Chemical apparatus and process disinfecting – deodorizing – preser – Chemical reactor
Reexamination Certificate
2001-02-09
2002-08-13
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Chemical reactor
C422S091000, C422S105000, C422S105000, C422S105000, C422S130000, C435S283100, C435S287100, C435S287800, C435S288200, C435S288400
Reexamination Certificate
active
06432366
ABSTRACT:
The present invention relates to apparatus for combinatorial drug research to be used in the simultaneous parallel solid and solution phase synthesis of large numbers of diverse organic compounds or for the final cleavage step of radio frequency tagged synthesis and more particularly to a modular apparatus designed for such purposes which employs a unique pinch valve block, which includes reactor vessels capable of receiving porus polyethelyene microcannisters with radio frequency transmitter tags and which can be used to discharge into all of the wells of a standard microtiter plate.
Efficient testing of organic compounds in the modern pharmaceutical laboratory requires the synthesis of large numbers of diverse organic molecules in an automated and high speed manner.
The apparatus of the present invention is designed for use in such a system, particularly one which employs solid phase synthesis techniques. It is useful in performing the entire synthesis or for performing only the final cleavage step of radio frequency tagged synthesis.
During the course of the synthesis, various operations must be performed on the samples, including reagent introduction and removal, agitation, washing, and compound removal by cleavage from a resin support. Precise control of temperature, pressure and atmospheric gas mixtures may be required at various stages. These operations are standard and can be performed at task specific work stations which have been designed or modified for use with one or more reactors.
Over the last few years, a number of different systems have been developed to produce libraries of large numbers of specific types of organic molecules, such as polynucleotides. However, the usefullness of such systems tends to be limited to the particular type of molecule the system was designed to produce. Our invention is much more general in application. It can be used to synthesize all types of organic compounds including those used in pharmaceutical research, the study of DNA, protein chemistry, immunology, pharmacology or biotechnology.
Aside from the lack of versatility, existing equipment for automated organic synthesis tends to be large and heavy, as well as very expensive to fabricate and operate. Known automated systems also tend to be quite complex, requiring equipment which is limited as to flexibility, speed, and the number and amount of compounds which can as be synthesized. As will become apparent, our system has a simple, elegant design. It is relatively inexpensive to fabricate and operate. However, it is extremely flexible and is capable of producing large numbers and amounts of all types of organic compounds in a high speed, automated manner. It is smaller in size than comparable equipment, permitting more reactors to be used at one time at a work station and it is lighter, thereby facilitating movement of the apparatus between work stations with less effort.
One system of which we are aware was developed for use at Zeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. That system is built around an XP Zymate laboratory robot (Zymark Corporation, Hopkinton, Mass.). The robot arm is situated in the middle of a plurality of stationary work stations arranged in a circle. The arm is programmed to move one or more tube racks from one station to another. However, the Zeneca system has a small throughput capability, as the number of tube racks which can be handled at one time is limited.
An automated peptide synthesizer developed for Chiron Corporation of Emeryville, Calif., which has similar limitations, is described by Ronald N. Zukermann, Janice M. Kerr, Michael A. Siani and Steven C. Banville in an article which appeared in the International Journal of Peptide and Protein Research, Vol. 40, 1992, pages 497-506 entitled “Design, Construction and Application of a Fully Automated Equimolar Peptide Mixture Synthesizer”. See also U.S. Pat. No. 5,240,680 issued Aug. 31, 1993 to Zuckermann and Banville and U.S. Pat. No. 5,252,296 issued Oct. 12, 1993 to Zukermann et al. entitled “Method and Apparatus For Biopolymer Synthesis”.
Another approach was developed at Takeda Chemical Industries, Ltd. and is described in an article published in the Journal of Automatic Chemistry, Vol. 11, No. 5 (September-October 1989) pp. 212-220 by Nobuyoshi Hayashi, Tobru Sugawara, Motoaki Shintani and Shinji Kato entitled “Computer-assisted Automatic Synthesis II. Development of a Fully Automated Apparatus for Preparing Substituted N-(carboxyalkyl) Aminio Acids”. The Takeda system includes a plurality of stationary units which are computer controlled. The reactor unit includes only two reaction flasks. A plurality of computer controlled solenoid valves regulate the input flow from the reactant supply unit and wash solvent supply unit as well as output to the purification unit, exhaust and drainage unit. Sensors and electrodes feed information back to the computer. That system is complex, costly and inflexible. It is also very limited with respect to the number of compounds which can be synthesized.
A more flexible approach has been suggested by the Parke-Davis Pharmaceutical Research Division of Warner-Lambert, as described by Sheila Hobbs DeWitt et al. in Proc. National Academy of Science, USA, Vol. 90, pp. 6909-6913 August 1993 and in the ISLAR '93 Proceedings. That system employs a Tecan robotic sample processor. A manifold of gas dispersion tubes are employed in combination with glass vials. The glass frits of the tubes contain the solid support during reactions. However, like many prior art systems, in this apparatus, samples from the reaction tubes must be removed from above, using a modified needle as a probe. There is no facility for removal from the bottoms of the tubes. Accordingly, obtaining product from the reactor vessels in the Parke-Davis system is awkward and time consuming.
U.S. Pat. No. 5,472,672 issued Dec. 5, 1995 to Thomas Brennan, entitled “Apparatus and Method for Polymer Synthesis Using Arrays”, teaches the use of an automated system in which a transport mechanism is used to move a base having an array of reactor wells in conveyor belt fashion from work station to work station. Sample removal is performed by creating a pressure differential between the ends of the wells. Aside from the difficulties with regard to discharge, this system is complex and lacks flexibility.
We are also aware of system designed by the Ontogen Corporation of Carlsbad, Calif. 92009 as disclosed by John Cargill and Romaine Maiefski in Laboratory Robotics and Automation, Vol. 6 pp. 139-147 in an article entitled “Automated Combinatorial Chemistry on Solid Phase” and disclosed in U.S. Pat. No. 5,609,826 entitled “Methods and Apparatus for the Generation of Chemical Libraries” issued Mar. 11, 1997 to John Cargill and Romaine Maiefski. The system disclosed in the article and patent utilizes a reactor block having an array of reactor vessels. The block is moved along an assembly line of work stations under computer control.
The Ontogen apparatus disclosed in the above mentioned article and patent has a number of shortcomings. It is highly complex and expensive. It does not include any valving structure capable of regulating the fluid discharge from the reactor chambers. Instead, it depends upon pressure differential to cause discharge through s-shaped trap tubes which snap into a fitting on the bottom of each reaction vessel. This takes up a lot of room, preventing the dense packing of the reactor vessels. It also makes product removal awkward.
Because the reactor vessels disclosed in the article and patent cannot be densely packed, mirror image reactors are required in the Ontogen system to discharge into all of the densely packed wells of a standard microtiter plate. As described in U.S. Pat. No. 5,609,826, two different reactor configurations, each capable of receiving a set of 48 reaction vessels, are required to deposit directly into all 96 of the microtiter wells.
Reactor vessels of the type commonly used in the art are not adapted to receive commercially av
Allen, Jr. John William
Li Wenjeng
Ruediger Waldemar
Weller, III Harold Norris
Babajko Suzanne E.
Bristol--Myers Squibb Company
Handy Dwayne K
Warden Jill
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