Omnipharm Ltd v Merial

European Patent (UK) No. 0 881 881 and UK Patent No. 2 317 564 which are the subject of this action (“the patents”, or “881” and “564” respectively) both relate to treatments for protecting pets or small mammals from fleas. By this action Omnipharm Limited seek revocation of the patents and certain declarations of non-infringement in respect of flea treatments which they claim that they plan to sell. Merial, the proprietors of the patents, have responded by making unconditional offers to amend.

Herman Melville wrote: “To produce a mighty book, you must choose a mighty theme. No great and enduring volume can ever be written on the flea, though many there be who have tried it.” By raising multiple issues on each side, both parties have tried to induce me to make another attempt in the latter tradition, an inducement I will try to resist. Henry Carr QC and Thomas Mitcheson argued the case for Omnipharm; Andrew Waugh QC and Thomas Hinchliffe argued the case for Merial.

Both patents are attacked on the grounds of obviousness and insufficiency. Added matter objections arise in relation to certain of the amendments. The UKIPO has raised a possible objection, not pursued by Omnipharm, to one of the amendments. The substance of the non-infringement points is no longer in issue. There is an issue, which now only goes to costs, as to whether Omnipharm have the necessary standing to seek a statutory declaration of non-infringement.

Each side called two expert witnesses: one veterinarian/parasitologist and one formulator. In addition, Omnipharm called its solicitor, Mr Ralph Cox, and Mr Donnelly, its sole director and shareholder.

Omnipharm’s veterinary/parasitologist expert was Mr Peter Watson. Mr Watson worked in a mixed (large and small) animal practice from 1975 to 1979, after which he joined Bayer Animal Health in the UK, where he worked until 2002. In that time he occupied the roles of Veterinary Advisor, Veterinary Technical Manager and Registration and Development Manager. Since 2002 he has operated his own consultancy company. Over the years his work involved him in various aspects of insecticides for both large and small animals.

Mr Waugh submitted that Mr Watson was unduly influenced by his experience at Bayer. Whilst it is true that his expert report did refer on occasions to unpublished work at Bayer, I am satisfied that this was done to show that Bayer’s activities reflected views which would be possessed by an average person skilled in the art. Mr Watson did his best to put himself in the position of a veterinary parasitologist without any special knowledge internal to Bayer. If one is too critical of the fact that witnesses have a background in industry with one or more companies, we will be left with those with no industrial experience at all. That is undesirable in a field concerned essentially with industry.

Dr Ken Walters was called as Omnipharm’s formulation expert. In 1974 he obtained a degree-equivalent qualification, membership of the Institute of Biology, whilst employed by ICI Limited. He obtained a PhD in 1979. From 1978 to 1980 he completed a postdoctoral fellowship at the University of Michigan where he gained experience in drug delivery into and through the skin and its appendages (such as hair follicles). From 1981 to 1986 he was employed by Fisons Pharmaceuticals Limited where he established a section concerned with skin drug delivery. From 1986 he worked for Kodak as a transdermal delivery scientist, and thereafter for Controlled Therapeutics Limited. In 1988 he formed Pharmaserve Limited, a contract research company, where he specialised in percutaneous absorption. Whilst at Pharmaserve he carried out some research for the predecessor of Merial, Rhone-Mérieux, to which I will come in due course. Thereafter, in 1992, he joined An-eX, a company specialising in the percutaneous absorption field. Professor Jonathan Hadgraft, Merial’s formulation expert, is a joint owner with Dr Walters, of An-eX. Dr Walters has authored and edited a number of textbooks on percutaneous absorption including a 1993 textbook “Pharmaceutical Skin Penetration Enhancement” which he co-edited with Professor Hadgraft.

Dr Walters undoubtedly is and was a leading figure in the field of delivery of drugs through the skin. In a section of his closing argument directed at the various witnesses, Mr Waugh criticised Dr Walters for some of the evidence he gave about the theory of non-systemic distribution, and other matters. Whilst I shall have to analyse that evidence in due course, I do not doubt that the views which Dr Walters expressed were genuinely held. My task is to assess the extent to which those views represented those of the ordinary and unimaginative skilled formulator.

Merial called Professor Michael Dryden as its veterinary/parasitology expert. Professor Dryden is a Distinguished Professor of Veterinary Parasitology at Kansas State University. He qualified as a veterinarian in the United States in 1984 and was employed in private practice in Kansas from 1984 to 1986 which prompted him to pursue academic research into the study of the flea. This led to an MS in 1988 and a PhD in 1990. He has published widely on flea biology. Since 1990, in addition to his academic work, he has acted as a consultant to the pharmaceutical industry. He was involved in a technical capacity in the launch of Merial’s Frontline products in Europe and the United States. He is such a leading figure in this field that he has become nicknamed, as he recognised, “Dr Flea”. I consider that he was a frank and helpful expert witness: Mr Carr did not submit otherwise.

Professor Hadgraft is an Emeritus Professor of Biophysical Chemistry at the School of Pharmacy, University of London. His PhD from the University of Oxford involved the application of physical chemistry to an understanding of interfacial transfer and skin penetration. He has held a number of academic appointments, including a chair in Pharmaceutical Chemistry at the University of Cardiff from 1984. He has worked primarily in the field of delivery of drugs through the human skin. He too has acted as a consultant to a number of pharmaceutical companies.

Professor Hadgraft struck me, by and large, as a very rigorous scientist, who seeks out the evidential base for any given scientific proposition. Mr Carr said that he was not representative of the ordinary skilled person because he did not accept that a spot-on topical formulation could be delivered non-systemically. As I shall explain, I accept that Professor Hadgraft’s view on this issue would not be held by the ordinary skilled formulator, but again I have no doubt that it was genuinely held. Mr Carr went on to say that Professor Hadgraft gave evidence which was inaccurate and lacked objectivity. There were occasions when Professor Hadgraft’s answers were rather combative and inadequately thought out. He sought to explain the fact that companies advertised their products as “non-systemic” on the basis that it was suggesting that the compound was non-systemic with respect to the flea. This was certainly a peculiar suggestion. He also made assertions as to the similarity of human and animal skin which were shown not to be justified. I have treated his evidence with a degree of caution as a result, endeavouring to judge the extent to which his evidence is supported by documents.

Mr Cox was cross-examined about the notes he prepared of a conversation with Professor Hadgraft, with which I deal below. His evidence was careful and considered. Mr Waugh said he had not kept a note of every word that was said on the telephone. That is not a criticism of Mr Cox, nor could it be of anyone.

Mr Donnelly was called to deal with Omnipharm’s standing to seek a declaration of non-infringement. He was a loquacious witness. His evidence at times was unsatisfactory, as for example when he answered a question put to him on Omnipharm’s financial affairs by saying “I am happy to accept that whatever you say is correct”. This was not an appropriate attitude to giving evidence on oath, or assisting the court. As a result I have treated his evidence with caution. That is not to say that I should reject the whole of his evidence.

Fleas are classified as ectoparasites, as they inhabit the exterior of the host animal. For present purposes it is sufficient to focus on fleas.

Flea saliva is highly allergenic. Constant exposure to flea bites leads to flea allergic dermatitis or FAD. Fleas can also spread disease. Their safe elimination is therefore an important priority for animal owners and vets.

The life cycle of the adult flea starts with the adult female flea taking a blood meal from the host, mating and laying small, non-sticky eggs on the host. The eggs fall from the host into the environment, together with flea faeces which contain partially digested blood and which provide a food source for the hatching larvae. The larvae crawl into dark areas such as under furniture or in carpets and continue to feed on organic debris. After a period of dormancy the larvae hatch into recognisable fleas, which are then capable of re-infesting the host animal.

A chemical agent for killing parasites is called a parasiticide, leading to the term “ectoparasiticide” for ectoparasites. Historically, the use of many compounds as ectoparasiticides has been discontinued when concerns about toxicity were raised. This was the fate of DDT and lindane. Organophosphorus compounds were popular as parasiticides after World War II and were still in use in 1995. Synthetic pyrethroids, chemically enhanced versions of the natural insecticide found in the pyrethrum plant, became available in the 1960s and were in use in 1995. Examples of this class are permethrin and cypermethrin.

Two new classes of parasiticide emerged in the 1980s. These were neo-nicotinoids and pyrazoles. Fipronil, the active ingredient of relevance in this case is a pyrazole.

