U.S. patent application number 10/624191 was filed with the patent office on 2004-01-29 for parallel reaction devices.
This patent application is currently assigned to IRM, LLC. Invention is credited to Backes, Brad, Burow, Kristina, Micklash, Kenneth J. II.
Application Number | 20040018122 10/624191 |
Document ID | / |
Family ID | 25485796 |
Filed Date | 2004-01-29 |
United States Patent
Application |
20040018122 |
Kind Code |
A1 |
Micklash, Kenneth J. II ; et
al. |
January 29, 2004 |
Parallel reaction devices
Abstract
The present invention relates to parallel reaction devices that
include reaction blocks having arrays of reaction wells. Devices of
the invention also typically include lids having arrays of
protrusions disposed thereon, which protrusions axially align with
the reaction wells, and/or attachment components that include
hinges that permit lids to be removed from reaction blocks.
Inventors: |
Micklash, Kenneth J. II;
(San Diego, CA) ; Burow, Kristina;
(Cardiff-by-the-Sea, CA) ; Backes, Brad;
(Cardiff-by-the-Sea, CA) |
Correspondence
Address: |
QUINE INTELLECTUAL PROPERTY LAW GROUP, P.C.
P O BOX 458
ALAMEDA
CA
94501
US
|
Assignee: |
IRM, LLC
|
Family ID: |
25485796 |
Appl. No.: |
10/624191 |
Filed: |
July 21, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10624191 |
Jul 21, 2003 |
|
|
|
09947236 |
Sep 5, 2001 |
|
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|
Current U.S.
Class: |
506/40 ; 422/130;
422/131; 422/400 |
Current CPC
Class: |
B01J 19/0046 20130101;
B01L 3/5025 20130101; B01L 3/50255 20130101; B01L 3/50853 20130101;
B01L 2200/025 20130101; B01J 2219/00286 20130101; B01L 9/523
20130101; B01J 2219/00319 20130101; B01J 2219/00335 20130101; B01L
2300/043 20130101 |
Class at
Publication: |
422/130 ;
422/131; 422/102; 422/99 |
International
Class: |
B01J 019/00 |
Claims
What is claimed is:
1. A parallel reaction device, comprising: (a) a reaction block
comprising an array of reaction wells, wherein at least one
reaction well in the array is disposed through the reaction block,
which reaction well comprises an inlet portion and an outlet
portion; (b) a top lid attached to the reaction block by at least
one top attachment component, which top lid comprises at least one
protrusion disposed on a surface that engages the reaction block,
which protrusion presses a top gasket into contact with the inlet
portion of the reaction well to seal the inlet portion; and, (c) a
bottom lid attached to the reaction block by at least one bottom
attachment component, which bottom lid presses a bottom gasket into
contact with the outlet portion of the reaction well to seal the
outlet portion.
2. The parallel reaction device of claim 1, wherein the reaction
block is disposable.
3. The parallel reaction device of claim 1, wherein the reaction
block comprises cavities disposed between and proximal to inlet
portions of adjacent reaction wells to direct fluidic materials
away from other inlet portions.
4. The parallel reaction device of claim 1, wherein at least a
segment of the reaction well comprises an inner and an outer
cross-sectional shape independently selected from the group
consisting of: a regular n-sided polygon, an irregular n-sided
polygon, a triangle, a square, a rounded square, a rectangle, a
rounded rectangle, a trapezoid, a circle, and an oval.
5. The parallel reaction device of claim 1, wherein at least two
regions of the reaction well comprise different inner or outer
cross-sectional dimensions.
6. The parallel reaction device of claim 1, wherein one or more
reaction wells further comprise a filter disposed therein.
7. The parallel reaction device of claim 1, wherein outlet portions
of the array of reaction wells comprise a footprint that
corresponds to wells of a micro-well plate.
8. The parallel reaction device of claim 1, wherein the outlet
portion comprises an outlet spout having a smaller inner
cross-sectional dimension than other regions of the reaction well,
and wherein a transition area between the outlet spout and the
other regions in the reaction well is abrupt or tapered.
9. The parallel reaction device of claim 1, wherein the protrusion
prevents leakage of fluidic materials from the inlet portion,
thereby reducing cross-contamination among the reaction wells.
10. The parallel reaction device of claim 1, wherein the protrusion
comprises at least one protruding annular ridge that presses the
top gasket into contact with the inlet portion of the reaction well
to radially seal the inlet portion.
11. The parallel reaction device of claim 1, wherein the top lid
comprises an array of protrusions that corresponds to the array of
reaction wells.
12. The parallel reaction device of claim 1, wherein the top lid
produces a substantially even clamp load across all inlet
portions.
13. The parallel reaction device of claim 1, wherein the top
attachment component comprises at least one hinge and at least one
latch.
14. The parallel reaction device of claim 1, wherein the bottom lid
produces a substantially even clamp load across all outlet
portions.
15. The parallel reaction device of claim 1, wherein the bottom
attachment component comprises at least one hinge and at least one
latch.
16. The parallel reaction device of claim 1, wherein the bottom lid
further comprises at least one protrusion disposed on a surface
that engages the reaction block, which protrusion presses the
bottom gasket into contact with the outlet portion of the reaction
well to seal the outlet portion.
17. The parallel reaction device of claim 1, wherein the top and
bottom lids are removably attached to the reaction block.
18. The parallel reaction device of claim 1, wherein the top and
bottom lids open independently of one another.
19. The parallel reaction device of claim 1, wherein the top and
bottom lids comprise metallic or polymeric materials.
20. The parallel reaction device of claim 1, wherein the top and
bottom lids each comprise at least a first alignment structure
complementary to at least a second alignment structure on a
controller apparatus to align the parallel reaction device relative
to the controller apparatus.
21. The parallel reaction device of claim 1, wherein the top gasket
comprises at least one protrusion, which protrusion axially aligns
with the inlet portion.
22. The parallel reaction device of claim 1, wherein the bottom
gasket comprises at least one protrusion, which protrusion axially
aligns with the outlet portion.
23. The parallel reaction device of claim 1, wherein the top and
bottom gaskets comprise sheets of gasketing material.
24. The parallel reaction device of claim 1, wherein at least one
of the top and bottom gaskets comprises an array of protrusions,
wherein at least one protrusion axially aligns with the reaction
well.
25. The parallel reaction device of claim 1, wherein the reaction
block comprises one or more of: glass, metal, or a polymer.
26. The parallel reaction device of claim 25, wherein the polymer
comprises polytetrafluoroethylene.
27. The parallel reaction device of claim 1, wherein the reaction
block comprises 6, 12, 24, 48, 96, 384, 1536, or more reaction
wells.
28. The parallel reaction device of claim 27, wherein each reaction
well is disposed through the reaction block.
29. The parallel reaction device of claim 1, wherein the top lid
further comprises an array of apertures disposed through the top
lid, wherein at least one aperture axially aligns with the reaction
well.
30. The parallel reaction device of claim 29, wherein fluidic
materials are introduced into the reaction well through the
aperture and the top gasket through a needle.
31. The parallel reaction device of claim 29, wherein the aperture
is tapered.
32. The parallel reaction device of claim 29, wherein each member
of the array of apertures axially aligns with a different reaction
well.
33. The parallel reaction device of claim 29, wherein the
protrusion comprises a protruding annular ridge disposed around the
aperture.
34. The parallel reaction device of claim 33, wherein the
protruding annular ridge presses the top gasket into contact with
the inlet portion of the reaction well to radially seal the inlet
portion.
35. The parallel reaction device of claim 1, wherein the reaction
block comprises at least one pair of substantially opposing
recessed regions disposed in opposing surfaces of the reaction
block proximal to a midpoint of each surface, which opposing
recessed regions mount the top and bottom attachment
components.
36. The parallel reaction device of claim 35, wherein the top and
bottom attachment components comprise: (i) a band disposed around
the reaction block in the opposing recessed regions, wherein the
band comprises at least one first top hinge component, at least one
first top latch component, at least one first bottom hinge
component, and at least one first bottom latch component; (ii) at
least one second top hinge component and at least one second top
latch component attached to the top lid, wherein the second top
hinge component removably engages the first top hinge component and
the second top latch component removably engages the first top
latch component; and, (iii) at least one second bottom hinge
component and at least one second bottom latch component attached
to the bottom lid, wherein the second bottom hinge component
removably engages the first bottom hinge component and the second
bottom latch component removably engages the first bottom latch
component.
37. The parallel reaction device of claim 36, wherein each hinge
component independently comprises a male or a female lift-off hinge
component.
38. The parallel reaction device of claim 36, wherein each latch
component independently comprises a latch body or a keeper
plate.
39. The parallel reaction device of claim 38, wherein the latch
body comprises a rotatable draw latch body.
40. A parallel reaction device, comprising: (a) a reaction block
comprising an array of reaction wells, wherein at least one
reaction well in the array is disposed through the reaction block,
which reaction well comprises an inlet portion and an outlet
portion; (b) a top lid attached to the reaction block by at least
one top hinge component and at least one top latch component, which
top lid presses a top gasket into contact with the inlet portion to
the reaction well to seal the inlet portion; and, (c) a bottom lid
attached to the reaction block by at least one bottom hinge
component and at least one bottom latch component, which bottom lid
presses a bottom gasket into contact with the outlet portion of the
reaction well to seal the outlet portion.
41. The parallel reaction device of claim 40, wherein the reaction
block is disposable.
42. The parallel reaction device of claim 40, wherein the reaction
block comprises cavities disposed between and proximal to inlet
portions of adjacent reaction wells to direct fluidic materials
away from other inlet portions.
43. The parallel reaction device of claim 40, wherein at least a
segment of the reaction well comprises an inner and an outer
cross-sectional shape independently selected from the group
consisting of: a regular n-sided polygon, an irregular n-sided
polygon, a triangle, a square, a rounded square, a rectangle, a
rounded rectangle, a trapezoid, a circle, and an oval.
44. The parallel reaction device of claim 40, wherein at least two
regions of the reaction well comprise different inner or outer
cross-sectional dimensions.
45. The parallel reaction device of claim 40, wherein one or more
reaction wells further comprise a filter disposed therein.
46. The parallel reaction device of claim 40, wherein outlet
portions of the array of reaction wells comprise a footprint that
corresponds to wells of a micro-well plate.
47. The parallel reaction device of claim 40, wherein the outlet
portion comprises an outlet spout having a smaller inner
cross-sectional dimension than other regions of the reaction well,
and wherein a transition area between the outlet spout and the
other regions in the reaction well is abrupt or tapered.
48. The parallel reaction device of claim 40, wherein the top lid
produces a substantially even clamp load across all inlet
portions.
49. The parallel reaction device of claim 40, wherein the top hinge
component comprises at least one lift-off hinge.
50. The parallel reaction device of claim 40, wherein the bottom
hinge component comprises at least one lift-off hinge.
51. The parallel reaction device of claim 40, wherein the bottom
lid produces a substantially even clamp load across all outlet
portions.
52. The parallel reaction device of claim 40, wherein the top lid
further comprises at least one protrusion disposed on a surface
that engages the reaction block, which protrusion presses the top
gasket into contact with the inlet portion of the reaction well to
seal the inlet portion.
53. The parallel reaction device of claim 40, wherein the bottom
lid further comprises at least one protrusion disposed on a surface
that engages the reaction block, which protrusion presses the
bottom gasket into contact with the outlet portion of the reaction
well to seal the outlet portion.
54. The parallel reaction device of claim 40, wherein the top and
bottom lids are removably attached to the reaction block.
55. The parallel reaction device of claim 40, wherein the top and
bottom lids open independently of one another.
56. The parallel reaction device of claim 40, wherein the top and
bottom lids comprise metallic or polymeric materials.
57. The parallel reaction device of claim 40, wherein the top and
bottom lids each comprise at least a first alignment structure
complementary to at least a second alignment structure on a
controller apparatus to align the parallel reaction device relative
to the controller apparatus.
