Court of Appeal confirms Genentech's trastuzumab dosage regimen patent is invalid

13 February 2015


The Court of Appeal has confirmed Birss J's finding that Genentech's dosage regimen patent, concerning the monoclonal antibody which is the active ingredient in Herceptin, was obvious. The appeal concerns the first of Birss J's judgments between Hospira and Genentech last year.

Background

The patent claimed a dosing schedule for the use of a monoclonal antibody, trastuzumab, which is the active ingredient in Herceptin, a cancer therapy. The claim was to an initial intravenous loading dose of 8 mg/kg followed by subsequent intravenous doses of 6mg/kg at three weekly intervals (abbreviated to 8 + 6 q3w). Hospira contended that it lacked inventive step in view of prior art, which was the first FDA label for Herceptin.

The FDA label disclosed a dosing regimen of 4 + 2 q1w and pharmacokinetic data, including that trastuzumab had a non-linear half-life which increases from 1.17 days (10mg) to 12 days (500mg).

The narrow scope of the appeal on obviousness

Birss J's first instance judgment on obviousness is available here

Before Birss J, Genentech's position was that the clinician would not think of a three weekly dosing regimen but this was not pursued in the Court of Appeal. Genentech also did not challenge Birss J's finding that following calculations involving the pharmacokinetic data leading to "Figure 1", a 500mg dose (which translates to 7.14 mg/kg)  would be above the target trough concentration after 21 days, and so a dosing regimen of 8 + 7.14 q3w was obvious.

Before the Court of Appeal, however, it remained Genentech's case that a dosing regimen of 8 + 6 q3w was not obvious. Hospira's position remained that it was obvious to try such a dose. At first instance, Hospira's expert's detailed reasoning that a lower limit of 5mg/Kg would still provide efficacy (referred to as "Figure 2") was not found adequately robust.  Birss J thought though that this did not matter and found the claim obvious in any case.

The Court of Appeal's decision on obviousness

The Court of Appeal's decision was handed down on 6 February 2015

The Court of Appeal noted that in an obvious to try case such as this, the party challenging the patent must show that the skilled team would embark on any necessary work with "a fair expectation of success" (Conor v Angiotech [2007] EWCA Civ 5 at [42]). Genentech argued that the failure of Hospira's Figure 2 evidence meant that Hospira had completely failed to prove its case.

The Court of Appeal reviewed the evidence concerning the inventiveness, if any, of moving from an 8 + 7.14 q3w to an 8 + 6 q3w dosing regimen and made three "important" points:

  1. Genentech (the patentee) was not contending that moving between 8 + 7.14 q3w and the claimed regimen brought with it any unanticipated or surprising advantage. Due to saturation of the receptor target, there was not expected to be any significant loss of efficacy in a dosing range at the lower dose.
  2. Genentech's case was "essentially negative", being that Hospira's evidence did not establish that the skilled team would get as far as trying 8 + 6 q3w with the necessary expectation of success.
  3. The case was not fought on the basis that the skilled team had to know that the three weekly regimen under test would work. 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.

Giving the only reasoned judgment, Floyd LJ concluded that there was "ample material before [the judge] 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". Further, "[t]he judge did not have to determine the lower limit of that range provided that he was satisfied on the balance of probabilities that 8 + 6 q3w lay within it".

The nature of this "obvious to try" decision is perhaps best summed up by the following comment from Floyd LJ (who gave the only reasoned judgment):

"Mr Meade showed us evidence which was adduced at the trial that, even during clinical trials, it was routine to consider adjusting doses by monitoring pharmacokinetic parameters.  To my mind it is completely self-evident that the skilled team would feel free to deliver any dose which they considered to fall within the therapeutic window."

Pleadings point

Floyd LJ noted that both parties complained that their opponent was running a new case from that run at trial, and made clear his disapproval of the arguments. Dismissing both parties' complaints, he stated:

"The judge was bound to consider how much of the evidence he could accept in the light of the cross-examination of Dr Earhart and the evidence of Professor Boddy (Genentech’s expert), to take stock of it, and to decide whether on the basis of the evidence which he accepted the claimed regimen was or was not obvious.  I do not think that Genentech can validly complain about the course of the trial or suggest that the judge’s conclusions were not procedurally open to him.  The question is whether the evidence did in fact support the conclusions which he reached.

"The crucial question is whether there was, in the end, sufficient evidence to support the judge’s conclusion that the claimed regimen was obvious."

Conclusion

This is an "obvious to try" decision in a case in which Genentech perhaps did not rely as strongly as it might on the "would/could" argument. (However, bearing in mind their failure to succeed on that point in the later fight between the same parties, they may not have fared much better – the judgment of Mr Justice Birss of 11 December 2014 has been appealed and we await guidance from the Court of Appeal on "could/would" in that case).

Ultimately, the Court of Appeal's recent decision may well prove to be relatively confined to the facts in issue. Although some important questions of the law on sufficiency and priority were the subject of Genentech's appeal, the Court of Appeal chose not to address them, following its finding that the patent lacked inventive step.


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