Neurim Pharmaceuticals (1991) Ltd v Generic Partners Pty Ltd

The Proposed Amendments 7 The Patent has a total of nine claims, eight of which Neurim seeks to amend. The proposed amendments (reproduced in mark-up form) are as follows: 1. Use of at least one compound selected from melatonin and melatonin agonists, 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 at least one compound melatonin is present in said medicament in an effective amount within the range of 0.0025 to 510 mg. 2. Use according to claim 1, wherein the medicament comprises at least one of the following features: (i) it is adapted for oral, rectal, parenteral, transbuccal, intrapulmonary (e.g. by inhalation) or transdermal administration; (ii) it is in unit dosage form, each unit dosage comprising an amount of said at least one compound which lies within the range of 0.025 to 10 mg; (iii) it is a prolonged release formulation; (ivi) it is in a depot form which will release the melatonin slowly in the body, over a preselected time period; (v) it comprises also at least one additional therapeutic agent selected from anxiolytics, antidepressants, hypnotics, sedatives, antihypertensives, analgesics, dopaminergic agonists antipsychotics, minor tranquilizers, anorectics and anti inflammatory drugs. 3. Use according to claim 2, wherein said prolonged release formulation includes an acrylic resin. 4. 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 0.0025 to 510 mg of at least one compound selected from melatonin and melatonin agonists, 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. 5. Method according to claim 4, wherein the melatonin is administered in the form of a medicament, which comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifier, adjuvant or carrier. 6. Method according to claim 5, wherein the medicament comprises at least one of the following features: (i) it is adapted for oral, rectal, parenteral, transbuccal, intrapulmonary (e.g. inhalation) or transdermal administration; (ii) it is in unit dosage form; each unit dosage comprises an amount of said at least one compound which lies within the range of 0.025 to 10mg; (iii) it is a prolonged release formulation; (ivi) it is in a depot form which will release said at least one compound slowly in the body, over a preselected time period; (v) it comprises also at least one additional therapeutic agent selected from anxiolytics, antidepressants, hypnotics, sedatives, antihypertensives, analgesics, dopaminergic agonists, antipsychotics, minor tranquilizers, anorectics and anti inflammatory drugs. 7. Method according to claim 6, wherein said prolonged release formulation includes an acrylic resin. 8. Use of at least one compound selected from melatonin and melatonin agonists, 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, substantially as herein described with reference to any one of the examples but excluding comparative examples. 9. Method for treating a patient suffering from primary insomnia characterized by non-restorative sleep and improving the restorative quality of sleep in said patient, substantially as herein described with reference to any one of the examples but excluding comparative examples. 8 The parties' submissions focused on claim 1 and four limitations sought to be introduced by the proposed amendments which I shall refer to as: the non-restorative sleep limitation; the melatonin limitation; the prolonged release limitation; the range limitation. 9 Of these four limitations, it was the non-restorative sleep limitation that the respondents acknowledged was of most significance, though they made it clear that they resisted all of the proposed amendments.

The Witnesses 10 Two witnesses gave evidence for Neurim. The first was Professor Nava Zisapel who is Neurim's chief scientific officer and managing director. She is also the inventor named in the Patent. She made two affidavits that were read on the application, one made 31 August 2017, and another made 26 February 2018. She was cross-examined over several hours by Mr Murray SC (who appeared with Ms St John for Apotex). The second witness was Mr Nicholas Tyacke of DLA Piper Australia. Mr Tyacke, who is Neurim's solicitor, made two affidavits, one on 4 May 2018 and another on 5 May 2018. He was not required for cross-examination.

The Grounds of Opposition 11 The respondents opposed the amendments on discretionary grounds which appear in statements of particulars of grounds of opposition on which they rely ("the grounds of opposition") filed on 1 August 2017. 12 Relevantly, the grounds of opposition state: … 6. Neurim is guilty of unreasonable delay in seeking the amendments. Particulars (a) Neurim should be taken to have known since at least August 2008 of the need for the proposed amendments because it (or its related parties, also Neurim) made amendments to its related patents in other jurisdictions that have the same effect as the proposed amendments to claim 1 of the Patent: (i) Neurim filed an amended set of claims for United States patent application no. 10/486,688 (which became the United States Patent) on 28 August 2008 to confine the claims to non-restorative sleep. (ii) Neurim filed an amended set of claims for Canadian patent application no. 2454699 on 25 July 2011 to confine the claims to non-restorative sleep. (iii) Neurim filed a request to amend the European patent application no. 02760523.7 (which became the European Patent) on 10 August 2011 to confine the claims: A. to non-restorative sleep; B. to prolonged release formulations; C. to melatonin alone; and D. to a narrower dose range. 7. Neurim failed to make full disclosure of all matters relevant to the proposed amendments. Particulars (a) Neurim asserted that one of its reasons for seeking the proposed amendments is to "better align the claims with the claims of the European Patent", consistently with its amendments to the United States Patent (SOGS [8(c)(ii)]). Alignment is not a substantive reason to amend the Patent. (b) Neurim asserted that the proposed amendments would "narrow the issues to be determined at trial" (SOGS [8(c)(i)]). It did not disclose how the amendments will have that effect - for example, whether the proposed amendments are designed to avoid prior art. (c) Neurim merely referred to the prosecution history documents for the related patents in Europe and the United States, rather than expressly identifying that similar narrowing amendments were propounded in each of those jurisdictions well before it made the present application to amend. 8. Neurim took unfair advantage of the Patent in its unamended (broader) form. Particulars (a) Neurim allowed the Patent to remain in its unamended form on the Register of Patents in Australia since 2008, or alternatively 2011. Contrary to the allegation in SOGS [8(f)], the failure to amend the Patent gave Neurim an advantage (including by restraining other parties' freedom to operate). (b) Neurim asserted the Patent against Generic Partners and Apotex prior to amendment. It sought and obtained injunctive relief in respect of the Patent in its unamended (broader) form.

The Specification 13 The specification begins with the following description of the field of the invention at page 1, lines 4 to 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 nonrestorative 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. 14 This is followed some background information to the invention. The Patent states at page 1, line 15 to page 2, line 27: 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 Diagnostic and Statistical Manual of Mental Disorders (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. 15 There is then a further discussion of another three published articles concerning the use of melatonin in subjects affected by primary insomnia. The specification contains at page 3, lines 12-20: 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. …

