The time and financial expense of bringing a novel drug to market is enormous and the process is fraught with risk. Very often, a putative novel chemical entity showing promising efficacy in pre-clinical or animal models will fail to reach the clinic due to unforeseen toxicology or dosing issues. As such, the repertoire of usable drugs in the clinic is finite and comparatively limited.
On the other hand, if a drug which has successfully negotiated the approval process and has reached the clinic can be found to have other clinical uses, the risks, timescales and costs of obtaining regulatory approval for such uses is significantly less. Thus, there is strong impetus in the pharmaceutical industry to repurpose their existing medicinal products to the treatment of second or further medical conditions (or “indications”), thereby expanding their drug portfolio in the most efficient way. As a result, more therapies can be made available to the public in a shorter period of time.
Classic examples of repurposed drugs include aspirin (a non-steroidal anti-inflammatory repurposed as an anticoagulant useful in preventing heart attack, stroke and DVT), thalidomide (a treatment for leprosy repurposed as a treatment of multiple myeloma), viagra (a treatment for angina repurposed as a treatment for erectile disfunction) and, more recently, remdesivir (a hepatitis C medicament repurposed to treat COVID-19). The latter example really shows the potential power of the system – a life-saving drug for a novel respiratory disease was in use in the clinic within a matter of months rather than the decade or so it sometimes takes to develop a new treatment from scratch.
Society at large is keen to have as many pharmaceutical treatments available as possible. To further incentivise the pharmaceutical industry to investigate new indications for known medicaments and bring those discoveries to the clinic, governments worldwide allow such new uses to be patented, thereby providing a 20 year monopoly protection for the further medical use of the drug. The conventional wisdom is that this monopoly gives the pharmaceutical company the chance to recover the costs of bringing a new therapy to the market and so encourages investment.
However, critics point out that this system is overly generous – giving the same compensation to the development of the original drug as the new use – and, if left unfettered, open to abusive practices by innovator companies who can game the system to “evergreen” patent protection for their original medicament and build patent thickets around their drug to keep generic competition off the market.
In the US, second or further medical uses of known compounds are claimed in patents as straightforward method of treatment claims. This means such claims must overcome inherency hurdles, which second medical use inventions do not encounter elsewhere, which will preclude such claims if the new use was inevitably achieved by following the prior art teachings. Moreover, protection is being awarded only for the new use, not the underlying product per se (the protection for which, in most instances, has expired or will expire before the patent on the new use).
Being methods, the subject matter of US medical treatment claims is performed by the clinician or patient. Of course, pursuing such entities for patent infringement is neither financially viable or especially palatable. The generic drug manufacturer or distributor is clearly a better target, but to assert a method of treatment patent claim against a generic competitor, the innovator company must rely on provisions for the indirect infringement of patent claims, namely contributory infringement and induced infringement.
Contributory infringement occurs when a component is sold for use in a patented product or process. Accordingly, the innovator company must first show that someone (for method of treatment claims this will be a clinician or patient) directly infringed the patent by using the method of treatment. Next, the innovator company must prove that the generic company had knowledge both of the patent and that its customers’ use of their product was infringement (Global-Tech Appliances Inc v SEB SA, 563 US 754 (2011)). However, the innovator company must also show that there is no substantial non-infringing use for the product in question. Of course, by definition, the product in question already has a substantial non-infringing use.
Induced infringement occurs when the generic company actively induces infringement of the patent. Here, the innovator company must show direct infringement and that the generic manufacturer had knowledge of the patent (or was wilfully blind as to its existence) and had an affirmative intent that its product be used to infringe (MGM Studios Inc v Grokster Ltd, 545 US 913, 936 (2005)).
In an attempt to address the issue of evergreening and patent thickets keeping generic competition out of the market, the US introduced provisions in the Hatch-Waxman act which permit a generic applicant to carve out from the summary of product characteristics (SmPC) and other product information for their generic medicinal product any medical indications, dosage regimes or patient groups that are the subject of patent protection. As such, in essence, the generic product is supplied only with instructions relating to non-infringing uses. In other words, at least in principle, a generic company is able to obtain authorisation for a generic version of an innovator company’s branded product and be able market that generic product for the original indication without being at risk of allegations that the product is intended to be used to treat the new indication for which the original product has been repurposed, thereby inducing infringement of the repurposed drug patent.
In reality, although the concept of a skinny label is an elegant solution to the issue from a perspective of patent law, the effects of the label on the relevant players in the health services is marginal at best and so use of the generic in the patented indication is not reliably prevented.
Like elsewhere, US healthcare professionals often (sometimes encouraged by electronic prescribing systems) prescribe a drug to a patient by the international non-proprietary name (INN) of the drug and no mention is made on the prescription of the condition to be treated. In the pharmacy, the pharmacist is may be obliged by law and/or by insurers/funding schemes to fill the prescription with the most cost-effective version of the drug as defined by INN. Without knowledge of the condition being treated, it is therefore common for a generic product to be taken by a patient to treat a patented medical indication – so called cross-label use.
