March 9, 2015

Summary

Mr Justice Arnold’s decisions in Warner-Lambert Company, LLC v Actavis Group PTC EHF & Ors [2015] EWHC 72 (Pat) and [2015] EWHC 223 (Pat) (respectively the first and second decisions) have provided some long awaited guidance on the requirements to establish infringement of second medical use claims in Swiss form.  He held that Swiss form claims will only be infringed where the manufacturer of the medicament actually (i.e. subjectively) intended that the product would be used for the patented indication.

This interpretation is by no means without controversy, and has been met with appreciable consternation among originators, and supporting practitioners.  The point will certainly be appealed, and if Arnold J’s approach is upheld, the practical effect will be to limit significantly the protection provided by Swiss form claims, absent a change in the system for prescribing and dispensing medicines.

Second medical use claims and the regulatory system

Second medical use claims have long been recognised in the UK as an important tool for incentivising research into new uses for known medicines, albeit the form of such claims has varied over time. Prior to the EPC 2000, such claims were allowed only in the ‘Swiss form’, i.e. ‘the use of compound X in the manufacture of a medicament for the treatment of disease Y’. The EPC 2000 allowed, for the first time, claims in the form ‘product X for treating disease Y’. Between December 2007 and January 2011 both forms of claim were allowed by the EPO, but the current practice of the EPO is to only allow the EPC 2000 form of claim. However, until all the patents containing Swiss form claims expire, Swiss form claims will continue to be an important weapon in the armament of pharmaceutical companies.

Given that Swiss form claims have been around for a long time, it is surprising that there has been little judicial guidance in the UK (or elsewhere) on their scope of protection.  As a result, there is significant uncertainty over the way in which such claims should be interpreted, and a number of practical difficulties arise when seeking to enforce them. This is particularly so in the light of regulatory constraints imposed by national healthcare systems.

For a drug protected by a second medical use patent, generic products may legitimately enter the market when the compound and first medical use patents expire.  However, until the second medical use patent expires, the generic version may be supplied legitimately only for the off-patent indication.  To cater for this situation, the procedure for obtaining marketing authorisation for generic products allows the product label to be limited to the off-patent indication (i.e. the patented indication is carved-out), a so-called “skinny label”[i].  However, the system by which medicines are prescribed and dispensed in the UK (and most other European countries) does not prevent (or even discourage) drugs with a skinny label from being supplied to patients who have been prescribed the drug for the patented indication.

In the UK, because substitution by pharmacists is not allowed[ii], to control costs doctors are encouraged to prescribe by the international non-proprietary name (INN) (i.e. generic) name such that the incidence of INN prescriptions is generally greater than 80%.  An even higher percentage of prescriptions (close to 95%) do not identify the indication for which the drug has been prescribed.  Accordingly, a pharmacist dispensing the drug will not normally know what indication the drug has been prescribed for, and if the prescription mentions only the INN name, there is nothing on the face of the prescription to tell the pharmacist not to dispense a skinny label generic product against that prescription.  As a result of this system, confining the use of generic drugs only to the off-patent indication has proved to be very difficult.

The background facts

Warner-Lambert (part of the Pfizer group) markets the drug pregabalin, under the trade mark ‘Lyrica’, for three indications: (i) epilepsy, (ii) generalised anxiety disorder and (iii) neuropathic pain. Patent protection for the drug itself expired, and protection under the SPC was allowed to lapse, in 2013.  However, Warner-Lambert has a second medical use patent in force with Swiss form claims directed to pregabalin for treating pain and, in particular neuropathic pain (the “Patent”).

Following the expiry of data exclusivity for pregabalin in July 2014, Actavis sought to obtain marketing authorisation for its generic pregabalin product with a skinny label, and it plans to market the product under the brand name ‘Lecaent’.

The evidence suggested that the UK market for pregabalin was worth $310 million in 2013, and that 54% of pregabalin was used to treat pain (of which 44% was neuropathic pain).

