Neurim Pharmaceuticals (1991) Ltd & Anor v Generics UK Ltd (t\a MYLAN)

INTRODUCTION (1) Background

The First Claimant – Neurim Pharmaceuticals (1991) Limited (Neurim (Footnote: ¹)) – is the registered proprietor of a patent, EP (UK) 1,441,702 B1 (the Patent). The Second Claimant – Flynn Pharma Limited (Flynn) – is the registered exclusive licensee under the Patent in the United Kingdom. Although it will be necessary, from time-to-time, to differentiate between Neurim and Flynn, where such differentiation is unnecessary, I shall refer to Neurim and Flynn collectively as the Claimants.

The Patent claims prolonged release pharmaceutical formulations concerning the active ingredient melatonin to improve the restorative quality of sleep in a patient suffering from primary insomnia characterised by non-restorative sleep. The Claimants have applied to amend the Patent unconditionally, which is not opposed by the Defendants and to which no other objection has been made. (Footnote: ²) Where appropriate, I shall identify the amendments proposed to the Patent.

The pharmaceutical formulation claimed by the Patent is sold under the brand name Circadin. Circadin is a medicine authorised for use in the European Union, including (for present purposes) the United Kingdom. A company within the Neurim group holds a marketing-authorisation for melatonin 2mg prolonged release tablets (the description of Circadin). That company is RAD Neurim Pharmaceuticals EEC SARL (RAD Neurim).

The Patent was filed on 12 August 2002 and claims priority from 14 August 2001 (the

Assuming the Patent to be valid, the Defendants – Generics UK Limited and Mylan UK Healthcare Limited (collectively, Mylan) – threaten to infringe the Patent in the following way:³

“The Defendants threaten and intend to infringe the Patent by threatening and intending to do the following act in the United Kingdom without the consent of the Claimants, namely: keep, use, dispose of and/or offer to dispose of a prolonged release melatonin product obtained directly by means of a process as claimed in at least claim 1 and being a product within the scope of claim 4 of the Patent.”

In fact, it may well be the case that Mylan has gone beyond threatening to infringe the Patent and has, by now, actually infringed. Neurim sought, but failed to obtain, an interim injunction restraining Mylan from infringing the Patent. (Footnote: ³) For the purposes of this judgment, nothing turns on this question.

The First Defendant is, itself, the holder of a marketing authorisation in the United Kingdom (as well as the European Union) for melatonin 2mg prolonged release products. Those products will be, or are already, commercialised in the United Kingdom by the Second Defendant.

Issues arising

This dispute came on for trial in late October / early November 2020. The issues before me all concerned the validity of the Patent. Infringement was not a separate issue before me: in other words, if the Patent is valid, Mylan accepts and admits infringement. (Footnote: ⁴)

Mylan contends that the Patent is invalid on the following grounds:

Further or in the further alternative the specification does not contain any directions or explanation as to the meaning of the term “restorative quality of sleep”. The term is so ambiguous, uncertain or lacking in sufficient meaning as to mean that the skilled person would be unable to determine whether they were working the invention of any of the Claims.

Further or in the further alternative, should the Claimants contend that the Claims require “non-restorative sleep” to be measured in any particular way, the skilled person would not be enabled, (either at all or without undue burden), by reading the specification with their common general knowledge to work the invention of the Claims.”

I noted in paragraph 1 above that Flynn is registered as the exclusive licensee of the Patent in the United Kingdom. If that is right, then Flynn is – by virtue of section 67(1) of the Patents Act 1977 – entitled to bring these proceedings in its own right. In this case, Flynn’s status as exclusive licensee – and so its standing to bring these proceedings – is in dispute.

Structure of the judgment

The issues of validity are, obviously, central to this judgment. Novelty (or the lack of novelty) is considered in Section E below; inventiveness (or the lack of any inventive step) is considered in Section F below; and (in)sufficiency is considered in Section G below.

Before considering these matters, however, it is necessary to consider a number of anterior matters:

Sections E, F and G, as I have described in paragraph 10 above, deal with the validity issues arising. Finally:

THE HEARING (1) The evidence

I heard evidence from three witnesses: two experts and one witness of fact. In the order in which they were called, I heard from:

The form of the hearing

The trial of these proceedings was conducted in public. Although there were elements of the documents before me that were confidential, it was possible to hold the proceedings in public without referring, in open court, to these confidential materials.

The trial was a “hybrid” hearing. This was not because Professor Roth gave his evidence remotely, by way of video-link, although that is indeed how Professor Roth gave his evidence. The courts have, for many years, taken evidence remotely by way of video-link, and Professor Roth’s manner of giving evidence was no more than an example of this established practice.

Apart from Professor Roth, all of the central participants in the trial – counsel, key persons in the litigation teams of the solicitors, representatives of the clients and witnesses – were present in court. However, although I had the use of the one of the Rolls Building’s “super-courts”, due to social distancing compelled by the COVID-19 pandemic, there was not enough room for all of the parties’ legal teams (broadly understood), and no room for the public.

The approach that should be taken in these circumstances was considered at the pretrial review. The approach which I ordered was that any person interested should obtain, via email from me, (Footnote: ¹⁷) a link to the video-stream of the proceedings. My order of 5 October 2020 provided as follows in paragraph 4:

“Subject to any alternative direction by the Court, the Trial will be heard as an in-person trial. Irrespective of this, the Trial shall also proceed on a hybrid basis in the following manner:

(a)

The Trial shall also be conducted via Skype for Business and the Trial participants, irrespective of whether the Trial is going ahead as an in person trial, shall have laptops available to be able to follow the proceedings via a link provided in advance (the “Link”) by Sparq, who will provide technical assistance. Sparq are permitted to set up audiovisual equipment in the Courtroom as needed to facilitate the display of the proceedings via the Link. Sparq and Marten Walsh Cherer shall have permission to record the proceedings solely for the purposes of the recording and transcription of the proceedings.

(b)

The parties shall provide to the Court a list of named individuals at least 3 days in advance to whom the Link is to be provided. Such individuals will be in various specific locations outside the physical courtroom. It shall be explained to the named individuals that following the Trial by way of the Link is an extension of the court proceedings and that their location outside the physical courtroom will be deemed by the Judge to be a part of and extension to the physical courtroom. Accordingly, the rules that apply in the ordinary course to court proceedings will apply to such remote locations. In particular, no recording or photographing of images on the screen is permitted; and to do so will amount to contempt of court.

(c)

The document management system CaseLines shall be used alongside (to the extent necessary) hard copy bundles.”

The manner in which proceedings are conducted in court is, subject to overriding mandatory rules, a matter for the trial judge. There are, of course, norms that judges will follow in the ordinary case, but – in exceptional cases – exceptional measures can and should be adopted. Obviously, it is important that proceedings be conducted as close as possible to the norm, but departures from the norm can be and are justified where the broader interests of public justice and the efficient conduct of proceedings require. In this case, the link to the video-stream was justified in order (i) to ensure public access to what were public proceedings; and (ii) to enable all of the relevant persons in the relevant legal teams to attend, if only (in some cases) remotely.

SKILLED PERSON AND COMMON GENERAL KNOWLEDGE (1) Summary of the law

The “person skilled in the art”

The “person skilled in the art” is expressly referred to in the statutory provisions relating to obviousness and insufficiency. The correct identification of such a person (or team of persons) can have important consequences for the identification of the common general knowledge in the art, the construction of the specification, and therefore for the issues of infringement and/or validity. (Footnote: ¹⁸) As Jacob LJ explained in Technip France SA’s

As Terrell notes,²⁵ disputes as to the identity of the person skilled in the art often involve the following questions:

The general characteristics or attributes of a person skilled in the art were described by Lord Reid in Technograph v. Mills & Rockley²⁶ and expanded upon by Jacob LJ in Technip France SA’s Patent:²⁷

“It is settled that this man, if real, would be very boring – a nerd. Lord Reid put it this way in [Technograph]:

“…the hypothetical addressee is a skilled technician who is well acquainted with workshop technique and who has carefully read the relevant literature. He is supposed to have an unlimited capacity to assimilate the contents of, it may be, scores of specifications but to be incapable of a scintilla of invention. When dealing with obviousness, unlike novelty, it is permissible to make a “mosaic” out of the relevant documents, but it must be a mosaic which can be put together by an unimaginative man with no inventive capacity.”

The no-mosaic rule makes him also very forgetful. He reads all the prior art, but unless it forms part of his background technical knowledge, having read (or learnt about) one piece of prior art, he forgets it before reading the next unless it can form an uninventive mosaic or there is a sufficient cross-reference that it is justified to read the documents as one.

He does, on the other hand, have a very good background technical knowledge – the so-called common general knowledge. Our courts have long set a standard for this which is set out in the oft-quoted passage from General Tire v. Firestone Tire & Rubber,²⁸ which in turn approves what was said by Luxmoore J in British Acoustic Films.²⁹ For brevity I do not quote this in full – Luxmoore J’s happy phrase “common stock of knowledge” conveys the flavour of what this notional man knows. Other countries within the European Patent Convention apply, so far as I understand matters, essentially the same standard.