Primary Insomnia 16 The above passages of the specification refer to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) (American Psychiatric Association, 1994) and the International Classification of Diseases (ICD-10) (World Health Organisation, 1991). Both of these documents are incorporated by reference. Relevantly, the DSM-IV states at para 307.42: Diagnostic Features The essential feature of Primary Insomnia is a complaint of difficulty initiating or maintaining sleep or of nonrestorative sleep that lasts for at least 1 month (Criterion A) and causes clinically significant distress or impairment in social, occupational, or other important areas of functioning (Criterion 13). The disturbance in sleep does not occur exclusively during the course of another sleep disorder (Criterion C) or mental disorder (Criterion D) and is not due to the direct physiological effects of a substance or a general medical condition (Criterion E). Individuals with Primary Insomnia most often report a combination of difficulty falling asleep and intermittent wakefulness during sleep. Less commonly, these individuals may complain only of nonrestorative sleep, that is, feeling that their sleep was restless, light, or of poor quality. Primary Insomnia is often associated with increased physiological or psychological arousal at nighttime in combination with negative conditioning for sleep. A marked preoccupation with and distress due to the inability to sleep may contribute to the development of a vicious cycle: the more the individual strives to sleep, the more frustrated and distressed the individual becomes and the less he or she is able to sleep. Lying in a bed in which the individual has frequently spent sleepless nights may cause frustration and conditioned arousal. Conversely, the individual may fall asleep more easily when not trying to do so (e.g., while watching television, reading, or riding in a car). Some individuals with increased arousal and negative conditioning report that they sleep better away from their own bedrooms and their usual routines. Chronic insomnia may lead to decreased feelings of well-being during the day (e.g., deterioration of mood and motivation; decreased attention, energy, and concentration; and an increase in fatigue and malaise). Although individuals often have the subjective complaint of daytime fatigue, polysomnographic studies usually do not demonstrate an increase in physiological signs of sleepiness. 17 These extracts from DSM-IV indicate that the term "primary insomnia" covers a variety of conditions in which the predominant complaint relates to the amount or quality of sleep. According to DSM-IV, the predominant complaint of those suffering primary insomnia is "difficulty initiating or maintaining sleep, or non-restorative sleep for at least one month". 18 The ICD-10 describes various non-organic sleep disorders including dyssomnias which are: … primarily psychogenic conditions in which the predominant disturbance is in the amount, quality, or timing of sleep due to emotional causes, i.e. insomnia, hypersomnia, and disorder of sleep - wake schedule. … Insomnia is a condition of unsatisfactory quantity and/or quality of sleep, which persists for a considerable period of time. The actual degree of deviation from what is generally considered as a normal amount of sleep should not be the primary consideration in the diagnosis of insomnia, because some individuals (the so-called short sleepers) obtain a minimal amount of sleep and yet do not consider themselves as insomniacs. Conversely, there are people who suffer immensely from the poor quality of their sleep, while sleep quantity is judged subjectively and/or objectively as within normal limits. 19 Non-restorative sleep (a term used in DSM-IV) describes a condition in which a person, although asleep, experiences a poor quality sleep. Some but not all individuals diagnosed with primary insomnia experience non-restorative sleep. Others experience only difficulty in initiating or maintaining sleep. Still others may suffer from a combination of these experiences. 20 Neurim's contention, to which I will return later in these reasons, is that the claims of the Patent would be interpreted by the skilled addressee as directed to the use of a medicament for the treatment of a patient suffering from primary insomnia characterised by non-restorative sleep. 21 Neurim contends that although the words "characterised by non-restorative sleep" do not appear in the existing claims, it would be apparent to the skilled addressee that a medicament for treating a patient suffering from primary insomnia and improving a restorative quality of sleep, is one that is directed to the treatment of patients suffering from primary insomnia characterised by non-restorative sleep. On Neurim's construction of the existing claims, they would cover the use of melatonin for the treatment of a patient who was suffering from primary insomnia characterised by non-restorative sleep, but not by other sleep disturbances (eg. difficulty initiating or maintaining sleep) that may also result in a diagnosis of primary insomnia. 22 None of the parties suggested that I should decide the construction issue that arises. Nonetheless, I do not think it possible to determine the present application without expressing some tentative views as to the meaning of the existing claims.

Prior Art 23 It is necessary to refer to some prior art that was relied on in the respondents' submissions.

Haimov et al, "Melatonin Replacement Therapy of Elderly Insomniacs" (1995) ("Haimov") 24 Professor Zisapel is one of six co-authors of this paper. It reports the results of a study which investigated the effects of melatonin replacement therapy on melatonin-deficient elderly insomniacs. 25 Subjects in the treatment group were given 2mg doses of melatonin in either a sustained or fast release formulation. The subjects' sleep-wake patterns were monitored using miniature actigraphs worn on their wrists. This was intended to facilitate measurement of sleep duration (ie. total sleep duration out of total bedtime), sleep latency (ie. time to fall asleep at bedtime) and mean activity level (ie. the mean sum of recorded movements during sleep divided by sleep duration). Accordingly to the paper, "[a]ctivity level during sleep can be viewed as an index of restfulness of the sleep period." 26 Haimov contains a discussion of the authors' findings. It states: 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. … 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. In conclusion, melatonin deficiency seems to be a key variable in the incidence of sleep disorders in the elderly. From the results of the present study, it seems likely that melatonin replacement therapy may be beneficial in the initiation and maintenance of sleep in this population. Further studies employing the chronic administration of melatonin, in varying dosages of different preparations, and the investigation of their effects by segmenting the long-term treatment into intervals must be pursued before determining the most efficient melatonin replacement therapy for elderly insomniacs. 27 The focus of Haimov appears to be on the effect of melatonin on sleep initiation and maintenance rather than quality of sleep.

European Patent Specification EP 0724878 ("EP 878") 28 EP 878 includes a discussion of prior art including another European Patent Specification, EP-A-513702 ("Biella"), which is said to describe the use of melatonin in the treatment of (inter alia) sleep disorders, optionally, in the presence of benzodiazepine drug treatment. EP 878 states that Biella does not suggest that melatonin might be useful when a patient has already become dependent on, tolerant of, or addicted to, a benzodiazepine drug. 29 EP 878 describes a number of melatonin formulations for use in accordance with the claimed invention. It is not necessary to refer to these in detail. They include a 2 mg tablet of melatonin that was accepted by Professor Zisapel in cross-examination to be very similar to the commercial embodiment of the medicament described in the Patent in suit. There does not appear to be any dispute that the medicament described in EP 878 would fall within the existing claims of the Patent in suit. 30 EP 878 contains a discussion of a number of examples. It includes the following discussion of Example 2: [0032] This Example illustrates the surprising action of melatonin in facilitating very rapid withdrawal from benzodiazepine drug tolerance. A 43 year old female, married with 2 children has been suffering from sleep onset insomnia for the last 10 years accompanied by frequent and severe migraine attacks. A thorough neurological assessment was negative. Psychiatric or other organic problems were also ruled out. Throughout these years she had been treated with benzodiazepines, tricyclic antidepressants and neuroleptic drugs, as well as by biofeedback and relaxation methods, with no apparent relief. For the last year she has been using 4-8 mg Lorazepam every night. [0033] A thorough psychological assessment at the Sleep Laboratory of Tel Aviv University, did not disclose any significant pathology. The quality of sleep was assessed by an actigraph tracing which automatically monitors the bedtime sleep-wake pattern through a small device attached to the hand wrist. The tracing was recorded for 3 consecutive days and showed a deranged sleep pattern: reduced efficiency, long sleep latency and multiple waking episodes. Urine was collected every 3 hours (for 36 hours) and assayed for the major melatonin metabolite: 6-sulphatoxymelatonin, as an indicator for the diurnal secretion of plasma melatonin. Results showed that 6-sulphatoxymelatonin excretion levels were lower than for aged-matched individuals, and lacked the typical circadian rhythm (TABLE 4). [0034] Oral administration of a controlled-release melatonin formulation in the form of tablets containing 1 mg melatonin (Neurim Pharmaceuticals, Israel) was initiated, in order to correct for the deficiency and distortion of the melatonin rhythm. One tablet was administered daily at 8:30 pm. The patient was asked to gradually reduce the number of benzodiazepine tablets taken each night. Surprisingly, within 2 days, the patient stopped using the benzodiazepine hypnotics altogether, and claimed that her insomnia has improved remarkably. In addition, her headaches also subsided gradually. A repeated actigraph tracing after 3 weeks treatment showed marked improvement in sleep pattern. [0035] The treatment was stopped and 2 weeks afterwards urine was collected again every 3 hours (for 36 hours) and assayed for 6-sulphatoxymelatonin. The results (Table 4) indicated an increase in amount and a clear nocturnal peak of urinary 6-sulphatoxymelatonin. A 5-month follow-up has confirmed that the patient still maintains her quality of sleep and hardly suffers from headaches. After 6 months without treatment sleep quality began to deteriorate and melatonin therapy was resumed. [0036] This case-report indicates potentially a breakthrough in relieving many patients whose quality of life has been impaired by addiction to benzodiazepine hypnotics. Administration of exogenous melatonin may moreover serve as a means of rapid and symptomless withdrawal from benzodiazepines in tolerant patients. 31 Example 3 is also said to illustrate the effects of long term administration of melatonin in the treatment of insomnia in patents dependent on a benzodiazepine drug as follows: [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 after- wards. Both were found to have low melatonin secretion, by determination of the amount of the metabolite 6-sulpha- toxymelatonin, 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. 32 EP 878 ends with four claims. Relevantly, claims 1-3 are to: 1. 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. 2. Use of melatonin according to claim 1 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. 3. Use of melatonin according to claim 1 in the manufacture of a controlled release medicament 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. 33 The focus of EP 878 is on the use of melatonin in the treatment of patients suffering from the effects of benzodiazepine drug addiction, a point that was heavily emphasised by Professor Zisapel in her evidence. However, I note that claim 1, while covering the use of melatonin in patients who are dependent on a benzodiazepine drug, extends to its use as a treatment of a patient who is diagnosed as suffering from a condition susceptible to alleviation by use of a benzodiazepine drug while preventing the occurrence in the patient of symptoms of benzodiazepine drug dependence. This would seem to cover patients who have never taken a benzodiazepine drug.

