Coating apparatus – Projection or spray type – Plural projectors
Reexamination Certificate
2002-03-26
2004-12-14
Edwards, Laura (Department: 1734)
Coating apparatus
Projection or spray type
Plural projectors
C118S315000, C427S421100, C422S091000, C436S180000
Reexamination Certificate
active
06830621
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a liquid discharge apparatus for producing a probe carrier having probes of plural kinds in different positions on a carrier, an apparatus for producing a probe carrier utilizing such liquid discharge apparatus, and a method for producing a probe carrier utilizing the same.
2. Related Background Art
In analyzing the base arrangement in a gene DNA or executing genetic diagnosis simultaneously on multiple items with high reliability, it is required to select the DNA of a desired base arrangement with plural probes. As means for providing the probes of plural kinds to be used for such selecting operation, so-called DNA microchip is attracting attention. Also in high throughput screening of pharmaceuticals or in combinatorial chemistry, it is required to execute systematic screening by arranging proteins or chemical solutions of plural kinds (for example 96, 384 or 1536 kinds). There are being developed methods for arraying chemical compounds of plural kinds for this purpose, automated screening technologies in such state, exclusively designed apparatuses therefor and softwares for controlling the screening operations and statistically processing the results.
Such parallel screening operation basically consists of applying so-called probe array, composed of an array of a plurality of known probes constituting selecting means, to a substance to be evaluated, thereby detecting the presence or absence of interaction or reaction with the probes under the same condition. In general, the nature of probes of which interaction or reaction is to be utilized is determined in advance, and, the probes to be mounted on a single probe array are consequently of one substance in general classification, for example a group of DNA probes with different base arrangements. For example, the substances to be utilized in a group of probes are DNA, proteins, synthesized chemical substances (pharmaceuticals) etc. In most cases, there is utilized the probe array containing a group of probes of plural kinds, but, in certain screening operations, there is utilized an array containing plural spots of DNA of the same base arrangement, protein of the same amino acid arrangement or the same chemical substance. Such array is principally utilized for example in the pharmaceutical screening.
More specifically, the probe array containing a group of probes of plural kinds usually assumes a form of arranging, on a substrate, a group of DNA's having different base arrangements, a group of proteins having different amino acid arrangements or a group of different chemical substances in an array form of a predetermined sequence of arrangement. Among such probe arrays, the DNA probe array is utilized in analyzing the base arrangement of the genetic DNA or in executing the genetic diagnosis simultaneously on multiple items with high reliability.
One of the issues in producing such probe array containing a group of probes of plural kinds is to amount the probes of as many kinds as possible, for example DNA probes of as many different base arrangements as possible, on a substrate. Stated differently, it is necessary to arrange the probes in as high density as possible.
Among the methods for fixing the probes of plural kinds in an array form on the substrate, the U.S. Pat. No. 5,424,186 discloses a method of preparing DNA probes of mutually different base arrangements in an array form, by successive DNA extending reactions utilizing photodecomposable protective radicals and photolithography on a carrier. Such method allows to prepare, for example, a DNA probe array bearing DNA probes of different base arrangements at a density of 10,000 kinds/cm
2
or even larger. In this method, the DNA probes of desired base arrangements are synthesized in the predetermined positions on the substrate, through the successive extending reactions, by executing a photolithographic step with an exclusive photomask for each of four bases (A, T, C and G) thereby selectively extending such bases in predetermined positions of the array. Therefore, the cost and time required for preparation increase as the DNA probe chain becomes longer. Also the proportion of the DNA probes including defects in the designed base arrangement is not small because the efficiency of nucleotide synthesis is not 100% in each extending step. Furthermore, in the finally obtained array, the proportion of the DNA probes having the designed base arrangement becomes inevitably smaller since the efficiency of synthesis is lower in the process utilizing the photodecomposable protective radicals in comparison with the ordinary process utilizing acid-decomposable protective radicals.
Furthermore, as the products synthesized directly on the carrier are to be used for the screening operation, it is naturally impossible to eliminate, from the DNA probes having designed base arrangements, those having defects in the base arrangement by a purification process. This method is also associated with a drawback that the base arrangement of the DNA probe synthesized on the substrate cannot be confirmed in the finally obtained array. This means that, in case the extension of a base is scarcely achieved in an extending step for example by an error in the process and the entire probe array becomes defective, the screening operation utilizing such defective probe array results in an erroneous result and there is no way of preventing such situation. The fact that the base arrangement cannot be confirmed is the largest and fundamental drawback of this method.
There is also proposed another method of preparing the probe array, by synthesizing and purifying the DNA for probe in advance, and, eventually after confirmation of the base length thereof, supplying each DNA onto the substrate by a suitable device such as a microdispenser. The PCT laid-open publication WO95/35505 discloses a method of supplying DNA with a capillary onto a membrane. This method in principle allows to prepare the DNA array bearing DNA probes at a density of about 1000 probes/cm
2
. Basically this method is to prepare the probe array by supplying solution of each probe with a capillary-shaped dispensing device to a predetermined position on the substrate and repeating such operation. This method can be satisfactorily executed if an exclusive capillary is employed for each probe, but, if the number of the available capillaries is limited, it is necessary to sufficiently wash the capillary in changing the kind of probe in order to avoid mutual contamination. It is also necessary to control the supplying position at each operation. Consequently, this method is not suitable for preparing an array bearing probes of many kinds at a high density. In addition, the reproducibility and reliability are not perfect since the supply of the probe solution onto the substrate is achieved by tapping on the substrate with the end of the capillary.
There is also commercially available the microdispenser device, such as HYDRA (trade name) from Robbins Scientific Corp., for feeding solutions of different chemicals to the wells of a microplate of 96 or 384 wells, commonly utilized for the high throughput screening of pharmaceuticals. Such device basically consists of a two-dimensional array of microsyringes with a minimum discharge amount of 100 nl. If such device is applied for the array preparation, the density of the probes will be limited by such minimum discharge amount.
There is also proposed a method, in solid-phase synthesis of DNA on the substrate, of supplying the substrate with a solution of the substance required for synthesis by ink jet method in each extending step. For example, EP publication EPO 703 825B1 discloses a method of executing solid-phase synthesis of plural DNAs of respectively predetermined base arrangements by supplying a nucleotide monomer and an activator, to be utilized in the solid-phase DNA synthesis, from separate piezo jet nozzles. Such supply (coating) by the ink jet method is more reliable, for example in the reproducibil
Hirosawa Toshiaki
Udagawa Kenta
Canon Kabushiki Kaisha
Edwards Laura
Fitzpatrick ,Cella, Harper & Scinto
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