Synthon B.v v Teva Pharmaceutical Industries Ltd
| Jurisdiction | England & Wales |
| Judge | Lord Justice Floyd,Lord Justice Briggs,Lord Justice Kitchin |
| Judgment Date | 21 March 2017 |
| Neutral Citation | [2017] EWCA Civ 148 |
| Docket Number | Case No: A3 2015 2155 |
| Court | Court of Appeal (Civil Division) |
| Date | 21 March 2017 |
[2017] EWCA Civ 148
IN THE COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Mr Justice Birss
Royal Courts of Justice
Strand, London, WC2A 2LL
Lord Justice Kitchin
Lord Justice Briggs
and
Lord Justice Floyd
Case No: A3 2015 2155
A3 2015 2162
Andrew Lykiardopoulos QC and Anna Edwards-Stuart (instructed by Bristows LLP) for the Appellant
Andrew Waugh QC and Thomas HinchliffeQC (instructed by Bird & Bird LLP) for the Respondent
Hearing date: 8 February 2016
Judgment Approved
Synthon B.V. ("Synthon") appeals from the decision of Birss J dated 21 May 2015 dismissing its action to revoke European patent (UK) 2 361 924 ("the patent") in the name of Teva Pharmaceutical Industries Ltd ("Teva"). A further patent, European patent (UK) 2 177 528, was in issue before the judge, but is not an issue before us. The judge held all claims of the patent to be valid notwithstanding attacks based on lack of novelty, obviousness and insufficiency, and dismissed the claim for revocation. On this appeal, Synthon only relies on obviousness. By a separate appeal, Teva challenges the judge's decision that certain claims of the patent, claim 20 and claims dependent on it, were invalid for added matter.
The patent relates to glatiramer acetate, which is a mixture of synthetic polypeptides made from the four amino acids, alanine, glutamic acid, lysine and tyrosine. The patent is particularly concerned with levels of free bromine and metal ion impurities which may be present in the manufacturing process and in the final product.
Teva markets a low molecular weight fraction of glatiramer acetate under the trademark Copaxone. Copaxone is used as a treatment for relapsing remitting multiple sclerosis and is responsible for $4.2 billion worth of annual sales worldwide, representing 21% of the Teva group's total revenues. It is not suggested, however, that the commercial success of the product has any bearing on the issues we have to decide.
Technical background
The judge summarised the common general knowledge relevant to the case starting at paragraph 29 of his judgment. What follows borrows heavily, and with gratitude, from that passage.
Polypeptides are made up from individual amino acid monomers joined together by peptide bonds. Each amino acid has a carboxylic acid group and an amino group. The peptide bonds are formed by reaction between the carboxylic acid group on one amino acid and the amino group on another. In this way a polypeptide is built up by a sequence of peptide bonds.
Each of the amino acids also has a side chain. Some side chains are inert in the conditions used to make the polypeptide, whilst others are able to react. It was common practice, when amino acids have reactive side chains, to mask (i.e. protect) those side chains during the polymerisation reaction. Lysine, glutamic acid and tyrosine all had potentially reactive side chains.
One method for making polypeptides involves a random polymerisation reaction in which the amino acids are attached to the chain in an unpredictable sequence. This random polymerisation reaction leads to a mixture of molecules with different sequences of amino acids. One method for random polymerisation is by the use of an activated amino acid in so-called N-carboxy anhydride (NCA) form. The NCAs of the four amino acids involved in glatiramer acetate can then be reacted together to form random polypeptides.
The masking or protecting of side chains is undertaken by using a protecting group. A well-known protecting group of glutamic acid is a benzyl group which forms a γ-benzyl ester. A well-known protecting group for lysine is a trifluoroacetyl (TFA) group.
One of the ways of removing the γ-benzyl protecting group from the glutamic acid side chain is acidolysis. Acidolysis uses a reagent such as hydrobromic acid (HBr) in glacial acetic acid (AcOH) i.e. HBr/AcOH. Following reaction with HBr/AcOH, the deprotected product may be precipitated out as a hydrobromide salt by the addition of a suitable solvent.
HBr is a strong acid and HBr/AcOH is a highly corrosive agent. Due to its highly corrosive nature, the reagent is supplied and stored in glass and plastic bottles or containers, and reactions involving it may be carried out in non-metallic vessels.