Bubenik et al, "Prospects of the Clinical Utilization of Melatonin" ("Bubenik") 34 Bubenik is a published paper co-authored by Professor Zisapel. It provides a summary of the present knowledge in relation to melatonin and discusses its potential clinical use. It includes a discussion of the effect of melatonin on sleep including its sleep-producing actions and its use in the treatment of insomnia. It also includes a discussion of what appears to be the study reported in Haimov (cited in footnote [106]) and a number of other studies concerning the use of melatonin in the treatment of poor sleep maintenance in the elderly population treatment with benzodiazepine drugs and other benzodiazepine users who develop dependency and experience "rebound insomnia" when trying to discontinue use of benzodiazepine drugs.

Garfinkel et al, "Improvement of sleep quality in elderly people by controlled-release melatonin," (1995) ("Garfinkel") 35 Garfinkel was published in the Lancet in 1995. Professor Zisapel is a co-author. It reports the results of a study of the effects on sleep quality of a 2 mg dose of melatonin given to elderly patients who were receiving various medications for chronic illnesses and who complained of insomnia. In this study, sleep quality was objectively monitored by wrist actigraphy. Garfinkel states that actigraphy is an established method that can discriminate sleep-wake patterns based on wrist movements. The use of wrist actigraphy in this study suggests that it focused on the quantitative aspects of sleep (ie. sleep initiation maintenance) rather than restorative quality of sleep.

Zisapel, "The Use of Melatonin for the Treatment of Insomnia" (1999) ("Zisapel") 36 In this paper Professor Zisapel discusses the effect of melatonin on sleep by increasing sleep propensity and by synchronising the circadian/biological clock. Various studies are referred to that are said to indicate that melatonin replacement therapy resulted in higher sleep efficiency and lower wake time after sleep onset. Haimov is one of the studies referred to by Professor Zisapel (cited in footnote 48). Again, the focus of this study appears to be on the quantitative aspects of sleep.

The Prosecution History 37 On 23 February 2004 Neurim notified IP Australia of its intention that its PCT application proceed as an application under the Act for a standard patent. The claims of the PCT application were different from those that were eventually included in the Patent as granted. In particular, claim 1 of the PCT application to: Use of at least one compound selected from melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists, in an effective amount within the range of 0.0025 to 50 mg, in the manufacture of a medicament, for treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia, wherein the medicament comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifier adjuvant or carrier. 38 A statement of proposed amendments was submitted by Shelston IP, the patent attorneys acting for Neurim in Australia, but these did not involve any change to what was then claim 1. 39 The First Examiner's Report was issued on 24 July 2006 noting that the invention as defined in claims 1 to 12 was not novel (and did not involve an inventive step) in light of a US patent (US 5498423) and an Australian patent (AU 199872857) which were said by the Examiner to disclose use of melatonin to correct abnormalities in the nocturnal plasma melatonin levels and as a soporific agent. 40 On 10 October 2006, Shelston IP forwarded a statement to IP Australia giving details of various search results in accordance with s 45(3) of the Act. At that time, s 45(3) of the Act provided: The applicant must inform the Commissioner, in accordance with the regulations, of the results of any documentary searches, whether conducted in Australia or elsewhere, for the purposes of assessing the patentability of an invention disclosed in the complete specification or a corresponding application filed outside Australia that are carried out by or on behalf of the applicant, or the applicant's predecessor in title1 prior to the grant of the patent. 41 Shelston IP's letter drew the Commissioner's attention to various search results referencing publications including, Haimov, Bubenik, Zisapel and Garfinkel. 42 On 14 December 2006, Shelston IP responded to the First Examiner's Report. In that letter Shelston IP stated: The claims of the above-referenced patent application, in most general terms, are based on the discovery of a new medical use for a broadly known group of chemical compounds. More particularly, the invention relates to treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia. "Primary insomnia", treatment of which is the new medical use of the present invention, is formally classified in "Diagnostic and Statistical Manual of Mental Disorders" DSM-IV 307.42 and also in "International Classification of Sleep Disorders" (ICD) 307.42-0; (Psychophysiological Insomnia), and "International Classification of Diseases" F51.0; (Nonorganic Insomnia). The classification of an insomnia as "primary" means that it is not caused by anything else (such as transient or chronic physical or mental comorbidity). Thus, in order for a document to be relevant to the presently claimed invention, it must at least disclose some recognized classification of insomnia. 43 This was followed by a more detailed discussion of the patent specifications cited in the First Examiner's Report. 44 In the first paragraph of Shelston IP's letter, it indicated that the invention relates to treating and improving the restorative quality of sleep in a patient suffering from primary insomnia. I think that reflects an accurate characterisation of claim 1 in the form that it then took. 45 A second set of proposed amended claims was submitted by Shelston IP to IP Australia on 14 December 2006. 46 On 21 December 2006 the Second Examiner's Report was issued advising that the objection was maintained to the claims including in their proposed amended form. The Examiner indicated that the claims were not novel (and did not involve an inventive step) in light of (inter alia) Haimov, Zisapel and Garfinkel, on the basis that those documents disclosed that sleep quality is improved by melatonin treatment. 47 On 31 January 2007 Shelston IP replied to the Second Examiner's Report. In that letter Shelston IP stated: With deference to the Examiner, the Applicant respectfully points out that the claims of the above-referenced patent application are based on the discovery of a new medical use for a broadly known group of chemical compounds. More particularly, the invention relates to treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia. "Primary insomnia", treatment of which is the new medical use of the present invention, is formally classified in "Diagnostic and Statistical Manual of Mental Disorders" DSM-IV 307.42 and also in "International Classification of Sleep Disorders" (ICD) 307.42-0; (Psychophysiological Insomnia), and "International Classification of Diseases" F51.0; (Nonorganic Insomnia). The classification of an insomnia as "primary" means that it is not caused by anything else (such as transient or chronic physical or mental comorbidity). Thus, in order for a document to be relevant to the presently claimed invention, it must at least disclose some recognition that it relates to treatment of primary insomnia as defined in such formal classification of insomnia. In other words, the Applicant asserts that the mere use in a document of the unqualified term "insomnia" or (e.g.) "treatment of sleep disorders", will not constitute an anticipation of the present invention or make it obvious. 48 The letter went on to discuss the papers referred to in the Second Examiner's Report. Shortly stated, Shelston IP sought to distinguish the disclosures made in these papers from the invention on the basis that they were based on measurements of quantitative aspects of sleep and were not concerned at all with non-restorative sleep. It was said that the term "sleep quality" as used in Haimov and Garfinkel related solely to the quantitative aspect of sleep. The letter concluded: For the reasons stated above, it is submitted that it would be clear to the skilled addressee that none of the cited articles is either concerned with, or suggests, the subject of the present invention, i.e. improving restorative sleep in patients suffering from primary insomnia. Accordingly, we submit that the present claims are neither taught nor suggested by the prior art and the present invention is both novel and inventive over the cited documents. 49 On 31 January 2007, Shelston IP submitted a third statement of proposed amendments. It was by these amendments that claim 1 came to be amended into the form that it now appears in the Patent. 50 A fourth statement of proposed amendments was submitted on 6 February 2007 including the claims in their existing form. 51 There is nothing in the evidence to explain why the language of the claims was changed from: … for treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia … (ie. the language used in the PCT application) to: … for treating a patient suffering from primary insomnia and improving the restorative quality of sleep in said patient … 52 On 26 February 2007, IP Australia wrote to Shelston IP advising that Neurim's patent application had been accepted. Thereafter, in the absence of any opposition, the Patent application proceeded to grant.