Warner-Lambert believes that the launch of Lecaent with a skinny label would infringe the Patent because a significant amount of Lecaent would be used for the treatment of pain. Actavis does not dispute that Lecaent is likely to be used for the treatment of pain, but disputes that this amounts to infringement of the Patent.

In separate proceedings, Actavis has challenged the validity of the Patent and, if successful in those proceedings, plans to market Lecaent for all indications.  The trial of the revocation action is listed for June 2015.  Pending the outcome of the revocation proceedings (in which Warner-Lambert has counterclaimed for infringement), Warner-Lambert sought interim relief, in the form of an unprecedented order, requiring Actavis to take certain steps designed to reduce the risk that its generic pregabalin product would be used to treat pain. In particular, Warner-Lambert requested (among other things) that Actavis:

(1)      include contractual provisions to require pharmacies dispensing Lecaent to use reasonable endeavours not to supply Lecaent to patients who have been prescribed pregabalin for the treatment of pain, by making reasonable enquiries of the person presenting a prescription and/or checks of pharmacy records to determine whether the prescription is for pain;

(2)      send letters prior to launch to pharmacies, Clinical Commissioning Groups (“CCGs”), NICE and the Department of Health informing them that Lecaent should not be prescribed or dispensed for the treatment of pain; and

(3)      include a removable notification on the packaging of Lecaent stating that the “product is not authorised for the treatment of pain and must not be dispensed for such purposes.”

By the hearing, both parties had taken steps to try to reduce the likelihood of Lecaent being prescribed or dispensed for the patented indication. Actavis had sought only a skinny label and had offered to comply with the requirements in (2) above, whilst Warner-Lambert had communicated its concerns to the Department of Health, NHS England, NICE, the CCGs and its own pharmacy customers. However, Actavis took issue with the relief sought at (1) and (3), not least as Warner-Lambert had first made these requests only shortly before the hearing.

The decisions

The decisions address two significant points of interest. First, what is the proper scope of protection conferred by a Swiss form claim?  Secondly, what steps (if any) does a generic company have to take to reduce the likelihood of its product being used for the patented indication?

Swiss form claims: scope of protection

It was common ground that Swiss form claims are process claims, and therefore Warner-Lambert advanced its case on the footing that Lecaent was a direct product of the claimed process.  It was also common ground that the word ‘for’ in Swiss form claims means ‘suitable and intended for’ (although Warner Lambert reserved its position to contend otherwise at trial).

It was not disputed that Lecaent is suitable for the treatment of pain. The key issue between the parties was whether Lecaent is a product obtained by the use of pregabalin for the manufacture of a medicament suitable and intended for the treatment of pain. The resolution of this issue required Arnold J to address two points: whose intention, and what type of intention, is relevant?

Following the dicta of Jacob LJ in Actavis v Merck [2008] EWCA Civ 444 at [75], Arnold J considered that Swiss form claims are directed only to the manufacturer of the medicament and so only the manufacturer’s intention could be relevant.

As to the nature of the requisite intention, Arnold J was persuaded that it was not enough to show that a foreseeable consequence of launching Lecaent was that it would be used to treat pain, or that Actavis had actual knowledge that Lecaent was being (or would be) used to treat pain.  Arnold J reasoned that if either of these scenarios were enough to establish infringement, then in circumstances where the first medical use and second medical use patents were owned by two unrelated entities, neither would be able to market their products without infringing the other’s patent (at least under the current prescribing and dispensing system) and the owner of the first medical use patent would have to withdraw their product from the market upon the grant of the second medical use patent.  Accordingly, Arnold J held that it was the subjective intention of the manufacturer that is relevant, i.e. the manufacturer of the generic product must actually intend that it is to be used for the patented indication.

