On the Pulse is brought to you by the Bristows Life Sciences Team.
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On a regular basis we comment on issues affecting those with an
In this issue
interest in the Life Sciences - changes to law, recent cases and market
trends. The Team is led by Sally Field
. This month, On the Pulse is
edited by Sahar Shepperd
. This November issue of On the Pulse
provides an overview of the most recent and significant developments
that affect the Life Sciences Industry.
European Commission proposes a new Clinical Trial
Italian Court overturns decision on Abuse
of Dominance in the Pharma Sector
The CJEU Decision in Solvay v Honeywell
Cross-Border Interim Injunctions now a reality?
Guide bring clarity to some grey areas regarding the promotion of medicines?
and Teva – Extended use of post-filed evidence?
The Italian Administrative Court (“Court”) recently reversed a decision taken earlier this year by the Italian Competition Authority (“ICA”) under which Pfizer was fined €10.7 million for an abuse of a dominant
position contrary to Article 102. The abuse concerned Pfizer’
concerning medicines based on the active ingredient latanoprost (sold
in Italy under the brand name Xalatan®), a treatment for glaucoma.
The ICA’s decision
The ICA found that Pfizer had developed a “complex strategy”
artificially extend the patent protection Xalatan® in Italy. This included
securing a divisional patent and obtaining an SPC in Italy, based on this divisional patent, as well as applying for a paediatric extension and
threatening legal proceedings to discourage generics. This was found to have had the effect of delaying the entry of generic latanoprost
to find out about
products into the Italian market. Pfizer offered various commitments to
s concerns, but these were rejected.
to see previous
The Court’s judgment
In granting the appeal, the Court first highlighted the ICA’
s proposed commitments, noting that these were in fact
“likely to diminish the legal uncertainty created by Pfizer’s strategy”
to their “objective substantive consistency”
. The Court then criticised the ICA’
s overall “complex strategy”
Court required evidence of a “clear exclusionary intent”
before an abuse could be found. The Court stated that Pfizer had merely defended its legitimate interests by relying on the available legal
provisions, and no “quid pluris”
s conduct did not fall “within the scope of
. In recognising that patents give rise to exclusionary rights, the Court’
broad-brush negative treatment of legitimate tools available for extending patent protection.
s decision had been based heavily on the European
s decision in AstraZeneca
, largely approved by the EU
General Court (final judgment of the EU Court of Justice is expected on 6 December). The Court criticised the ICA for interpreting AstraZeneca
too widely and noted that in contrast Pfizer had not presented any elusive or erroneous information to the EPO when pursuing its divisional patent.
strategy for being in conflict with the fundamental right of access to the courts under EU law, as set out in ITT-Promedia
. The Court noted that Pfizer’
s pre-litigation warning letters were justified by the SPC and that
the majority of the legal proceedings involving the SPC had been initiated by the generics, rather than Pfizer.
The Court also found fault with the ICA for basing its decision on the EPO’
s revocation of the divisional patent which formed the basis for
the SPC, a revocation that was at that time subject to appeal. The Court suggested that the proceedings should have been stayed until the final EPO decision, and indeed the divisional has since been found valid by the EPO Board of Appeal. Although the Court criticised the ICA for being motivated by the EPO proceedings, the recent validation of the divisional patent also seems to have influenced the Court itself in its competition law analysis.
possibility of further appeal by the ICA.
proposes a new Clinical Trial
On 17 July 2012, the European Commission published its long-awaited
proposed Regulation which is intended to replace the existing
Clinical Trials Directive 2001/20/EC (the “CTD
”). The proposal aims
to simplify the CTD and provide for a greater level of harmonisation as
regards the authorisation and reporting procedures. The proposal also
introduces new indemnity measures aimed at ensuring that
compensation for damages is commensurate to the level of risk
associated with the clinical trial.
The CTD was implemented in 2004 to simplify and harmonise the administrative requirements for clinical trials in the EU and it provides a standardised framework setting out how clinical trials, investigating the safety or efficacy of a medicinal product in humans, must be conducted throughout the EU. However, the harmonisation of the clinical trials legislation in the EU is currently affected by the fact that Member States have had to implement the CTD into national law and this has inevitably resulted in an inconsistent implementation of the CTD by the individual Member States, with the result that it has become increasingly difficult to undertake multinational clinical trials. Furthermore, the CTD does not distinguish between commercial (trials conducted by the pharmaceutical industry) and non-commercial (trials carried out primarily by academic researchers) clinical trials. In addition, application of the CTD has led to a greater administrative burden (with associated costs and delays) for clinical trials.
