Chemical apparatus and process disinfecting – deodorizing – preser – Chemical reactor – Bench scale
Reexamination Certificate
1997-12-16
2001-08-14
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Chemical reactor
Bench scale
C422S091000, C422S105000, C422S105000, C422S105000, C422S105000, C422S105000, C422S129000, C422S131000, C422S134000
Reexamination Certificate
active
06274094
ABSTRACT:
The present invention relates to apparatus for the simultaneous parallel synthesis of large numbers of diverse organic compounds for use in combinatorial drug research and more particularly to a nestable, modular apparatus designed for that purpose which is portable so as to be moveable among work station nest sites and which includes a reactor block with unique mechanical valve means.
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 system. The present invention is designed for use in such a system, particularly one which employs solid phase synthesis techniques.
During the course of the synthesis, various operations must be performed on the samples, including reagent introduction and removal, agitation, washing and compound removal. Precise control of temperature, pressure and atmospheric gas mixtures may be required at various stages. These operations are standard and can be performed at work stations which have been designed or modified for use with multiple reactors.
Over the last few years, a number of different systems have been developed to produce 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 versitility, existing equipment for automated organic synthesis tends to be either overly complex, requiring equipment which is exceedingly costly to fabricate and operate or too limited as to flexibility, speed, and the number and amount of compounds which can as be synthesized. As will become apparent, our invention has a simple, elegant design which is relatively inexpensive to fabricate and operate, is extremely flexible and is capable of producing large numbers and amounts of all types of organic compounds in a high speed, automated manner.
One existing system 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, such a system has limited 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 Emevyville, 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. 5,252,296 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. This 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. This 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, samples from the reaction tubes must be removed from above, using a modified needle as a probe, as there is no facility for removal from the bottom of the tubes. Accordingly, discharge 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 with 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 F. Cargill and Romaine R. Maiefski in Laboratory Robotics and Automation, Vol. 6 pp. 139-147 in an article entitled “Automated Combinatorial Chemistry on Solid Phase”. This system utilizes a reactor block having an array of reactor vessels. The block is moved along an assembly line of work stations under computer control. However, that system is highly complex, expensive and lacks flexibility. Moreover, it does not include any valving structure capable of regulating the removal of compounds from the bottom of the reactor vessels.
Our approach to the automation problem is to employ modules of relatively simple design and construction which can be arranged in sets to perform the required operations and which are easily moveable among nest sites situated at standard work stations. This system permits the greatest amount of flexibility at the least cost. The modules are relatively inexpensive and can be arranged as needed. As many of the module sets can be assembled and employed at one time as there are available nesting sites. Several nest sites may be created at a single work station, such as an orbital shaker. For time consuming operations, several work stations can be in use simultaneously, to permit parallel flow of module sets and therefore eliminate bottlenecks. For less time consuming operations, fewer work stations can be used, as long as the flow of module sets is not impeded. Accordingly, maximum throughput is achieved with minimum investment.
In addition, our apparatus includes a reactor module which is designed to permit sample removal from the bottom of the reactor vessels through the use of a novel multi-valve system located beneath the reactor block. The system includes rows of gang-controlled mechanical valves which regulate the passage of fluids through the reactor vessel outlets in an extremely efficient manner. The valves, in the form of stopcocks, can be closed and locked into position to prevent leakage. This is possible due to the use of pairs of uniquely configured control arm positioning rails associated with each row of stopcocks. All of the rail pairs can be manipulated simultaneously to open and close all of the stopcocks in unison.
The reactor module of the present invention also includes a temperature controllable reactor block located above the valve structure which accepts an array of reactor vessels. The vessels are preferably standard solid phase extraction
Lawrence R. Michael
Ruediger Waldemar
Weller, III Harold Norris
Epstein Robert L.
Handy Dwayne K.
James Harold
James & Franklin LLP
Warden Jill
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