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.
The Lyrica patent dispute – part the first - validity The Lyrica patent dispute – part the first - validity Reviewed by Darren Smyth on Friday, November 06, 2015 Rating: 5

33 comments:

  1. If a compound has been demonstrated for the first time to be of value in pain, albeit specifically in one type of pain, it is more than reasonable to claim the compound for use in pain generally, and it would be sensible to also claim other specific types of pain. It would be foolish to draft a patent with such limitations based on potential insufficiency arguments.

    Claims directed at specific pain types, without directly relevant data or a reasonable scientific rationale based on data in another pain type, can reasonably be invalidated on insufficiency grounds. However, I would argue that a claim to the genus that is 'pain' should be deemed sufficient if data demonstrates benefit in 2 or more pain types. Activity in pain is far removed from epilepsy (I haven't considered the prior art) so it would not be reasonable to expect a patentee to demonstrate activity in every sub-type of pain simply to enable them to fully benefit from their contribution to the art.

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  2. Are all first medical use claims insufficient because not all diseases can be treated with one compound?

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  3. According to Arnold, yes they are. He may be one of those people who believes even new compounds should only receive protection for the use demonstrated. Next step is the requirement of clinical evidence. Soon, we have the Indian patent system.

    Do we have a Court of Appeal with the relevant knowledge to get this overturned? We need proper scientists-turned lawyers on these cases. Has LJ Kitchin learnt from his misunderstanding of Biogen? Can we bring Hoffman back out of retirement.

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  4. Anonymous @ 19:55,

    How is having a specific utility related to what appears to be a slam of the Indian patent system?

    Does that system have a different classification of "things" such that it is only a combination of thing and its effect (I daresay "function") that is covered by a patent?

    My knowledge base of Indian patent law is admittedly weak. I can only compare to the US system, where the distinction between a "hard goods" type of invention and a "new use" of that (no longer novel) "hard good" is allowed, but that "new use" must itself be separably patentable. It sounds as if Indian law treats utility and functionality in a foundationally different manner. Here in the States, if I invent a Wodget, that invention protects the Wodget no matter how anyone else uses the Wodget. And yet, if another person invents a method of use distinct enough to obtain patent protection, that person may obtain a patent for that use - even if that person cannot sell a Wodget to begin with (since my patent prevents that).

    This distinction is one that drives the understanding that a patent is a "negative right" and also helps explain the rather deep aversion (here in the States) for "conscripted" taking of a patent by way of compulsory licensing.

    The US way is meant to create a dichotomous overlap, wherein follow-on invention proceeds, even before the first patent lapses, but wherein those follow-on inventions do not create a "positive right" to engage in commerce with "things" protected by what may be owed to others.

    This is something that seems to baffle a ton of people (even in the US). I have to wonder if the "negative right" aspect is not a part of the Indian patent system, and that is what you are referring to.

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  5. Excellent commentary Darren - understood and readable from start to finish.

    A

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  6. Dear US Anon, if you knew more about pharma patents (I understand this is not your area) in and outside India, then you would understand my comment.

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  7. Anonymous above writes of Arnold J. :

    "He may be one of those people who believes even new compounds should only receive protection for the use demonstrated"

    I'm another. I suppose what makes me think like that is 30+ years of practice before the EPO with its maxims i) only a new enabled and non-obvious solution to an objective technical problem is patentable and ii) the scope of protection given to such subject matter must be commensurate with the contribution to the art.

    Besides, the mood of the moment is to confine inventors ever closer to what they truly have contributed. Who says that's wrong?

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  8. A quick read through Idenix v Gilead from 1 December 2014 confirms that Arnold indeed believes that a claim to a compound per se should sometimes be read with a use (i.e. biological activity) limitation. However, I would say that it is clear from paragraphs 304 to 306 of that judgement that he does not necessarily think that this should always be the case.

    Interestingly, the parties in Idenix v Gilead agreed that a use limitation should be read into the claims. On the part of the patentee, this was presumably for reasons relating to validity.

