Are gene-editing therapies patentable? A WIPO side event investigates.

CRISPR Cas9, by the NIH.

On 6 December, Knowledge Ecology International (KEI) organised an interesting panel on the patentability of new gene- and cell-based medical therapies, as a side event during the 29th Session of the Standing Committee on the Law of Patents (SCP) of the World Intellectual Property Organization (WIPO).

The panel asked whether these therapies should be patentable according to the WTO TRIPS Agreement, and in particular, its Article 27.3(a), which permits WTO countries to exclude from patentability: (a) diagnostic, therapeutic and surgical methods for the treatment of humans or animals”. The panel was composed of James Love (KEI Director), Jayashree Watal (WTO Counsellor, Intellectual Property Division) and Dr. Els Torreele (Director of MSF Access Campaign).

Examples of gene- and cell-based therapies include therapies such as CAR T, involving autologous T-cell immunotherapy, or CRISPR, a gene editing tool, which is suspected of having been used with the twin babies recently born in China.

KEI showed that hundreds of patents had been filed or granted for these types of technologies but questioned this trend given that several countries, of all income categories, have included the exception of TRIPS Article 27.3(a) in their patent legislation in one way or another. The crux of the discussion was whether or not these new therapies fit the 27.3(a) criteria and, if so, are therefore excludable from patentability.

As a doctor “the oath is that you use any knowledge or skill you have to heal the patient,” said Torreele. “Thus those methods must be excluded from patentability.” The question at issue was if CAR-T or CRISPR constituted a therapeutic method [excludable under 27.3(a)], a medical product or process [patentable], or could potentially be simply ‘products-of-nature’ [not patentable].

The discussion focused on the CAR-T technology. With this therapy, a patient’s own cells are harvested from their body, re-engineered to fight a specific disease and then returned to the patient to treat their own specific disease. One the question debated was whether the cells are modified through this process. If not modified, they would remain “products-of-nature” and could not qualify as patentable inventions.

Given that both medicines using this technology are priced $373,000 and $475,000, non-patent approaches that delink R&D costs from prices, for example innovation inducement prize funds and market entry rewards, could have been more appropriate than patent awards to avoid unaffordable prices for promising technologies. It would for one thing put an end to the drive to turn medical acts into patentable commercial products.

CJEU Ruling on Truvada recalls ‘evergreening’ goes against public health interests

On 25th July 2018, the Court of Justice of the European Union (CJEU) rendered its preliminary ruling on the interpretation of Article 3(a) of Regulation (EC) No 469/2009 concerning the supplementary protection certificate (SPC) for medicinal products.

This preliminary ruling had been requested by the High Court of England in proceedings between Teva, Accord Healthcare, Lupin and Mylan, versus Gilead, concerning the validity of an SPC granted to Gilead for a pharmaceutical product containing tenofovir disoproxil (TD) and emtricitabine (FTC), brand name Truvada, recommended for the treatment and prevention of HIV.

The Court’s ruling makes clear that SPCs must be granted in such a way that is consistent with public health interests, and that they thus cannot merely be used for extending medicine patent protection.

Clarifying ‘basic patents’ in relation to SPCs

SPCs are a type of patent extension which can be granted to compensate patent holders for the period of a patent term that is “lost” during the lengthy regulatory processes of medicines approval, and thus, to provide “adequate effective protection”, according to the Regulation.

The CJEU ruling clarified the definition of ‘basic patent’, especially with regards to combination products, such as Truvada. Such definition is critical for the granting of SPCs, since Article 3(a) of the Regulation stipulates that “A certificate shall be granted if… the product is protected by a basic patent in force”.

The UK patent office granted Gilead the SPC for TD/FTC based on patent EP0915894, which extended the patent until 23rd February 2020 – two and half years after the original expiry date of the patent which was 24th July 2018. Generic manufacturers challenged this decision, arguing that while TD is specifically claimed in the ‘basic patent’, FTC is not, since the patent claims a pharmaceutical composition comprising tenofovir “and optionally other therapeutic ingredients”.

Given that the definition of ‘basic patent’ had given rise to different interpretations in European jurisdictions, the High Court of England referred the case to the CJEU, asking: “What are the criteria for deciding whether ‘the product is protected by a basic patent in force’ in article 3(a) of Regulation No 469/2009?”

The Court clarifies that the basic patent must “relate necessarily and specifically” to each of the active ingredients of the combination, which must be “specifically identifiable … in light of all the information disclosed by that patent”. Further, the Court notes that that EMA did not approve emtricitabine until 2003 and there is no evidence that at the date of the basic patent at issue, emtricitabine was an effective agent known for the treatment of HIV in humans.

