The use of solid supports in the synthesis, in parallel array or combinatorial techniques, of compounds such as peptides and a wide range of other types of chemical compounds is well-known. A widely used device for use in combinatorial techniques is sold by IRORI and is known as a MICROKAN (Trade Mark). It comprises a porous plastics tube containing solid support resin which supports chemicals being synthesised. Further details may be found in W096/36436 (Irori) especially Figure 14 thereof.

Another known device, described in WO 00/21658 (Cambridge Discovery Chemistry Limited), comprises a porous device made by sintering a carrier and a solid support resin.

In use, the MICROKANs and porous devices described are used to prepare multiple different compounds on the solid supports in combinatorial techniques. After the compounds have been prepared, they must be cleaved from the solid supports and isolated. Since there may be hundreds of different compounds prepared in separate MICROKANS and porous devices in a combinatorial technique, it will be appreciated that the cleavage and isolation step could be very time-consuming. This problem has been addressed by the provision of an apparatus comprising individual filter tubes, one for each compound to be isolated from

respective solid supports. In use, a MICROKAN is dropped into the tube so that it rests on the bottom thereof; a cleavage solution is delivered to the tube; the compound is thereby cleaved from the solid support; and then the compound is isolated.

However, disadvantageously, the apparatus described has a large footprint and is expensive due to its sophisticated nature. Accordingly, it is not practical to use the apparatus in many situations.

It is an object of the present invention to address problems associated with known cleavage apparatus.

According to a first aspect of the invention, there is provided a method of cleaving materials from a plurality of solid supports, the method using a cleavage apparatus which includes a plurality of cleavage receptacles, the method comprising: (a) arranging said solid supports at predetermined positions in respective cleavage receptacles; (b) contacting said solid supports with a cleavage formulation thereby to cleave materials from the solid supports; and (c) separating the solid supports from materials cleaved therefrom.

Said receptacles preferably have closed lower ends and said solid supports are preferably arranged so that they are spaced from said lower ends. A (suitably each) said solid support is preferably spaced from a said lower end of a said receptacle in which it is arranged by a distance

which is greater than the maximum diameter of said receptacle. Said solid support is suitably spaced by a distance of at least 5mm, preferably at least 10mm, more preferably at least 15mm, especially at least 20mm from said lower end. Said lower end of said receptacle preferably includes a convex surface or a surface which tapers inwardly towards a point on moving to its lowermost point.

Said solid supports preferably represent parts of respective solid support devices. Said solid support devices are preferably arranged at predetermined positions in the cleavage receptacles in the method, thereby to arrange said solid supports at predetermined positions therein. Said solid support devices are preferably arranged so that they are spaced from lower ends of the receptacles. The spacing of the solid support devices from the respective lower ends of said receptacles may be as described above for the spacing of said solid supports from said lower ends. Preferably, each solid support device is arranged so that it abuts a respective support surface associated with each respective receptacle.

Preferably, for a, preferably each, solid support device, the entire area of outer downwardly facing surfaces of the solid support device does not abut support surfaces associated with each receptacle. (For the avoidance of doubt, downwardly facing surfaces refer to surfaces which extend at an angle of greater than 90° and up to 180° to the horizontal). Preferably, for each solid support device, the ratio of the area of downwardly facing surface (s) which abut (s) support surface (s) associated with a receptacle to the total area of outer downwardly

facing surface (s) of the device is less than 0.8, preferably less than 0.7, more preferably less than 0.6.

Preferably, each said solid support device includes a central area which comprise an outer downwardly facing surface and an area enclosing the central area, wherein the central area does not abut a support surface associated with the receptacle in which it is arranged, but, suitably, at least a part of the area enclosing the central area abuts a support surface associated with the receptacle.

Said solid support devices may rest upon respective support surfaces. Preferably, a said support surface comprises a ledge on which a support device is seated.

Said ledge may include diametrically spaced apart ledge portions. Said ledge portions are preferably arcuate.

Between said ledge portions a vent opening may be defined for allowing air displacement from the receptacle in use.

