England and Wales High Court (Patents Court) Decisions

IN THE HIGH COURT OF JUSTICE
CHANCERY DIVISION
PATENTS COURT

		Rolls Building Fetter Lane, London, EC4A 1NL
		7 February 2013

MR JUSTICE ARNOLD :

Contents

Topic	Paragraphs
Introduction	1-4
The witnesses	5-11
Technical background	12-55
Malaria	12-21
Treatments of prophylactics	22
Anti-malarial drugs	23-40
Aminoquinolines	27-30
Folate inhibitors	31-32
Antibiotics	33
Hydroxynaphthoquinones	34
Artemisinins	35
Combinations of anti-malarials	36-40
Resistance	41-43
Recommended drugs in 1992	44-46
The outlook for malaria control in 1992	47-49
Drug development	50-53
Clinical trials	54-55
The Patent	56-66
The claims	67-69
The skilled team	70-71
Common general knowledge	72-88
Potentiation/potentiating	74
Pyrimidine synthesis	75-77
Limiting the spread of resistance	78-80
Combinations of anti-malarials	81-88
Additive combinations	82-87
Synergistic combinations	88
The prior art	89-107
The Hutchinson presentation	90-105
The Hudson abstract	106-107
Obviousness	108-155
The law	108-112
The skilled team and the common general knowledge	113
The inventive concepts of claims 1, 3 and 9	114
Differences between claim 1 and the Hutchinson presentation	115
Obviousness of claim 1 over the Hutchinson presentation	116-144
Atovaquone was not suitable for use on its own	119
The combination trial was small, uncontrolled and incomplete	120-121
No disclosure of synergism	122-125
Difficulties in testing for synergy	126-128
The combination was irrational if merely additive	129-130
Other avenues of research	131-133
Commercial factors	134-135
The experts' overall opinions	136-139
Secondary evidence: reactions of the audience	140-142
Secondary evidence: commercial success	143
Conclusion	144
Independent validity of claim 9	145-147
Obviousness over the Hudson abstract	148-155

Conclusion\156

Introduction

1. In these two actions the Claimants ("Glenmark" and "Mylan") seek revocation of European Patent (UK) No. 0 670 719 ("the Patent"). The Defendant and First Part 20 Claimant ("Wellcome") is the registered proprietor of the Patent. Beneficial ownership of the Patent has been assigned to the Second Part 20 Claimant ("Glaxo"), which is also the exclusive licensee. Wellcome and Glaxo are both part of the GlaxoSmithKline group of companies. In the remainder of this judgment I will refer to them both as "Wellcome".
2. The Patent relates to an anti-malarial pharmaceutical composition comprising a combination of atovaquone and proguanil in the ratio 5:2. The priority date of the Patent is 26 November 1992. The sole ground on which the Claimants allege that the Patent is invalid is that of obviousness.
3. Wellcome sell a composition comprising a 5:2 combination of atovaquone and proguanil under the trade mark Malarone. Malarone is the most successful anti-malarial prophylactic in the UK. Glenmark and Mylan each wishes to sell a generic version of Malarone. In the light of this threat, Wellcome have counterclaimed against both for infringement. There is no dispute that both Mylan's and Glenmark's proposed products would infringe the Patent if it is valid. Both Mylan and Glenmark have undertaken not to launch any atovaquone/proguanil product pending the trial of the actions. In return, Wellcome have given cross-undertakings in damages. Because of this, the trial has been expedited.
4. Wellcome have made an unconditional application to amend the Patent to delete granted claim 1. This is not opposed by either Glenmark or Mylan. Accordingly, I shall refer to the claims as proposed to be amended.

The witnesses

5. The Claimants called two expert witnesses, Professor Malcolm Molyneux and Professor Raymond Hill. Prof Molyneux is a clinician who has specialised in the treatment of malaria and other tropical diseases since 1974. Having qualified as a doctor in 1968, he practised in Malawi from 1974 to 1984. In 1984 he became Senior Lecturer and Honorary Consultant Physician at the University of Liverpool School of Tropical Medicine and in 1993 he became Professor of Tropical Medicine. His research interests have been focused on severe malaria in children and the efficacy of drugs to treat malaria. He has published extensively in those areas. He is currently Emeritus Professor of Tropical Medicine at the Liverpool School of Tropical Medicine and Honorary Professor of Medicine at the University of Malawi.
6. Counsel for Wellcome submitted that Prof Molyneux lacked experience which the person skilled in the art would have had since he had not been involved in drug development. I do not accept that submission for two reasons. First, Prof Molyneux had been involved in the development of the anti-malarial drug isoquinine, albeit after the priority date. Secondly and in any event, Prof Molnyeux was well qualified to assist the court as to the knowledge and attitudes of a clinician working in the field of malaria regardless of the extent to which he personally had been involved in drug development.
7. Prof Hill initially trained as a pharmacist and then obtained a PhD in neuropharmacology. From 1974 to 1983 he was a Lecturer in Pharmacology at the University of Bristol. From 1983 to 1988 he was a supervisor in Pharmacology at Downing College, Cambridge. From 1988 to 1990 he was employed by Smith Kline & French. From 1990 to 2008 he was employed in various roles by Merck, initially as Executive Director, Pharmacology. He is currently visiting Professor of Pharmacology at Imperial College, London as well as a non-executive director of a number of pharmaceutical development companies.
8. Counsel for Wellcome submitted that Prof Hill was unable to assist the court because his area of expertise was pain relief and he had no experience of anti-malarials or even other anti-infectives. I do not accept that submission. Prof Hill is an experienced pharmacologist. His evidence was directed to the dose-ranging studies that would be conducted if the clinician considered the Hutchinson presentation (as to which, see below) worth pursuing. It was not suggested that the approach to such studies is different in this field to that adopted in other fields such as pain relief. Indeed, Prof Hill's evidence was scarcely challenged.
9. Wellcome's only expert was Dr John Horton. Dr Horton qualified as a doctor in 1969 and worked in general practice. He joined Smith, Kline & French in 1977 to work as a clinical research physician. In 1985 he was appointed as Medical Director of the Overseas Division. Between 1985 and 2002, he was involved in the development of a number of anti-malarial drugs and other tropical anti-infectives successively for Smith Kline & French, SmithKline Beecham and GlaxoSmithKline. In 2002, Dr Horton left GSK and set up as an industry consultant. He was an Honorary Professor of Therapeutics at Liverpool University from 2003 to 2007.
10. Prof Molyneux and Dr Horton were both very knowledgeable, helpful and fair witnesses. Cross-examination revealed that there was not a great deal of difference between them on technical matters.
11. A number of factual witnesses also gave evidence. Some of these are no longer relevant due to the abandonment by Glenmark and Mylan of an item of prior art. Those who remain relevant are as follows. First, Dr David Hutchinson, who was employed by Wellcome as a clinical research physician from 1974 to 1997 and who is named as one of the inventors of the Patent. He gave the presentation which constitutes the principal item of prior art. Secondly, Professor Angus Bell of Trinity College, Dublin, who attended Dr Hutchinson's presentation. Thirdly, Professor David Arnot of the Universities of Edinburgh and Copenhagen, who also attended the presentation. All three were good witnesses, but they faced inevitable difficulties in trying to recall the contents of an oral presentation nearly 21 years ago. (Dr Horton also attended the meeting, and probably the presentation, but had no recollection of it.)

