Patent Grant
11149123
A variety of different ingestible compositions have been developed for nutritional, therapeutic and non-therapeutic uses. Examples of different types of ingestible compositions include orally ingestible tablets, capsules and liquids. A given orally ingestible formulation may include a variety of different components, such as active agents, carrier materials (including binders, bulking agents and other excipients), flavoring agents, coloring agents, etc. More recently, ingestible compositions which include a device component, such as an RFID tag or an ingestible event marker, have been developed.
As with many consumer products, ingestible compositions are not manufactured at the time of and location of use. Instead, they are generally manufactured at one or more fabrication facilities, stored for a period of time and then shipped to the end-user. Upon receipt, the end-user may further store them for a period of time before use.
During the multiple storage periods, and even manufacturing periods, such as mentioned above, the quality of the ingestible composition, e.g., in terms of effectiveness, may be degraded in some way. For example, exposure to humidity, elevated temperatures, microorganisms and oxidizing agents, as well other environmental hazards, can negatively impact the quality of the ingestible composition.
Highly-swellable polymeric films are provided. Aspects also include ingestible compositions that include the highly-swellable polymeric film and an ingestible component. Aspects further include methods of making and using the compositions.
Aspects of the invention are referred to in the following clauses:
1. A highly-swellable polymeric film that rapidly swells without disintegrating upon contact with an aqueous medium.
2. The highly-swellable polymeric film according to Clause 1, wherein the film rapidly swells to 10 times or greater in volume upon contact with an aqueous medium, preferably wherein the film swells to 10 times or greater in volume within 1 minute or less upon contact with an aqueous medium.
3. The highly-swellable polymeric film according to any of the preceding clauses wherein the film is configured to absorb 10 g or more of water per gram of film upon contact with an aqueous medium.
4. The highly-swellable polymeric film according to any of the preceding clauses wherein the film comprises one or more of the following; an ionic polymer, an anionic polymer, cationic polymer.
5. The highly-swellable polymeric film according to clause 4 wherein the ionic polymer comprises monomeric units having an acidic functional group, such as a carboxyl, sulfate, sulfonate, phosphate or phosphonate group, or a basic functional group, such as an amino, substituted amino or guanidyl group.
6. The highly-swellable polymeric film according to clause 4 or 5 wherein the anionic polymer is formed from the ionic polymer in an aqueous solution at a suitable pH range, e.g., 7 to 14 pH.
7. The highly-swellable polymeric film according to any of the clauses 4-6 wherein the cationic polymer is formed from the ionic polymer in an aqueous solution at a suitable pH range, e.g., 1 to 7 pH.
8. The highly-swellable polymeric film according to any of the clauses 4-7 wherein anionic polymers are chosen from the group comprising polysaccharide polymers for example alginates, e.g., alginic acid and salts thereof e.g., sodium alginate, calcium alginate, potassium alginate, which alginates may be cross linked, polyacrylic acid, dextran sulfate, carboxymethylcellulose, hyaluronic acid, polyglucuronic acid, polymanuronic acid, polygalacturonic acid, polyarabinic acid; chrondroitin sulfate and dextran phosphate.
9. The highly-swellable polymeric film according to any of the clauses 4-8 wherein cationic polymers are chosen from the group comprising chitosan, polyethylenimine, poly-L-lysine, and dimethylaminodextran.
10. The highly-swellable polymeric film according to any of the preceding clauses further comprising a polyacrylic acid.
11. The highly-swellable polymeric film according to clause 10 wherein the polyacrylic acid is chosen from the group comprising homopolymeric polyacrylic acid, copolymers, including both random and block copolymers, of acrylic acid residues and one or more non-acrylic acid residues, e.g., acrylate residues.
12. The highly-swellable polymeric film according to clauses 10 or 11 wherein the polyacrylic acid is cross-linked.
13. The highly-swellable polymeric film according to clause 12 wherein the dry weight ratio of the two types of polymers in the film may vary, and in some instances ranges from 25 to 95%, such as 50 to 80% and including 70 to 80% alginate.
14. The highly-swellable polymeric film according to any of the preceding clauses further comprising a conductivity enhancing agent, for example a porogen.
15. The highly-swellable polymeric film according to any of the preceding clauses having pores therein ranging in some instances from 1 to 1000 μm, such as 1 to 500 μm and including 1 to 250 μm.
16. The highly-swellable polymeric film according to clauses 14 or 15 comprising one or more porogens selected from both inorganic and organic porogens, for example inorganic salts, e.g., NaCl, MgCl2, CaCl2, NH4Cl, NH4PO4, NH4CO3; soluble biocompatible salts; sugars (e.g., sugar alcohols), polysaccharides (e.g., dextran (poly(dextrose)), water soluble small molecules, natural or synthetic polymers, oligomers, or monomers that are water soluble or degrade quickly under physiological conditions, including but not limited to: polyethylene glycol, polyvinyl alcohol, poly(vinylpyrollidone), pullulan, poly(glycolide), poly(lactide), poly(lactide-co-glycolide), other polyesters, and starches.
17. The highly-swellable polymeric film according to any of the clauses 14-16 wherein the amount of porogen component ranges from 1 to 40, including from 5 to 10 dry weight percent of the film.
18. The highly-swellable polymeric film according to any of the preceding clauses further comprising a binding agent, preferably selected from the group comprising celluloses, e.g., methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.; polyvinyl pyrrolidone; polyethylene oxides; gums, acrylate polymers; methacrylate polymers; copovidone.
19. The highly-swellable polymeric film according to clause 18 wherein the amount of binding agent is present in amount ranging from 1 to 50, such as 5 to 10 dry weight percent of the film.
20. The highly-swellable polymeric film according to any of the preceding clauses further comprising a plasticizing agent, preferably selected from the group comprising fatty acids, e.g., oleic acid, palmitic acid, etc.; dioctylphtalate; phospholipid; phosphatidic acid; polyethylene glycol; glycerine; butylhydroxytoluene; salts; saccharides, e.g., sucrose.
21. The highly-swellable polymeric film according to clause 20 wherein the amount of plasticizing agent ranges from 0.01 to 10, including from 2 to 5 dry weight percent of the film.
22. The highly-swellable polymeric polymeric film according to any of the preceding clauses being non-toxic and ingestible.
23. The highly-swellable polymeric film according to any of the preceding clauses which does not swell substantially upon contact with a gaseous medium, for example water vapour.
24. The highly-swellable polymeric film according to any of the preceding clauses comprising a mixture of sodium alginate and cross linked polyacrylic acid.
25. The highly-swellable polymeric film according to any of the preceding clauses which conducts electricity when swollen, and/or is swellable without disintegrating.
26. Use of a polymeric film according to any of the preceding clauses as a moisture protective coating for an electrical element, for example a battery and/or an ingestible event marker
27. An assembly for ingestion, comprising an ingestible component and a highly-swellable polymeric film according to any of the clauses 1-25 associated therewith.
28. Assembly according to clause 27 wherein the ingestible component is completely or partially coated with the highly-swellable polymeric film.
29. Assembly according to clauses 27 or 28 wherein the ingestible component comprises a pharmaceutically active component.
30. Assembly according to any of the clauses 27-29 wherein the ingestible component comprises an electronic unit and/or a mechanical unit, which electronic unit can comprise electronic circuitry, and is preferably an ingestible event marker.
31. Assembly according to clause 30 wherein the ingestible event marker comprises identifier circuitry and a current path extender.
32. Assembly according to clause 31 wherein the current path extender comprises
a highly-swellable polymeric film according to any of the preceding clauses 1-25.
33. Assembly according to any of the preceding clauses 30-32 wherein the ingestible event indicator comprises:
a support;
circuitry associated with the support;
a first material electrically coupled to the circuitry and associated with the support; and
a second material electrically coupled to the circuitry, wherein the second material is associated with the support and is electrically isolated from the first material;
wherein the first and second materials are selected to provide a voltage potential difference when in contact with a conducting fluid.
34. Assembly according to Clause 33, wherein the highly-swellable polymeric film covers at least a portion of one of the first material or second material.
35. Assembly according to clause 34 wherein the highly-swellable polymeric film inhibits reaction of at least one of the first material or second material with ambient moisture.
36. Assembly according to any of the clauses 33-35 wherein the highly-swellable polymeric film, when swollen, provides for conduction between at least one of the first material and the second material and an aqueous medium in which the composition is present.
37. Assembly according to any of the clauses 33-36 wherein the highly-swellable polymeric film covers at least a portion of the first material and/or the second material.
38. Assembly according to any of the clauses 33-37, wherein the second material is a salt, preferably selected from the group consisting of copper salts, iron salts and silver salts.
39. Assembly according to any of the clauses 33-38 wherein the first material comprises a metal.
40. Assembly according to Clause 39, wherein the metal is selected from the group consisting of magnesium, zinc, sodium, lithium and iron and alloys thereof.
41. Assembly according to any of the preceding clauses 33-40 wherein the highly-swellable polymeric film is associated with the support and is configured as a signal amplification that increases a length of a current path between the first and second materials.
42. The ingestible composition according to any of the preceding clauses 33-41 wherein the ingestible composition wherein the highly-swellable polymeric film is configured to separate the event indicator from the pharmaceutically active component upon swelling.
43. A system comprising:
an assembly according to any of the preceding clauses 33-42 and
a receiver configured to receive a communication associated with the ingestible component.
44. Use of a system according to clause 43 for providing information when the assembly is ingested.
45. An ingestible event marker coated with a highly-swellable polymeric film according to any of the preceding clauses 1-25.
46. Use of a highly-swellable polymeric film according to any of the preceding clauses 1-25 as a moisture barrier and/or as a conductor or electricity when in a swollen state.
47. Process for providing a highly-swellable polymeric film according to any of the preceding clauses 1-25 comprising the step of blending polymeric components with a solvent.
48. Process for stably associating highly-swellable polymeric film according to any of the preceding clauses 1-25 with an ingestible event marker or ingestible component comprising one or more protocols selected from the group consisting of laminating, pressing, stamping, extruding, molding, gluing and coating.
49. The method according to Clause 48, wherein at least a portion of the method is automated.
Highly-swellable polymeric films are provided. Aspects also include ingestible compositions that include the highly-swellable polymeric film and an ingestible component. Aspects further include methods of making and using the compositions.
Compositions
As summarized above, aspects of the invention include highly-swellable ingestible polymeric films, as well as compositions which include these films in addition to other components, e.g., ingestible components such as ingestible devices; minimally dimensioned components; etc.
Highly-Swellable Polymeric Films
Aspects of the invention include highly-swellable polymeric films. As used herein, the term “film” means a thin sheet or layer. While the dimensions of the film may vary, in some instances the film has a thickness of 10 microns or greater, such as 50 microns or greater, including 100 microns or greater, and ranges in thickness in some instances from 10 to 1000, such as 20 to 200 and including 30 to 60 microns. The top and bottom surfaces of the film may have a variety of different configurations, including but not limited to rectangular, trapezoidal, triangular, etc.; curvilinear, such as circular, ovoid or other curvilinear shape, etc. Where the film has surface which may be defined by length and width, these dimensions may vary, where in some instances the length ranges from 1 to 20, such as 2 to 10 and including 3 to 6 mm and the width ranges from 1 to 20, such as 2 to 10 and including 3 to 6 mm.
Films of interest are highly-swellable. By highly-swellable is meant that that the films are able to swell substantially upon contact with a liquid aqueous medium, such that they grow substantially in bulk (i.e., magnitude in three dimensions, e.g., which may be assessed in terms of a change in volume, etc.) by the absorption of water upon contact with an aqueous medium. Where the swelling results in a change in volume of the film, the volume may increase by a factor of 10 or greater, such as a factor of 15 or greater, including a factor of 20 or greater, e.g., a factor of 25 or greater, a factor of 30 or greater, a factor of 40 or greater, including a factor of 50 or greater, such as a factor of 100 or greater, for example a factor of 500 or greater, including a factor of 1000 or greater, as compared to the initial volume prior to contact with the liquid aqueous medium. Upon swelling, the mass of film may increase as well, where in some instances the mass increases by a factor of 10 or greater, such as a factor of 15 or greater, including a factor of 20 or greater, e.g., a factor of 25 or greater, a factor of 30 or greater, a factor of 40 or greater, including a factor of 50 or greater, such as a factor of 100 or greater, for example a factor of 500 or greater, including a factor of 1000 or greater, as compared to the initial mass prior to contact with the aqueous medium.
Highly-swellable polymeric films described herein rapidly swell upon contact with a liquid aqueous medium. By “rapidly swell” is meant that upon contact with a liquid aqueous medium, the films achieve substantially maximum swelling in a short period of time. As such, following contact with an aqueous medium, the films achieve 90% or more, such as 95% percent or more maximal swelling in a period of time of 10 minutes or less, such as 5 minutes or less, including 1 minute or less. In some instances, the films swell in volume by a factor of 10 or greater, such as a factor of 15 or greater, including a factor of 20 or greater, e.g., a factor of 25 or greater, a factor of 30 or greater, a factor of 40 or greater, including a factor of 50 or greater, such as a factor of 100 or greater, for example a factor of 500 or greater, including a factor of 1000 or greater, as compared to the initial volume prior to contact with the aqueous medium, in 10 minutes or less, such as 5 minutes or less, including 1 minute or less.
As mentioned above, films of interest are configured to absorb water upon contact with an aqueous medium. While the amount of water that is absorbed by a given film may vary, in some instances the films absorb 10 or more grams of water per gram dry weight of film, such as 25 or more grams of water per gram of dry weight of film, including 50 or more grams of water per gram of dry weight film, upon contact with an aqueous medium.
Highly-swellable polymeric films of interest are those that swell substantially upon contact with a liquid aqueous medium, but do not swell substantially, if at all, upon contact with a gaseous medium that includes water vapor. As such, upon contact with a gaseous medium that includes water vapor (e.g., where the partial pressure of water ranges from 1.0 to 49.8, such as 2.7 to 21.4 mmHg), the films swell little, if at all. As such, any swelling that occurs upon contact with such a gaseous medium as determined by a change in volume is a factor of five or less, such as a factor of 2 or less as compared to the film prior to contact with the gaseous medium.
Highly swellable polymeric films of interest exhibit rapidly swelling behavior without disintegrating upon contact with a liquid aqueous medium. As such, the films swell upon contact with an aqueous medium but do not break up or separate into parts, such that they do not lose intactness or solidness. As such, they do not dissolve upon contact with a liquid aqueous medium. Accordingly, a film that contacts a liquid aqueous medium will remain as a single entity following swelling, and will not go into solution. Therefore, following contact with a liquid aqueous medium, the film can still be manipulated, i.e., handled.
In some instances, the highly-swellable polymeric films are ingestible. As such films are ingestible, they are configured to be ingested or swallowed, i.e., taken into the stomach by drawing through the throat and esophagus with a voluntary muscular action. As such, the films themselves, as well as the components thereof, e.g., polymeric components, binders, plasticizers, porogens (such as described in greater detail below), do not exhibit an unacceptable level of toxicity when employed as intended. In other words, when the films are employed for their intended use, the toxicity level of the films, if present all, is acceptable.
Prior to contact with an aqueous medium, the freestanding films are mechanically stable. Films are flexible, able to easily wrap around rollers and rods and relatively strong under tension, but show little elongation under strain.
Films of interest may include an ionic polymer and may therefore be referred to as polymeric films. The phrase “ionic polymer” refers to a polymer comprising monomeric units having an acidic functional group, such as a carboxyl, sulfate, sulfonate, phosphate or phosphonate group, or a basic functional group, such as an amino, substituted amino or guanidyl group. When in aqueous solution at a suitable pH range, e.g., 7 to 14 pH, an ionic polymer comprising acidic functional groups will be a polyanion, and such a polymer is referred to herein as an “anionic polymer”. Likewise, in aqueous solution at a suitable pH range, e.g., 1 to 7 pH, an ionic polymer comprising basic functional groups will be a polycation. Such a polymer is referred to herein as a “cationic polymer”. As used herein, the terms ionic polymer, anionic polymer and cationic polymer refer to hydrophilic polymers in which the acidic or basic functional groups are not charged, as well as polymers in which some or all of the acidic or basic functional groups are charged, in combination with a suitable counterion. Suitable anionic polymers include alginates, e.g., alginic acid and salts thereof, polyacrylic acid, dextran sulfate, carboxymethylcellulose, hyaluronic acid, polyglucuronic acid, polymanuronic acid, polygalacturonic acid, polyarabinic acid; chrondroitin sulfate and dextran phosphate. Suitable cationic polymers include chitosan, polyethylenimine, poly-L-lysine, and dimethylaminodextran. Of interest in some instances are polysaccharide anionic polymers. Polysaccharide anionic polymers of interest include alginates, e.g., alginic acid and salts thereof. Alginic acid (i.e., alginate) is a linear copolymer with homopolymeric blocks of (1-4)-linked β-D-mannuronate (M) residues and α-L-guluronate (G) residues. The residues are covalently linked together in different sequences or blocks. The residues can appear in homopolymeric blocks of consecutive G-residues (G-blocks), consecutive M-residues (M-blocks) or alternating M and G-residues (MG-blocks). Also of interest are salts of alginic acid, e.g., sodium alginate, calcium alginate, potassium alginate, etc. The molecular weight of the alginate (e.g., alginic acid or alginate salt thereof) may vary, ranging in some instances from 10,000 to 600,000 Daltons, such as 50,000 to 100,000 Daltons. Alginates of interest will include a percentage of acidic groups sufficient to impart the above described swellability characteristic to the film. As such, where an alginate is employed that does not initially include the desired acidic groups, it may be modified as necessary to provide for the desired acidic groups. For example, where sodium alginate is employed, some of the sodium groups of the sodium alginate may be converted to acidic groups, e.g., by contacting the film with a suitable acid (such as HCl). To impart the desired mechanical properties to the film, the alginates may be cross-linked. For example, where sodium alginate is employed, the alginate may be cross-linked with a divalent cation salt, e.g., calcium chloride, magnesium chloride, etc.
Where desired, the film may include an additional component that provides for acidic, e.g., carboxyl, functional groups. For example, films of interest may include one or more additional polymers that provide for acidic functional groups, e.g., one or more additional anionic polymers that are present in addition to an alginate. Examples of additional anionic polymers of interest that may be present include, but are not limited to both natural and synthetic polymers.
In some instances, the film is a blend of both an alginate and a polyacrylic acid. Polyacrylic acids of interest include both homopolymeric polyacrylic acid as well as copolymers, including both random and block copolymers, of acrylic acid residues and one or more non-acrylic acid residues, e.g., acrylate residues, etc. Where desired, the polyacrylic acid may be cross-linked. When the film includes a blend of alginate to polyacrylic acid polymers, the dry weight ratio of the two types of polymers in the film may vary, and in some instances ranges from 25 to 95%, such as 50 to 80% and including 70 to 80% alginate.
In addition to the polymeric components, the films may further include one or more additional types of components. For example, films may include one or more agents that enhance conductivity of the film upon contact with an aqueous medium. Examples of such components include pore forming agents (i.e., porogens). The term “porogen” as used herein, refers to a chemical compound that is included in the film and, upon contact with an aqueous medium, is removed from the film, e.g., via diffusion, dissolution, and/or degradation, to leave a pore in the resultant film. The diameter of the pores produced by the porogen may vary, ranging in some instances from 1 to 1000 μm, such as 1 to 500 μm and including 1 to 250 μm. Porogens of interest include both inorganic and organic porogens. Inorganic porogens of interest include, but are not limited to: inorganic salts, e.g., NaCl, MgCl2, CaCl2, NH4Cl, NH4PO4, NH4CO3; soluble biocompatible salts; sugars (e.g., sugar alcohols), polysaccharides (e.g., dextran (poly(dextrose)), water soluble small molecules, natural or synthetic polymers, oligomers, or monomers that are water soluble or degrade quickly under physiological conditions, including but not limited to: polyethylene glycol, polyvinyl alcohol, poly(vinylpyrollidone), pullulan, poly(glycolide), poly(lactide), poly(lactide-co-glycolide), other polyesters, and starches. When present, the total amount of porogen component made up of one or more porogens may vary. In some instances, the amount of porogen component ranges from 1 to 40, including from 5 to 10 dry weight percent of the film.
