WO2004037405A1 - Biochip and method for processing a plurality of fiochips - Google Patents

Biochip and method for processing a plurality of fiochips Download PDF

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Publication number
WO2004037405A1
WO2004037405A1 PCT/EP2003/011900 EP0311900W WO2004037405A1 WO 2004037405 A1 WO2004037405 A1 WO 2004037405A1 EP 0311900 W EP0311900 W EP 0311900W WO 2004037405 A1 WO2004037405 A1 WO 2004037405A1
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biochip
biochips
plurality
data
means
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PCT/EP2003/011900
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French (fr)
Inventor
Marc Cuzin
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Apibio Sas
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Priority to EP02292672.9 priority Critical
Priority to EP02292672 priority
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Publication of WO2004037405A1 publication Critical patent/WO2004037405A1/en

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    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00497Features relating to the solid phase supports
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00497Features relating to the solid phase supports
    • B01J2219/00527Sheets
    • B01J2219/00529DNA chips
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/0054Means for coding or tagging the apparatus or the reagents
    • B01J2219/00565Electromagnetic means
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/0054Means for coding or tagging the apparatus or the reagents
    • B01J2219/00565Electromagnetic means
    • B01J2219/00569EEPROM memory devices
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/0054Means for coding or tagging the apparatus or the reagents
    • B01J2219/00572Chemical means
    • B01J2219/00576Chemical means fluorophore
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/0054Means for coding or tagging the apparatus or the reagents
    • B01J2219/00572Chemical means
    • B01J2219/00578Chemical means electrophoric
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
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    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00585Parallel processes
    • B01J2219/00587High throughput processes
    • BPERFORMING OPERATIONS; TRANSPORTING
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    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00596Solid-phase processes
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00653Making arrays on substantially continuous surfaces the compounds being bound to electrodes embedded in or on the solid supports
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00659Two-dimensional arrays
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00583Features relative to the processes being carried out
    • B01J2219/00603Making arrays on substantially continuous surfaces
    • B01J2219/00659Two-dimensional arrays
    • B01J2219/00662Two-dimensional arrays within two-dimensional arrays
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068Means for controlling the apparatus of the process
    • B01J2219/00686Automatic
    • B01J2219/00689Automatic using computers
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068Means for controlling the apparatus of the process
    • B01J2219/00686Automatic
    • B01J2219/00691Automatic using robots
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718Type of compounds synthesised
    • B01J2219/0072Organic compounds
    • B01J2219/00722Nucleotides
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718Type of compounds synthesised
    • B01J2219/0072Organic compounds
    • B01J2219/00725Peptides
    • CCHEMISTRY; METALLURGY
    • C40COMBINATORIAL TECHNOLOGY
    • C40BCOMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES, IN SILICO LIBRARIES
    • C40B40/00Libraries per se, e.g. arrays, mixtures
    • C40B40/04Libraries containing only organic compounds
    • C40B40/06Libraries containing nucleotides or polynucleotides, or derivatives thereof
    • CCHEMISTRY; METALLURGY
    • C40COMBINATORIAL TECHNOLOGY
    • C40BCOMBINATORIAL CHEMISTRY; LIBRARIES, e.g. CHEMICAL LIBRARIES, IN SILICO LIBRARIES
    • C40B40/00Libraries per se, e.g. arrays, mixtures
    • C40B40/04Libraries containing only organic compounds
    • C40B40/10Libraries containing peptides or polypeptides, or derivatives thereof

Abstract

The present invention provides a biochip (100) comprising a continuous solid support (101) whereby an array area (102) comprising a plurality of electrodes (103) for the fixation of modules is arranged on said solid support (101), said biochip (100) further comprising a labeling area (104) which is spaced apart from said array area, said labeling area (104) is in connection with transmitter means (105) capable of receiving and transmitting RF signals, said labeling area (104) further comprising remotely RF addressable memory means for storing a plurality of data relating to the identity of or to information related with the biochip (100). The invention further provides a system for the processing of a plurality of biochip arrays and a method for the processing of such biochip arrays.

Description

BIOCFΠP AND METHOD FOR PROCESSING A PLURALITY OF BIOCHIPS

The present invention relates to a biochip, a system and a method for processing a plurality of biochips and the use of this method for the individualization of a plurality of biochips.

