Liquid purification or separation – Processes – Chromatography
Reexamination Certificate
2002-06-24
2004-04-27
Therkorn, Ernest G. (Department: 1723)
Liquid purification or separation
Processes
Chromatography
C210S659000, C210S143000, C210S198200, C073S061520, C436S161000
Reexamination Certificate
active
06726843
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the evaluation of interactions between substances using inverse chromatography methods and apparatus. The term “substance” is used herein, i.e. throughout this specification, to mean a single element or compound, or a mixture of elements and/or compounds. The invention is particularly (but not exclusively) useful in the field of combinatorial science.
2. Introduction to the Invention
In the field of combinatorial science, there is a continuing need for improved methods for characterizing the members of libraries of substances.
The techniques of chromatography are well-known. In one widely used technique, often referred to as liquid solid chromatography, a liquid carrier (the “mobile phase”) is passed over a solid (the “stationary phase”) in a column. A sample is injected into the mobile phase before the mobile phase enters the column. The sample comprises at least one substance which interacts with the solid. The rate at which the substance migrates through the column depends on its relative affinity for the mobile and stationary phases. The technique can be used to separate two substances with different relative affinities for the phases, to characterize an unknown sample (using one or more known solids), or (in the process sometimes referred to as inverse chromatography) to characterize a known solid (using one or more known samples). Reference may made for example to U.S. Pat. No. 4,869,093 (Gilbert); J. Liquid Chromatography, 3 (3), (1983), 403-417, Schram et al.; Org. Geochem. (1989), 14 (2), 157-164, Antworth et al; Chromatographia 36 (1993), 259-262, Jerebak et al.; Sekitan Kagaku Kaigi Happyo Ronbunshu (1993), 30th, 122-125 (Morino et al.); Conf. Proc. Int. Conf. Coal Sci, 7th (1993, 1, 419-422, Takanohashi et al.; Energy Fuels (1996), 10 (4), 1012-1016, Morino et al.; Energy Fuels (1996), 10 (4), 1017-1021, Kaneko et al.; Anal. Biochem. 242 (1996), 104-111; Brissova et al; and Reactive Polymers 23 (1994), 173-182 Petro et al. Reference may also be made to U.S. Pat. Nos. 6,175,409, 6,406,632, 6,265,226, 6,260,407, 6,294,388 and PCT Publication WO 99/51980. The entire disclosure of each of the patents, publications and patent applications referred to above is incorporated herein by reference for all purposes.
SUMMARY OF INVENTION
This invention relates to methods and apparatus which are useful for evaluating the interaction between a receptor and a modifying agent in the presence of a liquid carrier, and which make use of novel and inventive variations of the known techniques of liquid solid chromatography. In the terminology often used in chromatography, the invention includes (but is not limited to) methods in which the receptor is the probe and the modifying agent is the sample, and methods in which the modifying agent is the probe and the receptor is the sample.
In a first aspect of the invention, one of the receptor, modifying agent and liquid carrier is a member of a library, preferably either the receptor or modifying agent is a member of a library, and in either case, the method includes evaluating members of the library in a number of test procedures, and using the results of test procedures to select at least one substance for further testing. The substance selected for further testing will generally be a member of the library, but may be a substance having a known relationship to a member of the library.
In other aspects, the invention provides various methods which are useful as test procedures in the first aspect of the invention, but which are also useful in other contexts, for example for evaluation of interaction between substances by inverse chromatography, and for the rapid testing of a sample withdrawn from a continuous process. In yet further aspects, the invention provides apparatus suitable for carrying out the methods of the invention.
The term “evaluating” is used herein in a broad sense to denote any useful assessment of the interaction between the receptor and the modifying agent. For example, in the first aspect of the invention, the term includes any assessment which makes it possible to select at least one substance for further testing. The term “receptor” is used herein to denote a substance which can form at least part of a solid phase. Thus, the receptor, alone or in combination with a solid, corresponds generally to the stationary phase in conventional liquid solid chromatography. The term “liquid carrier” is used herein to denote any liquid which can be passed continuously over the solid comprising the receptor while the solid is confined in a test chamber. Thus, the liquid carrier corresponds generally to the mobile phase in conventional liquid solid chromatography. The term “modifying agent” is used herein to denote a substance which can form at least part of a liquid sample which can be injected into a stream of the liquid carrier before the stream is passed over the solid in the test chamber. The term “library” is used herein in a broad sense to denote a plurality of identified substances, typically an associated collection of identified substances. The library is preferably a spatially determinate array of identified substances formed at or in or situated on a common substrate. Preferably, but not necessarily, the members of the library differ from each other in some systematic way, so that the variation of the results of the test procedures can be correlated with those differences. For example, the members can differ from each other in one or more quantified ways. Such differences can be quantified by measurements carried out during preparation of the substances, or by measurements carried out on the substances themselves. The differences can be ascertained before or after members of the library have been selected in accordance with the present invention.
The method of the first aspect of the invention comprises conducting a plurality of test procedures, each of the test procedures comprising the steps of
(a) injecting a liquid test sample comprising the modifying agent into a stream of the liquid carrier, the injection being carried out over a limited time so that a distinct test section of the stream contains the test sample;
(b) passing the stream of liquid carrier containing the test sample over a solid phase in a test chamber, the solid phase comprising the receptor; and
(c) examining the stream of liquid carrier leaving the test chamber to ascertain a variable which reflects the interaction of the modifying agent and the receptor in the presence of the liquid carrier.
Step (c) of the method will often comprise examining a distinct evaluation section of the stream corresponding to the test section in order to ascertain a property of the modifying agent. The term “to ascertain a property of the modifying agent” is used herein to include ascertaining a property of the modifying agent itself and/or ascertaining a property of a substance which is produced by the interaction of the modifying agent and the receptor and/or ascertaining a property of part only of the modifying agent.
The results obtained in the steps (c) of the test procedures can optionally be used to select at least one substance for further testing. The further testing can for example involve the interaction between (i) a selected member or members of the library and (ii) the other two of the receptor, modifying agent and liquid carrier used in the test procedures. The further testing can otherwise be unrelated to the original evaluation.
The term “examining the stream of liquid carrier leaving the test chamber to ascertain a variable which reflects the interaction of the modifying agent and the receptor in the presence of the liquid carrier” is used herein in a broad sense to denote any examination which enables the desired evaluation to be made. For example, as further explained below, it may be sufficient to compare the results of the test procedures without quantifying any property of the modifying agent. Preferably (but not necessarily) step (c), alone or in combination with othe
Nielsen Ralph B.
Petro Miroslav
Regan Jacqueline M.
Symyx Technologies Inc.
Therkorn Ernest G.
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