Technical background

Malaria

12. Malaria is one of the oldest, most debilitating and most prevalent of tropical diseases. It is caused by four species of parasitic protozoa (single-celled organisms) of the genus Plasmodia: P. falciparum, P. vivax, P. malariae and P. ovale.
13. Malaria parasites have a lifecycle consisting of a sexual stage in the mosquito and an asexual stage in humans or other vertebrates. When an infected mosquito bites a human, a small motile form of the parasite, called a sporozoite, is released into the blood. Sporozoites invade host liver cells where they undergo rapid asexual multiplication and differentiate into forms called merozoites inside a structure known as a schizont. The schizont and infected liver cell eventually rupture, releasing merozoites into the host's circulation. Here they invade the host's red blood cells and undergo further rounds of multiplication inside further schizonts. In time these further schizonts and the red blood cells rupture, releasing further waves of merozoites into circulation.
14. A proportion of the circulating merozoites during the blood stage of the infection differentiate into precursor sex cells called gametocytes. These are drawn up into the gut of subsequent biting mosquitos where they release gametes. These gametes fuse to form a genetically new zygote. The zygote multiplies inside a structure in the mosquito gut wall called a sporont. The sporont eventually ruptures, releasing sporozoites which migrate to the mosquito's salivary glands ready for injection into a new human host, completing the life cycle.
15. The destruction of red blood cells wrought by the rapid multiplication of parasite numbers during the blood stage of the infection and the accompanying release of toxins cause the symptoms associated with acute malaria. Untreated, infection will progress with ever increasing numbers of parasites, leading to severe anaemia and, eventually, damage to vital organs ("complicated" malaria). Complicated malaria is frequently fatal.
16. In areas where malaria is endemic, survivors of infections build up an immune response to the malaria parasite which prevents subsequent infections escalating to an acute blood stage. Mortality rates are therefore highest among children and travellers who have had no previous exposure to the disease.
17. Of the protozoa species that cause malaria, P. falciparum produces the most severe symptoms because it has the shortest lifecycle and produces the most merozoites.
18. In patients infected with P. vivax and P. ovale, malarial illness may recur months to years after apparently successful treatment. This phenomenon (known as relapse) is caused by dormant liver-stage forms of the parasite that resume their developmental cycle and release merozoites into the bloodstream.
19. Short-term recurrence of the illness within a matter of days or weeks of treatment is a different phenomenon common to all malaria species. This phenomenon, known as recrudescence, is caused by surviving blood stage parasites and may happen for a number of reasons. For example, the treatment may have failed to eliminate all the parasites because the dose of drug was too low through error on the part of the prescriber, non-compliance on the part of the patient or because part of the dose was lost through the patient vomiting. Alternatively, the dose may have been inadequate because some or all of the parasites exhibit resistance to the compound or group of compounds used for treatment.
20. Where recrudescence is associated with drug resistance, the response of a patient is usually classified as follows. Initial clearance of parasitaemia followed by recrudescence some time later (usually several days or weeks after treatment) is classified as an R1 response. An R2 response is characterised by a marked (but incomplete) initial reduction in parasitaemia. Where parasite numbers are wholly unaffected by the treatment, this is classified as an R3 response.
21. Malaria is more accurately viewed as multiple diseases rather than a single disease. The species of parasite, the behaviour of the mosquito host, the individual's immune status, the climate, human activities and access to health services all play important roles in determining the intensity of disease transmission, who will become infected, who will get sick and who will die. People living in regions where malaria is endemic and those who travel to such areas are regarded as distinct population groups.

Treatments and prophylactics

22. Anti-malarial drugs may be used for treatment or for prophylaxis or both. It should be borne in mind that in both uses the function of the drug is to kill the parasite. The difference is that in treatment drugs are used in an established infection (and consequently required to act quickly on the blood stage of the disease), whereas prophylactics are acting to prevent an infection becoming established (they can act on any stage of the disease and speed of action is less important). The standard approach used in drug development in 1992 was to look for a clear demonstration of efficacy as a treatment before considering prophylaxis.

Anti-malarial drugs

23. The first anti-malarial drug was quinine. Quinine is the principal alkaloid of Peruvian cinchona bark, the properties of which were first revealed to Europeans in the early 1600s. Quinine remained the only effective anti-malarial until the Second World War. It remains one of the front-line anti-malarial drugs, especially in the treatment of P. falciparum infections.
24. The search for synthetic anti-malarial drugs began at the end of the nineteenth century and was undertaken intensively by the Allies during the Second World War, whose source of quinine in Indonesia had been cut off by the Japanese Army. This led to the development of a number of drugs including chloroquine, amodiaquine and primaquine (developed in the US) and pyrimethamine and proguanil (developed in the UK).
25. In the 1940s and 1950s it was thought that malaria could be eradicated through the use of pesticides to combat mosquitoes and drugs to combat the disease. This belief was severely undermined by the emergence of insecticide-resistant mosquitoes and drug-resistant strains of malaria, the latter in around 1960, prompting a major search for new drugs. The programme was co-ordinated by the Walter Reed Army Institute of Research (WRAIR) in the US and involved the screening of many thousands of existing and newly-synthesised compounds. A number of promising candidates were identified, including mefloquine, halofantrine and tafenoquine.
26. By 1992 a number of different classes of anti-malarial drugs were known. The principal ones were as follows.
27. Aminoquinolines. This class comprised quinine, chloroquine, mefloquine and halofantrine.
28. Chloroquine was developed in the late 1940s. It was very effective and a short course of treatment would clear the parasite in a few days. However, resistance became a problem in the late 1960s and spread rapidly so that by 1990 it was of limited use in most of the world.
29. Mefloquine was first used in 1983 under the trade mark Lariam. It was initially very successful, although in a short time failures were reported in South East Asia where parasites were already chloroquinine resistant. By 1990, substantial resistance had developed in Thailand. However, the main problem with mefloquine was that it caused dizziness, nausea, vivid dreams and even hallucinations, and suicidal tendencies. These were first reported in the late 1980s and resulted in declining use over the next decade.
30. Halofantrine was in widespread use in 1992. It was withdrawn due to side effects after the priority date.
31. Folate inhibitors. The malaria parasite requires folate for DNA synthesis. Inhibition of the production of folate therefore inhibits parasite multiplication. Folate inhibitors in use in 1992 include pyrimethamine, the biguanides (proguanil and chlorproguanil), sulphones and the sulphonamides.
32. Proguanil first came into use in 1946. Initially, it was used as a treatment. Because it acts on the folate pathway, however, it has a rather slow action. Due to this slow action, it was mainly used in prophylaxis after the 1950s. By 1992 it was known that the action of proguanil is dependent on its metabolism to cycloguanil. It is cycloguanil, not proguanil, that has the antifolate activity. By 1992 resistance to proguanil was widespread.
33. Antibiotics. Tetracyclines, especially the longer acting doxycycline, have also found a use in malaria treatment and prophylaxis against the blood stage of the parasite. Because tetracycline is slow-acting, it is not used on its own.
34. Hydroxynaphthoquinones. The anti-malarial activity of certain hydroxynaphthoquinones was discovered in the 1940s. These included lapinone, which was shown to be effective, but required parenteral administration. Menoctone was developed in the 1960s, but failed to live up to its early promise. A series of substituted hydroxynaphthoquinones was later synthesised by Wellcome. The most potent of these was BW58C, but further development was stopped on account of its metabolism in humans. BW566C80 (atovaquone) was synthesised in the 1980s and shown to be resistant to metabolism and to have potent anti-protozoal activity against malaria parasites (and Pneumocystis carinii, which is often seen in AIDS patients).
35. Artemisinins. Artemisinin (qinghaosu) is a natural product isolated from the wormwood plant Artemisia annua, used for centuries in Chinese herbal medicine. Since artemisinin itself has low solubility and is rapidly metabolised, various derivatives were under development in 1992 for use as anti-malarials, including sodium artesunate and artemether.
36. Combinations of anti-malarials. Combination therapy with two or more drugs has long been a feature of treating bacterial and viral infections such as tuberculosis and HIV. It has also been widely deployed in the treatment and prophylaxis of malaria, for two main reasons. First, to improve efficacy: the drugs may have additive effects or may be synergistic (that is to say, have an effect greater than the sum of their separate effects). Secondly, to delay the onset of resistance, the rationale being that if two drugs operate in different ways, the probability of an individual parasite developing resistance to both compounds is greatly reduced.
37. Such combinations may be administered together or separately at the same time or one after the other. Even where the combination is administered together or at the same time, it may contain components which act at different times, typically a fast-acting component and a slow-acting one.
38. Combination therapy should be distinguished from true sequential therapy, in which a second drug is administered after a first drug has failed to effect a radical cure.
39. A number of commercial combination products had been used in the treatment or prophylaxis of malaria by 1992. These included Daraclor (pyrimethamine + chloroquine), Camoprim (amodiaquine + primaquine), Maloprim (pyrimethamine + dapsone), Avloclor/Paludrine (chloroquine + proguanil), Lapaquine (chloroquine + chlorproguanil), Fansidar (pyrimethamine + sulphadoxine), Metakelfin (pyrimethamine + sulphalene) and Fansimef (mefloquine + pyrimethamine + sulphadoxine). Many of these were no longer in use in 1992. The best known at that time was Fansidar, which was still in use although resistance to it was quite widespread.
40. In the 1960s many combinations were developed on a highly empirical basis. By 1992, however, scientists were looking for reasons to combine drugs.