Microarray biochips or genechips find increasingly use in a large number of chemical and biochemical tests or reactions. The underlying general principle in microarray techniques (see for example M. Schena (ed.), Microarray Biochip Technology, Eaton Publishing, Natic MA, 2000) is the use of immobilized probe biomolecules such as nucleic acid sequences (also referred to as oligonucleotides or (poly)nucleotides), proteins, peptides, antibodies, antigens, ligands, biological particles and the like on substrates for the study of biological and/or chemical interactions with target biomolecules.

For example, biochips are used to examine gene activity and identify gene mutations, using a hybridization reaction between oligonucleotide sequences on the microarray and a fluorescent sample. After hybridization, the chips are read with high-speed fluorescent detectors and the intensity of each detected spot is quantified. The location and intensity of each spot reveals the identity and amount of each sequence present in the sample.

Other applications include drug discovery via high-throughput-screening of molecular and biological libraries, combinatorial chemistry etc.

US 6,215,894 discloses imaging and analysis experiments performed on microarray biochips, especially to the automatic control of microarray scanners and selection of the proper protocols for analysis of the image maps provided by the scanners. For this purpose, a bar code is imprinted on the biochip which is preferably human readable. Problems arise due to the degradation and partial destruction of the bar code by mechanical stress or by interaction with samples. Even sophisticated protection measures provided for the bar code cannot prevent destruction over the life time of the biochip which is detrimental to the reuse of the biochips. Further, simultaneous processing of a plurality of biochips cannot be carried out, because the data of each biochip cannot be individually discriminated.

WO 02/33123 describes biochips comprising a labeling part of arrays including for example catalog number, gene sequence number etc to be read by a computer and a part comprising one or more microarrays with probe molecules. The labeling part is in the form of a bar code for digital optical recognition by a computer, which has to be printed on the surface of the biochip after its manufacture. Problems arise when the bar code has to be protected against external degradation and when simultaneous analysis of a plurality of biochips has to be carried out.

WO 96/36436 describes the labeling of biomolecule libraries on biochips by attaching to the immobilization substrate remotely addressable memory means, especially semiconductor memory devices. The biochips find application in combinatorial chemistry (split-and-pool synthesis), whereby at every step of the synthesis, information is sent from the biochip to a data storage and management system. The memory means are attached to the surface or embedded in a cavity of the substrate after manufacture of the biochip. This means that the memory means are exchangeable. The combination of the substrate with the attached embedded memory means has to be sealed and protected against external influences.

EP 1048723 Al discloses a biochip that allows unitary management of information, and a method for using the same. A glass substrate spotted with biopolymers such as nucleic acids or proteins is provided externally with a storage medium for storing information of spot locations on the biochip and information of the spotted biopolymer at each spot location. The stored data can be read by a reader/writer based on electromagnetic waves not further specified. The manufacture of the complete biochip is highly complicated and involves the manufacture of a glass substrate, where a chip has to be fit in a cavity etched out of the substrate in a previous step. A simultaneous manufacture of the chip together with the substrate is impossible thereby increasing the overall production costs. Also, simultaneous processing of a plurality of biochips is impossible.

The underlying problem of the present invention is therefore to provide a biochip with a labeling area allowing the unambiguous identification of the biochip, which is easy to manufacture and to assembly and which is protected against externally caused degradation so that the biochip according to the invention can be reused several times.

The problem of the invention is solved by a biochip comprising a continuous solid support whereby an array comprising a plurality of electrodes for the fixation of biomolecules is arranged on said solid support, said biochip further comprising a labeling area which is spaced apart from said array area, said labeling area being connected with transmitting means capable of receiving and transmitting RF signals, said labeling area further comprising remotely RF addressable memory means for storing a plurality of data relating to the identity of or to information related with the biochip, whereby the labeling area and the transmitting means are an integral part of the solid support.

The biochip according to the invention allows in particular the manufacture of the biochip support together with the labeling area and the transmitting means in the same manufacturing process and provides further an efficient protection of the labeling area against externally caused degradation as for example degradation by exposure to light, scratching, mechanical stress, etc. In the context of the present invention, the term "integral" means that labeling area and transmitting means are an inseparable part of the solid support, are manufactured in the same process and are not assembled from separate entities after manufacture of the support. The biochip according to the invention is after manufacture a single, integral shaped article.