Where desired, films may include one or more binding agents or binders. Binders of interest include, but are not limited to: celluloses, e.g., methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.; polyvinyl pyrrolidone; polyethylene oxides; gums, acrylate polymers; methacrylate polymers; copovidone; etc. When present, the total amount of binder component made up of one or more binding agents may vary. While the total amount of one or more binding agents in the film may vary, in some instances the amount ranges from 1 to 50, such as 5 to 10 dry weight percent of the film.
Where desired, films may include one or more plasticizing agents. Plasticizing agents of interest include, but are not limited to: fatty acids, e.g., oleic acid, palmitic acid, etc.; dioctylphtalate; phospholipid; phosphatidic acid; polyethylene glycol; glycerine; butylhydroxytoluene; salts; saccharides, e.g., sucrose; etc. When present, the total amount of plasticizer component made up of one or more plasticizing agents may vary. In some instances, the amount of plasticizer component ranges from 0.01 to 10, including from 2 to 5 dry weight percent of the film.
Ingestible Compositions
Aspects of the invention include ingestible compositions. In these instances, ingestible compositions of interest include both an ingestible component and a highly-swellable film component which is associated therewith. As the compositions are ingestible, they are configured to be ingested or swallowed, i.e., taken into the stomach by drawing through the throat and esophagus with a voluntary muscular action. Accordingly, the compositions are dimensioned so as to be capable of being ingested. In some instances, the compositions have a longest dimension of 30 mm or less, such as 20 mm or less, e.g., 10 mm or less. The volume of the ingestible composition may also vary so long as the composition is suitable for ingestion, where the volume in some instances may be 25 mm3 or less, such as 15 mm3 or less, including 10 mm3 or less.
In the ingestible compositions, the ingestible component is a portion or part of the ingestible composition that is configured for ingestion. The ingestible component may vary widely and may include one or more subcomponents, e.g., a pharmaceutically acceptable solid carrier (which may or may not include an active agent), a device (which may or may not include electronic circuitry), etc. In the ingestible composition, the highly-swellable polymeric film may be associated with an ingestible composition in a number of different ways, e.g., depending on the nature of the ingestible composition, depending on the purpose of the film, etc.
In some instances, the ingestible component includes a pharmaceutically acceptable solid carrier. Pharmaceutically acceptable solid carrier configurations include tablet and capsule configurations. While the pharmaceutically acceptable solid carrier may have a solid configuration, the solid configuration may include a liquid component, such as is found in a liquid capsule, which includes a liquid component present in a solid capsule. In some instances, the pharmaceutically acceptable solid carrier is configured to impart a controlled release profile to an active agent that is associated with the pharmaceutically acceptable solid carrier. Examples of pharmaceutically acceptable solid carriers of interest can be found in Remington's Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985). In such instances, among other non-mutually exclusive functions, e.g., as described below, the highly-swellable polymeric films may serve to separate the ingestible component from the carrier. For instance, upon contact with an aqueous medium, the resultant swelling of the film may result in the component to which the film is associated being pushed away and separated from the carrier, e.g., tablet or capsule. Such functionality of the film may be desirable, e.g., where association of the carrier material impedes functionality of the ingestible component (such as by blocking access of electrode material to an aqueous environment).
Where desired, the pharmaceutically acceptable solid carrier may include an active agent. Active agents of interest include pharmaceutically active agents as well as non-pharmaceutical active agents, such as diagnostic agents. The phrase “pharmaceutically active agent” (also referred to herein as drugs) refers to a compound or mixture of compounds which produces a physiological result, e.g., a beneficial or useful result, upon contact with a living organism, e.g., a mammal, such as a human. Pharmaceutically active agents are distinguishable from such components as excipients, carriers, diluents, lubricants, binders and other formulating aids, and encapsulating or otherwise protective components. The pharmaceutically active agent may be any molecule, as well as binding portion or fragment thereof, that is capable of modulating a biological process in a living subject. In certain aspects, the pharmaceutically active agent may be a substance used in the diagnosis, treatment, or prevention of a disease or as a component of a medication. The pharmaceutically active agent is capable of interacting with a target in a living subject. The target may be a number of different types of naturally occurring structures, where targets of interest include both intracellular and extracellular targets. Such targets may be proteins, phospholipids, nucleic acids and the like, where proteins are of particular interest. Specific proteinaceous targets of interest include, without limitation, enzymes, e.g., kinases, phosphatases, reductases, cyclooxygenases, proteases and the like, targets comprising domains involved in protein-protein interactions, such as the SH2, SH3, PTB and PDZ domains, structural proteins, e.g., actin, tubulin, etc., membrane receptors, immunoglobulins, e.g., IgE, cell adhesion receptors, such as integrins, etc., ion channels, transmembrane pumps, transcription factors, signaling proteins, and the like. Broad categories of active agents of interest include, but are not limited to: cardiovascular agents; pain-relief agents, e.g., analgesics, anesthetics, anti-inflammatory agents, etc.; nerve-acting agents; chemotherapeutic (e.g., anti-neoplastic) agents; neurological agents, e.g., anti-convulsants, etc. The amount of active agent that is present in the solid carrier may vary. In some instances, the amount of active agent that is present may range from 0.01 to 100% by weight.
Further examples of pharmaceutically acceptable solid carriers and active agents which may or may not be included therein are described in PCT Application Serial No. PCT/US2006/016370 published as WO/2006/116718; PCT Application Serial No. PCT/US2007/082563 published as WO/2008/052136; PCT Application Serial No. PCT/US2007/024225 published as WO/2008/063626; PCT Application Serial No. PCT/US2007/022257 published as WO/2008/066617; PCT Application Serial No. PCT/US2008/052845 published as WO/2008/095183; PCT Application Serial No. PCT/US2008/053999 published as WO/2008/101107; PCT Application Serial No. PCT/US2008/056296 published as WO/2008/112577; PCT Application Serial No. PCT/US2008/056299 published as WO/2008/112578; PCT Application Serial No. PCT/US2008/077753 published as WO2009/042812; PCT Application Serial No. PCT/US2008/085048 published as WO2009/070773; PCT Application Serial No. PCT/US2009/36231 published as WO2009/111664; PCT Application Serial No. PCT/US2009/049618 published as WO2010/005877; PCT Application Serial No. PCT/US2009/053721 published as WO2010/019778; PCT Application Serial No. PCT/US2009/060713 published as WO2010/045385; PCT Application Serial No. PCT/US2009/064472 published as WO2010/057049; PCT Application Serial No. PCT/US2009/067584 published as WO2010/068818; PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115; PCT Application Serial No. PCT/US2010/020142 published as WO2010/080765; PCT Application Serial No. PCT/US2010/020140 published as WO2010/080764; PCT Application Serial No. PCT/US2010/020269 published as WO2010/080843; PCT Application Serial No. PCT/US2010/028518 published as WO2010/111403; PCT Application Serial No. PCT/US2010/032590 published as WO2010/129288; PCT Application Serial No. PCT/US2010/034186 published as WO2010/132331; PCT Application Serial No. PCT/US2010/055522 published as WO2011/057024; the disclosures of which are herein incorporated by reference.
With such ingestible compositions, the highly-swellable polymeric film may be associated with the ingestible component in a number of different ways. For example, the highly-swellable polymeric film may form a coating or layer that substantially if not completely encloses the ingestible component. Such a configuration may be employed where it is desired to impart shelf-life stability to the ingestible composition. In such instances, the film imparts shelf-life stability to the composition, in that the film enhances the storage stability of the composition by a quantifiable measure as compared to a control or reference composition (i.e., a composition that lacks the shelf-life stability component). Highly-swellable polymeric films of interest may enhance the shelf-life stability of the composition as compared to a suitable control by a magnitude of 2-fold or greater, such as 5-fold or greater including 10-fold or greater, e.g., 25-fold or greater. The presence of the film allows the composition to be stable for extended periods of time during or following manufacture, where the ingestible composition may be stable for one year or longer, such as two years or longer, including five years or longer, following manufacture when the composition is maintained under conditions in which the temperature ranges from 10 to 40° C., the pressure ranges from 0.5 to 2.0 ATM and the relative humidity ranges from 10 to 100%. By “stable” is meant that the functionality of the composition does not degrade to a point that the composition is no longer suitable for use in its intended purpose. For example, if the composition includes an active pharmaceutical agent, the amount of active agent following the storage time period may be 85% or more, such as 90% or more, including 95% or more of the original amount present in the composition following manufacture, e.g., as determined using an HPLC protocol or other suitable analytical technique which can distinguish the amount of active agent from any degradation byproducts, such as oxidation byproducts.
In addition to or instead of a pharmaceutically acceptable solid carrier, ingestible compositions may include a device. The term “device” is used broadly to refer to a mechanical and/or electrical component configured for a particular purpose, where the device may or may not include a circuitry component.
Of interest as devices are ingestible devices, e.g., RFID-enabled devices; ingestible event indicators (also known as ingestible event markers or IEMS), etc. An ingestible event indicator is a device that is dimensioned to be ingestible and includes an identifier circuitry component and, optionally, a current path extender, e.g., a membrane, sometimes referred to herein as a “skirt”. Various aspects of an event indicator may include a control device for altering conductance; and a partial power source. The partial power source may include a first material electrically coupled to the control device; and a second material electrically coupled to the control device and electrically isolated from the first material, where the first and second materials are dissimilar.
Upon ingestion, the event indicator contacts a conducting fluid, e.g., stomach fluid. When the event indicator is in contact with the conducting liquid, a current path is formed through the conducting liquid between the first and second materials. The voltage potential created between the materials provides the power for operating the event indicator as well as produces the current flow through the conducting fluid and the system. In one aspect, the event indicator operates in direct current mode. In an alternative aspect, the event indicator controls the direction of the current so that the direction of current is reversed in a cyclic manner, similar to alternating current. The current path through the system is controlled by the control device. Completion of the current path allows for the current to flow and in turn a receiver, not shown, can detect the presence of the current and recognize that the system has been activated and the desired event is occurring or has occurred.
In one aspect, the two materials are similar in function to the two electrodes needed for a direct current power source, such as a battery. The conducting liquid acts as the electrolyte needed to complete the power source. The completed power source is defined by the electrochemical reaction between the dissimilar materials of the event indicator and the completion of the power source is enabled by the fluids of the body. The completed power source may be viewed as a power source that exploits electrochemical conduction in an ionic or a conducting solution such as gastric fluid, blood, or other bodily fluids and some tissues.
In certain aspects, the complete power source or supply is one that is made up of active electrode materials, electrolytes, and inactive materials, such as current collectors and packaging. The active materials are any pair of materials with different electrochemical potentials. Suitable materials are not restricted to metals, and in certain aspects the paired materials are chosen from metals and non-metals, e.g., a pair made up of a metal (such as Mg) and a salt (such as CuI). With respect to the active electrode materials, any pairing of substances—metals, salts, or intercalation compounds—with suitably different electrochemical potentials (voltage) and low interfacial resistance are suitable. Where desired, the voltage provided by the two dissimilar electrochemical materials upon contact of the materials of the power source with the target physiological site is 0.001 V or higher, including 0.01 V or higher, such as 0.1 V or higher, e.g., 0.3 V or higher, including 0.5 volts or higher, and including 1.0 volts or higher, where in certain aspects, the voltage ranges from about 0.001 to about 10 volts, such as from about 0.01 to about 10 V.
Anode materials of interest include, but are not limited to: magnesium, zinc, sodium, lithium, iron and alloys thereof, e.g., Al and Zn alloys of Mg, which may or may not be intercalated with a variety of materials such, as graphite with Li, K, Ca, Na, Mg, and the like. Cathode materials of interest include, but are not limited to, copper salts, such as copper salts of iodide, chloride, bromide, sulfate, formate, Fe3+ salts, e.g., orthophosphate, pyrophosphate, silver salts, etc. One or both of the metals may be doped with a non-metal, for example to enhance the voltage output of the battery. Non-metals that may be used as doping agents in certain aspects include, but are not limited to: sulfur, iodine and the like. In certain aspects, the electrode materials are cuprous iodine (CuI) or cuprous chloride (CuCl) as the anode and magnesium (Mg) metal or magnesium alloy as the cathode. Aspects of the present invention use electrode materials that are not harmful to the human body.
In such ingestible compositions, the film may be associated with the event indicator in a number of different ways, where the different ways are not mutually exclusive such that films may be associated with an event indicator in more than one way. For example, a highly-swellable polymer film may cover a portion of at least one of the first or second dissimilar materials. As such, the film may cover a portion or all of the cathode material. Alternatively or in addition, the film may cover a portion or all of the anode material. In such instances, the film may cover 10% or more, 20% or more, 25% or more, 50% or more, including 75% or more, e.g., 90% or more, etc., of the cathode and/or anode materials, including all of the cathode or anode materials.
With respect to current signatures produced by such event indicators, the current signatures may distinguish one class of event indicator from other types or may be universally unique, such as where the current signature is analogous to a human fingerprint which is distinct from any other fingerprint of any other individual and therefore uniquely identifies an individual on a universal level. In various aspects, the control circuit may generate a variety of different types of communications, including but not limited to: RF signals, magnetic signals, conductive (near-field) signals, acoustic signals, etc.
In various aspects, the event indicator may further include a current path extender, such as a membrane, which produces a virtual dipole length between the pair of dissimilar materials (functioning as transmission elements) that is longer than the actual dipole length. In addition to controlling the magnitude of the current path between the materials, such a membrane (sometimes referred to herein as “amplifier” or “skirt”) is used to increase the “length” of the current path and, hence, act to boost the conductance path, as disclosed in the PCT application no. PCT/US2008/077753 published as WO2009/042812 and in U.S. Pat. No. 7,978,064, the entire contents of which are incorporated herein by reference. Throughout the disclosure herein, the terms “membrane”, “skirt” and “amplifier” are used interchangeably with the term “current path extender” without impacting the scope or the present aspects and the claims herein.
Where desired, an ingestible event indicator may be stably associated in some manner to another ingestible component, e.g., pharmaceutically acceptable carrier component (e.g., as described above). By “stably associated” is meant that the event indicator and second ingestible component, e.g., a pharmaceutically acceptable carrier component, do not separate from each other, at least until administered to the subject in need thereof, e.g., by ingestion. As the event indicators are dimensioned to be ingestible, they are sized so that they can be placed in a mammalian, e.g., human or animal, mouth and swallowed. In some instances, event indicators have a longest dimension that is 30 mm or less, such as 20 mm or less, including 5 mm or less.
Various aspects of ingestible event indicators of interest (including protocols for the fabrication thereof) are described in PCT Application Serial No. PCT/US2006/016370 published as WO/2006/116718; PCT Application Serial No. PCT/US2007/082563 published as WO/2008/052136; PCT Application Serial No. PCT/US2007/024225 published as WO/2008/063626; PCT Application Serial No. PCT/US2007/022257 published as WO/2008/066617; PCT Application Serial No. PCT/US2008/052845 published as WO/2008/095183; PCT Application Serial No. PCT/US2008/053999 published as WO/2008/101107; PCT Application Serial No. PCT/US2008/056296 published as WO/2008/112577; PCT Application Serial No. PCT/US2008/056299 published as WO/2008/112578; PCT Application Serial No. PCT/US2008/077753 published as WO2009/042812; PCT Application Serial No. PCT/US2008/085048 published as WO2009/070773; PCT Application Serial No. PCT/US2009/36231 published as WO2009/111664; PCT Application Serial No. PCT/US2009/049618 published as WO2010/005877; PCT Application Serial No. PCT/US2009/053721 published as WO2010/019778; PCT Application Serial No. PCT/US2009/060713 published as WO2010/045385; PCT Application Serial No. PCT/US2009/064472 published as WO2010/057049; PCT Application Serial No. PCT/US2009/067584 published as WO2010/068818; PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115; PCT Application Serial No. PCT/US2010/020142 published as WO2010/080765; PCT Application Serial No. PCT/US2010/020140 published as WO2010/080764; PCT Application Serial No. PCT/US2010/020269 published as WO2010/080843; PCT Application Serial No. PCT/US2010/028518 published as WO2010/111403; PCT Application Serial No. PCT/US2010/032590 published as WO2010/129288; PCT Application Serial No. PCT/US2010/034186 published as WO2010/132331; PCT Application Serial No. PCT/US2010/055522 published as WO2011/057024; the disclosures of which are herein incorporated by reference.
In certain aspects, the ingestible event indicators are disrupted upon administration to a subject. As such, in certain aspects, the compositions are physically broken, e.g., dissolved, degraded, eroded, etc., following delivery to a body, e.g., via ingestion, injection, etc. The compositions of these aspects are distinguished from devices that are configured to be ingested and survive transit through the gastrointestinal tract substantially, if not completely, intact.
Where desired, an active agent (e.g., as described above) may be present in one or more of the event indicator components, e.g., in the electrochemical materials, the support, the membrane, etc. Examples of such configurations are described in PCT Application Serial No. PCT/US2010/032590 published as WO2010/129288; the disclosures of which are herein incorporated by reference.
In some instances the membrane may be made up partially or completely of a highly-swellable polymeric film. For example, the entire membrane may be fabricated from a highly-swellable polymeric film. Alternatively, a portion of the membrane, such as the outer-periphery of the membrane, may be made up of the highly-swellable polymeric film, with the remainder of the membrane being made up of one or more other suitable materials.
With reference to
In the specific example of the system 230 combined with the pharmaceutical product, as the product or pill is ingested, the system 230 is activated. The system 230 controls conductance to produce a unique current signature that is detected, thereby signifying that the pharmaceutical product has been taken. In other aspects, the current signature may contain information on the ingredients of the ingested pharmaceutical product which may include their chemical composition, date of manufacture, batch number, etc., among other desired information related to the pharmaceutical product which may be a placebo as well. The system 230 includes a framework 232. The framework 232 is a chassis for the system 230 and multiple components are attached to, deposited upon, or secured to the framework 232. In this aspect of the system 230, a digestible material 234 is physically associated with the framework 232. The material 234 may be chemically deposited on, evaporated onto, secured to, or built-up on the framework all of which may be referred to herein as “deposit” with respect to the framework 232. The material 234 is deposited on one side of the framework 232. The materials of interest that can be used as material 234 include, but are not limited to: Cu or CuI, e.g., as described above. The material 234 is deposited by physical vapor deposition, electro-deposition, or plasma deposition, among other protocols. The material 234 may be from about 0.05 to about 500 μm thick, such as from about 5 to about 100 μm thick. The shape is controlled by shadow mask deposition, or photolithography and etching. Additionally, even though only one region is shown for depositing the material, each system 230 may contain two or more electrically unique regions where the material 234 may be deposited, as desired.
At a different side, which may be the opposite side as shown in
Thus, when the system 230 is in contact with the conducting fluid, e.g., a liquid, a current path, an example is shown in
The voltage potential created between the materials 234 and 236 provides the power for operating the system as well as produces the current flow through the conducting fluid and the system. In one aspect, the system operates in direct current mode. In an alternative aspect, the system controls the direction of the current so that the direction of current is reversed in a cyclic manner, similar to alternating current. As the system reaches the conducting fluid or the electrolyte, where the fluid or electrolyte component is provided by a physiological fluid, e.g., stomach acid, the path for current flow between the materials 234 and 236 is completed external to the system 230; the current path through the system 230 is controlled by the control device 238. Completion of the current path allows for the current to flow, through conductive communication through the stomach, and in turn to a receiver, not shown, the receiver capable of detecting presence of the current signature containing information and further recognize that the system 230 has been activated and the desired event is occurring or has occurred.
In one aspect, the two materials 234 and 236 are similar in function to the two electrodes needed for a direct current power source, such as a battery. The conducting liquid acts as the electrolyte needed to complete the power source. The completed power source described is defined by the physical chemical reaction between the materials 234 and 236 of the system 230 and the surrounding fluids of the body. The completed power source may be viewed as a power source that exploits reverse electrolysis in an ionic or a conductive solution such as gastric fluid, blood, or other bodily fluids and some tissues. Additionally, the environment may be something other than a body and the liquid may be any conducting liquid. For example, the conducting fluid may be salt water or a metallic based paint.
