Cephalon Inc & Ors v Orchid Europe Ltd & Ors

This is an action for infringement of three patents related to the drug modafinil, which is used to treat sleep disorders such as narcolepsy. The claimants (collectively "Cephalon”) are respectively (1) the proprietor, (2) an exclusive licensee in the UK and (3) a sub-licensee of the patents. The first defendant (“Orchid”) is the manufacturer of generic modafinil which the second defendant (“Mylan”) intends to market in this country. The action has been stayed against Orchid pending judgment in the action against Mylan.

Mylan deny infringement and challenge the validity of all three Cephalon patents. The grounds of invalidity relied on are lack of inventive step and insufficiency. An added matter attack against one of the patents was not pursued. Cephalon has made a conditional application to amend two of the patents. Mr Henry Carr QC argued the case on behalf of Cephalon. Mr Michael Tappin QC argued the case for Mylan.

The active substance modafinil was discovered by Lafon in France in 1976. The story of the early development of modafinil was described in unchallenged evidence by Ms Thanh-Tam Nguyen, a Lafon scientist who joined Lafon in 1976. Lafon wanted to advance to the clinical trials stage of the development of modafinil as quickly as possible. Louis Lafon, the pharmacist who ran the company, gave specific instructions that a solid oral formulation of modafinil was to be developed as soon as possible.

The Lafon scientists first conducted compatibility tests with formulating materials (called “excipients” in the trade). In the course of tabletting trials they encountered a problem with friability (crumbling), which was solved by removing particles having a diameter greater than 315 μm. They considered removing particles of less than 80 μm to improve the processing characteristics, but concluded in the end that this was not necessary.

So far as dissolution tests were concerned, the Lafon scientists worked to a target specification that 75% of the modafinil would dissolve within 30 minutes. All tablets made in the laboratory satisfied this specification.

In 1986 Lafon took the decision to move to pilot scale manufacture. Their application for marketing authorisation refers to an investigation into particle size distribution. It includes a reference to the removal of the larger particles.

Modafinil was licensed to Cephalon in the US in 1994. In the course of clinical trials in the United States, Cephalon found that the formulation used by them displayed increased side effects as compared with equivalent doses tested in European clinical trials. The different effect was traced to the smaller particle size of the input active pharmaceutical ingredient (“API”) of the lots used in the US trials.

There are three patents in suit: European Patents (UK) Nos. 0 731 698 (“698”), 0 966 962 (“962”) and 1 088 549 (“549”). They contain very similar disclosure, the principal differences being in the claims. They all claim a priority date of 6^th October 1994.

It is sufficient to consider the disclosure of 698 for present purposes. The patent describes the invention at [0006] in the following terms:

“Our invention discloses a pharmaceutical composition comprising modafinil in the form of particles of a defined size, and the use of such composition. We have discovered that the size of modafinil particles is important to the potency and safety profile of the drug."

Strictly, potency is a property of a drug molecule related to its ability to bind to a receptor. The skilled person would understand that the ability to bind to a receptor, which only occurs when the drug is in solution, could not be affected by particle size. What is meant here is that the smaller particle size enables a smaller amount of drug to be used in a solid formulation to achieve the same effect.

In all the experiments in the patent the particle size is measured on the bulk drug substance. The patent explains at [0011] that:

“The size of the particles can be determined, e.g., by the methods provided below, and by conventional methods known to those of skill in the art”.

Thus [0017] explains that the size ranges defined are based upon measurements using “technology and instruments developed by the Hiac/Royco Division of Pacific Scientific”. It also explains that different results were obtained on a different machine, and that the size ranges are “relative”.

The patent tracks the historical development of the invention. The first human trials were performed on non-commercial samples of modafinil described as the “early lots”. These had a median particle size diameter of between 80 and 150 μm. Subsequent studies in the United States on modafinil from scaled-up commercial production, described as “late lots”, revealed unanticipated side effects at doses of 800 mg per day. The late lots employed a particle size of 30 to 50 μm. This led the patentee to conclude that the late lots could be more readily absorbed than the early lots. The patent explains at [0028]:

“Therefore, modafinil particles of a defined size provide at least two significant and unexpected advantages. First, potency is increased. A smaller average particle size allows achievement of a given modafinil plasma concentration at a lower oral dose. Second, with the knowledge of the importance of particle size on potency, the safety profile of the drug can be more accurately controlled because dosing with consistent and defined particle sizes allows for greater reliability in the dosing of the drug necessary to achieve a desired result.”

