AU2001270904A1 - System and method for characterising and sequencing polymers - Google Patents
System and method for characterising and sequencing polymersInfo
- Publication number
- AU2001270904A1 AU2001270904A1 AU2001270904A AU7090401A AU2001270904A1 AU 2001270904 A1 AU2001270904 A1 AU 2001270904A1 AU 2001270904 A AU2001270904 A AU 2001270904A AU 7090401 A AU7090401 A AU 7090401A AU 2001270904 A1 AU2001270904 A1 AU 2001270904A1
- Authority
- AU
- Australia
- Prior art keywords
- space
- components
- time map
- time
- sample
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44704—Details; Accessories
- G01N27/44717—Arrangements for investigating the separated zones, e.g. localising zones
- G01N27/44721—Arrangements for investigating the separated zones, e.g. localising zones by optical means
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44704—Details; Accessories
- G01N27/44717—Arrangements for investigating the separated zones, e.g. localising zones
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N27/00—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means
- G01N27/26—Investigating or analysing materials by the use of electric, electrochemical, or magnetic means by investigating electrochemical variables; by using electrolysis or electrophoresis
- G01N27/416—Systems
- G01N27/447—Systems using electrophoresis
- G01N27/44756—Apparatus specially adapted therefor
- G01N27/44791—Microapparatus
Abstract
A system and method of characterizing, in particular sequencing, polymeric samples, the system comprising: a space-time map generator for generating a space-time map of points representative of the signal peaks of signals detected at a plurality of spaced positions as passed by the migrating components of a plurality of separately-provided sample plugs; and a vertex finder for identifying vertices from the space-time map, with a single vertex being identified for the components of each separately-provided sample plug and the velocities of the sample components being determinable from the points in the space-time map.
Description
SYSTEM AND METHOD
The present invention relates to a system for and method of characterising, in particular sequencing, polymeric samples, in particular, but not exclusively, as measured electrophoretically. The technique of the present invention is the MITSO™ characterisation technique.
Electrophoretic separation techniques are separation techniques in which the components of a sample plug are separated in a separation column by the differences in the migration rates of those sample components on the application of an electric field therealong, where absorption, fluoroescence, electrochemistry, conductivity, radioactivity and mass spectrometry can be all used to detect the electrophoretic separation.
By way of example, DNA samples are commonly characterised by Sanger sequencing. Whilst Sanger sequencing is in common use, the technique is limited in a number of respects, not least because the DNA bands have to be labelled according to base pair termination.
It is an aim of the present invention to provide an improved system for and method of characterising, in particular sequencing, polymeric samples, such as DNA samples, which can be used with both labelled and non-labelled sample components.
Accordingly, the present invention provides a system for characterising, in particular sequencing, polymeric samples, comprising: a space-time map generator for generating a space-time map of points representative of the signal peaks of signals detected at a plurality of spaced positions as passed by the migrating components of a plurality of separately-provided sample plugs; and a vertex finder for identifying vertices from the space-time map, with a single vertex being identified for the components of each separately-provided sample plug and the velocities of the sample components being determinable from the points in the space-time map.
Preferably, the system further comprises a velocity sorter for determining the nominal velocities associated with the signal peaks in the signals and grouping those signal peaks into sets according to nominal velocity.
Preferably, the space-time map generator is configured to utilise a corrected time component in generating the space-time map according to a function of the electric current variation.
More preferably, the correction is according to the function tc = Jlo I(t')dt' in the range of 0 to t, where t is the measured time, tc is the corrected time, I is the measured current and I0 is the reference current.
Preferably, the space-time map generator is an equiphase space-time map generator for generating an equiphase space-time map of equiphase points.
More preferably, the equiphase space-time map generator is configured to transform each data set into a set of local slopes and determine the local minima as the minimum absolute local derivatives.
In one embodiment the components are non-labelled.
In another embodiment the components are labelled.
Preferably, the components are migrated through a channel.
More preferably, the channel comprises a separation channel through which the components are electrophoretically driven.
Preferably, the sample plugs respectively comprise DNA bands having one of the base pair terminations.
The present invention also extends to an electrophoresis apparatus including the above- described system.'
The present invention also provides a method of characterising, in particular sequencing, polymeric samples, comprising the steps of: generating a space-time map of points representative of the signal peaks of signals detected at a plurality of spaced positions as passed by the migrating components of a plurality of separately-provided sample plugs; and identifying vertices from the space-time map, with a single vertex being identified for the components of each separately-provided sample plug and the velocities of the sample components being determinable from the points in the space-time map.