According to the Commission the number of clinical trials conducted in the EU between 2007 and 2011 fell by 25% (from 5,000 to 3,800) . Concurrently, costs and delays for launching a clinical trial have also increased and certain aspects have emerged which have contributed to making the EU a less desirable location to carry out clinical trials. The objective of the new legislation therefore is “to restore [the] European Union’s competitiveness in clinical research and the development of new and innovative treatments and medicines for the ultimate benefit of patients
The legislation will also take the form of a Regulation, rather than a Directive, in order to ensure greater harmonisation across all EU Member States and avoid the difficulties of interpretation and diverging national transposition measures.
The proposed Regulation: streamlined, centralised, simplified and
The proposal establishes, inter alia
, a new simplified authorisation procedure for multinational clinical trials via a ‘
clinical trial data and information, as well as clinical trial applications, will be submitted. The Commission will manage the database in order to streamline and facilitate the flow of information for Member States and sponsors.
The assessment is divided into two parts. A reporting Member State, nominated by the sponsor, is responsible for validating the application and for coordinating Part I aspects of the trial. The Part I aspects include the anticipated therapeutic and public health benefits, the risks and inconveniences for the trial subjects, and the adequacy of the investigator’
s brochure. The reporting Member State carries out the
assessment in coordination with the concerned Member States. Part II aspects are assessed separately by each individual Member State and concern those features of the trial which have an ethical and local aspect, such as informed consent, the recruitment of subjects to the trial and compensation for both subjects and investigators. Strict deadlines exist for notifying the sponsor, via the EU-portal, as to whether the clinical trial has been authorised.
The proposed legislation introduces the concept of a 'low-intervention clinical trial' and provides less onerous requirements for these trials. Low-intervention clinical trials are clinical trials of authorised drugs used within the terms of their Marketing Authorisation (or where their use is a standard treatment in any of the Member States concerned)
and where the additional risk to patients, as a result of diagnostic or monitoring requirements, is negligible when compared to normal clinical practice. Under the proposal, such trials are subject to shorter authorisation timelines and sponsors would be exempt from the obligation to provide specific insurance or indemnification for harm suffered by trial subjects as a result of the clinical trial.
The proposal also simplifies the safety reporting rules. Suspected unexpected serious adverse reactions (SUSARs) that occur in a clinical trial should be reported by the sponsor directly through the EudraVigilance database. The annex to the proposal contains further detailed guidance in relation to the time limits for reporting SUSARs, based on the severity of the event. The EMA will be responsible for forwarding information relating to SUSARs to the relevant Members States.
The proposal recognises that frequently clinical trials can involve a number of institutions which may have difficulties in establishing a single sponsor. Accordingly, the Regulation expressly provides for co-sponsorship, whereby the responsibilities of several entities that join together to conduct a clinical trial are shared. Notably all sponsors are jointly responsible for the clinical trial unless contractual provisions determine otherwise.
The proposed Regulation also deals with other issues that commonly occur with clinical trials. For instance the proposal specifies that the Commission is empowered to conduct controls and inspections to verify that when clinical trials are conducted outside of the EU, they comply with the good clinical practice and ethical principles of the CTD and Declaration of Helsinki . Further, if the sponsor is located outside the EU, an ‘
s proposed Regulation goes some way towards
ensuring a consistent clinical research environment across EU Member States. It streamlines the authorisation process through a single application and addresses the burdensome obligations on low-risk clinical trials currently imposed by the CTD. The European Parliament and Council must now consider and debate the proposed legislation. It is unlikely that any new Regulation will be adopted before 2014 and consequently the earliest that the new Regulation could come into force would be 2016. If the Regulation is eventually adopted, it remains to be seen whether the Commission’
desired effect of harmonising the EU clinical trial framework, further protecting the safety and rights of the trial subjects and redressing the decline in EU clinical research.
 Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, Brussels, 17.7.2012, COM(2012) 369 final.
 Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the approximation of laws, regulations and administrative provisions of the Member States relating to the
implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.
 European Commission Memo: Proposal for a Clinical Trials Regulation - questions and answers, Brussels, 17 July 2012.
 The EudraVigilance database was established and is maintained by the European Medicines Agency.
 i.e. the regulatory system of third countries should comply with Annex 1, point 8 of Directive 2001/83/EC (as amended).