Resistance

41. Resistance tends to develop where parasite populations are exposed to sub-therapeutic levels of a drug. Resistance is particularly prevalent in South East Asia, where there is less natural immunity to malaria than other regions (such as Africa). This leads to more widespread use of anti-malarials, thereby creating locally sustained selection pressure in favour of resistance. As a result, parasites with a genetic mutation giving rise to resistance have an advantage over those without that mutation.
42. It should be appreciated that the emergence of resistant parasites in travellers, and even in inhabitants of regions with a low incidence of malaria, is much less of a concern than it is in populations living in endemic regions. This is because the resistant parasites are much less likely to be transmitted from individual to individual.
43. Because it generally occurs as a result of random mutations in the parasite, resistance usually takes some years to develop and spread, but the speed of this can vary considerably, depending on a variety of factors, including the scale on which the drug is deployed, cross-resistance to other drugs already in use and in some cases the plasma half-life of the drug. For example:

i) Resistance to quinine was first observed in the early 20^th century, but as stated above it remains in use as a frontline treatment in some situations.

ii) Resistance to chloroquine was first suspected in Thailand in 1957 and found in patients in Colombia in 1960. In due course, chloroquine resistance spread to other parts of the world and was widespread by the 1970s. This was hastened by the sheer scale of its use in the 1950s and 1960s. Such use had been largely uncontrolled and included administration to non-infected individuals, and even its addition to table salt in Brazil, in order to get the drug to the widest possible population as efficiently as possible.

iii) Resistance to proguanil and pyrimethamine developed within two years or so of their introduction.

iv) Resistance to Fansidar developed more slowly, but was quite widespread by the late 1980s.

v) Resistance to mefloquine was apparent in some areas even before it was generally introduced, possibly because of cross-resistance to chloroquine, but in most areas resistance took longer to appear.

vi) The efficacy of halofantrine gradually decreased over the course of the 1980s, probably due to cross-resistance to mefloquine.

Recommended drugs in 1992

44. In the United Kingdom, the following drugs were recommended for treatment and prophylaxis of malaria by the British National Formulary in 1992:
45. For treatment:

P.falciparum	Quinine followed by either Fansidar (if resistance to quinine is known or suspected) or tetracycline (if resistant to Fansidar). Alternatively treat with mefloquine or halofantrine.
P. malariae	Chloroquine.
P.vivax/P. ovale	Chlor oquine, followed by primaquine.

46. For prophylaxis:

N. Africa/Middle East:	Chloroquine or proguanil.
Sub-Saharan Africa:	Chloroquine and proguanil; or mefloquine (for short term travel in certain regions).
South Asia:	Chloroquine and proguanil.
South-East Asia:	Chloroquine and proguanil; or mefloquine (for short term travel).
Oceania:	Maloprim and chloroquine; or mefloquine (for short term travel).
Latin America:	Chloroquine or proguanil; chloroquine and proguanil; or mefloquine (for short term travel in certain regions)

The outlook for malaria control in 1992

47. The outlook for malaria control in 1992 was grim. In 1990, the World Health Organisation ("WHO") had estimated that more than 2 billion people (40% of the world's population at that time) were exposed to the risk of malaria, giving rise to some 110 million clinical cases and 1 million deaths every year. By 1992, the latter figure had increased to 1-2 million deaths per year and the WHO estimated that in Tropical Africa, malaria accounted for 20-50% of hospitalisations and 15-25% of infant deaths under the age of five.
48. An authoritative account of the position at the priority date is to be found in Malaria: Obstacles and Opportunities published by the United States Institute of Medicine in 1991 at pp. 1-2:

"The outlook for malaria is grim. The disease, caused by mosquito-borne parasites, is present in 102 countries and is responsible for 100 million clinical cases and 1 to 2 million deaths each year. Over the past two decades, efforts to control malaria have been met with less and less success. In many regions where malaria transmission had been almost eliminated, the disease has made a comeback, sometimes surpassing earlier recorded levels. The dream of completely eliminating malaria from many parts of the world, pursued with vigour during the 1950s and 1960s, has gradually faded. Few believe today that global eradication of malaria will be possible in the foreseeable future.

Worldwide, the number of cases of malaria caused by Plasmodium falciparum, the most dangerous species of the parasite, is on the rise. Drug-resistant strains of P. falciparum are spreading rapidly, and there have been recent reports of drug resistance in people infected with P.vivax, a less virulent form of the parasite. Furthermore, mosquitoes are becoming increasingly resistant to insecticides, and in many cases, have adapted so as to avoid insecticide-treated surfaces altogether.

In large part because of the spread of drug and insecticide resistance, there are fewer tools available today to control malaria than there were 20 years ago. In many countries, the few remaining methods are often applied inappropriately. The situation in many African nations is particularly dismal, exacerbated by a crumbling health infrastructure that has made the implementation of any disease control program difficult.

Malaria cases among tourists, business travellers, military personnel, and migrant workers in malarious areas have been increasing steadily in the last several years, posing new concerns that the disease will be introduced to current nonmalarious areas. Recent epidemics have claimed tens of thousands of lives in Africa, and there is an increasing realization that malaria is a major impediment to socioeconomic development in many countries. Unless practical, cost-effective strategies can be developed and successfully implemented, malaria will continue to exact a heavy toll on human life and health around the world."

49. Thus there was an urgent need to identify and develop new drugs for the treatment and prevention of malaria.

Drug development

50. Pharmacology is the science of drugs, including how they work, their effects and their use to cure diseases. In 1992, pharmacology was a well-established field. Many of the key principles remain unchanged to this day.
51. Chemotherapeutic agents are drugs that kill or inhibit the growth of infective agents (and cancerous cells). In general the activity of a chemotherapeutic agent is first demonstrated in vitro. Potential anti-malarials could in 1992 be tested in vitro on cultured P. falciparum protozoa. The standard assay involves measuring the effect of a range of concentrations of the drug on uptake by the parasite of radio-labelled hypoxanthine, a molecule incorporated into the DNA of replicating (and therefore healthy) parasite cells. This enables determination of the concentration which inhibits hypoxanthine uptake by 50% (or IC₅₀).
52. The efficacy of drug combinations can be tested in vitro using the same technique modified to enable exploration of the activity of the combination in a range of ratios. One question for such an investigation is whether the combination is antagonistic, additive or synergistic. To this end, data from in vitro combination studies are subjected to isobolographic analysis, a mathematical technique which enables quantitative comparison of the activity of the combination against the activity of its constituent components. The results can be expressed in terms of an I value. 0 indicates an additive combination, a positive value a synergistic one and a negative value an antagonistic one.
53. Once the efficacy of a drug or combination of drugs has been demonstrated in vitro, the main questions that arise upon administration to a patient are (a) whether the drug is absorbed by the patient to a sufficient degree and present in sufficient concentration at the desired site of action for a sufficient period to have the desired therapeutic effect and (b) whether the drug is safe to the patient. These questions are addressed by trials, initially in animals and then in humans.

Clinical trials

54. Phase 1 trials are undertaken with healthy volunteers. Phase 2 trials involve the treatment of patients with experimentally-induced malaria (individuals who have been inoculated with parasitised blood) or naturally acquired malaria. It was common in 1992 first to carry out small scale, uncontrolled trials to test the principle (nowadays such trials would be referred to as Phase 2a) and then to carry dose-ranging studies designed to determine empirically the relationship between the amount of the drug administered and its therapeutic effect (nowadays referred to as Phase 2b). Phase 3 trials are much larger and rigorously controlled either by comparison to a placebo or by comparison with another drug.
55. Clinical trials, particularly Phase 3 trials, are time-consuming and logistically demanding to carry out. They are usually not technically challenging to carry out, however, although care needs to be taken to ensure that sufficient patients are recruited to ensure that the results are statistically significant. (Nowadays it would be common to involve a medical statistician in the design of the trial.)