Warner-Lambert had not initially pleaded that Actavis, as the manufacturer, subjectively intended Lecaent to be used for the treatment of pain.  Therefore, in his first decision Arnold J had an easy task of rejecting Warner-Lambert’s application for interim relief on the basis that there was not a serious issue to be tried on Warner-Lambert’s primary case of infringement under s.60(1)(c).  He also rejected the alternative case based on s.60(2), on the basis that persons downstream of Actavis in the supply chain could not put the invention into effect because the invention was the manufacture of the medicament, and they would not be doing that (the medicament having already been made by Actavis).

Warner-Lambert applied to amend its case to plead subjective intention, and this application (together with an application by Actavis to strike out Warner-Lambert’s infringement case) was the subject of Arnold J’s second decision.

Measures required to avoid infringement

Having held that subjective intention was necessary to infringe the Patent and not pleaded, Arnold J did not need to consider the effectiveness of the relief sought or the steps that Actavis would have to take to avoid infringement in his first decision.  However, in case he was wrong about the interpretation of Swiss form claims, he nevertheless considered these matters in the context of weighing up the balance of the risk of injustice (which he held would favour refusal of the relief sought by Warner-Lambert) and considered them further in his second decision.

While the judge expressly approved of the steps that Actavis had agreed to take, namely (1) applying only for a skinny label, and (2) agreeing to write to pharmacists and relevant healthcare bodies to advise them that Lecaent should only be dispensed for the off-patent indications, he stopped short of saying that such steps were necessary to avoid infringement. In fact, Arnold J acknowledged in the second decision that no inference of subjective intention to use Lecaent for pain could be drawn in the event that Actavis failed to take any active steps to prevent Lecaent being dispensed for the treatment of pain. However, he did acknowledge that if Actavis were to market Lecaent under a full label (i.e. covering the patented indication) or if Actavis were to positively encourage the use of a skinny label version of Lecaent for the treatment of pain, then taking those steps would be strong evidence that Actavis subjectively intended Lecaent to be used for that purpose.

With regard to Warner-Lambert’s requests that Actavis place a notice on the packaging of Lecaent, and impose contractual terms on the pharmacists to verify the indication for which pregabalin had been prescribed, Arnold J was not convinced that either would be effective at preventing Lecaent from being dispensed for the patented indication.

The notice on the packaging would not help the pharmacist know whether the prescription they are presented with has been written for treating pain or one of the off-patent indications. Further, it was noted (but not decided) that this may put Actavis in breach of the legislation on labelling and packaging requirements and/or the ABPI’s code of conduct, and in any event it would cause delays to Actavis’ product launch because it would take time to obtain MHRA approval.

With regard to imposing contractual terms, Arnold J noted two problems. The first is that such terms would be difficult to enforce, and would likely deter pharmacists from stocking Lecaent. The second is that practically it may be difficult for the pharmacist to ascertain from the person presenting the prescription the indication for which pregabalin has been prescribed.  This is because the person presenting the prescription may not be the patient, and even if the patient is present, they may not know (for example because it is one of many medicines that they take, or because they have been taking it for such a long time that they do not remember the original reason it was prescribed) or may not wish to say what condition they are being treated for.

The judge’s impression that the measures sought by Warner-Lambert were unlikely to be effective will have been strengthened by Warner-Lambert’s refusal to concede that Actavis would avoid infringement if it complied in full with the terms of the order sought.  In contrast, Warner-Lambert had, prior to seeking interim relief against Actavis, agreed that another generic company would not infringe the Patent if certain protective measures were taken.  It is not clear from the judgment what steps that other generic company had agreed to take to avoid infringement, but it can be inferred from the position adopted by Warner-Lambert that the relief sought against Actavis was not as extensive.  In the second decision it is noted that one of the steps taken by the other generic company (and not taken by Actavis) was to remove from the product information leaflet a statement that pregabalin may be prescribed to treat conditions that are not listed. However, it seems fairly unlikely that this would have been the deciding factor.

Discussion

Is it right to focus on the intention of the manufacturer?