Parasiticides can be divided into adulticides and insect growth regulators or IGRs. Adulticides, as the name suggests, kill adult insects. The classes of compound mentioned above are examples of adulticides. IGRs, by contrast, interfere with the normal development of insects. Accordingly immature fleas treated with an IGR do not grow into adults with reproductive ability. IGRs take longer to act than adulticides. They may be used to treat the environment in which the animal resides, as well as the animal itself. The object is to break the life-cycle of the flea and prevent re-infestation. A well known example of an IGR used on animals to aid flea control was methoprene. It has been sold in a combined treatment with a pyrethroid called Ovitrol Plus.

A parasiticide may be described as having a “knock down effect”, which implies rapid activity in killing insects and “persistence” which reflects its ability to maintain its activity over the following days and weeks. To be effective a parasiticide must be distributed over the whole of the animal’s body.

The main methods of parasiticide application to animals were (in no particular order): sprays, dips, shampoos, collars, spot-ons and pour-ons. I consider spot-ons and pour-ons in more detail below.

The other methods of application had some drawbacks to which the evidence drew attention. Sprays were less convenient to apply than spot-ons and pour ons, as the use of the spray requires multiple actions by the user. In addition small animals did not like the application of a spray, and attempted to escape.

Merial’s product Fipronil was launched as Frontline spray in France in 1994. The product was sold as a pump action spray, and the dog or cat would be sprayed all over so as to wet the coat. It rapidly became recognised as a very effective product, better than anything else on the market. Mr Watson accepted that it damaged the position of the permethrin spot-on when launched.

An important distinction for the purposes of this case is that between systemic and non-systemic distribution of the parasiticide. Systemic distribution implies that the parasiticide is distributed through the bloodstream of the host animal. It will then exert its action on the insect when the insect ingests the blood of the host. A parasiticide may be administered systemically by giving the animal a pill or capsule, that is to say by oral administration. More relevantly for present purposes, the parasiticide may also be delivered for systemic distribution transdermally, that is to say by transmission through the layers of the skin and into the bloodstream. I will endeavour to use the term “transdermal distribution” to describe an active ingredient which passes into the host system through the layers of skin and into the bloodstream for systemic distribution. Transdermal distribution is one method in which a patch of active ingredient may be applied to one area of an animal’s body and be distributed by the bloodstream to other parts.

A parasiticide may also be applied non-systemically. Thus, in the case of a spray for example, the active ingredient is delivered to the surface of the skin by spraying the animal all over. The parasiticide is distributed over the host animal by the action of spraying, not by the circulation of the host animal’s blood. Dips and shampoos can also be examples of non-systemic application.

Once applied in this way the parasiticide works by contacting the insect’s cuticle, not by ingesting the blood of the host.

A separate question is whether a parasiticide can be distributed non-systemically. Thus, is it possible to apply a quantity of parasiticide to one part only of the animal’s body and find that it distributes over the rest of the body without passing through the bloodstream, to exert its action by contact with the insect? Professor Hadgraft did not accept that this was possible. However it was certainly the perception of those skilled in the art that it was possible, and the permethrin spot-on, and other spot-ons and pour-ons (see below) were claimed to work in this way.

A pour-on formulation is one which is applied by pouring a quantity of the product along the midline of the back of the animal. By contrast a spot-on formulation is applied to a small area of the animal’s back, usually between the shoulder blades.

The active ingredients which were available for cats and dogs in spot-on form in 1995 were essentially two: fenthion and permethrin. In addition, a number of pour-on and spot-on formulations were also available for livestock. Fenthion was known to act systemically. Permethrin was believed to act non-systemically.

The means by which spot-on formulations spread over the body was not fully understood. I return to this issue below, as there was a significant dispute as to the extent of the common general knowledge.

There were many combination products available. The combination could be of one product to treat the animal and another to treat the environment. There were also combination on-animal products. As I have mentioned, a combination of an adulticide and an IGR was sold as Ovitrol Plus. In fact the market had adopted the generic term “Plus” to indicate that the adulticide active was presented in combination with an IGR.

Professor Dryden said that he encountered resistance in relation to his own strongly-held view that adulticides should be administered in combination with an IGR. Nevertheless the evidence shows that the message had got across clearly to a number of manufacturers. Mr Watson called it the “gold standard”. Whether or not this was a slight exaggeration does not matter: the need for a combination of the two types of parasiticide for effective treatment was well understood.

The structure of the various layers of skin is well described by Dr Walters in his first expert report, and is not controversial. The following borrows heavily from that description.

Mammalian skin consists of three layers: the epidermis, the dermis and the subcutaneous tissues. The epidermis is the uppermost layer, and is usually coated by an emulsion of sweat and a substance called sebum, which is a mixture of lipids produced mainly in the sebaceous glands. Beneath the epidermis is the dermis which makes up the bulk of the skin and is a vascularised tissue, meaning drugs entering it are able to diffuse into the blood vessels and enter systemic circulation. Below the dermis is the fatty layer of subcutaneous tissues that spreads over most of the body. There are also a number of associated appendages that pass through the skin layers, such as hair follicles, sweat ducts, glands and nails. Below is a schematic cross-section of the skin, showing the dermis, epidermis and appendages.

The epidermis can be further divided into the stratum corneum (nonviable epidermis) and the viable epidermis, as shown below:

The stratum corneum consists of cells composed mainly of insoluble bundled keratins encased in a cell envelope and which are embedded in a lipid lamellae matrix. Intercellular lipids of the stratum corneum play a very important role in the skin barrier function. These highly hydrophobic materials control the passage of water across the stratum corneum (in either direction: without this layer humans would quickly lose water and dehydrate). They likewise strongly retard the ability of other hydrophilic compounds to cross the stratum corneum. On the other hand, lipophilic compounds are able to dissolve in these lipids and can much more easily diffuse into, and cross, the stratum corneum.

As indicated above, a compound may be delivered transdermally for systemic distribution in the host animal’s bloodstream. The primary requirement for a compound to penetrate into the skin is the ability of the drug to leave the delivery vehicle and diffuse into the stratum corneum. This will depend on the partition coefficient (relative affinity) of the drug between the stratum corneum lipids and the vehicle in which the compound is carried.

It was known that a parameter called log P, which is the log of the partition coefficient of the compound in question, is a measure of the suitability of a drug for transdermal delivery. A log P which is less than 1 indicates a hydrophilic/lipophobic compound, whereas a log P greater than 4 would indicate a hydrophobic/lipophilic compound. Ideally, for transdermal delivery, log P should be in the intervening region, say 1-3, and preferably about 2. Fipronil was known to have a log P of about 4.4.

The patents in suit are addressed to a team working in a veterinary healthcare company interested in the development of pesticides and their formulation. It is common ground that such a team at the priority date would comprise a veterinary parasitologist and a formulation scientist. There was a dispute about the inclusion in this notional research team of a marketing person. In the end I did not think that the dispute mattered, as the team would undoubtedly make themselves aware of the various products which existed on the market at the relevant date, as well as of their attributes and disadvantages. It was not really suggested that the marketing person on the team would provide anything more.

Whether a technical fact is common general knowledge, or merely known, can be of great importance to the resolution of disputes about the validity of patents. There was no dispute in this case about the law. Luxmoore J put it succinctly in British Acoustic Films v Nettlefold (53 RPC, 221 at 250):

"In my judgment it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less because it is widely circulated. Such a piece of knowledge only becomes general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art."

In General Tire v Firestone [1972] RPC 457 at 482, the Court of Appeal approved that statement of the law subject to reserving for another day the question of whether “accepted without question” did not pose too high a threshold. They preferred, for the purposes of that case, the terms “generally regarded as a good basis for further action”. Mr Waugh did not argue for the stricter test in this case.

There are therefore at least two separate aspects of whether a given fact is part of the relevant common general knowledge. The first is concerned with whether the fact is indeed generally known within the relevant art: facts known to some people in the art but not others are not part of the common general knowledge. The second relates to the quality and reliability of the knowledge itself. A theory which is not generally regarded as a good basis for action does not qualify as common general knowledge, even if the theory is widely published.

It is common ground that there existed on the market at the priority date at least one spot-on formulation of a parasiticide for cats and dogs which was thought to act non-systemically. In addition there were spot-ons and pour-ons for larger animals which were also thought to act non-systemically. It follows, therefore that it was generally perceived that some insecticides could be administered by a small spot at one point on the animal, or along a line down the back of the animal, and delivered without entering the bloodstream. However it was also common ground between the experts that the mechanism by which that distribution occurred was not fully understood in 1995, or even now.

