FI81505B - ANORDNING FOER PARALLELT UTFOERANDE AV ETT FLERTAL KEMISKA REAKTIONSSERIER. - Google Patents
ANORDNING FOER PARALLELT UTFOERANDE AV ETT FLERTAL KEMISKA REAKTIONSSERIER. Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
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- B01J2219/00279—Features relating to reactor vessels
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- B01J2219/00313—Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
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- B01J2219/00306—Reactor vessels in a multiple arrangement
- B01J2219/00324—Reactor vessels in a multiple arrangement the reactor vessels or wells being arranged in plates moving in parallel to each other
- B01J2219/00326—Movement by rotation
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- B01J2219/00479—Means for mixing reactants or products in the reaction vessels
- B01J2219/00488—Means for mixing reactants or products in the reaction vessels by rotation of the reaction vessels
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- B01J2219/00585—Parallel processes
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- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
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- B01J2219/00596—Solid-phase processes
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- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00718—Type of compounds synthesised
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- C40B40/04—Libraries containing only organic compounds
- C40B40/06—Libraries containing nucleotides or polynucleotides, or derivatives thereof
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- C40—COMBINATORIAL TECHNOLOGY
- C40B—COMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES
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- C40B60/14—Apparatus specially adapted for use in combinatorial chemistry or with libraries for creating libraries
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Abstract
Description
, 81505, 81505
Laite useiden kemiallisten reaktiosarjojen suorittamiseksi rinnakkainApparatus for carrying out several chemical reaction series in parallel
Keksintö koskee laitetta useiden reatkiosarjojen 5 suorittamiseksi. Sellainen laite soveltuu erityisesti poly-meerimolekyylien, kuten nukleotidien, proteiinien, jne. syntetisoimiseen kantaja-aineella, kuten esimerkiksi lasilla, piigeeIillä tai muulla soveltuvalla materiaalilla.The invention relates to an apparatus for performing a plurality of reaction sets 5. Such a device is particularly suitable for synthesizing polymer molecules, such as nucleotides, proteins, etc., on a support such as glass, silica or other suitable material.
Yleensä sellaisten polymeerimolekyylien rakentaminen 10 tapahtuu reaktiokammioissa (esimerkiksi sinttereissä, pylväissä, jne.), joissa syntetisoitavien molekyylien ensimmäinen rakenneosa on sidottuna käytettävälle polymeerimateriaalille ja joihin synteesiin tarvittavien reagenssien syöttö tapahtuu joko käsin tai automaattisesti.In general, the construction of polymer molecules takes place in reaction chambers (e.g. sinterers, columns, etc.) in which the first component of the molecules to be synthesized is bound to the polymeric material used and to which the reagents required for synthesis are fed either manually or automatically.
15 Reaktiosarjojen luonteeseen kuuluu se, että pitkähkö- ketjuisen molekyylin rakentamiseen kuluu suhteellisen paljon aikaa. Jos tarvitaan joukko erilaisia, samanlaisista rakenneosista muodostuvia polymeerimolekyylejä, on aika, joka kuuluu kaikkien haluttujen synteesituotteiden saamiseen, 20 useiden sietämättömän pitkä.Siten on olemassa tarve tehdä mahdolliseksi useiden erilaisten polymeerimolekyylien rakentaminen samoista reagensseista samanaikaisesti. Niinpä tämän keksinnön tehtävänä on saada aikaan laite, jolla voidaan toteuttaa samanaikaisesti useita reaktiosarjoja.15 The nature of the reaction series is that it takes a relatively long time to build a long chain molecule. If a number of different polymer molecules consisting of similar moieties are required, the time required to obtain all the desired synthetic products is several unbearably long. Thus, there is a need to allow the construction of several different polymer molecules from the same reagents simultaneously. Accordingly, it is an object of the present invention to provide an apparatus with which several series of reactions can be carried out simultaneously.
25 Tähän päästiin keksinnön mukaisesti patenttivaati- mukseesa määritellyllä laitteella.This was achieved according to the invention by a device as defined in the claims.