Again, the skilled person would understand that what is being discussed here is not potency in the technical sense, but an effect based on better dissolution due to smaller particle size. He or she would also understand references to the lots having a median particle size in a particular range as references to measurements made on the input bulk drug used to make up the pharmaceutical formulations administered to patients in the trials. Equally, when the specification says that the use of modafinil of defined particle size has advantages, the skilled person would understand particle size to be defined by reference to measurements made on the bulk drug using the measurement methods described in the patent.

The specification makes it clear that tablets were used as the formulation in both the US trials and the earlier trials (see [0034]). At [0054] it explains that the composition of the invention can be a “tablet, capsule, powder, pill liquid/suspension or emulsion”.

At [0034] the specification explains that:

“Although not obvious or readily apparent, one of several possible explanations which we posited [for the difference in bioavailability of the different lots] was a possible difference in the modafinil particle size used in the foreign and the United States studies.”

Consistently with other passages, the skilled person would understand this passage as referring to a difference in particle size as measured on the input API used in the foreign and United States trials. There is no suggestion that any other type of measurement was made.

The specification also contains a particle size analysis of the bulk drug used for the early and late lots, using the Hiac/Royco apparatus. This confirms the ranges of median particle size mentioned (80 to 150 μm and 30 to 50 μm for the early and late lots respectively). There are also dissolution rate experiments, investigating the effect of particle size on dissolution rate. Early and late lots, whose sizes are recorded in the earlier experiments, were used. The frame of reference for all of this is the particle size measured on the bulk drug.

At [0046] the specification reports on a dog trial using modafinil from the early and late lots. According to the specification, modafinil having a median particle size of 50 μm resulted in a higher peak plasma concentration than that obtained using the same dose of modafinil administered with particles of 90 to 95 μm median diameter. Whilst the results show large error bars, the skilled person would recognise a clear trend in the graphs (Figures 8 & 9) in favour of the smaller particle size.

Finally the specification explains how to obtain modafinil “having defined particle size”. It explains that this may be done by “conventional methods of milling and sieving”, giving references to the literature.

The claims relied on by Cephalon as independently valid are as follows:

698 therefore claims the pharmaceutical compositions themselves. 962 uses versions of the so-called “Swiss” form of claim designed to avoid the prohibition on claiming methods of treatment of the human body, although claims 1 and 16 focus on the particle size in the composition and the particle size used in manufacture respectively. 549 is to a manufacturing process.

A patent is taken as being addressed to an individual or team likely to have a practical interest in the subject matter of the patent. He or she lacks inventive capacity, but is taken to have the common general knowledge in the art in his or her head, or at least to know where to find it. In the present case the patent is addressed to a team involved in developing the drug modafinil. Such a team would include a formulation scientist. It would also have access to the wider drug discovery and development team as and when necessary for the development of the drug being formulated.

The common general knowledge would include the following matters:

One of the standard textbooks in the field, “Pharmaceutical Dosage Forms” by Lieberman and Lachman (1989) contains a chapter on pre-formulation testing by Wadke and others. Early on in the chapter the authors explain the importance of particle size evaluation in the case of sparingly soluble drugs:

“… a detailed investigation of dissolution is not warranted for a very soluble compound. On the other hand, particle size, surface area, dissolution, and the means of enhancing rate of dissolution are important considerations in the pre-formulation evaluation of a sparingly soluble drug."

In the section directed to “Particle size, shape, and surface area”, the authors make the point I have identified in [24](x). They point out at the same time that very fine materials can be difficult to handle (although measures may be taken to deal with this); and that size can affect homogeneity and stability. They go on:

“Because of these significant roles, it is important to decide on a desired size range, and thence to maintain and control it. It is probably safest to grind most new drugs having particles that are above approximately 100 µm in diameter. If the material consists of particles primarily 30 µm or less in diameter, then grinding is unnecessary, except if the material exists as needles - where grinding may improve flow and handling properties, or if the material is poorly water-soluble where grinding increases dissolution rate. Grinding should reduce coarse material to, preferably, the 10- to 40- µm range. Once this is accomplished, controlled testing can be performed both for subsequent in vivo studies and for in-depth pre-formulation studies. As the studies proceed, it may become apparent that grinding is not required and that coarser materials are acceptable. At that time, it is conceptually simpler to omit that step without jeopardizing the information already developed.”

I have no doubt that grinding into the 10-40 μm range represented a common general knowledge approach to pre-formulation testing. That is not to say that everyone would have adopted it. But the skilled person would know that it was one of the practical approaches.

Cephalon called Professor Alexander Mullen who is Professor of Pharmacy at the Strathclyde Institute of Pharmacy and Biomedical Sciences, the institution which awarded him his first degree. He qualified as a pharmacist in 1991 whilst working for Reckitt & Colman but returned to Strathclyde to commence work on his PhD in the same year. He commenced post-doctoral research in 1995, although for technical reasons his PhD was not awarded until later. From 1994 he worked in addition for a commercial contract research company: some of this work involved developing tablet formulations.