A said support surface (e. g. ledge) (preferably each support surface on which solid support devices may rest) is suitably spaced from a lower end of a respective receptacle by a distance of at least 5mm, preferably at least 10mm, more preferably at least 15mm, especially at least 20mm.

Said solid support devices preferably include a stepped arrangement thereby enabling them to be easily seated on support surfaces, for example on said ledges of said receptacles. Said solid support devices preferably include a first part of relatively wide diameter and a second part of relatively narrow diameter. Preferably,

said first part is of substantially circular cross- section. Preferably, said second part is of substantially circular cross-section. Preferably, a seat is defined between said first and second parts. Preferably, said solid supports are arranged in said receptacles by abutting said seats of the support devices and said support surfaces, for example said ledges, of said receptacles. Preferably, said solid support devices are arranged in said receptacles with at least part of the second parts of the support devices extending below the support surfaces (e. g. ledges) which support the devices.

A said solid support device (preferably each device) is preferably arranged in a respective cleavage receptacle so that a radially outwardly facing wall at the uppermost end of the device is spaced a distance measured radially of less than 10mm, preferably of less than 5mm, more preferably of less than 2mm, especially of less than lmm from an adjacent axially extending wall of the receptacle.

Said solid supports are preferably suspended in said respective cleavage receptacles.

Said solid support devices are preferably substantially identical to one another in their external physical size and shape. Internally, the support devices may differ in incorporating solid supports comprising different chemical compounds and any identifier for uniquely identifying the support devices one from the other will of course differ.

The solid supports and more particularly the solid support devices described may be as disclosed in W096/36436 or in WOOO/21658.

It will be appreciated that the solid supports suitably comprise a resin or other material which is arranged to support materials, for example chemical compounds prepared in solid supported syntheses. The resin (or other material) is preferably encapsulated to retain it in position. Preferably, said solid support devices include permeable walls (for example walls may be perforated) for passage of cleavage formulation into the devices thereby to contact said solid supports for cleaving materials therefrom. The solid supports together preferably support a library of materials, for example chemical compounds, prepared in a combinatorial (or similar) preparatory technique.

A first cleavage receptacle of the cleavage apparatus may be spaced a distance of less than 10mm, preferably less than 5mm, from an adjacent second cleavage receptacle.

Elongate axes of the first and second receptacles preferably extend parallel to one another and centres of said first and second receptacles which are coincident with said respective elongate axes are preferably spaced apart by a distances of less than 20mm, preferably less than 15mm, more preferably less than 12mm, especially by lamm.

Said cleavage apparatus may include at least 10, preferably at least 25, more preferably at least 40, especially at least 75 cleavage receptacles. In an especially preferred embodiment, said cleavage apparatus includes 96 cleavage receptacles preferably arranged in a 12 x 8 array.

Each cleavage receptacle of said cleavage apparatus preferably occupies a predetermined and/or fixed position relative to each other receptacle of the apparatus. Said cleavage receptacles are preferably unitary parts of the apparatus. Preferably, each receptacle is immovably fixed in position relative to each other receptacle.

Preferably, the method involves arranging respective solid supports in each cleavage receptacle of the cleavage apparatus.

Said cleavage formulation used in step (b) of said method may be any conventional cleavage formulation used to cleave materials, for example chemical compounds, from solid supports. Said formulation may comprise a single chemical or a mixture. It is suitably a fluid, especially a liquid.

Preferably, in step (b), a respective sample of cleavage formulation is introduced into each cleavage receptacle.

Preferably, each cleavage receptacle is filled with cleavage formulation to a level above the uppermost level of the solid supports in the receptacles. Thus, preferably the entirety of each solid support is immersed in cleavage formulation. After a period of time, materials will be cleaved from the solid supports and will be dispersed in the cleavage formulation. Preferably, in a subsequent step, the cleavage formulation is separated from materials cleaved. Any suitable separation technique may be used. A preferred technique involves evaporation of the cleavage formulation. The cleavage receptacles may be subjected to a centrifugal force, preferably during

evaporation. A centrifugal evaporator may be used to separate the cleavage formulation from materials cleaved.