United States of America 53 From an early stage in Neurim's prosecution of its US application (US 10/486,688) Neurim sought inclusion of claims that were directed to the use of a relevant medicament "in treating and improving the restorative quality of sleep in a patient suffering from primary insomnia". 54 On 16 July 2004, the attorneys for Neurim filed an information disclosure statement identifying relevant prior art including Haimov, Bubenik, Zisapel and Garfinkel. 55 On 16 April 2008, the USPTO notified the applicant's attorneys that the relevant claims were rejected on the grounds that they were either not novel (35 USC s 102) or obvious (35 USC s 103). The prior art relied upon by the USPTO in support of that decision included Zisapel. In its statement of reasons for this rejection the USPTO said: The claimed invention is a method for treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia, which comprises administering an effective amount of at least one compound selected from melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists, to the patient, the effective amount being within the range of 0.0025 to 50 mg. Zisapel … teaches that "in elderly insomniacs, melatonin replacement therapy significantly decreased sleep latency, and/or increased sleep efficiency and decreased wake time after sleep onset" … Zisapel … also teaches that "specific melatonin formulations may be useful to treat circadian-rhythm-related sleep disorders and age-related insomnia" … The reference also discloses that "in hypertensive patients treated with β-blockers (i.e. atenolol, propranolol or metoprolol) sleep disturbance was significantly correlated with the fall in melatonin" … Studies that assessed the effects of using 2mg melatonin formulation on sleep in melatonin-deficient elderly insomniacs indicated that "melatonin replacement therapy for 1 week or 3 weeks resulted in higher sleep efficiency and lower wake time after sleep onset" … "Administration of melatonin (2 mg) in a regular release formulation enhanced sleep initiation in healthy elderly subjects with insomnia. Sleep-promoting effects of melatonin in elderly subjects with insomnia were also reported at a dose of 0.3 mg in a regular-release formulation" … Therefore, the limitations of claim 7 are anticipated by the teachings of Zisapel … 56 So far as the rejection based on obviousness was concerned, the USPTO rejected the relevant claims "as being unpatentable over Zisapel … in view of Short et al (US 4,600,723)". It is not necessary to consider this ground of rejection beyond noting that it appears to have been based upon a process of reasoning that involved drawing upon the disclosures contained in two separate and apparently unrelated documents. 57 Neurim's US attorneys filed a reply dated 28 August 2008 that addressed a new form of claim proposed by Neurim directed to "a method of treating a patient suffering from primary insomnia characterised by non-restorative sleep". Attached to the reply was a declaration made by Professor Zisapel explaining that "primary insomnia" is a common sleep disorder, recognised and defined in both DSM-IV and ICD-10 as being characterised the following elements: difficulty in initiating sleep; difficulty in maintaining sleep; and/or non-restorative sleep. 58 Professor Zisapel made the point that non-restorative sleep is described as insomnia in which the issue is not one of lack of sleep quantity but of poor sleep quality, and that the diagnosis of poor sleep quality, by necessity, had to be based on subjective assessment. In paragraph 11 of her declaration, Professor Zisapel stated: It is clear that the patients in the previous studies were not patients suffering from primary insomnia characterised by non-restorative sleep. The references thus do not anticipate the method of the present claims. It also was not predictable from the cited references that melatonin could be effectively administered to treat primary insomnia characterised by non-restorative sleep. 59 The USPTO issued a response to Professor Zisapel's declaration which stated that it had been fully considered and was persuasive. The rejections previously communicated were withdrawn but new grounds for rejection were made based on (inter alia) Zisapel in view of an article by Zhdanova et al. 60 Ultimately, the USPTO was persuaded that it should allow the claims in amended form on the basis that the claimed invention was novel and not obvious over the prior art of record. The independent claim as allowed by the USPTO (with the final amendment shown in mark-up) was as follows: Method for treating and improving the restorative quality of sleep in a patient suffering from non-restorative sleep as an element of primary insomnia, which comprises administering an effective amount of at least one compound selected from the group consisting of melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists, to said patient, said effective amount being within the range of 0.0025 to 50 mg, wherein said at least one compound selected from the group consisting of melatonin, other melatonergic agents, melatonin agonists and melatonin antagonists is the only therapeutically active agent administered according to said method.

Canada 61 The application for what became Canadian Patent No 2454699 included claim 1 in the form that it appeared in the PCT application. 62 On 27 April 2009 the Examiner issued a requisition that identified defects in the application. The Examiner advised that the claims did not comply with para 28.2(1)(b) of the Canadian Patent Act because they included subject matter disclosed (inter alia) in EPO 878 and Biella. Other defects were identified including the use of the terms' "melatonin agonists" and "melatonin antagonists" (which were said to be too broad), the scope of the dosage range included in the claim (which was said to lack support) and what were said to be ambiguity arising out of the use of the term "an effective amount" in claim 1. Other points were raised with respect to claims 2 and 5 which need not be addressed in any detail. 63 Neurim's Canadian patent attorney's response dated 27 October 2009 enclosed amendments to the claims, none of which made any change to the words "for treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia …" in claim 1. 64 A second requisition was issued by the Examiner on 19 April 2010 in which she advised that what was claimed in claim 1 was either common general knowledge or disclosed in the cited prior art. 65 A response to the second requisition was provided by Neurim's attorneys on 23 July 2010. Further amendments were proposed to some of the claims but these did not involve any change to claim 1. The attorney's response emphasised that non-restorative sleep is insomnia in which the issue is not one of lack of sleep quantity, but of poor sleep quality. 66 A third requisition was issued on 24 January 2011 in which it was said that the claims do not comply with para 28.2(1)(b) of the Canadian Patent Act because they include subject matter disclosed in (inter alia) EP 878 and Biella. The Examiner explained her reasons for rejecting the claims as follows: In summary, the Applicant maintains that the amended claims in the present application are novel over the prior art since none of the prior art mentions that melatonine can be used for the restorative quality of sleep. Mainly, the Applicant's argues that the cited references do not outline explicitly the effect of the melatonin on the restorative quality of sleep in subjects suffering from primary insomnia. The Examiner would like to point out that all the cited references are using melatonin to improve or treat sleep disorders; and primary insomnia is a part of sleep disorders. The Applicant is just selecting a specific disorder, already a part of sleep disorders. The Applicant is reminded that the melatonine for improving treating or improving the restorative quality of sleep is not considered novel since improving restorative quality of sleep only offers an advantage and not a new use. The Applicant's alleged "new use" encompasses the discovery of the use of an old product of a previously unrecognized benefit and no new result has been achieved through what the Applicant asserts as their new use … In other words … the prior art anticipates the subject matter of the present application since there is no new use in the present application, only an old use with a previously unrecognized advantage, where an advantage is currently claimed in the present application. The Applicant merely discovered what already existed in the prior art even though it was not explicitly disclosed and explained. A discovery of an existing advantage should not be confused with an invention. 67 In short, the Examiner's objection to the claims was that the use of melatonin to improve restorative sleep was not novel. 68 On 25 July 2011 Neurim's attorneys responded to the third requisition. Their response included amended claims that included a new claim 1 for: Use of at least one compound selected from melatonin, and melatonin agonists, in an amount within the range of 0.0025 to 50 mg, in the manufacture of a medicament, for treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia characterized by non-restorative sleep, wherein the medicament comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifier adjuvant or carrier. 69 The attorneys enclosed with their response a copy of Professor Zisapel's declaration which had been submitted to the USPTO on 16 April 2008. They argued in their response that none of the references previously cited by the Examiner disclosed the use of melatonin for treating and improving the restorative quality of sleep in a patient suffering from primary insomnia. 70 On 12 December 2011 Neurim was notified that the Canadian patent application would be allowed.

