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Saturday, 13 February 2016

Mr Justice Arnold foresees no infringing saline use in Actavis' pemetrexed future

The AmeriKat taking a much needed
nap in preparation for opening all those
Valentine's Day cards...
If you were at a loss as to what to get that special patent litigator in your life this Valentine's Day, look no further.  Mr Justice Arnold seems to have heard your cries for help in handing down his decision in the latest Eli Lilly and Actavis battle concerning lung cancer treatment pemetrexed disodium.  Read with a plummy Joanna Lumley voice, Mr Arnold's decision in Actavis v Lilly [2016] EWHC 234 may be just the thing to set the mood for a romantic candlelight dinner (although, some may say it is a mood killer depending what side you are on).  Although the AmeriKat has not had a chance to fully digest each and every word of the mere 58 page judgment, she sets out a skeleton summary of the decision below:

The product

Lilly's pemetrexed disodium - a chemotherapeutic treatment for lung cancer.  Marketed under the brand name Alimta as a freeze-dried powder, it contains instructions as to how to reconstitute and then dilute it in a 0.9% solution of sodium chloride (saline).

The patent

European Patent No 1 313 508 protects the use of pemetrexed disodium in combination with vitamin B12 or a pharmaceutical derivative thereof and optionally a folic protein binding agent.  The patent expires on 15 June 2021.

The background

The case is the latest installment in the long-running dispute,which started in July 2012 when Actavis sought declarations for non-infringement (DNIs) in respect of the French, German, Italian, Spanish and UK designations of the patent. The DNIs were sought initially in respect of the dipotassium version of the product, then later diacid and ditromethamine.  This was in advance of the planned launch of their generic pemetrexed product.

Pemetrexed
Following a dispute as to the jurisdiction of the DNIs (see High Court and Court of Appeal decisions here and here), Lilly counterclaimed for infringement of the UK designation.   At the time, Actavis's product was planned to be reconstituted and/or diluted with sodium chloride (saline), but they didn't raise an issue with B12.  Two years later in May 2014, Arnold J held that Actavis's proposed dealings would not amount to direct or indirect infringement (see here).  The Court of Appeal upheld the decision in respect of direct infringement, but reversed the indirect infringement finding on the basis that if the products were reconstituted/diluted the saline solution would contain sodium ions and pemetrexed ions in a ratio of at least 2:1.  This would fall within the claims and thus the supply of Actavis's products would amount to indirect infringement.   Both sides have appealed to the Supreme Court.  In the meantime, the Court of Appeal's judgment is binding.

This action

Following the Court of Appeal's judgment, Actavis requested and the Court Appeal allowed to remit back to the Patents Court a new issue as to whether the supply of their products would constitute indirect infringement of the Patent if marketed with instructions to reconstitute and/or dilute the products with 5% dextrose solution instead of saline (the Dextrose Remission Issue).  Actavis therefore requested DNIs in respect of the UK, French, Italian and Spanish designations of the patent.
Actavis subsequently launched a pemetrexed diacid product which does not require reconstitution.  The Summary of Product Characteristics (SmPC) which forms part of Actavis's marketing authorization states that the product is only to be diluted with dextrose solution (not saline).  Lilly argued that it is foreseeable that the Actavis product will be diluted with saline by some customers  in light of concerns about the use of dextrose (glucose) in diabetic patients.  As soon as the stability data for Actavis's products with saline became available this switch will be foreseeable.  Lilly therefore resisted the DNI sought by Actavis in respect of the Dextrose Remission Issue.  It did not counterclaim for infringement.

Besides the Destrose Remission Issue, there was the so-called Letters Issue, relating to the effect of two letters written by Actavis's solicitors to Lilly's solicitors.  The issue was whether the letters were legally binding undertakings.  The judge held they were not (which will be subject to another post).

The question

Do Actavis know, or it would be obvious to a reasonable person in the circumstances, that the Actavis product is likely to be diluted at least in some cases by some of Actavis' customers?  Is it foreseeable?

The answer

No, because:

  • Pharmacists will follow Actavis's SmPC which states that the product must be diluted with dextrose.  The likelihood of pharmacists departing from the SmPC depends on when the saline stability data becomes available and whether it would motivate a pharmacist to actually use saline in light of the steps Actavis has taken to prevent the use of saline (including product labels, leaflets, letters and calls to hospitals, etc).  None of this was foreseeable, held Arnold J.
Lilly's Alimta
  • First, the stability data is unlikely to become available.  Actavis had undertaken not to make such data available and confirmed that they were willing to continue the undertaking.  Stability data would have to be obtained somewhere other than from Actavis.  It was unlikely that a third party would carry out further stability studies, especially given that the SmPC stated that the dextrose solution was stable for 14 days.  One of Actavis's experts stated that in he was not aware of any hospital storing Alimta for more than 24 hours.  It was further unlikely that a third party would carry out stability studies with saline (whether as a comparison with dextrose, or not).  Even if a third party carried out saline stability studies and the reliability of the study was confirmed, there would be concerns as to the potential for the formation of microparticles and bacterial growth.  If such data was published, it would be 2-3 years from Actavis' launch (meaning 2-3 years until the expiry of the patent).  
  • Second, even if the stability data was available there would be no motivation to use the saline rather than the dextrose solution.  There were no issues with dextrose (potential for phlebitis, saline being the default dilutant, risk of bacterial growth) that were significant enough to motivate the use of another dilutant.  Even if the saline stability data was available, this does not necessarily lead hospitals to change dilutants.  Case and point was the fact that although there was stability data available for Alimta with dextrose, hospitals still diluted it with saline.  The only plausible motivation for departing from the SmPC would be in respect of diabetic (or pre-diabetic) patients.  However, the expert evidence was that because 5mg of glucose (the amount to be administered) was so small (equivalent of one jelly baby - for non-UK readers these are tiny creepy fruit-flavored gelatin candies in the mold of a baby), an endocrinologist would not be concerned.  Other chemotherapy drugs, including carboplatin and oxaliplatin, are also routinely administered at 5% dextrose solutions and do not cause problems for diabetic patients.  The addition of dexamethasone (which is known to cause significant increases in blood sugar levels) to the treatment would not be an issue, as diabetic patients would be advised to monitor their glucose levels more frequently and adjust their medication accordingly.  None of pharmacists' evidence suggested that they were ever concerned about the use of dextrose in diabetic patients.  However, Mr Justice Arnold noted that he could not exclude the possibility that in a few years some pharmacists will decide to switch to saline.  
  • Third, even if the stability data was present that would motivate the use of saline, Actavis's safeguards would be effective in preventing such use.  

Lilly's potential appellant's notice re-imagined in
love hearts....
Mr Justice Arnold held that it was not foreseeable that Actavis's product would be diluted with saline.  Their product, for the foreseeable future, will not infringe Eli Lilly's patent.  He therefore granted the DNIs, but gave the parties liberty to apply in the event that at some point in the future should saline be used Lilly would be able to seek appropriate relief.

Although Mr Justice Arnold could not foresee the use of saline in the future, the AmeriKat can easily foresee one future event - an appeal to the Court of Appeal.  With the parties clashing since 2012 and the first round subject to at least three appeals (including a potential Supreme Court outing), the evidence points to another appellate visit.   Well, what could be more romantic than an appellant's notice this Valentine's Day...?

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