U.S. patent application number 11/732408 was filed with the patent office on 2007-08-09 for graphic design of combinatorial material libraries.
This patent application is currently assigned to Symyx Technologies, Inc.. Invention is credited to Lynn Van Erden, Steven D. Lacy, Eric W. McFarland, Adam L. Safir, Stephen J. Turner, Pei Wang.
Application Number | 20070185657 11/732408 |
Document ID | / |
Family ID | 26870603 |
Filed Date | 2007-08-09 |
United States Patent
Application |
20070185657 |
Kind Code |
A1 |
Lacy; Steven D. ; et
al. |
August 9, 2007 |
Graphic design of combinatorial material libraries
Abstract
Computer-implemented methods, programs and apparatus for
generating a library design for a combinatorial library of
materials. A library design includes a set of sources representing
components to be used in preparing the combinatorial library,
destinations representing arrangements of cells and mappings,
defining one or more distribution patterns for assigning components
to cells in the destination arrangement or arrangements. Mappings
include gradients and sets of user-defined equations, and are used
to calculate the amount of one or more components to be assigned to
a cell or cells in an arrangement. A library design can also
include one or more process parameters defined to vary over time or
across a plurality of destination cells. The invention outputs a
data file defining the library design, including electronic data
representing the sources, the destinations and the mapping, in a
format suitable for implementing manually or using automated
material handling apparatus.
Inventors: |
Lacy; Steven D.; (Houston,
TX) ; McFarland; Eric W.; (Santa Barbara, CA)
; Safir; Adam L.; (Berkeley, CA) ; Turner; Stephen
J.; (Cupertino, CA) ; Erden; Lynn Van;
(Livermore, CA) ; Wang; Pei; (Saratoga,
CA) |
Correspondence
Address: |
SYMYX TECHNOLOGIES INC;LEGAL DEPARTMENT
415 OAKMEAD PARKWAY
SUNNYVALE
CA
94085
US
|
Assignee: |
Symyx Technologies, Inc.
Sunnyvale
CA
|
Family ID: |
26870603 |
Appl. No.: |
11/732408 |
Filed: |
April 2, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09420334 |
Oct 18, 1999 |
7199809 |
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11732408 |
Apr 2, 2007 |
|
|
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09174856 |
Oct 19, 1998 |
|
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09420334 |
Oct 18, 1999 |
|
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Current U.S.
Class: |
702/19 |
Current CPC
Class: |
G16C 20/60 20190201;
G16B 35/00 20190201 |
Class at
Publication: |
702/019 |
International
Class: |
C40B 30/02 20060101
C40B030/02 |
Claims
1. A computer-implemented method for generating a library design
for a library of materials, comprising: providing a graphical user
interface including a workspace for designing a library of
materials; defining one or more sources and one or more
destinations, each source being electronic data representing a
chemical or mixture of chemicals to be used in preparing the
library of materials and each destination being electronic data
representing an arrangement of cells; displaying a visual
representation of one or more of the one or more defined
destinations in the workspace of the graphical user interface, each
destination representation including a representation of one or
more cells in the corresponding arrangement; receiving first user
input defining a first mapping, the first mapping being electronic
data defining a gradient distribution pattern for assigning a first
chemical or mixture of chemicals represented by one of the one or
more defined sources to a plurality of cells in the one or more
defined destinations, the input specifying a minimum and a maximum
amount of the first chemical or mixture of chemicals to be assigned
to any of the plurality of cells and a gradient to be applied
between the minimum and maximum amounts of the first chemical or
mixture of chemicals across the plurality of cells; receiving
second user input defining a second mapping, the second mapping
being electronic data defining a second distribution pattern
describing an amount or amounts of a second chemical or mixture of
chemicals to be distributed to one or more selected cells in the
one or more arrangements, the one or more selected cells including
one or more of the plurality of cells; using the first mapping and
the second mapping to determine amounts of the first chemical or
mixture of chemicals and the second chemical or mixture of
chemicals to be deposited in each of the one or more selected cells
included in the plurality of cells; and modifying the visual
representation of the one or more defined destinations to include a
visual indication of the determined amounts of the first and second
chemicals or mixtures of chemicals.
2. The method of claim 1, further comprising: generating a set of
synthesis instructions for use by one or more synthesis instruments
to create the library of materials based on the defined sources,
destinations, and mappings.
3. The method of claim 1, wherein the first input defining a first
mapping comprises a selection from a set of available mapping
types, the set of available mapping types comprising a one to one
mapping of a chemical or mixture of chemicals from a source to a
cell in the one or more arrangements and a one to many mapping of a
chemical or mixture of chemicals from a source to a plurality of
cells in the one or more arrangements.
4. The method of claim 3, wherein the set of available mapping
types further comprises a many to many mapping of a plurality of
chemicals or mixtures of chemicals from a plurality of sources to a
plurality of cells in the one or more arrangements.
5. The method of claim 4, wherein the set of available mapping
types further comprises a many to one mapping of a plurality of
chemicals or mixtures of chemicals from a plurality of sources to a
cell in the one or more arrangements.
6. The method of claim 1, wherein the second distribution pattern
includes electronic data identifying a fixed amount of the second
chemical or mixture of chemicals to be distributed to one or more
cells in the one or more arrangements.
7. The method of claim 1, wherein the second input specifies a
second gradient distribution pattern according to a minimum and a
maximum amount of the second chemical or mixture of chemicals to be
assigned to a second plurality of cells of the one or more
arrangements and a second gradient to be applied between the
minimum and maximum amounts of the second chemical or mixture of
chemicals across the second plurality of cells.
8. The method of claim 1, further comprising: receiving user input
modifying one or more of the first and second mappings; and
modifying the visual representation of the one or more defined
destinations according to the one or more modified mappings.
9. The method of claim 1, further comprising: receiving third user
input defining one or more parameters, each parameter being
electronic data corresponding to a process parameter to be applied
to one or more cells in the one or more the arrangements and
defining a parameter value for the one or more cells in the one or
more arrangements, the third user input defining a scheme for
varying the parameter values for at least one of the parameters
across two or more cells in the one or more arrangements; and
modifying the visual representation of the one or more defined
destinations to include a visual indication of the parameter
values.
10. The method of claim 9, wherein: the parameter value for one or
more of the parameters is defined to vary over time for one or more
cells in the one or more arrangements.
11. A computer program product on a computer-readable medium for
generating a library design for a library of materials, the
computer program product comprising instructions operable to cause
a programmable processor to: provide a graphical user interface
including a workspace for designing a library of materials; receive
an input defining one or more sources and one or more destinations,
each source being electronic data representing a chemical or
mixture of chemicals to be used in preparing the library of
materials and each destination being electronic data representing
an arrangement of cells; display a visual representation of one or
more of the one or more defined destinations in the workspace of
the graphical user interface, each destination representation
including a representation of one or more cells in the
corresponding arrangement; receive first user input defining a
first mapping, the first mapping being electronic data defining a
gradient distribution pattern for assigning a first chemical or
mixture of chemicals represented by one of the defined sources to a
plurality of cells in the one or more defined destinations, the
input specifying a minimum and a maximum amount of the first
chemical or mixture of chemicals to be assigned to any of the
plurality of cells and a gradient to be applied between the minimum
and maximum amounts of the first chemical or mixture of chemicals
across the plurality of cells; receive second user input defining a
second mapping, the second mapping being electronic data defining a
second distribution pattern describing an amount or amounts of a
second chemical or mixture of chemicals to be distributed to one or
more selected cells in the one or more arrangements, the one or
more selected cells including one or more of the plurality of
cells; use the first mapping to determine amounts of the first
chemical or mixture of chemicals to be deposited in each of the
plurality of cells and the second mapping to determine the amount
or amounts of the second chemical or mixture of chemicals to be
deposited in each of the one or more selected cells, wherein the
amounts of the first and second chemicals or mixture of chemicals
to be deposited in each of the one or more selected cells that are
included in the plurality of cells are determined according to both
the first mapping and the second mapping; and modify the visual
representation of the one or more defined destinations to include a
visual indication of the determined amounts of the first and second
chemicals or mixtures of chemicals.
12. The computer program product of claim 11, further comprising
instructions operable to cause a programmable processor to:
generate a set of synthesis instructions for use by one or more
synthesis instruments to create the library of materials based on
the defined sources, destinations, and mappings.
13. The computer program product of claim 11, wherein the first
input defining a first mapping comprises a selection from a set of
available mapping types, the set of available mapping types
comprising a one to one mapping of a chemical or mixture of
chemicals from a source to a cell in the one or more arrangements
and a one to many mapping of a chemical or mixture of chemicals
from a source to a plurality of cells in the one or more
arrangements.
14. The computer program product of claim 13, wherein the set of
available mapping types further comprises a many to many mapping of
a plurality of chemicals or mixtures of chemicals from a plurality
of sources to a plurality of cells in the one or more
arrangements.
15. The computer program product of claim 14, wherein the set of
available mapping types further comprises a many to one mapping of
a plurality of chemicals or mixtures of chemicals from a plurality
of sources to a cell in the one or more arrangements.
16. The computer program product of claim 11, wherein the second
distribution pattern includes electronic data identifying a fixed
amount of the second chemical or mixture of chemicals to be
distributed to one or more cells in the one or more
arrangements.
17. The computer program product of claim 11, wherein the second
input specifies a second gradient distribution pattern according to
a minimum and a maximum amount of the second chemical or mixture of
chemicals to be assigned to a second plurality of cells of the one
or more arrangements and a second gradient to be applied between
the minimum and maximum amounts of the second chemical or mixture
of chemicals across the second plurality of cells.
18. The computer program product of claim 11, further comprising
instructions operable to cause a programmable processor to: receive
an input modifying one or more of the first and second mappings;
and modify the visual representation of the one or more defined
destinations according to the one or more modified mappings.
19. The computer program product of claim 11, further comprising
instructions operable to cause a programmable processor to: receive
third user input defining one or more parameters, each parameter
being electronic data corresponding to a process parameter to be
applied to one or more cells in the one or more the arrangements
and defining a parameter value for the one or more cells in the one
or more arrangements, the third user input defining a scheme for
varying the parameter values for at least one of the parameters
across two or more cells in the one or more arrangements; and
modify the visual representation of the one or more defined
destinations to include a visual indication of the parameter
values.
20. The computer program product of claim 19, wherein: the
parameter value for one or more of the parameters is defined to
vary over time for one or more cells in the one or more
arrangements.
21. A computer-implemented method for generating a library design
for a library of materials, comprising: defining a set of one or
more sources and one or more destinations, each source being
electronic data representing a chemical or mixture of chemicals to
be used in preparing the library of materials and each destination
being electronic data representing an arrangement of cells;
receiving an input defining a mapping scheme for assigning the
chemicals or mixtures of chemicals represented by the one or more
sources to cells in the one or more destinations, the input
specifying a set of equations for calculating amounts of the
chemicals or mixtures of chemicals to be assigned to the cells in
the one or more destinations; using the set of equations to
calculate a composition of a plurality of materials to be prepared
in the cells in the one or more destinations; and displaying a
visual representation of the one or more defined destinations, the
visual representation including a visual indication of the
calculated compositions.
22. The method of claim 21, wherein at least one of the set of
equations is selected from the group consisting of: a ratio
equation defining an amount of one of the chemicals or mixtures of
chemicals to be assigned to one or more of the cells as a function
of an amount of another chemical or mixture of chemicals to be
assigned to the one or more of the cells; a volume equation
defining an amount of one of the chemicals or mixtures of chemicals
to be assigned to one or more of the cells as a function of a total
volume of a plurality of chemicals or mixtures of chemicals to be
assigned to the one or more of the cells; and a mass equation
defining an amount of one of the chemicals or mixtures of chemicals
to be assigned to one or more of the cells as a function of a total
mass of a plurality of chemicals or mixtures of chemicals to be
assigned to the one or more of the cells.
23. The method of claim 21, wherein using the set of equations
comprises solving the set of equations using matrix algebra
techniques.
24. The method of claim 21, wherein: the input defining the mapping
scheme comprises input associating the sources and equations with
cells or groups of cells in the defined destinations; and using the
equations comprises calculating the composition of a material to be
prepared in a given cell based on the equations and sources
associated with the given cell.
