Involving Bacterial Toxin That Has Modified Amino Acid Sequence Patents (Class 424/832)
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Patent number: 11925677Abstract: A method for treating chronic pancreatitis and diabetes type II in a patient in need thereof comprises administering botulinum toxin to the patient. The botulinum toxin may be administered by subcutaneous or intradermal injection. The subcutaneous or intradermal injection may be administered to and/or around the vicinity of a trigeminal nerve, a cervical nerve, a thoracic nerve, a lumbar nerve, a sacral nerve, or a combination thereof.Type: GrantFiled: July 11, 2022Date of Patent: March 12, 2024Assignee: Penland FoundationInventor: Roland M. Williams
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Patent number: 8158132Abstract: This invention describes a novel agent for the targeted control of a mammalian cell activity, in particular the agent is used to control the interaction of particular cell types with their external environment. The agent has applications as a pharmaceutical for the treatment of a variety of disorders. An agent according to the invention comprises three Domains B, T and E linked together in the following manner: Domain B-Domain T-Domain E where Domain B is the Binding Domain which binds the agent to a Binding Site on the cell which undergoes endocytosis to produce an endosome, Domain T is the Translocation Domain which translocates the agent (with or without the Binding Site) from within the endosome across the endosomal membrane into the cytosol of the cell, Domain E is the Effector Domain which inhibits the ability of the Recyclable Membrane Vesicles to transport the Integral Membrane Proteins to the surface of the cell.Type: GrantFiled: September 26, 2005Date of Patent: April 17, 2012Assignee: Syntaxin LimitedInventors: Keith Alan Foster, Michael John Duggan, Clifford Charles Shone
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Patent number: 8048985Abstract: The present invention relates to methods and compositions of modified variants of diphtheria toxin (DT) that reduce binding to vascular endothelium or vascular endothelial cells, and therefore, reduce the incidence of Vascular Leak Syndrome. One aspect of the present invention relates to a polypeptide toxophore from a modified DT, wherein the mutation is the substitution or deletion at least one amino acid residue at the amino acid residues 6-8, 28-30 or 289-291 of native DT. Another aspect of the present invention relates to a fusion protein which comprises a modified DT and a non-DT fragment. Another aspect of the present invention relates to the use of modified DT for the treatment of cancer.Type: GrantFiled: February 9, 2009Date of Patent: November 1, 2011Assignee: Anjin Group, Inc.Inventors: Robert J. Harrison, Johanna C. Vanderspek
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Patent number: 8026209Abstract: The present invention relates to nucleic acids and polypeptides encoded thereby, whose expression is modulated in brain microvascular endothelial cells undergoing early dynamic inflammation-induced changes in blood-brain barrier functionality. Such polypeptides are referred to as lipopolysaccharide-sensitive (LPSS) polypeptides herein. These nucleic acids and polypeptides may be useful in methods for controlling blood-brain barrier properties in mammals in need of such biological effects. This includes the diagnosis and treatment of disturbances in the blood-brain/retina barrier, brain (including the eye) disorders, as well as peripheral vascular disorders. Additionally, the invention relates to the use of anti-LPSS polypeptide antibodies or ligands as diagnostic probes, as blood-brain barrier targeting agents or as therapeutic agents as well as the use of ligands or modulators of expression, activation or bioactivity of LPSS polypeptides as diagnostic probes, therapeutic agents or drug delivery enhancers.Type: GrantFiled: February 10, 2004Date of Patent: September 27, 2011Assignee: BBB Holding B.V.Inventors: Pieter Jaap Gaillard, Albertus Gerrit De Boer, Arjen Brink
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Patent number: 8007815Abstract: Combination vaccines for treating or preventing Neisseria meningitidis infection are described. The vaccines include Neisseria meningitidis serogroup B proteoliposomic vesicles and Neissera meningitidis serogroup C conjugated oligosaccharides.Type: GrantFiled: May 28, 1999Date of Patent: August 30, 2011Assignees: Novartis AG, Statens Institutt for FolkehelseInventors: Dan M. Granoff, Howard Raff, Ingeborg S. Aaberge, Bjorn Haneberg, Johan Holst
