Classifications

• • C—CHEMISTRY; METALLURGY
  • C40—COMBINATORIAL TECHNOLOGY
  • C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
  • C40B70/00—Tags or labels specially adapted for combinatorial chemistry or libraries, e.g. fluorescent tags or bar codes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J19/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J19/0046—Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
  • B01J2219/00542—Alphanumeric characters
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/00277—Apparatus
  • B01J2219/0054—Means for coding or tagging the apparatus or the reagents
  • B01J2219/00572—Chemical means
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00686—Automatic
  • B01J2219/00689—Automatic using computers
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
  • B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
  • B01J2219/0068—Means for controlling the apparatus of the process
  • B01J2219/00695—Synthesis control routines, e.g. using computer programs

Definitions

• This invention relates, in general, to the encoding of combinatorial libraries and, in particular, to selectively choosing codes to be assigned to reaction conditions used during synthesis of a combinatorial library.
• Combinatorial techniques of chemical synthesis allow the creation of molecular libraries having immense diversity. These techniques entail a series of chemical steps with multiple choices of reaction conditions (e.g., reagents, temperature changes, etc.) for each step.
• reaction conditions e.g., reagents, temperature changes, etc.
• the complexity, or number of members in a combinatorial library is given by the product of the number of reaction conditions for each step of the synthesis, and can therefore, be quite large.
• the challenge in using combinatorial libraries is the characterization of members of the library with particular desired properties.
• tags e.g., tagging molecules
• the tags are used in combination with one another to form a binary record of the synthetic steps for each bead.
• the various reagents which can be used in any step are designated as binary 001 (Reagent 1), 010(Reagent 2), 011 (Reagent 3),... 111 (Reagent 7).
• a binary synthesis code describing any complete N-STEP synthesis using 3 x N binary digits can be written.
• Reagent 3 is used in the first step, the binary numerical description is 011. If Reagent 1 is used in the second step, the description is 001 011. Further, if Reagent 6 is used in the third step, the description is 110 001 Oi l.
• This 9-bit binary synthesis code describes the synthesis, and can be read from right to left in 3 -bit blocks to decode the reagents used in each step of the synthesis.
• a set of distinguishable, sensitively detectable molecules is used as tags, and the presence of a particular tag represents a binary " 1 " for the corresponding bit.
• T9-T1 a set of nine tagging molecules, for the above example, where T9 represents the leftmost binary bit and Tl represents the rightmost bit
• the tag mixture containing only T9, T8, T4, T2 and Tl represents the 110 001 011 synthesis code.
• Decoding is performed in order to determine the reaction history of a particular bead.
• any tag(s) attached to a bead is detached and identified to determine the particular conditions that occurred during synthesis.
• One technique for separating and identifying tags is known as Capillary Gas Chromatography (GC).
• the use of time spacing as a confirmation of whether a peak represents a tag or a contaminant is referred to herein as "self-clocking".
• the shortcomings of the prior art are overcome and additional advantages are provided through the provision of a method of determining codes usable in encoding combinatorial libraries.
• the method includes, for instance, selecting a plurality of codes to be assigned to a plurality of reaction conditions usable during synthesis of a combinatorial library.
• Each of the plurality of codes includes a plurality of tags, wherein none of the plurality of codes includes only a single tag.
• the method further includes assigning selected codes to reaction conditions.
• each of the plurality of codes is a binary code, and a binary "one" within the binary code represents the presence of a particular tag.
• the plurality of codes is selected using a predefined criterion.
• the predefined criterion specifies at least one of the following: each of the plurality of codes includes an even number of tags present therein; each of the plurality of codes includes an odd number of tags present therein; each of the plurality of codes includes up to a maximal number of tags present therein; each of the plurality of codes includes up to a maximal number of "zero" bits; and each of the plurality of codes does not include a predetermined pattern of bits.
• the plurality of codes is selected using a parity bit.
• a method of determining codes usable in encoding chemical libraries includes selecting, from N possible codes, a group of codes to be assigned to a plurality of reaction conditions usable during synthesis of a chemical library.
• the selecting includes using a predefined function to select the group of codes, wherein the predefined function selects fewer than N-1 codes from the N possible codes.
• the method further includes assigning selected codes to reaction conditions.
• a method of determining codes usable in encoding chemical libraries includes selecting, from N possible codes, a plurality of codes to be assigned to a plurality of reaction conditions, wherein the plurality of codes satisfies a predefined criterion.
• the predefined criterion is other than excluding an "all zeroes" code.
• the method further includes assigning selected codes to reaction conditions.
