Hospira (UK) Ltd v

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.

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:

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.

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 μg/ml target trough serum concentration the skilled person would derive from the common general knowledge. From this figure it is possible to determine that the predicted trough serum concentration after the single 500 mg dose would be 48 μg/ml on day 21. This figure gave the skilled team the information that a 500 mg dose would still be above the target trough concentration at 21 days, but that a 2 mg/kg dose (which converts to an absolute dose of 140 mg) would not. If Dr Earhart’s calculations faithfully reproduced the thinking of the ordinary, unimaginative skilled pharmacokineticist, this conclusion would enable one to conclude that the answer to be given to the clinician there was no reason from the pharmacokinetic standpoint not to try the three weekly dosage regimen.

The judge accepted Dr Earhart’s evidence based on Figure 1 and concluded that the pharmacokinetics expert would be prepared to support 500 mg three weekly. It was common ground before us that, in these circumstances, the 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. It was also common ground before us that an initial loading dose of 8 mg/kg would be considered safe as well.

It would however be wrong to give the impression that that harmonious state of affairs existed at the trial. Genentech challenged Hospira’s approach both in relation to the attitude of the clinician and of the pharmacokineticist at every step of the way. Genentech said that the clinician would not think of a three weekly dosing regimen at all, despite the fact that this was the interval at which paclitaxel was administered. Instead it suggested that the skilled team would rather switch to weekly administration of paclitaxel. A further point was that the convenience of three weekly dosing would not justify a change from the weekly regimen. It further relied on the half life of 5.8 days. And so on. Genentech now recognises, however, that there is no realistic prospect of this court re-visiting the judge’s conclusion that a dosing regimen of 8 + 7.14 q3w was obvious.

Had the evidence stopped there it would be said that the skilled team had not quite arrived at a dosage regime within the claim. 8 + 7.14 q3w is not quite the same as 8 + 6 q3w. There was no suggestion that the claim should be construed widely enough to include 8 +7.14 q3w as well.

Hospira sought to address this aspect of the claim through a further stage of Dr Earhart’s evidence. In a second set of calculations (displayed graphically in his Figure 2) Dr Earhart attempted to estimate 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. He calculated this minimum dose as 4.5 mg/kg, but rounded that figure up to 5 mg/kg based on a sensitivity analysis which he performed. If correct and reliable, this part of his reasoning 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.

However this part of Dr Earhart’s reasoning was subjected to attack by Genentech. The judge was “not convinced that the reasoning to support the lower limit of 4.5 mg/kg was robust”, but went on to say that he did not think it mattered. One of the reasons he gave was that:

In a subsequent extempore judgment given at the hearing on the form of order the judge recorded that:

The judge proceeded to hold the invention to be obvious on the following basis:

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 based on the first part of Dr Earhart’s reasoning.

Based on that reasoning a number of regimens were all obvious including the claimed regimen.

The Figure 2 reasoning was only concerned with investigating what dose below 500 mg would be feasible: even if the whole of it was rejected it would remain obvious to try the somewhat lower doses in the claim.

There was no basis in the specification to support the idea that it was inventive to select the particular claimed dosage regimen;

He concluded:

Section 3 of the Patents Act 1977 provides:

There was no detectable dispute between the parties as to how this provision is to be interpreted and applied. The judge followed the structured approach recommended by this court in Pozzoli SpA v BDMO SA and another [2007] EWCA Civ 588. That approach is well known, so I need not set it out again here.

The case of obviousness advanced was that the dosing regimen claimed in the patent was one which it was obvious to try. In deciding whether such a case is entitled to succeed it must be shown 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].

On this appeal Genentech challenges the judge’s approach in the following way. It submits that Hospira’s obviousness case required both the Figure 1 and the Figure 2 reasoning. Figure 1 simply established the basis for a regimen of 500 mg given repeatedly at three weekly intervals. The skilled team would have no basis for trying a claimed regimen which involved smaller doses. Figure 2 was designed to provide that basis, but the judge had rejected it. No case had been run by Hospira at the trial that the claim was obvious on the basis of Figure 1 alone. Genentech therefore submits that the judge simply failed to appreciate the consequences of his rejection of the Figure 2 reasoning, which was that Hospira had completely failed to prove its case. Further, the judgment cannot be supported on the basis that the skilled team would achieve success with 500 mg three weekly and be encouraged to experiment with lower doses: quite apart from the fact that no such case was advanced at trial, there was no evidence as to what the results of a clinical trial with 500 mg three weekly would be. In the absence of such results it was therefore speculative to conclude that the skilled team would have sufficient confidence of success to proceed with trials of lower doses.