25. The method of claim 21, further comprising: in response to the
input defining the mapping scheme, displaying a visual indication
of the equations associated with the cells or groups of cells in
the defined destinations.
26. The method of claim 21, wherein: defining the one or more
sources comprises associating one or more of the chemicals or
mixtures of chemicals with a type representing a class of chemicals
to be used in preparing the library of materials; receiving user
input specifying a mapping scheme comprises receiving input
specifying one or more of the set of equations as a function of the
type; and using the equations comprises solving the equations
specified as a function of the type for a given destination cell or
group of cells by substituting the corresponding chemical or
chemicals associated with the type.
27. A computer program product on a computer-readable medium for
generating a library design for a combinatorial library of
materials, the computer program product comprising instructions
operable to cause a programmable processor to: define a set of one
or more sources and one or more destinations, each source being
electronic data representing a chemical or mixture of chemicals to
be used in preparing the library of materials and each destination
being electronic data representing an arrangement of cells; receive
an input defining a mapping scheme for assigning the chemicals or
mixtures of chemicals represented by the one or more sources to
cells in the one or more destinations, the input specifying a set
of equations for calculating amounts of the chemicals or mixtures
of chemicals to be assigned to the cells in the one or more
destinations; use the set of equations to calculate a composition
of a plurality of materials to be prepared in the cells in the one
or more destinations; and display a visual representation of the
one or more defined destinations, the visual representation
including a visual indication of the calculated compositions.
28. The computer program product of claim 27, wherein at least one
of the plurality of equations is selected from the group consisting
of: a ratio equation defining an amount of one of the chemicals or
mixtures of chemicals to be assigned to one or more of the cells as
a function of an amount of another chemical or mixture of chemicals
to be assigned to the one or more of the cells; a volume equation
defining an amount of one of the chemicals or mixtures of chemicals
to be assigned to one or more of the cells as a function of a total
volume of a plurality of chemicals or mixtures of chemicals to be
assigned to the one or more of the cells; and a mass equation
defining an amount of one of the chemicals or mixtures of chemicals
to be assigned to one or more of the cells as a function of a total
mass of a plurality of chemicals or mixtures of chemicals to be
assigned to the one or more of the cells.
29. The computer program product of claim 27, wherein the
instructions operable to cause a programmable processor to use the
set of equations comprise instructions to solve the set of
equations using matrix algebra techniques.
30. The computer program product of claim 27, wherein: the input
defining the mapping scheme comprises input associating the sources
and equations with cells or groups of cells in the defined
destinations; and the instructions operable to cause the
programmable processor to use the equations comprise instructions
operable to cause the programmable processor to calculate the
composition of a material to be prepared in a given cell based on
the equations and sources associated with the given cell.
31. The computer program product of claim 27, further comprising
instructions operable to cause the programmable processor to: in
response to the input defining the mapping scheme, display a visual
indication of the equations associated with the cells or groups of
cells in the defined destinations.
32. The computer program product of claim 27, wherein: the
instructions operable to cause the programmable processor to define
the one or more sources comprise instructions operable to cause the
programmable processor to associate one or more of the chemicals or
mixtures of chemicals with a type representing a class of chemicals
to be used in preparing the library of materials; the instructions
operable to cause the programmable processor to receive user input
specifying a mapping scheme comprise instructions operable to cause
the programmable processor to receive input specifying one or more
of the set of equations as a function of the type; and the
instructions operable to cause the programmable processor to use
the equations comprise instructions operable to cause the
programmable processor to solve the equations specified as a
function of the type for a given destination cell or group of cells
by substituting the corresponding chemical or chemicals associated
with the type.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation of U.S. Ser. No. 09/420,334, now
issued as U.S. Pat. No. 7,199,809, which is incorporated by
reference in its entirety, and which is a continuation-in-part of
U.S. Ser. No. 09/174,856, filed Oct. 19, 1998, which is
incorporated by reference in its entirety and which is the basis of
a claim of priority under 35 U.S.C. .sctn. 120.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to the computer-implemented
design of combinatorial libraries of materials. Traditionally, the
discovery and development of materials has predominantly been a
trial and error process carried out by scientists who generate data
one experiment at a time. This process suffers from low success
rates, long time lines, and high costs, particularly as the desired
materials increase in complexity. When a material is composed of
multiple components, theory provides little guidance, and the large
variety of possible combinations of components takes a large amount
of time to prepare and analyze.
[0003] Combinatorial materials science addresses some of these
challenges. Combinatorial materials science refers generally to
methods for creating collections or libraries of chemically diverse
compounds or materials and/or to methods for rapidly testing or
screening these libraries for compounds or materials having
desirable performance characteristics and properties. By parallel
or rapid serial testing of many compounds or materials,
combinatorial techniques accelerate the speed of research,
facilitate breakthroughs, and expand the amount of information
available to researchers. Furthermore, the ability to observe the
relationships between hundreds or thousands of materials in a short
period of time enables scientists to make well-informed decisions
in the discovery process and to find unexpected trends.
[0004] Researchers employing combinatorial techniques design
libraries or arrays containing multiple combinations of starting
chemicals. It is desirable to design such libraries to explore a
desired phase space of starting components and realize good
experimental results at a reasonable cost and period of time.
Computer programs have been used for life science libraries, and
some software applications have been applied to materials. Many of
these programs allow for step-by-step input of a detailed protocol
for synthesizing a library of materials, but do not allow for
definition of chemical ratios or process parameters. To implement
such protocols, the user must manually determine the proper
concentration and quantity of each starting material to achieve a
desired ratio of starting materials in each library member. For
large libraries with shared starting solutions, this becomes
unwieldy to solve manually without significantly limiting the
diversity studied within one library. Other programs allow for
definition of chemical ratios or process parameters to apply to a
whole library, by do not provide for high level definition of
multi-dimensional variation of these ratios or parameters across
the spatial dimensions of the library, also limiting the diversity
that may be studied within a single library. Some of these programs
have been either spreadsheet based or graphic-based.
Spreadsheet-like interfaces are, for many users, non-intuitive and
difficult to learn. Graphic-based interfaces are somewhat more
intuitive, but are limited to supplying direct machine instructions
to move volumes of liquid on a specific robotic system. Such
interfaces fail to provide the comprehensive conceptual library
design assistance that materials discovery chemists would find
greatly beneficial. Many existing programs are limited to specific
chemistries, such as those used in the pharmaceutical industry, and
can only interface with a specific type of synthesis
instrument.
SUMMARY OF THE INVENTION
[0005] The invention provides computer implemented methods and
apparatus for designing combinatorial libraries of materials. The
invention provides a graphical user interface through which the
user designs a library conceptually, with the ability to specify
the desired material composition of multiple library members in
terms of a variety of interrelationships between component
materials, such as multiple interdependent gradients or ratios of
component materials. The resulting conceptual library design is not
constrained by the physical limitations of available library
substrates or equipment. The invention's graphical interface allows
the user to define variation of chemical ratios or process
parameters across a library or across one or more distinct,
partially intersecting or completely overlapping sub-regions of the
library. The invention receives the user's conceptual design and
performs the detailed calculations necessary to determine the
precise composition of each member of the library. The invention
outputs a data file in a format suitable for manual library
preparation or automated preparation using conventional material
handling apparatus. The output may include a list of mappings to be
performed in preparing a library.
[0006] In general, in one aspect, the invention features a
computer-implemented method for generating a library design for a
combinatorial library of materials. The method includes defining
one or more sources and one or more destinations, receiving an
input defining a first mapping, using the first mapping to
calculate a composition of one or materials assigned to one or more
of cells of the destination, and generating a data file defining
the library design. Each source is electronic data representing a
component to be used in preparing the combinatorial library. Each
destination is electronic data representing an arrangement of
cells. The first mapping is electronic data defining a distribution
pattern for assigning a component to cells in the arrangement. The
distribution pattern includes a minimum and a maximum amount of the
component to be assigned to any cell of the arrangement and a
gradient to be applied between the minimum and maximum amounts of
the component across the cells. The data file includes electronic
data representing the sources, the destinations and the
mapping.
[0007] Implementations of the invention can include one or more of
the following advantageous features. The method includes displaying
a representation of the library design graphically describing the
composition of one or more materials assigned to one or more of the
cells. The data file includes electronic data representing one or
more sets of properties, each set of properties being associated
with one of the sources, the destinations or the mapping. Defining
the sources and destinations includes receiving an input from a
graphical input device. The input defining a first mapping includes
a selection from a set of available mapping types, including a one
to one mapping of a component from a source to a cell in the
arrangement and a one to many mapping of a component from a source
to a plurality of cells in the arrangement. The set of available
mapping types also includes a many to many mapping of a plurality
of components from a plurality of sources to a plurality of cells
in the arrangement, a many to one mapping of a plurality of
components from a plurality of sources to a cell in the
arrangement, or a set of one or more user-defined equations. The
gradient is selected from the group consisting of linear,
logarithmic, exponential, polynomial and geometric progression. The
set of properties associated with the mapping includes a source
name, a source geometry, a destination name, a destination
geometry, a gradient type, and a set of gradient parameters
defining the gradient. The method includes receiving an input
defining a second mapping, and using the first and second mappings
to calculate a composition of one or more materials assigned to one
or more of the cells. The second mapping is electronic data
defining a second distribution pattern for distributing a second
component to cells in the arrangement. The second distribution
pattern includes electronic data identifying a fixed amount of the
second component to be assigned to one or more cells in the
arrangement. The second distribution pattern includes electronic
data identifying a minimum and a maximum amount of the second
component to be assigned to any of the cells of the arrangement and
a second gradient to be applied between the minimum and maximum
amounts of the second component across the cells. The method
includes generating a modified library design by receiving an input
redefining a source, a destination or a mapping, recalculating the
composition of one or more materials assigned to one or more of the
cells; and generating a data file defining the modified library
design. The method includes receiving an input defining one or more
parameters, and the data file includes electronic data representing
the one or more parameters. Each parameter is electronic data
corresponding to a process parameter and defines a parameter value
for one or more cells of the arrangement. The parameter values vary
between a minimum and a maximum amount. The arrangement comprises
two or more cells, ten or more cells, or about ninety-six or more
cells.
[0008] In general, in another aspect, the invention features a
computer-implemented method for generating a library design for a
combinatorial library of materials. The method includes defining a
set of one or more sources and one or more destinations, receiving
an input defining a set of first mappings, using the set of
equations to calculate a composition of a material assigned to one
or more cells in the destination, and generating a data file
defining the library design. Each source is electronic data
representing a component to be used in preparing the combinatorial
library. Each destination is electronic data representing an
arrangement of cells. The set of first mappings is electronic data
defining a set of equations for calculating an amount of one or
more components to be assigned to one or more cells in the
destination arrangement. The data file includes electronic data
representing the sources, the destinations and the mappings.
[0009] Implementations of the invention can include one or more of
the following advantageous features. The method includes displaying
a representation of the library design. The representation
graphically describes the composition of one or more materials
assigned to one or more of the cells. The component to be assigned
to a cell in the arrangement is determined by the location of the
cell within the arrangement. The composition of a material is
determined using a subset of the set of equations, the subset of
equations being determined by the location of the cell within the
arrangement. The method includes generating an error indicator
signal if the number of equations in the set of equations is not
equal to the number of sources in the set of sources. At least one
of the set of equations is selected from a ratio equation defining
an amount of a component to be assigned to a cell as a function of
an amount of another component to be assigned to the cell; a volume
equation defining an amount of a component to be assigned to a cell
as a function of a total volume of a plurality of components to be
assigned to the cell; and a mass equation defining an amount of a
component to be assigned to a cell as a function of a total mass of
a plurality of components to be assigned to the cell. The set of
equations includes a gradient equation defining an amount of a
component to be assigned to each of a plurality of cells according
to a gradient. Each of the set of equations is assigned to one or
more cells of the arrangement according to the location of the
cells within the arrangement. The method includes simultaneously
solving a set of interdependent equations. The method includes
using a matrix inversion technique to solve the set of equations.
The method includes receiving an input defining a second mapping
and using the first set of mappings and the second mapping to
calculate a composition of a material assigned to one or more of
the cells. The second mapping is electronic data defining a
distribution pattern for distributing a component to cells in the
arrangement. The distribution pattern includes a minimum and a
maximum amount of the component to be assigned to any cell of the
cells of the arrangement and a gradient to be applied between the
minimum and maximum amounts of the component across the plurality
of cells.