Mylan called Professor Graham Buckton and Dr David Rawlins. Professor Buckton is Professor of Pharmaceutics at the School of Pharmacy, University of London. He is also chief executive of Pharmaterials Limited, a company which provides contract services in the areas of pharmaceutical physical form of materials. He currently divides his time between University and Pharmaterials.

Mr Carr submitted that Professor Buckton was too willing to advance theories and criticisms which were helpful to Mylan, and, when they were shown to be incorrect or unhelpful, to abandon them and advance alternatives in equally strident terms. I do not think that this characterisation is in any way justified. I found Professor Buckton to be a helpful and balanced witness. It is true that he no longer maintained the criticisms which he had advanced at an earlier stage of Cephalon’s extraction experiments. I do not hold this against him. To my mind it shows that he was conscious of his duty to the court: it would be otherwise if he had maintained unjustified criticisms through thick and thin. Mr Carr drew attention to the fact that two sentences from the report Professor Buckton had made for the Swedish Court did not appear in his report for Denmark. He advanced a theory that Professor Buckton had deliberately excluded them because the Swedish Court had used them against Mylan. Not surprisingly Professor Buckton could not recall precisely why those sentences were omitted. I did not think that this reflected badly on him, and I reject any suggestion that the omission was a conscious attempt by him to keep anything back from the Danish court.

Dr Rawlins worked as a formulation scientist and section head at various pharmaceutical companies. In 1984 he moved to Merck Sharpe and Dohme where he rose to become Senior Director of Pharmaceutical R&D. He had wide practical experience of the approaches taken by pharmaceutical companies to formulation.

The approach to construction is not in dispute. It is as stated by Lord Hoffmann in Kirin Amgen v TKT [2005] RPC 9. The task for the court is to determine what a person skilled in the art would have understood the patentee to have used the language of the claim to mean.

In Virgin v Premium Aircraft [2009] EWCA Civ 1062, [2010] RPC 8 at [5], Jacob LJ said this, approving a summary by Lewison J of the applicable principles:

“5.

One might have thought there was nothing more to say on this topic after Kirin-Amgen v Hoechst Marion Roussel [2005] RPC 9. The judge accurately set out the position, save that he used the old language of Art 69 EPC rather than that of the EPC 2000, a Convention now in force. The new language omits the terms of from Art. 69. No one suggested the amendment changes the meaning. We set out what the judge said, but using the language of the EPC 2000:

[182] The task for the court is to determine what the person skilled in the art would have understood the patentee to have been using the language of the claim to mean. The principles were summarised by Jacob LJ in Mayne Pharma v Pharmacia Italia [2005] EWCA Civ 137 and refined by Pumfrey J in Halliburton v Smith International [2005] EWHC 1623 (Pat) following their general approval by the House of Lords in Kirin-Amgen v Hoechst Marion Roussel [2005] RPC 9. An abbreviated version of them is as follows:

(i)

The first overarching principle is that contained in Article 69 of the European Patent Convention;

(ii)

Article 69 says that the extent of protection is determined by the claims. It goes on to say that the description and drawings shall be used to interpret the claims. In short the claims are to be construed in context.

(iii)

It follows that the claims are to be construed purposively—the inventor's purpose being ascertained from the description and drawings.

(iv)

It further follows that the claims must not be construed as if they stood alone—the drawings and description only being used to resolve any ambiguity. Purpose is vital to the construction of claims.

(v)

When ascertaining the inventor's purpose, it must be remembered that he may have several purposes depending on the level of generality of his invention. Typically, for instance, an inventor may have one, generally more than one, specific embodiment as well as a generalised concept. But there is no presumption that the patentee necessarily intended the widest possible meaning consistent with his purpose be given to the words that he used: purpose and meaning are different.

(vi)

Thus purpose is not the be-all and end-all. One is still at the end of the day concerned with the meaning of the language used. Hence the other extreme of the Protocol—a mere guideline—is also ruled out by Article 69 itself. It is the terms of the claims which delineate the patentee's territory.

(vii)

It follows that if the patentee has included what is obviously a deliberate limitation in his claims, it must have a meaning. One cannot disregard obviously intentional elements.

(vii)

It also follows that where a patentee has used a word or phrase which, acontextually, might have a particular meaning (narrow or wide) it does not necessarily have that meaning in context.

(vii)

It further follows that there is no general "doctrine of equivalents."