The basic synthetic scheme for making glatiramer acetate was set out in a 1971 paper by Teitelbaum et al, in US Patent 3 849 550 and in Example 4 of international patent application WO 95/31990 ("Lemmon"). Example 4 of Lemmon is the prior art relied on by Synthon for its obviousness case. The process involves the following steps:
i) Polymerisation of the NCAs of tyrosine, alanine, γ-benzyl glutamate and N-TFA lysine.
ii) Deprotection of the γ-benzyl group used to protect the carboxylic acid group in glutamic acid. The product produced by this step is sometimes referred to as TFA-glatiramer acetate because the TFA protecting group is still present. This is the important step for the purposes of this case.
iii) A second deprotection step in which the TFA protecting group is removed by treatment with piperidine in water.
iv) Purification.
The amino acid composition of polypeptides can be characterised by a number of different analytical techniques. These include amino acid analysis, size exclusion chromatography (SEC), nuclear magnetic resonance spectroscopy (NMR) and matrix assisted laser desorption/ionisation time of flight mass spectrometry (MALDI-TOF).
Important issues in the case surrounded the possible presence of free bromine (Br2) in the HBr/AcOH used in the deprotection step. Free bromine imparts a deep red-brown colour to a solution. The judge's findings were that the skilled person: (a) would not be able to quantify the free bromine level based on colour; (b) would not assume that there was much free bromine in a solution simply because it was coloured; (c) would know that the colour might not be due in whole or in part to free bromine but would infer that this was the most likely explanation if prompted to think about it; (d) would think that the free bromine level in a solution which was light yellow to colourless was low, if he or she thought about it, although they would not know what the level actually was; (e) would think that the free bromine content was likely to be lower in less coloured material.
Importantly, the judge found that there was no reliable evidence from which he could infer what the bromine level in freshly prepared HBr/AcOH kept away from light and oxygen would actually be.
A major dispute about the common general knowledge was whether it included knowledge that there was a potential problem caused by free bromine in HBr/AcOH (when used in a deprotection reaction) undergoing an undesired side-reaction with the phenol group in the tyrosine residues. The judge's conclusion was that the skilled person did not, as a matter of his or her common general knowledge, have a concern about a risk of such a side reaction. Thus skilled persons told to perform that reaction would neither set out to use a solution free of bromine nor would they take steps to remove free bromine by using a scavenger. They would not think about free bromine at all. The fact that, given a prompt to do so, they would conclude that colour in HBr/AcOH is most likely caused by some free bromine made no difference. Firstly they would not be prompted to consider it. HBr/AcOH would be regarded as a robust reagent. Secondly, even if they thought there might be some free bromine in the material, they would not have any reason to expect it to create an appreciable risk of a side reaction with tyrosine in the relevant conditions.
The patent
The specification of the patent explains that there are two aspects to the invention. One aspect relates to the level of free bromine, and the other aspect relates to the presence of metal impurities. At paragraphs [0090] to [0093] the specification explains that during the development of the production process for glatiramer acetate it was found that some of the tyrosine residues were brominated and that free bromine present in the HBr/AcOH caused the bromination of the tyrosine residues. The patent describes how this reaction can be prevented by adding a bromine scavenger, to mop up the free bromine.
At paragraphs [0094] to [0099] the patent explains that a red colour was detected after syringes containing solutions of Copaxone were kept at room temperature for 12 to 24 hours and that the source of this colour was unknown. It was determined that production of HBr in metal apparatus led to trace metallic ion impurities in the HBr. When HBr was later mixed with protected glatiramer acetate, the metallic ion impurities in the HBr were chelated by TFA-glatiramer acetate and glatiramer acetate itself. These entities contributed to the red colouration.
The patent continues:
"As a result, another measure taken to ensure purity, e.g. in the GA product, was the use of a non-metal reactor for the production of 33% HBr/acetic acid solution. The reactor used for the production of HBr/acetic acid solution was glass lined in order to prevent the formation of impurities which could later affect the purity of, e.g., the GA. In order to prevent contact of HBr solution with metal, parts of the piping were Teflon-lined. Similarly, other types of non-reactive, acid resistant non-metal apparatus can be used to prevent the formation of trace metal ions in the HBr/acetic acid solution. The use of a non-metal apparatus for the production of HBr/acetic acid solution was successful in eliminating the red colour from the GA. When the non-metal apparatus was used for the production of...
To continue reading
Request your trial
-
Generics (U.K.) Ltd trading as Mylan and Another v Yeda Research and Development Company Ltd Teva Pharmaceutical Industries Ltd (Third Party)
...the exception of claims 20, 27 and 28 of 924. The Court of Appeal dismissed both Synthon's and Teva's appeals with respect to 924 ( [2017] EWCA Civ 148) and the Supreme Court refused Synthon permission to appeal. On 12 September 2017, however, a Technical Board of Appeal of the European Pa......