Generic Partners Pty Ltd v Neurim Pharmaceuticals Ltd
[2022] APO 79
•2 December 2022
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Generic Partners Pty Ltd v Neurim Pharmaceuticals Ltd. [2022] APO 79
Patent Application: 2016426598
Title:Melatonin mini-tablets and method of manufacturing the same
Patent Applicant: Neurim Pharmaceuticals Ltd.
Opponent: Generic Partners Pty Ltd
Delegate: Leslie F. McCaffery
Decision Date: 2 December 2022
Hearing Date: 31 August 2022 by video conference
Catchwords: PATENTS – opposition to the grant of a patent under section 59 – inventive step – clear enough and complete enough disclosure – support – utility – best method – opposition successful – Claims 1 to 21 lack support – specification is not clear enough and complete enough to be performed by the person skilled in the art in respect to the matter defined by Claims 1 to 21 – applicant given 2 months from date of decision to propose amendments – costs awarded.
Representation: Counsel for the applicant: David Shavin KC and Megan Evetts
Solicitors for the applicant: Nicholas Tyacke, Nikki Kahn and Ben Mawby of DLA Piper Australia
Counsel for the opponent: Richard Cobden SC and Rob Clark
Solicitor for the opponent: Robert Silberstein of Silberstein & Associates
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2016426598
Title:Melatonin mini-tablets and method of manufacturing the same
Patent Applicant: Neurim Pharmaceuticals Ltd.
Date of Decision: 2 December 2022
DECISION
The opposition is successful.
Claims 1 to 21 lack support.
The specification does not provide a clear enough or complete enough disclosure across the full scope of the invention as presently claimed in Claims 1 to 21.
The applicant has two (2) months from the date of this decision to file amendments to overcome the deficiencies.
Costs according to Schedule 8 are awarded against the applicant, Neurim Pharmaceuticals Ltd.
REASONS FOR DECISION
Background
Patent application 2016426598 (the application) entered national phase from PCT/IB2016/057190 on 26 April 2018, in the name of Neurim Pharmaceuticals Pty Ltd (the applicant). The application has a filing date of 29 November 2016, and an earliest priority date of 31 October 2016. The application is also related to several divisional applications and granted patents (2019200479, 2019101470 and 2021200268), but nothing turns on this point in the present opposition.
The application was accepted on 4 October 2018. A request for an amendment to the application under s104 was filed on 24 October 2018 and subsequently allowed on 23 January 2019. On 1 February 2019, Generic Partners Pty Ltd (the opponent) filed a notice of opposition to the grant of the application under section 59 of the Act.[1] A statement of grounds and particulars (SGP) was filed on 1 May 2019. A request for an amendment to the SGP was filed on 29 September 2019 and allowed on 28 October 2019. The SGP set out grounds under manner of manufacture, novelty, inventive step, utility, clear enough and complete enough disclosure (sufficiency), best method, clarity and support.
[1] Note: all reference in this decision to the SGP and evidence is in relation to the opposition under section 59.
Evidence in support (EIS) was completed on 5 August 2019. This comprised a declaration by Richard Charles Oppenheim (Oppenheim 1) dated 31 July 2019 together with an attachment, and a declaration by Robert Anthony Silberstein together with Annexures RAS-1 to RAS-6.
Evidence in answer (EIA) was completed on 6 November 2019. This consisted of a declaration by Martyn Christopher Davies (Davies) together with Annexures MD-1 to MD-9
The SGP and EIS had cited Schrier L. et al.[2] (D1) for the purposes of establishing lack of novelty and/or inventive step against at least some of the claims. On 9 December 2019, the applicant filed a request for an extension of time under s223(2)(a) and s223(2)(b) to rely upon the grace period with respect to D1. The opponent objected to the extension of time, and a hearing held on 23 February 2021. In a decision dated 14 January 2022, the applicant was granted an extension of time of eight (8) months pursuant to s223(2)(a) to file the application in time to claim the benefit of the grace period in relation to D1 pursuant to s24(1)(b) and Reg 2.2D.[3]
[2] Schrier L. et al., in Non-invasive monitoring of pharmacokinetics and pharmacodynamics for pharmacological drug profiling in children and adolescents, Universiteit Leiden, Chapter 8: Pharmacokinetics of prolonged-release melatonin mini-tablets in children with both autism spectrum disorder and a sleep disorder, pages 213 to 240, 15 April 2015.
[3] Generic Partners Pty Ltd v Neurim Pharmaceuticals Ltd. [2022] APO 2.
Evidence in reply (EIR) was completed on 4 September 2020. This consisted of a declaration by Richard Charles Oppenheim (Oppenheim 2) dated 4 March 2020 together with an attachment.
On 12 August 2022 the applicant sought to have a further declaration by Prof Davies considered by the Commissioner pursuant to regulation 5.23. The gist of the applicant’s submissions in support of their request was that the opponent’s EIR “misconstrues and misunderstands” the evidence provided by Prof Davies in the EIA. In a letter of 19 August 2022, the delegate declined to make a direction that the further declaration be considered. This declaration has therefore not been taken into account in this decision.
The matter was heard by video conference on 31 August 2022. At the hearing the opponent pressed the grounds of inventive step, utility, clear enough and complete enough disclosure (sufficiency), support, clarity, and best method.
Onus
The substantive amendments to the Patents Act 1990 (Cth) (the Act) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) (the Raising the Bar Act) apply to the present case. The standard of proof in opposition proceedings is the balance of probabilities. If the Commissioner is satisfied, on the balance of probabilities, that a ground of opposition to the grant of the standard patent exists, the Commissioner may refuse the application. The opponent bears the onus of proof.
The principles of construction
10. I note the guidance of Middleton J in Eli Lilly and Company Limited v Apotex Pty Ltd:
“It is well settled that the Court should, from the outset, approach the task of patent construction with a generous measure of common sense. The Court must place itself in the position of a person skilled in the relevant art, being the subject matter of the patent. From this perspective, the patent is to be read as a whole, in the context of the specification and in light of the prevailing common general knowledge and state of the relevant art at the priority date.”[4]
[4] [2013] FCA 214; 100 IPR 451 at [139].
11. The task of construing the specification is undertaken from the viewpoint of a person skilled in the art and the prevailing common general knowledge at the priority date. The person skilled in the art is a hypothetical non-inventive person or team likely to have a practical interest in the subject matter of the invention:[5]
“He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious.”[6]
[5] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70]-[72].
[6] Ibid at [70].
12. The parties were largely in agreement as to the characterisation of the person skilled in the art as a team of scientists involved in the formulation of pharmaceuticals including a formulation chemist, an analytical chemist, a medicinal chemist, a pharmacokineticist/pharmacologist, a regulatory scientist, and clinical experts.[7]
[7] OS at [28].
13. Evidence in the opposition was provided by two experts:
· Dr Oppenheim is the principal of an eponymous company that works with therapeutic goods and food industries.[8] He was previously employed by R P Scherer Australia,[9] holding senior managerial responsibilities in the Technical, Regulatory and Manufacturing departments. He also held a Senior Lecturership position at the Victorian College of Pharmacy (VCP), where he led a pharmaceutical product development team.[10]
· Prof Davies is an Emeritus Professor of Biomedical Surface Chemistry at the University of Nottingham where he was a professor in the same department up until 2017. During that time, he worked with large pharmaceutical companies and start-up companies to help them characterise and develop pharmaceutical formulations. He continues to consult in pharmaceutical development and formulations. In 1997 he co-founded and was chairman of the pharmaceutical company Molecular Profiles Limited and continued in that role until 2017.[11]
[8] Oppenheim 1, Appendix under Curriculum vitae, Employment section.
[9] Cardinal Health Australia from 2003.
[10] Oppenheim 1 at [18].
[11] Davies at [5] to [9].
14. Both experts clearly have relevant expertise in solid oral dosage forms and controlled release formulations. However, the parties both submitted that the evidence provided by their expert should be given greater weight on certain issues in dispute. The opponent noted that Prof Davies is based in the UK and therefore Dr Oppenheim’s evidence should be preferred on matters attributed to the skilled addressee in Australia.[12] I do not consider this submission relevant since the Raising the Bar Act applies to the present application and therefore common general knowledge is not limited to Australia, but in any case, given the international nature of the pharmaceutical industry I consider there is not likely to be any significant difference in the knowledge and skills of a skilled person in the UK as opposed to Australia. The applicant noted that Prof Davies has a much greater depth of experience, and particularly in the formulation of controlled release mini-tablets.[13] The relative depth of experience also does not lead me to entirely discount the evidence of either expert. The submissions on this point merely highlight a factor that needs to be taken into account when determining the weight I can give to the evidence on any particular point.
