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Bristol-Myers Squibb Company v. Baker Norton Pharmaceuticals Inc, Napro Biotherapeutics Inc [1998] EWHC Patents 300 (20th August, 1998)
CH 1997 N No. 2698
CH 1997 B No. 6446
IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT
Before: THE HON. MR. JUSTICE JACOB
B E T W E E N
BRISTOL-MYERS SQUIBB COMPANY
Respondent / Plaintiff- v -
BAKER NORTON PHARMACEUTICALS INC First Defendant
-and-
NAPRO BIOTHERAPEUTICS INC Petitioner / Second Defendant
Mr Andrew Waugh QC and Mr Justin Turner instructed by Messrs Simmons & Simmons, London EC2 for the Plaintiff Mr Simon Thorley QC and Mr Henry Whittle instructed by Messrs Roiter Zucker, London NW6 for the First Defendant Mr Simon Thorley QC and Mr Roger Wyand QC instructed by Messrs Bird & Bird, London EC4 for the Petitioner/Second DefendantHearing date: 7-10 July 1998
JUDGMENT
1. This is the official judgment of the court and I direct that no further note or transcript be made
DATED: 20 August 1998
MR JUSTICE JACOB
Jacob J
1. Stripped of procedural matters now irrelevant, this is an action for infringement of patent No. EP 0 584 001 (UK) by Bristol-Myers Squibb Company ("BMS") against Baker Norton Pharmaceuticals Inc. and Napro Biotherapeutics Inc. and a counterclaim for its revocation. For the purposes of these proceedings only the defendants accept joint responsibility for the acts of which BMS complain. Those acts were done during clinical trials at Guy's, the Royal Marsden and Hammersmith hospitals. The trials involved the 3-hour infusion of a chemical called taxol (also called paclitaxel) in patients with refractory ovarian cancer. Taxol was used as the anti-cancer agent. Premedication (the administration of a cocktail of drugs designed to ameliorate allergic responses) was used in all cases.
2. The priority date of the patent is 3rd August 1992. Taxol was well-known as a potential anti-cancer agent well before then, though its availability was limited and it had only been used in clinical trials. In broad terms what the patent would prevent is the use of taxol (with premedication) for 3-hour or less infusion in certain dosages. This is so even though:
(a) methods of medical treatment are unpatentable;
(b) the fact that clinical trials using taxol for 3-hour infusion in the specified dosages using premedication were being carried out was published shortly before the priority date at a widely attended lecture given in March 1992.
(c) the fact that taxol was active at 24-hour infusion with premedication was well publicised and had generated great interest amongst oncologists, and
(d) the use of a much shorter period of infusion (e.g. 3-hours) was well-known to be highly desirable if it could be used. The desirability is self-evident; treatment could be on an out-patient basis with all the saving in convenience and stress for the patients and all the saving in cost and time for the hospitals.
2. Obviously in these circumstances the patentee's case calls for careful examination.
The Relevant Legal Provisions
3. The key legal provisions in the UK concerning patentability and infringement are, of course, contained in the Patents Act 1977. But that Act does not stand just as a piece of UK inspired and created legislation. As its recitals say, the Act was "to establish a new law of patents" and it was "to give effect to certain international conventions on patents." Two of those Conventions are "The European Patent Convention" ("EPC") and "The Community Patent Convention," ("CPC"). The latter Convention never actually came into force. Nor did a substitute version (called the "Agreement Relating to Community Patents") reached in Luxembourg in 1989. In seeking to implement those Conventions, our Act in some places uses the same language as the English language version of those Conventions, English being one of the three authentic texts of the EPC (EPC Art. 177(1)), and an authentic text of the CPC. (CPC Art. 102) In other places the UK draftsman chose to use language differing in some respects from that of the Conventions. In all cases the Act uses different numbering from that of the corresponding provision of the Convention concerned. However there is no doubt that even in cases where different language has been used, there is no intention to convey a different meaning from that in the Conventions. Section 130(7) of the 1977 makes this clear in saying:
"Whereas by a resolution made, on the signature of the Community Patent Convention the governments of the member states of the European Economic Community resolved to adjust their laws relating to patents so as (among other things) to bring those laws into conformity with the corresponding provisions of the European Patent Convention, the Community Patent Convention and the Patent Co-operation Treaty, it is hereby declared that the following provisions of this Act, that is to say, sections 1(1) to (4), 2 to 6, 14(3), (5) and (6), 37(5), 54, 60, 69, 72(1) and (2), 74 82, 83, 100 and 125, are so framed as to have, as nearly as practicable, the same effects in the United Kingdom as the corresponding provisions of the European Patent Convention, the Community Patent Convention and the Patent Co-operation Treaty have in the territories to which those Conventions apply."
3. The "territories to which" the EPC and CPC apply include the United Kingdom. So s.130(7) is saying that the specified provisions of our Act are to have the same meaning as the corresponding provisions of the Conventions. The best way of achieving this is to work directly from those provisions and not to bother with the provisions of our Act. The provisions of the Convention are not merely an aid to interpretation - they are what our Act says its own provisions are intended to mean.
4. So I think that in future, save in the rare event of a specific contention that a provision of the 1977 Act has a different meaning from a corresponding provision of a Convention, it will be better for all concerned with patent matters in the UK (and, I hope, throughout Europe) to work on the basis that the corresponding provisions of the Conventions are of direct effect. In that way there are two advantages:
(1) Arguments based on detailed language in the 1977 Act not to be found in the Conventions are obviated. A recent example of such an argument, which completely dissolved when reference was made to the EPC, is to be found in Merrell Dow v Norton. ([1996] RPC 76) There, Lord Hoffmann (at p.86) rejected what he called "a rather refined inclusio unius construction" of words in s.2(2) of the 1977 Act by referring to the corresponding provision of the EPC, Art. 54, which simply does not use those words.
(2) As a practical matter it is much easier for all judges and practitioners across Europe to refer to the same provisions of the EPC using its numbering system. Experience of other fields (e.g. the Rome Treaty or the Brussels Convention) shows this to be so. "Article 85" for instance, gains immediate recognition amongst competition lawyers throughout Europe. By using Articles of the Conventions judgments of the EPO Boards of Appeal and of national patent judges all become that more readily intelligible across Europe. The practical value of direct use of the Convention provisions has been made all the more important by recent developments in European patent law, for instance the indication in Merrell Dow (at p.82) of the great significance to which decisions of the Boards of Appeal of the EPO are to be accorded by our courts, and the increasing extent to which decisions of the national courts of one country are being referred to in other countries. We all have to work in different languages, but we do not have to make things worse by using different numbers and different changes of expression and different numbering by different legislatures.
5. Of course in saying that direct use of the provisions of the Conventions should in future be the way, I am not precluding a deliberate argument that a provision of the 1977 Act actually has a different meaning from that to be found in the Convention. I think I am right in saying that there has only once been such a direct challenge in the 20 years since the 1977 Act came into force. That was in Beloit v Valmet. ([1997] RPC 705) The challenge was not pursued on the appeal. ([1977] RPC 489)
The Witnesses
6. All the witnesses were excellent, being careful, clear and fair. BMS called Dr Canetta, Professor Calvert and Mr Tomlin. The defendants called Dr Williams and Dr Judson. Dr Canetta is presently Vice President of BMS's Clinical Cancer Research Institute. He is named as one of the inventors and is not only an experienced doctor in medicine, particularly cancer, but is also a distinguished academic teaching at major medical schools, for instance the NYU School of Medicine. Professor Calvert holds the Chair of Medical Oncology at the University of Newcastle upon Tyne and is Director of the Cancer Research Unit there. He has wide experience as a clinical doctor in the field of cancer. Mr Tomlin is a pharmacist employed by BMS who gave uncontroversial evidence about the way taxol is prepared for use in practice. Dr Williams is a consultant physician of the Cochrane Cancer Network in Oxford and has considerable experience in the development of treatments for cancer and the co-ordination and systematic review of clinical trials. For many years he was a consultant physician and also a distinguished academic. Dr Judson is a cancer clinical pharmacologist at the Institute of Cancer Research at the Royal Marsden NHS Trust.