58. The parallel reaction device of claim 40, wherein the top
gasket comprises at least one protrusion, which protrusion axially
aligns with the inlet portion.
59. The parallel reaction device of claim 40, wherein the bottom
gasket comprises at least one protrusion, which protrusion axially
aligns with the outlet portion.
60. The parallel reaction device of claim 40, wherein the top and
bottom gaskets comprise sheets of gasketing material.
61. The parallel reaction device of claim 40, wherein at least one
of the top and bottom gaskets comprises an array of protrusions,
wherein at least one protrusion axially aligns with the reaction
well.
62. The parallel reaction device of claim 40, wherein the reaction
block comprises one or more of: glass, metal, or a polymer.
63. The parallel reaction device of claim 62, wherein the polymer
comprises polytetrafluoroethylene.
64. The parallel reaction device of claim 40, wherein the reaction
block comprises 6, 12, 24, 48, 96, 384, 1536, or more reaction
wells.
65. The parallel reaction device of claim 64, wherein each reaction
well is disposed through the reaction block.
66. The parallel reaction device of claim 40, wherein the top lid
further comprises an array of apertures disposed through the top
lid, wherein at least one aperture axially aligns with the reaction
well.
67. The parallel reaction device of claim 66, wherein fluidic
materials are introduced into the reaction well through the
aperture and the top gasket through a needle.
68. The parallel reaction device of claim 66, wherein the aperture
is tapered.
69. The parallel reaction device of claim 66, wherein each member
of the array of apertures axially aligns with a different reaction
well.
70. The parallel reaction device of claim 66, further comprising a
protruding annular ridge disposed around the aperture.
71. The parallel reaction device of claim 70, wherein the
protruding annular ridge presses the top gasket into contact with
the inlet portion of the reaction well to radially seal the inlet
portion.
72. A reaction block comprising an array of reaction wells, wherein
at least one reaction well in the array is disposed through the
reaction block, which reaction well comprises an inlet portion and
an outlet portion, which reaction block comprises at least one pair
of substantially opposing recessed regions disposed in opposing
surfaces of the reaction block proximal to a midpoint of each
surface, which opposing recessed regions mount at least one lid
attachment component.
73. The reaction block of claim 72, wherein the reaction block is
disposable.
74. The reaction block of claim 72, wherein the reaction block
comprises cavities disposed between and proximal to inlet portions
of adjacent reaction wells to direct fluidic materials away from
other inlet portions.
75. The reaction block of claim 72, wherein at least a segment of
the reaction well comprises an inner and an outer cross-sectional
shape independently selected from the group consisting of: a
regular n-sided polygon, an irregular n-sided polygon, a triangle,
a square, a rounded square, a rectangle, a rounded rectangle, a
trapezoid, a circle, and an oval.
76. The reaction block of claim 72, wherein at least two regions of
the reaction well comprise different inner or outer cross-sectional
dimensions.
77. The reaction block of claim 72, wherein one or more reaction
wells further comprise a filter disposed therein.
78. The reaction block of claim 72, wherein outlet portions of the
array of reaction wells comprise a footprint that corresponds to
wells of a micro-well plate.
79. The reaction block of claim 72, wherein the outlet portion
comprises an outlet spout having a smaller inner cross-sectional
dimension than other regions of the reaction well, and wherein a
transition area between the outlet spout and the other regions in
the reaction well is abrupt or tapered.
80. The reaction block of claim 72, wherein the reaction block
comprises one or more of: glass, metal, or a polymer.
81. The reaction block of claim 80, wherein the polymer comprises
polytetrafluoroethylene.
82. The reaction block of claim 72, wherein the reaction block
comprises 6, 12, 24, 48, 96, 384, 1536, or more reaction wells.
83. The reaction block of claim 82, wherein each reaction well is
disposed through the reaction block.
84. A parallel reaction device, comprising: (a) a reaction block
comprising an array of reaction wells, wherein at least one
reaction well in the array is disposed through the reaction block,
which reaction well comprises an inlet portion and an outlet
portion; (b) a top lid attached to the reaction block by at least
one top hinge component and at least one top latch component, which
top lid comprises at least one protrusion disposed on a surface
that engages the reaction block, which protrusion presses a top
gasket into contact with the inlet portion to the reaction well to
seal the inlet portion; and, (c) a bottom lid attached to the
reaction block by at least one bottom hinge component and at least
one bottom latch component, which bottom lid presses a bottom
gasket into contact with the outlet portion of the reaction well to
seal the outlet portion.
85. A reaction block container, comprising: (a) a band that
comprises at least one first top hinge component, at least one
first top latch component, at least one first bottom hinge
component, and at least one first bottom latch component, and
wherein portions of the band are capable of being mounted in
opposing recessed regions on a reaction block; (b) a top lid
comprising at least one second top hinge component and at least one
second top latch component attached to the top lid, wherein the
second top hinge component engages the first top hinge component
and the second top latch component removably engages the first top
latch component; and, (c) a bottom lid comprising at least one
second bottom hinge component and at least one second bottom latch
component attached to the bottom lid, wherein the second bottom
hinge component engages the first bottom hinge component and the
second bottom latch component removably engages the first bottom
latch component.
86. The reaction block container of claim 85, wherein each hinge
component independently comprises a male or a female lift-off hinge
component.
87. The reaction block container of claim 85, wherein each latch
component independently comprises a latch body or a keeper
plate.
88. The reaction block container of claim 87, wherein the latch
body comprises a rotatable draw latch body.
89. The reaction block container of claim 85, wherein the top lid,
the bottom lid, or both lids further comprise at least one
protrusion disposed on a surface that engages a reaction block,
which protrusion presses a gasket into contact with at least a
portion of at least one reaction well when the reaction block
container further comprises the reaction block and the gasket.
90. The reaction block container of claim 85, wherein the top and
bottom lids open independently of one another.
91. The reaction block container of claim 85, wherein the top lid
further comprises an array of apertures disposed through the top
lid, wherein at least one aperture axially aligns with at least one
reaction well disposed in a reaction block.
92. The reaction block container of claim 91, wherein each member
of the array of apertures axially aligns with a different reaction
well disposed in the reaction block.
93. The reaction block container of claim 91, further comprising a
protruding annular ridge disposed around the aperture.
94. A reaction block container, comprising: (a) a band that
comprises at least one first top hinge component, at least one
first top latch component, at least one first bottom hinge
component, and at least one first bottom latch component, and
wherein portions of the band are capable of being mounted in
opposing recessed regions on a reaction block; (b) a top lid
comprising at least one protrusion disposed on a surface that
engages a reaction block, which protrusion is capable of pressing a
gasket into contact with at least a portion of at least one
reaction well of the reaction block, and at least one second top
hinge component and at least one second top latch component
attached to the top lid, wherein the second top hinge component
engages the first top hinge component and the second top latch
component removably engages the first top latch component; and, (c)
a bottom lid comprising at least one second bottom hinge component
and at least one second bottom latch component attached to the
bottom lid, wherein the second bottom hinge component engages the
first bottom hinge component and the second bottom latch component
removably engages the first bottom latch component.
95. The reaction block container of claim 94, wherein each hinge
component independently comprises a male or a female lift-off hinge
component.
96. The reaction block container of claim 94, wherein each latch
component independently comprises a latch body or a keeper
plate.
97. The reaction block container of claim 96, wherein the latch
body comprises a rotatable draw latch body.
98. The reaction block container of claim 94, wherein the top and
bottom lids open independently of one another.
99. The reaction block container of claim 94, wherein the top lid
further comprises an array of apertures disposed through the top
lid, wherein at least one aperture axially aligns with at least one
reaction well disposed in a reaction block.
100. The reaction block container of claim 99, wherein each member
of the array of apertures axially aligns with a different reaction
well disposed in the reaction block.
101. The reaction block container of claim 99, wherein the
protrusion comprises a protruding annular ridge disposed around the
aperture.
102. A lid comprising at least one protrusion capable of pressing a
gasket into contact with at least a portion of at least one
reaction well of a reaction block comprising an array of reaction
wells to seal the reaction well when the lid is attached to the
reaction block.
103. The lid of claim 102, wherein the lid comprises an array of
protrusions corresponding to the array of reaction wells.
104. The lid of claim 102, further comprising an array of apertures
disposed through the lid, wherein at least one aperture axially
aligns with the reaction well.
105. The lid of claim 104, wherein the aperture is tapered.
106. The lid of claim 104, wherein each member of the array of
apertures axially aligns with a different reaction well.
107. The lid of claim 104, wherein the protrusion comprises a
protruding annular ridge disposed around the aperture.
108. The lid of claim 102, further comprising at least one
attachment component to attach the lid to the reaction block.
109. The lid of claim 108, wherein the attachment component
comprises at least one latch and at least one hinge.
110. A lid comprising at least one latch component and at least one
hinge component, which hinge component is capable of engaging at
least one other hinge component and which latch component is
capable of removably engaging at least one other latch component,
which other hinge and other latch components are attached to a
reaction block.
111. The lid of claim 110, further comprising at least one
protrusion disposed on a surface of the lid, which protrusion
presses a gasket into contact with at least a portion of at least
one reaction well of the reaction block.
112. The lid of claim 111, wherein the lid comprises an array of
protrusions corresponding to an array of reaction wells disposed in
the reaction block.
113. The lid of claim 110, further comprising an array of apertures
disposed through the lid, wherein at least one aperture axially
aligns with the reaction well.
114. The lid of claim 113, wherein the aperture is tapered.
115. The lid of claim 113, wherein each member of the array of
apertures axially aligns with a different reaction well.
116. A lid attachment component comprising a band having at least
one hinge component and at least one latch component attached
thereto, which band is capable of being mounted in opposing
recessed regions disposed on opposing surfaces of a reaction
block.
117. The lid attachment component of claim 116, wherein the hinge
component comprises a male or a female lift-off hinge
component.
118. The lid attachment component of claim 116, wherein the latch
component comprises a latch body or a keeper plate.
119. The lid attachment component of claim 118, wherein the latch
body comprises a rotatable draw latch body.
Description
COPYRIGHT NOTIFICATION
[0001] Pursuant to 37 C.F.R. .sctn.1.71(e), Applicants note that a
portion of this disclosure contains material which is subject to
copyright protection. The copyright owner has no objection to the
facsimile reproduction by anyone of the patent document or patent
disclosure, as it appears in the Patent and Trademark Office patent
file or records, but otherwise reserves all copyright rights
whatsoever.
CROSS-REFERENCES TO RELATED APPLICATIONS
[0002] Not Applicable.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH AND DEVELOPMENT
[0003] Not Applicable.
BACKGROUND OF THE INVENTION
[0004] Modem techniques for identifying compounds with desired
chemical or physical properties typically involve assembling
complex libraries of compounds that are systematically screened to
isolate members having the desired properties. One general approach
to library construction involves creating compounds using
combinatorial, parallel, or other synthetic processes in which sets
of compounds are prepared from sets of building blocks, e.g., via
multi-step solution- or solid-phase synthesis. For example,
split/pool combinatorial synthetic techniques can be used to
produce all possible combinations of a set of building blocks. In
particular, the methods typically include splitting an initial pool
of solid supports with attached chemical moieties into a selected
number of individual pools. Each pool is subjected to a first
randomization reaction that generates a different modification to
the solid supports in each separate pool. Following this first set
of reactions, the individual pools of solid supports are typically
combined, mixed, and split once again into separate pools. Each
split pool is then subjected to a second randomization, which again
is different for each pool. This process is repeated until the
desired library of target compounds is produced. Additional details
relating to library synthesis using combinatorial and parallel
approaches are described in, e.g., Houghten (2000) "Parallel array
and mixture-based synthetic combinatorial chemistry: Tools for the
next millennium," Annu. Rev. Pharmacol. Toxicol. 40:273-282,
Thompson (2000) "Recent applications of polymer-supported reagents
and scavengers in combinatorial, parallel, or multistep synthesis,"
Curr. Opin. Chem. Biol. 4:324-337, Bunin et al. (1999) "Application
of combinatorial and parallel synthesis to medicinal chemistry,"
Annu. Rep. Med. Chem. 34:267-286, and Brooking et al. (1999)
"Split-split. A multiple synthesiser approach to efficient
automated parallel synthesis, Tetrahedron Lett.
