Abstract
EU Legal and Regulatory Update
Granrut Avocats is a French law firm involved in intellectual property law, pharmaceutical law and European Union law that provides services to healthcare, biotech and pharmaceutical companies
This section is intended to be a synopsis of recent developments and is not intended to be all comprehensive. If any (issue) information referred to in this section is to be relied upon, specific advice should be sought. Please contact the Editor:
Richard Milchior and Séverine Charbonnel
SCP Granrut Avocats
91 rue du Faubourg Saint Honore
75008 Paris France
Tel: +33 (0)1 53 43 15 15
Fax: +33 (0) 1 53 43 15 00
Email: r.milchior@granrut.com
Preliminary injunctions revoked due to prima facie invalidity of Truvada® SPC
Commercial Court n. 4 of Barcelona, 20 October 2017
Background
Gilead is the holder of European patent EP0915894, which claims tenofovir disoproxil and of the supplementary protection certificate SPC C20050034 based on the same patent for the combination of tenofovir disoproxil + emtricitabine.
On 25 July 2017, the EP0915894 patent expired and SPC C20050034 entered into force.
Initially, the SPC was refused by the Spanish Patents and Trademarks Office. However, Gilead appealed the decision to the administrative Courts (Madrid High Court of Justice), which ultimately ruled in favour of granting the SPC by judgment dated 9 September 2016.
The claim 27 of EP0915894 served as basis for the grant of the SPC, despite the fact that it does not even mention emtricitabine, which is not mentioned either anywhere throughout the patent’s specification. The wording of claim 27 is as follows: ‘A pharmaceutical composition comprising a compound according to any one of claims 1-25 together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients’.
Gilead commercializes a tenofovir + emtricitabine medicinal product, Truvada®, for the treatment and prevention of viral infections, including HIV.
Facts
In May and June 2017, Gilead requested and was granted ex parte preliminary injunctions against the defendants (Mylan y Teva) for alleged imminent infringement of SPC C20050034.
The defendants opposed the preliminary injunctions alleging the invalidity of the SPC on the grounds of Article 15.1.a), in relation to Article 3, of the SPC Regulation 469/2009, and invoked the applicable case law from the CJEU.
More specifically, the defendants alleged that claim 27 would have exactly the same object and scope with or without the line ‘and optionally other therapeutic ingredients’, which, nevertheless, had been the sole grounds for the grant of the SPC for the combination of tenofovir + emtricitabine.
Thus, the basic patent claims an active ingredient (tenofovir), but not its specific combination with emtricitabine (or with any other active ingredient).
In this regard, and according to CJEU case law, the SPC for the combination would be contrary to Article 3.a) of the Regulation and therefore invalid.
For its part, Gilead pleaded that the SPC would be valid because the combination would be ‘comprised’ within the scope of protection of claim 27 of the patent. Gilead also argued that, in any event, the matter had already been decided by the Madrid High Court of Justice, whose decision would be binding for the Commercial Court in preliminary injunction proceedings.
Decision
The Court upheld the arguments of Mylan and Teva and revoked the preliminary injunctions by a decision dated 20 October 2017, which was deliberated by the three Patent Judges of Barcelona.
In its decision, the Judge first clarified that the judgment of the Madrid High Court of Justice had decided upon an appeal by Gilead itself regarding an administrative act (refusal of the SPC), and so it does not have a res iudicata effect in relation to third parties and therefore it is not binding.
Then, after reviewing the applicable case law from the CJEU since the Medeva case (C-322/10), the Judge concluded that claim 27 of the EP0915894 patent does not protect the combination of tenofovir + emtricitabine in the sense of Article 3.(a) of the Regulation, and therefore SPC C20050034 would be prima facie contrary to said provision and, hence, invalid.
Serious unexpected effects–fundamental freedom–emergency character–product levothyrox
A patient treated for several years with Levothyrox, which is a medicinal product made and marketed by laboratories Merck, is confronted with serious unexpected effects following the modification of the formula of this specialty.
This patient seized in urgency the Public Court of Paris to ask the Court, on the basis of article L. 521-2 of the French administrative public code, to order Minister of Health to provide the former formula of the speciality Levothyrox at the disposal of the sick people who need it.
French State Supreme Court raised a procedural irregularity.
Anyway on the merits, the Court dismisses the summary proceeding since the patient did not demonstrated that he had difficulty to obtain at this time the medicinal product prescribed by his doctor. In addition according to the Court the patient cannot usefully, in support of his demand, criticize the temporary nature of the measures taken to allow the parallel import of the speciality Euthyrox. The Court explained that the instruction does not reveal a deficiency characterized by Minister for Health, carrying a grave and obviously illegal infringement on a freedom fundamental and justifying that are taken the measures likely to protect such a freedom.
