Neurim Pharmaceuticals (1991) Ltd & Anor v Generics UK Ltd (t\a MYLAN) [2020] EWHC 3270 (Pat)

“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.”

“An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2(2) above…”

“368. The second, or so-called Biogen insufficiency (after the decision in the House of Lords in Biogen Inc v. Medeva plc, [1997] RPC 1), is concerned with breadth of claim. An insufficiency attack on Biogen lines accepts that the teaching of the patent is adequate to bring the skilled reader within the claims, but asserts that the claims encompass products or processes which owe nothing to the teaching of the patent and which are not enabled. It is important to see how far the Biogen principle goes. Enablement does not necessarily involve teaching how to make each member of a class. If it were not so, ingenious infringements could never be caught. If an element of the claim can be predicted to be of general application, the patentee is entitled to claim it in general terms: “…[I]f the patentee…has disclosed a beneficial property which is common to [a class of products] he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.” 369. In Kirin-Amgen Inc v. Hoechst Marion Roussel, [2005] RPC 9, Lord Hoffmann explained the notion of a principle of general application in this way: “This [i.e. the passage cited above] gave rise to a good deal of argument about what amounted to a ‘principle of general application’. In my opinion there is nothing difficult or mysterious about it. It simply means an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything which falls within the general term. For example, in Genentech I/Polypeptide expression, (T 292/85), [1989] OJ EPO 275, the patentee claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The patentee had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them. This is an example of an invention of striking breadth and originality. But the notion of a ‘principle of general application’ applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of ‘connecting means’ is enabled if the invention can reasonably be expected to work with any means of connection. The patentee does not have to have experimented with all of them.””

“…[I]f the patentee…has disclosed a beneficial property which is common to [a class of products] he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.” “This [i.e. the passage cited above] gave rise to a good deal of argument about what amounted to a ‘principle of general application’. In my opinion there is nothing difficult or mysterious about it. It simply means an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything which falls within the general term. For example, in Genentech I/Polypeptide expression, (T 292/85), [1989] OJ EPO 275, the patentee claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The patentee had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them. This is an example of an invention of striking breadth and originality. But the notion of a ‘principle of general application’ applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of ‘connecting means’ is enabled if the invention can reasonably be expected to work with any means of connection. The patentee does not have to have experimented with all of them.”” 11. that he has not enabled more – he has claimed the entire class of products which have the known desirable properties yet he has only enabled one member of that class. Such a case is to be contrasted with the present where the desirable end is indeed fully enabled—that which makes it desirable forms no part of the claim limitation.” (c). The patent is conceptually uncertain. Sometimes known as insufficiency on the grounds of ambiguity, this form of insufficiency is better understood as uncertainty insufficiency, for the reasons given by Floyd LJ in Anan Kasei v. Neo Chemicals and Oxides Ltd: [2019] EWCA Civ 1646. “24. The form of insufficiency exemplified by Kirin Amgen is sometimes, inaccurately, called “ambiguity”

“3. Further or in the alternative the scope of each of the Claims exceeds the technical contribution of the Patent: a. Each of the Claims specifies that the claimed formulation or medicament is for “improving the restorative quality of sleep in a patient suffering from primary insomnia characterized by non-restorative sleep” (the “Claimed Effect”). The Patent fails to make plausible that the Claimed Effect is achieved; there is no reason disclosed for supposing that the implied assertion of efficacy of the claim is true. b. Further or in the alternative the Patent fails to make plausible that the Claimed Effect is achieved for patients younger than 55 years old; there is no reason disclosed for supposing that the implied assertion of efficacy of the claim is true for patients younger than 55 years old. 4. 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”

“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 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.”

“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.”

“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.”

“because the skilled reader knows that the patentee is trying to claim something which he, the patentee, considers to be new, he will be strongly averse to ascribe to the claim a meaning which covers that which the patentee acknowledges is old.” 53. 8-50 Nevertheless, the question is one of construction and whether what is claimed is or is not new will depend on, rather than be determinative of, the construction of the claim. The court also held that the skilled reader would know about the practice of divisional applications and that this might affect their understanding of a claim because they will know that there are or may be aspects of what is described in the patent which are actually claimed in some other patent or patents divided out from the original application.”