Dr Walters’ evidence was that, despite the fact that the mechanism was not fully understood, steps could be taken to ensure what he described in his report as “dermal delivery”. It became clear that he was using the term “dermal delivery” to describe a mechanism by which a drug enters the stratum corneum and stays there, allowing it to diffuse laterally within the stratum corneum. In his first expert report he described this process of design in this way:

“If dermal delivery is required the drug can be designed to remain in the stratum corneum layer, rather than pass into the viable epidermis, and can spread laterally through the stratum corneum. Whereas for transdermal delivery rapid diffusion across the skin is desired, so a low molecular volume is preferable, for dermal delivery the molecular volume tends not to be a significant concern. A compound for dermal delivery, though, is preferably hydrophobic with a logP of 4 to 6.

These factors, and their theoretical and experimental analysis had been extensively reported by September 1995. They would certainly have been known to those working in the technical field of dermal or transdermal drug delivery and I would also have expected most formulators to have known them as at that date. They were taught on undergraduate courses at Cardiff University and also, I believe, at other universities.”

These propositions were the subject of head-on challenge by Merial and their expert Professor Hadgraft. In his second expert report, Professor Hadgraft said that by 1995, “little had been published suggesting any appreciable lateral movement in the stratum corneum”. He said that researchers in the field would consider, both then and now, that passive diffusion in the stratum corneum could not account for the distribution observed in the animal. I accept that as accurately reflecting the general knowledge at the time.

Some limited support for the theory of distribution advanced by Dr Walters can be found in Pharmaceutical Skin Penetration Enhancement, the book which Dr Walters co-edited with Professor Hadgraft in 1993. Chapter 16, which Dr Walters wrote together with Professor Michael Roberts of the University of Queensland, Australia, relates to veterinary applications of skin penetration agents. The chapter is mainly about transdermal distribution. However the chapter also reports on the application of synthetic pyrethroids by pour-on formulations. The text explains:

“Here, a highly concentrated formulation of the active agent is deposited along the animal’s back. The insecticide is then able to spread through the fleece, most likely by diffusion within the emulsion layer on the wool and skin surface. The concentration of active agents, therefore, decreases with distance from the application site (40; Johnson unpublished data)…. By using autoradiography, Jenkinson et al. found that cypermethrin, applied as a pour-on formulation, spread radially across the skin within the stratum corneum at a rate which exceeded 11 cm/hr. The spread was accompanied by some dermal infiltration which was most marked at the site of application.”

The passage in Walters and Hadgraft also cites unpublished data reporting the presence of cypermethrin on wool fibres above the surface of the skin, and in the follicles extending into the dermis. Most attention at the trial was focused on the paper by Jenkinson et al., which was accepted to have been published. The experts also referred to a further paper by Stendel.

Jenkinson et al. was not a paper that Professor Hadgraft recalled examining at the time it was published. It is dated 1986, and reports experiments with a pour-on preparation of radioactively labelled cypermethrin applied to sheep. The experiment was designed to test the hypothesis that pyrethroids can move across the skin within the stratum corneum. Jenkinson mentions in his introduction that:

“one possible route of transfer is by the intercellular channels of the stratum corneum of the epidermis which are permeated with a mixture , probably an emulsion of sweat and sebum.”

Jenkinson reports that he observed radioactive material in the stratum corneum 8 cm from the periphery of the application zone even after 45 minutes. He concludes that the cypermethrin in the solvent Barricade (which in fact contains xylene) was capable of movement in the stratum corneum at a rate which may exceed 11 cm per hour but which is likely to be highly variable between animals. On the basis of other work, he also suggested that intercellular movement in the stratum corneum “may be a more general phenomenon”. He continues, saying that:

“It is highly probable, although still not certain, that this effect is a result of lateral movement of the intercellular sweat/sebum emulsion. If, however, this proves to be the case, then the rates of movement of different products will be influenced by their capacity to mix with the emulsion and by the compatibility of the medium in which they are applied. Full understanding of the manner in which substances traverse the stratum corneum would appear therefore to depend on more detailed knowledge concerning the nature of the intercellular emulsion in different species. However, identification of the route of travel provides a basis for more detailed scrutiny of the rate and extent of travel of cypermethrin and of the ability of other substances … to move within the stratum corneum.”

These conclusions are expressed in a tentative way. The theory advanced appears to be based on movement of the sweat/sebum emulsion in the intercellular spaces, carrying the cypermethrin with it, rather than any diffusion process within that emulsion. The article makes clear that the observations are for one active substance in one animal species only, although it contains a suggestion that the theory might have more general application.

Stendel was referred to by Mr Watson in his oral evidence. It is a 1992 paper from workers at Bayer who were known to Mr Watson, relating to a pour-on preparation of another pyrethroid, flumethrin. The authors explain in their introduction that some members of the pyrethroid class are used as pour-ons “because of their physico-chemical properties”. They explain that “[in] contrast to the systemically acting organophosphorus pour-on formulations, the non-systemic pyrethroid pour-ons must have sufficient spreading characteristics on the body surface of cattle for full ectoparasiticidal action”.

Pairs of cattle treated with the pour-on flumethrin were kept unrestrained in boxes to allow contact between the animals and imitate herd contact. Stendel’s results showed that after initial uneven distribution, the flumethrin translocated rapidly within 72 hours all over the animal’s body. He does not explain how his results contribute to the discussion of mechanism, however. His discussion of mechanism is based on earlier work. He explains that it has been shown elsewhere that flumethrin has no systemic action against ticks; that flumethrin only exerts its action by dermal spreading; that there are indications that the flumethrin distribution is additionally mediated by tail and head movements. He goes on:

“It remains open to speculation whether dermal spreading of pour-on formulations is additionally mediated by dermal gland secretions (Pitman & Rostas, 1981) or possibly by movement in the intracellular space of the stratum corneum (McEwan Jenkinson et al., 1986).”

Thus, at least according to Stendel, Jenkinson’s 1986 theory was still regarded as open to speculation or possible in 1992. It had certainly not become accepted.

At the beginning of the trial Omnipharm introduced a 1994 brochure for Mallinckrodt Veterinary’s product Defend Exspot, a permethrin-based spot-on product for dogs. The brochure contains some reports of migration trials on dogs. Following application of the permethrin product, hair samples were taken and chemically analysed for permethrin concentration. The trials purported to show that the formulation spread to all parts of the animal quite rapidly. Neither expert was aware of any publication in a peer reviewed journal to support these data. I am not persuaded that the document formed part of the common general knowledge either in terms of the width of its publication or in terms of the acceptance which would be accorded to the data contained in it. It does not in any event contribute to the understanding of the route of distribution. It merely shows that the parasiticide had travelled to the coat in the regions of hair sampled.

The Jenkinson theory had of course been reported in Walters & Hadgraft by the priority date. The skilled person would not take that passage, buried as it is in a chapter on transdermal delivery, as teaching an accepted principle, far less an accepted principle of general application to all parasiticides. The evidence does not establish that, by the priority date, the Jenkinson theory, as reported in Walters & Hadgraft, or indeed any theory of non-systemic distribution, had become a settled one.

I am therefore unable to accept Dr Walters’ evidence as to the design of parasiticides for dermal delivery through the stratum corneum as being part of the common general knowledge.

Professor Hadgraft did not even accept that dermal delivery, in the sense in which that term was used by Dr Walters, could take place. His view, as expressed in his reports, was that the skilled person’s intuition would be that a spot on must act systemically. However, in his second report he made it clear that he did not accept Dr Walters’ theory:

“Dr Walters’ approach is based on the premise that it would be possible to target the stratum corneum with fipronil, such that lateral spreading could be achieved across the whole of the animal in the stratum corneum layer ... As I shall explain below, there was no general understanding of, nor accepted scientific basis for, this approach. It was not one that I was aware of, nor was it an approach that was taught or understood. I do not consider that the skilled person would have thought that fipronil (or any active) could be effectively administered non-systemically via lateral spreading in the stratum corneum.”

I have accepted that evidence in the light of the cross-examination of Dr Walters, supported as it is by the underlying publications themselves. As it emerged in cross examination, Professor Hadgraft’s view was more extreme. It was that some insecticide must first directly enter the animal’s bloodstream from the site of application and subsequently become concentrated at the surface, from whence it could contact the insect. He did not cite any support for this theory. As I have already said when dealing with the witnesses above, I do not consider that Professor Hadgraft’s theory would represent the thinking of the skilled person.

What I am left with, therefore, is that the skilled team would know of the existence of spot-on formulations of certain actives which were generally thought to act non-systemically. The team would not have any common general knowledge theory as to how such formulations in fact spread over the body of the animal.