The man can, in appropriate cases, be a team – an assembly of nerds of different basic skills, all unimaginative. But the skilled man is not a complete android, for it is also settled that he will share the common prejudices or conservatism which prevail in the art concerned.”

Common general knowledge

Drawing again from Terrell:³⁰

“Common general knowledge means “the information which, at the date of the patent in question, is common knowledge in the art or science to which the alleged invention relates, so as to be known to duly qualified persons engaged in that art or science”; in other words, it is part of the mental equipment necessary for competency in that art or science concerned, such as every worker in the art may be expected to have as part of his technical equipment. In the context of construction, Aldous LJ explained in Lubrizol v. Esso Petroleum:³¹

“Patent specifications are intended to be read by persons skilled in the relevant art, but their construction is for the Court. Thus the court must adopt the mantle of the notional skilled addressee and determine, from the language used, what the notional skilled addressee would understand to be the ambit of the claim. To do that it is often necessary for the Court to be informed as to the meaning of technical words and phrases and what was, at the relevant time, the common general knowledge; the knowledge that the notional skilled man would have.””

[1972] RPC 346 at 355.

[2004] RPC 32 at [7] to [10]. Quoted in Terrell at [8-42].

[1972] RPC 457 at 482.

53 RPC 221 at 250.

At [8-56].

[1998] RPC 727 at 738.

Territoriality and its significance

I bear in mind that the Patent is a United Kingdom designation of a European patent, and that when considering the identity of the skilled person and the common general knowledge that such a person would have, I must view matters from the perspective of a skilled person in the United Kingdom’s.

That, as it seems to me, follows from the nature of the property before me, that is, a United Kingdom patent. In Actavis v. Lilly, (Footnote: ²⁰) Lord Neuberger stated:

“A patent is interpreted on the basis that it is addressed to a person or group of persons who is or are likely to have a practical interest in the claimed invention, i.e., through the eyes of a person skilled in the art.”

The skilled person will be looking at an invention that is claimed within the United Kingdom and whose territorial ambit is defined by the United Kingdom, and that must be the starting point for determining the nature of the skilled person. A United Kingdom designation of a European patent confers no rights outside the territorial scope of the United Kingdom.

It follows that the common general knowledge of the skilled person must be known in the United Kingdom. In Generics v. Warner-Lambert, Arnold J stated: (Footnote: ²¹)

“…Counsel for Warner-Lambert submitted that matter relied on as being common general knowledge must be shown to be common general knowledge in the UK, but counsel for Mylan and Actavis disputed that this was necessary. Although I only received limited argument on the point, it seems to me that, at minimum, it must be shown that the matter in question was common general knowledge in the UK. The reason for this is that, whether one is concerned with the validity of a European Patent (UK), or a UK Patent, one is concerned with a right in respect of the UK. It is true that the prior art may have been published anywhere in the world, but I do not think that alters the need for the skilled team to consider that art as if they were located in the UK. I do not think it matters that a fact was common general knowledge in (say) China, if it was not common general knowledge here. The position may be different if all the persons skilled in a particular art in the UK are acquainted with the position in China, but no point of that kind arises here…”

Of course, that does not mean that the skilled person will not have an international outlook, and will not consider prior art published anywhere in the world.

Knowledge of the law

Patents are technical documents, and the skilled person must have sufficient understanding of patent law to appreciate the general nature and function of a patent specification and claims. Thus, in Kirin-Amgen v. Hoechst Marion Roussel (No 2),³⁴ Lord Hoffmann noted:

“But the person skilled in the art (who must, in my opinion, be assumed to know that basic principles of patentability) might well have thought that the claims were restricted to existing technology because of doubts about sufficiency rather than lack of foresight about possible developments.”

Terrell says this:

I labour this aspect of the skilled person because – for reasons that I have already mentioned and that I describe more fully in this judgment – it seemed to me that Professor Morgan lacked the necessary understanding of the “nuts and bolts” of patents and patent law, including as to the question of common general knowledge, and that this had the unfortunate effect of skewing in unpredictable ways his evidence and rendering it unreliable.

Approach

In reality, the patent in issue, the skilled person and the skilled person’s common general knowledge are three mutually supporting pillars in terms of determining what is required to understand the Patent.

My approach, in this case, is to begin with the content and terms of the Patent, and then to work from this to consider what other material and information would form part of the skilled person’s common general knowledge.

The present case

Indications from the Patent

The Patent describes the field of the invention claimed as follows: (Footnote: ²²)

“The present invention relates to a method for treating primary insomnia (as defined by DSMIV or nonorganic insomnia as defined by ICD-10) when characterised by non-restorative sleep, and to the use of melatonin in the manufacture of a medicament for this purpose.” -IV” and “ICD-10” are terms of art. DSM-IV refers to the 4^th edition

The terms “DSM

DSM-IV materially provides:

ICD-10 materially provides:

The Patent then describes the background to the invention. (Footnote: ²⁵) This description emphasises the quality of sleep aspect of inorganic insomnia (to use ICD-10 terminology) or non-restorative sleep aspect of Primary Insomnia (to use DSM-IV terminology). Thus:

The invention is then summarised. Referring to the terms of the Patent as amended, the relevant paragraphs provide as follows: (Footnote: ³¹)

“[0013] The present invention provides in one aspect, use of a prolonged release formulation comprising melatonin in unit dosage form, each unit dosage comprising 0.025 to 10 2 mg of melatonin, in the manufacture of a medicament for improving the restorative quality of sleep in a patient aged 55 years or older suffering from primary insomnia characterised by non-restorative sleep, wherein the medicament comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier.

[0014] In another aspect, the invention provides a medicament for use in improving the restorative quality of sleep in a patient aged 55 years or older suffering from primary insomnia characterised by non-restorative sleep, which comprises a prolonged release formulation comprising melatonin in unit dosage form, each unit dosage comprising 0.025 to 10 2 mg of melatonin, and at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier. Also disclosed is a medicament, for use in improving both the quality and quantity of sleep, in primary insomnia, which comprises at least one compound selected from melatonin, other melatonergic agents, melatonin agonists and melatonin angtagonists, and at least one additional therapeutic agent selected from anxiolytics, antidepressants, hypnotics, sedatives, antihypertensives, analgesics, dopaminergic agonists, antipsychotics, minor tranquilizers, anorectics and antiinflammatory drugs, in addition to at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers adjuvant or carrier.”

The words in bold are, I should stress, my emphasis. I shall return to their significance in due course. However, I should make clear now that I regard these words as essentially inconsistent with the teaching of the Patent and the inventions claimed therein.

A detailed description of the invention follows, at [0015] to [0021], which last paragraph refers to the fact that “[t]he invention will be illustrated by the following Examples”. There then follow five Examples, variously described as:

It will be necessary to consider various of these Examples in due course. For present purposes, however, it is important to note that the skilled person would appreciate their significance as follows:

Finally, the Claims are set out. Although only Claims 1 and 4 were of direct relevant to the issues before me, it is appropriate to set out the Claims (in their English form) in their entirety: (Footnote: ³⁵)

“1.

Use of a prolonged release formulation comprising melatonin in unit dosage form, each unit dosage comprising 0.025 to 10 2 mg of melatonin, in the manufacture of a medicament for improving the restorative quality of sleep in a patient aged 55 years or older suffering from primary insomnia characterised by non-restorative sleep, wherein the medicament comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier.

2.

Use according to claim 1, wherein the medicament is further characterised by at least one of the following features:

(i)

it is adapted for oral, rectal, parenteral, transbuccal, intrapulmonary (e.g., by inhalation) or transdermal administration;

(ii)

it is in depot form which will release the melatonin slowly in the body, over a preselected time period.

3.

Use according to claim 1 or claim 2, wherein said prolonged release formulation includes an acrylic resin.

4.

A medicament for use in improving the restorative quality of sleep in a patient aged 55 year or older suffering from primary insomnia characterised by non-restorative sleep, which comprises a prolonged release formulation comprising melatonin in unit dosage form, each unit dosage comprising 0.025 to 10 2 mg of melatonin, and at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier.

5.

Medicament for use according to claim 4, which is further characterised by at least one of the following features:

(i)

it is adapted for oral, rectal, parenteral, transbuccal, intrapulmonary (e.g., by inhalation) or transdermal administration;

(ii)

it is in depot form which will release the melatonin slowly in the body, over a preselected time period.

6.

Medicament for use according to claim 4 or claim 5, wherein said prolonged release formulation includes an acrylic resin.”

It is appropriate to say something about the nature and meaning of the Claims at this point:

The Skilled Person

It is trite that these matters all must be resolved as at the Priority Date, and that is the date that I use in this judgment.

The Patent relates – as I have described – to the prolonged release of melatonin to treat primary insomnia characterised by nonrestorative sleep. As is clear from ICD-10 (a publication of the World Health Organisation) and DSM-IV (a publication of the American Psychiatric Association), this was an area of medicine that was international in outlook.

