Chemical apparatus and process disinfecting – deodorizing – preser – Control element responsive to a sensed operating condition
Reexamination Certificate
2000-02-04
2002-11-12
Markoff, Alexander (Department: 1746)
Chemical apparatus and process disinfecting, deodorizing, preser
Control element responsive to a sensed operating condition
C422S091000, C422S105000, C422S106000
Reexamination Certificate
active
06479020
ABSTRACT:
TECHNICAL FIELD
The present invention relates generally to apparatus for synthesizing and culturing chemical and biological compounds, to chemical and biological filtration apparatus, and to multi-well apparatus, and more particularly to such apparatus used for performing multiple simultaneous syntheses and filtrations on a micro scale.
BACKGROUND ART
As the scale on which chemical compounds and biological materials are capable of being analyzed, tested, purified and otherwise manipulated for research and clinical purposes continues to decrease, there is a call for increasingly more efficient methods of synthesizing and culturing such compounds and materials. Numerous benefits, in particular, are offered by the extremely small or “micro” scale preparation of chemical and biochemical molecules. Among such benefits are that costs with respect to the reagents, solvents and other materials employed for reaction, workup and purification—many of which can be quite expensive—are greatly reduced. Further, the amounts of by-products and other waste materials generated are also greatly reduced, thereby lowering disposal costs and also reducing the potential for environmental damage by hazardous materials. Moreover, the speed with which large numbers of chemical compounds can be synthesized for biological screening purposes can be greatly increased, since a large number of such microscale reactions can potentially be run and processed simultaneously in a single piece of apparatus using batch equipment.
Given that only a very minute percentage of chemical entities that are investigated will exhibit the desired characteristics for which they have been targeted and synthesized, and given that relatively small changes in chemical structure can produce profoundly different biological properties, the ability to rapidly synthesize large numbers of new compounds and analogs for evaluation is of especially great commercial importance, indeed, it is often a matter of economic survival to pharmaceutical and biotechnological companies involved in the development of new therapeutic agents.
It has been the case for a number of years in the peptide field that use has been made of mechanized, computer-aided equipment capable of simultaneously synthesizing a number of different peptides by the sequential coupling of amino acids to functionalized solid supports. Such mechanized equipment may be employed because the conditions necessary for most such coupling reactions are uniformly simple and straightforward.
In the case of the synthesis of organic compounds generally, however, there is a great variance in the conditions and techniques which must be employed, which precludes or makes impractical the use of fully automated instruments. For example, magnetic stirring, shaking, or some other form of agitation may be needed, and heating or cooling to great temperature extremes may be required. With respect to reactions requiring heating, provision for the reflux of volatile solvent may also be necessary. Further, many chemical reactions are air sensitive and so may require an inert atmosphere for their performance. Reagents and substrates may be air sensitive (e.g., hygroscopic or pyrophoric) or corrosive and require special handling techniques, such as transfer via a syringe or cannula, or even handling in a glove box. Many organic synthetic procedures require the addition of materials in both solid and liquid form or employ an addition sequence that is complex. Additionally, some delicate reactions must be closely monitored through intermittent sampling in order to bring the reaction to a successful fruition. Where an instrument(s) is capable of performing any of the above, it is still the case that throughput is limited, further, such instruments are extremely expensive.
One prior art attempt at providing an apparatus for the simultaneous, multiple synthesis of organic compounds is found in U.S. Pat. No. 5,324,483 issued Jun. 28, 1994 to Cody et al. In Cody, which is directed toward solid phase synthesis, the lower ends of a plurality of reaction tubes (in the nature of conventional gas dispersion tubes) are each received by a plurality of reaction wells. The reaction tubes are held vertically in place by a holder block, while the reactions wells are contained by a reservoir block. A seal is provided between the holder block and the reservoir block. A manifold covers the reaction tubes, with a seal being provided between the manifold and the holder block. Means are provided for detachably fastening together the reservoir block to the holder block and the holder block to the manifold. The dispersion tubes provide a glass frit type of filtering capability so that a solid support may be retained and rinsed as necessary after performance of a coupling reaction or cleavage of product from the support.
The invention of Cody offers the advantage that multiple reactions may be carried out simultaneously—even at reflux at atmospheric pressure conditions and while under an inert atmosphere, if necessary. However, the apparatus appears to be rather complex, bulky, awkward to use, fragile, and difficult to clean. The apparatus also is not very amenable to use with standard liquid handling systems and other batch-processing type equipment. Additionally, the apparatus is not well-suited for true microscale synthesis because the surface area of the components, particularly the gas dispersion tubes, is such that undesirable “hold-up” of liquid material is prone to occur.
Shown in an article by Meyers et al. entitled “Multiple simultaneous synthesis of phenolic libraries,”
Molecular Diversity,
1 (1995), pp. 13-20, is an apparatus for multiple, simultaneous (solid phase) synthesis that is considerably better suited to use with batch processing techniques. As described at p. 16 of the article (FIG.
4
), Meyers uses a conventional “deep-well” multi-well plate in the standardized 96-well, 8×12 rectangular array format. Each well is modified by drilling a small hole in the well bottoms and then installing a filter frit in each well bottom. The deepwell plate is made to be liquid tight by sandwiching it between a clamping arrangement that utilizes a solid base element fitted with four threaded steel posts and a (open) frame element that sits on top of the plate and which is secured by knurl nuts. A planar rubber gasket, which rests on top of the base element, seals the openings at the bottoms of the wells, while the tops of the wells are sealed with
8
-well strip caps (a total of twelve such strips would be required for sealing all of the wells). The invention provides that reactions may be carried out within the wells, with the solid support upon which the chemistry is conducted able to then be filtered and washed within the same wells by virtue of the fritted nature of the wells and the removable sealing means at the bottom.
As noted in Meyers, the 96-well format is ubiquitous and used in numerous applications. Meyers' invention is therefore theoretically able to be used in conjunction with automated high-throughput screens and many other types of equipment (e.g., multi-channel pipettors) that are based on that (standard) 96-well format. However, Meyers is limited in several respects. Perhaps most importantly, the sealing arrangement that is used for the bottom of the wells, i.e., the provision of a clamping frame about the periphery of a multiwell plate having a standard footprint, causes the apparatus to lose that footprint because the frame is naturally dimensionally larger than the multi-well plate. Thus, the multi-well plate with the bottom openings sealed (i.e., with the frame attached) cannot be fitted within the holders of such instruments as automated dispensing equipment that are designed to hold an object that is no larger than the size of the multi-well plate itself.
Another problem is that the outlets at the bottom of the wells are simply holes. There is no provision for a directing nozzle or other structure to be present at the bottom of each well that would enable effluent to properly drain into
Bailey Chris N.
Robbins Paul B.
Stanchfield James E.
Wright David J.
Guernsey Larry B.
Intellectual Property Law Offices
Markoff Alexander
Robbins Scientific Corporation
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