40(7):1405-1408.
[0005] A standard tool for parallel chemistry, including
randomization steps in combinatorial protocols, such as split/pool
synthesis, is the multiple well reaction vessel that typically
includes a collection of tubes or a reaction block bored out with a
designated number of reaction wells or holes. These reaction wells
are generally fitted with a filter at one end, which allows the
individual wells to be employed for solid-liquid separations or
other purification processes. The footprint of such reaction blocks
typically corresponds to an array of wells in a standard micro-well
assay plate. A series of individually addressable open reactors is
generally formed within a reaction block by contacting a gasket to
the bottom or outlets of the reaction wells. In addition, a series
of enclosed reactors is typically made by sealing the top or inlets
to the reaction wells with another gasket. Sealed reaction wells
provide for aggressive agitation of well contents and for the use
of extreme reaction conditions.
[0006] Sub-optimal sealing and clamping mechanisms inhibit
throughput in multiple well reaction vessels of the prior art.
Specifically, preexisting technologies typically require users to
operate a series of latches, screws, and/or other fasteners, which
hinders safe and efficient access to reaction chambers. Further,
the clamping mechanisms of these devices generally do not provide
secure reaction well seals such that leakage of materials from the
reaction wells commonly results. Sample leakage typically causes
reaction failure for the reaction within the particular well from
which the leakage occurred and/or cross-contamination among
multiple reaction wells. One source of leakage in preexisting
devices is uneven clamp load over the reaction wells. In addition,
the inferior designs that characterize the prior art also suffer
from general losses of clamp load over time, which further
contributes to the aforementioned leakage-related problems.
[0007] From the above, it is apparent that there is a substantial
need for new parallel reaction devices that permit efficient and
rapid access to reaction wells. It would also be desirable to have
reaction blocks that remain securely sealed under diverse reaction
conditions, including varied extremes of temperature and agitation.
These and a variety of additional features of the present invention
will become evident upon complete review of the following.
SUMMARY OF THE INVENTION
[0008] The present invention relates to devices for performing
multiple reactions, such as combinatorial synthesis reactions, or
other processes in parallel. More specifically, the invention
provides parallel reaction devices that include secure and
efficient sealing or clamping mechanisms, which significantly
improve throughput relative to existing devices. The devices of the
invention incorporate reaction blocks that include arrays of
reaction wells. Reaction blocks are sometimes disposable or at
least not intended for indefinite use. In addition to reaction
blocks, the devices of the present invention include lids and
gaskets for sealing reaction wells within the reaction blocks and
attachment components for attaching the lids to the reaction
blocks. In preferred embodiments, lids include arrays of
protrusions that axially align with reaction wells in assembled
devices to further enhance reaction well seals. The lids of the
devices of the invention are also typically removably attached to
reaction blocks and produce substantially even clamp loads across
inlet or outlet portions of reaction blocks. Reaction block
containers, systems, and kits that include these devices or device
components are additionally provided.
[0009] In one aspect, the invention provides a parallel reaction
device that includes (a) a reaction block that includes an array of
reaction wells in which at least one reaction well in the array is
disposed through the reaction block, which reaction well includes
an inlet portion and an outlet portion, (b) a top lid attached to
the reaction block by at least one top attachment component, which
top lid includes at least one protrusion disposed on a surface that
engages the reaction block, which protrusion presses a top gasket
into contact with the inlet portion of the reaction well to seal
the inlet portion, and (c) a bottom lid attached to the reaction
block by at least one bottom attachment component, which bottom lid
presses a bottom gasket into contact with the outlet portion of the
reaction well to seal the outlet portion.
[0010] In another aspect, the invention relates to a parallel
reaction device that includes (a) a reaction block that includes an
array of reaction wells, wherein at least one reaction well in the
array is disposed through the reaction block, which reaction well
includes an inlet portion and an outlet portion, (b) a top lid
attached to the reaction block by at least one top hinge component
and at least one top latch component, which top lid presses a top
gasket into contact with the inlet portion to the reaction well to
seal the inlet portion, and (c) a bottom lid attached to the
reaction block by at least one bottom hinge component and at least
one bottom latch component, which bottom lid presses a bottom
gasket into contact with the outlet portion of the reaction well to
seal the outlet portion.
[0011] In yet another aspect, the invention provides a parallel
reaction device that includes (a) a reaction block that includes an
array of reaction wells in which at least one reaction well in the
array is disposed through the reaction block, which reaction well
includes an inlet portion and an outlet portion, (b) a top lid
attached to the reaction block by at least one top hinge component
and at least one top latch component, which top lid includes at
least one protrusion disposed on a surface that engages the
reaction block, which protrusion presses a top gasket into contact
with the inlet portion to the reaction well to seal the inlet
portion, and (c) a bottom lid attached to the reaction block by at
least one bottom hinge component and at least one bottom latch
component, which bottom lid presses a bottom gasket into contact
with the outlet portion of the reaction well to seal the outlet
portion.
[0012] The reaction blocks of the present invention include various
embodiments. For example, reaction blocks optionally include
cavities disposed between and proximal to inlet portions of
adjacent reaction wells to direct fluidic materials away from other
inlet portions. In certain preferred embodiments, each reaction
well is disposed through the reaction block. In other preferred
embodiments, one or more reaction wells further include a filter
disposed therein. Optionally, at least two regions of the reaction
well include different inner or outer cross-sectional dimensions.
Further, outlet portions of the array of reaction wells typically
include a footprint that corresponds to wells of a micro-well
plate. In addition, the outlet portion generally includes an outlet
spout having a smaller inner cross-sectional dimension than other
regions of the reaction well in which a transition area between the
outlet spout and the other regions in the reaction well is, e.g.,
abrupt, tapered, stepped, or the like.
[0013] In preferred embodiments, reaction blocks include at least
one pair of substantially opposing recessed regions disposed in
opposing surfaces of the reaction block proximal to a midpoint of
each surface, which opposing recessed regions mount the top and
bottom attachment components. In these embodiments, the top and
bottom attachment components typically include (i) a band disposed
around the reaction block in the opposing recessed regions in which
the band includes at least one first top hinge component, at least
one first top latch component, at least one first bottom hinge
component, and at least one first bottom latch component, (ii) at
least one second top hinge component and at least one second top
latch component attached to the top lid in which the second top
hinge component(s) removably engage(s) the first top hinge
component(s) and the second top latch component(s) removably
engage(s) the first top latch component(s), and (iii) at least one
second bottom hinge component and at least one second bottom latch
component(s) attached to the bottom lid in which the second bottom
hinge component(s) removably engage(s) the first bottom hinge
component(s) and the second bottom latch component(s) removably
engage(s) the first bottom latch component(s). Each hinge component
optionally independently includes, e.g., a male or a female
lift-off hinge component, whereas each latch component optionally
independently includes, e.g., a latch body (e.g., a rotatable draw
latch body or the like) or a keeper plate.
[0014] The present invention also relates to a lid that includes at
least one protrusion capable of pressing a gasket into contact with
at least a portion of at least one reaction well of a reaction
block that includes an array of reaction wells to seal (e.g.,
radially seal or the like) the reaction well when the lid is
attached to the reaction block. In particular, the protrusion
prevents leakage of fluidic materials from the inlet portion to
reduce cross-contamination among the reaction wells. The lid
typically includes an array of protrusions corresponding to the
array of reaction wells. Optionally, the lid further includes an
array of apertures disposed through the lid in which at least one
aperture (e.g., a tapered aperture, etc.) axially aligns with the
reaction well. For example, each member of the array of apertures
generally axially aligns with a different reaction well. Fluidic
materials are optionally introduced into reaction wells through
apertures and gaskets through a needle (e.g., a syringe needle or
the like). Further, the protrusion optionally includes a protruding
annular ridge disposed around the aperture. The lid also typically
further includes at least one attachment component (e.g., at least
one latch and at least one hinge, or the like) to attach the lid to
the reaction block.
[0015] The invention additionally relates to a lid that includes at
least one latch component and at least one hinge component, which
hinge component is capable of engaging at least one other hinge
component and which latch component is capable of removably
engaging at least one other latch component, which other hinge and
other latch components are attached to a reaction block.
Optionally, the lid further includes at least one protrusion
disposed on a surface of the lid, which protrusion presses a gasket
into contact with at least a portion of at least one reaction well
of the reaction block. For example, the lid optionally includes an
array of protrusions corresponding to an array of reaction wells
disposed in the reaction block. In another embodiment, the lid
further includes an array of apertures disposed through the lid in
which at least one aperture (e.g., a tapered aperture, etc.)
axially aligns with the reaction well. Typically, each member of
the array of apertures axially aligns with a different reaction
well.
[0016] The top and bottom gaskets typically include sheets of
gasketing material. The top gasket optionally includes at least one
protrusion, which protrusion axially aligns with the inlet portion.
As an additional option, the bottom gasket includes at least one
protrusion, which protrusion axially aligns with the outlet
portion. For example, at least one of the top and bottom gaskets
optionally includes an array of protrusions in which at least one
protrusion axially aligns with the reaction well.
BRIEF DESCRIPTION OF THE DRAWING
[0017] FIG. 1 schematically illustrates a front perspective view of
a preferred embodiment of the parallel reaction device of the
present invention.
[0018] FIG. 2 schematically shows an exploded perspective view of a
preferred embodiment of the parallel reaction device of the present
invention.
[0019] FIG. 3A schematically depicts the assembled reaction device
of FIG. 2 from a cutaway, front elevational view.
[0020] FIG. 3B schematically illustrates the assembled reaction
device of FIG. 2 from a side elevational view.
[0021] FIG. 3C schematically shows the assembled reaction device of
FIG. 2 from a perspective view.
[0022] FIG. 4A schematically depicts a partially cutaway, front
elevational view of a reaction block according to one embodiment of
the invention.
[0023] FIG. 4B schematically illustrates the reaction block of FIG.
4A from a side elevational view.
[0024] FIG. 4C schematically shows the reaction block of FIG. 4A
from a top plan view.
[0025] FIG. 4D schematically illustrates the reaction block of FIG.
4A from a bottom plan view.
[0026] FIG. 4E schematically depicts the reaction block of FIG. 4A
from a perspective view.
[0027] FIG. 5A schematically shows a top plan view of one
embodiment of a band according to the present invention.
[0028] FIG. 5B schematically illustrates a side plan view of the
band of FIG. 5A.
[0029] FIG. 5C schematically depicts an exploded top view of the
band of FIG. 5A.
[0030] FIG. 5D schematically shows an exploded perspective view of
a band being mounted in opposing recessed regions disposed on
opposing surfaces of a reaction block according to a preferred
embodiment of the invention.
[0031] FIG. 6A schematically illustrates a top plan view of one
embodiment of a top lid of a parallel reaction device of the
invention.
[0032] FIG. 6B schematically shows a top perspective view the top
lid of FIG. 6A.
[0033] FIG. 6C schematically illustrates a bottom plan view of the
top lid of FIG. 6A.
[0034] FIG. 6D schematically depicts a bottom perspective view of
the top lid of FIG. 6A.
[0035] FIG. 7A schematically shows a top plan view of one
embodiment of a bottom lid of a parallel reaction device according
to the present invention.
[0036] FIG. 7B schematically illustrates a top perspective view of
the bottom lid of FIG. 7A.
[0037] FIG. 7C schematically depicts a bottom plan view of the
bottom lid of FIG. 7A.
