Neurim Pharmaceuticals (1991) Ltd v Generic Partners Pty Ltd

Field of the Invention 9 The field of the invention is described in the Patent as follows at page 1, lines 4-9: The present invention relates to a method for treating primary insomnia (as defined by DSM-IV or nonorganic insomnia as defined by ICD-10) when characterized by non-restorative sleep, to the use of melatonin or certain other compounds in the manufacture of a medicament for this purpose, and to a medicament comprising a combination of compounds, for use in improving both the quality and quantity of sleep, in primary insomnia. 10 "DSM-IV" refers to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders which was first published in 1994 by the American Psychiatric Association. It is a diagnostic system used to diagnose patients suffering from mental disorders. A revised edition, DSM-IV-TR, was published in 2000 and was current at the priority date. However, the diagnostic criteria for primary insomnia are identical in DSM-IV and DSM-IV-TR and minor differences in the description of the primary insomnia between those versions of texts would not result in any change in how a person skilled in the art would understand the Patent. 11 "ICD-10" refers to the tenth edition of the International Statistical Classification of Diseases and Related Health Problems which was published in 1992, and which was current at the priority date. It is a diagnostic system published by the World Health Organization ("WHO").

Background to the Invention 12 The background to the invention is set out as follows at page 1, line 15 to page 3, line 24: Sleep disorders, which are complex, are widespread, especially in Western industrial countries, in which it is estimated that about one third of the adult population reports at least occasional difficulties with sleeping, while at least half of the sleep-disordered population have had sleep complaints for years. In US 5,776,969 (James), which discloses a method of treating various sleep disorders, by therapy with a specified combination of chemical compounds, there is discussed and defined inter alia, primary insomnia, which may or may not be characterized by non-restorative sleep. The definition of primary insomnia in the fourth revision of the [DSM-IV] (American Psychiatric Association, 1994) states: "The predominant complaint is difficulty initiating or maintaining sleep, or non-restorative sleep, for at least one month. The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational or other important areas of functioning." Furthermore, according to the definition, non-restorative sleep alone is sufficient to establish the diagnosis of primary insomnia, providing it results in impaired daytime functioning. The tenth revision of the International Classification of Diseases (ICD-10) (World Health Organisation, 1991) describes nonorganic insomnia as "a condition of unsatisfactory quantity and/or quality of sleep." It goes on to state that "there are people who suffer immensely from the poor quality of their sleep, while sleep in quantity is judged subjectively and/or objectively as within the normal limits." The diagnostic guidelines from ICD-10 state that the essential clinical features for a definitive diagnosis of primary insomnia are as follows: a) the complaint is either of difficulty falling asleep or maintaining sleep, or of poor quality sleep; b) the sleep disturbance has occurred at least three times per week for at least one month; c) there is preoccupation with the 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 social and occupational functioning. Thus, there is repeated emphasis in ICD-10 on the equal importance of quality of sleep and quantity of sleep in the diagnosis of insomnia. The invention thus relates to primary insomnia (DSM-IV) or nonorganic insomnia (ICD-10). Because, in normal humans, the natural hormone melatonin has an increased nocturnal concentration in the blood (according to a particular profile, see e.g. US 5,498,423 (Zisapel)), compared with its daytime concentration, and because also a lack of nocturnal melatonin appears to correlate with the existence of sleep disorders, especially although not exclusively in the elderly, the possibility of administering exogenous melatonin to ameliorate sleep disorders has been investigated and is the subject of many scientific papers. Thus, for example, in James, S.P., et al. (Neuropsychopharmacology 1990, 3:19-23), melatonin (1 and 5 mg) and placebo were given at 10:45 pm for one night each to 10 polysomnographically pre-screened insomniacs with a mean age of 33.4 years. These patients (who may not necessarily have had non-restorative sleep related insomnia) had quantitative sleep deficits that were demonstrable by PSG. Administration of melatonin did not alter sleep latency, sleep efficiency, total sleep time, or wake after sleep onset. The patients reported improved sleep quality, though they were not more rested in the morning and believed that their total sleep time had been shorter when on melatonin. In Ellis, C.M., et al. (J. Sleep Res., 1996, 5: 61-65), where melatonin (5 mg) was given at 8:00 pm for 1 week to patients with psychophysiological insomnia, there was no reported change in sleep quantity or quality; 8 patients out of 15 were unable to distinguish the period of active melatonin treatment. In Hughes, R.J., et al. (Sleep 1998, 21: 52-68), immediate release and controlled release formulations of melatonin (0.5 and 5 mg) were given 30 min before sleep and additionally, an immediate release preparation of 0.5 mg melatonin was given halfway through the night to polysomnographically prescreened elderly patients with sleep maintenance insomnia. They found that both melatonin preparations reduced sleep latency but did not alter wake time after sleep onset (an important variable in sleep maintenance insomnia) or total sleep time. No melatonin-induced changes in reported sleep quality or daytime measure of mood and alertness were found. MacFarlane J.G., et al. (Biol Psychiatry 1991, 30(4): 371-6) have reported that melatonin (75 mg per os), administered at 10 PM daily to 13 insomniac patients for 14 consecutive days gave a significant increase in the subjective assessment of total sleep time and daytime alertness, whereas 7/13 patients reported no significant effect on subjective feelings of well-being. 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 characterized by non-restorative sleep. 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. Suitable melatonin agonists and antagonists for use in the present invention include (but are not restricted to) such compounds described in US Patents Nos. US 5,151,446; US 5,318,994; US 5,385,944; US 5,403,851; and International Patent Specification No. WO 97/00069.

The Summary of the Invention 13 The Summary of the Invention includes two consistory statements (at p 4 line 23-p 4a line 5 in the marked-up copy of the Patent), the first of which uses the same language of claim 1, and the second of which uses the same language as claim 4: In a first aspect, the present invention provides use of melatonin in the manufacture of a medicament for treating a patient suffering from primary insomnia characterized by non-restorative sleep and improving the restorative quality of sleep in said patient, wherein said medicament comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifier, adjuvant or carrier, said medicament is a prolonged release formulation in unit dosage form, and said melatonin is present in said medicament in an effective amount within the range of 0.025 to 10 mg. In a second aspect, the present invention provides method for treating a patient suffering from primary insomnia characterized by non-restorative sleep and improving the restorative quality of sleep in said patient, which comprises administering an effective amount within the range of 0.025 to 10 mg of melatonin to said patient, wherein said melatonin is administered in the form of a medicament, said medicament is a prolonged release formulation in unit dosage form, and said melatonin is the only therapeutically active agent administered according to said method.

The Examples 14 The Patent states that the invention will be illustrated by examples ("Examples"). Five Examples are provided.

Example 1 15 Example 1 involved a randomised double-blind trial of 40 elderly primary insomnia patients treated with either a 2 mg prolonged-release melatonin formulation, or placebo. Melatonin (or placebo) was administered every evening for three weeks. 16 On the last two days of treatment, full-night polysomnographic recordings were used to measure quantitative aspects of sleep, and on each morning following sleep recording in the laboratory, a battery of psychomotor tests was administered to assess daytime vigilance. In addition, sleep diaries were used daily to record patient assessments of their perceived quality of sleep for the previous night. 17 In the results section, it is reported that sleep induction (as measured by sleep onset latency, duration of wake prior to sleep onset and percentage of time spent asleep prior to sleep onset) significantly improved with melatonin compared with placebo. Sleep maintenance variables (number of awakenings, duration of wake after sleep onset, sleep efficiency, total sleep time) did not improve. 18 The study conclusions were: These results show beneficial effects of melatonin on sleep initiation, similar to effects of hypnotic drugs. The hypnotic effects of melatonin were in line with reports in the literature showing that melatonin promotes sleep in humans without altering normal sleep architecture. In contrast to this apparently hypnotic effect, psychomotor skills were significantly higher in the melatonin compared to placebo-treated group: significant treatment effects for the Critical Flicker fusion test and total reaction time under melatonin vs. placebo were observed at the end of treatment. These results thus show for the first time the association of hypnotic effect (shortening of sleep latency) by melatonin with enhanced daytime vigilance in primary insomnia patients suggesting that the restorative value of sleep has increased in these patients. With hypnotic drugs shortening of sleep latency and improved quality of sleep is associated with impaired psychomotor skills in the morning or at best no significant deterioration. No hypnotic drug has ever been shown to increase daytime vigilance. Surprisingly, in their diaries, patients did not evaluate the ease of getting to sleep as being better with melatonin compared to placebo. In fact, the patients judged their quality of sleep to be improved with melatonin but not placebo treatment. The restorative value of sleep may thus be associated with a perceived improvement in quality of sleep. (Emphasis added) 19 It is apparent that this trial was assessing both quantitative aspects of the patients' sleep (such as sleep latency) and daytime vigilance, and the quality of sleep based on the patients' subjective reports. The patients' subjective reports indicated that the quality of sleep of the patients given melatonin improved, compared to the control arm. It is apparent that the phrase "restorative value of sleep" (which is not used in the claims) is referring to the objective measurements of patients' sleep latency and daytime vigilance rather than the patients' subjective assessment of their sleep quality. The final sentence in the passage quoted above is pointing to an association between improvements in the restorative value of sleep and improvements in perceived quality of sleep (i.e., a subjective measurement).

Example 2 20 Example 2 involved another randomised, double-blind trial in which 170 elderly patients suffering from primary insomnia were treated with either melatonin or placebo, to study the effects of a prolonged release melatonin formulation on subjectively assessed sleep quality and daytime vigilance. The subjects were treated for two weeks with a placebo to establish baseline characteristics, and then for three weeks with prolonged release melatonin (2 mg per night) or placebo. On the last three days of the baseline and treatment periods, patients were asked in the morning to indicate: (a) the quality of their sleep (when compared to their usual, non-medicated sleep) by marking on a visual analogue scale with the end points "more restless than usual" and "more restful than usual"; and (b) their feeling in the morning by responding to the question "how do you feel now?" using a visual analogue scale with the end points "tired" and "alert". 21 It was found that both quality of sleep and daytime alertness improved significantly with melatonin, compared to the placebo, showing a link between improved restful sleep and less fatigue in the morning. It was concluded that the results showed that melatonin enhanced the restorative value of sleep in the primary insomnia patients.

Example 3 22 Example 3 was also a randomised, double-blind trial of 131 insomnia patients aged between 20 and 80 years whose sleep quality and feeling at daytime was subjectively assessed. The subjects were treated for one week with a placebo to establish baseline characteristics, and then for three weeks with prolonged release melatonin (2 mg per night) 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. 23 In the results section, it is reported that: "[i]n the 55 years and older patients, there was an improvement of quality of sleep and daytime alertness… Surprisingly, it was found that in patients 0.91). … In the present study, we investigated the effect of melatonin treatment on melatonin-deficient insomnia in the elderly. To our knowledge, this is the first report examining the therapeutic effect of melatonin on the elderly population. … Our results suggest that melatonin replacement therapy, using a low dosage (1 or 2 mg) of melatonin, has specific effects on sleep initiation and maintenance in these patients. A 1-week treatment of 2 mg sustained-release melatonin was effective on sleep maintenance (i.e. sleep efficiency and activity level) of elderly insomniacs, while sleep initiation was improved after a 1-week, fast-release melatonin treatment. … [T]he benefit of the sustained-release tablets comes from the release of melatonin in small dosages during the entire night. The fact that sleep initiation was improved upon long-term treatment with sustained-release melatonin suggests stabilization of the sleep-wake cycle in melatonin-deficient elderly insomniacs. … This study suggests two important principles of melatonin replacement therapy of melatonin-deficient 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. … From the results of the present study, it seems likely that melatonin replacement therapy may beneficial in the initiation and maintenance of sleep in this population. (Emphasis added. Citations omitted) 350 The respondents argued that Haimov 1995 would be understood by the skilled addressee as disclosure of a method of using prolonged release melatonin to treat primary insomnia (however characterised) and improve the patient's sleep quality. 351 I accept that Haimov 1995 clearly discloses the use of prolonged release 2 mg melatonin as a treatment which it refers to as "sustained-released melatonin". However, the purpose of the use of the treatment as disclosed in Haimov is less clear.