Europe 71 The application for what eventually became European Patent No 1441702 granted on 10 May 2017 was the PCT application which included claim 1 in the form previously set out. 72 On 18 November 2004 a third party filed observations in respect of the European patent application under Art 115(1) of the European Patent Convention ("the EPC"). These observations contended that claim 1 lacked novelty and that other claims lacked any inventive step. The publications cited in support of these contentions included Haimov, Bubenik, Garfinkel and Zisapel. The observations were later provided to Neurim's attorneys with an invitation to comment in accordance with Art 115(2) of the EPC. These comments were provided on 24 February 2005. 73 The comments provided included the following: Much of the third party observations are based on a semantic error, whereby the term "sleep quality" that is often used in the scientific literature in the sense of sleep quantity (latency, maintenance of actual sleep), is confused with "sleep quality" which is defined by the official diagnostic classifications of sleep disorders in the sense of the restorative value of sleep (completely subjective self evaluation of refreshing sleep), which are distinct properties of sleep and are not treated by the same drugs. The two most widely used diagnostic classifications for sleep disorders are the International Classification of Diseases (10th revision, ICD-10) and the Diagnostic and the Statistical Manual of Mental Disorders (DSM-IV). According to both classifications the predominant complaint is difficulty initiating or maintaining sleep, as well as non-restorative sleep (in DSM-IV) or poor quality of sleep (in ICD-10), for at least 1 month. In both, the sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. There is however a difference in the wording used in the DSM-IV and ICD-10 classification systems to describe the totally subjective insomnia symptom that is related to sleep quality in the sense of the restorative value of sleep. DSM-IV, which is mostly used in North and South America, relates to the non-refreshing sleep as Non-Restorative Sleep, whereas ICD-10 which is more often used in Europe, defines Quality Of Sleep in conjunction with the absence of quantitative sleep deficits, not as a stand-alone definition. ICD-10 states: "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". Both classification systems define each sleep complaint alone (whether related to sleep quantity or restorative aspects) as sufficient to establish the diagnosis of primary insomnia, with equal importance of quality (restorative value) of sleep and quantity of sleep, and highlight the association of impaired sleep and impaired daytime functioning. In the scientific literature, the term quality of sleep is used to describe the quantitative aspect of sleep, as will also be exemplified in the case of the individual Exhibits. The subjective symptom of non-refreshing sleep is referred to as non-restorative sleep and has only recently gained major attention in the sleep medical community as well as with pharmaceutical companies. All exhibits cited in the third party observations that are related to the effects of melatonin on sleep quality do so only in the sense that melatonin improves the amount of sleep. (original emphasis) 74 This is followed by a detailed analysis of the cited publications which sought to demonstrate that they were directed to poor sleep quality due to difficulties in sleep initiation and maintenance rather than poor sleep quality due to non-restorative sleep. 75 On 4 November 2008 the EPO notified Neurim that the European application did not meet the requirements of the EPC. The conclusion set out in the enclosed reasons was that: Therefore, as no unexpected effect for the present compositions (as far as novel) over the prior art compositions has been demonstrated, these compositions do not apparently fulfil the requirements of Art. 56 EPC. (original emphasis) 76 The response from Neurim's attorneys dated 4 December 2008 traversed much of the same ground as their comments of 24 February 2004. The claims of the European application, according to Neurim's attorneys were: … based on the discovery of a new medical use for generally known substances, namely, melatonin and its agonists. More particularly, the invention relates to treating and improving the restorative quality of sleep, in a patient suffering from primary insomnia. 77 Amendments to the claims were proposed, but these were not directed to the words defining the purpose of the relevant treatment. 78 Neurim's response was not the subject of any substantive reply from the EPO until 2 February 2011. On that date the EPO wrote to Neurim's attorneys indicating that the European application did not meet the requirements of the EPC. The enclosed reasons cited (inter alia) EP 878, Biella and Haimov. The reasons indicate that the claims failed to meet the requirements of the EPC in the following respects: the relevant compounds (melatonin agonists) were insufficiently defined; the subject matter lacked novelty; the term "primary insomnia" was unclear because whether a person would be diagnosed as suffering from primary insomnia depended (inter alia) on the diagnostic classification used; the term "restorative sleep" was insufficiently defined; treating and improving the restorative quality of sleep does not represent a technical effect which could establish novelty; and the effect of treatment or improvement of restorative sleep cannot be clearly and reliably determined by indications in the description or by objective procedures used in the art which made it impossible to compare the claim which the prior art. 79 The Examiner's conclusion with regard to lack of novelty was expressed in these terms: … the subject-matter of at least claims 1 and 4 lacks novelty (Article 54 EPC) over D1, D3, D5, D6 and D13-D16. The additional features of dependent claims 2, 3, 5 and 6 are directly known from documents D1 or D3, these claims therefore also lack novelty (Article 54 EPC). The references to D1 and D6 are to EP 878 and Biella respectively; D13-16 refers to (inter alia) Haimov. 80 The subject matter of the relevant claims was also said to not involve an inventive step (Art 52(1) and 56 of the EPC). 81 On 10 August 2011 Neurim's attorneys responded by amending claim 1 and addressing the EPO's contentions in some detail. The attorney's contentions were to substantially the same effect as those that were developed in their previous correspondence with the EPO. Claim 1 in its amended form now reads: Use of a prolonged release formulation comprising melatonin in an amount of 2mg, in the manufacture of a medicament for treating and improving the restorative quality of sleep in a patient suffering from primary insomnia characterized by non-restorative sleep, wherein the medicament comprises also at least one pharmaceutically acceptable diluent, preservative, antioxidant, solubilizer, emulsifiers, adjuvant or carrier. 82 The EPO maintained its position as stated in its 2 February 2011 reasons and appears to have raised still more issues during a consultation with Neurim's attorneys in which it contended that the term "prolonged release" was a relative term "which introduced an obscurity in the subject-matter …". 83 Oral proceedings were held on 8 October 2013 before three members of the Examining Division at which Neurim was represented by different attorneys. Written submissions prepared by those attorneys in advance of the hearing addressed (inter alia) the clarity, novelty and inventive step issues raised by the EPO. 84 On 8 October 2013 (ie. the day of the oral proceedings) Neurim was informed that its European application was rejected because it did not meet the requirements of Art 83 of the EPC. Detailed reasons for the decision were provided to Neruim on 30 October 2013. The sole ground for refusing the application according to those reasons was that the application lacked sufficient disclosure. 85 Neurim filed an appeal against the EPO's decision. Oral proceedings before a Board of Appeal took place on 2 June 2016. On that date the Board of Appeal set-aside the decision under appeal and remitted the case to the Examining Division for further prosecution on the basis of what was referred to as "the first auxiliary request" which sought deletion of the words "for treating" from claim 1. 86 One might expect this account of events in Europe to end with the grant of a European patent. However, following the remittal, the Examining Division raised further issues with respect to the patentability of the relevant claims which it again contended lacked novelty and an inventive step. 87 Further oral proceedings were scheduled to take place on 14 February 2017. In preparation for the hearing, Neurim's attorneys lodged a further set of written submissions dated 27 December 2016. At the risk of repetition, it is useful to refer to at least some of what Neurim's attorneys said in these submissions (the tone of which may suggest some measurement of exasperation on their part) in relation to primary insomnia and non-restorative sleep: The Examining Division seems to question the definition of "primary insomnia" or the possible overlap between different definitions of patients suffering from primary insomnia or other sleep disorders. Primary insomnia actually is not a disorder, but a group of disorders. As previously explained … "primary" refers to the origin of the condition, i.e. it refers to insomnia that is not derivable from something else. Primary insomnia is sleeplessness that is not attributable to a medical, psychiatric or environmental cause … Besides the definition of the therapeutic indication, the document also refers to the diagnostic criteria from DSM-IV, that are also mentioned in the patent application. "Primary Insomnia" as a medical indication is referred in the literature and books … so it should be considered well-established and part of the Common General Knowledge. … As for the disclosures of the different documents we refer to our letter dated 1 October, 2013 … where we analysed all these documents in detail to conclude that primary insomnia relates to problems with sleep initiation, sleep maintenance and/or non-restorative sleep, it is primary because it is not derived from another medical or external cause such as medication or environment. The term insomnia refers to a group of sleep disorders as defined in DSM mental disorders classification system. Before DSM-IV insomnia was the disability to get enough sleep, either because of poor sleep initiation or maintenance. Only in DSM-IV the disorder characterized by non-restorative sleep (termed poor quality sleep in ICD-10) was grouped with insomnia but it represents a basically different type of disease, which deserved medical attention and proper treatment modalities. … The above discussed definitions of primary insomnia say that it can be characterized by difficulties initiating or maintaining sleep, or non-restorative sleep, it is a group of disorders. The invention is directed to one type of primary insomnia, the one which is characterized by non-restorative sleep. The term "characterized by non-restorative sleep" in claims 1 and 4 qualifies "primary insomnia" as a specific type of primary insomnia, it does not characterizes the patient or defines a subgroup of patients, as alleged by the Examining Division. (original emphasis) 88 It appears that the scheduled hearing did not take place. Instead Neurim was notified on 17 February 2017 that the Examining Division intended to grant the European patent. The European patent was granted on 10 May 2017.

