of modifying the functional characteristics of a protein including providing a protein and reacting the protein with a glycosylated methanethiosulfonate reagent under conditions effective to produce a glycoprotein with altered functional characteristics as compared to the protein. In addition, the present invention relates to methods of determining the structure-function relationships of chemically modified mutant proteins.Type: GrantFiled: July 2, 1999Date of Patent: January 28, 2003Assignees: Genencor International, Inc.Inventors: J. Bryan Jones, Benjamin G. Davis
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Publication number: 20030018169Abstract: The present invention relates to methods and compositions for lipid matrix-assisted chemical ligation and synthesis of membrane polypeptides that are incorporated in a lipid matrix. The invention is exemplified in production of a prefolded membrane polypeptide embedded within a lipid matrix via stepwise chemoselective chemical ligation of unprotected peptide segments, where at least one peptide segment is embedded in a lipid matrix. Any chemoselective reaction chemistry amenable for ligation of unprotected peptide segments can be employed. Suitable lipid matrices include liposomes, micelles, cell membrane patches and optically isotropic cubic lipidic phase matrices. Prefolded synthetic and semi-synthetic membrane polypeptides synthesized according to the methods and compositions of the invention also permit site-specific incorporation of one or more detectable moieties, such as a chromophore, which can be conveniently introduced during synthesis.Type: ApplicationFiled: July 30, 2002Publication date: January 23, 2003Inventors: Gerd G. Kochendoerfer, Christie L. Hunter, Stephen B.H. Kent, Paolo Botti
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Publication number: 20030013857Abstract: Reagents and methods are provided for crosslinking and immobilizing biomolecules, drugs and synthetic polymers. The reagents possess (i) a thiol or amino reactive group; and (ii) a hydrazino or oxyamino moiety. Conjugates and immobilized biomolecules are also provided.Type: ApplicationFiled: March 22, 2001Publication date: January 16, 2003Applicant: Solulink IncorporatedInventor: David A. Schwartz
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Patent number: 6500933Abstract: The present invention relates to the field of carbohydrate crosslinked glycoprotein crystals. Advantageously, such crosslinked glycoprotein crystals display stability to harsh environmental conditions, while maintaining the structural and functional integrity of the glycoprotein backbone. According to one embodiment, this invention relates to methods for concentrating proteins that have been modified by carbohydrates and for releasing their activity at controlled rates. This invention also provides methods for producing carbohydrate crosslinked glycoprotein crystals and methods for using them in pharmaceutical formulations, vaccines, immunotherapeutics, personal care compositions, including cosmetics, veterinary pharmaceutical compositions and vaccines, foods, feeds, diagnostics, cleaning agents, including detergents and decontamination formulations.Type: GrantFiled: March 3, 2000Date of Patent: December 31, 2002Assignee: Altus Biologics Inc.Inventors: Alexey L. Margolin, Chandrika P. Govardhan, Kalevi J. Visuri, Sinikka S. Uotila
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Patent number: 6497760Abstract: Modified soy protein adhesives are provided which have increased bonding abilities. The adhesives are prepared by forming a dispersion of soy protein, water, and a modifier selected from two classes of modifiers. The preferred modifiers are urea, sodium dodecylbenzene sulfonate, sodium dodecyl sulfate, and guanidine hydrochloride. The resulting dispersion is stirred, freeze-dried, and milled into a powder to be stored until use. The adhesives of the invention have superior bonding qualities while being safe for the environment. The urea-modified, GH-modified, SDS-modified, and SDBS-modified soy protein adhesives have higher water resistance than non-modified soy protein adhesives.Type: GrantFiled: July 2, 2001Date of Patent: December 24, 2002Assignee: Kansas State University Research FoundationInventors: Xiuzhi Sun, Ke Bian
