The Lyrica patent dispute – part the first - validity

This moggy posted a very brief note on the seminal substantive decision in the Lyrica case (see here for the post, containing links to the very lengthy history leading up to it).  Now the IPKat turns to a more detailed review, that will be in two parts in the order that the decision itself follows, taking validity first, and infringement second.

The background

The case concerns the treatment of pain, and in particular neuropathic pain.  A huge amount of the judgment is devoted to the technical detail of this, so simplifying hugely, while trying not to misrepresent, the key points emerged as follows.

In the healthy situation, a person experiences pain in response to a pain stimulus – this is termed “nociceptive pain”.  A type of nociceptive pain is inflammatory pain, which accompanies the inflammatory response to an injury.  Such pain resolves with treatment of the underlying cause.  Neuropathic pain on the other hand occurs when there is damage to either the central nervous system or peripheral nervous system, and results either in pain when there is no pain stimulus (neuralgia, of which there are several kinds), or that is disproportionate to the stimulus (hyperalgesia).

A cause of neuropathy is sensitisation of neurons.  When this occurs in the central nervous system it is termed central sensitisation.  Central sensitisation was a key aspect of the case, both as a general concept and in relation to a specific theory for its mechanism developed by Warner-Lambert’s expert witness, Professor Clifford Woolf.  This latter aspect became referred to as “central sensitisation in the italicised sense”.

The patent

The patent concerned use of a compound, pregabalin, previously known for as an anticonvulsant (and therefore used in the treatment of epilepsy), for the treatment of pain.  The patent belongs Warner-Lambert, a company that was acquired by Pfizer in 2000.  Warner-Lambert had itself acquired in 1970 Parke-Davis, which had conducted research into pregabalin and a related compound gabapentin.  Mylan and Actavis were seeking revocation of the patent. 

The relevant claims of the patent were as follows:

1. Use of [pregabalin] or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treating pain.

2. Use according to Claim 1 wherein the pain is inflammatory pain.

3. Use according to Claim 1 wherein the pain is neuropathic pain.

Further types of pain were enumerated in claims 4-14, of which claim 13 to “idiopathic pain” (that is, pain of no known origin) is noteworthy.

The claims above as litigated were not those as granted – the patent had previously been amended in limitation proceedings at the European Patent Office to restrict to pregabalin only, whereas in the claims as granted a broader class of compounds were recited.

The patent showed the results of tests in some animal models - carrageenin-induced mechanical and thermal hyperalgesia, and rat paw formalin test.  In the first of these, carrageenin, an inflammatory agent, is injected into the sole of the paw of a rat and tests are carried out to determine the extent of thermal and/or mechanical hyperalgesia (that is, increased pain experienced when a heat or mechanical based pain stimulus is applied).  In the second of these, formalin (a solution of formaldehyde in isotonic saline) is injected into a rat's paw. The rat's behaviour is then monitored over the next hour and the amount of time that the rat spends licking or biting the injected paw is recorded. There are two phases in the test: the early (or first) phase of licking and biting, which lasts around 10 minutes, followed by a late (or second or tonic) phase of licking and biting which starts at around 10 minutes and lasts for about 45 minutes.

The prior art

Pregabalin is structurally closely related to another compound gabapentin, which was also previously known as an anticonvulsant.  The prior art included a number of documents describing the use of pregabalin as an anticonvulsant, indicating its similarity to gabapentin.  There were also some documents describing the use of gabapentin for the treatment of pain.  There was no document describing the use of pregabalin for the treatment of pain.

In the USA, gabapentin had been widely used off-label for the treatment of pain (and indeed in July 1996 – the same time as the patent’s priority date – the US Food and Drug Administration complained about Parke-Davis promoting this off label use, eventually resulting in a $430 million fine).  This was reflected in a number of documents, which were however all published in the USA.  While Mr Justice Arnold considered that it was common general knowledge in the USA that gabapentin could be used for the treatment of pain, he considered that it was not general knowledge in the UK.  Moreover, to the surprise of this Kat, he ruled that common general knowledge must be known in the UK in order to count.  This is actually presaged in Teva UK Ltd v Merck & Co Inc [2009] EWHC 2952 (Pat), although in that case the issue did not actually arise.