Primary insomnia 352 The respondents said that the inclusion criteria of the study (including by exclusion of comorbidities, i.e., dementia and depression, ruling out of significant sleep apnoea syndromes and absence of other medical illness that could affect sleep), are consistent with the subjects having primary insomnia and therefore the disclosure of the paper should be understood as being a study in primary insomniacs. The respondents relied on the evidence of Professor Wheatley in Wheatley 1 where he stated that the inclusion criteria used in Haimov 1995 are consistent with the subjects in the study having been identified as suffering from primary insomnia. They also relied on Professor Wheatley's statement in JER 2 that it is likely that a majority of the subjects described in Haimov 1995 had primary insomnia based on the clinical description given and the context of the study. 353 In JER 2, Professor Roth disagreed with Professor Wheatley. Professor Roth contended that potentially none of the patients in the study populations had primary insomnia and that nowhere are they described as having been diagnosed with any type of primary insomnia or nonorganic insomnia. He noted that Haimov 1995 does not include the terms "primary insomnia", "nonorganic insomnia" or "non-restorative sleep" nor does it include any reference to DSM-IV or ICD-10. He also noted that there is a reference to ICSD, but only to note that ICSD does not include a diagnosis of "insomnia in the elderly". He stated that this suggested to him that neither DSM-IV nor ICD-10 were used in identifying the study populations and that, while ICSD was considered, ultimately no diagnostic criteria from any of those nosologies were utilised. 354 In JER 2, Professors Roth, Wheatley and Glozier all agreed they could not determine what proportion of the participants (if any) in Haimov 1995 may have met the diagnostic criteria for primary insomnia. They acknowledged that this was in part complicated by the fact that the authors did not use the term "primary insomnia" as an inclusion criterion. In addition, no specific inclusion and exclusion criteria was listed in Haimov 1995 to allow the experts to determine whether the participants did or did not meet the criteria for a diagnosis if primary insomnia. Professors Wheatley and Glozier also accepted in cross-examination that neither primary insomnia nor non-restorative sleep are discussed in Haimov 1995 and the participants were not selected on the basis of specifically meeting those criteria. 355 Neurim argued that the subjects in Haimov 1995 were elderly patients who could have a large burden of health problems that can cause secondary insomnia. Whilst patients were excluded from the study groups if they had certain health conditions, this was not a systematic exclusion of patients with health conditions that would cause them to be outside the DSM-IV or ICD-10 criteria for primary insomnia characterised by non-restorative sleep, including some conditions which are common in elderly patients, such as anxiety and mild sleep apnoea. 356 Additionally, Neurim relied on the evidence of Professor Roth that in his opinion, the majority of the patients in Haimov 1995 had a circadian rhythm disorder rather than primary insomnia disorder. This was based on the references in Haimov 1995 to the patients being "melatonin deficient", references to the cohort in Haimov 1995 overlapping with previous research conducted in elderly cohorts with delayed onset and peak times of excretion of a melatonin metabolite, and that the melatonin treatment results indicated "stabilization of the sleep-wake cycle in melatonin-deficient insomniacs", 357 Professor Glozier in Glozier 2 stated that he disagreed with Professor Roth's conclusions in Roth 1 that at least the majority of the patients discussed in Haimov 1995 had a circadian rhythm disorder for various reasons, including that he understood the ruling out of medical illness that might interfere with sleep in the patients in Haimov 1995 would have included circadian rhythm disorders. During cross-examination, Professor Roth subsequently conceded that he could not say if the patients had a circadian rhythm disorder as the patients sleep history was not reported in Haimov 1995. Accordingly, the respondents submitted that the evidence of Professor Roth should not be accepted as it was an overstatement in light of this concession. On this topic I found Professor Glozier more persuasive than Professor Roth. 358 At this point it is important to revisit the exclusion criteria in Haimov 1995 which stated that all patients were in good clinical condition, did meet the criteria for dementia or depression, were personally interviewed by an experienced physician to rule out significant sleep apnoea, and did not suffer from an illness or take any medication (for at least one month prior to the study) that might interfere with sleep. On the basis of this exclusion criteria, I am persuaded that the skilled addressee would understand from Haimov 1995 that a proportion of the subjects described by the authors as insomniacs, were suffering most likely from primary insomnia. I therefore accept the respondents' argument that Haimov 1995 discloses the use of prolonged release melatonin for treatment of primary insomnia generally.

Non-restorative sleep and improving the patient's restorative quality of sleep 359 The respondents argued that the patients' report of "sleeping poorly" in Haimov 1995 can be understood as a complaint of non-restorative sleep. The respondents also relied on the proposition that the authors of Haimov 1995 were using actigraphy as an index of subjective restfulness, and the study's conclusion that restfulness improved with the administration of 2 mg melatonin. The respondents submitted that this should be understood as disclosing an improvement in the patient's restorative quality of sleep. Accordingly, the respondents argued that this amounts to a disclosure of the use of prolonged released melatonin to treat primary insomnia characterised by non-restorative sleep to improve the restorative quality of sleep. In support of this submission, the respondents relied on the evidence of Professor Glozier in Glozier 2 where he stated: …The patients in Haimov 1995 were accepted if they reported '...sleeping poorly on at least 3 nights per week and if their insomnia had lasted for a minimum of 6 months'. I would consider these patients to be complaining about the quality of their sleep, which encompasses non-restorative sleep. I therefore disagree with Professor Roth's view at paragraph 213 of the Roth Affidavit that 'sleep quality' is used in Haimov 1995 to refer only to the quantity of the patient's sleep. (Emphasis added) 360 Professor Roth's evidence at para 212-214 of Roth 1 was as follows: 212. Separately, in the "Results" section, Haimov 1995 discusses the validation of the insomnia complaints made by insomnia patients when they were first enrolled into the study, stating that: "In order to validate the subjective sleep quality, we compared the maintenance (sleep efficiency and activity level during sleep) of those who complained of sleep disorders with that of those who did not". Later in the "Results" section, Haimov 1995 says: "to assess the efficacy of melatonin on sleep quality, the effects of melatonin treatment were studied during the first 6 hours after sleep onset". 213. It is clear that those references to "sleep quality" are not intended to, and do not, refer to "poor quality of sleep", as that term is used in relation to the diagnosis of nonorganic insomnia in the ICD-10. Poor quality of sleep in that diagnostic context in the ICD-10 is a subjective complaint, and distinct from a complaint of difficulty falling asleep or staying asleep. It has the same meaning as non-restorative sleep in the diagnosis of Primary Insomnia in the DSM-IV and cannot be measured objectively. Here, Haimov 1995 is discussing measuring objective parameters using actigraphy. It is clear that "sleep quality" is used in Haimov 1995 in a general sense to refer to the quantity of the patient's sleep. Haimov 1995 does not include any indication that any of the patients in the study populations subjectively assessed the restorative quality of their sleep prior to the start of the study or at the conclusion of any of the treatment periods. 214. In conclusion, I consider that Haimov 1995 would not have disclosed anything to me as at the Priority Date about a possible treatment for Primary Insomnia characterized by non-restorative sleep for the following reasons, which I have discussed more fully above: … (c) Haimov 1995 does not include any reports of the subjective assessment of the restorative quality of the sleep of the insomnia patients in the study populations either prior to the studies or at the end of any of the treatment periods. The DSM-IV is unequivocal that the restorative quality of an insomnia patient's sleep can only be measured by a patient's subjective assessment; (d) all of the sleep parameters measured in Haimov 1995 relate to sleep quantity, not quality, and were measured objectively by actigraphy; (e) the limited positive conclusions expressed in Haimov 1995 regarding the use of melatonin on the objectively measured quantitative aspects of sleep, which would not have disclosed anything to me as at the Priority Date about a possible treatment for Primary Insomnia characterized by non-restorative sleep, are of questionable validity and reliability for the numerous reasons that I have identified. (Emphasis added) 361 In JER 2, Professors Roth, Glozier and Wheatley disagreed on whether objective assays of sleep (in these cases various measures derived from actigraphy) can indicate efficacy in improving non-restorative sleep. All experts agreed that actigraphy was not a validated means of measuring non-restorative sleep. Professor Roth stated and confirmed in his course of cross-examination that he knew of no research justification or clinical validation of any actigraphic endpoint to measure non-restorative sleep. He explained that, at that time, no actigraphic measure had been shown to indicate that it was a measure of patients' reports of non-restorative sleep, and also pointed to research which had attempted, and failed, to identify objective measures of non-restorative sleep. Professor Glozier disagreed with Professor Roth's statement that an improvement in an objective assay of sleep could not indicate an improvement in the subjective self-report of non-restorative sleep. Professor Wheatley also disagreed with Professor Roth and believed that it was possible to have objective measures of sleep that are useful for assessing the symptoms related to non-restorative sleep and sleep quality. 362 During the cross-examination of Professor Roth, Mr Murray SC relied on two publications in support of the respondents' submission that a skilled reader would have understood that actigraphy can demonstrate improvements in non-restorative sleep. 363 The first publication was a book chapter entitled "Assessment and Differential Diagnosis" authored by Professor Colin Epsie, in the book "Treatment of Late-Life Insomnia" edited by Lichstein and Morin and published in 2000 ("Epsie Chapter"). Mr Murray SC relied on the following extract from the Epsie Chapter: 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, Reyner, Hume, & Diamond, 1994). 364 The second publication (which is not evidence) was the academic paper by Horne et al cited by Epsie for the above proposition published in 1994 ("the Horne Paper"). According to Professor Roth, the study in the Horne Paper had two important features that distinguished it from Haimov 1995. First, the Horne Paper was a study of people who lived near an airport, and it used actigraphy to measure movements across the night and led "to some questionnaire about sleep quality in people who sleep by airports". Secondly, the study did not involve insomniac patients and was conducted on healthy volunteers. Professor Roth stated that he did not know what the term "sleep quality" was referring to within the Horne Paper, but seemed to suggest that because of the differences between the Horne Paper and Haimov 1995, the term as used in each source had a different meaning. 365 During the cross-examination of Professor Roth, Mr Murray SC asked whether he agreed that a skilled reader, as at August 2001, reading Haimov 1995, would accept at face value the proposition that movement measured by actigraphy can be viewed as an index of the subjective perception of the restfulness of sleep. Professor Roth emphatically disagreed with that proposition and stated that there was no basis for it. 366 Mr Murray SC also asked Professor Roth whether, if a reader of Haimov 1995 made the assumption that "the activity level during sleep, as measured by actigraphy, is an index of the restfulness of the sleep period", then the observation of a statistically significant improvement in the actigraphy data in the melatonin treatment group would tell the reader that those subjects had been suffering from non-restorative sleep. Professor Roth agreed with that proposition, on the basis of the assumption he was asked to make by Mr Murray SC. He added, however, that he would have some level of concern about the measure because the actigraphy data was only recorded for the first six hours of sleep, and most sleep disturbances, especially in the elderly, tend to occur in the last two hours of sleep. 367 The respondents did not submit that the Espie Chapter or the Horne Paper were common general knowledge at the priority date. There was no evidence to suggest that any witness apart from Professor Roth was familiar with these publications. I accept the evidence of Professor Roth that the skilled addressee would not, at the priority date, have thought that movement measured by actigraphy can be viewed as an index of the subjective perception of the restfulness of sleep. I see no basis for the assumption postulated by Mr Murray SC, that in the Haimov 1995, the activity level during sleep (as measured by actigraphy) is an index of the subjective perception of restfulness of the sleep period. 368 The respondents also submitted that Professor Roth's evidence on this topic should be rejected, as it does not reflect the common general knowledge of the skilled addressee at the priority date and rather is informed by his own vast knowledge of non-common general knowledge literature, and his belief that objective measures have not been shown to correlate with subjective perception. However, to say that it was later found to be the case that objective measures do not correlate with subjective perception, does not establish that the converse was true at the priority date or that the skilled addressee would have understood there to be any such correlation. I accept Professor Roth's evidence that the skilled addressee would not approach Haimov 1995 with the understanding that activity levels as measured by actigraphy provided a basis from which to draw inferences as to the restorative quality of patients' sleep. 369 I find that Haimov 1995 does not provide any clear direction, recommendation or suggestion to use prolonged release melatonin to treat primary insomnia characterised by non-restorative sleep and to improve the patient's restorative quality of sleep. Haimov 1995 is not novelty defeating.

