Bristol-Myers Squibb -v- Baker Norton Pharmaceuticals and Napro Biotherapeutics

Bird & Bird represented the Second Defendant/Respondent, NaPro BioTherapeutics in this case.

On 23 May 2000 the English Court of Appeal (Aldous, Buxton, LJJ, and Holman J.) dismissed the appeal of Bristol-Myers Squibb (BMS) against the judgment of Jacob J. of 20 August 1998 [1999] RPC 253 (see WIPR, October 1998). Jacob J had held BMS's patent to be invalid on the basis of lack of novelty and/or obviousness, but had not found it to be unpatentable on the basis that it was a method of treatment. The Court of Appeal upheld the findings on novelty and obviousness and found the patent invalid as a method of treatment.

The patent in suit claimed a particular regime covering the dosage and the infusion duration of paclitaxel (also known as taxol) to cancer patients. Paclitaxel is a naturally occurring substance made from the bark of the Pacific Yew tree and was well known as an anti-cancer agent at the priority date of the patent. Like most drugs used in cancer chemotherapy it is highly toxic and doctors involved in clinical trials, such as those which produced the data on which BMS relied in their patent, were seeking to establish the optimum dosage by balancing efficacy on the one hand with the highly toxic side-effects on the other. One of the known side-effects of paclitaxel is neutropenia, ie, a fall in the patient's white blood cell count, specifically the infection-fighting cells, the neutrophils. BMS claimed that novelty resided in the surprising discovery of the "reduction" in the particular side-effect of neutropenia without sacrificing efficacy using the specified dosage/infusion regimen. The appeal judges noted that it is the administration of taxol which causes the neutropenia and it is misleading to speak about the reduction of neutropenia by the use of taxol. Lord Justice Aldous therefore placed a gloss upon the construction of the claim by substituting the words "lessening of the amount of" instead of the word "reducing".

Claim 1 (split into integers as agreed at the trial) read as follows:

1. use of taxol and sufficient medications to prevent severe anaphylactic reactions;

2. for manufacturing a medicamentation for simultaneous, separate or sequential application;

3. for the administration of from 135 mg/m2 up to 175 mg/m2 taxol over a period of about 3 hours or less;

4. as a means for treating cancer; and

5. simultaneously reducing (ie, lessening the amount of) neutropenia.

Novelty

The Court of Appeal upheld the decision of the trial judge that claim 1 lacked novelty on the basis of a prior public disclosure, namely a lecture by Dr Winograd, a BMS employee. Dr Winograd's oral presentation and accompanying slides was given at a new drugs symposium in Amsterdam to an audience estimated at 500. Dr Winograd described the object and design of the study which was to evaluate the efficacy and safety of taxol in patients with ovarian cancer who had previously failed to respond to platinum based chemotherapy. He described the Phase III clinical trials and in particular disclosed that they had involved a comparison of a 24 hour continuous infusion (which had been used for the Phase II trials) with a shorter 3 hour continuous infusion, in each case using two different dosages of 135 mg/m2 and 175 mg/m2. Dr Winograd concluded that the 3 hour infusion arms were as feasible and safe as the 24 hour infusion arms, and said 'responses were seen in all treatment arms...and the overall response rate seems to be in the ball park of what has been published up to now'.

BMS argued that claim 1 contained two novel features over the Winograd lecture. Firstly, it argued there had been no disclosure that taxol was effective for treating cancer when infused over a period of 3 hours (the data disclosed having been 'lumped data' drawing no distinction between the 3 hour and 24 hour results). The Court of Appeal construed the words "for treating cancer" to mean "suitable for trying to treat cancer". In other words the skilled addressee would realise that drugs which were suitable for treating cancer would not always be successful in every case. On that basis, the Court of Appeal held that the Winograd lecture disclosed that taxol was suitable for trying to treat cancer using a 3 hour treatment, even if it did not specifically disclose that it was as effective as the 24 hour treatment.

BMS's second argument was that there was no disclosure in the Winograd lecture of the "reduction" of neutropenia during a 3 hour infusion over what it would have been over a 24 hour period. This argument was also rejected. The information given in the Winograd lecture enabled the public to carry out an act which would have the inevitable consequence of less neutropenia. Such an inevitable consequence could not impart novelty to a claim. The lecture contained clear and unmistakable directions to carry out a 3 hour infusion. Anyone doing so would inevitably monitor the patient's blood cell count and would inevitably find the extent of neutropenia that occurred.

BMS argued that claim 1 related to a second medical use as sanctioned in the EISAI case (EPO Decision G 5/83, EISAI, OJEPO 1985, 64), namely, use of taxol at the specified amounts and infusion times for the reduction of neutropenia. The Defendants/Respondents had argued that novelty in a Swiss-type, ie, second medical use, claim had to reside in the "new second (or subsequent) therapeutic use". BMS disputed that novelty had to reside in a second or subsequent therapeutic use. BMS relied on the Mobil case (Decision of the Enlarged Board of the EPO, G 02/88, OJEPO, 1990, 93) for the proposition that novelty may arise from a new use reflecting a newly discovered technical effect. In Mobil the claim (to an additive in lubricating oil for reducing friction where the same additive was previously used for inhibiting rust) was interpreted as a claim to the product when used for that new purpose and was held to be novel if such prior use had not previously been made available to the public. The Court of Appeal noted, however, that claims interpreted as relating to the product when used cannot be applied in relation to a Swiss-type claim because that would constitute a method of treatment.

