Merck & Company Inc. v Generics (UK) Ltd
| Jurisdiction | England & Wales |
| Judge | Mr Justice Laddie |
| Judgment Date | 27 November 2003 |
| Neutral Citation | [2003] EWHC 2842 (Pat) |
| Docket Number | Case No: HC 03 C02266 |
| Court | Chancery Division (Patents Court) |
| Date | 27 November 2003 |
[2003] EWHC 2842 (Pat)
The Honourable Mr Justice Laddie
Case No: HC 03 C02266
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice
Strand, London WC2A 2LL
Mr David Kitchin QC and Mr Thomas Hinchliffe (instructed by Lovells for the claimant
Mr Christopher Floyd QC and Mr Adrian Speck (instructed by Taylor Wessing for the defendant)
Hearing dates: 10 —13 November 2003
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 do may be treated as authentic.
This is an action for infringement of Patent EP (UK) No 0,402,152 ('the Patent'). The claimant patentee is Merck & Co Inc. The defendant is Generics (UK) Limited. The Patent relates to a method of making a compound called 4-amino 1hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt trihydrate, that is to say the monosodium salt of alendronic acid. This salt is more commonly called monosodium alendronate, or simply "alendronate". I will refer to it by the latter name. Structural drawings of this compound and its parent acid, alendronic acid, are shown below.
[Drawings set out here]
Alendronic acid (Sodium) Alendronate
Alendronate is a valuable pharmaceutical. It has proved to be of use in inhibiting bone resorption. For this reason it has application in the treatment of diseases such as osteoporosis. It is, apparently, the largest selling osteoporosis medicine in the world.
The defendant is a supplier of pharmaceutical preparations to the United Kingdom market. At the end of last year it notified the claimant that it intended to sell here a medicament in which alendronate was the active ingredient. That ingredient is to be made by company in India referred to during the trial as "CIPLA". The defendant supplied the claimant with a confidential description of the CIPLA process. That description concentrates only on those features which could have a bearing on the question of whether or not the process falls within the scope of the Patent. The defendant gave the claimant a limited time to concede non-infringement, failing which it said it intended to commence proceedings for a declaration to that effect. In the event, the claimant commenced the current proceedings before the expiry of the time limit given by the defendant. The action is based on the confidential process description which had been supplied by the defendant. At a case management conference on 14 July of this year, before the defence had been served, a timetable was put in place allowing for a rapid hearing of the issue of infringement. It was also ordered that if the defendant chose to challenge validity the determination of that issue was to be stayed until after this trial on infringement. A counterclaim for invalidity has been served by the defendant. For the above reasons, it is not a matter which arises for determination now. Indeed, because there is no dispute as to the nature of the alleged infringing process, the only issue I have to decide is one of construction of the Patent.
Because CIPLA considers that its process is confidential, not only was the process description confidential but so was some of the evidence. At the beginning of the trial, I was invited to sit in private. Rather than do that for the whole of the trial, a code was used to identify certain key steps, ingredients or parameters in the CIPLA process and, as a result, the opening of Mr David Kitchin QC, who appeared for the claimant, was conducted in open court, I will adopt the same approach in this judgment. Anything which is arguably confidential will be referred to by a code letter or otherwise in a manner which will hide its identity.
Essential chemistry
The chemical reaction by means of which alendronic acid is made is the subject of US patent 4,407,761. The general procedure for making acids of this type involves reacting an aminocarboxylic acid with a phosphonating agent, and then hydrolysing (ie reacting with water) under the influence of a non-oxidising acid. When alendronic acid itself is to be made, the aminocarboxylic acid used is gamma-amino butyric acid ("GABA"), the phosphonylating mixture can consist of a mixture of phosphorous acid (H3P03) and phosphorous trichioride (PCI3) and the non-oxidising acid is hydrochloric acid (HC1). The GABA, phosphorous acid and phosphorous trichioride are mixed in a solvent, chlorobenzene (PhC1). The whole reaction can be depicted, semi-figuratively as follows:
[Drawing set out here]
GABA Alendronic acid
In the latter diagram, the hydrolysis stage using hydrochloric acid, is represented by the notation "(ii) H20" (the chemical formula for water).