Preferably, the method further comprises the steps of determining the nominal velocities associated with the signal peaks in the signals and grouping those signal peaks into sets according to nominal velocity.
Preferably, a time component corrected according to a function of the electric current variation is utilised in generating the space-time map.
More preferably, the correction is according to the function tc = jIo/I(t')dt' in the range of 0 to t, where t is the measured time, tc is the corrected time, I is the measured current and lo is the reference current.
Preferably, the space-time map is an equiphase space-time map of equiphase points.
More preferably, the equiphase points are determined by transforming each data set into a set of local slopes and determining the local minima as the minimum absolute local derivatives.
In one embodiment the components are non-labelled.
In another embodiment the components are labelled.
Preferably, the components are migrated through a channel.
More preferably, the channel comprises a separation channel through which the components are electrophoretically driven.
In one embodiment the sample plugs are provided at spaced time intervals.
In another embodiment the sample plugs are provided at spaced positions.
Preferably, the sample plugs are provided at substantially the same time.
Preferably, the sample plugs respectively comprise DNA bands having one of the base pair terminations.
A preferred embodiment of the present invention will now be described hereinbelow by way of example only with reference to the accompanying drawings, in which:
Figure 1 illustrates the detector chip of an electrophoresis apparatus in accordance with a preferred embodiment of the present invention;
Figure 2 illustrates the analysis system of the apparatus of Figure 1;
Figure 3 illustrates a three-dimensional representation of the intensity-time signals of one component of a sample plug as detected at positions zls z2, z3 spaced along the separation channel of the apparatus of Figure 1;
Figure 4 illustrates the intensity-time signals of three components of a sample plug as detected at positions zi, z2, z3 spaced along the separation channel of the apparatus of Figure 1;
Figure 5 illustrates a space-time map as generated from the intensity-time signals of Figure 4;
Figure 6 illustrates the velocity spectrum as determined from the vertexed space-time map of Figure 5; and
Figure 7 illustrates a space-time map as generated from the intensity-time signals from four separately-injected DNA sample plugs comprising DNA bands having different base pair terminations.
Figures 1 and 2 illustrate an electrophoresis apparatus in accordance with a preferred embodiment of the present invention.
The electrophoresis apparatus includes a detector chip 2 as microfabricated in a substrate chip, and an analysis system 3 for analysing the detection signals generated by the detector chip 2.
The detector chip 2 includes a separation channel 4, in this embodiment a meandering, gel- filled channel, through which the components of one or more sample plugs are in use driven by an applied electrophoretic voltage. The separation channel 4 has a length sufficient to allow separation of the components of the sample plugs. Preferably, the separation channel 4 has a width of from 25 to 100 μm and a length of from 20 to 300 mm. The separation channel 4 includes a plurality, in this embodiment first to fourth, spaced sample-injection ports 6, 8, 10, 12 through which sample plugs including a plurality of components, in this embodiment DNA bands having the respective base pair terminations A T, G and C, are separately injected into the separation channel 4.
The detector chip 2 further includes a light source 14, in this embodiment a UV light source, disposed along a length of one side of the separation channel 4, and a detector 16 disposed along the length of the other side of the separation channel 4 to detect light transmitted through the separation channel 4, with the presence of the migrating
components being detected by the change in the detected light intensity as caused bv absorbtion of the incident light. By detecting the sample components in this manner, the sample components need not necessarily be labelled. In this embodiment the detector 16 comprises a pixel detector array (PDA) which includes a plurality of pixels providing detecting elements for detecting the transmitted light at a plurality of positions zi, z2, z3 spaced along the length of the separation channel 4 and outputting a plurality of signals Si, S2, S3. For ease of description, the detector 16 is illustrated as including three detecting elements at three positions zi, z2, z3. It will, however, be understood that in practice the detector 16 comprises a plurality of detecting elements at a plurality of positions zl3 z2, z3, ... , zn, which each output a signal Si, S2, S3, ... , Sn. In an alternative embodiment the detector 16 could be provided by a plurality of separate detectors each providing a detecting element. In another alternative embodiment labelled sample components could be used, such as sample components including fluorescent or radioactive labels, which labels would be detected by the detector 16.
