Following his grant of an interim declaration (discussed in our December 2015 Update), Arnold J has now, following trial, granted Actavis declarations of non-infringement in respect of the UK, French, Italian and Spanish designations of Lilly’s European Patent no. 1313 508. The Patent (which expires in June 2021), is a second medical use patent relating to the use of pemetrexed disodium in combination with vitamin B12 or a pharmaceutical derivative thereof and optionally a folic protein binding agent. In our July 2015 Update, we discussed the Court of Appeal’s finding that Actavis’ proposed dealings in its generic product would, where reconstituted and/or diluted in a sufficient quantity of saline, indirectly infringe the Patent (because the resulting solution would contain both sodium ions and pemetrexed ions in a ratio of at least 2:1 and would therefore be within the claims).
Subsequently, Actavis launched a pemetrexed diacid product in the UK (in December 2015, with planned launches to follow later in 2016 in France, Italy and Spain). This product does not require reconstitution and the Summary of Product Characteristics (SmPC) specifies that it is only to be diluted with dextrose solution. Lilly argued that it was foreseeable (and therefore obvious) that the Actavis product will be diluted with saline by some customers. The burden of proof was on Actavis to show that it was not foreseeable. Lilly accepted that, to begin with, pharmacists would follow the SmPC and would dilute the product with dextrose solution. However, its case centred on the likely availability of stability data for the Actavis product in saline and the extent to which there would be a motivation to use saline rather than dextrose (in the face of a number of preventative steps Actavis has taken).
Arnold J accepted that there was some uncertainty as to what might happen a few years down the line but concluded that, for the present, it was not foreseeable that the Actavis product would be diluted in saline. Accordingly, he granted the declarations of non-infringement sought by Actavis. The key issues before the Court were as follows:
Is it likely that stability data for the Actavis product in saline will become available?
Arnold J said it was unlikely that data showing the Actavis product is stable in saline would be published in the foreseeable future (the evidence was clear that there was no motivation from a stability perspective to carry out further stability studies), and still less likely that pharmacists would rely upon such data from a stability perspective. He recognised that he could not rule out the possibility that this might occur before June 2021 but, even assuming that data did become available, it was likely to take two to three years.
If such data became available, would there be a motivation to use saline rather than dextrose as the diluent for the Actavis product?
Dextrose solution is a commonly used diluent (albeit not as common as saline) and is also the only diluent recommended for use with certain chemotherapeutic drugs. Arnold J identified that the “only remotely plausible” motivation for the use of saline was Lilly’s argument that oncologists and/or pharmacists would be concerned about the effect of administering dextrose to patients with diabetes. However, the evidence demonstrated that this was not a concern in practice and that in the "real world" there were no examples of hospitals, pharmacists or clinicians switching diluents in the manner suggested. That said, Arnold J again concluded that he could not exclude the possibility (remote as it seemed presently) that, in a few years, some pharmacists would decide to switch diluents.
Even if there was such a motivation, was it likely that saline would actually be used as a diluent despite the steps Actavis has taken to prevent this?
Actavis has taken a number of steps to prevent its product from being diluted in saline:
- Where Actavis’ representatives contact hospitals to promote the product, they explain the requirement of dilution in dextrose solution, and make sure the hospital is aware it cannot be diluted in saline.
- Actavis’ UK supply operation is structured so that supply to customers can be turned on and off at will.
- Actavis checks that worksheets are updated appropriately in relation to its product prior to supply.
- Actavis is pursuing the possibility of binding its customers contractually, albeit the Judge noted this was a complex issue, particularly in relation to sales by tender and where Actavis does not supply through its usual wholesalers.
Further, Actavis has taken steps to avoid publication of stability data of its product in saline including: undertaking not to disclose any such data; requiring customers to agree contractually that they will not carry out stability studies with the product in saline; and implementing procedures to remind enquirers from hospitals that they are not permitted to perform stability testing in saline. Arnold J concluded that these measures appeared to be working and that therefore it was probable (but not guaranteed) that they would be effective to prevent pharmacists from switching from dextrose solution to saline, even if there was a motivation to do so.
He therefore decided that, at present, it was not foreseeable that the Actavis product will be diluted in saline and that, for the foreseeable future, supply of the Actavis product will not indirectly infringe the Patent. Accordingly, he granted the declarations of non-infringement sought in each of the jurisdictions as Actavis had a real commercial interest in obtaining the DNIs, and they would serve a useful purpose in making it clear that supply of the product is lawful. Given the uncertainty he had identified, however, both parties could apply to Court if there was a material change in circumstances.
Arnold J noted that, in contrast to the steps taken by Actavis (and also in contrast to the steps Pfizer has taken in the pregabalin litigation), Lilly had taken no steps to prevent the Actavis product from being diluted in saline. Indeed, he went as far as to comment that Lilly appeared to be “…content for Actavis to have to assume the entire burden of policing…” Lilly’s patent.
He noted that both Actavis and Lilly have sought permission to appeal the Court of Appeal’s June 2015 decision to the Supreme Court. No doubt also Lilly will seek permission to appeal this latest decision of Arnold J to the Court of Appeal.