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  9. I do, because what you are talking about is confining the inventor to less than their contribution. If the USA find, land on and plant their flag on a new asteroid, they are entitled to the precious metals it contains, not just the right to have it named after them. An inventor who has "invented" a "new" (as in, ever before existed) compound should be entitled to all rights in the compound for the initial patent term, irrespective of the uses others later identify.

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  10. Last time I looked, novelty was not enough to warrant the grant of a patent. Last time I discussed the patentability of "Molecule X" with a chemistry patent attorney, a new molecule per see isn't inventive till you specify the effects you get with it. There is no "invention" in announcing a new compound per se.

    Even though we speak of "planting the flag" when we debate novelty, I find it irksome to compare patentable subject matter with landing on an asteroid. Not the same thing. The analogy is misleading. Just because somebody has invented the photocopier does not mean he can assume ownership of all the photocopier improvements that emerge in the following 20 years.

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  11. MaxDrei,

    Agreeing with you, Biogen said: ‘The Wright Brothers showed that heavier-than-air flight was possible, but that did not entitle them to a monopoly of heavier-than-air flying machines.’

    [http://www.bailii.org/uk/cases/UKHL/1996/18.html]

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  12. Anonymous at 22:23,

    I am more than willing to learn what it is that you think I am lacking from my specific Art-Field deficit.

    Let me see your reasoning, and not just your conclusion, please.

    MaxDrei at 13:19,

    Read my post above - you are falling to the fallacy of not understanding the baseline view of what a negative right means. No one is saying that all follow-on improvement inventions belong to the first inventor. No one. But that is a far cry from saying that any follow-on inventor has a positive right to that which the follow-on inventor is improving. They absolutely do not.

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  13. Max, I didn't quote that a patent claim needs to comply with Rule 42(b)(i)(a)X of the XPC either. I'm not sure many people attempt to patent new compounds that have no possible utility, so you can rest assured that inherent in my argument was a biological effect of the 'NEW' compound.

    Try speaking to the chemistry attorney again and he/she will explain how molecules are nothing like photocopiers. The analogy there would be an improvement to the photocopier would be equivalent to a new molecule. Try asking US anon to explain it.

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  14. Suleman, the heavier than air flying machines are also not a good analogy for molecules. In any case, Biogen was a product-by-process claim, said product being known. A 'NEW chemical entity' is by definition 'NEW'.

    I don't know why I am responding to US anon, but....

    The Indian patent act only allows certain pharma inventions to be patented if there is evidence of improved efficacy. This will require clinical data, even where the improvement has other unexpected, non-clinical benefits. I'm sure Max agrees with this being a mechanical person.

    Suleman probably also agrees being an attorney for that hard-done-by biotech field.

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  15. Just to throw into the mix here, for nucleic acids they must be 'functional' when infringment happens of the product claim according to the CJEU in Case C-428/08 ("Monsanto v. Cefetra"). So that is a half-way house to requiring the relevant activity to be part of infringement.

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  16. There is nothing sacred about "absolute Stoffschutz" claims to "Molecule X" per se. It isn't just India that has doubts. Until 1968 (as I understand it) Germany also declined to issue such claims. See
    https://de.wikipedia.org/wiki/Stoffschutz

    The current culture, of giving Big Pharma everything it asks for might not last for ever.

    Imagine a Party at the EPO, where you gain entry if you have invented something. Novelty isn't enough to get in. You have to be inventive too. Big Pharma rings the doorbell. What's your invention then? Molecule X. Is that by itself enough to get in? No.

    But, says Big Pharma, I have more than that. I have a technical effect. I have utility. Now we have a serious debate.

    One might say that the technical effect runs through the entire scope of the claim. So there ought not to be a problem with Agrevo-type obviousness.

    How about clarity though? Are there in the claim all the features needed to solve the problem? If the problem is effectively to treat disease Y, perhaps the claim should be to a medicament to treat disease Y. Giving the patient one molecule won't work, will it?