The analysis system 3 comprises a data collector 18 for receiving the signals Si, S2, S3 generated by the detector 16 and storing those signals Si, S2, S3 as data sets, a velocity sorter 19 for determining the nominal velocities vi, v2, v3 of the sample components associated with each of the signal peaks SPi, SP2, SP3 of each of the signals Si, S2, S3 and grouping those signal peaks SPt, SP2, SP3 into sets according to nominal velocity, an equiphase space-time map generator 20 for generating an equiphase space-time map of equiphase points from the signal peaks SPi, SP2, SP3 of the signals Si, S2, S3, and a vertex finder 22 for identifying the vertices of the equiphase points of the grouped sets of signal peaks SPi, SP2, SP3. In this embodiment the velocity sorter 19 is provided so as to be operable prior to the equiphase space-time map generator 20. In alternative embodiments the velocity sorter 19 could be provided so as to be operable after the space-time map generator 20 or the vertex finder 22.
Figure 3 is included for the purposes of illustration only and illustrates the signals Si, S2, S3 as including only a single peak SPi from a single component of a single sample plug. In reality, however, the signals Si, S2, S3 each include a plurality of signal peaks SPι-n, SPι.n,
SPι-n. Figure 4 illustrates the signals Si, S2, S3 as including three signal peaks SPi, SPj, SP3 from three components of a single sample plug.
The velocity sorter 19 is configured to determine the nominal velocities v1? v2, v3 of the sample components associated with each of the signal peaks SPi, SP2, SP3 in each of the signals Si, S2, S3 and then group those signal peaks SPi, SP2, SP3 into sets according to nominal velocity. The nominal velocities vi, v2, v3 can be calculated as the positions zi, z2, z3 of the detector elements are fixed and the elapsed time t is extractable from the signals Si, S2, S3, where the nominal velocities can be expressed as vι-„ = zι-n/t. By grouping the signal peaks SPi, SP2, SP3 into sets according to nominal velocity, and hence sample component, subsequent analysis is facilitated as the data points associated with each sample component can be fitted without requiring the use of complex data extraction techniques. Velocity sorting is encompassed by our earlier WO-96/35946, the content of which is incorporated herein by reference.
The equiphase space-time map generator 20 is configured to determine the local minima of the signal peaks SPi, SP2, SP3 in the signals Si, S2, S3 detected at the detection positions zi, z2, z3 and generate an equiphase map M in space-time dimensions from the determined local minima. Figure 5 illustrates the space-time map M generated from the local minima extracted from the signal peaks SPi, SP2, SP3 of the signals Si, S2, S3.
In this embodiment each electropherogram is transformed into a set of local slopes, where a triangular slope sequence defines a signal and the local extreme is the minimum absolute local derivative.
Also, in this embodiment the time component of the detected signals Si, S2, S3 is corrected as a function of the integrated electric current variation. Owing to the variation of various factors in electrophoretic detection, the temperature being one of the most significant, the characteristics of the separation medium, in this embodiment a gel, are altered. Firstly, the resistivity of the gel changes, leading to variations in the potential difference between the electrodes and a given point in the gel and fluctuations in the electric current. Secondly,
the sieving properties of the gel change, affecting the mobility of the electrophoresed components. By monitoring the electric current, the time component of the space-time map M can be corrected as set out hereinbelow. Specifically, the time component is curved as a function of the integrated electric current variation.
The velocity of a sample component is:
v = dz/dt (1)
For a transformation of the measured time component to a corrected time component t -→ tc, it follows that dt — » dtc and v — » vc. Thus:
The transformation v → vc can be defined as:
vJv = I(t)/Io (3)
where I is the measured current and lo is the reference current which corresponds to the frame where all velocities and time components are projected.
From equations (2) and (3), it follows:
dto = I0/I(t)dt → tc = JI0/I(t')d for O to t (4)
The justification for the velocity transformation (3) is that the velocity is approximately proportional to the applied electric field, which in turn is proportional to the electric current in the separation channel 4. This correction factor has been found to work well for small current changes, with the integral of equation (4) providing for an accurate time transformation.
The vertex finder 22 is configured, in this embodiment by the use of rotational matrices, to identify the vertices V of the equiphase points of the grouped sets of signal peaks SPl5 SP2, SP3 as determined by the equiphase space-time map generator 20, where the components of each injected sample plug have a common vertex V by virtue of being time and/or spatially separated in the space-time dimension. All of the sample components injected in a single sample plug are uniquely identified by a single vertex V in space-time coordinates, thus allowing for the identification of the sample components from each of a plurality of separately-provided sample plugs. Figure 5 illustrates the vertex V as determined from the generated space-time map M. This space-time map includes only a single vertex V as all of the components were provided in a single sample plug.
