Fluent material handling – with receiver or receiver coacting mea – Plural filling means
Reexamination Certificate
2002-03-27
2004-12-07
Huson, Gregory L. (Department: 3751)
Fluent material handling, with receiver or receiver coacting mea
Plural filling means
C141S001000, C141S101000, C141S104000, C141S130000, C141S243000
Reexamination Certificate
active
06827113
ABSTRACT:
COPYRIGHT NOTIFICATION
Pursuant to 37 C.F.R. § 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.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT
Not Applicable.
FIELD OF THE INVENTION
The present invention relates to fluid dispensing systems. More specifically, the invention provides automated systems for simultaneously producing multiple fluid mixtures in multiple multiwell plates with high throughput.
BACKGROUND OF THE INVENTION
Acquiring knowledge of the detailed three-dimensional structures of proteins and other macromolecules is central to structure-based drug development. A prominent methodology for solving high-resolution molecular structure is x-ray crystallography, which entails crystallizing the molecule under consideration. The process typically involves crystallizing a test sample that includes the target molecule in a fluid mixture formulated to provide stable and highly ordered crystals. The art of crystallization, however, is often difficult and time consuming. For example, each new protein crystallization generally requires a unique concentration and mixture of salts, precipitants, and other fluids for crystal growth to occur. It is typically necessary to screen a protein sample against hundreds or even thousands of varied fluid mixtures or crystallization mother liquors in order to identify the proper combination of fluids that will yield a crystallized form of the protein. To further illustrate, finding the proper fluid mixture may require varying the composition of the mixture using a multi-dimensional array of variables, such as different types of aqueous, salt, precipitant, organic, and buffer solutions, different concentrations and pH levels for those fluids, different atmospheric conditions, and the like.
Screens for suitable crystallization conditions are currently conducted manually using skilled technicians. Performing each screen is generally a labor intensive process, in part, because the different fluid mixtures into which the target molecules are deposited must themselves be dispensed, e.g., in very small amounts into the wells of multiwell plates, such as microwell plates. The physical act of dispensing these small amounts into such small fluid containers is itself a time consuming and inaccurate process. In addition, the amount of test sample available for each individual screen is often limited. Further, the screening fluids used in each screen are typically measured in microliter volumes or less. This requires a high level of precision and accuracy that can be difficult even for skilled technicians. The reliability and reproducibility of each screen are integral to the precision and accuracy of the screens. Accordingly, there exists a need to automate the screening process to increase throughput, and to increase the level of precision, accuracy, and reproducibility of the process.
As mentioned, conventional crystallization techniques generally require that each test sample to be crystallized be screened against numerous different fluid mixtures in order to find a proper composition that provides stable crystallization conditions for the particular target molecule in question. In a manual screening process, a technician is primarily responsible for measuring, mixing, and dispensing each unique fluid mixture. Such a manual process is time consuming and expensive, and therefore the variations of fluid mixtures are often limited because of time constraints in the screening process. Unfortunately, by reducing the granularity of the screen, a less than optimum fluid mixture will likely be selected. Further, such a manual screening process is highly susceptible to human mathematical and measurement errors in fluid preparation. As a consequence, the screen may yield erroneous, unreliable, and non-reproducible results.
Yet another problem associated with screening crystallization conditions is that many of the component fluids of crystallization mother liquors used in the screens are highly volatile. These volatile fluids can evaporate or change in character rapidly in a short period of time. Therefore, it is often difficult to manually prepare a screen that includes a large number of individual crystallization assays due to the time required to deposit the fluids into each well. As the different fluids are deposited in each well, the volatile fluids can evaporate or otherwise change composition, rendering the particular screen inaccurate or otherwise biased.
From the above, it is apparent that there is a substantial need for fluid dispensing systems that simultaneously produce multiple fluid mixtures (e.g., mother liquor solutions for crystallization screens, etc.) in multiple multiwell plates. These and a variety of additional features of the present invention will become evident upon complete review of the following disclosure.
SUMMARY OF THE INVENTION
The present invention provides highly automated fluid delivery systems and related methods with significantly improved throughput relative to preexisting technologies. In particular, the invention relates to a fluid dispensing system that simultaneously produces multiple fluid mixtures on-the-fly in multiple multiwell plates. The invention also includes software that, inter alia, directs fluid dispensing from multiple fluid dispensers and tracks fluid mixture compositions in the wells of multiwell plates. In addition, various systems and related methods are also provided for performing assorted downstream processes. Fluid mixtures prepared utilizing the systems and methods described herein are useful for essentially any purpose including, for example, preparation of mother liquor solutions for high throughput crystallization screens.
The present invention provides a fluid dispensing system that includes an array of fluid dispensers. In some embodiments, the array includes at least two fluid dispensers that are spaced at least a sufficient distance apart to simultaneously dispense a fluid into a well of a first multiwell plate and a corresponding well of a second multiwell plate when both plates are placed beneath the array of fluid dispensers. The number of fluid dispensers in the array is, in certain embodiments, at least as great as the number of wells in two lines of wells of a single multiwell plate; and in these embodiments the fluid dispensers are spaced an appropriate distance apart from one another to simultaneously dispense a fluid into wells of multiple multiwell plates when the plates are placed underneath the fluid dispensers. In some configurations, the array of fluid dispensers includes a plurality of linear arrays, each of which comprises at least two fluid dispensers that are spaced at least a sufficient distance apart to simultaneously dispense a fluid into a well of a first multiwell plate and a corresponding well of a second multiwell plate when both plates are placed beneath the array of fluid dispensers.
In one aspect, the present invention provides a fluid dispensing system that includes a linear array of fluid dispensers in which the linear array includes a number of fluid dispensers that is greater than the number of wells in a line of wells (e.g., a row or column of wells) of a single multiwell plate, which line of wells is parallel to a longitudinal axis of the linear array. Each dispenser is spaced an appropriate distance apart from an adjacent fluid dispenser to allow the two adjacent dispensers to simultaneously dispense a fluid into adjacent wells of a multiwell plate when the multiwell plate is placed underneath the fluid dispensers. Suitable spacings include, but are not limited to, 144 mm, 72 mm, 36 mm, 18 mm, 9 mm, 4.5 mm, 2.25 mm or less (center to center), depending upon the plate format. In some embodiment
Downs Robert C.
Weselak Mark R.
deVore Peter
Huson Gregory L.
IRM LLC
Quine Intellectual Property Law Group P.C.
Sappenfield Christopher C.
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