Chemistry: analytical and immunological testing – Involving diffusion or migration of antigen or antibody
Reexamination Certificate
2000-06-26
2003-03-04
Nguyen, Bao-Thuy L. (Department: 1641)
Chemistry: analytical and immunological testing
Involving diffusion or migration of antigen or antibody
C436S518000, C436S524000, C436S525000, C436S528000, C436S531000, C436S169000, C436S174000, C436S805000, C436S810000, C435S287100, C435S287900, C435S805000, C435S810000, C435S962000, C435S970000, C422S051000, C422S051000, C422S051000, C422S067000
Reexamination Certificate
active
06528321
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention is directed to assay devices for determination of characteristics of samples, unitized housings, kits incorporating the assay devices, and methods of determining the characteristics of samples using the assay devices.
Among the many analytical systems used for detection or determination of analytes, particularly analytes of biological interest, are chromatographic assay systems. Among the analytes frequently assayed with such systems are:
(1) hormones, such as human chorionic gonadotropin (hCG), frequently assayed as a marker of human pregnancy, as well as luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH);
(2) antigens, particularly antigens specific to bacterial, viral, and protozoan pathogens, such as Streptococcus, hepatitis virus, and Giardia;
(3) antibodies, particularly antibodies induced as a result of infection with pathogens, such as antibodies to the bacterium Helicobacter pylory and to human immunodeficiency virus (HIV);
(4) other proteins, such as hemoglobin, frequently assayed in determinations of fecal occult blood, an early indicator of gastrointestinal disorders such as colon cancer;
(5) enzymes, such as aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, and glutamate dehydrogenase, frequently assayed as indicators of physiological function and tissue damage;
(6) drugs, both therapeutic drugs, such as antibiotics, tranquilizers, and anticonvulsants, and illegal drugs of abuse, such as cocaine, heroin, amphetamines, and marijuana; and
(7) vitamins.
Such chromatographic systems are frequently used by physicians and medical technicians for rapid in-office diagnosis or therapeutic monitoring of a variety of conditions and disorders. They are also increasingly used by patients themselves for at-home monitoring of such conditions and disorders.
Among the most important of such systems are the “thin-layer” systems in which a solvent moves across a thin, flat, absorbent medium. Among the most important of tests that can be performed with such thin-layer systems are immunoassays, which depend on the specific interaction between an antigen or hapten and a corresponding antibody or other specific binding partner. The use of immunoassays as a means for testing for the presence or amount of clinically important molecules has been known for some time. As early as 1956, J. M. Singer reported the use of an immune-based latex agglutination test for detecting a factor associated with rheumatoid arthritis (J. M. Singer et al., Am. J. Med., 22:888-892 (1956)).
Among the chromatographic techniques used in conjunction with immunoassays is a procedure known as immunochromatography. In general, this technique uses a disclosing reagent or particle that has been linked to an antibody to the molecule to be assayed, forming a conjugate. This conjugate is then mixed with a specimen and, if the molecule to be assayed is present in the specimen, the disclosing reagent-linked antibodies bind to the molecule to be assayed, thereby giving an indication that the molecule to be assayed is present. The disclosing reagent or particle can be identifiable by color, magnetic properties, radioactivity, enzymatic activity, fluorescence, chemiluminescence, specific reactivity with another molecule, or another physical or chemical property. The specific reactions that are employed vary with the nature of the molecule being assayed and the sample to be tested.
Immunochromatographic assays fall into two principal categories: “sandwich” and “competitive,” according to the nature of the antigen-antibody complex to be detected and the sequence of reactions required to produce that complex. In general, the sandwich immunochromatographic procedures call for mixing the sample that may contain the analyte to be assayed with antibodies to the analyte. These antibodies are mobile and typically are linked to a label or disclosing reagent, such as dyed latex, a colloidal metal sol, a nonmetallic colloidal sol, or a radioisotope. This mixture is then applied to a chromatographic medium containing a band or zone. This band or zone contains immobilized antibodies to the analyte of interest. The chromatographic medium is often in the form of a strip resembling a dipstick. When the complex of the molecule to be assayed and the labeled antibody reaches the zone of the immobilized antibodies on the chromatographic medium, binding occurs and the bound labeled antibodies are localized at the zone. This indicates the presence of the molecule to be assayed. This technique can be used to obtain quantitative or semi-quantitative results.
Examples of sandwich immunoassays performed on test strips are described by U.S. Pat. No. 4,168,146 to Grubb et al. and U.S. Pat. No. 4,366,241 to Tom et al., both of which are incorporated herein by this reference.
In a competitive immunoassay, typically, a labeled analyte or analogue is supplied, and a competitive reaction is set up between the unlabeled analyte in the sample and the labeled analyte or analogue for binding to an immobilized specific binding partner on the test strip. In general, competitive immunoassays are more suitable for assay of haptens, because they do not require the formation of a ternary sandwich complex.
Although useful, currently available chromatographic techniques using test strips have a number of drawbacks. Many samples, such as fecal samples, contain particulate matter that can clog the pores of the chromatographic medium, greatly hindering the immunochromatographic process. Other samples, such as blood, contain cells and colored components that make it difficult to read the results of the tests. Even if the sample does not create interference, it is frequently difficult with existing chromatographic test devices to apply the sample to the chromatographic medium so that the sample front moves uniformly through the chromatographic medium to ensure that the sample reaches the area where the binding is to occur in a uniform, straight-line manner.
Sample preparation and waste generation are responsible for other problems with currently available devices and techniques for immunochromatography. The increased prevalence of diseases spread by infected blood and blood fractions, such as AIDS and hepatitis, has exacerbated these problems. It is rarely possible to apply a sample (such as blood or feces) or a sampling device (such as a throat swab) directly to the chromatographic medium. Several extraction and pretreatment reactions are usually required before the sample can be applied to the chromatographic medium. These reactions are typically carried out by the physician or technician performing the test in several small vessels, such as test tubes or microfuge tubes, requiring the use of transfer devices such as pipettes. Each of these devices is then contaminated and must be disposed of using special precautions so that workers or people who might inadvertently come into contact with the waste do not become contaminated and subject to infection by infectious agents contained in the waste.
When blood samples are involved, there are additional considerations. Whole blood samples are most easily accommodated by the reverse flow format, i.e., one that performs bidirectional chromatography. The reverse-flow format has the advantage of allowing the test results to be read against the clear white or translucent chromatographic medium, eliminating the potential for obscuring weak test results. However, in a such a reverse-flow format, the amount of sample that is brought into contact with the capture line or detection zone is very limited. In a typical assay, approximately only 3-5 &mgr;l of the applied sample is utilized, and hence assay sensitivity is “capture limited.” This is especially true if the immunological reagents used are of low affinity or avidity for the performance of immunochromatographic assays. Therefore, it would be desirable to have an immunochromatographic assay device that could perform assays for analytes found in blood with a unidirectiona
Chandler Howard M.
Fitzgerald Daniel
LaPointe Larry
Beckman Coulter Inc.
Hill D. David
Hogan & Hartson LLP
May William H.
Nguyen Bao-Thuy L.
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