[0010] In general, in another aspect, the invention features a
computer-implemented method for generating a library design for a
combinatorial library of materials. The method includes defining a
set of one or more sources and one or more destinations, defining a
plurality of mappings, receiving an input defining one or more
parameters, and generating a data file defining the library design.
Each source is electronic data representing a component to be used
in preparing the combinatorial library. Each destination is
electronic data representing an arrangement of cells. The mappings
in the aggregate define a composition for each of a plurality of
materials assigned to a plurality of cells in the arrangement. Each
parameter is electronic data corresponding to a process parameter
and defining a parameter value for one or more cells of the
arrangement. The parameter value varies between a minimum and a
maximum amount. The data file includes electronic data describing
the source elements, the destination elements, the mappings and the
parameters
[0011] Implementations of the invention can include one or more of
the following advantageous features. The parameter value is defined
to vary over time, across two or more cells in the arrangement, or
over time and across two or more cells in the arrangement. The
parameter value varies according to a gradient selected from the
group consisting of linear, logarithmic, exponential, polynomial
and geometric progression. The parameter value corresponds to a
process parameter selected from the group consisting of
temperature, pressure, time, flow rate and stirring speed.
[0012] In general, in another embodiment, the invention features a
computer-implemented method for preparing a combinatorial library
of materials on a substrate. The method includes creating a library
design by defining a set of design elements, generating a data file
comprising electronic data describing the set of design elements,
and using the data file to cause an automated material handling
apparatus to assemble the combinatorial library on a substrate. The
set of design elements includes one or more sources representing
components to be used in preparing the combinatorial library, one
or more destinations, each of which includes an arrangement of one
or more cells, and one or more elements selected from the group
consisting of a mapping defining a scheme for assigning one or more
amounts of a component to one or more cells of an arrangement and a
parameter corresponding to a process parameter. The parameter
defines a parameter value for one or more cells of the arrangement.
The parameter value varies between a minimum and a maximum
amount.
[0013] In general, in another embodiment, the invention features a
computer program product on a computer-readable medium for
generating a library design for a combinatorial library of
materials. The computer program includes instructions operable to
cause a programmable processor to receive an input defining one or
more sources and one or more destinations, receive an input
defining a first mapping, use the first mapping to calculate a
composition of one or materials assigned to one or more cells in
the destination, and generate a data file defining the library
design. Each source is electronic data representing a component to
be used in preparing the combinatorial library. Each destination is
electronic data representing an arrangement of cells. The first
mapping is electronic data defining a distribution pattern for
assigning a component to cells in the arrangement. The distribution
pattern includes a minimum and a maximum amount of the component to
be assigned to any cell of the arrangement and a gradient to be
applied between the minimum and maximum amounts of the component
across the plurality of cells. The data file includes electronic
data representing the sources, the destinations and the
mapping.
[0014] Implementations of the invention can include one or more of
the following advantageous features. The computer program includes
instructions operable to cause a programmable processor to display
a representation of the library design graphically describing the
composition of one or more materials assigned to one or more of the
cells. The data file includes electronic data representing one or
more sets of properties, each set of properties being associated
with one of the sources, the destinations or the mapping. The input
defining the sources and destinations includes an input from a
graphical input device.
[0015] The input defining a first mapping includes a selection from
a set of available mapping types. The set of available mapping
types includes a one to one mapping of a component from a source to
a cell in the arrangement and a one to many mapping of a component
from a source to a plurality of cells in the arrangement, a many to
many mapping of a plurality of components from a plurality of
sources to a plurality of cells in the arrangement, a many to one
mapping of a plurality of components from a plurality of sources to
a cell in the arrangement, or a set of one or more user-defined
equations. The gradient is selected from the group consisting of
linear, logarithmic, exponential, polynomial and geometric
progression. The set of properties associated with the mapping
comprises a source name, a source geometry, a destination name, a
destination geometry, a gradient type, and a set of gradient
parameters defining the gradient. The computer program includes
instructions operable to cause a programmable processor to receive
an input defining a second mapping and use the first and second
mappings to calculate a composition of one or more materials
assigned to one or more of the cells. The second mapping is
electronic data defining a second distribution pattern for
distributing a second component to cells in the arrangement. The
second distribution pattern includes electronic data identifying a
fixed amount of the second component to be assigned to one or more
cells in the arrangement. The second distribution pattern includes
electronic data identifying a minimum and a maximum amount of the
second component to be assigned to any of the cells of the
arrangement and a second gradient to be applied between the minimum
and maximum amounts of the second component across the cells. The
computer program includes instructions operable to cause a
programmable processor to generate a modified library design by
receiving an input redefining a source, a destination or a mapping;
recalculating the composition of one or more materials assigned to
one or more of the cells; and generating a data file defining the
modified library design. The computer program includes instructions
operable to cause a programmable processor to receive an input
defining one or more parameters and the data file includes
comprises electronic data representing the one or more parameters.
Each parameter is electronic data corresponding to a process
parameter and defining a parameter value for one or more cells of
the arrangement. The parameter value varies between a minimum and a
maximum amount. The arrangement comprises two or more cells, ten or
more cells, or about ninety-six or more cells.
[0016] In general, in another embodiment, the invention features a
computer program product on a computer-readable medium for
generating a library design for a combinatorial library of
materials. The computer program includes instructions operable to
cause a programmable processor to receive an input defining a set
of one or more sources and one or more destinations, receive an
input defining a set of first mappings, use the set of equations to
calculate a composition of a material assigned to one or more of
cells of the destination, and generate a data file defining the
library design. Each source is electronic data representing a
component to be used in preparing the combinatorial library. Each
destination is electronic data representing an arrangement of
cells. The set of first mappings is electronic data defining a set
of equations for calculating an amount of one or more components to
be assigned to one or more cells in an arrangement. The data file
includes electronic data representing the sources, the destinations
and the mappings.
[0017] Implementations of the invention can include one or more of
the following advantageous features. The computer program includes
instructions operable to display a representation of the library
design graphically describing the composition of one or more
materials assigned to one or more of the cells. The component to be
assigned to a cell in the arrangement is determined by the location
of the cell within the arrangement. The composition of a material
is determined using a subset of equations determined by the
location of the cell within the arrangement. The computer program
includes instructions operable to generate an error indicator
signal if the number of equations in the set of equations is not
equal to the number of sources in the set of sources. At least one
of the set of equations is selected from a ratio equation defining
an amount of a component to be assigned to a cell as a function of
an amount of another component to be assigned to the cell, a volume
equation defining an amount of a component to be assigned to a cell
as a function of a total volume of a plurality of components to be
assigned to the cell, and a mass equation defining an amount of a
component to be assigned to a cell as a function of a total mass of
a plurality of components to be assigned to the cell. The set of
equations includes a gradient equation defining an amount of a
component to be assigned to each of a plurality of cells according
to a gradient. The set of equations is assigned to one or more
cells of the arrangement according to the location of the cells
within the arrangement. The instructions operable to cause a
programmable processor to use the set of equations to calculate a
composition of a material assigned to one or more of the cells
include instructions simultaneously to solve a set of
interdependent equations. The instructions simultaneously to solve
the set of interdependent equations include instructions to use a
matrix inversion technique to solve the set of equations. The
computer program includes instructions operable to receive an input
defining a second mapping and use the first set of mappings and the
second mapping to calculate a composition of a material assigned to
one or more of the cells. The second mapping is electronic data
defining a distribution pattern for distributing a component to
cells in the arrangement. The distribution pattern includes a
minimum and a maximum amount of the component to be assigned to any
cell of the cells of the arrangement and a gradient to be applied
between the minimum and maximum amounts of the component across the
plurality of cells.
[0018] In general, in another embodiment, the invention features a
computer program product on a computer-readable medium for
generating a library design for a combinatorial library of
materials. The computer program includes instructions operable to
cause a programmable processor to receive an input defining a set
of one or more sources and one or more destinations, receive an
input defining a plurality of mappings, receive an input defining
one or more parameters, and generate a data file defining the
library design. Each source is electronic data representing a
component to be used in preparing the combinatorial library. Each
destination is electronic data representing an arrangement of
cells. The mappings in the aggregate define a composition for each
of a plurality of materials assigned to a plurality of cells in the
arrangement. Each parameter is electronic data corresponding to a
process parameter and defining a parameter value for one or more
cells of the arrangement. The parameter value varies between a
minimum and a maximum amount. The data file includes electronic
data describing the source elements, the destination elements, the
mappings and the parameters.
[0019] Implementations of the invention can include one or more of
the following advantageous features. The parameter value is defined
to vary over time, across two or more cells in the arrangement, or
over time and across two or more cells in the arrangement. The
parameter value varies according to a gradient selected from the
group consisting of linear, logarithmic, exponential, polynomial
and geometric progression. The parameter value corresponds to a
process parameter selected from the group consisting of
temperature, pressure, time, flow rate and stirring speed.
[0020] In general, in another aspect, the invention features a
computer program product on a computer-readable medium for
generating a library design for a combinatorial library of
materials. The computer program includes instructions operable to
cause a programmable processor to create a library design by
defining a set of design elements, generate a data file including
electronic data describing the design and use the data file to
cause an automated material handling apparatus to assemble the
combinatorial library on a substrate. The set of design elements
includes one or more sources representing components to be used in
preparing the combinatorial library, one or more destinations, and
one or more elements selected from the group consisting of a
mapping defining a scheme for assigning one or more amounts of a
component to one or more cells of an arrangement and a parameter
corresponding to a process parameter. Each destination includes an
arrangement of one or more cells. The parameter defines a parameter
value for one or more cells of the arrangement, the parameter value
varying between a minimum and a maximum amount.
[0021] Advantages that can be seen in implementations of the
invention include one or more of the following. The invention
allows users to design combinatorial libraries conceptually, while
automatically performing a large number of detailed calculations
required for the exact assignment of materials at each library
member in a process that is preferably invisible to the user,
although it may be shown if desired. The user can visualize a
conceptual library design and identify potential errors before
undertaking actual library synthesis. Separation of library design
from library synthesis allows the user to lay out a library design
conceptually, without regard for the physical limitations of a
particular destination substrate or synthesis apparatus. The
library design can flexibly define variation of chemical
composition across library members by specifying multiple,
interdependent material gradients or ratios defining the
composition of each library member. The library design can also
include variation of process parameters over time or across library
members, which enables the user combinatorially to explore the
effect of changing process conditions on material composition. The
output of the design process is a recipe file that allows the
automated synthesis of a library corresponding to the conceptual
design. Maintaining databases of chemical information, library
designs and composition data speeds up library design, avoids the
repetition of old experiments, and assists in the overall planning
and execution of experiments necessary to explore the preparation
and properties of diverse materials.
[0022] The details of one or more embodiments of the invention are
set forth in the
[0023] accompanying drawings and the description below. Other
features and advantages of the invention will become apparent from
the description, the drawings, and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 is a block diagram illustrating a system for
computer-implemented design of a combinatorial library of
materials.
[0025] FIG. 2 is a flow diagram generally illustrating a method of
designing a combinatorial library of materials.
[0026] FIG. 3 is a flow diagram illustrating a method of designing
a combinatorial library of materials.
[0027] FIG. 4 is a ternary phase diagram describing the design of a
conceptual triangular library of cells containing a mixture of
three components in varying degrees.
[0028] FIG. 5A is a user interface window for use by a user
designing a combinatorial library of materials.
[0029] FIG. 5B is an example of a window pane of the system user
interface for defining one or more stock materials.
[0030] FIG. 5C is an example of a dialog of the system user
interface for defining a destination object.
[0031] FIG. 6A is an illustrative library design window of the
system user interface including a pane for graphically defining a
library by mapping.
[0032] FIG. 6B is an example of a dialog for defining a gradient
mapping object.
[0033] FIG. 6C is an example of a mapping dialog displaying a
sequence of defined mappings defining a library.
[0034] FIG. 7A is an illustrative library design window including a
pane for defining a library using equations.
[0035] FIGS. 7B and 7C are illustrative dialogs for defining an
equation object.
[0036] FIG. 8A is an illustrative library design window depicting
an equation design.