Not the purpose of the SPC’ to evergreen patent protection

Critically, the CJEU clarifies in paragraph 40 that “it is not the purpose of the SPC to extend the protection conferred by that patent beyond the invention which the patent covers. It would be contrary to the objective of Regulation … to grant an SPC for a product which does not fall under the invention covered by the basic patent, in as much as such an SPC would not relate to the results of the research claimed under that patent.”

The Court further recalls that “In the light of the need, referred … in … the preamble to Regulation No 469/2009, to take into account all the interests at stake, including those of public health, to accept that an SPC could grant … protection which goes beyond … the invention it covers, would be contrary to the requirement to balance the interests of the pharmaceutical industry and those of public health as regards the encouragement of research within the European Union by the use of SPCs.”

In other words, the Court points to the risks of SPCs being used to “evergreen” patent protection, in contradiction with the text and spirit of the Resolution to take all interests at stake. And it specifically highlights the public health interests.

As illustrated by the Truvada case, pharmaceutical companies have several tools at their disposal to extend market exclusivity for as long as possible.

The Court interprets EU law to make sure it is applied in the same way in all EU countries. Therefore, national courts will have to take into account the CJEU interpretation in the Teva vs Gilead case and in similar proceedings. On 18 September 2018, the UK High Court of Justice followed the CJEU and concluded that the SPC must be revoked because it does not comply with Article 3(a). The CJEU judgement should pave the way for the rejection of most other SPCs on Truvada in the EU should those SPCs be challenged.

Price impact

While the SPC for TD/FTC based on patent EP0915894 was refused by patent offices or revoked in judicial proceedings in some countries (eg. Austria, France, Germany, Greece, Sweden, the Netherlands), we understand an SPC remains active at least in Belgium, Ireland and Switzerland.

In Switzerland, one box of 30 tablets of Truvada costs 900 CHF (Euro 800,–) compared to Euro 176,– in France. In the Netherlands, where the SPC was never granted, the lowest price for 30 tablets/capsules of generic TD/FTC is Euro 29,91.


How patents, data exclusivity and SPCs interact to extend market exclusivity of medicines: the example of Truvada

Patents usually confer 20-year exclusive rights on inventions. Data exclusivity laws confer, depending on the country, 5 to 10 years’ exclusive rights over safety and efficacy data submitted for the registration of new medicines by regulatory agencies. Supplementary protection certificates, or SPCs, are a form of patent term extension, granted at the expiry of the patent term to compensate for time lags due to the medicine’s registration process, during which the exclusive rights on the medicine could not be exploited commercially. These exclusivity rights are available for new medicines based on both patent and medicines laws.

Altogether, these measures provide a solid fence to generic competition for a certain period of time, even though the TRIPS Agreement does not require countries to grant either data exclusivity or patent extension beyond 20 years.

The delay to generic entry these additional protections can create is best illustrated by an example:

Gilead’s well-known antiretroviral medicine tenofovir disoproxil fumarate (TDF), available in fixed-dose combination with emtricitabine (FTC) under the brand name Truvada, is recommended by the World Health Organization as an essential part of first line treatment for HIV/AIDS and for HIV pre-exposure prophylaxis or PrEP, to prevent the acquisition of HIV infection by uninfected persons.

Gilead filed four categories of patents at the European Patent Office (EPO) which protect various aspects of TDF/FTC.

The first one, EP0915894, expired in July 2017, claimed essentially tenofovir disoproxil (TD). A second one, EP0998480, due to expire on 23rd July 2018, claims specifically the fumarate salt of tenofovir disoproxil. A third one, EP1583542, originally due to expire in 2024, claimed combinations of TDF and FTC but was revoked in March 2017 by the EPO for lack of inventive step. A fourth one, EP2386294, due to expire in 2026, claims the triple combination TDF/FTC/EFV, known under the brand name Atripla, which includes efavirenz as a third component. This is nine years after the first related patent (TD) expires.

This practice of applying for subsequent patents related to a single medicine, known as evergreening, is a common practice of pharmaceutical companies to extend patent protection for as long as possible, thereby keeping generic competition at bay.

