CN2603391Y - Typographic compound microarray - Google Patents
Typographic compound microarray Download PDFInfo
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- CN2603391Y CN2603391Y CN 03220489 CN03220489U CN2603391Y CN 2603391 Y CN2603391 Y CN 2603391Y CN 03220489 CN03220489 CN 03220489 CN 03220489 U CN03220489 U CN 03220489U CN 2603391 Y CN2603391 Y CN 2603391Y
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Abstract
The utility model relates to a biomacromolecule micro-array and the preparation method of the biomacromolecule micro-array, which belongs to biochemistry analysis technology field. The micro-array comprises a base plate and a substrate, at least two kinds of minimal block materials with different surface characters are fixed on the base plate according to predetermined arrangement rule, then a combined array imprint masks plate which can be attached to a reaction reagent is formed; a functional modification layer is disposed on the surface of the substrate, and at least a layer of reaction reagent combined array imprint, which is arranged according to the predetermined rule, is attached to the surface of the substrate through chemical conjugation. The utility model, which completely eliminates the expensive and complex making process of mask and has simple operation, has functions that automatic control can be easily realized, extremely high coupling efficiency can be guaranteed as well as accuracy and efficiency are improved. The utility model has an important value to the modernization of traditional medicine.
Description
Technical field
The utility model relates to a kind of compound microarray, and especially a kind of biomacromolecule microarray belongs to the biochemical analysis technical field.
Background technology
Biochip has extremely important meaning on biological detection, medical test and medical diagnosis on disease, drug screening and gene sequencing.During the traditional biological check fee, effort, cost height, can not satisfy the demand.For example, porous check-out console (as 96 orifice plates) is the existing a kind of conventional utensil that is used for medicine, biochemistry detection and screening that generally uses.Its essential structure is respectively different proteins, nucleic acid probe, cell line or biological tissue to be placed or be fixed among the different holes.During use, by adding different chemicals, or the compound combination, or biochemical reagents, or detected biological sample, observe the reaction of different chemical/biological substance, carry out fast parallel biochemical analysis, clinical examination or drug screening.96 reaction tanks on it are isolated from each other, and can select the number of reaction tank arbitrarily for use according to user's needs.As a kind of method of generally using in existing Biochemical Research and the exploitation,, make in the research process that compound is synthetic or buy to require a great deal of time and expense because research object compound number is huge.The ordered arrangement of sample also will spend a large amount of time simultaneously.
Classic method is being carried out in the improved process, is that the biochip technology of representative arises at the historic moment with the genetic chip.The strong means that provide are obtained and analyzed to the maturation of this technology and use and will bring a revolution for the exploitation and the life science association areas such as evaluation, food and environment of new drug for biological information.
The genetic chip technology of preparing can be divided into point sample method and in-situ synthesis.So-called point sample method, dna probe or the cDNA probe stationary of promptly using the whole bag of tricks (printing, spray printing, point sample) to synthesize in advance form microprobe array on slide or other solid slide glass.Original position is synthetic then to be directly probe to be synthesized on substrate according to the base sequence that designs in advance.The point sample method is suitable for the preparation of low density gene chip, and high slightly number of probes promptly needs very high cost.Also have various objective factors to cause the inhomogeneous thereby uneven shortcoming of hybridization signal of probe density in addition.
The utility model content
The purpose of this utility model is: at the deficiency that above prior art exists, propose that a kind of preparation technology is simple and direct, cost economy, typography compound microarray easy to use.
In order to reach above purpose, the basic technical scheme of the utility model typography compound microarray is: typography compound microarray comprises substrate and substrate, on the described substrate according to the predetermined rule of arranging, being fixed with at least two kinds of surface textures has other small block materials, and formation can described predetermined rule attachment reaction combination of agents array imprint masters; Described substrate surface is shaped on the functional modification layer, and is attached with the reaction reagent combination array embossed layer that one deck is at least arranged by the described predetermined rule of correspondence by chemical coupling.
The difference of above surface texture can be the difference of hydrophilic and hydrophobic difference, entity and porous body, or the difference of high protruding and indentation, also can be the mutual combination of above several properties and characteristicses.
Combination imprint masters of the present utility model has been exempted costliness in the original position synthetic technology and loaded down with trivial details mask manufacture process fully, not only make simple to operateization, easily realize control automatically, and provide and be similar to the liquid phase reactor environment, thereby ensured high coupling efficiency again, help improving work efficiency.