This decision is strange since at the time it was impossible to obtain in the French market the previous formulation of the Levothyrox.
Restriction of competition in pharmaceutical sector – Medicinal products
The agreement between the pharmaceutical groups Roche and Novartis designed to reduce the use of Avastin in ophthalmology and to increase the use of Lucentis might constitute a restriction of competition ‘by object’.
On January 23, CJEU rendered its judgement in the case opposing F. Hoffmann-La Roche Ltd to the Italian Competition Authority.
This case concerns the company Genentech, belonging to the group Roche, which gave to Novartis the commercial exploitation of ‘Lucentis’, a medicinal product authorized for the treatment of eye diseases, to the group Novartis.
Roche commercialized the ‘Avastin’ product for eye diseases, authorized for the treatment of tumoral pathologies but also used to handle eye diseases because of its lower price compared to the one of Lucentis.
In 2014, Italian Competition Authority decided to impose two fines, each amounting to over €90 million, on both Roche and Novartis, on the ground that those undertakings had put in place an arrangement designed to achieve an artificial differentiation between ‘Avastin’ and ‘Lucentis’.
According to the Italian Competition Authority, Avastin and Lucentis are equivalent in all respects for the treatment of eye diseases.
The Italian Tribunal dismissed the actions that Roche and Novartis had brought against those fines and Roche and Novartis lodged an appeal before the Council of State which referred the matter to the Court of Justice for a preliminary ruling on the interpretation of EU competition law.
The Court of justice notes that, for the treatment of eye diseases, there is a specific relationship of substitutability between Lucentis and Avastin when used off label.
The Court concludes that, if the competent authorities and courts have not examined whether the conditions for the repackaging and the off-label prescription of Avastin are unlawful, the Italian Italian Competition Authority may consider that the two products are in the same market and can therefore be regarded as competing medicinal products.
The Court precludes that the arrangement between the Roche group and the Novartis group referred to by the Italian Competition Authority may be justified as ancillary to their licensing agreement.
The Court notes that an arrangement between two undertakings marketing two competing medicinal products, which consists in the dissemination, in a context of scientific uncertainty, to the European Medicines Agency (EMA), healthcare professionals and the general public of misleading information relating to adverse reactions resulting from the off-label use of one of those products with a view to reducing the competitive pressure it exerts on the other product, constitutes a restriction of competition ‘by object’.
The Court explains that the information must be considered to be misleading (which is a matter for the national courts to determine) if its purpose is, first, to confuse the EMA and the Commission and, secondly, to emphasize, in a context of scientific uncertainty, the public perception of the risks associated with the off-label use of Avastin.
Lastly, the Court recalls that an arrangement cannot be exempt under Article 101(3) TFEU if it includes restrictions that are not indispensable. The dissemination of misleading information in respect of a medicinal product cannot be regarded as ‘indispensable’. An arrangement intended to disseminate such misleading information therefore cannot be exempt.
European Medicines Agency (EMA) – Anti-fraud strategy
EMA (Agence européenne des médicaments) on 15 December 2017, updated a document name « Anti-Fraud strategy».
For the year 2017, four new actions, different from the 12 already created between 2014 and 2016, had been added in the framework of anti-fraud strategy: –Maintain and develop the culture anti-fraud thanks to a high level of awareness, integrity, impartiality and transparency. –Maintain an effective system of report suspected frauds and irregularities. –Strengthen measures of detection of suspicious behaviors and dissuasion. –Focus on the reduction of the risk of fraud in certain zones of the blood transfusion.
Brexit – Recommendations – Centralized procedure – Human and veterinary medicinal products
The EMA published on 29 January 2018 guidelines named « Practical guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralized procedure».
These guidelines bring a clarification for the holders of AMM towards the procedures to be followed when the United Kingdom will become a third country.
The guidelines concern the procedure for submitting files (to obtain marketing authorization, pharmacovigilance, transfer…), different taxes…
Research – Embryonic cells – Study of the therapeutic potential – Identification of the genes – Study of the cellular therapy of the disease of Huntington
In four cases, the «Fondation Jérôme Lejeune», a non-profit association and engaged in the defense and care of patients suffering of Trisomy 21 and also in medical research, asked the annulation of several authorizations given by the Director of the biomedicine agency on 12 March, 2010 concerning researches leading to the use and the destruction of human embryonic stem cells.
Actually at the date of the contested decisions, French law applied the principle of interdiction of such researches.
The foundation argued that derogations provided constitutes a violation of regulatory and legal dispositions which regulates such kind of research.