[0037] FIG. 8B is an example of a dialog displaying the calculation
of composition for a cell in an equation design.
[0038] FIG. 8C is an illustrative library design window depicting
the composition of a combinatorial library.
[0039] FIG. 8D is an example of a dialog depicting the composition
of a library member.
[0040] FIG. 9A is an example of a dialog for defining a process
parameter object.
[0041] FIG. 9B is an example of a pane displaying the properties of
parameter objects.
[0042] FIG. 10 is an example of a library design window depicting a
virtual ternary library design mapped to a rectangular plate.
[0043] Like reference numbers and designations in the various
drawings indicate like elements.
DETAILED DESCRIPTION
[0044] As shown in FIGS. 1 and 2, a system 100 includes a computer
110 equipped with input/output devices 120. A typical user of
system 100 is a chemist. Through user interface 160, the user
initializes system 100 and generates a library design for a
combinatorial library of materials using design module 130 (step
200). As used in this specification, a combinatorial library is a
collection of two or more members that contain some variance in
chemical composition, chemical amount, reaction conditions, and/or
processing conditions, where a member is a single position in a
library containing one set of chemicals subject to one set of
reaction or processing conditions.
[0045] Based on the library design, design module 130 creates a set
of material handling instructions, which may take the form of a
data file or "recipe file" (step 210), which may be provided to
synthesis module 140 (step 220). Synthesis module 140 implements
the instructions, by causing material handling apparatus 180 to
synthesize a combinatorial library specified by the design, for
example (step 230). Implementation of material handling
instructions from recipe files to synthesize libraries of materials
is described in more detail in co-pending U.S. application Ser. No.
09/305,830, filed on May 5, 1999, which is incorporated herein by
reference in its entirety. Alternatively, design module 130 stores
the set of material handling instructions in a file or relational
database in memory 150 for later modification by design module 130
or implementation by synthesis module 140.
[0046] Using design module 130, the user designs a library by
defining a set of design elements corresponding to a design
workspace, one or more mappings or distribution schemes for
assigning materials to individual library members, and, optionally,
one or more process parameters to be applied to one or more library
members. FIG. 3 shows a method of using system 100 to design a
combinatorial library of materials in more detail. Through user
interface 160, the user defines a workspace by defining one or more
sources (step 300) and one or more destinations (step 310). As used
in this specification, a source is a chemical or mixture of
chemicals that will be used as a component in creating a library,
while a destination is a conceptual arrangement of cells
representing a combinatorial library. In one embodiment, a
destination may represent a physical substrate in or on which a
library is created. In other embodiments, however, a destination is
not constrained to represent an actual physical substrate, but can
correspond to a conceptual library environment. Thus, as shown in
FIG. 4 for example, a user may design a ternary library of three
components A, B and C on a triangular destination in which each
apex of triangle 400 corresponds to a composition of 100 percent of
the corresponding component, while design module 130 translates the
triangular conceptual design to a conventional rectangular grid
corresponding to locations on a wafer or wells in a microtiter
plate, as will be described in more detail below. The user defines
each source and destination by entering identifying information,
which may cause design module 130 to create a corresponding source
or destination data object having associated properties defined by
the user input, as will be described in more detail below.
Alternatively, the user defines a source or destination by
retrieving a pre-defined source or destination from memory 150.
[0047] The definition of sources and destinations is described in
more detail with reference to FIGS. 5A-C. The user defines the
necessary sources (meaning components to be used in designing and
synthesizing a library, which may include materials located at one
or more destination regions as will be described below) and
destinations using design window 500, which includes outline pane
510, definition pane 530 and graphical pane 540. Outline pane 510
depicts a hierarchical view of the library design and its contents.
At the top level, outline pane 510 displays a list of library
design folders 511, each containing a library design. The next
level lists sub-folders corresponding to the contents of each
design, including, for example, sources folder 512, destinations
folder 513, chemicals folder 514, equations folder 515 and
parameters folder 516. At the third level, outline pane 510
displays icons depicting the individual design elements, including,
for example, sources 517, destinations 518, chemicals 519,
equations and parameters. When the user selects an icon
corresponding to a desired element, user interface 160 displays
information relevant to that element--for example, selection of a
source 517 may result in display of a dialog identifying the names
of the source's constituent chemicals, or other relevant
properties. The hierarchical view in outline pane 510 also includes
an icon 520 representing a recipe file corresponding to the library
design.
[0048] The user defines a set of sources (such as stock solutions
containing one or more chemicals dissolved in a solvent) to be used
in creating the library, by, for example, selecting "Stock
Materials" tab 525 (or a corresponding button on toolbar 560, a
menu item in menus 570 or the like), which causes definition pane
530 to display a stock materials layer. Appropriate source
materials (i.e., components for use in library design) can include
chemical elements, chemical compounds or chemical compositions,
which may themselves include one or more elements or compounds.
Source materials can be in a gaseous, liquid or solid phase.
[0049] For each source material, the user assigns a source name in
field 531, and may enter information defining the source
properties, including attributes of each constituent chemical such
as type (or subtype), name (selected, for example, from a list of
defined chemicals), molecular weight, equivalents, structure,
density and concentration into corresponding fields 532-539. Values
corresponding to source properties may be entered in any convenient
units and are converted to common units for subsequent calculations
by design module 130. To facilitate graphic display, each source
may be assigned a distinct color. As sources are defined, they are
depicted as source icons 517 in sources folder 512 in outline pane
510. Each source is also represented by an icon or shape 541 in
graphical pane 540, which may be manipulated by the user--for
example, by using a mouse or other input device to move or drag the
icon to any desired location in graphical pane 540 or to resize the
icon as desired.
[0050] To define a chemical (a single material component within a
synthetic design, for example a reagent that is synthesized or
purchased for use in a source), the user makes an appropriate
selection, such as by selecting "Chemicals" tab 545 in layered
definition pane 530, causing that pane to toggle to a chemical
definition layer 550, as shown in FIG. 5B. Alternatively, the user
selects New Chemical button 561 on toolbar 560, an appropriate
entry from drop-down menus 570, or other selection device. The user
enters the chemical's name into Chemical Name field 552 and enters
information defining the chemical's properties, such as molecular
weight, equivalents, structure and density, into corresponding
fields 553, 554, 555 and 556. Optionally, the user also assigns a
chemical "Type"--a user-selected label describing a class of
chemicals that may be used as a design parameter in creating the
library--by entering a name into Type field 551. Each defined
chemical type may include one or more subtypes. Alternatively, the
user may retrieve the relevant data for a pre-defined chemical or
chemicals from a database in memory 150 and transfer the data
directly into the corresponding fields of the chemical definition
layer.
[0051] To facilitate implementation of a library design, in one
embodiment design module 130 outputs a stock solution preparation
worksheet that can be used for the manual or automated preparation
of actual stock solutions to be used to synthesize the library.
After the stock solutions are prepared, the user may enter actual
values for mass, volume and concentrations of stock solution
components, enabling design module 130 to recalculate its usage of
stock materials based on the actual composition of available stock
solutions.
[0052] The user defines one or more destinations by selecting an
appropriate button or menu item, such as New Destination button 563
on toolbar 560, and entering a destination name and geometry
information. Each destination includes one or more regions, each of
which may be represented as a cell or group of cells in an
arrangement (e.g., an array) of one or more cells. A destination
can include an arrangement of two or more cells, preferably four,
ten, twenty, or even ninety-six or more cells. The cells or regions
of a destination may, but need not, correspond to members of the
combinatorial library and/or locations on a physical substrate
(such as a microtiter plate, wafer or the like) on which the
library will be created. However, while the destination may
correspond to the geometry of the ultimate physical substrate, it
may also represent the library on a more conceptual level, and may
correspond to an abstract intermediate in the ultimate library
design as will be described in more detail below. A destination can
encompass one or more library designs; conversely, a library design
can encompass any number of regions or cells of a destination, from
a single cell to the total number of cells associated with the
destination. In the described embodiment, destinations are depicted
as square or rectangular arrays. However, destinations and the
libraries they represent may be designed in any convenient shape,
such as square, rectangle, circle, triangle or the like. Selection
of a desired arrangement is a choice that can be manipulated by
this invention. Strategies for designing combinatorial libraries
are described in co-pending U.S. application Ser. No. 09/156,827,
filed Sep. 18, 1998, and U.S. Pat. No. 5,776,359, both of which are
incorporated herein by reference.
[0053] Thus, the user defines a destination by, for example,
entering a number of rows and columns defining a bounding matrix of
the destination into fields 581 and 582 of Destination Property
dialog 580 shown in FIG. 5C. Each defined destination is
represented as destination icons 517 in destinations folder 513 and
as an appropriately-sized empty arrangement 542 of the appropriate
shape in graphical pane 550, which may be manipulated by the user,
such as by dragging to desired locations in graphical pane 550 or
by resizing, as described for sources above.
[0054] Referring again to FIG. 3, the user designs the
combinatorial library by assigning components (including chemicals)
from sources to destination regions to define the composition of
each library member (step 320). In one embodiment, described in
detail with reference to FIGS. 6A-6C, the user directly defines one
or more mappings that represent the assignment of one or more
components to one or more destination cells. After defining the
necessary sources and destination, represented as circles 601-603
and arrangement 607, respectively, in graphical pane 600, the user
designs the library by using toolbar 610 to define a sequence of
one or more mappings, each of which embodies a scheme or pattern
for assigning an amount of a component or components from a source
or sources to a destination region (i.e., a cell or group of
cells), or from a destination region to one or more other cells of
the same or a different destination. As described below, mappings
can be defined from a single source to a single destination region,
from one source to multiple destination regions or from multiple
sources (or destination regions) to multiple destination regions.
The user may define a mapping by specifying that one or more
components are to be assigned to one or more destination regions in
uniform amounts or in varying amounts defined by a mathematical
gradient or by a set of one or more governing equations applied to
one or more destination regions, or by some combination of these
methods.
[0055] To define a mapping, the user selects a mapping mode by, for
example, selecting the appropriate button in toolbar 610. In one
embodiment, to define a "one-to-one" mapping assigning a single
component to a single destination cell the user selects one-to-one
mapping button 615. The user then selects a desired source, for
example by highlighting an icon or shape in graphical pane 600 such
as circle 601. Next, the user selects a destination cell, for
example by selecting a cell 620 in destination arrangement 607. The
user is then prompted to enter an amount of the selected component
to be assigned to the selected destination cell. Alternatively, the
user may specify the amount of the component to be assigned to the
destination cell by defining an equation as will be described
below.
[0056] The user may define a mapping from multiple sources
(including multiple regions in one destination) to multiple regions
in another destination (or, if desired to another set of regions in
the same destination) by, for example, selecting "many-to-many"
mapping button 614. The user selects a group of cells in the
starting destination, for example by dragging a cursor over the
desired cells in destination arrangement 607, and a group of cells
in the target destination (which may or may not be the same as the
starting destination). The group of target cells may include any
number of cells in the destination, and may include one or more
rows or columns of cells, or parts of one or more rows or columns.
Design module 130 prompts the user to input an amount of a
component or components to be assigned from the selected starting
cells to the selected target cells through user interface 160.
[0057] Optionally, the user may define a one-to-one or many-to-many
mapping by reference to an appropriate text file, such as, for
example, a tab-delimited spreadsheet file generated by
Microsoft.RTM. Excel, by selecting an appropriate button 616 or
617. Design module 130 prompts the user to identify a source or
sources and destination region or regions, and prompts the user to
select a file containing the desired mapping information. Design
module 130 assigns the selected component or components to the
cells of the selected destination according to the contents of the
selected file. Thus, for example, the selected file may contain a
tab-delimited array of constant values used to assign components to
the corresponding cells of a selected destination array.
Alternatively, design module 130 may calculate the amount of one or
more components to be assigned to each cell in a selected
destination based on equations, such as exponential, logarithmic,
polynomial or geometric expressions or the like, contained in the
selected file.
[0058] The user defines a mapping from a source to multiple
destination cells by, for example, selecting a "one-to-many"
mapping button 613. Design module 130 prompts the user to select a
desired source and a group of cells in a desired destination, as
described above. Design module 130 then prompts the user to specify
a distribution scheme to be applied over the selected destination
cells, for example defining a linear distribution gradient by
entering starting and ending amounts, a direction and a
distribution pattern (such as rectangular, triangular or other
desired shape).
