Mayne Pharma Pty Ltd v Debiopharm SA
| Jurisdiction | England & Wales |
| Judge | Mr. Justice Pumfrey,THE HONOURABLE MR JUSTICE PUMFREY,Mr Justice Pumfrey |
| Judgment Date | 19 May 2006 |
| Neutral Citation | [2006] EWHC 164 (Pat),[2006] EWHC 1123 (Pat) |
| Court | Chancery Division (Patents Court) |
| Docket Number | Case No: HC05 C01298,Case No: HC0501298 |
| Date | 19 May 2006 |
[2006] EWHC 1123 (Pat)
The Honourable Mr Justice Pumfrey
Case No: HC05 C01298
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
Antony Watson QC and Thomas Mitcheson (instructed by Taylor Wessing) for the Claimants
Andrew Waugh QC and Thomas Hinchliffe (instructed by Bird & Bird) for the Defendants
Hearing dates: 7 th– 15 th March 2006
Approved Judgment
I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this Judgment and that copies of this version as handed down may be treated as authentic.
Mr Justice Pumfrey :
Introduction
In this action, the Claimants ("Mayne") originally sought revocation of ten patents standing in the names of the Defendants ("Debiopharm") and declarations that the marketing in the United Kingdom of a product manufactured in accordance with a Confidential Product and Process Description would not constitute an infringement of any one of those patents. By the time that evidence came to be exchanged, the scope of the dispute had narrowed to four of the specified patents, and in respect of two of those Debiopharm declined to file any evidence. Accordingly, before me the issues of infringement and validity were to be decided in respect of EP(UK) 0943331 ("'331") and EP(UK) 1308454 ("'454"). For various reasons which it is not necessary to go into, the timetable for experiments and repetitions ran for longer than it should have done, and the results of the repetitions of Debiopharm's experiments in relation to infringement of '331 only became available during trial. It became apparent that it would be difficult to maintain the allegation of infringement in relation to this patent and it was formally withdrawn. Accordingly, this judgment deals with the validity of '331 and with both infringement and validity of '454.
Both patents are concerned with oxaliplatin, which is an anti-neoplastic platinum complex. '331 is concerned with pharmaceutical formulations of oxaliplatin, and '454 with a process for its preparation. By their respective priority dates, February 1998 and April 1996, oxaliplatin was an old compound. Its preparation had been referred to in USP 4,169,846 (Kidani) published 2 nd October 1979. Dr Cleare, Mayne's expert, who was thoroughly familiar with the field, said that oxaliplatin could be viewed as the third generation platinum-based compound for use in cancer therapy. Three such compounds have been approved for clinical use: cisplatin in 1979, carboplatin in 1986 and oxaliplatin in 1996. Oxaliplatin is no longer protected by a patent.
The Skilled Addressee
Before turning to the patents themselves, it is convenient to deal with a question which was controversial at trial, the identity of the skilled addressee. Both these patents are what are sometimes called "second-tier" patents, in that they are concerned with improvements in formulation or in production method of a known active ingredient. On the face of it, therefore, they are addressed to persons already acquainted with the manufacture of the active ingredient and its pharmaceutical formulation. Mr Waugh QC, who appeared for Debiopharm, suggested that the addressee of the specification was a general organometallic chemist, represented by Professor Davies, who was Debiopharm's witness on this part of the case. Mr Watson QC, for Mayne, suggested that the addressee of the patents had at least knowledge of other platinum-based anti-cancer compounds. The reason for these contrasting contentions lies in the question of the common general knowledge. I think this is one of those cases where it is important to bear in mind that those primarily interested in the invention will be employees of pharmaceutical companies interested in improving, or making for the first time, pharmaceutical compositions containing oxaliplatin. Chief among those would be those manufacturers who have already made oxaliplatin, carboplatin or cisplatin. Those seeking to enter this field for the first time do not provide what I can call an appropriate template for the skilled addressee, who must represent the attainments of those already in the field in which the invention is made. New entrants to a field may have clearer sight than those already in it, and lack the prejudices properly to be attributable to those with experience. At the same time, a new entrant into the field, albeit a specialist field within his or her general knowledge, will not possess the degree of experience which must also be attributed to the skilled addressee if a proper balance is to be held between the two extremes, of too much stiffness in refusing, and of too much easiness in admitting, any alleged inventive step. It is not sensible not to attribute to the skilled person the common general knowledge of those presently engaged in the manufacture and formulation of platinum-based pharmaceuticals.