Laite soveltuu erityisesti useiden DNA- ja RNA-seg-menttien, joiden ketjun pituus ja sekvenssi on erilainen, syntetisoimiseen polymeerisellä kantaja-aineella. Tällöin 30 rakennetaan DNA-segmentit sinänsä tunnetulla tavalla mono-nukleotideista, jolloin voidaan käyttää kaikkia haluttuja, soveltuvia kantaja-aineita, edullisesti lasihiukkasia, ja erilaisia synteesitapoja, edullisesti triesteri- ja fosfiit-’ ’ tiesterimenetelmää.The device is particularly suitable for synthesizing several DNA and RNA segments with different chain lengths and sequences on a polymeric support. In this case, the DNA segments are constructed in a manner known per se from mononucleotides, in which case all desired, suitable carriers, preferably glass particles, and various synthetic methods, preferably the triester and phosphite ester methods, can be used.
2 81 5052 81 505
Seuraavassa kuvataan keksinnön erästä suoritusmuotoa liitteenä olevien piirrosten avulla. Piirroksista kuvio 1 on as>ittain aukileikattu perspektiivikuva laitteesta, jossa on kymmenen reaktiokiekkoa, ja 5 kuvio 2 esittää yhtä yksittäistä reaktiokiekkoa ylhäältä päin katsottuna.An embodiment of the invention will now be described with reference to the accompanying drawings. Of the drawings, Fig. 1 is an exploded perspective view of an apparatus having ten reaction discs, and Fig. 2 shows a single reaction disc seen from above.
Kuvio 1 esittää laitetta kymmenen erilaisen DNA-seg-mentin syntetisoimiseksi samanaikaisesti, jolloin kantajana käytetään polymeerigranulaattia. Kunkin syntetisoitavan 10 ketjun ensimmäinen rakenneosa on valmiina kantajalla ennen synteesin aloitusta.Figure 1 shows an apparatus for synthesizing ten different DNA segments simultaneously using a polymer granulate as a carrier. The first component of each of the 10 chains to be synthesized is ready on the carrier prior to the start of the synthesis.
Laite koostuu pinosta samankeskisesti päällekkäin olevia pyöreitä kiekkoja, joihin on tehty useita kanavajär-jestelmiä. Niin kutsutut reaktiokiekot 1-10 on tarkoitettu 15 kymmenelle syntetisoitavalle oligonukleotidille, ts. kussakin reaktiokiekossa rakennetaan tietty oligonukleotidi.The device consists of a stack of concentrically superimposed round discs on which several duct systems are made. The so-called reaction discs 1-10 are intended for 15 oligonucleotides to be synthesized, i.e. a specific oligonucleotide is constructed in each reaction disc.
Tätä tarkoitusta varten on esimerkiksi reaktiokiekossa 1 reaktiokammio 11. Reaktiokammio 11 on suunnilleen kiekon akselin ja reunan puolivälissä sijaitseva, kiekon yläpintaan 20 aukeava syvennys, jonka syvyys on noin 3/4 kiekon paksuudesta. Kammioon sijoitetaan kantaja-ainegranulaatti. Kammion yläosassa on levennys, johon sijoitetaan sintteri 12, joka sulkee reaktiokammion 11 ylhäältä päin.Kammion pohjan samankeskisessä kavennuksessa on toinen sintteri 13, joka 25 muodostaa sulun kammion 11 ja kammion pohjasta kiekon alapintaan johtavan kanavan, jonka läpimitta on sangen pieni, esimerkiksi 1 mm, välille.For this purpose, for example, the reaction chamber 1 has a reaction chamber 11. The reaction chamber 11 is a recess located approximately halfway between the axis and the edge of the disc and opening to the upper surface 20 of the disc, having a depth of about 3/4 of the thickness of the disc. A carrier granulate is placed in the chamber. At the top of the chamber there is a widening in which a sinter 12 is placed, which closes the reaction chamber 11 from above. The concentric constriction of the bottom of the chamber has a second sinter 13 forming a barrier chamber 11 and a channel leading from the bottom of the chamber to the bottom of the disc. between.
Reaktiokiekossa on reaktiokammion 11 lisäksi neljä kanavaa 14, joilla on samanlainen pieni läpimitta, esi-30 merkiksi 1 mm. Nämä kanavat on sijoitettu reaktiokammioon nähden 72, 144, 216 ja 288 asteen kulmaan.In addition to the reaction chamber 11, the reaction disc has four channels 14 of similar small diameter, for example 1 mm. These channels are located at an angle of 72, 144, 216 and 288 degrees to the reaction chamber.
Muiden reaktiokiekkojen rakenne on samanlainen. Niitä voidaan pyörittää keskellä olevan yhdistävän osan ympäri toisistaan riippumattomasti.The structure of the other reaction discs is similar. They can be rotated around the connecting part in the middle independently of each other.
