Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving oxidoreductase
Reexamination Certificate
1999-12-22
2003-04-01
Leary, Louise N. (Department: 1654)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving oxidoreductase
C435S019000, C435S018000, C435S283100, C435S287100, C435S817000, C435S015000
Reexamination Certificate
active
06541216
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the determination of the concentration of analytes in fluids and more specifically to an amperometric biosensor for use in such determination. Most particularly, this invention relates to an amperometric biosensor used in the determination of 3-hydroxybutyric acid levels in fluids.
BACKGROUND OF THE INVENTION
3-hydroxybutyric acid (hereinafter “3-HBA”) is produced by incomplete fatty acid metabolism in the liver under conditions involving the impaired utilization or inadequate supply of carbohydrates. Whenever increased amounts of fats are metabolized, such as when the carbohydrate intake is restricted, the concentration of ketone bodies such as 3-HBA, acetone, and acetoacetic acid can increase. If ketone bodies are present in the blood in an excessive amount, the condition is termed ketosis.
Diabetes mellitus is a disorder associated with ketosis. Diabetes mellitus is a disorder of glucose metabolism. In insulin-deficient diabetes, glucose metabolism is sufficiently impaired such that fatty acids are utilized to meet the energy requirements of the body. If excessive amounts of fatty acids are metabolized, ketone bodies accumulate in the blood, i.e., ketosis, and are excreted in urine, i.e. ketonuria. In addition, ketone bodies are excreted from the body in combination with normal basic ions, thereby reducing the carbon dioxide combining power of the body and causing systemic acidosis, i.e. increased acidity of the blood. The term ketoacidosis designates the combined ketosis and acidosis conditions associated with diabetes. At elevated levels, 3-HBA is diagnostic of ketoacidosis.
Detecting ketoacidosis in a patient with diabetes mellitus is beneficial in that it often indicates the necessity of a change in insulin dosage or other management procedures. One approach to determine the presence or concentration of ketone bodies in a sample has been to subject the sample to a colorimetric assay. For example, it is well known to determine the presence or concentration of ketone bodies by contacting a liquid sample with an indicator reagent composition that undergoes a color transition upon contact with the sample. See for example, U.S. Pat. Nos. 4,803,158; 5,326,697; 5,510,245; and 5,190,863.
Amperometric assays for ketone bodies have also been used. See for example, PCT/US98/21815, filed Oct. 16, 1998, and Batchelor, et al.,
Amperometric Assay for the Ketone Body Hydroxybutyrate,
Analytic Chimica Acta. 289-294 (1989). These assays utilize enzymes to catalyze the oxidation of 3-HBA, the oxidizable form of a cofactor, and an oxidant such as, for example, a quinone.
SUMMARY OF THE INVENTION
Biosensor and method of the present invention allows the user to test blood ketones in an amperometric meter that is also used to test for glucose. Biosensor test strip of this invention is compatible with commercially available amperometric glucose measuring sensors. The test strip comprises a reagent that is reactive with the sample in a manner effective to generate an electrical output signal indicative of the level of 3-hydroxybutyric acid (hereinafter “3-HBA”) in the sample. The reagent comprises a ferricyanide salt, a catalytic amount of a first enzyme operative to catalyze the oxidation of 3-HBA in the sample, a mediator corresponding to said first enzyme, and a catalytic amount of a second enzyme operative to catalyze the electrochemical oxidation of a reduced form of the cofactor.
The test strip includes at least two electrically conducting tracks insulated from each other. Each of the tracks is adapted to be in electrical contact with the reagent. One of the tracks accepts electron transfer from the reagent, wherein the amount of the electron transfer is indicative of the level of 3-HBA in the sample.
A method is also provided for determining information indicative of the level of 3-HBA in a sample is provided, which is compatible with commercially available amperometric glucose measuring sensors. The method comprises reacting the sample with a reagent comprising a ferricyanide salt, a catalytic amount of a first enzyme operative to catalyze the oxidation of 3-HBA in the sample, a cofactor corresponding to said first enzyme, and a catalytic amount of a second enzyme to catalyze the electrochemical oxidation of a reduced form of the cofactor. The reagent generates an electrical output indicative of the level of 3-HBA in the sample. The electrical output is then measured and the level of 3-HBA in the sample is determined using information comprising the measured electrical output.
Still further, in accordance with the present invention a method for determining information indicative of the level of 3-HBA in a sample is provided. The method comprises the steps of providing a sensor including a working and counter electrodes and a reagent in communication with the electrodes, the reagent comprising a ferricyanide salt, a catalytic amount of a first enzyme operative to catalyze the oxidation of 3-HBA in the fluid sample, a cofactor corresponding to said first enzyme, and a catalytic amount of a second enzyme to catalyze the electrochemical oxidation of a reduced form of the cofactor. The reagent is contacted with the fluid sample and a direct potential difference is applied between the electrodes that is sufficient to generate an electrical output from the reagent indicative of the level of 3-HBA in the fluid sample.
Additional features and advantages of the invention will become apparent to those skilled in the art upon consideration of the following detailed description and preferred embodiments exemplifying the best mode of carrying out the invention as presently perceived.
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Persson, B., “Dete
Burke David W.
Wilsey Christopher Douglas
Leary Louise N.
Roche Diagnostics Corporation
Woodburn Jill L.
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