• a system of determining codes usable in encoding combinatorial libraries includes means for selecting a plurality of codes to be assigned to a plurality of reaction conditions, in which each of the plurality of codes includes a plurality of tags, such that none of the plurality of codes includes only a single tag.
• the system further includes means for assigning selected codes to reaction conditions.
• a system of determining codes usable in encoding chemical libraries includes means for selecting, from N possible codes, a group of codes to be assigned to a plurality of reaction conditions usable during synthesis of a chemical library.
• the means for selecting includes means for using a predefined function to select the group of codes, wherein the predefined function selects fewer than N-1 codes from the N possible codes.
• the system further includes means for assigning selected codes to reaction conditions.
• a system of determining codes usable in encoding chemical libraries includes means for selecting, from N possible codes, a plurality of codes to be assigned to a plurality of reaction conditions, wherein the plurality of codes satisfies a predefined criterion, wherein the predefined criterion is other than excluding an "all zeroes" code.
• the system further includes means for assigning selected codes to reaction conditions.
• an article of manufacture including at least one computer usable medium having computer readable program code means embodied therein for causing the determining of codes usable in encoding combinatorial libraries.
• the computer readable program code means includes computer readable program code means for causing a computer to select a plurality of codes to be assigned to a plurality of reaction conditions usable during synthesis of a combinatorial library, each of the plurality of codes including a plurality of tags, wherein none of the plurality of codes includes only a single tag; and computer readable program code means for causing a computer to assign selected codes to reaction conditions.
• At least one program storage device is provided, which is readable by a machine, tangibly embodying at least one program of instructions executable by the machine to perform a method of determining codes usable in encoding chemical libraries.
• the method includes selecting, from N possible codes, a group of codes to be assigned to a plurality of reaction conditions usable during synthesis of a chemical library.
• the selecting includes using a predefined function to select the group of codes, wherein the predefined function selects fewer than N-1 codes from the N possible codes.
• the method further includes assigning selected codes to reaction conditions.
• At least one program storage device is provided, which is readable by a machine, tangibly embodying at least one program of instructions executable by the machine to perform a method of determining codes usable in encoding chemical libraries.
• the method includes selecting, from N possible codes, a plurality of codes to be assigned to a plurality of reaction conditions, wherein the plurality of codes satisfies a predefined criterion.
• the predefined criterion is other than excluding an "all zeroes" code.
• the method further includes assigning selected codes to reaction conditions.
• a coding capability is provided that eliminates ambiguous code reading. Further, the capability of the present invention advantageously enables the selective choosing of codes, from N possible codes, to be assigned to reaction conditions. Further, the capability of the present invention guarantees the presence of enough tag peaks in a chromatogram that, even in the presence of significant variability in the absolute timing of the run, the relative timing can be determined. Additionally, the present invention is advantageously self-clocking. The use of the present invention in each synthesis step can result in the avoidance of single bit codes for reaction conditions.
• FIG. 1 depicts a generalized method of the present invention
• FIG. 2 depicts one embodiment of the logic associated with the selection capability of the present invention
• FIG. 3 depicts one example of N possible codes, in which a subset is selected (or "accepted”) therefrom, in accordance with the principles of the present invention
• FIG. 4 depicts one example of a table of accepted codes, in accordance with the principles of the present invention.
• FIG. 5 depicts one embodiment of the table of accepted codes of FIG. 4, in which the codes are assigned to reaction conditions, in accordance with the principles of the present invention
• FIG. 6 depicts another example of accepted codes, in accordance with the principles of the present invention.
• FIG. 7a depicts another example of N possible codes, in which a subset is selected (or accepted) therefrom, in accordance with the principles of the present invention
• FIG. 7b depicts one example of adding a parity bit to the N possible codes of FIG. 7a in order to make a selection of the codes to be included in the subset of accepted codes, in accordance with the principles of the present invention
• FIG. 8 depicts one example in which it is difficult to determine whether a tag is present in a sample
• FIG. 9 illustrates one example of output from a gas chromatograph, in accordance with the principles of the present invention.
• FIG. 10 depicts another example of output from a gas chromatograph, in accordance with the principles of the present invention.
• FIG. 11 depicts one embodiment of a computer environment providing and/or using the capability of the present invention.
• a capability in which codes to be assigned to reaction conditions are selectively chosen based on one or more criterion. That is, out of N possible codes, a subset of the N codes is selected based on some constraint or some predefined function.
• the codes are, for instance, binary codes, and each code represents the tags used during a particular stage of synthesis of members of a combinatorial library. Specifically, the tags define the reaction condition used during that particular stage of synthesis.
• a generalized technique of one embodiment of the present invention is described with reference to FIG. 1.
• a group of acceptable codes is selectively chosen, from N possible codes, based upon a predefined function or one or more criterion, as described in detail below, STEP 100.