[0059] FIG. 6B shows one implementation of a dialog for defining a
mapping distribution in more detail. Dialog 630 includes a pane 635
of radio buttons providing the user with a choice of various
gradient shapes, such as rectangular or triangular. In pane 640,
the user selects a gradient orientation--the direction or
directions in the destination array along which the amount of the
component increases. The user inputs the minimum and maximum values
for the gradient in fields 645 and 650, and enters a number of rows
or columns in the destination specifying the step size of the
gradient in field 655. Design module 130 calculates an amount for
each selected cell in the destination, beginning with the minimum
amount in the first cell and increasing to the maximum amount
according to the specified gradient.
[0060] In other embodiments, user interface 160 and design module
130 can be configured to define mappings based on other
distribution schemes. For example, while the embodiment shown in
FIG. 6B illustrates a dialog for defining a linear gradient, user
interface 160 and design module 130 can be configured to define
gradients according to one or more other well known mathematical
forms, such as exponential, logarithmic, polynomial or geometric
functions. Likewise, design module 130 can be configured to define
"many-to-one" mappings for assigning amounts of material from
multiple sources to a single destination region, using constant
amounts of material from each source or varying amounts defined by
gradients as described above. In still another embodiment, design
module 130 can be configured to permit mapping from one source or
sources to one or more others sources (or from a destination region
or regions) to one or more sources.
[0061] While the embodiment shown in FIG. 6B provides for the
definition of the gradient without reference to specific units of
measure, user interface 160 and design module 130 can be configured
to permit the user to input values in any convenient measure, such
as, for example, units of molarity, weight, volume or thickness. In
such embodiments, design module 130 automatically converts the
selected units into appropriate units for calculation of mapping
amounts, relieving the user of responsibility for making the
necessary conversions. Thus, the user may define the sources for a
library design using units that are most convenient for preparing
stock solutions of components and design the library in another set
of units more appropriate for that purpose, while design module 130
outputs a recipe file in still another set of units appropriate for
synthesis of the library.
[0062] The user may view the properties of each defined mapping
object (e.g., sources, destinations, amounts, shape, and the like)
and the overall mapping sequence through an appropriate mapping
dialog, such as dialog 660 in FIG. 6C, accessed, for example, by
selecting an appropriate menu item, toolbar button or other
graphical device in user interface 160. The results of applying
each defined mapping to a selected destination are displayed in
graphical pane 600, which graphically depicts the composition of
each destination region in the current library design. In the
embodiment illustrated in FIG. 6A, composition data for destination
arrangement 607 is displayed in layered chart form, with each cell
in the destination being divided into colored or patterned layers
or bars the size of which represents the relative amount of each
component assigned to that cell. By selecting or unselecting the
check box associated with each source (or chemical, depending on
the selected view option) in outline pane 670 in FIG. 6A, the user
may view the relative proportion of some or all components assigned
to a given cell. Thus, for example, if the user deselects source A
check box 675, design module 130 removes the layer corresponding to
that source from each cell in array 607, allowing the user to view
the relative proportions of the remaining components without regard
to the amount of that source assigned to each destination region.
Optionally, the user can view composition data in the form of an
set of pie charts, described in more detail in connection with FIG.
8C, below, with each individual pie chart being divided into
colored wedges depicting the relative amount of a corresponding
component assigned to that destination region. The user can also
access numerical compositional data in spreadsheet form by
selecting an appropriate menu item, toolbar button or similar
graphical device in user interface 160.
[0063] User interface 160 and design module 130 are also configured
to enable the user to define a distribution scheme using systems of
one or more equations defining the amount of a component or
components, or the ratio between two or more such components, to be
assigned to one or more destination regions. The user can employ
such a "design by equations" mapping scheme to define mappings for
the entire combinatorial library, or to define one or more mappings
of a multi-mapping library design in combination with the gradient
mapping implementation discussed above.
[0064] As shown in FIG. 7A, the user defines an equation by
selecting an appropriate menu item or toolbar button, such as
equation design button on toolbar 610, causing user interface 160
to display equation design arrangement 705 and associated equation
design toolbar 710 in pane 700. The user initiates equation design
by selecting Equation Design button 711, and partitions array 705
into regions, such as regions 706, 707, 708 and 709, for example by
selecting the desired regions with a mouse or other input device.
Selection of row partition or column partition buttons 715 and 716
causes design module 130 to insert a row or column header, such as
column header 720, and creates a group of destination cells--for
example, the group of cells in region 706--that will be governed by
any equations assigned to the corresponding header. By repeating
the partitioning operation with various sizes of destination
regions, the user can create multiple row and column headers
capable of applying multiple equations to the cells of destination
arrangement 705 as will be described below.
[0065] The user may assign a component (i.e., a source or sources,
including a chemical or chemicals) to a header by selecting the
appropriate icon (e.g., icon 731) from the current library design
folder in outline pane 730, and dragging the selected source and
dropping it into the desired header 720 in destination arrangement
705. This action causes design module 130 to assign the component
represented by source icon 731 to all cells assigned to header 720
for use in equations governing those cells as described below.
Optionally, the user may assign components (sources or chemicals)
to one or more individual cells or groups of cells by dragging the
selected component and dropping it into the desired cell or cells.
The user may also assign multiple components to a destination by
first defining an appropriate array of sources--for example an
array of different chemicals of the same type--and dragging the
source array onto the desired destination.
[0066] The user defines an equation by, for example, selecting a
desired header and causing design module 130 to prompt the user to
enter the relevant equation properties, for example through an
equation property dialog 740 as shown in FIG. 7B. In dialog 740,
the user defines a ratio equation describing a relationship
between, for example, two or more components or chemical types as a
sum of weighted terms. In fields 742, the user identifies the
desired terms, which may include user-defined types or subtypes
(e.g. catalysts, co-catalysts, solvents, initiators, monomers,
surfactants, ligands, metals and the like), sources, chemicals or
synthesis parameters such as total mass, total volume and the like.
In one embodiment, terms in fields 742 may be selected from a list
of available types, sources, chemicals and synthesis parameters by
activating an arrow button 744 associated with a field 742 that
invokes a pull-down menu identifying the available choices that
have been defined as discussed above. The user enters coefficients
defining the weighting of the selected term in coefficient fields
746. Additional types or subtypes, sources, chemicals or synthesis
parameters can be incorporated in an equation by selecting box 748,
which appends an additional line 750 to the equation, with
additional term and coefficient fields 752 and 754. The user also
selects an appropriate unit in unit field 755. Selection of OK
button 756 causes design module 130 to assign the specified
equation to the selected header. An icon representing the newly
defined equation object is added to Equations folder 736 in outline
pane 730.
[0067] Referring to FIG. 7C, more complex relationships can be
defined by using coefficient functions, accessed in this embodiment
by selecting coefficient box 760. This feature permits the user to
use equations to define gradients to be applied across the cells in
a region governed by a particular equation. As described above, the
user selects appropriate terms (types, sources, chemicals,
synthesis parameters) in term fields 762, and enters minimum and
maximum coefficient values in fields 763 and 764, entering a step
value for the gradient in step width field 765. The user then
selects a desired function defining the change in coefficient
values, such as linear, exponential or logarithmic functions, in
function field 767, and selects a gradient direction, such as
horizontal, vertical or diagonal, in direction field 768. A
starting point for application of the gradient is selected using
radio buttons 769. Selection of OK button 770 causes design module
130 to assign the defined function to the selected header, and to
add an icon representing the equation object to the Equations
folder in outline pane 730.
[0068] The user may assign equations to individual destination
cells or groups of cells. A pre-defined equation can be assigned to
a cell or group of cells, for example by selecting the equation
icon from Equations folder 736 in outline pane 730 and dragging the
equation to a desired cell or group of cells, or dragging the
equation to a header governing a desired group of cells. The user
may view a list of all equations defined for a particular cell,
group of cells, or for the entire destination, for example in an
equation list dialog window, and may copy equations from one cell
or group of cells and assign those equations to another cell or
group of cells, or to a header governing another group of
cells.
[0069] FIG. 8A depicts a pane 800 illustrating a destination 810
for which a number of governing equations have been defined as
described above. The user accesses this equation view of
destination 800 by, for example, selecting an appropriate menu item
or toolbar button, or by selecting arrangement 705 in FIG. 7A or
array 607 in FIG. 6A with a mouse or other input device.
Destination 810 includes rows and columns of cells 815 that
correspond to the cells of arrangements 607 and/or 705. In this
example, each cell 815 is depicted as including an equation
designated as E7, E8, E9 or E10. The equations themselves are
displayed as items in Equations folder 806 in outline pane 805.
[0070] Thus, for example, cells 801 to which equation E8 is
assigned are subject to the equation [Mole Equiv.]
CoCatalyst=1.0*Catalyst, where CoCatalyst and Catalyst are chemical
Types defined in the Chemicals layer of the corresponding
definition pane. Each cell 801 is also governed by equations
appearing in headers located above the column and to the left of
the row in which that cell appears. The cell identified by
reference numeral 802, for example, is subject to the following
equations: [Mole Equiv.] CoCatalyst=0.1*Catalyst [uL]
TotalVolume=200 [mg] Substrate=0.12*Total Mass [Mole Equiv.]
Catalyst=0.0001*Substrate while the cell identified by reference
numeral 803 is subject to the following equations: [Mole Equiv.]
CoCatalyst=0.1*Catalyst [uL] TotalVolume=200 [mg]
Substrate=0.12*Total Mass [Mole Equiv.] Catalyst=0.01*Substrate As
discussed above, the location of a given cell 801 also determines
which specific components (chemicals or sources) are to be used to
supply the Types specified by the relevant equations. Thus, for
cell 802 discussed above, design module 130 will use Sources SolvA,
SubB, CatD and CoCatE for Types Solvent, Substrate, Catalyst and
CoCatalyst, respectively, in solving the set of equations that
determine the composition of the corresponding region. That is,
design module 130 will solve the following set of equations to
calculate the composition of cell 802: [Mole Equiv.]
CoCatE=0.1*CatD [uL] TotalVolume=200 [mg] SubB=0.12*Total Mass
[Mole Equiv.] CatD=0.0001*SubB
[0071] The use of subtypes provides the user additional flexibility
in designing a library using equations. For example, a user may
design a library for copolymerizing pairs of monomers, with the
monomers being added at different times during the polymerization
reaction. By defining two chemical subtypes--for example, "first
monomer" and "second monomer"--under single chemical type
"monomer", the user may define the total amount of combined monomer
using one equation (e.g., [(mg) monomer=0.2 Total Mass]), while
defining the ration of the first monomer to the second monomer
using a second equation (e.g., [(mg) first monomer=0.3 second
monomer]).
[0072] In one embodiment, the user may cause design module 130 to
verify that the set of defined equations is solvable at any time
during the library design process, for example by selecting Check
Mode button 812. In response to this selection, design module 130
performs a number of checks to determine whether the user has
provided sufficient information to enable design module 130 to
solve the set of equations. Thus, for example, design module 130
determines whether the user has provided all source information,
such as chemical molecular weight, concentration, density and the
like, that will be required by the set of equations. If design
module 130 determines that all necessary source information has not
been defined, design module 130 prompts the user to enter the
necessary information through user interface 160. Design module 130
also determines whether the number of defined equations matches the
number of defined sources (and whether chemicals or sources of all
appropriate Types have been assigned to each cell) and verifies
that no equations are duplicated. For any cells that fail this
equation check, design module 130 informs the user of an equation
error through user interface 160, for example by displaying an
appropriate error message or displaying the destination array with
failed cells identified by an appropriate color or pattern, such as
by displaying cells for which sufficient information has been
defined in green and all other cells in red. Optionally, design
module 130 also informs the user of the reason or reasons why the
equations defined for a given cell cannot be solved.
[0073] Upon receiving user input indicating that equation design is
complete (for example, by selection of Solve Equations button 813),
design module 130 uses conventional matrix algebra techniques to
solve the equations defined for a given destination to calculate
the composition of the corresponding destination cells,
substituting the appropriate Chemicals and Sources for Types
included in the set of equations defined for each cell. Thus, for
example, design module 130 uses techniques such as LU decomposition
to solve a set of defined ratio equations, providing results in the
form X=X.sub.1+X.sub.2, where X.sub.1 is a sub-vector of chemical
masses and X.sub.2 is a sub-vector of volumes of stock materials.