The Patent

56. The specification begins at [0001] by stating that the invention relates to synergistic combinations of atovaquone and proguanil which have anti-parasitic activity, pharmaceutical compositions containing such combinations and their use in the treatment of protozoal parasitic infections including malaria. The specification acknowledges at [0002]-[0003] that both atovaquone and proguanil are known, saying that the latter is a well-known drug for prophylaxis, but not treatment, of malaria and one of the safest anti-malarial drugs. However, resistance of P. falciparum to proguanil has begun to emerge.
57. The specification states at [0004] that it is becoming standard practice to combat drug resistance with combinations, but many such combinations are antagonistic, resulting in less effective treatment and a complex dosing regimen. It is therefore said to be an object of the invention to provide a combination that is not antagonistic and does not require a complex dosing regimen.
58. The solution to this problem is said at [0005] to be the surprising finding that by combining atovaquone and proguanil, potentiation of anti-parasitic, and particularly anti-malarial activity, is achieved. Furthermore, a potentiating combination of atovaquone and proguanil can be simply presented in a single pharmaceutical formulation.
59. The specification goes on to say at [0007] that atovaquone and proguanil are administered in a "potentiating ratio" in the range of 1:1-1:3 of proguanil:atovaquone. It explains that the term "potentiating ratio" means a ratio at which the combination of the two drugs is synergistic ([0009]).
60. The specification states in [0020] that the combination "may conveniently be presented as a pharmaceutical formulation in unit dose form" and that "typical unit doses may contain for example 500 mg of atovaquone and 200 mg of proguanil or 500 mg of atovaquone and 500 mg of proguanil." There is no other reference to proguanil and atovaquone being used in a ratio of 2:5 other than in the tablet formulations of Example 2. None of the biological tests disclosed in the Patent utilises the combination in that ratio.
61. Example 1 describes a method for the preparation of atovaquone. Example 2 describes two "conventional pharmaceutical formulations" both of which contain 500 mg of atovaquone and 200 mg of proguanil. One is a film-coated tablet, the other a dispersible film-coated tablet.
62. Example 3 involves use of the in vitro technique described in paragraph 52 above to test the activity of atovaquone in combination with a range of other known anti-malarials. For this experiment, a starting solution of each drug was prepared at a concentration of 20-50 times its estimated IC50 ([0039]). Combination solutions of atovaquone and the partner drug were prepared by mixing these starting solutions in four ratios 1:5, 1:2, 2:1 and 5:1 ([0040]. It should be noted that the ratios described do not appear to be mass ratios, but represent instead the ratio of starting solutions used to prepare each combination. These were then tested against three malaria parasite strains: a multi-drug resistant clone W-2, a drug-sensitive but mefloquine resistant clone D-6 and an isolate resistant to atovaquone C2B ([0041]). Curiously, however, many of the drug combinations were only tested against one or two of these strains.
63. The results are set out in Table 1. Nothing is said about the reproducibility of the data or the significance of the numerical values recorded, but as the specification says at [0046], it can be seen that the best results are achieved with the atovaquone and proguanil combination. The results for tetracycline, proguanil and cycloguanil are as follows:

Drug	W-2	D-6	C2B
Tetracycline	1.27	1.11	0.02, -0.08
Proguanil	2.43, 2.88	2.56	2.56
Cycloguanil	2.21	1.66	0.13, -0.73

64. The specification goes on at [0047] to say that the "optimum ratio" of proguanil to atovaquone was estimated for each strain. These figures, which are set out in Table 2, range from 1:5 (C2B strain) to 4036:1 (D-6 strain). The values in Table 2 appear to be simply the ratios of the IC50s for proguanil and atovaquone for each strain.
65. Examples 4 and 5 relate to the activity of atovaquone and proguanil against Toxoplasma gondii. The data in Example 4 was obtained from a mouse model using proguanil and atovaquone in the ratio of 5:2 and 1:1. The ratios used in Example 5 (in vitro testing) were 1:1, 1:3 and 3:1.
66. Example 6 relates to the activity of atovaquone and proguanil in a mouse model of Pneumocystis pneumonia (PCP) in the ratio of 2:1 and 1:1.

The claims

67. Claim 1 is as follows:

"A combination of [atovaquone] and proguanil wherein the ratio of proguanil:[atovaquone] is 2:5."

68. The only other claim asserted by Wellcome to have independent validity is claim 9, which is as follows:

"A pharmaceutical composition comprising a combination according to claims 1 or 2 in association with one or more pharmaceutically acceptable carriers therefor."

69. There is no dispute as to the construction of these claims.

The skilled team

70. A patent specification is addressed to those likely to have a practical interest in the subject matter of the invention, and such persons are those with practical knowledge and experience of the kind of work in which the invention is intended to be used. The addressee comes to a reading of the specification with the common general knowledge of persons skilled in the relevant art, and he (or, once and for all, she) reads it knowing that its purpose is to describe and demarcate an invention. He is unimaginative and has no inventive capacity. In some cases, such as the present one, the patent may be addressed to a team of persons having different skills.
71. There is little dispute as to the skilled team to whom the Patent is addressed. The Claimants contend that it is directed to a team consisting of a clinician experienced in treating malaria, a clinical pharmacologist and a malaria biologist. Wellcome contend that it is directed to a team consisting of a clinician and a clinical pharmacologist, or a clinician with experience of clinical pharmacology with access to the expertise of a malaria biologist. There is no real difference between these formulations.

Common general knowledge

72. I reviewed the law as to common general knowledge in KCI Licensing Inc v Smith & Nephew plc [2010] EWHC 1487 (Pat), [2010] FSR 31 at [105]-[115]. That statement of the law was approved by the Court of Appeal [2010] EWCA Civ 1260, [2011] FSR 8 at [6].
73. There is little dispute that the skilled team would know all the information I have set out under the heading "technical background" as part of their common general knowledge. There are certain areas of dispute, however.

Potentiation/potentiating

74. The Claimants contend that the skilled team would understand the terms "potentiation" and "potentiating" to be synonyms for synergism and synergistic (i.e. having an effect greater than the sum of the parts involved). Wellcome contend that some people would have understood these in a looser sense which might include merely additive action. On the evidence I have no doubt that the Claimants are correct on this point.

Pyrimidine synthesis

75. The Claimants contend that it was part of the common general knowledge of the clinical pharmacologist that:

i) there was some evidence that the hydroxynaphthoquinones act by inhibiting electron transport at ubiquinone-sensitive sites in the malaria parasite. This inhibition is coupled to inhibition of dihydroorotate dehydrogenase (DHOR), which is necessary for pyrimidine synthesis.

ii) A combination of a hydoxynaphthoquinone (acting on the pyrimidine pathway) and a dihydrofolate reductase inhibitor (acting on the folate pathway) might be synergistic or might be additive.

76. Wellcome dispute that these matters were common general knowledge.
77. Although counsel for the Claimants got a measure of agreement from Dr Horton that these matters were common general knowledge, there is no evidence from either Prof Molyneux or Prof Hill to support this proposition. Still less is there any documentary evidence. I am therefore not satisfied that it has been shown that they were common general knowledge.

Limiting the spread of resistance

78. The Claimants contend that it was common general knowledge that the spread of resistance to a new drug can be limited (but not eliminated) by taking one of the following precautions:

i) restricting importation and distribution in an endemic country (as was recommended by the WHO to protect the efficacy of mefloquine in 1983);

ii) using the drug only as a second line anti-malarial;

iii) using the drug only for, say, complicated malaria (as was the case with quinine, which was reserved for such use in Africa); or

iv) using the drug only for travellers.

79. Counsel for Wellcome submitted that this contention was not open to the Claimants because it had not been advanced in Prof Molyneux's reports or in the Claimants' opening submissions. As counsel for the Claimants pointed out, however, these points emerged during Prof Molyneux's oral evidence (including in the passage quoted in paragraph 85 below) and were then put to Dr Horton in cross-examination. I would add that no objection was taken when Dr Horton was cross-examined about these matters.
80. Counsel for Wellcome also disputed that it had been shown that these matters were common general knowledge in any event. Having considered the evidence of the experts and the documentary materials relied on by counsel for the Claimants, however, I am satisfied that these matters were common general knowledge.