Reasons for Amendments 89 Professor Zisapel gave evidence as to Neurim's reasons for seeking amendments to the Patent. Her evidence was that the idea of amending the Patent was first raised with Neurim by its solicitor, Mr Tyacke, in late March 2017 around the time it was considering commencing infringement proceedings. Professor Zisapel said that Neurim's rationale for seeking the amendments was to narrow the scope of the claims of the Patent and potentially reduce the scope of the issues that may need to be determined in any such proceedings. In particular, she said that the proposed amendments would narrow the claims so as to avoid a potential dispute in relation to the use of therapeutic agents other than melatonin, avoid a potential dispute in respect of the patient population to which the claims are directed, and avoid a potential dispute with regard to the identified dosage range. 90 Professor Zisapel said that she is, and had always been, of the view that the Patent is valid in its current form. However, she acknowledged that the Court may take a different view and that, as a result, it is possible that the proposed amendments, if made, could improve Neurim's prospects of successfully defending the challenge to the validity of the Patent. 91 In cross-examination it was put to Professor Zisapel that Mr Tyacke's review of the European prosecution history gave rise to advice that there was a better chance of the Patent being found valid if it was amended. Professor Zisapel denied this. Her answer, as I understood it, reiterated her understanding that the purpose of the amendments was to narrow the issues in any infringement proceedings and thereby save time and costs. 92 I have already mentioned that Mr Tyacke was not cross-examined. In his evidence, Mr Tyacke referred to correspondence passing between the solicitors for Neurim and the solicitors for GPPL in which Neurim sought undertakings from GPPL that it would not infringe the Patent. In their response to this request, the solicitors for GPPL asserted that the claims of the Patent were invalid on the basis that they lacked any inventive step in light of the common general knowledge and various documents (including Haimov, Bubenik and Garfinkel), that they lacked utility, and that they also lacked fair basis. It is perhaps worth pointing out that the alleged lack of utility was based upon what was said to be a negative result reported in the discussion of Example 3 of the Patent rather than any reference in the claims to melatonin agonists or the width of the dosage range. 93 Mr Tyacke also said in his evidence that the amendments were sought "so as to narrow the claims and accordingly narrow the issues to be determined at trial". He also gave evidence of his conversations with Professor Zisapel in March 2017 and the scope of the documents that were available to him at or about that time relevant to the proposed amendments which appear to have been confined to the Patent and the prosecution files published online by the EPO and the USPTO and the US patent. 94 There are some brief and somewhat perfunctory records in evidence recording Mr Tyacke's discussions with Professor Zisapel and other employees of Neurim in relation to the proposed amendments, which are of little assistance in determining what was discussed. The same is true of a file note recording discussions between Mr Tyacke and counsel who was at that time retained to act for Neurim. However, there is nothing in these file notes inconsistent with the evidence given by Professor Zisapel or Mr Tyacke.

Delay 95 Apotex submitted that Neurim should be taken to have been on notice since at least 10 August 2011 that the claims of the Patent required amendment to the same or similar effect as those made in the US, Canada, and Europe. It submitted that Neurim's patent applications in the US, Canada, and Europe are very similar in scope and subject matter to the Patent, that Neurim amended all three of its claims in those jurisdictions to include the "non-restorative limitation" and that it also amended the European application to include the melatonin limitation, the prolonged release limitation, and the range limitation. 96 Apotex placed considerable reliance on what was said by Jessup J in CSL Limited v Novo Nordisk Pharmaceuticals Pty Ltd (No 2) (2010) 190 FCR 522 at [76]: I consider that to restrict the circumstances in which an application to amend might be successfully resisted to those in which it was common ground, or had been established, that the unamended patent was invalid, and the applicant knew of it, would be to take a position which is altogether too categorical, and one for which there is no support in the decided cases. It must be allowed that there may be situations in which some lesser degree of a need to amend, and an applicant's actual or constructive knowledge of it, should be recognised as sufficient, with other circumstances, to disentitle the applicant to the favourable exercise of the Court's discretion. A patentee who has been exposed to facts from which it was, or reasonably ought to have been, apparent to him or her that a claim might well be invalid unless amended, and who later seeks the favourable exercise of the Court's discretion under s 105 is, in my opinion, in no position to say that there was, on the earlier occasion, no "need" to amend simply because it had not then been conclusively established that the claim was in fact invalid. All will depend, in my view, upon the extent and quality of the applicant's appreciation (actual or constructive) of the circumstances from which a need to amend is said to arise, and from the nature of those circumstances themselves. 97 His Honour's judgment makes clear that an order allowing an amendment may be refused where the patentee had reasonable grounds to believe that the relevant claim might well be invalid but delayed taking steps necessary to make the amendment. 98 Apotex submitted that by at least 10 August 2011 Neurim was on notice that amendments to the claims of the Patent were needed and that it should have at that time moved promptly to amend the Patent. It submitted that it was not sufficient, when considering whether a delay in seeking amendment of the Patent was reasonable, to point to a lack of advice suggesting that the Patent was invalid without amendment. 99 Apotex also submitted that the problems that led to the amendments made in other jurisdictions are the same or similar to the problems Neurim seeks to cure by its proposed amendments to the Patent which Apotex said is demonstrated by the fact that Neurim's Australian lawyers, having reviewed the prosecution histories from Europe and the US, advised Neurim to make the same or very similar amendments to the Patent.

