In a decision dated 21 May 2015, Mr Justice Birss found Teva’s patents EP(UK) 2177528 and 2361924, relating to processes for the production of Glatiramer acetate (GA) (sold commercially as Copaxone), to be mainly valid. Thus, Synthon B.V’s assertion of invalidity was found to be largely unconvincing and the claims were found to be novel, inventive and sufficient.
GA is a polypeptide, generally produced by random polymerisation, which is known to be an effective treatment for relapsing remitting multiple sclerosis. GA is formed from four amino acids, namely tyrosine, glutamic acid, lysine and alanine, where the glutamic acid and lysine used are normally protected with a benzyl group and a trifluoroacetyl (TFA) group, respectively, to prevent their reaction during random polymerisation. After polymerisation, a step of deprotecting the glutamic acid residues is usually carried out by acidolysis using HBr in AcOH and a second step of deprotecting the lysine residues is usually carried out. Teva’s patents are directed to improved methods of production, where the HBr/AcOH used in the first deprotection step is treated with a bromine scavenger molecule to prevent or reduce the presence of free bromine in HBr/AcOH, which can cause bromination of the tyrosine residues in GA. The examples in the patents show the bromotyrosine impurity generated when using untreated HBr/AcOH and the reduction of the impurity when HBr/AcOH is used which has been treated with a scavenger molecule. Further, certain claims define the level of metal ions in the HBr/AcOH solution, where a low level of metal ions (and thus a colourless GA product) can be obtained by using HBr/AcOH which has been produced in non-metallic vessels.
Claim 1 of the ‘528 patent thus states “A process for obtaining a mixture of trifluoroacetyl glatiramer acetate, wherein during the process a batch of a mixture of polypeptides, each of which consists of alanine, γ-benzyl glutamate, tyrosine and trifluoroacetyl lysine is deprotected with a solution of hydrobromic acid in acetic acid, the improvement comprising use of a solution of hydrobromic acid in acetic acid, which solution comprises less than 1000ppm of metal ions, and less than 0.5% of free bromine”.
Claim 1 of the ‘924 patent states “In a process for obtaining a mixture a trifluoroacetyl glatiramer acetate, wherein the mixture has a desired average molecular weight and wherein during the process a batch of a mixture of polypeptides, each of which consists of alanine, γ-benzyl glutamate, tyrosine and trifluorolysine is deprotected with a solution of hydrobromic acid in acetic acid, the improvement comprising use of a solution of hydrobromic acid in acetic acid, which solution comprises less than 0.1% free bromine”.
Claim 22 of the ‘924 patent states “The mixture of claim 21, where in the mixture comprises less than 100ppm metal ion impurities”.
The two parties each used an expert witness during proceedings, where Synthon’s witness in particular was criticised for swearing to a report that she had made, where she was aware that certain points required qualification. Her legal advisors were also criticised for advising that she proceed in this way and Mr Justice Birss indicated that the primary duty of an expert is to the court. Her oral evidence was however commended by Birss.
The common general knowledge was generally agreed upon by the parties, with the exception of three points relating to the free bromide amount and colouration. Thus, the common general knowledge was found to comprise peptide synthesis including random polymerisation, the protection of amino acid groups, the synthesis of GA by random polymerisation and subsequent deprotection of the amino acids. Although Mr Justice Birss thought that a skilled person would think the reason for the colouration of HBr/AcOH would be due to the presence of free bromine, it was found after much consideration that the problem of the presence of free bromine and the solution of using a scavenger molecule was not part of the common general knowledge with respect to a deprotection reaction.
The product claims 22-26 of the ‘924 patent were found to be novel in view of the pre-priority date sales of Copaxone, as it was held that there was no evidence that the metal ion content of the previously sold Copaxone was within the scope of the claims.
Further, the claims of both patents were found to be novel over Lemmon (WO 95/31990), as there was held to be no disclosure in Lemmon of using HBr/AcOH with a free bromine concentration of that described in the claims (or with a metal ion concentration as claimed, with respect to the ‘528 patent).
With regard to inventive step, Synthon’s main case was that it was obvious to get rid of or avoid free bromine in HBr/AcOH as it was obvious that there was a risk that free bromine in the HBr/AcOH might react with tyrosine residues and it was obvious that there was a need for a scavenger to remove the free bromine. Mr Justice Birss rejected this argument and it was held that there was nothing in the common general knowledge or Lemmon that would alert a skilled person to the idea that bromination of tyrosine could result from using HBr/AcOH. Birss indicated that a skilled person would not consider coloured HBr/AcOH to be a contaminated reagent.
Further, Synthon argued that a skilled person would analyse their product and would determine the presence of the contaminant, which they would then take steps to eliminate. This was argued by Teva to be a hindsight argument and that normal analysis approaches would not enable a skilled person to identify the contaminant. Mr Justice Birss agreed with this argument.
Synthon also submitted that there is no technical advantage indicated in the patents and that the patents concern purified products which cannot support a patent. An EPO decision (T990/96) was referred to in this respect. However, Mr Justice Birss ruled that the EPO purity decision was made in relation to products and is not relevant for processes. Further, he held that the product claims of the case are defined by an impurity rather than purity and that the EPO decision related to low molecular weight compounds and not to polypeptides.
Mr Justice Birss indicated that there is an advantage in the patents and that improvements to manufacturing processes for drugs are patentable and important. He further held that patents do not need to indicate that any part of the invention is surprising in view of the prior art.
With regard to the metal ion impurities, Synthon alleged that it would be obvious to skilled person that the development of a red colour in Copaxone would be due to metal ions. As HBr/AcOH is known to be highly corrosive to metals, this would be a likely source of such metal ions and it would be obvious to reduce the metal ion content by using a non-metallic vessel for production. Whilst Mr Justice Birss thought this argument to be compelling up to a point, he indicated that the presence of metal ions would be only one of a number of possible explanations for the colouration of the product. He thus thought it not obvious that the level of metal ions should be reduced.
The patents were thus found to be inventive.
The lack of sufficiency arguments raised by Synthon in relation to the metal ion impurity also failed to convince Mr Justice Birss, who thought that a skilled person would know how to ensure the absence of metal ions.
Finally, Synthon had some success with regard to their added matter objections and claim 20 was found to contain added matter.
Mr Justice Birss finally commented on the recent Dutch decision which revoked the Dutch designations of these patents. He indicated that Teva did not defend novelty in the Netherlands and that there were key differences in the evidence before each court which resulted in a different outcome for inventive step.
This is thus a good outcome for Teva, particularly given that Copaxone is responsible for $4.2 billion worth of annual sales, which represents approximately 21% of the Teva group’s total revenue.