3 815053 81505
Seuraava reaktiokiekko 2 esitetään piirroksessa kierrettynä 144°, niin että sen reaktiokammio 15 sijaisee saman-keskisesti ensimmäisen kiekon 1 kanavan 14 kanssa.The next reaction disc 2 is shown in the drawing rotated 144 ° so that its reaction chamber 15 is located concentrically with the channel 14 of the first disc 1.
Seuraava reaktiokiekko 3, jota ei enää esitetä 5 piirroksessa aukileikattuna, on taas asennossa, jossa sen reaktiokammio - tunnistettavissa sintteristä 16 - on saman-keskisesti kiekon 1 reaktiokammion 11 kanssa. Kiekossa 3 on näkyvissä kulmassa 72° sijaitseva kanava 17.The next reaction disc 3, which is no longer shown in section 5 in an open section, is again in a position in which its reaction chamber - identifiable from the sinter 16 - is concentric with the reaction chamber 11 of the disc 1. The disc 3 has a visible channel 17 at an angle of 72 °.
Reaktiokiekkojen 1-10 muodostamaa pinoa rajoittaa 10 ylempi liitoskiekko 18 reagenssien syöttöletkujen liittämiseksi ja alempi liitoskiekko 21 poistoletkujen liittämiseksi. Ylemmässä liitoskiekossa 18 näkyvät reaktiokiekkojen kanavien ja reaktiokammioidenkanssa samankeskiset aukot 19, joissa on kierteistys syöttöletkujen sovitteiden kiinni ruu-15 vaamista varten. Aukot 19, joiden syvyys on noin 3/4 kiekon paksuudesta jatkuvat samalla tavalla kuin reaktiokammiot, kapeina kanavina kiekon pohjaan. Alempi liitoskiekko 21 voi olla joko samanlainen kuin ylempi tai siinä voi olla yksinkertainen kokoojakanava (ei kuvassa), ellei käytettyjä rea-20 gensseja enää tarvitse kuljettaa erikseen.The stack of reaction discs 1-10 is limited by an upper connecting disc 18 for connecting reagent supply hoses and a lower connecting disc 21 for connecting outlet hoses. The upper connecting disc 18 shows concentric openings 19 with the channels and reaction chambers of the reaction discs, with threading for holding the feed hose fittings closed. Apertures 19 having a depth of about 3/4 of the thickness of the disk continue in the same manner as the reaction chambers, as narrow channels to the bottom of the disk. The lower connecting disc 21 may either be similar to the upper one or may have a simple collecting channel (not shown), unless the reagents used no longer need to be transported separately.
Reaktiokiekkojen 1-10 ja liitoskiekon 18 alapinnalla on kapeiden kanavien aukkojen ympärillä rengasmaiset urat, joihin sijoitetaan 0-renkaat, joiden avulla kanavat tiivis-tetään kiekkojen välisellä rajapinnalla. Tämä tiivistejär-25 jestelmä on jätetty pois kuvasta.The lower surface of the reaction discs 1-10 and the connecting disc 18 has annular grooves around the openings of the narrow channels, in which 0-rings are placed, by means of which the channels are sealed at the interface between the discs. This sealing-25 system is omitted from the figure.
Ylemmän liitoskiekon 18 päällä on ylempi puristus-kiekko 20. Vastaavasti on alemman liitoskiekon 21 alapuolella alempi puristuskiekko 22. Nämä puristuskiekot 20 ja 22 välittävät kiekkopinoon voiman, jonka saa aikaan kes-30 kellä olevana yhdistävänä osana toimiva pultti 23, joka sijaitsee koko pinon läpi kulkevassa keskuskanavassa, ja onrarustettu ruuvilla (mutteri 24). Tämän puristusvoiman avulla painetaan levyt kiinni toisiinsa siten, että saadaan aikaan kanavien ehdoton tiiviys ja eliminoidaan tii-35 vistysrenkaiden sisäpuolelle mahdollisesti jäävä tyhjä tila.On top of the upper connecting disc 18 there is an upper compression disc 20. Below the lower connecting disc 21 there is a lower compression disc 22. in the central duct, and is equipped with a screw (nut 24). With this compressive force, the plates are pressed together so as to provide absolute tightness of the channels and to eliminate any void space that may remain inside the ti-35 compression rings.
