Thermocycler and lifting element

- Applera Corporation

Some of the blind holes (6) between indentations (4) of a heating surface (3) contain lifting elements (7) which, after opening of a cover, release a microtitre plate (13) from the heating surface (3) and raise said microtitre plate about 2 to 3 mm, so that it can be removed without application of force. Each lifting element (7) consists of a coil spring (8) and a contact pin (9) made of, for example, PEEK which is inserted into said coil spring and presses with a round flat abutting surface (12) against the lower surface of the microtitre plate (13). The spring constant of the lifting element (7) is about 6 N/mm.

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Description
FIELD OF THE INVENTION

The invention relates to a thermocycler. Such devices are used for subjecting the content of the wells of microtitre plates to temperature cycles which initiate specific chemical reactions. It also relates to lifting elements for use in thermocyclers.

PRIOR ART

In known thermocyclers of the generic type, there is the problem that the microtitre plate which, in the interests of good heat transfer, rests closely against the heating surface frequently becomes baked onto it and can then be detached from it only with very great difficulty. This either necessitates complicated manipulations or requires suitable and correspondingly heavy and expensive handling devices for applying relatively large forces of 150 N or more. A possible aid is the use of Teflon spray, which can prevent the microtitre plate from baking on. However, this must be repeated for every plate and complicates the procedures.

SUMMARY OF THE INVENTION

It is the object of the invention to improve a known thermocycler of the generic type so that the microtitre plates can be raised and removed after each treatment without particular application of force. This object is achieved by the features in the characterizing clause of claim 1.

It has been found that, as a result of the measures according to the invention, the microtitre plate is raised after removal of the cover, which permits convenient gripping and lifting thereof without application of force. This may substantially facilitate the manual removal of the microtitre plate, but in particular the removal can also be effected without any manual intervention, by means of handling devices of the type otherwise usual in the laboratory.

Furthermore, the invention provides particularly suitable lifting elements for thermocyclers according to the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is explained in more detail below with reference to Figures which show only an embodiment.

FIG. 1 shows a plan view of the heating plate of a thermocycler according to the invention,

FIG. 2 shows, on a larger scale, a cut-out from a plan view according to FIG. 1,

FIG. 3 shows a perspective view of a lifting element according to the invention,

FIG. 4a shows a section along IV—IV in FIG. 2, in addition with microtitre plate and cover, and

FIG. 4b shows a section corresponding to FIG. 4a with the cover removed.

 DESCRIPTION OF THE PREFERRED EMBODIMENTS

The thermocycler, which may be suitable, for example, for holding an 8×12 microtitre plate having the dimensions 85 mm×130 mm, has a heating plate 1 which forms a heating surface 3 which is surrounded by an edge strip 2 and is somewhat higher than said edge strip and in which round indentations 4 are arranged in a regular square grid, each of which indentations is surrounded by an all-round wall 5 (FIG. 2) projecting beyond the base level of the heating surface 3. In each case, a blind hole 6 is provided between four indentations 4.

Six lifting elements 7 are arranged in six of the blind holes 6 altogether, distributed approximately uniformly over the heating surface 3. Each of the lifting elements 7 consists (FIG. 3) of a cylindrical coil spring 8 of stainless steel, the lowermost winding of which is somewhat wider than the other windings, and a contact pin 9 whose approximately cylindrical shaft 10 is inserted into the upper end of the coil spring 8 and is held therein by friction.

The shaft 10 carries an approximately disc-like head 11 which projects laterally from it and against whose lower surface the upper end of the coil spring 8 abuts, while its upper surface forms a round flat abutting surface 12. The contact pin 9 is rotationally symmetrical and is produced as a single piece from a heat-resistant plastic, such as PEEK, PTFE, FP, PPS or PI, for example by the injection moulding process. It may also consist of, for example, ceramic, but the production is then as a rule more complicated and more expensive. The contact pin 9 is between 3 mm and 8 mm, preferably about 6 mm, long. The diameter of the abutting surface 12 is between 3 mm and 7 mm, preferably about 5 mm.

The lifting element 7 has a length of between 15 mm and 20 mm, preferably of about 16 mm. Its spring constant in the relaxed position is between 5 N/mm and 7.5 N/mm, in particular 6 N/mm. It is of course also possible to choose other dimensions and properties in adaptation to different designs of the heating plate and depending on the density with which the lifting elements 7 are arranged on the heating surface and which is 1 per 18.4 cm2 in the case described above and, as a rule, is at least 1 per 30 cm2.

The coil spring 8 is dimensioned in each case so that the somewhat wider lowermost winding is slightly radially compressed in the blind hole 6 so that there is a frictional lock between said winding and the wall of the blind hole 6. The lifting element 7 is thus adequately fixed but can nevertheless easily be removed. The other windings are free from the wall of the blind hole 6 so that the compression of the coil spring 8 is not hindered.