[12] Opponent’s submissions (OS) at [7].
[13] Applicant’s submissions (AS) at [79] to [82].
The specification
15. Melatonin is an indole-derived hormone produced at night by the pineal gland. Melatonin is produced and secreted into the plasma in a circadian rhythm which parallels the sleep-wake cycle. Exogenous melatonin is often administered as a sleep aid and has been shown to produce positive effects on sleep induction, sleep quality, day-time functioning, as well as quality of life.[14] Melatonin is available in several oral dosage forms, including immediate release forms for the treatment of delayed sleep onset, and prolonged release forms which are useful for sleep maintenance.[15]
[14] Specification at page 1, lines 12 to 20.
[15] Specification at page 1, lines 21 to 25.
16. The specification states that the goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site in the body to achieve and then maintain the desired drug concentration. The most convenient and commonly employed route of drug delivery has been by solid oral dosage forms, particularly tablets and capsules. However, some patients have difficulty swallowing tablets and capsules, which can lead to a variety of adverse events and patient non-compliance with treatment regimens.[16]
[16] Specification at page 1, lines 5 to 11.
17. The invention provides mini-tablets that are said to satisfy long-felt, but unmet therapeutic needs to provide effective melatonin therapy to a patient suffering from impaired swallowing and/or undergoing polypharmacy therapy.[17] Apparently existing melatonin products, such as the prolonged-release Circadin® tablets, suffer from poor patient compliance due to patients having difficulty swallowing the tablets, which have an 8.1 mm diameter and 3-5 mm thickness. Some patients break, crush or chew the tablets, which results in a loss of the prolonged-release properties of the tablet.[18]
[17] Specification at page 3, lines 18 to 20.
[18] Specification at page 1, line 26 to page 2, line 3.
18. The present mini-tablets are said to have improved swallowing, flexible dosing, and better patient compliance, as well as a controlled-release profile that achieves the same minimal blood levels of melatonin present at night in the brain of a human with a normal endogenous melatonin profile, shown in Fig. 1 of the specification (Annex A), as well as an acceptable safety profile.[19] The minitablets are said to range in diameter from 1.0 to 4.0 mm.[20]
[19] Specification at page 4, lines 1 to 5.
[20] Specification at page 5, lines 7 to 9.
19. The specification comprises 21 claims, of which Claims 1, 5, 19 and 21 are independent claims. These correspond to the broad description of the invention, so for convenience I will refer to the claims. Claim 1 defines the mini-tablets of the invention as follows:
A controlled-release melatonin mini-tablet comprising:
a therapeutically effective amount of melatonin; and
one or more pharmaceutically acceptable carriers;
wherein the mini-tablet has a diameter of less than or equal to 4 mm and has a release profile of less than 50% melatonin release within 1 hour, and greater than 70% melatonin release within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C.
20. The mini-tablet is referred to here as a controlled-release formulation. The experts did not differ significantly in their understanding of the term controlled-release. Dr Oppenheim stated that the various terms prolonged-release, controlled-release, extended-release, modified-release and sustained-release are sometimes loosely used interchangeably, but there are subtle differences between the terms. He considered the term controlled-release to describe all modified-release formulations in which the rate and type of release of the active ingredient from the dosage form is controlled by the formulation technique used. Prolonged-release, extended-release and sustained-release are used to describe a sub-set of modified-release formulations in which release of the active ingredient, once it commences, continues over a pre-determined time until the payload is exhausted.[21]
[21] Oppenheim at [132] to [135].
21. The implication here is that while the problem to be solved by the invention refers to there being a long-felt but unmet need for a prolonged-release dosage form of melatonin,[22] Claim 1 does not appear be limited to such a form. The mini-tablets are characterised by their ability to provide a release profile of less than 50% melatonin release within 1 hour, and greater than 70% melatonin release within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C. At first blush these timeframes might be suggestive of a prolonged release, but Dr Oppenheim stated that that this profile could be achieved by applying, for example, an enteric coating to an immediate-release tablet, such that the whole of the payload would be “dumped” in the gastrointestinal tract (that is, none would be released within the first hour, followed by complete release in the gastrointestinal tract at some time after that).[23] He stated that such a pulsed-release profile would be consistent with the term controlled-release.
[22] Specification at page 3, lines 28 to 29.
[23] Oppenheim 2, attachment at row 51.
22. The evidence shows that the term controlled-release has a well-established, albeit loosely used, meaning in the art. There is no definition given in the application for the term controlled-release, and the specification uses the terms controlled-release and prolonged-release separately. For example, the detailed description of the invention specifically refers to Circadin® tablets as prolonged-release, but to the tablets of the invention as controlled-release. This contrasts with the specific reference to prolonged (PR) mini-tablets “according to the invention” in Example 3. Furthermore, in reference to dose-flexibility, the specification states that the mini-tablets may include immediate release, delayed release, and/or controlled release formulations. The reference here indicates that the term controlled-release is intended to be a generic term, consistent with the expert evidence above, rather than a specific term for prolonged-release. The different references to prolonged-release and controlled-release seem to me to be a deliberate choice of words, and indeed the use of different terminology by the drafter would infer that a different meaning was intended.
23. Under the circumstances I consider that to read the reference in the claim to controlled-release as being limited to prolonged-release formulations would import an impermissible gloss from the specification. I therefore take the reference to controlled-release in the claims to take the broader meaning that the release of the drug has been controlled by the formulation or method of manufacture, rather than being limited to prolonged-release dosage forms. In contrast, dependent claims 2 and 3 further characterise the formulation by the minimal blood level of melatonin over 4 hours following administration of about 60 to about 200 picograms melatonin per millilitre, consistent with a prolonged-release profile.
24. Claim 5 defines the manufacture of a mini-tablet by combining the ingredients and compressing them to a diameter of less than or equal to about 4 mm. The formulation prepared by the method corresponds to that defined in Claim 1, so the interpretation given to that claim also applies to Claim 5.
25. Claim 19 defines a method of treatment that incorporates mini-tablets having the dissolution characteristics defined by Claim 1 and the method of manufacture defined by Claim 5. The claim does not specifically refer to the mini-tablets as controlled-release, but the method is further characterised by the minimum blood level of melatonin over 4 hours following administration of about 60 to about 200 picograms melatonin per millilitre and I therefore understand it to inherently define a prolonged release of melatonin. Claim 19 also defines the optional step of providing multiple mini-tablets in a single capsule.
26. Claim 21 defines a mini-tablet formulation that is not limited to having the same properties of the mini-tablets defined in Claim 1:
A pharmaceutical mini-tablet formulation comprising melatonin in combination with at least one pharmaceutical carrier, diluent or coating, wherein, upon administration to a patient, the mini-tablet formulation releases melatonin over time such that the patient's melatonin plasma profile substantially simulates the melatonin plasma profile of a human having a normal endogenous melatonin profile.
27. Notably, the tablet is defined in terms of the patient’s melatonin plasma profile following administration of the mini-tablet, rather than any specific size, constituents, and/or dissolution characteristics of the mini-tablet itself. The claim therefore essentially defines any mini-tablet formulation in which melatonin is released over an (undefined) time period to substantially simulate a normal endogenous melatonin profile in a patient.