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Patent number: 7892560Abstract: This invention describes a novel agent for the targeted control of a mammalian cell activity, in particular the agent is used to control the interaction of particular cell types with their external environment. The agent has applications as a pharmaceutical for the treatment of a variety of disorders. An agent according to the invention comprises three Domains B, T and E linked together in the following manner: Domain B-Domain T-Domain E where Domain B is the Binding Domain which binds the agent to a Binding Site on the cell which undergoes endocytosis to produce an endosome, Domain T is the Translocation Domain which translocates the agent (with or without the Binding Site) from within the endosome across the endosomal membrane into the cytosol of the cell, Domain E is the Effector Domain which inhibits the ability of the Recyclable Membrane Vesicles to transport the Integral Membrane Proteins to the surface of the cell.Type: GrantFiled: June 28, 2007Date of Patent: February 22, 2011Assignee: Syntaxin, LtdInventors: Keith Alan Foster, Michael John Duggan, Clifford Charles Shone
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Patent number: 7887810Abstract: This invention describes a novel agent for the targeted control of a mammalian cell activity, in particular the agent is used to control the interaction of particular cell types with their external environment. The agent has applications as a pharmaceutical for the treatment of a variety of disorders. An agent according to the invention comprises three Domains B, T and E linked together in the following manner: Domain B-Domain T-Domain E where Domain B is the Binding Domain which binds the agent to a Binding Site on the cell which undergoes endocytosis to produce an endosome, Domain T is the Translocation Domain which translocates the agent (with or without the Binding Site) from within the endosome across the endosomal membrane into the cytosol of the cell, Domain E is the Effector Domain which inhibits the ability of the Recyclable Membrane Vesicles to transport the Integral Membrane Proteins to the surface of the cell.Type: GrantFiled: June 28, 2007Date of Patent: February 15, 2011Assignee: Syntaxin, LtdInventors: Keith Alan Foster, Michael John Duggan, Clifford Charles Shone
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Patent number: 7867498Abstract: The invention relates to polypeptide carrier proteins that comprise at least five CD4+ T cell epitopes, for conjugation to capsular polysaccharides. The carrier proteins are useful as components of vaccines that can elicit a T-cell dependent immune response. These vaccines are particularly useful to confer protection against infection from encapsulated bacteria in infants between the ages of 3 months and about 2 years.Type: GrantFiled: March 25, 2009Date of Patent: January 11, 2011Assignee: Novartis AGInventors: Rino Rappuoli, Guido Grandi
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Patent number: 7807184Abstract: The present invention relates to a hybrid bacterial toxin subunit, to a hybrid bipartite bacterial toxin and to nucleic acid molecules comprising a nucleotide sequence encoding such bacterial toxins. Furthermore, the invention relates to vaccines comprising bacterial toxins and to their use in vaccines. Finally, the invention relates to methods for the preparation of such vaccines and to the use of such bacterial toxins for the manufacture of such vaccines.Type: GrantFiled: July 16, 2004Date of Patent: October 5, 2010Assignee: Interuet International B.V.Inventor: Paul Vermeij
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Patent number: 7628992Abstract: A chemical conjugate for treating a nerve cell related disorder is provided. This conjugate includes an active or inactive Clostridial toxin having specificity for a target nerve cell. The toxin is conjugated to a drug or other bioactive molecule without affecting the toxin's ability to enter the target nerve cell.Type: GrantFiled: September 28, 2000Date of Patent: December 8, 2009Assignee: Invent DCU LimitedInventors: James Oliver Dolly, Larry Allen Wheeler, Kei Roger Aoki, Michael Elwood Garst
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Patent number: 7279169Abstract: Mucosal DTPa vaccines, especially intranasal vaccines, comprising (a) a diphtheria antigen, a tetanus antigen and an acellular pertussis antigen, and (b) a detoxified mutant of cholera toxin (CT) or E. coli heat labile toxin (LT). Component (b) acts as a mucosal adjuvant. The acellular pertussis antigen preferably comprises pertussis holotoxin (PT) and filamentous haemagglutinin (FHA) and, optionally, pertactin. The mucosally-delivered combined DTPa formulation is capable of generating a level of protection against B. pertussis infection equivalent to that observed by alum-adjuvanted parenteral administration.Type: GrantFiled: September 28, 2000Date of Patent: October 9, 2007Assignee: Novartis Vaccines and Diagnostics SRLInventors: Rino Rappuoli, Mariagrazia Pizza