Combinations of anti-malarials

81. As I have indicated, there is little dispute that the general matters I set out in paragraphs 36-40 above were common general knowledge. Wellcome contend, however, that it is important to consider the common general knowledge of the skilled team concerning combinations in more detail, and specifically the circumstances in which the skilled team would have regarded it as appropriate to combine two drugs. I shall therefore do so here.
82. Additive combinations. As Prof Molyneux agreed, if drug A cures 70% of patients (the remainder having parasites with resistance to that drug) and drug B cures 80% (the remainder having parasites with resistance to that drug), then administration of both drugs would be expected, if the combination is additive, to cure 94% of patients. This demonstrates the potential advantage of combining drugs even where there is some resistance to both drugs and even in the absence of synergy.
83. Counsel for Wellcome put it to Prof Molyneux that, if a particular patient had a parasite that was resistant to drug A but sensitive to drug B, so that administration of the combination cured the patient, drug B could be said to be masking the deficiency of drug A. Prof Molyneux did not accept this, explaining that one would administer such a combination in circumstances where one was aware of the possibility or likelihood of resistance to drug A, but not if one knew that drug A was useless.
84. Counsel for Wellcome also put to Prof Molyneux a passage from an article by L. Donno, "Drug Combinations in the Treatment of Malaria", J. Chemotherapy, 1989, vol. 1 no. 1, 52-58, stating that "the main advantage of additive combinations is the prevention of plasmodial resistance, and their therapeutic use for strains that are already resistant to the more active drug is ostensibly irrational". As counsel for the Claimants pointed out, this passage must be treated with caution for at least three reasons. First, it was not suggested, let alone proved, that the article was a well-known one. On the contrary, it was published in a journal which Dr Horton did not read regularly. That may explain why it was not exhibited to, or referred to in, either of his reports. Secondly, it was not correct to say that the main advantage expected from an additive combination was the prevention of resistance. As I have already said, the other advantage expected was improved efficacy. Thirdly, the passage relied upon by counsel for Wellcome must be read in context. As counsel for the Claimants pointed out, the author worked for the pharmaceutical company Farmitalia Carlo Erba and, although he does not explain when he says that use of an additive combination is "ostensibly irrational", it may be presumed that he was considering widespread use of such combinations.
85. In any event, although Prof Molyneux was initially disposed to agree with the proposition I have quoted from Donno, in later evidence he made it clear that it did not accurately reflect his opinion:

"… I am not convinced that it needs to be synergistic in order to be useful especially -- here we have to consider the possibility that there are different uses for drugs and the spread of a resistant mutant is dependent upon being in a population. If you, for example, were trying to develop a drug for people who are not in a situation where they could spread their resistant parasites, then an additive combination might be sufficient. What is not killed by one is killed by the other, and then they get no further. It is better for that individual. There is no reason why resistance should be found -- either should develop initially or should particularly be spread in such individuals -- it depends. I think one has to bear in mind that there are different ways in which drugs can be deployed, and it is not only global large population deployment. As I have said, with quinine, we restrict it to the severely ill. You could restrict a drug to non-endemic areas, for example."

86. As both this passage and the evidence I have referred to in paragraph 82 above makes clear, there is nothing irrational about using an additive combination in appropriate circumstances, in particular where there is not complete resistance to either of the drugs and where use of the combination is controlled so as to limit the spread of resistance.
87. Prof Molyneux could not think of an example which would have been known to the skilled team in 1991 where an additive combination had demonstrably reduced the spread of resistance, but this does not detract from the point I have just made.
88. Synergistic combinations. In malaria research it was generally believed that, in order to be synergistic, the two drugs needed to act at consecutive points on the same pathway. A combination that was found to be significantly synergistic in vitro would encourage the skilled person to go forward to in vivo trials.

The prior art

89. The Claimants relied in their closing submissions on just two items of prior art. The principal item relied on is the first.

The Hutchinson presentation

90. On 13 February 1992 Dr Hutchinson presented a paper by Professor Sornchai Looareesuwan (of the Hospital for Tropical Diseases in Bangkok, Thailand), himself and J. Farquhar (also of Wellcome) entitled "Evaluation of the hydroxynaphthoquinone, 566C80, in the treatment of acute uncomplicated P. falciparum malaria" at the Fourth Malaria Meeting of the British Society of Parasitology held at the Natural History Museum in London.
91. There are a number of sources of evidence as to what Dr Hutchinson disclosed in his presentation:

i) The abstract which Dr Hutchinson prepared in advance of the meeting and which was included in the programme.

ii) The slides with which Dr Hutchinson illustrated his presentation.

iii) The text which Dr Hutchinson prepared for his own use. Although there are a number of versions of this, it is common ground that it is probable that the version he used was that exhibited as DBAH-3 to his first witness statement.

iv) Dr Hutchinson's own recollection.

v) A contemporaneous note made by Prof Bell. Prof Bell did not have an independent recollection of the presentation.

vi) The recollection of Prof Arnot, who did not make a contemporaneous note.

vii) A summary of the presentation by C.P.J. Ash in a report of the meeting published in Parasitology Today, vol. 8 no. 8, 1992, 252-255.

viii) A summary of the presentation which was published in R & D Focus News on 24 February 1992.

92. Although there is much common ground as to what Dr Hutchinson disclosed, there are also a couple of disputed points. Taking all of the evidence into account, my findings are as follows.
93. Dr Hutchinson began by saying that the hydroxynaphthoquinone atovaquone, previously designated 566C80, was a stable analogue of a chemical series that has been noted for its anti-malarial activity since the early 1940s. He then gave a brief summary of the chemistry of atovaquone and of the promising results of in vitro, animal and Phase I clinical studies with the compound. These had shown that the predicted therapeutic profile was obtained with a single 225 mg dose.
94. On the strength of these results, a single 500 mg dose was selected for evaluation in an open Phase II study in the UK. All 10 patients were cleared of their initial parasitaemia, but six recrudesced three weeks later. The conclusion drawn from this was that insufficient drug had been given to effect a radical cure. Accordingly, a second study was carried out in Bangkok using a schedule of four doses of 750 mg taken at eight hour intervals. All 25 patients were cleared of their initial parasitaemia, but seven recrudesced between day 14 and day 25. On the basis that this might be explained by inadequate duration of therapy, a further cohort of patients was treated with 750 mg three times daily for seven days. All 23 patients were cleared of their initial parasitaemia, but nine still recrudesced.
95. Dr Hutchinson and his colleagues deduced from the fact that two of the recrudescent patients in the third trial had an R2 response following re-treatment with atovaquone, and from in vitro susceptibility studies on paired isolates from six of the recrudescent patients in the second trial, that resistance to atovaquone, whether through selection or induction, must be at least part of the explanation for the recrudescence. They also concluded that atovaquone was not appropriate as a single entity for the treatment of P. falciparum malaria.
96. This led them to try combination therapy. Tetracycline and proguanil were selected as candidates for co-administration with atovaquone. Dr Hutchinson's text states that this was "on the basis of in vitro potentiation studies", and Dr Hutchinson's evidence was that he thought that that is what he would have said. Prof Bell's note records Dr Hutchinson as saying "best in vitro potentiation", and he believed that that was what Dr Hutchinson had actually said.
97. Wellcome relies on the fact that, in the abstract, Dr Hutchinson merely stated that the combinations were "additive", but the audience would have appreciated that the abstract had been prepared in advance and thus may not have reflected the most up-to-date-information available to Dr Hutchinson by the time of the presentation. Furthermore, some members of the audience might not have read the abstract.
98. There is no other evidence other than Prof Bell's note to suggest that Dr Hutchinson said that potentiation had been shown in vitro, but nevertheless Prof Bell's note is the best evidence as to what was said, or at least understood by him. The conclusion I draw is that the words Dr Hutchinson actually used were those in his text, but that he was understood by the audience to mean that the combinations of atovaquone with tetracycline and proguanil gave the best in vitro potentiation of the combinations studied.
99. In the combination trials four doses of 750 mg atovaquone at eight hourly intervals was combined with 250 mg of tetracycline at six hourly intervals for seven days and with 200 mg of proguanil daily for seven days.
100. Dr Hutchinson said that the results were dramatic. The atovaquone/ tetracycline combination effected a radical cure in all 25 patients treated. The atovaquone/proguanil combination effected a radical cure in 20 patients out of 24 patients with 28 day follow up. Three patients had been lost to follow up after 28 days and one patient had recrudesced, having vomited on three occasions during the first 24 hours of treatment. According to the slide accompanying this part of the presentation, there were six unknowns, suggesting that an additional three patients had not yet completed the 28 day follow up.
101. In all the studies atovaquone alone and in combination with tetracycline or proguanil had been well tolerated.
102. Dr Hutchinson ended his presentation with the following four conclusions:

i) Recrudescences precluded the use of 566C80 (i.e. atovaquone) alone in the treatment of falciparum malaria.

ii) Co-administration of tetracycline or proguanil overcame the problem of recrudescence.

iii) All patients had been cleared of their initial parasitaemia and fever within an acceptable time-frame.

iv) Further dose ranging studies of combination therapy were clearly justified.