Unfair Advantage 100 Apotex accepted that there was no evidence to indicate that Neurim had sought to enforce the Patent by making demands or threatening legal proceedings before commencing this proceeding against GPPL and Apotex. However, it submitted that Neurim's lengthy delay in seeking to amend provided Neurim with an unfair advantage in that Neurim has retained the benefit of a monopoly that it should have appreciated was broader than was justified.

Failure to make full disclosure 101 Apotex submitted that Neurim had failed to make a full and frank disclosure of matters relevant to the proposed amendments. In substance, this submission amounted to a contention that Neurim failed to fully and frankly disclose its reasons for wishing to make the proposed amendments which, according to Apotex's submission, must have been motivated, at least in part, by a desire to avoid relevant prior art (including Haimov, EP 878, and Bubenik) and the threat that these publications posed to the validity of the relevant claims. The submission focused on the absence of any acknowledgment or acceptance in the evidence of Professor Zisapel that Neurim's prospects of successfully defending the claims against a challenge to their validity would be strengthened if the proposed amendments were allowed.

Neurim's Submissions 102 Neurim submitted that the discretion to order amendments pursuant to s 105 of the Act exists for the benefit of the patentee and that, generally, amendments would be allowed unless there are circumstances which would lead the Court to refuse amendment. In support of this submission Neurim referred to Les Laboratories Servier v Apotex (2016) 247 FCR 61 (Bennett, Besanko and Beach JJ) at [243], Les Laboratories Servier v Apotex (2010) 89 IPR 219 at [59]-[61] and Bayer Pharma Aktiengesellschaft v Generic Health (2012) 99 IPR 59 at [61]-[62]. 103 Neurim placed particular reliance on the summary of the relevant considerations referred to in the judgment of the Full Court in Les Laboratories Servier v Apotex (2016) 247 FCR 61. In relation to delay, the Full Court said at [243]: … • Amendment should be sought promptly and where a patentee delays for an unreasonable period, the patentee has the onus of showing that it delayed on reasonable grounds, such as a belief, on reasonable grounds, that an amendment was not necessary. • Unreasonable delay is a circumstance likely to lead to refusal of the amendment. • In assessing delay, the time when the patentee was unaware and reasonably did not know of the need for amendment is not taken into account. The relevant delay is from when the patentee knows of the likely invalidity, or has its attention drawn to a defect in the patent, or is advised to strengthen the patent by amendment. That is, amendment will not be permitted in cases where a patentee knows or ought to know that amendment should be sought and fails to do so for a substantial period of time. Thus the reasonableness of the conduct of the patentee is a relevant consideration when assessing delay. • Mere delay is not, of itself, sufficient to refuse to exercise the discretion to amend. The fact of delay is, however, relevant to whether the respondent or the general public have suffered detriment. … 104 In its submissions Neurim emphasised that the Patent had already been granted in Australia by the time the relevant objections were raised with Neurim in the USA, Canada and Europe. It also submitted, and invited me to find, that Neurim did not seek to make the proposed amendments for the purpose of strengthening the validity of the Patent although it understood that the amendments, if allowed, could improve Neurim's position in relation to validity if the Court was to reject Neurim's construction of claim 1. 105 Neurim also submitted that the opposition to the amendments based on alleged delay should be rejected on the basis that there was no reasonable basis for Neurim to believe that claim 1 was invalid, or may well be found to be invalid, if it were not amended. This was because, according to Neurim's submissions, there was no reasonable likelihood of the Court adopting the broad interpretation of claim 1 which Apotex says it should be given when the claim is read in the context of the specification as a whole. 106 Neurim submitted that at all relevant times it reasonably believed that no amendment was necessary. It was only when Mr Tyacke raised with Professor Zisapel the possibility of making amendments to the Patent that she considered making them. Neurim submitted that from that moment it has moved promptly.