(viii)

On the other hand purposive construction can lead to the conclusion that a technically trivial or minor difference between an element of a claim and the corresponding element of the alleged infringement nonetheless falls within the meaning of the element when read purposively. This is not because there is a doctrine of equivalents: it is because that is the fair way to read the claim in context.

(ix)

Finally purposive construction leads one to eschew the kind of meticulous verbal analysis which lawyers are too often tempted by their training to indulge.

That last injunction is of particular resonance in the present case. Purposive construction is the antithesis of literalism as Lord Hoffmann’s speech in Kirin Amgen makes clear.

I should also say something about the relevance of the alleged infringement to the issue of construction. It is clear that one does not start with the alleged infringement, read the patent, and ask whether the patentee meant to cover it. But it is sometimes necessary to have regard to the infringement in order to identify the question which has to be asked on construction. In Technip France’s Patent [2004] RPC 46 Jacob LJ put it in this way:

“Although it has often been said that the question of construction does not depend on the alleged infringement (“as if we had to construe it before the defendant was born”) per Lord Esher M.R. in Nobel’s Explosives Co. v Anderson (1894) 11 R.P.C. 519 at 523), questions of construction seldom arise in the abstract. That is why most sensible discussions of the meaning of language run on the general lines "does it mean this, or that, or the other?" Rather than the open-ended "what does it mean?"

The principal issue which divided the parties on the issue of construction is whether the claims were referring to the particle size within the composition (Cephalon’s contention) or whether they were referring to the particle size in the active ingredient used to make the composition (Mylan’s contention). Normally this would not matter. But suppose the process of manufacture were to cause a reduction in particle size from a value which fell outside the claimed ranges to one which falls within. What does one measure then?

There was a certain amount of background evidence to this issue, from which I draw the following:

Mr Carr submits that, as the benefits of the invention are concerned with the administration of the composition, it is the particle size in the composition which matters for the purposes of the invention. He submits that the specification is written on the assumption that particle size stays the same when the bulk active ingredient is made into tablets or other formulations. But he submits that it does not follow that a tablet which in fact contains modafinil with a particle size within the claim does not infringe. On the other side, Mr Tappin asks forensically “How can it be right that the document is construed as being directed to something which would not occur to the formulator, which he had never come across being measured and which, even if he had it suggested to him, he would not know how to go about measuring?”

Both sides point to individual claims that best support their respective cases. Cephalon favour the claims of 698 where the relevant phrase is: “… composition comprising … modafinil particles, wherein at least about 95% …”. They say that means, literally, the size of the particles when they are in the tablet. On the other side Mylan prefer claim 16 of 962 where the invention is expressed as “… use of a substantially homogenous mixture of modafinil particles whereof at least about 95% of the cumulative total of said particles have a diameter of less than about 200 micrometers for the manufacture of a pharmaceutical composition …”. They say that points clearly to the particle size in the input API, as it is used in the manufacturing process.

Both parties argued the case on the basis that there was a single invention which forms the basis of all three patents and that the choice for the court was between the two constructions advanced by the parties. However the language used in the claims is different in relevant respects, and I do not think it is right to adopt such a polarised approach at the outset. To do so would fail to afford the language of the claims the significance it is required to have. I will therefore consider each of the claims individually, even though, as will be seen, I have reached the same conclusion in each case.

I take first 698, which contains claims to the composition “comprising” the particles. The skilled person would approach this claim with the teaching of the patent and the background knowledge, both of which I have summarised above, firmly in mind. So far as the patent is concerned, he would have seen that the patentee had described his experiments by reference to measurements on the bulk API and that, throughout the specification, the patentee uses measurement on bulk API to explain the observation of different clinical effects observed in clinical trials on tablets of modafinil. This background and context would give rise to a very strong presumption that the patentee was using the language of the claim to mean the particle size of the input API, even though this was not what he had expressly said.

Professor Mullen had given some evidence about the skilled person’s understanding in his report. His cross examination went like this:

Q. … If you take any of the patents, when they talk about measuring and defining the particle size of modafinil, do you agree that the formulator, in 1994, would understand that they are speaking about measuring and defining the particle size of the API, which is introduced into the manufacturing process?

A. Certainly, it was commonplace. Some of the instrumentation is described to measure particle size being used, yes.

Q. Making sure I have understood correctly, when they are talking about "measuring and defining the particle size of modafinil", the reader of those patents in 1994 would understand that they are talking about measuring and defining the particle size of the API, which is being introduced into the process of manufacture.

A. Yes.

Q. So references in patents to particles of modafinil would be understood by the formulator as referring to the particles which are being introduced into the manufacturing process.