[0038] FIG. 7D schematically illustrates a bottom perspective view
of the bottom lid of FIG. 7A.
[0039] FIG. 8 schematically shows a perspective view of a gasket
sheet that includes an array of protrusions disposed over a lid
according to one embodiment of the invention.
[0040] FIG. 9 schematically shows an exploded perspective view of
reaction block container according to one embodiment of the
invention.
[0041] FIG. 10 is a block diagram showing a representative example
synthesis system including a logic device in which various aspects
of the present invention may be embodied.
DETAILED DISCUSSION OF THE INVENTION
[0042] I. Definitions
[0043] Before describing the present invention in detail, it is to
be understood that this invention is not limited to particular
devices or systems, which can, of course, vary. It is also to be
understood that the terminology used herein is for the purpose of
describing particular embodiments only, and is not intended to be
limiting. Further, unless defined otherwise, all technical and
scientific terms used herein have the same meaning as commonly
understood by one of ordinary skill in the art to which the
invention pertains. In describing and claiming the present
invention, the following terminology will be used in accordance
with the definitions set out below.
[0044] An "array" refers to an ordered, regular, or spatially
defined pattern, grouping, or arrangement of components. For
example, an array of reaction wells in a reaction block includes a
spatially defined pattern of reaction wells of essentially any
number (e.g., 2, 4, 6, 12, 24, 48, 96, 384, 1536, or more reaction
wells). For a given number reaction wells or other device
components (e.g., apertures, protrusions, or the like), alternative
spatial patterns are typically possible. To illustrate, a 48-well
reaction block optionally includes an array of 4 rows by 12 columns
of wells (i.e., a 4.times.12 array), a 6.times.8 array, or the
like. In preferred embodiments, arrays of, e.g., reaction wells,
apertures, protrusions, or the like have footprints that correspond
to arrays of wells in commercially available micro-well plates or
other sample containers (e.g., 6 wells in a 3.times.2 array, 12
wells in 3.times.4 array, 24 wells in a 6.times.4 array, 48 wells
in a 6.times.8 array, 96 wells in a 8.times.12 array, or the
like).
[0045] A "footprint" refers to the area on a surface covered by or
corresponding to a device component or portions thereof. For
example, outlet portions or spouts of a reaction block of the
invention typically correspond to (e.g., fit into, match, align
with, etc.) wells in a selected micro-well plate or other sample
container. In preferred embodiments of the invention, device
components (e.g., reaction wells, apertures, protrusions, etc.) and
wells of micro-well plates have substantially the same footprint,
such that they axially align with one another (e.g., for fluid
communication with respect to reaction wells and apertures or wells
of micro-well plates).
[0046] The term "top" refers to the highest point, level, surface,
or part of a device, or device component, when oriented for typical
designed or intended operational use, such as dispensing a fluidic
material into a reaction well. For example, the parallel reaction
devices of the invention generally include a top lid, top
attachment components (e.g., top hinge and/or latch components,
etc.), or the like. In contrast, the term "bottom" refers to the
lowest point, level, surface, or part of a device, or device
component, when oriented for typical designed or intended
operational use. To illustrate, the devices of the invention
typically include a bottom lid, bottom attachment components (e.g.,
bottom hinge and/or bottom components, etc.), or the like.
[0047] The phrase "substantially even clamp load or force" refers
to an applied force that is approximately uniformly distributed
across a contact surface towards which the force is directed. For
example, when reaction wells are sealed in a device of the present
invention, the force applied by a surface of a lid that engages a
reaction block (e.g., through a sheet of gasketing material, etc.)
is substantially the same at, e.g., any two points of contact with
the reaction block (e.g., at any two inlet portions, at any two
outlet portions, or the like).
[0048] The term "engages" refers to the bringing or coming
together, interlocking, or meshing of device components. To
illustrate, when a lid is attached to a reaction block to seal,
e.g., inlet or outlet portions of the reaction block, the lid
(e.g., a surface of the lid, etc.) is brought together with the
reaction block, e.g., with a sheet of gasketing material disposed
therebetween. Attachment components also engage one another, e.g.,
when male and female hinge components interlock or mesh with one
another in operable alignment, when latch bodies and keeper plates
interlock, or the like.
[0049] The phrase "radial seal" refers to the closure of a reaction
well that is substantially uniform around a central axis, which
seal secures the well against leakage.
[0050] II. Overview of Preferred Embodiments
[0051] The present invention relates to devices in which a diverse
range of chemical, biological, filtration/separation, and/or other
processes are optionally simultaneously performed with
significantly improved throughput relative to other devices. In
particular, the invention provides parallel reaction devices that
permit users to rapidly and easily seal or unseal multiple reaction
wells of the devices. In contrast, preexisting technologies require
users to contend with a series of latches, screws, and/or other
fasteners, which inhibits safe and efficient access to reaction
wells. The reaction wells of the devices of the present invention
also remain securely sealed under varied operational conditions,
including thermal elevation, rotation/centrifugation, agitation, or
the like. Many preexisting designs suffer from problems associated
with leakage of reaction well contents due, e.g., to uneven clamp
load over the reaction wells. Unlike the devices of the invention,
the inferior designs that characterize the prior art are
additionally plagued by general loss of clamp load over time. In
addition, the vastly improved parallel reaction devices of the
present invention are economical to manufacture. These and other
superior features of the devices of the invention will become
apparent upon complete review of the following detailed
description.
[0052] FIG. 1 schematically illustrates a front perspective view of
a parallel reaction device according to a preferred embodiment of
the invention. As shown, device 100 includes reaction block 102,
which contains multiple reaction wells. Reaction block 102 is
designed so that band 104 can be placed around reaction block 102
and easily locked in place by, e.g., captured fasteners or latch
bodies 106. Band 104 typically includes two latch bodies 106 (one
is not within view) and four lift-off hinges 108 (two are not
within view) attached for both top lid 110 and bottom lid 112. When
sealing reaction block 102, mating portions of lift-off hinges 108,
which are attached to top and bottom lids (110 and 112), are slid
into or onto corresponding mating portions of lift-off hinges 108,
which are attached to band 104. Top and bottom lids (110 and 112)
are then closed and hooked portions of latch bodies 106 are placed
over corresponding keeper plates or clasps 114, which are attached
to top and bottom lids (110 and 112). Latch bodies 106 are turned
to pull top and bottom lids (110 and 112) tightly closed, which
compresses gaskets (not shown) between reaction block 102 and top
and bottom lids (110 and 112), respectively. The compressed gaskets
securely seal reaction wells in reaction block 102.
[0053] Top lid 110 is generally fabricated with small raised
features or protrusions 116 (shown as annular ridges) corresponding
to each well. In certain embodiments, bottom lid 112 also includes
these features. Protrusions 116 push the gasket partially into each
well to create radial seals. This type of seal is generally more
robust than simple facial seals, which are produced in the absence
of protrusions 116. Since band 104 is held in place by reaction
block 102, top and bottom lids (110 and 112) can be opened
independently of one another. As described herein, the features or
components of parallel reaction device 100 are optionally
customized to provide for general utility. For example, different
footprints of reaction block 102 are optionally utilized for
specialized equipment, e.g., different micro-well plates or the
like. Further, a variety of well formats and numbers are optionally
provided, e.g., to increase the volume or numbers of individual
wells. In addition, many different gasketing materials are
optionally included to efficiently seal the wells depending on,
e.g., the contents of the wells and reaction conditions.
[0054] FIG. 2 schematically shows an exploded perspective view of a
preferred embodiment of a device of the present invention. As
shown, parallel reaction device 200 includes reaction block 202,
band 204, top lid 206, bottom lid 208, top gasket sheet 210, and
bottom gasket sheet 212. Reaction block 202 includes array of
reaction wells 214 in which individual reaction well 216 includes
inlet portion 218 and outlet portion 220. Band 204 includes first
top hinge components (not within view), first top latch component
222, first bottom hinge components 224, and first bottom latch
component (not within view). As shown, band 204 is mounted in
opposing recessed regions 226 of reaction block 202. Top lid 206
includes second top hinge components 228 (one not within view) and
second top latch component 230 (shown as a keeper plate). As also
shown, top lid 206 includes array of apertures 232, which axially
align with members of array of reaction wells 214 in reaction block
202. Although not viewable in FIG. 2, top lid 206 also typically
includes an array of protrusions (e.g., an array of annular ridges
disposed around members of array of apertures 232) disposed on a
surface of top lid 206 that engages reaction block 202 (e.g., a
surface that forces top gasket sheet 210 into contact with reaction
block 202 in an assembled device). Bottom lid 208 includes second
bottom hinge components 234 and second bottom latch component 236.
Top and bottom lids (206 and 208, respectively) can also include
alignment structures 238, e.g., for aligning parallel reaction
device 200 relative to a corresponding alignment structure on a
controller apparatus, such as an X-Y-Z translational device. All
device elements introduced above are described in greater detail
below.
[0055] FIGS. 3A and B schematically depict the assembled reaction
device of FIG. 2 from a cutaway, front elevational view and a side
elevational view, respectively. As shown, first top latch component
222 of band 204 engages second top latch component 230 of top lid
206. Band 204 is seated or mounted in recessed regions 226 of
reaction block 202. Top gasket sheet 210 is disposed between top
lid 206 and reaction block 202 to seal, e.g., inlet portion 218 of
reaction well 216 in parallel reaction device 200. As also shown,
first bottom hinge components 224 of band 204 engage second bottom
hinge components 234 of bottom lid 208. Bottom gasket sheet 212 is
disposed between bottom lid 208 and reaction block 202 to seal,
e.g., outlet portion 220 of reaction well 216. As additionally
schematically depicted in FIG. 3B, second top hinge components 228
(one not within view) of top lid 206 engage first top hinge
components 240 (one not within view) of band 204. First bottom
latch component 242 of band 204 engages second bottom latch
component 236 of bottom lid 208. FIG. 2C schematically shows the
assembled reaction device of FIG. 2 from a perspective view.
[0056] III. Reaction Blocks
[0057] The reaction blocks of the present invention generally
include arrays of reaction wells in which at least one reaction
well in a given array is disposed (e.g., vertically disposed)
through the particular reaction block. While in preferred
embodiments all reaction wells are disposed completely through a
reaction block, in other embodiments, fewer than all wells in an
array are disposed completely through a reaction block. Further,
reaction blocks are sometimes disposable components of the parallel
reaction devices, whereas lids, attachment components, and bands
are typically intended to be used indefinitely. The reaction blocks
of the invention also include many alternative arrays of reaction
wells and are fabricated from assorted materials or combinations of
materials.
[0058] FIG. 4A schematically illustrates a partially cutaway, front
elevational view of reaction block 400 according to a preferred
embodiment of the invention. As shown, reaction block 400 includes
array of reaction wells 402 in which each reaction well 404 is
disposed through reaction block 400. Reaction well 404 includes
inlet portion 406, which extends upward from upper surface 410 of
reaction block body 412, and outlet portion 408 (e.g., an outlet
spout, etc.), which extends downward from lower surface 414 of
reaction block body 412. As also shown, reaction block 400 includes
cavities 416 disposed between and proximal to inlet portions of
adjacent reaction wells, e.g., to direct fluidic materials away
from other inlet portions in the event fluid is spilled, e.g.,
while reaction block 400 is unsealed. Outlet portion 408 includes a
smaller inner cross-sectional dimension than other regions of
reaction well 404. Transition area 418 between outlet portion 408
and the other regions in reaction well 404 is abrupt. In other
embodiments, transition area 418 is, e.g., tapered, stepped, or the
like. Although not shown in FIG. 4A, a filter (e.g., a disk of
filtering material, etc.) is typically disposed proximal to
transition area 418, e.g., to prevent resin or other reaction
components from flowing into outlet portion 408 during solid-phase
synthesis. Reaction block 400 also includes substantially opposing
recessed regions 420 disposed in opposing surfaces of reaction
block 400 proximal to a midpoint of each surface. Opposing recessed
regions 420 are used to mount or seat lid attachment components,
e.g., a band (not shown) with attached latch bodies, latch clasps,
and/or hinge components. Lid attachment components are discussed
further below.