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Patent number: 7223412Abstract: The present invention relates to a method of producing recombinant modified Staphylococcal toxin having improved stability, comprising the steps of preparing a modified toxin in which a specific amino acid sequence is substituted and a vector for expressing the modified toxin, and culturing E. coli transformed with the vector, and a use thereof for the vaccine.Type: GrantFiled: October 31, 2000Date of Patent: May 29, 2007Assignee: LG Chem-Investment Ltd.Inventors: Hong-Kyun Lee, Yong-Ho Park, Kyu-Boem Han, Byoung-Sun Chang, Yong-Jun Lee
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Patent number: 7169392Abstract: The present invention pertains generally to novel Neisseria meningitidis serogroup B glycoconjugates. More particularly, the invention pertains to glycoconjugates formed from a Neisseria meningitidis serogroup B capsular oligosaccharide derivative (MenB OS derivative) in which sialic acid residue N-acetyl groups are replaced with N-acyl groups. The invention also pertains to vaccine formulations containing the glycoconjugates, methods of making the vaccine formulations, and methods of using the vaccine formulations to treat or prevent Neisseria meningitidis serogroup B or E. coli K1 disease in a mammalian subject.Type: GrantFiled: August 19, 2003Date of Patent: January 30, 2007Assignee: Chiron SrlInventor: Robert Seid
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Patent number: 7070781Abstract: A non-toxic mucosal adjuvant is provided which may be admixed with further antigens to provide a vaccine administrable to mucosal surfaces in organisms including man. Preferably, the non-toxic mucosal adjuvant is a detoxified mutant of a bacterial ADP-ribosylating toxin, optionally comprising one or more amino acid additions, deletions or substitutions.Type: GrantFiled: January 24, 2003Date of Patent: July 4, 2006Assignee: Chiron SRLInventor: Rino Rappuoli
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Patent number: 6962703Abstract: The invention relates to an agent specific for peripheral sensory afferents. The agent may inhibit the transmission of signals between a primary sensory afferent and a projection neutron by controlling the release of at least one neurotransmitter or neuromodulator from the primary sensory afferent. The agent may be used in or as a pharmaceutical for the treatment of pain, particularly chronic pain.Type: GrantFiled: May 20, 2002Date of Patent: November 8, 2005Assignees: Ipsen Limited, Health Protection AgencyInventors: Keith Alan Foster, Michael John Duggan, Clifford Charles Shone
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Patent number: 6855321Abstract: The invention relates to polyepitope carrier proteins that comprise at least five CD4+ T cell epitopes, for conjugation to capsular polysaccharides. The carrier proteins are use useful as components of vaccines that can elicit a T-cell dependent immune response. These vaccines arm particularly useful to confer protection against infection from encapsulated bacteria in infants between the ages of 3 months and about 2 years.Type: GrantFiled: April 27, 1999Date of Patent: February 15, 2005Assignee: Chiron S.r.l.Inventors: Rino Rappuoli, Guido Grandi
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Patent number: 6835818Abstract: This invention is directed to mutant SPE-C toxins or fragments thereof, vaccine and pharmaceutical compositions, and methods of using the vaccine and pharmaceutical compositions. The preferred SPE-C toxin has at least one amino acid change and is substantially non-lethal compared with the wild type SPE-C toxin. The mutant SPE-C toxins can form vaccine compositions useful to protect animals against the biological activities of wild type SPE-C toxin.Type: GrantFiled: July 14, 1999Date of Patent: December 28, 2004Assignee: Regents of the University of MinnesotaInventors: Patrick M. Schlievert, Douglas Ohlendorf, David T. Mitchell, Pamala J. Gahr
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Patent number: 6723321Abstract: Provided are compositions and methods useful for modulating the activity of autoinducer synthase catalysts. A method for identifing modulators of the autoinducer synthesis reaction is also provided. Such modulators are useful for controlling bacterial growth and can be used for therapeutic treatment of bacterial infections particularly in immunocompromised subjects. They are also useful in treating disease states associated with autoinducer synthesis and biofilm development.Type: GrantFiled: January 6, 1999Date of Patent: April 20, 2004Assignees: The Board of Trustees of the University of Illinois, The University of Iowa Research FoundationInventors: E. Peter Greenberg, John E. Cronan, Jr., Bryce V. Plapp, Matthew R. Parsek