A. Yes.

And later:

What I want you to focus on here is the first sentence that you quote: "Modafinil particles of a defined particle size provide at least two significant and unexpected advantages." When the patents talk about the advantages of using modafinil particles of a defined particle size, they are talking about the advantages of a defined particle size of the input API, are they not?

A. Yes.

Q. Again, if you look at paragraphs 64 and 66 of your report, what the patentee has discovered is a link between the particle size of the input API and these properties which are being referred to in the passages which you quote.

A. That is right.

Q. In the patents, the beneficial properties are always linked to the particle size of the input API.

A. That is correct.

So if the skilled person were to be asked about the possibility of the changes in particle size during manufacture of the dosage form, he would be likely to answer “That has been allowed for by the patentee: the properties I am aiming at are linked to the particle size of the bulk API”. Professor Mullen suggested in his cross-examination that the specific nature of the Orchid API, which was out of line with most drugs of which the formulator would have been aware in 1994, would have justified a different approach. But I do not think it is legitimate to derive a different meaning for the claims to cope with an unknown and unforeseen circumstance such as this.

The background common general knowledge also points strongly in favour of the conclusion that the patentee must have meant particle size to be measured on the bulk API. Particle size is never measured in the dosage form, and the skilled person would not know how to do so. The skilled person would be pre-disposed to understanding the language of the claims to mean particle size as measured in the bulk API.

A further factor which points in this direction is the uncertainty as to the physical structures which will exist in the solid dosage form. There was no dispute that the skilled person would be aware that some form of bonding may take place. This would make it even less likely that the patentee intended his monopoly to be defined by measurements to be made on the particles, assuming they remain properly described as such, within the tablet.

Against this one has to place the considerations of language and purpose urged by Mr Carr. So far as the language of the claim is concerned, it is true that construed literally, and acontextually, it means the particle size within the dosage form. In relation to purpose, if alerted to the case where the particle size in the dosage form is significantly different from the input API, it is also true that the skilled person would say that the particle size in the composition was what mattered, as that is what the patient will swallow. In the end, however, I cannot accept that this is how the skilled person would understand the language of the claims to be used. The patent is intended to be a practical document addressed to technical people in industry. I have no doubt that to such an addressee the term “composition comprising … modafinil particles, wherein at least about 95%” would be understood as referring to the input API. The matters on which Mylan rely would lead him to reject the alternative meanings as impractical. He would see nothing illogical, or contrary to the purpose of the invention, in the use of the API measurement as a measure of how to achieve the beneficial effects of the patent. So purpose and meaning are aligned: only literalism stands in the way.

Next I take claim 1 of 962. This is a claim to the use of modafinil for the manufacture of a composition comprising particles of the relevant size. The considerations I have referred to lead me to the same conclusion here. Only a literal construction would lead the reader to conclude that the monopoly was defined by reference to the particle size in the solid formulation.

Claim 16 of 962 is to the use of modafinil of the claimed particle size range for the manufacture of a composition. A literal meaning would be that the claim is infringed whenever the process of manufacture involves the use of such modafinil particles. So, for example, if the process of granulation results in the presence of such particles, they are used for manufacture, as they will be if they are present prior to the completion of the tablet. But, considerations similar to those which I have outlined above lead me to the conclusion that it is the API input into the process which is relevant for the size determination, just as it was in the work described in the patent.

I take claim 1 of 549, the process patent last. 549 was not relied on at all by Cephalon at the stage of the interim injunction. This claim is not a happy example of claim drafting, particularly given the simplicity of the subject matter. But I am satisfied that the skilled person would understand that, in the case of the process, it is the bulk API which he had to measure, and not that in the formulation.

It was common ground that if Mylan’s construction of the claims was the correct one, there was no infringement. The Orchid API falls outside the scope of all the claims if they are construed to mean the particle size in the input API as opposed to the tablet. It has a 95% cumulative particle size of greater than 220 μm. There is accordingly no infringement.

I should nevertheless briefly consider the question of infringement on the assumption I am wrong about construction. In order to prove infringement on their construction of the claims, Cephalon performed experiments on modafinil extracted from the Orchid tablets. At the interim injunction stage, Mylan, supported by Professor Buckton, attacked the experimental method used by Cephalon. It is no longer necessary to consider that attack, as Mylan and Professor Buckton now accept that Cephalon have established that the particles which were measured after extraction from the tablet, fall within the relevant claims.

It might be thought that this would be sufficient to dispose of the issue of infringement. However, Mylan maintain that Cephalon have not proved that there are particles present in the solid formulation (as opposed to those extracted from the solid formulation) which fall within the claims. They rely on the fact that the tabletting procedure is known to cause particles to bond together. These bonds may fracture when the tablet disintegrates, so that the particles measured in the Cephalon experiments do not represent whatever it is that exists within the tablet.

