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Wednesday, 18 November 2009

Leo v Sandoz - follow the instructions or lose the case

According to UK and European patent law, an invention in a patent claim is not new if what is claimed has been made available to the public before the priority date of the application. There may, for example, be a clear statement in a prior published document that describes a chemical compound and how to make it, which would make a claim to that particular compound not novel. If, however, there is some doubt about whether the actual form of compound claimed would result from the described process, it needs to be determined whether following the process would inevitably arrive at the claimed compound.

This was the situation in Leo Pharma v Sandoz EWCA Civ 1188, which was decided by Lords Justice Jacob and Patten yesterday (17 November), on appeal from Floyd J's decision in the High Court earlier this year ([2009] EWHC 996 (Pat)). The case related to the chemical compound calcipotriol, a vitamin D analogue used for the treatment of skin conditions. Sandoz had been attempting to invalidate Leo's patent EP0679154 for calcipotriol monohydrate, which the patent claimed was "a new crystalline form of calcipotriol - with superior technical properties e.g. in the manufacture of crystal suspension formulations, and with superior stability properties". Whether these particular advantages were true or not was not in issue. What was in issue (among other things) was whether this crystalline form would be the inevitable result of following the instructions for making calcipotriol found in a previously published document, WO8700834.

Sandoz's task seemed therefore to be straightforward (at least to this untrained Kat): simply follow the instructions in the document and show that calcipotriol monohydrate would result. Unfortunately, this is not what Sandoz did. Instead of using the starting materials that were specified in the document, Sandoz used a material supplied by Teva that was developed only after the document was published, and instead of ensuring a seed-free environment Sandoz seeded the reaction with monohydrate crystals. These differences were sufficient to at least sow some seeds of doubt as to whether, if the instructions had been followed to the letter, the claimed compound would actually result.

Although Sandoz bravely argued that the changes would not make any difference because monohydrate crystals would be produced anyway, the judge at first instance was not convinced and found that the claimed invention was not anticipated. As only points of law were on the table for discussion at the court of appeal, Sandoz were unable to get any new decision on the facts, and failed to persuade the appeal judges that Floyd J had made any error in law. Jacob LJ summarised the situation as follows:
"One would have thought that the task of proving this would be undertaken in a straightforward way. I set it out when at first instance in Synthon's Patent [2003] RPC 33 at [57]:

'Given the "inevitable result" branch of the law of anticipation (see below) one might have thought (a) that a team of ordinary ability might have been engaged (one is concerned with the ordinary skilled man or team, not world champions) and (b) that the team concerned would simply have been given the Synthon patent and asked to carry out its teaching to make paroxetine mesylate crystals

Experience shows that some parties attacking patents simply do not follow this straightforward path. Instead they depart from the prior art. Then, as here, an argument starts about the nature of the departure and whether it mattered. For the life of me I cannot understand why they do this. It inflates the costs and time, and seldom if ever does the defendant any good" (paragraphs 17-18).
Sandoz's attempts at having the finding of lack of anticipation overturned therefore failed, and the appeal was dismissed.

The IPKat wonders how, given the long-running nature of this case (see the IPKat's previous posts here and here), Sandoz had failed to find the time and resources to run an experiment that simply followed the instructions correctly. The IPKat can see why, if the experiment had been run properly and had not shown the desired result, Sandoz would not want to make this known, but cannot understand how they could have thought that altering the experiment in a way that made it look as if it was fixed to get the result they wanted (by seeding with crystals of the type required) would actually succeed in getting past the critical eye of a patent judge. As Jacob LJ suggested, all this merely seems to have had the effect of further inflating costs, which presumably Sandoz will now have to pay for.


Luke Ueda-Sarson said...

"Experience shows that some parties attacking patents simply do not follow this straightforward path. Instead they depart from the prior art. Then, as here, an argument starts about the nature of the departure and whether it mattered. For the life of me I cannot understand why they do this."

Because they are fools. It's the only logical conclusion. Living proof that common sense, or even a brain, is, sadly, not a prerequisite to engaging with the law.