Design module 130 may be configured to accept and solve other types
of equations, such as mass equations defined as: [ - I ] .times. X
1 + [ D ] .times. X 2 = 0 ##EQU1## or , .times. [ - I D ]
.function. [ X 1 X 2 ] = 0 , ##EQU1.2## where X.sub.1 is a
sub-vector of chemical masses and X.sub.2 is a sub-vector of
volumes of stock materials, I is the identity matrix and D is the
density matrix.
[0074] The calculations with which design module 130 solves the set
of equations for each cell may be internal to the computer and
invisible to the user; optionally, design module 130 displays the
calculations in a window through user interface 160. As described
above in connection with Check Mode button 812, when solving
equations design module 130 optionally identifies each cell for
which the assigned equations have a valid solution with an
appropriate color, pattern or other visual display scheme, while
identifying cells for which the assigned equations are not solvable
with another appropriate display scheme (such as, for example,
displaying cells with a valid solution in green and other cells in
red). Design module 130 is configured to allow the user to
"diagnose" the reason for the failure to solve a cell's equations
by, for example, displaying in response to appropriate user input
an Equation Matrix dialog 830, as shown in FIG. 8B. For a selected
cell, here cell 802 in array 810, dialog 830 displays a status for
the cell (e.g., "Equation solving failed"), as well as a
spreadsheet 835 with regions corresponding to values derived from
the equations assigned to the selected cell (840), values
calculated from stock material concentrations defined in the
definition pane (845) and equation solutions for chemical mass and
stock solution volume (850). In the example depicted in FIG. 8B,
solutions region 850 reveals that the calculated volume for SolvA
is negative, rendering the equations assigned to cell 802 not
solvable.
[0075] As shown in FIG. 8C, the user may view a graphic display of
the calculated composition data resulting for an equation design by
selecting an appropriate menu item of toolbar button, such as
Display Data button 856 of graphical pane 855. The user may elect
to view composition data by chemical mole or mass ratio, for
example by selecting chemical button 860 and mole or mass buttons
862 or 863, respectively; alternatively, composition data may be
displayed by source volume ratio by selecting source button 865 and
corresponding volume button 866. Selection of pie chart button 868
causes design module 130 to display the composition data as an
arrangement 870 of cells 872. Each cell 872 contains a pie chart
875 representing the calculated composition of the corresponding
destination region determined by solution of the set of equations
assigned to that cell. The relative proportion of each component
assigned to the destination region (in units determined by the
selected viewing option--volume for stock material solutions, mass
or molarity for chemicals) is represented in each chart 875 by the
size of a corresponding pie wedge depicted in a color or pattern
associated with a given component (e.g., by colors assigned to each
source component in Sources folder 877 in outline pane 880. By
selecting or unselecting the check box associated with each source
(or chemical, depending on the selected view option) in outline
pane 880, the user may view the relative proportion of some or all
components assigned to a given cell. Thus, for example, if the user
deselects SolvA check box 882, design module 130 removes the pie
wedge corresponding to that source from each pie chart 875 in
arrangement 870, allowing the user to view the relative proportions
of the remaining components without regard to the amount of solvent
(SolvA) assigned to each destination region. The user may also view
the calculated composition data in layered chart form as described
above in connection with FIG. 6A, above. Numerical composition data
for each destination region may be displayed through a cell
composition data dialog 885, as shown in FIG. 8D.
[0076] Referring again to FIG. 3, in one embodiment, design module
130 is configured to enable the user to incorporate varying process
parameters into a library design through parameters specifying a
scheme of varying values across one or more destinations.
Parameters can include any external conditions, such as
temperature, pressure, mixing speed, quench time, flow rate and the
like. The user defines a parameter by, for example, selecting an
appropriate menu item or toolbar button (step 330). Design module
130 prompts the user to enter the necessary information by
displaying an appropriate dialog, such as Parameter Property dialog
900 shown in FIG. 9A. The user assigns a parameter name in name
field 905 and selects a parameter type and appropriate units in
fields 910 and 915. The user identifies one or more destinations in
field 920 to which design module 130 will apply the defined
parameter. In field 925, the user selects a scheme for varying the
parameter values, which may include schemes such as temporal
variation, spatial variation and the like, as well as combinations
of such variation schemes. Design module 130 is configured to vary
parameter values spatially, across one or more rows or columns,
specified by the user in fields 930 and 935, respectively.
Similarly, the user defines a temporal variation by specifying a
time function (such as a linear function or a step function), a
number of time steps and an appropriate time unit (such as seconds,
minutes or hours) in fields 950, 940 and 945, respectively. The
user may enter comments describing the parameter in comment field
955. Upon completion, signified, for example, by the user's
selection of OK button 960, design module 130 stores the parameter
in memory 180, adds a corresponding parameter icon to parameter
folder 515 in outline pane 510, and allocates space in the
parameter layer of definition pane 530, as will be described
next.
[0077] As shown in FIG. 9B, a parameter layer 965 is accessed by
selecting parameter tab 970 in definition pane 968. Parameter layer
965 includes an entry for each defined parameter, such as
Temperature parameter 975 and Pressure parameter 980. Each defined
parameter is identified by an expandable entry identifying the
parameter type (975, 980), which, upon expansion, displays the
parameter properties input through Parameter Property dialog 900,
as discussed above, such as a name 976, a step identifier 977, a
start time 978 for each step, and a description or value for the
parameter at that step 979. As appropriate, parameter layer 965
includes a spreadsheet-type display 985 depicting a parameter value
for each cell in the destination to which the parameter is assigned
in field 920 of Parameter Property dialog 900, as described above.
Design module 130 is configured to allow the user to enter
parameter values manually into parameter layer 965; alternatively,
design module 130 populates parameter values according to a
variation scheme defined in Parameter Property dialog 900, such as
applying a constant or gradient function to a selected group of
destination cells. The user can modify parameter values through
Parameter Property dialog 900, or directly through parameter layer
965.
[0078] When library design is complete, the user may optionally
store design files, including some or all of the design
information--ie. the sources, destinations and parameters, as well
as the mapping scheme and other related information--in memory 180.
In one embodiment, design module 130 outputs a text file (or a
tab-delimited spreadsheet file in a format suitable for a program
such as Microsoft.RTM. Excel), describing the relative or absolute
amounts of components to be deposited at each library member to
allow a chemist to manually prepare the designed library.
Alternatively, design module 130 can be configured to output an
image file, such as Microsoft.RTM. PowerPoint file, depicting the
graphical layer chart or pie chart display of composition data for
a selected destination.
[0079] Design module 130 is also configured to generate a recipe
file containing a set of synthesis instructions in a generic format
that can be retrieved by synthesis module 140 for automated
processing by material handling apparatus 180 (step 340 in FIG. 3).
Appropriate apparatus 180 can include, for example, automated
liquid handling robots, such as the RSP 900 Robotic Sample
Processor, available from Cavro Scientific Instruments, Inc. of
Sunnyvale, Calif. Apparatus 180 can also include automated systems
performing different types of physical or chemical vapor
deposition. In liquid handling, mixtures of solutions are typically
dispensed in an array of miniature wells to create a library. In
vacuum deposition, solid elements or chemicals or mixtures of solid
elements or chemicals are vaporized and deposited as individual
components on a substrate. The deposition may be controlled by a
series of shutters and masks to manufacture the library. For an
example of deposition equipment, see WO98/47613 (U.S. application
Ser. No. 08/841,423), filed on Apr. 22, 1997.
[0080] In one embodiment, an appropriate data file or recipe file
includes an entry for each source, each destination, each
parameter, and each mapping created as described above, such as
shown in Table 1 for the component labeled "CatA" in the equation
design illustrated in FIG. 8A. TABLE-US-00001 TABLE 1 [COMPONENT_1]
compLabel = CatA libRegBegin = NULL libRegEnd = NULL arrayGeom =
RECT numRows = 1 numColumns = 1 [MAPPING_1] Source = CatA
SourceRect = (1, 1),(1, 1) Destination = Plate DestRect = (2,
2),(7, 11) GradientType = LIN GradientParams = 10.000000 0.0 0.0
-2.000000 0.000000 0.0 0.0 1 0 Tag =
Design module 130 graphically represents the recipe file for the
current design as an icon 520 in outline pane 510 shown in FIG.
5A.
[0081] As described above, design module 130 creates a library
design unconstrained by the physical limitations of available
synthesis apparatus and library substrates. Thus, while the user
may design a library using a destination arrangement containing the
number of library members (i.e. individual reactors) in the same
geometry (e.g., the number of rows and columns) as the physical
substrate on which the library will ultimately be prepared, design
module 130 enables the user to design libraries without regard to
these constraints. Thus, the user may design a conceptual "virtual"
library containing vast numbers of individual members (thus
spanning multiple physical libraries), yet connected by a central
chemical concept. Similarly, the user may also design a library in
a preferred design environment (e.g., a geometry that best defines
a library concept such as the ternary design shown in FIG. 4),
while the design can be implemented in a different physical
geometry for convenience of library synthesis. One such virtual
library design is shown in FIG. 10. The user designs a library of
varying compositions of sources A and B in ternary form on "Virtual
Plate" destination 1000, with the amount of source A assigned to
each cell determined by a linear gradient defined in equation 1010.
Design module 130 then maps the 91 occupied cells of destination
1000 onto rectangular "Physical Plate" 1020 for implementation by
conventional synthesis apparatus.
[0082] The user can also define a library design for use as a
template in the design and preparation of multiple related
libraries. Thus, for example, a library design of 96 different
catalyst formulations may be used as a template to explore the
polymerization of various organic monomers. Alternatively, a design
can be defined for a portion of a single destination and used as a
template to define multiple designs covering the entire
destination--for example, the user may create a template design for
a library of polymerization catalysts that covers only a single
quadrant of an 8.times.12 destination and use the template to
define a set of four library designs in which four different
monomers are polymerized in the presence of the catalyst library.
In this embodiment, the user designs the library as described
above, with one source defined to correspond to one desired
monomer, and stores the design in memory 150. The user may then
retrieve the design and use design module 130 to create a series of
library, one for each desired monomer, by simply replacing the
defined monomer in the template design, recalculating the
composition of each destination cell and generating the
corresponding recipe file. More generally, the user may create a
template design using a set of n design elements, where, for
example, n defines the number sources used in the design, and
instruct design module 130 and synthesis module 140 to generate a
series of m libraries, where m>n and m is a number of actual
sources used in preparing the libraries. Thus, while the library
design may specify a combination of a limited number of design
elements--for example, a quaternary library of inorganic materials
in which each cell contains a mixture of four materials--the
library design can be implemented for a larger number of elements,
by creating a set of libraries encompassing all possible
combinations/iterations of sources from the set of available
sources--for example, by creating all possible combinations of four
materials from a set of six available materials. Similar template
designs can be created for designs involving any design
elements--for example, multiple equation coefficients, multiple
parameter values, or any combination of elements.
[0083] In one embodiment, design module 130 is configured to
interact with a database 150 associated with system 100 that is
capable of archiving information pertaining to available chemicals,
stock materials, composition data for existing library designs and
the like. In this embodiment, the user may search the database for
chemicals based on relevant identifying information, such as
chemical name, formula, identification number (e.g., CAS number) or
the like. The user may select any chemicals identified in such a
search, and design module 130 downloads chemical attribute
information into the Chemicals layer in the current library design
(e.g., definition pane 530 in FIG. 5A). To facilitate archiving and
tracking of existing library designs, the user may register one or
more libraries on a designed destination in a database 150
associated with system 100. Design module 130 assigns each library
so registered an identification number with which each library may
later be retrieved from database 150. Similarly, the user may load
composition data for one or more libraries on a destination to
database 150 for later retrieval.
[0084] The design methods and programs of the present invention can
be advantageously applied in connection with the design and
synthesis of libraries or arrays of diverse materials. Preferably,
such diverse materials are candidate materials (e.g., catalysts)
being evaluated for a desired chemical property, for example a
capability to enhance a chemical process (e.g., chemical reaction)
of interest.