By using each vertex V as a constraint to extract the velocity spectrum of the sample components, the resolution is approximately proportional to "Vn, where n is the number of components. In this way, the velocity of one component is calculated using the velocities of all of the other components from the same sample plug, and thus, as the number of components in a sample increases, the resolution of the analysis increases accordingly. Such space parameterisation which results in multiple vertex formation in the form of intensity enhanced regions in space-time co-ordinates is particularly suited to the cases of multiple sample injections and multiple column correlation. The power of this technique has been demonstrated on DNA samples which include large numbers of fragments (>100) having lengths of one base pair difference, thereby providing a sequencing technique having a greatly extended dynamic range.
From the determination of the vertices V in the space-time map M, high resolution of the electrophoresis data is achieved, allowing accurate determination of the velocities of the sample components as illustrated in Figure 6.
Use of the above-described electrophoresis apparatus to sequence DNA samples having the base pair terminations A, T, G and C will now be described hereinbelow.
In use, four sample plugs comprising DNA bands having different length and one of he base pair terminations A, T, G and C are separately introduced into the ports 6, 8, 10, 12 of the separation channel 4, and electrophoretically driven therealong. In one mode of use, the sample plugs are introduced simultaneously into the ports 6, 8, 10, 12 which are spatially separated along the separation channel 4. In another mode of use, the sample plugs are introduced sequentially into one of the ports 6, 8, 10, 12 so as to be time spaced. The signals Si, S2, S3, ... , Sn detected by the detector 16 as the DNA bands pass the detecting elements at the detecting positions zi, z2, z3, ... , zn are collected by the data collector 18. The velocity sorter 19 then determines the nominal velocities vi, v2, v3, ..., vn of the sample components associated with each of the signal peaks SPi, SP2, SP3, ..., SPπ of the signals Si, S2, S3, ... , S„ and groups those signal peaks SPi, SP2, SP3, ..., SP„ into sets according to nominal velocity. The equiphase space-time map generator 20 then determines the local minima of the signal peaks SPi, SP2, SP3, ..., SPn of the signals Si, S2, S3, ... , Sn, and generates an equiphase space-time map M. The vertex finder 22 then identifies the vertices VA, VT, VG, VC of the determined local minima for each of the grouped sets of signal peaks SPi, SP2, SP3, ..., SPn. In this embodiment the space-time map M includes four vertices VA, VT, VG, VC as four sample plugs were separately injected into the separation channel 4, each being attributable to DNA bands having one of the base pair terminations A, T, G and C. In this way, the DNA sample can be sequenced, with the lengths of the DNA bands being determined from the migration velocities.
Finally, it will be understood that the present invention has been described in its preferred embodiment and can be modified in many different ways without departing from the scope of the invention as defined by the appended claims.
Claims (28)
1. A system for characterising, in particular sequencing, polymeric samples, comprising: a space-time map generator for generating a space-time map of points representative of the signal peaks of signals detected at a plurality of spaced positions as passed by the migrating components of a plurality of separately- provided sample plugs; and a vertex finder for identifying vertices from the space-time map, with a single vertex being identified for the components of each separately-provided sample plug and the velocities of the sample components being determinable from the points in the space-time map.
2. The system of claim 1, further comprising a velocity sorter for determining the nominal velocities associated with the signal peaks in the signals and grouping those signal peaks into sets according to nominal velocity.
3. The system of claim 1 or 2, wherein the space-time map generator is configured to utilise a corrected time component in generating the space-time map according to a function of the electric current variation.
4. The system of claim 3, wherein the correction is according to the function tc = jϊo/I(t')dt' in the range of 0 to t, where t is the measured time, tc is the corrected time, I is the measured current and lo is the reference current.
5. The system of any of claims 1 to 4, wherein the space-time map generator is an equiphase space-time map generator for generating an equiphase space-time map of equiphase points.
6. The system of claim 5, wherein the equiphase space-time map generator is configured to transform each data set into a set of local slopes and determine the local minima as the minimum absolute local derivatives.
7. The system of any of claims 1 to 6, wherein the components are non-labelled.
8. The system of any of claims 1 to 6, wherein the components are labelled.
9. The system of any of claims 1 to 8, wherein the components are migrated through a channel.
10. The system of claim 9, wherein the channel comprises a separation channel through which the components are electrophoretically driven.
