Hospira (UK) Ltd v Genentech, Inc.
| Jurisdiction | England & Wales |
| Judge | Lord Justice Floyd,Lord Justice Kitchin,Lord Justice Elias |
| Judgment Date | 06 February 2015 |
| Neutral Citation | [2015] EWCA Civ 57 |
| Court | Court of Appeal (Civil Division) |
| Docket Number | Case No: A3 2014 1800 |
| Date | 06 February 2015 |
[2015] EWCA Civ 57
IN THE COURT OF APPEAL (CIVIL DIVISION)
ON APPEAL FROM THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
THE HON MR JUSTICE BIRSS
Royal Courts of Justice
Strand, London, WC2A 2LL
Lord Justice Elias
Lord Justice Kitchin
and
Lord Justice Floyd
Case No: A3 2014 1800
Mr Michael Tappin QC and Mr Mark Chacksfield (instructed by Marks & Clerk Solicitors LLP) for the Appellant
Mr Richard Meade QC, Mr Tom MitchesonQC andMr Jeremy Heald (instructed by Taylor Wessing LLP) for the Respondent
Hearing dates: 13 & 14 January 2015
Introduction
This appeal concerns the validity of European Patent (UK) No 1210115, which relates to a dosing regimen for the anti-cancer drug trastuzumab (Herceptin). The patent belongs to the appellant Genentech, Inc. Birss J, in a judgment dated 10 April 2014, held that the patent was invalid for obviousness, or alternatively for insufficiency (and other grounds of invalidity arising from loss of priority date). He refused permission to appeal, but permission was subsequently granted on the papers by Lewison LJ.
On this appeal Mr Michael Tappin QC and Mr Mark Chacksfield appeared for Genentech; Hospira was represented by Mr Richard Meade QC, Mr Tom Mitcheson QC and Mr Jeremy Heald.
Background and the judgment of Birss J
At the claimed priority date of the patent, 27 August 1999, Herceptin was a known drug for treating breast cancer. It had recently been approved for this purpose by the American drug regulator, the FDA, which, contemporaneously, published certain information about its safety and efficacy.
Herceptin is a monoclonal antibody, and therefore differed from conventional chemo-therapeutic agents which were mainly small molecules. It is a highly specific agent, targeted to a particular group of cancer cells, namely those over-expressing a receptor known as HER-2 (or Erb2). Compared to conventional cytotoxic agents it is well tolerated by the patient. However, like most drugs, it is not entirely without side effects, including a risk of cardiotoxicity. It has proved highly successful. It achieved worldwide sales of £33 billion in the period 1999 to 2013.
Because the drug was already approved for use in humans, the patent could not claim the idea of using Herceptin to treat breast cancer. Instead it claims a dosing regimen consisting of an initial intravenous loading dose of 8 mg/kg followed up by at least two subsequent intravenous doses of 6 mg/kg at three weekly intervals. The technical abbreviation for such a dosage regimen is 8 + 6 q3w. This differed from the FDA approved regimen which was an initial dose of 4 mg/kg and subsequent weekly doses of 2 mg/kg, or 4 + 2 q1w. It was common ground that the claimed regimen was novel.
When the FDA approves a drug it issues a formal document as part of the approval process, called the "FDA label". The FDA label for Herceptin described the approved 4 + 2 q1w regimen. The issue for the judge was whether, given the information contained in the FDA label, the 8 + 6 q3w regimen of the patent was an obvious one.
A three weekly regimen has advantages for the patient in that it involves fewer visits for the patient to hospital to receive the intravenous administration. This convenience factor was, as the judge found, an important one for cancer treatment in general and metastatic disease in particular. The skilled clinician would routinely consider how to improve quality of life for patients and consider conducting tests to ensure safety and efficacy.
It is common ground that the hypothetical skilled team, the notional body which the law uses to determine questions of inventive step, would include an oncologist clinician and a pharmacokineticist (an expert in the movement of drugs within the body).