[0059] FIGS. 4B-E schematically depict reaction block 400 from
various viewpoints. In particular, FIG. 4B schematically
illustrates reaction block 400 from a side elevational view. FIG.
4C schematically shows reaction block 400 from a top plan view,
whereas FIG. 4D schematically illustrates reaction block 400 from a
bottom plan view. FIG. 4E schematically depicts reaction block 400
from a perspective view.
[0060] The reaction blocks of the present invention optionally
include various numbers and arrays of reaction wells. For example,
in certain embodiments reaction blocks include, e.g., 6, 12, 24,
48, 96, 384, 1536, or other numbers of reaction wells. As shown in
FIG. 4C, for example, reaction block 400 includes 96 reaction wells
arrayed in a rectangular 8.times.12 format. In preferred
embodiments, outlet portions or spouts of reaction wells have
footprints that correspond to wells in a micro-well plate or other
sample container (e.g., plates having 6, 12, 24, 48, 96, 384, 1536,
or other numbers of wells). For example, outlet portions or spouts
of reaction blocks are optionally spaced at regular intervals, such
as 9 mm centers for 96 well plates, 4.5 mm centers for 384 well
plates, 2.25 mm centers for 1536 well plates, or the like. The
overall dimensional area of a reaction block generally provide a
footprint of about the same size as a selected standard micro-well
plate to permit interchangeable use of the reaction block with
standard equipment holders, automated well washers, X-Y-Z
translational devices, or the like. It will be appreciated that the
present invention may use any of a variety of arrays other than the
format depicted in, e.g., FIG. 4C, such as non-rectangular arrays
of reaction wells.
[0061] As referred to above, individual reaction wells of reaction
blocks typically include inlet portions (see, e.g., inlet portion
406 in FIG. 4A) and outlet portions (see, e.g., inlet portion 408
in FIG. 4A). Inlet and outlet portions of a particular reaction
well are typically in fluid communication with one another via a
cavity disposed through a reaction block body and are, e.g.,
integrally fabricated with the reaction block body. Reaction block
fabrication is described further below. As mentioned above, in
preferred embodiments, inlet portions are separated from one
another by a series of cavities (e.g., orthogonally intersecting
cavities (see, e.g., cavities 416 in FIG. 4C), etc.). The cavities
are typically narrow voids between adjacent inlet portions that
extend vertically, e.g., from the upper surface of a reaction block
body to the tops of the inlet portions. Cavities such as these are
generally fabricated to reduce cross-contamination among reaction
wells, e.g., in the event fluidic materials are spilled when the
top lid and gasket sheet are not positioned to seal the reaction
wells. In particular, the cavities direct fluids away from the
reaction wells. Outlet portions are typically formed as outlet
spouts (see, e.g., FIG. 4A) having,. e.g., slightly tapered shapes
(e.g., as a Luer tip) to which commercially available syringe
needle hubs are optionally attached. Such needles are optionally
attached to outlet spouts, e.g., when a smaller effluent opening is
desired to elute very small volumes from reaction wells, when
transferring sensitive fluidic materials under an inert atmosphere
from reaction wells, or the like. Tapered outlet spouts also assist
in directing fluid streams and reducing cross-contamination of
eluted materials.
[0062] Reaction well dimensions (e.g., internal length or height,
cross-sectional dimension/area, or the like) are typically selected
according to the volume of fluidic material desired for containment
within a particular well. For example, reaction wells of the
present invention generally include volume capacities of between
about 0.1 ml and about 100 ml, typically between about 1 ml and
about 50 ml, more typically between about 1 ml and about 25 ml, and
still more typically between about 1 ml and about 2 ml. Optionally,
reaction blocks are designed to accommodate fluid volumes in excess
of about 100 ml. In certain embodiments, different reaction wells
in a given reaction block include different fluid volume
capacities. In preferred embodiments, each well in a reaction block
includes about the same fluid volume capacity. Additional reaction
well configurations, e.g., which effectively increase individual
well volumes without altering reaction block footprints, that are
optionally adapted to the reaction blocks of the present invention
are described in, e.g., U.S. Pat. No. 6,054,100, entitled
"APPARATUS FOR MULTI-WELL MICROSCALE SYNTHESIS," to Stanchfield et
al., issued Apr. 25, 2000, which is incorporated by reference in
its entirety for all purposes.
[0063] A reaction well, or a portion thereof, optionally includes
uniform inner or outer cross-sectional dimensions. However, at
least two regions of a particular reaction well typically include
different inner or outer cross-sectional dimensions. For example,
in preferred embodiments, an outlet portion is formed as an outlet
spout, which includes a smaller inner cross-sectional dimension
than other regions of the reaction well. In these embodiments,
internal transitional areas between, e.g., outlet spouts and other
regions within a reaction well are abrupt or gradual (e.g.,
tapered, incremental, stepped, or the like). These transitional
areas optionally serve as a seat for a filter, which is used, e.g.,
in certain solid-phase synthesis reactions. Filters are described
further below. Although schematically depicted in, e.g., FIG. 4C as
having a substantially cylindrical shape (i.e., a circular
cross-section), reaction wells of the present invention optionally
include other cross-sectional shapes. To illustrate, at least a
segment of a reaction well optionally includes an inner and an
outer cross-sectional shape independently selected from, e.g., a
regular n-sided polygon, an irregular n-sided polygon, a triangle,
a square, a rounded square, a rectangle, a rounded rectangle, a
trapezoid, a circle, an oval, or the like. Rounded internal
reaction well surfaces are generally preferred to reduce
undesirable fluid wicking which typically occurs with angled
internal well surfaces.
[0064] Filters are typically utilized in the parallel reaction
devices of the present invention, e.g., to retain solid supports or
resins within reaction wells (e.g., during various solid-phase
synthesis protocols, etc.) and/or to filter fluidic materials
(e.g., when eluting solvents or other solution components from
solid supports during various post-reaction work-up procedures).
Filters generally have shapes corresponding to inner
cross-sectional shapes of reaction wells and are typically press
fitted into reaction wells, such that they are seated proximal to
transitional areas between outlet portions and other regions of
reaction wells. Essentially any material, e.g., capable of
retaining the selected resin size in the reaction well is
optionally used as a filter in the devices of the invention. In
preferred embodiments, the filters are frits of glass or plastic.
For example, in certain embodiments, filters include semi-permeable
membranes that retain material based upon size. Suitable
semi-permeable membrane materials generally include a pore sizes of
at least about 1 nm. For example, semi-permeable membrane materials
optionally utilized in the devices of the invention includes pore
sizes of between about 1 .mu.m and about 100 .mu.m, typically
between about 5 .mu.m and about 50 .mu.m, and more typically
between about 10 .mu.m and about 25 .mu.m.
[0065] More specifically, suitable semi-permeable membrane
materials are optionally selected from, e.g. polyaramide membranes,
polycarbonate membranes, porous plastic matrix membranes (e.g.,
POREX.RTM. Porous Plastic, etc.), porous metal matrix membranes,
polyethylene membranes, poly(vinylidene difluoride) membranes,
polyamide membranes, nylon membranes, ceramic membranes, polyester
membranes, polytetrafluoroethylene (TEFLON.RTM.) membranes, woven
mesh membranes, microfiltration membranes, nanofiltration
membranes, ultrafiltration membranes, dialysis membranes, composite
membranes, hydrophilic membranes, hydrophobic membranes,
polymer-based membranes, a non-polymer-based membranes, powdered
activated carbon membranes, polypropylene membranes, glass fiber
membranes, glass membranes, nitrocellulose membranes, cellulose
membranes, cellulose nitrate membranes, cellulose acetate
membranes, polysulfone membranes, polyethersulfone membranes,
polyolefin membranes, or the like. Filters (e.g., semi-permeable
membrane materials) optionally used in the present invention are
widely available from various commercial suppliers, such as, P. J.
Cobert Associates, Inc. (St. Louis, Mo.), Millipore Corporation
(Bedford, Mass.), or the like. Additional details regarding
filtration and membranes are described in various publications
including, e.g., Ho and Sirkar (Eds.), Membrane Handbook, Van
Nostrand Reinhold (1992), Cheryan, Ultrafiltration and
Microfiltration Handbook, 2.sup.nd Ed., Technomic Publishing
Company (1998), and Mulder, Basic Principles of Membrane
Technology, 2.sup.nd Ed., Dordrecht: Kluwer (1996).
[0066] Reaction blocks of the present invention are typically
fabricated as single integral units. Optionally, reaction blocks
are assembled from individually fabricated component parts (e.g.,
individual reaction wells, etc). Reaction block fabrication
materials or substrates are generally selected according to
properties, such as reaction inertness, durability, expense, or the
like. In preferred embodiments, reaction blocks, or components
thereof, are fabricated from various polymeric materials such as,
polytetrafluoroethylene (TEFLON.RTM.), polypropylene, polystyrene,
polysulfone, polyethylene, polymethylpentene, polydimethylsiloxane
(PDMS), polycarbonate, polyvinylchloride (PVC),
polymethylmethacrylate (PMMA), or the like. Polymeric parts are
typically economical to fabricate, which affords reaction block
disposability (i.e., replacing the reaction block without replacing
other device components, such as lids or attachment components).
Reaction blocks or component parts are also optionally fabricated
from other materials including, e.g., glass, metal (e.g., stainless
steel, anodized aluminum, etc.), silicon, or the like. For example,
reaction blocks are optionally assembled from a combination of
materials permanently or removably joined or fitted together, e.g.,
polymer or glass reaction wells with a stainless steel frame to
position the reaction wells relative to one another.
[0067] The reaction blocks or reaction block components are
optionally formed by various fabrication techniques or combinations
of such techniques including, e.g., injection molding, cast
molding, machining, embossing, extrusion, etching, or other
techniques. These and other suitable fabrication techniques are
generally known in the art and described in, e.g., Rosato,
Injection Molding Handbook, 3.sub.rd Ed., Kluwer Academic
Publishers (2000), Fundamentals of Injection Molding, W. J. T.
Associates (2000), Whelan, Injection Molding of Thermoplastics
Materials, Vol. 2, Chapman & Hall (1991), Fisher, Extrusion of
Plastics, Halsted Press (1976), and Chung, Extrusion of Polymers:
Theory and Practice, Hanser-Gardner Publications (2000). After
reaction block fabrication, reaction blocks or components thereof,
such as reaction wells, are optionally further processed, e.g., by
coating surfaces with, e.g., a hydrophilic coating, a hydrophobic
coating, or the like.
[0068] In preferred embodiments, reaction blocks of the invention
are fabricated with opposing recessed regions, which are used to
mount a band that includes various attachment components.
Attachment components are described in greater detail below. To
illustrate, a reaction block typically includes a pair of
substantially opposing recessed regions disposed (e.g., fabricated)
in opposing surfaces of the reaction block proximal to a midpoint
of each surface. Optionally, reaction blocks are fabricated with
multiple pairs of opposing recessed regions disposed in opposing
reaction block surfaces. For example, in one embodiment, the
reaction block includes a substantially continuous recessed region
disposed on each of four sides of the reaction block. In still
other embodiments, the reaction blocks include multiple pairs of
opposing recessed regions, e.g., to mount multiple bands with
attachment components.
[0069] In certain embodiments, attachment components are fabricated
as integral parts of reaction blocks. For example, attachment
components, such as hinge components (e.g., male or female lift-off
hinge components, etc.), latch components (e.g., keeper plates,
latch bodies, etc.), or the like are fabricated as components of
reaction block surfaces, e.g., using injection molding or other
fabrication techniques as described above.