It is really hard to see how this behaviour comes about. To a chemist, it looks bizarre. Budding chemists in high school are taught how to follow an experimental procedure - which amounts to no more than the "follow the instructions on the tin" that every teenagers knows about from rudimentary kitchen experience. And it hardly looks any better from a legal point. Can "do what the judge/case law clearly directs" really be such a foreign thought pattern to a lawyer?

Can anybody come up with some sort of rational explanation for this that doesn't invoke idiocy? I'm all ears, because I'd like to think these people (and it happen in many cases) are not *all* idiots.

Anonymous said...

From a technical point of view, crystal seeding is fraught with difficulties. Some companies forbid staff from one production site producing one crystal form of a compound, to visit another site producing another crystal form of the same compound. This is because such visits inevitably mean the inadvertent exchange of seed crystals between sites and the tiniest amount of seed crystal of the more stable crystal form will cause the site producing the less stable crystal form to spontaneously switch to producing the more stable form and it is extremely difficult to reverse this once it has happened. Consequently, not only crystallisation conditions are important (temperature, concentration, solvent(s) etc), but also factors which are beyond the control of the experimenter - the presence of undesired seed crystals, which can cause a totally different result when executing an otherwise identical crystallisation process.

Anonymous said...

I agree with the above...

Crystallising a compound from solution is indeed a dark art, and seemingly routine proceedures that have produced one particular form hundreds of times can, apparently spontaneously, start producing another (almost always more stable) from overnight.

It may seem foolish to modify conditions presented in the orginal document, but it's my suspicision that the chemists involved would have been aware (or at least suspected) that the orginal proceedure was not as detailed as it should have been. For example, it's often virtually impossible to get a compound to (re)crystallise from solution without some form of seeding. If this was indeed the case, the chemists involved may have suspected that the need for such seeding was omited from the earlier description and so decided to read between the lines, i.e. how could they have done this without seeding?.. and.. if they needed to seed, why would they have seeded with anything other than the well-known, more stable from.

As for switching starting material supplier, does anyone know if the material was chemically different in any way? Was the material used in the description still available?

On the other hand, it is worth noting that if a solution is seeded with the most stable crystal from in order to induce crystallisation, it would be a rare event indeed if another form was to result.

In any event, there is probabaly a good explanation that just didn't cut it this time...

Luke Ueda-Sarson said...

I'm aware of the problems of seeding; I failed to get more compounds to crystallize properly than I care to remember in the days when I was a researcher.

You talk about why the original procedure might not have worked, if followed, and how they might have modified things accordingly. But they didn't so much as try to follow that original procedure according to the record, and that's the big problem here.

If I was doing an experiment - for a court case for pity's sake - I would start off with following the original procedure to the letter, even if I was convinced it couldn't work. When it didn't work, as expected, I would make sure I said exactly not only at what point deviation from the literature occurred, but, most importantly, why.

That most elementary step was missing from this case, and it doomed them. And it's not as if they didn't have explicit instructions that this is what was in fact required. Because Lord Jacob has said all this before - in a seeding case, no less. You can't get more on point. The standard "crystallization is an art" and need-for-virgin-lab comments can all be found in his judgement on Synthon's paroxetine case.

Just look at his comments in paragraphs 57 to 64 regarding the need to follow the prior art exactly (

And yet they were not followed. In a case about the same topic before the same judge. Does not compute!

Cheers, Luke

MaxDrei said...

Luke you say "Does not compute". The only rational explanation I can come up with is that the litigation is world-wide, and UK is a relatively small jurisdiction. Could it be that the litigant has other (and much bigger) fish to fry somewhere else in the world? Maybe it was thought that doing the experiments "right" for the UK would endanger that frying process?

Anonymous said...

It is easy to be a general after the battle. Example 4 of acne patent has many gaps to be filled.

Starting with: mill calcipotriol below 5 microns - what is below 5 microns? .... suspend in an aqueous solution - what if the amount of solvennts is so big that is already dissolved and not suspended?

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