On the second day of the 11th Annual Legal Affairs Forum held by the European Generic and Biosimilar Medicines Association, additional exclusivity and intellectual property concerns were covered, including key case updates and strategies (see here for a summary of day one). Similar to the U.S., European generic companies are grappling with issues concerning new indications and dose regimen claims and skinny labeling, orphan drug exclusivities, Bolar-type research provisions during the patent term, clinical data transparency, patent eligibility, and biosimilar patent challenges. Aside from certain European twists to these issues, there is also a unique “sunset clause”. Due to differences in market exclusivity provisions, there is very little exclusivity incentive in the European Union (EU) to develop new indications (one year versus three in the U.S.), and only more recently have patents been allowed for new (second) indications (purpose-limited product claims), which are often accompanied by new dose regimen claims.
On the other hand, orphan drug indications, which confer 10 years of market exclusivity for the same or similar medicinal product following approval of an orphan indication (with the potential for an additional two years of exclusivity for performing pediatric studies), have proven to have an enormous advantage. Approximately 20% of the products approved by the European Medicines Agency (EMA) via the centralized procedure process include orphan indications. In addition, as with Hatch-Waxman, innovator companies have been able to extract additional advantages from interpretations of the orphan exclusivity provisions themselves. For instance, the similarity provision has been interpreted to mean that a molecule is 50% or more identical to a previously-approved molecule, not just the same active ingredient, as is often interpreted in the U.S. And orphan drug exclusivity can be “broken” by more than just “clinical superiority,” as in the U.S.; it may also be “broken” by consent of the original market authorization holder (MAH) or inability of the MAH to supply sufficient quantities. This may lead to results where the original MAH may consent to itself to break exclusivity or a different sponsor may benefit from the 10-year exclusivity for a second subset of an orphan condition, if the first MAH obtained approval for a first subset of the orphan condition. Finally, while the EU (unlike the U.S.) has a provision for reducing orphan drug exclusivity to six years if at the end of five years the product no longer meets the orphan drug designation criteria (e.g., the product is sufficiently profitable and maintenance of exclusivity is no longer justified), this provision has never been applied.
The EMA has a set of provisions called the “sunset clause” that is different than the approvals in the U.S. with its own set of interesting twists. The sunset clause provides that if an actual product is not marketed within three years after a market authorization (approval) or is not marketed for three consecutive years, the market authorization is no longer valid. Some twists, however, surface, when combined with SPCs and an exception for “public health grounds” that are “duly justified.”
U.S. provisions following a court case Bolar leading to the coining of the term “Bolar-exemption” or “Bolar provisions,” permit research and experimentation that would otherwise infringe a patent if limited to purposes for seeking regulatory approval (but not actually marketed yet) under the Federal Food Drug and Cosmetic Act. Similar provisions were first copied in Canada and found compliant with the Agreement on Trade-Related Aspects of Intellectual Property Rights (“TRIPS”), which then found their way into the EU. The EU compromise, however, did not permit production for export or stockpiling and added the term “practical requirements” to permit additional use and studies to obtain and maintain the approval. Different EU nations, however, have implanted the provisions in varying degrees, either more broadly to cover all kinds of market authorizations within the EU and abroad, or more narrowly to only abridged market authorizations (generic drugs, hybrids (U.S. – 505(b)(2) NDAs), or and biosimilars) within the EU or EEA. Following the enactment of the unitary patent (UP) and unified patent court (UPC), however, it is possible that a more broad approach will be followed for UPs with country-specific approaches for national patents.
The EMA policy on clinical data transparency appears to be that there is no harmonization of such disclosure via the freedom of information provisions in its member states. While there is a directive for access to documents after a market authorization is granted, significant debate may ensue over what is commercial confidential and must be redacted. There is a European ombudsman that is involved in the redaction process. Further, there is a type of agreement between the EMA and user that access to the clinical data does not confer any intellectual property rights, that the information cannot be used to obtain market authorizations in the EU or anywhere in the world, and that the information will not be used for unfair commercial use. While the clinical data transparency was meant to foster additional academic and institutional research, in practice most of the information (~70%) appears to be requested by competitors.
