27 April, 2015
Facts
The case of Hospira UK Ltd v Genentech Inc [2015] EWCA Civ 57 (6 February 2015) involved an application for a patent in relation to a dosing regimen. The appellant, Genentech, Inc. (“Genentech”) applied for the patent which related to a dosing regimen for the anti-cancer drug trastuzumab, Herceptin, for treating breast cancer (“Drug”). As the Drug was already approved for use in humans, the patent claimed 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.
The patent application was opposed by Hospira (UK) Limited (“Hospira”) and the patent application was rejected in the English High Court on the ground that the patent was obvious. Under section 3 of the UK Patents Act 1997, “an invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art…”. Subsequently, Genetech appealed the matter to the Court of Appeal.
As the American drug regulator, the Food and Drug Administration (“FDA”), had previously approved of the Drug’s 4 + 2 q1w regimen in its labels, the issue for the judge was whether the information contained in the FDA label would lead to the conclusion that the 8 + 6 q3w regimen of the patent was an obvious one.
It was agreed 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).
Further, the High Court held that the following technical propositions would form part of the common general knowledge of the skilled team:
- 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);
- 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;
- 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);
- An initial higher dose, called a loading dose, was a well known way of reducing the time to reach a steady state concentration; and
- 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.
On reviewing the evidence, the High Court held that:
- the idea of three weekly dosing was something which would occur to the skilled clinician;
- by virtue of the FDA label, the team would be aware that a dose of 500 mg (which translates to 7.14 mg/kg) had been safely administered; and
- such a dose had a half-life of 12 days.
In particular, the High Court accepted the expert evidence submitted by Hospira, that 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 (“Figure 1”). The High Court concluded that Figure 1 would lead the pharmacokineticist to support 500 mg three weekly. Accordingly, pharmacokineticist would report back to the clinician that there was no reason why a dose of 7.14 mg/kg three weekly should not be tried. Figure 1 would also suggest that an initial loading dose of 8 mg/kg would be considered safe.
Hospira’s expert also submitted a second set of calculations which estimated the lowest dose below 500 mg (7.14 mg/kg) which could be administered and yet still give a serum concentration above the 20 μg/ml trough level at the end of three weeks (“Figure 2”). This minimum dose was calculated to be at 4.5 mg/kg, but that figure up was rounded up to 5 mg/kg based on a sensitivity analysis. This would have allowed Hospira to submit that any regimen in a dosage window between 5 and 7.14 or even 8 mg/kg given three weekly was suitable to be tried.
The High Court was not convinced by the calculations submitted in Figure 2. Nevertheless, the High Court stated that its rejection of Figure 2 would not affect the outcome of its decision. This is because the pharmacokinetics expert would still be prepared to support 500mg three weekly and it would have been wholly obvious to try to use somewhat lower doses on the three weekly schedule if the schedule was efficacious.
Accordingly, the High Court held that the patent was invalid for obviousness on the basis that:
- Figure1 illustrates that there was no evidence that the claimed 8 + 6 q3w range would be inventive once the skilled team had decided to conduct a trial using three weekly dosing and a number of regimens were all obvious including the claimed regimen;
- Even if Figure 2 (which was concerned with investigating what dose below 500mg would be feasible) was rejected, it would remain obvious to try the somewhat lower doses in the claim; and
- There was no basis in the specification to support the idea that it was inventive to select the particular claimed dosage regimen.
Decision
Genetech challenged the High Court’s approach to the declaration of invalidity by submitting that:
- Hospira’s obviousness claim required both Figures 1 and 2 to be accepted since the skilled team would have no basis for trying a claimed regimen which involved smaller doses and the High Court judge had failed to consider the consequences of his rejection of Figure 2; and
- It was speculative to conclude that the skilled team would have sufficient confidence of success to proceed with trials of lower doses since there was no evidence as to what the results of a clinical trial with 500 mg three weekly would be.
The Court of Appeal observed that the criterion for deciding whether the claimed regimen was obvious was whether the skilled team would consider the prospects of it working to be sufficiently good to warrant a small clinical trial.
The Court of Appeal proceeded to scrutinise the expert evidence submitted by Hospira and concluded that on the basis of Figure 1 alone, it was clear that as one reduces the repeat dose from 7.14 mg/kg, the confidence that the drug will be efficacious in a clinical trial will reduce and the question to be considered is whether such confidence would have ebbed away so much at the 6 mg/kg level that the skilled team would no longer have the confidence to try it.
Further, the Court of Appeal recognised that the field of clinical pharmacokinetics is plainly one where much depended on the judgment of the pharmacokineticist, and not mere arithmetic calculation. This would justify High Court’s findings that the skilled team would not regard a reduction from 7.14 to 6 mg/kg as significant.
In light of the foregoing, the Court of Appeal dismissed Genetech’s appeal and held that regardless of whether Figure 2 was rejected, there was ample material to conclude, solely on the basis of Figure 1 and the evidence given in relation to it, that the FDA label would render obvious a range of doses which included 8 + 6 q3w.
The Court of Appeal agreed that Hospira had demonstrated that there was a range of dosages about which the skilled team would have the necessary degree of confidence and there was nothing inventive in selecting 6 rather than 7.14 mg/kg.
The Court of Appeal also held that the skilled team would have gone on to try somewhat lower doses on the three weekly schedule if the schedule was efficacious. Further, it was clear from the evidence adduced that it was routine, at clinical trials, to consider adjusting doses by monitoring pharmacokinetic parameters. In this regard, the skilled team would feel free to deliver any dose which they considered to fall within the therapeutic window.
Our Comments / Analysis
Section 3 of the UK Patents Act 1997 mirrors section 15 of the Singapore Patents Act 1994 where an invention is taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art as set out in the respective legislations.
This case is fairly fact-specific, but serves to demonstrate some of the issues which a court may consider when establishing what would constitute the common general knowledge of a skilled team.
For further information, please contact:
Chung Nian Lam, Partner, WongPartnership
chungnian.lam@wongpartnership.com
Jeffrey Lim, Partner, WongPartnership
jeffrey.lim@wongpartnership.com