7. There was very little dispute between the witnesses. As a result I do not need to refer specifically to their detailed words: I can summarise the effect of the evidence more generally without attribution to any particular witness.
Knowledge of Taxol
8. I begin by summarising what was known about taxol before 1992. When I say "known" I am satisfied the matter concerned was known to oncologists and manufacturers of drugs for cancer therapy generally in 1992 - indeed the contrary was not suggested. By 1992 the potential of taxol was of great interest to oncologists because it might provide a new drug for use against cancer - particularly ovarian cancers which would not respond to other chemotherapy (particularly the use of the platinum compounds, cisplatin and carboplatin).
9. Taxol was first identified in 1960 as part of a screening programme for antitumour agents initiated by the US National Cancer Institute ("NCI") in 1960. It was derived from the Pacific Yew, growing in Washington State. The active agent was first isolated in 1971 and at about the same time it was shown to have antitumour activity in mice. Further work was hampered because of difficulties with procurement, extraction and isolation. Those difficulties have now to some extent been overcome by the development of semi-synthetic routes of manufacture. In particular ways of extracting the compound from pine needles rather than whole trees have been devised.
10. Taxol is poorly soluble and, partly for this reason, it was not until about 1980 that a formulation was devised. Animal studies were done using this and by 1983 the NCI were in a position to apply for regulatory permission to try the drug in humans. Initial trials are known as "Phase I" trials. It is necessary to describe in a little more detail the various phases of the development of a drug, which were not in dispute. I can do so by quotation from the report Dr Williams.
"24. Phase I describes those initial studies carried out in human beings to investigate safety and tolerance, dose range and pharmacological effect. At this stage the body's handling of the drug - how it absorbs, breaks down and clears the drug (pharmacokinetics) should be measured. Each individual test compound will raise questions which necessitate alterations in the exact protocol to be followed in any Phase I investigation. Indeed the protocol will specify how the researchers respond to side effects as they are discovered and how many patients will be treated at each dose level. In Phase 1 studies of anti-cancer drugs it is normal to start with a low dose considered to be safe and then in groups of patients to escalate the dose until unacceptable toxicity is encountered. The dose below this level (the maximum tolerated dose) is then usually used in subsequent Phase II and III trials. As well as dose, Phase I trials may vary the schedule of the treatment delivery (duration of infusion and whether the treatment is daily, weekly etc.). Although it is commonplace for this phase of development to take place in normal human volunteers, this is not the case in cancer where patients who have failed conventional therapy are included.
25. Phase II trials evaluate the efficacy of a treatment in a particular clinical setting, for example addressing the question of whether a treatment is effective in achieving a therapeutic result in patients suffering from the disease in question. In the field of cancer this may mean that the drug is tested in a group of patients with various cancers or, as is more common nowadays, in a group of patients with one sort of cancer. Most Phase II trials have no randomised comparator group though recently this has become more common when there is already some evidence showing that the drug has activity.
26. A Phase III trial progresses the treatment from the Phase II study through using it at an earlier stage in the course of the disease. It is usually designed to test whether a therapy is safe and potentially as effective as shown in Phase II trials. It is most common for Phase III clinical trials to be randomised. That is, if the standard treatment for condition a is treatment y but a new treatment x looks to be active in the Phase II study, the patients with condition a may be asked to give consent for randomisation in a Phase III trial to receive either treatment x or y."
11. Turning back to the history of taxol, as I have said Phase I trials started in 1984. Problems soon emerged. In the words of Dr Canetta:
"During the initial days of the clinical development of paclitaxel severe hypersensitivity reactions to paclitaxel occurred in many patients. After receiving just a few milligrams of paclitaxel, these patients started developing an acute reaction, including skin rash, shortness of breath, reduction of blood pressure and cardiac rhythm abnormalities, forcing interruption of the paclitaxel infusion."
4. Various doses and periods of infusion were under test in the Phase I trials. One of the Phase I trials, called Kris, involved a fatality from hypersensitivity. The patient died when infusion began. As a result the NCI (who at the time were supplying the taxol) required all Phase I trials to have an infusion time of 24 hours initially (coming down to a minimum of 6 hours if there was no adverse reaction) and the use of premedication. The idea was to minimise the danger of toxic shock. The slower infusion rate meant that the body was not exposed to the taxol as quickly as in the case of shorter infusion times and the use of premedication likewise reduced the danger of shock. It was not known at the time what caused the shock - the taxol or the solvent (Cremophor) or both. Premedication was a well-known technique. Having used slower infusion and premedication together, when it later proved that allergic reactions were becoming much less of a problem, it was not clear whether this was due to the premedication, or the prolonged infusion or a combination of the two. None of this mattered at the time. The heart of the trials was to see whether taxol really worked - particularly in refractory cases. Avoiding allergic reaction by using both slow infusion and premedication enabled this to be done.
12. Thus it was that taxol entered Phase II trials to discover what tumour types it affected. The NCI concentrated upon ovarian cancer and malignant melanoma particularly, but the melanoma studies gave results not as positive as had been hoped. By 1989 out of all the studies then conducted (15 in all) only 427 patients had been treated. It was apparent that the NCI could not go it alone. So it sought a commercial partner. It did so by a competition for a Collaborative Research and Development Agreement. Notice of the competition was given in August 1989. The selected partner was to have exclusive rights to NCI data and would have to provide taxol and fund further clinical trials leading to an application for regulatory permission. 20 companies were interested, 4 were interested enough to enter the competition and it was BMS which was successful in January 1991. BMS tackled the problem of supplies and undertook responsibility for all the trials outside the US, including in particular the Canadian/European study early results from which led to the patent in suit. This was called the "OV.9" study.
Neutropenia
13. Like many other drugs used in cancer chemotherapy, taxol interferes with cell division (mitosis). The idea is to stop the cancer (neoplastic) cells replicating which they do rapidly. But some other, normal, body cells also replicate rapidly, for instance cells at the base of hair follicles, and bone marrow cells. The latter are important because they divide rapidly to produce red and certain kinds of white blood cells. Borrowing Dr Canetta's words:
"Bone marrow suppression (myelosuppression) is therefore an inevitable consequence of treating the body with a chemotherapeutic agent that targets rapidly dividing cells. Indeed myelosuppression is a well known side effect of most forms of chemotherapy."
5. And, borrowing Dr Williams words:
"A fall in the white cell count (including the infection fighting cells, the neutrophils), leading to an increased risk of infections. The reduction in the blood neutrophil count is known as neutropenia."
6. So neutropenia is one of a number of undesired but inevitable side effects of chemotherapy. The patient's blood is regularly monitored to assess the degree of neutropenia. In the case of clinical trials that monitoring is particularly essential and carried out more frequently than in the case of an established treatment. Reduction of neutrophils renders the body more prone to infection and it may be necessary to administer antibiotics as a prophylactic or, if an infection occurs (febrile neutropenia), to cure it. There are other undesirable side effects of chemotherapy (e.g. anaemia, nausea, neuropathy, various allergic reactions). After all, the chemicals used are in their essence poisonous.
14. Severe neutropenia can be dangerous for obvious reasons. So both the depth (i.e. degree of reduction of neutrophils) and duration are matters of concern. Although clinical oncologists have to live with the fact that chemotherapy produces neutropenia and speak of "acceptable levels" as a result, it is self-evident that the less neutropenia caused by a particular drug or regime with a drug the better. Moreover there may be a concern that the degree or duration of neutropenia produced by a particular dosage of drug is simply too much - neutropenia may be dose limiting, either in terms of the dose which can be administered at any one time or in terms of the frequency with which it can be given.