Referring again to
As described above, in various aspects, the event indicator may further include a current path extender such as a membrane which, for example, produces a virtual dipole length between the pair of transmission elements that is larger than the actual dipole length. As illustrated in
As can be seen in the aspect depicted in
Referring now to
Referring now to
In one aspect, at the surface of the material 234, there is chemical reaction between the material 234 and the surrounding conducting fluid such that mass is released into the conducting fluid. The term “mass” as used herein refers to protons and neutrons that form a substance. One example includes where the material is CuCl and when in contact with the conducting fluid, CuCl becomes Cu (solid) and Cl− in solution. The flow of ions into the conduction fluid is depicted by the ion paths 550. In a similar manner, there is a chemical reaction between the material 236 and the surrounding conducting fluid and ions are captured by the material 236. The release of ions at the material 234 and capture of ion by the material 236 is collectively referred to as the ionic exchange. The rate of ionic exchange and, hence the ionic emission rate or flow, is controlled by the control device 238. The control device 238 can increase or decrease the rate of ion flow by altering the conductance, which alters the impedance, between the materials 234 and 236. Through controlling the ion exchange, the system 230 can encode information in the ionic exchange process. Thus, the system 230 uses ionic emission to encode information in the ionic exchange.
The control device 238 can vary the duration of a fixed ionic exchange rate or current flow magnitude while keeping the rate or magnitude near constant, similar to when the frequency is modulated and the amplitude is constant. Also, the control device 238 can vary the level of the ionic exchange rate or the magnitude of the current flow while keeping the duration near constant. Thus, using various combinations of changes in duration and altering the rate or magnitude, the control device 238 encodes information in the current flow or the ionic exchange. For example, the control device 238 may use, but is not limited to any of the following techniques namely, Binary Phase-Shift Keying (PSK), Frequency modulation, Amplitude modulation, on-off keying, and PSK with on-off keying.
As indicated above, the various aspects disclosed herein, such as systems 230 and 540 of
As indicated above, the system, such as system 230 and 240, control the conductance between the dissimilar materials and, hence, the rate of ionic exchange or the current flow. Through altering the conductance in a specific manner the system is capable of encoding information in the ionic exchange and the current signature. The ionic exchange or the current signature is used to uniquely identify the specific system. Additionally, the systems 230 and 240 are capable of producing various different unique exchanges or signatures and, thus, provide additional information. For example, a second current signature based on a second conductance alteration pattern may be used to provide additional information, which information may be related to the physical environment. To further illustrate, a first current signature may be a very low current state that maintains an oscillator on the chip and a second current signature may be a current state at least a factor of ten higher than the current state associated with the first current signature.
Referring now to
The control module 662 is also electrically coupled to and in communication with the sensor modules 672 and 274. In the aspect shown, the sensor module 672 is part of the control device 238 and the sensor module 274 is a separate component. In alternative aspects, either one of the sensor modules 672 and 274 can be used without the other and the scope of the present invention is not limited by the structural or functional location of the sensor modules 672 or 274. Additionally, any component of the system 230 may be functionally or structurally moved, combined, or repositioned without limiting the scope of the present invention as claimed. Thus, it is possible to have one single structure, for example a processor, which is designed to perform the functions of all of the following modules: the control module 662, the clock 664, the memory 666, and the sensor module 672 or 274. On the other hand, it is also within the scope of the present invention to have each of these functional components located in independent structures that are linked electrically and able to communicate.
Referring again to
Referring now to
As indicated above, the control device 238 can be programmed in advance to output a pre-defined current signature. In another aspect, the system can include a receiver system that can receive programming information when the system is activated. In another aspect, not shown, the switch 664 and the memory 666 can be combined into one device.
In addition to the above components, the system 230 may also include one or other electronic components. Electrical components of interest include, but are not limited to: additional logic and/or memory elements, e.g., in the form of an integrated circuit; a power regulation device, e.g., battery, fuel cell or capacitor; a sensor, a stimulator, etc.; a signal transmission element, e.g., in the form of an antenna, electrode, coil, etc.; a passive element, e.g., an inductor, resistor, etc.
As mentioned above, highly-swellable polymeric films may be associated with the ingestible event marker in a number of different, non-mutually exclusive ways. For example, the film may cover a portion of at least one of the first or second dissimilar materials. As such, the film may cover a portion or all of the cathode material. Alternatively or in addition, the film may cover a portion or all of the anode material. In such instances, the film may cover 10% or more, 20% or more, 25% percent or more, 50% or more, including 75% percent or more, e.g., 90% or more, of the cathode and/or anode material, including all of the cathode material or anode material.
Highly-swellable polymeric films such as 740 illustrated in
Another function that the film may serve is to provide for conduction between at least one of the first and second materials and an aqueous medium when the ingestible composition is placed in the aqueous medium. As the films are conductive upon swelling, when compositions containing such films are placed into an aqueous medium and the film swells, the films provide for conduction between the first and/or second materials and the aqueous medium. As such, the films can serve to improve the functionality of the ingestible indicator, by providing for conductive communication between the marker and the aqueous environment into which it is placed during use. In some instances, the films provide for a region of conductivity which is known to provide for a signal that is sufficient for the intended purpose of the event marker. In other words, the films may provide a region of consistent conductivity that is known to provide for adequate functionality of the event marker, despite variations in the local environment. For example, the presence of food particles in the local environment, proximity to the gastric mucosa, or variations in the pH and composition of stomach contents may alter the local aqueous environment in which the event marker may be present. The conductivity of the film in the swollen state may be selected to provide for a consistent local environment over a broad range of differing stomach conditions
In some instances, improvement of functionality results because the presence of the swollen conductive film impedes the blockage of the first and/or second materials by non-conductive entities that may be present in the environment of the ingestible event marker. Examples of such non-conductive potentially interfering entities that may be present in the environment of the ingestible composition include, but are not limited to: food particles, tissue such as gastrointestinal lining, non-conductive components of the ingestible event marker, and the like. By forming a conductive film over the first and second materials upon swelling, the film serves to prevent contact of non-conductive entities to the materials and thereby improves the function of the composition.
In some instances, event indicators include a highly-swellable film associated with the first and/or second materials and a distinct protective barrier made up of different components and in turn associated with the film, such that the film is between the protective barrier and the first and/or second dissimilar material. Protective barriers which may be employed in such compositions may vary. Examples of such barriers include, but are not limited to, layers that may include one or more of: lipids and functionally analogous materials; pharmaceutically acceptable polymeric materials, etc., e.g., as described in pending U.S. application Ser. No. 13/304,260, the disclosure of which application is herein incorporated by reference.
An example of such a composition is depicted in
In an event indicator as illustrated in
Other Minimally Dimensioned Components
Aspects of the invention further include compositions that are not necessarily ingestible. Such compositions may include a highly-swellable polymeric film (e.g., as described in greater detail above) physically associated with a minimally dimensioned component. While the minimally dimensioned component may vary, e.g., as described above, in some instances the minimally dimensioned component is a micro-battery. Micro-batteries of interest may include “all-solid” batteries, and may include components of a battery, such as current collectors, positive and negative electrodes, an electrolyte, in a minimally dimensioned structure, e.g., as described above. In some instances, micro-batteries of interest are thin films, which may be obtained by deposition, such as by physical vapor deposition (PVD) or chemical vapor deposition (CVD). The micro-battery may take a variety of different configurations, such as but not limited to: a chip configuration, a cylinder configuration, a spherical configuration, a disc configuration, etc., where a particular configuration may be selected based on intended application, method of manufacture, etc. In some instances, the micro-battery is dimensioned to have a width ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm; a length ranging from about 0.05 mm to about 1 mm, such as from about 0.1 mm to about 0.2 mm and a height ranging from about 0.1 mm to about 1 mm, such as from about 0.05 mm to about 0.3 mm, including from about 0.1 mm to about 0.2 mm. In certain instances, the micro-battery is 1 mm3 or smaller, such as 0.1 mm3 or smaller, including 0.2 mm3 or smaller. In such instances the film may serve to enhance stability of the component, e.g., by improving shelf-life, etc., such as described above.
Systems
Also provided are systems that include an ingestible device, e.g., an event indicator, and a detection component, e.g., in the form of a receiver. Receivers of interest are those configured to detect, e.g., receive, a communication from an ingestible device, e.g., RFID ingestible device, event indicator, etc. The signal detection component may vary significantly depending on the nature of the communication that is generated by the ingestible device. As such, the receiver may be configured to receive a variety of different types of signals, including but not limited to: RF signals, magnetic signals, conductive (near field) signals, acoustic signals, etc. In certain aspects, the receiver is configured to receive a signal conductively from an event indicator, such that the two components use the body of the patient as a communication medium. As such, communication that is transferred between event indicator and the receiver travels through the body, and requires the body as the conduction medium. The event indicator communication may be transmitted through and received from the skin and other body tissues of the subject body in the form of electrical alternating current (a.c.) voltage signals that are conducted through the body tissues. This communication protocol has the advantage that the receivers may be adaptably arranged at any desired location on the body of the subject, whereby the receivers are automatically connected to the required electrical conductor for achieving the signal transmission, i.e., the signal transmission is carried out through the electrical conductor provided by the skin and other body tissues of the subject.
The receivers of interest include external, semi-implantable, and implantable receivers. In external aspects, the receiver is ex vivo, by which is meant that the receiver is present outside of the body during use. Examples include wearable patches, e.g., adhesive patches, torso bands, wrist(s) or arm bands, jewelry, apparel, mobile devices such as phones, attachments to mobile devices, etc. Where the receiver is implanted, the receiver is in vivo. Examples include cardiac can and leads, under-the-skin implants, etc. Semi-implantable devices include those designed to be partially implanted under the skin.
In certain aspects, the receiver may be configured to provide data associated with a received signal to a location external to said subject. For example, the receiver may be configured to provide data to an external data receiver, e.g., which may be in the form of a monitor (such as a bedside monitor), a computer, a personal digital assistant (PDA), phone, messaging device, smart phone, etc. The receiver may be configured to retransmit data of a received communication to the location external to said subject. Alternatively, the receiver may be configured to be interrogated by an external interrogation device to provide data of a received signal to an external location.
Receivers may be configured variously, e.g., with various signal receiving elements, such as electrodes, various integrated circuit components, one or more power components (such as power receivers or batteries), signal transmission components, housing components, etc.
In one aspect, for example, the receiver includes one or more of: a high power-low power module; an intermediary module; a power supply module configured to activate and deactivate one or more power supplies to a high power processing block; a serial peripheral interface bus connecting master and slave blocks; and a multi-purpose connector, as further described in PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115, infra.
Receivers of interest include, but are not limited to, those receivers disclosed in: PCT Application Serial No. PCT/US2006/016370 published as WO 2006/116718; PCT Application Serial No. PCT/US2008/52845 published as WO 2008/095183; PCT Application Serial No. PCT/US2007/024225 published as WO 2008/063626; PCT Application Serial No. PCT/US2008/085048 published as WO 009/070773; PCT Application Serial No. PCT/US2009/068128 published as WO2010/075115; and PCT Application Serial No. US2012/047076 filed on Jul. 21, 2012; the disclosures of which applications (and particularly receiver components thereof) are herein incorporated by reference.
In certain instances, the signal receiver includes a set of two or more, such as two or three, electrodes that provide for dual functions of signal receiving and sensing. For example, in addition to receiving signal, the electrodes can also serve additional sensing functions. Where desired, the electrodes may be used to generate electrocardiogram data. From that data, there are many kinds of processing that can be done, e.g., to detect various cardiac events, such as tachycardia, fibrillations, heart rate, etc. The obtained electrocardiogram data can be used to titrate medications, or be used for alerts when an important change or significant abnormality in the heart rate or rhythm is detected. This data may also be helpful in monitoring heart rate in patients who do not have pacemakers or as an alternative to patients who might normally require a Holter monitor or a Cardiac Event Monitor, portable devices for continuously monitoring the electrical activity of the heart for twenty-four hours or other devices. An extended recording period is useful for observing occasional cardiac arrythmias that are difficult to identify in shorter time periods.
In some instances, two or more different demodulation protocols may be employed to decode a given received signal. In some instances, both a coherent demodulation protocol and a differential coherent demodulation protocol may be employed.
In addition to demodulation, the trans-body communication module may include a forward error correction module, which module provides additional gain to combat interference from other unwanted signals and noise. Forward error correction functional modules of interest include those described in PCT Application Serial No. PCT/US2007/024225 published as WO 2008/063626; the disclosure of which application is herein incorporated by reference. In some instances, the forward error correction module may employ any convenient protocol, such as Reed-Solomon, Golay, Hamming, BCH, and Turbo protocols to identify and correct (within bounds) decoding errors.
Receivers of the invention may further employ a beacon functionality module. In various aspects, a beacon switching module may employ one or more of the following: a beacon wakeup module, a beacon signal module, a wave/frequency module, a multiple frequency module, and a modulated signal module.
A view of a beacon module is provided in the functional block diagram shown in 11. The scheme outlined in
Multiplexer 1320 is electrically coupled to both high band pass filter 1330 and low band pass filter 1340. The high and low frequency signal chains provide for programmable gain to cover the desired level or range. In this specific aspect, high band pass filter 1330 passes frequencies in the 10 KHz to 34 KHz band while filtering out noise from out-of-band frequencies. This high frequency band may vary, and may include, for example, a range of 3 KHz to 300 KHz. The passing frequencies are then amplified by amplifier 1332 before being converted into a digital signal by converter 834 for input into high power processor 1380 (shown as a DSP) which is electrically coupled to the high frequency signal chain.
Low band pass filter 1340 is shown passing lower frequencies in the range of 0.5 Hz to 150 Hz while filtering out out-of-band frequencies. The frequency band may vary, and may include, for example, frequencies less than 300 Hz, such as less than 200 Hz, including less than 150 Hz. The passing frequency signals are amplified by amplifier 1342. Also shown is accelerometer 1350 electrically coupled to second multiplexer 1360. Multiplexer 1360 multiplexes the signals from the accelerometer with the amplified signals from amplifier 1342. The multiplexed signals are then converted to digital signals by converter 1364 which is also electrically coupled to low power processor 1370.
In one aspect, a digital accelerometer (such as one manufactured by Analog Devices), may be implemented in place of accelerometer 1350. Various advantages may be achieved by using a digital accelerometer. For example, because the signals the digital accelerometer would produce signals already in digital format, the digital accelerometer could bypass converter 1364 and electrically couple to the low power microcontroller 1370—in which case multiplexer 1360 would no longer be required. Also, the digital signal may be configured to turn itself on when detecting motion, further conserving power. In addition, continuous step counting may be implemented. The digital accelerometer may include a FIFO buffer to help control the flow of data sent to the low power processor 1370. For instance, data may be buffered in the FIFO until full, at which time the processor may be triggered to turn awaken from an idle state and receive the data.
Low power processor 1370 may be, for example, an MSP430 microcontroller from Texas Instruments. Low power processor 1370 of receiver 800 maintains the idle state, which as stated earlier, requires minimal current draw—e.g., 10 μA or less, or 1 μA or less.
High power processor 1380 may be, for example, a VC5509 digital signal process from Texas Instruments. The high power processor 1380 performs the signal processing actions during the active state. These actions, as stated earlier, require larger amounts of current than the idle state—e.g., currents of 30 μA or more, such as 50 μA or more—and may include, for example, actions such as scanning for conductively transmitted signals, processing conductively transmitted signals when received, obtaining and/or processing physiological data, etc.
The receiver may include a hardware accelerator module to process data signals. The hardware accelerator module may be implemented instead of, for example, a DSP. Being a more specialized computation unit, it performs aspects of the signal processing algorithm with fewer transistors (less cost and power) compared to the more general purpose DSP. The blocks of hardware may be used to “accelerate” the performance of important specific function(s). Some architectures for hardware accelerators may be “programmable” via microcode or VLIW assembly. In the course of use, their functions may be accessed by calls to function libraries.
The hardware accelerator (HWA) module comprises an HWA input block to receive an input signal that is to be processed and instructions for processing the input signal; and, an HWA processing block to process the input signal according to the received instructions and to generate a resulting output signal. The resulting output signal may be transmitted as needed by an HWA output block.
An example of a system of the invention is shown in
Systems of the invention may include an external device which is distinct from the receiver (which may be implanted or topically applied in certain aspects), where this external device provides a number of functionalities. Such an apparatus can include the capacity to provide feedback and appropriate clinical regulation to the patient. Such a device can take any of a number of forms. By example, the device can be configured to sit on the bed next to the patient, e.g., a bedside monitor. Other formats include, but are not limited to, PDAs, phones, such as smart phones, computers, etc. The device can read out the information described in more detail in other sections of the subject patent application, both from pharmaceutical ingestion reporting and from physiological sensing devices, such as is produced internally by a pacemaker device or a dedicated implant for detection of the pill. The purpose of the external apparatus is to get the data out of the patient and into an external device. One feature of the external apparatus is its ability to provide pharmacologic and physiologic information in a form that can be transmitted through a transmission medium, such as a telephone line, to a remote location such as a clinician or to a central monitoring agency.
Manufacturing Methods
Also provided are methods of manufacturing highly-swellable polymeric films, as well as compositions that include the same. Highly-swellable polymeric films may be prepared as free-standing films in some instances. For example, solvent casting fabrication methods may be employed in which a liquid composition of the one or more polymers, e.g., an alginate, a polyacrylic acid, a blend of the two, etc., may be prepared by combining the polymeric components and a suitable solvent(s). Solvents of interest include, but are not limited to: water and aqueous solvents which include one or more solutes (e.g., salts); organic solvents, e.g., alcohols, such as ethanol, propanol, isopropanol, methanol, butanol, etc.; polyols, e.g., propylene glycol, glycerin, butylene glycol, ethoxydiglycol, polyethylene glycol, methyl or ethyl ethers of diglycols, cyclic polyols, ethoxylated or propoxylated glycols; and other organic solvents, e.g., Heptane, Isobutyl acetate, Butyl acetate, Methylethylketone, tert-Butylmethyl ether, Methylisobutylketone, Dimethyl sulfoxide, Pentane, Toluene, Trichloroethylene, and Xylene; etc. In the liquid composition, the amount of polymer component may vary, ranging in some instances from 1 to 20 weight percent, such as 2 to 10 and including 3 to 4. Additives may be included in the liquid as desired, e.g., binders, plasticizers, porogens, etc., such as described above. The amount of additives that is included, if employed, may vary, and in some instances ranges from 1 to 50%, such as 5 to 10%. The liquid composition may be prepared at any convenient temperature, e.g., 15 to 45° C., using any convenient protocol, e.g., stirring, etc. Following preparation of the liquid composition, the liquid composition may be shaped as desired, e.g., by placing into a mold, by casting on a suitable substrate, etc., following which the solvent is separated from the remainder of the liquid composition to produce the desired film. Solvent separation may be achieved a number of different ways, e.g., via evaporation, which may occur at room temperature or elevated temperatures, such that the temperature may range in some instances from 25 to 100° C., such as 45 to 75° C.
Where desired, following preparation the film may be further treated to provide for desired characteristics, e.g., swellability, solubility, mechanical strength, etc. For example, the film may be contacted with a suitable acidic solution, e.g., HCl, for a period of time sufficient to exchange protons for sodium ions. This can reduce the solubility and swelling nature of the film desired. Contact of the film with the acid may be achieved using any convenient protocol, e.g., dipping the film in the acid solution, spraying the film with the acid solution, etc.
Mechanical strength of the resultant film may be increased in a number of different ways. In some instances, the film may be contacted with a cross-linking agent to enhance the mechanical properties of the film. For example, where the film is an alginate, such as sodium alginate, the film may be contacted (such as by spraying) with a divalent cation solution, such as CaCl2, MgCl2, etc. Alternatively, the alginate may be contacted with a basic solution, e.g., sodium hydroxide, to enhance the mechanical properties of the film.
