Baxter Healthcare Corp & Anor v Abbott Laboratories & Anor

This is an application by the Defendant Patentees, Abbott Laboratories and Central Glass Company Limited (together “Abbott”), to compel the Claimants (“Baxter”) further to specify the Product and Process Description forming the subject of their action for a declaration of non-infringement and revocation of EP (UK) 0 967 975, “Fluoroether compositions and methods for inhibiting their degradation in the presence of a Lewis acid”.

The action is one aspect of a dispute between the parties now some five or six years old. The present proceeding is unusual in that, although it is on the face of it an action for a declaration of non-infringement, the parties are agreed, or appear to be agreed, that aspects of what Baxter in fact do by way of manufacture of their fluoroether composition, sevoflurane, its formulation and the impurities in fact present in it, are all relevant in some way to the dispute which the court has to decide.

To explain briefly the state of the action is difficult, but I shall begin with the broadest method claim, claim 2. This is as follows:

“A method of preventing degradation by a Lewis acid of a quantity of sevoflurane, the method comprising the steps of:

providing a quantity of sevoflurane;

providing a Lewis acid inhibitor in an amount sufficient to prevent degradation of said quantity of sevoflurane by a Lewis acid; and

combining said quantity of sevoflurane and said Lewis acid inhibitor.”

This claim (unlike the other claims of the patent in suit) does not specify the “Lewis acid inhibitor” that is to be used or to be present. Lewis acid inhibitors, or Lewis bases, comprise a very large class of chemical compounds. They include water (the subject matter of claims 1 and 4) and, more relevantly to the current discussion, amines. So the invention consists of adding enough of a Lewis acid inhibitor, or Lewis base, to prevent degradation of sevoflurane, which is an important anaesthetic.

The Claim Form and Particulars of Claim were accompanied by the Product and Process Description to which I have referred. This is a lengthy document which sets out, first, a description of the product and its packaging, accompanied by a regulatory specification for both the drug substance, or API, and the finished product. The quantity of water is specified to be not more than 130 parts per million by a specified analytical technique. The total impurities are stated to be not more than 300ppm, the impurity profile containing a large number of possible impurities. The method of manufacture is also described in some detail. It is a three-step process to the crude sevoflurane, and the purification of that product is described in detail. By their Defence, Abbott deny that the Product and Process Description accompanying the Particulars of Claim is adequate to enable a determination of whether the acts in respect of which a declaration of non-infringement is sought infringe the patent. They do not advance any positive case on infringement. On 6^th December 2005, Mann J ordered them to set out what their case was in relation to the issue of non-infringement. The Defendants’ Statement of Case in relation to infringement, served in response to Mann J’s order, is to a large extent a disappointing document. Paragraph 1 says that:

“The Defendants raise no positive case of infringement within this action. The burden is on the Claimants to prove non-infringement of claims 2 to 4 of the patent.”

Then, after referring to the Product and Process Description, Abbott identify two components of the Defendants’ product which they say have the “capacity” to inhibit (in whole or in part) the degradation of sevoflurane by Lewis acid. These two components are the water surviving from the purification step and the material lining the aluminium cans in which sevoflurane is supplied. That material is an epoxyphenolic resin. No affirmative case is advanced for supposing that the water and resin, alone or together, in fact inhibit the degradation of sevoflurane, but it is asserted that they have that capacity. The final paragraph of the Statement of Case asserts that it is for Baxter to prove that the resin and the water are not (alone or together) present in an amount sufficient to prevent degradation of the sevoflurane by a Lewis acid, and again repeats that Abbott raise no positive case.

The proceedings were started on 1^st June 2005, and I made an order for directions on 28^th July 2005. Mann J’s order was made on 6^th December 2005. The Statements of Case pursuant to Mann J’s order were served on 12^th December 2005. Meanwhile, the action had proceeded more or less in conformity with the order for directions, and lists of documents in relation to infringement had been exchanged on 30^th September 2005.

Abbott’s evidence is that on 16^th February 2006, Professor Chambers (one of the experts employed by Abbott for the purposes of the trial) identified the possibility that a further Lewis acid inhibitor would be present in sevoflurane manufactured according to the Product and Process Description. In his third report, made 17^th March 2006, Professor Chambers says that on 16^th February, during a meeting with Abbott’s solicitors, he considered paragraphs 63 to 68 of a report from Dr Lessor (a Baxter witness) describing the three-step process. He says that he raised for the first time at that meeting the possibility that Baxter’s product may contain amines that are not completely removed by the washing steps described in the Product and Process Description. Amines being Lewis bases, this would indicate the potential for the presence of a material having (at least in part) the capability to act as called for by the claim. The statement of impurities in the Product and Process Description contained no reference to such amines. He says that he suggested to Abbott’s solicitors that further information should be obtained; and two documents were subsequently shown to him on 6^th and 9^th March respectively. The first document was a copy of an “Abbreviated New Drug Application” or ANDA, which is a US regulatory document filed with the FDA for the purpose of obtaining what we would call marketing authorisation. Like all such documents, the ANDA contains a detailed description of the manufacturing process employed by the applicant. Baxter’s original ANDA is a multi-volume document, volume 2 of which is concerned with the process for manufacturing the API. Page 14 of this document describes a typical chemical reaction and aqueous “workup” and gives the relevant proportions of the reagents (total weight about 7.5 tons). The product description, page B031713 of the ANDA, does refer to the production of 2-chloropropane as an impurity. Professor Chambers recognised that if there is free di-isopropylethylamine present in the reaction mixture, it is possible to form 2-chloropropane in two ways. In either case, the result would be 2-chloropropane and an amine, the amine being fluorinated in the case of the route which Professor Chambers refers to as Route 2.