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Patent number: 6448226Abstract: The present invention relates to transformed plants and plant cells comprising DNA molecules encoding Bacillus thuringiensis proteins with insecticidal activity. The invention relates more particularly to transformed plants and plant cells comprising DNA molecules encoding the protease resistant toxins BTS02618Aa or BTS02618Ab, as well as to methods of rendering plants or plant cells resistant to insects using these DNA molecules.Type: GrantFiled: December 23, 1999Date of Patent: September 10, 2002Assignee: Aventis CropScience N.V.Inventors: Bart Lambert, Stefan Jansens, Katrien Van Audenhove, Marnix Peferoen, Jeroen Van Rie, Roel Van Aarssen
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Patent number: 6337075Abstract: The invention encompasses a method for treating hyperinsulinemic type 2 diabetes by local administration of a neurotoxin, such as a botulinum toxin, into the pancreas, thereby reducing insulin secretion from a B cell, and a method for treating hypoinsulinemic type 2 diabetes by local administration of a neurotoxin, such as a botulinum toxin, into a sympathetic ganglion, thereby reducing an inhibitory effect upon insulin secretion.Type: GrantFiled: January 26, 2000Date of Patent: January 8, 2002Assignee: Allergan Sales, Inc.Inventor: Stephen Donovan
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Patent number: 6203794Abstract: A chemical conjugate for treating a nerve cell related disorder is provided. The conjugate includes an active or inactive Clostridial toxin having specificity for a target nerve cell. The toxin is conjugated to a drug or other bioactive molecule without affecting the toxin's ability to enter the target nerve cell.Type: GrantFiled: May 1, 1997Date of Patent: March 20, 2001Assignee: Allergan Sales, Inc.Inventors: James Oliver Dolly, Kei Roger Aoki, Larry Allen Wheeler, Michael Elwood Garst
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Patent number: 6150156Abstract: The subject invention concerns novel Bacillus thuringiensis strains containing parasporal proteins with pesticidal properties against whitefly, aphid, jassid, and possibly other sucking insects of agronomic importance, and peptide sequences to these proteins that can be used to obtain structural genes. The spores or crystals of these microbes, or mutants thereof, are useful to control hymenopteran pests in various environments. The genes of the invention can be used to transform various hosts wherein the novel toxic proteins can be expressed.Type: GrantFiled: February 10, 1998Date of Patent: November 21, 2000Assignee: Calgene, Inc.Inventor: Sheikh Riazuddin
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Patent number: 6110470Abstract: A vaccine for immunizing animals against diseases caused by microorganisms producing an osteolytic toxin comprising an immunologically effective amount of a recombinant, immunogenic, detoxified Pasteurella multocida toxin or toxin analog, the vaccine being encoded by a nucleotide sequence coding for a Pasteurella multocida toxin or toxin analog which is inserted in an expression vector capable of replicating in a suitable host microorganism in which the said sequence may be expressed. Optionally, the produced toxin or toxin analog is subjected to posttranscriptional modifications to provide the detoxified toxin or toxin analog. Alternatively, the nucleotide sequence may be modified prior to insertion into the expression vector so as to provide the toxin or toxin analog in a detoxified form.Type: GrantFiled: August 22, 1994Date of Patent: August 29, 2000Assignee: Akzo Nobel N.V.Inventors: Niels Taekker Foged, Svend Petersen
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Patent number: 6051239Abstract: Compositions and methods of oral delivery of an antigen or therapeutic agent to the general circulation using a modified botulinum toxin which is capable of translocating from the gut to the general circulation but which is altered to be nontoxic are provided.Type: GrantFiled: October 20, 1997Date of Patent: April 18, 2000Assignee: Thomas Jefferson UniversityInventors: Lance Simpson, Nikita Kiyatkin, Andrew Maksymowych
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Patent number: 6033673Abstract: The present invention is directed towards a novel composition which is a genetically distinct mutant of E. coli heat-labile enterotoxin (LT). Specifically, the mutant LT designated LT(R192G/L211A) is modified by two amino acid substitutions, i.e., the arginine at amino acid position 192 is replaced by glycine and the leucine at amino acid position 211 is replaced by alanine. The invention relates to compositions and methods for use of the novel double mutant of LT as an adjuvant.Type: GrantFiled: March 18, 1998Date of Patent: March 7, 2000Assignee: The Administrators of Tulane Educational FundInventor: John D. Clements