For ingestible compositions that include a highly-swellable polymeric film and a second component, e.g., as described herein, aspects of the methods include combining an ingestible component (which may or may not include a device, such as an IEM) and a highly-swellable polymeric film, e.g., as described above, in a manner sufficient to produce a desired ingestible composition. Any convenient manufacturing protocol may be employed, where protocols of interest include both manual and automated protocols, as well as protocols that include both manual and automated steps. Protocols of interest that find use in various aspects of the fabrication methods described herein include lamination, molding, pressing, extrusion, stamping, coating (such as spray coating and dipping), gluing, etc. In some instances, fabrication protocols as described in PCT application serial nos. PCT/US2010/020142 published as WO 2010/080765; PCT/US2006/016370 published as WO 2006/116718 and PCT/US2008/077753 published as WO2009/042812 (the disclosures of which applications are herein incorporated by reference); are employed.
Aspects of the fabrication protocols include stably associating the ingestible component with a highly-swellable polymeric film component. By “stably associating” is meant that the ingestible component and highly-swellable polymeric film component do not separate from each other, at least until desired during intended use, e.g., upon administration to a subject in need thereof, such as by ingestion. Any convenient approach for stably associating the ingestible component and the highly-swellable polymeric film component may be employed.
Where an ingestible event marker having one of its dissimilar materials covered by a highly-swellable polymeric film is desired, e.g., as illustrated in
In a variation of the above protocol, a fabrication process may be one in which the highly-swellable polymeric film is fabricated at the same time that the ingestible component is stably associated therewith. For example, a molding process may be employed where liquid film precursor composition, e.g., as described above, is positioned in a mold, followed by placement of an ingestible component (e.g., IEM) on the precursor material. The solvent component of the liquid composition may be removed to associate the film with the dissimilar material of the ingestible event marker. Temperature modulation may be employed where appropriate. Following solidification of the precursor material, the resultant final product may be removed from the mold.
In yet another fabrication protocol of interest, a stamping protocol may be employed. For example, an ingestible component may be positioned between two sheets of prefabricated highly-swellable polymeric films. Once positioned between the two sheets, a stamping tool may be used to stamp and seal the two sheets around the ingestible component in a manner that encases the ingestible component in a sealed multilayer of the highly-swellable polymeric film. The stamping tool may be configured to produce a product having any convenient shape, such as a disc, etc. Where desired, temperature modulation may be employed in such protocols.
In yet another fabrication protocol of interest, a coating process may be employed to stably associate the ingestible component with the highly-swellable polymeric film component. For example, a premade ingestible component in the form of a tablet may be provided, e.g., as described in PCT application serial nos. PCT/US2010/020142 published as WO 2010/080765; PCT/US2006/016370 published as WO 2006/116718 and PCT/US2008/077753 published as WO2009/042812; the disclosures of which applications are herein incorporated by reference. This premade ingestible component may then be spray coated with a liquid precursor composition (e.g., as described above). Following spray coating, the coating material may be allowed to harden (e.g., by maintaining the coated tablet at a suitable temperature, such as room temperature) to produce the desired product.
Where desired, aspects of the above described or other suitable protocols may be combined to produce a fabrication protocol. For example, a molding process may be employed to make a product and the product spray coated with a further material, such as a soluble material.
Methods of Use
Aspects of the invention further include methods of using the compositions, such as those described above. Aspects of such methods include administering an ingestible composition to a subject, e.g., by self-administration or via the assistance of another, such as a health care practitioner. Such methods may include placing the ingestible composition in the mouth of a subject such that the subject swallows the ingestible composition. In this manner, the subject ingests the ingestible composition. Ingestible compositions may be employed with a variety of subjects. Subjects of interest include “mammals” including animals classified in the orders carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs, and rats), and primates (e.g., humans, chimpanzees, and monkeys). In certain aspects, the subjects will be humans.
Following ingestion, the methods may include receiving a signal emitted from an ingestible composition, such as an IEM comprising ingestible composition, e.g., at a receiver, such as described above. In some instances, the received signal is a conductively transmitted signal.
Ingestible compositions may be employed in a variety of different applications. Applications of interest in which the ingestible composition comprises an IEM include, but are not limited to: monitoring patient compliance with prescribed therapeutic regimens; tailoring therapeutic regimens based on patient compliance; monitoring patient compliance in clinical trials; monitoring usage of controlled substances; monitoring the occurrence of a personal event of interest, such as the onset of symptoms, etc., and the like. Applications of interest are further described in PCT Application Serial No. PCT/US2006/016370 published as WO/2006/116718; PCT Application Serial No. PCT/US2007/082563 published as WO/2008/052136; PCT Application Serial No. PCT/US2007/024225 published as WO/2008/063626; PCT Application Serial No. PCT/US2007/022257 published as WO/2008/066617; PCT Application Serial No. PCT/US2008/052845 published as WO/2008/095183; PCT Application Serial No. PCT/US2008/053999 published as WO/2008/101107; PCT Application Serial No. PCT/US2008/056296 published as WO/2008/112577; PCT Application Serial No. PCT/US2008/056299 published as WO/2008/112578; and PCT Application Serial No. PCT/US2008/077753 published as WO2009/042812; the disclosures of which applications is herein incorporated by reference.
Kits
Also provided are kits that include one or more ingestible compositions, such as described above. In those aspects having a plurality of ingestible compositions, the ingestible compositions may be packaged in a single container, e.g., a single tube, bottle, vial, and the like, or one or more dosage amounts may be individually packaged such that certain kits may have more than one container of ingestible compositions. In certain aspects the kits may also include a receiver, such as reviewed above. In certain aspects, the kits may also include an external monitor device, e.g., as described above, which may provide for communication with a remote location, e.g., a doctor's office, a central facility etc., which obtains and processes data obtained about the usage of the composition.
The subject kits may also include instructions for how to practice the subject methods using the components of the kit. The instructions may be recorded on a suitable recording medium or substrate. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other aspects, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g. CD-ROM, diskette, etc. In yet other aspects, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this aspect is a kit that includes a web address where the instructions can be viewed and/or from which the instructions can be downloaded. As with the instructions, this means for obtaining the instructions is recorded on a suitable substrate.
Some or all components of the subject kits may be packaged in suitable packaging to maintain sterility. In many aspects of the subject kits, the components of the kit are packaged in a kit containment element to make a single, easily handled unit, where the kit containment element, e.g., box or analogous structure, may or may not be an airtight container, e.g., to further preserve the sterility of some or all of the components of the kit.
The following examples are offered by way of illustration and not by way of limitation.
Experimental
As an example, a free standing film consisting of a mixture of sodium alginate and cross-linked poly acrylic acid can be formed by creating an aqueous solution of the two components and casting into a recessed mold. For example, 1.5 g of sodium alginate and 0.5 g of cross-linked polyacrylic acid may be added to a beaker of water under constant stirring. Once both components are fully dissolved, this viscous solution is poured into a Teflon® coated mold to a desired thickness, and placed into an oven to dry at 45° C. Once dried, the remaining polymer solids can be removed from the mold as a free standing film.
The free standing alginate/polyacrylic acid film can then be heat press laminated to existing IEM sensor sheets of the same lateral form factor. A wide range of equipment can be utilized to create this laminate, and specific conditions ultimately depend on the film composition, but generally pressing temperatures from 130-150° C. and moderate pressures (e.g., 50 to 100 psi) are sufficient to thermally bond the film to the IEM sensor sheet. The film and IEM sensor sheet are placed into the press or roll laminator with non-stick liners made of a fluorinated polymer (Teflon or fluorinated ethylene propylene (FEP)) placed on both the top and bottom of the film stack. Following pressing, the assembled stack is cooled and individual IEM sensors with alginate/polyacrylic acid overlayers can be singulated to a variety of form factors by mechanically punching the film stack.
Currently, these films are showing a robust ability to provide moisture protection at humidities considered very aggressive to the battery material on the IEM sensor. For example, the cuprous chloride battery material for a standard IEM will have completely degraded is battery charge due to moisture related reaction in ˜10 days at 25° C. and 70% relative humidity. IEMs with an alignate/polyacrylic acid film show minimal degradation of cupric chloride battery material at 25° C. and 70% relative humidity for over 28 days of aging.
It is to be understood that this invention is not limited to particular aspects described, as such may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, representative illustrative methods and materials are now described.
All publications and patents cited in this specification are herein incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference and are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
It is noted that, as used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely,” “only” and the like in connection with the recitation of claim elements, or use of a “negative” limitation.
As will be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it is readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.
Accordingly, the preceding merely illustrates the principles of the invention. It will be appreciated that those skilled in the art will be able to devise various arrangements which, although not explicitly described or shown herein, embody the principles of the invention and are included within its spirit and scope. Furthermore, all examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to furthering the art, and are to be construed as being without limitation to such specifically recited examples and conditions. Moreover, all statements herein reciting principles, aspects, and aspects of the invention as well as specific examples thereof, are intended to encompass both structural and functional equivalents thereof. Additionally, it is intended that such equivalents include both currently known equivalents and equivalents developed in the future, i.e., any elements developed that perform the same function, regardless of structure. The scope of the present invention, therefore, is not intended to be limited to the exemplary aspects shown and described herein. Rather, the scope and spirit of present invention is embodied by the appended claims.
This application is the U.S. National Stage application filed under 35 U.S.C. § 371(c) of International Application No. PCT/US2014/013382, filed on Jan. 28, 2014, which claims the benefit, under 35 USC § 119(e), of U.S. Provisional Patent Application Ser. No. 61/758,030 filed Jan. 29, 2013; the entirety of both applications are incorporated by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2014/013382 | 1/28/2014 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2014/120669 | 8/7/2014 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 1548459 | Hammer | Aug 1925 | A |
| 2587158 | Hofberg | Feb 1952 | A |
| 2973555 | Schwepke | Mar 1961 | A |
| 3048526 | Boswell | Aug 1962 | A |
| 3079824 | Schott | Mar 1963 | A |
| 3096248 | Rudzki | Jul 1963 | A |
| 3176399 | Marino et al. | Apr 1965 | A |
| 3589943 | Grubb et al. | Jun 1971 | A |
| 3607788 | Adolph | Sep 1971 | A |
| 3642008 | Bolduc | Feb 1972 | A |
| 3679480 | Brown et al. | Jul 1972 | A |
| 3682160 | Murata | Aug 1972 | A |
| 3719183 | Schwartz | Mar 1973 | A |
| 3799802 | Schneble, Jr. et al. | Mar 1974 | A |
| 3828766 | Krasnow | Aug 1974 | A |
| 3837339 | Aisenberg et al. | Sep 1974 | A |
| 3849041 | Knapp | Nov 1974 | A |
| 3893111 | Cotter | Jul 1975 | A |
| 3944064 | Bashaw et al. | Mar 1976 | A |
| 3967202 | Batz | Jun 1976 | A |
| 3989050 | Buchalter | Nov 1976 | A |
| 4017856 | Wiegand | Apr 1977 | A |
| 4055178 | Harrigan | Oct 1977 | A |
| 4062750 | Butler | Dec 1977 | A |
| 4077397 | Ellis | Mar 1978 | A |
| 4077398 | Ellis | Mar 1978 | A |
| 4082087 | Howson | Apr 1978 | A |
| 4090752 | Long | May 1978 | A |
| 4106348 | Auphan | Aug 1978 | A |
| 4129125 | Lester | Dec 1978 | A |
| 4139589 | Beringer et al. | Feb 1979 | A |
| 4143770 | Grimmell et al. | Mar 1979 | A |
| 4166453 | McClelland | Sep 1979 | A |
| 4239046 | Ong | Dec 1980 | A |
| 4251795 | Shibasaki et al. | Feb 1981 | A |
| 4269189 | Abraham | May 1981 | A |
| 4331654 | Morris | May 1982 | A |
| 4345588 | Widder et al. | Aug 1982 | A |
| 4418697 | Tama | Dec 1983 | A |
| 4425117 | Hugemann | Jan 1984 | A |
| 4439196 | Higuchi | Mar 1984 | A |
| 4494950 | Fischell | Jan 1985 | A |
| 4559950 | Vaughan | Dec 1985 | A |
| 4564363 | Bagnall et al. | Jan 1986 | A |
| 4635641 | Hoffman | Jan 1987 | A |
| 4654165 | Eisenber | Mar 1987 | A |
| 4663250 | Ong et al. | May 1987 | A |
| 4669479 | Dunseath | Jun 1987 | A |
| 4687660 | Baker et al. | Aug 1987 | A |
| 4725997 | Urquhart et al. | Feb 1988 | A |
| 4749575 | Rotman et al. | Jun 1988 | A |
| 4763659 | Dunseath | Aug 1988 | A |
