Laboratoires Servier v Apotex Inc.
| Jurisdiction | England & Wales |
| Judge | THE HONOURABLE MR JUSTICE PUMFREY |
| Judgment Date | 11 July 2007 |
| Neutral Citation | [2007] EWHC 591 (Pat),[2007] EWHC 1538 (Pat),[2009] EWHC 3289 (Pat),[2006] EWHC 3443 (Pat),[2006] EWHC 2137 (Pat) |
| Court | Chancery Division (Patents Court) |
| Date | 11 July 2007 |
| Docket Number | Case No: HC06C03050 |
[2007] EWHC 1538 (Pat)
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice
Strand, London, WC2A 2LL
The Honourable Mr Justice Pumfrey
Case No: HC06C03050
Iain Purvis QC and Andrew Lykiardopoulos (instructed by Bristows) for the Claimants
Antony Watson QC and Colin Birss (instructed by Taylor Wessing) for the Defendants
Hearing dates: 13 th March – 20 th March 2007
Approved Judgment
I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this Judgment and that copies of this version as handed down may be treated as authentic.
Mr Justice Pumfrey:
This is an action for infringement of EP (UK) 1 296 947. The claimants are, respectively, the proprietor and an exclusive licensee under the patent in suit. It is not necessary to distinguish between them and I shall refer to them together as “Servier”. The defendants are members of a Canadian group of companies widely concerned in the manufacture of generic pharmaceuticals, and I shall refer to them collectively as “Apotex”. Apotex challenges the validity of the patent in suit. Servier seeks to amend the specification and claims in a manner I shall describe in more detail below.
The language of the specification of the patent is French, and the filed translation was, by agreement, taken to be definitive. The invention is entitled a “New a crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it”. Perindopril is an ACE inhibitor used in the treatment of hypertension. The patent in suit claims priority (which is not disputed) from a French application made on 6 th July 2000. The original patent for the compound itself was filed with the EPO on 29 th September 1981, claiming priority from 2 nd October 1980. The first marketing authorisation was granted in France in June 1988 and the supplementary protection certificate for the UK was applied for on 30 th June 1993 and expired on 21 st June 2003.
The other relevant protection for this compound is EP 0 308 341 in respect of “the industrial synthesis of perindopril” which was filed with the EPO on 16 th September 1988, claiming priority from a French application of 17 th September 1987. This patent will (if still in force) expire on 16 th September 2008.
The patent is a valuable one: Servier's turnover in the United Kingdom is about £70m, and Apotex sold perindopril having a value of £4m in the short period before Mann J granted an interlocutory injunction restraining further importation, which remains in force. A number of generic companies have interested themselves in perindopril, and two others, known in these proceedings as Krka and Lupin, have both settled with Servier.
The Patent
The patent is a very brief document. It opens with a statement that the present invention relates to a new a crystalline form of perindopril tert-butylamine salt, setting out the structural chemical formula upon which nothing turns. A brief passage (page 1 line 5ff of the translation) describes the valuable pharmacological properties of perindopril, as to which there is no dispute. Then at line 15, the following passage appears:
“In view of the pharmaceutical value of this compound, it has been of prime importance to obtain it with excellent purity. It has also been important to be able to synthesise it by means of a process that can readily be converted to the industrial scale, especially in a form that allows rapid filtration and drying. Finally, that form had to be perfectly reproducible, easily formulated and sufficiently stable to allow its storage for long periods without particular requirements for temperature, light, humidity or oxygen level.
The patent specification EP 0 308 341 describes an industrial synthesis process for perindopril. However, that document does not specify the conditions for obtaining perindopril in a form that exhibits those characteristics in a reproducible manner.
The Applicant has now found that a particular salt of perindopril, the tert-butylamine salt, can be obtained in a well defined, perfectly reproducible crystalline form that especially exhibits valuable characteristics of filtration, drying and ease of formulation.”
Curiously, on the same day as the application in suit was filed, Servier filed two other patent applications: number EP 1 294 689 in respect of the ß crystalline form of the tert-butylamine salt of perindopril, and number EP 1 296 948 in respect of the ? crystalline form of the tert-butylamine salt of perindopril. It is not, as I understand it, suggested that there are any other crystalline forms of this salt, and the same passage as that quoted above appears also in the other two patents.
More surprising still is that patent EP 0 308 341 is said to be in respect of a process for the industrial synthesis of the tert-butylamine salt of perindopril which is, as I understand it, the only salt of perindopril hitherto used. The principal point of interest about the synthesis described in 341 is that the crystalline form of perindopril is obtained in stage 3D of the process (the final step) as follows:
“Place in a reactor approximately 140 litres of ethyl acetate and 10 kg of [material obtained previously]. Add gradually approximately 2.20 kg- of tert-butylamine, heat to reflux until all has dissolved; filter. Cool, filter off and dry. Yield: 95%.”