878 Patent 370 The 878 Patent is an EU patent in the name of Neurim and was published on 13 October 1999. The invention is described in paragraph 1 of the 878 Patent as relating to: melatonin for use in the manufacture of a medicament for treating, or for preventing, symptoms of dependence on, tolerance of, or addiction to benzodiazepine drugs, for treating multidrug addicts and to a pharmaceutical formulation, for use in such treatments. (Emphasis added) 371 Other parts of the 878 Patent relevant to novelty and inventive step are extracted below: … [0002] Dependence on benzodiazepines often develops in insomniacs who use them for the induction of sleep and in multi-drug addicts who in the process of withdrawal from narcotics, become addicted to benzodiazepines to ease anxiety and convulsions. … [0004] It has surprisingly been found in connection with the present invention that administration of melatonin concurrently with benzodiazepine drugs can potentially (1) wean a patient away from dependence on, addiction to, or tolerance of such drugs, and (2) in the case of a patient who has been diagnosed as requiring a benzodiazepine drug (where such undesired symptoms have not yet occurred), prevent the occurrence of such symptoms. … DESCRIPTION OF THE INVENTION [0008] The present invention thus provides use of melatonin in the manufacture of a medicament for treating addiction to benzodiazepines in a multidrug addict, or a patient who has symptoms of having become dependent on, tolerant of, or addicted to a benzodiazepine drug, or for treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, wherein said medicament contains at least an amount of melatonin effective for any of said treatments, said amount being adapted for a daily rate of administration within the range of 0.01-100 mg, provided that such use excludes use in the manufacture of a medicament containing 10-100 mg melatonin for treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug. [0009] The said medicament may be a pharmaceutical formulation adapted for oral, rectal, parenteral or transdermal administration and which comprises at least one diluent, carrier or adjuvant, and may be additionally characterized by at least one of the following features: (i) it is in unit dosage form, each unit dosage comprising an amount of melatonin which lies within the range of 0.0025-100 mg; (ii) it is in the form of a controlled release formulation, wherein the melatonin is preferably released at a predetermined controlled rate; (iii) it comprises also at least one melatonin receptor modifier and/or melatonin profile modifier. The medicament may comprise also, and the pharmaceutical formulation according to the invention comprises, at least one benzodiazepine drug, such as at least one of Alprazolam, Chlordiazepoxide, Clorazepate, Diazepam, Flunitrazepam, Flurazepam, Halazepam, Lorazepam, Oxazepam, Prazepam, Temazepam and Triazolam. The formulation which comprises at least one benzodiazepine drug may also be characterized further by one or more of the features (i), (ii) and (iii) as described above. … [0015] In applying the invention for preventive purposes, i.e. in treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, a benzodiazepine drug is administered in an amount effective to alleviate said condition, while concurrently administering to the patient an amount of melatonin which is effective to prevent at least one of such symptoms. The various embodiments described above as applicable to treating a patient having the stated symptom(s) are also correspondingly applicable to preventive purposes, except insofar as they will not be applicable for reasons which are self-evident to a person of the art, e.g. in this instance treatment with a benzodiazepine drug is a desideratum, so that evidently the amount of benzodiazepine administered, while possibly being reduced in any particular case as determined by a physician, will not be reduced to zero. [0016] However, it will be within the scope of the preventive application of the invention, not only to administer, concurrently with melatonin, the benzodiazepine drug(s) at the conventional daily dosage rate to achieve a particular purpose, but in the alternative to similarly administer such drug(s) at a daily rate which is less than that which is conventionally administered to a patient in order to alleviate said condition. … EXAMPLE 3 [0037] This example illustrates the effects of long term administration of melatonin in the treatment of insomnia in patients dependent on a benzodiazepine drug. [0038] Two volunteers, Y.L, an 80 year old male, and E.L., a 73 year old female, had each suffered for a number of years from insomnia and/or frequent awakenings during the night accompanied by difficulty in resuming sleep afterwards. Both were found to have low melatonin secretion, by determination of the amount of the metabolite 6-sulphatoxymelatonin, in the urine. Both patients had been taking 1 -2 mg of flunitrazepam orally prior to retiring each evening. [0039] Each patient was weaned off the flunitrazepam by gradually reducing the dose and simultaneously administering melatonin orally (2 mg melatonin daily in controlled release form) over a two-month period. Since the end of that period, each patient has continued taking melatonin in the same form and at the same dosage rate over approximately two years. [0040] Each patient has subjectively reported good sleep inducement and a substantial improvement in sleep quality. Specifically, patient E.L. noted an improvement in sleep quality at the beginning of the weaning period and Y.L noted a similar effect about two weeks into the weaning period. Each patient reported reduced fatigue during the daytime within several days after the beginning of the weaning period, and also indicated that the melatonin has caused neither residual tiredness in the morning, nor any hangover feeling. No side effects were reported by either patient. (Emphasis added) 372 In their written closing submissions, the respondents argued that three scenarios are identified in para 8 of the 878 Patent. The first is treating addiction in a multi-drug addict. The second is treating a person who has symptoms of having become dependent, tolerant, or addicted to benzodiazepines. The third is use in a preventative sense to prevent a patient from becoming dependent, tolerant, or addicted to benzodiazepines by administering melatonin to a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug ("i.e. preventative use"). 373 The respondents submitted that insomnia, including primary insomnia, is a condition susceptible to alleviation by administration of a benzodiazepine drug. The respondents submitted that this interpretation arose in light of the common general knowledge, given that benzodiazepine receptor agonist drugs were known to be a drug of choice for the treatment of insomnia including primary insomnia. Accordingly, they submitted that the 878 Patent, insofar as it teaches "preventative use" of melatonin in insomniacs, contains an express disclosure of the method of the Patent, in that it is the patients' insomnia that is being treated by the use of melatonin.

Primary insomnia 374 The term "primary insomnia" does not appear in the 878 Patent. Neurim relied on the agreement of Professors Roth, Glozier and Wheatley in JER 2 that they could not determine what proportion of the participants (if any) in the 878 Patent may have met the diagnostic criteria for primary insomnia. Neurim submitted that this alone is sufficient to dispose of the lack of novelty case based on the 878 Patent. 375 As I have noted above in relation to para 8 of the 878 Patent, the respondents submitted that the 878 Patent discloses the use of melatonin in patients with primary insomnia because primary insomnia is "a condition susceptible to alleviation by administration of a benzodiazepine drug." In support of this submission, the respondents relied on the evidence of Professor Wheatley in Wheatley 1 where he explained that given the context of para 4 and the examples of the 878 Patent, he "would understand the patient group described to be insomnia patients including, but not limited to, patients with primary insomnia." 376 The respondents also relied on the evidence of Professor Roth during cross-examination, where he agreed that the statement in para 2 "dependence on benzodiazepines often develops in insomniacs" would include primary insomniacs because benzodiazepines were a treatment of choice for insomnia, including primary insomnia. Professor Roth also agreed during cross-examination that insomnia would be an example of "a condition susceptible to alleviation by administration of a benzodiazepine". However, he observed that such a "condition" would also include Generalized Anxiety Disorder, seizures, depression, and REM behaviour disorder, as all of these conditions are treatable with benzodiazepines. On balance, I am not persuaded that there is a disclosure of the treatment of patients suffering from primary insomnia in the 878 Patent.

Use of prolonged release melatonin to treat primary insomnia 377 It is not in dispute that the melatonin disclosed in the 878 Patent was a prolonged release formulation. It is described in dependent claim 5 as a "controlled release formulation, wherein the melatonin is released at a predetermined controlled rate." 378 As stated above, the respondents submitted that the preventative use disclosed in paras 1 and 8 of the 878 Patent, is the use of melatonin to treat a patient who has a condition susceptible to alleviation by administration of a benzodiazepine, such as primary insomnia, who is not dependent, tolerant, or addicted to benzodiazepines. According to the respondents' submission, the 878 Patent discloses the use of melatonin in place of benzodiazepines to treat the relevant condition (i.e. insomnia, including primary insomnia) and to prevent the occurrence of symptoms of dependence, tolerance, or addiction to benzodiazepines. On this interpretation of the 878 Patent, the patient, who has not developed a tolerance, dependence or addiction to benzodiazepines, uses melatonin to treat the condition and avoid the development of such a dependence, tolerance or addiction. 379 The respondents accepted in their written closing submissions that there is no specific example in the 878 Patent that is directed to the preventative use of melatonin. They submitted that this does not negative the existence of such a disclosure. 380 The respondents relied on Example 3 to support the proposition that the 878 Patent discloses melatonin as a monotherapy to treat insomnia, including primary insomnia. Example 3 states that it "illustrates the effects of long term administration of melatonin in the treatment of insomnia in patients dependent on a benzodiazepine drug". In Example 3, two patients who each suffered for a number of years from insomnia and/or frequent awakenings during the night, accompanied by difficulty in resuming sleep afterwards, who had been taking a benzodiazepine before retiring each evening, were simultaneously administered benzodiazepines with melatonin for two months during a "weaning off period". Following that period, the 878 Patent states that the patients had continued to take melatonin in the same form and same dosage for approximately two years. 381 Example 3 specifically focuses on the patient's sleep quality improvement during the two-month weaning off period only and does not describe the patient outcomes during and after the two-year treatment with melatonin alone. The experts were not asked to give their opinion about what could be deduced from the use of melatonin alone (i.e. as monotherapy) during and after this two-year period. Accordingly, I am not persuaded that Example 3 provides any direction, recommendation or suggestion to use melatonin to treat primary insomnia, or primary insomnia characterised by non-restorative sleep to improve the quality of restorative sleep in such a patient. 382 During cross-examination, Professor Roth agreed that he understood the third category identified in paragraph 8 of the 878 Patent to be a preventative use of melatonin to prevent a patient becoming dependent, tolerant, or addicted to benzodiazepines. He further explained that his understanding of the "preventative use" of melatonin was that melatonin was given simultaneously with benzodiazepines. He stated that when he read the 878 Patent as a whole (noting that none of the examples included the preventative use relied on by the respondents), he recognised the possibility that the 878 Patent disclosed the use of melatonin alone (i.e. instead of benzodiazepines) to treat a condition (that could be treated with benzodiazepines) and in doing so prevented the development of symptoms of dependence, tolerance or addiction to benzodiazepines. However, he drew particular attention to paragraphs 15 and 16 which state: [0015] In applying the invention for preventive purposes, i.e. in treating a patient who has been clinically diagnosed as having a condition susceptible to alleviation by administration of a benzodiazepine drug, while simultaneously preventing the occurrence in the patient of symptoms of dependence on, tolerance of, or addiction to said benzodiazepine drug, a benzodiazepine drug is administered in an amount effective to alleviate said condition, while concurrently administering to the patient an amount of melatonin which is effective to prevent at least one of such symptoms. The various embodiments described above as applicable to treating a patient having the stated symptom(s) are also correspondingly applicable to preventive purposes, except insofar as they will not be applicable for reasons which are self-evident to a person of the art, e.g. in this instance treatment with a benzodiazepine drug is a desideratum, so that evidently the amount of benzodiazepine administered, while possibly being reduced in any particular case as determined by a physician, will not be reduced to zero. [0016] However, it will be within the scope of the preventive application of the invention, not only to administer, concurrently with melatonin, the benzodiazepine drug(s) at the conventional daily dosage rate to achieve a particular purpose, but in the alternative to similarly administer such drug(s) at a daily rate which is less than that which is conventionally administered to a patient in order to alleviate said condition. (Emphasis added) 383 I consider that paragraphs 15 and 16 make clear that Professor Roth's understanding of the preventative use, described in the 878 Patent, is correct. Accordingly, I accept that the 878 Patent discloses the use of benzodiazepines co-administered with melatonin in patients that are not yet dependent, tolerant or addicted to benzodiazepines. When co-administered with melatonin, the benzodiazepine treats the condition (i.e. insomnia, General Anxiety Disorder, depression), whilst the melatonin prevents or reduces symptoms of dependence, tolerance, or addiction to the benzodiazepine. I am not persuaded that there is any clear direction, recommendation or suggestion conveyed by the 878 Patent to use melatonin to treat insomnia, or primary insomnia or primary insomnia characterised by non-restorative sleep. In the result, the novelty challenge based on the 878 Patent fails.