28. The specification sets out 3 examples which describe the process of developing the mini-tablets of the invention. The first example describes an attempt to prepare a “first mini-tablet” by direct compression using the same ingredients as those used in the commercial Circadin® 2 mg formulation. The resulting mini-tablets had an unacceptable release rate because decreasing the tablet size from the standard 8 mm to 4 mm diameter increases the surface to volume ratio and results in faster drug release. Alternative formulations were attempted, with optimal results being provided by mini-tablets having the ratio of ingredients shown in the following table.[24]
[24] Specification, Table 1 bridging pages 14 and 15.
| Melatonin | Calcium hydrogen phosphate dihydrate (CHPD) | Ammonio methacrylate copolymer, type B or A (AMC) | Lactose | |
| First mini-tablet | 1 | 8.25 | 5.87 | 8.75 |
| Circadin® | 1 | 20 | 20 | 40 |
29. In the above table the formulation of Circadin® is shown for comparison. The dissolution rate of the first mini-tablet is said to fall between low and high limit dissolution specifications,[25] though the specific values of these limits is not provided. Ammonio methacrylate copolymer components (hereinafter referred to as AMC), are commercially available as Eudragit®.[26] The table indicates that the AMC used is type B or type A, but the corresponding description only specifically refers to the use of AMC type B.[27]
[25] Specification at page 14, lines 20 to 25.
[26] Oppenheim 1 at [124].
[27] Specification at page 14, lines 17 to 24.
30. Example 2 describes studies towards a second acceptable melatonin mini-tablet. The initial formulations are said to be based on the first mini-tablet formulation shown above, but my understanding is that the proportion of melatonin is significantly higher. The seven formulations described in Example 2 are shown in Table II (Ex. 1 to Ex. 7) as follows.
Ex.1 Ex.2 Ex.3 Ex.4 Ex.5 Ex.6 Ex.7 Melatonin 1 1 1 1 1 1 1 AMC type B B B B B A A AMC 1.17 0.78 0.6 0.8 0.8 1.18 0.78 CHPD 0.85 0.85 0.6 0.4 0.4 0.85 0.85 Lactose 1.75 2.15 2.58 2.58 2.58 1.75 2.15
31. Various modifications to the first mini-tablet described in Example 1 were made using different proportions of CHPD, AMC and lactose to obtain acceptable dissolution profiles.[28] Using a lower proportion of CHPD to compensate for the greater comparative amount of melatonin resulted in too slow a dissolution profile (Ex.1). The proportion of lactose in this tablet was therefore increased in the second prototype, based on the assumption that lactose increases dissolution. AMC (type B) was decreased to provide for the increase in lactose. The profile of this mini-tablet (Ex.2) was also too slow.[29]
[28] Specification at page 15, lines 2 to 7.
[29] Specification at page 15, lines 8 to 16.
32. Retaining the higher lactose content of Ex.2 and reducing both the AMC and CHPD of this example provided a dissolution profile similar to the first mini-tablet, but there was an unacceptably high variability among the tested samples (Ex.3). This was thought to be due to incomplete matrix formation, so a formulation was prepared with an increased AMC (type B) content (Ex.4). CHPD content was reduced to accommodate the additional AMC. The mean dissolution rate of this formulation was unacceptably slow.[30]
[30] Specification at page 15, lines 17 to 28.
33. In order to obtain a faster dissolution rate, a formulation using a different quality of lactose, having smaller particle size, was prepared (Ex.5), but this did not influence dissolution. Finally, a more permeable grade of AMC, type A, was used (Ex.6 and Ex.7) to give formulations having an acceptable dissolution profile.[31]
[31] Specification at page 16, lines 1 to 9.
34. Example 3 describes a clinical trial of the prolonged-release (PR) mini-tablets of the invention in 125 children with autism spectrum disorder and/or neurogenetic diseases. Patients were given 2 mg melatonin (2x1 mg PR mini-tablet), or in patients that did not respond to treatment at this dosage, 5 mg melatonin (5x1 mg PR mini-tablet). The study concluded that treatment with PR melatonin mini-tablets improved sleep in children suffering from sleep disturbances by shortening sleep initiation and improving sleep maintenance.
Clarity
35. Subsection 40(3) requires that the claims must be clear. A claim will lack clarity if a third party would be unable to ascertain whether an act would fall within the scope of the claim.[32] There was some dispute between the parties as to the meaning of the feature “substantially simulates… a normal endogenous melatonin profile” as defined in Claim 21. The opponent submitted that:
It is unclear what a normal endogenous melatonin profile is. The opponent acknowledged the common general knowledge was such that the skilled addressee would understand that endogenous melatonin levels start to rise soon after sunset, reach a peak some hours later, remain at high levels for some time and decline as sunrise approaches,[33] but argued that this does not provide any certitude to determine whether a particular formulation would fall within or outside the scope of the claim.[34] They also argued that the amount of melatonin in blood varies between patient groups, and to the extent that the application relied on Figure 1, it does not provide sufficient information to extrapolate the blood melatonin levels at any particular point in time.
There is no guidance or definition in the specification as to what the phrase “substantially simulates” means, and as a consequence it is unclear what release profiles will and will not fall within the scope of the term.
[32] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59.
[33] Oppenheim 1 at [113].
[34] OS at [95(a)].
36. The applicant drew my attention to the specification at page 1, lines 16 to 18, which states:
“Melatonin is also used to treat dependence on, tolerance of, or addiction to a benzodiazepine, as described in U.S. Pat. No. 6,469,044,[35] the disclosure of which is incorporated herein by reference in its entirety”.
[35] US 6,469,044 (D6) was also raised under the ground of inventive step.
37. The applicant submitted that the incorporation by reference to D6 provides clear boundaries and meaning to the claim as to the meaning of the term “substantially simulates”. To this end D6 defines the term “substantially simulate a normal melatonin profile” as meaning that a minimal blood level of about 60 to about 200 picograms melatonin per millilitre for a period of at least four hours during the night. Maximal blood melatonin levels in a person with a normal melatonin profile are said to typically be about 60±20 µg/ml.[36] Figure 1 of D6 is said to illustrate the nocturnal plasma profile of melatonin in a healthy human adult.
[36] D6, paragraph bridging columns 3 and 4.
38. The opponent referred me to the decision of the Federal Court in Albany Molecular Research Inc v Alphapharm Pty Ltd, [37] where a claim defining a “substantially pure” compound was found to be not clear. This decision is relevant to the present consideration, not simply because of the use of the term “substantially”, but because it serves as a reminder that:
“A court may not either expand or contract the meaning of claims in a patent by reference to language derived from other parts of the complete specification. However, if there is some ambiguity in the language of the claims themselves, it is legitimate to have reference to the specification for the purpose of resolving that ambiguity. Although “substantially” is a word often found in instruments having legal effect, such as statutes, its content is almost always to be derived from the content, purpose and subject matter of the instrument as a whole.”
[37] [2011] FCA 120; (2011) 90 IPR 457 at [175].
39. Thus, the key consideration is not merely whether the term “substantially” makes the claim unclear in meaning, but whether it is clear in meaning in the context in which it is used here, including the effect that the incorporation by reference imports on its meaning. For example, in Merck Sharp & Dohme Corporation v Wyeth LLC,[38] Burley J considered whether an incorporation by reference of an earlier document was for the entirety of the document, or whether it was for the limited purpose of identifying a reference in the prior art where it had been suggested that silicone oil may be responsible for aggregation seen in protein pharmaceutical preparations. He determined that the manner in which the incorporation by reference was made represented an invitation for the skilled addressee to consider the document more generally for understanding the problems caused by silicone oil. He distinguished this from the more limited context of a reference in Idenix Pharmaceuticals LLC v Gilead Sciences Pty Ltd.[39] Similarly, in Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (No 4),[40] where a reference to earlier documents was held to be limited to the relevant disclosures method of preparing compounds (the matter specifically referred to by the specification), rather than the incorporation of the documents in their entirety.
[38] [2020] FCA 1477; (2020) 155 IPR 1 at [891].
[39] [2017] FCAFC 196; (2017) 134 IPR 1 at [165].
[40] [2015] FCA 634 at [367].
40. In the present case, even though the discussion of D6 is in relation to specific treatments, D6 is stated to be incorporated in its entirety which includes information relating to the normal endogenous melatonin profile. In this regard, even though Figure 1 of the present application uses a different representation of plasma melatonin levels (being represented as a percentage of area under curve), the detailed description of the pharmacokinetic and pharmacodynamic properties of the mini-tablets according to the invention, including the minimal blood plasma levels, is consistent with that given in D6.
41. But even if I am wrong on this point, neither expert appeared to have difficulty with the terminology used in the claim. Dr Oppenheim stated that:
“I did not know what the value of the normal endogenous plasma concentration of melatonin was at any stage during its profile in the untreated patient. I could determine these concentration values either by conducting a standard literature search or by standard experimentation… I conducted a very cursory and basic Google search and found many articles dated before the priority date.”[41]
[41] Oppenheim 1 at [113].