81505 481505 4
Reaktiokiekkojen 1-10 keskinäisen asennon ollessa sopiva, ovat niiden reaktiokammiot ja kanavat samankeskisestä niin ettäpinossa on neljä kanavaa, joista kukin täytetään yhdellä mononukleotideista A, T, C tai G (mer-5 kitty piirroksessa nuolilla), millä tavalla kasvatettavia DNA-jaksoja pidennetään samanaikaisesti sopivalla nukelo-tidilla.When the relative positions of the reaction discs 1-10 are suitable, their reaction chambers and channels are concentric so that the stack has four channels, each filled with one of the mononucleotides A, T, C or G (indicated by arrows in the drawing), in which case the DNA sequences to be grown are simultaneously extended. with a suitable nucleotide.
Tätä varten viedään kiekon 1 reaktiokammio 11 kulloinkin tarvittavaksi ajaksi siihen kanavaan, jonka nukleo-10 tidia tulee syöttää (kuviossa kanavassa, jossa tapahtuu pidennys T:llä, kun taas kiekon 2 kammio on C-kanavassa: siihen syötetään siis Citä samanaikaisesti kuin kiekkoon 1 T:tä). Kaikki mononukleotidien liittämiseen tarvittavat reaktiot ja huuhtelut (suojausryhmien poistaminen, cap-ra-15 kenteen liittäminen, mahdollisesti hapetus) tapahtuvat samoin samanaikaisesti (jatkuva läpivirtausmenetelmä). Liittämissyklin päätyttyä kierretään kutakin kiekkoa taas siten, että sen kammio on seuraavaksi lisättävän nukleotidin kanavassa. Kiekkojen kiertämistä varten avataan mutte-20 ria 24 ja suljetaan se sitten taas. Jos DNA-fragmentin synteesi on saatettu loppuun jossakin levyistä, asetetaan tämän levyn kammio lepoasentoon, jolloin levyn jäljellä olevat neljä kapeaa kanavaa toimivat yhdistävinä kanavina muissa reatkiokiekoissa tapahtuvaa DNA-segmenttien pidentä-25 mistä varten.To this end, the reaction chamber 11 of the disc 1 is introduced for the time required in each case into the channel to which the nucleo-10 is to be fed (in the figure in the channel with elongation by T, while the chamber of the disc 2 is in the C-channel: O). All the reactions and rinses required for the coupling of mononucleotides (deprotection, coupling of the cap-ra-15 field, possibly oxidation) also take place simultaneously (continuous flow-through method). At the end of the annealing cycle, each disc is rotated again so that its chamber is in the channel of the next nucleotide to be added. To rotate the discs, the mutte-20 is opened 24 and then closed again. If the synthesis of the DNA fragment is completed in one of the plates, the chamber of this plate is placed in the rest position, whereby the remaining four narrow channels of the plate act as connecting channels for the lengthening of the DNA segments in the other reaction discs.
Kun kaikkien DNA-segmenttien synteesit on saatettu loppuun reaktiokiekoissa, poistetaan niistä kantaja-aine siihen tarttuina syntetisoituine nukleotidisekvenssei-neen, sen jälkeen kun laite on purettu ja sintteri 12 pois-30 tettu. Kun suojausryhmät on poistettu ja tuote irroitettu kantaja-aineelta, erotetaan halutut suojaamattomat DNA-segmentit epäpuhtaista seoksista puhtaassa muodossa soveltuvien puhdistusmenetelmien avulla.Once the syntheses of all the DNA segments have been completed in the reaction discs, the carrier is adhered to them with the nucleotide sequences synthesized attached thereto, after the device has been disassembled and the sinter 12 removed. After deprotection and removal of the product from the support, the desired unprotected DNA segments are separated from the impure mixtures in pure form by appropriate purification methods.
Kunkin reaktiokiekon kiertämisen rajoittamiseksi 35 tapahtuvaksi järkevin 72 asteen kulmavälein, täytyy käyttää ainakin näkyviä merkintöjä. Parempi on kuitenkin mekanismi, 5 81 505 joka on varustettu oikeassa kulma-asennossa olevalla lukituksella.In order to limit the rotation of each reaction disc at reasonable angular intervals of 72 degrees, at least visible markings must be used. However, a mechanism 5 81 505 with a locking in the correct angular position is better.