The question raised in front of the Supreme Court was the existence of alternatives method of research allowing to obtain efficient results comparable to the one proposed in derogation to the principle of interdiction of these researches, and also the validity of the authorization obtained from the mothers and fathers of those embryos.
On the basis of the scientific knowledge and due to the specificity of the case, the French judges consider that the authorizations were sufficiently grounded legally and dismiss the request of the foundation.
Patent – Infringement–sufficiency disclose
Regeneron v. Kymab & Novo Nordisk (2018) EWCA Civ 671
UK Court of Appeal judged that Regeneron’s patent EP1360287, and its division numbered EP2264163, were insufficient.
The Regeneron patent EP1360287 relates to methods of producing transgenic mice possessing human antibody genes.
The divisional patent EP2264163 claims the mouse itself.
Historically, the development of therapeutic antibodies relied on the cloning of specific human antibody genes into a mouse.
The Regeneron transgenic mice (Veloclmmune) produces antibodies having a human variable region and a mouse constant region, which respond naturally to antigenic challenge and thus mirror the normal immune reaction.
This facilitates production of a diverse spectrum of antibodies against the same target within a single mouse.
The Regeneron patents particularly relates to a method for genetically modifying the antibody variable regions of a mouse cell by replacement of the mouse antibody variable genes with the equivalent human genes.
The resulting mouse cells contain a human antibody light chain or heavy chain variable region that undergoes natural homologous recombination during B-cell development.
Regeneron has brought a number of therapeutic antibodies to market using the platform and have many others currently undergoing clinical trial.
In 2007, Regeneron agreed a six-year US$120 million non-exclusive licence with AstraZeneca for use of the technology, under which Regeneron receives royalties on the sale of any products produced using the platform.
Astellas Pharma, one of the largest pharmaceutical companies in Japan, has also agreed a non-exclusive license for use of the VelocImmune technology until 2023.
UK High Court’s position
In the UK, Regeneron brought infringement proceedings against Kymab and Novo, for infringement of the EP (UK) patents.
The defendants counterclaimed that the patents were invalid on the grounds that the claimed invention was not sufficiently disclosed and lacked novelty and inventive step.
UK Court rejected the novelty and inventive step objections, but agreed with the defendants regarding the lack of sufficiency, on the basis of which he revoked the patents.
UK Court found that the claims were insufficient in view of expert evidence that the method provided in Example 3 of the specification would not have worked in the hands of the skilled person at the priority date (Regeneron’s own work after the priority date confirmed this).
The method claim specifies ‘in situ replacement of V, D and J gene segments of the endogenous locus with orthologous human V, D and J gene segments’. UK Court interpreted this as covering the deletion of mouse sequences of at least one V segment and all the D and J segments (>100 kb) and the insertion of the equivalent human regions (>75 kb).
On the basis of expert evidence that the insertion and deletion of such large pieces of DNA was not possible at the time of the invention,
The Court of Appeal
In their appeal, Regeneron did not challenge the finding that a skilled person would not have been able to delete 100 kb and insert 75 kb of DNA.
Instead Regeneron argued that a skilled team would have made adjustments to the method of Example 3, so as to reduce the size of the inserts to a manageable length, by reducing the number of V, D and J regions and removing unnecessary intergenic regions of sequence, the ‘minigene’ approach.
The deletion of the mouse regions could be carried out in a single step, and additional human V regions (10 kb) added as necessary.
Kymab argued that Regeneron had not previously raised the minigene argument and that it was now too late for it to be submitted.
The Court of Appeal did allow submission of Regeneron’s arguments on the basis that Regeneron had, in fact, previously contended that the claims did not necessitate insertion of the entire human locus or deletion of the entire mouse locus, and those shorter sequences in the form of minigenes could be used.
In contrast to UK Court, the Court of Appeal found that the concept of the minigene was common general knowledge at the priority date, and that a skilled team would have appreciated that the claimed method could be achieved by producing a VDJ minigene without undue effort.
This conclusion was based on the previous testimony of Kymab’s expert witnesses Professor Stewart and Professor Howard.
Conclusion
The Court of Appeal did not disagree with the trial judge that Example 3 would not have worked, or that at the priority date a skilled person would not have known how to delete 100 kb of mouse sequence and insert 200–300 kb of human sequence.
However, the Court of Appeal noted that the skilled person is not bound to carry out the invention precisely as described, and can use common general knowledge to make obvious changes.
Furthermore, the expert testimony indicated that a skilled person would have recognized Example 3 to be considerably challenging, and would have considered it obvious to shorten the inserts.
Finally, the court of appeal pointed out that ‘a patent does not cease to be sufficient simply because the specification promises too much’.