Chemical apparatus and process disinfecting – deodorizing – preser – Analyzer – structured indicator – or manipulative laboratory... – Sample mechanical transport means in or for automated...
Reexamination Certificate
2000-09-29
2003-07-15
Warden, Jill (Department: 1743)
Chemical apparatus and process disinfecting, deodorizing, preser
Analyzer, structured indicator, or manipulative laboratory...
Sample mechanical transport means in or for automated...
C422S050000, C422S068100, C422S105000
Reexamination Certificate
active
06592819
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to an apparatus for manufacturing microarray chip for use in DNA analysis, immunological analysis, and the like, and more particularly to an improvement in the structure for spotting specific binding substances onto a chip.
2. Description of the Related Art
Recently, genetic engineering has exhibited rapid progress, and the human genome project for decoding the base sequence of human genomes which amount to 100,000 in number is progressing. Further, enzyme immunoassay, fluorescent antibody technique and the like utilizing antigen-antibody reactions have been used in diagnoses and studies, and studies for searching DNAs which affect genetic diseases are now progressing. In such a situation, a microarray technique is now attracting attention.
In the microarray technique, a microarray chip (sometimes called DNA chip) comprising a plurality of known cDNAs (an example of specific binding substances) spotted in a matrix on a chip such as of a membrane filter or a slide glass at a high density (at intervals of not larger than several hundred &mgr;m) as shown in
FIG. 5
is used and DNAs (an example of organism-originating substances) taken from cells of a normal person A and labeled with a fluorescent dye a and DNAS taken from cells of a genetic-diseased person B and labeled with a fluorescent dye b are dropped onto the microarray chip by pipettes or the like, thereby hybridizing the DNAS of the specimens with the cDNAs on the microarray chip. Thereafter, exciting light beams which respectively excite the fluorescent dyes a and b are projected onto the cDNAS by causing the exciting light beams to scan the microarray chip and fluorescence emitted from each of the cDNAS is detected by a photodetector. Then the cDNAs with which the DNAs of each specimen are hybritized are determined on the basis of the result of the detection, and the cDNAs with which the DNAs of the normal person A are hybridized and those with which the DNAs of the diseased person B are hybridized are compared, whereby DNAs expressed or lost by the genetic disease can be determined. This information contributes to gene therapy.
The number of specific binding substances such as cDNAs have been spotted on a chip such as of a membrane filter or a slide glass at a high density by means of a microarray chip manufacturing apparatus(a spotter or an arrayer) as shown in FIG.
3
.
In the microarray chip manufacturing apparatus shown in
FIG. 3
, there is used a microtiter plate
10
having a number of specific binding substance holes
10
a
which are two-dimensionally arranged at pitches P larger than pitches at which the specific binding substances
11
are to be spotted onto a chip
20
. The specific binding substance holes
10
a
are respectively filled with the specific binding substances
11
. The microarray chip manufacturing apparatus comprises a spot head
30
provided with a plurality of, e.g., two×two, specific binding substance picking pins
31
which are arranged at the same pitches as the pitches P at which the specific binding substance holes
10
a
of the microtiter plate
10
are arranged, and a means for moving the spot head
30
.
The microtiter plate
30
is about 8 cm×12 cm in size and the number of the specific binding substance holes
10
a
on the microtiter plate
30
is generally in the range of 8×12 (=96) to 32×48 (=1536). To the contrast, the chip
20
on which the specific binding substances
11
are spotted is about 2 cm×2 cm in size operation of a microarray chip manufacturing apparatus which spots
96
specific binding substances
11
onto a chip
20
by the use of a microtiter plate
10
having 8×12 specific binding substance holes
10
a
will be described, hereinbelow.
First the spot head
30
is moved to a position where the four picking pins
31
are aligned with the upper left four (2×2) specific binding substance holes
10
a
and then moved downward so that the picking pins
31
are inserted into the respective specific binding substance holes
10
a
and the specific binding substances
11
therein adheres to the picking pins
31
. Thereafter, the spot head
30
is moved upward and to the chip
20
and then moved downward so that the picking pins
31
are brought into contact with the chip
20
, whereby the specific binding substances
11
on the respective picking pins
31
are spotted onto the chip
20
as shown in FIG.
4
A. In FIG.
4
A and the following
FIGS. 4B
to
4
D, the small circles indicated at × show the specific binding substance holes
10
a
into which the picking pins
31
are inserted at that time. When a plurality of microarray chips are to be manufactured, the same procedure is repeated the like number of times.
Then the specific binding substances
10
a
in the four holes
10
a
on the right side of the holes
10
a
the specific binding substances
11
in which are initially spotted (i.e., third and fourth holes
10
a
in the uppermost line as numbered from the left and third and fourth holes
10
a
in the second uppermost line as numbered from the left) are picked. At this time, since the specific binding substances
11
in the respective holes
10
a
are generally different from each other, it is necessary to clean the pins
31
by ultrasonic cleaning and to dry the same prior to picking the next specific binding substances
11
in order to prevent the preceding specific binding substances
11
from mingling with the next specific binding substances
11
. After cleaning and drying the pins
31
, the pins
31
are inserted into the next four holes
31
and the spot head
30
are moved so that the specific binding substances
11
in the holes
31
are spotted onto the chip
20
on the right side of the preceding spots at distances therefrom smaller than the distance (pitch) P between the pins
31
(e.g., P/6) as shown in FIG.
4
B.
After these procedure (including picking, spotting, cleaning and drying) is repeated six times and the specific binding substances
11
in the upper right four holes
10
a
(i.e., first and second holes
10
a
in the uppermost line as numbered from the right and first and second holes
10
a
in the second uppermost line as numbered from the right) are spotted onto the chip
20
, twenty-four specific binding substances
11
are spotted onto the chip
20
in two lines as shown in FIG.
4
C.
Thereafter, the specific binding substances
11
in the holes
10
a
on the third and fourth lines are spotted onto the chip
20
on the lower side of the preceding spots at distances therefrom smaller than the distance (pitch) P between the pins
31
(e.g., P/4) as shown in
FIG. 4
c.
The procedure described above is repeated until the specific binding substances
11
in all the ninety-six holes
10
a
are spotted onto the chip
20
as shown in FIG.
4
D.
In the conventional microarray chip manufacturing apparatus, the picking pins must be cleaned and dried each time they spot four specific binding substances. This means that cleaning and drying must be repeated twenty-four times four a chip
20
bearing thereon ninety-six (96) specific binding substances
11
(96/4=24) and three hundred and eighty-four (384) times for a chip
20
bearing thereon one thousand five hundred and thirty-six (1536) specific binding substances
11
(1536/4=384). The operation of cleaning and drying the picking pins requires a long time and deteriorates the efficiency of the spotting.
Further, the preceding specific binding substances
11
adhering to the picking pins cannot be perfectly cleaned, which gives rise to a problem that there is fear that the next specific binding substances
11
can be contaminated by the preceding specific binding substances.
SUMMARY OF THE INVENTION
In view of the foregoing observations and description, the primary object of the present invention is to provide a microarray chip manufacturing apparatus which can spot specific binding substances onto a chip in a shorter time.
The microarray chip manuf
Fuji Photo Film Co. , Ltd.
Sines Brian
Warden Jill
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