Inventive Step 384 An invention is a patentable invention if the invention, when compared with the prior art base, involves an inventive step: see s 18(1)(b)(ii) of the Act. Section 7(2) of the Act uses the word "obvious" in the course of describing what must be established before an invention can be held not to involve an inventive step. Something may be "obvious" in light of the common general knowledge, or the common general knowledge coupled with relevant s 7(3) information. 385 An invention may be obvious in light of the common general knowledge if the person skilled in the art faced with the same problem as the inventor would have taken, as a matter of routine, whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not. If the person skilled in the art would be directly led as a matter of course to take such steps in the expectation that doing so might well produce a useful or better alternative to the prior art then the invention will be obvious: Wellcome Foundation Limited v VR Laboratories (Aust.) Proprietary Limited (1981) 148 CLR 262 ("Wellcome") at 286 per Aickin J, Alphapharm at [50]-[53]. In Alphapharm at [53] the plurality approved what is commonly referred to as the reformulated or modified Cripps question as providing an acceptable approach to obviousness. 386 A claimed invention is not obvious merely because the person skilled in the art would consider that it was "worthwhile to try". However, there will be some cases in which the person skilled in the art will be directly led, as a matter of course, to try a number of different alternatives in the expectation that each may well produce a useful alternative. Merely because one pathway to an invention is shown to be obvious, does not mean that another such pathway might not also be obvious. Two or more pathways may be obvious, even though some of them might be more obvious than others. 387 Further: The question is not whether the claimed invention is obvious to the Court, but whether it would be obvious to the person skilled in the art who is taken to be equipped with the relevant common general knowledge as it stood at the priority date together with any relevant s 7(3) information but who lacks any capacity for inventiveness. A "scintilla of invention" can sustain a valid patent, but there must be "some difficulty overcome, some barrier crossed" or something "beyond the skill of the calling": Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173 ("Lockwood (No 2)") at [52]; RD Werner & Co Inc v Bailey Aluminium Products Pty Ltd (1989) 25 FCR 565 at 574; Allsop Inc v Bintang Ltd (1989) 15 IPR 686 at 701. The court must be wary of the misuse of hindsight or ex post facto analysis in deciding whether a claimed invention lacks any inventive step: see Aicken J in 3M at 293-294 and Wellcome at 286, and the plurality in Alphapharm at [21]. 388 When postulating the modified Cripps question solely in the context of s 7(2) of the Act (i.e., in the absence of any relevant s 7(3) information) the prior art referred to must be confined to prior art information that forms part of the common general knowledge in the field at the relevant date. To the extent it is shown that there is any additional information of the kind referred to in s 7(3) then the person (or team) skilled in the art will also be taken to be in possession of that information. 389 The respondents' obviousness case relies on the common general knowledge and the following documents ("7(3) documents"): (1) Haimov 1995; (2) Garfinkel et al, "Improvement of sleep quality in elderly people by controlled-release melatonin", The Lancet, 346:541-544 (1995) ("Garfinkel 1995"); (3) Zisapel, "Development of a Melatonin-Based Formulation for the Treatment of Insomnia in the Elderly", Drug Development Research, 50:226-234 (2000) ("Zisapel 2000"); and (4) Garfinkel et al, "Facilitation of Benzodiazepine Discontinuation by Melatonin", Arch Intern Med, 159:2456-2460 (1999) ("Garfinkel 1999"). Garfinkel 1999 is relied on by the respondents as a 7(3) document but only in combination with other 7(3) documents. 390 The respondents did not advance any obviousness case based on the common general knowledge alone. However, they said that the invention as claimed was obvious at the priority date in light of the common general knowledge together with Haimov 1995, Garfinkel 1995 and Zisapel 2000 each considered separately. In addition, the respondents also relied on the following combinations of 7(3) documents: (1) Haimov 1995 and Zisapel 2000; (2) Haimov 1995, Garfinkel 1995, and Zisapel 2000; and (3) Haimov 1995, Garfinkel 1995, Garfinkel 1999 and Zisapel 2000. 391 The first question to be answered is whether a person skilled in the art would be reasonably expected to have ascertained, understood and regarded each of the 7(3) documents as relevant to treating a patient with primary insomnia characterised by non-restorative sleep and improving the restorative quality of sleep in such patient. If the answer to this question is yes, it must then be determined whether the person skilled in the art could reasonably have been expected to combine the documents in the combinations proposed by the respondents. The next question is whether the invention as claimed is obvious in the light of the common general knowledge together with any of the 7(3) documents considered separately or in any permissible combination of those documents.

Reasonably expected to have ascertained, understood and regarded the prior art documents as relevant 392 The operation of s 7(3) was summarised by Kiefel J (with whom Gageler and Keane JJ agreed) in AstraZeneca HCA at [68]-[70]: [68] Before a document containing prior art information can be used along with the common general knowledge for the purposes of the s 7(2) inquiry, it is necessary that it meet the requirements of s 7(3). In [Lockwood (No 2)] it was explained that prior art information which is publicly available in a single document is "ascertained" if it is discovered or found out, and "understood" means that, having discovered the information, the skilled person would have comprehended it or appreciated its meaning or import. The Court also explained that the phrase "relevant to work in the relevant art" is directed to publicly available information, not part of the common general knowledge, which the skilled person could be expected to have regarded as relevant to solving a particular problem, or meeting a long-felt want or need, as the patentee claims to have done. [69] [Lockwood (No 2)] also explains [at [127]] that, in answering the question of obviousness, the information referred to in s 7(3), like that part of the prior art base which is the common general knowledge, is considered for a particular purpose. That purpose is to look forward from the prior art base to see what the skilled person is likely to have done when faced with a problem similar to that which the patentee claims to have solved with the claimed invention. It is this aspect of the s 7(2) inquiry which assumes particular importance on these appeals. [70] In addressing s 7(2), it is to be borne in mind that the skilled person is an artificial construct, intended as an aid to the courts in addressing the hypothetical question of whether a person, with the same knowledge in the field and aware of the problem to which the patent was directed, would be led directly to the claimed invention. The statute's creation of the skilled person construct for this purpose is not to be taken as an invitation to deal with the question posed by s 7(2) entirely in the abstract. Whilst the question remains one for the courts to determine, the courts do so by reference to the available evidence including that of persons who might be representative of the skilled person. (Footnotes omitted) 393 Her Honour's reference to "a problem similar to that which the patentee claims to have solved" reflects what was said by the plurality in Lockwood (No 2) at [127]. However, I note that the plurality in Lockwood (No 2) at [153] and Aickin J in Wellcome at 286 referred to "the same problem" rather than "a similar problem". In light of those authorities, it is appropriate to ask whether the documents containing the prior art information would be perceived by the person skilled in the art as relevant to the same or a similar problem to that addressed by the Patent. 394 The meaning of the component parts of "reasonably expected to have ascertained, understood and regarded as relevant" was also considered by Beach J in Sequenom, Inc v Ariosa Diagnostics, Inc. (2019) 143 IPR 24 ("Sequenom"). His Honour observed at [556]-[570]: [556] As at the priority date, in order for information in addition to common general knowledge to be able to be taken into account in assessing inventive step, it was a requirement pursuant to s 7(3) (in its then terms) that a person skilled in the art could, before the priority date, be reasonably expected to have ascertained, understood, and regarded as relevant that information. [557] The word "ascertained" means "discovered or found out". The fact that a document has been published does not mean that a person skilled in the art could be reasonably expected to have ascertained that information. The relevant question is whether the document was published in such a manner or form that it could reasonably have been expected to be found by a person skilled in the art. [558] In assessing whether a person skilled in the art could be reasonably expected to have ascertained the information, it is important to consider the characteristics of the person skilled in the art, the nature of the problem, and the information typically used by the persons skilled in the art. Section 7(3) does not assume an ascertainability by any and all skilled persons, of whatever description, of all publicly available prior art documents anywhere in the world. … [564] Further, the requirement of "reasonableness" is applied to each of the "ascertained", "understood" and "regarded as relevant" limbs of the s 7(3) test. [565] In Aspirating IP Ltd v Vision Systems Ltd (2010) 88 IPR 52; [2010] FCA 1061, it was explained at [457] to [458] that whether something could be reasonably expected requires a prediction and that in the context of s 7(3) the question is whether, having regard to the evidence, it may be reasonably predicted that the hypothetical non-inventive skilled worker faced with the relevant problem before the priority date would have ascertained, understood and regarded as relevant the particular s 7(3) information in question. … [570] So a mere "possibility" of an alleged s 7(3) document being ascertained or treated as relevant is not sufficient for the purposes of s 7(3). And the relevant question is to be posed in terms of "would find" rather than "could find". 395 The respondents' relied on the evidence of Professor Wheatley concerning a hypothetical research exercise he undertook with the assistance of a researcher, Mr Jennings, to prove that the skilled addressee could reasonably be expected to have ascertained each of the 7(3) documents.

Professor Wheatley's Task 396 The respondents' solicitors, Herbert Smith Freehills ("HSF"), asked Professor Wheatley to describe what treatments he would prescribe for an insomnia patient who: (1) has no underlying condition that causes the insomnia; and (2) complains of day time fatigue and/or not feeling rested after sleep. ("the Task"). 397 Professor Wheatley completed the Task prior to being shown the Patent and considering the claims. I will reiterate here that Professor Wheatley's evidence was that, at the priority date, he knew of but did not use DSM-IV and that the term "non-restorative sleep" was unfamiliar to him. Furthermore, during cross-examination, Professor Wheatley accepted that at the priority date, he was not familiar with primary insomnia characterised by non-restorative sleep within the meaning of the DSM-IV. 398 In Wheatley 1, Professor Wheatley first gave evidence of the available and existing treatments he would have prescribed at the priority date for an insomnia patient of the kind described in the Task. He identified the approaches he already used at the date, including sleep hygiene therapy, behavioural therapy and prescribing temazepam, zolpidem and zopiclone. 399 HSF then asked Professor Wheatley if there were any additional treatments that he would want to prescribe if they were available to him. He responded that he would (and did) refer some patients to sleep clinics for cognitive behavioural therapy ("CBT"), and he would also consider prescribing melatonin which he did not do at the time because it was not available in Australia. He said that he would have prescribed melatonin because: (1) at the priority date, even though the safety profile of melatonin was not well-established through clinical trials, melatonin was readily available over the counter and popular in the United States; (2) melatonin is short-lived, being rapidly metabolised following its absorption over the course of a few hours; (3) there was a significant amount of research conducted on the effect of melatonin on circadian rhythms including the safety and side effect profile of melatonin doses; (4) melatonin had been shown to be a mild hypnotic at doses of between 1 to 3 mg; (5) melatonin likely had a wide safety margin based on extensive use in the United States including at doses which exceeded 10 mg; and (6) no significant adverse effects were known to be associated with melatonin despite the wide use and he therefore did not have any significant concerns about the safety of melatonin use in the short-term. Professor Wheatley said he would have had been more interested in an oral tablet dosage form rather than liquid formulation. 400 Professor Wheatley acknowledged that there was uncertainty surrounding the dose or dose range that would be safe or efficacious for treatment of insomnia at the priority date. He gave evidence that he would have consulted the textbook Sleep Medicine to find information about a dose or dose range of melatonin that may be useful for the treatment of an insomnia patient described in the Task. He identified Chapter 31 as being relevant to his task. He explained at paras 130-131 of Wheatley 1: 130. …In general terms, I considered that Chapter 31 provided a very useful and contemporary summary of studies that examined the effect of melatonin on sleep regulation (and also circadian rhythms) at around the time of publication of the text, including its effect as a hypnotic to induce and / or maintain sleep across a range of physiological and pharmacological doses (0.3 - 80 mg) in both healthy subjects and in people with chronic insomnia. A 'physiological' dose of melatonin is a dose of a size up to 1 mg that produces similar peak levels of melatonin in the blood to that produced in normal circadian cycles. A 'pharmacological' dose of melatonin is a dose of a size intended to exert a therapeutic effect, as opposed to replacement of normal endogenous melatonin levels. Consistent with my understanding of textbooks generally (discussed at paragraph 122 above), the authors took a cautious approach to their recommendations and conclusions, noting the lack of carefully controlled clinical trials regarding the efficacy and safety of melatonin, including for the treatment of sleep disorders. The caution expressed by the authors of this text does temper my approach to the Task, by which I mean that I would need to review any clinical trial research reports with an awareness that there is not a large body of clinical research that supports the efficacy and safety of melatonin for the treatment of insomnia. Although, as stated in paragraph 112 above, the need for further clinical research to establish the long-term safety and appropriate dose for melatonin in insomnia is something that I was aware of at the time. In general terms, I found Chapter 31 to support the view that melatonin may be a useful treatment for primary insomnia and for the patients described in the Task. 131. Chapter 31 contained references to several published papers on the use of melatonin. If I had read Chapter 31 as at August 2001 with the Task in mind, then I would have obtained copies of the following footnoted articles that I consider, based on the context in which the footnotes appear in Chapter 31 and the title of the articles, likely to be of relevance to the Task: … (g) Footnote 38: Garfinkel D, Laudon M, Nof D, et al. 'Improvement of sleep quality in elderly people by controlled-release melatonin.' Lancet (1995) 346: 541 - 544 (Garfinkel 1995); and (h) Footnote 39: Haimov I, Lavie P. 'Potential of melatonin replacement therapy in older patients with sleep disorders.' Drugs Aging (1995) 7: 75 - 78 (Haimov). 401 The article referred to in Footnote 38 is Garfinkel 1995. The article by Haimov and Lavie referred to in Footnote 39 ("Haimov") is not the same article as Haimov 1995 which is referred to above and relied on by the respondents in support of their novelty and inventive step case. However, Haimov 1995 is referenced at footnote 35 of Haimov. Professor Wheatley explained the relevance and usefulness of Haimov and Haimov 1995 in para 133 of Wheatley 1 as follows: Haimov is a review article related to the potential use of melatonin as replacement therapy in elderly patients with sleep disorders that includes a summary of recent clinical trials with melatonin. Haimov includes reference to a study 'recently' conducted by the authors using 2 mg sustained release (SR) and conventional release melatonin where sleep-wake patterns of subjects were monitored objectively using actigraphs. This study is footnote 35 in Haimov and is to an article in Sleep titled 'Melatonin replacement therapy of elderly insomniacs'. The article is stated to be 'in press'. I would have obtained a full text copy of the article in Sleep to review because I consider that it would likely contain information that would assist me with the Task. 402 In Wheatley 1, Professor Wheatley contended that textbooks including Sleep Medicine tend to take a cautious approach to recommendations, as they are targeted at reflecting established practice rather than newer or evolving approaches, and do not necessarily capture the most recent research. Therefore, in addition to consulting Sleep Medicine, he said that he would also seek to obtain information about melatonin to assist with the Task by conducting a literature search. His objective in requesting a literature search was to identify the dose or dose range of melatonin that would be safe and efficacious for the treatment of an insomnia patient. 403 A crucial feature of Professor Wheatley's approach to the Task was his decision to try melatonin as a treatment for patients suffering from insomnia not caused by any underlying condition (i.e. what might generally be termed primary insomnia) who complain of day time fatigue and/or not feeling rested after sleep. It is notable, as well, that the complaints described by the Task are complaints which may be made by patients whose insomnia is solely attributable to difficulties initiating or maintaining sleep leading to inadequate sleep duration, but might also be made by patients who do not experience inadequate sleep duration, but complain of day time fatigue and/or not feeling rested after sleep in the sense of non-refreshing sleep. The Task as presented to Professor Wheatley does not distinguish between non-restorative sleep, and other symptoms of insomnia, which may or may not occur in isolation.