42. Dr Oppenheim went on to state that once he had determined the patient’s normal endogenous melatonin plasma level (or found the commonly accepted plasma levels in the literature), he could then develop a dosage form that would substantially simulate the patient’s endogenous melatonin levels.[42] His language here indicates that the skilled person would be able to give meaning to the terminology used in the present claims.
[42] Oppenheim 1 at [126].
43. I therefore consider that the opponent is unsuccessful on this ground of opposition.
Support
44. The opponent’s submissions on support and sufficiency overlapped considerably. I have dealt with the issues raised as I see most appropriate to each ground.
45. Section 40(3) of the Act requires that the claims must be supported by matter disclosed in the specification. At the heart of this consideration is the principle that the “extent of the patent monopoly, as defined by the claims, should correspond to the technical contribution to the art in order for it to be supported, or justified.”[43]
[43] EXXON/Fuel Oils (T409/91) [1994] OJ EPO 653.
46. Guidance on the determination of the technical contribution disclosed in a specification was provided by the UK Supreme Court in Regeneron Pharmaceuticals Inc. v Kymab:[44]
i) The requirement of sufficiency imposed by article 83 of the EPC exists to ensure that the extent of the monopoly conferred by the patent corresponds with the extent of the contribution which it makes to the art.
ii) In the case of a product claim, the contribution to the art is the ability of the skilled person to make the product itself, rather than (if different) the invention.
iii) Patentees are free to choose how widely to frame the range of products for which they claim protection. But they need to ensure that they make no broader claim than is enabled by their disclosure.
iv) The disclosure required of the patentee is such as will, coupled with the common general knowledge existing as at the priority date, be sufficient to enable the skilled person to make substantially all the types or embodiments of products within the scope of the claim. That is what, in the context of a product claim, enablement means.
v) A claim which seeks to protect products which cannot be made by the skilled person using the disclosure in the patent will, subject to de minimis or wholly irrelevant exceptions, be bound to exceed the contribution to the art made by the patent, measured as it must be at the priority date.
vi) This does not mean that the patentee has to demonstrate in the disclosure that every embodiment within the scope of the claim has been tried, tested and proved to have been enabled to be made. Patentees may rely, if they can, upon a principle of general application if it would appear reasonably likely to enable the whole range of products within the scope of the claim to be made. But they take the risk, if challenged, that the supposed general principle will be proved at trial not in fact to enable a significant, relevant, part of the claimed range to be made, as at the priority date.
vii) Nor will a claim which in substance passes the sufficiency test be defeated by dividing the product claim into a range denominated by some wholly irrelevant factor, such as the length of a mouse’s tail. The requirement to show enablement across the whole scope of the claim applies only across a relevant range. Put broadly, the range will be relevant if it is denominated by reference to a variable which significantly affects the value or utility of the product in achieving the purpose for which it is to be made.
viii) Enablement across the scope of a product claim is not established merely by showing that all products within the relevant range will, if and when they can be made, deliver the same general benefit intended to be generated by the invention, regardless how valuable and ground-breaking that invention may prove to be.
[44] [2020] UKSC 27 at [56].
47. In CSR Building Products Limited v United States Gypsum Company (CSR), the delegate took the following approach to determine whether the claimed matter is supported by the matter disclosed in the specification:
(a)Construe the claims to determine the scope of the invention claimed.
(b)Construe the description and the technical contribution to the art, that is how far the concept has carried forward the state of the art.
(c)Decide whether the claims are supported by the technical contribution to the art. [45]
[45] [2015] APO 72 at [115].
48. The Federal Court has approved of this approach.[46]
[46] Cytec Industries Inc v Nalco Company (2021) 162 IPR 202.
49. The gist of the opponent’s submissions was that, with the exception of the consistory clauses, the specification only provided a disclosure of mini-tablets formulated using specific manufacturing methods and using certain specified ratios of certain excipients, and the use of the mini-tablets for the treatment of children with ASD and/or neurogenetic diseases.[47] They argued that the technical contribution to the art does not go beyond these specific disclosures.
[47] OS at [91].
50. The applicant submitted that the opponent’s approach sets out a narrow and incomplete summary of information from the specification without engaging with the substantive question of what Neurim has contributed to the art.[48] Prof Davies stated that, given the problem, he would never have gone down the path of attempting to formulate a controlled-release mini-tablet. The technical contribution to the art was therefore to provide a starting point for formulating a controlled-release melatonin mini-tablet that the skilled person would not otherwise have had, general principles or directions as to the types of carriers that would work, and a series of exemplary and preferred formulations that did, in fact, work.
[48] AS at [281].
51. On balance I do not find the applicant’s submissions persuasive. As noted by the delegate in CSR:
"An important question will often be whether the technical contribution to the art is a general principle or the specific examples in the specification."[49]
[49] [2015] APO 72 at [113].
52. In this regard, the applicant’s submissions that the specification provides a starting point from which the skilled person, through routine trial and error could prepare other formulations using other excipients appears inconsistent with the teaching in the specification. Consistent with the opponent’s submission, the specification refers to generic classes of carriers (diluents, lubricants, binders, glidants, anti-adherents, and other excipients). The only specific carriers given in the specification are lactose, CHPD and acrylic resin carriers (e.g., Eudragit®),[50] with alternative excipients only being provided for lactose, which can apparently be replaced by another fast-dissolving sugar.[51]
[50] Specification at page 5, lines 19 to 24.
[51] Specification at page 6, lines 1 to 2.
53. The applicant drew my attention to the specification, which states that:
“The drug-release profile is strongly affected by formulation parameters. The type and amount of release-controlling agent (usually polymer) used in mini-tablets similarly determines the drug-release patterns mainly by diffusion. The instant inventors found that, in matrix mini-tablet studies, increasing the amount of rate-controlling compound led to slower drug release, which may be due to the increase hydrophobicity of the system. It was discovered that increasing water insoluble compounds (e.g., lactose) provides faster drug release due to their water solubility and drug diffusion promotion.”
54. They submitted that this informed the approach of the skilled person in combining melatonin, the release-controlling excipient and the water-soluble excipient, and then adjusting the balance of these excipients by routine trial and error to obtain the desired dissolution rate.[52] However, I note that the specification goes on to state that:
“The present inventors discovered that it was not possible to use known information about Circadin® tablets to make a priori assumptions or predictions about the resultant flowability, dissolution and release characteristics of mini-tablet formulations. In addition, the present inventors discovered that it was not possible to use known information about a developed mini-tablet dosage form, e.g., the first melatonin mini-tablet, to make a priori assumptions or predictions about the resultant flowability, dissolution and release characteristics of a mini-tablet having a different dosage amount, e.g., a second mini-tablet.”
[52] AS at [240] to [242].
55. I understand this to suggest that even once a specific group of excipients has been identified, it is not possible to predict the characteristics, including the dissolution profile, of another mini-tablet formulation. This appears to be consistent with the evidence of Prof Davies, who considered this indicative of the problems commonly encountered when attempting to create a controlled release mini-tablet.[53] One of the disadvantages he identified in using mini-tablets included that it can be more difficult to achieve the required release profile than for conventional tablets and it may be necessary to use different materials in order to achieve the desired release rate.[54]
[53] Davies at [247].
[54] Davies at [129].
56. Thus, rather than a principle of general application that would support substantially the entire scope of the claims as presently drafted, the specification enables a more limited range of specific embodiments based on empirical experiments and the technical contribution to relate to a specific group of excipients in a limited range of proportions.
57. On this basis Claims 1 to 17, and 19 to 21 lack support. Claim 18 does not lack support on this basis as the ranges defined are based on the empirical experiments described in the specification and therefore provide a basis for determining suitable combinations having the desired dissolution profile.
58. As an additional point, I have construed the claim as not being limited to prolonged-release formulations, and as indicated in Dr Oppenheim’s evidence the dissolution profile defined by Claim 1 would include, for example, a pulsed-release formulation where the mini-tablet is coated with an enteric coating or the like to release the API in the gastro-intestinal tract after a period of time. There are no other features defined in Claim 1 that would otherwise limit its scope to prolonged release formulations. I therefore do not consider Claim 1 is limited to the technical contribution described in the specification since it is not limited to prolonged release formulations. This also applies to Claims 4, 5 to 18, and 20. I note this issue was raised by the opponent under the ground of utility, but I consider the ground of support to apply for substantially the same reasons given therein.[55]
[55] OS at [72].