The final panel addressed recent patent case trends including the presumption of validity, changed in genomic testing via the U.S. Supreme Court in Myriad, and biosimilars patent litigation. Another look at new indications / second medical uses explained how it may not be possible for generic applicants to “carve out” or “skinny label” their products to exclude an indication protected by a patent. For instance, Netherlands courts have held that if the excluded indication is the major indication for the product, whether it is included in the labeling may be immaterial based on anticipated offlabel use, resulting in a finding of contributory infringement. On the other hand, UK courts have looked to a subjective intent on behalf of the manufacturer, when looking for contributory infringement.
Taking a look at the presumption of validity in Europe, it appears that the prima facie validity of patents in preliminary injunction proceedings is no longer “untouchable” and may be challenged in these proceedings in certain instances. One issue has been the Opposition process, which is challenge to the patent at the European Patent Office (EPO), and has been presumed valid until the final outcome, even if revoked by the EPO Opposition Division. Traditionally, certain countries, such as Belgium, have been more likely to maintain patent validity when considering a preliminary injunction, even if the patent has been revoked by the EPO or invalidated in other countries, abstaining from taking into all facts and circumstances related to the patent. Other countries, such as the Netherlands, have no presumption of validity and look to whether there is a reasonable chance of success to invalidate the patent. More recently, however, even Belgium has started taking more of a totality of circumstances approach, and the UPC approach appears to include provisions requiring the patent holder to demonstrate that the patent is valid to obtain an preliminary injunction.
Then there was a closer look at guidance from U.S. courts in Prometheus and Myriad, where it became clear that when looking at biological processes, such as clinical effects of drugs, or known genes to have a potential for disease, patentability becomes a more complicated question. And to the extent there are questions regarding patentability, such challenges may be raised early upon patent grant, for example in post-grant review (PGR) proceedings or inter partes review (IPR).
The closing presentation on biosimilars patent litigation, by Brian Malkin, Senior Counsel, McGuireWoods, took a look at the different approaches to litigating biosimilar patents in the European Union and the U.S. While the definitions of biosimilars have become somewhat more aligned (although there is no “interchangeable” biosimilar in the EU), European biosimilar patent litigation includes a centralized and multi-national approach. As a result, the first most common tactic is to attack the patent first at the EPO Opposition level, often prior to biosimilar product development, because such challenges must be raised within 9 months of patent grant. The initial EPO Opposition may be appealed and during the Opposition process, an infringement or declaratory judgment action may be brought in one or more member country courts, often with different standards for review and deference for the Opposition process, as well as multiple standards for patent validity scrutiny during preliminary injunctions, and non-infringement and invalidity proceedings, including different evidentiary approaches. Several common patent country courts in the Netherlands, Germany, the UK, and Belgium were examined, as well as the UP/UPC procedure and strategies to consider, when they become relevant. Next, the U.S. “patent dance” procedure for exchanging biosimilar application and patent information was examined, as well as the current trend to choose to avoid dancing, which is currently being litigated. Sandoz’s imminent possibility for a launch at risk of its Zarxio® (filgrastim-sndz) in the U.S. was explored, along with future considerations and unresolved legal issues in both Europe and the U.S., particularly as the biosimilars market continues its global product development trend.
In sum, the Legal Affairs Forum covered a wide variety of legal issues confronting the generics and biosimilars industries with food for thought as both markets become increasingly global in their approaches. Perhaps TTIP and other trade discussions, as well as antitrust considerations, will align more country practices to prevent venue shopping and will make it easier to develop more aligned global strategies. And despite the variety of legal issues addressed here, there are many more legal and regulatory approval and review challenges that await further harmonization and discussion at future Legal Affairs Forums and related events.