[0070] IV. Attachment Components
[0071] The parallel reaction devices of the present invention
include various attachment components for attaching top and bottom
lids to reaction blocks. As described above, a preferred embodiment
of a reaction block of the invention includes at least one pair of
substantially opposing recessed regions disposed in opposing
surfaces of the reaction block proximal to a midpoint of each
surface, which opposing recessed regions mount the top and bottom
attachment components. In this embodiment, the top and bottom
attachment components generally include a band disposed around the
reaction block in the opposing recessed regions in which the band
includes at least one first top hinge component (e.g., a pair of
hinge components, etc.), at least one first top latch component, at
least one first bottom hinge component (e.g., a pair of hinge
components, etc.), and at least one first bottom latch component.
At least one second top hinge component (e.g., a pair of hinge
components, etc.) and at least one second top latch component are
typically attached to the top lid in which the second top hinge
component(s) removably engage(s) the first top hinge component(s)
and the second top latch component(s) removably engage(s) the first
top latch component(s). At least one second bottom hinge component
(e.g., a pair of hinge components, etc.) and at least one second
bottom latch component are typically attached to the bottom lid in
which the second bottom hinge component(s) removably engage(s) the
first bottom hinge component(s) and the second bottom latch
component(s) removably engage(s) the first bottom latch
component(s). Each hinge component optionally independently
includes a male or a female lift-off hinge component or another
type of hinge component, whereas each latch component optionally
independently includes a latch body (e.g., a rotatable draw latch
body or the like), a keeper plate, or the like.
[0072] The methods of attaching lids to reaction blocks in the
devices of the invention provide significant advantages relative to
prior art devices. In particular, a preferred embodiment of the
invention includes a single latch for each lid of a given device.
This provides for facile, rapid, and safe access to reaction wells
within reaction blocks, e.g., for adding reagents to the wells, for
removing fluidic materials, for washing the wells, or the like.
Access to prior art devices typically includes manipulating
multiple clips, screws, and/or other components, which limits
throughput and is often unsafe. The ease with which reaction wells
are accessed in the devices of the invention is further enhanced in
embodiments that include removable lids. In addition, lids are
optionally opened (and removed, in embodiments that include
removable hinges) independently of one another. The arrangements of
hinges and latch components also generates substantially even clamp
loads or forces across inlet or outlet portions of reaction wells
to uniformly compress gaskets and to securely seal reaction wells,
which prevents reaction failure and cross-contamination among
reaction wells due to sample leakage. Hinge and latch
configurations of the devices of the invention also ensure that
lids (and protrusions disposed on lid surfaces) are properly
aligned with reaction blocks and with one another when attached to
reaction blocks.
[0073] FIG. 5A schematically shows a top plan view of an assembled
band according to a preferred embodiment the present invention. As
shown, assembled band 500 includes first band portion 502 and
second band portion 504. First band portion 502 and second band
portion 504 are attached to one another by fasteners 506 (e.g.,
bolts, rivets, screws, nuts, etc.). Optionally, bands for
attachment components of the present invention are fabricated as
single integral components or are composed of more than two
portions. Bands are typically fabricated or machined using known
techniques (e.g., conventional stamping and forming techniques,
injection molding, etc.) from various materials, such as heavy
gauge stainless steel sheet metal, durable plastics, or the like.
As further shown, top latch body 508 (shown as a rotatable draw
latch body) and bottom hinge components 510 (shown as male lift-off
hinge components) are attached (e.g., screwed, riveted, bolted,
welded, adhered, bonded, etc.) to first band portion 502, whereas
bottom latch body 512 and top hinge components 514 are attached to
second band portion 504. FIG. 5B schematically illustrates
assembled band 500 from a side plan view. FIG. 5C schematically
depicts an exploded top view of the band of FIG. 5A. FIG. 5D
schematically shows an exploded perspective view of a band being
mounted in opposing recessed regions disposed on opposing surfaces
of a reaction block according to a preferred embodiment of the
invention.
[0074] The attachment components of the present invention include
various embodiments and optional configurations. For example, latch
components are typically draw latch components, although other
types of latching or clamping mechanisms may also be adapted for
use with the devices of the present invention. Latch components
generally include latch bodies and keepers, keeper plates, or other
catches. Keepers or other catching devices, e.g., provide for latch
body pawl retention. In preferred embodiments, latch bodies are
rotatable draw latch bodies. Optionally, latch bodies are attached
to reaction blocks, e.g., directly (i.e., integral with the
reaction block) or via a band (see, e.g., FIG. 5A) with
corresponding keeper plates attached to lids. Alternatively, latch
bodies are attached to lids with corresponding keeper plates
attached (e.g., directly or via a band) to the reaction block.
Although a single latch per lid is typically preferred, other
arrangements that include multiple latches per lid are optionally
adapted to the devices of the invention.
[0075] In preferred embodiments, lids are removably attached to
reaction blocks. Accordingly, hinge components, such as lift-off
hinges that include male and female components are generally used
in the devices of the invention. Male or female hinge components
are typically attached to reaction blocks directly (e.g.,
fabricated as a molded part of a reaction block or the like) or
indirectly via a band, as described above, with counterpart hinge
components attached to lids. As shown in FIG. 5A, for example,
hinge components 510 and 514 are male lift-off hinge components. In
certain embodiments, female hinge components are attached to, e.g.,
a band. Although, two hinges are typically used per lid, other
configurations are also optionally utilized. For example, a lid is
optionally attached to a reaction block by two latches and a single
hinge (e.g., a hinge centrally positioned on a reaction block or
band to effect substantially even clamping force across reaction
block inlet or outlet portions).
[0076] As shown in FIG. 5A, pairs of hinge components (see, e.g.,
bottom hinge components 510) are oriented to provide for removing
the lid of a device. In certain embodiments, however, lids are
optionally non-removable. In these embodiments, for example, one
member of a pair of hinge components is typically oriented in the
opposite direction from that depicted in, e.g., FIG. 5A.
Optionally, other types of hinges, aside from lift-off hinges are
utilized in the devices of the invention. Suitable hinges and
latching mechanisms that are optionally adapted for use with the
devices of the present invention are generally known in the art.
These attachment components are optionally fabricated by known
techniques, such as injection or cast molding, etc. from various
materials including, e.g., steel, stainless steel, plastic, rubber,
elastomers, or the like. Attachment components such as the hinges
and latching mechanisms described herein are also optionally
acquired from assorted commercial suppliers including, e.g.,
Southco, Inc. (Concordville, Pa.).
[0077] V. Lids
[0078] The parallel reaction devices of the present invention
include top and bottom lids for sealing reaction wells of reaction
blocks. Lids typically include attachment components, such as hinge
and latch components which are capable of engaging corresponding
attachment components disposed, e.g., on a reaction block band, as
described above. In preferred embodiments, the top and bottom lids
are removably attached to the reaction block and open independently
of one another. Further, the top and bottom lids each typically
include at least a first alignment structure complementary to at
least a second alignment structure on, e.g., a controller apparatus
to align the parallel reaction device relative to the controller
apparatus. In addition, the lids produce a substantially even clamp
load or force across inlets and outlets to reaction wells arrayed
in reaction blocks to effectively seal the reaction wells without
leakage.
[0079] FIG. 6A schematically illustrates a top plan view of one
embodiment of a top lid of a parallel reaction device of the
invention. As shown, top lid 600 includes hinge components 602
(e.g., lift-off hinge components, as described above) and keeper
plate 604 attached (e.g., screwed, riveted, adhered, bonded, or the
like) to top lid 600. As described above, a latch body is
optionally attached to top lid 600 instead of keeper plate 604. In
an assembled device, top lid 600 produces a substantially even
clamp load across all inlet portions of a reaction block. Also
shown is array of apertures 606 disposed through top lid 600 in
recessed top surface 608. In preferred embodiments, each aperture
610 axially aligns with a different reaction well in a reaction
block and is tapered (e.g., having a larger cross-sectional
dimension on the top surface of top lid 600 than on a bottom
surface of top lid 600). The inclusion of apertures allows, e.g.,
fluidic materials (e.g., reagents, buffers, or the like) to be
introduced into or removed from reaction wells through, e.g.,
needles of syringes. For example, a needle optionally pierces a
gasket disposed between a reaction block and top lid 600 in an
assembled device, as necessary according to the particular protocol
being performed. Apertures also allow for the establishment and/or
maintenance of an inert atmosphere in a reaction well through,
e.g., a needle-fitted tube, which draws from, e.g., nitrogen,
argon, or other gas sources. Tapered apertures are typically
included to guide or otherwise facilitate the entry of needles into
reaction wells. In certain embodiments, apertures are not included
in top lids of parallel reaction devices. FIG. 6B schematically
shows a top perspective view top lid 600.
[0080] FIG. 6C schematically illustrates a bottom plan view of top
lid 600, whereas FIG. 6D schematically depicts a bottom perspective
view of top lid 600. As shown, recessed bottom surface 612 includes
protruding annular ridges 614 disposed around each aperture 610. In
an assembled device, protruding annular ridges 614 press a top
gasket into contact with inlet portions of reaction wells to
radially seal the inlet portions. The radial seals produced by
protruding annular ridges 614 prevent leakage of fluidic materials
from the inlet portions, e.g., to reduce cross-contamination among
reaction wells. Protrusions such as those depicted in FIGS. 6C and
D typically extend between about 0.5 mm and about 5 mm from
recessed bottom surface 612 and more typically between about 1 mm
and about 3 mm from recessed bottom surface 612. Arrays of
protrusions are also typically included on bottom surfaces of top
lids even in the absence of apertures. Such protrusions are
optionally formed (e.g., fabricated as an integral component of the
lid) as annular ridges, knobs, mounds, cones, or any other
structure that effectively radially seals the reactions wells of
the devices of the invention. A gasket (e.g., a sheet gasket) is
typically disposed in recessed bottom surface 612, which positions
the gasket relative to the reaction wells of the reaction block in
an assembled device. Top lip 600 also includes lateral overhangs
616, which retain the gasket in position even when top lid 600 is
not latched to the device. Top lid 600 additionally includes
alignment structure 618, e.g., for aligning a parallel reaction
device relative to components of a controller device, such as a
translational stage or the like.
[0081] FIG. 7A schematically shows a top plan view of one
embodiment of a bottom lid of a parallel reaction device according
to the present invention. As shown, bottom lid 700 includes hinge
components 702 (e.g., lift-off hinge components, as described
above) and keeper plate 704 attached to bottom lid 700. Latch
bodies are optionally attached to bottom lid 700 instead of keeper
plates. In an assembled device, bottom lid 700 produces a
substantially even clamp load across all outlet portions of a
reaction block. With top lids shut, bottom lids may be opened
without loss of fluidic materials from reaction wells due to the
effective vacuum produced within reaction wells by the securely
sealed inlet portions of reaction blocks. Bottom lid 700 includes
recessed top surface 706 in which a gasket is typically disposed in
an assembled device. To hold a gasket in position, bottom lid 700
also includes lateral overhangs 708. Although not shown, bottom lid
700 optionally further includes, e.g., an array of protrusions
similar to those described above with respect to top lid 600
disposed on recessed top surface 706. Such an array of protrusions
presses a bottom gasket into contact with the outlet portions of
the reaction wells to seal the outlet portions in an assembled
device. In certain embodiments, bottom lids also include arrays of
apertures disposed through the lids, which apertures axially align
with outlet portions of reaction blocks, e.g., for sample
extraction from reaction wells via needles (e.g., syringe needles,
etc.) or the like. Similar to top lid 600 (discussed above), bottom
lid 700 also includes alignment structure 710. FIG. 7B
schematically illustrates bottom lid 700 from a top perspective
view. In addition, FIG. 7C schematically depicts bottom lid 700
from a bottom plan view, whereas FIG. 7D schematically illustrates
bottom lid 700 from a bottom perspective view. As further shown in
FIGS. 7C and D, bottom lid 700 includes recessed bottom surface
712.