When the thermocycler is used, the microtitre plate 13, which usually consists of plastic, e.g. polypropylene, is placed on the heating surface 3 (FIGS. 4a, 4b) manually or preferably by means of a suitable handling device, e.g. a robot arm, and a hinged cover 14 of the thermocycler is lowered onto said microtitre plate so that each of its wells is pressed into a corresponding indentation 4 and rests against its wall (FIG. 4a). This ensures good heat transfer between the heating plate 1 and the samples in the wells 15. The coil springs 8 of the lifting elements 7, which, in the relaxed state, project about 6 mm above the edges of the walls 5, are compressed by the pressure exerted by the microtitre plate 13 on the abutting surfaces 12 of its contact pins 9 and are shortened by 2 to 3 mm.

After the thermal treatment of the samples in the microtiter plate, which, for example to initiate a PCR reaction, may undergo a relatively large number of temperature cycles, each of which may consist of, for example, heating from 4° C. to 96° C. with subsequent cooling to 4° C., the cover 14 is swivelled up again. Each of the compressed lifting elements 7 exerts an upward force of about 15 N on the microtitre plate 13. This is sufficient to detach the microtitre plate 13 from the heating surface 3 even if it is baked onto the latter and to raise it, possibly with a delay of a few seconds (FIG. 4b). The microtitre plate 13 raised in this manner and no longer connected to the heating surface 3 can now be removed easily and without application of great force, which again can be effected by a robot arm.

It has been found that it is generally sufficient if the lifting elements together exert a force of about 0.8 N/cm2, preferably 1 N/cm2, on the microtitre plate. Contact pins made of PEEK have proved suitable in that they are thermally stable and do not bake onto microplates of the conventional materials, such as polypropylene, so that the slight frictional lock is sufficient to hold the lifting elements 7 in the blind holes 6.

Apart from the lifting elements 7, the thermocycler can correspond to a known type, e.g. PTC 225 Tetrad from MJ Research, Inc. It is also possible to retrofit known thermocyclers with lifting elements.

Claims

1. A thermocycler having a heating plate which forms a heating surface for holding a microtitre plate whose wells are held in indentations provided in the heating surface, and have a cover which can be lowered and raised relative to the heating surface, said cover serving for pressing the microtitre plate against the heating surface, wherein a plurality of elastically compressible lifting elements for rising and detaching of the microtitre plate from the heating surface are distributed over the heating surface, said lifting elements projecting beyond the edges of the indentations at least when the cover is raised.

2. The thermocycler according to claim 1, wherein the projection of the lifting elements is at least 2 mm, preferably at least 5 mm.

3. The thermocycler according to claim 1, wherein the density of the lifting elements is at least 1 per 30 cm2.

4. The thermocycler according to claim 1, wherein each lifting element is removably fixed to the heating surface.

5. The thermocycler according to claim 1, wherein each lifting element is inserted into a blind hole in the heating surface.

6. The thermocycler according to claim 4, wherein the fixing of the lifting element is effected by frictional locking with the walls of the blind hole.

7. The thermocycler according to claim 1, wherein the lifting element comprises an elongated spring element which is compressible in the longitudinal direction and carries a contact part which forms an abutting surface, oriented transversely to the longitudinal direction, at the upper end of the lifting element.

8. The thermocycler according to claim 7, wherein the contact part consists of plastic, preferably PEEK, PTFE, FP, PPS or PI.

9. The thermocycler according to claim 7, wherein the spring element is in the form of a coil spring and the contact part is in the form of a contact pin which comprises a shaft surrounded by the upper part of the coil spring and a laterally projecting head which rests on the upper end of the coil spring and whose upper surface forms the abutting surface.

10. The thermocycler according to claim 9, wherein the lowermost winding of the coil spring is somewhat wider.

11. The thermocycler according to claim 9, wherein the contact pin is rotationally symmetrical.

12. The thermocycler according to claim 11, wherein both the shaft and the head of the contact pin are essentially cylindrical.

13. The thermocycler according to claim 7, wherein the length of the lifting element is between 15 mm and 20 mm and the diameter of the abutting surface is at least 3 mm.

14. The thermocycler according to claim 7, wherein the spring constant of the lifting element is at least 5 N/mm.

15. A thermocycler comprising:

a heating plate which forms a heating surface for holding a microtitre plate whose wells are held in indentations provided in the heating surface;
a cover which can be lowered and raised relative to the heating surface, said cover serving for pressing the microtitre plate against the heating surface; and
a plurality of elastically compressible lifting elements for rising and detaching of the microtitre plate from the heating surface positioned over the heating surface.