Both experts addressed their understanding of the skilled person in their reports and in their evidence before me:

Accordingly, the skilled person for the purposes of this case is a sleep medicine clinician, who has studied and/or practised extensively in the area of Primary Insomnia and who has significant expertise in Primary Insomnia and the diagnostic guidelines used in the diagnosis of insomnia, including the DSM and ICD (the Skilled Person).

However, I should say that I am in no sense using Professor Roth as a proxy for the Skilled Person, albeit that the Skilled Person would have a background, training and experience similar to that of Professor Roth. Even in 2001, Professor Roth had a level of experience and expertise above that of the Skilled Person and – it would follow – a personal common general knowledge in excess of the Skilled Person. I take that very much into account when considering the common general knowledge that the Skilled Person would have as at the Priority Date.

Common general knowledge

Introduction

In this case, at least, common general knowledge is not to be identified by reference simply to a list of publications, which the Skilled Person would have read and digested. Still less is the Skilled Person going to be informed by lists of publications obtained through a keyword search of the scientific literature. (Footnote: ⁴²) Whilst I have no doubt that the Skilled Person would or could use searches to augment his or her learning and knowledge, the Skilled Person would not be primarily reliant on such searches for his or her common general knowledge.

The Skilled Person’s common general knowledge is best understood and explained by reference to a series of topics or issues arising out of the subject-matter of the Patent, with which the Skilled Person would have been familiar and would have been concerned to understand. These topics or issues would have been as follows:

The nature of Primary Insomnia and the position of non-restorative sleep within Primary Insomnia

It was common ground that the starting point for ascertaining the Skilled Person’s common general knowledge would be DSM-IV and ICD-10. Not only are these taken as read in the Patent, it was the clear evidence of Professors Roth and Morgan that these materials would have formed part of the Skilled Person’s common general knowledge. (Footnote: ⁴³)

Although their terminology differs, the diagnostic approach described in each document is – in fundamental terms – the same:

The co-existence (or otherwise) of non-restorative sleep with other indications of Primary Insomnia

It would, of course, be entirely wrong to consider that these diagnostic indicators or criteria only present alone and not in conjunction with other indicators or criteria. Whilst it is perfectly possible for an individual to present only with non-restorative sleep/poor quality of sleep, equally an individual may suffer from two or more such issues. The Skilled Person would know this.

Professor Morgan referred to a paper (Ohayon 1997) (Footnote: ⁴⁶) which (amongst other things) provided data in relation to the extent to which poor quality of sleep co-existed with other diagnostic indicators:

Primary Insomnia and Circadian Rhythm Sleep Disorder

I have referred above to Circadian Rhythm Sleep Disorder, which typically occurs where – for instance, due to transmeridian travel or shift work – an individual’s “body clock” gets out of synchronisation with the times at which that individual would like to sleep.

Although there is a similarity between Primary Insomnia and Circadian Rhythm Sleep Disorder, it is superficial only. The individual suffering from Circadian Rhythm Sleep Disorder has no difficulty going to sleep per se, merely as to when that individual goes to sleep. In other words, instead of feeling sleepy at bedtime, the individual feels sleepy when he or she wants to be awake. By contrast, an individual suffering from Primary Insomnia has difficulty getting to sleep.

The distinction was made very clearly by Professor Roth in cross-examination: (Footnote: ⁴⁸)

It is clear to see why DSM-IV sought to differentiate Circadian Sleep Rhythm Disorder from Primary Insomnia, and the Skilled Person would have been well aware of the need to be able to differentiate the two.

Diagnosing non-restorative sleep

It was Professor Roth’s position that the diagnosis of Primary Insomnia generally, and non-restorative sleep in particular, was subjective. Because this was a point on which he and Professor Morgan did not necessarily see eye-to-eye, I begin by a quotation from Roth 3, which sets out Professor Roth’s position on this: (Footnote: ⁴⁹)

“6.35

As at the Priority Date, I would expect the skilled person to have a working understanding of the definition of primary insomnia in the DSM-IV and the definition of nonorganic insomnia in the ICD-10, and to understand that those diagnoses are intended to be equivalent. I would expect the skilled person to understand the following as part of their background/common general knowledge.

6.36

First, primary insomnia is a persistent complaint of difficulty falling asleep, maintaining sleep, or of non-restorative sleep (called “poor quality of sleep” in the ICD-10). Both the DSM-IV and the ICD-10 diagnostic criteria direct attention to the patient’s “complaint”. This underscores that the diagnosis of primary insomnia is made based on the patient’s subjective report of difficulty falling asleep or maintaining sleep, or their subjective feeling that their sleep has not been restorative.

…

6.39

Because primary insomnia is diagnosed based on the patient’s complaint of difficulty falling asleep, maintaining sleep, or of non-restorative sleep, the primary method of diagnosis is by taking a thorough medical (including sleep) history. In addition to exploring the nature and duration of the patient’s dissatisfaction with their sleep, the sleep history should cover other aspects of the diagnostic criteria, such as daytime impairment and distress (criterion B in the DSM-IV; criteria C and D in the ICD-10). The history taking will also elicit information relevant to determining whether the insomnia is “primary” or “nonorganic”, for example by discussing other symptoms or medical conditions and substance use (criteria C to E in the DSM-IV; general discussion under the “Diagnostic guidelines” heading in the ICD-10).

6.40

A comprehensive medical (including sleep) history should be supplemented by a physical examination. In some cases, it may also be helpful to ask the patient to complete a sleep diary in which the patient records matters such as their bedtime, arising time, medications, alcohol use, estimated time to fall asleep, estimated duration of sleep, estimated number of awakenings, and the quality of their sleep/restorative quality of their sleep. A physical examination and a sleep diary can assist in identifying whether the insomnia is “primary/nonorganic” or secondary to some other cause. A sleep diary may also assist in assessing the nature and severity of the patient’s sleep disturbances.

6.41

As at the priority date, objective methods for monitoring a patients sleep – polysomnography and actigraphy – were used frequently in research but were not indicated for the routine assessment, diagnosis and treatment of insomnia. If abnormal physiological events during sleep (such as sleep apnea or periodic limb movements) are the suspected cause of insomnia, polysomnography is necessary to confirm or exclude those possibilities. Actigraphy, which provides data on activity patterns over multiple days, can be useful in assessing sleep-wake schedule disorders, i.e. circadian rhythm sleep disorders.

6.42

I have been asked by the Instructing Solicitors whether actigraphy and/or polysomnography can be useful in assessing whether an insomnia patient’s sleep is non-restorative or whether that patient has experienced an improvement in the restorative quality of their sleep. Both actigraphy and polysomnography have a multitude of outputs such as total sleep time, sleep latency and sleep efficiency. Importantly, no output of actigraphy or polysomnography has been validated for the purpose of determining whether a patient’s sleep is non restorative, or whether that patient has experienced an improvement in the restorative quality of their sleep. The restorative quality of sleep can only be determined based on the patient’s subjective report. There are no data to suggest that an improvement in the qualitative aspects of sleep can be measured objectively. In addition, there are no data to support the use of techniques such as actigraphy or polysomnography with an improvement in an insomnia patient’s subjective experience of the restorative quality of their sleep.”

It is clear that Professor Roth considered that all aspects of Primary Insomnia – difficulty in initiating sleep, difficulty in maintaining sleep and nonrestorative sleep – were subjective in their nature and in their diagnosis. Indeed, whilst it may be possible to measure some of these aspects – for instance, the time a person spends asleep – a purely objective diagnosis (i.e., a diagnosis based upon purely external measures) is difficult because “difficulty in initiating sleep”, “difficulty in maintaining sleep” and “non-restorative sleep” all contain subjective elements based upon the individual experience of the (non-) sleeper. Thus, whilst it may be possible, through polysomnography and actigraphy, to say that an individual fell asleep at 11:00pm, such external measures cannot say how long that individual was actually trying to fall asleep (i.e., latency is, inevitably, subjective).

Whatever the position as regards Primary Insomnia characterised by difficulty in initiating sleep and difficulty in maintaining sleep, it is clear that Primary Insomnia characterised by non-restorative sleep is a purely subjective phenomenon because only the individual in question can say whether his or her sleep has been restorative. More specifically:

I find that the Skilled Person would understand that Primary Insomnia characterised by non-restorative sleep would be diagnosed in the manner described by Professor Roth in the passages set out in paragraph 60 above, that is by ascertaining (typically by taking a history) how, subjectively, the patient considered his or her quality of sleep (using that term in the ICD-10 sense).

Questionnaires might be used to obtain this data. Because it featured in the trial, I should describe one such questionnaire, namely the Leeds Sleep Evaluation Questionnaire:

Methods of treatment for Primary Insomnia in general, and non-restorative sleep in particular

I should stress that I am, in this section, considering the Skilled Person’s common general knowledge as at the Priority Date, but disregarding the teaching of the Patent, whatever that teaching might be. I should also say that I am – for the purposes of this section – disregarding the pleaded prior art. I will, of course, consider that prior art in detail when I turn to consider the issues of (in)validity that arise in this case.