The term "connected" means that labeling and transmitting means are linked to each other in such a way that a signal transmission (electrical, optical, electrooptical) via said connection can be carried out.

Preferably, the continuous solid support comprises silicon. The use of silicon allows for example the application of modified manufacturing processes known from IC-packaging processes and transistor technology to the manufacture of the biochip according to the invention. It is understood, that also glass with silicon supports, doped-silicon materials etc fall within the scope of the invention. Other materials suitable for the present purpose comprise amorphous silicon, SOI (silicon on insulator), polymeric materials, especially organic polymers ("plastics"). It is understood that this selection of suitable materials is not limiting and a person skilled in the art is fully aware of other materials suitable for the same purpose. The application of the aforementioned manufacturing processes essentially known by a person skilled in the art allows for the manufacture of each component i.e. comprising but not limited to the labeling area, the transmitting means and the solid support during the same manufacturing process. The manufacture can be carried out either simultaneously or sequentially for each component, or two or more components are manufactured in the same manufacturing step and the remaining components in one of the following manufacturing steps. The choice of the best manufacturing mode for each or all components depends on the specific manufacturing requirements. As a result, labeling area, support and transmitting means are packaged together and form an inseparable article.

In a preferred embodiment, the memory means are passive memory means. In this context the term "memory" means a data storage unit or a medium with programmable memory, preferably with non- volatile memory. Passive memory means as used preferably within the context of the present invention contain no independent power source which allows further miniaturization of the passive memory means as well as of the biochip. Although active memory means are also applicable in the context of the present invention, the additional power source needed for such active memory means would be an unnecessary complication of the biochip set-up.

It is further preferred that the memory means are EEPROM (electrically erasable programmable read-only memory) or flash memories, thereby allowing for the detection of a single biochip even after several use-cycles. The use of EEPROM means further enables the implementation of security and access protocols at a predetermined moment before the use of the biochip which cannot be altered by unauthorized persons. The moment for reading and/or storing the data on the EEPROM is freely selectable. The reading of the data may take place at any steps of the manufacturing process or afterwards, during, afterwards or even just before use, depending on the specific customer requirements.

In an especially preferred embodiment, the memory means further comprise discrimination means allowing for identification of a single biochip or a defined group of biochips out of a plurality (a "pool") of biochips. In the context of the present invention the term "single biochip" is understood to also mean a subgroup (or subset) of two or more biochips out of a plurality (set) of biochips. The term "plurality (or pool) of biochips" denotes two or more biochips, usually a large number. The biochips of this "pool" are either the same (i. e. having the same probe biomolecules attached to their surface) or different (i. e. having different probe biomolecules attached to their surface). The biochips of a selected group or subgroup usually share common characteristics, like for example the biomolecules fixed to the electrodes, manufacturing date, etc. Therefore, lecture means reading information stored in the memory means according to the invention will automatically be able to identify each single chip or a group of biochips out of a plurality of chips read at the same time. The discrimination means are either present as specifically adapted software or hardware or a combination of both.

The problem of the present invention is further solved by providing a system for processing a plurality of biochips, said system comprising

a) a plurality of biochips according to the invention

b) lecture means for reading data obtained from the labeling regions of said biochips.

The system according to the invention offers the unique possibility to identify a single biochip in a plurality of biochips, especially when the plurality of biochips is processed at the same time. The term "processing" as used herein means for example the identification and analysis (quantitative and qualitative) of the interactions between the immobilized probe biomolecules on the biochip and target biomolecules in a sample. For example, fluorescence detection of fluorescence labeled target biomolecules can take place at the same time for a plurality of biochips, because the labeling region of each biochip allows to discriminate each single biochip and to assign the fluorescence data to each single biochip. Other detection methods include but are not limited to colorimetry, electric detection, chemiluminescence and electrochemical detection. It is therefore preferred that the lecture means comprise further means for reading said data from each single biochip. The system according the invention further comprises a computer system for storing, reading and processing data obtained from, related to, and sent to the biochip. The computer system comprises data, which can for example read from other external sources, like the internet, databases on computers, storage media like CD, DND, floppy disks, harddisks, etc. and allow for example the processing and the use of the biochips according to the invention. In preferred embodiments, the computer system contains a library comprising data relating to the identity of and information related to a plurality of biochips.