The judge found that the following (amongst other) technical propositions would form part of the common general knowledge of the skilled team:
i) The effect which a drug has on a patient is normally dependent on the concentration of the drug in the serum at the site of action, normally measured in micrograms per millilitre (µg/ml).
ii) Pharmacokineticists attempt to model the absorption, distribution, metabolism and excretion of the drug, and by this means to calculate the concentration of a drug at a site of action at given times after its administration.
iii) The serum half-life of a drug is the time for the serum concentration to drop to one half (from its initial level after a dose).
iv) An initial higher dose, called a loading dose, was a well known way of reducing the time to reach a steady state concentration.
v) Doses are either expressed in absolute terms (in milligrams, mg) or as an amount per kilogram of body weight (mg/kg). It is a standard assumption that the patient weighs 70 kg: so one type of measurement can be converted into the other. A dose of 7.14 mg/kg is treated by convention as the same thing as an absolute dose of 500 mg.
The notion of a steady state concentration needs a little further explanation. When a drug is administered repeatedly the serum concentration rises to a peak and falls to a trough just before the next dose is given, so the graph of concentration against time never flattens out. A steady state is where the repeated doses cause the concentration to fluctuate between peaks and troughs of the same height and depth.
It is important that the peak does not take the concentration into a region where the drug will be unacceptably toxic. Equally it is important that the trough is not below the concentration at which the drug continues to be efficacious. An assessment is routinely made of the target trough serum concentration which is needed for the drug to be efficacious. The aim will be to have a dosing regimen which keeps the trough serum concentration above the target. A typical plot of serum concentration against time looks like this:
The lower saw-tooth line shows the peaks and troughs building up to the steady state. The upper line shows the typical effect of a loading dose, and reduces or eliminates the build-up period to steady state when such a dose is not administered.
The FDA label showed that the approved 4 +2 q1w regimen was effective to treat breast cancer when combined with another drug (paclitaxel). Paclitaxel was administered on a three weekly schedule. The judge identified the difference between the FDA label and the inventive concept of the patent as the three weekly dosing regimen (8 + 6 q3w), as well as the fact that that regimen was effective to treat breast cancer.
The FDA label also conveyed the following additional pharmacokinetic data. The serum half-life for Herceptin was dose-dependent. As the absolute weekly dose increases from 10 mg to 500 mg, the half-life increases from 1.7 days to 12 days. This is a non-linear dependency. The reported half-life for the approved 4 + 2 q1w regimen was 5.8 days. Additionally on the approved regimen, the serum concentration reached a steady state between weeks 16 and 32 with a trough concentration of 79 µg/ml.
The judge concluded after considering the evidence that the idea of three weekly dosing was something which would occur to the skilled clinician, particularly given the existing three weekly regimen for paclitaxel. The clinician would, however, not know whether such a regimen would be safe and efficacious to treat breast cancer. He would not dismiss the idea on the basis of the 5.8 day half-life for the 4 + 2 q1w regimen, as was suggested by one expert, because he would know that the half-life was dose dependent, and would therefore know that longer half-lives could be achieved by higher dosing. He would accordingly consult the pharmacokineticist as to whether it would be worth conducting a small clinical trial to test the safety and efficacy of a three weekly dosing regimen. The pharmacokineticist would report back with his answer and the clinician would decide whether to perform a clinical trial. This sequence of notional events was the structure or "choreography" which the parties and the judge used to decide the issue of obviousness. No issue about its appropriateness arose before us.
It was also common ground before the judge that the skilled person would discover information from the published literature about the target trough concentration for Herceptin and use a figure of 20 µg/ml as a conservative choice even though the literature supported a lower figure of 10 µg/ml as well.
The judge also found that two further matters would be clear to the skilled team. Firstly, on the basis of the FDA label, the team would know that a dose of 500 mg (which translates to 7.14 mg/kg) had been safely administered. This was a higher dose than involved in the 4 + 2 q1w regimen. Such a dose had a half-life of 12 days.
Hospira's expert Dr Earhart showed that the information available allowed the pharmacokineticist to estimate the serum level at three weeks after a single dose of 500 mg as well as that after the approved repeat dose of 2 mg/kg. This led to his Figure 1:
The upper sloping line (blue in colour) represents the serum concentration after a 500 mg (7.14 mg/kg) dose with a 12 day half life. The lower sloping line (green) represents the serum concentration after a single 2 mg/kg dose with a 5.8 day half life. The upper (red) dashed horizontal line represents the 79 µg/ml trough serum concentration reported in the FDA label as achieved by the approved regimen. The lower (purple) dashed line represents the 20...
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