“The sleep disorders are organised into four major sectors according to presumed etiology. Primary Sleep Disorders are those in which none of the etiologies listed below (i.e., another mental disorder, a general medical condition, or a substance) is responsible. Primary Sleep Disorders are presumed to arise from endogenous abnormalities in sleep-wake generating or timing mechanisms, often complicated by conditioning factors. Primary Sleep Disorders in turn are subdivided into Dyssomnias (characterised by abnormalities in the amount, quality or timing of sleep) and Parasomnias (characterised by abnormal behavioral or psychological events occurring in association with sleep, specific sleep stages, or sleep-wake transitions).” (2) The skilled person would have understood the term Primary Sleep Disorder, and that it was a sleep disorder that could be distinguished from what can be termed a Secondary Sleep Disorder, where there is: To adopt the terminology used in DSM-IV. (a) Sleep Disorder Related to Another Mental Disorder. (b) Sleep Disorder due to Another Medical Condition. (c) Substance-Induced Sleep Disorder. In short, Primary Sleep Disorders are characterised by the absence of certain factors that (may) render sleep disordered. (3) Under “Dyssomnias” at 553: “Dyssomnias are primary disorders of initiating or maintaining sleep or of excessive sleepiness and are characterised by a disturbance in the amount, quality, or timing of sleep…” (4) Primary Insomnia is considered in Section 307.42. That section concludes with a “box” summarising the “Diagnostic criteria for 307.42 Primary Insomnia”, which provides as follows: “A. The predominant complaint is difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least 1 month. B. The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The sleep disturbance does not occur exclusively during the course of Narcolepsy, Breathing-Related Sleep Disorder, Circadian Rhythm Sleep Disorder, or a Parasomnia. D. The disturbance does not occur exclusively during the course of another mental disorder (e.g., Major Depressive Disorder, Generalised Anxiety Disorder, a delirium). E. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.” (5) Section 307.42 says this under “Diagnostic Features” at 553: “The essential feature of Primary Insomnia is a complaint of difficulty initiating or maintaining sleep or of nonrestorative sleep that lasts for at least 1 month (Criterion A) and causes clinically significant distress or impairment in social, occupational, or other important areas of functioning (Criterion B). The disturbance in sleep does not occur exclusively during the course of another sleep disorder (Criterion C) or mental disorder (Criterion D) and is not due to direct physiological effects of a substance or a general medical condition (Criterion E). Individuals with Primary Insomnia most often report a combination of difficulty falling asleep and intermittent wakefulness during sleep. Less commonly, these individuals may complain only of nonrestorative sleep, that is feeling that their sleep was restless, light, or of poor quality. Primary Insomnia is often associated with increased physiological or psychological arousal at nighttime in combination with negative conditioning for sleep. A marked preoccupation with and distress due to the inability to sleep may contribute to the development of a vicious cycle: the more the individual strives to sleep, the more frustrated and distressed the individual becomes and the less he or she is able to sleep. Lying in a bed in which the individual has frequently spent sleepless nights may cause frustration and conditioned arousal. Conversely, the individual may fall asleep more easily when not trying to do so (e.g., while watching television, reading, or riding in a car). Some individuals with increased arousal and negative conditioning report that they sleep better away from their own bedrooms and their usual routines. Chronic insomnia may lead to decreased feelings of well-being during the day (e.g., deterioration of mood and motivation; decreased attention, energy, and concentration; and an increase in fatigue and malaise). Although individuals often have the subjective complaint of daytime fatigue, polysomnographic studies usually do not demonstrate an increase in physiological signs of sleepiness.” (6) The skilled person would have been aware that Primary Insomnia is indicated by one or more of three characteristics: (a) Difficulty in initiating sleep – which is also called sleep (onset) latency. (b) Difficulty in maintaining sleep. (c) Non-restorative sleep. These characteristics, I stress and as the skilled person would have known, can co-exist or exist separately without affecting the characterisation of Primary Insomnia. (7) Criterion C in the “box” referred to – amongst other aspects of an individual’s sleep condition – Circadian Rhythm Sleep Disorder. Because circadian rhythms feature in the common general knowledge at issue in this case, it is necessary to set out what a skilled person would understand by this from DSMIV. Under the heading “Differential Diagnosis”, at 555-556, is the following passage: ““Normal” sleep duration varies considerably in the general population. Some individuals who require little sleep (“short sleepers”) may be concerned about their sleep duration. Short sleepers are distinguished from those with Primary Insomnia by their lack of difficulty falling asleep and by the absence of characteristic symptoms of Primary Insomnia (e.g., intermittent wakefulness, fatigue, concentration problems, or irritability). Daytime sleepiness, which is a characteristic feature of Primary Hypersomnia, It is unnecessary to consider Primary Hypersomnia further for the purposes of the matters here in issue. Suffice it to say that the essential feature of Primary Hypersomnia, according to DSM-IV, is “excessive sleepiness for at least 1 month as evidenced either by prolonged sleep episodes or by daytime sleep episodes occurring almost daily…” (at 557). can also occur in Primary Insomnia, but is not as severe in Primary Insomnia. When daytime sleepiness is judged to be due to insomnia, an additional diagnosis of Primary Hypersomnia is not given. Jet Lag and Shift Work Types of Circadian Rhythm Sleep Disorder are distinguished from Primary Insomnia by the history of recent transmeridian travel or shift work. Individuals with the Delayed Sleep Phase Type of Circadian Rhythm Sleep Disorder report sleep-onset insomnia only when they try to sleep at socially normal times, but they do not report difficulty falling asleep or staying asleep when they sleep at their preferred times. …”

“This group of disorders includes: (a) dyssomnias: primarily psychogenic conditions in which the predominant disturbance is in the amount, quality, or timing of sleep due to emotional causes, i.e., insomnia, hypersomnia, and disorder of sleep-wake schedule; and (b) parasomnias: abnormal episodic events occurring during sleep; in childhood these are related mainly to the child’s development, while in adulthood they are predominantly psychogenic, i.e., sleepwalking, sleep terrors, and nightmares. This section includes only those sleep disorders in which emotional causes are considered to be a primary factor. Sleep disorders of organic origin such as Kleine-Levin syndrome (G47.8) are coded in Chapter VI (G47.-) of ICD-10. Nonpsychgenic disorders including narcolepsy and cataplexy (G47.4) and disorders of the sleep-wake schedule (G47.2) are also listed in Chapter VI, as are sleep apnoea (G47.3) and episodic movement disorders which include nocturnal myoclonus (G25.3). Finally, enuresis (F98.0) is listed with other emotional and behavioural disorders with onset specific to childhood and adolescence, while primary nocturnal enuresis (R33.8), which is considered to be due to a maturational delay of bladder control during sleep, is listed in Chapter XVIII of ICD-10 among the symptoms involving the urinary system. In many cases, a disturbance of sleep is one of the symptoms of another disorder, either mental or physical. Even when a specific sleep disorder appears to be clinically independent, a number of associated psychiatric and/or physical factors may contribute to its occurrence. Whether a sleep disorder in a given individual is an independent condition or simply one of the features of another disorder (classified elsewhere in Chapter V or in other chapters of ICD-10) should be determined on the basis of its clinical presentation and course, as well as of therapeutic considerations and priorities at the time of the consultation. In any event, whenever the disturbance of sleep is among the predominant complaints, a sleep disorder should be diagnosed…”