In a word, the utility model will be accelerated the speed of new drug development greatly, reduce cost of development, raise the efficiency and accuracy, realize that the high flux of a plurality of bodies of many diseases detects simultaneously and analyzes, and the modernization of conventional medicament (comprising Chinese medicine) is had significant values.
Description of drawings
Below in conjunction with the drawings and specific embodiments to the technical solution of the utility model is described in further detail.
Fig. 1 is the structural representation of the utility model embodiment one.
Fig. 2 is the structural representation of the utility model embodiment two.
Fig. 3 is the structural representation of the utility model embodiment three.
Embodiment
What should particularly point out is: in following examples, the contained base number of oligonucleotides is 8, and the oligonucleotide microarray dot matrix number that is synthesized is 16, pure just for principle of specification simply, be not so limited, the number that the contained base number of oligonucleotides can any existing dna synthesizer of as many as can reach in the actual demand, and the lattice point number can be very high in microarray dot matrix sum and the unit area, the level that can reach depends on existing microfabrication level fully.It should also be noted that, in above-mentioned explanation, small block a and b being required to some extent, combination imprint masters base material g and chip substrate material S are only required that they and agents useful for same do not have chemical action to get final product each other, others do not have any special requirement, can be any suitable organic or inorganic materials.The for example polypropylene of the teflon of glass, functionalization, functionalization, nylon, silicon chip, mica, metal, pottery, natural and regenerated fiber etc.Embodiment one: the structure of set of planes combined pressure seal mother matrix and the original position of 8 mer, 16 lattice point oligonucleotides micro-array chip of chemical compound are synthetic.
In Fig. 1, Fig. 1-1a, b are two kinds of small block materials, constitute combination imprint masters c, d, e, f among Fig. 1-2 on substrate g.The solid geometry shape of two small block materials a, b does not have certain restriction, both can be formed by the whole block material cutting, also can direct little die casting go out, or directly granulation.A kind of in two kinds of materials have hydrophobic property (be made as a), another kind of possess hydrophilic property matter (being made as b), its different surface nature can determine owing to self intrinsic property, also can come by the Surface Physical Chemistry modification.For example plasma treatment modification, grafting modification, surface-assembled modification etc.
In order to improve surperficial contact reaction microenvironment, wherein a kind ofly can be entity, and another kind can be porous.When two kinds of materials are all entity, two kinds of small block materials surface naturies must be different, need reaction reagent is spread upon whole imprint masters surface before each reaction, reach by the effect of designing requirement at imprint masters surface constituency distribution reaction reagent by means of the difference of two kinds of molecule material surface character.
When wherein small block b was porosint, two kinds of material surface character can be the same or similar, only need allow the small block b of porous be filled saturated reaction reagent in advance, just do not need to smear reaction reagent in the moulding process of back at every turn again.As Figure 1-3, substrate S surface process functional modification, method of modifying can be grafting modification, plasma modification, or the surface chemistry assembling modification.When the imprint masters that the surface is scribbled or is filled A, T, C, G reaction reagent respectively is impressed on the microarray substrate S respectively, with regard to corresponding in constituency coupling on the substrate S A, T, C, G (referring to Fig. 1-3 (1) and (2)), change another set of imprint masters then, but just in the coupling second layer monomer shown in Fig. 1-3 (3), ... ... ..., and the like, can be in coupling on the microarray substrate S several layers monomer.Fig. 1-the 4th, the synoptic diagram of 8 layers of monomer of coupling is understood easily, if having only four kinds of monomers, each layer just only needs with four imprint masters of two kinds of small block combined members of a, b.When coupling n layer monomer altogether, only need to make up n * 4 imprint masters with two kinds of small blocks combinations of a, b.
