Chemical apparatus and process disinfecting – deodorizing – preser – Analyzer – structured indicator – or manipulative laboratory... – Sample mechanical transport means in or for automated...
Reexamination Certificate
2000-05-15
2003-01-14
Soderquist, Arlen (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Analyzer, structured indicator, or manipulative laboratory...
Sample mechanical transport means in or for automated...
C422S051000, C422S131000, C435S004000, C435S006120, C435S007100, C436S518000, C436S523000, C436S524000, C436S527000, C436S528000, C436S531000, C365S151000
Reexamination Certificate
active
06506342
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to an apparatus and method for use in identifying an oligomeric compound (or molecule) that is synthesized into other chemical compounds, particularly those compounds such as pharmaceuticals and biochemicals, by the techniques of combinatorial chemistry. The identification of the oligomeric is performed by identifying the chemical reaction exposure and assay steps that the oligomeric compound has undergone in its synthesis.
The tracking of the progress of chemical reactions through long sequences of synthesis operations is a matter of ever increasing importance in the development and production of new biochemicals and pharmaceuticals.
One particular example of sequences of reactions of the above described type is known as combinatorial synthesis. Combinatorial synthesis may be defined as the generation of a large and diverse series of compounds by the parallel application of different sequences of synthetic reaction steps, or the addition of different functional chemical groups to a population of previously synthesized molecules. These molecules may be peptides, nucleotides, small organic molecules, etc. These large and diverse series of compounds are referred to as combinatorial libraries. Combinatorial libraries are made by forming all possible combinations of a series of sets of precursor molecules, and applying the same sequence of reactions to each combination. Developments in automation have made it possible to synthesize thousands to billions of distinct compounds in parallel. Early work on processes of this type are described in U.S. Pat. No. 4,833,092 (Geysen), which discusses the parallel synthesis of multiple peptides for use in antibody recognition studies.
Research involving pharmaceuticals and biochemicals is particularly well suited for the use of combinatorial synthesis. An objective of combinatorial synthesis is to create libraries of potential pharmaceutically active compounds. Each of these library compounds can then be examined to determine their binding affinity for a target molecule, where in a pharmaceutical application that binding affinity is characterized as bioactivity. After an assay step in which where there is a binding reaction, the identity or reaction history of a library compound must be determined. This is particularly important because the complex synthesis of biomolecules and potential pharmaceuticals involve a large number of reaction steps.
Furthermore, the techniques described herein can be well utilized in creating libraries for many types of complex molecular syntheses, such as lipids used in detergents, heterocyclic compounds used in fuels, and long chain polymers used in materials. One skilled in the art would recognize that the apparatus and method described herein has utility in identifying each of the compounds in combinatorial libraries that are the products of synthesis reactions used in various areas of commerce.
There are at least three approaches to the determination of these novel compounds: direct structural determination; geometric separation of synthetic and assay steps in defined areas; and identification of the initial oligomeric compound and the chemical reaction sequence that the initial oligomeric compound has undergone by attaching these compounds to tagged beads that record this information by chemical, physical, or electronic; or alternatively transmit a distinct identification (ID) code for each bead. Beads of this type are ordinarily used in large numbers that are processed simultaneously in the same reaction vessel. During a series of synthetic steps, these beads are combined, separated and recombined in new combinations as they pass through a series of reaction vessels to produce a number of different end products simultaneously.
Direct structural determination is often not desirable, because each different molecule is often synthesized in quantities too small for structural determination via standard techniques such as nuclear magnetic resonance spectroscopy, mass spectroscopy or chromatographic fragment identification.
Geometric separation of synthetic and assay steps is exemplified by a chip developed by Fodor et al., and described in Science 251, p. 767 (1991). These investigators developed a process to perform a photochemical linkage of peptides and nucleotides on a planar substrate. Different molecules are made in checkerboard pattern on a board. Assay of receptor binding occurs in place on the board. However, this device is not generally applicable to the standard steps used to synthesize organic pharmaceuticals, many of which are not light driven.
The third identification approach in combinatorial synthesis is to tag small beads. Each tagged bead either includes an identification code distinct from each of the other beads, or includes a recording apparatus that records the sequence of reaction it undergoes during the combinatorial process. The tracking process includes a terminal apparatus that examines the beads and determines information about the chemical reactions to which each bead has been exposed. When this information is analyzed, the reaction history of a complex of series of reactions is determinable. Combinatorial bead libraries comprise combinatorial libraries wherein the generated compounds are attached to beads. Combinatorial chemical bead libraries for drug discovery applications comprise 10
2
-10
6
beads. Future libraries may be substantially larger. Thus, a requirement of a bead identification method is high information readout rate.
In most combinatorial synthetic systems that have been implemented to date, information about each synthetic step that the bead has been, or is to be exposed to, is encoded in the bead either prior to placement in a reaction vessel where a particular synthetic step is to be carried out, in the reaction vessel, or after removal from the reaction vessel, and before subsequent placement in a next reaction vessel. At the completion of a given synthetic protocol, chemicals synthesized on the beads are assayed. Information encoded in those beads whose attached synthesized chemicals perform well in the assay is decoded. That information provides the reaction history of each particular bead to enable replication of its attached chemical.
An alternative tagging approach is to tag beads physically with a distinct identification number or code that is predetermined (permanent) during the reaction process. Read out of the bead identification number or code is accomplished by electrical or alternatively electromagnetic radiation transmission. In this approach, each bead is interrogated as to its identification number or code and location prior to, during, and/or after each synthetic reaction, and that information is recorded. That interrogation and recording is accomplished by means of a terminal apparatus computing device because the high readout rate requirement imposed by a relatively large number of beads and a relatively brief available read out time. At the completion of a given synthetic protocol, chemicals synthesized on those beads are assayed. Tag identification of beads on which the chemicals that perform well in the assay are is then determined, and the bead is uniquely identified and correlated with the stored reaction step information to provide the reaction history of each bead, and thus enable replication of the attached oligomeric compound.
There are many possible tagging systems. Beads may be tagged chemically or electronically during the course of a combinatorial synthesis, and alternatively may be tagged with a predetermined (or permanent) electrical, electromagnetic, or physical Identification number or code.
Chemical tags have been implemented by multiple groups and companies. In these protocols, distinct chemical moieties that represent, or code for each step in the synthetic process are added to the bead. After each synthetic and labeling step, the beads are combined, resorted, and a new step in the process is performed. At the end of the process, after the binding assay, beads that hav
Frankel Robert D.
Soderquist Arlen
Wall Marjama & Bilinski LLP
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