“Insomnia is a condition of unsatisfactory quantity and/or quality of sleep, which persists for a considerable period of time. The actual degree of deviation from what is generally considered as a normal amount of sleep should not be the primary consideration in the diagnosis of insomnia, because some individuals (the so-called short sleepers) obtain a minimal amount of sleep and yet do not consider themselves as insomniacs. Conversely, there are people who suffer immensely from the poor quality of their sleep, whilst quantity is judged subjectively and/or objectively as within normal limits. Among insomniacs, difficulty falling asleep is the most prevalent complaint, followed by difficulty staying asleep and early final wakening. Usually, however, patients report a combination of these complaints. Typically, insomnia develops at a time of increased life-stress and tends to be more prevalent among women, older individuals and psychologically disturbed and socioeconomically disadvantaged people. When insomnia is repeatedly experienced, it can lead to an increased fear of sleeplessness and a preoccupation with its consequences. This creates a vicious circle which tends to perpetuate the individual’s problem. …” (3) Under the heading “Diagnostic guidelines” (p183): “The following are essential clinical features for a definite diagnosis: (a) the complaint is either of difficulty falling asleep or maintaining sleep, or of poor quality of sleep; (b) the sleep disturbance has occurred at least three times per week for at least 1 month; (c) there is preoccupation with sleeplessness and excessive concern over its consequences at night and during the day; (d) the unsatisfactory quantity and/or quality of sleep either causes marked distress or interferes with ordinary activities in daily living. Whenever unsatisfactory quantity and/or quality of sleep is the patient’s only complaint, the disorder should be coded here. The presence of other psychiatric symptoms such as depression, anxiety or obsessions does not invalidate the diagnosis of insomnia, provided that insomnia is the primary complaint or the chronicity and severity of insomnia cause the patient to perceive it as the primary disorder. Other coexisting disorders should be coded if they are sufficiently marked and persistent to justify treatment in their own right. It should be noted that most chronic insomniacs are usually preoccupied with their sleep disturbance and deny the existence of any emotional problems. Thus, careful clinical assessment is necessary before ruling out a psychological basis for the complaint.”

“[0011] Thus, there appears to be little or no evidence from published articles, that administration of exogenous melatonin (or other melatonergic agents, melatonin agonists or melatonin antagonists), in the dosages contemplated by the present invention, would be likely to improve the restorative quality of sleep in subjects affected by primary insomnia characterised by non-restorative sleep. [0012] However, in contrast with the results of the above published papers, the present inventors have surprisingly found that melatonin (and other melatonergic agents, melatonin agonists or melatonin antagonists) in fact improves the restorative quality of sleep in subjects suffering from primary insomnia…”

“Conclusions. These results show that melatonin enhanced the restorative value of sleep in these primary insomnia patients.” 50 A document that I shall come to consider. that it applies to patients with insomnia characterised by non-restorative sleep. In other words, all of them have non-restorative sleep and we are basing that on question 4 from the [Leeds Sleep Questionnaire 50]. Q (Mr Waugh, QC) That is your take, Professor. A (Professor Morgan) That is what it says in the Patent. Q (Mr Waugh, QC) Professor Roth has a different take, and in that sense, Professor, you agreed with me earlier that the patients in the Patent, there would be a cohort of patients in there that had non-restorative sleep? A (Professor Morgan) Yes, there would have been some, likely. Q (Mr Waugh, QC) Therefore, if you gave melatonin, and you saw that the non-restorative sleep was improved, as Professor Roth says, you can conclude that there were patients in that cohort who were characterised by having nonrestorative sleep? A (Professor Morgan) I would agree with that, but that is different from saying that the cohort, the entire group, were characterised by non-restorative sleep. They were not. Q (Mr Waugh, QC) Where does it say that? I do not think anybody has ever said… A (Professor Morgan) The Patent says that. Q (Mr Waugh, QC) The Patent says that you can treat patients characterised by non-restorative sleep with melatonin, and the Examples are an example of treating a cohort of patients, some, many, who… A (Mr Waugh, QC) Whose insomnia is characterised by non-restorative sleep. That is what it says. This passage shows the very reverse of a meeting of minds, in terms of a basic understanding of patent law concepts. I do not consider that Professor Morgan could, if he were a layman (which, of course, he was not holding himself out to be), particularly be blamed for reading Patent/[0028] literally. The conclusion expressed in Example 2 is that: “These results show that melatonin enhanced the restorative value of sleep in these primary insomnia patients.”

“5.4 Primary insomnia is a term of art whose meaning is understood by the skilled person, and which I consider in more detail below. The diagnostic criteria for primary insomnia provide that primary insomnia may be characterised by, among other things, a complaint of non-restorative sleep. 5.5 The Patent is for a pharmacological treatment, or medication, specifically using sustained release melatonin to treat a patient with primary insomnia characterised by non-restorative sleep. Therefore, the person to whom the Patent is directed will have experience in the pharmacological management of primary insomnia. 5.6 The Patent is directed to a sleep medicine clinician like myself, 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.” (2) Professor Morgan’s understanding of the skilled person was altogether broader and vaguer than that of Professor Roth, who did not accept Professor Morgan’s description of the skilled person. See Roth 4 at paragraph 3.11. Professor Morgan noted that, in 2001, “[s]leep medicine was an emerging field in the UK…with few specialist sleep research clinicians with a practice that was limited to the treatment of sleep disorders”

“Subjects were classified as either satisfied or dissatisfied with quality of sleep (SQS or DQS), with or without insomnia indicators (+I or -I).”