It was well-understood, as at the Priority Date, that benzodiazepines and related drugs were hypnotics capable of use in ameliorating or eliminating Primary Insomnia and so could be indicated for the treatment of Primary Insomnia. However, there were distinct disadvantages to the use of such hypnotics, particularly in the aged. This was common general knowledge in the United Kingdom (as well as internationally, including the United States). Where there was a difference – but I do not consider it to be a relevant one – was the extent to which the use of benzodiazepines differed according to jurisdiction. That, in my judgment, had nothing to do with the common general knowledge as to these drugs, but merely reflected a different attitude to the known disadvantages in their use. More specifically:

Professor Roth was clear in his evidence that, as at the Priority Date, there was no treatment for non-restorative sleep and – relatedly – there was no recognition that melatonin might play a role in the successful treatment of complaints of non-restorative sleep. Professor Morgan’s evidence on this point was, I am sorry to say, not satisfactory when coming from someone presenting as an expert in this area. That evidence was, in the first place, nebulous in the extreme; and, to the extent that Professor Morgan could be understood to be advancing clear propositions, they were simply unsupported by the other evidence before me (including the material referred to by Professor Morgan in his own reports). Once again, it is important to state with specificity why this is the case, since I am disbelieving and rejecting Professor Morgan’s evidence:

At least, that is what I take the Professor to be saying in paragraph 4.64. The double negative makes the paragraph hard to follow.

Thus:

Baskett, Cockrem and Todd, Melatonin Levels in Hospitalized Elderly Patients: A Comparison with Community Based Volunteers, (1991) 20 Age and Aging 430-434 (Baskett et al 1991, cited at paragraph 4.64 of Morgan 1) concerned twenty one-hour melatonin plasma profiles studied in 15 normal elderly volunteers from the community.

Garfinkel, Laudon, Nof and Zisapel, Improvement of sleep quality in elderly people by controlled-release melatonin, (1995) 346 The Lancet 541-544 (Garfinkel et al 1995, cited at paragraph 4.65 of Morgan 1) concerned 12 elderly subjects “who were receiving various medications for chronic illnesses and who complained of insomnia”. Although all subjects complained of “long term insomnia”, this was not further specified. (That is not, I stress, a criticism of the study: it merely highlights that the study was focussed not on primary insomnia but sleep more generally in old people.)

Haimov and Lavie, Potential of Melatonin Replacement Therapy in Older Patients with Sleep Disorders, (1995) 7(2) Drugs & Aging 75-78 (Haimov and Lavie 1995, cited at paragraph 4.65 of Morgan 1) concerned the use of a “sustained-release melatonin formulation to effectively restore melatonin levels in the elderly to those present in younger individuals throughout the night, in comparison with conventional-release tablets and placebo.”

THE TRUE CONSTRUCTION OF THE PATENT

The person skilled in the art and his or her common general knowledge is, as I have said, relevant to various of the matters before me. The first of these is the true construction of the Patent. I must construe the Patent through the notional addressee, who is the Skilled Person described above, with the common general knowledge that I have also described. (Footnote: ⁷⁵)

In this case, it is very clear that the Patent claims by way of Claims 1 and 4 the use of melatonin (in the form described) for improving the restorative quality of sleep in a patient suffering from Primary Pnsomnia characterised by non-restorative sleep. (Footnote: ⁷⁶)

The Skilled Person would appreciate the references in Patent/[0001] to DSM-IV and ICD-10, and would, as a result, understand that the terms “primary insomnia”, “nonorganic insomnia” and “non-restorative sleep” would bear the technical meanings that I have described in Section C above. Patent/[0001] does not, itself, refer to “quality of sleep” or “sleep quality”, but there are other, multiple references in later paragraphs of the Patent to quality of sleep. The Skilled Person would, inevitably, understand such terms in their technical sense. Specifically, the Skilled Person would understand that “quality of sleep” was the ICD-10 equivalent of “non-restorative sleep” and would understand the Patent to be using these terms in this way.

Claims 1 and 4 both refer to the invention “improving the restorative quality of sleep”. Professor Morgan had an issue with the phrase “improving the restorative quality of sleep”, which appears in Claims 1 and 4 of the Patent.¹⁰⁵ In Morgan 1/§6.40, Professor Morgan said:

“The invention is said to “improve the restorative quality of sleep”. “Restorative quality of sleep” was not a term of art used in sleep research and medicine in 2001. It is not a term I was familiar with before reading the Patent and the skilled person would not be familiar with it either. It is not a term of art and no definition is given in the Patent.”

I reject this evidence as fanciful. Both Claims 1 and 4 refer to a patient “suffering from primary insomnia characterised by non-restorative sleep”. The Skilled Person would understand this to mean an individual suffering from the sort of insomnia that I have described in Section C above. Absent the words in bold that I have highlighted in paragraph 39 above, which confuse and distract from what the Patent claims to teach, there is no room for any misunderstanding or alternative meaning within the terms of the Patent. On the whole, the Patent is clear. The phrase “improve the restorative quality of sleep” is coloured by the nature of the symptoms of this individual and the Skilled Person would understand that the invention was claiming to ameliorate or eliminate this particular symptom. The meaning of the phrase is clear from the Patent.

LACK OF NOVELTY OR ANTICIPATION (1) Introduction

I turn, then, to the question of whether the Patent lacks novelty or whether the Patent has been anticipated by prior art. The basis on which it is suggested by Mylan that the Patent lacks novelty is Haimov 1995. (Footnote: ⁷⁷) It is necessary for me to consider first the relevant law (Section E(2)) and then Haimov 1995 (Section E(3)). My conclusions are stated in Section E(4).

The law

The law on novelty – in particular in the context of second medical use patents – was set out by Floyd J in Regeneron Pharmaceuticals Inc v. Genentech Inc:¹⁰⁷

“96.

Section 2(1) of the Patents Act 1977 provides:

“(1)

An invention shall be taken to be new if it does not form part of the state of the art.

(2)

The state of the art in the case of an invention shall be taken to comprise all matter (whether a product, a process, information about either, or anything else) which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way.”

31 LJ Ch (NS) 457 at 463 and the judgment of the Court of Appeal in General

At [22], Lord Hoffmann says this:

“If I may summarise the effect of these two well-known statements, the matter relied upon as prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent. That may be because the prior art discloses the same invention. In that case there will be no question that performance of the earlier invention would infringe and usually it will be apparent to someone who is aware of both the prior art and the patent that it will do so. But patent infringement does not require that one should be aware that one is infringing: “whether or not a person is working [an]…invention is an objective fact independent of what he knows or thinks about what he is doing”: Merrell Dow Pharmaceuticals Inc v. HN Norton & Co Ltd, [1996] RPC 76, 90. It follows that, whether or not it would be apparent to anyone at the time, whenever subject-matter described in the prior disclosure is capable of being performed and is such that, if performed, it must result in the patent being infringed, the disclosure condition is satisfied. The flag has been planted, even though the author or maker of the prior art was not aware that he was doing so.”

The claims in the present case specify a medical use for a product either in the so called Swiss form (“use of compound X in the manufacture of a medicament to treat disease Y”) or in the form permitted by the European Patent Convention 2000 (“compound X for use in treating disease Y”). In the European Patent Office the view is taken that, with claims in either form, the actual achievement of the therapeutic effect is a functional technical feature of the claim, as opposed to a mere statement of purpose or intention. That this is so can be seen from decision T 0609/02 The Salk Institute for Biological Studies, at [9] of the Reasons and the cases cited there, which include, in the non-medical field, the well known Mobil decision G2/88. The claimants did not have any convincing reason why that should not apply here.

Mr Waugh reminded me that novelty is not created merely by describing something old in different language, or merely by providing new information about what is old. He had in mind, no doubt, cases such as Bristol Myers Squibb v. Baker Norton Pharmaceuticals, [2001] RPC 1. That submission is correct.”

The law is also clearly set out in Terrell, which states:

“11-03 The current law was concisely summarised by Lord Hoffmann sitting in the Court of Appeal in H Lundbeck A/S v. Generics (UK) Ltd as follows:

“In order to anticipate a patent, the prior art must disclose the claimed invention and (together with common general knowledge) enable the ordinary skilled person to perform it.

11-04

To “disclose the claimed invention” as here required, the prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent.

11-05

The need for an “enabling disclosure” is equally important. A disclosure of, e.g. the existence of a chemical substance is not enabling (and therefore not an anticipation) if the skilled reader would not know from the information given how to produce or obtain it, or how to obtain or to make the required starting materials. Merely being told it exists is not of itself enough.”

Enablement is of particular importance in the case of the anticipation of second medical use patents, such as this. It is the second medical use that must be anticipated – not the medicament itself nor some other use: (Footnote: ⁷⁸)

“Medical use claims owe their novelty to the discovery of the new therapeutic use of the medicament. The actual achievement of the therapeutic effect is a functional technical feature of such a claim. This is true for Swiss-style claims and EPC 2000 claims. Therefore, in order for prior art to deprive a medical use claim of novelty, there must be an enabling disclosure of the claimed therapeutic effect. So if and to the extent that plausibility forms part of the requirement for enablement in the context of sufficiency (so held in Regeneron), logically it must play the same role in the context of novelty.”