In still a further advantageous embodiment, the computer system comprises means for comparing the data obtained from the labeling region with said library and assigning the compared data to an individual biochip, therefore discriminating each single biochip or a group of biochips out of a plurality of biochips which are processed simultaneously.

The problem underlying the invention is further solved by a method for processing biochips, said method comprising the steps of

a) providing a plurality of biochips according to the invention

b) attaching a plurality of biomolecule probes to the plurality of electrodes of the array

c) recording in a computer system data relating to the identity of and information related to the biochip and/or the biomolecule probes

d) reading said data from the computer system into the memory means

e) storing the data in said memory means

The method according to the invention allows to store data in biochips related to relevant information about the biochip (production batch, date of manufacture, nature and number of probe biomolecules, customer data, data about the application of the biochip etc). It is preferred that the data stored in the biochip are read-only data. The data allow to follow the test protocols for each application and to relate the stored information/data with the results of tests/chemical or biological reactions etc. This allows for the identification or for the retrieval of a specific biochip or a group of biochips in a pool of identical or different biochips.

After performing a test or an chemical or biological assay, i.e. usually bringing probe biomolecules attached on the electrodes of the plurality of biochips or of a single biochip in contact with a sample containing target biomolecules, allowing for an interaction between the target biomolecules and the probe biomolecules followed by the detection of an interaction of said probe biomolecules with said target biomolecules. Preferably subsequent to or at the same time as the detection takes place, the stored data are sent from the memory means to a library comprising data of a plurality of biochips according to the invention. Preferably, upon comparing the stored data with the data in said library the stored data are assigned to a single biochip or to two or more (for example a specified group) biochips out of a plurality (a "pool") of identical or different biochips.

This allows further after transforming the interaction into data by techniques essetially known by a person skilled in the art to compare the interaction date with data stored in the biochip and with data in a library.

A person skilled in the art is fully aware, that the scope of the invention does not only comprise the above mentioned features alone but also combinations thereof and that the scope of the invention comprises also every single feature in relation to the invention as described herein.

The invention is further described in detail in the following description of preferred embodiments with respect to the figures. Figure 1 shows a schematic representation of a biochip according to the invention;

Figure 2 shows a schematic sectional view of a system for processing biochips according to the invention;

Figure 3 shows in Figures 3a to 3d different arrangements for the antennas of the labeling region with respect to a reading device

Biochip 100 in figure 1 comprises a continuous solid support 101 consisting essentially of silicon or doped silicon. In another embodiment, the solid support comprises glass with silicon. But also usual supports as known in transistor technology, especially integrated circuit packaging like amorphous silicon, doped silicon, silicon nitride, SOI (silicon on insulator), plastic materials etc. and essentially known to a person skilled in the art, can be used for the purpose of the present invention.

Solid support 101 comprises an array 102 of regularly arranged electrodes 103 for the fixation of probe biomolecules. The form of array 102 and the exact spatial arrangement of electrodes 103 underlies no specific restrictions and will be chosen freely by a person skilled in the art according to the specific needs and requirements and the specific system setup. In a preferred embodiment the electrode material is a metal or a metal alloy, like for example gold. It is understood that any other electrically conducting metal such as silver or copper or corresponding alloys are also comprised within the scope of the invention on the metal electrode. In another embodiment, the electrode material is an electronically conducting polymer, such as for example polypyrrole, polythiophene and the like. In still another embodiment, an electronically conducting polymer film or polymer chain is attached to the metallic electrode prior to the attachement of a probe biomolecule.