After removal of cleavage formulation, materials cleaved will suitably be positioned at lower ends of the receptacles. The solid supports may be removed from the receptacles by suitable means. For example, in some cases where materials cleaved are fixed within the receptacles (eg by being compressed in the bottom thereof) it may be possible simply to invert the cleavage apparatus to cause the solid supports to fall from the apparatus without losing any of the materials cleaved. Lower ends of the receptacles preferably taper to a point. This may aid the compression of the materials in the bottom of the receptacles. In other cases, for example where materials cleaved are liquids, the solid supports may be lifted from the apparatus either by hand or using a robot.

Materials cleaved may be removed from the receptacles by suitable means as and when required.

The cleavage receptacles are preferably defined in a material which is not reactive with the cleavage formulation or materials cleaved from the solid supports.

The material may be a plastics material (e. g. polypropylene), metal or glass.

According to a second aspect of the invention, there is provided an assembly comprising a cleavage apparatus which includes a plurality of cleavage receptacles and solid supports arranged at predetermined positions in respective said cleavage receptacles.

Said solid supports preferably support materials, for example chemical compounds, which suitably can be cleaved therefrom using a cleavage formulation. Said cleavage receptacles may contain a said cleavage formulation which is suitably a liquid. Said solid supports preferably support material of different types. Preferably, materials supported may define a library of materials which has preferably been prepared by a combinatorial (or similar) technique.

Said assembly of the second aspect may have any feature of the apparatus described according to said first aspect.

According to a third aspect of the invention, there is provided a cleavage apparatus for use in a method of cleaving materials from a plurality of solid supports, the apparatus comprising a plurality of cleavage receptacles and means for arranging said solid supports at predetermined positions in the cleavage receptacles so that said solid supports can be immersed in a cleavage formulation contained within the receptacles.

Said cleavage receptacles preferably include support surfaces, for example ledges, between the upper and lower ends for arranging said solid supports in said predetermined positions. Lowermost parts of said support surfaces are preferably spaced from lower ends of the receptacles by a distance of at least 5mm and, preferably, less than 50mm, more preferably less than 40mm. Said cleavage receptacles suitably have a length of at least 30mm, preferably at least 40mm. The length is preferably less than 200mm, more preferably less than 100mm, especially less than 75mm. Adjacent receptacles are

preferably spaced apart by a distance of less than lOmm, preferably less than 5mm, more preferably less than 2mm.

Said cleavage receptacles are preferably arranged in an array, suitably a two dimensional array, having 3 to 14 receptacles in a first row and 6 to 18 receptacles in a second row perpendicular to said first row. The array preferably includes 3 to 14 multiplied by 6 to 18 receptacles, more preferably 8 x 12 (= 96) receptacles.

Said cleavage apparatus of the third aspect may have any feature of the cleavage apparatus of the first and/or second aspects.

According to a fourth aspect of the invention, there is provided the use of an assembly according to the second aspect or an apparatus according to said third aspect for cleaving materials from a plurality of solid supports.

Any feature of any aspect of any invention or embodiment described herein may be combined with any feature of any aspect of any other invention or embodiment described herein mutatis mutandis.

Specific embodiments of the invention will now be described, by way of example, with reference to the accompanying diagrammatic drawings, in which: Figure 1 is a top plan view of a cleavage block ; Figure 2 is a cross-section along line II-II of Figure 1 but showing a single MICROKAN in position;

Figure 3 is an enlarged view of the region within boundary III of figure 2; and Figure 4 is an enlarged view of parts of the block of Figure 1 showing a detailed top plan view of a receptacle.

The cleavage block 2 comprises a substantially rectangular solid metal block in which ninety-six elongate receptacles 4 are defined in parallel straight rows. Each receptacle has a lower region 6 (Figure 3) of relatively narrow diameter and an upper region 8 of wider diameter so that an annular ledge 10 is defined between the two regions.

End 12 of each lower region tapers to a point.

