Ratiopharm GmBh and another v Napp Pharmaceutical and another

JurisdictionEngland & Wales
CourtChancery Division (Patents Court)
JudgeTHE HON MR JUSTICE FLOYD,Mr Justice Floyd
Judgment Date16 December 2008
Neutral Citation[2008] EWHC 3070 (Pat)
Docket Number>Case Nos: HC07 C03453

[2008] EWHC 3070 (Pat)

IN THE HIGH COURT OF JUSTICE

CHANCERY DIVISION

PATENTS COURT

Royal Courts of Justice

Strand, London, WC2A 2LL

Before:

The Hon Mr Justice Floyd

>Case Nos: HC07 C03453

HC07 C03478

Between:
Ratiopharm Gmbh
Claimant
and
Napp Pharmaceutical Holdings Limited
Defendant
and
Andbetween:
Sandoz Limited
Claimant
and
Napp Pharmaceutical Holdings Limited
Defendant

Michael Silverleaf QC, Piers Acland and Anna Edwards-Stuart (instructed by Nabarro LLP) for ratiopharm GmbH

Michael Silverleaf QC and Tom Mitcheson (instructed by SJ Berwin LLP) for Sandoz Limited

Henry Carr QC and Michael Tappin (instructed by Powell Gilbert LLP) for the Defendants

Hearing dates: October 28–31, November 3–4 2008

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.

THE HON MR JUSTICE FLOYD Mr Justice Floyd

Mr Justice Floyd:

Introduction

1

These two actions started life as actions by ratiopharm GmbH (“ratiopharm”– for some reason it does not dignify itself with a capital letter) and Sandoz Limited (“Sandoz”) to revoke two patents, European Patent (UK) Nos. 722730 and 1258246 in the name of Napp Pharmaceutical Holdings Limited (“Napp”), and for declarations of non-infringement in respect of pharmaceutical products which ratiopharm and Sandoz wished to market in the United Kingdom. Napp responded in both cases with a counterclaim for infringement, asserting that the patents were both valid and infringed. The declaratory proceedings thus became unnecessary and fell away. The case is now a conventional patent action brought by Napp against each of ratiopharm and Sandoz, and was so treated at the trial. Napp opened the case and called its evidence first.

2

This judgment is divided into the following main sections:

paragraphs

Introduction

1–7

Technical Background

8–25

Expert Witnesses

26–34

The Patents

35–50

Construction

51–96

Infringement

97–111

Added Matter —Law

112–122

Added Matter —Facts

123–151

Obviousness —Law

152–159

Inventive concept

160

The skilled addressee

161–166

Obviousness over common general knowledge

167–221

Obviousness over Oshlack

222–252

Obviousness over Goldie

253–257

Controlled release oxycodone after the priority date

258–260

The application to amend

261–262

Conclusion

263–266

3

The two patents in suit, which I will refer to by their last three digits, 730 and 246, are concerned with a known opioid pain killer (analgesic) oxycodone. They have a priority date in 1991. The patents are not concerned with the discovery of the drug – that occurred in 1916, and it has been in clinical use in from 1917. Instead the patents are concerned with a formulation of the drug which achieves slow release. The case is perhaps unusual, in that there was nothing to prevent the manufacture of a slow release version of the drug for many years before 1991.

4

ratiopharm and Sandoz deny infringement on a number of grounds, most of which depend on the proper construction of the claims.

5

Validity of both patents is attacked on the basis of added matter. Certain of the added matter attacks are met by an application to amend. The application to amend is not opposed. The application is conditional in the case of 730, but unconditional in respect of 246. The amendments to 246 do not affect the scope of the claims.

6

Validity of both patents is also attacked on the ground of obviousness. The principal attack is over common general knowledge alone. There are also attacks based on two specific citations, referred to as Oshlack and Goldie.

7

Both sides have taken too many points, probably revealing that neither considered they had the “killer” blow described by Jacob LJ in Corus UK Ltd v Qualchem [2008] EWCA Civ 1177 at [2]. The case is indeed a finely balanced one. The result is that the reader is subjected to a long judgment, for which I apologise.