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Patent number: 6468978Abstract: A hedgehog conjugate which is characterized in that it contains: a) a polypeptide composed of 10 to 30 hydrophobic amino acids and/or amino acids which form transmembrane helices and are positively charged, b) 1 to 4 aliphatic, saturated or unsaturated hydrocarbon residues with a chain length of 10 to 24 C atoms and with a hydrophobic action or c) a hydrophobic thio compound covalently bound to a hedgehog protein and which has a several-fold increased activity and is suitable as a pharmaceutical agent.Type: GrantFiled: April 28, 1999Date of Patent: October 22, 2002Assignee: Curis, Inc.Inventors: Angelika Esswein, Kurt Lang, Petra Rueger, Tilman Seytter
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Publication number: 20020146736Abstract: The present invention pertains to luminescent dyes and methods for covalently attaching the dyes to a component or mixture of components so that the components may be detected and/or quantified by luminescence detection methods. The dyes are cyanine and cyanine-type dyes that contain or are derivatized to contain a reactive group. The reactive group is covalently reactive with amine, hydroxy and/or sulfhydryl groups on the component so that the dye can be covalently bound to the component. In addition, the dyes are preferably soluble in aqueous or other medium in which the component is contained. The components to be labeled can be either biological materials, such as antibodies, antigens, peptides, nucleotides, hormones, drugs, or non-biological materials, such as polymers, glass, or other surfaces. Any luminescent or light absorbing detecting step can be employed in the method of the invention.Type: ApplicationFiled: March 22, 2002Publication date: October 10, 2002Applicant: Carnegie Mellon UniversityInventor: Alan S. Waggoner
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Publication number: 20020142340Abstract: The present invention pertains to luminescent dyes and methods for covalently attaching the dyes to a component or mixture of components so that the components may be detected and/or quantified by luminescence detection methods. The dyes are cyanine and cyanine-type dyes that contain or are derivatized to contain a reactive group. The reactive group is covalently reactive with amine, hydroxy and/or sulfhydryl groups on the component so that the dye can be covalently bound to the component. In addition, the dyes are preferably soluble in aqueous or other medium in which the component is contained. The components to be labeled can be either biological materials, such as antibodies, antigens, peptides, nucleotides, hormones, drugs, or non-biological materials, such as polymers, glass, or other surfaces. Any luminescent or light absorbing detecting step can be employed in the method of the invention.Type: ApplicationFiled: March 22, 2002Publication date: October 3, 2002Applicant: Carnegie Mellon UniversityInventor: Alan S. Waggoner
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Patent number: 6458923Abstract: The substitution of the L-Pro at the 7-position of the peptide hormone bradykinin or other substituted analogs of bradykinin with an isoquinoline derivative which converts bradykinin agonists into bradykinin antagonists. The invention further includes the novel 7-position modified bradykinin antagonists which increase enzyme resistance, antagonist potency, and/or specificity of the new bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected as by insect bites.Type: GrantFiled: September 12, 1994Date of Patent: October 1, 2002Assignee: Scios Inc.Inventor: Donald James Kyle
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Patent number: 6451569Abstract: The present invention features biarsenical molecules. Target sequences that specifically react with the biarsenical molecules are also included. The present invention also features kits that include biarsenical molecules and target sequences. Tetraarsenical molecules are also featured in the invention.Type: GrantFiled: August 11, 1999Date of Patent: September 17, 2002Assignee: The Regents of the University of CaliforniaInventors: Roger Y. Tsien, B. Albert Griffin