Laitetta voidaan käyttää joko käsin tai myös mekaanisesti sopivien käyttöelinten avulla. Jälkimmäiseen käyttö-5 tapaan voidaan yhdistää myös ohjelmoitu ohjaus.The device can be operated either manually or mechanically by means of suitable actuators. Programmed control can also be combined with the latter mode of operation.
Tässä suoritusmuotoesimerkkinä kuvattu laite koostuu reaktiokiekoista, joiden läpimitta on noin 60 mm ja paksuus noin 10 mm. Kanavien 14 läpimitta on, kuten jo mainittiin, noin 1 mm. Reaktiokammioiden läpimitta on noin 6 mm. Näillä 10 mitoilla on kuitenkin merkitystä ainoastaan määrätyn synteesiohjelman yhteydessä. Rakenne- ja toimintaperiaatteeltaan samanlaisilla laitteilla voi olla laajoissa rajoissa valittavat mitat, ja ne voivat erityisesti olla oleellisesti suurempia kuin kuvattu suoritusmuotoesimerkki. Myös kana-15 vien lukumäärä kiekkoa kohden voi olla suurempi kuin edellä kuvatussa esimerkissä. Tämä on tärkeää esimerkiksi peptidi-synteesien yhteydessä.The device described here as an exemplary embodiment consists of reaction discs having a diameter of about 60 mm and a thickness of about 10 mm. The diameter of the channels 14 is, as already mentioned, about 1 mm. The diameter of the reaction chambers is about 6 mm. However, these 10 dimensions are only relevant in the context of a particular synthesis program. Devices of similar construction and operation may have a wide range of dimensions to choose from, and in particular may be substantially larger than the described exemplary embodiment. The number of chickens per disc may also be higher than in the example described above. This is important, for example, in connection with peptide syntheses.
Myöskään kiekkojen ja erityisesti reaktiokammioiden muoto ei luonnollisesti millään tavalla rajoitu tähän 20 suoritusesimerkkiin. Niinpä olisi esimerkiksi mahdollista korvata pyöreässä kiekossa olevat renkaan muotoon sijoitetut kanavat lineaarisella kanavien asennolla sekä vastaavasti kiekon kiertäminen sen lineaarisella siirtämisellä.Also, the shape of the wafers, and in particular the reaction chambers, is of course not limited in any way to this embodiment. Thus, for example, it would be possible to replace the annular channels in a circular disk with a linear channel position and, accordingly, to rotate the disk by linear displacement.
Claims (5)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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CH499484 | 1984-10-18 | ||
CH499484 | 1984-10-18 |
Publications (4)
Publication Number | Publication Date |
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FI854050A0 FI854050A0 (en) | 1985-10-17 |
FI854050L FI854050L (en) | 1986-04-19 |
FI81505B true FI81505B (en) | 1990-07-31 |
FI81505C FI81505C (en) | 1990-11-12 |
Family
ID=4286104
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
FI854050A FI81505C (en) | 1984-10-18 | 1985-10-17 | Device for parallel execution of a plurality of chemical reaction series |
Country Status (11)
Country | Link |
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EP (1) | EP0181491B1 (en) |
JP (2) | JPS61118141A (en) |
AT (1) | ATE44244T1 (en) |
AU (1) | AU558709B2 (en) |
CA (1) | CA1304916C (en) |
DE (1) | DE3571207D1 (en) |
DK (1) | DK466285A (en) |
ES (1) | ES8705352A1 (en) |
FI (1) | FI81505C (en) |
IL (1) | IL76662A0 (en) |
NO (1) | NO166582C (en) |
Families Citing this family (15)
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ES533260A0 (en) * | 1983-06-15 | 1985-02-01 | Schering Ag | PROCEDURE FOR THE PREPARATION OF 13A-ALQUILGONANOS |
EP0164206B1 (en) * | 1984-05-02 | 1988-11-02 | Brendan James Hamill | An apparatus for the chemical synthesis of oligonucleotides |
DE3631662A1 (en) * | 1986-09-17 | 1988-03-24 | Biotechnolog Forschung Gmbh | METHOD FOR SIMULTANEOUS SYNTHESIS OF SEVERAL PEPTIDES ON A SOLID PHASE |