On balance I think Cephalon’s theory as to what happens to the Orchid particles during tabletting is the correct one. The particles extracted from the tablets are representative of particles within the tablet. To the extent that the particles are to some extent bonded together, they are not sufficiently bonded together to lose their character as particles.

I think it is far less likely that the structures within the tablet are not recognisable as particles having the relevant size distribution. The most that is established as likely to happen is some form of point to point bonding. It is likely to be these point to point bonds which separate when the particles are extracted.

I should emphasise, however, that I reach that conclusion in the light of the elaborate evidence on the Orchid tablets in this case. That finding does not impact on my approach to construction. The skilled person reading the patent would have been wholly unaware of the extent of fracture and bonding which was likely to occur in the tablets proposed.

Notwithstanding those conclusions, on the basis of the correct construction of the claims, there is no infringement of the claims relied upon.

Mylan say that the patent is invalid for lack of inventive step over two publications (Drugs of the Future and a patent application naming Ms Nguyen as inventor, “Nguyen”). They also rely on insufficiency as a squeeze on construction.

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?”

In Conor v Angiotech [2007] 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.”

I have dealt with the skilled person and the common general knowledge above. So far as inventive concept is concerned, it was not suggested that the issue of inventive step was in any way affected by the issue of construction, or that it turned on the precise numbers in the claims. I will take the inventive concept as being the use of modafinil particles with reduced particle size (i.e. 95% cumulative particle size <200 μm/median particle size <50-60 μm) to make a modafinil formulation.

Mylan’s first starting point is an entry in Drugs of the Future which identifies modafinil, a method for its manufacture, its dosage range and contains summaries of some clinical trials in human volunteers. The article says nothing about formulation, and nothing about particle size. It is relied on simply to foreclose any suggestion that there was any invention in deciding to make a formulation of modafinil at the relevant dose. There was none.

Mylan’s case is that given the task of formulating modafinil, it would be obvious to the skilled team to produce modafinil in small particle sizes falling within the claims. To do so, the team would simply be using its common general knowledge.

Cephalon’s case is that the skilled person would work to a target dissolution rate: say 75% in 30 minutes. Such a target could be met with modafinil having a particle size greater than that defined in the claims. The skilled team would reject any suggestion of reducing particle size further than was necessary to satisfy the target dissolution rate test. For this proposition they rely on the fact that this is what Lafon did. They also rely on the evidence of Dr Van Campen, whose unchallenged evidence went largely to the extraction experiments, but who took the opportunity to comment on this aspect of the case. Cephalon submit that this approach is justified given the potential downsides associated with reducing particle size too far.

The evidence does not reveal that there was a uniform common general knowledge approach to how the effect of particle size was investigated. I have already summarised the approach recommended by Wadke above. I set out below a summary of the approaches of the witnesses.

I have summarised what Lafon and Cephalon did by reference to the evidence of Ms Nguyen and the patent specification above. Ms Nguyen stressed the instructions which the scientists at Lafon had received to get a product into trials as quickly as possible: hence she worked to the target specification which she mentions.

In his first report, Professor Mullen explained by reference to the work at Lafon, that “there would be no motivation for a formulator working on modafinil to specify a reduced particle size”. The fast dissolution target specification could be reached without the need to undertake any particle size reduction. Professor Mullen did not really seek to suggest, however, that it was not technically obvious that one could achieve improved dissolution, and hence better absorption and bioavailability, by reducing particle size. He agreed that optimising particle size and optimising excipients made a cumulative contribution, and one would expect to be able to work towards one’s therapeutically optimal formulation by using one or the other or both. He expressed a preference for optimising excipients first. Significantly he accepted that the technical advantages of the invention set out in the Cephalon patents would not have been regarded as unexpected by the skilled formulator. Moreover, Professor Mullen said, and I accept, that the effect of particle size on dissolution would be one the things routinely investigated by the skilled team in the course of pre-formulation studies. Particle size would be prominent in the thought processes and considerations of the formulator. Although the Professor had reservations about what particle size range might ultimately be adopted, I did not understand him to challenge the proposition that it was obvious to investigate particle size.

It is established on the evidence that the skilled formulator in the case of modafinil would have found from dissolution tests that there were potential benefits to be gained by reducing particle size into all of the claimed ranges. Cephalon sought to challenge this proposition by reference to some dissolution rate data accompanying Lafon’s 1993 marketing application. The increase in dissolution rate shown in these particular experiments, which were not explained in any detail in the evidence, was not as great as would be predicted by the application of theory. Nevertheless the expected trend of increasing dissolution rate as a function of particle size was clearly visible.