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Patent number: 5989545Abstract: The invention relates to an agent specific for peripheral sensory afferents. The agent may inhibit the transmission of signals between a primary sensory afferent and a projection neuron by controlling the release of at least one neurotransmitter or neuromodulator from the primary sensory afferent. The agent may be used in or as a pharmaceutical for the treatment of pain, particularly chronic pain.Type: GrantFiled: January 12, 1998Date of Patent: November 23, 1999Assignees: The Speywood Laboratory Ltd., Microbiological Research AuthorityInventors: Keith Alan Foster, Michael John Duggan, Clifford Charles Shone
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Patent number: 5932209Abstract: An improved Bacillus thuringiensis (B.t.) delta-endotoxin is created by the modification of the gene encoding the toxin. The toxicity of a B.t. toxin was improved by replacing the native protoxin segment with an alternate protoxin segment by constructing a chimeric toxin gene.Type: GrantFiled: March 6, 1997Date of Patent: August 3, 1999Assignee: Mycogen CorporationInventors: Mark Thompson, George E. Schwab, H. Ernest Schnepf, Brian Stockhoff
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Patent number: 5925546Abstract: Immunological active polypeptides with no or reduced toxicity useful for the preparation of an antipertussis vaccine. Method for the preparation of said polypeptides which comprises, cultivating a microorganism transformed with a hybrid plasmid including the gene/s which codes for at least one of said polypeptides in a suitable medium and recovering the desired polypeptide from the cells or from the culture medium.Type: GrantFiled: June 7, 1995Date of Patent: July 20, 1999Assignee: Chiron S.p.A.Inventors: Mariagrazia Pizza, Antonella Bartoloni, Rino Rappuoli
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Patent number: 5889172Abstract: Immunologically active polypeptides with no or reduced toxicity useful for the preparation of an antipertussis vaccine. Method for the preparation of said polypeptides which comprises, cultivating a microorganism transformed with a hybrid plasmid including the gene/s which codes for at least one of said polypeptides in a suitable medium and recovering the desired polypeptide from the cells or from the culture medium.Type: GrantFiled: June 7, 1995Date of Patent: March 30, 1999Assignee: Chiron S.p.A.Inventors: Mariagrazia Pizza, Antonella Bartoloni, Rino Rappuoli
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Patent number: 5871750Abstract: New proteins and subunit antigens from P. haemolytica for use in stimulating immunity against respiratory diseases such as pneumonia, including shipping fever pneumonia, are disclosed. The subunit antigens include immunogenic amino acid sequences of P. haemolytica fimbrial protein, P. haemolytica plasmin receptor protein, and P. haemolytica 50K outer membrane protein and P. haemolytica leukotoxin. The antigens can be used in a vaccine composition, either alone or in combination. Also disclosed are methods of vaccination as well as methods of making the subunit antigens employed in the vaccines.Type: GrantFiled: December 14, 1994Date of Patent: February 16, 1999Assignee: University SaskatchewanInventor: Andrew A. Potter
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Patent number: 5837265Abstract: The invention consists of modified Clostridium neurotoxin compounds, pharmaceutical compositions containing such compounds and methods for preparing such compounds. In particular, the compounds of the invention are purified Clostridium botulinum and Clostridium tetani neurotoxins in which the tyrosine residues have been modified to have a negative charge (e.g., by covalent attachment of a phosphate or sulphate thereto) or in which the tyrosine residues have been substituted with amino acids having a negative charge (e.g., glutamate, aspartate, or negatively charged, non-natural amino acids). Toxins having phosphorylated tyrosine residues in both the light and heavy chains of the toxins are preferred. Methods for enzymatic and chemical modification of tyrosine residues in purified Clostridium neurotoxins are provided.Type: GrantFiled: March 8, 1996Date of Patent: November 17, 1998Assignee: The Regents of the University of CaliforniaInventors: Mauricio Montal, Antonio Ferrer-Montiel
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Patent number: 5821238Abstract: This invention relates to the production and use of recombinant Pseudomonas-derived toxins modified to increase their toxicity and potency in therapy. More particularly, the invention relates to certain deletions in domain II of the amino acid sequence of Pseudomonas exotoxin the domain which relates to the toxin's natural proteolytic processing.Type: GrantFiled: June 5, 1995Date of Patent: October 13, 1998Assignee: The United States of America as represented by the Department of Health and Human ServicesInventors: Ira H. Pastan, David J. Fitzgerald