The effect of the judge’s finding that it is only the intention of the manufacturer that is relevant has the potential to limit the scope of protection of Swiss form claims significantly and to distinguish markedly the scope of Swiss form claims from the scope of EPC 2000 claims.  In the second decision, Arnold J did accept that it was at least arguable that the term ‘manufacturer’ might include the person who packages and labels the product, and this might help to temper these effects.

However, even if an extended meaning is given to the term ‘manufacturer’, this approach has the potential to give rise to absurd results in anything but the simplest of cases, where the manufacturer of the finished dosage form, the holder of the marketing authorisation and the distributor are the same entity or within the same group of companies.  For example, take the following two scenarios:

Scenario 1 – The finished dosage form is manufactured outside the UK by a person who subjectively intends it to be used for all known indications, at least in countries where there is no second medical use patent. The product is then imported into the UK by the holder of a marketing authorisation with a skinny label who subjectively intends the product to be used only for the off-patent indications.

Scenario 2 – The finished dosage form is manufactured by a person who subjectively intends it to be used only for the off-patent indications. The manufacturer of the product applies for a marketing authorisation in the UK with a skinny label.  However, the manufacturer then transfers the granted marketing authorisation to a distribution partner who subjectively intends the product to be used for the patented indication.

In the first scenario, on Arnold J’s test, it would seem that the sale of the product ought to infringe notwithstanding that the party who is active in the UK and who applies for the marketing authorisation does not have the requisite subjective intention.  By contrast, in the second scenario, it would seem that the sale of the product ought not to infringe because the distributor is not the ‘manufacturer’ (i.e. the person making the product or responsible for its packaging and labelling).

A further consequence of this focus on the intention of the manufacturer is that claims of indirect infringement become more difficult to establish.  This marks a further point of distinction with the scope of protection conferred by ECP 2000 claims and would seem to be inconsistent with the previous approach.  Indeed, as noted by Birss J in Hospira v Genentech [2014] EWHC 3857 at [127] infringement of Swiss form claims has often been argued only under s.60(2) to avoid the problem of deciding whether they are product- or process- claims.  This also seems to be a preferred approach in other countries (see for example the decision of the Dutch Court of Appeal dated 27 January 2015 in Novartis v Sun Pharmaceuticals concerning zoledronic acid, where the court allowed Novartis’ claim for indirect infringement of a Swiss form claim under the Dutch equivalent of s.60(2)).

Does construction of Swiss form claims require a ‘special approach’?

Swiss form claims are a unique creature of pharmaceutical patent law.  They were devised to allow patent protection for second medical use inventions and to encourage research in this area.  The formulation ‘use of X for the manufacture of a medicament for the treatment of Y’ was adopted as a legal construct to avoid second medical use inventions falling within the method of treatment exclusion to patentability.  However, a “special approach”[iii] was required to confer novelty upon such claims: it is the use to which the medicament will be put that is novel and not the method of manufacture.  In view of this, construing them as manufacturing claims seems rather artificial and, if the effect of construing them in this way is to significantly limit their scope of protection, then it hardly seems apt to meet the policy aims underpinning their adoption.

Purposive construction requires that the words of the claim are construed having regard to the patentee’s purpose as set out in the rest of the specification.  Further, the skilled person reading the claims is taken to appreciate the explicit drafting conventions by which the patent and its claims are framed.  In the context of Swiss form claims, the skilled person would therefore know that what is being claimed is the second medical use and not the method of manufacture.  As Kitchin J (as he then was) said in Ranbaxy v AstraZeneca [2011] EWHC 1831 (Pat) at [54]:

“But for the [method of treatment] exclusion contained in Article 52(4) EPC 1973, the claim would have been directed to the new and non obvious use…”

However, stripping a Swiss form claim of its method of manufacture cloak for the purpose of determining its scope of protection exposes it to an invalidity attack on the basis that it then impermissibly covers a method of treatment.  It was in this context that Jacob LJ said in Actavis v Merck that Swiss form claims are directed at the manufacturer and do not touch the doctor.  It does not appear however that he had in mind that it was the mens rea of the manufacturer that would be important in determining infringement.