• the selected codes are assigned to reaction conditions, and those conditions may be used during synthesis of library members, STEP 102.
• the assignment may be arbitrary or may be based on one or more factors. For instance, the first code may be assigned to the first condition to be used during synthesis, etc.
• the criterion can include many different possibilities.
• the criterion can select codes having an even number of "one" bits (i.e., an even number of tags); an odd number of "one” bits; an odd number, greater than one, of "one” bits; more than one tag (i.e., more than one binary "one” bit); up to a total number of "zero” bits; up to a total number of "one” bits; up to a maximal allowed sequence of "zero” or "one” bits; an even parity; an odd parity; codes that do not include a predefined sequence of bits (e.g., the codes that do not include a sequence of 101), etc.
• the above criteria are only provided as examples. There are many more possibilities, and each of those possibilities is considered a part of the claimed invention.
• the predefined function includes all those codes that have up to a total of two "zeroes".
• the process continues with determining which of the codes of FIG. 3 meet this criterion.
• a code is considered from the possible codes, STEP 202.
• code 0000 is considered from the codes depicted in FIG. 3.
• a determination is made as to whether the considered code meets the criterion of having no more than two zeroes, STEP 204. Since code 0000 has more than two zeroes, it does not meet the criterion, and thus, is not an acceptable code.
• next code is 0001. Again, since code 0001 does not meet the criterion, STEP 204, and there are more codes, INQUIRY 206, another code is selected. This procedure continues. At some point, a code is selected that does meet the criterion, INQUIRY 204. For instance, code 0011 meets the criterion of having at a maximum two "zeroes", thus, this code is selected as an acceptable code.
• the acceptable code is placed in a table of acceptable codes, STEP 208.
• a table of acceptable codes STEP 208.
• One instance of such a table is depicted in FIG. 4. The above process continues until all of the acceptable codes are selected from the possible codes based on the predefined criterion.
• each of the acceptable codes can be assigned, respectively, to one of a plurality of reaction conditions, as depicted in FIG. 5.
• ten reaction conditions are represented by ten unique codes.
• Another example of a predefined function used to select acceptable codes from N possible codes is one in which all codes having an even number of tags is selected. This is depicted in FIG. 6. In this particular example, five bits are considered necessary to represent the various reaction conditions to be used during synthesis. Thus, there are 32 possible codes. Out of the 32 possible codes, 15 codes are acceptable (designated by "used" in the table). That is, 15 codes meet the criterion of having an even number of tags.
• parity bits may be added to the N possible codes in order to determine the acceptable codes. For example, assume there are eight possible codes, as shown in FIG. 7a. Further, assume that even parity is to be used, in this example. Thus, for each code in which the addition of a binary "one" provides an even number of "one” bits, a parity "one” bit is added, as shown in FIG. 7b.
• the codes having the parity "one" bit are selected from the N possible codes.
• the following codes are chosen: 0011, 0101, 1001 and 1111.
• each code is a binary code
• each binary "one" represents the existence of a tag and each binary "zero" represents the absence of a tag.
• the tags represented by the binary code associated with that reaction condition are also added during that synthesis step. This provides a record of the conditions used during synthesis of a particular library member.
• Reaction Condition 3 (FIG. 5) is used during a first synthesis step
• Reaction Condition 1 is used during a second step
• Reaction Condition 6 is used during a third step
• the synthesis code representing the three reaction conditions is 0111 0011 0110.
• This synthesis code can be read from right to left, in 4-bit blocks, to decode the reaction conditions used during each step of the synthesis.
• the 10 different reaction conditions in FIG. 5 would be alternatives for a single reaction step.
• a different set of reaction conditions, encoded by a different set of tags, would be used for the next reaction step.
• T12-T1 twelve (12) bits were used to represent 3 reaction conditions and 3 steps and, thus, a set of twelve tagging molecules are used, T12-T1.
• T12 represents the leftmost binary bit and Tl represents the rightmost bit of the synthesis code. Therefore, the following tags would represent the 0111 0011 0110 synthesis code: Ti l, T10, T9, T6, T5, T3 and T2.
• the tags associated with that bead are decoded.
• a chromatogram is produced showing peaks where tags are present. From the peaks, a binary code is determined. For instance, in the above example, since a chromatogram would show that T2 and T3 are present and Tl and T4 are absent, the binary code 0110 is provided, This code indicates that Reaction Condition 3 was used during the first synthesis step.