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Patent number: 6451543Abstract: The present invention relates to methods and compositions for lipid matrix-assisted chemical ligation and synthesis of membrane polypeptides that are incorporated in a lipid matrix. The invention is exemplified in production of a prefolded membrane polypeptide embedded within a lipid matrix via stepwise chemoselective chemical ligation of unprotected peptide segments, where at least one peptide segment is embedded in a lipid matrix. Any chemoselective reaction chemistry amenable for ligation of unprotected peptide segments can be employed. Suitable lipid matrices include liposomes, micelles, cell membrane patches and optically isotropic cubic lipidic phase matrices. Prefolded synthetic and semi-synthetic membrane polypeptides synthesized according to the methods and compositions of the invention also permit site-specific incorporation of one or more detectable moieties, such as a chromophore, which can be conveniently introduced during synthesis.Type: GrantFiled: August 26, 1999Date of Patent: September 17, 2002Assignee: Gryphon SciencesInventors: Gerd. G. Kochendoerfer, Christie L. Hunter, Stephen B. H. Kent, Paolo Botti
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Patent number: 6448435Abstract: A process that can be used for sulfonating, sulfating, or sulfamating an organic compound is disclosed. The process can comprise, consist essentially of, or consist of, contacting the organic compound with sulfur trioxide under a condition sufficient to effect the sulfonation, sulfation, or sulfamation of the organic compound. The organic compound can be an aromatic compound, alcohol, carbohydrate, amine, amide, protein, or combinations of two or more thereof. The sulfur trioxide can be present in a complex comprising an inorganic support such as zeolite, silicalite, silica, titanosilicate, borosilicate, clay, aluminophosphate, and combinations of two or more thereof.Type: GrantFiled: February 4, 2002Date of Patent: September 10, 2002Assignee: E. I. du Pont de Nemours and CompanyInventors: Stephen Ernest Jacobson, David Richard Corbin
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Patent number: 6420556Abstract: The subject invention involves novel acyl isothiocyanate resins of formula (I) and processes for making them: (a) starting with a phenyl carboxy resin, treating the resin with any reagent that converts the carboxy to an acyl halide, followed by treatment with tetranikylammonium thiocyanate or an alkali metal salt thereof, to provide the acyl isothiocyanate resin. The subject invention also involves processes for making guanidine compounds and related cyclized compounds using an acyl isothiocyanate resin, comprising the following steps: (b) reacting the acyl isothiocyanate resin with a primary amine; (c) reacting the product from Step (b) with a sulfur activating agent and ammonia or a primary or secondary amine; (d) treating the product from Step (c) with a strong base or medium strength acid to cleave product from the resin, providing the guanidine compound or/and the related cyclized compound.Type: GrantFiled: June 12, 2001Date of Patent: July 16, 2002Assignee: The Procter & Gamble CompanyInventor: Lawrence Joseph Wilson
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Patent number: 6417347Abstract: A method for producing a S-nitrosylated species is provided. The method comprises: (a) providing a deoxygenated, alkaline aqueous solution comprising a thiol and a nitrite-bearing species; (b) acidifying the solution by adding acid to the solution while concurrently mixing the solution (e.g., by vigorously stirring the solution) to produce the S-nitrosylated species; and (c) isolating the S-nitrosylated species. The nitrite-bearing species can be, for example, an inorganic nitrite, such as an alkali metal nitrite, or an organic nitrite, such as an alkyl nitrite (e.g., ethyl nitrite, amyl nitrite, isobutyl nitrite or t-butyl nitrite). The thiol is preferably a thiol-containing polysaccharide, a thiol-containing lipoprotein, a thiol-containing amino acid or a thiol-containing protein, and more preferably a thiol-containing polysaccharide such as thiolated cyclodextrin. In many preferred embodiments, the S-nitrosylated species is insoluble in the acidified solution, precipitating upon formation.Type: GrantFiled: August 24, 2000Date of Patent: July 9, 2002Assignee: Scimed Life Systems, Inc.Inventors: Robert A. Herrmann, David Knapp
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Publication number: 20020082400Abstract: Chemically-defined, non-polymeric valency platform molecules and conjugates comprising chemically-defined valency platform molecules and biological or chemical molecules including polynucleotide duplexes of at least 20 base pairs that have significant binding activity-for human lupus anti-dsDNA autoantibodies.Type: ApplicationFiled: December 29, 2000Publication date: June 27, 2002Inventors: Stephen M. Coutts, David S. Jones, Douglas Alan Livingston, Lin Yu