The CJEU Decision in Solvay
V Honeywell – Are Cross-
Border Interim Injunctions
now a reality?
The Court of Justice of the European Union (“CJEU”) has confirmed that national courts are not prohibited from granting pan-European interim injunctions in patent disputes even where exclusive jurisdiction is granted to a court of another Member State pursuant to Regulation (EC) No. 44/2001 (“the Brussels Regulation”).
Solvay, a Belgium company, brought proceedings before the Dutch national courts for infringement of the national parts of its European Patent No 0 858 440 by three Honeywell companies, one based in the Netherlands and two based in Belgium (the “Defendants”). Solvay’
EP patent was in force and said to be infringed by the Defendants in a number of European countries, but notably not in the Netherlands. In December 2009, Solvay lodged an interim claim against the Defendants seeking provisional relief in the form of a cross-border prohibition against infringement to last until a decision was made in the main proceedings.
In the interim proceedings, but not the main action proceedings, the Defendants raised invalidity of the national parts of the patent as a defence but took no further steps to advance this claim. Faced with complex issues of jurisdiction and cross-border relief, the Dutch court decided to stay the proceedings and refer several questions to the CJEU on the interpretation of the Brussels Regulation.
The CJEU ruled on two issues relevant for cross border litigation: jurisdiction over defendants domiciled in other Member States and the availability of a pan-European interim injunction in patent matters.
In relation to the first issue, the CJEU held that Article 6(1) of the Brussels Regulation should be interpreted as allowing a Member State court to have jurisdiction over co-defendants domiciled in different Member States, provided that one of the defendants is domiciled in the Member State of the courts seized and the defendants each infringe, in relation to the same product, the same national parts of the European
patent in issue. The CJEU made it clear however, that it was up to the national court to determine whether, taking into account all relevant factors, the claims were so closely connected that there was a risk of irreconcilable judgments.
The second question revolved around the interplay between Article 22(4) and Article 31 of the Brussels Regulation. Article 22(4) provides that the national courts of the Member State in which patents (and other IP rights) are registered has exclusive jurisdiction in proceedings concerning their validity. Article 31 provides that national courts may order provisional and protective measures, in spite of the fact that the courts of another Member State have jurisdiction as to the substance of the matter.
The CJEU interpreted Article 22(4) as not precluding, in circumstances such as those at issue in the main proceedings in this case, the application of Article 31. Considering that the court in which the interim proceedings are brought does not make a final decision on the validity of the patent, the CJEU felt there was no risk of conflicting decisions.
s judgments in Roche/Primus
right to have full cross-border national patent infringement proceedings was effectively prohibited. However, these cases did not consider the specific issue of interim injunctions and this latest decision of the CJEU confirms that, at least in certain situations, national courts do have the ability to grant pan-European interim injunctions against the infringement of European patents.
Does the MHRA’s new Blue
Guide bring clarity to some
grey areas regarding the
promotion of medicines?
The MHRA recently published the 3rd edition of its Blue Guide on Advertising and Promotion of Medicines in the UK, 7 years after the publication of the previous edition. The revisions reflect the MHRA’
contemporaneous review and consolidation of all the medicines legislation, guidance issued by the MHRA in specific areas over the past years, developments in the jurisprudence at the EU level and trends in the issues faced by the MHRA. This article addresses each of these aspects in turn and explains how the new Blue Guide brings some clarity to the issues faced by the pharmaceutical industry.
The new medicines legislation and latest guidance
The law relating to the promotion of medicinal products in the UK is now contained in Part 14 of the Human Medicines Regulations 2012, which codifies and replaces the Medicines (Advertising) Regulations 1994 and the Medicines (Monitoring of Advertising Regulations) 1994. The new Blue Guide therefore refers to the latest statutory provisions and includes a useful concordance table at Annex 2.
The new Blue Guide also consolidates guidance separately developed since the 2nd edition was published in 2005. One example is in relation to websites promoting services to consumers which may lead to the use of a prescription only medicine (for example, treatments for lines and wrinkles). The guidance provides some useful tips on how to avoid promoting prescription only medicines to the public (for example, special offers on prices of medicines should not be highlighted).