The skilled formulator would have at his or her disposal a variety of excipients to assist in delivery of an active substance.

Solvent mixtures were used in topical pharmaceutical preparations for dissolving drugs with diverse physico-chemical characteristics.

Solvents could also be used to enhance the spreading of a formulation across the skin. But care needs to be taken here: there is a difference between using a solvent to make a preparation less viscous so it may be spread by rubbing on the surface, and using a solvent to enable the substance to spread on its own. There was not much evidence of the selection of appropriate solvents for the latter purpose, which was not established to be common general knowledge.

Surfactants were used in veterinary applications, for various purposes including solubilising materials. Some surfactants could be used as penetration enhancers. They could also be used to aid wetting and spreading.

881 has a priority date of 29^th September 1995. The specification is entitled “Antiparasitic composition for treating and protecting pets”. The specification explains at [10] – [14] that the purposes of the invention include ease of use, provision of compositions which do not require spraying of the whole animal body, and provision of compositions which, applied locally, will then spread over the animal’s whole body, and then dry, while avoiding as much as possible any crystallisation phenomenon.

As originally granted, the specification described and claimed, as an active ingredient, a wide class of pyrazole compounds. However the claims are now to be limited to fipronil. At [23] the specification explains:

“The compositions according to the invention, intended for pets, especially dogs and cats, are generally applied by depositing on the skin (in English “spot on” or “pour on”); it is generally a question of localised application on a surface area of less than 10 sq. cm., especially between 5 and 10 sq. cm, in particular at two points and preferably located between the animal's shoulders. After being put on, the composition spreads, particularly over the animal's whole body, and then dries, without crystallisation and without changing the appearance (in particular there is no whitish deposit or dusty appearance), or the feel of the animal's coat.”

The words “or “pour-on”” in [23] are sought to be deleted by amendment. In addition to fipronil at 1-20% by weight of the composition, the formulations of the invention must contain a crystallisation inhibitor which satisfies a specified crystallisation test; an organic solvent of specified dielectric constant and an organic co-solvent with a boiling point below 100^oC and specified dielectric constant. The specification contains lists of suitable compounds to choose for each of these excipients, as well as a number of specific examples. The examples include details of the excipients and report that in tests on dogs, the formulations achieved a reduction in total flea population above 95% compared with control.

Merial rely on a large number of claims as being independently valid. Claim 1 as proposed to be amended is in the following form, which I have simplified for ease of exposition:

Composition useful for treating and protecting pets infested or likely to be infested with parasites, characterised in that it comprises, in the form of a ready-to-use solution:

a)

[fipronil];

b)

a crystallisation inhibitor which meets [a glass plate test];

c)

an organic solvent with a dielectric constant between 10 and 35, preferably between 20 and 30;

d)

an organic cosolvent with a boiling point below 100°C, preferably below 80°C, and a dielectric constant between 10 and 40, preferably between 20 and 30;

wherein [fipronil] is present at the rate of 1 to 20% weight:volume in the composition.

Merial put forward by way of amendment a claim 1A, which is the same as claim 1 except that the introductory words are as follows:

Composition useful for treating and protecting pets infested or likely to be infested with parasites, characterised in that it comprises, in the form of a ready-to-use spot on solution for localised application on a surface area of less than 10 sq cm:

Claim 21 proposes a linguistic variation on claim 1 in which the composition is claimed with the words “Composition for use…”. Claim 30 claims a composition for the use according to claim 21 wherein the composition is applied by spot-on application to a surface area of less than 10 sq cm.

Each of claims 1/1A and 21 has subsidiary claims in which Merial claim independent validity. The features introduced are:

564 has a priority date of 29^th March 1996, some 6 months after 881. 881 had not by that date entered the state of the art. The specification is entitled “Insecticidal combination effective against fleas on animals particularly cats and dogs”. Like 881 it started life by claiming a large class of pyrazoles, but is now to be limited to fipronil alone.

The specification explains on page 1 lines 2-7 that the invention relates to a composition for controlling mammal fleas, for example fleas on cats and dogs “based on a synergistic combination of parasiticides which are already known.” At page 2 line 24 onwards it claims that the “very high efficacy of the composition according to the invention implies not only high immediate efficacy but also long-lasting efficacy after the animal has been treated”. The composition of the invention consists of fipronil and “at least one compound ... of IGR (insect growth regulator) type”. Preferred compounds of this type include methoprene and pyriproxyfen as well as others.

In a passage sought to be deleted at page 7 lines 22 to 28 the patentee explains that the two compounds, fipronil and the IGR, may be administered separately in accordance with one embodiment of the invention, with one application being separated from the other in time by, for example, one month.

At page 10 lines 24 to 36 the specification describes the application of the combined product:

“The compositions according to the invention intended for pets, preferably cats and dogs, are generally applied by being deposited onto the skin ("spot-on" or "pour-on" application); this is generally a localized application over a surface area of less than 10 cm², especially of between 5 and 10 cm², preferably at two points and preferably localized between the animal's shoulders. Once deposited, the composition diffuses, preferably over the animal’s entire body, and then dries without crystallizing or modifying the appearance (preferably absence of any whitish deposit or dusty appearance) or the feel of the fur.”

The words “or pour on” in the above passage are sought to be deleted by amendment. In a further passage on page 13 it is explained how the compositions are made:

“The compositions for spot-on application according to the invention are usually prepared by simple mixing of the constituents as defined earlier; advantageously, to begin with, the active material is mixed in the main solvent and the other ingredients or adjuvants are then added.”

At page 14 the specification claims at lines 30-35 that the compositions of the invention “for spot-on application, have proven to be extremely effective for the very long-lasting treatment of fleas on animals, and in particular small mammals such as dogs and cats”. It then says this at page 14 line 35 to page 15 line 2:

“The discovery that the compound (A), such as fipronil, dissolves in the sebum so as to cover the entire animal and becomes concentrated in the sebaceous glands, from which it is gradually released over a very long period, is a plausible explanation of this long-lasting efficacy for these compositions, and could perhaps also explain the long-lasting action of the associated compound (B).”

In contrast to the examples in 881, the examples of 564 simply specify different concentrations of the active ingredients. The examples do not contain any formulation details, beyond saying that there should be present a crystallisation inhibitor, an organic solvent and an organic co-solvent.

Claim 1 of 564 as proposed to be amended is in the following form, again simplified as for 881:

A composition which provides small mammals with long-lasting protection against fleas, which includes, on the one hand, [fipronil]

and, on the other hand, at least one ovicidal compound (B), of insect growth regulator (IGR) type,

in a fluid vehicle which is acceptable to the mammal and suitable for local application on the skin;

wherein the fluid vehicle and the concentration of the [fipronil] and (B) are adapted for point application to the skin by deposition of the "spot-on" type;

wherein in the composition:

[fipronil] is present in a proportion of from 5 to 15 % (percentage as a weight per unit volume W/V); and

(B)

is present in a proportion of from 1 to 20 % (percentage as a weight per unit volume W/V).

Claim 48 is a “use” claim:

Use, on the one hand, of [fipronil];

and, on the other hand, at least one ovicidal compound (B), of insect growth regulator (IGR) type,

for the preparation of a composition in a fluid vehicle for local application to the skin of small mammals by spot on application over a surface area of less than 10 cm2 for long-lasting protection against fleas;

wherein the fluid vehicle and the concentration of the [fipronil] and (B) are adapted for point application to the skin by deposition of the "spot-on" type;

wherein in the composition:

[fipronil] is present in a proportion of from 1 to 20 % (percentage as a weight per unit volume W/V); and

(B)

is present in a proportion of from 1 to 20 % (percentage as a weight per unit volume W/V).

Each of claims 1 and 48 has subsidiary claims in which Merial claim independent validity. The features introduced are:

There was no dispute as to the principles of construction of the claims of a patent. In Kirin Amgen v TKT [2005] RPC 9 the House of Lords explained that the determination of the extent of protection only involves asking what a person skilled in the art would have understood the patentee to have used the language of the claim to mean. Guidelines to assist the court in construing the patent are summarised by the Court of Appeal in Virgin Atlantic v Premium Aircraft [2010] FSR 10 at paragraph 5. In the end this was not a case which turned to any great degree on issues of construction.

There was an arid dispute as to whether, in 881, the language of claims 1 and 1A – “composition useful for treating and protecting pets infested or likely to be infested with parasites” – was materially different to the language of claim 21 “composition for use in treating and protecting pets infested or likely to be infested with parasites.” For present purposes I do not think it matters, because Mr Carr accepts in paragraph 167(b) of his written closing submissions that the obviousness questions in the present case are unaffected by the difference.