Diametrically spaced apart arcuate section channels 14 are defined in walls 16 of the receptacles and in material of the block 2 surrounding the receptacles (Although only one receptacle is shown to have channels, it should be appreciated that each receptacle includes channels in suitable positions). Respective openings 14 extend from upper ends 18 of the receptacles and through ledges 10 and are arranged to allow air displacement from the receptacles as they are being filled with fluid, in use.

The respective diameters of each upper part 8 and lower part 6 of the receptacles are 9 mm and 7.5 mm respectively and the centres of the receptacles are spaced apart by 10mm. The depth of each upper part 8 is 22 mm and the total length of each receptacle is 55 mm. Each channel 14 extends a distance of 30 mm from upper end 18.

The receptacles are arranged to accommodate devices used in combinatorial chemistry techniques, for example MICROKANs or the sintered devices described in the

introduction of this specification. In the figures, a MICROKAN 20 is shown. It comprises a plastics hollow body which includes an upper wider diameter region 22 (figure 3) and a lower narrower diameter region 24, there being an annular seat 23 defined between the upper and lower regions. The lower region 24 accommodates a radio- frequency tag carrying a identifer which enables each MICROKAN to be uniquely identified. The upper region 22 include a hollow region in which a solid support resin (supporting a chemical compound) is positioned and perforated side walls which are arranged to allow the passage of fluid into the upper region to contact the solid support resin therewithin.

As shown in Figure 3, the MICROKAN 20 fits snugly within the receptacle 4 with its annular seat 23 resting upon ledge 10. For regions of the MICROKANS 20 which rest on ledges 10, there is a relatively narrow gap (or substantially no gap) between the outer wall of the wider diameter region 22 and the adjacent material of the block 2. However, for regions of the MICROKANS 20 which are adjacent channels 14, there will be a significant gap between the outer wall of the MICROKAN and the adjacent material of the block 2.

In use, solid supported chemical compounds are prepared in MICROKANs by conventional techniques. Apparatus including the cleavage block 2 is then used to cleave the chemical compounds from solid support resin arranged within the MICROKANs to isolate the compounds. To this end, ninety- six MICROKANs are inserted into respective receptacles 4 in the block 2, either manually or using a robot. The MICROKANs are seated as shown in Figure 3. Then the

receptacles are filled with cleavage formulation. During the filling process air is displaced from the receptacles via the channels 14. The cleavage formulation is arranged to cleave the chemical compounds, from the solid support material on which such compounds were constructed. The cleavage formulation fully immerses the MICROKANs, and penetrates into the hollow region thereof to contact the solid support material. The cleavage block could be agitated or placed in a heated environment to aid the cleavage.

After cleavage formulation has been in contact with the solid support materials for sufficient time to cleave the chemical compounds, the receptacles 4 in the block are subjected to centrifugal evaporation thereby to remove the cleavage formulation and leave behind the (usually solid) chemical compounds cleaved in the receptacles. It is found in practice that the chemical compounds generally become"welded"to the bottom of the receptacles, thereby allowing the MICROKANs to be removed with ease from the receptacles simply by inverting the cleavage block so the MICROKANs fall out. Alternatively, if chemical compounds in the receptacles may be liable to fall out of the receptacles upon inversion (e. g. if some of the compounds are oils) then the MICROKANs may be removed by a robot or by the use of tweezers.

Advantageously the cleavage block described can be used with conventional microtiter plates and other apparatus and robots used in combinatorial chemistry since its footprint is the same as that of a microtiter plate and since it is based on a 12 x 8 array of receptacles. Thus, not only is the block relatively cheap to produce but it

requires insignificant new ancilliary equipment (over and above that conventionally available in combinatorial chemistry) to enable it to be used.

The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive.

Each feature disclosed in this specification (including any accompanying claims, abstract and drawings), may be replaced by alternative features serving the same, equivalent or similar purpose, unless expressly stated otherwise. Thus, unless expressly stated otherwise, each feature disclosed is one example only of a generic series of equivalent or similar features.

The invention is not restricted to the details of the foregoing embodiment (s). The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.