    To repeat: Inventors should get a scope of protection commensurate with their contribution to the art. The UK Patents Act of 1949 had many grounds of invalidity that we don't see in the EPC. Grounds like lake of support, specifically, lack of "fair basis". Such notions of "fair basis" are inherent in any patent system, regardless whether they are announeced explicitly as a statutory ground of revocation.

    That's all I'm saying.

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  17. My, don't you have to watch like a hawk the operations of the infernal spell "checkers"? Otherwise you will miss their depradations, like (above) changing "lack of support" into "lake of support". Sorry about that folks.

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  18. Agrevo is a different issue.

    What happened in olden days is not relevant. There use to be a statutory ban in many places on compound patents. Not being over 80 I can't explain the rationale, but times have moved on. They may well move back, but it is not a political argument. Without adequate protection investment in R&D will not be made. Plenty of drugs have fallen down in clinical trials for their first-patented utility and then been developed for other indications only because they have compound per se protection. I'm sure most people will not be able to name many drugs protected by second medical use claims. The history of the Lyrica and Viagra patents a lesson on the subject.

    If Max or US anon had patented the first ever photocopier device, would they have object of if someone manufactured copies and sold them for other purposes (scanning for example), irrespective of off-label photocopying use? No, didn't think so. Glad we are now all in agreement.


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  19. At yesterday, anonymous wrote:

    "Plenty of drugs have fallen down in clinical trials for their first-patented utility and then been developed for other indications only because they have compound per se protection"

    which strikes me as the Don Corleone argument, namely, if you grant me absolute Stoffschutz you might get some new drugs. But if you deny me absolute Stoffschutz well then, you just might never get any more new drugs, ever again. It's up to you.

    Is there a counter-argument, namely, that a purpose-limited claim will not only give the original inventor enough protection to recover his investment but also will stimulate other researchers to explore, without delay, the efficacy of the new molecule for other medical indications because, if they find one, they can not only patent it straighaway but also exploit it, straightaway, which is good for the respective inventors and good for the public and good for the patent attorneys too.

    It's a tricky thing, to get right the balance between inventors and their competitors, such that patents promote rather than stifle technical progress in the useful arts.

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  20. "But if you deny me absolute Stoffschutz well then, you just might never get any more new drugs, ever again. It's up to you"

    eeerrrmmmm yes.

    second point - too long to copy and quote. Ans No.

    Several reasons why not:

    There is an assumption they can patent their new indication right away. Lyrica (UK) managed to find non-obvious claims, but Viagra (UK) didn't. There is a good reason why it is less than likely to be the normal case. Third parties will look at the published activities of the molecule and will then use publicly available knowledge to identify a potential new use. E.g. compound X is proven to have some activity as an antagonist of receptor Y. According to Prof. B.I.G in last months "Science for Nerd's" he has demonstrated a link between receptor Y and disease Z and has postulated that antagonists of Y will be suitable for treating the disease. etc.

    Compound X bombs in its clinical trials after many millions being spent. The originator company drops it like a lead balloon because they don't have guaranteed investment for new indications. Other companies see the compound has been dropped and make the rational decision not to touch it with a barge pole. Clearly there is something wrong with the thing. Not worth the risk.

    Take a look at the recent Private members bill that didn't make its way through the UK parliament re. repurposing of off-patent medicines. Nice idea but had no substance as to how it would have operated and would never have worked.

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  21. Anonymous @17:12:00 shows a complete lack of understanding where and by whom R&D is done nowadays. Most of the money, brains and infrastructure come from public funds through grants, government contracts and (at least in Europe) public university research. To assume that no new drugs will come to the market would there be no full protection is disingenuous and not factually correct. One could even argue why so many drugs are privately patented when they have been publicly funded?

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  22. To 09:18:

    1. Please provide the evidence to back you opinion on financing. Figures should compare with the R&D spent by companies - Pfizer AZ, GSK, Merck Lilly, etc.

    2. Please provide examples of new drugs that have been developed without protection.

    3. Please provide examples of new drugs that have come to market without investment from companies such as those mention in 1.