[0082] The lids of the present invention typically each have a
footprint that is dimensionally about the same as a standard
multi-well plate, such that an assembled parallel reaction device
may, e.g., be placed into the holders of automated devices designed
for standard micro-well plates. The lids of the devices of the
invention are typically fabricated from various durable materials
including, e.g., metallic materials (e.g., steel, stainless steel,
anodized aluminum alloys, etc.) or certain polymeric materials.
Generally, any sturdy, non-corrosive material suitable for
laboratory conditions may be employed. Furthermore, lids are
typically fabricated utilizing various well-known techniques, such
as injection molding, cast molding, machining, or the like.
[0083] VI. Gaskets
[0084] To effectively seal the reaction wells in the devices of the
present invention, gaskets are generally disposed between lids and
the reaction block in assembled devices. In preferred embodiments,
top and bottom gaskets are sheets of gasketing material. Gaskets
are typically disposable or consumable components of the parallel
reaction devices of the invention. In particular, gasket sheets
suitable for use in the devices of the present invention are
optionally made from essentially any chemically resistant rubber or
elastomeric material, many of which are well known in the art. For
example, suitable gasket sheets are optionally fabricated from,
e.g., Viton.RTM., Santoprene.RTM., Teflon.RTM., Gore-Tex.RTM.,
Celerus.RTM., or the like. Many of these materials are readily
available from various commercial suppliers, such as W. L. Gore
& Associates (Newark, Del.). Combinations of materials, e.g.,
in the form of laminates are also optionally utilized as gasketing
sheets in the devices of the invention. Gasket materials are also
typically selected based upon abilities to maintain seals without
leakage of fluidic materials even after sustaining repeated
punctures and withdrawals of syringe needles. This characteristic
is especially significant for top gaskets in devices of the present
invention that include arrays of apertures in top lids, as
described above.
[0085] In certain embodiments, gaskets are fabricated with at least
one protrusion disposed on a surface, which protrusion axially
aligns with, e.g., an inlet or outlet portion of a reaction block.
Such protrusions are included to further effect radial seals of
reaction wells in the devices of the invention. In these
embodiments, the at least one protrusion typically includes an
array of protrusions in which each protrusion in the array axially
aligns with a different reaction well in a reaction block. An
example gasket sheet that includes an array of protrusions that
correspond to reaction wells in a 96-well reaction block is
schematically illustrated in FIG. 8. As shown in perspective view,
gasket sheet 800 includes array of protrusions 802 disposed on a
surface that engages a reaction block in an assembled device. As
also shown, gasket sheet fits into recessed area 804 of lid 806. In
certain embodiments, gasket sheets (e.g., cap mats, etc.) that
include arrays of protrusions are also used with lids that include
arrays of protrusions, such as those described above. In other
embodiments, multiple gasket sheets (e.g., 2, 3, 4, etc.) are
disposed between a lid and reaction block surface. In these
embodiments, one or more of the multiple gasket sheets optionally
include arrays of protrusions.
[0086] VII. Reaction Block Containers
[0087] The invention also provides reaction block containers, which
typically include non-disposable components of the parallel
reaction devices described herein. In particular, reaction block
containers generally include attachment components (e.g., bands,
hinge components, latch components, etc.), top lids, and bottom
lids. Components of reaction block containers of the invention are
described in greater detail above.
[0088] In one embodiment, a reaction block container includes a
band that includes at least one first top hinge component, at least
one first top latch component, at least one first bottom hinge
component, and at least one first bottom latch component. Portions
of the band are capable of being mounted in opposing recessed
regions on a reaction block. The reaction block container also
includes a top lid that includes at least one second top hinge
component and at least one second top latch component attached to
the top lid. The second top hinge component(s) engage(s) the first
top hinge component(s) and the second top latch component(s)
removably engage(s) the first top latch component(s). In addition,
the reaction block container includes a bottom lid that includes at
least one second bottom hinge component and at least one second
bottom latch component attached to the bottom lid. The second
bottom hinge component(s) engage(s) the first bottom hinge
component(s) and the second bottom latch component(s) removably
engage(s) the first bottom latch component(s).
[0089] In another embodiment, a reaction block container of the
invention includes a band that includes at least one first top
hinge component, at least one first top latch component, at least
one first bottom hinge component, and at least one first bottom
latch component. Portions of the band are capable of being mounted
in opposing recessed regions on a reaction block. The reaction
block container further includes a top lid that includes at least
one protrusion (e.g., an array of protrusions or the like) disposed
on a surface that engages a reaction block. The protrusion(s)
is/are capable of pressing a gasket into contact with at least a
portion of a reaction well(s) of the reaction block. The top lid
also includes at least one second top hinge component and at least
one second top latch component attached to the top lid. The second
top hinge component(s) engage(s) the first top hinge component(s)
and the second top latch component(s) removably engage(s) the first
top latch component(s). The reaction block container additionally
includes a bottom lid that includes at least one second bottom
hinge component(s) and at least one second bottom latch
component(s) attached to the bottom lid. The second bottom hinge
component(s) engage(s) the first bottom hinge component(s) and the
second bottom latch component(s) removably engage(s) the first
bottom latch component(s).
[0090] In preferred embodiments, the top lids of the reaction block
containers of the invention also include an array of apertures
disposed through the top lid. At least one aperture axially aligns
with at least one reaction well disposed in a reaction block.
Typically, each member of the array of apertures axially aligns
with a different reaction well disposed in the reaction block. To
illustrate, FIG. 9 schematically shows an exploded perspective view
of reaction block container according to one embodiment of the
invention in which the top lid includes an array of apertures.
[0091] VIII. Synthesis Systems
[0092] The present invention also provides synthesis systems (e.g.,
automated workstations or the like) that include the parallel
reaction devices described herein, e.g., for synthesizing and
screening combinatorial libraries. In addition to parallel reaction
devices, a system of the invention typically includes other vessels
(e.g., flasks, test tubes, micro-well plates (e.g., deep-well
collection plates), or the like) and a handling system (including,
e.g., bead handlers, fluid handlers, device carriers, etc.)
configured to translocate solid supports (e.g., individual beads,
tea-bags, microvessels, or other containers having multiple beads
or other solid supports disposed therein) and/or reagents to and
from the reaction blocks or other vessels. Additional details
regarding solid support containers that are optionally used in the
devices of the present invention, including those that provide for
molecular tracking and identification are described in, e.g., U.S.
Pat. No. 6,136,274, entitled "MATRICES WITH MEMORIES IN AUTOMATED
DRUG DISCOVERY AND UNITS THEREFOR," to Nova et al., issued Oct. 24,
2000, which is incorporated by reference in its entirety for all
purposes. Other system components optionally include, e.g., vacuum
manifold systems for eluting fluidic materials from reaction wells,
incubators/ovens for regulating temperatures within reaction wells,
centrifuges, shakers or other agitation devices, or the like. The
systems of the invention also typically include a detection system
(e.g., a mass spectrometer or the like) to detect chemical or
physical properties of selected members of, e.g., synthesized
libraries, and a computer (e.g., an information appliance, digital
device, or the like) operably connected to the handling, detection,
and/or other systems. An example system is described below.
[0093] Additional details relating to synthesis systems, which are
optionally adapted for use with the devices of the invention, and
to the automation of combinatorial synthetic methods are described
in, e.g., Cargill and Maiefski (1996) "Automated combinatorial
chemistry on solid phase," Lab. Robotics. Automation 8:139-148,
Zuckermann et al. (1992) "Design, construction and application of a
fully automated equimolar peptide mixture synthesizer," Int. J.
Peptide Prot. Res. 40:497-506, Castelino et al. (2000) "Automated
sample storage for drug discovery," Chim. Oggi. 17:32-35, Davis and
Swayze (2000) "Automated solid-phase synthesis of linear
nitrogen-linked compounds," Biotechnol. Bioeng. 71:19-27, Grogeret
al. (2000) "1,3,5-Triazines, versatile industrial building blocks:
Synthetic approaches and applications," Chim. Oggi. 18:12-16, Haag
(2000) "Chemspeed Ltd.: Automated and unattended parallel synthesis
integrating work-up and analysis," Chimia 54:163-164, Hu et al.
(2000) "Automated solid-phase synthesis and photophysical
properties of oligodeoxynucleotides labeled at 5'-aminothymidine
with Ru(bpy)(2)(4-m-4'-cam-bpy)(2+)," Inorg. Chem. 39:2500-2504,
Lewis et al. (2000) "Automated high-throughput quantification of
combinatorial arrays," American Pharmaceutical Review 3:63-68,
North (2000) "Implementation of analytical technologies in a
pharmaceutical development organization-looking into the next
millennium," Journal of Automated Methods and Management in
Chemistry 22:41-45, and Keifer et al. (2000) "Direct-injection NMR
(DI-NMR): A flow NMR technique for the analysis of combinatorial
chemistry libraries," Journal of Combinatorial Chemistry 2;
151-171.
[0094] A. Controllers
[0095] The handling systems of the invention typically incorporate
one or more controllers, either as separate or integral components,
which are generally utilized, e.g., to regulate the quantities of
reagents dispensed, and the segregation and distribution of solid
supports. A variety of available robotic elements (robotic arms,
movable platforms, etc.) can be used or modified for these
purposes.
[0096] To illustrate, controllers typically direct dipping of bead
handling elements of the handling systems into, e.g., selected
reaction wells of reaction blocks, wells on micro-well plates, or
other reaction vessels, to dispense or extract, e.g., selected
beads or other solid supports. Typically, the controller systems of
the present invention are appropriately configured to receive or
interface with a parallel reaction device or other system component
as described herein. For example, the controller optionally
includes a stage upon which the reaction devices of the invention
are disposed or mounted to facilitate appropriate interfacing
among, e.g., a bead/fluid handler and/or detector and a particular
parallel reaction device. Typically, the stage includes an
appropriate mounting/alignment structural element, such as
alignment pins and/or holes, a nesting well, or the like, e.g., to
facilitate proper device alignment.
[0097] B. Detectors
[0098] The systems of the present invention optionally include
various signal detectors, e.g., which detect mass, concentration,
fluorescence, phosphorescence, radioactivity, pH, charge,
absorbance, refractive index, luminescence, temperature, magnetism,
or the like. Detectors optionally monitor one or a plurality of
signals from upstream and/or downstream of the performance of,
e.g., a given synthesis step. For example, the detector optionally
monitors a plurality of optical signals, which correspond in
position to "real time" results. Example detectors or sensors
include photomultiplier tubes, CCD arrays, optical sensors,
temperature sensors, pressure sensors, pH sensors, conductivity
sensors, scanning detectors, or the like. The detector optionally
moves relative to assay components, or alternatively, assay
components, such as samples of selected synthesis products move
relative to the detector. Optionally, the systems of the present
invention include multiple detectors. Each of these types of
sensors is optionally readily incorporated into the systems
described herein. In these systems, such detectors are typically
placed either in or adjacent to, e.g., a particular reaction
vessel, such that the detector is within sensory communication with
the reaction vessel. The phrase "within sensory communication" of a
particular region or element, as used herein, generally refers to
the placement of the detector in a position such that the detector
is capable of detecting the property of the reaction vessel or
portion thereof, the contents of a portion of the vessel, or the
like, for which that detector was intended. The detector optionally
includes or is operably linked to a computer, e.g., which has
system software for converting detector signal information into
assay result information or the like.
[0099] The detector optionally exists as a separate unit, or is
integrated with the handling or controller system, into a single
instrument. Integration of these functions into a single unit
facilitates connection of these instruments with the computer
(described below), by permitting the use of few or a single
communication port(s) for transmitting information between system
components.