There was also a dispute about what was meant by a “crystallisation inhibitor”. Dr Walters’ evidence was that a more common name for such an excipient would be an anti-nucleating agent. There is a difference between preventing crystals from nucleating at all, and restricting the growth of crystals once they have formed. Both might properly be regarded as crystallisation inhibitors. In my judgment the term crystallisation inhibitor as used in these patents is not restricted to agents which prevent nucleation altogether, but extends to substances which inhibit crystal growth as well. The patent makes it clear that it is concerned with the appearance of the animal’s coat, see e.g. [23] and [32], so it is visible crystals which the formulator would be concerned to prevent. In the end this did not matter much either.

Claim 1 of 881 and claim 1 of 564 are to “composition” and “a composition”. There is an issue on this which I deal with when dealing with amendment below.

In Conor v Angiotech [2008] UKHL 49; [2008] RPC 28 at [42] Lord Hoffmann approved the following statement by Kitchin J in Generics (UK) Ltd v H Lundbeck A/S [2007] RPC 32 at [72]:

“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.”

Expectation of success can be a relevant consideration, the weight to be attached to it depending on the facts of the case. Mr Waugh reminded me of the words of Jacob LJ in St Gobain v Fusion Provida [2005] EWCA Civ 177 where he explained the role of “obvious to try” in the assessment of inventive step:

“Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions which were patentable. The only research which would be worthwhile (because of the prospect of protection) would be in areas totally devoid of prospect. The “obvious to try” test really only works where it is more-or-less self evident that what is being tested ought to work.”

Subsequently, in Conor v Angiotech [2007] EWCA Civ 5, Jacob LJ in the Court of Appeal again dealt with the authorities in relation to “obvious to try”, including his own earlier judgment in St Gobain v Fusion Provida. He summarised the position at [45]:

“In the end the question is simply "was the invention obvious?" This involves taking into account a number of factors, for instance the attributes and cgk of the skilled man, the difference between what is claimed and the prior art, whether there is a motive provided or hinted by the prior art and so on. Some factors are more important than others. Sometimes commercial success can demonstrate that an idea was a good one. In others "obvious to try" may come into the assessment. But such a formula cannot itself necessarily provide the answer. Of particular importance is of course the nature of the invention itself.”

However, Jacob LJ went on to say at [48] that Conor was not an “obvious to try” case, nevertheless finding that the invention was obvious. The House of Lords came to a different conclusion from the trial judge and the Court of Appeal on the issue of obviousness. Lord Hoffman said this about “obvious to try” 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 in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case.”

Lord Justice Jacob’s St Gobain phrase “more-or-less self-evident that what is being tested ought to work” is thus explained by Lord Hoffmann as a “fair expectation of success”, with the degree of expectation depending on the facts of the case. I also note that Lord Walker expressed reservations about allowing the “obvious to try” approach to take on “a life of its own”: see [47] -[48].

It is, in my judgment, vitally important to keep in mind that there is only one question which the Court is being called upon to decide, namely whether the invention was obvious. Thus it is critical to understand what the invention is, and to analyse the argument as to how it is alleged that the hypothetical skilled person would have arrived at it without invention. It was in the understanding of what the invention was that the House of Lords differed from the trial judge and the Court of Appeal in Conor. The invention in that case was a product said to be suitable for preventing restenosis in arteries. The defendants’ case was that the claimed invention should be understood as saying no more than that the invention might work to achieve this effect. Lord Hoffmann dismissed this approach at [27] to [28]:

“In my opinion it is absolutely clear that the teaching of the specification, so far as it supported claim 12, was that a taxol-coated stent would prevent or treat restenosis. I agree with the opinion of the Dutch court (at paragraph 4.17):

…[T]he patentee sufficiently clearly indicates in the patent that it is advantageous to use taxol (inter alia but also specifically for restenosis) and states as reason for this that taxol…scores well in the CAM assay to demonstrate its anti-angiogenic effect, bearing in mind that the patentee saw the solution for restenosis in the use of an anti-angiogenic factor."

The question was whether that was obvious and not whether it was obvious that taxol (among many other products) might have this effect.”

Lord Hoffmann went on to point out that the achievement of the advantage in question must be plausible as opposed to speculative: see [29] to [36].

Accordingly I propose to approach the question of obviousness on the basis that:

It is convenient to address the question of obviousness by using the structured approach explained by the Court of Appeal in Pozzoli v BDMO [2007] EWCA Civ 588; [2007] FSR 37. This involves the following steps:

“(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)

Ask whether, when 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?”

I have identified the skilled team and the common general knowledge above. Mr Waugh, whilst not formally conceding the invalidity of claim 1, directed the majority of his argument to the inventiveness of a spot-on formulation of fipronil for pets. This is the subject matter of claim 1A rather than claim 1. It was also at claim 1A that Mr Carr directed Omnipharm’s primary obviousness attack. This does not discharge me from the duty of deciding whether claim 1 is invalid, as would have been the case if claim 1A had been put forward as an unconditional amendment. I will have to return to this claim in due course.

Mr Carr submitted that the question on obviousness for the purposes of claim 1A was whether it was obvious to the person skilled in the art to have considered that the dosage form in question would or might be suitable for the treatment of pets infested with parasites. In my judgment, the inclusion of the words “or might” is contrary to the approach I have summarised above and which was explained by Lord Hoffmann in Conor. The inventive concept is not that the dosage form might be suitable, but that it is. Thus, in the case of claim 1A, the inventive concept is a spot-on formulation of fipronil, having the indicated excipients, which is suitable for treatment of pets infested or likely to be infested with parasites.

Both sides rely on some factual evidence in support of their respective cases of inventiveness/obviousness which it is now necessary to summarise.

Dr Walters was employed by Pharmaserve for a period in excess of a year in 1991-2 on a project concerned with fipronil. In his first expert report Dr Walters acknowledged that he had been involved in contract work for Rhone-Poulenc Agrochemie and May & Baker on fipronil. The former was in fact for Rhone Merieux, Merial’s predecessor. Dr Walters accepted that he directed the work at Pharmaserve, but, so far as he could recall, he did not do the actual experiments in the laboratory. He had no recollection of the work until he saw the laboratory notebooks when looking through Pharmaserve’s records for the purposes of his report, to set out his prior experience. He did not review the notebooks at that stage, although they were subsequently disclosed.

The project falls outside the two-year disclosure window before and after the priority date which was applied in this case. Merial had not therefore given any disclosure at the normal stage of documents relating to this Pharmaserve project. Very shortly before trial, Merial disclosed a file of documents on the Pharmaserve project, notwithstanding that they fall outside the two year window. Merial have not given general disclosure of documents outside that window. I have therefore to proceed with caution as to what may be properly inferred from the documents as to the approach of a skilled team. I have no detailed information as to what was going on within Rhone Merieux, either on this project or on related ones. Merial called no witness to deal with their involvement in any of this. I also have to bear in mind that Dr Walters had very limited knowledge at this stage of what fipronil did, in particular he did not know and could not have known of the Frontline spray.

Rhone Merieux confirmed in the autumn of 1990 that they had decided “to proceed with a collaborative work on the development of a spot-on formulation for [fipronil] with Pharmaserve.” A meeting was held in Cardiff in November 1990. The purpose of the meeting was for Dr Walters to outline the methodology he would use to achieve a spot-on formulation of fipronil, a timetable, and his needs in terms of information on the physico-chemical properties of the substance, and the supply of the active including in radio-labelled form. On 20^th November 1990 Dr Walters wrote with a quotation. The first stage of the investigations proposed was to determine the maximum flux across rat dermatomed skin from a predicted optimum vehicle over a 48 hour period. Rat dermatomed skin is a thin section of rat skin, in this case less than 500 microns in thickness. Diffusion cells, a standard method for measuring transdermal delivery, were to be used to measure the rate of transdermal permeation. The formulation in question is placed in a chamber on one side of the skin sample in the cell, with the stratum corneum facing the chamber. On the other side of the sample is a receptor chamber with another medium which collects any sample which has permeated.

The second stage of the Pharmaserve project would be to develop five (subsequently altered to four) prototype formulations and to determine the skin permeation of those formulations using the same method. Various other stages were proposed dependent on the success of the prior stages. A confidentiality agreement was subsequently signed specifying (in Schedule A) that Pharmaserve’s instructions were to determine the maximum flux of the active across the skin.