Professor Mullen’s technical reservations about using particle size to obtain an optimal formulation were those which I have outlined above in dealing with the common general knowledge. But it was quite clear to me from his cross- examination that he considered reducing particle size as an obvious route to go down. The skilled person would only be dissuaded on technical grounds from going down that route if he or she actually encountered one of the problems referred to:

Q. I think maybe this is where the difference is between us, but if the formulator can see from his dissolution data that reducing particle size is going to give him improved absorption and bioavailability, then taking that step takes him towards his therapeutically optimal formulation?

A. Possibly, but again, in that particle size reduction, in reducing that and getting a dissolution gain, do you get a disadvantage in some other aspect of the overall manufacturing process? So some of the things which I had highlighted in terms of physical and chemical stability or the flow patterns of powder, if the gain that you anticipate from the change in the dissolution is perhaps less than the potential negative impact upon particle size reduction, you might be dissuaded from going down that obvious route.

Q. Right, but in order to be dissuaded from going down that obvious route, you would have to see that in fact there was a down side to taking that course?

A.

And you might realise that during the actual particle size reduction.

The evidence did not support a suggestion that any of the “downsides” identified by Professor Mullen would have represented any real obstacle in the present case. Lafon did identify a problem of stickiness which was overcome by the common general knowledge measure of wet granulation. It is true that extra milling would represent an added manufacturing cost, but it was not suggested that, in the context of pharmaceutical manufacture, the cost of milling would be such as to deter the skilled team from reducing particle size.

Professor Mullen thought that the extent to which one might utilise (as opposed to investigate) particle size reduction in a commercial environment might be controlled by the results which one got on a prototype formulation, and the desire only to clear the regulatory threshold for dissolution. He suggested that, depending on results from dissolution tests on a prototype formulation, the skilled team might decide not to reduce particle size any further. Many of the Professor’s answers were qualified by reference to an innovator company desirous of obtaining a rapid return on investment, and seeking to do only what was adequate from the regulatory perspective, rather than what was optimal from the point of view of therapeutic effect.

Dr Rawlins described an alternative approach. For a poorly soluble drug like modafinil he would have started by reducing particle size to around 25 μm and would have carried out in vitro dissolution tests and in vivo studies of absorption and bioavailability. This was not universal practice, but other companies adopted this approach. It was not suggested to him that this was not an obvious approach. Professor Mullen did not suggest that this approach was not a reasonable one, although he thought it emphasised the use of particle size rather than the use of excipients.

There was some inconclusive cross examination of Dr Rawlins on the basis of a dog study conducted by Lafon which showed no statistically significant difference in the animal tests between particles of 50 μm median diameter and particles of 90-95 μm. There was, however, a clear trend in favour of the smaller particle size.

I am unable to attach much weight to the evidence of Mr Heacock, Cephalon’s Vice-President of pharmaceutical development, relating to further work carried out within Cephalon in 1995. This showed that there was relatively little advantage to be gained in reducing particle size below 50 μm. Whilst that is so, there were clearly gains to be made by reducing the particle size to 50 μm, and no reason to suppose that the skilled person would not find this to be so.

Dr Van Campen’s evidence on this topic was a single paragraph in her second report. It is right to note that she had extensive experience of pre-formulation with a number of pharmaceutical companies: Boehringer Ingelheim, Synergen and Inhale. Her experience was that particle size would not be reduced more than was necessary to achieve a “satisfactory bioavailability”.

I have come to the conclusion that the inventive concept of each of the claims relied upon was obvious in the light of Drugs of the Future and common general knowledge.

Firstly, it is important to bear in mind that the target dissolution rates set by regulators are definitions of what is acceptable rather than what is optimal. Such a general target could not possibly define an optimal dissolution rate for any given drug. No witness suggested that these target dissolution rates represented any sort of limit of what is achievable in terms of dissolution rate.

Secondly, the skilled team would understand that it was desirable to achieve rapid and complete dissolution and hence better bioavailability. Considerations of safety and efficacy both drive in this direction. Purely commercial motivation to do better than the threshold may be more muted, but the technical motivation to do better remains.

Thirdly, the skilled person would approach the formulation exercise in the very confident expectation that reducing particle size would improve bioavailability, and therefore provide benefits in terms of achieving the optimal formulation.

Fourthly, the skilled person would, as a matter of routine, conduct dissolution tests which would confirm the benefits of reducing particle size into the range of the claims. Whether he did this by following Professor Mullen’s approach or that of Dr Rawlins does not matter. These dissolution tests would fortify what was already a strong expectation of success.

Fifthly, the skilled person who conducted such tests would not encounter any significant obstacle to reducing particle size into the range of the claims.