15. Since the mechanism of a chemotherapeutic drug on the cancer cells and the bone marrow is the same, there was a general expectation that the degree of neutropenia and the degree of effect on the cancer cells went "hand in hand". The expectation was called a "tenet" of oncologists. The consequence of the tenet is that those strategies that maximised tumour treatment also increased myelosuppression.
The OV.9 Trial/The Winograd lecture
16. I have already mentioned this important trial. It was a joint BMS/NCI trial. The protocol was discussed between BMS, the FDA and the NCI. Dr Canetta had a considerable hand in the protocol which was finally settled in January 1991 though there were a number of amendments made whilst the trial was conducted. The accrual of patients to the OV.9 Study between 23rd July 1991 and 6th March 1992 was one of the fastest in the history of medical oncology. By 6th March 1992, 407 patients had been entered. Oncologists interested in working with taxol knew the study was being conducted and were eagerly waiting for its results. The rapid accrual of patients was partly for this reason and partly because there was a hope that the patients concerned (who were refractory cases) might respond. It was taxol, or, sadly, probably nothing, for them.
17. The protocol for the OV.9 Study was itself published. Whether it was known generally prior to a public lecture given at a major symposium in Amsterdam by Dr Winograd I am not sure. I do not think it matters because the relevant details were admittedly made public by this lecture which forms the sole piece of specific prior art relied upon by the defendants in these proceedings. At an earlier stage the defendants also relied upon an abstract of the lecture but sensibly, in my view, confined their attack to their best shot.
18. Dr Winograd gave early results of the OV.9 trial to an audience estimated at 500 people. He said, according to the agreed transcript:
"The objective and design of this study was to evaluate the efficacy and safety of taxol in patients with ovarian cancer previously treated with platinum containing chemotherapy and what we wanted to address is, in a two by two design, long term infusion which is the 24 hours continuous infusion as used in most ... in all of the up to now presented and published Phase II studies versus a short time infusion which is a 3 hours' continuous infusion and at the same time we wanted to look at a high dose arm which is 175mg/m2 versus the low dose."
7. He went on to say that the "low dose" was 135mg/m2. [I should say that the method of assessing the appropriate dose by weight of drug to skin area of patient had been well established for many years in the case of cancer treatments. In practice one estimates the skin area from height and weight measurements. It means that the dose for any individual patient is specific to that patient, a point prayed in aid by the defendants on the "method of treatment" point].
19. Thus it was firmly disclosed that OV.9 was divided into four "arms": 24-hour infusion at 175 and 135mg/m2 and 3 hour infusion at 175 and 135mg/m2. It was also disclosed that the patients of all four arms were given premedication against potential toxic shock and the details of the premedication were given. The audience were reminded of the hypersensitivity problem encountered in earlier trials and were told that:
"maybe all or the main impact on the hypersensitivity problem was really the premedication"
8. Dr Winograd went on to say:
"the statistics designed for the study said we would not plan, because we were expecting a rather fast accrual, no interim analysis for efficacy and it had built in an early stopping rule for the short infusion arms if the incidence of significant hypersensitivity reaction would be higher than 15%".
20. The audience would have been somewhat disappointed by the reference to "no interim analysis for efficacy." This meant that until the study was done there would be no real indication from this trial as to how effective taxol was or what the best dosage or period of treatment was. "Efficacy" means efficacy against cancer. The paper gave only a slight hint of this (see below). It was common ground that it takes much longer to detect efficacy (i.e. tumour reduction) than to detect neutropenia (the latter involving merely testing blood samples). Of course earlier studies had provisionally indicated a real possibility of efficacy - that was the whole reason for the trial.
21. What Dr Winograd did go on to disclose was that 407 patients had been recruited to OV.9 and that there was preliminary data in relation to 157 of these who, between them, had had 270 courses of treatment. Dr Winograd did address one question which must (in view of the earlier problems with hypersensitivity) have been important to the audience. He said:
"Overall, we had 45 patients showing some type of hypersensitivity reaction out of 112 evaluable. However, if we look into the non-significant versus what we call significant, you have only 3 out of the 112 with significant hypersensitivity reaction, and we have broken down here the 42 patients which the highest incidence is from flushing, 3 patients with hypertension, 1 chest tightness, 6 skin rash, 2 dyspnoea, 1 urticaria, 8 others and 3 patients with respiratory distress requiring therapy."
9. There was no indication that hypersensitivity was significantly different as between the different periods of infusion. That would have been seen as important because of the earlier worry that short infusion might have something to do with it.
22. He then went to discuss haematological toxicity . He said:
"Looking at the worst haematological toxicity and this is, of course, what we expected is ... and the numbers here for the grades of the 111 patients are given in percent. So, 70% of the patients had a Grade III or a Grade IV granulocytopenia, about 15% haemoglobin toxicity and this is not distinguishing between normal, base line or abnormal base line haemoglobin and as has been presented in the previous presentation virtually very very (sic) little effect on the platelet count. Again the nadir was very very ... very very sharp and deep. Their recovery was almost in all patients at day 21 and only 10 of 270 courses needed to be delayed. Looking at the overall 270 of the evaluable courses we have up to now is giving you again the percentage which gives you overall a 55% in the Grade III or Grade IV granulocytopenia, and 4% of those were a Grade IV granulocytopenia lasting for more or equal of 7 days, the haemoglobin ..., the anaemia and the very little thrombocytopenia".
10. Again he drew no distinction between the effects in different arms. There was no hint of what the patent (and the report of the completed study) were later to disclose, namely that 3-hour infusion produced markedly less neutropenia than equivalent 24-hour infusion. The impact of what he did disclose is that the general order of granulocytopenia was not markedly different from the sort of thing oncologists were used to in chemotherapy. In other words, taxol from the haematological point of view, could be used: Granulocytopenia was not seen as dose limiting from the point of view of dosage size, frequency of infusion or period of infusion.
23. The other side effects observed were likewise not indicated as dose limiting. He said of these:
"Looking at the list of non-haematologic effects, and this slide gives you numbers which means 90 patients out of the 112 have hair loss. This is somewhat less than we would have expected from the previous published data. 42 patients, peripheral neuropathy and only one of them is a Grade III. Nausea and vomiting very mild, some stomatitis, diarrhoea and some myalagia and arthralgia."
24. He concluded with the following résumé:
"In summary what I have presented to you is a study with a very fast accrual with balanced patient and balanced pre-treatment characteristics of patients in the four arms. The incidence of significant hypersensitivity reactions is minimal with the premedication used, 3 out of 112. The non-significant hypersensitivity reactions were not more frequent in the 3 hour arms as compared to the 24 hour arms which means the 3 hour arms is feasible and as safe as the 24 hour arms. Responses were seen in all treatment arms. It's too early really to give you a breakdown of that because the follow-up of the patients is relatively short and the overall response rate seems to be in the ball park of what has ... and again this is a multi-centre study; the overall response rate seems to be in the ball park of what has been published up to now and has been presented in the previous presentation."
25. It is common ground that the statement "3 hour arms is feasible and safe as the 24 hour arm" would have been understood by a skilled man as feasible from the point of view of safety only, not feasible from the point of view of efficacy. As a layman one might have perhaps read the word "feasible" as also covering efficacy against the cancer, but it is quite clear from the experts on both sides that the words would not have been so read. The only indication of efficacy against cancer is in the sentence "Responses were seen in all treatment arms" and the general statement that "the overall response rate seems to be in the ball park of what has been published up to now and has been presented in the previous presentation". What had been published before and had been disclosed again in the previous paper by McGuire was that taxol did have efficacy.