59. Finally, the opponent submitted that the claims define the use of the mini-tablets in all patients to induce and/or maintain sleep or induce a phase shift in circadian rhythm. However, the specification provides no clinical base for the use of the mini-tablets, or at best their use in a subset of paediatric patients.[56] The specification does indeed only provide a clinical trial involving a particular paediatric patient group. Furthermore, the specification identifies paediatric and geriatric patient populations as typically having an inability to swallow tablets. But I do not understand the language of the specification to limit the use of the melatonin mini-tablets to these particular patient populations. The opponent has not made out their case on this point.
Conclusion on support
[56] OS at [92].
60. In summary, I consider the claims, as a whole, lack support.
Clear and complete enough disclosure (sufficiency)
61. Section 40(2)(a) of the Act requires that the complete specification must disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the relevant art.
62. In CSR Building Products Ltd v United States Gypsum Company,[57] the delegate formulated the following three steps:
1. Construe the claims to determine the scope of the invention as claimed;
2. Construe the description to determine what it discloses to the person skilled in the art; and
3. Decide whether the specification provides an enabling disclosure of all the things that fall within the scope of the claims.
[57] CSR at [95].
63. In Evolva SA,[58] the third question was reformulated as the following two-step consideration:
1. Is it plausible that the invention can be worked across the full scope of the invention?
2. Can the invention be performed across the full scope of the claims without undue experimentation?
[58] [2017] APO 57.
64. This approach has found approval with the Federal Court.[59] EP and UK decisions have provided some general guidance on factors that come into consideration when determining whether the specification is sufficient, including uncertainty and a lack of predictability, incomplete experimental details, and a lack of guidance in the specification including instructions on how to proceed in case of failure.[60]
[59] Cytec Industries Inc v Nalco Company, supra at [143]-[146].
[60] Evolva at [34].
65. The opponent made submissions on a number of points, and while my determination in respect to support probably renders the issues moot, for completeness I will deal with these in turn.
Excipients
66. The opponent submitted that there is no disclosure of any method to make mini-tablets containing excipients other than those specifically described in the examples (and defined in Claims 16 to 18).
67. I have found that Claims 1 to 17 and 19 to 21 lack support as the specification does not disclose a principle of general application, but rather relates to specific embodiments having certain excipients in a limited range of proportions. For similar reasons I consider that the specification is insufficient in relation to this matter. Given the unpredictability, even for the same excipients, and the lack of guidance provided by the specification in this regard, I consider the specification does not provide a clear enough or complete enough disclosure across the full scope of the invention as presently claimed in Claims 1 to 17 and 19 to 21.
68. Furthermore, as noted under the ground of support, Claims 4, 5 to 18, and 20 exceed the technical contribution disclosed in the specification. For similar reasons I consider the description does not provide a clear enough and complete enough disclosure across the full scope of “controlled-release” formulations encompassed by the claims.
Tablet size
69. The opponent submitted that the claims encompass mini-tablets of any size between 1 mm and 4 mm, but there would be a need for significant reformulation to achieve those various sizes. They noted that the variation in the defined range was similar to the difference in size between a standard tablet and the exemplified minitablet of 4 mm diameter (for example, there is a 50% change in going from 8 mm to 4 mm, and similarly a 50% change in going from 4 mm to 2 mm). Given the purported challenges between going from a standard tablet to a mini-tablet to obtain suitable formulations, there would be similar challenges within the claimed range.[61]
[61] OS at [78] to [82].
70. I acknowledge that the variation in diameter within the range defined by the claims is relatively large. However, the specification indicates that a key factor impacting on the dissolution profile is the increased surface area in comparison to the volume of the tablet.[62] This was also noted by Prof Davies,[63] and was not disputed by Dr Oppenheim.[64] Diameter alone does not reflect changes in this regard, and my understanding is that the relative volume:surface area difference between an 8 mm and 4 mm tablet is significantly greater than between a 4 mm and 2 mm tablet.
[62] Specification at page 14, lines 4 to 6.
[63] Davies at [113].
[64] Oppenheim 2, attachment at row 113.
71. It would therefore seem plausible to me that similar formulations could be used to achieve similar dissolution profiles within the claimed range of tablet diameters. In any case, no evidence was provided by the opponent based on the relative surface area to volume of different mini-tablets, so I do not consider the opponent has made out their case on this point.
Lactose alternatives
72. The opponent submitted that Claim 9 defines the use of a fast-dissolving sugar or alcohol instead of lactose, but the only disclosure in the examples is lactose. Dr Oppenheim stated that he did not recall ever seeing a product in which a fast-dissolving sugar or alcohol had been used in place of lactose for the same purpose. He did not consider these alternatives would, provide a workable formulation.[65] Prof Davies stated that he had experience in the use of various fast-dissolving sugars, and he considered there was no reason why these substances would not function as a fast-dissolving sugar in the formulations of the invention.[66]
[65] Oppenheim 1 at [165].
[66] Davies at [359].
73. Given the purpose of the water-soluble excipient is to form pores in the matrix to facilitate diffusion of the API from a tablet,[67] it would seem plausible that alternative water-soluble excipients could be dispersed in the polymer matrix to achieve the same outcome. I therefore consider that the opponent has not made out their case on this point.
Lack of examples in the claimed range (Claim 18)
[67] Oppenheim 1 at [65].
74. Claim 18 defines ratios of various excipients to melatonin, but the specification provides no disclosure of formulations containing the excipients in the full range claimed. The only example considered suitable which falls within the range defined in Claim 18 is the first mini-tablet formulation described in Example 1. Neither of the other two “acceptable” candidates (Ex.6 and Ex.7 of example 2) fall within the scope of Claim 18. The ratios of the first mini-tablet formulation are at one end of the range of excipients and provide no guidance on how to prepare suitable formulations at the other end of the range.
75. Admittedly it does appear unusual for the claimed range in Claim 18 to exclude specific embodiments that are identified as having suitable dissolution profiles. However, there is no requirement that every claim includes all preferred embodiments, so I do not consider there to be an issue on that account. The opponent’s submissions go to the principle that a single example may be enough to establish sufficiency for a range of alternatives, but in most cases embodiments from across the scope of the claim will be required. In this case, the additional embodiments at the “other end” fall outside the claimed range, but nevertheless they do provide a disclosure across a range of values, albeit one which is greater in scope than claimed in Claim 18. I therefore do not consider that the opponent has made out their case in this regard.
Normal endogenous plasma profile
76. The opponent submitted that Claim 21 defines the mini-tablet formulation in terms that the melatonin plasma profile substantially simulates the melatonin plasma profile of a human having a normal endogenous plasma profile. There is no disclosure in the specification which ties the in vitro dissolution profiles to the endogenous in vivo dissolution profile, and no means described that would enable the skilled person to make a formulation which would meet the definition given in Claim 21.
77. The applicant noted that the specification provides a direction as to the desirable in vitro dissolution profile needed to achieve the desired in vivo response in a patient (referred to as IVIVC) which has already been established by clinical testing. They submitted that in view of the teaching of the specification the skilled person would be able to produce not only the preferred embodiments provided in the specification, but other controlled-release mini-tablets using different excipients but nonetheless meeting the required dissolution specification.
78. IVIVC appears to be a plausible assessment technique to identify formulations that may achieve the normal endogenous melatonin blood levels. I consider the key issue is that the technique does not in itself inform of the types of excipients required to achieve a particular dissolution profile. My determination in relation to the excipients addresses that concern. Claim 21 lacks support and the specification is insufficient as far as the matter claimed, but I do not consider the opponent to have made out their case on the issue of the correlation of in vitro and in vivo activity.
Conclusion on sufficiency
79. In summary, the specification does not provide a clear enough or complete enough disclosure across the full scope of the invention as presently claimed in Claims 1 to 21.