Technical background

8

This case is concerned with formulations of oxycodone for oral administration. There are two main types of oral drug delivery system for present purposes: “immediate release” and “controlled release”. In immediate release systems the drug is intended to be released rapidly and completely when it reaches the stomach. In controlled release systems, the rate of the drug release is controlled. These systems may be either delayed release systems, in which the release of the drug is held up altogether for a period, or extended (or sustained) release systems in which the drug is released more slowly from the dosage form than in immediate release in order to provide a longer period of therapeutic effectiveness. The case is concerned with the latter type of release.

9

Drugs have a so-called “pharmacokinetic profile”. This is the graph of the concentration of the drug in plasma or serum as a function of time after administration. The concentration first reaches a peak, which must be below the maximum safe concentration, and then tails off. After a time, the concentration falls below the minimum therapeutic concentration and the drug ceases to exert its effect. A typical pharmacokinetic profile for an immediate release system looks like this:

10

The difference in plasma levels between the maximum safe concentration and the minimum effective concentration is called the therapeutic range. Pharmacokinetics, the science of the kinetics of how drugs reach the bloodstream, is to be distinguished from pharmacodynamics. Pharmacodynamics is concerned with the patient's response to the drug.

11

The object of a sustained release system is to create a flattened pharmacokinetic profile, so that the plasma concentration remains within the therapeutic range for longer in consequence of a single dose. This has the obvious advantage in terms of convenience, in that the patient does not have to take repeated doses to keep the plasma level within the therapeutic range. It also means that there is less fluctuation in the plasma concentration.

12

At the priority date of the patent there were a number of well known formulation methods for achieving sustained release versions of a drug.

13

One method of creating a controlled release version of a drug would be to use a controlled release matrix. The active drug is embedded into a pharmaceutical excipient which provides a matrix into which water can diffuse. The behaviour is determined by the characteristics of the excipient and of the drug.

14

An alternative method is to use a so called reservoir system. Here the drug is surrounded by a barrier which controls the release of the drug. This can be achieved by coating so called non-pareil sugar beads with the drug, and adding the barrier on top, and in a variety of other ways.

15

Opioid analgesics are substances that have an affinity for opioid receptors. The term opioids includes (i) opiates —the naturally occurring alkaloids which are found in the opium poppy (which include morphine and codeine); (ii) semi-synthetic opioids – substances chemically derived from the natural opiates, including heroin, dihydromorphone, dihydrocodeine, oxycodone and others; (iii) fully synthetic opioids from several chemical classes, including pethidine, fentanyl, methadone, and others and (iv) the opioid peptides.

16

Opioids can be classified pharmacologically according to their efficacy, that is to say their ability to activate the opioid receptors. Full agonists have high efficacy and therefore fully activate the receptor, leading to the highest biological effect. Partial agonists have reduced efficacy, and may have an antagonistic effect on the efficacy of a full agonist which is present.

17

Opioids were also classified as either “weak” or “strong” according to the severity of pain they were used to alleviate. Weak opioids were used to alleviate mild to moderate pain, whereas strong opioids were used for moderate to severe pain.

18

By 1991 the WHO had classified drugs according to a sequential ladder containing three stages. A patient should not be progressed to the next step on the ladder until it proves impossible to relieve pain with appropriate doses of drugs on the previous step. Patients suffering low levels of pain (step 1) should use non-opioid analgesics (paracetamol or aspirin). Those suffering from mild to moderate pain (step 2) should take a weak opioid. Those suffering moderate to severe pain (step 3) should take a strong opioid.

19

The drug of choice for severe pain, the highest step on the ladder, was morphine. The potency of other drugs for the relief of severe pain is given in terms of their potency relative to morphine.

20

At the priority date there were considered to be three principal types of opioid receptor, identified by the Greek letters, mu kappa and delta: The mu receptor is activated by morphine, which is therefore considered a mu agonist. The majority of clinically available opioid analgesics were mu agonists.

21

Mu agonists as a class suffer from a number of potential side effects. These include nausea, vomiting, itching, somnolence, constipation and respiratory depression.

22

Mu agonists also suffered from a perception that they give rise to addiction and dependence. This is in fact a false perception at least in so far as it relates to acute pain, as the controlled therapeutic use of these agents is in fact perfectly safe. Because of their extensive use in terminal illness, morphine and similar agents also have an association with dying. These and other matters had led researchers into looking for drugs with equivalent analgesic effect, but with fewer side effects, or some distinct advantage over morphine. At the priority date there was widespread scepticism amongst opioid pharmacologists that the goal of separating analgesic...

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