Literature search 404 In Wheatley 1, Professor Wheatley explained his process at the priority date of conducting or requesting a literature search as follows: 123. Prior to August 2001, I had experience with both conducting literature searches myself and requesting literature searches to be conducted on my behalf, and reviewing the result of those searches. Most commonly, I requested a researcher from our research unit to conduct the searches on my behalf. We had, and continue to have, a dedicated research unit in the Department of Respiratory and Sleep Medicine at Westmead Hospital to assist clinicians with research. The research staff were (and are) familiar with the use of databases for conducting these searches, and I relied upon their expertise to identify appropriate databases to search and to formulate appropriate search terms and techniques to ensure that the searches produced optimal results. By optimal results I mean that the number of titles/abstracts generated by the search would be in the order of around 50, and that those titles or abstracts would be relevant to the research task. In my experience, around 50 documents is a manageable number of documents to review in abstract form and make an informed decision regarding the need and benefit of a full text review of any of the documents. 124. Prior to August 2001, when requesting literature searches, I typically provided the researcher assisting me with background information about the search task including a description of the nature of the information I was seeking and some potential search terms to consider. I then asked the researcher to use their expertise to formulate and conduct an appropriate search to address the task I had given them. I would expect that if the researcher encountered any difficulties or if the search was not returning any useful results, the researcher would come back to me for some further input on the search. I would also expect the researcher to narrow the search until about 50 abstracts/titles were identified. I would then review this relatively short list of results to identify the articles that I would want to review in full. 405 Professor Wheatley devised the following task and instructions that he would have given to a researcher prior to August 2001 for the purpose of carrying out the literature search: TASK I would like to find information about: (a) the use of melatonin for an insomnia patient who: (i) has no underlying condition that causes the insomnia, such as respiratory sleep disorders or periodic limb movement disorder; and (ii) complains of day time fatigue and/or not feeling rested after sleep. (Insomnia Patient); and (b) the dose or dose range of melatonin that would be safe and efficacious for the treatment of an Insomnia Patient. Instructions • Please include all available types of information that you consider to be relevant. Please use your expertise to determine the appropriate databases to search. • Please search for documents published in English; • Search terms to consider are 'melatonin', 'insomnia', 'hypnotic', and 'dose'. However please use your expertise in formulating appropriate search terms and techniques to address the task and to generate about 50 titles or abstracts for my review. 406 HSF retained a patent and literature searcher, Mr Anthony Jennings, to conduct both literature and patent searches and he presented Professor Wheatley with two sets of search results. Whilst Professor Wheatley did not request patent searches, HSF explained to him that this course was the typical practice of Mr Jennings in response to Professor Wheatley's instructions. 407 Professor Wheatley reviewed the literature and patent results to identify any records that he considered potentially relevant to the Task and which he would like to review in full. Based on his review, he was comfortable that the searches had identified a sufficient number of literature articles that would likely assist him in the Task, being 45 literature records. He did not identify any patents that were of interest to him as potentially relevant to the Task. 408 From the 45 literature records, Professor Wheatley considered 14 literature records were of interest to him because the titles and abstracts indicated that these publications all involved a consideration of the efficacy and/or safety of one or more doses of melatonin in adults to improve sleep. He reviewed (in full) the 14 literature records while considering the following parameters in order to assess their relevance to the Task: (a) the dose of melatonin studied (he was particularly interested in papers reporting on the use of pharmacological doses), (b) any side effects of melatonin treatment and (c) efficacy of melatonin in the treatment of insomnia. Following this review, he identified 12 literature records relevant to the Task including Zisapel 2000, Garfinkel 1999 and Garfinkel 1995. He also observed that Zisapel 2000, as well as two other literature records identified in the search, included a reference to Haimov 1995 and that based on these references, and the fact that the article was published in the journal Sleep (which he read regularly), he would have obtained a full copy of Haimov 1995 to see if it was relevant to the Task.

Neurim's criticism of the Task 409 It is useful at this point to refer to a number of criticisms made by Neurim in relation to Professor Wheatley's evidence concerning obviousness. First, Neurim submitted that Professor Wheatley was not a person skilled in the art and therefore could not give admissible evidence on the topic. That argument has already been considered and rejected. Next it was submitted that the Task was "fundamentally flawed" because it was not directed to a patient suffering from primary insomnia characterised by non-restorative sleep. In particular, Neurim submitted that "the Patent defines primary insomnia characterized by non-restorative sleep according to the DSM-IV criteria, and a patient that had "daytime fatigue" or "not feeling rested after sleep" (but not both), does not meet those criteria" (emphasis in original). Neurim also submitted that in addressing the Task, Professor Wheatley "was inappropriately led towards melatonin" by HSF. As a consequence of what Neurim characterised as "inappropriate leading", Professor Wheatley is said by Neurim to have had recourse to various publications which he would not otherwise have ascertained or considered relevant. 410 Further, Neurim was highly critical of the follow-up question asked by HSF after Professor Wheatley first identified a range of available treatments for insomnia patients, which asked whether there were any additional treatments that he would want to prescribe if they were available. Neurim submitted that, in addressing the Task, Professor Wheatley was "steered away" from the use of a range of different treatments that he might otherwise have considered worth trying as a treatment for the patient described in the Task. 411 There were also a number of criticisms made by Neurim of the search processes undertaken by Mr Jennings. Neurim criticised the fact that Mr Jennings searched for patents and patent applications, notwithstanding that Professor Wheatley did not ask him to do so. In circumstances where none of the s 7(3) documents identified by Professor Wheatley or relied on by the respondents include any such documents, that criticism goes nowhere. Considerable emphasis was placed on the fact that Mr Jennings chose not to include the search term "hypnotic", and did not explain why, even though this term was specified by Professor Wheatley. Neurim submitted that the use of that search term may have returned results relating to various hypnotic drugs which Professor Wheatley identified as being suitable to the pharmaceutical management of insomnia, and those which he identified as specifically suitable for treating primary insomnia. I do not think there is any substance to that criticism. Professor Wheatley's instructions make clear that he was interested in obtaining information about melatonin, not any hypnotic, so Mr Jennings' decision to exclude that term is understandable. As Neurim's submission implicitly acknowledges, use of the search term "hypnotic" may well have produced many search results that had nothing to do with melatonin. What is in my opinion more important, is the fact that Professor Wheatley identified melatonin as a potential treatment before providing any instructions to Mr Jennings. In this regard, the instructions provided by Professor Wheatley to Mr Jennings were directed to the use of melatonin as a treatment for primary insomnia and the suitable dose or dose range.

Analysis 412 Chapter 31 of Sleep Medicine suggests that melatonin can induce and maintain sleep due to its mild hypnotic effect. However, the authors make the point that few attempts had been made to determine the effects of melatonin as a hypnotic in persons with insomnia. Rather, the Chapter indicates that a number of studies to that time had examined the effects of melatonin in the treatment and alleviation of perceived effects of jetlag and to elicit changes in endogenous circadian rhythms. Even there, the authors refer to a study that concluded the effect of melatonin was not sufficient to warrant its use as a phase shifting agent for alleviation of the effects of jetlag. The authors state in their conclusions that "the combined circadian and hypnotic effects of melatonin would make it an attractive candidate for the treatment of sleep disorders related to inappropriate circadian timing". They refer to the need for carefully controlled clinical trials that focus on the possible beneficial effects of melatonin on specific sleep disorders. They also warn against the chronic use of melatonin for any sleep disorder because "neither the therapeutic nor the potential toxic effects of long-term use of this hormone, which has profound effects on the reproductive system of other mammals, are known". 413 Professor Roth stated in his affidavit evidence that, at the priority date, melatonin was known as an effective chronobiotic but not thought to be useful in the treatment of insomnia. That evidence, originally admitted provisionally, is now admitted by me as evidence of his opinion. It is broadly consistent with what appears in Chapter 31 of Sleep Medicine which highlighted the potential for melatonin to be used in the treatment of sleep disorders related to inappropriate circadian timing. However, there is nothing in Chapter 31 of Sleep Medicine (or any other chapter in evidence) which directly suggests that melatonin may be useful in treating patients whose primary insomnia is characterised by non-restorative or unrefreshing sleep. 414 The various considerations that led Professor Wheatley to say that he would have prescribed melatonin (if it was available) primarily related to what he regarded as melatonin's wide safety margin. With regard to its potential as an efficacious treatment, he referred to melatonin's effect on circadian rhythms and its mild hypnotic effect. The first of those effects was known at the priority date as was the possibility that melatonin may also act as a mild hypnotic. 415 However, Professor Wheatley's evidence does not explain why he would be led to try melatonin as a treatment for a patient complaining of non-restorative or unrefreshing sleep. In this regard, Professor Wheatley acknowledged (as previously discussed) that there are some patients suffering from primary insomnia who complain of unrefreshing sleep that is not associated with any complaint of difficulty initiating or maintaining sleep. His evidence does not explain why he would have viewed melatonin as a promising treatment for such patients, or patients who experience the symptom of non-restorative or unrefreshing sleep alongside difficulties initiating or maintaining sleep. To some extent this is due to the terms in which the Task was formulated. 416 Professor Wheatley was not asked to advise on a potential treatment for primary insomnia where the patient's complaint was of unrefreshing sleep either independent of any difficulty initiating or maintaining sleep, or in tandem with those symptoms. The respondents submitted that it would not have been appropriate to frame the Task in those terms because, as I understood the submission, this would have involved leading Professor Wheatley to the invention. I do not accept that submission. Identifying in the Task the problem addressed in the Patent would not amount to leading unless the inventor's perception of the problem was said to involve an inventive step. It was also submitted that it would not have been appropriate to use, in describing the Task, terminology which Professor Wheatley did not use in practice. However, that submission still does not answer the criticism made, which is that the language in the Task misdescribes the problem addressed by the Patent. 417 The way in which the Task was formulated (i.e., "complains of daytime fatigue and/or not feeling rested after sleep") was broad enough to include potential treatments for primary insomnia that were solely directed to improving sleep initiation or maintenance rather than quality of sleep in the sense of the restorative quality of a sleep. This meant that the scope of the question prompted Professor Wheatley to consider new treatments which assisted in sleep initiation and maintenance regardless of whether such treatments might also contribute to any improvement in a patient's non-restorative (or unrefreshing) sleep. In circumstances where the claimed invention is directed specifically to the treatment of primary insomnia characterised by non-restorative sleep, I do not consider that the Task given to Professor Wheatley is directed to the same or a similar problem to that addressed by the Patent. 418 While I considered Professor Wheatley to be an impressive witness, there are a number of other matters which to my mind diminish the persuasiveness of his evidence in relation to obviousness. While it is true that he had not been shown the Patent prior to addressing the Task, there is no doubt that by the time he completed the Task he had been aware for some years that melatonin was approved for use in Australia as a treatment for patients suffering from primary insomnia. Melatonin had not been approved at the priority date for the approved indication or any other indication. This is a common problem in cases where the invention becomes well-known to persons skilled in the art after the priority date. In that respect, to the extent that Professor Wheatley's evidence is affected by hindsight, it is difficult to see how that problem could have been avoided. But the fact that the problem of hindsight could not be avoided does not mean that it can be ignored and, in this particular case, it diminishes considerably the weight which I give to Professor Wheatley's evidence as to what he would have done if asked to address the Task at the priority date.