Sixthly, I cannot accept that the fact that some companies would be satisfied with a sub-optimal product which clears the regulatory threshold means that it is inventive to produce an optimised one. Not surprisingly, there is no support for such an approach in the literature. The fact that Lafon were content with this in the particular circumstances of bringing a drug to market very quickly does not begin to dislodge this conclusion.

One must, of course, take into account the environment or “milieu” in which the notional formulation project is supposed to be taking place (see e.g. Dyson v Hoover [2001] EWCA Civ 1440; [2002] RPC 22 at [88]). But the evidence did not establish that there was any established mindset that anything which met the target dissolution rate would be good enough. In fact the position was to the contrary. The companies which Dr Rawlins referred to would seek to achieve the best formulation. I do not accept that this was because they were large companies and could therefore take a “no stones unturned” approach. I have no difficulty in accepting that ethical pharmaceutical companies would be motivated to achieve the best formulation which the application of common general knowledge could provide. Indeed the technical mindset was, in stark contrast to that in Dyson, that improvements in bioavailability could be made by reducing particle size, and that the target dissolution rates did not represent any sort of limit.

Nguyen is a PCT application applied for by Lafon and published in September 1994. Mylan accept that the case based on Nguyen is of limited significance, as the claims can be saved by amendment without any impact on the issues of infringement. The only impact of the case would be to eliminate those claims characterised only by the 95% cumulative particle size of less than 200 μm. The attack, as Mr Tappin put it graphically, was capable of inflicting no more than a flesh wound on the patent. Moreover, in the light of the conclusion which I have reached as to the invalidity of all the claims based on Drugs of the Future and common general knowledge, it is not necessary for me to address this case at all. I will state my conclusions as shortly as possible.

Nguyen is concerned with a process for extrusion and freeze drying ingredients useful in, amongst other things, therapeutics. Examples 16 and 17 describe microbead formulations containing modafinil having particle sizes in the range 2-5 μm. It would be clear to the skilled reader that these examples were intended to be pharmaceutical formulations.

The only difference between the disclosure of Nguyen and those claims which are limited only by the 95% less than 200 μm criterion is that the dosage is not specified. There was no suggestion that the skilled person would have any difficulty in finding the appropriate dose.

Cephalon’s case in answer to this obviousness attack was to say that making a product according to the examples of Nguyen would involve significant investment and much work. I was wholly unimpressed with this as an answer to the obviousness case. The skilled person is entitled to implement a disclosure in a technically obvious way, even if doing so might not appear commercially attractive. Had I not come to the conclusions I had already reached in relation to obviousness, I would have required the claims to be limited so as to avoid the attack.

It is also unnecessary for me to reach a conclusion on insufficiency, which was relied on by Mylan as a squeeze on construction. On the construction which I have held to be correct no question of insufficiency arises.

Mylan submit that if, contrary to the conclusion which I have reached, the claims require measurement of particle size in the solid formulation, then the specification does not describe the invention clearly enough or completely enough for it to be performed by a person skilled in the art.

The evidence established that the skilled person would not know how to measure particle size in the formulation and would have to exercise invention in order to devise a method of so doing.

Mr Carr submitted that what had to be enabled was the invention, and not the infringement. Accordingly it did not matter that measuring particle size in the infringement was both necessary and impossible without inventive effort. He submitted that in the normal case there would be no difficulty in making something which fell within the claims, provided that one started with API which was within the claimed ranges. The skilled person would know that the particles would not get larger and therefore fall outside the upper end of the range and would also know that they would not drop out of the bottom end of the range as either the claims did not have a bottom limit or it was so low as to make it unlikely that the particle size in the formulation would go below it.

I think Mylan’s insufficiency attack in the case of 698 resolves itself in substance into an allegation that the skilled person would not know how to make the claimed products using modafinil with a particle size distribution which changed significantly (from outside to inside the claimed range) in the course of its incorporation into a formulation. Given that a product claim is adequately enabled by a single method of making the product (see Lundbeck v Generics [2009] RPC 13) I do not think that these product claims are rendered insufficient on the present facts.

I would not reach the same conclusion for the process patent, 549. On Cephalon’s construction, these claims cover a class of processes in which the particles in the API are outside the claim but the particles in the composition are within it. On this basis the specification of the patent is clearly insufficient. The skilled person would have no way of telling, in the case of this class of processes, whether he was using the invention or not. I reach the same conclusion for the use claims of 962, and for the same reason.

It follows that, if I had adopted Cephalon’s construction, I would have held the claims of 962 and 549 invalid for insufficiency, but not those of 698.

The Cephalon patents are all invalid for obviousness over Drugs of the Future and common general knowledge. Had they been valid they would not have been infringed.