Attached to electrodes 103' are probe biomolecules, being able to selectively interact with target molecules in a sample to be investigated. Exemplary biomolecules comprise but are not limited to natural and artificial oligonucleotide sequences (nucleic acid sequences), peptides, proteins, antibodies etc. which may be derivatized in order to ensure a better fixation onto electrodes 103. The fixation/immobilization is achieved by a number of different pathways, for example by the formation of covalent bonds, adsorption phenomena, ionic bonds, host-guest interactions and the like and depends on the nature of the electrode and of the probe biomolecule to be attached thereto. The fixation may be either directly or indirectly via linker, magnetic (which in turn may be bonded magnetically to the support) or non-magnetic beads. An exhaustive review of methods for the fixation of biomolecules on substrates essentially known by any person skilled in the art is described in WO 96/36436. It is understood that the probe biomolecules fixed on the electrodes may all be the same i.e. on each electrode is the same type of probe biomolecule or in another preferred embodiment they are different so that on each or on two or more electrodes with a different type of biomolecules is attached.

Solid support 101 further comprises a labeling region 104 which is an integral part of solid support 101 and made during the same manufacturing process as solid support 101. As mentioned in the foregoing, this manufacturing process is a process known per se from usual manufacturing processes in IC packaging and microelectronics. The labeling region comprises remotely RF addressable memory means for the storage of data. For typical labeling regions and their manufacture, suitable for the purpose of the present invention, reference is made to EP 1093636 and EP 1030314 which are incorporated herein by reference. These manufacturing processes are only understood as illustrative examples and it is clear that an artisan will use any other process suitable for this purpose.

It is preferred that the memory means are EEPROM, so that the data contained in said memory means cannot be changed by unauthorized persons. These data are for example data related to the identification of the single chip, for example data of manufacture, specific batch etc., the nature and identity of the probe biomolecules fixed to the electrodes (for example oligonucleotide or peptide sequences etc). This allows for a single biochip to be identified and followed over its total lifetime. The corresponding data can be read or stored in the memory means at any time during the manufacturing process or afterwards when desired. The memory means comprise further means which act as discriminating means in order to read simultaneously data from a plurality of biochips but to be able to discriminate each single biochip from one another even when the plurality of biochips are identical or each of the biochips is different from one another. The means which may be either software or hardware or a combination of both can be termed as a "anti-collision" protocol, as for example disclosed in US 5,528,221.

Connected to the labeling region are transmitting means 105, which receive and transmit data from and to a emitter/receiver not shown in Figure 1. The transmitting means are conventionally termed as an "antenna". The embodiment in Figure 1 makes use of antenna 105 which is termed "coil on chip" and which is for example a metal layer comprised within solid support 101. Any metal or metal alloy suitable for the intended purpose can be used. Antenna 105 may be invisible, i.e. embedded in an inner layer of solid support 101 or visibly arranged on the surface of solid support 101. In another embodiment of the invention antenna 105 is a copper or copper alloy coil with a usual thickness of about 10 μm and a diameter of up to the diameter of the biochip, for example, up to 4mm. The copper coil or any other antenna is for example manufactured by the so-called "Above IC" technique and is also embedded in an inner layer of the solid support. In still another embodiment of the invention, antenna 105 is a printed circuit board copper coil antenna. In this case, the antenna is connected to the labeling region by bonding techniques using for example gold wires or using flip-chip techniques that provide lower impedance connection and better bandwidth.

In a preferred embodiment of the manufacturing process, not only one biochip is manufactured separately but a plurality of preferentially interconnected biochips is manufactured at the same time. A detailed description of an exemplary manufacturing process for such a plurality of interconnected biochips is disclosed in EP 0774662 and EP 0774780, whereby the content of these documents is incorporated by reference herein in its entirety. A wafer made of suitable material, preferably comprising silicon, comprises the biochips and is cut into single biochips after the manufacture of the biochips. A "pick- and-place" system allows for placing the single biochip at the bottom of the wells of a microplate. The "pick-and-place" system essentially comprises a device which dispenses usual adhesive means, for example glue or other suitable means essentially known to an artisan. Parallel to dispensing the adhesive means, transfer means take the single biochip, for example with pincers or via aspiration, and place it into wells of an usual microplate.