26. It is also common ground that a skilled man would want more information than this before he was satisfied that 3 hour infusion would be a satisfactorily efficacious regime. 24 hours might still be better and in any event the completed OV.9 study might perhaps (though this was not likely) have revealed that taxol was not as efficacious as the earlier studies had indicated it was likely to be prove to be. That is not in any way to suggest that there was not great interest in a 3-hour regime. On the contrary there obviously was. Not only was such a regime self-evidently highly desirable if it could be used, but Winograd's résumé concludes with the statement:
"in Europe we will have a multi centre follow-up study for the present study in which patients with two prior regimens will receive 175 in the 3 hours infusion and patients with 3 prior regimens will receive 135 milligrams per square metre in the 3 hours infusion arm."
11. This demonstrates the great interest in 3-hour infusion. If it could be, it would be done.
The teaching of the patent
27. The body of the patent begins by saying that "The present invention is directed to the use of products containing taxol for cancer therapy and more particularly is directed to improvements in the use of taxol in the treatment of cancer."
28. So it is quite open in what it seeks to protect - not only products but the use of taxol in a medical treatment. Whether it does in fact do the latter is one of the things I have to decide.
29. The patent then goes on to describe the "background of the invention". It acknowledges that:
"taxol is a naturally occurring compound which has shown great promise as an anti-cancer drug. For example, taxol has been found to be an active agent against drug-refractory ovarian cancer by McGuire et al."
12. It goes on to assert, correctly, that:
"Unfortunately, taxol has extremely low solubility in water, which makes it difficult to provide a suitable dosage form. In fact, in Phase I clinical trials, severe allergic reactions were caused by the emulsifiers administered in conjunction with taxol to compensate for taxol's low water solubility; at least one patient's death was caused by an allergic reaction induced by the emulsifiers."
It then says:
" Dose limiting toxicities include neutropenia, peripheral neuropathy, and hypersensitivity reactions."
13. The defendants dispute that statement. Certainly nothing in the prior art suggests that it was accepted that there were dose-limiting toxicities of the kinds mentioned. However I do not think it really matters one way or the other.
30. There is then some detailed discussion of some of the well-known papers concerned with Phase I trials of taxol. I do not believe I need to refer to these in detail: I have summarised what was generally known above. The patent acknowledges an abstract of the lecture given by Dr Winograd (in fact written by Dr ten Bokkel Huinink) but not the lecture itself. So when the patent goes on to say:
"The conflicting recommendations in the prior art concerning whether premedication should be used to avoid hyper-sensitivity reactions when using prolonged infusion durations, and the lack of efficacy data for infusions done over a six hour period has led to the use of a 24-hour infusion of high doses (above 170 mg/m2) of taxol in a Cremaphor EL emulsion as an accepted cancer treatment protocol,"
it does not mention the disclosure of Winograd that with premedication "the incidence of significant hypersensitivity reactions is minimal." Moreover to say the 24-hour infusion with premedication was "accepted" is putting things a bit high - after all taxol was still only in the early stages of its development and had not even gone much beyond Phase II trials.
31. The patent then acknowledges that short infusion times are highly desirable and makes a point about the limited supply of taxol upon which no-one relies. It then sets out a number of objects of the invention:
"Therefore, it is a primary object of the present invention to provide new products containing taxol which allow (sic) to administer taxol over a shorter period of time than the present 6 to 24-hour infusion protocols, while minimising toxic effects induced by the administration of taxol.
It is another object of the present invention to provide new products containing taxol for administration of taxol which reduce the amount of taxol administered to a patient, without sacrificing the antineoplastic effects desired by administering taxol.
It is yet a further object of the present invention to provide new products containing taxol for administration of taxol which utilises both lower dosages of taxol and shorter infusion periods, without sacrificing the antineoplastic benefits of the administration of taxol."
14. The objects are all the provision of "new products containing taxol". BMS place particular reliance on the reference in the second and third objects to "without sacrificing the antineoplastic effects/benefits". The patent goes on to say that:
"These and other objects of the present invention are accomplished by using products containing an anti-neoplastically effective amount of taxol and sufficient medications to prevent severe anaphylactic-like reactions formulated and packaged for separate or sequential or simultaneous administration in cancer therapy with a patient over a period of about 3 hours or less."
15. This is not the same as the language of claim 1. In particular the products here referred to, shortly taxol and pre-medication, are specifically described as "formulated and packaged". I have to consider whether the claim is in fact so limited.
32. After reciting some lesser aspects of the invention the specification goes on to say:
"In a preferred embodiment, antineoplastic effects are achieved in patients suffering from cancer through administration of about 135 mg/m2 administered via a 3-hour infusion following premedication to reduce or eliminate hypersensitivity responses. These results are surprising in view of the conventional understanding that a bolus injection or short (1-3 hour infusions) will induce anaphylactic reactions or other hypersensitivity responses, and that only premedication coupled with extension of the infusion time to 6-24 hours would reduce or eliminate the most serious allergic reactions.
33. I do not think the evidence bears out the alleged "conventional understanding", i.e. that you needed both more than 6-hour (up to 24) infusion and premedication to avoid hypersensitive reactions. I have recounted already that those who were conducting clinical trials were told to take both precautions, and, up to, but not including, OV.9 had done so. But there was no conventional understanding that both were necessary. And even if there was, anyone who attended the Winograd lecture would have been disabused - it was as clear as anything that 3-hour infusion could be used if premedication was given. The patent itself returns to the theme of the perceived necessity to use long infusion in several other places (e.g. "the conventional understanding that it is necessary to infuse patients over a 24-hour period", "the surprising discovery that taxol could be safely administered via a short infusion"). What I have just said goes for these passages too.
34. However the patent does disclose for the first time something which was unexpected:
"Of great significance is a surprising discovery that the short term infusion causes less myelosuppression, which leads to a lower incidence of infections and fever episodes (e.g., febrile neutropenia)."
16. It is not disputed that one would have expected levels of myelosuppression (and particularly neutropenia, whether febrile or not) to be independent of time of infusion. So one learns from the patent not only that 3-hours (with premedication) is safe (already disclosed by Winograd), but that from the point of view of neutropenia it is better than 24-hour infusion.
35. The patent then says:
"The surprising discovery that taxol could be safely administered via a short infusion (e.g., over about 3 hours) means that it will now be possible to administer taxol on an out-patient basis, saving patients the time and expense of yet another hospitalisation while improving patient quality of life.
36. All that was in substance already known. What remained unknown was efficacy at 3-hours compared with longer infusion. The patent lumps results for 3 and 24-hours together, summarising the position as achieving "greater than 10% objective response"
18. It has also been surprisingly discovered that lower taxol dosages, such as about 135 mg/m2 can be administered via infusions having about 3-hours, and still be anti-neoplastically effective.
19. But it gives no data on effectiveness as compared with 24-hour infusion. All it says is that 3-hours can be used and is effective. True it says its object is to use shorter infusion "without sacrificing the antineoplastic benefits" of taxol, but it gives no data upon which a skilled man would rely before accepting the assertion - if that is indeed to be read as an assertion that the antitumour effects at 24 and 3 hours are equal.
37. The patent then goes on to describe the experimental protocol. This is the OV.9 protocol so I need not go into it further. It then describes the "administration of the new products containing taxol". Nothing turns on the detail of this. What matters is what one can glean to be the "new products". The administration refers simply to a premedication regime and a taxol solution. No pack of premedication and taxol is referred to, or is necessary for the regime.
38. Next one comes to the results under the heading "efficacy and safety". It emerges that 528 courses were given to 157 patients distributed over the four arms of the trial. So the patent was applied for at about the same stage of the trial as the Winograd lecture. More data is given, however, in particular the information about efficacy (over 10%) and the information about less neutropenia for short infusion times. The latter is spelt out with more particularity under the heading "Hematologic Toxicity". The information is given in table 2 and is effectively summarised in the following sentence:
20. Of particular significance is that Grade IV neutropenia was reported almost five times more frequently in the patients treated with the 24-hour taxol infusion than the patients treated with a 3-hour taxol infusion.