Was Professor Wheatley steered towards melatonin as a starting point? 419 As I have explained above, apart from the formulation of the Task, Neurim was highly critical of a "follow up" question HSF asked Professor Wheatley (i.e., were there any additional treatments that he would have wanted to prescribe if they were available). 420 The drugs known to Professor Wheatley in August 2001 that had a hypnotic effect included various benzodiazepines (including temazepam, triazolam, flunitrazepam and nitrazepam), zolpidem (stilnox), zopiclone, various antianxiety agents, various tricyclic anti-depressants, anti-histamines and various herbal products. He was aware that benzodiazepines, zolpidem, zopiclone, antianxiety agents, and tricyclic anti-depressants had been prescribed for the management of insomnia patients by general practitioners and by respiratory and sleep physicians prior to August 2001. He was also aware that anti-histamines and herbal products (both over-the-counter medications) were taken by patients suffering from primary insomnia. 421 As at August 2001, Professor Wheatley had prescribed temazepam, zolpidem and zopiclone for the treatment of primary insomnia. He knew that there was some use by general practitioners of tricyclic anti-depressants for their hypnotic qualities in the treatment of insomnia though he did not suggest that tricyclic anti-depressants or antianxiety agents had been prescribed for the treatment of primary insomnia. I infer that those drugs were primarily prescribed for the treatment of other disorders (e.g. depression and anxiety) and that, to the extent they were used to treat insomnia, it was most likely in the context of a comorbidity. 422 In cross-examination Professor Wheatley was referred to that part of Wheatley 1 in which he states (para 121) that he would have considered prescribing melatonin if it had been available in Australia as at August 2001. Having been referred to that part of his affidavit, Mr Shavin QC, asked Mr Wheatley "of all the possible treatments for insomnia, professor, what caused you to jump to melatonin?" Professor Wheatley gave this evidence in response to that and related questions: PROF WHEATLEY: As I understand of [sic] this point of the task, I have been asked what treatments I would prescribe, and we went through the routine ones in the paragraph before that I would normally have employed. It moved to a discussion about CBT which I was not qualified to perform but was certainly well aware was a very valuable adjunct to the treatment. And it was available in a very limited fashion in Australia at that time. So I would have potentially wanted to trial that. And I guess the context of this question was were there any additional treatments I would want to prescribe if they were available to me. The context that I understood that was being put to me was, are there other medications or therapies that you, potentially, could consider? And I'm not - I don't profess to understand why I would have been wanting to do that at the time, having not necessarily gone through the existing treatments, but that was the question I was asked. And really, the only medication that I was aware of that potentially might be being used in insomnia management would be melatonin. I had no other drug knowledge of development of new drugs in insomnia that I could pursue. And an awareness that melatonin, albeit, not in a licensed form that was being used in the US to a large degree. And that's - a lot of discussions both at meetings and with colleagues around the availability of that medication in the US but not - it was not available in Australia. I don't think it was even available as a - as a herbal supplement at that time it was more controlled in this country. MR SHAVIN: Can I take you back to paragraph 101 … did you turn your mind to whether you would want to explore whether there were other drugs within the class of benzodiazepines that you would want to undertake research into? PROF WHEATLEY: No, I think I had assumed that benzodiazepines were covered in standard response to managing a patient with insomnia. MR SHAVIN: Did you understand the question to which you've referred at paragraph 121, to be specifically pointing you to something that was not in the list at paragraph 101? PROF WHEATLEY: The - yes, that would be my reading of that question at the moment, yes. And ..... - - - MR SHAVIN: So that you understood yourself to having been directed away from considering whether there was prospective research that could be undertaken in relation to any of the drugs in paragraph 101 or any analogues of them? PROF WHEATLEY: It's - yes. I - I think my attention is being pushed away from the existing list of medications that I was aware of and towards something else if it was available. So it's looking at new drugs. (Emphasis added) 423 It would be logical for a clinician such as Professor Wheatley who was presented with the Task to explore the range of treatments that were available in Australia as at August 2001 for the purpose of determining whether they might alleviate the patient's primary insomnia. This would include a range of different drugs with hypnotic effect that were available, including tricyclic anti-depressants and antianxiety agents. I note that the chapter on primary insomnia in Sleep Medicine (Chapter 55) states that some patients suffering from idiopathic insomnia (which, according to the same chapter, is a free-standing form of insomnia which is subsumed by primary insomnia under DSM-IV) had responded to tricyclic anti-depressants. However, the manner in which Professor Wheatley was asked to address the Task effectively excluded consideration of tricyclic anti-depressants and any other drugs that were approved for use in Australia when addressing the Task. He was instead directed to what he referred to as "new drugs" which I took to mean drugs that had not at that time been approved for use in Australia. Melatonin was the only new drug that he was aware of that he thought might be useful in insomnia management. 424 In the circumstances, I am not persuaded that a sleep physician such as Professor Wheatley would have, as at the priority date, been led directly to try melatonin as a treatment for primary insomnia characterised by non-restorative sleep in the expectation it may well provide an effective treatment. In saying this I recognise that the respondents do not contend that the invention of the claims was obvious at the priority date in light of the common general knowledge considered alone. Nevertheless, the starting point for Professor Wheatley's search for a new treatment was melatonin and it is necessary to consider whether a person skilled in the art would have, at the priority date, adopted his starting point. I am not persuaded that a person skilled in the art would have done so.

Analysis of 7(3) Documents 425 Each of s 7(3) publications relied on by the respondents is specifically concerned with the use of melatonin as a treatment for insomnia. It is apparent that the research task given by Professor Wheatley to Mr Jennings was specifically targeted at the use of melatonin as a treatment for primary insomnia. It follows that the search results obtained by Mr Jennings, which includes most of the s 7(3) documents on which the respondents relied, were ascertained as a result of Professor Wheatley's decision to propose melatonin as a treatment for the condition described in the Task. It also follows that the search and selection process followed by Professor Wheatley was fundamentally shaped by his decision to adopt melatonin as his starting point. The following analysis of the s 7(3) documents relied on by the respondents reflects the fact that Professor Wheatley was searching specifically for publications relevant to the use of melatonin as a treatment for primary insomnia.

Haimov 1995 426 Haimov 1995 was identified by Professor Wheatley as a result of consulting Chapter 31 of Sleep Medicine. Haimov 1995 is referred to in the footnotes of another paper, Haimov, which was referred to in the footnotes of Chapter 31 of Sleep Medicine. Haimov 1995 was also referred to in the footnotes of two other papers (one of which was Zisapel 2000) identified by Mr Jennings. 427 The respondents' argued that Haimov 1995 would have been reasonably ascertained because it was published in the leading journal Sleep (which Professor Wheatley read at the priority date), has "melatonin" and "insomniacs" in the title, has "melatonin" in the keywords, and was one of the 13 articles ultimately selected by Professor Wheatley as relevant to the Task. 428 Assuming for present purposes that the person skilled in the art would have regarded melatonin as a promising candidate for use in the treatment of primary insomnia characterised by non-restorative sleep, then I do not think there is any doubt that Haimov 1995 would have been ascertained. It was published in what Professor Wheatley and Professor Roth agreed to be a leading journal in the field of sleep medicine. The title refers to melatonin and the abstract refers to the use of melatonin in the treatment of melatonin-deficient elderly insomniacs. The abstract also describes the dosages used in the course of the trial and refers to improvement in patients' sleep maintenance and initiation. I am satisfied based on the subject matter of Haimov 1995 and the journal in which it appeared that it would have been ascertained by the person skilled in the art looking for information relating to the use melatonin in the treatment of primary insomnia. 429 The next question is whether the person skilled in the art would have understood Haimov 1995 in the sense of comprehending or appreciating the information it disclosed, and also regarded it as relevant to the problem addressed by the invention. I have previously discussed Haimov 1995 in the context of novelty. Among other things, I accepted Professor Roth's evidence that the skilled addressee would not approach Haimov 1995 with an understanding that activity levels as measured by actigraphy provide a basis from which to draw inferences about the restorative quality of a patient's sleep. 430 Professor Wheatley in Wheatley 1 said that he understood Haimov 1995 to provide convincing objective data that melatonin both in fast release and slow release formulations shortens sleep latency. He said that the data was consistent with his understanding that melatonin has a hypnotic effect which would reduce sleep latency. He understood reduced sleep latency and improvements to other objective parameters reported in Haimov 1995 would correlate with patients feeling more rested after sleep and less fatigued during the day because they would have less disrupted sleep. He said: In summary, I consider that Haimov 1995 provides convincing objective data that [sustained release] melatonin causes a decrease in sleep latency, an increase in sleep efficiency and a decrease in the mean level of activity during sleep. These improvements indicate less disrupted, more continuous sleep. I accept that evidence. However, I do not accept that the person skilled the art would have understood Haimov 1995 as suggesting that reduced levels of activity during sleep was indicative of improvements in the restorative sleep of patients. The abstract to Haimov 1995 and the discussion of the results makes clear that the therapy investigated by the authors led to improvements in sleep initiation and maintenance. 431 Professor Glozier gave evidence that Haimov 1995 suggests melatonin as a possible treatment for primary insomnia where a patient experiences non-restorative sleep. I am not persuaded that it does so. That said, I accept that the person skilled in the art would regard Haimov 1995 as relevant in that it provides potentially useful information concerning the safety of melatonin at dosages of 1 mg and 2 mg for sustained release and fast release formulations used in the study. 432 There is in my opinion no information disclosed in Haimov 1995 which would, if considered together with the common general knowledge as it stood at the priority date, directly lead a person skilled in the art to try melatonin as a treatment for primary insomnia characterised by non-restorative sleep. While Haimov 1995 provides useful information as to the safety of melatonin in a 1 mg or 2 mg dosage and indicates that it can reduce sleep latency (i.e. time to fall asleep) and improve sleep efficiency (i.e. ratio of time spent asleep to the time spent in bed), it does not suggest that the restorative quality of the patients' sleep may be improved by administration of melatonin.

Garfinkel 1995 433 Garfinkel 1995 was identified by Professor Wheatley in the footnotes of Chapter 31 of Sleep Medicine. Garfinkel 1995 was also identified in the literature search conducted by Mr Jennings. 434 Garfinkel 1995 includes a summary which states that the authors investigated the effects of a 2 mg controlled release ("CR") formulation of melatonin on sleep quality in 12 elderly subjects who were receiving various medications for chronic illnesses and who complained of insomnia. The subjects were suffering from a variety of medical conditions including heart disease, Parkinson's disease and diabetes. All subjects also had documented melatonin deficiency. 435 The subjects' "[s]leep quality was objectively monitored by wrist actigraphy". The sleep variables measured were sleep efficiency, sleep latency, total sleep time (i.e. time spent asleep after sleep onset) and WASO (i.e. accumulated time awake after sleep onset). Garfinkel 1995 states: Melatonin deficiency may have an important role in the high frequency of insomnia among elderly people. Controlled-release melatonin replacement therapy effectively improves sleep quality in this population. … This study shows that despite the presence of chronic diseases and the use of drugs, controlled-release melatonin has an overall beneficial effect on sleep quality in melatonin-deficient elderly people. The therapeutic effects of melatonin on circadian-based sleep disorders in blind people, travellers with jet-lag, and patients with delayed-sleep-phase syndrome are well established. In people with chronic insomnia and in healthy adults with artificially induced insomnia, however, melatonin in doses of 1-75 mg given for up to a week failed to show consistent hypnotic effects, though there was some improvement of sleep. Before treatment the sleep variables in our 12 subjects were similar to those previously reported for insomniac elderly people. These findings objectively confirmed our subjects' complaints of poor sleep quality. After 3 weeks' treatment with controlled-release melatonin, values for both sleep efficiency and WASO were similar to actigraphic and polysomnographic values reported for healthy elderly people without insomnia … (Footnotes omitted) 436 In Wheatley 1 Professor Wheatley said that he considered the results described in Garfinkel 1995, "specifically the demonstrated effects in decreasing WASO (and increasing sleep efficiency as a result) and tendency to reduce sleep latency, indicate that treatment of insomnia patients with 2 mg CR melatonin was quite effective in reducing disruption to sleep, and improving sleep continuity". He also said: If I had read Garfinkel 1995 in connection with the Task prior to August 2001, I would have wanted to use 2 mg CR melatonin for treatment of the insomnia patient described in the Task. If the cause of the insomnia patient's day time fatigue and/or not feeling rested after sleep are the result of a disrupted pattern of sleep or of fragmented sleep, based on Garfinkel 1995 my expectation would have been that 2 mg CR melatonin would likely assist to improve sleep continuity and thereby reduce day time fatigue and/or a feeling of not being rested after sleep (i.e. I expect that this use of melatonin would help alleviate the patient's symptoms). I would also have had the expectation that 2 mg CR melatonin would be a safe treatment for the insomnia patient given my knowledge regarding melatonin safety noted above at paragraph 112 and also given that 2 mg CR melatonin was well tolerated by the elderly subjects who complained of insomnia in Garfinkel 1995. 437 The respondents' submitted that Garfinkel 1995 would have been ascertained by the person skilled in the art because it was published in a leading journal, The Lancet, and has "sleep", "sleep quality" and "melatonin" in the title, and was one of the 13 articles ultimately selected by Professor Wheatley. They also relied on the fact that Garfinkel 1995 was cited in a number of other publications that Professor Wheatley considered as part of his review, including Zisapel 2000. 438 In Wheatley 1, Professor Wheatley indicated that he did not regard Garfinkel 1995 as relevant after requesting and reviewing it at that time. Shortly before the trial, Professor Wheatley sought to amend Wheatley 1 to indicate that he had in fact identified both Garfinkel 1995 and another paper by MacFarlane et al as papers of interest at that time. When questioned about this amendment during cross-examination, Professor Wheatley stated that he had an "independent memory" of being interested in Garfinkel 1995, but not MacFarlane. Neurim suggested, as I understood its submission, that the change in Professor Wheatley's evidence was indicative of Professor Wheatley having been led to Garfinkel 1995 by HSF. 439 I have no doubt that a person skilled in the art would have ascertained and understood Garfinkel 1995. I do not accept that Professor Wheatley was led to it. The title of the article and the well-known journal in which it appears are proof enough that the article was reasonably ascertainable to a person skilled in the art looking for information relating to the use of melatonin in the treatment of primary insomnia. As to the relevance of Garfinkel 1995 to the problem addressed by the invention, the respondents submitted that it was not only relevant, but that: The invention is obvious in the light of Garfinkel 1995. Taking Garfinkel 1995 as a starting point, there is "no barrier crossed" to arrive at the invention in the context of the Task. Further and alternatively, it would lead a skilled reader to try PR [prolonged release] melatonin within the claimed dose range to treat primary insomnia (however characterized) with an expectation that it would (or may well) improve the quality of the patient's sleep (however measured). 440 Much of what I have said in relation to Haimov 1995 applies to Garfinkel 1995. It does not suggest melatonin would make a suitable treatment for primary insomnia characterised by non-restorative sleep. Improvements in quality of sleep investigated in Garfinkel 1995 were assessed using objective measures of time spent asleep or awake either before or after sleep onset. In addition, the subjects in Garfinkel 1995 were suffering from a variety of chronic diseases. While some of these conditions may not cause insomnia, it is clear that some (e.g. Parkinson's disease) would contribute to a patient's sleep disturbance. Moreover, all of the subjects were suffering from a melatonin deficiency. The focus of the discussion in the article is on the use of melatonin to treat "melatonin-deficiency-related insomnia", i.e. as a "replacement" therapy. 441 I find that a person skilled in the art would have considered Garfinkel 1995 as relevant in that it provides potentially useful information concerning the safety of a 2 mg controlled release formulation of melatonin. I am not persuaded that a person skilled in the art would have considered Garfinkel 1995 as relevant to the treatment of primary insomnia characterised by non-restorative sleep. There is in my opinion no information disclosed in Garfinkel 1995 which would, if considered together with the common general knowledge as it stood at the priority date, directly lead a person skilled in the art to try melatonin as a treatment for primary insomnia characterised by non-restorative sleep.