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Publication number: 20020052443Abstract: Branched, substantially non-antigenic polymers are disclosed. Conjugates prepared with the polymers and biologically active molecules such as proteins and peptides demonstrate extended circulating life in vivo. Substantially fewer sites on the biologically active material are used as attachment sites. Methods of forming the polymer, conjugating the polymers with biologically active moieties and methods of using the conjugates are also disclosed.Type: ApplicationFiled: April 7, 2000Publication date: May 2, 2002Inventors: Richard B Greenwald, Anthony J Martinez
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Publication number: 20020035243Abstract: The present invention relates to transport system conjugates as transmembrane transport systems for topical and transdermal applications, especially in dermatology and cosmetics, and for pharmaceutically active ingredients with a systemic action. The transport system according to the invention can be used for peptide active ingredients as well as for non-peptide active ingredients, such as vitamins, hormones and antibiotics. There are numerous fields of application of the topical and transdermal use of the transport system conjugates according to the present invention, including the transport of active ingredients into and through the skin for healing wound, protecting the skin, and controlling various disorders including skin aging, inflammation, cellulitis, psoriasis, melanoma, arthritis, acne, neurodermatitis, eczema, paradontitis, burns, and so forth.Type: ApplicationFiled: May 29, 2001Publication date: March 21, 2002Inventors: Dominik Imfeld, Christian Ludin, Thomas Schreier
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Patent number: 6359118Abstract: The present invention relates to the field of carbohydrate crosslinked glycoprotein crystals. Advantageously, such crosslinked glycoprotein crystals display stability to harsh environmental conditions, while maintaining the structural and functional integrity of the glycoprotein backbone. According to one embodiment, this invention relates to methods for concentrating proteins that have been modified by carbohydrates and for releasing their activity at controlled rates. This invention also provides methods for producing carbohydrate crosslinked glycoprotein crystals and methods for using them in pharmaceutical formulations, vaccines, immunotherapeutics, personal care compositions, including cosmetics, veterinary pharmaceutical compositions and vaccines, foods, feeds, diagnostics, cleaning agents, including detergents and decontamination formulations.Type: GrantFiled: May 19, 1999Date of Patent: March 19, 2002Assignee: Altus Biologies, Inc.Inventors: Alexey L. Margolin, Chandrika Poorna Govardhan, Kalevi Visuri, Sinikka Uotila
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Patent number: 6358489Abstract: Thiol-containing peptides can be radiolabeled with fluorine-18 (F-18) by reacting a peptide comprising a free thiol group with an F-18-bound labelling reagent which also has a group that is reactive with thiols. The resulting F-18-labeled peptides may be targeted to a tissue of interest using bispecific antibodies or bispecific antibody fragments having one arm specific for the F-18-labeled peptide or a low molecular weight hapten conjugated to the F-18-labeled peptide, and another arm specific to the targeted tissue. The targeted tissue is subsequently visualized by clinical positron emission tomography.Type: GrantFiled: August 24, 2000Date of Patent: March 19, 2002Assignee: Immunomedics, Inc.Inventor: Gary L. Griffiths
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Patent number: 6342585Abstract: The invention relates to a method for forming a mixed disulfide of recombinant proteins, by solubilizing with a denaturing agent in the presence of a disulphide component, and then adding a disulphide component plus a denaturing agent, at a concentration sufficient to form a mixed disulfide.Type: GrantFiled: February 1, 1999Date of Patent: January 29, 2002Assignee: Roche Diagnostics GmbHInventor: Adelbert Grossmann
