Further Brexit Complications: On Patents

John Rizos

Milan: home of fashion, of a historic soccer rivalry, and of… intellectual property protection? Well, of course! Milan is a center of life science innovators and international property expertise[1]. The Milanese Court manages most of Italy’s patent litigation and hosts the majority of Italy’s intellectual property practitioners[2].

In response to the Brexit vote,  the Italian Trade Body in Milan (L’Ordine dei Consulenti in Proprietà Industriale) wants to replace the Court of First Instance in London, which handles claims related to pharmaceutical patents, since the court would apply EU law and Court of Justice of European Union (CJEU) rulings.  The UK Intellectual Patent Office (UKIPO), however, stated that it will preserve and implement EU regulations and abide by them as signatory to the Unified Patent Court Agreement (UPCA)[3]. The UK was historically one of the main supporters of the unified patents, had lobbied extensively to host the court in London, and had worked in advance in preparation for the system[4].

Intellectual property protection is a huge factor in the EU’s goal of harmonizing domestic laws, mainly achieved by removal of technical obstacles and implementation of directives[5]. Recently, the focus has been on harmonizing the intellectual property industry, especially patents[6]. The European Patent Convention (EPO) was signed in agreement in 1973[7], independent from the EU, comprised of EU and non-EU members. In 2013, 25 EPO States signed the Unified Patent Court Agreement (UPCA). It aims to establish the Unified Patent Court (UPC)[8] and a system of uniform patent protection throughout EPO States on new patents from any other EPO State[9]. Although it is independent from the EU, it comprises mostly EU law and can only be ratified by EU members[10]. The UPC will centralize disputes[11] through a main court in Paris with jurisdiction over legal disputes regarding patents, and two courts with jurisdiction over patents with specialized subject matter; one in Munich for engineering issues and one in London for disputes in pharmaceuticals and life sciences[12].

UK patent laws are formed by a mixture of domestic and EU laws, as many have been enacted in response to treaties and European cooperation. The UK’s ratification will not have an effect on its domestic laws, since it already includes EU law and is a signatory of the EPO. The organization will carry out the patent process as scheduled[13].The current UK patent system is governed by the Patents Act of 1977[14]. This act was framed to comply with the terms of international agreements, mainly the Cooperative Patent Classification (CPC), which although was never ratified by the EU, it was created by its predecessor, the EEC, pursuant to which the UK aligned its patent infringement provisions.[15] UK patent law is within the EU legislative framework in the areas of competition law defenses and relief for infringement for intellectual property[16]. UK supplemental protection certificates, a form of intellectual property protection which compensates for a period between filing and granting of a patent application for pharmaceuticals, is also governed by legislation implemented pursuant to EU regulation[17]. Additionally, the UK is expected to be an EU member until at least 2019[18]. During this period, the country will operate under a transitional framework pursuant to EU legislation. The government has stated that it will keep implementing EU directives and that the courts will continue to interpret EU law[19].

In the case of an actual Brexit, the UK will likely ratify the court through the transitional framework of an EU exit or will lose its ratification vote and the UPC will be established through the very likely ratification of the rest of the EU. Even if the UK does not ratify the UPC, its patent law will be heavily influenced by EU law and it will remain an EPO member. If the UK does ratify the new court system, it would entwine UK law even closer to EU law by granting the court jurisdiction to resolve patent disputes covering EU members that have chosen to participate in the system[20]. In the case of Brexit, there would be no fundamental reason for the UK not to participate, but its participation would have to be secured by separate agreements with other countries. Since the agreements would have to be done with EU members, the UK government would have to implement laws to ensure compliance with EU laws[21]. The UK will likely consider three agreements: It remains a European Economic Area (EEA) member, it joins the European Free Trade Agreement (EFTA), or it maintains a trade partnership with the EU[22].

First, if it remains part of the EEA, court references will be made to EFTA courts and not the CJEU. However, EFTA functions to ensure uniform interpretation of EU law and the EEA has adopted EU intellectual property regulation regarding medicinal and plant protection products[23]. That may not seem important, but patent protection on medicinal products serve as “life blood” of the pharmaceutical industry, which generates 10% of the UK’s GDP, employs 100,000 people, and allows the UK to host clinical trial markets, foreign companies[24], and European medicinal organizations[25]. Second, if the UK joins EFTA, some of the remaining EU legislation could be expected to apply, especially through the transitional framework[26]. Third, if the UK decides to just trade with the EU, it would operate pursuant to a bilateral trade agreement, making it subject to CJEU jurisdiction and to EU law implementation to prevent gaps in legislation and in judicial opinions. Historically, UK judges have been influenced by decisions from other European judges, meaning they will keep referencing to CJEU rulings[27].