““Non-restorative sleep” is defined as the subjective feeling that sleep has been insufficiently refreshing…”; also paragraph 4.20 of Morgan 1. In a book co-authored by him, Morgan and Closs, Sleep Management in Nursing Practice: An Evidence-Based Guide, 1999 (Morgan and Closs 1999) at p74. Professor Morgan stated: “Sleep is a very private experience and subjective reports provide descriptions of sleep as it is experienced by the sleeper. Broadly, these reports may be of two kinds: experiences of sleep quality; and estimates of sleep quantity. As regards sleep quality, it should be emphasised that the experience of sleep is accessible only to the individual sleepers. Only they know whether their sleep has been restful and refreshing. In addition, criteria for a ‘good night’s sleep’ are also, to some extent, personal. Whether individuals sleep for 2 hours per night, or for 10 hours per night, if they awake, satisfied with their sleep quality, and can function efficiently during the day, then their sleep may be considered satisfactory (or normal for them).” (3) However, despite this acceptance, Professor Morgan appeared to suggest that it was common general knowledge that this essentially subjective phenomenon could be objectively measured: Morgan 1 (emphasis added). “4.47 Actigraphy is another objective method of monitoring a person’s rest/activity cycles. A small device is worn to measure gross motor activity. The unit is usually in a wristwatch-like package worn on the wrist… 4.48 At its most simple, actigraphic measurements are movement ‘counts’ recorded over time. Signal processing algorithms can then be applied to determine whether the movement patterns are associated with the sleeping or waking state. From this, sleep latency and total sleep duration can be determined, and the sleep duration used to calculate sleep efficiency. The activity level can also indicate motility of the subject during sleep (activity level). By 2001, more sophisticated actigraphs measured not only movement but also heart rate, etc and different algorithms were applied to assess different aspects of a patient’s sleep. It was found that actigraphy “may also provide an index of sleep quality”: Lichstein and Morin (2000). Therefore, actigraphy, with the appropriate interpretive algorithm, could be used to assess/estimate not only the physical characteristics of sleep which the actigraph measured/monitored but also as a proxy for the subjective aspects such as “quality” of sleep. The skilled person would understand that lower activity levels (representing more restful sleep) would mean the subject is more likely to report an increase in the quality of sleep. Higher activity levels would indicate the subject is experiencing restless sleep, and would be a proxy for poorer quality of sleep (in the context of ICD-10, i.e. non-restorative sleep). 4.49 A ‘state-of-the-science’ review of actigraphy findings, commissioned by the American Sleep Disorders Association (ASDA), was published in May 1995 (Sadeh et al 1995). Saheh, Hauri, Kripke and Lavie, An American Sleep Disorders Association Review: The role of actigraphy in the evaluation of sleep disorders, published in (1995) 18(4) Sleep 288-302. This review informed the official ASDA guidance, which was simultaneously published in the same journal. ASDA, An American Sleep Disorders Association Report: Parameters for the Use of Actigraphy in the Clinical Assessment of Sleep Disorders (ASDA 1995), published in (1995) 18(4) Sleep 285-287. In the section on the use of actigraphy in drug studies, [Sadeh et al 1995] notes: “In most studies, the anticipated decrease in activity (associated with higher sleep quality) has been reported.”

“Many researchers have used some measures of activity counts that are to some extent arbitrary and relate to the physical features of the analog movement detector as well as to the sampling rates and summary interval used. Because different researchers have used different devices with distinct physical and electronic features, such measures preclude interstudy comparison, and the results are hard to interpret.” 4.51 The quote reflects the position at the Priority Date in that it was difficult to compare subjective results and data from different studies as there was not a reporting standard on the threshold value and epoch duration. This allowed for differing results based on differing parameters.”

“Actigraphy may also provide an index of sleep quality; it has been shown that movement during sleep is strongly related to sleep diary ratings of sleep quality (Horne, Pankhurst, Hume and Diamond, 1994).”

“This field study assessed the effects of nighttime aircraft noise on actimetrically measured sleep in 400 people (211 women and 189 men; 20-70 years of age; one per household) habitually living at eight sites adjacent to four UK airports, with different levels of night flying. Subjects wore wrist-actimeters for 15 nights and completed morning sleep logs. A sample of 178 nights of sleep electroencephalograms (EEGs) were recorded synchronously with actigrams. The EEG was used to develop filters for the the raw actigrams, in order to (1) estimate sleep onset and (2) compare actigrams with aircraft noise events (ANEs). Actigrams, filtered to detect the onset of discrete movements, were able to detect 88% of all EEG-determined periods of interim wakefulness of > 15 seconds and periods of movement time of > 10 seconds. The main findings were: (1) actimetry and self-reports showed that only a minority of ANEs affected sleep, and, for most of our subjects, the domestic and idiosyncratic factors have much greater effects; (2) despite large between site variations in ANEs, the difference between sites in overall sleep disturbance was not significant; (3) there was a diminished actimetric response to ANEs in the first hour of sleep and, apparently, also in the last hour of sleep; (4) men had significantly more discrete movements than women and were more likely to respond to ANEs…” (iii) It is quite clear that this article, whilst it has a great deal to contribute to the correlation between sleep and aircraft noise, says literally nothing about actigraphy and the measurement of nonrestorative sleep in insomniacs. Indeed, it is not even known whether the individuals in the study were insomniacs. That does not appear to have been screened for (either way) in the compilation of the sample population. I do not consider that the passage that I have underlined in the quote of paragraph 4.48 of Morgan 1 to be supported by the literature cited by Professor Morgan in that paragraph. I do not consider that this passage reflects what Lichstein and Morin 2000 was saying. Professor Morgan’s failure to reference Horne 1994 is disappointing; and does not reflect what I would expect an expert to say in these circumstances when providing expert opinion evidence. (b) Turning to Sadeh et al 1995 – which was quoted in paragraphs 4.49 and 4.50 of Morgan 1 – there is (again) no support for the proposition advanced by Professor Morgan that actigraphy can be used to diagnose non-restorative sleep. The paper concludes: “The role of actigraphy in the assessment of sleep disorders have been strongly supported in some areas and only partially supported or rejected in others… The following statements summarize our impressions and best judgment on the role of actigraphy in the evaluation of sleep disorders. Actigraphy provides a cost effective method for longditudinal, natural, assessment of sleep-wake patterns. The method can be used to distinguish between wakeful and sleep states, with wide margins of error for subjects lying awake motionless (e.g., insomnia patients). Despite differences in its accuracy level, actigraphy can assess the restactivity patterns of insomniacs and individuals with schedule disorders who require repeated, longitudinal monitoring (or when a more elaborated sleep analysis is not required). Although actigraphy is sensitive to sleep-related respiratory disturbances, it is not suitable for assessing such disturbances. A clinical diagnosis and consideration of treatment should always be based on fulllaboratory testing. Finally, actigraphy is not suitable for clinical assessment in cases in which the subject may have some underlying motivation to feign a sleep problem (e.g., insurance claims, avoiding undesired jobs or military tasks).”

“…Even though actigraphy is less intrusive and less expensive than PSG [polysomnography], the findings from these two objective tests do not usually add to the diagnosis of insomnia in most patients. The diagnosis of insomnia is best determined by obtaining an accurate and thorough history. … Actigraphy is not indicated for the routine diagnosis, assessment of severity, or management of any of the sleep disorders, including the insomnias, obstructive sleep apnea syndrome and periodic limb movement disorder.” (Sadeh et al 1995). Saheh, Hauri, Kripke and Lavie, An American Sleep Disorders Association Review: The role of actigraphy in the evaluation of sleep disorders, published in (1995) 18(4) Sleep 288-302. This review informed the official ASDA guidance, which was simultaneously published in the same journal. ASDA, An American Sleep Disorders Association Report: Parameters for the Use of Actigraphy in the Clinical Assessment of Sleep Disorders (ASDA 1995), published in (1995) 18(4) Sleep 285-287. In the section on the use of actigraphy in drug studies, [Sadeh et al 1995] notes: “In most studies, the anticipated decrease in activity (associated with higher sleep quality) has been reported.” “Many researchers have used some measures of activity counts that are to some extent arbitrary and relate to the physical features of the analog movement detector as well as to the sampling rates and summary interval used. Because different researchers have used different devices with distinct physical and electronic features, such measures preclude interstudy comparison, and the results are hard to interpret.” “Actigraphy may also provide an index of sleep quality; it has been shown that movement during sleep is strongly related to sleep diary ratings of sleep quality (Horne, Pankhurst, Hume and Diamond, 1994).”

“This field study assessed the effects of nighttime aircraft noise on actimetrically measured sleep in 400 people (211 women and 189 men; 20-70 years of age; one per household) habitually living at eight sites adjacent to four UK airports, with different levels of night flying. Subjects wore wrist-actimeters for 15 nights and completed morning sleep logs. A sample of 178 nights of sleep electroencephalograms (EEGs) were recorded synchronously with actigrams. The EEG was used to develop filters for the the raw actigrams, in order to (1) estimate sleep onset and (2) compare actigrams with aircraft noise events (ANEs). Actigrams, filtered to detect the onset of discrete movements, were able to detect 88% of all EEG-determined periods of interim wakefulness of > 15 seconds and periods of movement time of > 10 seconds. The main findings were: (1) actimetry and self-reports showed that only a minority of ANEs affected sleep, and, for most of our subjects, the domestic and idiosyncratic factors have much greater effects; (2) despite large between site variations in ANEs, the difference between sites in overall sleep disturbance was not significant; (3) there was a diminished actimetric response to ANEs in the first hour of sleep and, apparently, also in the last hour of sleep; (4) men had significantly more discrete movements than women and were more likely to respond to ANEs…” (iii) It is quite clear that this article, whilst it has a great deal to contribute to the correlation between sleep and aircraft noise, says literally nothing about actigraphy and the measurement of nonrestorative sleep in insomniacs. Indeed, it is not even known whether the individuals in the study were insomniacs. That does not appear to have been screened for (either way) in the compilation of the sample population. I do not consider that the passage that I have underlined in the quote of paragraph 4.48 of Morgan 1 to be supported by the literature cited by Professor Morgan in that paragraph. I do not consider that this passage reflects what Lichstein and Morin 2000 was saying. Professor Morgan’s failure to reference Horne 1994 is disappointing; and does not reflect what I would expect an expert to say in these circumstances when providing expert opinion evidence. “The role of actigraphy in the assessment of sleep disorders have been strongly supported in some areas and only partially supported or rejected in others… The following statements summarize our impressions and best judgment on the role of actigraphy in the evaluation of sleep disorders. Actigraphy provides a cost effective method for longditudinal, natural, assessment of sleep-wake patterns. The method can be used to distinguish between wakeful and sleep states, with wide margins of error for subjects lying awake motionless (e.g., insomnia patients). Despite differences in its accuracy level, actigraphy can assess the restactivity patterns of insomniacs and individuals with schedule disorders who require repeated, longitudinal monitoring (or when a more elaborated sleep analysis is not required). Although actigraphy is sensitive to sleep-related respiratory disturbances, it is not suitable for assessing such disturbances. A clinical diagnosis and consideration of treatment should always be based on fulllaboratory testing. Finally, actigraphy is not suitable for clinical assessment in cases in which the subject may have some underlying motivation to feign a sleep problem (e.g., insurance claims, avoiding undesired jobs or military tasks).”

