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Court of Appeal confirms validity of patent for purification of MS drug

05/04/2017
In Synthon BV v Teva Pharmaceutical Industries Ltd [2017] EWCA Civ 148, the Court of Appeal upheld the validity of a patent for purification of a drug used in treating multiple sclerosis, holding, in particular, that "the judge was plainly entitled to reject as unreliable" the evidence of obviousness adduced by Synthon's expert witness. The court also affirmed the High Court's ruling that two claims of the patent were invalid for added matter.

In Synthon BV v Teva Pharmaceutical Industries Ltd [2017] EWCA Civ 148, the Court of Appeal upheld the validity of a patent for purification of a drug used in treating multiple sclerosis, holding, in particular, that "the judge was plainly entitled to reject as unreliable" the evidence of obviousness adduced by Synthon's expert witness.  The court also affirmed the High Court's ruling that two claims of the patent were invalid for added matter.

The case serves as a reminder that the court is the ultimate arbiter on questions of patent validity. It is bound to consider, but not necessarily follow, the experts' views on obviousness (and other grounds of invalidity such as novelty and sufficiency). The case also highlights the delicate task facing those instructing expert witnesses in patent cases. The High Court judge was critical of the written evidence of Synthon's expert attributing this to overreliance on Synthon’s legal team. By contrast, in the witness box, she had struck the judge as candid, answering questions without equivocation

Background

Teva Pharmaceutical Industries Limited (Teva) developed glatiramer acetate (under the brand name "Copaxone") in the 1960s as an injection treatment for relapsing remitting multiple sclerosis, a form of MS which affects an estimated 2 million people worldwide. MS is a debilitating condition which causes inflammatory T cells circulating in the bloodstream to attack myelin, a coating which surrounds and protects nerve tissue in the body's central nervous system. The attack leaves lesions or plaques on the neurons which disrupt the body’s ability to send signals from one part of the nervous system to another.

Copaxone is one of a limited number of drugs which have been found to be effective in the treatment of MS; it accounts for $4.2 billion worth of annual sales worldwide and 21% of the Teva's group's total revenue.

This claim was an invalidity action brought by Synthon BV (Synthon) against two of Teva's UK patents which describe an improved manufacturing process for the drug. In brief, Copaxone is a mixture of synthetic polypeptides and is manufactured through acidolysis using a glacial acetic acid called HBR/AcOH. The patents provide for a process which, firstly, reduces the levels of free bromine in the HBR/AcOH solution by adding a 'scavenger' to absorb the bromine and, secondly, uses glass or teflon-lined vessels to keep the formation of metal ion impurities below a specified level.

Synthon sought revocation of the patents on the grounds of lack of novelty, obviousness and added matter.

High Court decision

In the High Court, Synthon submitted a number of arguments in relation to both the free bromine aspect of the patents and that relating to metal ion impurities.

Firstly, it argued that the patents were not novel because the basic scheme for making the drug was set out in an existing international application referred to as 'Lemmon'. The High Court rejected this argument because Lemmon did not contain any express teaching to produce the HBr/AcOH solution in a glass-lined vessel. While it was likely that a skilled person would only ever use a non-metallic vessel during the process, this did not mean that it was necessary to keep impurities below the levels stated under the patent.

Secondly, Synthon argued that the presence of free bromine in the HBr/AcOH solution would be revealed by routine analysis and the use of a bromine scavenger as an expedient was obvious to a skilled person. The judge, Mr Justice Birss, accepted the proposition that a skilled person, if prompted, would use a bromine scavenger as an expedient but did not consider that a skilled person would be able to infer the level of bromine from the analysis methods which were available. The point was moot, therefore, because the skilled person would not necessarily be alerted to the issue in the first place.

Synthon submitted a similar argument in respect of the metal ion impurities, arguing that the presence of impurities could be readily established by standard analytical techniques which would result in a discolouration of the HBr/AcOH solution. Once detected, the need to use non-metallic apparatus would be obvious to a skilled person since it was well known that the solution was highly corrosive to metal. Again, Birss J acknowledged that a skilled person would seek to identify the cause of the discolouration but held that they would not necessarily attribute the discolouration to the presence of metal ions, which was only one in a number of possible causes of the discolouration. In reaching these conclusions, the judge placed particular emphasis on the evidence of the parties' respective expert witnesses.

Finally, Synthon argued that one claim of the patent involved added matter, namely that the glatiramer acetate mixture contained less than 1000ppm metal ion impurities. While Teva accepted that the concentration of metal ions in the final product had not been expressly disclosed, it submitted that this was implicit due to the disclosure of equivalent levels in the HBr/AcOH solution. The judge dismissed this argument and upheld the opposition against this claim of the patent.

Synthon appealed against the finding on obviousness, while Teva cross-appealed the finding of added matter.

Court of Appeal decision

On appeal, Synthon submitted that Birss J had lost sight of the fact that the context of the invention was the manufacture of a pharmaceutical. The evidence submitted by Teva, it argued, had addressed what would be done in a university research laboratory where less stringent requirements for purity would apply, but in the pharmaceutical context purity was an important consideration and impurities such as free bromine would be identified and removed.

The Court of Appeal dismissed this argument succinctly: keeping the HBr/AcOH solution away from metal surfaces and creating a solution with less than 500 ppm metal ion impurities were not the same thing. Synthon had not adduced any evidence to show that merely keeping the solution away from metal surfaces would achieve the levels of purity claimed in the patent. Lord Justice Floyd (who gave the main judgment), described Birss J as a highly experienced judge and did not accept that he would not have considered that the relevant context was a pharmaceutical process which might demand a more stringent attitude toward impurities than in a research laboratory.

In terms of Teva's appeal against the finding of added matter, the Court of Appeal accepted that a patent's subject matter could include an implicit disclosure, as per European Central Bank v Document Security Systems Inc [2007] EWHC 600 (Pat). However, the court held that disclosure should be direct and unambiguous: a general teaching to minimise the levels of impurity from metal ions was not equivalent to the disclosure of a specified concentration of metal ions and Teva could not rely on the disclosure of one claim to infer the same in another.

Comment

This case serves as a reminder that each claim of a patent application should be disclosed in full and that an applicant may not be able to rely on the disclosure of one claim to infer equivalent disclosure in another.

Of additional note is the criticism of the written evidence submitted by Synthon's expert witness, Professor Tabor, by the High Court judge. While she was described as a 'model witness' in the stand, cross-examination had revealed a number of assertions in her written report which required qualification in light of the reply report produced by Teva's expert. Professor Tabor had not appeared as an expert witness before and had been advised by Synthon's lawyers that there was no need for her to serve a reply report as the points were better raised in cross-examination. While the judge criticised Professor Tabor for swearing to a report which contained statements which she knew needed qualification, he levelled particular reproach at Synthon's legal team for failing to advise her of the need to produce a reply report.

Where experts are selected for their technical experience rather than their skills as witnesses, they will be even more reliant on the advice and support given by their instructing solicitors. "This episode", as Birss J stated, "is a lesson in what can go wrong".

With thanks to Richard Lawne for writing this blog

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