In more detail Mr Tappin drew attention to the various assumptions which Dr Earhart had made in arriving at Figure 1, and about which he was cross-examined. These were:

the half-life after the administration of a single dose was the same as that derived from the FDA label which related to a repeated 500 mg dose;

the half life remained the same throughout the 21 day period of administration.

These assumptions were not in fact correct as the half-life is dose dependent. This meant that the straight, inclined, solid lines in Figure 1 should instead be curves, and the consequent estimate of a trough concentration of 48 mg/kg was an overestimate. Dr Earhart had accepted this point, and acknowledged that he was not able to say by how much the figure was an overestimate. Accordingly, Mr Tappin submits that Figure 1 does not provide any evidential basis for a dosing regimen below 7.14: only Figure 2 which the judge rejected could have done so.

Mr Tappin also submits that the judge wrongly placed reliance on the fact that there was no positive evidence in the patent or elsewhere that the particular figure of 6 mg/kg was inventive. He submits that this places a burden on Genentech when there should be none. It remained Hospira’s burden throughout to show that the invention was obvious.

In response Hospira submits that the judge was entirely justified in holding that the patent was obvious on the basis of Dr Earhart’s evidence about Figure 1. The judge had been correct to hold that the expectation of the pharmacokineticist would be that the target trough serum concentration would be exceeded probably by a substantial margin and so one would have sufficient confidence that the drug would be efficacious with the claimed dosage regimen. Hospira also submitted that Genentech’s reliance on the precise dosage specified in the claim: 8 + 6 q3w as opposed to 8 + 7.14 q3w was something which it had not relied on at trial. Hospira also submits, if necessary, that the judge did not reject the whole of Dr Earhart’s Figure 2 reasoning: only that part which established the minimum dose.

As I have already noted, both parties complained that their opponent was running a new case from that run at trial. Genentech says that Hospira’s only case was that based on Figure 1 and 2 and that once Figure 2 had been rejected Hospira had nothing left, and certainly no case sufficiently articulated for Genentech to know what it had to meet. Figure 2 provided one side of the window which included the claimed range and which would enable a suitably confident prediction to be made. Stripped of Figure 2, the skilled team would have no basis for a prediction that figures lower than 7.14 mg/kg would work. Thus Genentech submits that the judge was not entitled to find for Hospira on the basis he did, and that it is not open to Hospira to support the judgment in reliance on anything other than Dr Earhart’s Figure 1 and Figure 2.

For its part Hospira maintained that reliance on the precise dose had never been part of Genentech’s case at trial. It pointed to various parts of the transcript where their counsel had said that Figure 2 was only relied on if Genentech had any case on the precise numbers.

I am not impressed by either of these arguments. Hospira’s case throughout was that 8 + 6 q3w was obvious. It adduced the evidence of Dr Earhart to support that case, but success or failure of its case did not depend on every part of or step in his evidence being accepted, and Genentech cannot have supposed that this was so. Moreover, the way in which Genentech met Hospira’s case based on Dr Earhart’s evidence was to attack it at every step of the way. It is not therefore surprising that the arguments did not focus precisely on what the result would be if the judge did not accept the totality of the evidence. 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.

So far as Hospira’s suggestion of a new point is concerned, I do not see how Hospira can be disadvantaged by Genentech’s reliance on the express numerical limits of the claim. Hospira cannot and does not go as far as to suggest that it believed that Genentech had conceded that there was nothing independently inventive in the numerical limits. We were shown various parts of the transcript where Mr Meade threw down one or other gauntlets, but each was met with silence from Mr Tappin. In hard fought litigation such as this, that is the sign that you have to prove your case, which is what Hospira tried to do. The crucial question is whether there was, in the end, sufficient evidence to support the judge’s conclusion that the claimed regimen was obvious.

It is, I think, very important to make three points at the outset. The first is that Genentech was not contending that moving between 8 + 7.14 q3w and the claimed regimen of 8 + 6 q3w brought with it any unanticipated or surprising advantage. It can sometimes be contended that a surprising advance achieved by taking the step in issue is an indication of non-obviousness. No such contention could be advanced here. As the uncontested evidence showed, a drug which operates at receptors cannot in principle become more effective when the point is reached where all the receptors are occupied. The evidence showed that receptor occupancy would be estimated at 96% at the 20μg/ml serum concentration and would be expected to be 99% at the 79μg/ml concentration which is the steady state trough achieved with the approved regimen. It was therefore the case that there would not be expected to be any significant loss of efficacy in a range extending all the way down to the target level.

The second point, which follows from the first, is that Genentech’s case is now the essentially negative one, namely that although the 8 + 7.14 q3w was on the evidence worth trying, the evidence did not establish that the skilled team would get as far as trying 8 +6 q3w with the necessary expectation of success.