On 25^th January 2011 Dr Walters wrote stating his requirements. These included requests for solubility values of fipronil in a variety of solvents, including transcutol. In February samples of the product and associated data were sent to Pharmaserve. The toxicity data indicated that the compound was not well absorbed through human skin.

The protocol for the Phase 1 tests was prepared in March 1991. In May 1991 Dr Walters reported that the Phase 1 tests had shown levels of transdermal permeation through the rat skins to be very low. Despite this Dr Walters sought the go-ahead for Phase 2, the preparation of the five formulations. He pointed out that he would include a penetration enhancer which could be expected to improve matters.

In September 1991 Dr Walters made some proposals for a further formulation, including specified solvents and surfactants. The choice of the surfactant appears to have been influenced by work going on in parallel at Rhone Merieux. Dr Walters was unable to obtain the same surfactant, but suggested an alternative available from ICI called Brij 96. In October, Pharmaserve provided a protocol for skin penetration tests on four formulations with various combinations of methyl cellosolve, ethanol and Brij 96.

Pharmaserve produced their final report in March 1992. The report first pointed out as an entirely general matter that the “most rapid permeants” have a logP of 1.0 to 2.0. Fipronil’s estimated logP was 4.41 “from which it could be reasonably predicted that the compound would be an intrinsically slow rate penetrant but one which could be significantly influenced by formulation.” The report went on to explain that the ability of the active to partition out of the delivery vehicle and into the upper layers of the stratum corneum was driven essentially by the degree of saturation of the permeant in the vehicle. The experimental results obtained showed:

Dr Walters was asked why he had not mentioned the possibility of lateral movement within the stratum corneum at that point, particularly as he had established that the material was getting into the skin and could diffuse downwards into the underlying tissue. If that were so it would surely occur to him to mention his lateral spreading theory. His reply was that, within a diffusion cell, the material could not move sideways. Pharmaserve went on in the report to suggest further experiments in which the transdermal permeation rate could be increased.

There was some suggestion that there was widespread scepticism about non-systemic spot-ons. Mr Waugh accepted that this could not amount to a “technical prejudice” as that term is used in the cases, given the existence of the permethrin spot-on. I think it was established that the permethrin spot-on would have been seen as a sub-optimal product by the priority date, in the light of the comparison with the Frontline spray.

Merial rely on the fact that Professor Dryden did not have the idea of a fipronil spot-on product, despite being actively involved in the launch of the fipronil spray product, which is the principal staring point for Omnipharm’s obviousness attack. I do not think there is anything in this point. Professor Dryden was not asked to turn his mind to alternative formulations: it can hardly be suggested that it was inventive even to consider that general topic at all.

Omnipharm, for their part point to a pharmaceutical expert report used for regulatory registration purposes dated November 1995. The report, prepared by a M. Courtot of the Veterinary School in Lyon, identified the formulation vehicle as comprising transcutol as a solvent, polyvidone as a film forming crystallisation inhibitor, polysorbate 80 as a surfactant and ethanol. The author emphasised that the choice of vehicles was “highly logical”.

The document is of course looking at the choices made by Rhone Merieux post hoc. Such an approach is dangerous when considering obviousness. At most it indicates that there was nothing unusual in the choice of materials. It says nothing about whether the skilled team would have been able to predict success, even if it had chosen such a formulation. I know nothing of M Courtot’s qualifications to express opinions on the choice of formulation excipients.

Omnipharm also placed reliance on comments made by Professor Hadgraft in a telephone conversation he had with Omnipharm’s solicitor before it became clear that he had already arranged to meet the solicitors acting for Merial. Omnipharm suggest that the advice he gave in the telephone conversation is different from the evidence which he gave subsequently.

Omnipharm rely on a particular answer given by Professor Hadgraft in the telephone conversation as to how one would go about formulating a pour-on. It was noted as follows:

“You would just go through the fairly logical steps and rational judgments on the properties you wanted. You would use certain compounds if you wanted it to permeate the skin, and others if you did not.”

However, Professor Hadgraft went on to explain that he recalled debates in the past about how a pour-on permeates, to reflect the uncertainty in the manner in which the substance distributed, to refer to the possibility that uptake was systemic until it comes out of the system again, and to explain that, following simple physical laws, the substance would take years to disperse to the tail. He also agreed that there would be some physical distribution from tail movements.

Omnipharm also rely on the fact that Professor Hadgraft quickly suggested the use of a volatile solvent and an anti-nucleant polymer such as PVP or HPMC. These were clearly in the context of a transdermal formulation, however, because he went on to refer to the need for a logP in the range 1-2, and a small molecule. He pointed out that he had not worked on contact pesticides. He explained that, for that purpose, one would be looking to minimise penetration into the skin of the host whilst maximising permeation of the insect’s cuticle, something he was not sure he had dealt with.

Professor Hadgraft, on the other hand, was very critical of the preparation of the note of his conversation. I do not consider his criticisms were in any way justified. With one or two exceptions the note was a faithful record of what was said. As with any document one needs to be careful to understand it in context.

The Frontline spray was a mechanical pump spray for all-over application to cats and dogs. It contained 0.25mg per 100ml fipronil. From the instructions which accompanied the product it is possible to calculate that the dose to be applied to the animal would be 7.5 to 15 mg per kg of the animal’s weight. If given a sample of the spray, the skilled person would have been able to tell that the solvent was iso-propanol from its smell. Dr Walters suggested that identification of the remaining ingredients would have been possible by gas chromatography, HPLC or mass spectrometry.

The differences between the Frontline spray and claim 1A are that the formulation contains less than the specified range of fipronil (0.25% rather than 1-20%); there is also no disclosure of a crystallisation inhibitor or a co-solvent to go with the iso-propanol.

I can summarise Omnipharm’s case of obviousness over the Frontline spray as follows:

Merial challenge each stage of this argument. As to the first stage they say that the available spot-ons for pets, essentially permethrin and fenthion, were not perceived as good products and the disadvantages of the spray products (and consequent advantages of spot-ons) were exaggerated. Next they say that if one were to conclude that a non-systemic spot-on should be tried, the skilled team would think that it would be worse than the spray product. Moreover the skilled team would have no scientific basis for supposing that it would distribute non-systemically from the point of application. Lastly they submit that the choices of excipients made by Dr Walters were not those that would be made by a skilled person.

In my judgment the evidence clearly establishes there was a motivation for the skilled team at least to ask itself whether a spot-on formulation of fipronil could be made. Such a formulation would have advantages over the spray if one confined oneself to ease of application. The skilled team would realise that the ease of application of a spot-on could come at a cost in terms of efficacy – there would, at the very least, be a trade-off. How much efficacy was lost in the move to a spot-on, and indeed whether the spot-on would work at all would not be predictable in advance.

The real question for the skilled team would be whether a spot-on formulation of fipronil could be made to work. The team would be faced with a choice as to whether to seek to make a systemic or non-systemic spot on formulation. The evidence establishes that the skilled formulator on the team would very rapidly perceive a real difficulty with producing a systemic formulation, namely that fipronil has a log P in a range which makes it unsuitable for such transdermal distribution. I accept that fenthion had been made to work transdermally, but that was the single example of an active with a log P above 4. Even if the skilled team were encouraged to try, the Pharmaserve work shows that it would require a significant effort to achieve.

The skilled team would accordingly have to turn to non-systemic delivery if the project were to have a sufficient prospect of success. The team would know that the fipronil spray acted non-systemically. The spray, however, delivers the active ingredient mechanically to the whole animal body. The question for the skilled team to consider was whether a fipronil spot-on would distribute from the point of application over the surface of the skin.

I have rejected the theory of dermal distribution as being part of the common general knowledge of the skilled team. The skilled team would therefore approach the task of creating a spot-on formulation of fipronil for non-systemic distribution without that theory in mind. They would know, however, that a number of non-systemic spot-ons and pour-ons had been shown to work for livestock and (in the case of the permethrin spot-on) for pets.

It is therefore tempting to say that the skilled team would consider a non-systemic spot-on formulation of fipronil worth trying. As I have held, however, for a finding of obviousness it is necessary to consider whether the skilled team would have a fair expectation of success. Here, the absence of any common general knowledge theory as to how non-systemic spot-ons work presents an obstacle. I do not accept Dr Walters’ evidence that a log P value of above 4 would give the skilled team any encouragement. Mr Carr submitted that the team would nevertheless have an expectation of success based on two additional grounds, namely: (a) the efficacy of fipronil as an active and (b) the other non-systemic spot-ons and pour-ons which worked.