11. The system of any of claims 1 to 10, wherein the sample plugs respectively comprise DNA bands having one of the base pair terminations.
12. A method of characterising, in particular sequencing, polymeric samples, comprising the steps of: generating a space-time map of points representative of the signal peaks of signals detected at a plurality of spaced positions as passed by the migrating components of a plurality of separately-provided sample plugs; and identifying vertices from the space-time map, with a single vertex being identified for the components of each separately-provided sample plug and the velocities of the sample components being determinable from the points in the space-time map.
13. The method of claim 12, further comprising the steps of determining the nominal velocities associated with the signal peaks in the signals and grouping those signal peaks into sets according to nominal velocity.
14. The method of claim 12 or 13, wherein a time component corrected according-to a function of the electric current variation is utilised in generating the space-time map.
15. The method of claim 14, wherein the correction is according to. the function tc = Jl0/I(t')dt' in the range of 0 to t, where t is the measured time, tc is the corrected time, I is the measured current and lo is the reference current.
16. The method of any of claims 12 to 15, wherein the space-time map is an equiphase space-time map of equiphase points.
17. The method of claim 16, wherein the equiphase points are determined by transforming each data set into a set of local slopes and determining the local minima as the minimum absolute local derivatives.
18. The method of any of claims 12 to 17, wherein the components are non-labelled.
19. The method of any of claims 12 to 17, wherein the components are labelled.
20. The method of any of claims 12 to 19, wherein the components are migrated through a channel.
21. The method of claim 20, wherein the channel comprises a separation channel through which the components are electrophoretically driven.
22. The method of any of claims 12 to 21, wherein the sample plugs are provided at spaced time intervals.
23. The method of any of claims 12 to 21, wherein the sample plugs are provided at spaced positions.
24. The method of claim 23, wherein the sample plugs are provided substantially_aJ: the same time.
25. The method of any of claims 12 to 24, wherein the sample plugs respectively comprise DNA bands having one of the base pair terminations.
26. An electrophoresis apparatus including the system of any of claims 1 to 11.
27. A system for characterising, in particular sequencing, polymeric samples substantially as hereinbefore described with reference to the accompanying drawings.
28. A method of characterising, in particular sequencing, polymeric samples substantially as hereinbefore described with reference to the accompanying drawings.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB0019499.3A GB0019499D0 (en) | 2000-08-08 | 2000-08-08 | system and method |
| GB0019499 | 2000-08-08 | ||
| PCT/GB2001/003286 WO2002013122A2 (en) | 2000-08-08 | 2001-07-20 | System and method for characterising and sequencing polymers |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2001270904A1 true AU2001270904A1 (en) | 2002-02-18 |
Family
ID=9897238
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001270904A Abandoned AU2001270904A1 (en) | 2000-08-08 | 2001-07-20 | System and method for characterising and sequencing polymers |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US7425251B2 (en) |
| EP (1) | EP1309922B1 (en) |
| JP (1) | JP4845329B2 (en) |
| KR (1) | KR20030064741A (en) |
| AT (1) | ATE344497T1 (en) |
| AU (1) | AU2001270904A1 (en) |
| BR (1) | BR0113076A (en) |
| CA (1) | CA2417144A1 (en) |
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| IL (1) | IL154181A0 (en) |
| NZ (1) | NZ523887A (en) |
| PT (1) | PT1309922E (en) |
| WO (1) | WO2002013122A2 (en) |
| ZA (1) | ZA200300792B (en) |
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|---|---|---|---|---|
