COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION (PATENTS COURT)
The Hon Mr Justice Pumfrey
HC 06 C03050
Strand, London, WC2A 2LL
B e f o r e :
LORD JUSTICE JACOB
LORD JUSTICE LLOYD
| Les Laboratoires Servier
Servier Laboratories Limited
|- and -
Apotex Pharmachem Inc
Apotex Europe Limited
Apotex UK Limited
for the Claimants/Appellants
Antony Watson QC and Colin Birss (instructed by Messrs Taylor Wessing)
for the Defendants/Respondents
Hearing date: 28 April 2008
Crown Copyright ©
Lord Justice Jacob (giving the first judgment at the invitation of the Lord Chief Justice):
Professor Motherwell [Servier's expert] accepted that it seems that form a is the stable form of perindopril and, absent special circumstances, it follows that any process for producing perindopril from ethyl acetate will produce this form in the absence of impurities. The ß form, identified in the patent to which I have referred, is not stable and is created by special crystallisation techniques. Professor Motherwell said that eventually it reverts to the a form. The ? form is not produced by recrystallisation from ethyl acetate and is accordingly irrelevant.
"Place in reactor approximately 140 litres of ethyl acetate and 10kg [of the acid]. Add gradually approximately 2.20 kg of ter-butylamine, heat to reflux until all has dissolved; filter. Cool, filter off and dry. Yield 95%"
It does not say anything about the nature of the crystallisation which takes place during cooling, or indeed explicitly that the product is crystalline at all. But no one disputes that you will get crystals there is no suggestion that the salt has an amorphous form.
Q. When you talk about commercial batches, you are including the post 2000 method as well?[clarification from the judge]
A. In as much as they all cool, filter and dry, they are all the same (inaudible). Generally speaking, I observed linear cooling regimes both in Apotex and in Servier. The degree may have changed. I think later on, if I remember correctly, it may have been slightly more rapid, but that may not be true.
Q. But taking all the regimes, both pre 2000 and post 2000, they are all obvious ways of implementing the instruction, cool, filter and dry?
A. In the most general terms, yes. It is not as sophisticated as 947 [the Patent] but
Q. Now, we saw that dropping from 76 to 55 there was a range of 1:4, one hour or four hours. Are you suggesting that there is anything unusual in adopting a linear cooling regime where you drop the temperature from, say, 76 to 55 in a range of between one and four?
A In general terms I agree with Dr Spargo that two hours is typical.
Professor Motherwell accepted that Servier's cooling regime, at least so far as that is described in the evidence, is an obvious implementation of 341
"a crystalline form of [the tert-butylamine salt of perindopil] characterised by the following powder X-ray diffraction diagram measured [details specified]"
The "diagram" (more accurately it is a table) sets out a range of angle 2? values (from "7.680o" to 29.213o") 25 results for the inter-planar distance, intensity and relative intensity. The table is the same as that set out in the body of the specification.
"A comparison of the results obtained for Experiments 2 and 4 of the Notice with the 25 peaks claimed in the Patent shows that most of the peaks, including the major peak at 9 degrees 2?, occur at identical angles. Only 3 of the peaks show a noticeable shift from the peaks claimed in the Patent and the other Experiments. This is the kind of result that might be expected from a slight distortion of the crystal structure"
"As a crystallographer, I would not say that they were a different form but that they are a distorted form of that produced in Experiments 1, 2 and 4 of the Repeats."
"Given all of the above, in my opinion, the results of the Notice and Repeats all show the alpha crystalline form (both distorted and undistorted)"
Lord Justice Lloyd:
The Lord Chief Justice of England and Wales: