“One point that must be observed is that whereas ‘non-restorative sleep’ would appear to be a technical term, without a lay alternative meaning, the term ‘poor quality of sleep’ contains within it a critical ambiguity: it can refer to the technical, ICD-10, term; but it can, equally, be used in the ordinary sense of ‘I had a bad night’s sleep last night’. Which meaning is intended is a question of context and construction …”
“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).”
“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.”
“(3) There was a good deal of debate before me about what these questions - in particular, questions 4 and 5 - were getting at. [Counsel for Mylan] contended that questions 4 and 5 were directed at quality of sleep in the non-technical sense. In other words, the answers to such questions would take account of factors like slow sleep latency or wakefulness in the middle of the night, which (whilst obviously relevant to insomnia in general terms) are not relevant to insomnia characterised by non-restorative sleep. Professor Roth did not accept this characterisation of the questions, and considered that they were in fact directed to quality of sleep in the ICD-10 sense and were, therefore, directed to the question of non-restorative sleep. (4) I do not consider that this debate was particularly helpful in terms of resolving the issues before me. The fact is that the questionnaire is only as good as the use it is put to by a clinician or researcher. In a poorly conducted trial, participants may not be appropriately selected in terms of what is being tested for, and the questionnaire may not be fit for purpose or appropriately explained. Context is everything, and I do not consider that I am particularly assisted by consideration of the questionnaire independent of a particular study or research programme. (5) That said, since the matter was debated before me, I should express a view as to what the Skilled Person would understand by the questionnaire, viewing it on its own and independent of a particular study or research programme. Viewed in this light, I have no doubt that the Skilled Person would attach a technical meaning to the term ‘quality of sleep’ - i.e., would understand it to be a reference to non-restorative sleep - rather than using it as a layman would, to take into account all factors that make up a “good night’s sleep” - i.e., difficulty going to sleep, waking up in the night, waking up early, and not being restored by sleep (and so on). (6) I reach this conclusion for the following reasons: (a) The Skilled Person will be seeking answers to the questions posed in the questionnaire for a reason. The Skilled Person will be seeking to measure something - and it is obvious that the Skilled Person will regard the questions in the questionnaire as being directed to the established characteristics of insomnia. In short, the Skilled Person, using the questionnaire for purposes of understanding Primary Insomnia, will consider that the questions are directed to the diagnostic criteria for that condition. (b) Indeed, it is very clear from [Parrott and Hindmarch] that that is exactly how the authors perceive the questions [the judge quoted a passage describing the chronological grouping of the questions]. (c) Accepting that the significance of these questions would be coloured (i) by the date at which the questions would be asked (here: the Priority Date is the relevant date when seeking to understand what the person asking these questions would be intending) and (ii) by the nature of the investigation itself (a factor unknown in this context), I have no doubt that the Skilled Person would regard QOS or quality of sleep as being used in its technical sense, in particular given that the questions are targeted at specific and separate chronological aspects of a night’s sleep of a given individual. Thus, QOS is chronologically distinct from (i) GTS and (ii) AFS. To allow difficulty in getting to sleep to colour perceived quality of sleep would be to misunderstand the significance of the chronological segmentation of these questions.” (a) The Skilled Person will be seeking answers to the questions posed in the questionnaire for a reason. The Skilled Person will be seeking to measure something - and it is obvious that the Skilled Person will regard the questions in the questionnaire as being directed to the established characteristics of insomnia. In short, the Skilled Person, using the questionnaire for purposes of understanding Primary Insomnia, will consider that the questions are directed to the diagnostic criteria for that condition. (b) Indeed, it is very clear from [Parrott and Hindmarch] that that is exactly how the authors perceive the questions [the judge quoted a passage describing the chronological grouping of the questions]. (c) Accepting that the significance of these questions would be coloured (i) by the date at which the questions would be asked (here: the Priority Date is the relevant date when seeking to understand what the person asking these questions would be intending) and (ii) by the nature of the investigation itself (a factor unknown in this context), I have no doubt that the Skilled Person would regard QOS or quality of sleep as being used in its technical sense, in particular given that the questions are targeted at specific and separate chronological aspects of a night’s sleep of a given individual. Thus, QOS is chronologically distinct from (i) GTS and (ii) AFS. To allow difficulty in getting to sleep to colour perceived quality of sleep would be to misunderstand the significance of the chronological segmentation of these questions.”
“Professor Morgan considered that the Skilled Person would not understand the questionnaire in this way: paragraphs 3.10 to 3.11 of Morgan 2. He considered (paragraph 3.11 of Morgan 2) that a response to question 4 of the questionnaire ‘reflects the totality of a subject’s experience of different insomnia symptoms. Certainly, this is how the skilled person as at 2001 would have understood responses to questionnaire items which required those with insomnia symptoms to rate their quality of sleep’. For the reasons I have given, I do not accept this evidence.”