• the peaks of the chromatogram are not well defined, and thus, it is difficult to determine whether a tag is present. For instance, it is possible that during the tagging reaction, one tag may not be incorporated in a particular bead at the same quantitative level as others within the set. It is also possible that during the detagging/gas chromatograph (GC) portion of the process, some impurities can be introduced into the tag mixture, which may have retention times similar to that of one of the tags in the set. Both of these occurrences can result in chromatogram data in which the tagging code is ambiguous. An example of such is depicted in FIG. 8. In the example of FIG. 8, a 5 place binary code is represented. Clearly, tags 5 and 2 are present, while tags 1 and 3 are not. However, because the peak having the retention time in the expected range for tag 4 is of much lower height than either of the other two, its identity is in question. As a result, the binary code, from left to right, can be either 11010 or 10010.
• the encoding protocol of the present invention is used, in which a specially chosen subset of the N possible binary codes is employed. For example, if a group of codes is selected from the 32 (2 5 ) (see FIG. 6) possible codes, based on a selection criterion of only those codes where the sum of the individual digits is even, then 11010 would not be an acceptable code. Thus, 10010 must be the code that represents the sample depicted in FIG. 8. With this strategy, 2 (N"1) -1 unique sets of conditions can be encoded with N tags.
• FIGs. 9-10 depict a sample chromatogram, and each tag within the chromatogram is labelled by CnnCLn.
• peak 900 has tag C12CL5.
• binary code 1001 reference number 904 must be the correct code. Therefore, in accordance with the present invention, that peak does not have a tag.
• peak 1000 is in question.
• the peak is determined to be tagged.
• a binary "one" represents that peak (see reference number 1002).
• peak 1004. The capability of the present invention can readily be automated by creating a suitable program, in software, hardware, microcode, firmware or any combination thereof.
• any type of computer or computer environment can be employed to provide, incorporate and/or use the capability of the present invention.
• One such environment is depicted in FIG. 11 and described in detail below.
• a computer environment 1100 includes, for instance, at least one central processing unit 1102, a main storage 1104, and one or more input/output devices 1106, each of which is described below.
• central processing unit 1102 is the controlling center of computer environment 1100 and provides the sequencing and processing facilities for instruction execution, interruption action, timing functions, initial program loading and other machine related functions.
• the central processing unit executes at least one operating system, which as known, is used to control the operation of the computing unit by controlling the execution of other programs, controlling communication with peripheral devices and controlling use of the computer resources.
• Central processing unit 1102 is coupled to main storage 1104, which is directly addressable and provides for high speed processing of data by the central processing unit.
• Main storage may be either physically integrated with the CPU or constructed in stand alone units.
• Main storage 1104 is also coupled to one or more input/output devices 1106. These devices include, for instance, keyboards, communications controllers, teleprocessing devices, printers, magnetic storage media (e.g., tape, disks), direct access storage devices, and sensor based equipment. Data is transferred from main storage 1104 to input/output devices 1106, and from the input/output devices back to main storage. Described in detail above is an improvement of the coding process of combinatorial libraries, in which group coding is used. Group coding includes selectively choosing a subset of codes, from N possible codes, that meets one or more predetermined criterion. The subset can include codes that are selected based on a parity bit or by some other mechanism.
• the code selection capability of the present invention guarantees the presence of enough tag peaks in the chromatogram that, even in the presence of significant variability in the absolute timing of the run, the relative timing can be determined and the "zero" bits identified reliably.
• the group coding thus is considered self-clocking.
• the selection capability of the present invention allows more than 2 (N"1) -1 possibilities for N bits. Further, no bit can be claimed to be merely extraneous to the code. A bit is considered extraneous to the code when the bit is added to the code just for the sake of adding a bit and that bit can really be ignored when the code is read. With the present invention, these extraneous bits are avoided and thus, more efficient use of tags can be made.
• the use of the present invention at each synthesis step can result in avoiding single-bit codes for reaction conditions. Additionally, it advantageously allows for more reliable interpretation of an individual chromatogram by using the guaranteed presence of a minimum number of tags to create an "internal standard" for the shifts in that chromatogram. Further, it allows for independent error checking of the validity of the tags at each step based on the frequency of the code occurrence and the identification of invalid codes.
• the present invention is also applicable to higher order coding or other types of coding. Thus, these are considered a part of the claimed invention.
• the present invention can be included in an article of manufacture (e.g., one or more computer program products) having, for instance, computer usable media.
• the media has embodied therein, for instance, computer readable program code means for providing and facilitating the capabilities of the present invention.
• the article of manufacture can be included as a part of a computer system or sold separately.
• At least one program storage device readable by a machine, tangibly embodying at least one program of instructions executable by the machine to perform the capabilities of the present invention can be provided.

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• 1999
  • 1999-10-07 WO PCT/US1999/023444 patent/WO2000021909A2/en not_active Ceased
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