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Patent number: 6340742Abstract: Erythropoietin glycoprotein products are disclosed which have the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells. The present conjugates have an increased circulating half-life and plasma residence time, decreased clearance, and increased clinical activity in vivo. In addition, compared with conventional PEG-EPO conjugates, the conjugates of this invention have superior clinical properties. The present invention also includes a method for the treatment of anemia in a human employing the novel erythropoietin glycoprotein products as well as a method for preparing the erythropoietin glycoprotein products.Type: GrantFiled: June 28, 2000Date of Patent: January 22, 2002Assignee: Roche Diagnostics GmbHInventors: Josef Burg, Bernd Hilger, Hans-Peter Josel
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Patent number: 6333164Abstract: There can be provided a fungal antigen which is an insoluble fraction obtainable from fungal cells of which cell wall has been substantially removed or at least partially removed; a process for producing the same; a nucleic acid encoding the fungal antigen; a biologic product containing the fungal antigen; a method of stimulating immunological responses by using the biologic product; a method of suppressing allergic reaction to fungi in a vertebrate; and a method for diagnosing a disease caused by fungi in a vertebrate.Type: GrantFiled: March 4, 1999Date of Patent: December 25, 2001Assignee: Takara Shuzo Co., Ltd.Inventors: Kazutoh Takesako, Shigetoshi Mizutani, Masahiro Endo, Ikunoshin Kato
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Publication number: 20010051348Abstract: A process is disclosed for modifying a parent ligand by attaching to the parent ligand a conjugation agent that is reactive with a moiety of a target receptor to which the parent ligand binds such that a covalent bond is formable between the conjugation agent and the receptor moiety. Also disclosed are compositions, probes and methods of detecting and/or quantifying receptors using the modified ligands of the invention.Type: ApplicationFiled: January 26, 2001Publication date: December 13, 2001Inventor: Chee Wee Lee
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Patent number: 6310039Abstract: Conjugates of transferrin, albumin and polyethylence glycol consisting of native or thiolated transferrin or albumin or of polyethylene glycol (MW between approximately 5,000 and 20,0000) with at least one HS—, HO— or H2N group and cytostatic compounds derived through maleinimide or N-hydroxysuccinimide ester compounds, such as doxorubicin, daunorubicin, epirubicin, idarubicin, mitoxandrone, chloroambucil, melphalan, 5-fluorouracyl, 5′-desoxy-5-fluorouridine, thioguanine, methotrexate, paclitaxel, docetaxel, topotecan, 9-aminocamptothecin, etoposide, teniposide, mitopodoside, vinblastine, vincristine, vindesine, vinorelbine or a compound of general formula A, B, C or D, where n=0-6, X=—NH2, —OH, —COOH, —O—CO—R—COR*, —NH—CO—R—COR*, where R is an aliphatic carbon chain with 1-6 carbon atoms or a substituted or unsubstituted phenylene group and R* H, phenyl, alkyl with 1-6 carbon atoms.Type: GrantFiled: May 21, 1999Date of Patent: October 30, 2001Inventor: Felix Kratz
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Patent number: 6303569Abstract: The present invention is directed to double prodrugs containing polymeric-based transport forms.Type: GrantFiled: August 21, 1998Date of Patent: October 16, 2001Assignee: Enzon, Inc.Inventors: Richard B. Greenwald, Yun H. Choe, Annapurna Pendri
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Patent number: 6288036Abstract: The substitution of the L-Pro at the 7-position with D-Phe or D-Tic and substitution of the L-Phe at the 8-position with hydroxyproline ethers and thioethers of the peptide hormone bradykinin and other additional substituted analogs of bradykinin converts bradykinin agonists into bradykinin antagonists. The invention further includes additional modifications at other positions within the novel 7- and 8-position modified bradykinin antagonists, which increase enzyme resistance, antagonist potency, and/or specificity of the new bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected as by insect bites.Type: GrantFiled: December 16, 1993Date of Patent: September 11, 2001Assignee: Scios Inc.Inventors: Donald James Kyle, Roger Neal Hiner
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Publication number: 20010018201Abstract: Nine efficient aldolase antibodies were generated using hapten 2. This hapten combines, in a single molecule, structural components employed for reactive immunization with structural components employed for forming a transition state analog of the aldol reaction. Characterization of two of these antibodies reveals that they are highly proficient (up to 1000-fold better than any other antibody catalyst) and enantioselective catalysts for aldol and retro-aldol reactions and exhibit enantio- and diastereo-selectivities opposite that of antibody 38C2.Type: ApplicationFiled: April 2, 2001Publication date: August 30, 2001Inventors: Carlos F. Barbas, Richard A. Lerner, Guofu Zhong
