Novartis v Ivax Pharmaceuticals UK Ltd
| Jurisdiction | England & Wales |
| Judge | THE HONOURABLE MR JUSTICE PUMFREY,Mr Justice Pumfrey |
| Judgment Date | 16 October 2006 |
| Neutral Citation | [2006] EWHC 2506 (Pat) |
| Docket Number | Case No: HC05C02457 |
| Date | 16 October 2006 |
| Court | Chancery Division (Patents Court) |
[2006] EWHC 2506 (PAT)
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
The Honourable Mr Justice Pumfrey
Case No: HC05C02457
Daniel Alexander QC and Andrew Lykiardopoulos (instructed by Bristows) for the Claimant
Simon Thorley QC, Thomas Mitcheson and Miles Copeland (instructed by Roiter Zucker) for the Defendant
Hearing dates: 21 st—26 th June 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 :
This is an action for infringement of two patents relating to the formulation of cyclosporin, which is a pharmaceutical of particular utility in producing immunosuppression in recipients of allogenic organ transplants. UK Patent 2,222,770 ("770" or "the Microemulsion Patent") claims priority from September 1988. The second patent, UK Patent 2,380,674, claims priority from March 1998 and has been referred to as either "674" or "the Second Component Patent".
The Defendant ("Ivax") wishes to launch a cyclosporin formulation in the UK under the name "Equoral". Both infringement and validity of both patents are in issue.
GB 2,222,770: The Microemulsion Patent
Before turning to the disclosure and the claims of this patent, I should consider the addressee of the specification. The patent is plainly directed to a pharmaceutical formulator wishing to provide a formulation of cyclosporin. By 1988, cyclosporin was a well-understood pharmaceutical, and in 1988 it was known to present difficulties in formulation. The patentees, the well-known Swiss pharmaceutical company Sandoz, were marketing a formulation of cyclosporin that attempted to overcome its almost complete insolubility in water. Pharmaceuticals that are insoluble in water may well be soluble to a greater extent in oils, and this fact was exploited by the existing formulation, "Sandimmun". Because cyclosporin therapy will last potentially for the whole of the recipient's life, it is desirable to formulate the drug so as to be as conveniently administered as possible. Oral administration is desirable, and Sandimmun was an oral formulation. It was based upon olive oil, a surfactant (Labrafil) and ethanol (alcohol). Sandimmun was what is called a pre-concentrate: when diluted with an aqueous phase (as for example the aqueous contents of the gut) it forms an oil-in-water (o/w) emulsion.
Emulsions
An emulsion is one example of a colloidal system. In very general terms, such systems consist of two "phases": a discontinuous or dispersed phase and a dispersing or continuous phase. An oil-in-water emulsion comprises very small particles of oil dispersed through a continuous aqueous medium. Such emulsions are generally cloudy or milky in appearance and are generally stabilised, at least to some extent, so that they do not separate out, or at least separate out sufficiently slowly to make them useful. The stabilisation is achieved by the use of surfactants, mixtures of surfactants, or a surfactant and a co-surfactant. Surfactants are molecules which have both a hydrophilic and a lipophilic part, and form a monolayer between the oily phase and the aqueous phase. Such molecules are called amphiphilic. Co-surfactants are also amphiphilic molecules, but, as I understand the evidence, typically rather smaller than a surfactant: for example, ethanol, propanol, butanol and pentanol may be co-surfactants. These molecules also are amphiphilic, being soluble in water and in some lipids.
The relative proportions of the different phases present in an emulsion are commonly shown on ternary plots (Figures I and II of '770 are examples) in which the relative concentrations yielding the desired emulsion are shown as areas within a triangle whose apices represent 100% of each component. In Figure I, for example, components 1.1, 2 and 3 are respectively the hydrophilic, lipophilic and surfactant components. Region A represents a region where the mixture works, and Region B a preferred region.