“The Sleep Evaluation Questionnaire How would you compare getting to sleep using the medication with getting to sleep normally, i.e., without medication? 1. Harder than usual / easier than usual 2. Slower than usual / quicker than usual 3. Felt less drowsy than usual / felt more drowsy than usual How would you compare the quality of sleep using the medication with non-medicated (your usual) sleep? 4. More restless than usual / more restful than usual 5. More periods of wakefulness than usual / fewer periods of wakefulness than usual How did your awakening after medication compare with your usual pattern of awakening? 6. More difficult than usual / easier than usual 7. Took longer than usual / took shorter than usual How did you feel on waking? 8. Tired / alert How do you feel now? 9. Tired / alert How was your sense of balance and coordination upon getting up? 10. More clumsy than usual / less clumsy than usual Note. A 10cm line separates the 2 halves of each question. The questionnaire instructions are: ‘Each question is answered by placing a vertical mark on the answer line. If no change was experienced, then place your mark in the middle of the line. If change was experienced, then the position of your mark will indicate the nature and extent of the change, i.e. large changes near the ends of the line, small changes near the middle.’”

“Benzodiazepine receptor agonists are, and were at the Priority Date, the mainstay for the pharmacological management of insomnia. As reflected in the balance of the Consensus Paper [a document that I shall come to describe later on in this judgment], benzodiazepine receptor agonists include classic benzodiazepines (such as triazolam, temazepam and flunitrazepam) and the newer non-benzodiazepine-receptor agonists. The latter, including zopiclone, zolpidem and zaleplon, are sometimes referred to as the “zdrugs”

“4.32 In 2001, treatments for insomnia included sleep hygiene advice, cognitive behavioural therapy (CBT) and pharmacological treatments. Pharmacological treatments included benzodiazepines and “Z” drugs, antidepressants, antipsychotics, sedating antihistamines and herbal remedies. Pharmacological treatments were effective in the short term but, by 2001, longer-term use (which was common) had become the subject of clinical and social concern. All benzodiazepines were associated with tolerance, dependence, withdrawal symptoms, and psychomotor performance deficits. Some of these drugs were also associated with psychiatric symptoms and personality changes. Cognitive Behavioural Therapy for Insomnia (CBT-I) was, in comparison, both effective and safe. Reviewing 48 clinical studies of Cognitive Behavioral Therapy for Insomnia (CBT-I), Morin et al (1999) concluded that an average of 5 hours CBT-I produced significant and lasting improvements in both sleep structure and subjective sleep satisfaction among 70-80% of treated patients. 4.33 In 2001, we were at a cross-over point where the disadvantages of long-term benzodiazepine use were widely recognised and clinical and research attention was increasingly focussed on drugs (and non-pharmacological treatments) that could treat insomnia without side effects. As referenced in paragraph 4.3(d) the (then) Committee on the Review of Medicines published a systemic review of benzodiazepine drugs which was relevant at this time. It was conducted to update prescribing guidance on official “data sheets” for all benzodiazepines (i.e., benzodiazepines used as both anti-anxiety and hypnotic drugs) information from which accompanies any given drug in the British National Formulary. The shorter acting benzodiazepine hypnotics were indicated for “short term treatment of insomnia (this indication is not applicable to oxazepam)”

“In relation to paragraph 4.33 [of Morgan 1], Professor Morgan suggests that in 2001 there was a “cross-over point” in relation to new treatments for insomnia. I do not consider that the skilled person would consider 2001 as a cross-over point and I am not aware of any reason why it would be regarded in that way.” (ii) Professor Roth was cross-examined on this: Transcript Day 1/pp.186ff. Q (Mr Vanhegan, QC) As at the Priority Date, the skilled person knew that there were severe problems with benzodiazepine agonists to treat insomnia and primary insomnia, especially in elderly patients. Is that not correct? A (Professor Roth) It depends how you define severe problems and how you define in terms of prevalence. Q (Mr Vanhegan, QC) Let us again see if we can break it down, Professor. This is all in the UK, all as at 2001. It had been known that for a long time, prior to 2001, all benzodiazipine therapy should be withdrawn unless used or given on an occasional basis, in relation to the elderly? A (Professor Roth) I have no idea why that became an issue in 2001. I think it was an issue before 2001 and continues to be an issue beyond 2001…There is great concern. There is great concern about the use of benzodiazepines in the elderly, absolutely. … Q (Mr Vanhegan, QC) What I am suggesting is that all of those [i.e., downsides to prescribing benzodiazepines, which Professor Roth accepted] would have been well-known to the skilled person as at 2001 and that as a result of those known effects in the elderly people, there was a strong demand in the UK not to prescribe benzodiazepines to elderly patients, if at all possible? A (Professor Roth) I do not know how to answer that question other than they are still and were then and continue to be the most commonly prescribed treatments for insomnia. Q (Mr Vanhegan, QC) The fact that they may be the most common does not negate the point I am putting to you, is it, professor, which is, as at 2001, there was a strong drive not to prescribe them to the elderly because of all those side effects? A (Professor Roth) First of all, I do not think it has anything to do with 2001. There has been a continuous concern about the…use of benzodiazepines in all populations, including the elderly. (d) As I noted in paragraph 66(2)(a) above, Professor Morgan considered that the use of benzodiazepines and other hypnotics in the case of Primary Insomnia would be used to treat all presentations of Primary Insomnia and would be considered to benefit all such presentations. I do not understand Professor Morgan to be saying that the treatment of non-restorative sleep had specifically been considered and that benzodiazepines were specifically beneficial to the case of non-restorative sleep. Rather, Professor Morgan was saying that benzodiazepines were prescribed with an altogether broader brush, where no distinction was drawn between the three different symptoms of Primary Insomnia. If Professor Morgan was going further, then I do not accept his evidence. (e) In reply, Professor Roth said this: Paragraph 4.20 of Roth 4. “In paragraphs 4.34 to 4.35 [of Morgan 1], Professor Morgan suggests that treatment of primary insomnia would typically be the same “irrespective of the diagnostic symptom” (i.e., sleep initiation, sleep maintenance, [non-restorative sleep]) and that a treatment found to be effective for one of the diagnostic complaints of primary insomnia reported by a patient would also typically be expected to benefit patients suffering from other complaints of primary insomnia. I do not agree. In 2001, no treatment had been found to be effective in treating [non-restorative sleep] in primary insomnia patients…”