And:
"As is clear from Table 2, grade IV neutropenia was reported almost 5 times more frequently in patients treated with the 24-hour taxol infusion compared to patients treated by a 3-hour infusion. 58% (51/88) of the patients treated with the 24-hour taxol infusion had grade 4 neutropenia in comparison to 12% (8/68) of the patients treated by a 3-hour infusion. When the incidence of grade 3 and grade 4 are pooled, it is clear that severe leukopenia occurs more frequently in patients treated with a 24-hour taxol infusion than with a 3-hour infusion. With reference to Table 3 below, analysis of median values for nadir count confirms the severity of taxol induced neutropenia, especially in the two 24-hour treatment arms."
21. The incidence of severe neutropenia in the long-term infusion versus the short-term infusion Arms was 85% versus 32%. The incidents of severe neutropenia in the high dose Arms was 74% (55/74) versus 52% (43/83) in the low dose Arms. Thus, it is clear that both reducing the dosage and the infusion time will lower hematologic toxicity, however, reducing the infusion to 3 hours from 24 hours appears to have a greater impact on reducing toxicity than reducing the taxol dosage from about 175 mg/m2 to 135 mg/m2.
22. The patent then goes on to discuss side effects in detail (including hypersensitivity) but nothing turns on these details.
23. It then goes on to make inter, alia, the broad general assertions:
"The success of the use of the new taxol products and infusion protocol of the present invention in the treatment of ovarian cancer makes it readily apparent that anti-neoplastically effective dosages of taxol can be infused over much shorter time periods than was previously believed possible, without inducing severe hypersensitivity reactions or inducing fatal anaphylactic shock. Thus, it is contemplated that the infusion protocol of the new products of the present invention may be utilised to treat solid tumours and leukemias, such as but not limited to lung cancer, breast cancers, and ovarian cancers. It is to be understood that treatment of different forms of cancer may require the adjustment of the taxol dosage to have optimal efficacy.
The foregoing clearly establishes that taxol is both safe and effective in the treatment of cancer, such as ovarian cancer, when administered with the products and according to the protocol of the present invention. In particular, by use of a 3-hour infusion of about 135 mg/m2 taxol, following premedication, a substantial reduction results in the frequency of myelotoxicity and neuropathy associated with the administration of taxol to patients suffering from cancer.
Claim 1, its construction and Swiss-form claims
39. The case all turns on claim 1, it not being suggested that any of the subsidiary claims add anything of value. It is convenient to divide up the claim into elements as suggested by Mr Thorley QC, for the defendants:
(1) Use of taxol and sufficient medications to prevent severe anaphylatic reactions
(2) For manufacturing a medicamentation for simultaneous, separate or sequential application
(3) For the administration of from 135mg/m2 up to 175mg/m2 taxol over a period of about 3 hours or less
(4) As a means for treating cancer and
(5) Simultaneously reducing neutropenia.
40. Short though it is, the claim has a number of difficulties. Is it to a method of medical treatment? Is it limited to use of taxol and a premedication cocktail for making a package to be used in administration? What does "medicamentation" mean? What is meant by "reducing neutropenia", given that taxol actually causes neutropenia? What does element (4) add? And what does element (5) add to element (4)?
41. I can get one matter out of the way because it is common ground. Whether they are words which assist validity or not it is agreed that element (5) means "reducing neutropenia as compared with what it would be if administration was for 24 hours". There remained a slight dispute about whether the reduction is in depth or period (or both) but I do not think it matters and do not propose to resolve that dispute.
42. "For treating cancer" was, surprisingly, somewhat in dispute, albeit to minor degree. The defendants said it meant no more than "for trying to treat cancer" BMS half suggested that something more was involved. I was not quite sure of the submission. It was something along the lines of "for treating cancer successfully." The purpose of the submission was to accentuate the "newness" of features (4) and (5), which BMS said should be read together. In the end I do not think the dispute matters, and in any event I have no doubt that the defendants are right: feature (4) means "suitable for trying to treat cancer". Sadly no-one can give an assurance of 100% success, and the skilled man, reading the claim purposively, would not imagine that it was limited to cases of success. Moreover, if the claim did require success it would probably in substance be to a means of medical treatment (see below).
43. Before going further I must now say something about the general structure of the claim. I daresay that an ordinary skilled man (to whom it is notionally addressed) would find it puzzling, unless he had been initiated in some of the Byzantine logic of patent law and jurisprudence. The explanation lies in Art. 54(4) of the EPC and the decided cases. The material parts of Art.54 read:
"(1) European patents shall be granted for any inventions which are susceptible of industrial application, which are new and which involve an inventive step.
(4) Methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body shall not be regarded as inventions which are susceptible of industrial application within the meaning of paragraph 1. This provision shall not apply to products, in particular substances or compositions, for use in any of these methods."
44. By taking the form it does, the claim is trying to steer clear of two obstacles to patentability, namely the requirement of novelty and the ban on methods of treatment of the human body by therapy. The claim is, or attempts to be, in so-called "Swiss form", following a statement of practice regarding "use claims" issued by the Swiss Federal Intellectual Property Office. ([1984] OJ EPO 581) The generalised form of such a claim is "the use of compound X in the manufacture of a medicament for a specified (and new) therapeutic use". Such claims are unnecessary when X is new, for then X can be patented in itself by virtue of the last sentence of Art.52(4). But when X is old, the Swiss form of claim is said to confer novelty and yet not be to a method of treatment. The Enlarged Board so held in Eisai. (G5/83 [1985] OJ EPO 64). It said:
"It is legitimate in principle to allow claims directed to the use of a substance or composition for the manufacture of a medicament for a specified new and inventive therapeutic application, even in a case where the process of manufacture as such does not differ from known processes using the same active ingredient."
24. So the manufacture of an old pill for use in a new treatment was considered by the Enlarged Board to be novel. The justification for novelty was the new therapeutic use. And since the claim was to the manufacture of the pill, it was not a claim to a method of treatment. How that might work so far as infringement was concerned was, so far as the Enlarged Board was concerned, not a matter to be considered. It said:
"It is particularly important to bear in mind that Art. 64(3) leaves questions of infringement to be dealt with by national law".
25. Actually Art.64(3) merely provides that "Any infringement of a European patent shall be dealt with by national law." It does not mean that questions of validity (especially novelty) or extent of protection are matters for national law. On the contrary both are specifically matters covered by the EPC (novelty in Art. 54(1) and extent of protection in Art. 69 and its Protocol). In my view it is essential for the granting authority to consider fully the implications of the claims it grants in relation to both validity and scope. It is not helpful to take a view on validity (particularly novelty) which simply leaves intractable problems for an infringement court - and for the public who need to know what they can and cannot do.
45. There are obvious difficulties with Eisai. Take a newly discovered use for aspirin (one was discovered not so long ago, namely its use to reduce risks of heart attacks). The manufacture of aspirin pills is old. So why is the manufacture rendered new because there is a new use? Or why does adding the purpose of the manufacture of aspirin to the claim make the manufacturing process any newer? The English Patents Court, sitting en banc (Whitford and Falconer JJ) in Wyeth and Scherings Appns. ([1985] R.P.C. 545) had to consider Eisai. The Court formed the view that a Swiss-type claim was clearly a claim to a method of manufacture and so to an invention capable of industrial application. As the court said, it was the requirement of novelty which "provides the real difficulty". And it plainly thought that the device of putting a claim into Swiss form did not confer novelty:
"we think the better view would be that a claim in the Swiss form to an invention directed to the use of a known pharmaceutical to manufacture a medicament, not in itself novel, for a second or subsequent and novel medical use would not be patentable as lacking the required novelty. (p.565)
However, in view of the decision in
Eisai and "having regard to the desirability of achieving conformity" the Patents Court decided not to follow what it regarded as the better view. It followed Eisai. Before me, Mr Thorley, did not challenge Eisai, though he reserved the right to do so on appeal. I think he was right. For me, as a judge of first instance, to go against Eisai would involve not only refusing to follow a decision of law of the Enlarged Board of Appeal, but also refusing to follow a considered judgment of the English Patents Court. Under the present English rules of precedent I am strictly bound by neither court. But, so far as the Enlarged Board is concerned the desirability of following its decisions on points of law has been reinforced since Eisai. Lord Hoffmann in Merrell Dow ( [1996] RPC 76 at p.82) said that the UK courts:"must have regard to the decisions of the EPO on the construction of the EPC. These decisions are not strictly binding upon courts in the UK but they are of great persuasive authority; first because they are decisions of expert courts (the Boards of Appeal and Enlarged Board of Appeal of the EPO) involved daily in the administration of the EPC and secondly because it would be highly undesirable for the provisions of the EPC to be construed differently in the EPO from the way they are interpreted in the national courts of a Contracting State."