Precisely say, as shown in Figure 1, two kinds among Fig. 1-1 small block a, b are bonded on the substrate g, be built into combination imprint masters c, d, e, f among Fig. 1-2.Because being used for the synthetic monomer reagent of oligonucleotides is polarity, press designing requirement transfer printing reaction reagent with small block materials b.Therefore, small block materials a surface is hydrophobic (as polymerization dimethylsilane PDMS).When small block materials b was solid material, its surface should have suitable polarity (as polyester, polyamine fat, surface polarity functional modification PDMS, functionalization polytetrafluoroethylmaterial material etc.).When small block b was porosint, then b can be that polarity also can be non-polar material.During impression, monomer reaction reagent dA is coated on the combination imprint masters c, be impressed into then on the substrate S, monomer A just is coupled to corresponding zone on the substrate.Similarly, combination mother matrix d, e, the f that is coated with monomer dT, dC and dG is impressed on the substrate S, then monomer T, C, G are shifted respectively and are coupled to corresponding zone on the substrate, see Fig. 1-3.Then behind washing, oxidation, washing, deprotection and washing process; be that available four combination imprint masters corresponding to the second layer begin the impression coupling of second layer monomer; ... ...; circulation is gone down successively; until all processes of finishing design; finally obtain 8mer dot matrix number shown in Fig. 1-4 and be 16 oligonucleotide microarray chip, the single step coupling efficiency is greater than 98%.Embodiment two: the structure of convex-concave combination imprint masters and the original position of 8mer 16 lattice point oligonucleotides chemical array chips are synthetic.
Present embodiment as shown in Figure 2, its principle, method and process are identical with embodiment one, but because adopt the combined printing mother matrix of convex-concave structure, monomer reaction reagent was to the pollution of non-reaction zone when the height that protrudes was enough to prevent to impress, so need not be that the nonpolar infiltration that stops reaction monomers is polluted especially corresponding to the surface of the small block a of non-reaction zone.Others and concrete operations are equal to embodiment one fully.Finally obtain 8mer dot matrix number shown in Fig. 2-5 and be 16 oligonucleotide microarray chip.The single step coupling efficiency is greater than 98%.
Specifically, in Fig. 2, two kinds of small block materials of a, b of Fig. 2-1 are fixed on substrate g go up combination imprint masters c, d, e, f among the pie graph 2-2.Reaction reagent is not to needing the pollution of imprinting area in order to prevent to impress effectively, specially make that to intend the molecule block (being made as b) of impression reactant by design higher than the small block a that does not impress reactant, the small block b that promptly impresses reaction reagent protrudes from the combination imprint masters plane that is formed by a, b combination structure.Because b protrudes from the surface, small block a can not contact with substrate during impression, so a, b can have identical surface nature.In order to obtain best impression effect, two kinds of best tools of material of a, b are in different surface naturies.In order to improve surperficial contact reaction microenvironment, in two kinds of small blocks, wherein a can be entity, and b can be porous.This moment, two kinds of materials can have duplicate surface nature.
When two kinds of materials are all entity, need reaction reagent is spread upon whole imprint masters surface before each coupling reaction, but the small block b that has only protrusion can be impressed into reaction reagent substrate S and be taken in wherein small block b when being porosint, only need allow the small block b of porous be filled saturated reaction reagent in advance, in the moulding process of back, just not need to smear again reaction reagent at every turn.Shown in Fig. 2-3, when the imprint masters that the surface is scribbled or is filled A, T, C, G reaction reagent respectively is impressed on the substrate S respectively, with regard to corresponding in constituency coupling on the substrate S A, T, C, G (synoptic diagram is seen Fig. 2-3 (1) and (2)), change another set of imprint masters then, but just in the coupling second layer monomer shown in Fig. 2-3 (3) ... ... ..., and the like, can be in coupling on the substrate several layers monomer, ... ... ..., Fig. 2-the 5th, the synoptic diagram of 8 layers of monomer of coupling.When coupling n layer monomer altogether, only need to make up n * 4 imprint masters with two kinds of small blocks combinations of a, b.Embodiment three: the original position with the structure of combination imprint masters of little groove and reservoir and 8 mer, 16 lattice point oligonucleotides chemical array chips is synthetic.
Present embodiment as shown in Figure 3, its principle, method and process and embodiment one and embodiment two are basic identical, but whether the small block b or the b ' that are used for the stamp transfer monomer are porous, be that polarity does not then have strict requirement to its surface.The small block of all porous on the whole combined printing mother matrix is interconnected and is connected by the minute groove on the substrate.Again because of having reservoir and be convenient to liquid-soaked and the little groove that flows on the combination impression substrate, so fill with reaction monomers in groove earlier before the preparation of whole oligonucleotide microarray chip by the aperture on the reservoir on the combined printing substrate, reaction monomers promptly riddles among small block b of porous or the b ' by little groove, consume in the chip preparation process and can be replenished via minute groove by the monomer solution of laying in the reservoir, so this embodiment is except the various advantages with embodiment one and two, the reagent that more responds distributes does not need the characteristics of make-up monomers reaction reagent in ideal extremely and the entire chip original position building-up process.Control to reaction monomers becomes very simple, and others and concrete operations are equal to embodiment one fully.Finally obtain 8 mer dot matrix numbers shown in Fig. 3-5 and be 16 oligonucleotide microarray chip.The single step coupling efficiency is greater than 98%.
