In the next instalment of the long-running patent action between Actavis and Lilly in relation to the anti-cancer drug pemetrexed, on Friday 12 February Arnold Jhanded down his judgment on the issues remitted by the Court of Appeal in this action. Actavis was granted declarations of non-infringement in respect of the UK, France, Italy and Spain in relation to its pemetrexed products (pemetrexed dipotassium, pemetrexed diacid and pemetrexed ditromethamine) when diluted in dextrose.

The patent in suit (EP 1 313 508) claims the use of pemetrexed disodium in combination with vitamin B12 and optionally a folic binding protein agent for inhibiting tumour growth. The SPC in respect of the basic patent for pemetrexed expired on 10 December 2015. Lilly's pemetrexed disodium product is marketed under the brand name Alimta.

Having been postponed from the original hearing date in November 2015, the trial of the remitted issues was heard on 25 to 29 January 2016.

Background to the remitted issue

Following an unsuccessful jurisdictional challenge by Lilly ([2012] EWHC 3316 (Pat), as reported here, and [2013] EWCA Civ 517, [2013] RPC 37), the High Court had held that Actavis was entitled to declarations of non-infringement in respect of the UK, France, Italy and Spain in relation to its pemetrexed dipotassium, pemetrexed diacid and pemetrexed ditromethamine products ([2014] EWHC 1511 (Pat), as reported here). However, this decision was overturned on Appeal in June 2015 ([2015] EWCA Civ 555).

In its judgment the Court of Appeal reasoned that Actavis' pemetrexed products are means relating to an essential element of the invention under section 60(2) of the Patents Act 1977 as they are a means of releasing pemetrexed ions into solution and that the invention is put into effect when the pharmacist reconstitutes and/or dilutes Actavis' pemetrexed product in sufficient saline to achieve a molar ratio of sodium ions to pemetrexed ions of 2:1 or greater.

On receipt of the draft judgment, Actavis requested that declarations were granted to reflect the Court of Appeal's decision that there would only be infringement under s60(2) if saline were used as a diluent for Actavis' products and that certain issues relating to use of dextrose (i.e. glucose) as a diluent be remitted to the High Court. The Court of Appeal declined to make the declarations sought by Actavis, but remitted the "dextrose remission issue" to the High Court.

The Dextrose Remission Issue

The basis of the Dextrose Remission Issue was Actavis' statement that it intended to amend all information relating to its pemetrexed products to specify that they should only be diluted in dextrose, including its SmPCs for the UK, France, Italy and Spain. Actavis also stated that it would write to all medical centres stating that its products should only be used in dextrose and to the NHS (and other relevant competent authorities) to request that they issue central guidance to this effect. Actavis sought declarations that if such steps were taken there would be no infringement of the patent.

By the trial in January marketing authorisations had been approved for Actavis' pemetrexed diacid product covering all of the relevant jurisdictions and containing a direction to use only dextrose. Following expiry of Lilly's SPC in December 2015, Actavis also sent out guidance letters to medical centres in the UK and the NHS and had launched its pemetrexed diacid product in the UK.

Expert evidence was adduced by both parties from pharmacists from each of the UK, France, Italy and Spain and from oncologists from the UK. Both parties also relied on expert evidence from Italian and Spanish lawyers in relation to the legal framework within which pharmacists work in each of those countries. Lilly also relied on witness evidence from a Spanish oncologist and Actavis of an endocrinologist.

Lilly's central argument was that it was known to Actavis (or obvious to a reasonable person in the circumstances) that some pharmacists would intentionally dilute Actavis' product in saline, despite any directions to use only dextrose. The reasons which had been given by Lilly were numerous and included: use of saline as the diluent by mistake, for convenience, out of habit, out of preference and/or due to concerns relating to diabetic patients.

Publication of saline stability data

It was accepted by Lilly that, at least initially, pharmacists would follow the SmPC for Actavis' pemetrexed product and use dextrose as the diluent, as they could not do otherwise unless data had been published showing that Actavis' product was stable in saline.

Lilly contended that there was a motivation for people to generate such stability data in saline, even though the SmPC stated that the product should only be diluted in dextrose and Actavis had stability data of its product in dextrose of up to 42 days. Lilly attempted to argue that it was foreseeable to Actavis that stability data for its pemetrexed product in saline would be published before the patent expired in [2021].

Actavis argued that the dextrose stability data given in its SmPCs was more than sufficient and that it would advise any pharmacists who made enquiries about stability data that its product was stable for up to 42 days in dextrose and that its product should not be diluted in saline. In addition, Actavis' evidence was that it had taken and would continue to take steps to avoid publication of any saline stability data for its product.

Arnold J agreed that such steps meant that it was unlikely that stability data in saline would be published in the foreseeable future (he estimated it would take at least 2-3 years) and even less likely that pharmacists would rely on such data. This included findings of fact that pharmacists would only deviate from the SmPC with very good reason and that to do so would result in liability for the product passing from the manufacturer to the pharmacist.

Diabetic patients

Actavis adduced evidence from an UK endocrinologist in response to Lilly raising an argument that clinicians would request a change of diluent from dextrose to saline due to concerns surrounding the treatment of diabetic patients. Whilst Lilly had permission to do so, it did not call a diabetes expert.

Arnold J accepted Actavis' unchallenged evidence that the small amount of dextrose per dose was clinically insignificant (being equivalent to 100ml of skimmed milk or a single jelly baby and therefore much less than a normal meal), particularly as the blood sugar levels of all patients receiving pemetrexed should be being monitored due to the co-administration of corticosteroids (which have a significant impact on blood sugar levels).

Lilly suggested that oncologists might be sufficiently concerned about administration of dextrose to diabetic patients to request a change of diluent to saline (without consulting an endocrinologist), but as Arnold J pointed out this was not supported by the evidence.

Additional steps taken by Actavis to prevent use of saline

Arnold J concluded that, in the light of all the evidence, it appeared that even if saline stability data for Actavis' product were published and even if pharmacists were motivated to change diluent, the various commercial steps being taken by Actavis it would probably prevent its product being used in saline. These included making it clear to customers that if they were to use saline to dilute the product it would lead to supply of the Actavis product being stopped.

Infringement from launch

Despite the parties' acceptance that Actavis' product will not be diluted in saline until such time as saline stability data becomes available, Lilly contended that Actavis will infringe from launch. Lilly gave two reasons for this. Firstly, Lilly said that the fact that Actavis' product has a self-life of 18 months meant that stock purchased by hospitals at launch would be held until after stability data became available; however, the evidence showed that hospitals only held stock for a very few weeks and Arnold J held that stability data would not become available for 2-3 years. Secondly, Lilly argued that if Actavis won a tender to supply its product for a period extending beyond such time as saline stability data is published, their bid would have constituted an offer to supply at a time at which it is foreseeable that there would be infringement; but Arnold J concluded that the evidence did not support such an argument.

The Letters Case

In a side issue, the Court also granted declarations to Actavis that certain letters which contained a statement of its intentions not to launch were not legally binding and Actavis were not estopped from retracting them.

Concluding remarks

In granting the declarations requested by Actavis, Arnold J held that for the foreseeable future supply of Actavis' product will not indirectly infringe Lilly's patent, but granted the parties permission to apply for appropriate relief should the circumstances materially change. Therefore, Arnold J may see this case before him for a third time.