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Publication number: 20010018200Abstract: The present invention relates to a chemically modified mutant protein including a cysteine residue substituted for a residue other than cysteine in a precursor protein, the substituted cysteine residue being subsequently modified by reacting the cysteine residue with a glycosylated thiosulfonate. Also, a method of producing the chemically modified mutant protein is provided. The present invention also relates to a glycosylated methanethiosulfonate. Another aspect of the present invention is a method of modifying the functional characteristics of a protein including providing a protein and reacting the protein with a glycosylated methanethiosulfonate reagent under conditions effective to produce a glycoprotein with altered functional characteristics as compared to the protein. In addition, the present invention relates to methods of determining the structure-function relationships of chemically modified mutant proteins.Type: ApplicationFiled: July 2, 1999Publication date: August 30, 2001Inventors: BRYAN J. JONES, BENJAMIN G. DAVIS
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Patent number: 6258774Abstract: A carrier for in vivo delivery of a therapeutic agent comprising a thiol group is provided, wherein the therapeutic agent is conjugated to the carrier via a biodegradable disulfide bond. Since extracellular fluids in vivo do not provide the appropriate environment to efficiently reduce a disulfide bond, while cellular cytosol does provide an appropriate environment, the agent will remain substantially coupled to the carrier while circulating through the body until the carrier crosses a cell membrane. As a result, the therapeutic agent is protected from degradation and renal clearance, and the potential for the therapeutic agent to elicit an immune response is limited.Type: GrantFiled: March 19, 1998Date of Patent: July 10, 2001Assignee: University of Medicine and Dentistry of New JerseyInventors: Stanley Stein, Michael J. Leibowitz, Patrick J. Sinko
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Patent number: 6255277Abstract: A method for preventing adverse effects associated with the use of a medical device in a patient by introducing into the patient a device of which at least a portion includes a prophylactic or therapeutic amount of a nitric oxide adduct. The nitric oxide adduct can be present in a matrix coating on a surface of the medical device; can be coated per se on a surface of the medical device; can be directly or indirectly bound to reactive sites on a surface of the medical device; or at least a portion of the medical device can be formed of a material, such as a polymer, which includes the nitric oxide adduct. Also disclosed is a method for preventing adverse effects associated with the use of a medical device in a patient by introducing the device during a medical procedure and before or during said procedure locally administering a nitric oxide adduct to the site of contact of said device with any internal tissue.Type: GrantFiled: May 10, 1995Date of Patent: July 3, 2001Assignees: Brigham and Women's Hospital, NitroMed, Inc.Inventors: Jonathan Stamler, Joseph Loscalzo, John D. Folts
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Patent number: 6248334Abstract: A process for preparing a protein-polysaccharide conjugate includes reacting a protein with a polysaccharide to produce a mixture including a protein-polysaccharide conjugate and free protein. At least one unreacted reagent or low molecular weight component is removed from this mixture, without removing all of the free protein, to provide a purified mixture that contains the protein-polysaccharide conjugate and free protein. This purified mixture can be used as a conjugate vaccine, immunogen, or immunological reagent. Keeping the free protein in the purified mixture with the conjugate saves time and money in the conjugate production process. In another aspect of the invention, the purified mixture of the protein-polysaccharide conjugate and free protein is reacted with a hapten to produce a conjugate mixture including a hapten-protein conjugate and a hapten-protein-polysaccharide conjugate.Type: GrantFiled: January 6, 1998Date of Patent: June 19, 2001Assignee: Henry M. Jackson Foundation for the Advancement of Military MedicineInventors: Andrew Lees, James Mond