In 2017, generic companies found a way around Gilead’s second, third and fourth TDF patents to bypass Gilead’s evergreening strategy for TDF and to market more affordable versions of the medicine. Generic manufacturers demonstrated that other salts of tenofovir disoproxil, e.g. tenofovir disoproxil phosphate or – maleate were bio-equivalent to Gilead’s TDF. As a result, the European Medicines Agency (EMA) approved several generic tenofovir products (now called TDX) as standalone products or in combination with FTC and EFV for sale in the EU as soon as Gilead’s rights on TD expired in July 2017. Had generic companies not developed TDX and the EPO not rejected the patent on TDF/FTC, evergreening might have extended patent protection of TDF/FTC until 2024 and of TDF/FTC/EFV until 2026.

What about data and market exclusivity?

In Europe, original drug manufacturers enjoy 8 years of data exclusivity plus 2 years of market exclusivity as of the date of approval of their medicine. This means that generic manufacturers can:

  • start to apply for the approval of a generic version only 8 years after the original medicine was approved, and 
  • launch their approved generic in the European market only 10 years after the original medicine was approved, assuming that the patent has also expired by this time. For more information about data exclusivity in the EU see here.

Gilead’s market exclusivity on TDF, TDF/FTC and TDF/FTC/EFV expired respectively in 2012, 2015 and 2017 because these products were approved respectively in 2002, 2005 and 2007. Generic companies could apply for registration of generic TDX, TDX/FTC and TDX/FTC/EFV at EMA but Gilead’s patent on TD prevented any marketing until it expired in July 2017.

What about patent extension in the form of supplementary protection certificate (SPCs)?

Like data exclusivity, SPCs are subject to EU regulation but the decision to grant an SPC is made by national patent offices. SPCs extend the monopoly period for a medicinal “product” (active ingredient or a combination of active ingredients) that is protected by a patent to an ‘effective patent life’ of maximum 15 years. 

Gilead could not obtain an SPC for TD because the time lapse between the patent filing date (July 1997) and the market approval (February 2002) was less than 5 years, and the company still had more than 15 years to enjoy the exclusivity conferred by the patent.

Gilead requested SPC’s in several European countries, based on the marketing approval of TDF/FTC, to extend its patent claiming tenofovir disoproxil EP0915894, which expired on 31 July 2017 in most European countries. Several countries refused to grant such SPCs (including the Netherlands and Greece), but others (e.g. France, Ireland, Switzerland) did extend the monopoly until February 2020 (eg. 15 years from the date of approval of TDF/FTC). 

The UK Patent Office had initially rejected Gilead’s request for an SPC to extend its TD patent, based on TDF/FTC (Truvada)’s marketing approval in 2005. But Gilead appealed and obtained the grant of the SPC until 23 February 2020. Generic manufacturers (Teva, Accord Healthcare, Lupin and Mylan) challenged this decision, asserting that Gilead’s TD patent does not claim Truvada specifically and therefore Gilead cannot obtain an SPC to extend its TD patent based on Truvada market approval. 

The UK High Court deferred the case to the Court of Justice of the European Union (CJEU) to clarify if Gilead’s marketing authorization for Truvada could form the basis for an SPC on Gilead’s TD patent.

The upcoming decision of the CJEU could have major repercussions not only for Gilead’s pending SPC in the UK, and potentially other countries where they have been granted and remain active, but also on the practice of pharmaceutical companies SPC applications for medicinal products containing multiple active ingredients. See here for more information about the case before the CJEU. 

Will the European Court of Justice put a stop to the evergreening of Truvada patents?

Photo by lewishamdreamer on Flickr; used under Creative Commons.

Truvada, the fixed-dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) is a critical medicine in both HIV treatment and prevention. It is used as pre-exposure prophylaxis (PrEP), which can reduce HIV transmission by over 90% in sero-discordant couples. Affordable pricing of the product is therefore important for public health.

Since July 2017, Truvada has been available in generic forms in some European countries (eg. the Netherlands, France) but not in others (eg. UK, Switzerland). This is because the key patent covering tenofovir disoproxil expired in July 2017 in most countries, but not in all. In Europe, some countries have extended the duration of the tenofovir patent beyond the 20-year patent term by granting a supplementary protection certificate (SPC).

SPCs can be granted by national patent offices when necessary to ensure that a medicine benefits from 15 years of effective patent protection after the date of the first market approval. Although such patent extensions are not a requirement of the TRIPS agreement, most high-income countries have adopted prolonging patents to compensate for delays linked to drug market approval, regardless of whether such delays affect the profitability of the product.

In Europe, SPCs are granted based on EU regulation n°469/2009 [pdf], but patent offices and national courts have had different interpretations of the EU regulation. Hence, an SPC was granted on the tenofovir patent by the French, UK and Swiss patent offices, while the Netherlands, Italy and Greece rejected its grant.