In my judgment, even taking account of the motivation to achieve a more convenient application method than a spray, the skilled team would not have a sufficient expectation of success to render the invention obvious. The team would have no common general knowledge basis on which to make such a prediction. The fact that other compounds had worked in spot-ons and pour-ons provides no technical basis for predicting that fipronil will do so, particularly when there is no scientific theory as to which properties of a compound, or characteristics of a formulation would make it do so. There is no evidence to suggest that the ability of a compound to distribute non-systemically is independent of its physico-chemical properties. The fact that fipronil is an efficacious compound in spray form does teach one that it works by contact with the insect’s cuticle, and could in theory be made to work as a spot-on provided only that it will spread over the animal’s body from the point of application. The skilled team would have no basis for predicting that that result could be achieved, or what formulation tools would be suitable for achieving that goal.

It is very clear from Dr Walters’ reports that his recommended formulation for non-systemic delivery is based on his theory of dermal distribution. His evidence was that the skilled person would be looking for solvents which would assist in spreading the formulation over the skin to give a large surface area from which the active could penetrate into the sebum and stratum corneum from where it can spread over the animal’s skin surface. He said that,

“As well as spreading, the formulator would consider techniques for ensuring that the active ingredient can penetrate into the sebum and surface layers of the stratum corneum at a rate which will encourage lateral diffusion. The active ingredient must, therefore, be kept in solution at a relatively high concentration but one that is not too close to saturation so as to avoid precipitation (including over the shelf-life of the typically two years). If precipitation is likely to occur, it will be necessary it will be necessary to add an anti-nucleant ..”

There are several aspects of this which I consider would have posed too significant a challenge for the ordinary skilled formulator. Whilst techniques for encouraging an active to penetrate into and across the sebum and stratum corneum were known, what is proposed here is a technique for causing the active to go into these layers and start diffusing laterally. This would not, in my judgment, have been perceived as an easy or even a possible objective. The idea behind the established techniques was to cause the drug to pass into the underlying tissue and then into the bloodstream. This is the converse of what Dr Walters was setting out to achieve. Secondly, the use of solvents to aid spreading was not, as I have said, in the context of causing drugs to spread out on their own.

Overall, I formed the conclusion that Dr Walters was forced to use a considerable degree of imagination in deciding how this active would be formulated for dermal spreading according to his theory. For example he proposed a combination of a lower alcohol and transcutol (a glycol ether penetration enhancer). His idea was that the alcohol would aid spreading and the transcutol would aid penetration. He was cross-examined about what he had in mind:

Q. And you say, "... as the alcohol evaporated, a concentration of the active ingredient in the main solvent would be formed that would be appropriate to facilitate penetration of the active into the sebum the outer layer ..." If you take fipronil as an example in a Transcutol ethanol system, which is what you are postulating, as I understand it -- yes?

A. Yes.

Q. -- as the ethanol evaporates, it will not leave fipronil at the high activity state in the residual Transcutol, will it?

A. No.

Q. Because it is less soluble than [in] ethanol?

A. Yes.

Q. How is it going to help?

A. You will notice I say "facilitate penetration", I do not say "enhance penetration".

Q. You say "facilitate" but not "enhance".

A. Yes.

Q. Could you please clarify for me.

A. I certainly will, although I thought I said this earlier in my testimony. What I am envisaging here is a formulation that will have the ethanol present to help the spread on the surface because it has a lower surface tension than the other materials and will facilitate the spreading of the liquid on the surface of the skin. As the ethanol evaporates, the fipronil will become less saturated in the residual solvent, which will be Transcutol or some other version of diethylene glycol monoethyl ether. In doing so the permeation from the residual solvent into the skin should be reduced. What I am trying to do is load the stratum corneum in such a way that I am not giving it that overload of the drug which will push it deeper into the stratum corneum. I am just letting the drug trickle into the stratum corneum which will give it a greater chance to diffuse laterally. Bear in mind that I have spread it over as wide as I can already with the ethanol and also with the help of the surfactant that I am putting in there.

In my judgment, what Dr Walters was doing was propounding an untested theory based on a distribution mechanism which was not part of the common general knowledge. That is not a sound basis for an allegation of obviousness.

I do not think that the Pharmaserve evidence really assists in supporting my conclusion. It is true that Dr Walters failed to mention the alternative of non-systemic delivery in his final report. But Mr Carr correctly points out that the work was done at a time when the Frontline spray was not known. I cannot therefore be certain that Dr Walters knew that fipronil would work as a contact insecticide on the cuticle of the insect. Without that knowledge, which the Frontline spray implicitly provides, it was simply not relevant to mention that dermal distribution might take place.

Likewise I do not think that any of the other secondary evidence takes the matter much further. If Professor Hadgraft did suggest on the telephone that there are excipients which were part of the common general knowledge which could be used to ensure dermal distribution, then the evidence does not, even at this stage, clearly establish what they would be. I have taken no account of Professor Dryden’s failure to suggest the idea, or the supposed scepticism about spot-ons, beyond the perception that the permethrin spot-on was not perceived as a particularly good product, and the absence of any definitive common general knowledge as to how it worked.

It follows that I reject the obviousness attack against claim 1A over the fipronil spray.

Omnipharm had an alternative case of obviousness over a publication by Sumitomo. However they recognised that they could not succeed on Sumitomo if they did not succeed on Frontline spray, so I do not consider it further.

The only claim which is wider than claim 1A is claim 1. None of the arguments focused on it, because, as I suspect, it does not matter to either side commercially. It is limited to a concentration greater than would be used for a spray, albeit not spelling out that it was for spot-on use. In the end I was not persuaded that it had been established that it would be obvious to make such a formulation, not least because no theory was advanced as to why that would be done with any real expectation of success.

Omnipharm contend in paragraph 3 of the grounds of Invalidity that:

“Insofar as the Patent is not invalid [for lack of inventive step] the Claimant will say that the disclosure is no more enabling than that of the prior art cited above and accordingly the specification of the Patent does not disclose the invention clearly enough or completely enough for it to be performed by a person skilled in the art.”

There is a short answer to this allegation, which is that the specification contains examples of formulations which are accepted to work as spot-on formulations for dogs and cats. The teaching of the specification accordingly goes further in a material respect than anything to be found in the Fipronil spray or Sumitomo. Omnipharm’s attack was in effect something rather different, namely that, if it was not obvious how to make a spot-on of fipronil from the prior art, then the specification was not sufficient across its full width. It was just a series of examples which worked, without any guiding theory or principle to enable the skilled person to make anything but the examples actually claimed.

In Zipher Limited v Markem Systems Limited [2008] EWHC 1379 (Pat); [2009] FSR 1, at [367] to [370] I summarised the effect of the authorities on the type of insufficiency which “accepts that the teaching of the patent is adequate to bring the skilled reader within the claims, but asserts that the claims encompass products or processes which owe nothing to the teaching of the patent and which are not enabled.” I said that an insufficiency of this kind involves an assertion that the claim extends “to products or processes which owe nothing to the teaching of the patent and which are not enabled”

Mr Carr relies on the following passage in the oral evidence of Professor Hadgraft:

Q. Well, presumably given that you have long lists of solvents, long lists of cosolvents, and long lists of surfactants, anti-nucleating agents, you would have to, as it were, consider, "Well, which ones from these lists am I going to use"?

A. You would have to make a judgment as to which ones you thought were most suitable.

Q. And how would you go about doing that?

A. I think that you go on and you find that there are specific examples given.

Q. So if you did not want to copy the examples, what would you do?

A. You would have to do some experiments to find out which ones were suitable and which ones were not.

Mr Carr also relies on the fact that Professor Hadgraft was unable to predict definitively whether the formulations which Dr Walters made at Pharmaserve, one of which fell within the claims of 881, would work as a spot on. He submits that this illustrates that Merial are in a squeeze between obviousness and insufficiency.

In my judgment the evidence does not establish that the claims of 881 are invalid for insufficiency. I must approach this issue on the basis of my findings that the skilled team would not have been able to make a fair prediction that they could make a spot-on formulation of fipronil starting only with the prior art and without the help of the patent. I must also approach the issue on the basis that the prior art provided no guiding principle for the selection of components of the formulation. On the other hand, the skilled team would have the patent in hand, together with practical information about specific examples which work. I do not regard the fact that the team would have to do some experiments based on the teaching of the specification and the examples to arrive at other spot-on formulations within the claim as adequately probative of insufficiency. It is true that the specification does not teach that the dermal theory of distribution is correct: but it does not have to. What is important is that it provides sufficient practical guidance to enable the skilled person to work the invention across its full breadth. It was not established that the guidance in the specification, starting with the examples, failed to do this. The allegation of insufficiency against 881 therefore fails.