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Patent number: 5792458Abstract: A potent and specific immunotoxin is prepared by coupling an inactivated diphtheria toxin to a binding moiety such as a monoclonal antibody or transferrin. The immunotoxins are specific for human tumors and leukemias and are indistinguishable in cell toxicity from that of the native toxin linked to the binding domain without the toxicity to other cells. The immunotoxin is useful in treating graft versus host disease as well as selectively killing tumor cells, such as medulloblastoma and glioblastoma cells.Type: GrantFiled: October 17, 1994Date of Patent: August 11, 1998Assignees: The United States of America as represented by the Department of Health and Human Services, Cetus CorporationInventors: Virginia G. Johnson, Larry Greenfield, Richard J. Youle, Walter Laird
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Patent number: 5770203Abstract: The development of subunits and subunit analogs of the cholera exotoxin by recombinant DNA techniques provides vaccine products that can retain their biological activity and immunogenicity, and can confer protection against disease challenge. Genetically-engineered modifications of the subunits result in products that retain immunogenicity, yet are reduced in, or are essentially free of, enzymatic activity associated with toxin reactogenicity.Type: GrantFiled: May 24, 1995Date of Patent: June 23, 1998Assignees: Amgen Inc., University of Southern CaliforniaInventors: W. Neal Burnette, Harvey R. Kaslow
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Patent number: 5728383Abstract: Potent and specific immunotoxins are prepared by conjugation of moieties binding to receptors on the surface of tumor cells to a mutant diphtheria toxin having A-chain translocation activity, but lacking membrane-binding activity. The immunotoxins are used to treat primary tumors of neurologic origin, metastatic tumors of small cell lung carcinoma or breast carcinoma origin, leptomeningeal leukemia and leptomeningeal carcinomatosis. The preferred route of administration of the immunotoxin is to a compartment of the body containing cerebrospinal fluid.Type: GrantFiled: June 13, 1994Date of Patent: March 17, 1998Assignee: The United States of America as represented by the Secretary of the Department of Health and Human ServicesInventors: Virginia Johnson, Richard J. Youle
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Patent number: 5601827Abstract: A DNA encoding an immunologically cross-reactive form of diphtheria toxin Fragment A, wherein the codons corresponding to Val-147 and Glu-148 of naturally-occurring diphtheria toxin are deleted from the DNA.Type: GrantFiled: May 23, 1995Date of Patent: February 11, 1997Assignee: President and Fellows of Harvard CollegeInventors: R. John Collier, Kevin Killeen, John Mekalanos
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Patent number: 5360897Abstract: An immunogenic conjugate which is the reductive amination product of an immunogenic capsular polymer fragment having at least one reducing group and derived from a bacterial capsular polymer of a bacterial pathogen, and a bacterial toxin or toxoid. The invention also relates to methods for the preparation of the conjugates, a vaccine containing the conjugates which elicits effective levels of anti-capsular polymer antibodies in humans. Also disclosed are methods for inducing active immunization against systemic infection in young mammals caused by bacterial pathogens comprising the administration of an immunogenic amount of the above-described conjugate. In a preferred embodiment, the capsular polymer fragment prior to conjugation has at least one aldehyde group at each end of the fragment. The final conjugate made with such capsular polymers has a lattice or network structure, and provides extremely high levels of anti-capsular polymer antibodies in infants.Type: GrantFiled: January 9, 1992Date of Patent: November 1, 1994Assignee: The University of RochesterInventors: Porter W. Anderson, Ronald J. Eby
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Patent number: 5352447Abstract: A potent and specific immunotoxin is prepared by coupling a binding-site inactivated diphtheria toxin (CRM 107) to a new binding moiety consisting of transferrin or a monoclonal antibody against the human transferrin receptor. These immunotoxins are tumor specific and lack the nonspecific toxicity produced by the binding activity of the native toxin. The immunotoxin is useful in treating primary brain tumors, metastatic tumors to the brain, CSF-borne tumors, leptomeningeal leukemia and leptomeningeal carcinomatosis.Type: GrantFiled: August 10, 1992Date of Patent: October 4, 1994Assignee: The United States of America as represented by the Secretary of the Department of Health and Human ServicesInventors: Virginia Johnson, Richard J. Youle