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Patent number: 6217873Abstract: Provided by this invention are essentially homogeneous, defined compositions of matter and hetero-polyoximes of defined structure comprising a baseplate structure having a plurality of oxime bonds, wherein each oxime bond links a specifically active molecule to the baseplate. Also provided are novel baseplates having a plurality of oxime forming complementary reactive groups and novel specifically reactive molecules having an oxime forming complementary reactive group. Also provided by this invention are methods of preparing these novel compositions of matter by chemoselectively ligating via oxime bond formation a complementary orthogonal reactive group on the baseplate to a complementary reactive orthogonal group on a specifically active molecule. Methods of using these defined compositions of matter as well as pharmaceutical compositions comprising these defined compositions of matter and methods of their use are also provided by this invention.Type: GrantFiled: January 5, 1996Date of Patent: April 17, 2001Assignee: Gryphon SciencesInventors: Keith Rose, Robin E. Offord
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Patent number: 6207806Abstract: Disclosed is an improved process for obtaining purified, monomeric, intact, correctly-folded insulin-like growth factor-I (also known as somatomedin-C). The improvements, consisting primarily of the addition of an IGF-I unfolding/refolding step and the substitution of a reverse phase chromatography step for a gel filtration chromatography step result in a three-fold increase in final yield. The process includes the following steps, in order: first cation exchange, unfolding/refolding, hydrophobic interaction chromatography, second cation exchange, and reverse phase chromatography.Type: GrantFiled: May 5, 1997Date of Patent: March 27, 2001Assignee: Cephalon Inc.Inventors: Russell A. Brierley, Joan N. Abrams, John M. Hanson, Francis C. Maslanka
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Patent number: 6187284Abstract: Thiol-containing peptides can be radiolabeled with fluorine-18 (18F) by reacting a peptide comprising a free thiol group with an 18F-bound labelling reagent which also has a group that is reactive with thiols. The resulting 18F-labeled peptides may be targeted to a tissue of interest using bispecific antibodies or bispecific antibody fragments having one arm specific for the 18F-labeled peptide or a low molecular weight hapten conjugated to the 18F-labeled peptide, and another arm specific to the targeted tissue. The targeted tissue is subsequently visualized by clinical positron emission tomography.Type: GrantFiled: September 3, 1998Date of Patent: February 13, 2001Assignee: Immunomedics, Inc.Inventor: Gary L. Griffiths
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Patent number: 6183498Abstract: Methods and products for rapidly sealing a fluid leak in a tissue are provided. A polymerizable protein is applied to a tissue having an opening which creates a fluid leak in the tissue, in order to seal the opening. The tissue area and opening coated with the polymerizable protein are exposed to an initiator in order to polymerize the covering in situ, and create a seal over the opening that prevents fluid leakage. The methods and products to the invention may be used, for example, to seal airholes in lung injuries and to seal anastomoses and suture lines for blood vessels.Type: GrantFiled: September 20, 1999Date of Patent: February 6, 2001Inventors: Dale P. Devore, Charles Putnam, James M. Pachence
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Patent number: 6180095Abstract: The present invention is directed to double prodrugs containing polymeric-based transport forms.Type: GrantFiled: October 30, 1998Date of Patent: January 30, 2001Assignee: Enzon, Inc.Inventors: Richard B. Greenwald, Annapurna Pendri, Yun H. Choe