In conclusion, in the field of patent protection, the EU has ostensibly achieved its goal of unity through embedded values, from which the UK will find it hard to separate. Europe does not have to worry as Brexit will not adversely affect European patent protection or UK patent law. The UK will still be guided by EU law regardless of whether it leaves the Union.

John Rizos is a 3L at the University of Baltimore School of Law with a concentration in International Law. He has an interest in human rights and international criminal law. In addition to being a CICL Fellow, John has served as the Secretary for Phi Alpha Delta Law Fraternity and is currently enrolled in HarvardX’s online course, “Humanitarian Response to Conflict and Disaster.” In June 2016, John was a member of the CICL Fellows team that, under the supervision of Professor Moore, assisted in drafting an amicus brief to the Extraordinary Chambers in the Courts of Cambodia, which was later approved and published. John graduated with honors from Towson University with a BA in International Studies (2013). He has interned at the Press Office of the Greek Embassy in Washington, D.C. and the International Civil Advocacy Network (ICAN), a non-profit organization advocating for women’s rights in the Middle East.

[1] https://www.thelawyer.com/issues/online-october-2016/brexit-mean-end-unified-patent-court/

[2] Id.

[3] http://www.lexology.com/library/detail.aspx?g=06cd3962-2c1d-4e8f-9618-c63b784b0875

[4] http://arstechnica.co.uk/tech-policy/2016/09/brexit-eu-unitary-patent-plans-legal-analysis/

[5] http://www.europedia.moussis.eu/books/Book_2/3/6/02/1/?all=1

[6] http://www.europedia.moussis.eu/books/Book_2/3/6/02/1/?all=1

[7] https://www.epo.org/about-us/office/timeline.html

[8] https://www.unified-patent-court.org/

[9] https://www.ft.com/content/9199ea86-80c8-11e6-8e50-8ec15fb462f4

[10] https://www.thelawyer.com/issues/online-october-2016/brexit-mean-end-unified-patent-court/

[11] http://www.lexology.com/library/detail.aspx?g=06cd3962-2c1d-4e8f-9618-c63b784b0875

[12] https://www.ft.com/content/9199ea86-80c8-11e6-8e50-8ec15fb462f4

[13] https://www.ft.com/content/9199ea86-80c8-11e6-8e50-8ec15fb462f4

[14] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[15] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[16] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[17] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[18] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[19] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[20] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[21] http://arstechnica.co.uk/tech-policy/2016/09/brexit-eu-unitary-patent-plans-legal-analysis/

[22] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[23] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[24] http://www.lexology.com/library/detail.aspx?g=06cd3962-2c1d-4e8f-9618-c63b784b0875

[25] http://www.lexology.com/library/detail.aspx?g=06cd3962-2c1d-4e8f-9618-c63b784b0875

[26] http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

[27]http://www.lexology.com/library/detail.aspx?g=dd074ec3-2c21-486f-b33e-5c0af5512ae8

A Comparative Look at Off-Label Pharmaceutical Use

Jasen Lau

On December 2012, the Second Circuit of the U.S. ruled in favor of the defendant in U.S. v. Caronia, stating that the non-misleading speech of off-label^[1] promotion by a pharmaceutical representative is protected by the First Amendment. The case drew nationwide attention by pharmaceutical companies, public health scholars, government officials, and health lawyers. Many worried that First Amendment protections trumped public safety in off-label promotion. While the actual ramifications are debatable, Caronia certainly warrants further inquiry. After all, the U.S. is not the only country where off-label prescription and promotion of medications take place. From France to Germany to Japan to India, off-label prescriptions and policies thereof exist, and while most of the policies are similar on the overarching principles, the subtle nuances reflect an ulterior motive that may or may not be noble. Many nations of the world have different yet very similar approaches to off-label prescription use regulation.

The Caronia case arose out of the promotion of a drug called Xyrem, a very powerful central nervous system depressant.^[2] The Food and Drug Administration (FDA) deemed the medication’s side effects so severe that the drug warranted a black box warning, the most serious kind of warning the FDA may give.^[3] Caronia and Dr. Peter Gleason, representatives for Xyrem’s manufacturer, promoted an off-label use; Gleason said he personally treated patients far younger and older than the approved scope of use. However, the court found that the actual speech of the off-label promotion is protected. In the U.S., off- label promotion is not inherently illegal, but off-label promotion may be used as evidence of misbranding, which is illegal.^[4] However, the U.S. does not entirely prohibit all kinds of off-label promotion. In fact, the system is set-up such that pharmaceutical manufacturers may fund research that helps find new off-label uses. The manufacturers may then disseminate the research results.^[5] Many concerns arise from Caronia’s ruling: manufacturers will start promoting, while disregarding  public safety; research will no longer be funded; the FDA will be limited in power, and so forth. However, the U.S. is not the only country to tackle the issue of off-label prescription use.