Of course, any instance of cross-label use eats into the market share of innovator companies and strangles their revenue streams. The situation on the ground is clearly unsatisfactory for innovator companies seeking to recoup their investment in the novel second medical uses they have brought to market. As a result, a number of such companies have launched litigation against generics in an attempt to push the boundaries of skinny labelling practice in more pro-innovator direction, and make the it more difficult for a generic to enjoy the fruits of cross-label use whilst hiding behind the protection of a skinny label.
Prior to GSK suing Teva for infringement of their Coreg® drug with a skinny labelled generic version of carvedilol which carved out the apparent second medical use of CHF, the prevailing understanding following Takeda Pharmaceuticals U.S.A. v. West-Ward Pharmceutical Corp., 785 F.3d 625 (Fed. Cir. 2015) and Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348 (Fed. Cir. 2003) was that a skinny label alone was sufficient for a generic medicament to be safe from allegations of inducement to infringe.
After some to-ing and fro-ing in the District Court, the Federal Circuit issued a decision which went against this received wisdom saying that statements of therapeutic equivalence in the US Orange Book and potentially suggestive assertions in marketing collateral about interchangeability in general, was enough to reach a finding of induced infringement. This sent shockwaves through the generic industry as, in effect, it rendered a skinny label essentially impotent, despite the good faith actions of the generic in meeting the criteria of the Hatch-Waxman provisions.
However, upon rehearing the case, the Federal Circuit judges rowed back from some of their positions and instead found that this particular skinny label was in fact inappropriately drafted and so ineffective in the specific circumstances of the case, rather than finding that skinny labels were not effective as a general rule.
This decision was however not unanimous and by finding infringement for different reasons, the original thinking of the Federal Circuit judges in the original hearing of the case was not formally reversed. Thus, the generics industry rightly fears that this glimpse into the mindset of certain Federal Circuit judges might suggest that future cases could have more pro-Innovator outcomes.
In an attempt to provide greater resolution and clarity, Teva had sought to have the case reheard en banc, but this was rejected on account of the case being so dependent on the facts. Nevertheless, the dissenting views within the refusal to rehear were scathing, pointing out the uncertainty in this important field that this decision has unleashed, and the inevitable chilling effect this will have on generic entry – generic companies will now have to contend with the risk of facing law suits when launching at risk, or have to engage with more complex, and therefore, costly prelaunch Hatch-Waxman litigation.
To their credit, Teva have taken the issue to the Supreme Court with a request for judicial review to try and push for clarity on the matter. It is not known at the time of writing whether that has been granted, but it is encouraging to see that the Solicitor General has been invited to provide an opinion.
In other developments, in a case between Amarin and Hikma at the District Court, the court has chosen to distinguish the facts of that case from the specific facts of the GSK vs Teva rehearing, and instead reaffirm the original position that a properly prepared skinny label is sufficient to avoid allegations of induced infringement when brining a generic to market and that that statements of therapeutic equivalence in the US Orange Book and references thereto by the generic company without the mention of protected uses, are not enough to alter this general consensus.
At a bare minimum, generic companies considering entering the US market with a skinny-labelled product at risk will need to draft their carve outs diligently, making sure they consider both the originally defined indications submitted to the official medicines agencies by the innovator company, but also the wording in the patent claims in question. A patent attorney should be consulted. Where the protected medical use concerns dosage regimens and/or patient subgroups defined by usual parameters the advice of counsel experienced in pharmaceutical regulatory matters should be taken to ensure appropriate wording can be crafted within the bounds of regulatory law.
Generic companies must also coordinate with their marketing and sales divisions to ensure the Company’s conduct in those areas does not contradict the messaging from the skinny label and leave them open to allegations that they have induced infringement despite the skinny label.
Taking the lead from developments in Europe in this area where progressively pro-innovator lines are being taken, generic companies entering the US market might consider taking steps in advance of market entry, and on an ongoing basis, to engage with all players in the market to educate them of the patented indication and the fact that the generic product is not to be used therein. A still further measure to minimise risk is to engage with the IT systems underpinning the prescribing and dispensing of drugs to ensure IT processes are in place to minimise cross label dispensing.
The present flux in the position of the US courts over the past few years means innovator companies might be bold in protecting their market position for their most valuable drugs and/or in those markets which are seeing the greatest erosion. However this remains largely untested. Pro-innovator positions have been expressed by certain Federal Circuit judges even if, ultimately, final decisions not been based on such positions. Moreover, the most recent decision from the lower courts has reaffirmed the previous pro-generic positions. Given the arguably more pro-innovator thinking on behalf of certain judges within the Federal Circuit, a test case might develop a more pro-innovator position, which requires generic companies to take some responsibility to minimise off-label use, like is being seen in Europe.
The contributions of both generic and innovator companies to our healthcare systems are essential, and a balance must be struck between their competing interests to ensure the system works at its best. At the moment, that longstanding balance has been disrupted by the Federal Circuit and the ripples are still being felt in the generics industry even if the court has tried to take some of the sting out of its earlier actions. The issues seems ripe for the Supreme Court to intervene and settle the matter once and for all. Teva’s application for judicial review is welcome therefore and this author hopes the Supreme Court accepts. The fact that the Solicitor General has be invited to submit an opinion is taken as a promising sign.