Précis

In a recent decision (Actavis & ors v Eli Lilly [2016] EWHC 234 (Pat)), the English High Court has granted declarations of non-infringement to Actavis, which was “clearing the path” across Europe for its pemetrexed dipotassium chemotherapy product for the treatment of lung cancer. The judgment is an interesting decision on the effectiveness of various steps taken by Actavis to “clear the path”, as well as on the likely behaviour of medical and pharmaceutical practitioners when presented with alternative products with different directions for use.

Background

In the previous edition of this newsletter, we reported on the Court of Appeal decision in Actavis UK Limited and ors v Eli Lilly and Company Limited [2015] EWCA Civ 555 (“UK: patent alchemy in the Court of Appeal: turning sodium into potassium”). Actavis had argued that its proposed supply of a product containing pemetrexed dipotassium (or alternatively pemetrexed diacid or pemetrexed ditromethamine) as the active ingredient would not infringe European Patent No. 1 313 508 (“the Patent”) which claimed the "Use of pemetrexed disodium in the manufacture of a medicament...”. However, whilst Actavis only planned to supply the lyophilised (freeze-dried) solid dosage form, it admitted that its Summary of Product Characteristics (‘SmPC’) would contain instructions to reconstitute and dilute it in saline (sodium chloride solution) and so the resulting solution at the point of administration would contain pemetrexed ions and sodium ions. The Court of Appeal therefore ruled that Actavis’ application for declarations of non-infringement failed because the supply of the solid dosage form would amount to indirect infringement, as the supply of means relating to an essential element of the claim.

Both parties sought permission to appeal from the UK Supreme Court, which was granted. The appeal is due to be heard in June 2016.

However, in the meantime, and following the expiry on 10 December 2015 of the Supplementary Protection Certificates protecting the active moiety, pemetrexed, Actavis launched a pemetrexed diacid product (the ‘Actavis Product’) in the UK. It also plans to launch the Actavis Product in France, Italy and Spain later in 2016. The Actavis Product is a liquid product (rather than a lyophilised powder), and so does not require reconstitution in a solvent. However, it does require further dilution before administration to a patient. the SmPC for the Actavis Product does specifying that such dilution must take place in 5% dextrose solution (rather than saline solution). The issue of whether that would amount to infringement was remitted for trial in the Patents Court, and Arnold J delivered judgement on 12 February 2016.

Eli Lilly accept that the Actavis Product does would not infringe if actually diluted with dextrose solution rather than saline. The issue before Arnold J in relation to infringement was whether, as Eli Lilly argued, it was foreseeable that saline would be used by some hospital pharmacists to dilute the Actavis product. He also gave a useful summary of the court's jurisdiction to grant negative declaratory relief (the declaration of non-infringement sought by Actavis).

The judgment

Jurisdiction

Arnold J stated that the English court has a broad discretionary power under its inherent jurisdiction to grant a negative declaration if it is in the interests of justice to do so. The old restrictive approach no longer applied; the modern law was that a negative declaration will be granted if it is right in all the circumstances to do so, in particular if it will serve a useful purpose. It will do so if the claimant has a real commercial interest in the declaration sought or a real commercial reason for it to be granted.

Arnold J went on to hold that a declaration can be made based on assumed, hypothetical or contingent facts. However, if the facts on which the application is based are assumed, hypothetical or contingent, that may be relevant to whether the court exercises its discretion to grant the declaratory relief.

Infringement

Arnold J set out the test for indirect infringement in the circumstances of this case as: does Actavis know, or would it be obvious to a reasonable person in the circumstances, that Actavis’ product will be diluted in saline by some of Actavis’ customers. (Speculative or unlikely use is to be disregarded.) The Actavis SmPC specifies that it is only to be diluted with dextrose solution, not saline. However, Eli Lilly argued that, although pharmacists would initially follow that instruction, concerns about the use of dextrose solution for diabetic patients meant that it was foreseeable that they would begin to use saline once stability data became available for the Actavis product diluted in saline.