“[0032] 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. [0033] 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. [0034] Table 1: Effects of melatonin and placebo on subjectively assessed quality of sleep and daytime alertness in primary insomnia patients. [0035] Conclusions. These results show that melatonin enhanced the restorative value of sleep in these primary insomnia patients.”
“[0036] 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. [0037] 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 Example 2). Surprisingly, it was found that in patients <55 years of age there was a significant worsening of the quality of sleep and daytime alertness compared to placebo. The results are tabulated in Table 2. [0038] Table 2: Effects of melatonin and placebo on subjectively assessed quality of sleep and daytime alertness in primary insomnia patients aged 55 and higher. [0039] Conclusions. The elderly are more likely to have maintenance and non-restorative sleep problems, as 40% of older individuals complain about sleep problems, including disturbed or “light” sleep, and undesired daytime sleepiness (Vitiello, Michael Geriatrics Vol 54(11):47-52 1999). Younger people typically have sleep onset problems (Roth, Thomas and Roehrs, Timothy Sleep Vol 19(8): S48-49 1996), and their main problem may be due to sleep deficit not non-restorative sleep. These results (Table 2) clearly indicate that melatonin was effective in primary insomnia related to non-restorative sleep, but can be detrimental to insomnia related to other aetiologies (e.g., sleep deficit due to inability to initiate sleep).”
“Use of at least one compound selected from melatonin in an effective amount within the range of 0.025 to 50 2 mg, 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 characterized by non-restorative sleep, wherein the medicament is a prolonged release formulation and comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier.”
“36. … The principle is that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true. Plausibility is not a distinct condition of validity with a life of its own, but a standard against which that must be demonstrated. Its adoption is a mitigation of the principle in favour of patentability. It reflects the practical difficulty of demonstrating therapeutic efficacy to any higher standard at the stage when the patent application must in practice be made. The test is relatively undemanding. But it cannot be deprived of all meaning or reduced … to little more than a test of good faith. … 37. Plausibility is not a term of art, and its content is inevitably influenced by the legal context. In the present context, the following points should be made. First, the proposition that a product is efficacious for the treatment of a given condition must be plausible. Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. As Lord Hoffmann observed in Conor Medsystems Inc v Angiotech Pharmaceuticals Inc[2008] 4 All ER 621 , para 28, ‘it is hard to see how the notion that something is worth trying or might have some effect can be described as an invention in respect of which anyone would be entitled to a monopoly’. But, third, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, i.e. not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. This is in substance what the Technical Board of Appeal has held in the context of article 56, when addressing the sufficiency of disclosure made in support of claims extending beyond the teaching of the patent. In my opinion, there is no reason to apply a lower standard of plausibility when the sufficiency of disclosure arises in the context of EPC articles 83 and 84 and their analogues in section 14 of the Patents Act. In both contexts, the test has the same purpose. Fourth, although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true. Fifth, that reasonable prospect must be based on what the TBA in Salk (T-609/02), para 9, called ‘a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se’. Sixth, in Salk (T-609/02) this point was made in the context of experimental data. But the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. For example, and it is no more than an example, the specification may point to some property of the product which would lead the skilled person to expect that it might well produce the claimed therapeutic effect; or to some unifying principle that relates the product or the proposed use to something else which would suggest as much to the skilled person. Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the patentee can prove that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the patent.”
“How would you compare the quality of sleep using the medication with nonmedicated (your usual) sleep?”
“These results (Table 2) clearly indicate that melatonin was effective in primary insomnia related to non-restorative sleep, but can be detrimental to insomnia related to other aetiologies (e.g., sleep deficit due to inability to initiate sleep).”
“6. The lay-patient argument turned on the contention that Examples 2 and 3 were insufficient to render the Patent … plausible. This was because the questionnaire that may have been used to interrogate the patients as to their sleep referred only to the ‘quality of sleep’. As is clear from the Main Judgment, the term ‘quality of sleep’ ‘contains within it a critical ambiguity: it can refer to the technical, ICD-10, term; but it can, equally, be used in the ordinary sense of “I had a bad night’s sleep”
“… The question asked is within the range of questions one would typically expect to see used in the field of sleep medicine. The skilled person would understand it to be an acceptable way to assess a patient’s subjective restorative quality of sleep. It is important to understand that the terms ‘restful’ and ‘restless’ used in the context of a patient’s subjective report about the quality of their sleep such as this are not terms concerned with the patient’s sleep onset or sleep maintenance (i.e. parameters that can be assessed objectively, such as by actigraphy). If I had been presented with this question and endpoints in a draft paper for peer review at the Priority Date, I would have accepted them as suitable measures of a patient’s subjective restorative quality of sleep.”