Utility
80. Section 18(1)(c) of the Act requires that the claimed invention be useful. A summary of relevant principles was provided by the Full Court of the Federal Court in Artcraft Urban Group v Streetworx:
It is “no objection” to the validity of an innovation patent granted under the Act that it is “commercially impracticable”. The utility of the patent depends upon whether, by following the teaching of the specification, the result claimed is produced...
The “basic principle” of inutility is that if an invention “does what it is intended by the patentee to do, and the end attained is itself useful, the invention is a useful invention”... What the invention is “intended” to do is a matter to be gathered from the “title and the whole of the specification”.
Put another way, the two questions are: first, what is the promise of the invention derived from the whole of the specification?; second, by following the teaching of the specification, does the invention, as claimed in the patent, attain the result promised for it by the patentee?... Further, “everything” that is within the scope of a claim must be useful, that is, attain the result promised for the invention by the patentee.[68] [citations omitted]
[68] Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd [2016] FCAFC 29 at [118]-[121].
81. For completeness, I note that Section 7A states that an invention is taken to not be useful unless a specific, substantial and credible use for the invention (so far as claimed) is disclosed in the complete specification.
82. The opponent submitted that:
· The claims (save for Claims 2, 3, 19 and 21) define an in vitro dissolution of less than about 50% melatonin release within 1 hour and greater than 70% within 6 hours. This dissolution profile would be met by a formulation providing a pulsed release as discussed previously. These formulations would not meet the promise of the invention of a prolonged-release profile, or a profile that simulates a normal endogenous melatonin profile.
· The claims encompass, for example, a single 2 mg mini-tablet. This dosage does not provide for flexible dosing since the dosage amount is fixed at 2 mg for regulatory purposes, so there is no flexibility available in its use.
· The use of multiple mini-tablets in a capsule would result in a dosage form that would have to be at least the size of the existing Circadin® tablet and would therefore not meet the promise of a dosage form being easier to swallow.
· The use of a fast-dissolving sugar or alcohol that is not lactose would not produce a workable controlled-release formulation falling within the scope of the claims.[69]
[69] OS at [71] to [75] and references therein.
83. They argued that the promise of the invention is given in the specification as follows:
… before the present invention, there was a long-felt, but unmet need for a prolonged-release dosage form of melatonin with improved swallowing, flexible dosing, and better patient compliance. The present invention satisfies the need in the field by providing melatonin mini-tablets having improved swallowing, flexible dosing, and better patient compliance, as well as a controlled-release profile that achieves the same minimal blood levels of melatonin present at night in the brain of a human with a normal endogenous melatonin profile, shown in Fig. 1, as well as an acceptable safety profile.”[70]
[70] OS at [119] referring to the specification at the paragraph bridging pages 3 and 4.
84. The applicant submitted that the opponent had inaccurately construed this excerpt in arriving at a composite problem involving three elements: easier swallowing and/or improved patient compliance, flexible dosing, and a prolonged-release profile. However, when properly construed the specification and claims sets forth several distinct problems.[71] They submitted that the above excerpt is canvassing the various problems addressed by the present application and therefore lists them all in a single sentence. Other parts of the specification discuss the various problems and explain how various embodiments of the invention can be used to address them.[72] When read as a whole, they submitted, the promise of the invention is a controlled-release of melatonin in a dosage form that is easy to swallow. They further submitted that the opponent had not put forward sufficient arguments to support their assertions that any elements of the composite problem are not met by the claimed invention.
[71] AS at [201].
[72] AS at [202].
85. On balance I find the applicant’s submissions persuasive. As noted by the applicant, the opponent has not provided evidence that the claimed invention, including a hypothetical pulsed-release formulation, does not achieve the composite promise proposed by the opponent.[73] I consider the key consideration with the first and last dot points above relates to support and sufficiency. I have already made these determinations above and see no reason to consider them under the ground of utility.
[73] AS at [213].
86. The opponent’s remaining submissions are based on a specific embodiment and the extrinsic regulatory approvals that relate to those products. I see little relevance in these submissions. All pharmaceutical products are subject to regulatory approvals and limitations. Those requirements do not determine whether they can be the subject of a claim in a patent. Furthermore, dose flexibility seems to me to be an additional benefit provided by mini-tablets in being capable of use in polypharmacy and dose-flexibility because they can be filled into capsules. This provides for the administration of specifically tailored dosage amounts or drug cocktails.[74] That the resulting capsules may be a larger dosage form does not change the inherent property of the mini-capsules being capable of use by patients having difficulty in swallowing.
[74] Specification at page 4, lines 18 to 26.
87. In summary the opposition is unsuccessful on this ground.
Best method
88. Subsection 40(2)(aa) requires that a complete application disclose the best method known to the applicant of performing the invention. In Expo-Net Danmark A/S v Buono-Net Australia Pty Ltd (No 2), the court held that in order to establish that the applicant has failed to disclose the best method of carrying out the invention it must be established that:
(a) the method which the patentee failed to disclose is a method of performing the invention;
(b) the method is in fact a better method of performing the invention than the method disclosed in the specification;
(c) the method was known to the patentee at the time when the application for the patent was lodged at the Patent Office;
(d) the method is not disclosed in the specification; and
(e) the patentee knew that the method was better than the method(s) described in the specification.
89. To put it another way, it is necessary to determine what method is disclosed in the specification, and then to ask whether there is any evidence that the applicant was aware of a better method of performing the invention.[75]
[75] Kineta, Inc. [2017] APO 45 at [24].
90. The opponent submitted that
Example 3 refers to a clinical trial of melatonin mini-tablets in children with ASD or other neurological diseases. A clinical trial will invariably only be attempted with the most promising formulation of a particular drug. Example 3 merely states that the melatonin mini-tablets used were “according to the present invention”.[76] There is no cross-reference to any of the candidate formulations in Examples 1 and 2, which would be expected if example 3 used one of those formulations.
Example 2 refers to the need to make at least 10 formulations. However only the first seven formulations are referred to, and none of these fall within the scope of Claim 18, suggesting that they were not the best formulation. At least three other trial formulations were made, which may or may not have been the formulations used in Example 3. The opponent considered it tolerably clear on the face of the specification alone that the applicant has developed a better formulation than those referred to in Example 2.
[76] Specification at page 16, paragraph 2.
91. The applicant argued that the opponent’s arguments were founded on a misapplication of the law. They noted that the best method of performing the invention does not have to be identified as being the best method in the specification – the obligation is merely to disclose that method.[77] They submitted that the fact that the specification does not call out the best formulation or identify the specific formulation used in Example 3 is irrelevant. The specification may disclose a number of different methods of performing the invention and need not identify the best method of performing the invention known to the applicant at the time of filing the complete application.
[77] Firebelt Pty Ltd v Brambles Australia Ltd [2000] FCA 1689 at [52].
92. They noted that the opponent had failed to establish that the applicant was aware of a better formulation at the time of filing. The applicant argued that the opponent’s submissions on this point were merely circumstantial, and do not rise above a suggestion that a better formulation must have been known because the specification does not state which formulation was best or which formulation was used in the clinical trial.
93. I find these submissions persuasive. I acknowledge that the formulation used in Example 3 is not specifically identified. However, even on the face of the specification I do not consider that a failure to disclose the best method has been established or that an inference can be drawn that one of the three additional test formulations of example 2 must be better than those detailed. To the contrary the specification states that the table shows seven different formulations for which the excipients have been varied to obtain adequate tablet properties and to obtain acceptable dissolution. The inference could equally be drawn that the other three formulations did not possess acceptable properties. As noted by the applicant there is no requirement that the specification specifically identify the best method known to the applicant at the time of filing, and the opponent has provided no evidence to establish that a better method was known.
94. The opposition is unsuccessful on this ground.
Inventive step
95. Section 7(2) of the Act sets out that an invention is taken to involve an inventive step unless it would have been obvious to the person skilled in the art in the light of the common general knowledge, either considered alone or together with information of the kind set out in section 7(3) of the Act. The opponent’s submissions related to obviousness in view of the common general knowledge alone, as well as obviousness in view of the common general knowledge together with US 6,469,044 (D6).