    4. I hope the number of examples is significant in comparison to those stemming from private investment.

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  23. p.a. to Anon at 09:18


    Please describe how the government sponsored product development covered by the UK Private member's bill that has just failed to get through parliament would have worked in practice. Costs, decision-making processes, risk-assessment, etc.

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  24. Six months ago I killed plans to develop a product. The project has died. The company is winding up. I didn't make this decision. I didn't have power to cast a vote. The result just happened with no opinion from me one way or another over whether investment should be made in the project.

    The only part I played was to advise the potential investors that they would have patent exclusivity for a certain period. The regulatory advice was that they would have no data exclusivity. I can only guess that the investors felt the period of monopoly was insufficient for them to consider the risk worth taking.

    Next time I'll mention the wisdom of MaxDrei, and 09:18 Anon. Next time their decision may be different? Still, there is a chance to Max's friends and the public bodies 09:18 anon refers to will take this project on for the good of the suffering?

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  25. @anonyous 10:20:00 I cannot and therefore will not comment on a bill of the UK parliament. I am not familiar neither with the British legislative process nor with this bill in particular.

    What I can say however is that data shows that big pharma companies fund their risky research with taxpayers money and concentrate their own investment into sure gains.

    http://www.economist.com/news/business/21584307-new-book-points-out-big-role-governments-play-creating-innovative-businesses

    http://www.theguardian.com/commentisfree/2014/may/11/pfizer-bid-astrazeneca-big-pharma-rotten-banks

    This book is full of references for your perusal.

    Is it sensible that taxpayers' money is directed towards that then benefit solely from the products obtained thereof? I don't think so.

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  26. The UK Bill takes 5 minutes to read. Feast yourself.

    The two articles are nothing more than old rhetoric. Everyone knows taxpayer-funded research (at least that of the NIH) is high. But, to use my least favourite expression: the story is not 'on point'.

    As you are clearly unable to answer any of my questions it is clear that it is you (yes, you!) that is lacking in understanding.

    Hey Ho.

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  27. MaxDrei,

    Ever with your mind closed...

    Above you state " they can not only patent it straighaway but also exploit it, straightaway"

    Just.
    Not.
    So.

    Leastwise, in the U.S., the notion of a negative right is Supreme, and follow-on patents do NOT disturb the original right. AFTER that first right slips into the public domain is it fair game for anyone. But only after that time of protection.

    Is this concept not understood? Is this concept not understandable?

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  28. ...and yet another fallacy in use:

    "It's a tricky thing, to get right the balance between inventors and their competitors, such that patents promote rather than stifle technical progress in the useful arts."

    Patent block.

    That is what they do.

    The ability to promote comes (in no uncertain part), BECAUSE one is blocked.

    When faced with the option of:
    a) paying what the rights holder wants (if the rights holder is even willing to accept payment - which is part of the rights holder's set of rights), or
    b) doing without, or

    and this is critical

    c) inventing a new way around the block

    WAY WAY WAY too many people forget the adage that "necessity is the mother of invention" and think "oh, well, I am blocked - how "unfair"

    The answer, my friends, is in STRONG patent rights - embrace the nature of what a patent is, and please, please, please, stop the emotive "that's unfair" attempts at weakening patents.

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  29. The fallacy argument of "Is it sensible that taxpayers' money is directed towards that then benefit solely from the products obtained thereof? I don't think so."

    has been SOUNDLY defeated in the US.

    RE: the move to allow Universities to obtain patents that they will own stemming from government supplied grants.

    Those numbers are clear and unmistakable as to which system works in the real world.

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  30. Re THE US anon

    The fallacy argument you mentioned has not been defeated. What the US allows is exactly the solution many observers have been waiting for in Europe. Give public institutions, be it universities, health institutes, etc... patent rights to the research that has been publicly funded. That is my opinion the right approach. I was not aware that is the US approach. Always glad to learn from colleagues on the other side of the pond.

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  31. UK institutions (e.g universities) have full entitlement to inventions they have made with public funding. What they have to do to secure those rights is quite complicated, but I shall try to summarise:

    Step 1. File a patent application.
    Step 2. Obtain grant of said patent application.

    ReplyDelete

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