16. The thermocycler according to claim 15, wherein at least a portion of each lifting element is positioned above the edges of the indentations at least when the cover is raised.

17. The thermocycler according to claim 15, wherein said lifting elements are positioned between the heating surface and the microtiter plate at least when the cover is raised.

18. The thermocycler according to claim 15, wherein each lifting element is removably fixed to the heating surface.

19. The thermocycler according to claim 15, wherein each lifting element is inserted into a blind hole in the heating surface.

20. The thermocycler according to claim 18, wherein the fixing of the lifting element is effected by frictional locking with the walls of a blind hole in the heating surface.

21. The thermocycler according to claim 15, wherein at least one of the lifting elements comprises an elongated spring element which is compressible in the longitudinal direction.

22. The thermocycler according to claim 21, wherein the elongated spring element carries a contact part which forms an abutting surface, oriented transversely to the longitudinal direction, at the upper end of the lifting element.

23. The thermocycler according to claim 15, wherein at least one of the lifting elements comprises an elongated spring element in the form of a coil spring which is compressible in the longitudinal direction.

24. The thermocycler according to claim 23, wherein the lowermost winding of the coil spring is wider than the other windings of the coil spring.

25. A thermocycler comprising:

a heating plate which forms a heating surface for holding a microtitre plate whose wells are held in indentations provided in the heating surface;
a cover which can be lowered and raised relative to the heating surface, said cover serving for pressing the microtitre plate against the heating surface; and
a plurality of elastically compressible lifting elements for rising and detaching of the microtitre plate from the heating surface positioned over the heating plate.

26. The thermocycler of claim 25, wherein the lifting elements are positioned over the heating surface of the heating plate.

27. The thermocycler of claim 25, wherein the lifting elements project beyond the edges of the indentations at least when the cover is raised.

28. A thermocycler comprising:

a heating plate which forms a heating surface for holding a microtitre plate whose wells are held in indentations provided in the heating surface;
a cover which can be lowered and raised relative to the heating surface, said cover serving for pressing the microtitre plate against the heating surface; and
a plurality of lifting elements for rising and detaching of the microtitre plate from the heating surface positioned over the heating surface.

29. The thermocycler of claim 28, wherein the lifting elements are elastically compressible.

30. The thermocycler of claim 28, wherein the lifting elements comprise spring elements.

31. The thermocycler of claim 30, wherein the spring elements comprise coil springs.

32. The thermocycler of claim 28, wherein the lifting elements project beyond the edges of the indentations at least when the cover is raised.