Inventive step

The inventive step argument was essentially – gabapentin is similar to pregabalin, gabapentin is known for the treatment of pain, so it is obvious that pregabalin would also be effective to treat pain.  This did not find favour with the judge for a number of reasons:

1) The use of gabapentin for the treatment of pain was not common general knowledge (as mentioned above under “prior art”).  Moreover, the documentary disclosures were all case reports or reviews referring to them; a case report is essentially an anecdotal disclosure which merely indicates that some specific patients have apparently been successfully treated – it does not indicate to the skilled person that the drug is actually successful in treating the indication, for which a proper clinical trial is required.

2) Although the documents did disclose that both gabapentin and pregabalin had anticonvulsant activity, the mechanism of action was not known – the “Taylor II” document disclosed that both compounds bound to the same receptor, but it was not clearly established that it was this that gave rise to the pharmacological effect.

3) To the extent that the skilled team considered that gabapentin showed promise and was worth investigating for the treatment of pain, the mechanism of this activity was also not known, so it could not be known whether pregabalin would also have this activity.  Therefore, it was not obvious to test pregabalin – it might be obvious to test gabapentin, but even here the judge considered that the skilled team would have little expectation of success.

Insufficiency

According to the caselaw relating to sufficiency developed in MedImmune Ltd v Novartis Pharmaceuticals UK Ltd [2011] EWHC 1699 (Pat) at [458]-[484] and summarised in Sandvik Intellectual Property AB v Kennametal UK Ltd [2011] EWHC 3311 (Pat) at [121]-[124], also set out in Regeneron Pharmaceuticals Inc v Genentech Inc [2013] EWCA Civ 93 at [100]-[101], the specification must make it “plausible or credible” that the invention would work across the scope of the claim, otherwise the patent is insufficient.  Moreover, if the specification does not satisfy the “plausible” criterion, this cannot be remedied by later data.

Because the animal models used in the patent clearly represent models of inflammatory pain, it was not challenged that the patent was sufficient in relation to inflammatory pain.  However, Mylan and Actavis contended that the patent was insufficient in relation to all the other types of pain recited, including neuropathic pain.

Some rats may have been harmed
during the making of this invention

The patent did not state that the data presented show that pregabalin is effective in the treatment of neuropathic pain, nor did it mention central sensitisation at all.  Nevertheless, the judge was persuaded that central sensitisation was known to play a role in the second phase of the rat paw formalin test used in the patent, and moreover that central sensitisation was known to be involved in peripheral neuropathic pain.  Therefore, he considered the patent sufficient in respect of peripheral neuropathic pain.  However, the judge was not persuaded that the patent was sufficient in respect of central neuropathic pain, in which central sensitisation was not thought to have any role.  But claim 3 recited “neuropathic pain” generally, thus including both central neuropathic pain and peripheral neuropathic pain, and there was no application to amend it, and so the patent was held insufficient in respect of claim 3.

In an attempt to avert the finding of insufficiency, Warner-Lambert advanced the (to the mind of this Kat, extraordinary) argument that the patent would be read by the skilled person as limited to “pain with a central sensitisation component”, and its claims accordingly restrictively construed, so that claim 3 would essentially be limited to peripheral neuropathic pain, notwithstanding that the patent did not actually mention “central sensitisation” at all.  This construction was rejected by the judge.

Speculating idly, this Kat wonders whether the patent might have fared better if limited (at the same time as it was restricted to pregabalin) to inflammatory pain and neuropathic pain only.  It seems that then perhaps the distinction between central and peripheral neuropathic pain may not have arisen, and claim 3 might have survived.  At the very least it is surprising that the claim to “idiopathic pain” was left in the patent – this is by definition pain of unknown origin and it is hard to see how efficacy of its treatment with pregabalin could ever have been plausible based on the disclosure of the patent.

Conclusion

The claims of the patent were held to be not obvious, but claims 1, 3, 4, 6, 13 and 14 of the Patent were invalid on the ground of insufficiency.  This includes all the claims (1 and 3) that were alleged to have been infringed by Actavis.  It is to the infringement aspect that the IPKat will turn in the next post.