The Court of Appeal concluded that the Mobil case did not qualify the conclusion reached in EISAI. They agreed with the Defendants/Respondents that novelty in a Swiss-type claim must reside in "the new second (or subsequent) therapeutic use" and agreed with the trial judge in his conclusion that this was not a claim for second therapeutic use. The medicaments in question (taxol and pre-medication) were known to be suitable for treating cancer. The remainder of the claim related to the way that such a medicament was to be used. It was not treating a different illness, nor was it treating the same disease in a different way; it was therefore the same therapeutic use not a second therapeutic use, as was considered in EISAI. A similar conclusion had been reached by the Dutch Court of Appeal in Bristol-Myers Squibb v Yew Tree Pharmaceuticals (25 June 1998).

Although invited to do so (and recognising the widespread criticism of both cases) the Court of Appeal did not have to decide whether or not EISAI or Mobil were correctly decided and it declined to do so. It did however note that EISAI had been applied by the EPO since at least 1985 and that it had been accepted as correctly stating the law by the UK Patents Court (en banc) in John Wyeth and Schering's Applications [1985] RPC 545. It also noted that Mobil had been considered in depth and applied by the House of Lords in Merrell Dow Pharmaceuticals Inc v H. N. Norton & Co Ltd [1996] RPC 76 and that although the issues raised in the House of Lords were not the same as those arising in this case, it thought it unlikely that the Court of Appeal would conclude Mobil to be wrongly decided when the House of Lords had not so concluded.

Obviousness

BMS argued that it was not obvious to carry out the 3 hour infusion as disclosed in the Winograd lecture without evidence that it was effective. It relied on evidence from oncologists that they would not have risked changing patient's treatment from a 24 to a 3 hour infusion without the full results of the study showing that it would be as effective. The Court of Appeal however concluded that it was obvious, in the sense of lacking invention, to carry out trials which had been disclosed in the lecture, ie, administering to a patient pre-medication and taxol with a 3 hour infusion in the claimed amount, with the inevitable lessening of the amount of neutropenia. The Court of Appeal therefore agreed with the trial judge that the claim was obvious.

Method of Treatment

The Court of Appeal departed from the trial judge in its finding that the claim amounted to an unpatentable method of treatment. It held that in essence the invention claimed was the discovery that by changing the treatment from a 24 hour to a 3 hour infusion a similar effect was obtained with less neutropenia. The Court of Appeal held that to be a discovery that a change in the method of treatment provided the result. The claim was

"...an unsuccessful attempt to monopolise the new method of treatment by drafting it along the lines of the Swiss-type claim. When analysed it is directed step by step to the treatment. The pre-medication is chosen by the doctor, and administered prior to the taxol according to the directions of the doctor. The amount of taxol is selected by the doctor as is the time of administration. The actual medicament that is said to be suitable for treatment is produced in the patient under supervision of the medical team. It is not part of a manufacture".

As such the invention made and claimed was said to be a method of treatment precluded from patentability by Section 4(2) of the UK Patents Act 1977 (Article 52(4) of the EPC).

The trial judge had construed the claim as being limited to the manufacture of the medicament to be used in treatment. The Court of Appeal accepted that if the claim had been limited to the manufacture of the medicine to be used in the treatment then it would not have been automatically excluded from patentability as a method of treatment. In this case, however, in considering how the claim was alleged to be infringed by the conduct of the clinical trials and in particular the involvement of doctors at each stage of the process in administering the drug and monitoring the process, including the side-effects, the claim had to be construed as a method of treatment.

The Court of Appeal refused BMS leave to appeal to the House of Lords. BMS may however seek such leave from the House of Lords itself.

Commentary

Second medical use patents have been sanctioned in principle by the English Court of Appeal, although the ambit of what may be properly protected may have been circumscribed in narrower terms than some patents granted by the EPO. Patents attempting to claim improvements in respect of the same therapeutic use of a drug, in particular improved dosage regimes of known drugs in respect of the same illness, will not escape the method of treatment exclusion merely by formulating the claims in 'Swiss form'. It is interesting to note that the EPO itself may be reigning back on the availability of Swiss-type claims to protect treatment regimes. For example, in Procter & Gamble / Gastrointestinal compositions (T317/95 [1999] E.P.O.R.) the Technical Board of Appeal of the EPO doubted whether a prescribing regime could amount to a further medical indication. Unresolved questions remain as to the extent of patentability of new uses of known drugs for the same illness where the new use of the drug is to target it at, say, specific population sectors, eg, genetic groups or patients with a particular medical susceptibility. Patent protection should in principle still be available if the claims focus on the manufacture of the drug rather than the treatment of the patient. However, it is not clear precisely where the line will be drawn between a new therapeutic application and a mere discovery of further information about an existing medical indication.

First published in WIPR in June 2000.