26. What Lord Hoffmann said has all the more force in relation to a court of first instance. If all the courts of first instance of the member states of the EPC felt able readily to differ from the questions of law decided by the Boards of Appeal (and particularly an Enlarged Board) the result would be an all too easy fragmentation of the European system of patent law. It is a matter of the utmost seriousness for any court to depart from a decision of an Enlarged Board EPO on a point of law, and, if it is to be done at all by a national court, I think it should only be done by a higher national court and not one of first instance. For the sake of coherence of the system as a whole first instance courts should exercise self-restraint, however erroneous they may think a particular decision of law of an Enlarged Board may be.
46. I turn back, then to this particular claim. It is not as simple as a typical claim in Swiss form because it is not simply to manufacture of a single medicament for a particular therapeutic use. Taxol and the premedication are both involved. The premedication is, as I have said, a cocktail of drugs which prevent toxic shock. Mr Thorley submitted that the claim had a narrow construction - in substance he said it was to a kit of drugs (taxol and premed), the kit being a specially made up kit for administration. On that basis, of course, his clients did not infringe. No-one would make up special kits (e.g. in special packs with instructions). The normal form of treatment would involve administering to the patient a number of different medicines as the premedication (for instance, particularly, by telling the patient to take several different pills so many hours before the hospital treatment is due). At the hospital a dose of taxol is be made up for the particular patient, using a combination of height and weight measurements to calculate surface area. The taxol is then administered. So the premedication is separate from the taxol and the taxol is made up to be patient specific. What, asks, Mr Thorley is the "medicamentation" of this claim, if it covers medicines administered in this sort of way? Mr Thorley says this is going further than has ever been gone by an EPO Board of Appeal. That court has allowed claims to compositions presented side-by-side to be administered simultaneously or at intervals, see Asta-Werke (T09/81 OJ EPO 1983 372). But here there is no side-by-side presentation, just administration of the premedication cocktail followed by the making up and administration of the patient specific dose of taxol. So, says Mr Thorley, if the claim is not limited to the manufacture of a special kit, then it is in substance merely to a method of treatment and so unpatentable.
47. Mr Waugh QC, for BMS, contends that the medicamentation of the claim comprises the taxol made up to be patient-specific and the premedications. They are a loose assembly, drawn together by their intended use for a particular patient. The claim is for the manufacture of what is administered to the patient but stops short of being a claim actually to administration. It does not matter that the assembly is patient-specific, just as it does not matter with a conventional Swiss-form claim whether the manufacture takes place in a factory or a particular pharmacy.
48. Now there is nothing in the claim which speaks of a special kit. Construing it purposively I see no reason why the skilled man would put any such limitation on the claim. It is directed at the use of taxol for making a medicamentation for administration (using premedication) under specified dosages and times. Whether the taxol and premedication come in a specially made up kit or not is irrelevant to that purpose. If the skilled man went to the body of the specification he would not find any specific description of a kit. On the contrary he would find a description of premedication (various components of the cocktail being taken at 12, 6 and ½ hour before taxol infusion) and of administration of taxol. No kit is described.
49. Accordingly I think Mr Waugh is right on construction.
Method of treatment
50. Nor do I accept that on his construction the claim amounts to merely to a method of treatment. It is to the manufacture of the medicines to be used in that treatment. I am reinforced in that view by the consideration that the Art. 54(4) provision about methods of treatment is an exception to patentability and as an exception should be construed narrowly. As the Board of Appeal in Harvard/Oncomouse (T0015/90 OJ EPO [1990] 476) said, speaking of another exception:
"Art. 53(b) is an exception, for certain kinds of inventions, to the general rule under Art. 52(1) that European patents 'shall be' granted for all inventions which are susceptible of industrial application, which are new and which involve an inventive step. Any such exception must, as repeatedly pointed out by the Boards of Appeal, be narrowly constructed (cf. in particular T320/87, point 6 OJ EPO 1990 76)."
51. A like approach is indicated in Plant Genetic Systems/plant cells. (T0356/93 OJ EPO [1995] 545) There is also the limited purpose of the exception to be considered. It is not so broad as to stop doctors using whatever they feel they need to treat patients. If that were the purpose then one would not allow patents for medicines or medical implements at all. The purpose of the limitation is much narrower, merely to keep patent law from interfering directly with what the doctor actually does to the patient. Patent monopolies are permitted to control what he administers to, or the implements he uses on, the patient. The thinking behind the exception is not particularly rational: if one accepts that a patent monopoly is a fair price to pay for the extra research incentive, then there is no reason to suppose that that would apply also to methods of treatment. It is noteworthy that in the US any such exception has gone, and yet no-one, so far as I know, suggests that its removal has caused any trouble.
Relevance of the file history
52. Before passing from construction, I should mention one argument that Mr Waugh mentioned but, I think rightly, did not take. The original claim as filed was indeed to a kit - "products packaged for administration." The argument is that the dropping of this indicates a deliberate widening. So if one has regard to the prosecution history one can see that the wider meaning now contended for was intended, thus reinforcing that construction. Now there are several points to be made about a claim construction argument based on the prosecution history. First, whether that history can, and if so how, be used as an aid to construction should not be governed by national rules of construction. Claim construction is no longer a matter for national law but is governed by Art.69 and the Protocol. Thus, by way of example, specific English law notions of estoppel, cannot, as such, be used to construe the claim. Preventing him from asserting such a wide construction may be different - a specific English law defence. Second there is an obvious important practical difference between merely referring to the specification as originally filed as an aid to construction and referring to detailed matter (e.g. contentions in correspondence or evidence) as contained in the EPO file. The specification as filed is a published document (the "A" specification) and is referred to in the specification as granted. The intermediate processing correspondence with the examiner is different in volume and character, not least because it is not normally translated. Thirdly, there is another obvious difference between using the prosecution history to widen the claim and using that history to narrow it. It would be unfair on the public if material they would not normally look at could serve as a basis for supporting a wide construction of the claim. But there is not the same sort of unfairness if a patentee having contended for a narrow construction of his claim during prosecution is held to that construction later (cf. Furr v Truline ([1986] FSR 553), an English case). Fourthly there is a difference between merely resolving a puzzle in the specification (though not the claim) by reference to the specification as filed and using the specification as filed as an aid to construction of the claim itself. I used the former in relation to an example in the patent in Milliken v Walk Off ([1996] FSR 292 at 299). All these are matters to be considered, perhaps by the Enlarged Board of Appeal or, if current proposals were to proceed, by a European Patent Court. Fortunately I do not have to consider them here.
Novelty
53. The defendants say that claim 1 is not novel: the Winograd lecture published the use of taxol with premedication for a 3-hour infusion. Such a treatment would inevitably involve the loose assembly of drugs forming the subject of the claim on BMS's construction (which I have held to be right). BMS say what was not published by Winograd was the fact that you get reduced (as compared with 24-hour) neutropenia. It is essentially upon that fact that they base their claim to novelty. I regard their minor supplementary argument (that the patent asserts effectiveness though no doctor would accept the assertion without better evidence) as so much weaker as hardly worthy of further consideration. It certainly could not tip the argument. So, if there be novelty, it must rest on the disclosure for the first time in the patent of reduced neutropenia for 3-hour infusion as compared with 24-hour infusion.