“In relation to paragraph 4.33 [of Morgan 1], Professor Morgan suggests that in 2001 there was a “cross-over point” in relation to new treatments for insomnia. I do not consider that the skilled person would consider 2001 as a cross-over point and I am not aware of any reason why it would be regarded in that way.” (ii) Professor Roth was cross-examined on this: Transcript Day 1/pp.186ff. Q (Mr Vanhegan, QC) As at the Priority Date, the skilled person knew that there were severe problems with benzodiazepine agonists to treat insomnia and primary insomnia, especially in elderly patients. Is that not correct? A (Professor Roth) It depends how you define severe problems and how you define in terms of prevalence. Q (Mr Vanhegan, QC) Let us again see if we can break it down, Professor. This is all in the UK, all as at 2001. It had been known that for a long time, prior to 2001, all benzodiazipine therapy should be withdrawn unless used or given on an occasional basis, in relation to the elderly? A (Professor Roth) I have no idea why that became an issue in 2001. I think it was an issue before 2001 and continues to be an issue beyond 2001…There is great concern. There is great concern about the use of benzodiazepines in the elderly, absolutely. … Q (Mr Vanhegan, QC) What I am suggesting is that all of those [i.e., downsides to prescribing benzodiazepines, which Professor Roth accepted] would have been well-known to the skilled person as at 2001 and that as a result of those known effects in the elderly people, there was a strong demand in the UK not to prescribe benzodiazepines to elderly patients, if at all possible? A (Professor Roth) I do not know how to answer that question other than they are still and were then and continue to be the most commonly prescribed treatments for insomnia. Q (Mr Vanhegan, QC) The fact that they may be the most common does not negate the point I am putting to you, is it, professor, which is, as at 2001, there was a strong drive not to prescribe them to the elderly because of all those side effects? A (Professor Roth) First of all, I do not think it has anything to do with 2001. There has been a continuous concern about the…use of benzodiazepines in all populations, including the elderly. “In paragraphs 4.34 to 4.35 [of Morgan 1], Professor Morgan suggests that treatment of primary insomnia would typically be the same “irrespective of the diagnostic symptom” (i.e., sleep initiation, sleep maintenance, [non-restorative sleep]) and that a treatment found to be effective for one of the diagnostic complaints of primary insomnia reported by a patient would also typically be expected to benefit patients suffering from other complaints of primary insomnia. I do not agree. In 2001, no treatment had been found to be effective in treating [non-restorative sleep] in primary insomnia patients…”

“Melatonin is a hormone secreted by the pineal gland. Its secretion has a circadian rhythm and is inversely related to light exposure. Because peak melatonin secretion is at night, it has received attention as a possible soporific. However, melatonin secretion peaks at night in both diurnal and nocturnal animals, making it unlikely it is fundamentally involved in sleep processes. Although this hormone acts as a chronobiotic and may be useful in treating abnormalities of the circadian rhythm, it is premature to propose a primary role for this hormone in the treatment of insomnia.”