Say in particular in conjunction with Fig. 3, reaction reagent is to the pollution of non-embossed region and avoid constantly replenishing in the entire reaction course the loaded down with trivial details of reagent in order to avoid impressing better, it is porous to the small block b on the chip substrate that present embodiment not only is used to impress the coupling monomer, has also adopted g ' and g among Fig. 3-1 especially " shown in the combined printing substrate.Especially, " bottom surface has little groove wgc, promptly can be used for storing reagent, the reagent of extruding in the time of can absorbing impression again at combination imprint masters substrate g ' and g.And " side more is provided with airtight reservoir cyc and is used to lay in reaction reagent, has an aperture cyk that can open and seal to be used to refill reagent on the reservoir cyc at substrate g.Being arranged so that of this reservoir cyc has better buffering regulating action, not only can be constantly reactant liquor by the small block supplement consumed of the porous of little groove wgc on substrate on the substrate, and the reagent of extruding can absorb impression again better the time.The distribution of reaction reagent in the small block b of porous and constantly filling are convenient in design like this, Fig. 3-1a, b and b ' are three kinds of small block materials, a is the same with b high, b ' is than b height, at substrate g ' and g " goes up pie graph 3-2 combination imprint masters a, d, e, f and Fig. 3-3 combination imprint masters c ', d ', e ', f '.In fact a, b, its solid geometry shape of b ' do not have certain restriction, and they can be by whole block material cutting, also can direct little mold, or direct granulation.But reaction reagent is not to needing the pollution of imprinting area in order to prevent to impress effectively, specially make that to intend the molecule block (being made as b ') of impression reactant by design higher than the small block a that does not impress reactant, the small block b ' that promptly impresses reaction reagent protrudes from the combination imprint masters plane that is formed by a, b ' combination structure.Because b ' protrudes from the surface, small block a can not contact with substrate during impression, so a, b ' can have identical surface nature.In order to obtain best impression effect, two kinds of best tools of material of a, b ' are in different surface naturies, that is, (be made as a), (be made as b ', this moment, reactant was a polar reagent to another kind of possess hydrophilic property matter can a kind ofly to have hydrophobic property; If reactant is nonpolar reagent, small block a surface is given birth to for the utmost point 1, small block b ' surface is nonpolar), two kinds of surface naturies that material is different, can be because self intrinsic property determines, also can be to come by the Surface Physical Chemistry modification, for example plasma treatment modification, grafting modification, surface-assembled modification etc.In order to improve surperficial contact reaction microenvironment, in two kinds of small blocks, wherein a can be entity, and b ' then is a porous.During impression, earlier the small block b ' of porous is filled saturated reaction reagent in advance, in the moulding process of back, does not just need postreaction reagent again.Have only the small block b ' meeting of protrusion that reaction reagent is impressed on the substrate S.The reaction reagent that consumes is constantly added among the small block a of porous by the small groove on the combination imprint masters by reservoir, as shown in Figure 3-4, when being filled A respectively, T, C, when the imprint masters of G reaction reagent is impressed on the substrate S respectively, pressing in the coupling of designing requirement constituency A on the substrate S with regard to corresponding, T, C, G, synoptic diagram is seen Fig. 3-4 (1) and (2)), change another set of imprint masters then, but just in the coupling second layer monomer shown in Fig. 3-4 (3), ... ..., similarly, can be in coupling on the substrate several layers monomer, Fig. 3-the 5th, the synoptic diagram of 8 layers of monomer of coupling, be readily appreciated that if having only four kinds of monomers, each layer just only needs to use a, two kinds of small block combinations of b or b ' make up four imprint masters.When coupling n layer monomer altogether, only need to make up n * 4 imprint masters with a, b or two kinds of small blocks combinations of b '.