54. BMS rest their case for novelty primarily on the decision of the Enlarged Board in Mobil/Friction Reducing Additive. (G02/88 [1990] OJ EPO 93) It was a case solely concerned with novelty. The Enlarged Board held (para.10.3) that:
"With respect to a claim to a new use of a known compound, such new use may reflect a newly discovered technical effect described in the patent. The attaining of such a technical effect should then be considered as a functional technical feature of the claim (e.g. the achievement in a particular context of that technical effect). If that technical effect has not been previously made available to the public by any of the means as set out in Art.54(2) then the claimed invention is novel, even though such technical effect may have inherently taken place in the course of carrying out what has previously been made available to the public."
27. On the facts of Mobil it was alleged by the patentees that although the addition of a particular compound to lubricating oil for the purposes of preventing rust was known, it was not known that the additive reduced friction. So the claim was held to be novel. The heart of the Enlarged Board's reasoning lies in the following passages:
"The word "available" carries with it the idea that, for lack of novelty to be found, all the technical features of the claimed invention in combination must have been communicated to the public, or laid open for inspection.
A line must be drawn between what is in fact made available, and what remains hidden or otherwise has not been made available.
The respondent submitted that in cases where, for example, a compound has previously been described as having been used but for a different purpose from the claimed use, and the previously described use had inherently had the same technical effect as the claimed use, on this basis there was lack of novelty (a so-called "doctrine of inherency")".
28. The Enlarged Board would emphasise that under Article 54(2) EPC the question to be decided is what has been "made available" to the public: the question is not what may have been "inherent" in what was made available (by a prior written description, or in what has previously been used (prior use), for example). Under the EPC, a hidden or secret use, because it has not been made available to the public, is not a ground for objection to validity of a European patent.
29. So, submitted Mr Waugh, the feature of reduced neutropenia, although it may have been inherent in the prior art, was only "inherent". It was a "hidden" feature of the prior art and thus was not made available to the public. He reinforced his argument by reference to what Lord Hoffmann said in Merrell Dow (at p.86):
"an invention is a piece of information. Making matter available to the public within the meaning of s.2(2)[i.e. Art.54(2)] therefore requires the communication of information."
55. Here, submitted Mr Waugh, the information that 3-hour infusion produces less neutropenia was new. It was not made available to the public by the prior art. It follows BMS made an invention which was new. Mr Waugh further buttressed his case to the classic English case of Hills v Evans ((1862) 31 L.J.Ch. 457), namely that:
"the information as to the alleged information given by the prior publication must, for the purpose of practical utility, be equal to that given by the subsequent patent."
30. He also relied on a decision of my own, Union Carbide v BP ([1998] RPC 1 at p.13) where I held that a prior art disclosure not to do something because it would not work (or, as the EPO Board of Appeal put was "not a feasible option") was not novelty-destroying. The new information in the patent of that case, that the prior statement was wrong and that the something was useful, was enough to support novelty. So here the information that 3-hour infusion produced a better result from the point of view of neutropenia should support novelty.
56. Mr Thorley riposted with several lines of argument. His first was a full-scale assault on Mobil. He said it was wrong and it was my duty so to hold. For the reasons I have already given I conceive it my duty to refuse to do so. I am fully aware of the difficulties of the decision, indeed I gave a number of examples in a paper on the subject to the 7th Symposium of European Patent Judges. ((1996) IIC vol. 27 p.170) Mr Floyd QC has also trenchantly criticised Mobil in the 1996 Herschel Smith lecture. ([1996] EIPR 481) But the House of Lords in Merrell Dow, given the opportunity to say that Mobil was bad law, clearly declined to take it.
57. There is a further strong reason why it would be inappropriate for me, at this level, to go into the correctness of Mobil. It is arguable that there is no logical or reasonable distinction between it and the decision in Eisai. After all it is the novel (second medical use) purpose of the product of manufacture of the Swiss-type claim which is said to create novelty. The product and its method of manufacture are old. So to try and to steer a course between accepting Eisai and yet holding Mobil wrong is at best going to involve more Byzantine logic.
58. I turn to Mr Thorley's alternative approach - distinguishing Mobil and Eisai. First he says a subsequent patent cannot be used to stop people doing what was taught before - whatever the form of that teaching was. Thus in Merrell Dow the prior use of terfenadine in clinical trials did not invalidate the patent for the metabolite because it did not give any information (of whatever sort) which would lead to the manufacture of the metabolite. On the other hand the terfenadine patent did give instructions on how to make the metabolite in the human body in the sense that it told you how to make terfenadine and to administer it to patients. It did not go further than that by way of instruction, which is why it was possible to amend the patent to exclude from the claim the metabolite in the body when made by the body from terfenadine (or some similar amendment). Here, says Mr Thorley, the prior art taught 3-hour infusion with premedication - a recipe. That being so, the later patent cannot stop that use.
59. I think another way of putting this point is to say this is not a case of second medical use at all. The use is the same. All you have new in the patent is more information about that use. I think that is right. As Laddie J said in Evans Medical's Patent: ([1998] RPC 517 at 576)
"First one must identify what the alleged invention is, that is to say what is covered by the claims of the patent, and then one must decide whether or not that invention, or any part of it, would be made inevitably by following the instruction in the prior art. If it would be, then it does not matter whether the skilled reader of the prior art would realise that he was working within the area claimed in the subsequent patent."
31. It is implicit in what Laddie J said, I think, that Mobil has its limits. It should be remembered that Mobil was treated as a case where the new use was different from the old. Perhaps a clearer example is case T231/85 (OJ EPO 1989, 74) , 74 of the discovery that a particular compound (previously used for influencing plant growth) also controlled fungi. One can imagine cases where it was used for one purpose or the other. The purposes do not necessarily overlap. That is simply not the case here. All you have is more information about the old use. In due course no doubt more information about the exact mode of action of taxol will emerge. No-one could obtain a patent for its use simply by adding "for" at the end of the claim and then adding the newly discovered details of the exact mode of action.
60. In holding that this is not a second medical indication case at all, I am glad to find myself in agreement with the Court of Appeal of the Hague (Judges Brinkhof, Passeur-van Santen and Grootnoonk) who were considering the corresponding Dutch European Patent in Bristol-Myers Squibb v Yew Tree (25th June 1998) They said:
"It must be assumed that there is not a single expert/doctor in the present field of science, who would believe that what is involved here is a second medical indication in the sense of an application of a substance for a different therapeutic purpose (for example, to fight another illness or for prevention instead of as a cure."
61. Secondly Mr Thorley points out that the EPO Boards of the Appeal themselves have, subsequent to Mobil, started to draw a distinction between case of true new uses (i.e. "technical effects") and cases of mere more information about old uses. Thus in Dow(T958/90) the claim was for the use of A to increase the ability of B to sequester calcium from solution. So A was an additive to B for a specified purpose. The patentee argued that the case was the same as Mobil. But it was known to use a mixture of A and B for sequestering. The only new information in the patent was that the activity of the mixture was better than of A alone. The Board tersely observed in rejecting the patent:
"A known effect cannot become novel for the sole reason that it is present to a hitherto unknown (greater) extent"
"The present claims .... do not disclose a new use of A in the known mixture, but merely suggest to use it for the same purpose for which it was already used."
33. This finding is further confirmed by considering the question whether the additional information, which results from carrying out the technical instructions contained in the disputed patent amounts to a technical contribution to the state of the art in the sense that it teaches the person skilled in the art to do something which he would not have done without this additional information [my italics]."