Haimov 1995

The summary in Haimov 1995 states:

“Changes in sleep-wake patterns are among the hallmarks of biological ageing. Previously, we reported that impaired melatonin secretion is associated with sleep disorders in old age. In this study we investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. The study comprised a running-in, no-treatment period and four experimental periods. During the second, third and fourth periods, subjects were administered tablets for 7 consecutive days, 2 hours before desired bedtime. The tablets were either 2 mg melatonin administered as sustained-release or fast-release formulations, or an identical-looking placebo. The fifth period, which concluded the study, was a 2-month period of daily administration of 1 mg sustained-release melatonin 2 hours before desired bedtime. During each of these five experimental periods, sleep-wake patterns were monitored by wrist-worn actigraphs. Analysis of the first three 1-week periods revealed that a 1-week treatment with 2 mg sustained-release melatonin was effective for sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved by the fast-release melatonin treatment. Sleep maintenance and initiation were further improved following the 2month 1-mg sustained-release melatonin treatment, indicating that tolerance had not developed. After cessation of treatment, sleep quality deteriorated. Our findings suggest that for melatonindeficient elderly insomniacs, melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.”

As is clear from this summary, Haimov 1995 is concerned with what Professor Morgan would call the “melatonin theory of insomnia”, where poor sleep was attributed to a melatonin deficiency that increased as a function of age (i.e., the older a person, the lower the levels of melatonin). That explains the broad-brush approach taken in the selection of the individuals participating in the study. The subjects of the study were described in the following terms: (Footnote: ⁷⁹)

“The study population comprised three groups: i) independently living insomniacs (eight patients: four male, four female; aged 73.1 ± 3.9 years); ii) institutionalised insomniacs (18 patients: six male, 12 female; aged 81.1 ± 8.9 years) living a minimum of 6 months in a nursing home; iii) elderly without sleep disorders (25 patients: 19 male, six female; aged 71.4 ± 5.2 years) living independently in the community. The purpose of recording the elderly group without sleep disorders was to validate the subjective complaints of insomnia. This group was not included in the treatment part of the study. These subjects overlap with those in our previous report of sleep disorders and melatonin rhythm in the elderly. The insomnia patients (the independently living insomniacs and the institutionalised insomniacs) were considered

“melatonin-deficient” because they had significantly lower peaks of secretion than did the elderly without sleep disorders…All subjects were in good clinical condition, and none met any criteria for dementia or depression according to the Mini-Mental State Examination or the Hamilton rating scale. Subjects were personally interviewed by an experienced physician to rule out significant sleep apnea syndromes which could be related to physiologically based insomnia, or any medical illness that might interfere with sleep. None of the subjects used any medication that could affect sleep or the noradrenergic system for at least 1 month prior to the study. Because in the International Classification of Sleep Disorders (ICSD) there is no diagnosis of insomnia in the elderly, we accepted volunteers if they reported sleeping poorly on at least 3 nights per week and if their insomnia had lasted for a minimum of 6 months. Volunteers also had to report that their insomnia clearly affected their daytime functioning, that it was not caused by chronic pain or any known medical disease and that the volunteer did not use either alcohol or drugs that might affect sleep. Volunteers were then sent a number of questionnaires, including a one-week sleep log, a mini-sleep questionnaire (MSQ) and the Technion Sleep Questionnaire.”

As can be seen from the summary, the effect of melatonin on the group was beneficial. The study concluded:

“This study suggests two important principles of melatonin replacement therapy of melatonindeficient, elderly insomniacs: i) melatonin appears to have a beneficial effect when administered in the form of sustained-release tablets and ii) to ensure efficacy, long-term treatment is recommended.

In conclusion, melatonin deficiency seems to be a key variable in the incidence of sleep disorders in the elderly. From the results of the present study, it seems likely that melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep in this population. Further studies employing the chronic administration of melatonin, in varying dosages of different preparations, and the investigation of their effects by segmenting the longterm treatment into intervals must be pursued before determining the most efficient melatonin replacement therapy for elderly insomniacs.”

Both Professor Roth and Professor Morgan considered Haimov 1995 in their evidence. As to their evidence:

Conclusion on novelty

I conclude that Haimov 1995 in no way anticipates the Patent and that the Patent is novel over Haimov 1995. Haimov 1995 simply does not address the inventive step which is taught in the Patent. That is not surprising, since the study was directed to a completely different matter. However, to be clear, the Patent was not even “accidentally” anticipated by Haimov 1995: the Skilled Person would have learned nothing about the effect of melatonin on Primary Insomnia characterised by nonrestorative sleep from Haimov 1995.

LACK OF INVENTIVE STEP OR OBVIOUSNESS (1) Introduction

As I have described in paragraph 8(2) above, Mylan contends that Patent does not disclose an inventive step and is obvious in light of Haimov 1995, Melatonex and the Melatonex Webpage and Zisapel 1999.

What is obvious – and what is not obvious – is not a matter that can further be deconstructed or defined. The word means what is says. (Footnote: ⁸⁶) The question of obviousness is approached in the following way. In light of the common general knowledge of the person skilled in the art, and having construed the inventive concept of the claim in question:

Unless the prior art can properly be seen as part of a mosaic, each piece of prior art must be considered separately, to see if the invention claimed by the patent is actually inventive or whether it is, in light of the prior art, obvious.

Although these matters have already been traversed in this judgment, I should be clear that the inventive step claimed by the Patent is that the use of melatonin (in the form described) improves the restorative quality of sleep in a patient suffering from Primary Insomnia characterised by non-restorative sleep. (Footnote: ⁸⁷) The question is whether the three items of prior art pleaded by Mylan render this obvious in the manner that I have described. I consider these three items in turn below.

Haimov 1995

It is unnecessary for me to repeat the description of the content of Haimov 1995 contained in paragraphs 77ff above. I fully recognise that the test for novelty/anticipation is a materially higher one than that of obviousness/lack of inventive step, and the mere fact that the invention disclosed by the Patent has not been anticipated by Haimov 1995 does not mean that Haimov 1995 does not render the claims in the Patent not inventive.

However, in this case, I conclude that Claims 1 and 4 are original and are inventive over Haimov 1995. The Skilled Person, having the common general knowledge that I have described, but lacking inventive capacity, would draw nothing from Haimov 1995 to render the invention of the Patent obvious. As I have described, Haimov 1995 suggests that the administration of melatonin may have beneficial effects on aged persons suffering from a deficiency in melatonin. Haimov 1995 says literally nothing about the effect of melatonin on an individual (of whatever age) suffering from Primary Insomnia characterised by non-restorative sleep.

The Patent is not obvious over Haimov 1995.

Melatonex and the Melatonex Webpage

As I have described, melatonin is available on a non-prescription basis in the United States, but not in the United Kingdom. It is, therefore, possible to purchase melatonin or products containing melatonin in the United States in a manner that is not possible in the United Kingdom. I am prepared to assume that this is something that the Skilled Person would know, and I proceed on that basis.

The Melatonex Webpage describes Melatonex in the following terms:

“Sleep better to feel better

MELATONEX is a dietary supplement containing melatonin, a substance produced by our own bodies that regulates the body’s natural sleep/wake cycle. After we reach maturity, melatonin production declines with age which can make restful sleep more difficult to achieve. Melatonin production can also diminish through our use of substances like alcohol, tobacco, caffeine, aspirin and many common medications. MELATONEX supplementation can help to restore the melatonin we need for a restful, natural sleep.^*”

Pausing there, the webpage – by way of the asterisk footnote – then refers to a warning in bold type in a box:

“These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease.”

The text then continues:

“Unique time release delivery

MELATONEX uses a unique time-release delivery system that releases melatonin the way the body does, gradually while you sleep.

Antioxidant action

Research shows melatonin to be a highly effective antioxidant against hydroxyl free radicals, toxic by-products or normal metabolism that can cause cell damage.^*”

The asterisk refers to the same warning as above. The rest of the webpage contains suggestions as to use, supplement facts and cautions as to use, which it is unnecessary to set out.

In Roth 3, Professor Roth makes the point that the Skilled Person would view

Professor Morgan appeared to share Professor Roth’s view that the Melatonex Webpage amounted to no more than advertising copy, but he considered that this would nevertheless motivate the Skilled Person to “conduct further research”:¹²¹

“8.16

The skilled person, given what was known in 2001, would expect the product being advertised here to share the same qualities and impact as what was known in 2001 about slow release melatonin. Melatonin’s role in inducing sleep was well-known, albeit that its mechanism of action was not.

8.17

The difference between Melatonex and the claim of the Patent is therefore a disclosure that prolonged release melatonin is effective in improving the restorative quality of sleep in this patient population. There is no data presented in the label, but Melatonex refers to achieving a “restful, natural sleep”. In light of what was known about melatonin in 2001 and the potential of melatonin replacement therapy, the skilled person would be motivated to conduct further research. The skilled person would conduct a trial to test melatonin doses, including the 3 mg used within the Melatonex formulation, with a reasonable expectation of showing an improvement in the subject’s experience of getting to sleep, maintaining sleep and non-restorative sleep.”

