Synthon BV v Smithkline Beecham Plc (No.2)

I have had the privilege of reading in draft the opinion of my noble and learned friend Lord Hoffmann. I am in full agreement with it and would, for the reasons he gives, allow the appeal and restore the decision of Jacob J.

The invention

Paroxetine is a compound used to treat depression and related disorders. It has for some time been marketed in the form of its hydrochloride hemihydrate salt under the name Paxil or Seroxat. These proceedings arise out of the more or less simultaneous discovery in about 1997 by the appellants Synthon BV, a Dutch pharmaceutical company, and the respondents, Smithkline Beecham plc ("SB"), a UK pharmaceutical company, that a different paroxetine salt, paroxetine methanesulfonate ("PMS"), has properties which make it more suitable for pharmaceutical use. It is more stable, less hygroscopic and much more soluble, so that it can be prepared in higher concentrations.

The Synthon disclosure

On 10 June 1997 Synthon filed an international application under the Patent Cooperation Treaty for a patent which claimed a broad class of sulfonic acid salts including PMS. This was published on 17 December 1998. The specification said that a known useful salt of paroxetine was the hydrochloride in various forms but that each of them had, to a greater or lesser extent, disadvantages for safe handling and formulation. The object of the invention was to provide a compound with improved characteristics. It then set out, by reference to a formula with a number of variables, a class of compounds which were said to exhibit good stability and high solubility. These included PMS.

The specification, as is customary in patents for chemical compounds, then narrowed its focus to a preferred group within the class which was said to exhibit a very high degree of solubility and then, by way of illustration, to a particular compound in that group. That compound was PMS, which features in the first example of the preparation of a salt of paroxetine suitable for pharmaceutical use. Under the heading "Example 1", the specification describes how to make PMS in crystalline form.

The notion of crystalline form may require some explanation. The same substance may exist in different solid forms, depending upon the arrangement of its molecules. In crystalline form the molecules arrange themselves in an organised pattern called a lattice which gives the crystal a distinctive shape. On the other hand, in an amorphous form or an oil, the molecules are randomly distributed and the substance has no particular shape. Some substances have only one crystalline form. They are called monomorphic. But others have a variety of patterns into which the molecules may arrange themselves. They are polymorphic. Different crystalline forms can be distinguished by a number of conventional tests. Infra-red radiation (IR) will result in a spectrum of readings of absorbance which are characteristic of that particular crystal. X-ray diffraction (XRD) will likewise give a characteristic series of readings. The IR and XRD readings are the crystal's fingerprint. Some compounds form one or more types of crystals which include, as part of their crystalline structure, molecules of the solvent from which the crystal has been precipitated. They are called solvates or, if the solvent is water, hydrates.

Example 1 teaches how to make PMS from a solution of paroxetine, prepared in accordance with a procedure disclosed in a previous US patent, by adding methane sulphonic acid. This is the standard method of producing a salt by adding an acid to a base. In the example, crystallisation is obtained by the use of a seeding crystal which induces precipitation of crystals from the solution. This is said to produce a 99.5% yield of crystals having a 98% purity. The characteristics of the crystals are described in Table 1, giving their melting point (142° to 144°C), DSC (differential scanning calorimetry) curve, IR spectrum and NMR (nuclear magnetic resonance) readings which map the hydrogen and carbon atoms in the structure of the crystal. A note after Table 1 draws attention to the fact that "the compounds of the invention are crystalline, with defined melting points, DSC curves and IR spectra" but that they may be polymorphic and exist in other crystalline forms. The crystals of the acid addition salts with organic sulphonic acids, like PMS, are "substantially free of bound organic solvents", that is to say, they are not solvates, but some "may contain crystallisation water and also unbound water, that is to say water which is other than water of crystallisation." The particular example in Table 1, however, is said to be a crystal of 98% purity and therefore not a hydrate.

Example 1, as I have said, requires a seeding crystal to start the process of crystallisation and is preceded by a description of how such a seeding crystal had been obtained. It involved dissolving paroxetine in hot ethanol, adding methanesulfonic acid, cooling and then freezing the mixture and evaporating it to reduce it to an oil. After being left for a month, a waxy solid was obtained, part of which was dissolved in EtOAc and the rest used to precipitate crystals from the solution in a freezer.

The SB patent

After Synthon had filed its application but before it was published, SB filed a document dated 6 October 1998 which gave it priority for a UK patent application filed on 23 April 1999. The patent was published on 10 May 2000 as UK Patent No 2 336 364. SB, like Synthon, appears at first to have thought that PMS was a novel compound. The SB specification began by saying that it had been surprisingly discovered. The title of the patent is "Paroxetine Salt". But during the course of prosecution, it appeared that there was prior art in which PMS had been identified as one of many paroxetine salts suitable for a method of treatment patented in the United States. SB therefore confined its claim to a particular form of crystalline PMS. It is described in claim 1, upon which other claims are dependent:

"Paroxetine methanesulfonate in crystalline form having inter alia the following characteristic IR peaks: 1603, 1513, 1194, 1045, 946, 830, 776, 601, 554, and 539 ± 4cm ^-1.; and/or the following characteristic XRD peaks: 8.3, 10.5, 15.6, 16.3, 17.7, 18.2, 19.8, 20.4, 21.5, 22.0, 22.4, 23.8, 24.4, 25.0, 25.3, 25.8, 26.6, 30.0, 30.2, and 31.6 ± 0.2 degrees 2 theta."

It will be seen that the claim identified a particular crystalline form by reference to its IR and XRD peaks. If, as the specification said was possible, PMS turned out to be polymorphic, no other forms of crystal were claimed. And it is of particular importance to notice that the IR peaks in claim 1 are different from those in Table 1 of the Synthon application. A person skilled in the art, reading both documents, would think that they identified different polymorphs.

Although the specification does not spell out the advantages of PMS or sulfonate salts in general in the way that the Synthon application does, the specification makes it clear that the inventive step was the discovery of the sulfonate salt of paroxetine as an alterative to the hydrochloride salt.

The specification suggests a variety of solvents which may be used for dissolving paroxetine before mixing it with commercially available methanesulfonic acid and goes on to say that "the salt may be isolated in solid form by conventional means from a solution thereof obtained as above." Examples of non-crystalline and crystalline solids are given. As for the crystalline form, the specification says:

"A crystalline salt may be prepared by various methods such as directly crystallising the material from a solvent in which the product has limited solubility or by triturating for example with ethers such as diethyl ether or otherwise crystallising a non-crystalline salt. A number of solvents may be used for the crystallisation process including those that are useful industrially; eg paroxetine methanesulfonate may be crystallised from a relatively crude feedstock such as is commonly produced during the final stage of the chemical synthesis of paroxetine."

A number of other alternative methods are then given over the following pages. But there is no suggestion that any of them involved an inventive step. They are all described as involving commonly used solvents and conventional methods (eg "vigorous stirring is particularly useful").

The proceedings

On 7 March 2001 Synthon commenced proceedings to have the SB patent revoked on the ground that the crystalline form of PMS described in claim 1 was not new.Section 1(1)(a) of the Patents Act 1977 provides that a patent may be granted only for an invention which is new.Section 2(1) provides that an invention shall be taken to be new if it does not form part of the state of the art.Section 2(2) and (3) define the state of the art:

"(2) The state of the art in the case of an invention shall be taken to comprise all matter (whether a product, a process, information about either, or anything else) which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way.

(3) The state of the art in the case of an invention to which an application for a...