103. Following Dr Hutchinson's talk, there were questions and comments from the audience. Dr Hutchinson's recollection was that he was bitterly disappointed at how poorly the presentation was received: a number of comments were made which challenged his conclusion that atovaquone recrudescence could be overcome by combining it with tetracycline or proguanil. Reference was made to the small numbers of patients in the combination studies and to the absence of controls. Furthermore, the rationale for combining atovaquone with proguanil was questioned. Prof Arnot's recollection was similar.
104. The report in R & D Focus Drug News summarised the presentation as follows:

"It appears that atovaquone/tetracycline and atovaquone/proguanil combination therapy overcomes the problem of recrudescence encountered in previous trials using atovaquone alone.

In recent trials, radical cures were achieved in all 25 patients given atovaquone with tetracycline and in 20 of the 27 patients given atovaquone and proguanil. The treatment is well-tolerated and no dose-related clinical effects have been observed."

105. Ms Ash summarised the presentation in her report as follows:

"Despite initial parasite clearance, about 25% of patients [treated with atovaquone] suffered a recrudescence 14-28 days later. …. Combination therapy with tetracycline or proguanil was used very effectively on these patients, with atovaquone plus proguanil resulting in near zero recrudescence rates. Ideally, something other than a prophylactic drug like proguanil should be used in such regimens."

The Hudson abstract

106. On 8 July 1992 Dr A.T. Hudson of Wellcome gave a plenary lecture entitled "Atovaquone – a novel agent for the treatment of malaria, PCP and toxoplasmosis" at the First International Symposium on Recent Advances in the Chemistry of Anti-Infective Agents held at Churchill College, Cambridge. Dr Hudson prepared an abstract of the lecture which was included in the conference programme ("the Hudson abstract"). The Claimants rely upon the Hudson abstract, but not the lecture itself.
107. The Hudson abstract is sufficiently short to quote in full:

"Atovaquone is a novel hydroxynaphthoquinone with clinical activity against malaria and the AIDS – associated diseases, PCP and toxoplasmosis. The compound resulted from a programme of research designed to produce a hydroxynaphthoquinone which would have potent activity towards the human malaria parasite Plasmodium falciparum and be resistant to metabolism in man. Derivatives of 2-cyclohexyl-3hydroxy-1, 4-naphthoquinone were synthesised with the metabolically labile 4'-position of the cyclohexyl ring blocked by various substituents. Compounds were assayed for antimalarial activity against P. falciparum in vitro and for metabolic stability using human liver microsome preparations. Atovaquone, 2-[trans 4'-(4-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone has outstanding potency towards the human parasite (IC₅₀ ca. 1nM) and unlike previous members of the series was totally resistant to metabolism.

In healthy volunteers atovaquone was well tolerated, had a plasma half-life of ca. 70 hours and was not degraded to any extent. Clinical studies were carried out in Thailand in patients with P. falciparum infections. The drug rapidly relieved clinical disease symptoms giving an overall cure rate of 75%. In combination with either proguanil or tetracycline this increased to 100%.

Because PCP and toxoplasmosis respond to various anti-protozoal agents, atovaquone was tested in animal models of these diseases and in vitro against the causative agents Pneumocystis carinii and Toxoplasma gondii. Although less potent than in the malaria assays the compound was sufficiently active to warrant clinical investigation. In trials in AIDS patients with mild to moderate PCP, atovaquone achieved a 79% cure rate and was considerably less toxic than established therapies. Encouraging clinical responses with minimal side effects have also been observed against toxoplasmosis in AIDS patients who have failed or were intolerant of standard therapies.

The clinical evaluation of atovaquone is continuing in order to optimise dosing schedules, formulations etc. but all indications to date are that the compound will find a role in the clinical management of malaria, PCP and toxoplasmosis."

Obviousness

The law

108. The familiar structured approach to the assessment of allegations of obviousness first articulated by the Court of Appeal in Windsurfing International Inc v Tabur Marine (Great Britain) Ltd [1985] RPC 59 was re-stated by Jacob LJ in Pozzoli v BDMO SA [2007] EWCA Civ 588, [2007] FSR 37 at [23] as follows:

"(1)(a) Identify the notional 'person skilled in the art';

(b) Identify the relevant common general knowledge of that person;

(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;

(3) Identify what, if any, differences exist between the matter cited as forming part of the 'state of the art' and the inventive concept of the claim or the claim as construed;

(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?"

109. The correct approach to the fourth step in a case such as the present was recently summarised by Kitchin LJ, with whom Lewison and Moore-Bick LJJ agreed, in MedImmune Ltd v Novartis Pharmaceuticals Ltd [2012] EWCA Civ 1234 as follows:

"90. One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research.

91. For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way. Lord Hoffmann summarised the position in this way in Conor at [42]:

'In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case.'

92. Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck, [2008] EWCA Civ 311, [2008] RPC 19, at [24] and in Conor [2008] UKHL 49, [2008] RPC 28 at [42], Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck:

'The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success.'

93. Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim…."

110. What matters is whether or not the invention was technically obvious, not whether it was commercially obvious: see Hallen Co v Brabantia (UK) Ltd [1991] RPC 195 at 213 (Slade LJ). This does not necessarily mean that commercial considerations are irrelevant. The mindset of the skilled person may be conditioned by commercial considerations only to consider certain types of technical solutions, as in Dyson Appliances Ltd v Hoover Ltd [2002] RPC 22.
111. The primary evidence as to obviousness is that of properly qualified experts and secondary evidence needs to be kept in its place: see Mölnlycke AB v Procter & Gamble Ltd [1994] RPC 49 at 112-114 (Sir Donald Nicholls V-C). Nevertheless there are cases in which secondary evidence is important: see Schlumberger Holdings Ltd v Electromagnetic Geoservices AS [2010] EWCA Civ 819, [2010] RPC 33 at [76]-[85] (Jacob LJ).
112. In assessing whether a claimed invention is obvious, it is always important, although difficult, to avoid hindsight. The fact that, after the event, it is easy to see how the invention could be arrived at by starting from an item of prior art and taking a series of apparently simple steps does not necessarily show that it was obvious at the time: British Westinghouse Electric & Manufacturing Co Ltd v Braulik (1910) 27 RPC 209 at 230 (Fletcher Moulton LJ), Non-Drip Measure Co Ltd v Strangers Ltd (1943) 60 RPC 135 at 142 (Lord Russell) and Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346 at 362 (Lord Diplock).

The skilled team and the common general knowledge

113. I have identified these above.

The inventive concepts of claims 1 and 9

114. The inventive concept of claim 1 is a combination of atovaquone and proguanil in the ratio 5:2. The inventive concept of claim 9 is a pharmaceutical composition comprising such a combination.

Differences between claim 1 and the Hutchinson presentation

115. It is common ground that the only difference between claim 1 and the Hutchinson presentation is that the presentation did not disclose the ratio of 5:2.