DE3813671A1 (en) * | 1988-04-22 | 1989-11-02 | Europ Lab Molekularbiolog | DEVICE FOR CARRYING OUT CHEMICAL REACTIONS |
GB8823182D0 (en) * | 1988-10-03 | 1988-11-09 | Ici Plc | Reactor elements reactors containing them & processes performed therein |
DE4206488C2 (en) * | 1992-03-02 | 1993-12-23 | Deutsches Krebsforsch | Device for carrying out chemical reactions taking place simultaneously or sequentially |
CH684554A5 (en) * | 1992-09-22 | 1994-10-14 | Sotax Ag | Sample collector. |
JPH08505604A (en) * | 1992-11-06 | 1996-06-18 | カイロン ミモトープス プロプライエトリー リミテッド | Support for synthesizing modular polymers |
FR2714061B1 (en) | 1993-12-16 | 1996-03-08 | Genset Sa | Process for the preparation of polynucleotides on solid support and apparatus allowing its implementation. |
US6469157B1 (en) | 1993-12-16 | 2002-10-22 | Proligo Llc | Process for preparing polynucleotides on a solid support |
AU2990595A (en) * | 1994-07-26 | 1996-02-22 | Sydney Brenner | Multidimensional conduit combinatorial library synthesis device |
US6083682A (en) | 1997-12-19 | 2000-07-04 | Glaxo Group Limited | System and method for solid-phase parallel synthesis of a combinatorial collection of compounds |
US6989133B1 (en) | 1998-12-30 | 2006-01-24 | Mwg-Biotech Ag | Device for carrying out chemical reactions |
DE10042871A1 (en) * | 2000-08-31 | 2002-05-16 | Hte Ag The High Throughput Exp | Three-dimensional material library and method for producing a three-dimensional material library |
DE112004003058B4 (en) * | 2004-08-18 | 2009-05-07 | Agilent Technologies Inc., Santa Clara | Microfluidic coupling device with variable flow resistance and microfluidic arrangement |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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US3876881A (en) * | 1973-10-24 | 1975-04-08 | Hoffmann La Roche | Protein monitor |
US4483964A (en) * | 1983-06-20 | 1984-11-20 | Chiron Corporation | Reactor system and method for polynucleotide synthesis |
EP0164206B1 (en) * | 1984-05-02 | 1988-11-02 | Brendan James Hamill | An apparatus for the chemical synthesis of oligonucleotides |
-
1985
- 1985-10-02 CA CA000492051A patent/CA1304916C/en not_active Expired - Fee Related
- 1985-10-08 EP EP85112725A patent/EP0181491B1/en not_active Expired
- 1985-10-08 DE DE8585112725T patent/DE3571207D1/en not_active Expired
- 1985-10-08 AT AT85112725T patent/ATE44244T1/en not_active IP Right Cessation
- 1985-10-11 IL IL76662A patent/IL76662A0/en not_active IP Right Cessation
- 1985-10-11 DK DK466285A patent/DK466285A/en not_active Application Discontinuation
- 1985-10-14 AU AU48561/85A patent/AU558709B2/en not_active Ceased
- 1985-10-17 ES ES547950A patent/ES8705352A1/en not_active Expired
- 1985-10-17 JP JP60232267A patent/JPS61118141A/en active Pending
- 1985-10-17 NO NO854138A patent/NO166582C/en unknown
- 1985-10-17 FI FI854050A patent/FI81505C/en not_active IP Right Cessation
-
1987
- 1987-03-09 JP JP62053910A patent/JPS6344948A/en active Pending
Also Published As
Publication number | Publication date |
---|---|
FI81505C (en) | 1990-11-12 |
NO166582C (en) | 1991-08-14 |
AU4856185A (en) | 1986-04-24 |
NO854138L (en) | 1986-04-21 |
IL76662A0 (en) | 1986-02-28 |
CA1304916C (en) | 1992-07-14 |
EP0181491A1 (en) | 1986-05-21 |
ES547950A0 (en) | 1987-05-01 |
JPS6344948A (en) | 1988-02-25 |
AU558709B2 (en) | 1987-02-05 |
FI854050L (en) | 1986-04-19 |
ATE44244T1 (en) | 1989-07-15 |
NO166582B (en) | 1991-05-06 |
DE3571207D1 (en) | 1989-08-03 |
DK466285D0 (en) | 1985-10-11 |
DK466285A (en) | 1986-04-19 |
FI854050A0 (en) | 1985-10-17 |
JPS61118141A (en) | 1986-06-05 |
EP0181491B1 (en) | 1989-06-28 |
ES8705352A1 (en) | 1987-05-01 |
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MM | Patent lapsed |
Owner name: F. HOFFMANN-LA ROCHE AG |