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Patent number: 6174530Abstract: Provided by this invention are essentially homogeneous, defined compositions of matter comprising a baseplate structure having a plurality of oxime bonds, wherein each oxime bond links a specifically active molecule to the baseplate. Also provided are novel baseplates having a plurality of oxime forming complementary reactive groups and novel specifically reactive molecules having an oxime forming complementary reactive group. Also provided by this invention are methods of preparing these novel compositions of matter by chemoselectively ligating via oxime bond formation a complementary orthogonal reactive group on the baseplate to a complementary reactive orthogonal group on a specifically active molecule. Methods of using these defined compositions of matter as well as pharmaceutical compositions comprising these defined compositions of matter and methods of their use are also provided by this invention.Type: GrantFiled: August 31, 1993Date of Patent: January 16, 2001Assignee: Gryphon SciencesInventors: Keith Rose, Robin Ewart Offord
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Patent number: 6136612Abstract: The present invention is directed to fluorescent dyes and its valence tautomers of the formula wherein Q represents a conjugated moiety that increases the fluorescent quantum yield of the compound; R.sub.1 is a functionalized group of the formula--(CH.sub.2).sub.j Y, wherein Y is selected from the group consisting of SO.sub.3 H, COOH, NH.sub.2, CHO, NCS, epoxy, phthalimido, and COOZ, wherein Z represents a leaving group; R.sub.2 is a functionalized group of the formula --(CH.sub.2).sub.k Y', wherein Y' is selected from the group consisting of SO.sub.3 H, COOH, NH.sub.2, CHO, NCS, epoxy, phthalimido, and COOZ, wherein Z represents a leaving group; M.sup.+ is a counterion selected from the group consisting of ammonium, alkali metal cations, and alkaline earth metal cations; n=1 to 4; m=1 to 4; j=2 to 10; and k=2 to 10.Type: GrantFiled: June 18, 1998Date of Patent: October 24, 2000Assignee: Sorin Biomedica Cardio S.p.A.Inventors: Leopoldo Della Ciana, Andrea Grignani, Mariacristina Cassullo, Giuseppe Caputo
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Patent number: 6133229Abstract: A protein stabilizer additive comprises two or more of a tris compound of the formula (1): (HOCH.sub.2).sub.3 --C--R, wherein R is: C.sub.1 -C.sub.4 alkyl, substituted C.sub.1 -C.sub.4 alkyl, NH.sub.2 ; NR.sup.1 R.sup.2 wherein R.sup.1 and R.sup.2 may be independently: H, C.sub.1 -C.sub.4 alkyl sulphonate, C.sub.1 -C.sub.4 hydroxyalkyl sulphonate; C.sub.1 -C.sub.4 alkyl NHC(CH.sub.2 OH).sub.3, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 hydroxyalkyl; C.sub.1 -C.sub.4 alkyl carboxylate; a polyelectrolyte; a buffer; and one or more additional components for example divalent metal salts.Type: GrantFiled: July 1, 1996Date of Patent: October 17, 2000Assignee: The University of Leeds Innovations, Ltd.Inventors: Timothy David Gibson, Barry L. Pierce, Jeanette Irene Webster
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Patent number: 6113906Abstract: Branched, substantially non-antigenic polymers are disclosed. Conjugates prepared with the polymers and biologically active molecules such as proteins and peptides demonstrate extended circulating life in vivo. Substantially fewer sites on the biologically active material are used as attachment sites. Methods of forming the polymer, conjugating the polymers with biologically active moieties and methods of using the conjugates are also disclosed.Type: GrantFiled: December 29, 1998Date of Patent: September 5, 2000Assignee: Enzon, Inc.Inventors: Richard B. Greenwald, Anthony J. Martinez
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Patent number: 6107272Abstract: The invention relates to novel modified polypeptides, with or without variations in noncoding regions, with altered biological activity. The invention discloses methods of preparing the modified polypeptides and methods of use.Type: GrantFiled: May 18, 1999Date of Patent: August 22, 2000Assignee: Beth Israel Deaconess Medical CenterInventor: Arthur J. Sytkowski
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Patent number: 6057426Abstract: The present invention relates to the discovery of novel genes and proteins, which function in pathways involved in brain pathogenesis. In particular, the novel genes and proteins relate to inflammatory tissue responses caused by brain injuries such trauma, ischemia or autoimmune-inflammation or other diseases or processes related to neuroinflammation. The compounds disclosed in the present invention are useful as therapeutics, diagnostics and in screening assays.Type: GrantFiled: April 30, 1998Date of Patent: May 2, 2000Assignee: Hoffmann-La Roche Inc.Inventors: Werner Lesslauer, Ulrike Utans-Schneitz