Figure 2 shows a schematic representation of a system 200 for processing a plurality of biochips according to the invention. System 200 comprises a section 201 where detection and identification of the specific interactions between probe biomolecules and target biomolecules on the array of a biochip 210 (or a plurality of biochips 210) takes place. These interactions are detected by a reader 202. The nature of the interaction varies according to the nature of the selected probe and target biomolecules. In preferred embodiments, the interactions lead to new chemical entities which can additionally be labeled with marker substances in order to facilitate recognition of these chemical entities. These are detectable by reader 202, for example by fluorescence or electrochemical methods. But any other method known in this field is also applicable. At the same time or before or after the detection of the interactions with reading device 202, each single biochip 210 (or a group of biochips) is identified by reading device 203 addressing the labeling area of the biochip via RF and receiving data from each single biochip thus allowing for its identification. Reading device 203 is typically termed "interrogating emitter/receiver" and is described in more detail in the following. Reading device 203 and reader 202 may be arranged within the same section 201 or arranged at different locations. For the purpose of the present invention the order of reader 202 and reading device 203 may vary. This means that in a first step reader 202 detects the interactions between probe and target molecules followed by identification of the single biochip 210 or a plurality of biochips 210 by reading device 203 or vice versa.

It is preferred that detection and identification take place at a plurality of biochips at the same time thus enabling high-throughput-screening of large numbers of biochips at the same time. The data from reader 202 and lecture means 203 are then sent to a computer system 204 where the data are further processed, i.e. the data sent are compared with a library of data related to a plurality of biochips and subsequently assigned to each single biochip.

Figure 3 shows in Figures 3a to 3d different arrangements of transmitting means 311, 321,

331 and 341, in the foregoing also referred to as "antenna", of a biochip with respect to a reading device 314, 324, 334 and 344. The reading device comprises lecture means 312, 322, 332 and 342, also termed as "interrogating emitter/receiver antenna". Furthermore, the reading device comprises interrogating emitter/receiver means 313, 323, 333 and 343 for emitting and receiving data and/or signals to and from transmitting means 311, 321, 331 and 341 via lecture means 312, 322, 332, 342. The combination of lecture means 312, 322, 332 and 342 with reading device 314, 324, 334 and 344 are exemplarily disclosed in EP 0942385 and EP 0301127 the disclosure of which is incorporated herein by reference.

The single biochips are not shown in Figures 3a to 3d. The plurality of single biochips are interconnected or form a regular array of single isolated biochips. The plurality of biochips can form a so-called microplate 310, 320, 330 and 340. Alternatively each biochip is placed in a well of a microplate 310, 320, 330, 340. The form, material and appearance of the wells and microplates are essentially known to a person skilled in the art. The manufacture of a plurality of interconnected biochips is described in the foregoing. It should be noted that each single biochip may comprise the same or different probe biomolecules attached to its surface.

Apart from the different arrangements shown in Figures 3a - 3d it is obvious that an artisan will also consider the simplest case, that an antenna of the biochip is read by a reading device respectively its lecture means which are only capable of detecting and reading the content transmitted by one antenna only. This means that the size of an antenna of the biochip and the size of the lecture means are nearly the same. In case that a microplate comprising a plurality of interconnected or single biochips attached thereto, lecture means 312, 322, 332, 342 and/or interrogating emitter/receiver means 313, 323, 333, 343 have to move in order to read every single antenna from each biochip. Antennas 311, 321, 331 and 341 are copper coils as described in the foregoing. The material of the biochips and/or microplates 310, 320, 330 and 340 comprises silicon or any suitable plastic material or combinations thereof.

With respect to all Figures 3a - 3d it will become apparent that not only the microplates but also the lecture means and/or interrogating emitter/receiver means are arranged on or attached to moving means, for example steppers, essentially known to an artisan in order to move every single component with respect to another.

Figure 3a shows a microplate 310 with 16 biochips not shown in Figure 3a. Each biochip is connected to an antenna 311. When reading the data via interrogating emitter/receiver means 313 in Figure 3 a, one possibility for lecture means 312 is to read one column of the biochip array at a time and to move from one column to the next in order to read the information of every antenna from each biochip.

Alternatively, the microplate will move and interrogating emitter/receiver 313 and/or lecture means 312 remain in place. In still another embodiment, microplate 310 and interrogating emitter/receiver will move perpendicularly to one another. From the foregoing it is evident, that instead of reading one column at a time it is also possible and comprised within the scope of the invention to read one row of the biochip array at a time.

Figure 3b shows another arrangement for lecture means 322 with respect to a plurality of antennas 321 in a microplate 320 comprising 16 different or identical biochips. In the case of Figure 3b lecture means 322 can read four antennas 321 arranged rectangularly at a time. The lecture means and/or microplate 320 also have to move in order to read all the information from every biochip stored in the corresponding biochips.