Meeting the policy aims underlying Swiss form claims may call for a “special approach” to claim construction.  For example, construing Swiss form claims as claims to the manufacture of a medicament (to ensure that the distinction from methods of treatment is maintained), but to read the purpose limitation as applying, not to the process of manufacture, but to the direct product of that process, i.e. the medicament itself.  Such a construction might be consistent with what the skilled person would have understood the patentee to have used the language of the claims to mean, especially if it is apparent from the description that the thought process for using the medicament for the new indication arises once the medicament is in hand, rather than at the manufacturing stage.

Is a requirement for subjective intention setting the bar too high?

Most acts of primary infringement are a matter of strict liability, i.e. the state of mind of the infringer is irrelevant.  A notable exception is provided in s. 60(1)(b) in respect of the offer of a process for use in the UK where to infringe the person must know or it must be obvious to a reasonable person in the circumstances that the use of the process in the UK would (without the patentee’s consent) be an infringement.  A similar knowledge (of the infringer) requirement, together with a separate intention (of the end user) requirement, must be established for indirect infringement under s. 60(2).  In neither of these cases is there a requirement to show subjective intention on the part of the infringer.  Against this background, the requirement for subjective intention in the case of second medical use claims is a novelty in patent law, and is perhaps a little surprising given that the mental element required for direct infringement is generally less demanding than for indirect infringement.

As mentioned above, in holding that subjective intention was required the judge was persuaded that requiring anything less would, in the case of second medical use claims, make it nigh on impossible to avoid infringement with a skinny label given the current system for prescribing and dispensing medicines in the UK.  Although this reasoning deserves great sympathy, it may not withstand scrutiny.

Ultimately, the meaning of ‘for’ in a second medical use claim and the mental element that must be established to prove infringement is a matter of construction.  Although it might be appropriate to take the regulatory environment into consideration when considering whether a particular act constitutes infringement, it seems more doubtful that the system for prescribing and dispensing medicines is a relevant factor for the purpose of claim construction.

Even if it is assumed that the regulatory regime would be in the mind of the skilled person (because Swiss form claims are unique to pharmaceuticals) and might influence how they would interpret the claims, it does not seem to follow that the skilled person would understand the patentee to mean that the most exacting standard of intention (i.e. subjective intention) is required.  In the case of a second medical use patent, but for the prohibition on patenting methods of treatment, the patentee would have claimed the use of the drug for the new indication.  Imposing a requirement for subjective intention would not appear to be consistent with this purpose, unless, like with indirect infringement under s. 60(2), the intention of persons downstream (e.g. the doctor, the pharmacist or the patient) can be taken into account.  Further, the fact that the regulatory environment means that it will be difficult for others to avoid infringement is unlikely to motivate the patentee to seek narrower protection.

If the requirement for subjective intention sets the bar too high (and does not create a fair and balanced system), is there a better solution?  Superficially, at least, it is attractive to propose a system where the generic company is required to take reasonable steps to ensure that its product is not prescribed for the patented indication.  However, as noted by the judge, steps taken by generic companies to influence doctors and pharmacists may not be particularly effective in practice (at least without prejudicing the generic company’s ability to access the off-patent segment of the market).  Therefore, such an approach may not do much to improve the effective protection conferred by second medical use claims and may create greater uncertainty as to what needs to be done to satisfy the requirement to take reasonable steps.

Where does this leave EPC 2000 claims?

Arnold J was clear that his judgment should not be taken to necessarily apply to EPC 2000 claims, and noted that the Technical Board of Appeal of the EPO has held that the two forms of claim have a different scope of protection (see T 1780/12). However, it is clear from comments made in G 02/08 and the explanatory notes to the Swiss proposal for Article 54(5) EPC that the intention of the legislator in introducing purpose limited product claims was to provide a claim format which afforded equivalent protection to the Swiss form claim.