In my judgment, the Patent is plainly not obvious over Melatonex and the Melatonex Webpage:

Zisapel 1999

I referenced this publication in paragraph 8(2)(c) above. The article is characterised by the keywords “Melatonin – Insomnia – Sleep – Circadian Rhythms – Therapy”. The abstract for the article provides:

“The pineal product melatonin is involved in the regulation of the sleep/wake cycle in humans. In blind individuals and in people travelling through time zones, melatonin rhythms are sometimes unsynchronised with the diel cycle, and nocturnal sleep may be disturbed. Low or distorted melatonin rhythms have repeatedly been reported in middle aged and elderly insomniacs. Melatonin administration effectively synchronised the sleep wake cycle in blind individuals and in subjects suffering from jet lag and advanced sleep onset in subjects suffering from delayed sleep phase syndrome. In elderly insomniacs, melatonin replacement therapy significantly decreased sleep latency, and/or increased sleep efficiency and decreased wake time after sleep onset. In addition, melatonin substitution facilitated benzodiazepine discontinuation in chronic users. These data show an association between melatonin rhythm disturbances and difficulties to promote or maintain sleep at night. Specific melatonin formulations may be useful to treat circadian-rhythm-related sleep disorders and age-related insomnia.”

The article concludes:

“Based on the current scientific and clinical knowledge, there seem to be at least three distinct clinical indications for melatonin therapy in insomnia: (a) replacement therapy in case of low or absent nocturnal melatonin concentrations. In these patients regaining of a robust melatonin rhythm may be better met with the controlled-release melatonin formulation. (b) Phase-shifting of the circadian clock for phase resetting in blind people, jet lag or delayed sleep phase syndrome, regular release melatonin has proven efficacy. (c) Benzodiazepine discontinuation. Presently, no melatonin formulation has been approved for clinical use by any regulatory authority. The decisions of whether to use melatonin therapy, when to use it and for what period of time, and what formulation to use await further scientific attention.”

Professor Roth regarded Zisapel 1999 as a review of the literature in the area of melatonin treatment. It neither reported any original research nor did it give any metaanalysis of the data reviewed. (Footnote: ⁹¹) Per se, therefore, Zisapel 1999 is an unpromising piece of prior art from the point of view of demonstrating obviousness in the Patent, since one would expect the relevant prior art to appear elsewhere than what is purely a review article. To this end, Professor Roth reviewed the references in Zisapel 1999 in the way that he considered the Skilled Person would have done.

Professor Roth concluded that the paper – whilst obviously directed at the effects of melatonin on insomniacs, including what the paper called primary insomniacs – did not render the inventive concept in the Patent obvious:¹²⁴

“13.2

Zisapel 1999 is not concerned with primary insomnia as defined by DSM-IV (or nonorganic insomnia as defined by ICD-10) characterised by non-restorative sleep. While there are references to primary insomnia, Zisapel 1999 does not address the therapeutic use of melatonin for treating primary insomnia (whether characterised by non-restorative sleep or otherwise).

13.3

A number of observations are reported by Zisapel 1999 on melatonin rhythms or levels in patients which it incorrectly asserts have primary insomnia. The observations also do not always match up with the data cited in the underlying paper, see for example my comments on Rodenbeck and Pollak above. Zisapel 1999 does not report any relationship between melatonin and the restorative quality of sleep of patients.

13.4

Zisapel 1999 does not mention non-restorative sleep. If the skilled person was interested specifically in the sub-population of primary insomnia patients with non restorative sleep, Zisapel 1999 provides nothing about how to treat that population.

13.5

Zisapel 1999 does not assess whether a patient’s restorative quality of sleep is improved by melatonin, other than in benzodiazepine-dependent patients, and even there infrequently.

13.6

Moreover, those papers reviewed in Zisapel 1999 in which the effect of melatonin on the patients’ subjective assessment of their “sleep quality” was assessed…, tend to point away from melatonin being of use in patients with primary insomnia.”

Professor Morgan’s views were as follows: (Footnote: ⁹²)

“8.18

The skilled person would understand from Zisapel that prolonged release melatonin doses within the range claimed specific 1-2 mg in the Patent may effectively improve sleep quality in elderly insomnia patients.

8.19

The difference between Zisapel and the claim of the Patent is that Zisapel does not expressly discuss the use of slow-release melatonin in relation to primary insomnia characterised by non-restorative sleep and its impact on “restorative quality of sleep”. Sleep onset and maintenance problems expressly mentioned in relation to the cited studies, but there is no mention of non-restorative sleep. For the reasons given in paragraph 5.51, the skilled person would understand that the conclusions of Zisapel are applicable to primary insomnia, and this would include patients complaining of nonrestorative sleep.

8.20

The skilled person would understand that improvement of sleep quality (when used in a general sense) would be reasonably expected to improve a patient’s responses on aspects of sleep that would lead to a complaint of non-restorative sleep. If the skilled person were to incorporate such testing into a subsequent trial, they would reasonably expect improvements in the subject’s quality of sleep, demonstrating improvements in the subject’s experience in getting to sleep, maintaining sleep and non-restorative sleep.”

I conclude that the views of Professor Roth are to be preferred over those of Professor Morgan. Zisapel 1999 goes nowhere close to exploring any relationship between nonrestorative sleep in Primary Insomniacs and melatonin. The point is neither mentioned in the article itself, nor adverted to in the prior art referenced. There is nothing to render the invention in the Patent obvious to the Skilled Person.

INSUFFICIENCY (1) Introduction

The various aspects of insufficiency were described in paragraph 8(3) above. By the time of closing submissions, Mylan ran insufficiency on two different grounds:

Insufficiency on a stand-alone basis

Type of insufficiency alleged

The insufficiency alleged by Mylan appears to be a combination of uncertainty insufficiency (Footnote: ⁹⁶) and lack of plausibility insufficiency. (Footnote: ⁹⁷) It is logical to begin with uncertainty insufficiency and then move on to lack of plausibility insufficiency.

Uncertainty insufficiency

Paragraphs 4 and 5 of Mylan’s Grounds of Invalidity suggest that the meaning of the term “restorative quality of sleep” is both (i) ambiguous and uncertain and (ii) incapable of measurement such that the Skilled Person would not be enabled to work the invention of the claims.

I have, in effect, dealt with both of these points when considering the true meaning of the Patent (in Section D above) and the nature of non-restorative sleep (in Section C above). I can therefore state my conclusions on uncertainty insufficiency relatively briefly:

Lack of plausibility insufficiency

Approach

Since the Patent is a patent for a second medical use of a known medicinal compound, the Patent must plausibly disclose the effect that it claims. I have described, in the preceding paragraphs, the effect that the Patent claims: see, in particular, paragraph 103(1) above.

The answer to this question depends upon the data contained in the Examples set out in the Patent. That is trite: it was common ground between the parties that bare assertion was not enough to found plausibility and (self-evidently) if the data was not disclosed in the Patent, but had been published elsewhere then, whilst the Patent might be plausible, it would likely be unoriginal.

I have already considered Professor Morgan’s approach to the Examples in the Patent, and given my reasons for rejecting his approach to construing or understanding these Examples. (Footnote: ⁹⁹) Of course, the meaning of the Patent, the nature of the Skilled Person, that person’s common general knowledge and the nature of that common general knowledge are all matters for me, assisted by the expert (and other) evidence adduced. In providing me with such assistance, it is almost inevitable that experts will stray into what is properly judicial territory when explaining their understanding, for example, of what the Patent teaches. Questions of construction and interpretation are inevitably a part of this, and I have benefitted from the experts’ explanation as to how they regarded the materials that were adduced in evidence before me.

Whilst I have not accepted Professor Morgan’s approach to interpreting the Examples,

With that introduction, I turn to the Examples in the Patent. As I noted in paragraph 41 above, the Patent identified five examples, but only two are material for present purposes. Examples 1 and 4 are both “reference” examples, which the Skilled Person would appreciate were not purporting to describe something within the Claims. (Footnote: ¹⁰¹) Example 5 concerns the preparation of the prolonged release melatonin formulation and is irrelevant for present purposes.

I therefore focus on Examples 2 and 3 and consider whether they render the Patent plausible.