[0085] A library of such materials can be a physical array of
candidate materials, comprising a substrate and two or more
different candidate materials, and preferably four or more
different candidate materials at separate portions of the
substrate, corresponding to library members. Each candidate
material can consist essentially of two components (or source
materials--e.g., a combination of sources A and B). Alternatively,
additional components can be incorporated in the library design,
resulting in libraries of diverse materials having compositions
that are essentially ternary, quaternary or higher order. Such
higher-order compositions can be designed to include the same
components (e.g., A, B and C) in each composition, but in varying
amounts or ratios, or alternatively, to include different
components (e.g., A, B and C; A, B and D; A, B and E; A, B and F,
etc.) in two or more of the compositions. In one preferred library,
the is a spatially addressable array of materials that comprises a
substrate having a surface and nine or more materials having
different compositions at nine or more discrete regions of the
substrate surface, with each material-containing region consisting
essentially of one material. The nine or more materials preferably
comprising two or more common components of interest, A and B, with
the amount of at least one of the common components, A, preferably
varying incrementally and uniformly between the nine or more
materials, such that the nine or more materials form a uniform
compositional gradient with respect to component A. The gradient
can be linear, exponential, etc., as described above. The amount of
one or more additional components (e.g., component B) can also
vary. Non-gradient applications are also considered, as explained
above in connection with the various mappings. In a particularly
preferred library, the array comprises eleven or more materials at
eleven or more discrete regions of the substrate, and at least one
of the materials comprises component A and an essential absence of
component B.
[0086] Appropriate candidate materials can include elements,
compounds or compositions comprising a plurality of elements and/or
compounds, and can be in a gaseous, liquid or solid phase.
Solid-phase materials are preferred for some applications. The
particular elements, compounds or compositions to be included in a
library of candidate materials will depend upon the particulars of
the chemical phenomenon or process being investigated. However, the
nature of the particular chemical phenomenon or process being
investigated is not critical, such processes can include, for
example, chemical reactions and chemical separations, among
others.
[0087] For example, candidate materials can include compositions
that catalyze reactions including activation of, breaking and/or
formation of H--Si, H--H, H--N, H--O, H--P, H--S, C--H, C--C,
C.dbd.C, C.ident.C, C-halogen, C--N, C--O, C--S, C--P, C--B and
C--Si bonds among others. Exemplary chemical reactions for which
reaction-enhancing materials may be identified according to the
present invention include, without limitation, oxidation,
reduction, hydrogenation, dehydrogenation (including transfer
hydrogenation), hydration, dehydration, hydrosilylation,
hydrocyanation, hydroformylation (including reductive
hydroformylation), carbonylation, hydrocarbonylation,
amidocarbonylation, hydrocarboxylation, hydroesterification,
hydroamination, hetero-cross-coupling reaction, isomerization
(including carbon-carbon double bond isomerization), dimerization,
trimerization, polymerization, co-oligomerization (e.g. CO/alkene,
CO/alkyne), co-polymerization (e.g. CO/alkene, CO/alkyne),
insertion reaction, aziridation, metathesis (including olefin
metathesis), carbon-hydrogen activation, cross coupling,
Friedel-Crafts acylation and alkylation, Diels-Alder reactions,
C--C coupling, Heck reactions, arylations, Fries rearrangement,
vinylation, acetoxylation, aldol-type condensations, aminations,
reductive aminations, epoxidations, hydrodechlorinations,
hydrodesulfurations and Fischer-Tropsch reactions, asymmetric
versions of any of the aforementioned reactions, and combinations
of any of the aforementioned reactions in a complex reaction
sequence of consecutive reactions. For chemical reactions,
candidate materials can be generally classified as those materials
which are chemically altered or consumed during the course of the
reaction (e.g., co-reactant materials, cataloreactants) and those
materials which are not chemically altered or consumed during the
course of the reaction (e.g., catalysts, selective blocking
moieties). In preferred applications, candidate materials are
catalysts, which term, as used herein, is intended to include a
material that enhances the reaction rate of a chemical reaction of
interest or that allows a chemical reaction of interest to proceed
where such reaction would not substantially proceed in the absence
of the catalyst.
[0088] Appropriate candidate materials preferably include elements
or compounds selected from the group consisting of inorganic
materials, metal-ligand complexes and non-biological organic
materials. In some applications, candidate materials will consist
essentially of inorganic materials, consist essentially of
metal-ligand materials, or consist essentially of non-biological
organic materials. Moreover, in some applications, source and/or
candidate materials will be compositions comprising mixtures of
inorganic materials, metal-ligand materials, and/or non-biological
organic materials in the various possible combinations.
[0089] Inorganic materials include elements (including carbon in
its atomic or molecular forms), compounds that do not include
covalent carbon-carbon bonds (but which could include carbon
covalently bonded to other elements, e.g., CO.sub.2), and
compositions including elements and/or such compounds. Inorganic
candidate materials that could be investigated in libraries
designed according to the approaches described herein include, for
example: noble metals such as Au, Ag, Pt, Ru, Rh, Pd, Ag, Os and
Ir; transition metals such as Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Y,
Zr, Nb, Mo, Ta, W and Re; rare-earth metals such as La, Ce, Pr, Nd,
Sm, Eu, Th, Th and U; alloys of noble metals, transition metals
and/or rare-earth metals; metal oxides such as CuO, NiO and
CO.sub.3O.sub.4; noble-metal-doped metal oxides such as
noble-metal-doped CuO, NiO and CO.sub.3O.sub.4; multi-metal oxides
such as binary oxides of Cu--Cr, Cu--Mn, Cr--Mn, Ni--Cr, Ni--Mn,
Ni--Cu, Ni--Mo, Cu--Mo, Ni--Co, Co--Mo, Ni--Fe, Fe--Mo, Cu--Fe,
Mn--Ag, Mn--Sn, Ag--Sn, Cu--Ag, Cu--V, Ag--V, Cu--V, Ni--V, Bi--Mo,
Bi--V, Mo--V, V--Zr, V--Ti, Zr--Ti, V--Nb, Nb--Mo, V--P, P--Mo,
Ni--P, P--Cu, Co--P, Co--Fe, P--Fe, Mg--V, Mg--Sn, V--Sn, K--Ti,
K--Bi, Ti--Bi, Cr--Sb, Cr--V, Sb--V, Bi--Mo, Bi--Nb, K--Cr, K--Al,
Al--Cr, Zn--Cu, Zn--Al, Cu--Al, La--Cr, La--Zr, Cr--Zr, La--Mo,
Mo--Zr, La--W, W--Zr, Mo--W, W--V, Cu--W, Bi--W, Fe--Sb, Fe--V and
Ni--Ta, Ni--Nb and Ta--Nb, and such as ternary oxides of
Cu--Cr--Mn, Ni--Cr--Mn, Ni--Cu--Mo, Ni--Co--Mo, Ni--Fe--Mo,
Cu--Fe--Mo, Mn--Ag--Sn, Cu--Ag--V, Cu--Ni--V, Bi--Mo--V, V--Zr--Ti,
V--Nb--Mo, V--P--Mo, Ni--P--Cu, Co--P--Fe, Mg--V--Sn, K--Ti--Bi,
Cr--Sb--V, Bi--Mo--Nb, K--Cr--Al, Zn--Cu--Al, La--Cr--Zr,
La--Mo--Zr, La--W--Zr, Mo--W--V, Cu--Mo--W, Bi--Mo--W, Bi--V--W,
Fe--Sb--V and Ni--Ta--Nb; metal carbides such as PdC; metal
sulfates, metal sulfides, metal chlorides, metal acetates,
polyoxometallates (POM); metal phosphates such as
vanadylpyrophosphates (VPO); Bronstead acids such as HF; Lewis
Acids such as AlCl.sub.3; and mixtures of any of the aforementioned
inorganic materials, among others. Exemplary inorganic material
libraries could include, for example, triangular-shaped arrays of
ternary metal oxides (e.g. such as oxides of the ternary metal
partners described above) with single metal oxide compounds at each
corners, binary metal oxide compositions along each of the sides
with varying ratios of constituents, and ternary metal oxide
compositions in the interior regions of the triangular array with
varying ratios of constituents. Libraries of inorganic candidate
materials can be prepared, for example, according to the methods
disclosed in U.S. Pat. No. 5,776,359 to Schultz et al. Metal-ligand
complexes comprise a central metal atom or ion surrounded by,
associated with and/or bonded to other atoms, ions, molecules or
compounds--collectively referred to as "ligands"--typically through
a carbon (to form, e.g., an organometallic), nitrogen, phosphorous,
sulfur or oxygen atom and/or one or more linker moieties. The one
or more ligands typically bind to one or more metal center and/or
remain associated therewith, and by such association, modify the
shape, electronic and/or chemical properties of the active metal
center(s) of the metal-ligand complex. The ligands can be organic
(e.g., .eta..sup.1-aryl, alkenyl, alkynyl, cyclopentadienyl, CO,
alkylidene, carbene) or inorganic (e.g., Br.sup.-, Cl.sup.-,
OH.sup.-, NO.sup.2-, etc.), and can be charged or neutral. The
ligand can be an ancilliary ligand, which remains associated with
the metal center(s) as an integral constituent of the catalyst or
compound, or can be a leaving group ligand, which may be replaced
with an ancillary ligand or an activator component. Exemplary
metals/metal ions include ions derived from, for example, simple
salts (e.g., AlCl.sub.3, NiCl.sub.2, etc.), complex or mixed salts
comprising both organic and inorganic ligands (e.g., [({acute over
(.eta.)}5-C.sub.5Me.sub.5)IrCl.sub.2].sub.2, etc.) and metal
complexes (e.g., Gd(NTA).sub.2, CuEDTA, etc.), and can generally
include, for example, main group metal ions, transition metal ions,
lanthanide ions, etc.
[0090] Libraries of metal-ligand candidate materials designed
according to the methods and programs described herein can be
prepared, for example, according to the methods disclosed in PCT
Patent Application WO 98/03521 of Weinberg et al. Briefly, a
desired ligand can be combined with a metal atom, ion, compound or
other metal precursor compound. In many applications, the ligands
will be combined with such a metal compound or precursor and the
product of such combination is not determined, if a product forms.
For example, the ligand may be added to a reaction vessel at the
same time as the metal or metal precursor compound along with the
reactants. The metal precursor compounds may be characterized by
the general formula M(L).sub.n (also referred to as ML.sub.n or
M-L.sub.n) where M is a metal and can include metals selected from
the group consisting of Groups 5, 6, 7, 8, 9 and 10 of the Periodic
Table of Elements. In some embodiments, M can be selected from the
group consisting of Ni, Pd, Fe, Pt, Ru, Rh, Co and Ir. L is a
ligand and can be selected from the group consisting of halide,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted
aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, hydroxy,
boryl, silyl, hydrido, thio, seleno, phosphino, amino, and
combinations thereof, among others. When L is a charged ligand, L
can be selected from the group consisting of hydrogen, halogens,
alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,
heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl,
substituted aryl, heteroaryl, substituted heteroaryl, alkoxy,
aryloxy, silyl, boryl, phosphino, amino, thio, seleno, and
combinations thereof. When L is a neutral ligand, L can be selected
from the group consisting of carbon monoxide, isocyanide, nitrous
oxide, PA.sub.3, NA.sub.3, OA.sub.2, SA.sub.2, SeA.sub.2, and
combinations thereof, wherein each A is independently selected from
a group consisting of alkyl, substituted alkyl, heteroalkyl,
cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted
heterocycloalkyl, aryl, substituted aryl, heteroaryl, substituted
heteroaryl, alkoxy, aryloxy, silyl, and amino. Specific examples of
suitable metal precursor compounds include Pd(dba).sub.2
(dba=dibenzylydieneacteone), Pd.sub.2(dba).sub.3, Pd(OAc).sub.2
(Ac=acetate), PdCl.sub.2, Pd(TFA).sub.2, (TFA=trifluoroacetate),
(CH.sub.3CN).sub.2PdCl.sub.2, and the like. In this context, the
ligand to metal precursor compound ratio is in the range of about
0.01:1 to about 100:1, more preferably in the range of about 0.5:1
to about 20:1. The metal atom, ion or metal precursor may be
supported or not. Supports may be organic or inorganic. Similar to
the ligands, the support may be an L. In other embodiments, the
support will not form part of the metal precursor and suitable
supports include silicas, aluminas, zeolites, polyethyleneglycols,
polystyrenes, polyesters, polyamides, peptides and the like.