Obviousness of claim 1 over the Hutchinson presentation

116. As counsel for the Claimants pointed out, Wellcome do not contend that there is any technical significance in the ratio 5:2. Thus the only feature which confers novelty in respect of claim 1 is not itself said to involve an inventive step. That in itself does not mean that claim 1 is obvious. What it emphasises, however, is that the issue is whether it would be obvious to proceed with the combination of atovaquone and proguanil at all.
117. The Hutchinson presentation not only disclosed the combination of atovaquone and proguanil for the treatment of malaria, but also disclosed apparently encouraging trial results for that combination and positively advocated further development of it. Accordingly, the Claimants contend that it would have been entirely obvious to the skilled team to take the development of the combination forward to the next step, namely dose-ranging studies (i.e. Phase 2b) preparatory to a full Phase 3 trial.
118. As counsel for the Claimants accepted, however, the law does not deem the skilled person to assume that the prior art has any relevance to the problem he is addressing or require him to take it forward. Having considered it, he may conclude that it is simply not a worthwhile starting point and so put it to one side: see Eli Lilly and Co v Human Genome Sciences Inc [2008] EWHC 1903 (Pat), [2008] RPC 29 at [295] (Kitchin J) (a point unaffected by the decisions of the Court of Appeal and Supreme Court in that case). Wellcome contend that this is such a case. It is therefore necessary to consider the reasons why Wellcome say that the skilled team would not proceed with the development of the combination of atovaquone and proguanil.
119. Atovaquone was not suitable for use on its own. The skilled team would note that, although atovaquone on its own had initially cleared parasitaemia from 54 out of 54 patients, it had a recrudescence rate of between 28% and 60%. Accordingly, it is common ground that the skilled team would agree with Dr Hutchinson that it should not be used on its own. Wellcome do not suggest that this in itself would put the skilled team off developing the combination, but contend that it forms an important part of the background against which the skilled team would consider whether to develop the combination. I agree with this.
120. The combination trial was small, uncontrolled and incomplete. The skilled team would note that the combination of atovaquone and proguanil achieved a radical cure in 20 out of 21 patients for whom results were available, with six unknowns. No control is reported with proguanil alone (nor with tetracycline). In his reports Dr Horton opined that the small number of patients, absence of any control and incomplete state of the study would discourage the skilled team from pursuing the combination. In cross-examination, however, he accepted that the skilled team would appreciate that the trial was a proof of concept study and a first clinical trial, which would account for the small number of patients and lack of controls. As for the trial being incomplete, I did not understand there to be any real dispute between the experts that, while the skilled team would prefer to have complete data, the skilled team would be able to form a view based on the available data.
121. What about the patient who recrudesced? The skilled team would note that he or she had vomited three times during the first 24 hours. The Claimants contend that the skilled team would be uncertain whether he or she had received a full dose. Wellcome contend that the skilled team would expect the patient to have been re-dosed, since that was usual practice after vomiting, and in any event to conclude that that the patient had probably received the whole of one out of four doses of atovaquone. In my view the skilled team would certainly not ignore the fact that one patient had recrudesced, but nor would they ignore the fact that one could not be certain that that patient had received anything like the intended dose.
122. No disclosure of synergism. Wellcome contend that there was no disclosure of synergy in the Hutchinson presentation, whereas the Claimants contend that there was such a disclosure. There are three aspects to this debate. The first is what Dr Hutchinson said about the in vitro studies. I have concluded that the words Dr Hutchinson actually used were those contained in his notes, but that he would have been understood by the audience to mean what Prof Bell recorded in his note. It follows that the skilled team would have understood that synergy had been demonstrated in vitro.
123. The second aspect is the in vivo results. It is common ground that Dr Hutchinson did not say that these demonstrated synergy. It was Prof Molyneux's evidence, however, that the contrast between the results obtained with the combination and those obtained with atovaquone alone would have suggested to the skilled team that the combination might be synergistic, particularly once it was borne in mind that they would not expect very good results from proguanil alone. For his part Dr Horton accepted that the results provided some evidence of synergy. The witnesses were agreed that the results did not actually demonstrate synergy, however.
124. The third aspect is that the Claimants contend that the skilled team would appreciate from their common general knowledge that a combination of a hydroxynaphthoquinone such as atovaquone and a DHFR inhibitor such as proguanil might be synergistic. This has not been proved to be common general knowledge, however.
125. My overall conclusion is that, although there was no express disclosure of synergy by Dr Hutchinson, the skilled team would have understood that synergy had been demonstrated in vitro and would have concluded that the in vivo results also provided some evidence of synergy.
126. Difficulties in testing for synergy. Wellcome contend that, if the skilled team thought that there was a possibility of synergy, they would need to carry out a proper in vitro test to construct an isobologram, but would encounter difficulties. The expert evidence does not establish, however, that the skilled team would necessarily carry out further in vitro tests before proceeding to a Phase 2b trial. In any event, I am unimpressed with the supposed difficulties.
127. First, it is suggested that it would be difficult to obtain an atovaquone-resistant strain of parasite. There are two answers to this. The first is that the skilled team could use a multi-drug resistant strain such as W-2, which was an established laboratory strain. The second is that the skilled team could isolate a resistant strain from patients treated with atovaquone. That would take some time and effort, but there is no evidence that it would have been technically difficult.
128. Secondly, it is suggested that the skilled person would test cycloguanil rather than proguanil. The significance of this is that it is now believed that the synergy between atovaquone and proguanil is attributable to a property of proguanil rather than cycloguanil. Again, there are two answers to this. The first is that, while Dr Horton's evidence establishes that the skilled team would probably include cycloguanil in the test, it does not establish that they would not include proguanil. It may be noted that Table 1 in the Patent includes both, and there is no evidence that the inventors were idiosyncratic in adopting that approach. The second is that, as Table 1 shows, if the skilled team tested against the W-2 strain, they would find good synergy with both proguanil and cycloguanil. (The same goes for D-6.)
129. The combination was irrational if merely additive. Wellcome contend that the skilled team would consider it irrational to combine atovaquone and proguanil if the combination was merely additive. For the reasons given above, I do not accept that the skilled team would approach the Hutchinson presentation with the preconception that it would be irrational to combine drugs if the effect was merely additive. On the contrary, the skilled team would be aware that, in general, additive combinations offer potential advantages.
130. Dr Horton's view was that the skilled team would be concerned that, given that resistance to atovaquone had been found to exist even in the first trials, increasing resistance to atovaquone might lead to rapid disappearance of efficacy. He accepted, however, that, if the combination was reserved for second line therapy or used only for complicated malaria or for travellers, it would be a valuable addition to the hard-pressed armamentarium of drugs for treating malaria.
131. Other avenues of research. Wellcome rely on the fact that there were many other avenues of research that the skilled person could pursue. Two particular suggestions were made.
132. The first is that the way forward would be to see if it was possible to design around the apparent innate resistance to atovaquone. That would involve first trying to learn more about the cause of the recrudescence by testing in vitro against different strains of parasite from different locations with a view to identifying the biochemical pathways, enzymes and mutations involved. As Dr Horton accepted, this would be a potentially lengthy and challenging research programme with an uncertain outcome, since the skilled team might not be able to establish the cause of the resistance. By contrast, proceeding to a Phase 2b trial of the combination would be much quicker and simpler, and would offer a much greater promise of success.
133. The second is that the skilled team could pursue other avenues of research altogether, such as halofantrine and the artemisinins. But that would mean writing off the potential of atovaquone in combination with proguanil entirely. Wellcome have not identified any specific line of research that the skilled team with knowledge of the Hutchinson presentation would expect to offer a greater prospect of success.
134. Commercial factors. It is common ground that relatively few pharmaceutical companies were active in the development of anti-malarial drugs in 1992. This was because it was perceived that malarial drugs were not profitable, given the low purchasing power of developing countries and the relatively small number of travellers from developed countries to endemic areas. This was exacerbated by concerns that resistance would mean that a new drug might have a limited shelf-life if used on a large scale and that tailoring drugs to specific situations would be uneconomic.
135. Counsel for Wellcome suggested that these were factors which would have coloured the thinking of the skilled team. I do not accept this. These factors are purely commercial, not technical. The development of anti-malarials was not a field in which the mindset of the skilled person had become conditioned by commercial considerations to exclude certain kinds of technical solutions from consideration.
136. The experts' overall opinions. Prof Molyneux's opinion was that the skilled person would consider the combination to be one which should be taken forward. Indeed, he said that it would have been irresponsible not to do so. Counsel for Wellcome relied upon a passage of cross-examination in which Prof Molyneux went some way to agreeing that the idea that the combination was going to be a useful therapeutic was one of hope rather than expectation. As Prof Molyneux explained, however:

"…. there is quite a fuzzy margin, border, between those two. When you are in a situation where people are really worrying about us having no drugs to treat malaria, then that border between hope and expectation might be stretched a bit. In other words, you would pursue something on the basis of hope, even if your expectations were not 100% high."