The cloudy appearance of an oil-in-water emulsion, and of other emulsions such as egg-yolk in olive oil, is caused by the size of the particles of the dispersed phase being sufficiently large to disperse light. As I understand the evidence, the droplet size of the dispersed phase in typical emulsions ranges from about 0.2 to 10 microns diameter. (This case is vexed by using three units for sizes in this general region: nanometres or nm = 10– -3 microns = 10 angstrom units = 10– -9 metres. The limit for optical visibility is about one wavelength of light, which at the blue end is about 400 nm, or 4,000 angstroms. The red end is about 700 nm. Any emulsion contains a distribution of particle sizes, and will tend to look bluish in reflected light (and reddish in transmitted light) as the centre of the distribution moves closer to sizes comparable with the wavelength of blue light.)
The scattering of light by colloids forms the basis for instruments that are capable of measuring the particle size distribution of the colloids. These instruments, in existence and standard pieces of laboratory equipment at the priority date, have various limitations to which I shall return in considering the experiments in this case. For present purposes, it is only necessary to note that the measurement of particle size distribution in colloidal materials was well-understood at the priority date.
At the priority date, cyclosporin was, as I have indicated, a generally accepted drug for immunosuppression. It was known to be nephrotoxic (liver-damaging) and the "therapeutic window" between the minimum effective dose and a toxic dose was not wide.
Chemically, the drug is unusual, being an 11-unit cyclic peptide. In 1988, it was known to be very hydrophobic. It could not be delivered in tablet form, and there was no commercial formulation for topical administration.
It is accordingly against the background of Sandimmun and the salient properties of the active ingredient summarised above that the disclosure of the patent in suit is to be assessed.
After describing cyclosporin itself and its actual and potential applicability, the specification identifies (page 5, final paragraph) the problems with formulations, such as Sandimmun, containing both ethanol and olive oil:
"First, the necessity to use oils or oil based carriers may lend the preparations an unpleasant taste or otherwise reduce palatability, in particular for the purposes of long-term therapy. These effects can be masked by presentation in gelatine capsule form. However, in order to maintain the cyclosporin in solution, the ethanol content has to be kept high. Evaporation of the ethanol, e.g. from capsules or from other forms, e.g. when opened, results in the development of a cyclosporin precipitate. Where such compositions are presented in e.g. soft gelatine encapsulated form, this particular difficulty necessitates packaging of the encapsulated product in an air-tight compartment, for example an air-tight blister or aluminium-foil blister-package. This in turn renders the product both bulky and more expensive to produce. The storage characteristics of formulations as aforesaid are far from ideal."
Thus the first problem with existing formulations that is identified is the problem caused by the presence of alcohol in the formulation. The second is variation between groups of patients and, even for a single patient, of bioavailability of the active ingredient:
"Bioavailability levels achieved using existing oral cyclosporin dosage systems are also low and exhibit wide variation between individuals, individual patient types and even for single individuals at different times during the course of therapy. Thus reports in the literature indicate that currently available therapy employing the commercially available Ciclosporin drink solution provides an average absolute bioavailability of ca. 30% only, with marked variation between individual groups, e.g. between liver (relatively low bioavailability) and bone-marrow (relatively high bioavailability) transplant recipients. Reported variation in bioavailability between subjects has varied from anything between one or a few percent for some patients to as much as 90% or more for others. And as already noted, marked change in bioavailability for individuals with time is frequently observed."
On page 7 of the specification, the proposals already made to meet these problems are discussed, and it is observed that the overriding difficulty is the consequence of the inherent insolubility of the cyclosporins in aqueous media. The specification refers to the additional need for a topical delivery system for the drug, and sets out its solution to the problem at the foot of page 7:
"By the present invention there are provided novel cyclosporin galenic formulations in the form of a micro-emulsion pre-concentrate and/or based on the use of particular solvent media as hereinafter defined, which meet or substantially reduce difficulties in cyclosporin, e.g. Ciclosplorin, therapy hitherto encountered in the art. In particular it has been found that the compositions of the invention permit the preparation of solid, semi-solid and liquid compositions containing a cyclosporin in sufficiently high concentration to permit, e.g. convenient oral administration, while at the same time achieving improved efficacy, e.g. in terms of bioavailability characteristics."
It is said (foot of page 8) that the invention of the patent in suit enables the preparation of compositions which are...
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