The third point is that the case was not fought on the basis that the skilled team had to arrive at the point where they would 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. The necessary work would not be extensive and would be reasonably clearly defined. It involved the use of a drug which had been granted approval for use in humans at a wide range of doses. The judge plainly had this aspect of the case well in mind at [112] of his judgment, quoted in paragraph 27 above.

We were taken carefully through Dr Earhart’s report and passages from his cross examination. He stated his conclusion simply on the basis of Figure 1 in the following terms:

Dr Earhart’s reference to the serum concentration being, on the basis of Figure 1, “well above the targeted level” is reflected, fairly in my judgment, in the judge’s finding at [93]:

Later the judge characterised Dr Earhart’s expectation in this way:

It would therefore be a misreading of Dr Earhart’s evidence to conclude that he thought, on the basis of Figure 1 alone, that nothing less than 500 mg (7.14 mg/kg) would do. It is obviously a fair point to make 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. The question which the judge had to assess, based on all the evidence, was whether that confidence would have ebbed away so much at the 6 mg/kg level that the skilled team would no longer have confidence to try it.

A further point to bear in mind in deciding whether the judge was justified in holding, in effect, that the skilled team would not regard a reduction from 7.14 to 6 mg/kg as significant is the lack of mathematical precision which it is in fact possible to bring to bear on considerations such as those which would face the skilled team in this case. We were shown the passages in the evidence of Dr Earhart which clearly support this consideration. For example Dr Earhart said in his third report:

Dr Earhart was cross-examined on a sensitivity analysis he had produced which showed the effect of changes in half-life on his calculations. He said:

Moreover, the field of clinical pharmacokinetics is plainly one where much depended on the judgment of the pharmacokineticist, and not merely calculation. The judge recognised this aspect of the art at [112], which I have quoted in paragraph 27 above.

It was no doubt considerations such as these which led Genentech to accept that a loading dose of 8 mg/kg would be thought entirely obvious in the light of the FDA label’s teaching of dosages up to 7.14. This shows, to my mind, that the skilled pharmacokineticist does not regard himself as tightly bound to the arithmetic results of the modelling calculations which he carries out: indeed it would be very surprising if it were otherwise.

There was other material before the judge which suggested that a 500 mg (7.14 mg/kg) three weekly dose would clear the target trough by a significant margin. Thus:

Dr Earhart’s analysis was not performed at steady state, that is to say after repeated 500 mg doses, but on a single dose. In terms of the figure I have reproduced in paragraph 12 above, Dr Earhart’s analysis was carried out on the first downward trough of the rising saw-tooth. This is in all likelihood the lowest trough in the entire span of administration of the drug. Dr Earhart was therefore applying, as Mr Meade put it, the most demanding test he could have set himself.

The Figure 1 analysis also included no loading dose. The effect of the loading dose is to accelerate the arrival of a steady state. Thus any concern you might have that lowering the dose below 7.14 mg/kg might bring you closer to the target trough level would be alleviated by the fact that the skilled pharmacokineticist would know that he could include a loading dose. Dr Earhart pointed out more than once that the fact that he did not model the loading dose was “a safety factor” inherent in his Figure 1. The judge accepted his evidence about this at [103].

The target trough serum concentration of 20 μg/ml is itself a cautious estimate. The literature also supported the use of 10 μg/ml. I would describe this as a minor point, given that the experts agreed that they would probably work to 20 μg/ml, but it is entitled to some weight as indicating that the figure of 20 μg/ml would not be regarded as an irreducible minimum. The judge recognised that taking the 20 μg/ml figure was a cautious approach.

Accordingly, whether the judge rejected the whole of the Figure 2 reasoning, or simply rejected it as a basis for a numerical lower limit, I believe I have said enough to show that there was ample material before him 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 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.

I do not think Mr Tappin’s points concerning the judge’s reference to the absence of positive evidence of inventiveness (see paragraphs 26(i) and (iv) above) take Genentech’s case any further. I do not accept that the judge was reversing the burden of proof. Hospira had shown that there was a range of dosages about which the skilled team would have the necessary degree of confidence. Given the apparent breadth of that range, it was a fair point to make that it had nowhere been suggested that there was anything inventive in selecting 6 rather than 7.14 mg/kg.

There was a subsidiary dispute about whether there was basis for what might appear to be a two-stage approach in the judge’s finding in [108]. That was that the skilled team who supported a trial of 500 mg three weekly would have gone on to try somewhat lower doses on the three weekly schedule if the schedule was efficacious. 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.

Despite Mr Tappin’s able and sustained submissions, the appeal on obviousness fails. In those circumstances the further issues relating to sufficiency and priority do not arise.

For the reasons I have given I would therefore dismiss this appeal.

I agree.

I also agree.