Specific examples of Pd supported metals include Pd/C,
Pd/SiO.sub.2, Pd/CaCO.sub.3, Pd/BaCO.sub.3, Pd/aluminate,
Pd/aluminum oxide, Pd/polystyrene, although any of the metals
listed above could replace Pd in this list, e.g., Ni/C, etc. In
other applications, the ligand will be mixed with a suitable metal
precursor compound prior to or simultaneous with allowing the
mixture to be contacted to the reactants. When the ligand is mixed
with the metal precursor compound, a metal-ligand complex may be
formed, which may be employed as a candidate material.
[0091] Non-biological organic materials include organic materials
other than biological materials. Organic materials are considered
to include compounds having covalent carbon-carbon bonds.
Biological materials are considered to include nucleic acid
polymers (e.g., DNA, RNA) amino acid polymers (e.g., enzymes) and
small organic compounds (e.g., steroids, hormones) where the small
organic compounds have biological activity, especially biological
activity for humans or commercially significant animals such as
pets and livestock, and where the small organic compounds are used
primarily for therapeutic or diagnostic purposes. While biological
materials are of immense commercial interest with respect to
pharmaceutical and biotechnological applications, a large number of
commercially significant applications involve chemical processes
that are enhanced by other than biological materials. Moreover,
while fundamental screening approaches for many pharmaceutical and
biological activities are known or readily adapted from known
approaches, screening approaches for non-biological materials have
not heretofore been widely investigated and reported. Although
candidate materials being screened are preferably not, themselves,
biological organic materials, candidate materials included in
libraries designed according to the invention (e.g., inorganic
materials) can be employed to enhance reactions directed to
producing a biological organic material as the product of a
chemical reaction (e.g., materials that enhance chemical-based,
non-enyzmatic DNA synthesis, or materials that enhance a synthetic,
non-enyzmatic route to a particular hormone or steroid).
[0092] The amount of an individual candidate material located in a
particular library member varies depending upon the required
application and the method by which the library is prepared. For
thin films, for example, the amount of material will depend on the
surface area of the film and the required thickness of the film,
each of which will, in turn, vary depending upon the chemical
process of interest. For catalyst applications, the geometry of the
reactor, and the required residence time or contact time of
reactants in the reactor, among other factors, will also be
important. In general, the amount of an individual candidate
material is typically not more than about 25 mg, preferably not
more than about 10 mg, and can be not more than about 7 mg, not
more than about 5 mg, not more than about 3 mg and not more than
about 1 mg. In preferred embodiments, the amount of an individual
candidate material can range from about 0.1 .mu.g to about 100 mg,
preferably from about 1 .mu.g to about 10 mg, more preferably from
about 10 .mu.g to about 1.0 mg and most preferably from about 100
.mu.g to about 1 mg.
[0093] Libraries designed according to the methods discussed above
can be prepared on any convenient substrate, including any suitable
material having a rigid or semi-rigid surface on which the
candidate materials can be formed or deposited or to which the
candidate materials can be linked. The substrate preferably
consists essentially of materials that are inert with respect to
the materials and chemical processes of interest. Certain materials
will, therefore, be less desirably employed as a substrate material
for certain reaction process conditions (e.g., high
temperatures--especially temperatures greater than about
100.degree. C.--or high pressures) and/or for certain reaction
mechanisms. The substrate material is also preferably selected for
suitability in connection with microfabrication techniques, such as
selective etching (e.g., chemical etching in a liquid or gaseous
phase, plasma-assisted etching, and other etching techniques)
photolithography, and other techniques known or later-developed in
the art. Silicon, including polycrystalline silicon, single-crystal
silicon, sputtered silicon, and silica (SiO.sub.2) in any of its
forms (quartz, glass, etc.) are preferred substrate materials.
Other known materials (e.g., silicon nitride, silicon carbide,
metal oxides (e.g., alumina), mixed metal oxides, metal halides
(e.g., magnesium chloride), minerals, zeolites, and ceramics) may
also be suitable for a substrate material. Organic and inorganic
polymers may also be suitably employed in some applications of the
invention.
[0094] Appropriate substrates may, but need not necessarily, have
at least one substantially flat, substantially planar surface, and
may preferably, but not necessarily, be a substantially planar
substrate such as a wafer. The surface of the substrate can be
divided into physically separate regions and can have, for example,
dimples, wells, raised regions, etched trenches, or the like formed
in the surface. In still other embodiments, small beads or pellets
may be the substrate, and such beads or pellets may be included in
an array, for example, for example, placing the beads within
dimples, wells or within or upon other regions of the substrate's
surface. Frits can be used to hold such beads or pellets in place.
In other applications, the substrate can be a porous material. The
substrate can, and is preferably, passive--having an essential
absence of any active microcomponents such as valves, pumps, active
heating elements, active mixing elements. The substrate also
preferably has an essential absence of passive microcomponents such
as microfluidic channels or apertures used for fluid distribution,
heat-transfer elements, mass-transfer elements (e.g., membranes),
etc., or combinations thereof. In some applications, however, the
substrate can include such active microcomponents or such passive
microcomponents. In a preferred application, the substrate has a
substantially flat upper surface with a plurality of substantially
coplanar indentations or wells of sufficient depth to allow a
quantity of candidate material to be deposited, formed or contained
therein. The overall size and/or shape of the substrate is not
limiting to the invention. The size can be chosen, however, to be
compatible with commercial availability, existing fabrication
techniques (e.g., silicon wafer availability and/or fabrication),
and/or analytical measurement techniques. Generally, the substrate
will be sized to be portable by humans and/or to be manipulated by
automated substrate-handling devices. Hence, two inch and three
inch wafers are suitably employed. The choice of an appropriate
substrate material and/or form for certain applications will be
apparent to those of skill in the art based on the guidance
provided herein.
[0095] In libraries prepared from library designs generated
according to the methods discussed above, the candidate materials
are generally deposited in a plurality of library members arranged
on a substrate. The desired configuration of the candidate material
with respect to the substrate depends upon the application. Thus,
for example, for a library of candidate catalyst materials, the
library can be configured in any design that allows for one or more
reactants to contact the candidate material during the chemical
reaction or other chemical process. Hence, it can be appreciated
that the exact configuration of the candidate materials and the
substrate are not limiting to the invention. Typical configurations
generally allow for fluid flow past and around a candidate material
formed on a surface of a reaction cavity, for unidirectional flow
of reactants through a porous substrate or through a bed of beads,
or for flow of reactants into and out of a well comprising a porous
or non-porous substrate.
[0096] The candidate materials are preferably spatially separated
in the library of candidate materials, preferably at an exposed
surface of the substrate, such that the array of materials can, for
example, be integrated with a plurality of microreactors to include
different candidate materials within different microreactors for
screening individual candidate materials for chemical properties of
interest. Moreover, individual library members are also preferably
separately addressable, for example, for analytical
characterization thereof. The two or more different candidate
materials are therefore preferably located at discrete,
non-contiguous, individually addressable regions of the substrate,
with the regions being spaced to accommodate inclusion into a
plurality of microreactors. The different candidate materials may,
nonetheless, also be contiguous with each other (e.g. as in a
continuous gradient of different material compositions). However,
even where a spatially separated, individually addressable array of
candidate materials is desired in the ultimate physical library,
the library design need not have these features, which may be
incorporated by appropriate synthesis apparatus or by software
controlling such apparatus.
[0097] If the two or more candidate materials are to be deposited
on distinct, individually addressable regions of the substrate, the
separation between adjacent regions can range from about to about
50 .mu.m to about 1 cm, more preferably from about 100 .mu.m to
about 7 mm, and most preferably from about 1 mm to about 5 mm. The
inter-region spacings can be not more than about 1 cm, not more
than about 7 mm, not more than about 5 mm, not more than about 4
mm, not more than about 2 mm, not more 1 mm, not more than about
100 .mu.m, and not more than about 50 .mu.m. Exemplary
inter-regions spacings (center-to-center) based on preferred
embodiments of the invention are 4 mm for having 256 addressable
regions on a three-inch wafer substrate, and 2 mm for having 1024
addressable regions on a three-inch wafer substrate. As such, the
surface density of discrete candidate material regions can range
from about 1 region/cm.sup.2 to about 200 regions/cm.sup.2, more
preferably from about 5 regions/cm.sup.2 to about 100
regions/cm.sup.2, and most preferably from about 10
regions/cm.sup.2 to about 50 regions/cm.sup.2. The planar density
can be at least 1 region/cm.sup.2, at least 5 regions/cm.sup.2, at
least 10 regions/cm.sup.2, at least 25 regions/cm.sup.2, at 50
regions/cm.sup.2, at least 100 regions/cm.sup.2, and at least 200
regions/cm.sup.2. For some reactions, lower or mid-range densities
may be preferred. For other reactions, higher densities may be
suitable. Additionally, even higher densities may be achieved as
fabrication technology develops to nano-scale applications.
[0098] The number of candidate materials to be included on a
physical library is not narrowly critical, and can range, for
example, from two to about a million or more, ultimately depending
on available fabrication techniques and the nature of the chemical
phenomenon or process being investigated. More specifically, the
number of different candidate materials incorporated in a library
is at least 2, preferably at least 5, more preferably at least 10,
still more preferably at least 25, even more preferably at least
50, yet more preferably at least 100, and most preferably at least
250. Present microscale and nanoscale fabrication techniques can be
used, however, to prepare arrays having an even greater number of
different candidate materials. For higher throughput operations,
for example, the number of different candidate materials can be at
least about 1000, more preferably at least about 10,000, even more
preferably at least about 100,000, and most preferably at least
about 1,000,000 or more. The fabrication of arrays comprising very
large numbers of different candidate materials is enabled by
fabrication techniques known in the integrated circuit arts. See,
for example, S. M. Sze, Semiconductor Sensors, Chap. 2, pp. 17-96,
John Wiley & Sons, Inc. (1994). Such approaches have been
adapted in other aspects of catalyst research. See, for example,
Johansson et al., Nanofabrication of Model Catalysts and
Simulations of their Reaction Kinetics, J. Vac. Sci. Technol., 17:1
(January/February 1999).
[0099] The invention can be implemented in digital electronic
circuitry, or in computer hardware, firmware, software, or in
combinations of them. Apparatus of the invention can be implemented
in a computer program product tangibly embodied in a
machine-readable storage device for execution by a programmable
processor; and method steps of the invention can be performed by a
programmable processor executing a program of instructions to
perform functions of the invention by operating on input data and
generating output. The invention can be implemented advantageously
in one or more computer programs that are executable on a
programmable system including at least one programmable processor
coupled to receive data and instructions from, and to transmit data
and instructions to, a data storage system, at least one input
device, and at least one output device. Each computer program can
be implemented in assembly or machine language if desired, or in a
high-level procedural or object-oriented programming language, in
which case individual design elements can be embodied as data
objects in classes having sets of associated properties; in any
case, the language can be a compiled or interpreted language.
Suitable processors include, by way of example, both general and
special purpose microprocessors. Generally, a processor will
receive instructions and data from a read-only memory and/or a
random access memory. Generally, a computer will include one or
more mass storage devices for storing data files; such devices
include magnetic disks, such as internal hard disks and removable
disks; magneto-optical disks; and optical disks. Storage devices
suitable for tangibly embodying computer program instructions and
data include all forms of non-volatile memory, including by way of
example semiconductor memory devices, such as EPROM, EEPROM, and
flash memory devices; magnetic disks such as internal hard disks
and removable disks; magneto-optical disks; and CD-ROM disks. Any
of the foregoing can be supplemented by, or incorporated in, ASICs
(application-specific integrated circuits).
[0100] To provide for interaction with a user, the invention can be
implemented on a computer system having a display device such as a
monitor or LCD screen for displaying information to the user and a
keyboard and a pointing device such as a mouse or a trackball by
which the user can provide input to the computer system. The
computer system can be programmed to provide a graphical user
interface through which computer programs interact with users.
[0101] The invention has been described in terms of particular
embodiments. Other embodiments are within the scope of the
following claims. For example, the steps of the invention can be
performed in a different order and still achieve desirable
results.
* * * * *