It is this passage to which the specification in suit is referring when it says that 341 does not specify the conditions for obtaining perindopril in a form that exhibits the characteristics set out in paragraph 5 in a reproducible manner, and, indeed, detailed conditions for the crystallisation of the salt are not stated.
The directions contained in the specification for obtaining the a crystalline form are described generally (page 3 lines 1–4) as heating the tert-butylamine salt in ethyl acetate at reflux and then “cool[ing] gradually until crystallisation is complete”. A number of bullet points on page 3 of the translation give additional instruction as to concentrations and rates of cooling. Thus, at lines 9–10, it is suggested that the concentration of the tert-butylamine salt in ethyl acetate is preferably from 70–90 grams per litre – the concentration specified in 341 falls within this range (87 g/litre). Secondly, it is stated that it is advantageous to carry out the cooling in two stages, first from reflux to between 55°C and 65°C at a rate of from 5 to 10°C/hour, preferably from 6 to 8°C/hour, and then to ambient temperature. It is also suggested that it is advantageous to seed during the cooling step.
It is said that the resulting product is in the form of individual needles about 0.2mm long, permitting rapid and efficient filtration and drying.
The use of a terminology such as 'a form' is merely a matter of convenience. The only published characterising information relating to the a form of perindopril is this patent specification: at the priority date and at the publication date this was, on the evidence, just a new name for a crystalline form of perindopril. Such terminology is commonplace, but should not be taken in this context to refer to anything previously identified.
The manner in which the a crystalline form of perindopril tert-butylamine salt is characterised is by means of a powder X-ray diffraction profile. During the proceedings, this was referred to variously as the spectrum or pattern produced by XRPD or PXRD. In the body of the specification, the stated spectrum is described as having been obtained on a particular diffractometer, and full experimental details are given. Generally speaking, powder X-ray diffraction is a technique employed for the purpose of elucidating the different inter-planar distances between parallel planes in which the atoms of a crystalline material are located. There are many such planes even in a simple crystal, and the powder X-ray diffraction pattern provides a series of inter-planar distances which are determined by the actual structure of the crystal. The technique does not describe the actual crystal structure, for which a single crystal is required. The technique is extremely widely used, a database being maintained by international cooperation containing over half a million reference materials. The technique yields a spectrum which has two essential characteristics: a diffraction angle (conventionally expressed as 2?) and the relative intensity of the peaks. If plotted out on a piece of paper, it shows peaks and troughs: here is an example:
Computer software is used to identify the position of the peaks and to compare the relative intensities of the diffracted beams. Such software identified the peaks in the example above and labelled each of them with their respective angle 2?. This is not, as I understand it, a process reliably performed by computer alone. Dr Tarling, who gave evidence for Servier, said that when the computer program has done its work, the peaks that it selects must be reviewed by a technician to ensure that they accurately reflect the data. The technician will have in mind the conditions under which the analysis has been performed. Matters of particular concern are overlapping peaks, peaks entirely lost underneath others, and peaks that have been smoothed out by averaging routines within the computer program or which have been obscured by noise suppression techniques. So there is a degree of subjective assessment in any XRPD analysis.
The claim contains a tabulated version of the form a XRPD spectrum.
No continuous spectrum is shown, and would, no doubt, give rise to...
To continue reading
Request your trial
-
The Secretary of State for Health v Servier Laboratories Ltd
...the patent was held to be invalid by Pumfrey J since it lacked novelty, or alternatively was obvious over another existing patent ( [2007] EWHC 1538 (Pat)). That decision was upheld in the Court of Appeal in May 2008 ( [2008] EWCA Civ 445). In 2009 the EPO Technical Board of Appeal revoke......
-
Les Laboratoires Servier v Apotex Inc.
...on 7 August 2006, Mann J granted an interim injunction until trial for the reasons given in his judgment dated 8 August 2006 ([2006] EWHC 2137 (Pat)). In his judgment he considering the adequacy of damages for each side at [20]-[23]. He summarised Apotex's case on this question at [20] and ......
-
The Secretary of State for Health and Others v Servier Laboratories Ltd and Others
...patent 947 was issued by Lupin; (g) 21 December 2006, being the date when Pumfrey J handed down a judgment in the Apotex proceedings ( [2006] EWHC 3443) in which he stated that there was a counterclaim alleging invalidity of patent 947; (h) 2 February 2007, being the date when D1 and D3 mad......
-
Les Laboratoires Servier v Apotex Inc.
...On 8 August 2006 he continued the interim injunction until trial. In paragraphs [20] to [23] of his judgment on 8 August 2006 ( [2006] EWHC 2137 (Pat)) he considered the adequacy of damages for each side. He recorded (at paragraph [22]) Servier's submission that "Apotex would be adequately......