| 4767627 | Caldwell et al. | Aug 1988 | A |
| 4775536 | Patell | Oct 1988 | A |
| 4784162 | Ricks | Nov 1988 | A |
| 4793825 | Benjamin et al. | Dec 1988 | A |
| 4814181 | Jordan et al. | Mar 1989 | A |
| 4844076 | Lesho | Jul 1989 | A |
| 4847090 | Della Posta et al. | Jul 1989 | A |
| 4876093 | Theeuwes et al. | Oct 1989 | A |
| 4891223 | Ambegaonakar et al. | Jan 1990 | A |
| 4896261 | Nolan | Jan 1990 | A |
| 4900552 | Sanvordeker et al. | Feb 1990 | A |
| 4975230 | Pinkhasov | Dec 1990 | A |
| 4987897 | Funke | Jan 1991 | A |
| 5000957 | Eckenhoff et al. | Mar 1991 | A |
| 5016634 | Vock et al. | May 1991 | A |
| 5018335 | Yamamoto et al. | May 1991 | A |
| 5079006 | Urguhart | Jan 1992 | A |
| 5110441 | Kinlen et al. | May 1992 | A |
| 5160885 | Hannam et al. | Nov 1992 | A |
| 5167626 | Casper | Dec 1992 | A |
| 5176626 | Soehendra | Jan 1993 | A |
| 5187723 | Mueller | Feb 1993 | A |
| 5213738 | Hampton et al. | May 1993 | A |
| 5218343 | Stobbe et al. | Jun 1993 | A |
| 5261402 | DiSabito | Nov 1993 | A |
| 5263481 | Axelgaard et al. | Nov 1993 | A |
| 5273066 | Graham | Dec 1993 | A |
| 5279607 | Schentag et al. | Jan 1994 | A |
| 5281287 | Lloyd | Jan 1994 | A |
| 5283136 | Peled et al. | Feb 1994 | A |
| 5288564 | Klein | Feb 1994 | A |
| 5305745 | Zacouto | Apr 1994 | A |
| 5310301 | Aono | May 1994 | A |
| 5318557 | Gross | Jun 1994 | A |
| 5331953 | Andersson et al. | Jul 1994 | A |
| 5394882 | Mawhinney | Mar 1995 | A |
| 5395366 | D'Andrea et al. | Mar 1995 | A |
| 5436091 | Shackle et al. | Jul 1995 | A |
| 5443461 | Atkinson et al. | Aug 1995 | A |
| 5443843 | Curatolo et al. | Aug 1995 | A |
| 5458141 | Neil et al. | Oct 1995 | A |
| 5458994 | Nesselbeck et al. | Oct 1995 | A |
| 5485841 | Watkin et al. | Jan 1996 | A |
| 5506248 | Nikfar et al. | Apr 1996 | A |
| 5551020 | Flax et al. | Aug 1996 | A |
| 5567210 | Bates et al. | Oct 1996 | A |
| 5596302 | Mastrocola et al. | Jan 1997 | A |
| 5600548 | Nguyen et al. | Feb 1997 | A |
| 5603363 | Nelson | Feb 1997 | A |
| 5634468 | Platt | Jun 1997 | A |
| 5645063 | Straka et al. | Jul 1997 | A |
| 5659247 | Clements | Aug 1997 | A |
| 5703463 | Smith | Dec 1997 | A |
| 5705189 | Lehmann et al. | Jan 1998 | A |
| 5724432 | Bouvet et al. | Mar 1998 | A |
| 5738708 | Peachey et al. | Apr 1998 | A |
| 5740811 | Hedberg | Apr 1998 | A |
| 5757326 | Koyama et al. | May 1998 | A |
| 5772575 | Lesinski et al. | Jun 1998 | A |
| 5792048 | Schaefer | Aug 1998 | A |
| 5802467 | Salazar | Sep 1998 | A |
| 5833716 | Bar-Or | Nov 1998 | A |
| 5842324 | Grosskopf et al. | Dec 1998 | A |
| 5845265 | Woolston | Dec 1998 | A |
| 5862803 | Besson | Jan 1999 | A |
| 5868136 | Fox | Feb 1999 | A |
| 5914132 | Kelm et al. | Jun 1999 | A |
| 5914701 | Gersheneld et al. | Jun 1999 | A |
| 5925030 | Gross et al. | Jul 1999 | A |
| 5957854 | Besson et al. | Sep 1999 | A |
| 5963132 | Yoakum et al. | Oct 1999 | A |
| 5974124 | Schlueter, Jr. et al. | Oct 1999 | A |
| 5981166 | Mandecki | Nov 1999 | A |
| 5999846 | Pardey et al. | Dec 1999 | A |
| 6018229 | Mitchell et al. | Jan 2000 | A |
| 6038464 | Axelgaard et al. | Mar 2000 | A |
| 6042710 | Dubrow | Mar 2000 | A |
| 6047203 | Sackner | Apr 2000 | A |
| 6068465 | Wilson | May 2000 | A |
| 6068589 | Neukermans | May 2000 | A |
| 6076016 | Feierbach et al. | Jun 2000 | A |
| 6081734 | Batz | Jun 2000 | A |
| 6091975 | Daddona et al. | Jul 2000 | A |
| 6095985 | Raymond et al. | Aug 2000 | A |
| 6115636 | Ryan | Sep 2000 | A |
| 6122351 | Schlueter, Jr. et al. | Sep 2000 | A |
| 6141592 | Pauly | Oct 2000 | A |
| 6149940 | Maggi et al. | Nov 2000 | A |
| 6200265 | Walsh et al. | Mar 2001 | B1 |
| 6206702 | Hayden et al. | Mar 2001 | B1 |
| 6217744 | Crosby | Apr 2001 | B1 |
| 6231593 | Meserol | May 2001 | B1 |
| 6245057 | Sieben et al. | Jun 2001 | B1 |
| 6269058 | Yamanoi et al. | Jul 2001 | B1 |
| 6285897 | Kilcoyne et al. | Sep 2001 | B1 |
| 6287252 | Lugo | Sep 2001 | B1 |
| 6288629 | Cofino et al. | Sep 2001 | B1 |
| 6289238 | Besson et al. | Sep 2001 | B1 |
| 6315719 | Rode et al. | Nov 2001 | B1 |
| 6317714 | Del Castillo | Nov 2001 | B1 |
| 6342774 | Kreisinger et al. | Jan 2002 | B1 |
| 6344824 | Takasugi et al. | Feb 2002 | B1 |
| 6358202 | Arent | Mar 2002 | B1 |
| 6364834 | Reuss | Apr 2002 | B1 |
| 6366206 | Ishikawa et al. | Apr 2002 | B1 |
| 6371927 | Brune | Apr 2002 | B1 |
| 6374670 | Spelman | Apr 2002 | B1 |
| 6380858 | Yarin et al. | Apr 2002 | B1 |
| 6390088 | Nohl et al. | May 2002 | B1 |
| 6394997 | Lemelson | May 2002 | B1 |
| 6426863 | Munshi | Jul 2002 | B1 |
| 6432292 | Pinto et al. | Aug 2002 | B1 |
| 6440069 | Raymond et al. | Aug 2002 | B1 |
| 6441747 | Khair | Aug 2002 | B1 |
| 6453199 | Kobozev | Sep 2002 | B1 |
| 6477424 | Thompson et al. | Nov 2002 | B1 |
| 6496705 | Ng et al. | Dec 2002 | B1 |
| 6526315 | Inagawa | Feb 2003 | B1 |
| 6531026 | Takeichi et al. | Mar 2003 | B1 |
| 6544174 | West | Apr 2003 | B2 |
| 6547994 | Monkhouse et al. | Apr 2003 | B1 |
| 6564079 | Cory | May 2003 | B1 |
| 6567685 | Takamori et al. | May 2003 | B2 |
| 6572636 | Hagen et al. | Jun 2003 | B1 |
| 6577893 | Besson et al. | Jun 2003 | B1 |
| 6579231 | Phipps | Jun 2003 | B1 |
| 6595929 | Stivoric | Jul 2003 | B2 |
| 6599284 | Faour et al. | Jul 2003 | B2 |
| 6602518 | Seielstad et al. | Aug 2003 | B2 |
| 6605038 | Teller | Aug 2003 | B1 |
| 6609018 | Cory | Aug 2003 | B2 |
| 6612984 | Kerr | Sep 2003 | B1 |
| 6632175 | Marshall | Oct 2003 | B1 |
| 6632216 | Houzego et al. | Oct 2003 | B2 |
| 6635279 | Kolter et al. | Oct 2003 | B2 |
| 6643541 | Mok et al. | Nov 2003 | B2 |
| 6654638 | Sweeney | Nov 2003 | B1 |
| 6663846 | McCombs | Dec 2003 | B1 |
| 6673474 | Yamamoto | Jan 2004 | B2 |
| 6680923 | Leon | Jan 2004 | B1 |
| 6689117 | Sweeney et al. | Feb 2004 | B2 |
| 6694161 | Mehrotra | Feb 2004 | B2 |
| 6704602 | Berg et al. | Mar 2004 | B2 |
| 6720923 | Hayward et al. | Apr 2004 | B1 |
| 6738671 | Christophersom et al. | May 2004 | B2 |
| 6739455 | Yamamoto et al. | May 2004 | B2 |
| 6740033 | Olejniczak et al. | May 2004 | B1 |
| 6741731 | Yamamoto et al. | May 2004 | B1 |
| 6745082 | Axelgaard et al. | Jun 2004 | B2 |
| 6755783 | Cosentino | Jun 2004 | B2 |
| 6757523 | Fry | Jun 2004 | B2 |
| 6759968 | Zierolf | Jul 2004 | B2 |
| 6767200 | Sowden et al. | Jul 2004 | B2 |
| 6773429 | Sheppard et al. | Aug 2004 | B2 |
| 6800060 | Marshall | Oct 2004 | B2 |
| 6801137 | Eggers et al. | Oct 2004 | B2 |
| 6816794 | Alvi | Nov 2004 | B2 |
| 6822554 | Vrijens et al. | Nov 2004 | B2 |
| 6824512 | Warkentin et al. | Nov 2004 | B2 |
| 6836862 | Erekson et al. | Dec 2004 | B1 |
| 6839659 | Tarassenko et al. | Jan 2005 | B2 |
| 6840904 | Goldberg | Jan 2005 | B2 |
| 6842636 | Perrault | Jan 2005 | B2 |
| 6845272 | Thomsen | Jan 2005 | B1 |
| 6864780 | Doi | Mar 2005 | B2 |
| 6879810 | Bouet | Apr 2005 | B2 |
| 6888337 | Sawyers | May 2005 | B2 |
| 6889165 | Lind et al. | May 2005 | B2 |
| 6909878 | Haller | Jun 2005 | B2 |
| 6922592 | Thompson et al. | Jul 2005 | B2 |
| 6928370 | Anuzis et al. | Aug 2005 | B2 |
| 6929636 | Von Alten | Aug 2005 | B1 |
| 6937150 | Medema | Aug 2005 | B2 |
| 6942616 | Kerr | Sep 2005 | B2 |
| 6942770 | Cai et al. | Sep 2005 | B2 |
| 6946156 | Bunick | Sep 2005 | B2 |
| 6951536 | Yokoi | Oct 2005 | B2 |
| 6957107 | Rogers et al. | Oct 2005 | B2 |
| 6958603 | Kondo | Oct 2005 | B2 |
| 6960617 | Omidian et al. | Nov 2005 | B2 |
| 6968153 | Heinonen | Nov 2005 | B1 |
| 6977511 | Patel et al. | Dec 2005 | B2 |
| 6982094 | Sowden | Jan 2006 | B2 |
| 6987965 | Ng et al. | Jan 2006 | B2 |
| 6990082 | Zehavi et al. | Jan 2006 | B1 |
| 7002476 | Rapchak | Feb 2006 | B2 |
| 7004395 | Koenck | Feb 2006 | B2 |
| 7009634 | Iddan et al. | Mar 2006 | B2 |
| 7009946 | Kardach | Mar 2006 | B1 |
| 7013162 | Gorsuch | Mar 2006 | B2 |
| 7016648 | Haller | Mar 2006 | B2 |
| 7020508 | Stivoric | Mar 2006 | B2 |
| 7024248 | Penner et al. | Apr 2006 | B2 |
| 7031745 | Shen | Apr 2006 | B2 |
| 7031857 | Tarassenko et al. | Apr 2006 | B2 |
| 7039453 | Mullick | May 2006 | B2 |
| 7044911 | Drinan et al. | May 2006 | B2 |
| 7046649 | Awater et al. | May 2006 | B2 |
| 7061236 | Britton | Jun 2006 | B2 |
| 7083578 | Lewkowicz | Aug 2006 | B2 |
| 7116252 | Teraguchi | Oct 2006 | B2 |
| 7118531 | Krill | Oct 2006 | B2 |
| 7122143 | Sowden et al. | Oct 2006 | B2 |
| 7127300 | Mazar et al. | Oct 2006 | B2 |
| 7146228 | Nielsen | Dec 2006 | B2 |
| 7146449 | Do et al. | Dec 2006 | B2 |
| 7149581 | Goedeke et al. | Dec 2006 | B2 |
| 7154071 | Sattler et al. | Dec 2006 | B2 |
| 7155232 | Godfrey et al. | Dec 2006 | B2 |
| 7160258 | Imran | Jan 2007 | B2 |
| 7164942 | Avrahami | Jan 2007 | B2 |
| 7171166 | Ng et al. | Jan 2007 | B2 |
| 7171177 | Park et al. | Jan 2007 | B2 |
| 7171259 | Rytky | Jan 2007 | B2 |
| 7176784 | Gilbert et al. | Feb 2007 | B2 |
| 7187960 | Abreu | Mar 2007 | B2 |
| 7188199 | Leung et al. | Mar 2007 | B2 |
| 7188767 | Penuela | Mar 2007 | B2 |
| 7194038 | Inkinen | Mar 2007 | B1 |
| 7196495 | Burcham | Mar 2007 | B1 |
| 7206630 | Tarler | Apr 2007 | B1 |
| 7209790 | Thompson et al. | Apr 2007 | B2 |
| 7215660 | Perlman | May 2007 | B2 |
| 7215991 | Besson | May 2007 | B2 |
| 7218967 | Bergelson | May 2007 | B2 |
| 7231451 | Law | Jun 2007 | B2 |
| 7243118 | Lou | Jul 2007 | B2 |
| 7246521 | Kim | Jul 2007 | B2 |
| 7249212 | Do | Jul 2007 | B2 |
| 7252792 | Perrault | Aug 2007 | B2 |
| 7253716 | Lovoi et al. | Aug 2007 | B2 |
| 7261690 | Teller | Aug 2007 | B2 |
| 7270633 | Goscha | Sep 2007 | B1 |
| 7273454 | Raymond et al. | Sep 2007 | B2 |
| 7289855 | Nghiem | Oct 2007 | B2 |
| 7291497 | Holmes | Nov 2007 | B2 |
| 7292139 | Mazar et al. | Nov 2007 | B2 |
| 7294105 | Islam | Nov 2007 | B1 |
| 7311665 | Hawthorne | Dec 2007 | B2 |
| 7313163 | Liu | Dec 2007 | B2 |
| 7317378 | Jarvis et al. | Jan 2008 | B2 |
| 7318808 | Tarassenko et al. | Jan 2008 | B2 |
| 7336929 | Yasuda | Feb 2008 | B2 |
| 7342895 | Serpa | Mar 2008 | B2 |
| 7346380 | Axelgaard et al. | Mar 2008 | B2 |
| 7349722 | Witkowski et al. | Mar 2008 | B2 |
| 7352998 | Palin | Apr 2008 | B2 |
| 7353258 | Washburn | Apr 2008 | B2 |
| 7357891 | Yang et al. | Apr 2008 | B2 |
| 7359674 | Markki | Apr 2008 | B2 |
| 7366558 | Virtanen et al. | Apr 2008 | B2 |
| 7368190 | Heller et al. | May 2008 | B2 |
| 7368191 | Andelman et al. | May 2008 | B2 |
| 7373196 | Ryu et al. | May 2008 | B2 |
| 7375739 | Robbins | May 2008 | B2 |
| 7376435 | McGowan | May 2008 | B2 |
| 7382247 | Welch et al. | Jun 2008 | B2 |
| 7382263 | Danowski et al. | Jun 2008 | B2 |
| 7387607 | Holt | Jun 2008 | B2 |
| 7388903 | Godfrey et al. | Jun 2008 | B2 |
| 7389088 | Kim | Jun 2008 | B2 |
| 7392015 | Farlow | Jun 2008 | B1 |
| 7395106 | Ryu et al. | Jul 2008 | B2 |
| 7396330 | Banet | Jul 2008 | B2 |
| 7404968 | Abrams et al. | Jul 2008 | B2 |
| 7413544 | Kerr | Aug 2008 | B2 |
| 7414534 | Kroll et al. | Aug 2008 | B1 |
| 7414543 | Rye et al. | Aug 2008 | B2 |
| 7415242 | Ngan | Aug 2008 | B1 |
| 7424268 | Diener | Sep 2008 | B2 |
| 7424319 | Muehlsteff | Sep 2008 | B2 |
| 7427266 | Ayer et al. | Sep 2008 | B2 |
| 7442164 | Berrang et al. | Oct 2008 | B2 |
| 7443290 | Takiguchi | Oct 2008 | B2 |
| 7458887 | Kurosawa | Dec 2008 | B2 |
| 7469838 | Brooks et al. | Dec 2008 | B2 |
| 7471665 | Perlman | Dec 2008 | B2 |
| 7471992 | Schmidt et al. | Dec 2008 | B2 |
| 7492128 | Shen | Feb 2009 | B2 |
| 7499674 | Salokannel | Mar 2009 | B2 |
| 7510121 | Koenck | Mar 2009 | B2 |
| 7512448 | Malick | Mar 2009 | B2 |
| 7515043 | Welch | Apr 2009 | B2 |
| 7519416 | Sula et al. | Apr 2009 | B2 |
| 7523756 | Minai | Apr 2009 | B2 |
| 7525426 | Edelstein | Apr 2009 | B2 |
| 7527807 | Choi et al. | May 2009 | B2 |
| 7537590 | Santini, Jr. et al. | May 2009 | B2 |
| 7539533 | Tran | May 2009 | B2 |
| 7542878 | Nanikashvili | Jun 2009 | B2 |
| 7547278 | Miyazaki et al. | Jun 2009 | B2 |
| 7551590 | Haller | Jun 2009 | B2 |
| 7554452 | Cole | Jun 2009 | B2 |
| 7558620 | Ishibashi | Jul 2009 | B2 |
| 7575005 | Mumford | Aug 2009 | B2 |
| 7616111 | Covannon | Nov 2009 | B2 |
| 7617001 | Penner et al. | Nov 2009 | B2 |
| 7626387 | Adachi | Dec 2009 | B2 |
| 7639473 | Hsu et al. | Dec 2009 | B2 |
| 7640802 | King et al. | Jan 2010 | B2 |
| 7645262 | Greenberg et al. | Jan 2010 | B2 |
| 7647090 | Frisch et al. | Jan 2010 | B1 |
| 7647112 | Tracey | Jan 2010 | B2 |
| 7647185 | Tarassenko et al. | Jan 2010 | B2 |
| 7653031 | Godfrey et al. | Jan 2010 | B2 |
| 7672714 | Kuo | Mar 2010 | B2 |
| 7673679 | Harrison et al. | Mar 2010 | B2 |
| 7678043 | Gilad | Mar 2010 | B2 |
| 7686839 | Parker | Mar 2010 | B2 |
| 7697994 | VanDanacker et al. | Apr 2010 | B2 |
| 7720036 | Sadri | May 2010 | B2 |
| 7729776 | Von Arx et al. | Jun 2010 | B2 |
| 7733224 | Tran | Jun 2010 | B2 |
| 7736318 | Costentino | Jun 2010 | B2 |
| 7756587 | Penner et al. | Jul 2010 | B2 |
| 7760104 | Asp | Jul 2010 | B2 |
| 7782991 | Sobchak et al. | Aug 2010 | B2 |
| 7796043 | Euliano et al. | Sep 2010 | B2 |
| 7797033 | D'Andrea et al. | Sep 2010 | B2 |
| 7809399 | Lu | Oct 2010 | B2 |
| 7844341 | Von Arx et al. | Nov 2010 | B2 |
| 7881799 | Greenberg et al. | Feb 2011 | B2 |
| 7975587 | Schneider | Jul 2011 | B2 |
| 7978064 | Zdeblick et al. | Jul 2011 | B2 |
| 7983189 | Bugenhagen | Jul 2011 | B2 |
| 8036731 | Kimchy et al. | Oct 2011 | B2 |
| 8036748 | Zdeblick et al. | Oct 2011 | B2 |
| 8054047 | Chen et al. | Nov 2011 | B2 |
| 8054140 | Fleming et al. | Nov 2011 | B2 |
| 8055334 | Savage et al. | Nov 2011 | B2 |
| 8082919 | Brunnberg et al. | Dec 2011 | B2 |
| 8119045 | Schmidt et al. | Feb 2012 | B2 |
| 8131376 | Faraji et al. | Mar 2012 | B1 |
| 8177611 | Kang | May 2012 | B2 |
| 8185191 | Shapiro et al. | May 2012 | B1 |
| 8185646 | Headley | May 2012 | B2 |
| 8200320 | Kovacs | Jun 2012 | B2 |
| 8207731 | Moskalenko | Jun 2012 | B2 |
| 8224596 | Agrawal et al. | Jul 2012 | B2 |
| 8253586 | Matak | Aug 2012 | B1 |
| 8254853 | Rofougaran | Aug 2012 | B2 |
| 8271146 | Heber et al. | Sep 2012 | B2 |
| 8298574 | Tsabari et al. | Oct 2012 | B2 |
| 8343068 | Najafi et al. | Jan 2013 | B2 |
| 8374698 | Ok et al. | Feb 2013 | B2 |
| 8389003 | Mintchev et al. | Mar 2013 | B2 |
| 8404275 | Habboushe | Mar 2013 | B2 |
| 8425492 | Herbert et al. | Apr 2013 | B2 |
| 8443214 | Lee et al. | May 2013 | B2 |
| 8454528 | Yuen et al. | Jun 2013 | B2 |
| 8532776 | Greenberg et al. | Sep 2013 | B2 |
| 8540664 | Robertson et al. | Sep 2013 | B2 |
| 8547248 | Zdeblick et al. | Oct 2013 | B2 |
| 8558563 | Zdeblick | Oct 2013 | B2 |
| 8564432 | Covannon et al. | Oct 2013 | B2 |
| 8597186 | Hafezi et al. | Dec 2013 | B2 |
| 8634838 | Hellwig et al. | Jan 2014 | B2 |
| 8660645 | Stevenson et al. | Feb 2014 | B2 |
| 8666687 | Kaneko | Mar 2014 | B2 |
| 8668643 | Kinast | Mar 2014 | B2 |
| 8685451 | Toneguzzo et al. | Apr 2014 | B2 |
| 8698006 | Bealka et al. | Apr 2014 | B2 |
| 8758237 | Sherman et al. | Jun 2014 | B2 |
| 8784308 | Duck et al. | Jul 2014 | B2 |
| 8802183 | Frank et al. | Aug 2014 | B2 |
| 8816847 | Zdeblick et al. | Aug 2014 | B2 |
| 8836513 | Hafezi et al. | Sep 2014 | B2 |
| 8838217 | Myr | Sep 2014 | B2 |
| 8858432 | Robertson | Oct 2014 | B2 |
| 8908943 | Berry et al. | Dec 2014 | B2 |
| 8912908 | Berkman et al. | Dec 2014 | B2 |