And:
"An additional reason to do what has already been proposed earlier as a solution to the same technical problem cannot be regarded as a new functional feature in the sense of Mobil."
62. Similarly, and perhaps even more to the point, in American Cyanamid(T279/93) the claim was for the use of A in a for preparing B in order to reduce the formation of impurities. The prior art disclosed the use of A with B in a process but did not reveal the fact that there were less impurities. The Board said:
"The facts of the present case differ significantly from those underlying Mobil. The Board is unable here to find that the words "in order to reduce impurities" require any new physical activity not already required by the old use of using A [in the process] to make B. Thus there is no new technical effect in the sense required by Mobil.
The Board acknowledges that the prior art does not state that [A} produces less impurities than other combinations..... But noticing that an old product has the properties of less impurities .. is a mere discovery. To convert this into a patentable invention, and to show the characteristic of a new technical effect as required by Mobil, the use referred to in the claim would have to be some new use of the product which exploits the discovery that the impurities are low .. for some new technical purpose. However the patent in suit discloses no such new use, but merely gives the person skilled in the art reasons for preferring one known product over other known ones for the uses for which it has already been suggested. Giving such reasons for preferring one known compound is not a new industrial application.
Put another way, the additional information contained in the patent in suit does not teach the person skilled in the art to do something which would not have been done without knowing the content of the patent in suit [my italics]."
63. All that was said there I think applies mutatis mutandis to this case. Noticing that the old 3-hour infusion causes less neutropenia is a mere discovery. It does no more than give the skilled man yet another motive to use 3-hour infusion with premedication. Nor does the case get any better by saying that the prior art contained no information about effectivity at 3-hours. The patent does not either - the mere assertion of effectivity being, as the evidence on both sides accepted, one which the skilled man would not accept on the data in the patent.
64. Mr Waugh was constrained to accept that American Cyanamid was indistinguishable from the present case. His answer to it was to say it was wrong as being inconsistent with Mobil and to rely upon another EPO Board of Appeal decision which he said was in conflict with American Cyanamid. This was ICI/Cleaning Plaque(T290/86 1992 OJ EPO 414). I think he was perhaps right about the latter point. For there the Board of Appeal said:
"When a prior document and a claimed invention are both concerned with a similar treatment of the human body for the same therapeutic purpose, the claimed invention represents a further medical indication as compared within the meaning of Eisai if it is based upon a different technical effect which is both new and inventive over the disclosure of the prior document."
34. The prior art had disclosed a toothpaste (which of course inevitably removed plaque to some extent) which contained lanthanum. The latter was included not to improve plaque removal but to depress the solubility of tooth enamel. The Board's decision meant a repatenting of the old toothpaste because of the discovery that the lanthanam in it also improved plaque removal.
65. Given the conflict between this decision and those in American Cyanamid and Dow, I unhesitatingly prefer the reasoning in the latter cases. If Mobil is right, then I think it must be confined to true new uses not mere discoveries about old uses.
66. Thus, I think Mr Thorley is right. This is not a case of a second or other medical use. It is a case of a mere discovery about an old use. In so holding I do not forget Mr Waugh's submissions based on Merrell Dow, Hills v Evans and Union Carbide recorded above. The flaws in the arguments are as follows. All that Lord Hoffmann said was that an invention is information. It does not follow that further information about the prior art is itself an invention. The passage relied upon from Hills v Evans is about what you learn from a prior publication. Earlier on Lord Westbury had drawn the distinction between the case where the skilled man "would at once perceive, understand and be able practically to apply the discovery without the necessity of making further experiments." Using the information in Winograd the skilled man here would be able to do 3-hour infusion with premedication without any information from the patent. And, as to Union Carbide, I think there is a big difference between new information that a prior proposal previously thought unworkable in fact works and new information to the effect that a prior proposal has an additional advantage.
67. In the end, therefore I unhesitatingly conclude that the claim lacks novelty. I should only add that it is apparent that the decision in Mobil is causing considerable difficulty to national courts. It is not good enough for these difficulties to be brushed aside, as for instance was done by Mr Paterson (a member of the Mobil Enlarged Board) in extra-judicial lectures (to the 7th European Patent Judges Symposium ((1996) 27 IIC 179 ) and in an article in the European Intellectual Property Review ([1991] 1 EIPR 16). Substantive European patent law demands a holistic approach to infringement and validity. Moreover by virtue of the EPC and CPC it should have it. For myself, although I have no power of direct reference (as I have to the European Court of Justice on questions of European Union law), I hope that the EPO will find a way of convening a fresh Enlarged Board (ideally including judges with experience of infringement) to reconsider Mobil. After all Mobil seems to have no parallel in other jurisdictions, such as the USA. One way might be for the President of the EPO to decide (under Art. 112(b)) that different Boards of Appeal have given different decisions on the question of law - as indeed submitted by Mr Waugh in his submission concerning the American Cyanamid and ICI cases. In so saying, I am of course aware of the policy reasons behind Mobil (and that in Eisai), namely encouragement of research. But it may well be that it is not for patent law to be distorted with recourse to devices and sophistry. There are, after all, other ways of such encouragement. For instance, in the US, in the field of pharmaceuticals, an advantage is given to the first introducer of a pharmaceutical. He gets 5 years protection from the date of clinical approval for that clinical use under the Waxman-Hatch Act. And in any event it is not self-evident that the decisions in Eisai or Mobil have in fact encouraged research.
Obviousness
68. I finally come to obviousness. I think this is a very plain case. Winograd had disclosed 3-hour infusion with premedication was safe from the point of view of toxic shock. It was unknown how efficacious the 3-hour treatment was, save for Winograd's hint that there were "responses in all arms." But there was every motive to find out. And in further testing of 3-hour infusion you would surely test for neutropenia. As I have said blood tests were routine in this sort of clinical trial. There simply cannot be any invention in pressing on with the OV.9 trial and finding out about the comparative levels of neutropenia.
69. Mr Waugh submitted that there was no way that one could tell from the prior art that 3-hour infusion was efficacious. To this extent his submission did not rely upon the unexpected reduced neutropenia. His argument went on to the effect that there was no expectation of success from the point of view of efficacy. So in finding out that there was indeed efficacy BMS had found out that which was not obvious. There are two flaws here. First the patent does not disclose efficacy to the skilled man (whatever it may assert). Second it was quite clear that efficacy at 3-hours was of great interest to the skilled man. It was obvious to him to find out.
70. To my mind the case hardly warrants the elaboration of the structured analysis of the type approved in Windsurfing.( [1995] RPC 59) Mr Waugh manfully tried to force the case into that form in a way which would support the patent. It went like this:
Step 1. The skilled person? - A physician experienced in the use of chemotherapeutic agents for treating cancer.
Step 2. The inventive step of claim 1 of the patent is the use of taxol within the particular dose range in an infusion over about 3 hours or less as a means for treating cancer and simultaneously reducing neutropenia (by comparison to the neutropenia observed were the same dose of taxol to be administered over 24 hours).
Step 3. The difference over the prior art? - This step goes beyond that disclosed in the prior art which failed to disclose that a 3 hour or less treatment regimen was a means for treating cancer and that at the same time it reduced neutropenia (by comparison to the neutropenia observed were the same dose of taxol to be administered over 24 hours).
Step 4. Is the difference obvious? - The reduction in neutropenia observed with a 3 hour treatment regimen by comparison to that observed following a 24 hour treatment regimen is a technical feature of the invention which was not obvious to the skilled man.
71. The short answer to this is provided by Mr Thorley as follows. The true question is, do the directions given by Winograd make the discovery of the neutropenic effect obvious? It is wrong to ask whether you would have predicted that effect. The obvious course of action as a result of the talk would have revealed the result. Reduced neutropenia was truly ob via - in the way - to go back to the Latin root of the word "obvious". There is no inventive step. I agree with that analysis.
72. Accordingly I hold the patent bad for want of novelty and obviousness.
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