Nicola Dagg of Allen & Overy explores the issue of "Second Medical Use" patents as an important component of the potential second-line patent protection.
Patent cliffs remain one of the biggest issues facing the pharmaceutical industry. In 2012 and 2013 a number of high-value branded drugs have lost or will lose their patent protection (for example Sanofi and Bristol-Myers’ “Plavix”, Novartis’ “Diovan”, Eli Lilly’s “Cymbalta”, Novartis’ “Reclast” and Merck’s “Propacae”). The resultant erosion of earnings is vast. In the light of this, originators’ ability to extend the patent life of their medicines through securing good secondary patents (composition patents, patents for new polymorphs/formulations, synthesis patents and patents for new therapeutic uses) is key.
“Second Medical Use” patents (new therapeutic uses for known active ingredients) are an important component of the potential second-line patent protection. In the UK, patentability of a second medical use was confirmed by the Court of Appeal decision in Actavis v Merck. The Court held that second medical use claims were allowable even where the novelty resided solely in a new dosage regime or other form of administration of a known substance. The Court of Appeal noted that “Research into new and better dosage regimes is clearly desirable, and that there is simply no policy reason why, if a novel non-obvious regime is invented, there should not be an appropriate patent reward”. Second medical use patents are now expressly permitted by section 4A (4) of the Patents Act 1977, provided the claim is in the form “substance x for use in the treatment of disease y”, following the Enlarged Board of Appeal of the European Patent Office’s G2/08 Kos decision. The latter confirmed that EPC art 54(5) expressly allowed patent protection for second medical uses, and that new dosage regimes per se, were patentable as a “new use”, as long as this use satisfied the requirement of novelty and inventive step.
The very recent case of Hospira v Novartis in the UK illustrates that intrinsically “open-ended” dosage regime claims (in this case the claimed second medical use was the method of administering zoledronic acid, a bisphosphonate, intravenously at intervals of at least six months for the treatment of osteoporisis) remain vulnerable to invalidity attacks for insufficiency. In this case Arnold J found that the claims, which he concluded extended to any dose and dosage interval that worked, had a broad scope placing an undue burden on “a skilled team to carry out a substantial programme of clinical trials to find out what doses and dosing intervals are efficacious, and then claim the results”. They were accordingly invalid for insufficiency (but not for obviousness).
But do these second-use patents really afford the originator the effective protection that it seeks against aggressive generic entry? Arguably they do not for two reasons. First, European regulatory legislation is drafted to facilitate access to generic drugs in the EU, and second, there is current uncertainty around how an originator establishes a case for infringement of a second medical use patent.
What is happening in practice? As soon as the originator’s first-use patent expires, generics can enter the market with their competing products to the patented first use. However in so doing they may still face the originator’s second-use patent wall. European regulatory law affords generics (having already obtained a marketing authorisation for their generic drug by an “abridged procedure” by reference to the originator’s drug) the option of adopting “skinny” labelling. That is, they are entitled to “carve out” of the Summary of Product Characteristics and patient information leaflet, any references to indications or dosage forms, which are protected by patents in force. The permission for a carve out must be obtained at national level in recognition of the fact that the second use patent may not be valid in all the member states. Furthermore when a carve out is requested, the individual member state decides if a statement to explain why certain therapeutic indications or dosage forms are missing from the package leaflet should be included. If such a statement is included it should use the “blue box concept”: “(Active substance) which is contained in (product) (may also be/is also) authorised to treat other conditions which are not mentioned in this leaflet. Ask your doctor or pharmacist if you have further questions”.
These carve outs ignore market realities. In the UK where 86 per cent of physicians’ prescriptions are by reference to a drug’s active ingredient name, the dispensing pharmacist, not being aware of the indication for which the product is prescribed, can supply the active ingredient without regard for whether it is the innovator product or generic product for any ongoing second medical use patent. Under these circumstances it is almost inevitable that significant amounts of the generic drug will be dispensed for the patented second medical use.
Currently originators cannot rely on the use of patent litigation in these circumstances to stop generic product being dispensed for the second medical use. This is because it is unlikely that the UK courts will find this generic substitution to be a direct infringement of their patent rights under section 60(1) Patents Act 1977 - the generic’s “skinny” label denying the originator the possibility of showing that the drug is manufactured or sold for the patented second medical use (Court of Appeal in Actavis v Merck). This interpretation is supported by the Dusseldorf court’s 2004 judgment in Ribavirin, where the court stated that the defendant’s leaflet did not set out the patient group named in the patent, and hence the product was not “manifestly prepared” for the use specified in the patent.
However two 2010 judgments of the English Court of Appeal, concerning liability for indirect patent infringement under section 60(2) of the Patents Act 1977 (by supplying any of the means relating to an essential element of the invention) could improve the ligation prospects of originators holding second medical use patents. In Grimme Maschinenfabrik v Scott it was held that the knowledge and intention requirements of the provision were satisfied if, at the time of supply or offer of supply, “the supplier knows, or it is obvious in the circumstances, that ultimate users will intend to put the invention into effect”. In other words if it was reasonably foreseeable that the generic drug would be dispensed for the patented second medical use this would suffice to show indirect infringement. In KCI v Smith & Nephew the Court of Appeal reaffirmed this, and observed that there was no requirement that the users at the end of the supply chain need to have an already formed intention (in relation to the patented use), but that an “inherently probable” view is sufficient. These requirements must be proved on the usual standard of probabilities, and “it is likely to be the case where the supplier proposes or recommends or even indicates the possibility of such use in his promotional material” that there will be secondary infringement.
On the basis of these judgments, will the originator be able to argue that the generic “knows” or that “it is obvious in the circumstances”, that when it puts its products on the market with a skinny label that at least some of this product will used for the patented second medical use indication? The scope of section 60(2) of the Patents Act 1977 in the highly regulated pharmaceutical field is (as yet) unclear; highly fact dependent; and the evidential requirements for the originator can be difficult to meet. For example one may have to look to the plausibility of quantities sold by the generic in the light of the market demand for the first use indication. One would also have to look very carefully at all the circumstances surrounding the promotion, sale and marketing of the generic drug. Maybe the current European approved wording for the “skinny label” (“may also be/is also, authorised to treat other conditions which are not mentioned in this leaflet”) could be enough to indicate the generic supplier’s proposed or recommended second medical use?
Even if the originator can prove infringement of its second medical use patent, it may face the additional challenge of obtaining an injunction to prevent this use. The difficulty lies in the fact that only that proportion of the marketed generic drug that is being used for the second medical use is infringing. In these circumstances the originator’s liability in a cross undertaking in damages to cover the permissible use of the generic drug will be significant. For these reasons it has been suggested that judges will have to be flexible with regards to the scope of injunctions (namely, that they grant an injunction only in respect of the infringing use). One possibility is to suspend the injunction pending the ascertainment of the infringing use, provided that the generic pays a royalty to compensate the patent owner for infringing use (but is this not effectively compulsory licensing?). It is interesting to note that in France where the generic has clearly carved out certain indications it is virtually impossible in practice to obtain an injunction on the basis of an originator’s dosage regime patent (judgment of the Paris court of first instance, Actavis v Merck (2010), currently under appeal).
One solution for originators is to work to reform the current European regulatory labelling system so as to inform health-care providers, pharmacists, and the public that a generic drug with the skinny label is only authorised for use in relation to the uses or indications specified in the label.