[0100] Specific detection systems that are optionally used in the
present invention include, e.g., a mass spectrometer, an emission
spectroscope, a fluorescence spectroscope, a phosphorescence
spectroscope, a luminescence spectroscope, a spectrophotometer, a
photometer, a nuclear magnetic resonance spectrometer, an electron
paramagnetic resonance spectrometer, an electron spin resonance
spectroscope, a turbidimeter, a nephelometer, a Raman spectroscope,
a refractometer, an interferometer, an x-ray diffraction analyzer,
an electron diffraction analyzer, a polarimeter, an optical rotary
dispersion analyzer, a circular dichroism spectrometer, a
potentiometer, a chronopotentiometer, a coulometer, an amperometer,
a conductometer, a gravimeter, a thermal gravimeter, a titrimeter,
a differential scanning calorimeter, a radioactive activation
analyzer, a radioactive isotopic dilution analyzer, or the
like.
[0101] C. Computer
[0102] As noted above, the systems of the present invention
optionally include a computer (or other information appliance)
operably connected to or included within various system components.
The computer typically includes system software that directs the
handling and detection systems to, e.g., segregate or distribute
solid supports into selected reaction wells or other vessels,
deliver various reagents (e.g., different components or building
blocks, scaffolds, or the like) to selected reaction wells of
reaction blocks, deliver gases to maintain inert environments
within reaction wells via syringe needles, or the like.
Additionally, the handling/controller system and/or the detection
system is/are optionally coupled to an appropriately programmed
processor or computer which functions to instruct the operation of
these instruments in accordance with preprogrammed or user input
instructions, receive data and information from these instruments,
and interpret, manipulate and report this information to the user.
As such, the computer is typically appropriately coupled to one or
both of these instruments (e.g., including an analog to digital or
digital to analog converter as needed).
[0103] Standard desktop applications such as word processing
software (e.g., Microsoft Word.RTM. or Corel WordPerfect.RTM.) and
database software (e.g., spreadsheet software such as Microsoft
Excel.RTM., Corel Quattro Pro.RTM., or database programs such as
Microsoft Access.RTM. or Paradox.RTM.) can be adapted to the
present invention by inputting character strings corresponding to
reagents or masses thereof. For example, the systems optionally
include the foregoing software having the appropriate reagent
information, e.g., used in conjunction with a user interface (e.g.,
a GUI in a standard operating system such as a Windows, Macintosh
or LINUX system) to manipulate reagent information.
[0104] The computer can be, e.g., a PC (Intel x86 or Pentium
chip-compatible DOS.RTM., OS2.RTM., WINDOWS.RTM., WINDOWS NT.RTM.,
WINDOWS95.RTM., WINDOWS98.RTM., LINUX-based machine, a
MACINTOSH.RTM., Power PC, or a UNIX-based (e.g., SUN.RTM. work
station) machine) or other common commercially available computer
which is known to one of skill. Software for performing, e.g.,
library synthesis is optionally easily constructed by one of skill
using a standard programming language such as Visual basic,
Fortran, Basic, Java, or the like. Any controller or computer
optionally includes a monitor which is often a cathode ray tube
("CRT") display, a flat panel display (e.g., active matrix liquid
crystal display, liquid crystal display), or others. Computer
circuitry is often placed in a box, which includes numerous
integrated circuit chips, such as a microprocessor, memory,
interface circuits, and others. The box also optionally includes a
hard disk drive, a floppy disk drive, a high capacity removable
drive such as a writeable CD-ROM, and other common peripheral
elements. Inputting devices such as a keyboard or mouse optionally
provide for input from a user.
[0105] The computer typically includes appropriate software for
receiving user instructions, either in the form of user input into
a set of parameter fields, e.g., in a GUI, or in the form of
preprogrammed instructions, e.g., preprogrammed for a variety of
different specific operations. The software then converts these
instructions to appropriate language for instructing the operation
of one or more controllers to carry out the desired operation,
e.g., varying or selecting the rate or mode of movement of various
system components, directing X-Y-Z translation of the bead/fluid or
other reagent handler, or of one or more micro-well plates or other
reaction vessels, or the like. The computer then receives the data
from the one or more sensors/detectors included within the system,
and interprets the data, either provides it in a user understood
format, or uses that data to initiate further controller
instructions, in accordance with the programming, e.g., such as in
monitoring reaction temperatures, regulating agitation rates, or
the like.
[0106] IX. Kits
[0107] The present invention also provides kits that include
parallel reaction devices, or components of such devices. For
example, a kit typically includes at least one reaction block, a
band with attached hinge and latch components, top and bottom
gaskets, and top and bottom lids, as described herein. The devices
of the kits of the invention are optionally pre-assembled or
unassembled. Kits are optionally packaged to further include
reagents, control/calibrating materials, and solid supports for
performing selected solid phase synthesis reactions in the devices
of the invention. In the case of pre-packaged reagents, the kits
optionally include pre-measured or pre-dosed reagents that are
ready to incorporate into a synthetic protocol without measurement,
e.g., pre-measured fluid aliquots, or pre-weighed or pre-measured
solid reagents that can be easily reconstituted by the end-user of
the kit. Generally, reagents are provided in a stabilized form, so
as to prevent degradation or other loss during prolonged storage,
e.g., from leakage. A number of stabilizing processes are widely
used for reagents that are to be stored, such as the inclusion of
chemical stabilizers (i.e., enzymatic inhibitors,
microcides/bacteriostats, anticoagulants), the physical
stabilization of the material, e.g., through immobilization on a
solid support, entrapment in a matrix (i.e., a gel),
lyophilization, or the like. In certain embodiments, kits include
only selected device components, such as disposable reaction blocks
and/or gaskets, or other components (e.g., lids, attachment
components, reaction block containers, etc.). Kits typically
include appropriate instructions for operating and maintaining
devices or components thereof. Kits also typically include
packaging materials or containers for holding kit components.
[0108] X. Utility
[0109] The parallel reaction devices of the present invention are
designed for use in essentially any chemical synthesis procedure,
including solid- or solution-phase organic synthesis. The devices
of the invention provide particular utility where numerous,
individual reactions are performed simultaneously and, e.g., where
filtration is a necessary step during the synthesis and/or workup
process. Other exemplary uses for the parallel reaction devices, or
device components, of the invention include performing multiple,
simultaneous chromatographic or affinity-based
separations/purifications. To illustrate, each reaction well of a
device optionally serves as a column for chromatographic separation
of chemical mixtures on, e.g., silica gel, alumina, or many other
adsorbents/resins that are commonly known in the relevant art. The
elution of samples or other materials is typically gravity-based or
dependent on an applied pressure. Additional details regarding
synthetic pathways, separations, and other processes optionally
performed in the devices of the invention are described in, e.g.,
Seneci, Solid-Phase Synthesis and Combinatorial Technologies, John
Wiley & Sons, Inc. (2000), Albericio and Kates, Solid-Phase
Synthesis: A Practical Guide, Marcel Dekker (2000), An and Cook
(2000) "Methodologies for generating solution-phase combinatorial
libraries," Chem. Rev. 100: 3311-3340, Wu (Ed), Column Handbook for
Size Exclusion Chromatography, Harcourt Brace & Company (1998),
and in the references cited therein. Other general resources
include, e.g., March, Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, 4.sup.th Ed., John Wiley & Sons,
Inc. (1992), Smith and March, March's Advanced Organic Chemistry:
Reactions, Mechanisms, and Structure, 5.sup.th Ed., John Wiley
& Sons, Inc. (2001), Carey and Sundberg, Advanced Organic
Chemistry Part A: Structure and Mechanism, 4.sup.th Ed., Plenum
Press (2000), and in the references provided therein.
[0110] The parallel reaction devices of the invention are also
optionally used to process various biological samples. For example,
large numbers of microorganisms, including anaerobic organisms, or
tissue samples can be cultured in parallel in the reaction wells in
these devices. Methods of culturing tissues or cells are described
in various publications including, e.g., Ausubel et al., eds.,
Current Protocols in Molecular Biology, a joint ventures between
Greene Publishing Associates, Inc. and John Wiley & Sons, Inc.
(supplemented through 2000), Freshney, Culture of Animal Cells, a
Manual of Basic Technique, 3.sup.rd Ed., Wiley-Liss (1994), and
Humason, Animal Tissue Techniques, 4.sup.th Ed., W. H. Freeman and
Company (1979), and the references cited therein. Other
non-limiting illustrations include performing various cell-based
assays, such as pharmaceutical candidate screening, apoptosis
analyses, or many other assays known in the art. Components of cell
lysates are also optionally separated using, e.g., frit materials
or assorted commonly known resins disposed in the arrays of
reaction wells of the devices of the invention.
XI. EXAMPLE
[0111] A. Example Synthesis System
[0112] FIG. 10 is a schematic showing a representative example
synthesis system including a logic device in which various aspects
of the present invention may be embodied. As will be understood by
practitioners in the art from the teachings provided herein, the
invention is optionally implemented in hardware and software. In
some embodiments, different aspects of the invention are
implemented in either client-side logic or server-side logic. As
will be understood in the art, the invention or components thereof
may be embodied in a media program component (e.g., a fixed media
component) containing logic instructions and/or data that, when
loaded into an appropriately configured computing device, cause
that device to perform according to the invention. As will also be
understood in the art, a fixed media containing logic instructions
may be delivered to a viewer on a fixed media for physically
loading into a viewer's computer or a fixed media containing logic
instructions may reside on a remote server that a viewer accesses
through a communication medium in order to download a program
component.
[0113] FIG. 10 shows information appliance or digital device 1000
that may be understood as a logical apparatus (e.g., a computer,
etc.) that can read instructions from media 1017 and/or network
port 1019, which can optionally be connected to server 1020 having
fixed media 1022. Apparatus 1000 can thereafter use those
instructions to direct server or client logic, as understood in the
art, to embody aspects of the invention. One type of logical
apparatus that may embody the invention is a computer system as
illustrated in 1000, containing CPU 1007, optional input devices
1009 and 1011, disk drives 1015 and optional monitor 1005. Fixed
media 1017, or fixed media 1022 over port 1019, may be used to
program such a system and may represent a disk-type optical or
magnetic media, magnetic tape, solid state dynamic or static
memory, or the like. In specific embodiments, the aspects of the
invention may be embodied in whole or in part as software recorded
on this fixed media. Communication port 1019 may also be used to
initially receive instructions that are used to program such a
system and may represent any type of communication connection.
Optionally, aspects of the invention is embodied in whole or in
part within the circuitry of an application specific integrated
circuit (ACIS) or a programmable logic device (PLD). In such a
case, aspects of the invention may be embodied in a computer
understandable descriptor language, which may be used to create an
ASIC, or PLD.
[0114] FIG. 10 also includes handling system 1024 and detection
system 1026, both of which are operably connected to digital device
1000 via server 1020. Optionally, handling system 1024 and/or
detection system 1026 are directly connected to digital device
1000. During operation, handling system 1024 typically distributes
reagents and/or solid supports (e.g., individual beads, tea-bags,
etc.) to selected reaction wells of parallel reaction device 1028.
Between synthetic steps, handling system 1024 optionally pools
and/or segregates solid supports for additional rounds of
synthesis, or for product analysis, e.g., following product
cleavage. Detection system 1026 optionally includes a mass
spectrometer for detecting masses of selected members of a library
following synthesis. Digital device 1000 digitizes, stores, and
manipulates signal information detected by detection system 1026
using one or more logic instructions.
[0115] While the foregoing invention has been described in some
detail for purposes of clarity and understanding, it will be clear
to one skilled in the art from a reading of this disclosure that
various changes in form and detail can be made without departing
from the true scope of the invention. For example, all the
techniques and apparatus described above may be used in various
combinations. All publications, patents, patent applications, or
other documents cited in this application are incorporated by
reference in their entirety for all purposes to the same extent as
if each individual publication, patent, patent application, or
other document were individually indicated to be incorporated by
reference for all purposes.
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