Rejecting the SPC can result in significant improvements in the medicine’s affordability: In the Netherlands, for example, the price of TDF/FTC has dropped from 344,28 Euro (Gilead’s Truvada) for a 30 day supply to 47,95 Euro for the generic version. The main reason for the rejection of the SPC is that the patent in question claims tenofovir but not emtricitabine, so there is no reason to extend the patent on tenofovir based on the date of market approval of the combination tenofovir/emtricitabine. In France, the generic drug maker Mylan challenged the French SPC and the courts confirmed that the SPC was invalid [pdf]. The same happened in Spain. In the UK – where several generic companies challenged the SPC – the judge of the high Court asked clarification to the European Court of Justice on how to interpret the EU directive. The ECJ Attorney General recently concluded that the patent on tenofovir should not have been granted an SPC because this patent does not claim emtricitabine specifically, in accordance with the EU regulation.

Why didn’t Gilead request an SPC to extend this tenofovir patent based on the marketing approval of TDF (sold under brand name Viread) instead? The tenofovir patent was filed in July 1997 and Viread (tenofovir) was then approved by the European Medicines Agency (EMA) in February 2002. Viread enjoyed more than 15 years of effective patent protection between February 2002 and July 2017, at the expiration of the 20-year patent term, and therefore does not deserve an SPC according to the EU regulation. Truvada was approved three years later in 2005. Gilead’s request for a tenofovir patent extension based on Truvada’s approval therefore appears to have been an attempt to obtain a patent extension in contradiction with the spirit and letter of the EU regulation. It is hoped that the ECJ will follow the opinion of the attorney general, clarify the legal basis for obtaining SPCs and clear away the barrier to access of generic Truvada.

This will also hopefully give food for thought to the review of SPCs and other pharmaceutical incentives by the European Commission. According to the SPC regulation, “At the moment, the period that elapses between the filing of an application for a patent for a new medicinal product and authorisation to place the medicinal product on the market makes the period of effective protection under the patent insufficient to cover the investment put into the research.” Given that Gilead’s sales of Truvada are around 3Bn US$ a year, maybe it is time to review the SPC regulation.

Modifier la législation européenne pour mettre en œuvre la licence d’office en France

Selon le Dr Thierry Philip, Président de l’institut Curie, la hausse des prix des nouveaux traitements contre le cancer « est devenue intenable. »

L’augmentation croissante du prix des nouveaux médicaments contribue substantiellement à l’explosion des coûts de la santé et commence à mettre en péril le principe d’accès universel aux soins en France.

Les laboratoires utilisent le monopole conféré par leurs brevets pour imposer leurs prix au gouvernement.

L’argument utilisé habituellement pour justifier des prix exorbitants est l’augmentation des coûts de la recherche. Pourtant, un nombre croissant d’études indiquent que ces coûts sont très largement surestimés et qu’une plus grande transparence s’impose.

Dès lors, nous partageons l’opinion du Dr Philip concernant la nécessité d’utiliser la licence d’office lorsque les laboratoires refusent d’ajuster leurs prix à un niveau acceptable permettant la prise en charge de tous les patients.

Le code de la Propriété intellectuelle autorise en effet le gouvernement à soumettre, par arrêté ministériel, un brevet de médicament au régime de la licence d’office en cas de « prix anormalement élevés, ou lorsque le brevet est exploité dans des conditions contraires à l’intérêt de la santé publique ». Le régime de la licence d’office permet donc au gouvernement de faire fabriquer ou d’importer des médicaments génériques à prix compétitifs, faute d’accord sur un prix raisonnable avec le laboratoire du médicament breveté.

Pourtant, d’autres types d’exclusivité délivrées au niveau européen pourraient entraver l’utilisation de la licence d’office en France. Une exclusivité de marché de 10 ans est en effet accordée par l’Agence européenne des Médicaments pour tout nouveau médicament. Cette exclusivité empêche de fait la mise en œuvre de la licence d’office car elle bloque toute homologation de médicament génériques durant cette période de dix ans.

Il serait donc important de modifier la réglementation européenne en question afin de permettre l’homologation de médicaments génériques à tout moment lorsque le gouvernement français, ou tout autre gouvernement européen, décide de faire usage du régime de la licence d’office dans l’intérêt de la santé publique. Le gouvernement français devrait porter une telle initiative au niveau européen, afin de permettre aux gouvernements européens de répondre au défi des prix élevés des nouveaux médicaments.

Plus d’information sur cette proposition dans notre article publié dans le Journal of Pharmaceutical Policy and Practice.