Off-label use is not a rare phenomenon and nor is it exclusive to the U.S. In fact, off-label use is a very common medical technique used to treat numerous patients worldwide. In Paris, a statistical study suggests that nearly 62% of prescriptions are for an unauthorized use.^[6] In the first quarter of 1999, nearly 13% of all prescriptions for children and adolescents in Germany were prescribed off-label.^[7] Similarly, 22 German medical centers said off-label use was “common” for a vast majority of the physicians.^[8] In Spain, 61% of pediatric physicians prescribe for medications in an off-label manner.^[9] 

Yet, how each nation regulates off-label use and the public policies that stem therefrom differ in only the subtlest of ways.The European Union (EU) has established a general policy for off-label use; drugs should be approved and authorized for specific treatments. However, the EU also believes that its Member States should incentivize further research. One possible incentive is a six-month extension to a Supplementary Protection Certificate,^[10] extending a manufacturer’s exclusive property rights.^[11]  Second, the manufacturer is granted an extra two years of market exclusivity if research is done on a drug that affects less than 5 in 10,000 patients or has become a drug where, without incentives, no pharmaceutical company would want to conduct further research for lack of a justification to the necessary investment of research but the drug still holds potential to treat a condition that otherwise cannot be treated with alternative medicines – also called an orphan drug.^[12] The EU did not want “rigid and compelling legal regulations” but a system of incentives to nurture the desire for research over penalizing the lack thereof.^[13] This desire stems from the need for pediatric research. Nearly 21% of the EU’s population – nearly 100 million – are vulnerable children with inadequate drug supply.^[14] In fact, 50% of medications were never even tested for children before becoming orphan drugs.^[15] However, many of the Member States are silent on the issue of off-label prescription in their legislation, relying mostly on the EU. On the other hand, France has a very specific approach that defies the EU’s principles.

In France, a manufacturer may apply for a “temporary recommendations for use” (RTU) application with the Agence Nationale de Sécurité du Médicament et des Produits de Santé (ANSM). A RTU allows manufacturers to promote a current drug for an off-label use for 3 years. However, this approval is a contractual relationship; upon approval, the manufacturer is legally obligated to scientifically observe and evaluate the affected population.^[16] To obtain a RTU, the manufacturer must prove that no other viable treatment for a current disease except for the off-label use of the drug in question.^[17] This approach places the burden on the manufacturer, with much less incentive than the EU’s approach. Yet, there are other approaches in the world warrant further analysis. For example, in India, off-label use of any kind is strictly prohibited without exception.^[18] In Japan, if the medication is for certain diseases, it can be approved for off-label use without the “preliminary clinical evidence of [the drug’s] effectiveness.”^[19] So, approaches vary greatly between nations.

More importantly, the underlying policy behind these regulations – or lack thereof – must be assessed. In the U.S., the ability to prescribe for off-label use is a necessary “corollary of the FDA’s mission to regulate pharmaceuticals.”^[20] The goals of pharmaceutical regulation are to protect the public safety, ensure a drug benefits specific patients groups as well as the overall population, and ensuring justice and equity in patients’ access to safe and effective drugs.^[21] The regulation of drugs is specifically to ensure that physicians know that off-label use is prescribing a drug for a use that the “regulatory body has not stated is safe and effective.”^[22] While these are very noble goals, a nation must not forget that off-label use is integral in medicine since many market drugs have no labeling or approved uses for specific populations.^[23] For example, in Calabria, “less than 15%” of all the drugs on their market are meant for children on the basis of clinical trials.^[24] While many people also fear off-label use for its inherent risks, the use of medicine is always a balancing act of benefit vs. risk. The FDA’s drug approval process requires drugs to be “safe and effective,” with the definition of safety changing on a case-by-case basis.^[25] Drugs cannot always be completely void of risks, which is why a balancing act is necessary. However, if all off-label use is prohibited (as it is in India)  or, arguably, greatly stifled (like in France), then it is impossible to do a risk-benefit analysis since there is no chance to know of the benefits.^[26] Therefore, a careful analysis of which underlying principle to adopt is necessary.