In fact, the ANDA makes it clear that an excess of the relevant starting material, di-isopropylethylamine (DIEA), is in fact used in the Baxter process, but Professor Chambers was also aware from his own private knowledge, in consequence of work done by one of his graduate students, that even in a stoichiometric mixture of DIEA and hydrogen fluoride there is in fact an equilibrium between free amine and protonated amine.

At this stage, therefore, it is established that the starting material used inevitably involves the risk of producing amines as a consequence of side-reactions. The last piece of relevant information is provided by a Baxter chemical development report, 21705-2, the author of which is Dr Lessor, which is footnoted to the relevant page of the ANDA. This paper, on examination, excludes what Professor Chambers refers to as Route 1, and so indicates that if this side-product is present, and survives washing, it will more likely be the fluorinated amine.

The ANDA is sufficient to identify the possible amine-producing side-reactions. It was listed in Baxter’s list of documents served on 30^th September 2005. This list preceded the formation of a “confidentiality club” after a suggestion that there should be a let-in agreement in respect of the disclosure already made between the parties in the United States had been rejected by Abbott. Nonetheless, inspection was offered by Baxter to “external counsel” (solicitors and barristers), nominated expert witnesses and one named in-house lawyer from each party. In fact, that offer was only accepted on 18^th November 2005 by Abbott’s solicitors. On 29^th November 2005, Abbott’s solicitors stated that it was accepted that sufficient details had been given in the Product and Process Description. It turns out that the first time that Professor Chambers had seen the ANDA (making it clear that DIEA was present in excess) was at the meeting on 16^th February to which I have referred. Although the disclosure, and in particular the ANDA, had been available for scrutiny by the experts at the latest by 18^th November and, if one accepts the offer made by Bird & Bird on 28^th September of the confidentiality club that Baxter would accept (since 30^th September), they had not been shown any of the disclosure.

In this case, this is a surprising omission. It is plain that Abbott have confronted difficulties in attempting to demonstrate that Baxter’s sevoflurane is stabilised by water, and it is equally obvious from the emphasis on the epoxy lining to the aluminium container that every possible source of Lewis base has been investigated in the hope of demonstrating infringement. The difficulty is made still more clear by Abbott’s steady refusal to make any assertion of infringement in the present proceedings, stating themselves content to rely upon the burden of proof.

In these circumstances, an omission to consider the one formal regulatory filing that explains in detail how the synthesis of the product proceeds and what impurities are to be expected, along with references to supporting documentation, is, in my judgment, surprising indeed. In a normal application for declaration of non-infringement, this would not be the case, but the parties proceed, as I have indicated, upon the footing that what Baxter actually does is relevant to the issues in the action. Since Professor Chambers had the information relating to the possible availability of unreacted DIEA in the reaction mixture, his failure to identify this possibility must be attributable to the fact that he was not shown the ANDA at a much earlier stage. As it is, it is absolutely clear from the Product and Process Description that DIEA is present in the reaction mixture.

Against this background, it is urged upon me that the late suggestion that there is a possibility that fluorinated amines are present in Baxter’s product is not only not the responsibility of Abbott, but positively of Baxter’s own doing. It is said that the failure to disclose the chemical product report footnoted to the ANDA has caused this late additional suggestion. I cannot accept this contention. Whilst it is true that the report is necessary in order to eliminate one of the two possible routes for the production of amines, and so determine the nature of the amine present, its disclosure was not necessary to establish the possibility. Nor has it ever been explained why the suggestion that there may be DIEA present in the final product has not been raised before. Nothing has changed in relation to DIEA since the action started, save the information made available that it was present in excess in the reaction mixture as described in the ANDA. Baxter wish to have time to determine whether amine impurities are of such a level that they can change the product description so as to specify their presence at less than 0.5ppm, a level at which it is accepted that their presence does not affect matters. Had this point been taken in October or November, this investigation would not be necessary so late, and it would not have been necessary to put off the trial.

In these circumstances, Abbott must pay the costs thrown away by the adjournment.

One other matter arises. This is the scope of the pleading relating to fluorinated amines. At present, as Mr Thorley QC frankly admits, only that resulting from Route 2 can be identified. That, then, is the only one to be considered at trial. If Abbott wish to raise other possibilities, they must do so explicitly.