Mr Waugh QC argues that since the specification enables a wider class of persons – organometallic chemists – to put the invention into effect, then that class of persons is the relevant class. I do not think this follows. After all, obviously the patent is in principle of interest to anybody, whether or not an organometallic chemist, who wishes to enter the field. That fact cannot be relevant to identifying the skilled addressee. It is not legitimate to draw the class of addressee so wide that the specific knowledge and prejudices of those most closely involved in the actual field with which the patent is concerned do not form part of the prejudices and attributes of the skilled person.
With that introduction, I can turn to the patents themselves. It is convenient to start with '454.
EP(UK) 1308454
The title of the invention is "Process of preparing platinum compound" and is said to relate to a process of preparing cis-oxalato (trans-l-1,2-cyclohexanediamine) Pt(II), which is oxaliplatin. Paragraph [0002] describes the general reaction scheme for the preparation of oxaliplatin. For present purposes, the scheme has the following important features:
a) The so-called trans dichloro material is reacted with silver nitrate to produce the so-called trans diaquo complex (also referred to as diaquo trans Pt DACH 1); and
b) The diaquo complex is reacted either with oxalic acid or with an oxalate.
The reaction is said to be disclosed in (inter alia) Kidani. It looks like this:
Paragraph [0003] describes the problem which the patent sets out to overcome. This is the problem of the formation of impurities by side-reactions. The principal side-reaction in question is the dimerization of the diaquo material. This competes with the reaction with oxalic acid, with the consequences stated in paragraph [0003]:
"While a high purity product with a small amount of by-products can be obtained when the reaction between the diaquo complex and the oxalic acid is completed in such a short period of time as two hours in the above process of preparation, its yield is disadvantageously lowered to 50 to 60%. Although, on the other hand, the yield may be elevated to about 70% when the reaction time is extended to about 24 hours, an amount of by-products or impurities produced during the reaction process increases with the reaction time so that the desired oxalate complex is contaminated with the impurities to lower its purity."
Paragraph [0004] points out that pharmaceuticals of this description are required to have high purity, and paragraph [0005] points out that the labour and cost of separation and removal of impurities is large and will involve the loss of a proportion of the desired product. Accordingly, as paragraph [0006] observes, it is desirable to depress the formation of impurities by shortening the reaction time while nonetheless increasing the yield. The solution to the problem is correctly stated in paragraph [0007] to be a simple one: it is to adjust the pH of the solution in which the reaction is taking place so as to increase the level of dissociation of the oxalate ion. This is clearly described in paragraphs [0009] – [0012]:
"[0009] In accordance with the aspect of the present invention, the depression of dissociation of an oxalate ion due to the low pH which has been an inhibition factor of a conventional reaction between a diaquo complex and an oxalate ion may be dissolved by shifting the pH range of a solution to the range in which the dissociation of the oxalate ion occurs at a satisfactory level by means of adding an alkali solution.
[0010] Accordingly, the degree of dissociation of the oxalic acid is elevated to produce a large amount of the oxalate ion so as to promote the reaction between the diaquo complex and the oxalate enabling to synthesize a target oxalate complex in a relatively short period of time.
[0011] When the pH is too low in this case, sufficient dissociation of the oxalic acid cannot be obtained, and while pH is too high, the formation of a poly-complex [this is the impurity] is accelerated. Accordingly, the promotion of the reaction and the depression of the formation of the poly-complex are achieved by shifting the pH of the solution to a range of 3.0 to 6.0 by means of the addition of the alkali solution in the present invention.
[0012] However, in this pH range, if the reaction promotion and the depression of the formation of the poly-complex can be attained to some degree, these may not [be] achieved to a sufficiently satisfactory degree. In order to obtain the sufficient degree of the reaction promotion and the depression of the poly-complex formation, it is desirable that the pH range is made to be 4.0 to 5.0 by the alkali addition."
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