Zisapel 2000 442 Zisapel 2000 is a review article which discusses the potential use of prolonged release melatonin in the treatment of insomnia particularly in elderly patients. The article was published in the journal Drug Development Research which is not one that Professor Wheatley read or that Professor Roth read routinely at the priority date. Zisapel 2000 was only identified through Mr Jennings' literature search. However, while the evidence suggests that the journal was a "low impact" publication, there is nothing in the evidence which would lead me to conclude that it was obscure or that a clinician seeking information in relation to the use melatonin for the treatment of primary insomnia would be unlikely to access it. 443 It is useful to refer to the abstract to Zisapel 2000: Melatonin, a hormone produced by the pineal gland at night, influences circadian rhythms, most notably the sleep-wake cycle. Much scientific evidence indicates that melatonin has sleep-enhancing properties. Sleep after melatonin administration is more similar to that recorded during normally occurring sleep than after administration of currently available hypnotic agents. Impairment in melatonin production may contribute to the well-known increased incidence of insomnia in the aged. In addition, some medications may impair sleep by inhibiting or distorting the melatonin rhythm. Insomnia associated with diminished nocturnal melatonin secretion may benefit from melatonin replacement therapy. Melatonin is rapidly eliminated from the body. Hence, to maintain effective serum concentrations of melatonin throughout the night, a prolonged-release (PR) formulation of melatonin (Circadin™) has been developed which provides a melatonin profile that simulates the normal nocturnal increase in melatonin concentrations. The sleep-inducing effects of PR-melatonin, at a dosage strength of 2 mg, have been demonstrated in exploratory studies in elderly insomnia patients and patients with depression or schizophrenia and sleep complaints. In the USA melatonin is available without any medical indication as a nutritional supplement. Animal toxicological studies and clinical experience has not revealed any consistent pattern of adverse events or laboratory test value alterations associated with the administration of the PR-melatonin. Clinical trials in a large population of elderly insomniacs have been set up to provide the regulatory bodies with the required evidence on the safety and efficacy of PR-melatonin. 444 There are a couple of points to note in relation to Zisapel 2000. The article is concerned with insomnia generally and not primary insomnia specifically. In the introduction insomnia is defined by the author as "the subjective complaint of insufficient or inadequate sleep [that] is characterized by difficulty in initiating and/or maintaining sleep (increased nocturnal awakenings and sleep fragmentation)". This definition of insomnia makes no reference to non-restorative or unrefreshing sleep. The discussion of melatonin therapy that follows is solely concerned with the effects of melatonin on sleep initiation and maintenance. The author refers to the influence of melatonin on the sleep-wake cycle and its sleep-enhancing properties. The author also observes that "there is a medical need for a safe and efficacious alternative treatment for chronic insomnia, particularly for older patients". Referring to the need for such treatment, the article concludes that the safety of Neurim's prolonged release formulation of melatonin has been established especially in older persons who, in addition to poor sleep quality, have other health problems which require drug treatment. 445 I find that a person skilled in the art would have considered Zisapel 2000 as providing information relevant to the safety of a 2 mg prolonged release dose of melatonin. However, as with Haimov 1995, I am not persuaded that a person skilled in the art would have considered Zisapel 2000 as relevant to a treatment for primary insomnia characterised by non-restorative sleep.

Garfinkel 1999 446 This article, entitled "Facilitation of Benzodiazepine Discontinuation by Melatonin", was published in November 1999 in the Archives of Internal Medicine. The authors include Dr Garfinkel and Dr Zisapel. As previously mentioned, Garfinkel 1999 is not relied on by the respondents except in combination with other s 7(3) documents. 447 The study reported in Garfinkel 1999 included 34 subjects receiving benzodiazepine therapy as long term treatment for insomnia. They were randomised to either the treatment arm or the placebo arm; those in the treatment arm received 2 mg of melatonin in a controlled release formulation ("CRM"). 448 There were two periods of study. In period 1, patients received the CRM or placebo for six weeks. They were encouraged to reduce their benzodiazepine dosage in weeks two, three and four and to discontinue it completely during weeks five and six. In period 2, CRM was administered for another six weeks to 30 subjects (after four dropped out). Those who had not discontinued benzodiazepine therapy in period 1 were over the next six weeks again encouraged to reduce and then stop. 449 Benzodiazepine consumption and subjective sleep quality scores were reported daily by all subjects using a simple questionnaire every morning. Sleep quality scores were reported using a numerical rating (1-10). Subjects were allowed to continue melatonin therapy after the end of period 2 and reassessed six months later. 450 Various results were reported including for the six month follow up which showed that of the 24 patients who discontinued benzodiazepine therapy and received melatonin therapy, 19 maintained good sleep quality. The conclusion drawn by the authors was that controlled release melatonin may effectively facilitate discontinuation of benzodiazepine therapy while maintaining good sleep quality. The authors also reported that overall safety and tolerability were good and that no subjects withdrew from the study due to adverse effects. 451 In Wheatley 1, Professor Wheatley said: 210. If I had read Garfinkel 1999 in connection with the Task prior to August 2001, I would have considered it supportive of my knowledge that melatonin has a hypnotic effect and therefore could be useful in the treatment of insomnia; further, that a dose of 2 mg CR melatonin would be likely to have this effect. Although the results in Garfinkel 1999 do not provide data on the sleep quality experienced by patients taking melatonin in the absence of benzodiazepine use, the results support the conclusion that CR melatonin at a dose of 2 mg assists insomnia patients with the discontinuation of long-term benzodiazepine therapy with no deterioration of subjectively assessed sleep quality. I would therefore want to try 2 mg CR melatonin for treatment of the insomnia patient described in the Task with the expectation that use of a 2 mg dose of CR melatonin would improve the quality of their sleep by having some degree of hypnotic effect. This hypnotic effect may lead to an improvement in sleep efficiency and a reduction in the time taken to fall asleep. This would like likely [sic] result in the patient feeling more rested and less fatigued. 211. Given the absence of any reported safety issues in Garfinkel 1999, and my knowledge that much higher doses were available OTC in the United States and had not caused any serious adverse events that I was aware of, I would have considered using a dose up to 4 mg if necessary. I would have first observed the effect of 2 mg in the individual patient before increasing the dose up to 4 mg if necessary. 452 It is apparent from the passage of evidence extracted above that, despite considering Garfinkel 1999 to be supportive of his view that melatonin had a hypnotic effect and therefore could be used in the treatment of insomnia, Professor Wheatley did not understand Garfinkel 1999 to suggest that melatonin may improve the restorative quality of patients' sleep.

