This article originally appeared in the Life Sciences Intellectual Property Review.
The drug discovery and development path for a New Chemical Entity (NCE) can take 10 to 15 years and cost 1 to 2 billion dollars. Repurposing is the practice of finding novel therapeutic indications for existing drugs . Typically the selected drug will have already been shown to be safe in patients, thereby significantly reducing the time it takes to bring the drug to market. Indeed it has been reported that repurposed agents are more than twice as likely across all disease indications to make it to market compared to NCEs. Furthermore, price support for a repurposed drug is in principle no different to an NCE, being likewise dependent on its substitutability and its clinical and economic advantages.
Policymakers, being aware of these benefits, have made efforts to encourage repurposing – for example the US National Institutes of Health (NIH) have programs aimed at utilising existing, partially developed therapeutic candidates in new disease indication . In the UK an “off-patent” drugs bill has was recently proposed with one of its aims being to give generic drug-makers new marketable indications for their products.
However even if the repurposed drug in question is “off-patent”, bringing it to market is still a considerable challenge, and such an investment requires a clear exclusivity strategy. Unfortunately, clarity is something which is in short supply when considering obtaining and enforcing patents in this field.
PATENTS – HISTORY AND FORMATS
In order to protect innovations in repurposing, “second medical use” patents are available in most territories, although notable exceptions exist, including the so-called “pharmacy of the world” India . The precise wording of such claims is a matter of national laws and a bewildering array of formats are used, examples of which are provided in Table 1. For example in Europe two claim formats have been permissible:
- “Use of substance X in the manufacture of a medicament for the treatment of condition Y” (Swiss-form claim);
- “Substance X for use in the treatment of condition Y (EPC2000 form claim)”
Click here to view table.
The Swiss-form of claim was first permitted in the EPO landmark Enlarged Board of Appeal (EBA) decision G5/83 which found that such claims could be granted “for a specified new and inventive therapeutic application, even in a case in which the process of manufacture as such does not differ from known processes using the same active ingredient”. As elsewhere the patentability of Swiss-form claims at the EPO is predicated critically on the new “purpose” (or “repurpose”) of the known medicament.
The EPC 2000 form of claim was introduced in 2007, and was intended to match as closely as possible the scope of protection to the scope provided by a ‘Swiss type claim”. Later the EBA decided that Swiss-type claims were effectively redundant in view of the new law, and would no longer be permitted in new applications . However the very fact that the claims available to applicants are worded differently leads to uncertainty about their scope.
For example the UK courts have to-date treated Swiss-form claims as process claims whereas EPC 2000 claims are purpose-related product claims. Although in some respects the difference may be academic, for example because the product obtained directly from the process claimed under the Swiss-form claim may be protected in the same way as the product claimed under the equivalent EPC 2000 claim, in other contexts there may be key differences. For example it is questionable whether the Swiss-form claim actually requires that the recited drug be present in the final medicament (as is believed to be the case for the EPC 2000 form) or whether it could merely be present during the manufacture? The latter argument was rejected in one UK case , based on particular facts, but certainly remains arguable. The complex relationship between the claims has also lead to confusing practice at the EPO in respect of applicants pursuing protection for both types of claim. For example in one recent decision the EPO prohibited both types in the same application as the Board was not persuaded that the claims were treated differently by national courts whereas other Boards of appeal have allowed that the applicant had a legitimate interest in pursuing both types of claims, accepting that the protection offered was not identical.
Irrespective of the format of the claim, a first hurdle for obtaining a patent for a new medical use for a substance is that the new use must be supported by evidence, in the application as-filed, that the substance is effective for the specified use. In some territories, such as the EPO, the burden is not a high one; rudimentary tests may suffice - full, detailed and rigorous testing of the drug for the proposed condition is not necessary as long as the teaching is plausible . By contrast in China, at least historically, examiners have required that the applications as filed provides more complete evidence of efficacy.