It is elementary chemistry that if a base reacts with an acid, the salt of the acid is produced. Thus if Sodium Hydroxide (NaOH), a base, is reacted with Hydrogen Chloride (HC1), an acid, the salt called Sodium Chloride (table salt) is produced. Water is a by-product.
NaOH+HC1 NaC1+H20
At all relevant times it has been common general knowledge that when a substance ("solute") is dissolved in a solvent, it can be made to crystallise out in a number of ways. One of the most simple involves cooling the solution. As the temperature falls the amount of solute which the solvent can dissolve falls. If there is too much solute in the solvent for the latter to dissolve at the lower temperature, the excess comes out of solution. It crystallises out. A well known alternative method involves changing the nature of the solvent. This can be achieved by adding an agent called an anti-solvent to the solution. The solution now has a lowered ability to dissolve the solute and, again, the excess crystallises out.
The Patent specification
The Patent is short and simple to understand. The specification starts with the following passage:
"This invention relates to 4-amino-1-hydroxybutylidene-1, 1-bisphosphonic acid monosodium salt trihydrate and a process therefor, where the end product is obtained in particularly pure form and at high yields in a one-pot procedure, and compositions containing said salt and its use in their manufacture."
Although this passage says that the invention relates to alendronate and a process for making it, the claims now are limited to the process alone, all claims to the product having been abandoned by the claimant just before the commencement of another trial. For present purposes, therefore, it is only necessary to consider the process disclosed and claimed in the Patent.
The specification continues by referring to a number of prior art patents. In particular it refers to US Patent No 4,407,761 and the latter's disclosure of a method of making alendronic acid. However, it notes that there is a problem with that process which it describes as follows:
"Problems result from this reaction whereby it does not remain homogeneous and local solidification occurs. This solidification causes variable yields, which in part results from the exothermic nature of the reactions with development of hotspots."
The parties agreed that the notional skilled addressee, of the Patent would also read the US patent. That does state that the reaction product is solid and it also states:
"If desired, inert organic diluents, which do not solublise the reaction product, particularly chlorinated hydrocarbons, such as chlorobenzene, tetrachloroethane tetrachloroethylene, and trichloroethylene, and dioxane can be used in the reaction." (US 4,407,761 Column 3 lines 8 to 12).
In fact that piece of prior art does not state that the formation of solid is a problem and it does not refer to any defects caused thereby. It does not address the question of why the reaction product is solid, that is to say what the mechanism is which makes it solidify, nor does it address the question of why that product is insoluble in the inert organic diluents it identifies. Similarly, the Patent in suit does not address either of these questions. The Patent then sets out the advantages which its process claims to achieve:
"Our new process allows the reaction to remain fluid and homogeneous and makes manufacturing of [alendronate] possible. It also has the advantage of requiring only one process step and provides a yield of 85–90 per cent."
The inventors' discovery is then explained as follows:
"It has been found that pure crystalline [alendronate] can surprisingly be obtained (in high yields) by the reaction of 4-aminobutyric acid with phosphonating reactants in the presence of methanesulfonic acid at a temperature of less than 85°C to yield a reaction mixture containing [alendronic acid]; the crystalline monosodium salt trihydrate [ie alendronate] is crystallised directly from the reaction mixture in about 90 per cent yield after quenching, hydrolysis, and pH adjustment to about 4.3 with no further purification necessary."
A number of features of this paragraph should be noted. The discovery is stated in wide terms. Although GABA is identified as one of the reagents, the phosphonating reactants are not specified. However, it does specify that methanesulphonic acid (MSA) is present. What the latter ingredient does, or how it facilitates the reaction is not stated. Furthermore, there are many other features of the discovered process which are not identified. For example, the method and ingredients used in the quenching and hydrolysis stages are not expressly identified. Although it is said that the pH is adjusted to about 4.3, there is no limitation to any particular method of pH adjustment, in particular no reference to the use of any particular alkali to counter the acidity of the reaction product, nor any...
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