Example 2

The Patent states: (Footnote: ¹⁰²)

“[0026] Method. The effect of a prolonged-release formulation of melatonin on subjectively assessed sleep quality and daytime vigilance in 170 elderly primary insomnia patients (aged 68.5 [SD 8.3] years) were studied in a randomised, double-blind, two parallel group study. The subjects were treated for 2 weeks with placebo to establish baseline characteristics and then for 3 weeks with melatonin (2 mg per night of prolonged-release formulation) or placebo. On the last three days of the baseline and treatment periods patients were asked to assess the quality of their sleep the previous night and their feeling in the morning. The quality of sleep question was “How would you compare the quality of sleep using the medication with non-medicated (your usual) sleep?” The patients marked the level of their perceived quality of sleep on a 100mm, non-hatched horizontal line with two endpoints. The left endpoint was labelled “more restless than usual”and the right endpoint was labelled “more restful than usual”. The waking state question was “How do you feel now?” The patients marked the level of their perceived waking state on a 100mm, non hatched horizontal line with two endpoints. The left endpoint was labelled “tired” and the right endpoint was labelled “alert”. The distance of the patient mark from the right endpoint in mm was measured (a reduction in value therefore indicates a better sleep or less tired state). The mean distance across the three nights was calculated.

[0027] Results. It was found that both quality of sleep and daytime alertness significantly improved with melatonin compared to placebo (Table 1) showing a link between improved restful sleep and less fatigue in the morning.

The test of plausibility is obviously met. This was a reasonably large study (of 170 elderly individuals) who were Primary Insomniacs at least some of whose sleep was characterised by its non-restorative quality. The study was conducted on established lines (use of placebos and blind testing) and resulted in a statistically significant outcome in that it enabled the conclusion that melatonin enhanced the restorative value of sleep.

Professor Morgan made the following points regarding the plausibility of Example 2, which it is necessary to consider:

I conclude that, by reason of Example 2 alone, the Patent is sufficiently plausible.

Example 3

The Patent states: (Footnote: ¹⁰⁶)

“[0029] Method. The effect of melatonin on subjectively assessed sleep quality and daytime vigilance in 131 primary insomnia patients (aged 20-80 years) were studied in a randomised, double-blind, parallel group study. The subjects were treated for 1 week with placebo to establish baseline characteristics and then for 3 weeks with melatonin (2mg per night of prolonged-release formulation) or placebo. On the last three days of the baseline and treatment periods patients were asked to assess the quality of their sleep the previous night and their feeling at daytime as described in Example 2.

[0030] Results. In the 55 years and older patients, there was an improvement of quality of sleep and daytime alertness as found in the other studies in the elderly (see

I consider that Example 3 (as with Example 2) of itself enables the Patent to demonstrate that the invention is plausible. Again, the language used in Example 3 makes clear that the focus of the study was the effect of melatonin on non-restorative sleep in Primary Insomniacs. Although the results are not statistically significant (Footnote: ¹⁰⁷) – obviously a relevant factor – the fact is that the study shows that there is “something in” the invention. Example 3 goes well-beyond mere assertion.

Professor Morgan’s points regarding Example 3 are similar to those that he makes in relation to Example 2: the selection criteria for the study group are unclear, and the outcome not clearly consistent with the invention claimed. (Footnote: ¹⁰⁸) I accept that there is some force in these points: but they have nothing like the force needed to render the Patent invalid for a lack of plausibility insufficiency.

Conclusion

For all these reasons, I reject the contention that the Patent is invalid by reason of insufficiency.

The “squeeze”

I do not consider that the “squeeze” argument advanced by Mylan to be soundly based, and I reject it. That is because the logic that underpins the argument is based upon the existence of a terminological equivalence between Haimov 1995 and the Patent. But – for the reasons set out in detail in paragraphs 77 to 81 above – there is no such equivalence. A “squeeze”, in order to work, requires the two opposing elements of the squeeze to meet, as it were, in the middle, with the result that there is no “validity” gap between the two elements in which the patent in question can exist. In such a case, the patent is either invalid for one reason (here: because it is anticipated) or invalid for another (here: because it is insufficient).

In this case, there is quite simply no “squeeze” argument because Haimov 1995 and the

EXCLUSIVE LICENCE (1) Introduction

Paragraph 3 of the Re-Amended Particulars of Claim provides:

“[Flynn] is the exclusive licensee under the Patent pursuant to a licence agreement dated 22

January 2020 (the “Agreement”) (as clarified and varied by the 19 May 2020 Clarification Agreement). The Agreement was registered and recorded at the UK Intellectual Property Office on 18 February 2020.”

Mylan’s Re-Amended Defence and Counterclaim pleads as follows in response:

“As to paragraph 3, it is denied that the Agreement (as varied by the agreement dated 19 May 2020 between Neurim Pharmaceuticals (1991) Ltd, Rad-Neurim Pharmaceuticals EEC Limited and Flynn Pharma Ltd) is an exclusive licence under the Patent because it is not a licence for [Flynn] to carry out any relevant act in respect of the claimed invention to the exclusion of all others. It is admitted that the Agreement was registered at the UK Intellectual Property Office on 18 February 2020. Paragraph 3 is otherwise not admitted.”

As was common ground, the question of whether Flynn was an exclusive licensee was determinative of the question of Flynn’s standing as a claimant in these proceedings. Section 67(1) of the Patents Act 1977 provides:

“Subject to the provisions of this section, the holder of an exclusive licence under a patent shall have the same right as the proprietor of the patent to bring proceedings in respect of any infringement of the patent committed after the date of the licence; and references to the proprietor of the patent in the provisions of this Act relating to infringement shall be construed accordingly.”

Section 130(1) of the Patents Act 1977 – the interpretation section – defines an exclusive licence as meaning:

“…a licence from the proprietor of or applicant for a patent conferring on the licensee, or on him and persons authorised by him, to the exclusion of all other persons (including the proprietor or applicant), any right in respect of the invention to which the patent or application relates…”

Since the nature of an exclusive licence under this definition is central to this issue, in particular the ability for the interests in a patent to be sliced many ways, with each slice maintaining its aliquot of “exclusivity”, it is as well to set out what Terrell says about the definition of exclusivity:

“16-25 There may, therefore, be several exclusive licensees, each having an exclusive licence in their own field and each may sue in respect of an infringement committed in contravention of their particular right. The definition of an exclusive licence may not prevent the proprietor retaining some measure of control of sub-licences, perhaps through an agency relationship.

16-26 An exclusive licensee who has the right to grant sub-licences may grant an exclusive licence to another and such a licence will fall within the definition of section 130(1) if it deprives the first exclusive licensee of rights in respect of the invention to which the patent relates. However, a person who merely has the exclusive right to manufacture to an exclusive licensee’s specification is not an exclusive licensee within the definition of section 130(1) because an exclusive right to manufacture to another’s specification does not constitute an exclusive licence of a right “in respect of the invention to which the patent…relates.”

16.27

In the absence of evidence establishing that the claimant is an exclusive licensee their

claim will be struck out but there should be no additional finding to the effect that they are not in fact an exclusive licensee unless there is evidence to justify that finding.” 125. This section considers the following matters in the following way:

(1)

Section H(2) set out the terms of the relevant contractual provisions. According to Neurim and Flynn, these provisions were provisions of extreme commercial sensitivity, and I have endeavoured to respect that sensitivity in this judgment. However, Neurim and Flynn both failed to appreciate that it is for the exclusive licensee to establish that status of exclusivity, where it is disputed, and that it is a necessary part of that burden to put the licence into evidence, so that the court may consider it. Neurim and Flynn’s disinclination to make good their case by producing, in unredacted form, the contractual documentation on which Flynn relied until the eleventh hour, meant that the points that Mylan took in relation to exclusivity were inevitably framed late and that the issues were not – for that reason – as clearly articulated as they might have been.

(2)

Section H(3) considers whether, in light of these provisions, and in light of the claims in the Patent, Flynn can properly be said to be within the meaning of “exclusive licensee” in the sense of the Patents Act 1977.

The contractual provisions

The contractual relations between Neurim and Flynn are set out in the following documents:

Neurim and Flynn only provided unredacted forms of the totality of the agreements setting out their legal relationship at the last minute and only after a very clear indication from me that they would be most unlikely to succeed in demonstrating an exclusive licence within the meaning of section 130(1) of the Patents Act 1977 unless they did so. Given that instruments like contracts must be construed as a whole, taking into account all their provisions, as well as the “factual matrix” surrounding such agreement, I do not consider that redaction of such instruments on the basis that the redacted provisions are “confidential and irrelevant” is permissible. A party may very well take the view that certain sensitive provisions add nothing to the construction of the contract: but that is not something that one party can simply assert as against its litigation counterparty. If the point is in issue – as it was here – the document must be disclosed to the other side and to the court. (Footnote: ¹⁰⁹) If the document can be disclosed, (Footnote: ¹¹⁰) but is not, then the disclosing party is not entitled to an inference that what that party asserts is correct. To the contrary.¹⁴⁶

Ultimately, all of the relevant agreements were disclosed to nominated lawyers in Mylan and to the court, and Mylan was able to state by reference to the contracts why the licence granted to Flynn was not exclusive. (Footnote: ¹¹¹)

Clause 3 of the November 2011 Agreement provides:

“3.1

Neurim grants Flynn which accepts, under the Neurim Patents, the Neurim Confidential Information, the Existing Marketing Authorisation and the Trademark, a licence to Distribute the Product in the Territory for use in the Field during the Term.

3.2

Flynn shall not have any right to grant sub-licences rights under or in respect of the rights granted in clause 3.1. Flynn may use a pre-wholesaler.