96. The courts have formulated different tests to determine whether a claimed invention is obvious. In Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (Wellcome), Aickin J considered whether faced with the same problem, it would have been a matter of routine to proceed to the claimed invention.[78] In Aktiebolaget Hassle v Alphapharm Pty Ltd (Alphapharm),[79] the High Court accepted the approach taken by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd (Olin Mathieson), where he posed the reformulated Cripps question:
“Would the notional research group at the relevant date, in all the circumstances, ... directly be led as a matter of course to try [the claimed combination] in the expectation that it might well produce a [useful or better result]?”[80]
[78] [1981] HCA 12; 148 CLR 262 at 286 (Wellcome).
[79] [2002] HCA 59 at [53]; (2002) 212 CLR 411 at [53].
[80] Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at [187].
97. These were said by the High Court in Alphapharm to have an affinity.[81] While the problem-solution approach has been accepted by the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd, the court has cautioned that:
“However, it is worth repeating that the ‘problem and solution’ approach may be particularly unfair to an inventor of a combination, or to an inventor of a simple solution, especially as a small amount of ingenuity can sustain a patent in Australia. Ingenuity may lie in an idea for overcoming a practical difficulty in circumstances where a difficulty with a product consisting of a known set of integers is common general knowledge. This is a narrow but critical point if, as here, the circumstances are that no skilled person in the art called to give evidence had thought of a general idea or general method of solving a known difficulty with respect to a known product, as at the priority date.” [citations omitted][82]
[81] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [53].
[82] [2007] HCA 21; (2007) 235 CLR 173 at [65].
98. Furthermore, in formulating the problem, care must be taken if incorporating information from the specification into the problem:
“If the problem addressed by a patent specification is itself common general knowledge, or if knowledge of the problem is s 7(3) information, then such knowledge or information will be attributed to the hypothetical person skilled in the art for the purpose of assessing obviousness. But if the problem cannot be attributed to the hypothetical person skilled in the art in either of these ways then it is not permissible to attribute a knowledge of the problem on the basis of the inventor’s “starting point” such as might be gleaned from a reading of the complete specification as a whole.”[83]
The common general knowledge
[83] AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99 at [203].
99. The inventive step determination requires a consideration of the common general knowledge:
“The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.”[84]
[84] Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd supra at 292.
100. It is not sufficient that a document is publicly available for it to be considered part of the common general knowledge in the art. There must be evidence of its general acceptance and assimilation by the person skilled in the art.[85] However, common general knowledge is not limited to information that the skilled person has committed to memory, and also includes material in the field in which he is working which he knows exists and to which he would refer as a matter of course.[86]
[85] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [31].
[86] ICI Chemicals and Polymers Ltd v Lubrizol Corporation Inc 1999 FCA 345 at [111].
101. The experts were largely in agreement on a number of aspects of the common general knowledge in the art. Some of the more relevant points are:
Many drug delivery systems are available, including enteral (administered via the gastrointestinal tract), parenteral (administered via injection), oral (including solid and liquid), inhalant, and transdermal.[87]
Various different kinds of oral dosage forms are commonly used in the art, such as tablets, capsules, liquids, mini-tablets, micro-particulates and powders.[88]
Controlled-release formulations may be in the form of tablets or capsules. The two main types of controlled release formulations are coated and matrix formulations. Coated formulations use a semi-permeable membrane which allows water to dissolve the drug and release it through the membrane. Coatings may be on the outside of the tablet, or they can be over granules making up a tablet.[89] These coated granules can also be used in capsules. Matrix formulations comprise polymers which hydrate slowly and gradually dissolve. This forms a gel layer around the tablet through which the drug diffuses. Materials can be incorporated to produce pores that facilitate diffusion of the drug, and combinations of coatings, matrices and other ion exchange or osmotic constituents can be used to control release.[90]
Various dosage forms are available to deliver a drug to a patient with difficulty swallowing. These include non-oral drug delivery systems (including parenteral, suppository, and transdermal systems),[91] liquids (though these may be difficult to formulate), mini-tablets which may be coated or comprise a matrix,[92] and micro-particulates which may include extrudates, microspheres, or coated beads (including combinations of beads having different release profiles).[93]
Melatonin has a role in the induction and regulation of sleep. Both experts were aware that formulations containing melatonin were used in the treatment of sleep-related issues such as insomnia.[94]
[87] Davies at [56].
[88] Davies at [57].
[89] Davies at [103].
[90] Davies at [78] to [79].
[91] Davies at [110].
[92] Davies at [111] to [113].
[93] Davies at [116] to [117].
[94] Davies at [130], Oppenheim 1 at [111] to [112].
102. The experts differed in respect to whether they would routinely have regard to the Australian Register of Therapeutic Goods (the ARTG) for information about existing dosage forms.[95] This potentially impacts on the determination of whether documents D45,[96] D62[97] and D63[98] constitute information that would be considered common general knowledge by the skilled person.
[95] OS at [34].
[96] Product Information Circadin® Prolonged Released Tablets, dated 9 June 2016.
[97] Consumer Medicine Information Circadin® Prolonged Released Tablets, dated May 2016.
[98] Australian Public Assessment Report for Melatonin issued December 2009.
103. As an initial point I note that the publication dates of these documents have been taken from the documents themselves. D45 states that the date of the most recent amendment is 9 June 2016,[99] while D62 states that the leaflet was prepared in May 2016.[100] I will proceed on the assumption that these are indeed the publication dates of the documents, but ultimately this probably does not significantly impact on the determination. In the case of D62, I will assume that the publication date is the final day in May 2016.
[99] D45, page 13/13.
[100] D62, last page.
104. The applicant noted that a grace period applies to the document D1 pursuant to a direction by the delegate of the Commissioner in Generic Partners Pty Ltd v Neurim Pharmaceuticals Ltd.[101] They submitted that D45 and D62 comprise information that pursuant to section 24 must be disregarded for the purpose of assessing inventive step because they were published within the grace period (both the “extended” grace period and the grace period that would have applied prior to the direction by the delegate).[102] To this end, D45 (9 June 2016) and D62 (May 2016) were published within 12 months of the filing date of the application and therefore appear to fall within the time set out in section 24(1)(a).
[101] Generic Partners Pty Ltd v Neurim Pharmaceuticals Ltd., supra footnote 3.
[102] OS at [46].
105. The opponent drew my attention to the distinction in section 7 between common general knowledge as referred to in subsection 7(2), and prior art information as used in subsection 7(3). The dictionary in Schedule 1 of the Act defines prior art information for the purposes of subsection 7(3) as “information that is part of the prior art base in relation to deciding whether an invention does or does not involve an inventive step…” They submitted that when subsection 24(1) is read with section 7, it is clear that the information referred to in section 24 is prior art information and not common general knowledge.[103] They submitted that this distinction inferred that common general knowledge disclosed by a document is not subject to the exclusion set out in section 24. It would seem to me that there could be instances where a document subject to the provisions of section 24 might be used as contemporaneous evidence of the common general knowledge. That would seem consistent with the opponent’s submissions in relation to the distinction between information and knowledge in the relevant sections of the Act. In that regard, my understanding of the opponent’s submissions on D45 and D62 are essentially that these documents provide contemporaneous evidence that the properties of Circadin® were common general knowledge in the art at the relevant time. A similar consideration was argued for D63, which was published well before the filing date and therefore is not subject to the same constraints that might apply to D45 and D62 in relation to a grace period.
[103] Additional written submissions provided by the applicant at hearing.
106. Neither expert recalled the specific formulations used to administer melatonin. Dr Oppenheim expressly stated that he was not aware of Circadin® prolonged-release tablets,[104] while Prof Davies stated that he was generally aware of melatonin solid oral dosages but could not recall whether they were tablets or capsules.[105]
[104] Oppenheim 1 at [117].
[105] Davies at [131].
107. The main difference between the experts was the approach they would have taken if tasked with making a new formulation of a product and the information they would have regard to in that process. Dr Oppenheim “habitually” consulted the ARTG for information about existing dosage forms, and if tasked with making a new formulation of an existing dosage form, he would consult ARTG information related to that solid oral dosage to find information about it.[106] The opponent submitted that D62, being the Australian Consumer Medical Information for Circadin®, was no different to a standard handbook or textbook, and therefore the information in the document must be considered as common general knowledge.[107] Dr Oppenheim stated that he would have found D45, D62 and D63 in his search of the ARTG.[108] To the extent that Prof Davies would not consult these documents, the opponent suggested that this could simply be based on the fact that he is based in the UK and would not have been familiar with the relevant ARTG information.[109] As previously noted this is not a relevant consideration for inventive step under the Raising the Bar Act.