| 8926509 | Magar et al. | Jan 2015 | B2 |
| 8932221 | Colliou et al. | Jan 2015 | B2 |
| 8945005 | Hafezi et al. | Feb 2015 | B2 |
| 8951234 | Hafezi et al. | Feb 2015 | B2 |
| 8989837 | Weinstein et al. | Mar 2015 | B2 |
| 9031658 | Chiao et al. | May 2015 | B2 |
| 9088168 | Mach et al. | Jul 2015 | B2 |
| 9107806 | Hafezi et al. | Aug 2015 | B2 |
| 9119918 | Robertson et al. | Sep 2015 | B2 |
| 9158890 | Meredith et al. | Oct 2015 | B2 |
| 9189941 | Eschelman et al. | Nov 2015 | B2 |
| 9226663 | Fei | Jan 2016 | B2 |
| 9226679 | Balda | Jan 2016 | B2 |
| 9268909 | Jani et al. | Feb 2016 | B2 |
| 9270025 | Robertson et al. | Feb 2016 | B2 |
| 9271897 | Costello et al. | Mar 2016 | B2 |
| 9277864 | Yang et al. | Mar 2016 | B2 |
| 9415010 | Hafezi et al. | Aug 2016 | B2 |
| 9433371 | Hafezi et al. | Sep 2016 | B2 |
| 9439599 | Thompson et al. | Sep 2016 | B2 |
| 9517012 | Lane et al. | Dec 2016 | B2 |
| 9599679 | Taylor et al. | Mar 2017 | B2 |
| 9649066 | Zdeblick et al. | May 2017 | B2 |
| 9681842 | Zdeblick et al. | Jun 2017 | B2 |
| 9741975 | Laulicht et al. | Aug 2017 | B2 |
| 9756874 | Arne et al. | Sep 2017 | B2 |
| 9968284 | Vidalis et al. | May 2018 | B2 |
| 10441194 | Robertson et al. | Oct 2019 | B2 |
| 10517506 | Robertson et al. | Dec 2019 | B2 |
| 10797758 | Shirvani et al. | Oct 2020 | B2 |
| 20010027331 | Thompson | Oct 2001 | A1 |
| 20010044588 | Mault | Nov 2001 | A1 |
| 20010051766 | Gazdinski | Dec 2001 | A1 |
| 20020002326 | Causey et al. | Jan 2002 | A1 |
| 20020026111 | Ackerman | Feb 2002 | A1 |
| 20020032384 | Raymond et al. | Mar 2002 | A1 |
| 20020032385 | Raymond et al. | Mar 2002 | A1 |
| 20020040278 | Anuzis et al. | Apr 2002 | A1 |
| 20020077620 | Sweeney et al. | Jun 2002 | A1 |
| 20020099423 | Berg et al. | Jul 2002 | A1 |
| 20020103425 | Mault | Aug 2002 | A1 |
| 20020128934 | Shaer | Sep 2002 | A1 |
| 20020132226 | Nair | Sep 2002 | A1 |
| 20020136744 | McGlynn | Sep 2002 | A1 |
| 20020161354 | Christiansen et al. | Oct 2002 | A1 |
| 20020179921 | Cohn | Dec 2002 | A1 |
| 20020192159 | Reitberg | Dec 2002 | A1 |
| 20020193669 | Glukhovsky | Dec 2002 | A1 |
| 20020198470 | Imran et al. | Dec 2002 | A1 |
| 20030015672 | Gallagher | Jan 2003 | A1 |
| 20030017826 | Fishman et al. | Jan 2003 | A1 |
| 20030023150 | Yokoi et al. | Jan 2003 | A1 |
| 20030028226 | Thompson | Feb 2003 | A1 |
| 20030040685 | Lewkowicz | Feb 2003 | A1 |
| 20030062551 | Chen et al. | Apr 2003 | A1 |
| 20030065536 | Hansen | Apr 2003 | A1 |
| 20030076179 | Branch et al. | Apr 2003 | A1 |
| 20030083559 | Thompson | May 2003 | A1 |
| 20030091625 | Hariharan et al. | May 2003 | A1 |
| 20030126593 | Mault | Jul 2003 | A1 |
| 20030130714 | Nielsen et al. | Jul 2003 | A1 |
| 20030135128 | Suffin et al. | Jul 2003 | A1 |
| 20030135392 | Vrijens et al. | Jul 2003 | A1 |
| 20030152622 | Louie-Helm et al. | Aug 2003 | A1 |
| 20030158466 | Lynn et al. | Aug 2003 | A1 |
| 20030158756 | Abramson | Aug 2003 | A1 |
| 20030162556 | Libes | Aug 2003 | A1 |
| 20030164401 | Andreasson et al. | Sep 2003 | A1 |
| 20030167000 | Mullick et al. | Sep 2003 | A1 |
| 20030171791 | KenKnight | Sep 2003 | A1 |
| 20030171898 | Tarassenko et al. | Sep 2003 | A1 |
| 20030181788 | Yokoi et al. | Sep 2003 | A1 |
| 20030185286 | Yuen | Oct 2003 | A1 |
| 20030187337 | Tarassenko et al. | Oct 2003 | A1 |
| 20030187338 | Say et al. | Oct 2003 | A1 |
| 20030195403 | Berner et al. | Oct 2003 | A1 |
| 20030213495 | Fujita et al. | Nov 2003 | A1 |
| 20030214579 | Iddan | Nov 2003 | A1 |
| 20030216622 | Meron et al. | Nov 2003 | A1 |
| 20030216625 | Phipps | Nov 2003 | A1 |
| 20030216666 | Ericson et al. | Nov 2003 | A1 |
| 20030216729 | Marchitto | Nov 2003 | A1 |
| 20030219484 | Sowden et al. | Nov 2003 | A1 |
| 20030232895 | Omidian et al. | Dec 2003 | A1 |
| 20040008123 | Carrender et al. | Jan 2004 | A1 |
| 20040018476 | LaDue | Jan 2004 | A1 |
| 20040034295 | Salganicoff | Feb 2004 | A1 |
| 20040049245 | Gass | Mar 2004 | A1 |
| 20040073095 | Causey et al. | Apr 2004 | A1 |
| 20040073454 | Urquhart et al. | Apr 2004 | A1 |
| 20040077995 | Ferek-Petric | Apr 2004 | A1 |
| 20040082982 | Gord et al. | Apr 2004 | A1 |
| 20040087839 | Raymond et al. | May 2004 | A1 |
| 20040092801 | Drakulic | May 2004 | A1 |
| 20040106859 | Say et al. | Jun 2004 | A1 |
| 20040115507 | Potter et al. | Jun 2004 | A1 |
| 20040115517 | Fukada et al. | Jun 2004 | A1 |
| 20040117062 | Bonney et al. | Jun 2004 | A1 |
| 20040121015 | Chidlaw et al. | Jun 2004 | A1 |
| 20040148140 | Tarassenko et al. | Jul 2004 | A1 |
| 20040153007 | Harris | Aug 2004 | A1 |
| 20040167226 | Serafini | Aug 2004 | A1 |
| 20040167465 | Mihai et al. | Aug 2004 | A1 |
| 20040167801 | Say et al. | Aug 2004 | A1 |
| 20040193020 | Chiba | Sep 2004 | A1 |
| 20040193029 | Gluhovsky | Sep 2004 | A1 |
| 20040193446 | Mayer et al. | Sep 2004 | A1 |
| 20040199222 | Sun et al. | Oct 2004 | A1 |
| 20040215084 | Shimizu et al. | Oct 2004 | A1 |
| 20040218683 | Batra | Nov 2004 | A1 |
| 20040220643 | Schmidt | Nov 2004 | A1 |
| 20040224644 | Wu | Nov 2004 | A1 |
| 20040225199 | Evanyk | Nov 2004 | A1 |
| 20040253304 | Gross et al. | Dec 2004 | A1 |
| 20040258571 | Lee et al. | Dec 2004 | A1 |
| 20040259899 | Sanghvi et al. | Dec 2004 | A1 |
| 20040260154 | Sidelnik | Dec 2004 | A1 |
| 20050003074 | Brown et al. | Jan 2005 | A1 |
| 20050017841 | Doi | Jan 2005 | A1 |
| 20050020887 | Goldberg | Jan 2005 | A1 |
| 20050021370 | Riff | Jan 2005 | A1 |
| 20050024198 | Ward | Feb 2005 | A1 |
| 20050027205 | Tarassenko et al. | Feb 2005 | A1 |
| 20050038321 | Fujita et al. | Feb 2005 | A1 |
| 20050043634 | Yokoi et al. | Feb 2005 | A1 |
| 20050043894 | Fernandez | Feb 2005 | A1 |
| 20050054897 | Hashimoto et al. | Mar 2005 | A1 |
| 20050055014 | Coppeta et al. | Mar 2005 | A1 |
| 20050062644 | Leci | Mar 2005 | A1 |
| 20050063906 | Kraizer | Mar 2005 | A1 |
| 20050065407 | Nakamura et al. | Mar 2005 | A1 |
| 20050070778 | Lackey | Mar 2005 | A1 |
| 20050075145 | Dvorak et al. | Apr 2005 | A1 |
| 20050090753 | Goor et al. | Apr 2005 | A1 |
| 20050092108 | Andermo | May 2005 | A1 |
| 20050096514 | Starkebaum | May 2005 | A1 |
| 20050096562 | Delalic et al. | May 2005 | A1 |
| 20050101843 | Quinn | May 2005 | A1 |
| 20050101872 | Sattler | May 2005 | A1 |
| 20050115561 | Stahmann et al. | Jun 2005 | A1 |
| 20050116820 | Goldreich | Jun 2005 | A1 |
| 20050117389 | Worledge | Jun 2005 | A1 |
| 20050121322 | Say et al. | Jun 2005 | A1 |
| 20050131281 | Ayer et al. | Jun 2005 | A1 |
| 20050143623 | Kojima | Jun 2005 | A1 |
| 20050146594 | Nakatani et al. | Jul 2005 | A1 |
| 20050148883 | Boesen | Jul 2005 | A1 |
| 20050154428 | Bruinsma | Jul 2005 | A1 |
| 20050156709 | Gilbert et al. | Jul 2005 | A1 |
| 20050165323 | Montgomery | Jul 2005 | A1 |
| 20050177069 | Takizawa | Aug 2005 | A1 |
| 20050182389 | LaPorte | Aug 2005 | A1 |
| 20050187789 | Hatlestad et al. | Aug 2005 | A1 |
| 20050192489 | Marshall | Sep 2005 | A1 |
| 20050197680 | Delmain et al. | Sep 2005 | A1 |
| 20050208251 | Aisenbrey | Sep 2005 | A1 |
| 20050228268 | Cole | Oct 2005 | A1 |
| 20050234307 | Heinonen | Oct 2005 | A1 |
| 20050240305 | Bogash et al. | Oct 2005 | A1 |
| 20050245794 | Dinsmoor | Nov 2005 | A1 |
| 20050259768 | Yang et al. | Nov 2005 | A1 |
| 20050261559 | Mumford | Nov 2005 | A1 |
| 20050267556 | Shuros et al. | Dec 2005 | A1 |
| 20050267756 | Schultz et al. | Dec 2005 | A1 |
| 20050277912 | John | Dec 2005 | A1 |
| 20050277999 | Strother et al. | Dec 2005 | A1 |
| 20050279054 | Mauze et al. | Dec 2005 | A1 |
| 20050280539 | Pettus | Dec 2005 | A1 |
| 20050285746 | Sengupta | Dec 2005 | A1 |
| 20050288594 | Lewkowicz et al. | Dec 2005 | A1 |
| 20060001496 | Abrosimov et al. | Jan 2006 | A1 |
| 20060028727 | Moon et al. | Feb 2006 | A1 |
| 20060036134 | Tarassenko et al. | Feb 2006 | A1 |
| 20060058602 | Kwiatkowski et al. | Mar 2006 | A1 |
| 20060061472 | Lovoi et al. | Mar 2006 | A1 |
| 20060065713 | Kingery | Mar 2006 | A1 |
| 20060068006 | Begleiter | Mar 2006 | A1 |
| 20060073204 | Goyal | Apr 2006 | A1 |
| 20060074283 | Henderson | Apr 2006 | A1 |
| 20060074319 | Barnes et al. | Apr 2006 | A1 |
| 20060078765 | Yang et al. | Apr 2006 | A1 |
| 20060095091 | Drew | May 2006 | A1 |
| 20060095093 | Bettesh et al. | May 2006 | A1 |
| 20060100533 | Han | May 2006 | A1 |
| 20060109058 | Keating | May 2006 | A1 |
| 20060110962 | Powell | May 2006 | A1 |
| 20060111777 | Chen | May 2006 | A1 |
| 20060122474 | Teller et al. | Jun 2006 | A1 |
| 20060122494 | Bouchoucha | Jun 2006 | A1 |
| 20060122667 | Chavan et al. | Jun 2006 | A1 |
| 20060129060 | Lee et al. | Jun 2006 | A1 |
| 20060136266 | Tarassenko et al. | Jun 2006 | A1 |
| 20060142648 | Banet | Jun 2006 | A1 |
| 20060145876 | Kimura | Jul 2006 | A1 |
| 20060148254 | McLean | Jul 2006 | A1 |
| 20060149339 | Burnes | Jul 2006 | A1 |
| 20060155174 | Glukhovsky et al. | Jul 2006 | A1 |
| 20060155183 | Kroecker | Jul 2006 | A1 |
| 20060161225 | Sormann et al. | Jul 2006 | A1 |
| 20060179949 | Kim | Aug 2006 | A1 |
| 20060183993 | Horn | Aug 2006 | A1 |
| 20060184092 | Atanasoska et al. | Aug 2006 | A1 |
| 20060204738 | Dubrow et al. | Sep 2006 | A1 |
| 20060210626 | Spaeder | Sep 2006 | A1 |
| 20060212096 | Stevenson | Sep 2006 | A1 |
| 20060216603 | Choi | Sep 2006 | A1 |
| 20060218011 | Walker | Sep 2006 | A1 |
| 20060235489 | Drew | Oct 2006 | A1 |
| 20060243288 | Kim et al. | Nov 2006 | A1 |
| 20060247505 | Siddiqui | Nov 2006 | A1 |
| 20060253005 | Drinan | Nov 2006 | A1 |
| 20060270346 | Ibrahim | Nov 2006 | A1 |
| 20060273882 | Posamentier | Dec 2006 | A1 |
| 20060276702 | McGinnis | Dec 2006 | A1 |
| 20060280227 | Pinkney | Dec 2006 | A1 |
| 20060282001 | Noel | Dec 2006 | A1 |
| 20060289640 | Mercure | Dec 2006 | A1 |
| 20060293607 | Alt | Dec 2006 | A1 |
| 20070000776 | Karube et al. | Jan 2007 | A1 |
| 20070002038 | Suzuki | Jan 2007 | A1 |
| 20070006636 | King et al. | Jan 2007 | A1 |
| 20070008113 | Spoonhower et al. | Jan 2007 | A1 |
| 20070016089 | Fischell et al. | Jan 2007 | A1 |
| 20070025739 | Moore et al. | Feb 2007 | A1 |
| 20070027386 | Such | Feb 2007 | A1 |
| 20070027388 | Chou | Feb 2007 | A1 |
| 20070029195 | Li et al. | Feb 2007 | A1 |
| 20070038054 | Zhou | Feb 2007 | A1 |
| 20070049339 | Barak et al. | Mar 2007 | A1 |
| 20070055098 | Shimizu et al. | Mar 2007 | A1 |
| 20070060797 | Ball | Mar 2007 | A1 |
| 20070060800 | Drinan et al. | Mar 2007 | A1 |
| 20070066929 | Ferren et al. | Mar 2007 | A1 |
| 20070073353 | Rooney et al. | Mar 2007 | A1 |
| 20070096765 | Kagan | May 2007 | A1 |
| 20070106346 | Bergelson | May 2007 | A1 |
| 20070114140 | Portier | May 2007 | A1 |
| 20070123772 | Euliano | May 2007 | A1 |
| 20070129622 | Bourget | Jun 2007 | A1 |
| 20070130287 | Kumar | Jun 2007 | A1 |
| 20070135803 | Belson | Jun 2007 | A1 |
| 20070142721 | Berner et al. | Jun 2007 | A1 |
| 20070156016 | Betesh | Jul 2007 | A1 |
| 20070160789 | Merical | Jul 2007 | A1 |
| 20070162089 | Mosesov | Jul 2007 | A1 |
| 20070162090 | Penner | Jul 2007 | A1 |
| 20070167495 | Brown et al. | Jul 2007 | A1 |
| 20070167848 | Kuo et al. | Jul 2007 | A1 |
| 20070173701 | Al-Ali | Jul 2007 | A1 |
| 20070179347 | Tarassenko et al. | Aug 2007 | A1 |
| 20070179371 | Peyser et al. | Aug 2007 | A1 |
| 20070185393 | Zhou | Aug 2007 | A1 |
| 20070191002 | Ge | Aug 2007 | A1 |
| 20070196456 | Stevens | Aug 2007 | A1 |
| 20070207793 | Myer | Sep 2007 | A1 |
| 20070208233 | Kovacs | Sep 2007 | A1 |
| 20070213659 | Trovato et al. | Sep 2007 | A1 |
| 20070237719 | Jones | Oct 2007 | A1 |
| 20070244370 | Kuo et al. | Oct 2007 | A1 |
| 20070255198 | Leong et al. | Nov 2007 | A1 |
| 20070255330 | Lee | Nov 2007 | A1 |
| 20070270672 | Hayter | Nov 2007 | A1 |
| 20070279217 | Venkatraman | Dec 2007 | A1 |
| 20070282174 | Sabatino | Dec 2007 | A1 |
| 20070282177 | Pilz | Dec 2007 | A1 |
| 20070299480 | Hill | Dec 2007 | A1 |
| 20080000804 | Carey et al. | Jan 2008 | A1 |
| 20080014866 | Lipowshi | Jan 2008 | A1 |
| 20080020037 | Robertson et al. | Jan 2008 | A1 |
| 20080021519 | DeGeest | Jan 2008 | A1 |
| 20080021521 | Shah | Jan 2008 | A1 |
| 20080027679 | Shklarski | Jan 2008 | A1 |
| 20080033273 | Zhou | Feb 2008 | A1 |
| 20080038588 | Lee | Feb 2008 | A1 |
| 20080039700 | Drinan et al. | Feb 2008 | A1 |
| 20080045843 | Tsuji et al. | Feb 2008 | A1 |
| 20080046038 | Hill | Feb 2008 | A1 |
| 20080051647 | Wu et al. | Feb 2008 | A1 |
| 20080051667 | Goldreich | Feb 2008 | A1 |
| 20080058614 | Banet | Mar 2008 | A1 |
| 20080062856 | Feher | Mar 2008 | A1 |
| 20080063703 | Gross et al. | Mar 2008 | A1 |
| 20080065168 | Bitton et al. | Mar 2008 | A1 |
| 20080074307 | Boric-Lubecke | Mar 2008 | A1 |
| 20080077015 | Botic-Lubecke | Mar 2008 | A1 |
| 20080077028 | Schaldach et al. | Mar 2008 | A1 |
| 20080077188 | Denker et al. | Mar 2008 | A1 |
| 20080091089 | Guillory et al. | Apr 2008 | A1 |
| 20080091114 | Min | Apr 2008 | A1 |
| 20080097549 | Colbaugh | Apr 2008 | A1 |
| 20080097917 | Dicks | Apr 2008 | A1 |
| 20080103440 | Ferren et al. | May 2008 | A1 |
| 20080112885 | Okunev et al. | May 2008 | A1 |
| 20080114224 | Bandy et al. | May 2008 | A1 |
| 20080117968 | Wang | May 2008 | A1 |
| 20080119705 | Patel | May 2008 | A1 |
| 20080119716 | Boric-Lubecke | May 2008 | A1 |
| 20080121825 | Trovato et al. | May 2008 | A1 |
| 20080137566 | Marholev | Jun 2008 | A1 |
| 20080139907 | Rao et al. | Jun 2008 | A1 |
| 20080140403 | Hughes et al. | Jun 2008 | A1 |
| 20080146871 | Arneson et al. | Jun 2008 | A1 |
| 20080146889 | Young | Jun 2008 | A1 |
| 20080146892 | LeBoeuf | Jun 2008 | A1 |
| 20080154104 | Lamego | Jun 2008 | A1 |
| 20080166992 | Ricordi | Jul 2008 | A1 |
| 20080175898 | Jones et al. | Jul 2008 | A1 |
| 20080183245 | Van Oort | Jul 2008 | A1 |
| 20080188837 | Belsky et al. | Aug 2008 | A1 |
| 20080194912 | Trovato et al. | Aug 2008 | A1 |
| 20080208009 | Shklarski | Aug 2008 | A1 |
| 20080214901 | Gehman | Sep 2008 | A1 |
| 20080214985 | Yanaki | Sep 2008 | A1 |
| 20080240325 | Agazzi et al. | Oct 2008 | A1 |
| 20080243020 | Chou | Oct 2008 | A1 |
| 20080249360 | Li | Oct 2008 | A1 |
| 20080262320 | Schaefer et al. | Oct 2008 | A1 |
| 20080262336 | Ryu | Oct 2008 | A1 |
| 20080269664 | Trovato et al. | Oct 2008 | A1 |
| 20080275312 | Mosesov | Nov 2008 | A1 |
| 20080284599 | Zdeblick et al. | Nov 2008 | A1 |
| 20080288027 | Kroll | Nov 2008 | A1 |
| 20080294020 | Sapounas | Nov 2008 | A1 |
| 20080299197 | Toneguzzo et al. | Dec 2008 | A1 |
| 20080300572 | Rankers | Dec 2008 | A1 |
| 20080303638 | Nguyen | Dec 2008 | A1 |
| 20080306357 | Korman | Dec 2008 | A1 |
| 20080306359 | Zdeblick et al. | Dec 2008 | A1 |
| 20080306360 | Robertson et al. | Dec 2008 | A1 |
| 20080311852 | Hansen | Dec 2008 | A1 |
| 20080312522 | Rowlandson | Dec 2008 | A1 |
| 20080316020 | Robertson | Dec 2008 | A1 |
| 20090009330 | Sakama et al. | Jan 2009 | A1 |
| 20090009332 | Nunez et al. | Jan 2009 | A1 |
| 20090010321 | Chalopin et al. | Jan 2009 | A1 |
| 20090024045 | Prakash | Jan 2009 | A1 |
| 20090024112 | Edwards et al. | Jan 2009 | A1 |
| 20090030293 | Cooper et al. | Jan 2009 | A1 |
| 20090030297 | Miller | Jan 2009 | A1 |
| 20090034209 | Joo | Feb 2009 | A1 |
| 20090043171 | Rule | Feb 2009 | A1 |
| 20090047357 | Tomohira et al. | Feb 2009 | A1 |