3.3

The licence to use the Existing Marketing Authorisation shall not include any extensions and amendments to the Existing Marketing Authorisation.

3.4

For the avoidance of any doubt:

3.4.1

Combination Products are expressly excluded from this Agreement and shall at all times be the subject of separate discussion and agreement between the parties provided that neither party shall be obliged to enter any discussions with the other party in respect of Combination Products. Notwithstanding the foregoing, each Party shall keep the other Party informed of its plans for any Combination Products prior to starting any development of such Combination Products. In case of such project or development, Neurim grants to Flynn a right of first notice and negotiations in the Territory when the Combination Product is based on Melatonin.

3.4.2

This Agreement does not grant Flynn distribution or other rights in relation to melatonin products other than the Product.”

Clause 3 contains a number of defined terms. Not all are material, but the following are:

Clause 17 concerns litigation regarding the Patent. Clause 17.3 provides:

“Neurim shall have the sole right to bring an infringement action or any other appropriate action directly related to infringement of that Neurim Patent or misuse of Neurim Confidential

Information at Neurim’s expense. Flynn shall, and shall procure that its [sic], cooperate reasonably with Neurim at Neurim’s expense in any such action where it relates to the Territory. To the extent that the infringement or misuse takes place in the Territory and Neurim elects not to take action within ninety (90) days of notification thereof to or by Flynn may do so [sic] at its expense, provided that Flynn shall keep Neurim informed of any legal proceedings or settlement negotiations in relation thereto and the terms of any settlement Flynn proposes to enter into shall be subject to Neurim’s prior written approval, not to be unreasonably withheld. Neurim shall cooperate with Flynn reasonably at Flynn’s expense in any such action.”

In his evidence, Dr Fakes expressed the view that the November 2011 Agreement gave Flynn “the exclusive right and licence under the Neurim Patents”. (Footnote: ¹¹²) Strictly, such views are irrelevant to questions of contractual interpretation – although I shall consider what Dr Fakes’ says, in case this sheds light on the “factual matrix”. In this case, Dr Fakes’ evidence does not. Moreover, his subjective view as to the meaning of the licence in clause 3.1 is unsustainable. I can see no basis for the view that the November 2011 Agreement precludes Neurim from working the invention itself or granting other licences in the jurisdiction. The only contrary indicator is clause 17.3, which confers on Flynn a contingent right to commence an infringement action – which Flynn could only do if it were an exclusive licensee. However, I do not consider that clause 17.3 can permit me to import exclusivity into clause 3.1, when there is no other indication in the agreement that this was the intention of the parties. It seems to me that clause 17.3 is simply a case where the agreement has sought to confer on Flynn a standing to pursue a claim which does not exist as a matter of law, Flynn not otherwise being an exclusive licensee.

I turn then to the January 2020 Agreement. This agreement expressly modifies the November 2011 Agreement, which otherwise remains in full force and effect. (Footnote: ¹¹³) Defined words and expressions in the November 2011 Agreement bear the same meaning in the January 2020 Agreement, unless the context specifically requires otherwise. (Footnote: ¹¹⁴) However, if there is any conflict between the January 2020 Agreement and the November 2011 Agreement, the former (the January 2020 Agreement) prevails.¹⁵¹

By clause 3.6 of the January 2020 Agreement, clause 3.1 of the November 2011

By clause 3.7 of the January 2020 Agreement, clauses 17.2 to 17.4 of the November 2011 Agreement were deleted and different clauses regarding the prosecution of infringers inserted. It is unnecessary – and, in view of their confidentiality, undesirable – to set these out in full. It is sufficient to note that Flynn’s ability to maintain infringement proceedings like the present independent of Neurim are even more circumscribed than under the old clause 17. Clause 17 makes provision for joint proceedings, with Neurim very much taking the lead. If Neurim does not seek to vindicate its rights, the January 2020 Agreement is silent, and it would appear that the agreement contemplates no independent action on the part of Flynn being commenced in these circumstances.

Finally, the May 2020 Agreement provides that the parties to it “wish to confirm and give effect to their understanding of the meaning of the term “Product”” in the preceding two agreements that I have already described. In substance, this agreement deletes and replaces the definition of “Product” in the November 2011 Agreement. “Product” is now defined as “the prolonged release prescription product containing 2mg Melatonin known as Circadin including any generic equivalent or version thereof for use in the Field as covered by the Existing Marketing Authorisation namely, for the treatment of primary insomnia patients aged 55 and older.” (Footnote: ¹¹⁶)

Exclusivity

Points taken by Mylan

Mylan contends that the licence between Neurim and Flynn was not exclusive for two reasons:

“Salami slicing”

Whether the licence granted by Neurim to Flynn is exclusive or non-exclusive is, essentially, one of construction. Drawing on the decisions of Pumfrey J in Dendron v. University of California (Footnote: ¹²⁰) and Henry Carr J in Illumina Inc v. Premaitha Health plc, (Footnote: ¹²¹) Mr David Stone (sitting as a Deputy High Court Judge) helpfully summarised the law in the following propositions in Oxford Nanopore Technologies Ltd v. Pacific Biosciences of California Inc at [44]: (Footnote: ¹²²)

“(i)

Whether or not a licence is an exclusive licence for the purposes of section 67(1) of the Patents Act is a matter for English law: Dendron…at [9];

(ii)

A licence which purports to be an exclusive licence may not necessarily be so. Identifying an exclusive licence depends on a proper construction of the document or documents: Dendron at [9]. An exclusive licence will be expressly so: circumstances in which an exclusive licence will be implied will be rare, if they exist at all;

(iii)

It is for the party asserting that it is an exclusive licensee to demonstrate that it is: Dendron at [9];

(iv)

The assessment of whether or not a licence is exclusive is not a “once and for all assessment”: Dendron at [11]. An exclusive licence may confer upon the patentee a power to convert the licence into a non-exclusive licence: Dendron at [11];

(v)

The “essential element” of an exclusive licence is that it is a licence to the exclusion of all other person, including the patentee or applicant: Dendron at [11];

(vi)

It is possible to have a plurality of exclusive licences in respect of any one patent: Courtauld, [1956] RPC 208 at [210]; Illumina at [475];

(vii)

But each exclusive licence may only be granted to one person – a licence will not be exclusive if granted to a number of entities, even if they are under the same control: Illumina at [254];

(viii)

An exclusive licensee may grant sub-licences to “persons authorised by him”: Dendron at [11]; Illumina at [254];

…”

In this case, I conclude that Neurim, having originally retained a right itself to work the

For these reasons, I find that Mylan’s first attack on the exclusivity of Flynn’s licence fails.

An inability in Flynn to vindicate its own rights

Section 67(1) of the Patents Act 1977 provides that the holder of an exclusive licence under a patent shall have the same right as the proprietor of the patent to bring proceedings in respect of any infringement of the patent committed after the date of the licence. This is expressed to be a consequence of the grant of an exclusive licence as defined by section 130(1). The right to bring proceedings for infringement is not expressed to be a necessary condition for “exclusivity”.

However, an essential part of the grant of a right is the ability to vindicate it. The 1977 Act confers on an exclusive licensee the ability to enforce another’s rights, namely those of the patent holder. What if, as here, the licence itself takes away the very rights conferred in such a case by section 67 of the 1977 Act?

It seems to me – and the point is not covered by authority – that this has the effect of rendering the licence non-exclusive. The whole point of the section is to confer an additional right to claim for infringement on the licence-holder, and not to deprive the patent-holder of its rights. (Footnote: ¹²⁷) There is, therefore, created by section 67, an additional cause of action, vesting in the licence-holder. (Footnote: ¹²⁸)

The provisions of the licence in this case, as it seems to me, essentially take away Flynn’s ability to prosecute such a claim. Referring to the new clause 17.2, inserted by the January 2020 Agreement:

The upshot is that what appears, on its face, to be an exclusive licence to Flynn, is actually no such thing when the provisions regarding the enforcement of Flynn’s rights under the licence are taken into account. These provisions make absolutely clear that Flynn has no rights independent of Neurim, and that an infringement action such as this is in reality being prosecuted as a single cause of action by Neurim, with Flynn as little more than a cypher. I do not need to consider whether the exclusivity conferred by the new clause 3.1 amounts to a “sham” within the meaning of Snook v. London- and West Riding Investments Ltd,¹⁶⁹ simply because the effect of clause 17, also as amended, deprives clause 3.1 of substantially all meaning. Viewing clause 3.1 on its own – without considering clause 17 – an entirely misleading view of Flynn’s rights is obtained. Viewing the licence agreement between Neurim and Flynn as a whole, this is not a case where two interested persons can separately prosecute separate rights.

Accordingly, I conclude that, construing the agreement as a whole, Flynn is not Neurim’s exclusive licensee, and that it has no standing in these proceedings.

CONCLUSIONS AND DISPOSITION

For the reasons given in this judgment, I find that:

I invite the parties to draw up an order reflecting the conclusions that I have reached. I should conclude by making two points: