INNsight articles by Duncan Curley, September 09

European Patent (UK) No. 0,679,154 B1 (‘the Patent’) claims the crystalline monohydrate of a vitamin D analogue, calcipotriol, that is used in the treatment of psoriasis.  The Patent is owned by Leo Pharma A/S, the Danish specialist innovative player in the field of dermatology.  At the priority date, 15th January 1993, calcipotriol was already known for the topical treatment of psoriasis, but in the form of anhydrous crystals.  Calcipotriol monohydrate was unknown.  The Patent claims certain superior properties for calcipotriol monohydrate, including better properties for the manufacturing of crystal suspension formulations of calcipotriol and better stability than the anhydrous form. 

Whilst the Patent was in force, Sandoz marketed in the UK an ointment and a cream which contained calcipotriol.  Unfortunately, the Sandoz cream included a tiny (de minimis) amount of calcipotriol monohydrate.  In 2008, Leo sought and was granted an interim injunction and at the trial on the merits at the beginning of April 2009, Sandoz counterclaimed for revocation of the Patent, on the grounds of lack of novelty and obviousness. 

Only two years ago, few experienced legal patent practitioners would have rated Leo’s chances of defending in the English Patents Court the validity of a patent to a monohydrate crystalline form, especially when the anhydrate was already known before the relevant priority date.  There has however been something of a sea change in recent years, with a new crop of specialist patent judges who appear to be much more respectful of the validity of patent rights than perhaps their predecessors were.

The basis of the lack of novelty attack on the Patent was as follows.  An example in a prior published PCT patent application (WO 91/12807) disclosed a suspension cream of calcipotriol anhydrate used for the treatment of acne.  The example taught the manufacture of an emulsion to which an aqueous suspension of calcipotriol anhydrate was added.  The directions given as to how to make the aqueous suspension were to mill the calcipotriol anhydrate to a particle size below 5 µm and to suspend it in an aqueous solution of disodium hydrogenphosphate.  Sandoz claimed that although the person skilled in the art would carry out the instructions given in this example using anhydrous calcipotriol as the starting material, the monohydrate would inevitably be formed in the course of making the suspension cream.  They tried to prove this by means of experiments.  The Judge called this part of the case ‘Experimental proof of anticipation’.

Sandoz claimed to have repeated the example from the prior art and to have obtained calcipotriol monohydrate.  They used as the starting material for these experiments calcipotriol anhydrate from commercial production batches.  However, Leo claimed that it was likely that the starting material for the Sandoz experiments was contaminated with trace amounts of calcipotriol monohydrate.  These trace amounts would, said Leo, act as seeds for the growth of monohydrate crystals.  Thus, the results that Sandoz had obtained in their experiments could not be relied upon as an exact repetition of the prior art example.  Based on the evidence before him, the Judge agreed with Leo.  Sandoz had an alternative approach, which was to prove on paper (i.e. on the balance of probabilities) what would happen if the prior art example was carried out with a starting material of calcipotriol anhydrate, but without any seeds of calcipotriol monohydrate.   Again, the Judge was not satisfied that the inevitable result of a calcipotriol monohydrate ‘seed free’ repetition of the prior art example would produce a cream containing calcipotriol monohydrate. 

These failed attempts by Sandoz to prove anticipation by means of a repetition of instructions in a prior art document demonstrate the importance of following the instructions given in the disclosure precisely, in order to get home in a case based on lack of novelty.  They also illustrate the strict approach to novelty that is now taken by the English Patents Court, in line with the practice of the European Patent Office. 

The attack based on obviousness was as follows.  Given the instructions disclosed in the prior art for the manufacture of an aqueous suspension cream containing calcipotriol, it was obvious to find and use calcipotriol monohydrate.  The case was developed by Sandoz in several ways.  First, it was claimed that the skilled person who submitted an application for regulatory approval for a calcipotriol aqueous suspension cream would be expected by the relevant regulatory authority to check whether an alternative crystalline form (such as a hydrate) was produced during manufacture.  Second, it was obvious to conduct a polymorph screen in the course of pre-formulation studies for APIs such as calcipotriol and such a screen would have revealed calcipotriol monohydrate.  Third, the skilled person would always check for the presence of a hydrate, in the course of routine stability studies. 

The problem with each of the approaches outlined by Sandoz was that the skilled person would have not necessarily have had any expectation of finding calcipotriol monohydrate.  In relation to the first case, the Judge did not think that the demands of the regulatory authorities could be equated to the knowledge of the skilled person.  The Judge was not satisfied that the skilled person would undertake a polymorph screen and so the second case failed as well.   Finally, the Judge was not convinced that the skilled person developing a suspension cream of calcipotriol would always investigate the formation of hydrates.  

All of the attacks based on lack of inventive step therefore failed.  Whilst essentially all of the approaches outlined by Sandoz were plausible, in the end, an attack based on ‘obvious to try’ has to have a fair expectation of success in the mind of the skilled person.  Sandoz v Leo is yet another recent example of an obviousness attack that has foundered in the English Courts when trying to meet the relatively high standard for a case based on ‘obvious to try’.