That in turn raised the following issues:

  1. whether stability data for the product in saline would become available;
  2. if so, whether there would be a motivation to use saline rather than dextrose solution as the diluent;
  3. even if stability data became available and even if there was a motivation to use saline rather than dextrose solution, whether it was likely that saline would actually be used as the diluent despite Actavis' steps to prevent that.

Both sides adduced expert evidence in relation to the situation in each of the UK, France, Italy and Spain. Arnold J addressed that evidence in detail in his judgment.

On (i), Actavis undertook to the Court not to disclose any such data (other than to regulators and as ordered by the Court). In addition, it wrote to prospective customers, stating that the terms on which the product would be sold would contain a prohibition on the customer carrying out stability studies with the product in saline. It also put in place procedures to respond to enquiries about the stability of the product in saline by pointing out that such testing is not permitted.

The Judge found that there would be no motivation for hospitals and pharmacists to carry out their own stability studies. The UK SPC for the Actavis product stated that it is stable in dextrose solution for 14 days, and in practice that would be enough: it was rare to keep the product for more than 24 hours once diluted. In any event, rather than incur the cost of its own studies, it was likely that the hospital or pharmacy would contact Actavis to obtain the information. If it did so, it would be told that use in saline solution was not permitted, either for treatment or studies. There was unlikely to be reliance on data published by a third party, given the need to be satisfied of its reliability.

The Judge therefore found that it was unlikely that any such data would be published or relied upon in the foreseeable future.

As regards issue (ii), Eli Lilly faced the difficulty that dextrose solution is commonly used as a diluent.

Even in the case of diabetic patients, Arnold J found that there would be no motivation to use saline. The only evidence given by an expert on diabetes, the endocrinologist called by Actavis, was that the 3 to 5g of dextrose which would be administered in the diluent for a dose of the Actavis product is a small amount and would not cause any problem for a diabetic patient. This was supported by the evidence of the eight pharmacists. None of them were concerned about giving dextrose to diabetic patients, and only one of them had ever been asked to change a diluent from dextrose solution to something else (a single request which was not approved in any case). Moreover, diabetic cancer patients have routinely been treated with various drugs which are diluted with dextrose solution.

As regards (iii), Actavis had taken a number of steps to prevent such use of saline as a diluent. These included:

  • sending a letter to relevant competent authorities (such as Specialist Procurement Pharmacists of NHS regional procurement services) and medical centres in the UK, requesting that guidance be issued that the Actavis product should be diluted only with dextrose solution. The Judge was satisfied by the evidence of such guidance which had actually been given to hospitals. No general guidance had been issued centrally from NHS England or the equivalent authorities in Wales, Scotland and Northern Ireland, but the judge pointed out that such general guidance was less important in this case than in the recent case of pregabalin (as to which, see “UK: The English Patents Court waxes Lyrica®-l about infringement of Swiss-type patent claims” in the previous edition of this newsletter) since pemetrexed is not prescribed by GPs.
  • pursuing the possibility of imposing contractual terms on its customers prohibiting their use of saline as a diluent. The Judge recognised that this process is complicated and Actavis faced particularly difficulties in relation to sales by tender, and sales through wholesalers. However, the Judge found that at least one customer had agreed to those terms and that, even if they were not legally effective, the attempt to introduce them at least had the effect of alerting customers to the potential infringement and consequent loss of supply.

Overall, the Judge concluded that it was not foreseeable that the Actavis product would be diluted with saline and so its supply would not amount to indirect infringement of the patent. Actavis had a real commercial interest in obtaining a declaration of non-infringement, given Eli Lilly’s pursuit of its infringement claim against Actavis. Arnold J acknowledged that, since the Patent will not expire until 2021, there was uncertainty about what may happen in future. He held that this should be addressed not by refusing the declaration of non-infringement, but by giving the parties liberty to apply to the Court if there were a material change in circumstances.

Conclusion

Actavis’ strategy of seeking a declaration of non-infringement of the European patent in respect of several jurisdictions in a single set of proceedings in the English Court had succeeded in principle in the earlier decisions in those proceedings, but failed on the facts.

It has now succeeded in practice too, as the Court found that Actavis’ steps to work around the finding of indirect infringement by the Court of Appeal were effective.