A second hurdle for applicants is to establish novelty and inventiveness over the previous use: for known drugs, there will usually be a considerable literature or history of testing in a therapeutic context. Again, the EPO and UK Courts have frequently adopted a pro-patentee approach when assessing novelty. An earlier medical use should not anticipate a – different - later one because, unlike other areas of patent law, the doctrine of inherency does not apply. Nevertheless there is a squeeze between these two requirements. In claims to medical uses, the term “for” is typically taken to mean not just ‘suitable and intended for’ but also imbues a requirement for a level of therapeutic efficacy. The effect of this is that such claims are generally regarded as novel over a mere proposal to administer the drug to patients in the manner claimed, because a mere proposal does not disclose that the treatment is efficacious. However the disclosure requirements placed on the application itself, and the potentially anticipatory prior art, should be a seamless fit: it cannot be argued by that experimental data provides support for a claimed use, but the same data does not anticipate it.
Obtaining claims of one type or another is however only the first challenge for applicants in this area. An arguably greater difficulty arises in seeking to enforce them to protect the new market created by approval of the known therapeutic for the new use. Purpose or intention can be a challenging concept when applied to a product or even an act but is nevertheless the defining technical feature of any form of second medical use claim. The supply chain from manufacture (of the drug substance) to distribution, labelling, prescription and final use is likely to involve multiple parties, possibly in multiple jurisdictions, who may have disparate knowledge or intention regarding the final purpose of the medicament,
Where a drug is produced or marketed by a party with label instructions which describe a patented use, or is clearly adapted for that patented use (perhaps in terms of dosage or administration route) it may not be difficult in practice to identify infringement.
However a particular challenge arises in “cross-label” use, whereby a medicament has regulatory approval for both a non-patented and patented indication, and a generic version is marketed (“skinny labelled”) for only the non-patented indication but then ultimately used for the patented indication. To make matters worse, off-label (including cross-label) may be officially sanctioned by authorities. For example the MHRA and NHS UK websites provide guidance to doctors regarding off-label prescribing, with little or no reference to patents or IP. The French National Assembly recently backed a draft bill to let doctors use drugs off label even where alternative drugs are approved. The FDA does not prohibit physicians from prescribing the drugs for off-label uses, including patented uses.
Patentees are unlikely to wish to sue doctors and patients, but it may be challenging to show direct infringement by any party higher in the supply chain. In the absence of evidence of constructive or actual knowledge or intention by these other parties, for example based on sales volumes or promotional literature, a court may simply find the “skinny label” is decisive that the medicament was not ‘intended for’ the claimed medical use .
It such cases it may be possible for the patentee to show ‘indirect infringement’ . Here it would be necessary to show that a party in the supply chain “knew”, or it would have been “obvious to a reasonable person in the circumstances”, that the products were to be used in an infringing manner. The developing case law in the UK around indirect (or ‘contributory’ infringement) has been surprisingly pro- patentee allowing that even the knowledge or suspicion of probable infringement may be sufficient to find liability. Nevertheless difficulties remain when applying this to second medical use claims, particularly Swiss claims where the infringing act itself would seem to be focussed on the manufacture, rather than final use. In these cases it may be necessary to look at the possibility of “joint tortfeasorship” and seek to demonstrate that multiple parties in the chain were acting in a concerted fashion or common design to infringe the claims, but again this can provide evidentiary difficulties for patentees.
Another legal strategy for patentees trying to identify infringement in a supply chain is to show inducement of infringement, for example by suppliers seeking to influence health providers. However in the UK there is no tort in merely facilitating an infringing act and the evidentiary burden to demonstrating induction or procurement of such an act is likely to be high. Interesting the recent US Supreme Court decision of Limelight Networks, Inc. v. Akamai held that there can be no liability for induced infringement when there has been no direct infringement. Since the final health care providers in the chain may benefit from statutory defenses to infringement, or may not in any case perform all the required steps in a medical use claim, there is likely to be considerable challenges for patentees seeking to demonstrate inducement in the context of medical use claims.
Drug repurposing will be increasingly important for finding new cures in the years to come, so it is critically important that exclusivity strategies, including patent strategies, exist to provide incentives for companies to innovate in this area. If society is to benefit from new treatments for diseases based on existing drugs, it will be in everyone’s interests that greater clarity and uniformity is brought to this complex and inconsistent area of patent law.