The EU’s incentive approach certainly drives more research because there is seldom a greater incentive than financial. However, France’s approach to patient safety and care – while noble – places a greater burden on drug manufacturers without necessarily promising greater investment returns. However, if patient safety were the only concern, perhaps India’s approach to absolute prohibition would be the best, forcing manufacturers to conduct research for each and every possible use. Yet, Japan’s take could also allow much needed access to medications that would otherwise be either unavailable or not covered by insurance.^[27] In the U.S., the approach is to allow research funding but not off-label promotion directly by the manufacturer. Each nation has a specific approach but what is truly at hand is the underlying idea of why each regulation is – or is not – viable. Indeed, it is a balancing act between the public safety, the preservation of regulatory authority, incentivizing research, keeping the manufacturers liable, and ensuring patient access to much needed drugs. Certainly, there is no one true answer – merely a set of ideas that should be adopted only after a nation knows what would be best for its people.

Jasen Lau is a third year law student at the University of Baltimore School of Law. He graduated from the University of Maryland in 2013 with a Bachelor of Arts in English. Jasen took it upon himself to become a certified pharmacy technician and studied several continuing education credits that focus on Medicare Fraud and Abuse prevention, HIPAA privacy and security laws, and ethics in the pharmacy workplace. Jasen has long been in the health care field either working directly with patients or as an assistant to providers. During that time, his obsession with working in health care has grown into policy analysis and counseling. Along with being a CICL fellow, he is also a law clerk for Johns Hopkins Hospital.

^[1] The term “off-label” is defined as any use that is not authorized by the FDA.

^[2] U.S. v. Caronia, 703 F.3d. 149 (2012) (Xyrem’s active ingredient is gamma-hydroxybutyrate more commonly known as the “date rape drug”).

^[3] Id. at 155.

^[4] 21 U.S.C. § 355.

^[5] Mariestela Buhay, Off-Label Drug Promotion Is Lost in Translation: A Prescription for A Public Health Approach to Regulating the Pharmaceutical Industry’s Right to Market and Sell Its Products, 13 J. Health Care L. & Pol’y 459, 488 (2010).

^[6]Christian Lenk & Gunnar Duttge, Ethical and legal framework and regulation for off-label use: European perspective, 10 Therapeutics and Clinical Risk Mgmt. 537 (2014).

^[7] Id.

^[8] N. Ditsch, et al., Off-label use in germany – a current appraisal of gynaecologic university departments, 16 European J. Med. Res. 7 (2011) (22 medical centers responded to a questionnaire, and of those physicians who responded, 91% said they commonly prescribed off-label use medications).

^[9] Roi Piñeiro Pérez, Results from the 2012-2013 paediatric national survey on off-label drug use in children in Spain (OL-PED study), 81 Anales de Pediatría (English Edition) 16 (2014).

^[10] Lenk, supra.

^[11] REGULATION (EC) No 1901-2006 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768-92, DIrective 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726-2004, Official Journal of the European Union, Dec. 27, 2006, http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2006:378:0001:0019:en:PDF.

^[12] REGULATION (EC) No 141/2000 OF THE EUROPEAN PARLIMENT AND OF THE COUNCIL of 16 December 1999 on orphan medicinal products, Official Journal of the European Communities, Jan. 22, 2000, http://ec.europa.eu/health/files/eudralex/vol-1/reg_2000_141/reg_2000_141_en.pdf

^[13] Id.

^[14] Id.

^[15] Id.

^[16] Lenk, supra.

^[17] Joseph Emmerich, et al., France’s New Framework for Regulating Off-Label Drug Use, 367 New Eng. J. Med. 1279 (2012)

^[18] Sukhvinder Singh Oberoi, Regulation off-label drug use in India: The arena for concern, 6 Persp. In Clinical Res. 129 (2015).

^[19] Id.

^[20] 124 Am. Jur. Trials 487 (Originally published in 2012).

^[21] Lenk, supra.

^[22] Id.

^[23] Oberoi, supra.

^[24] Francesca Saullo, et al., A questionnaire-based study in Calabria ont he knowledge of off-label drugs in pediatrics, 4 J. Pharmacology * Pharmacotherapeutics 51 (2013).

^[25] 2013 Aspatore Special Rep. 5.

^[26] Oberoi, supra.

^[27] Ditsch, supra; Pérez, supra; see also E. L. Trimble, et al., International models of investigator-initiated trials: implications for Japan, 23 Annals of Oncology 3151 (2012) (In all nations, unless some form of off-label use is either properly documented or approved, the state health insurance will not cover the medication).