| 20090048498 | Riskey | Feb 2009 | A1 |
| 20090062634 | Say et al. | Mar 2009 | A1 |
| 20090062670 | Sterling | Mar 2009 | A1 |
| 20090062730 | Woo | Mar 2009 | A1 |
| 20090069642 | Gao | Mar 2009 | A1 |
| 20090069655 | Say et al. | Mar 2009 | A1 |
| 20090069656 | Say et al. | Mar 2009 | A1 |
| 20090069657 | Say et al. | Mar 2009 | A1 |
| 20090069658 | Say et al. | Mar 2009 | A1 |
| 20090069724 | Otto et al. | Mar 2009 | A1 |
| 20090076343 | James | Mar 2009 | A1 |
| 20090076350 | Bly et al. | Mar 2009 | A1 |
| 20090082645 | Hafezi et al. | Mar 2009 | A1 |
| 20090087483 | Sison | Apr 2009 | A1 |
| 20090088618 | Ameson | Apr 2009 | A1 |
| 20090099435 | Say et al. | Apr 2009 | A1 |
| 20090105561 | Boydon et al. | Apr 2009 | A1 |
| 20090110148 | Zhang | Apr 2009 | A1 |
| 20090112626 | Talbot | Apr 2009 | A1 |
| 20090124871 | Arshak | May 2009 | A1 |
| 20090124965 | Greenberg et al. | May 2009 | A1 |
| 20090131774 | Sweitzer | May 2009 | A1 |
| 20090135886 | Robertson et al. | May 2009 | A1 |
| 20090142853 | Warrington et al. | Jun 2009 | A1 |
| 20090149839 | Hyde et al. | Jun 2009 | A1 |
| 20090157113 | Marcotte | Jun 2009 | A1 |
| 20090157358 | Kim | Jun 2009 | A1 |
| 20090161602 | Matsumoto | Jun 2009 | A1 |
| 20090163789 | Say et al. | Jun 2009 | A1 |
| 20090171180 | Pering | Jul 2009 | A1 |
| 20090171420 | Brown et al. | Jul 2009 | A1 |
| 20090173628 | Say et al. | Jul 2009 | A1 |
| 20090177055 | Say et al. | Jul 2009 | A1 |
| 20090177056 | Say et al. | Jul 2009 | A1 |
| 20090177057 | Say et al. | Jul 2009 | A1 |
| 20090177058 | Say et al. | Jul 2009 | A1 |
| 20090177059 | Say et al. | Jul 2009 | A1 |
| 20090177060 | Say et al. | Jul 2009 | A1 |
| 20090177061 | Say et al. | Jul 2009 | A1 |
| 20090177062 | Say et al. | Jul 2009 | A1 |
| 20090177063 | Say et al. | Jul 2009 | A1 |
| 20090177064 | Say et al. | Jul 2009 | A1 |
| 20090177065 | Say et al. | Jul 2009 | A1 |
| 20090177066 | Say et al. | Jul 2009 | A1 |
| 20090182206 | Najafi | Jul 2009 | A1 |
| 20090182207 | Riskey et al. | Jul 2009 | A1 |
| 20090182212 | Say et al. | Jul 2009 | A1 |
| 20090182213 | Say et al. | Jul 2009 | A1 |
| 20090182214 | Say et al. | Jul 2009 | A1 |
| 20090182215 | Say et al. | Jul 2009 | A1 |
| 20090182388 | Von Arx | Jul 2009 | A1 |
| 20090187088 | Say et al. | Jul 2009 | A1 |
| 20090187089 | Say et al. | Jul 2009 | A1 |
| 20090187090 | Say et al. | Jul 2009 | A1 |
| 20090187091 | Say et al. | Jul 2009 | A1 |
| 20090187092 | Say et al. | Jul 2009 | A1 |
| 20090187093 | Say et al. | Jul 2009 | A1 |
| 20090187094 | Say et al. | Jul 2009 | A1 |
| 20090187095 | Say et al. | Jul 2009 | A1 |
| 20090187381 | King et al. | Jul 2009 | A1 |
| 20090192351 | Nishino | Jul 2009 | A1 |
| 20090192368 | Say et al. | Jul 2009 | A1 |
| 20090192369 | Say et al. | Jul 2009 | A1 |
| 20090192370 | Say et al. | Jul 2009 | A1 |
| 20090192371 | Say et al. | Jul 2009 | A1 |
| 20090192372 | Say et al. | Jul 2009 | A1 |
| 20090192373 | Say et al. | Jul 2009 | A1 |
| 20090192374 | Say et al. | Jul 2009 | A1 |
| 20090192375 | Say et al. | Jul 2009 | A1 |
| 20090192376 | Say et al. | Jul 2009 | A1 |
| 20090192377 | Say et al. | Jul 2009 | A1 |
| 20090192378 | Say et al. | Jul 2009 | A1 |
| 20090192379 | Say et al. | Jul 2009 | A1 |
| 20090194747 | Zou et al. | Aug 2009 | A1 |
| 20090197068 | Yamaguchi et al. | Aug 2009 | A1 |
| 20090198115 | Say et al. | Aug 2009 | A1 |
| 20090198116 | Say et al. | Aug 2009 | A1 |
| 20090198175 | Say et al. | Aug 2009 | A1 |
| 20090203964 | Shimizu et al. | Aug 2009 | A1 |
| 20090203971 | Sciarappa | Aug 2009 | A1 |
| 20090203972 | Heneghan | Aug 2009 | A1 |
| 20090203978 | Say et al. | Aug 2009 | A1 |
| 20090204265 | Hackett | Aug 2009 | A1 |
| 20090210164 | Say et al. | Aug 2009 | A1 |
| 20090216101 | Say et al. | Aug 2009 | A1 |
| 20090216102 | Say et al. | Aug 2009 | A1 |
| 20090227204 | Robertson et al. | Sep 2009 | A1 |
| 20090227876 | Tran | Sep 2009 | A1 |
| 20090227940 | Say et al. | Sep 2009 | A1 |
| 20090227941 | Say et al. | Sep 2009 | A1 |
| 20090227988 | Wood et al. | Sep 2009 | A1 |
| 20090228214 | Say et al. | Sep 2009 | A1 |
| 20090231125 | Baldus | Sep 2009 | A1 |
| 20090234200 | Husheer | Sep 2009 | A1 |
| 20090243833 | Huang | Oct 2009 | A1 |
| 20090253960 | Takenaka et al. | Oct 2009 | A1 |
| 20090256702 | Robertson | Oct 2009 | A1 |
| 20090260212 | Schmett et al. | Oct 2009 | A1 |
| 20090264714 | Chou | Oct 2009 | A1 |
| 20090264964 | Abrahamson | Oct 2009 | A1 |
| 20090265186 | Tarassenko et al. | Oct 2009 | A1 |
| 20090273467 | Elixmann | Nov 2009 | A1 |
| 20090281539 | Selig | Nov 2009 | A1 |
| 20090287109 | Ferren et al. | Nov 2009 | A1 |
| 20090295548 | Ronkka | Dec 2009 | A1 |
| 20090296677 | Mahany | Dec 2009 | A1 |
| 20090303920 | Mahany | Dec 2009 | A1 |
| 20090306633 | Trovato et al. | Dec 2009 | A1 |
| 20090312619 | Say et al. | Dec 2009 | A1 |
| 20090318303 | Delamarche et al. | Dec 2009 | A1 |
| 20090318761 | Rabinovitz | Dec 2009 | A1 |
| 20090318779 | Tran | Dec 2009 | A1 |
| 20090318783 | Rohde | Dec 2009 | A1 |
| 20090318793 | Datta | Dec 2009 | A1 |
| 20100001841 | Cardullo | Jan 2010 | A1 |
| 20100010330 | Rankers | Jan 2010 | A1 |
| 20100019848 | Rossi | Jan 2010 | A1 |
| 20100033324 | Shimizu et al. | Feb 2010 | A1 |
| 20100036269 | Ferren et al. | Feb 2010 | A1 |
| 20100049004 | Edman et al. | Feb 2010 | A1 |
| 20100049006 | Magar | Feb 2010 | A1 |
| 20100049012 | Dijksman et al. | Feb 2010 | A1 |
| 20100049069 | Tarassenko et al. | Feb 2010 | A1 |
| 20100056878 | Partin | Mar 2010 | A1 |
| 20100056891 | Say et al. | Mar 2010 | A1 |
| 20100056939 | Tarassenko et al. | Mar 2010 | A1 |
| 20100057041 | Hayter | Mar 2010 | A1 |
| 20100062709 | Kato | Mar 2010 | A1 |
| 20100063438 | Bengtsson | Mar 2010 | A1 |
| 20100063841 | D'Ambrosia et al. | Mar 2010 | A1 |
| 20100069002 | Rong | Mar 2010 | A1 |
| 20100069717 | Hafezi et al. | Mar 2010 | A1 |
| 20100099967 | Say et al. | Apr 2010 | A1 |
| 20100099968 | Say et al. | Apr 2010 | A1 |
| 20100099969 | Say et al. | Apr 2010 | A1 |
| 20100100077 | Rush | Apr 2010 | A1 |
| 20100100078 | Say et al. | Apr 2010 | A1 |
| 20100106001 | Say et al. | Apr 2010 | A1 |
| 20100118853 | Godfrey | May 2010 | A1 |
| 20100130837 | Matott | May 2010 | A1 |
| 20100139672 | Kroll et al. | Jun 2010 | A1 |
| 20100168659 | Say et al. | Jul 2010 | A1 |
| 20100179398 | Say et al. | Jul 2010 | A1 |
| 20100191073 | Tarassenko et al. | Jul 2010 | A1 |
| 20100210299 | Gorbachov | Aug 2010 | A1 |
| 20100222652 | Cho | Sep 2010 | A1 |
| 20100228113 | Solosko | Sep 2010 | A1 |
| 20100233026 | Ismagliov et al. | Sep 2010 | A1 |
| 20100234706 | Gilland | Sep 2010 | A1 |
| 20100234715 | Shin | Sep 2010 | A1 |
| 20100234914 | Shen | Sep 2010 | A1 |
| 20100245091 | Singh | Sep 2010 | A1 |
| 20100249541 | Geva et al. | Sep 2010 | A1 |
| 20100249881 | Corndorf | Sep 2010 | A1 |
| 20100256461 | Mohamedali | Oct 2010 | A1 |
| 20100259543 | Tarassenko et al. | Oct 2010 | A1 |
| 20100268048 | Say et al. | Oct 2010 | A1 |
| 20100268049 | Say et al. | Oct 2010 | A1 |
| 20100268050 | Say et al. | Oct 2010 | A1 |
| 20100274111 | Say et al. | Oct 2010 | A1 |
| 20100280345 | Say et al. | Nov 2010 | A1 |
| 20100280346 | Say et al. | Nov 2010 | A1 |
| 20100295694 | Kauffman et al. | Nov 2010 | A1 |
| 20100297640 | Kumar et al. | Nov 2010 | A1 |
| 20100298650 | Moon et al. | Nov 2010 | A1 |
| 20100298668 | Hafezi et al. | Nov 2010 | A1 |
| 20100298730 | Tarassenko et al. | Nov 2010 | A1 |
| 20100312188 | Robertson et al. | Dec 2010 | A1 |
| 20100312580 | Tarassenko et al. | Dec 2010 | A1 |
| 20110009715 | O'Reilly et al. | Jan 2011 | A1 |
| 20110054265 | Hafezi | Mar 2011 | A1 |
| 20110065983 | Hafezi et al. | Mar 2011 | A1 |
| 20110077660 | Janik et al. | Mar 2011 | A1 |
| 20110082356 | Yang et al. | Apr 2011 | A1 |
| 20110105864 | Robertson et al. | May 2011 | A1 |
| 20110124983 | Kroll et al. | May 2011 | A1 |
| 20110134906 | Garudadri et al. | Jun 2011 | A1 |
| 20110160549 | Saroka et al. | Jun 2011 | A1 |
| 20110224912 | Bhavaraju et al. | Sep 2011 | A1 |
| 20110230732 | Edman et al. | Sep 2011 | A1 |
| 20110243483 | Crump et al. | Oct 2011 | A1 |
| 20110270135 | Dooley et al. | Nov 2011 | A1 |
| 20120004520 | Whitworth et al. | Jan 2012 | A1 |
| 20120011699 | Hafezi et al. | Jan 2012 | A1 |
| 20120016005 | Samarsky | Jan 2012 | A1 |
| 20120016231 | Westmoreland | Jan 2012 | A1 |
| 20120032816 | Cho et al. | Feb 2012 | A1 |
| 20120059257 | Duck et al. | Mar 2012 | A1 |
| 20120062371 | Radivojevic et al. | Mar 2012 | A1 |
| 20120071743 | Todorov et al. | Mar 2012 | A1 |
| 20120109112 | Strand et al. | May 2012 | A1 |
| 20120179004 | Roesicke et al. | Jul 2012 | A1 |
| 20120189589 | Van Epps | Jul 2012 | A1 |
| 20120191123 | Brister | Jul 2012 | A1 |
| 20120244221 | Dill | Sep 2012 | A1 |
| 20120245043 | England | Sep 2012 | A1 |
| 20120276451 | Lestriez et al. | Nov 2012 | A1 |
| 20120299723 | Hafezi et al. | Nov 2012 | A1 |
| 20130030366 | Robertson et al. | Jan 2013 | A1 |
| 20130129869 | Hafezi et al. | May 2013 | A1 |
| 20130129872 | Kruger | May 2013 | A1 |
| 20130131283 | Wang et al. | May 2013 | A1 |
| 20130144132 | Hafezi et al. | Jun 2013 | A1 |
| 20130171596 | French | Jul 2013 | A1 |
| 20130172690 | Arne et al. | Jul 2013 | A1 |
| 20130185228 | Dresner | Jul 2013 | A1 |
| 20130196012 | Dill | Aug 2013 | A1 |
| 20130199662 | Gebbink | Aug 2013 | A1 |
| 20130209877 | Kren et al. | Aug 2013 | A1 |
| 20130223028 | Arne et al. | Aug 2013 | A1 |
| 20130244002 | Sanofi | Sep 2013 | A1 |
| 20130275296 | Tietzen et al. | Oct 2013 | A1 |
| 20130328416 | Whitworth et al. | Dec 2013 | A1 |
| 20140009262 | Robertson et al. | Jan 2014 | A1 |
| 20140066734 | Zdeblick | Mar 2014 | A1 |
| 20140179221 | Whitworth et al. | Jun 2014 | A1 |
| 20140180202 | Zdeblick et al. | Jun 2014 | A1 |
| 20140280125 | Bhardwaj et al. | Sep 2014 | A1 |
| 20140308930 | Tran | Oct 2014 | A1 |
| 20140349256 | Connor | Nov 2014 | A1 |
| 20140374276 | Guthrie et al. | Dec 2014 | A1 |
| 20150017486 | Lai | Jan 2015 | A1 |
| 20150059922 | Thompson et al. | Mar 2015 | A1 |
| 20150080677 | Thompson et al. | Mar 2015 | A1 |
| 20150080678 | Frank et al. | Mar 2015 | A1 |
| 20150080679 | Frank et al. | Mar 2015 | A1 |
| 20150080680 | Zdeblick et al. | Mar 2015 | A1 |
| 20150080681 | Hafezi et al. | Mar 2015 | A1 |
| 20150112243 | Hafezi et al. | Apr 2015 | A1 |
| 20150127737 | Thompson et al. | May 2015 | A1 |
| 20150127738 | Thompson et al. | May 2015 | A1 |
| 20150149375 | Thompson et al. | May 2015 | A1 |
| 20150150480 | Zdeblick et al. | Jun 2015 | A1 |
| 20150164746 | Costello et al. | Jun 2015 | A1 |
| 20150173646 | Berkman et al. | Jun 2015 | A1 |
| 20150223751 | Zdeblick et al. | Aug 2015 | A1 |
| 20150230729 | Zdeblick et al. | Aug 2015 | A1 |
| 20150248833 | Arne et al. | Sep 2015 | A1 |
| 20150352343 | Hafezi et al. | Dec 2015 | A1 |
| 20160033667 | Schmidt et al. | Feb 2016 | A1 |
| 20160345906 | Johnson et al. | Dec 2016 | A1 |
| 20160380708 | Dua et al. | Dec 2016 | A1 |
| 20170000179 | Cheng et al. | Jan 2017 | A1 |
| 20170014046 | Hafezi et al. | Jan 2017 | A1 |
| 20170020182 | Schmidt et al. | Jan 2017 | A1 |
| 20170216569 | Hafezi et al. | Aug 2017 | A1 |
| 20170265813 | Zdeblick et al. | Sep 2017 | A1 |
| 20170274194 | Robertson et al. | Sep 2017 | A1 |
| 20170296799 | Hafezi et al. | Oct 2017 | A1 |
| 20180026680 | Shirvani et al. | Jan 2018 | A1 |
| 20180110441 | Frank et al. | Apr 2018 | A1 |
| 20180184698 | Arne et al. | Jul 2018 | A1 |
| 20180214048 | Zdeblick et al. | Aug 2018 | A1 |
| 20180229996 | Thompson | Aug 2018 | A1 |
| 20190191006 | Thompson et al. | Jun 2019 | A1 |
| Number | Date | Country |
|---|---|---|
| 1588649 | Mar 2005 | CN |
| 1650844 | Aug 2005 | CN |
| 101287411 | Oct 2008 | CN |
| 101795202 | Aug 2010 | CN |
| 10313005 | Oct 2004 | DE |
| 102005007576 | Aug 2006 | DE |
| 0344939 | Dec 1989 | EP |
| 0526166 | Feb 1993 | EP |
| 0981152 | Feb 2000 | EP |
| 1246356 | Oct 2002 | EP |
| 1534054 | May 2005 | EP |
| 1702553 | Sep 2006 | EP |
| 1244308 | Dec 2007 | EP |
| 2143369 | Jan 2010 | EP |
| 827762 | Feb 1960 | GB |
| 2419110 | Apr 2006 | GB |
| 61072712 | Apr 1986 | JP |
| H01285247 | Nov 1989 | JP |
| 05-228128 | Sep 1993 | JP |
| H11195415 | Jul 1999 | JP |
| 2000-506410 | May 2000 | JP |
| 2002263185 | Sep 2002 | JP |
| 2002282219 | Oct 2002 | JP |
| 2003050867 | Feb 2003 | JP |
| 2004-313242 | Nov 2004 | JP |
| 2005-073886 | Mar 2005 | JP |
| 2005-087552 | Apr 2005 | JP |
| 2005-304880 | Apr 2005 | JP |
| 2005102959 | Apr 2005 | JP |
| 2005124708 | May 2005 | JP |
| 2005514966 | May 2005 | JP |
| 2005343515 | Dec 2005 | JP |
| 20055332328 | Dec 2005 | JP |
| 2006006377 | Jan 2006 | JP |
| 2006509574 | Mar 2006 | JP |
| 2007200739 | Aug 2007 | JP |
| 2007-313340 | Dec 2007 | JP |
| 2009514870 | Apr 2009 | JP |
| 2009528909 | Aug 2009 | JP |
| 2006077523 | Jul 2006 | KR |
| 200406192 | May 2004 | TW |
| 200916136 | Apr 2009 | TW |
| 201231091 | Aug 2012 | TW |
| WO1988002237 | Apr 1988 | WO |
| WO1992021307 | Dec 1992 | WO |
| WO1993008734 | May 1993 | WO |
| WO1993019667 | Oct 1993 | WO |
| WO1994001165 | Jan 1994 | WO |
| WO1997039963 | Oct 1997 | WO |
| WO1998043537 | Oct 1998 | WO |
| WO1999037290 | Jul 1999 | WO |
| WO1999059465 | Nov 1999 | WO |
| WO2000032474 | Jun 2000 | WO |
| WO2000033246 | Jun 2000 | WO |
| WO2001047466 | Jul 2001 | WO |
| WO2001058236 | Aug 2001 | WO |
| WO2001074011 | Oct 2001 | WO |
| WO2001080731 | Nov 2001 | WO |
| WO2002000920 | Jan 2002 | WO |
| WO2002045489 | Jun 2002 | WO |
| WO2002058330 | Jul 2002 | WO |
| WO2002062276 | Aug 2002 | WO |
| WO2002087681 | Nov 2002 | WO |
| WO2002095351 | Nov 2002 | WO |
| WO2003005877 | Jan 2003 | WO |
| WO2003050643 | Jun 2003 | WO |
| WO2003068061 | Aug 2003 | WO |
| WO2004014225 | Feb 2004 | WO |
| WO2004019172 | Mar 2004 | WO |
| WO2004039256 | May 2004 | WO |
| WO2004066833 | Aug 2004 | WO |
| WO2004066834 | Aug 2004 | WO |
| WO2004066903 | Aug 2004 | WO |
| WO2004068881 | Aug 2004 | WO |
| WO2004075032 | Sep 2004 | WO |
| WO2004109316 | Dec 2004 | WO |
| WO2005011237 | Feb 2005 | WO |
| WO2005020023 | Mar 2005 | WO |
| WO2005024687 | Mar 2005 | WO |
| WO2005041438 | May 2005 | WO |
| WO2005047837 | May 2005 | WO |
| WO2005051166 | Jun 2005 | WO |
| WO2005053517 | Jun 2005 | WO |
| WO2005083621 | Sep 2005 | WO |
| 2005105053 | Nov 2005 | WO |
| WO2005110238 | Nov 2005 | WO |
| WO2005123569 | Dec 2005 | WO |
| WO2006021932 | Mar 2006 | WO |
| WO2006027586 | Mar 2006 | WO |
| WO2006028347 | Mar 2006 | WO |
| WO2006055892 | May 2006 | WO |
| WO2006055956 | May 2006 | WO |
| WO2006075016 | Jul 2006 | WO |
| 2006087288 | Aug 2006 | WO |
| WO2006100620 | Sep 2006 | WO |
| WO2006104843 | Oct 2006 | WO |
| WO2006116718 | Nov 2006 | WO |
| WO2006127355 | Nov 2006 | WO |
| WO2007001724 | Jan 2007 | WO |
| WO2007001742 | Jan 2007 | WO |
| WO2007013952 | Feb 2007 | WO |
| WO2007014084 | Feb 2007 | WO |
| WO2007014527 | Feb 2007 | WO |
| WO2007021496 | Feb 2007 | WO |
| WO2007027660 | Mar 2007 | WO |
| WO2007028035 | Mar 2007 | WO |
| WO2007036687 | Apr 2007 | WO |
| WO2007036741 | Apr 2007 | WO |
| WO2007036746 | Apr 2007 | WO |
| WO2007040878 | Apr 2007 | WO |
| WO2007067054 | Jun 2007 | WO |
| WO2007071180 | Jun 2007 | WO |