Although it is easy to justify why the person whose intention is relevant differs depending on whether it is a Swiss form (i.e. process) or EPC 2000 (i.e. product) claim under consideration (there being no reason to focus on the manufacturer in the latter case), it is not so easy to see why a different standard of intention would apply.  The reasoning of Arnold J for preferring subjective intention over any lower standard would hold true for claims in the EPC 2000 form as much as for those in Swiss form. If intention is an inherent feature of EPC 2000 claims, might it be possible to clarify in the claims (and the specification) whose intention and what type of intention this is?

Need for regulatory reform?

As may be apparent from the discussion above, much of the difficulty in striking a fair balance between allowing a generic product onto the market with a skinny label and protecting the originator’s monopoly for the patented indication lies with the way in which medicines are prescribed and dispensed in the UK.  Unfortunately, the regulatory system and patent system are incompatible in this respect and it is not easy to conceive of a fix to the patent system that would deal with the problem.  However, there are some changes that could be made to the regulatory system which would allow the two systems to operate more harmoniously in this area.

For example, the problem would be largely avoided if doctors were to prescribe by brand name when the drug is to be used for the patented indication and by INN for the off-patent indication.  Pharmacies would then be required to dispense the patentee’s product for the patented indication but would be free to dispense the generic product against the INN prescriptions.  This solution to the problem was endorsed by the judge, but it remains to be seen whether Warner-Lambert will be successful in its attempts to persuade NHS England and NHS Wales to issue guidance to prescribers to this effect, at least so far as pregabalin is concerned, and if so whether this guidance will actually be followed by prescribers.  In the second decision it was noted that there had been a mixed reception to Warner-Lambert’s requests that doctors prescribe Lyrica when treating pain: the Chair of the Pharmaceutical Advisers Group and Chief Pharmacist of Wandsworth CCG supported this proposal whereas the North of Tyne Area Prescribing Committee decided not to change its prescribing guidance on grounds that it was not “clinically necessary to prescribe pregabalin by brand name”.  It may therefore prove to be quite difficult in practice to change prescribing habits in this way.

Furthermore, if such changes are to be made to prescribing habits, then it would make more sense to effect such changes at a policy level, rather than on a product-by-product basis.  Mechanisms for notifying prescribers and updating the software used by prescribers could then be developed to keep track of changes in patent coverage.  Adjustments may also have to be made to the reimbursement system to allow the originator’s product to be reimbursed at a higher price when it is dispensed for the patented indication.  An alternative fix would be for the indication to be noted on the prescription (a coding system could be used to address privacy concerns) so that the pharmacist knows what the drug has been prescribed for and can dispense the appropriate product (with encouragement to do so, if necessary).

Whilst regulatory reform certainly seems desirable from the perspective of both generic and originator companies and the wider international intellectual property community[iv], any such reform is likely to take some time to come to fruition and may meet considerable resistance from the doctors, pharmacists and providers of prescribing software who will likely bear the responsibility and cost of implementing any new system.  Furthermore, there may be resistance from policy makers to change the current system to address what they may perceive to be a problem of modest scale.  In the meantime, the courts will have to grapple with some difficult issues arising from the enforcement of second medical use claims.

Published with minor alternations in CIPA Journal, February 2015, Vol. 44, No. 2, which can be viewed here.

Footnotes:

[i] Art. 11 of the Medicinal Products for Human Use Directive 2001/83/EC

[ii] If a pharmacist is presented with a prescription specifying the brand name, they must dispense the branded product and cannot substitute it for a cheaper generic version

[iii] Paragraph 21 of EISAI/second medical indication, G5/83 [1985] OJ EPO 64

[iv] See for example the International Resolution of AIPPI on second medical use and other second indication claims (Q238) dated 17 September 2014 which urged “relevant health authorities to implement the necessary measures so that effective protection of second medical uses is not jeopardized by regulatory frameworks”