“Insomnia is a common disorder that is associated with significant impairments in quality of life and serious co-morbidities. Despite its prevalence, insomnia is not sufficiently recognised or treated. Patients should be treated only after a complete history and physical examination are conducted to characterise the disorder and detect the presence of associated or complicating conditions. The treatment plan should be tailored to the individual patient but can include a combination of pharmacological and non-pharmacological (e.g., behavioral) therapies. Benzodiazepine-receptor agonists are the drugs of choice in patients with insomnia. The newer benzodiazepine-receptor agonists are important additions to our therapeutic armamentarium. Non-benzodiazepine benzodiazepine-receptor agonists offer the benefits of the older agents and more closely approach the characteristics of the ideal hypnotic (e.g., less rebound insomnia and less sleep stage effect). The physician treating the patient with insomnia now has a range of medications that can be used to tailor therapy to the individual patient. The goal of treatment should be to treat in direct response to sleeplessness with medications that minimise residual effects. These consensus recommendations should serve to improve both direct patient care and the response of governmental/regulatory bodies to the management of this disabling condition.” (b) The second such paper is a consensus statement co-ordinated by Professor Josephine Arendt (a leader in the understanding of melatonin, based at the University of Surrey), and endorsed by a number of other researchers/clinicians in this field (the Arendt Consensus Paper 2000). The paper, entitled In what circumstances is melatonin a useful sleep therapy? Consensus statement, WFSRS This is the World Federation of Sleep Research Societies. Focus Group, Dresden, November 1999, was published in (2000) 9 Journal of Sleep Research 397398. The paper states: “Many claims have been made for the efficacy of melatonin as a sleep therapy (and indeed as a treatment for numerous other conditions). Induction of sleepiness by melatonin taken during the day has been known for many years. This focus group was assembled in order to define as far as possible the conditions in which there is good evidence for the usefulness of melatonin, those where evidence is lacking and the dose range for specific objectives. An important objective was to assess any known risks of long-term or short-term treatment. … Daily melatonin administration (5 mg) is able to maintain synchronised sleep wake and core temperature rhythms in sighted subjects transferred to a dim light environment conducive to free-running and in some sighted subjects it will resynchronise free-running rhythms…Blind subjects frequently suffer from sleep disorders. There is a clear association between degree of visual loss and the incidence of free-running circadian rhythms with the consequent non-24h sleepwake disorder…Melatonin (5 mg or less) clearly helps blind subjects to sleep when the internal clock is in antiphase to the 24h day. Most recently, when treatment is timed to the advance portion of the PRC, it has become clear that melatonin will fully synchronise the circadian clock to 24h in some blind subjects, and this can be maintained when the dose of 5-10 mg is reduced…There is positive data concerning the use of timed melatonin in delayed sleep phase syndrome…It has been used to treat sleep disorders in very disabled children, many with visual problems… Evidence that melatonin can be useful in the treatment of insomnia in older people is inconsistent. Although a ‘melatonin deficiency’ syndrome associated with poor sleep has been reported in old age (Haimov et al 1994; Haimov et al 1995) there is inconsistency in the findings and both medication and the health status of older subjects may be partial causes of this apparent melatonin deficiency. In fact, most recent data suggest that nocturnal melatonin concentrations in most healthy older people are comparable to those in young adults (Zeitzer et al 1999) and that it is not the amount of melatonin produced, but rather circadian phase, which may be related to sleep quality. There appears to be no point in addressing sleep disorders of unknown origin with melatonin treatment. All participants considered that care was essential in the use of melatonin. Reports of deleterious effects are rare (e.g., Middleton et al 1996). Although no significant side-effects have been reported in normal healthy volunteers, there is no long term safety data and little information on its use with concomitant medication. Of particular concern are its effects on reproductive function, which remain to be fully assessed. Moreover, there is no conclusive information on the residual effects of melatonin. They include exacerbation of epilepsy (but with other data that has shown beneficial effects) and possible withdrawal problems in psychiatric patients. In countries where melatonin is freely available, the uncontrolled use without regard to its functional properties is likely to lead to disillusion in terms of its therapeutic benefit.” (2) Professor Roth’s view was that the Consensus Papers set out the common general knowledge of the Skilled Person as at the Priority Date. In particular, he noted: At paragraph 6.63 of Roth 3. 86 Transcript Day 3/p.442 “…it was known that melatonin could be useful in the treatment of circadian rhythm disorders, but it was not thought to be useful for the treatment of primary insomnia. In some countries where melatonin was available for sale as an over-the-counter dietary supplement, it was marketed using claims that it could improve sleep generally, but I did not take those claims seriously nor, in my opinion, were they taken seriously in the sleep medicine community generally.”

“…I had no recollection of The obvious question arises as to why no such reference was made. As to this: (i) Professor Morgan’s explanation was as follows:88 “I well knew of their existence and, as I said, I felt the issue raised in both consensus statements I felt had been addressed within the report I had already written. That is how I felt. I could explain which elements of my report I felt appropriately addressed the key features, as I saw them, in the consensus reports, if you wish.”

“There are no published long-term safety data on the use of melatonin for whatever purpose, assuming long-term to mean more than 6 months of daily medication. In the light of its physiological role in animals, the potential deleterious effects include inhibition of reproductive function, delayed timing of puberty, and influence (when taken during pregnancy and lactation) on the circadian status of the fetus and neonate and on future development. Its interactions with other medications are virtually unexplored.” 4.57. Melatonin is fairly rapidly metabolised, with an elimination half-life (the time it takes for levels in plasma to diminish by 50%) of approximately 40-60 minutes. Because of this, “controlled release” formulations are necessary to maintain blood concentrations at ‘therapeutic’ levels. 4.58. As referenced earlier in paragraph 4.3(b), a key textbook in insomnia was Lichstein and Morin (2000). In the chapter “Pharmacological Treatment” (Buysse & Reynolds) melatonin receives about 2 pages of attention (less than benzodiazepines or antidepressants and about the same as antihistamines). In this chapter, the lack of efficacy trials to support melatonin use among older patients is emphasised by Buysse and Reynolds. The authors point out that melatonin was widely used as a sleep-promoting substance, but that its use “…was not preceded by properly controlled empirical clinical trials”

“likely to impact on sleep symptoms” in paragraph 4.62; “treatment of insomnia” in paragraph 4.61; even “quality of sleep” in paragraph 4.59 is made less clear by the addition of “generally”. 94 See paragraphs 4.55 and 4.59. (ii) Professor Morgan has deployed at least two irrelevant “redherrings”

“4.60 ...Not all of these studies involve exogenous melatonin (i.e., melatonin given as a drug), but most do… 4.61 The doses of melatonin reported to be effective in the treatment of insomnia were reaching agreement by the mid 1990s (i.e., 0.3 – 2 mg)”

“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.”

“(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.” “(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.” 97. This part of the law of patents was reviewed by the House of Lords in Synthon v. SKB, [2006] RPC 10. There are two requirements for a claim to be anticipated by a prior document: disclosure and enablement. As to disclosure, Lord Hoffmann, who gave the leading judgment, began by citing passages from what he described as two judgments of “unquestionable authority”: the speech of Lord Westbury LC in Hills v. Evans, (1862). 31 LJ Ch (NS) 457 at 463 and the judgment of the Court of Appeal in General Tire and Rubber Co v. Firestone Tyre and Rubber Co Ltd, [1972] RPC 457 at 485–486. In the latter case the Court of Appeal said: “If the prior inventor's publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee's claim if carried out after the grant of the patentee's patent, the patentee's claim will be shown to lack the necessary novelty. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's claim were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated. If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented…A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.” 98. 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.” 99. 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. 100. 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.”

“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.”

“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.”

“From the results of the present study, it seems likely that melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep.”