The added matter/lack of clarity objection arises out of the deletion of the words “or pour on” from [23] of 881. Mr Carr submits, firstly, that the boundary between a spot-on and a pour-on is not clear. Consequently the amendment falls foul of Article 84 of the European Patent Convention. Secondly he submits that the effect of the amendment is to change the meaning of “composition” in the claims, when this meaning is not disclosed in the application. Lastly he submits that, on Professor Hadgraft’s evidence, spot-ons work by a different mechanism to pour-ons (systemic versus non-systemic), and the effect of the amendment would be to limit the claims to systemic distribution.

I reject these submissions. The difference between a spot-on and a pour-on would be clearly understood by the skilled person. A pour-on is a larger volume product used to treat livestock over a line of application or around an infested area. A spot-on application is a smaller volume applied by point application. The deletion does not alter the meaning of “composition”. I have not accepted Professor Hadgraft’s evidence that all spot-ons are systemic.

The UKIPO, in their observations on the amendments, queried whether the invention had been shown to work over the range of concentrations now specified in claims 1, 1A and 22, i.e. 1 to 20% w.v. The UKIPO was of the view that the amendments satisfied the requirements of section 14(5)(c) (supported by the description), but suggested that the court might wish to consider whether the claim satisfied the requirements of section 14(3) (sufficiency). Omnipharm have not made submissions in relation to this point, saying that it is a matter between Merial and the Court.

The mere fact that a claim is broad is not a basis for holding that it is insufficient. There is no a priori reason for assuming that a concentration of fipronil of 1% will not work. I am accordingly not persuaded that there is any basis for holding that the claim as amended is insufficiently enabled.

Donahue & Young, published in 1992, is an article in the journal Veterinary Medicine entitled “Evaluating a synergized pyrethrin-(S)-methoprene spray against feline fleas infestation”. It reports tests on a combination spray product which is a mixture of a pyrethroid and an IGR. The results of the study are said to demonstrate the value of adding methoprene to a pyrethrin pump spray, in that the adulticide provides immediate relief whereas the IGR prevents reinfestation. The product was commercialised as Ovitrol Plus.

The differences between Donahue & Young and the inventive concept of claim 1 of 564 are that it discloses a combination of pyrethrin and an IGR, rather than fipronil and an IGR, that it is a spray and not a spot-on and, in consequence does not have the claimed active concentration.

I have already held that a spot-on formulation of fipronil would not have been obvious. The claims of 564 are narrower and therefore no more susceptible to an obviousness attack than 881. Nothing in Donahue & Young, which relates to a spray formulation of a different product leads to a different conclusion on that issue.

If I had come to the conclusion that a spot-on formulation of fipronil was obvious, there would be the further question, which it is not necessary for me to decide, as to whether the combination spot-on was obvious in the light of Donahue & Young. I will shortly state my conclusion. This question requires me to assume that the skilled team has some principle in mind for the formulation of spot-on products which act non-systemically. If the skilled team had such a principle in mind, the evidence shows that the task faced in formulating a combination product would be more challenging then that for a single active. Nevertheless, given the strong rationale for combining an adulticide and an IGR, and the convenience of application provided by the spot-on formulation, I consider that the skilled team would, in these hypothetical circumstances, have succeeded in formulating a product according to claim 1 of 564.

It is not necessary to consider the two alternative cases put forward, over Sumitomo and Frontline spray.

An insufficiency attack is also run against 564: if the formulations are not obvious, then the patent is no more enabling than the prior art. Mr Carr submits that the case here is stronger than the case against 881 for two reasons: there are no formulation examples and the skilled person has to formulate the combination of actives, not just fipronil. Accordingly the attack is what is sometimes called “classical insufficiency”: the directions in the patent are simply inadequate to enable the skilled person to arrive within the claims without undue effort.

With 881, as Professor Hadgraft explained, the skilled person would have the examples to work from coupled with the patentee’s statements about efficacy. His cross-examination went like this:

Q. Do you consider, assuming that you do not wish to copy the examples, that putting these two patents into practice would be a major research project with uncertain and unpredictable results?

A. I think because the patents give you guidance and they show that with examples that you can actually produce a product that works that it gives you confidence in them.

Q. So it is the examples that give you confidence?

A. Pardon?

Q. It is the examples.

A. If you have examples that you know work, then it proves that it is a possibility. It is possible to produce something that is commercially viable.

Q. In the '564 patent the examples do not give any formulations

A. '564 is the second?

Q. This is the patent we are looking at at the moment.

A. But it gives you guidance that you need a solvent, a cosolvent and anti-nucleant agents.

Q. And that is it.

A. But it also gives you a restricted list of solvents and cosolvents and a restricted list of the anti-crystallisation materials.

Q. From which you would have to choose?

A. You would choose, yes. I mean, you cannot give a definitive answer because some of those anti-nucleants will be soluble in some solvents and not soluble in others and so you would have to find out or know personally which ones they are.

Q. Now, you have mentioned how challenging it would be to produce a formulation which combined two active ingredients like, as it were, fipronil plus an IGR, yes?

A. It would be significantly more challenging than just having one active.

Q. Yes.

I think that the absence of any proper exemplification of the formulation of a spot-on involving the two actives is fatal to the sufficiency of 564. It is true that the specification teaches the need for a solvent, co-solvent and anti-nucleating agent. But that teaching is inadequate, in my judgment, to guide the skilled person to success. It is also true that the specification propounds the theory of dermal distribution, but I have held that the skilled person’s general knowledge does not assist him to formulate a fipronil composition based on this theory. The bald proposition that the combination is efficacious undoubtedly goes beyond the teaching of the prior art, but is of no real practical assistance.

The rule of law that you “must not give people … problems and call them specifications” is as good now as when it was first uttered by Jessell MR in 1876 in Plimpton v Malcomson 3 Ch D 531 at 576. I do not think that the very broad indication of the components of the formulation, either in the main claims or the subsidiary ones, is a sufficient description to enable the skilled person to arrive at a formulation within the claims without undue effort.

An added matter objection is said to have arisen out of the deletion of the description relating to separate administration of the two components. On a reading of the application the term “composition” would, in the light of this passage, be taken to include within its scope a kit containing the two ingredients for separate administration. As amended, in my judgment, the term “composition” would no longer be understood to include within its scope a kit for separate administration. I am unable to see how this difference in scope of the claims can render the amendment unallowable. The skilled person would be able to derive directly and unambiguously from the unamended specification a composition which requires the actives to be combined in the same formulation. The fact that he would also be able to derive from the unamended specification a disclosure of a composition for separate administration makes no difference. The amendment is not unallowable on this ground.

Section 71 of the Patents Act 1977 allows a person who is “doing or proposing to do” an act to apply for a declaration of non-infringement. A number of things can be noted about this requirement:

Mr Waugh submitted that the purpose behind the requirement that a person must at least “propose” to do the act is to prevent applications being made on the basis of what he described as “wishful thinking”. He said the requirement should be understood to mean that those who could show a settled, firm and realistic plan to do an act could seek a declaration. Patentees should not be vexed by anything less certain. In particular applicants should not be able to put forward hypotheticals or a range of alternatives said to be contingent on possible events.

I do not think that the requirement that an applicant should propose to do an act requires any investigation into how settled, firm or commercially realistic the proposal is. A requirement for an investigation into the seriousness of a proposal would detract from the underlying purpose of the section, not contribute to it. It is sufficient for the applicant to propose to do the act. Moreover the application is of its nature conditional: almost all applications on the “proposing to do” basis will be contingent on the court declaring that the proposed act is not an infringement. Accordingly it is perfectly proper for an applicant to have a range of alternative proposals all of which he would be content to proceed with if declared not to infringe. If that is “wishful thinking”, then the section allows it.

Mr Donnelly was cross-examined on the ability of Omnipharm to make, import and sell fipronil products. The suggestion put to him was that Omnipharm proposed at most to obtain marketing authorisations only, and that these would be sold on to others without any trading by Omnipharm in the goods concerned.

Notwithstanding the points that were put to him, I was satisfied by Mr Donnelly’s evidence that Omnipharm in fact proposed, as one option available to it, itself to deal in fipronil products, and that all the proposed formulations were encompassed within that overall proposal. That is the end of the issue of standing.

881 is valid but 564 is not. The amendments are allowable. Omnipharm are entitled to a declaration of non-infringement in relation to the formulations which are agreed not to infringe.