Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
1997-08-19
2001-03-06
Chin, Christopher L. (Department: 1641)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C436S514000, C436S169000, C436S170000, C436S177000, C436S178000, C436S808000, C436S810000, C422S051000, C422S051000, C422S105000, C435S002000, C435S004000, C435S007100, C435S007920, C435S287100, C435S287200, C435S287700, C435S287800, C435S287900, C435S805000, C435S810000, C435S962000, C435S970000
Reexamination Certificate
active
06197598
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention is directed to methods and devices for separating cellular elements of blood from the liquid portion of blood, particularly in connection with the determination of characteristics of blood samples.
Among the many analytical systems used for detection and/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;
(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 antibody to the bacteria
Helicobacter pylori
and to human immunodeficiency virus (HIV);
(4) other proteins, including tumor markers such as carcinoembryonic antigen and &agr;-fetoprotein;
(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, and marijuana;
(7) environmental pollutants such as pesticides and aromatic hydrocarbons; and
(8) vitamins.
Such chromatographic systems are frequently used by physicians and medical technicians for rapid in-office diagnosis and 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” system 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 the corresponding antibody to form antigen-antibody complexes. The antigen to be detected can itself be an antibody, such as in serological assays for
H. pylori
-specific antibody. In such cases, the antibody to be detected can also be bound to a specific antigen. Alternatively, the antigen to be detected can be detected indirectly by using a labeled second antibody that binds to the first antibody to the analyte to be detected. These immunoassays as a means for testing for the presence and/or amount of clinically important molecules have 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 (Singer et al.,
Am. J. Med
. 22:888-892 (1956)).
Immunoassays generally use a disclosing reagent or particle that has been linked to an antibody, i.e., a labeled reagent or component, 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, 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. Immunoassays have been used with chromatographic methods and devices; this combination is known as immunochromatography.
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 a disclosing reagent, such as dyed latex, a colloidal metal sol, or a radioisotope. This mixture is then applied to a chromatographic medium containing a band or a zone of 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.
In other variations of this technique, if an antibody is to be detected, the immobilized material on the dipstick can be a corresponding antigen, and the labeled antibody can be a second antibody that binds the first antibody on the basis of a specificity such as species or class specificity. For example, if a human antibody to a particular bacterial antigen is to be detected, the bacterial antigen can be immobilized on the dipstick and the antibody can be detected with labeled goat anti-human antibody.
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 competitive immunoassays, the disclosing reagent is typically coupled to an analyte or analyte analog which competes for binding with an antibody with any unlabeled analyte present in this sample. Competitive immunoassays are typically used for detection of analytes such as haptens, each hapten being monovalent and capable of binding only one antibody molecule. Examples of haptens include therapeutic drugs such as theophylline and digoxin and drugs of abuse such as cocaine and heroin and their metabolites. Examples of competitive immunoassay devices are those disclosed by U.S. Pat. No. 4,235,601 to Deutsch et al., U.S. Pat. No. 4,442,204 to Liotta, and U.S. Pat. No. 5,208,535 to Buechler et al., all of which are incorporated herein by this reference.
One of the samples most frequently assayed for an analyte using test strips or similar devices is blood. Most typically, the analyte to be assayed is a soluble component in the liquid portion of blood, i.e., serum or plasma. The compositions of the two are similar, except that serum, obtained from a blood sample that has been allowed to clot, is lacking in fibrinogen and certain other clotting factors that are depleted as a result of the clotting process.
Most typically, the clinician or technician will draw a blood sample, which is often a fairly small sample. It would be preferable to be able to use the entire blood sample for the assay, avoiding the necessity of a bulk preparation of serum or plasma from the blood sample. However, with most test strips and similar analytical devices, the use of whole blood as a sample, or even a blood sample from which the cells, particularly the erythrocytes, have been partially removed, is undesirable.
The blood cells, particularly the erythrocytes, first slow the flow of serum or plasma along the membrane and ultimately stop it by clogging the pores of the membrane. This results in an invalid test. The migration of red blood cells or other blood cells can also create high backgrounds or otherwise interfere with the performance of the test carried out by the assay device. Although blood cells can be removed by filtration through microporous filters, the action of such filters is generally too slow to permit efficient .assay of cell-free blood.
Additionally, even if the blood cells are effectively removed, methods for doing so frequently result in hemolysis. The occurrence of hemolysis is undesirable because it results in the release of enzymes, hemoglobin, other pigments, and stromata into the cell-free portion of blood. This ca
Jaseph Corey L.
Ruggeri Franco
Schoengold Ronald J.
Schrier Wayne H.
Beckman Coulter Inc.
Chin Christopher L.
Do Pensee T.
Kivinski Margaret A.
May William H.
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