Generally speaking, above embodiment is by being divided into fritter with whole block material, or directly uses small block materials, and the scheme of these small block materials by design in advance made up, and constitutes a series of combined planars or concaveconvex structure mother matrix.Do not need to prepare imprint masters through complex processes such as photoetching, quick especially, simple and convenient especially; The impression site that needs has very high compatibility to reaction reagent, thereby reaction efficiency is similar to homogeneous system.When small block was poromerics, because reaction reagent is stored in the micropore, the impression effect of being squeezed can riddle the interface, thereby obtains a reaction environment that is similar to liquid phase process, thereby has guaranteed very high coupling efficiency.Use the combinations thereof mother matrix, can very fast prepare especially biomacromolecule compound microarray of compound cheaply.
The remarkable advantage of above embodiment is that the combination imprint masters that is proposed can be exempted costliness in the existing oligonucleotide microarray original position synthetic technology and loaded down with trivial details mask manufacture process fully, when probe density when not being high especially, practical especially, efficient, succinct and cost is cheap; And the micropore imprint masters that is proposed because of storing reagent and can exempting existing molecular seal method because the volatilization of reagent must be smeared the weak point of reagent and the volatilization of restive reagent and impression the best time repeatedly, not only make simple to operateization, easily realize control automatically, and provide and be similar to the liquid phase reactor environment, thereby ensured high coupling efficiency again, help improving work efficiency.In addition because reaction environment with the liquid phase of being similar to, thereby to consume reagent very little, can significantly reduce cost.Also can adopt method accelerated reaction processes such as light, sound, electricity, magnetic.In a word, can synthesize simultaneously or a large amount of different compounds of covering at substrate surface on Cheap highly effective ground.Utilize these different compounds can carry out the qualitative or quantitative test of biochemical informations such as a large amount of genes or albumen, methods such as the gained result can use up, electricity, heat, sound, nanometer technology or chemistry detect.For example available ordinary optical microscope, laser confocal microscope, CCD observe or surperficial excimer resonance (SPR), the surface interferes reflection (RIFS), nanoparticle label to detect optics, electroporation and chemical methodes such as (mark-Yin dyes as gold), quartz crystal oscillator and detect, increase work efficiency greatly, reduce reagent dosage, really accomplish quick, real-time, accurate, robotization and pollution-free.It can be used for the high flux screening of compound and combination, biomolecule or medicine, the high flux of a plurality of bodies of many diseases detects simultaneously and analyzes, the Study on Modernization of conventional medicament, and genome or cDNA library screening, the discovery of new gene and the research of gene function, the research of proteomics etc.
The utility model will be accelerated the speed of new drug development greatly, reduce cost of development, raise the efficiency and accuracy, and the modernization of conventional medicament (comprising Chinese medicine) is had significant values.
Claims (6)
1. typography compound microarray, comprise substrate and substrate, it is characterized in that: according to the predetermined rule of arranging, being fixed with at least two kinds of surface textures has other small block materials on the described substrate, and formation can described predetermined rule attachment reaction combination of agents array imprint masters; Described substrate surface is shaped on the functional modification layer, and is attached with the reaction reagent combination array embossed layer that one deck is at least arranged by the described predetermined rule of correspondence by chemical coupling.
2. according to the described typography compound of claim 1 microarray, it is characterized in that: described small block materials is respectively water wetted material and hydrophobic material, and described imprint masters is set of planes combined pressure seal mother matrix.
3. according to the described typography compound of claim 1 microarray, it is characterized in that: described small block materials is respectively high protruding material and indentation material, and described imprint masters is concavo-convex combination imprint masters.
4. according to claim 1,2 or 3 described typography compound microarraies, it is characterized in that: described small block materials is respectively solid material and porosint.
5. according to the described typography compound of claim 4 microarray, it is characterized in that: described substrate surface is shaped on little groove, described little groove with have the small block of porous to interconnect perforation.
6. according to the described typography compound of claim 5 microarray, it is characterized in that: described substrate surface one side is provided with airtight reservoir, and the aperture that injects reagent is arranged on the described reservoir.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 03220489 CN2603391Y (en) | 2003-03-20 | 2003-03-20 | Typographic compound microarray |
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| CN 03220489 CN2603391Y (en) | 2003-03-20 | 2003-03-20 | Typographic compound microarray |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180538B (en) * | 2005-04-26 | 2012-02-15 | 奥胡斯大学 | Bio-surface structure array |
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2003
- 2003-03-20 CN CN 03220489 patent/CN2603391Y/en not_active Expired - Lifetime
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101180538B (en) * | 2005-04-26 | 2012-02-15 | 奥胡斯大学 | Bio-surface structure array |
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Expiration termination date: 20130320 Granted publication date: 20040211 |