As regards the EU jurisprudence, the new Blue Guide reflects the ruling in Novo Nordisk
(Case C-249/09) where the CJEU held that an advertisement may include statements that are not directly taken from the Summary of Product Characteristics (the “SmPC”), so long as the claims are consistent with the SmPC. The MHRA provides some useful guidance on what this means in practice with the following examples:
• A comparative claim is permissible in principle even if the SmPC
makes no mention of any comparative study, (provided that the claim related to the licensed use of the product and was supported by robust evidence);
• However, if the SmPC initially reports that a comparative study
shows non-inferiority but a subsequent study shows superiority, then the SmPC would need to be amended before a superiority claim could be made in advertising.
It is hoped that the PMCPA will take a similarly pragmatic view in its rulings under Clause 3 of the ABPI Code (which provides that promotional claims must not be inconsistent with the SmPC).
s ruling in Merck
(Case C-316/09), the
new Blue Guide clarifies that in addition to publishing the SmPC, the Patent Information Leaflet (“PIL”) and non-promotional information about a disease, a company may also publish (i) non-promotional reference information that fairly reflects the current body of evidence and (ii) the product’
Trends in the issues faced by the MHRA
Compared to its predecessor, the new Blue Guide provides more examples of the sorts of claim that are likely to be considered unacceptable, reflecting the issues faced by the MHRA in recent years.
For example, the MHRA makes clear that claims presenting findings
from in vitro
or animal studies as directly relevant to the clinical use
the product would be considered to exaggerate the benefits of the
Another point worth noting is that the MHRA advises caution for
advertising in which the products promoted are linked with other
products with similar names
marketed by the same company (for
example, where the other product available is not classed as a
medicine, or where one product is indicated for infants/children and the
other is not).
The MHRA has also provided more clarification on when information
can be provided to budget holders
in advance of product launch,
following some recent decisions in this area (including Grünenthal
particular, approaches which encourage budget holders to include the
product in a local formulary when it becomes available are likely to be seen as promotional.
It is additionally interesting to note that the MHRA clarifies in the
context of advertisements to the public (of non-prescription only
medicines) that comparative claims
for a medicine against another
named product such as “works faster than xyz®” are prohibited (although category claims, such as “works faster than standard tablets” are not).
There are many uncertainties inherent in the law relating to the advertising of medicinal products. This is partly because new technology and media are pushing the boundaries of communication, but also because the permissibility or otherwise of a promotional claim depends typically on the specific context and sometimes subjective interpretation. Whilst grey areas remain, the new Blue Guide adds some colour to the field, and we can only hope that the MHRA will in the future update the publication on a more regular basis.
Generics (t/a Mylan) v Yeda
and Teva – Extended use of
In the case of Generics (t/a Mylan) v Yeda and Teva  EWHC 1848 Pat
, the High Court decided that Yeda’s patent was valid and infringed by Mylan’
s proposed generic version of Copaxone. Of
particular interest was a discussion relating to obviousness, namely, whether post-filed evidence can be used to cast doubt on a finding at the priority date that the claimed invention had sufficient technical merit.
By way of background, Yeda is the proprietor of a patent for copolymer-1 with reduced molecular weight. Teva is the exclusive licensee of the patent, selling Copaxone (aglatiramer acetate product) which is used for treating relapsing-remitting multiple sclerosis. Mylan sought to clear the way for its launch of a generic glatiramer acetate product, by filing a revocation action and seeking a declaration of non-infringement.
A number of matters were at issue, many of which were resolved in a relatively uncontroversial manner. However, the court’
obviousness, and in particular with regards to determining whether the selection of the claimed molecular weight characteristics of copolymer-1 had technical merit, is worth further comment.
The House of Lords in Conor v Angiotech  UKHL 49, held that a patent must disclose sufficient information to make the claimed invention plausible. Post-priority and post-filing evidence can be used to assist in determining whether the relevant disclosure in the patent was sufficient to make the invention plausible at the priority date. However, in this instance Mylan argued that even though a skilled person assessing the specification at the priority date came to the conclusion that the invention was plausible and had a technical effect, any evidence to the contrary, published subsequent to the filing date of
the patent ought to be admissible. In Mylan’
demonstrated that the patent in fact, did not have a technical effect and thus lacked validity. The court disagreed, noting that a patent that was thought to be a good invention on filing, could not subsequently be revoked when later scientific advances showed that the technical problem was not solved.
It follows that, as post-filing evidence cannot
be used to cast doubt on the conclusion that the specification makes it plausible that the invention solved the technical problem, the patentee shall not bear the burden of subsequently proving that the invention does, in fact, solve the technical problem. The court also noted that the patentee cannot rely on post-dated evidence to establish a technical effect which was not made plausible by the specification.
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