| GB0030708D0 (en) | 2000-12-15 | 2001-01-31 | Imperial College | Single channel proteomics concepts |
| DE60212620T2 (en) | 2002-08-16 | 2006-11-02 | Agilent Technologies, Inc. (n.d.Ges.d.Staates Delaware), Palo Alto | Method and apparatus for analyzing a sample mixture |
| AU2004235331B2 (en) * | 2003-04-25 | 2008-12-18 | Sequenom, Inc. | Fragmentation-based methods and systems for De Novo sequencing |
| WO2005024068A2 (en) | 2003-09-05 | 2005-03-17 | Sequenom, Inc. | Allele-specific sequence variation analysis |
| EP2395098B1 (en) | 2004-03-26 | 2015-07-15 | Agena Bioscience, Inc. | Base specific cleavage of methylation-specific amplification products in combination with mass analysis |
| GB201404756D0 (en) | 2014-03-17 | 2014-04-30 | Analytica Llc Q | Profiling apparatus and method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US610353A (en) * | 1898-09-06 | Grip-pulley | ||
| US514609A (en) * | 1894-02-13 | Dial-cap for knitting-machines | ||
| JPS61233370A (en) * | 1985-04-09 | 1986-10-17 | Fuji Photo Film Co Ltd | Signal processing method for determining base sequence of nucleic acid |
| US5141609A (en) | 1990-11-16 | 1992-08-25 | The Trustees Of The Leland Stanford Junior University | Method and device employing time-delayed integration for detecting sample components after separation |
| US5114551A (en) | 1991-09-30 | 1992-05-19 | Bio-Rad Laboratories, Inc. | Multi-point detection method for electrophoresis and chromatography in capillaries |
| SE500702C2 (en) * | 1992-04-07 | 1994-08-15 | Staffan Birnbaum | Methods and apparatus for optical analysis of samples separated into thin capillaries |
| GB9509410D0 (en) * | 1995-05-10 | 1995-07-05 | Imperial College | Molecular imaging |
| US6130559A (en) | 1997-04-04 | 2000-10-10 | Board Of Regents Of The University Of Texas System | QMOS digital logic circuits |
| AU727083B2 (en) * | 1997-04-25 | 2000-11-30 | Caliper Life Sciences, Inc. | Microfluidic devices incorporating improved channel geometries |
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2000
- 2000-08-08 GB GBGB0019499.3A patent/GB0019499D0/en not_active Ceased
-
2001
- 2001-07-20 KR KR10-2003-7001837A patent/KR20030064741A/en not_active Application Discontinuation
- 2001-07-20 PT PT01949789T patent/PT1309922E/en unknown
- 2001-07-20 ES ES01949789T patent/ES2273862T3/en not_active Expired - Lifetime
- 2001-07-20 AU AU2001270904A patent/AU2001270904A1/en not_active Abandoned
- 2001-07-20 EP EP01949789A patent/EP1309922B1/en not_active Expired - Lifetime
- 2001-07-20 NZ NZ523887A patent/NZ523887A/en unknown
- 2001-07-20 US US10/344,070 patent/US7425251B2/en not_active Expired - Lifetime
- 2001-07-20 AT AT01949789T patent/ATE344497T1/en not_active IP Right Cessation
- 2001-07-20 BR BR0113076-5A patent/BR0113076A/en not_active Application Discontinuation
- 2001-07-20 CA CA002417144A patent/CA2417144A1/en not_active Abandoned
- 2001-07-20 IL IL15418101A patent/IL154181A0/en unknown
- 2001-07-20 JP JP2002518405A patent/JP4845329B2/en not_active Expired - Lifetime
- 2001-07-20 WO PCT/GB2001/003286 patent/WO2002013122A2/en active IP Right Grant
- 2001-07-20 DE DE60124262T patent/DE60124262T2/en not_active Expired - Lifetime
- 2001-07-20 DK DK01949789T patent/DK1309922T3/en active
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Also Published As
| Publication number | Publication date |
|---|---|
| PT1309922E (en) | 2007-01-31 |
| DE60124262T2 (en) | 2007-06-28 |
| IL154181A0 (en) | 2003-07-31 |
| ATE344497T1 (en) | 2006-11-15 |
| GB0019499D0 (en) | 2000-09-27 |
| US20040014231A1 (en) | 2004-01-22 |
| ES2273862T3 (en) | 2007-05-16 |
| NZ523887A (en) | 2003-05-30 |
| WO2002013122A2 (en) | 2002-02-14 |
| US7425251B2 (en) | 2008-09-16 |
| JP4845329B2 (en) | 2011-12-28 |
| EP1309922A2 (en) | 2003-05-14 |
| KR20030064741A (en) | 2003-08-02 |
| ZA200300792B (en) | 2004-02-19 |
| DK1309922T3 (en) | 2007-03-12 |
| DE60124262D1 (en) | 2006-12-14 |
| EP1309922B1 (en) | 2006-11-02 |
| JP2004505642A (en) | 2004-02-26 |
| WO2002013122A3 (en) | 2002-08-08 |
| BR0113076A (en) | 2003-07-08 |
| CA2417144A1 (en) | 2002-02-14 |
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