| WO2007096810 | Aug 2007 | WO |
| WO2007101141 | Sep 2007 | WO |
| WO2007115087 | Oct 2007 | WO |
| WO2007120946 | Oct 2007 | WO |
| WO2007127316 | Nov 2007 | WO |
| WO2007127879 | Nov 2007 | WO |
| WO2007128165 | Nov 2007 | WO |
| WO2007130491 | Nov 2007 | WO |
| WO2007143535 | Dec 2007 | WO |
| WO2007149546 | Dec 2007 | WO |
| WO2008008281 | Jan 2008 | WO |
| WO2008012700 | Jan 2008 | WO |
| WO2008030482 | Mar 2008 | WO |
| WO2008052136 | May 2008 | WO |
| WO2008063626 | May 2008 | WO |
| WO2008066617 | Jun 2008 | WO |
| WO2008076464 | Jun 2008 | WO |
| WO2008089232 | Jul 2008 | WO |
| WO2008091683 | Jul 2008 | WO |
| WO2008095183 | Aug 2008 | WO |
| WO2008097652 | Aug 2008 | WO |
| WO2008101107 | Aug 2008 | WO |
| WO2008112577 | Sep 2008 | WO |
| WO2008112578 | Sep 2008 | WO |
| WO2008120156 | Oct 2008 | WO |
| WO2008133394 | Nov 2008 | WO |
| WO2008134185 | Nov 2008 | WO |
| WO2008150633 | Dec 2008 | WO |
| WO2009000447 | Dec 2008 | WO |
| WO2009001108 | Dec 2008 | WO |
| WO2009006615 | Jan 2009 | WO |
| WO2009029453 | Mar 2009 | WO |
| WO2009031149 | Mar 2009 | WO |
| WO2009036334 | Mar 2009 | WO |
| WO2009051829 | Apr 2009 | WO |
| WO2009051830 | Apr 2009 | WO |
| WO2009063377 | May 2009 | WO |
| WO2009081348 | Jul 2009 | WO |
| 2009106952 | Sep 2009 | WO |
| WO2009111664 | Sep 2009 | WO |
| WO2009146082 | Dec 2009 | WO |
| WO2001000085 | Jan 2010 | WO |
| WO2010009100 | Jan 2010 | WO |
| WO2010011833 | Jan 2010 | WO |
| WO2010019778 | Feb 2010 | WO |
| WO2010057049 | May 2010 | WO |
| WO2010080765 | Jul 2010 | WO |
| WO2010080843 | Jul 2010 | WO |
| WO2010107563 | Sep 2010 | WO |
| WO2010129288 | Nov 2010 | WO |
| WO2010132331 | Nov 2010 | WO |
| WO2010135516 | Nov 2010 | WO |
| WO2011068963 | Jun 2011 | WO |
| WO2011133799 | Oct 2011 | WO |
| WO2011159336 | Dec 2011 | WO |
| WO2011159337 | Dec 2011 | WO |
| WO2011159338 | Dec 2011 | WO |
| WO2011159339 | Dec 2011 | WO |
| WO2012112561 | Aug 2012 | WO |
| WO2015112603 | Jul 2015 | WO |
| WO2015112604 | Jul 2015 | WO |
| 2018018034 | Jan 2018 | WO |
| Entry |
|---|
| Wang, X. et al “Resistance to Tracking and Erosion of Silicone Rubber Material under Various Types of Precipitation”, Jpn. J. Appl. Phys. vol. 38 (1999) pp. 5170-5175. |
| International Search Report for PCT/US2014/013382, dated May 26, 2014 (3 pages). |
| AADE, “AADE 37th Annual Meeting San Antonio Aug. 4-7, 2010” American Association of Diabetes Educators (2010); http://www.diabeteseducator.org/annualmeeting/2010/index.html; 2 pp. |
| Arshak et al., A Review and Adaptation of Methods of Object Tracking to Telemetry Capsules IC-Med (2007) vol. 1, No. 1, Issue 1, 12pp. |
| “ASGE Technology Status Evaluation Report: wireless capsule endoscopy” American Soc. For Gastrointestinal Endoscopy (2006) vol. 63, No. 4; 7 pp. |
| Aydin et al., “Design and implementation considerations for an advanced wireless interface in miniaturized integrated sensor Microsystems” Sch. of Eng. & Electron., Edinburgh Univ., UK; (2003); abstract. |
| Barrie, Heidelberg pH capsule gastric analysis. Texbook of Natural Medicine, (1992), Pizzorno, Murray & Barrie. |
| Bohidar et al., “Dielectric Behavior of Gelatin Solutions and Gels” Colloid Polym Sci (1998) 276:81-86. |
| Brock, “Smart Medicine: The Application of Auto-ID Technology to Healthcare” Auto-ID Labs (2002) http://www.autoidlabs.org/uploads/media/MIT-AUTOID-WH-010.pdf. |
| Carlson et al., “Evaluation of a non-invasive respiratory monitoring system for sleeping subjects” Physiological Measurement (1999) 20(1): 53. |
| Coury, L. “Conductance Measurement Part 1: Theory”; Current Separations, 18:3 (1999) p. 91-96. |
| Delvaux et al., “Capsule endoscopy: Technique and indications” Clinical Gastoenterology (2008) vol. 22, Issue 5, pp. 813-837. |
| Description of ePatch Technology Platform for ECG and EMG, located it http://www.madebydelta.com/imported/images/DELTA_Web/documents/ME/ePatch_ECG_EMG.pdf, Dated Sep. 2, 2010. |
| Dhar et al., “Electroless nickel plated contacts on porous silicon” Appl. Phys. Lett. 68 (10) pp. 1392-1393 (1996). |
| Eldek A., “Design of double dipole antenna with enhanced usable bandwidth for wideband phased array applications” Progress in Electromagnetics Research PIER 59, 1-15 (2006). |
| Fawaz et al., “Enhanced Telemetry System using CP-QPSK Band-Pass Modulation Technique Suitable for Smart Pill Medical Application” IFIP IEEE Dubai Conference (2008); http://www.asic.fh-offenburg.de/downloads/ePille/IFIP_IEEE_Dubai_Conference.pdf. |
| Ferguson et al., “Dielectric Constant Studies III Aqueous Gelatin Solutions” J. Chem. Phys. 2, 94 (1934) p. 94-98. |
| Furse C. M., “Dipole Antennas” J. Webster (ed). Wiley Encyclopedia of Electrical and Electronics Engineering (1999) p. 575-581. |
| Gaglani S. “Put Your Phone, Or Skin, on Vibrate” MedGadget (2012) http://medgadget.com/2012/03/put-your-phone-or-skin-on-vibrate.html 8pp. |
| Gilson, D.R. “Molecular dynamics simulation of dipole interactions”, Department of Physics, Hull University, Dec. 2002, p. 1-43. |
| Given Imaging, “Agile Patency Brochure” (2006) http://www.inclino.no/documents/AgilePatencyBrochure_Global_GMB-0118-01.pdf; 4pp. |
| Gonzalez-Guillaumin et al., “Ingestible capsule for impedance and pH monitoring in the esophagus” IEEE Trans Biomed Eng. (2007) 54(12): 2231-6; abstract. |
| Greene, “Edible RFID microchip monitor can tell if you take your medicine” Bloomberg Businessweek (2010) 2 pp.; http://www.businessweek.com/idg/2010-03-31/edible-rfid-microchip-monitor-can-tell-if-you-take-your-medicine.html. |
| Heydari et al., “Analysis of the PLL jitter due to power/ground and substrate noise”; IEEE Transactions on Circuits and Systems (2004) 51(12): 2404-16. |
| Hoeksma, J. “New ‘smart pill’ to track adherence” E-Health-Insider (2010) http://www.e-health-insider.com/news/5910/new_‘smart_pill’_monitors_medicines. |
| Hoover et al., “Rx for health: Engineers design pill that signals it has been swallowed” University of Florida News (2010) 2pp.; http://news.ufl.edu/2010/03/31/antenna-pill-2/. |
| Intromedic, MicroCam Innovative Capsule Endoscope Pamphlet. (2006) 8 pp (http://www.intromedic.com/en/product/productinfo.asp). |
| ISFET—Ion Sensitive Field-Effect Transistor; MICROSENS S.A. pdf document. First cited by Examiner in Office Action dated Jun. 13, 2011 for U.S. Appl. No. 12/238,345; 4pp. |
| Jung, S. “Dissolvable ‘Transient Electronics’ Will Be Good For Your Body and the Environment” MedGadget; Oct. 1, 2012; Onlne website: http://medgadget.com/2012/10/dissolvable-transient-electronics-will-be-good-for-your-body-and-the-environment.html; downloaded Oct. 24, 2012; 4 pp. |
| Juvenile Diabetes Research Foundation International (JDRF), “Artificial Pancreas Project” (2010); http://www.artificialpancreasproject.com/; 3 pp. |
| Kamada K., “Electrophoretic deposition assisted by soluble anode” Materials Letters 57 (2003) 2348-2351. |
| Kendle, Earl R. and Morris, Larry A., “Preliminary Studies in the Development of a Gastric Battery for Fish” (1964). Nebraska Game and Parks Commission White Papers, Conference Presentations, & Manuscripts. Paper 22. p. 1-6. |
| Kim et al., “A Semi-Interpenetrating Network System for a Polymer Membrane”; Eur. Polym. J. vol. 33 No. 7; pp. 1009-1014 (1997). |
| Li, P-Y, et al. “An electrochemical intraocular drug delivery device”, Sensors and Actuators A 143 (2008) p. 41-48. |
| Lifescan, “OneTouch UltraLink™” http://www.lifescan.com/products/meters/ultralink (2010) 2 pp. |
| Mackay et al., “Radio Telemetering from within the Body Inside Information is Revealed by Tiny Transmitters that can be Swallowed or Implanted in Man or Animal” Science (1991) 1196-1202; 134; American Association for the Advancement of Science, Washington D.C. |
| Mackay et al., “Endoradiosonde” Nature, (1957) 1239-1240, 179 Nature Publishing Group. |
| McKenzie et al., “Validation of a new telemetric core temperature monitor” J. Therm. Biol. (2004) 29(7-8):605-11. |
| Medtronic, “CareLink Therapy Management Software for Diabetes” (2010); https://carelink.minimed.com/patient/entry.jsp?bhcp=1; 1 pp. |
| Medtronic, “Carelink™ USB ” (2008) http://www.medtronicdiabetes.com/pdf/carelink_usb_factsheet.pdf 2pp. |
| Medtronic “The New MiniMed Paradigm® REAL-Time Revel™ System” (2010) http://www.medtronicdiabetes.com/products/index.html; 2 pp. |
| Medtronic, “Mini Med Paradigm® Revel™ Insulin Pump” (2010) http://www.medtronicdiabetes.com/products/insulinpumps/index.html; 2 pp. |
| Medtronic, Mini Med Paradigm™ Veo™ System: Factsheet (2010). http://www.medtronic-diabetes.com.au/downloads/Paradigm%20Veo%20Factsheet.pdf ; 4 pp. |
| Melanson, “Walkers swallow RFID pills for science” Engadget (2008); http://www.engadget.com/2008/07/29/walkers-swallow-rfid-pills-for-science/. |
| Minimitter Co. Inc. “Actiheart” Traditional 510(k) Summary. Sep. 27, 2005. |
| Minimitter Co. Inc. Noninvasive technology to help your studies succeed. Mini Mitter.com Mar. 31, 2009. |
| Mini Mitter Co, Inc. 510(k) Premarket Notification Mini-Logger for Diagnostic Spirometer. Sep. 21, 1999. |
| Mini Mitter Co, Inc. 510(k) Premarket Notification for VitalSense. Apr. 22, 2004. |
| Minimitter Co. Inc. VitalSense Integrated Physiological Monitoring System. Product Description. (2005). |
| Minimitter Co. Inc. VitalSense Wireless Vital Signs Monitoring. Temperatures.com Mar. 31, 2009. |
| Mojaverian et al., “Estimation of gastric residence time of the Heidelberg capsule in humans: effect of varying food composition” Gastroenterology (1985) 89:(2): 392-7. |
| O'Brien et al., “The Production and Characterization of Chemically Reactive Porous Coatings of Zirconium Via Unbalanced Magnetron Sputtering” Surface and Coatings Technology (1996) 86-87; 200-206. |
| Park, “Medtronic to Buy MiniMed for $3.7 Billion” (2001) HomeCare; http://homecaremag.com/mag/medical_medtronic_buy_minimed/; 2 pp. |
| Philips Respironics Products, Noninvasive Technology to Help Your Studies Succeed. 510 (k) Permanent Notification for Vital Sense. Apr. 22, 2004; http/minimitter.com/products.cfm. |
| Radio Antennae, http://www.erikdeman.de/html/sail018h.htm; (2008) 5 pages. |
| “RFID “pill” monitors marchers” RFID News (2008) http://www.rfidnews.org/2008/07/23/rfid-pill-monitors-marchers/. |
| Rolison et al., “Electrically conductive oxide aerogels: new materials in electrochemistry” J. Mater. Chem. (2001) 1, 963-980. |
| Roulstone, et al., “Studies on Polymer Latex Films: I. A study of latex film morphology” Polymer International 24 (1991) pp. 87-94. |
| Sanduleanu et al., “Octave tunable, highly linear, RC-ring oscillator with differential fine-coarse tuning, quadrature outputs and amplitude control for fiber optic transceivers” (2002) IEEE MTT-S International Microwave Symposium Digest 545-8. |
| Santini, J.T. et al, “Microchips as controlled drug delivery-devices”, Agnew. Chem. Int. Ed. (2000), vol. 39, p. 2396-2407. |
| “SensiVida minimally invasive clinical systems” Investor Presentation Oct. 2009 28pp; http://www.sensividamedtech.com/SensiVidaGeneralOctober09.pdf. |
| Shawgo, R.S. et al. “BioMEMS from drug delivery”, Current Opinion in Solid State and Material Science 6 (2002), p. 329-334. |
| Shin et al., “A Simple Route to Metal Nanodots and Nanoporous Metal Films”; Nano Letters, vol. 2, No. 9 (2002) pp. 933-936. |
| Shrivas et al., “A New Platform for Bioelectronics-Electronic Pill”, Cummins College, (2010).; http://www.cumminscollege.org/downloads/electronics_and_telecommunication/Newsletters/Current%20Newsletters.pdf; First cited in third party client search conducted by Patent Eagle Search May 18, 2010 (2010). |
| “Smartlife awarded patent for knitted transducer” Innovation in Textiles News: http://www.innovationintextiles.com/articles/208.php; 2pp. (2009). |
| “The SmartPill Wireless Motility Capsule” Smartpill, The Measure of GI Health; (2010) http://www.smartpillcorp.com/index.cfm?pagepath=Products/The_SmartPill_Capsule&id=17814. |
| Solanas et al., “RFID Technology for the Health Care Sector” Recent Patents on Electrical Engineering (2008) 1, 22-31. |
| Soper, S.A. et al. “Bio-Mems Technologies and Applications”, Chapter 12, “MEMS for Drug Delivery”, p. 325-346 (2007). |
| Swedberg, “University Team Sees Ingestible RFID Tag as a Boon to Clinical Trials” RFID Journal Apr. 27, 2010; http://www.rfidjournal.com/article/view/7560/1 3pp. |
| Tajalli et al., “Improving the power-delay performance in subthreshold source-coupled logic circuits” Integrated Circuit and System Design. Power and Timing Modeling, Optimization and Simulation, Springer Berlin Heidelberg (2008) 21-30. |
| Tatbul et al., “Confidence-based data management for personal area sensor networks” ACM International Conference Proceeding Series (2004) 72. |
| Tierney, M.J. et al “Electroreleasing Composite Membranes for Delivery of Insulin and other Biomacromolecules”, J. Electrochem. Soc., vol. 137, No. 6, Jun. 1990, p. 2005-2006. |
| Trutag Technologies, Inc., Spectral Microtags for Authentication and Anti-Counterfeiting; “Product Authentication and Brand Protection Solutions”; http://www.trutags.com/; downloaded Feb. 12, 2013; 1 pp. |
| Walkey, “MOSFET Structure and Processing”; 97.398* Physical Electronics Lecture 20; 24 pp. |
| Watson, et al., “Determination of the relationship between the pH and conductivity of gastric juice” Physiol Meas. 17 (1996) pp. 21-27. |
| Whipple, Fred L.; “Endoradiosonde,” Nature, Jun. 1957, 1239-1240. |
| Winter, J. et al. “The material properties of gelatin gels”; USA Ballistic Research Laboratories, Mar. 1975, p. 1-157. |
| Wongmanerod et al., “Determination of pore size distribution and surface area of thin porous silicon layers by spectroscopic ellipsometry” Applied Surface Science 172 (2001) 117-125. |
| Xiaoming et al., “A telemedicine system for wireless home healthcare based on bluetooth and the internet” Telemedicine Journal and e-health (2004) 10(S2): S110-6. |
| Yang et al., “Fast-switching frequency synthesizer with a discriminator-aided phase detector” IEEE Journal of Solid-State Circuits (2000) 35(10): 1445-52. |
| Yao et al., “Low Power Digital Communication in Implantable Devices Using Volume Conduction of Biological Tissues” Proceedings of the 28th IEEE, EMBS Annual International Conference, Aug. 30-Sep. 3, 2006. |
| Zimmerman, “Personal Area Networks: Near-field intrabody communication” IBM Systems Journal (1996) 35 (3-4):609-17. |
| Zworkin, “A Radio Pill” Nature, (1957) 898, 179 Nature Publishing Group. |
| Au-Yeung, K., et al., “A Networked System for Self-Management of Drug Therapy and Wellness”, Wireless Health '10, Oct. 5-7, 2010, San Diego, 9 pages. |
| Target Innovations, Tablet Metal Detector, https ://web. arch ive.org/web/20 130215063351/http://www. metaldetectorindia.com/tablet-metal-detector. html, Feb. 15, 2013. |
| TargetPharmaceutical Metal Detector, Feb. 15, 2013 downloaded from Target Innovations, Tablet Metal Detector, Feb. 15, 2013. |
| Youtube video Pharmaceutical Metal Detector/Tablet Metal Detector/ Capsule Metal Detector/ Dry Fruits; https://www.youtube.com/watch?v=I0126txam_s, May 12, 2012. |
| Number | Date | Country | |
|---|---|---|---|
| 20150361234 A1 | Dec 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| 61758030 | Jan 2013 | US |