Consideration 107 The discretion arising under s 105 of the Act is broad. However, it is generally exercised by reference to a number of guiding principles that seek to balance the right of the patentee to apply to amend its patent in an appropriate case and the public interest in ensuring that an amendment application is made promptly, for proper purposes, and not so as to allow the patentee to obtain an unfair advantage were it to be allowed. The most well-known statement of the guiding principles appears in the following passage from judgment of Aldous J in Smith Kline & French Laboratories Ltd v Evans Medical Ltd [1989] 1 FSR 561 at 569: The discretion as to whether or not to allow amendment is a wide one and the cases illustrate some principles which are applicable to the present case. First, the onus to establish that amendment should be allowed is upon the patentee and full disclosure must be made of all relevant matters. If there is a failure to disclose all the relevant matters, amendment will be refused. Secondly, amendment will be allowed provided the amendments are permitted under the Act and no circumstances arise which would lead the court to refuse the amendment. Thirdly, it is in the public interest that amendment is sought promptly. Thus, in cases where a patentee delays for an unreasonable period before seeking amendment, it will not be allowed unless the patentee shows reasonable grounds for his delay. Such includes cases where a patentee believed that amendment was not necessary and had reasonable grounds for that belief. Fourthly, a patentee who seeks to obtain an unfair advantage from a patent, which he knows or should have known should be amended, will not be allowed to amend. Such a case is where a patentee threatens an infringer with his unamended patent after he knows or should have known of the need to amend. Fifthly, the court is concerned with the conduct of the patentee and not with the merit of the invention. 108 The fact that a patentee failed to act promptly after becoming aware of facts or circumstances that would lead a reasonable person to apply to amend the claim may provide a sufficient basis for refusing an application to amend. Such facts and circumstances will usually include the state of the prior art and the patentee's knowledge of it and the scope of the relevant claim including, for example, the absence of any limitation that the patentee may wish to introduce. Ultimately, however, these are matters that must be considered in light of all other facts and circumstances relevant to the exercise of a broad statutory discretion. 109 An assumption underlying Apotex's submissions is that Neurim understood, or ought reasonably to have understood, that there was a need to amend claim 1 to avoid the relevant prior art. The correctness of that assumption depends upon a consideration of the scope of claim 1 and the relevant prior art. 110 Although Professor Zisapel's understanding of the prior art was explored at length in her cross-examination, the scope of claim 1 received less attention in cross-examination and Apotex's closing submissions. Professor Zisapel's evidence indicates that she has always understood claim 1 of the Patent to be confined to the use of the relevant compounds in the manufacture of a medicament for treating and improving the restorative quality of sleep in a patient suffering from primary insomnia. Apotex did not suggest that Professor Zisapel's evidence of her understanding should not be accepted or that it did not reflect her honest and reasonable belief. 111 On Professor Zisapel's interpretation, claim 1 only covers one medical use, namely, the treatment of lack of restorative sleep in patients suffering from primary insomnia. On her view of claim 1, the words "and improving the restorative quality of sleep in said patient" would convey to the skilled addressee that the patient's primary insomnia is characterised by non-restorative sleep. The proposed amendment would, if allowed, make this clear. 112 However, claim 1 of the Patent is open to a broader interpretation that covers the use of the relevant compounds in the manufacture of a medicament for the treatment of primary insomnia or for improving the restorative quality of sleep. If the claim was to be interpreted in that manner then the case for finding the claim invalid on the basis that it was either not novel or obvious would seem to me to be quite strong. In these circumstances, I think the application for amendment should be approached on the basis that the patentee in this case either knew or ought reasonably to have known that if claim 1 was given the broader interpretation to which I have referred then there would be a substantial risk that claim 1 would be invalid. The question that then arises is whether Neurim should have appreciated that claim 1 might well be given the broader interpretation to which I have referred. 113 Professor Zisapel's evidence as to her understanding of claim 1 was not challenged in cross-examination and I accept that she has always believed that the claim should be interpreted as covering one medical use. Although her own understanding of the meaning of claim 1 is relevant, it is of course necessary to look to see what objective support exists for that understanding and what other facts and circumstances should have alerted Professor Zisapel to the possibility that the claim might be more broadly interpreted. It is in this regard that Apotex points to the amendments made in the USA, Canada and Europe. 114 The USPTO did not raise any issue as to the proper construction of the words "in treating and improving the restorative quality of sleep in a patient suffering from primary insomnia." The amendments made on 16 April 2008 appear to me to have been aimed at making clear what the USPTO may well have understood to be the effect of the claims before amendment, namely, that it was directed to the use of the relevant compounds in the treatment of primary insomnia resulting from a lack of restorative sleep. In my view, the objections raised by the USPTO had more to do with a lack of understanding of the different types of primary insomnia and, in particular, the differences between lack of sleep and poor sleep quality (ie. a lack of restorative sleep). I do not think the prosecution history of the US patent supports the view that Professor Zisapel should have appreciated that claim 1 of the Patent as granted was, or may well be, invalid in the absence of an amendment making clear that it was directed to a treatment for primary insomnia characterised by non-restorative sleep. 115 The position in Canada was not dissimilar. As previously explained, the objection that was raised by the Examiner in Canada was that the use of melatonin to improve restorative sleep was not novel. The amendment to claim 1 appears to have been aimed at bringing it into alignment with the claim allowed by the USPTO following the USPTO's consideration of Professor Zisapel's declaration on which Neurim also relied in Canada. 116 In Europe the objections raised by EPO as set out in its response of 2 February 2011 raised numerous issues, but did not suggest that claim 1 (which had not been amended at that stage) would be invalid merely because the prior art showed that melatonin had been used in the treatment of primary insomnia. On the contrary, my reading of the correspondence between the EPO and Neurim's attorneys suggests that it understood that claim 1 in its original form was directed to treating and improving the restorative quality of sleep in patients suffering primary insomnia due to poor sleep quality. 117 Accordingly, I do not think the prosecution history in the USA, Canada or Europe should have indicated to Neurim that, absent the amendments now sought to be made, claim 1 of the Patent was, or may well be, invalid. 118 Another matter that needs to be taken into account is the patent specification itself. The specification expressly states that the invention relates to a method of treating primary insomnia when characterised by non-restorative sleep and proceeds to discuss the invention in the context of improving the restorative quality of sleep in subjects suffering from primary insomnia. While I do not propose to decide the question of construction, I think I can say that Professor Zisapel's interpretation of claim 1 finds considerable support when read in the context of the specification as a whole. 119 In a situation where amendments made to claims in a patent application in a foreign jurisdiction are relied upon as a basis for inferring that the owner of an Australian patent that has previously been granted should have been aware of the need to make amendments in the same or similar terms to the claims of the Australian patent, it would be wrong to assume that the amendments made in the foreign jurisdiction were made because the patent applicant understood, or should have understood, that the claims would or may be invalid in the absence of those amendments. This is because a patent applicant may reasonably believe that the claims granted in unamended form would be valid but that it is nonetheless desirable to amend in order to overcome an objection. 120 The history of the European application (the European patent having been granted some 15 years after the PCT application was filed) provides a vivid illustration of why a patentee might think it expedient to amend to overcome an objection which the patent applicant believed, on reasonable grounds, lacked substance. 121 Another reason to be cautious in drawing an inference against a patent applicant in such circumstances is that the patent laws of the foreign jurisdictions are quite different to the laws against which the validity of the Australian patent is to be assessed. In the present case the principles applicable to a challenge to the claims of the Patent based on alleged insufficiency, lack of fair basis and obviousness are different from the principles that the EPO was required to apply when considering the European application. However, I accept that this point will have considerably less force when the alleged invalidity is founded upon an alleged lack of novelty. 122 In the result, I do not accept Apotex's submission that Neurim has known, or ought reasonably to have known, since at least 10 August 2011, that claim 1 of the Patent in its current form was, or may well be, invalid on the ground that it was not novel or did not involve an inventive step in the absence of the non-restorative sleep limitation. On the contrary, I am satisfied that Neurim had reasonable grounds to believe that there was no need for such an amendment because it reasonably believed that claim 1 would be construed in accordance with Professor Zisapel's interpretation of it. 123 The other proposed amendments to claim 1 remain to be considered. 124 The claims of both the US patent and the Canadian patent do not include the melatonin limitation. The objection raised by the EPO (ie. that the class of compounds described as "melatonin agonists" was insufficiently defined) was not raised in the USA, Canada or Australia. Nor is there any evidence from which I would infer that the melatonin limitation was introduced due to a concern that the term "melatonin agonists" is not sufficiently clear or that its continued presence would have any impact on the validity of the claim. For that reason I do not accept that Neurim delayed bringing its amendment application in circumstances where it knew, or ought reasonably to have known, that claim 1 may be invalid in the absence of the melatonin limitation. 125 As to the prolonged release limitation, it also does not appear in either the US patent or the Canadian patent. It is not clear why the prolonged release limitation was introduced into the claims of the European Patent. While the amendment may have more fully described the invention, there is no evidence to indicate that it was introduced into the European application for the purpose of avoiding relevant prior art. I do not think there is any basis to find that Neurim knew, or ought reasonably to have known, that claim 1 of the Patent may be invalid in the absence of the prolonged release limitation. 126 The range limitation is not included in the independent claims of the US patent or the Canadian patent both of which specify "an effective amount within a range of 0.0025 to 50 mg". In Europe, claim 1 in the amended form proposed by Neurim on 10 August 2011 specified 2 mg rather than a range. There is nothing in the evidence to indicate that Neurim concluded that it was necessary to confine claim 1 of the European application to a the 2 mg dosage in order to avoid prior art. 127 It follows that I do not accept that Neurim has been guilty of unreasonable delay in seeking to amend the Patent or that it has taken any unfair advantage by retaining the benefit of a monopoly that it should have appreciated was broader than was justified. 128 With regard to disclosure, I am not persuaded that there has been any failure by Neurim to make full and frank disclosure of matters relevant to the proposed amendments. In particular, I do not accept the submission that Neurim has failed to give a full and frank disclosure of its reasons for seeking to make the relevant amendments. In my view they have been adequately disclosed in Professor Zisapel's written and oral evidence. 129 In the circumstances, I am satisfied that this is a case in which the proposed amendments to claim 1 should be allowed. 130 The respondents did not advance any separate or different arguments in opposing the proposed amendments to the other claims or to the body of the specification. I am satisfied that all of the other proposed amendments should be allowed. 131 The respondents submitted that there should be an order that Neurim pay the respondents' costs of the interlocutory application in accordance with what they referred to as the usual practice: see Bayer Pharma Aktiengesellschaft v Generic Health (2012) 99 IPR 59 at [232]. Neurim did not make any contrary submission and, in those circumstances, I am satisfied that this is the appropriate costs order to make. 132 There will be orders accordingly. I certify that the preceding one hundred and thirty-two (132) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Nicholas.