Figure 3c shows another arrangement whereas lecture means 332 can read each single biochip which has an antenna 331 and is arranged on a microplate 330 at the same time. In this case it is particularly important to provide anti-collision means in order to discriminate between the information received from each biochip at one time. Lecture means 332 are also connected to interrogating emitter/receiver means 333.

Figure 3d shows still another arrangement for lecture means 342 in connection with interrogating emitter/receiver means 343 with respect to an array of 8x12 biochips (96 per microplate). Lecture means 342 will read all 96 antennas from the biochips not shown on microplate 340. It is obvious, that any other geometrical arrangement of antenna 342 will also serve the purpose of the present invention. Therefore, only a very restricted movement of microplate 340 and/or interrogating emitter/receiver means 343 and/or lecture means 342 has to take place in order to detect all the information from each biochip individually. In the case in Figure 3d it is also a critical feature to have an anti-collision means in order to discriminate each biochip individually when the biochips are read simultaneously by lecture means 342.

* * * * *

Claims

PATENT CLAIMS
1. Biochip (100) comprising a continuous solid support (101) whereby an array (102) comprising a plurality of electrodes (103) is arranged on said solid support, said biochip (100) further comprising a labeling area (104) which is spaced apart from said array area (102), said labeling area (104) being connected with transmitting means (105) capable of receiving and transmitting RF signals, said labeling area (104) further comprising remotely RF addressable memory means for storing a plurality of data relating to the identity of or to information related with the biochip (100),
characterized in that
the labeling area (104 ) and the transmitting means (105) are an integral part of the solid support (101).
2. Biochip according to claim 1, further comprising biomolecules attached to said electrodes (103).
3. Biochip according to claim 1 or 2, whereby the continuous solid support (101) comprises silicon.
4. Biochip according to claim 3, whereby the labeling area (104), the transmitting means (105) and the solid support (101) are manufactured in the same manufacturing process.
5. Biochip according to one of the preceding claims, whereby the memory means are passive memory means
6. Biochip according to claim 5, whereby the memory means are EEPROM memory means.
7. Biochip according to claim 6, whereby the memory means comprise discrimination means allowing the identification of each single biochip or a group of biochips.
8. System for processing a plurality of biochips, said system comprising
a) a plurality of biochips according to anyone of the preceding claims
b) lecture means for reading data obtained from the labeling regions of said biochips.
9. System according to claim 8, whereby the lecture means comprise further means for reading said data from each single biochip or a group of biochips.
10. System according to claim 9 further comprising a computer system.
11. System according to claim 10, whereby said computer system contains a library comprising data relating to the identity of and information related to a plurality of biochips.
12. System according to claim 11, said computer system further comprising means for comparing the data obtained from the labeling region with said library and assigning the compared data to an individual biochip or a group of biochips.
13. A method for processing biochips, said method comprising the steps of
a) providing a plurality of biochips according to anyone of claims 1 to 7
b) attaching a plurality of biomolecule probes to the plurality of electrodes of the array
c) recording in a computer system data relating to the identity of and information related to the biochip and/or the biomolecule probes
d) reading said data from the computer system into the memory means
e) storing the data in said memory means
14. Method according to claim 13, whereby said data are read-only data.
15. Method according to anyone of the preceding claims, further comprising the step of bringing the plurality of biochips or a single biochip of the plurality of biochips in contact with a sample containing target molecules.
16. Method according to claim 15 further comprising the step of detecting an interaction of said probe biomolecules with said target molecules.
17. Method according to claim 16 further comprising the step of transforming the results of the interaction in data.
18. Method according to claim 14 or 16 to 17 further comprising the step of sending the stored data from the memory means to a library comprising data of a plurality of biochips.
19. Method according to claim 18 further comprising the step of comparing the stored data with the data in said library and assigning the stored data to a single biochip or a group of biochips.
0. Use of a method according to one of the preceding claims for the individualization of a single biochip out of a plurality of biochips.
PCT/EP2003/011900 2002-10-28 2003-10-27 Biochip and method for processing a plurality of fiochips WO2004037405A1 (en)

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