Combination of s 7(3) documents 453 Each of the combinations relied on by the respondents includes Zisapel. The respondents submitted: 280. Professor Roth's evidence in the concurrent session makes it clear that a skilled reader interested in the use of melatonin reading Zisapel 2000 and wishing to understand what was being discussed in Haimov 1995, Garfinkel 1995, or any other paper in the document, would go and read that document. Garfinkel 1995, Haimov 1995, Garfinkel 1999 and Zisapel all appear to be from the same research group, and this group was engaged in continuous pursuit of a research program relating to use of melatonin in insomnia. 281. As Professor Glozier observed in JER2, Zisapel 2000 describes what seems to be a drug development program by reference to the findings of the previous studies. The continuity of the research program told him it was having success. (Citations omitted) 454 Professor Wheatley asserted in his affidavit that if he had read each of Garfinkel 1995, Haimov 1995, Garfinkel 1999 and Zisapel 2000 in connection with the Task prior to August 2001, then he would have combined the information in them. He would do so, as I understood his evidence, because each of those documents contains information that would be useful to him in identifying a dose or dosage range of melatonin suitable to the Task and because they appear to be from the same research group. He said in Wheatley 1: If I had read Garfinkel 1995, Haimov 1995, Garfinkel 1999 and Zisapel [2000], I would have considered that together these papers provided strong support for the use of a dose of 2 mg PR melatonin in the treatment of the insomnia patient noted in the Task. I would therefore have started treatment with a 2 mg dose of PR melatonin in the expectation that such a dose would be likely to improve the symptoms of the insomnia patient described in the Task. Given the absence of any reported safety issues I would have considered using a dose up to 4 mg if necessary. If the treatment at a 2 mg dose successfully treated a patient's insomnia, that is their symptoms of day time fatigue and/or not feeling rested after sleep had resolved, I would consider the possibility of titrating the dose of PR melatonin down to a 1 mg PR dose of melatonin. 455 There is detailed reference made to Haimov 1995, Garfinkel 1995 and Garfinkel 1999 in Zisapel 2000. Haimov 1995 and Garfinkel 1995 are discussed under the heading "Efficacy of PR-Melatonin in Insomnia" while Garfinkel 1999 is discussed under the heading "PR-Melatonin use with Benzodiazepines". All are said to have involved the study of Neurim's 2 mg prolonged release melatonin on insomniacs, and all are relied on to support the following conclusion to Zisapel 2000: In response to the clinical need for a safe and efficacious alternative treatment for insomnia, Neurim Pharmaceuticals began preclinical toxicology and clinical program with the PM formulation of melatonin. This program systematically and rigorously addressed the toxicology, safety, and efficacy issues of melatonin therapy for insomnia. The studies were designed to provide regulatory authorities with sufficient information to demonstrate the efficacy of the product at the recommended doses, timing, and duration of melatonin use. In addition, the safety of the product has been established, especially in older persons who, in addition to poor sleep quality, quite often have additional health problems which require drug treatment. 456 It would be readily apparent to the persons skilled in the art that they could obtain more detailed information concerning the clinical program referred to in Zisapel 2000 by consulting Haimov 1995, Garfinkel 1995 and Garfinkel 1999. I accept that a person skilled in the art who had ascertained Zisapel 2000, Haimov 1995, Garfinkel 1995 and Garfinkel 1999 and was interested in obtaining more information concerning the safety and efficacy of melatonin as a potential treatment for insomnia could reasonably be expected to combine the information in these four documents on the basis that they all concern trials of a 2 mg prolonged release melatonin formulation conducted by the same research group which are said to have established that the formulation was safe for use in patients requiring treatment. 457 I also accept that those documents would when taken together provide strong support for the view that a 2 mg prolonged release melatonin formulation would be safe to use as a treatment for insomnia at least in the short term. However, even when read in combination, Zisapel 2000, Haimov 1995, Garfinkel 1995 and Garfinkel 1999 do not suggest that melatonin may improve the restorative quality of a patient's sleep. As previously explained, the focus of Haimov 1995 and Garfinkel 1995 is on the use of melatonin to initiate or maintain sleep while the focus of Garfinkel 1999 is on the use of melatonin to facilitate the discontinuation of benzodiazepine therapy in patients with insomnia. None of those publications when read together with Zisapel 2000 would suggest to the person skilled in the art that melatonin may be useful in treating primary insomnia characterised by non-restorative sleep. 458 What was known about the mechanism of action of melatonin at the priority date suggested that due to either its effect on circadian rhythms and the sleep-wake cycle, or its potential hypnotic effect, melatonin may assist a patient suffering from insomnia to initiate or maintain sleep. Assuming that the person skilled in the art would have considered melatonin as worth trying as a treatment for primary insomnia in the case of patients who experienced difficulty initiating or maintaining sleep, and also assuming that they would have done so in the expectation that it may well provide a useful treatment for such patients (both of which assumptions I consider justified on the evidence), I do not think the person skilled in the art would have reason to think that the treatment would (or may well) improve the restorative quality of a patient's sleep. While the common general knowledge and the individual or combined s 7(3) documents considered together suggest that melatonin may assist patients who experience difficulty initiating or maintaining sleep, they do not offer any support or encouragement for the view that the restorative quality of the patient's sleep may be improved. 459 In the result, I do not consider that any of the s 7(3) documents considered alone or in any of the combinations relied on by the respondents together with the common general knowledge as it stood at the priority date would have directly led the hypothetical non-inventive person skilled in the art to try melatonin in the expectation that it may well provide a useful treatment for primary insomnia characterised by non-restorative sleep. I am not persuaded that the invention of the claims does not involve an inventive step. 460 Neurim referred extensively in its submissions to the paper by Hughes et al published in Sleep in 1998 ("Hughes 1998") which is cited in a footnote to Chapter 31 of Sleep Medicine. Hughes 1998 includes a discussion of Garfinkel 1995 and Haimov 1995. Ultimately, it was submitted by Neurim that in light of Hughes 1998 and the authors' criticisms of those studies, the skilled addressee would not have been motivated to pursue melatonin as a treatment for insomnia generally, including primary insomnia characterised by non-restorative sleep. 461 I do not think Hughes 1998 can be relied on for that purpose in circumstances where it is not shown to be common general knowledge. The relevant enquiry contemplated by s 7(2) of the Act as it stood at the relevant time is whether a piece of prior art information, or pieces of prior art information which the skilled addressee could be reasonably expected to have combined, ascertained pursuant to s 7(3), would render the invention obvious to the skilled addressee in light of the common general knowledge: see AstraZeneca HCA at [113] per Gageler and Keane JJ. Such an enquiry does not make allowance for the use of Hughes 1998. 462 Hughes 1998 was also relied on by Neurim as providing support for Professor Roth's evidence as to the common general knowledge and the statement in the Consensus Statement relied on by Neurim, that "[t]here appears to be no point in addressing sleep disorders of unknown origin with melatonin treatment". However, there is nothing in Hughes 1998 which would lead me to modify or qualify my previous findings as to the common general knowledge. 463 For completeness I should add that if I am mistaken about the application of the changes made to s 7(3) by the 2001 Amendment Act, then I would agree with Neurim that none of the combinations of documents relied on by the respondents could be justified given the terms of s 7(3) as it stood before its amendment. In my opinion, there is no evidence which could support a finding that the person skilled in the art could reasonably be expected to have treated any one or more of the s 7(3) documents as "a single source of information": cf. Bristol-Myers Squibb Company v Apotex Pty Ltd (No 5) (2013) 104 IPR 23 at [281], Orion Corporation v Actavis Pty Ltd [2015] FCA 909 at [227]. In this case the s 7(3) documents appeared in different journals over a period of some five years. The fact that the earlier publications are all discussed in Zisapel 2000 and that they appear to be the work of the same research group is insufficient to meet the more stringent test.

Lack of Fair Basis 464 The respondents alleged that each of the claims is invalid for lack of fair basis. The test to be applied for the purpose of determining whether a claim is fairly based on the matter described in the specification as required by s 40(3) of the Act (as it stood at the relevant time) requires that the specification contain "a real and reasonably clear disclosure" of what is claimed: Lockwood Security Products Pty Limited v Doric Products Pty Limited (2004) 217 CLR 274 ("Lockwood (No 1)") at [68]-[69]. In support of their submission that the claims were invalid for lack of fair basis, the respondents placed particular reliance on the High Court's analysis in Lockwood (No 1) of the decision in Atlantis Corporation Pty Ltd v Schindler (1997) 39 IPR 29. The High Court said at [87]: Finally, it is necessary to consider the trial judge's citation of Atlantis Corporation Pty Ltd v Schindler for the proposition that to couch a claim "in the same terms as the description of the invention in the specification" did not of itself, by that mere "coincidence of language", establish fair basing. That proposition is correct, but it is not fatal to the Patentee's position in this case. A "coincidence of language" between a claim and part of the body of a specification does not establish fair basing if that part of the language of the specification does not reflect the description of the invention in the light of the specification as a whole. In the Atlantis Case, the specification, read as a whole, described an apparatus limited to a particular use as a sub-soil drainage system. The claims, however, were "pure apparatus" claims without that limitation on use. The Full Court of the Federal Court of Australia refused to construe them narrowly so as to conform with the description in the specification. A statement in the specification of a description of the invention in similar language to the first claim was not treated as the description of the invention. While the Full Court did not engage in close textual analysis, it did distinctly hold that the statement in the specification: "should not be allowed to disguise the fact that the invention disclosed in the body of the specification is truly 'a sub-soil drainage method based on a particular apparatus' or 'a particular apparatus in its application to sub-soil drainage'. The claims, however, are 'pure apparatus claims'. They are not subject to any limitation as to use. They travel beyond, and are not fairly based on, the matter described in the specification." In short, the case is distinguishable. Here, the Patentee does not rely on mere "coincidence of language": it contends that the language used, unlike that employed in the Atlantis Case, does describe the invention. (Footnotes omitted) 465 The High Court also said at [99]: ... the correct position is that a claim based on what has been cast in the form of a consistory clause is not fairly based if other parts of the matter in the specification show that the invention is narrower than that consistory clause. The inquiry is into what the body of the specification read as a whole discloses as the invention [Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 at 612-613]. An assertion by the inventor in a consistory clause of that of which the invention consists does not compel the conclusion by the court that the claims are fairly based nor is the assertion determinative of the identity of the invention. The consistory clause is to be considered by the court with the rest of the specification. 466 The respondents' lack of fair basis case was based on what was said by the respondents to be the different effects of the invention as claimed in patients below the age of 55 from those in patients above the age of 55, in circumstances where the claims are not qualified by reference to the age of the patients to be treated. As developed by Mr Murray SC in his oral submissions, the respondents' point is that "[a]s a matter of disclosure, this [P]atent is telling you it is directed towards over 55s" and what is disclosed is an invention for treatment of that cohort. 467 I do not accept the respondents' submission. The basis for the submission rests solely on the observation that in Example 3 of the Patent, the increase in perceived quality of sleep and daytime alertness in those aged less than 55 given melatonin was less than the increase reported for those given the placebo. However, there are a number of explicit disclosures in the Patent, which make it clear that the invention is not limited to the treatment of patients aged 55 or over. In particular, the section of the Patent entitled "Field of the Invention" describes the invention as relating to the treatment of primary insomnia as defined in the DSM-IV, or nonorganic insomnia as defined by ICD-10, when characterised by non-restorative sleep. There is no suggestion that only patients of certain ages suffer from primary insomnia, or that only certain patients would benefit from the method of treatment of the invention depending on their age. There are also the two consistory clauses using language commensurate with that of the claims. Similarly, the sections of the Patent entitled "Detailed Description of the Invention" contains a description of various preferred embodiments. There is nothing contained in that section of the Patent to suggest that only patients suffering from primary insomnia aged 55 and over would benefit from the invention. The consistory clauses are consistent with the other disclosures in the Patent and, when read with those other disclosures, provide fair basis for the claims. 468 In my opinion there is a real and reasonably clear disclosure in the body of the specification of the invention as claimed that is not limited to a method of treatment for use in patients aged 55 or over.

EVIDENTIARY RULINGS 469 There were objections taken by the parties to evidence which was admitted provisionally. The most important evidence in this category was the affidavit evidence of Professor Wheatley and Professor Roth. For reasons previously explained, I consider that Professor Wheatley is a person skilled in the art, qualified to give admissible evidence as to the state of the art at the priority date. Similarly, for reasons previously explained, I am of the view that Professor Roth is also a person skilled in the art. Evidence given by them that was received provisionally has been admitted, subject to specific rulings referred to below. 470 Neurim raised numerous objections to documents first published after the priority date which it contended were not relevant to construction of the Patent. The first of these objections relates to the second sentence of para 103 in Wheatley 3. I agree with Neurim that the Circadin AusPAR document is not relevant to the proper construction of the Patent and the prior art. I reject that part of para 103 in Wheatley 3. 471 Various other objections of this kind were raised by Neurim in relation to Glozier 2. My rulings in relation to these objections are set out in Annexure A to these reasons. 472 There were also many objections taken by the respondents to particular parts of Professor Roth's affidavits. His affidavits were prolix and often argumentative and speculative. With regard to those parts of Roth 1 which were admitted provisionally, I reject those parts of paras 111, 119 (but only the last sentence), 402, 575, 578, 591, 602, 613 and 617. As to those parts of Roth 2 that were admitted provisionally, I reject those parts of paras 32, 37-39, 44, 46-50, 56-57, 62, 115, 183, 188, 193 and 257. The other parts of the paragraphs that were objected to and admitted provisionally which I have not rejected are in my opinion admissible as evidence of Professor Roth's opinion. 473 Of course, the fact that Professor Roth's opinions are admitted into evidence says nothing about the weight which is to be given to them. In that regard, much of what Professor Roth has said in his affidavit evidence that was the subject of objection concerns the "Person Skilled in the Art". In circumstances where I have held that Professor Wheatley and other sleep medicine physicians with a similar background and experience in the diagnosis and treatment of insomnia (including primary insomnia) are skilled addressees, it will be apparent that I have given little weight to Professor Roth's evidence concerning the identity of the person skilled in the art and his assertion that they must be familiar with DSM-IV.

DISPOSITION 474 I find that claims 4-7 of the Patent were infringed by the respondents by the supply of Melotin (s 117(2)(b)) and by authorisation of medical practitioners prescribing it as a treatment for primary insomnia characterised by non-restorative sleep in patients aged 55 and over (s 13). I also find that each of the respondents is jointly liable for infringement of those claims on the basis that they were at all relevant times acting in concert and pursuant to a common design to supply Melotin in Australia. I am not persuaded that any claim of the Patent is invalid. 475 It is not necessary to express any view as to whether it would have been appropriate to grant an injunction (and, if so, in what terms) had the Patent not expired. However, given my findings about the extent to which the respondents' products are likely to be used for non-infringing purposes and the relative infrequency with which melatonin is prescribed by medical practitioners as a treatment for primary insomnia characterised by non-restorative sleep, it seems to me that this was not a case in which it would have been appropriate to grant an injunction in general terms restraining the respondents from supplying their products. In this regard, the reasoning of the Full Court in AstraZeneca FFC at [444] would be directly applicable. 476 So far as other relief is concerned, Neurim is entitled to declaratory relief in appropriate terms and an inquiry in relation to pecuniary relief in respect of all infringing sales of Melotin and any other Generic Partners Products or Apotex Products supplied by the respondents during the term of the Patent. While Neurim has asserted an entitlement to both an award of compensatory and additional damages, my understanding is that it has not yet made an election between damages and an account of profits. 477 The parties will be given an opportunity to submit agreed minutes of order including declaratory relief in appropriate terms, an order dismissing the cross-claim, and procedural orders relating to the determination of Neurim's claim to pecuniary relief. 478 Given that Neurim has established that the Patent was valid and infringed by each of the respondents, costs should in my opinion follow the event. The respondents should pay Neurim's costs of the proceeding including the cross-claim but excluding the costs previously awarded to the respondents, and the costs reserved on 11 December 2020. Who should pay the costs reserved on 11 December 2020 can be determined at the same time as Neurim's claim for pecuniary relief is determined. I certify that the preceding four hundred and seventy-eight (478) numbered paragraphs are a true copy of the Reasons for Judgment of the Honourable Justice Nicholas.