33. A thermocycler comprising:

a heating plate which forms a heating surface for holding a microtitre plate whose wells are held in indentations provided in the heating surface;
a cover which can be lowered and raised relative to the heating surface, said cover serving for pressing the microtitre plate against the heating surface; and
at least one elastically compressible lifting element for rising and detaching of the microtitre plate from the heating surface, said lifting element positioned between the heating surface and the microtiter plate at least when the cover is raised.
Referenced Cited
U.S. Patent Documents
3080759 March 1963 McQuaid
3634651 January 1972 Siegel et al.
3933165 January 20, 1976 Budzak et al.
4094641 June 13, 1978 Friswell
4096965 June 27, 1978 Lessnig et al.
4909992 March 20, 1990 Björkman
4948564 August 14, 1990 Root et al.
5030418 July 9, 1991 Miyata
5159197 October 27, 1992 Wannlund
5210015 May 11, 1993 Gelfand et al.
5282543 February 1, 1994 Picozza et al.
5346672 September 13, 1994 Stapleton et al.
5378433 January 3, 1995 Duckett et al.
5459300 October 17, 1995 Kasman
5464541 November 7, 1995 Aysta et al.
5475610 December 12, 1995 Atwood et al.
5538848 July 23, 1996 Livak et al.
5582665 December 10, 1996 Eigen et al.
5602756 February 11, 1997 Atwood et al.
5604130 February 18, 1997 Warner et al.
5616301 April 1, 1997 Moser et al.
5681492 October 28, 1997 Van Praet
5710381 January 20, 1998 Atwood et al.
5721136 February 24, 1998 Finney et al.
5741463 April 21, 1998 Sanadi
5780717 July 14, 1998 Wise et al.
5928907 July 27, 1999 Woudenberg et al.
6015674 January 18, 2000 Woudenberg et al.
6159368 December 12, 2000 Moring et al.
6162400 December 19, 2000 Schembri
6190619 February 20, 2001 Kilcoin et al.
6197572 March 6, 2001 Schneebeli
6251662 June 26, 2001 Day
6272939 August 14, 2001 Frye et al.
6315957 November 13, 2001 Feygin et al.
6406670 June 18, 2002 Earley et al.
6423948 July 23, 2002 Kwasnlski et al.
6514750 February 4, 2003 Bordenkircher et al.
6638761 October 28, 2003 Shin et al.
6719949 April 13, 2004 Barzilai et al.
20020028507 March 7, 2002 Heimberg et al.
Foreign Patent Documents
195 01 298 February 1996 DE
197 39 119 March 1999 DE
19739119 March 1999 DE
0 379 437 July 1990 EP
542422 May 1993 EP
0 542 422 May 1993 EP
0 606 534 July 1994 EP
0 810 030 December 1997 EP
0 810 030 December 1997 EP
0810030 December 1997 EP
0 836 884 April 1998 EP
0 895 240 February 1999 EP
0 955 097 November 1999 EP
1 088 590 April 2001 EP
1 427 034 March 1976 GB
S63-008537 January 1988 JP
H05-501647 April 1993 JP
H06-233670 August 1994 JP
H07-5180 January 1995 JP
2645916 May 1997 JP
2727015 December 1997 JP
H09-325100 December 1997 JP
H10-267933 October 1998 JP
H11-326157 November 1999 JP
2001-149801 June 2001 JP
WO 90/08298 July 1990 WO
WO 91/17239 November 1991 WO
WO 97/36681 October 1997 WO
WO 98/42442 October 1998 WO
WO 98/43740 October 1998 WO
WO 98/56506 December 1998 WO
WO 99/17881 April 1999 WO
WO 99/20395 April 1999 WO
WO 01/28684 April 2001 WO
Other references
  • U. Landegren et al., “A Ligase-Mediated Gene Detection Technique,” Science, 241:1077-80 (Aug. 1988).
  • D. Nickerson et al., “Automated DNA diagnostics using an ELISA-based oligonucleotide ligation assay,” Proc. Natl. Acad. Sci USA, 87:8923-27 (Nov. 1990).
  • D.C. Uber et al., “Application of Robotics and Image Processing to Automated Colony Picking and Arraying,” Bio Techniques, vol. 11, No. 5, 642-44 (1991).
  • Peter Jones et al., “Integration of Image Analysis and Robotics into a Fully Automated Colony Picking and Plate Handling System,” Nucleic Acids Research, vol. 20, No. 17, 4599-4606 (1992).
  • P. Grossman et al., “High-density multiplex detection of nucleic acid sequences: oligonucleotide ligation assay and sequence-coded separation,” Nucl. Acids Res., 22:4527-34 (1994).
  • Co-pending U.S. Appl. No. 09/848,270, Inventors: Frye et al., Filed: May 4, 2001, Title: System and method for filling a substrate with a liquid sample.
  • Co-pending U.S. Appl. No. 09/977,225, Inventors: Freudenthal et al., Filed Oct. 16, 2001, Title: System for filling substrate chambers with liquid.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Notice Declaring Interference,” Paper No. 1, dated Aug. 13, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Interference Initial Memorandum,” attached to Aug. 13, 2003 Notice Declaring Interference (Paper No. 1).
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Shin List of Intended Preliminary Motions Under 37 C.F.R. § 1.633,” dated Sep. 29, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Elsener List of Intended Preliminary Motions,” dated Sep. 29, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Order Setting Times,” Paper No. 18, dated Oct. 2, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Order,” Paper No. 19, dated Oct. 7, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,411, “Summary of Telephone Conference,” Paper No. 22, dated Oct. 28, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Shin Stipulation to Level of Ordinary Skill in the Art,” datead Nov. 14, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Summary of Telephone Conference,” Paper No. 24, dated Nov. 18, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Shin Revised Stipulation to Level of Ordinary Skill in the Art,” dated Nov. 25, 2003.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Senior Party Notification of Change of Ownership of the Elsener Patent and Request for Termination of the Interference Proceedings Under 37 C.F.R. § 1.602,” dated Jun. 10, 2004.
  • Elsener et al. v. Shin et al., Patent Interference No. 105,141, “Judgment—Rule 602,” Paper No. 40, dated Jul. 20, 2004.
  • Opposition to EP 1 088 590 B1 (European Patent Application No. 00 810 855.7), filed Jan. 16, 2003 at European Patent Office, on behalf of AB Applied Biosystems.
  • Opposition to EP 1 088 590 B1 (European Patent Application No. 00 810 855.7), Decision on the Termination of the Opposition Proceedings, issued Jun. 30, 2004, with English translation.
Patent History
Patent number: RE39566
Type: Grant
Filed: Apr 28, 2005
Date of Patent: Apr 17, 2007
Assignee: Applera Corporation (Foster City, CA)
Inventors: Donat Elsener (Thun), Werner Ryser (Huhen), Daniel Ryser (Stafa)
Primary Examiner: Joseph Pelham
Attorney: Finnegan Henderson Farabow Garrett & Dunner, L.L.P.
Application Number: 11/116,441