137. Although in his reports Dr Horton discussed the technical matters I have considered above, it became clear in cross-examination that his main reason for thinking that the skilled team would not pursue the combination was that it would be difficult to convince a large pharmaceutical company to spend the money required to progress matters on the basis solely of the Hutchinson presentation. In particular, a substantial amount of work would be required to establish the safety and efficacy of the combination ahead of any further clinical trials. This point was not mentioned in either of Dr Horton's expert reports, nor was it put to the Claimants' experts. In any event, the skilled person would have no reason to suppose that the combination would be toxic or otherwise unacceptable. On the contrary, the Hutchinson presentation disclosed that the combination had been well tolerated, albeit in a small study. Furthermore, although such toxicology and pharmacology studies would be time-consuming and expensive, they would not be technically challenging.
138. Leaving aside the commercial aspect, Dr Horton accepted that carrying out a larger trial would be straightforward, that the skilled team would expect the same or similar cure rates in such a trial, and that if the combination proved successful it would be a valuable addition to the armoury.
139. Thus the expert evidence does not establish that technical considerations would lead the skilled team not to pursue the combination of atovaquone and proguanil. On the contrary, it establishes that, from a technical perspective, the skilled team would consider that the combination was well worth developing further.
140. Secondary evidence: reactions of the audience. Wellcome rely upon the reactions of the audience at the Hutchinson presentation as constituting powerful secondary evidence that it was not obvious to develop a combination of atovaquone and proguanil. Wellcome also rely on the fact that Dr Hutchinson's presentation received a similar reaction when he repeated it at a meeting of the Wellcome-Mahidol-Oxford Tropical Medicine Research Unit on 21 February 1992.
141. I agree that this is important evidence, and that it does provide some support for the proposition that the skilled team would not have pursued the combination of atovaquone and proguanil. Nevertheless I am not persuaded that it gets Wellcome home. In my judgment, the audience were simply behaving as good scientists do, and considering Dr Hutchinson's presentation critically. I think it is clear from Dr Hutchinson's and Prof Arnot's evidence that the reason why the questions and comments were somewhat negative was that the audience considered that Dr Hutchinson had overstated the conclusions to be drawn from the data.
142. The most significant point in Wellcome's favour is that the rationale for combining atovaquone with proguanil was questioned. I consider, however, that Ms Ash's report accurately reflects the tenor of the discussion, namely that ideally some other drug should be used in combination with atovaquone. As Prof Molyneux pointed out, the skilled team would appreciate that the speculative possibility that there might be a better combination should not be allowed to prevent the development of something which was very promising. No other candidate was identified in the discussion, although the next presentation at the meeting reported some other work that a colleague of Dr Hutchinson's had been doing on possible potentiators.
143. Secondary evidence: commercial success. Wellcome also rely upon the commercial success of Malarone as secondary evidence of non-obviousness. There is no dispute that Malarone has been commercially successful. It is unnecessary to go into the details, which are confidential. Counsel for the Claimants submitted that the commercial success of Malarone was irrelevant for two reasons. First, this was not a case in which it was pertinent to ask, "if it was obvious, why had it not been done before?". The Hutchinson presentation was only nine months before the priority date of the Patent. Secondly, atovaquone was itself the subject of patent protection, and therefore no one other than Wellcome could have developed the combination. I accept those submissions.
144. Conclusion. In my judgment, the skilled team would not have concluded that the combination of atovaquone and proguanil was not worth pursuing. On the contrary, they would have concluded that it was worth taking forward. There was an urgent need for new anti-malarials. Dr Hutchinson's presentation disclosed a combination which showed promising results, albeit in a small number of patients and in an uncontrolled and incomplete study. It would have been straightforward to carry out a larger trial. The skilled team would have expected to achieve similar cure rates in such a trial. In short, the skilled team would have agreed with Dr Hutchinson that a Phase 2b trial was justified. That would have led them to an appropriate ratio of the drugs. It follows that claim 1 was obvious.

Independent validity of claim 9

145. Counsel for Wellcome relied upon an answer from Prof Molyneux that, at this stage of the research, it would be premature to consider co-formulating atovaquone and proguanil as showing that claim 9 was independently valid. On the other hand, Prof Molyneux gave unchallenged evidence that the design of the Phase 2b trial would be a matter of discussion between the clinician and the pharmacologist. Prof Hill's unchallenged evidence was that the skilled pharmacologist would consider it sensible to conduct even Phase 2b trials with co-formulated medication if at all possible.
146. Furthermore, both Prof Molyneux and Prof Hill gave unchallenged evidence that the ultimate goal of the skilled person developing the combination of atovaquone and proguanil as an anti-malarial would be a co-formulated combination which offered a simple dosing regimen and therefore maximum patient compliance. Dr Horton's evidence was that the skilled person would only consider developing a co-formulated product once efficacy had been proven in the clinic. It is implicit in this statement that, once efficacy had been proven in the clinic, the skilled person would consider co-formulating the combination.
147. I therefore conclude that it was obvious to develop a pharmaceutical composition containing a combination of atovaquone and proguanil for use in the treatment and/or prophylaxis of malaria. It follows that claim 9 is invalid.

Obviousness over the Hudson abstract

148. Given my conclusions in relation to the Hutchinson presentation, I will deal with this briefly.
149. The Hudson abstract discloses the chemistry of atovaquone, its high in vitro potency against the malaria parasite, its metabolic stability, its good tolerability and its efficacy in clearing initial parasitaemia. It discloses the combination of atovaquone with proguanil, the fact that that combination had produced a cure rate of 100% against P. falciparum infections in clinical trials and that clinical trials of the combination are continuing. It also discloses that the author considers that all indications are that atovaquone will find a role in the clinical management of malaria.
150. Both experts were agreed that the skilled team would be interested in the information that a combination of atovaquone and proguanil had produced a cure rate of 100% in clinical trials.
151. Prof Molyneux's written evidence was that, while the skilled team would ordinarily wish to see the data underlying that figure, the skilled team would not be deterred from wishing to move forward by the absence of the underlying data. On the contrary, they would consider this a project worth proceeding with. In cross-examination, he said that, presented with the abstract alone, the skilled team would try to obtain the underlying data. He did not say that, if such information was unavailable, the skilled team would simply discard the abstract despite their interest.
152. Dr Horton accepted that the skilled person would have no reason to doubt that Wellcome had in fact achieved a cure rate of 100%. He also accepted that there was sufficient information to warrant the skilled team replicating what Wellcome were doing, but said that there would be a need for considerable "back-winding", including in vitro work. When pressed on why the skilled person could not simply design a Phase 2b trial on the strength of the information in the document, it became evident that Dr Horton's focus was on the approach taken by "big pharma". He accepted that "small pharma" might simply seek to replicate what Wellcome were doing.
153. It is therefore clear that the skilled team faced no technical obstacle in replicating Wellcome's work as reported in the Hudson abstract. As the experts were agreed that the skilled person would consider the project worthy of further development, it follows that claim 1 is obvious over the Hudson abstract.
154. I would add that it is Wellcome's case that the skilled team would find out that the data referred to in the Hudson abstract were those in the Hutchinson presentation and would obtain that data. Even if that is correct, that would not lead the skilled team to the conclusion that the combination of atovaquone and proguanil should not be pursued for the reasons given above.
155. Claim 9 is also obvious over the Hudson abstract for similar reasons to those I have given in relation to the Hutchinson presentation.

Conclusion

156. The Patent is invalid and must be revoked.