[106] OS at [34].
[107] OS at [36].
[108] Oppenheim 1 at [116].
[109] OS at [37].
108. The applicant submitted that a standard text is something which is consulted regularly and the details of which are likely to be provable to have been generally accepted and assimilated into the knowledge of the pharmaceutical formulating community. They argued that D62 is clearly not of the same character as textbooks. They also noted that the evidence did not support the statement that the skilled addressee would have habitually consulted these documents, and that, at best, Dr Oppenheim’s evidence is that, if given the task, he would have sought out them out. This was not evidence of habitual consultation of a work the contents of which are well known and widely accepted by persons skilled in the art, but rather a targeted literature search.[110] They acknowledged that documents retrieved in such a search could constitute relevant prior art for the determination of inventive step under subsection 7(3) but argued that this was not determinative of common general knowledge.
[110] AS at [108] to [109].
109. I agree with the applicant on this point. The opponent’s submission is essentially that a document retrieved from the ARTG is considered a “source of truth” in the same way as a textbook or handbook. The subsequent implication is that the information in the document that has entered in the ARTG is so widely accepted that it can be accepted as common general knowledge. I do not consider that the evidence establishes either of these.
110. In that regard, Dr Oppenheim was asked to describe the manner in which he kept up to date with developments in the field of formulation of pharmaceutical products. He stated that he initially used textbooks and reference texts.[111] He went on to state that:
“By their very nature, such textbooks can only provide a contemporary approach to such formulation activities. To ensure that I included current developments in this field of formulation, I routinely read the latest volumes of research journals and publication summaries held by VCP and nearby research institutions.”
…
“With the introduction of publicly available data bases during this period [his employment with R. P. Scherer], I was able to search the Australian Register of Therapeutic Goods (ARTG) and the databases of the Australian Patent Office for innovations in the formulation of solid oral dosage forms, which I regularly did”.[112]
[111] Oppenheim 1 at [23].
[112] Oppenheim 1 at [24] to [31].
111. Here, Dr Oppenheim appears to make a distinction between the “contemporary approaches” provided in textbooks and reference texts which I equate to the common general knowledge in the art, and “current developments” set out in research journals and the like which I understand to be at the forefront of the technology and too recent to be considered common general knowledge.[113] The information provided by the ARTG and patents is referred to differently again, being described by Dr Oppenheim as “innovations” in the technology.[114] This reference does not indicate a widespread acceptance of the material.
[113] Oppenheim 1 at [24].
[114] Oppenheim 1 at [31].
112. The present circumstances therefore appear to be consistent with those considered by the High Court in Alphapharm, where the court rejected a submission that certain information was common general knowledge because there was no evidence of its general acceptance and assimilation by skilled persons in the art:
“The primary judge rejected Alphapharm's submission that the common general knowledge of the skilled formulator in Australia included material which the formulator might find by conducting computer searches and the like, being means available to and used by formulators. His Honour correctly did so because the corollary of the submission was that information should be treated as part of the common general knowledge in Australia, even in the absence of evidence of its general acceptance and assimilation by what he called "the formulating community". This was a proposition which Lehane J recognised was foreclosed by the authority of this Court…”[115] [citations omitted].
[115] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [31].
113. The mere inclusion of information in the ARTG, as acknowledged by the opponent at hearing, does not mean that it is common general knowledge, even if the source of information is one which is available and accessed by those working in the art. In short, I consider that the evidence shows that Circadin® was public knowledge at the relevant time, but it does not establish that D45, D62 or D63, or the properties of Circardin®, had risen to the level of being common general knowledge in the art.
114. None of D45, D62 or D63 were relied upon under subsection 7(3), noting that D45 and D62 also appear to fall within the time set out in section 24(1)(a). I will have no further regard to them in this determination.
The problem to be solved
115. The opponent submitted that the problem to be solved is the development of a new formulation of an existing solid oral dose controlled-release form of melatonin for patients with difficulty swallowing. This articulation of the problem requires that the product Circadin® and its properties, or indeed some other known form of controlled-release formulation, forms part of the common general knowledge. But as noted above, this has not been established by the evidence provided. Inclusion of Circadin® in the problem also risks aspects of the solution provided by the present invention being incorporated in the problem and leading to an ex post facto analysis of the inventiveness of the claimed invention.
116. The applicant submitted that the problem to be solved has several prongs: to provide a useful alternative to existing dosage forms of melatonin tablet in populations with difficulty swallowing, to provide for flexible dosing, to address poor patient compliance, and to overcome problems in the development of a suitable formulation.[116] I consider dose flexibility to be one of several therapeutic benefits provided by mini-tablets, and the other “problems” to be additional properties provided by the solution rather an aspect of the problem.
[116] AS at [98] and [143].
117. The specification states that:
“There exists a need in the art for improved drug delivery systems for use in patient populations having an inability to swallow tablets and capsules, e.g., pediatric and geriatric populations. Specifically, there exists a need in the art for novel mini-tablet formulations. Even more specifically, there exists a need in the art for novel melatonin mini-tablet formulations having precise pharmacologic and pharmacokinetic properties.”[117]
[117] Specification at page 1, line 26 to page 2, line 8.
118. In view of the stated need for improved drug delivery systems, I therefore consider the problem (more broadly) lies in the development of a prolonged-release formulation of melatonin for patients with difficulty swallowing.
Obviousness in view of the common general knowledge alone.
119. The opponent submitted that prior to being given the application, or any details about it, Dr Oppenheim provided evidence of the formulation process,[118] including:
[118] OS at [41].
The API and its dose would be considered, and in the case of a new formulation of an existing oral dosage form the API and dosage would be known from a search of the ARTG.
The target in vitro dissolution profile of the API over time would be determined. In the case of a new formulation of an existing formulation this could be obtained from the existing formulation.
A series of trials would be made varying certain parameters in the formulation which would be iterated over time to achieve the desired dissolution profile. The standard formulation process involves the creation of a series of candidate formulations with various parameters which are then tested. Dr Oppenheim stated that he preferred synthetic polymers, and in particular mixes of grades of Eudragit polymers. These had the drawback of being relatively slow to degrade in the GI tract, so if any immediate release was required, he would mix the Eudragit with a water-soluble excipient like lactose.
Once a suitable trial formulation was established it would have to be manufactured. The process requires routine optimisation based on the particular needs of the formulation, but Dr Oppenheim stated that his preferred approach would be to use dry granulation over wet granulation because wet granulation requires more steps for optimisation and validation.
120. Dr Oppenheim stated that mini-tablets are tablets, so the same approach would be followed. If creating a mini-tablet version of an existing formulation, the existing formulation would be used as the starting point for the new formulation. Changes would be required such as the reduction of particle size so that the flow and compression characteristics could be optimised for the smaller cross-sectional area of the smaller tablet. Because of the tablet’s smaller volume, the existing formulation would need to be adjusted to give a slower rate of release of the API. These were purported to be routine variations to the formulation such as the increase of the hydrophobic excipient or variation of excipients.[119]
[119] OS at [42].
121. Once Dr Oppenheim was made aware of the problem proposed by the opponent (including Circadin® in the problem), he explained that he would identify information about the existing formulation of Circadin® and follow the approach given above. He stated that he was confident that he would be able to formulate a mini-tablet with the dissolution profile of Claim 1. The opponent noted that the process of Examples 1 and 2 closely mirrored the approach Dr Oppenheim said he would have taken before he had been given details of the invention.
122. The applicant submitted that the questions put to Dr Oppenheim led him to the particular solution of mini-tablets,[120] and therefore his evidence should be given lesser weight. At hearing the opponent accepted these criticisms but submitted that Dr Oppenheim reconsidered the position following Prof Davies’ evidence, with the choice of alternatives, given the problem, being reduced to microparticulates or mini-tablets.
[120] AS at [125].
123. I agree with the applicant on this point. Dr Oppenheim’s evidence is predicated on Circadin® and its properties being common general knowledge, and his evidence is specifically focussed on the particular characteristics of melatonin and Circadin® 2 mg.[121] As a consequence, this imports knowledge into the problem which is not part of the common general knowledge, but rather is based on the inventor’s starting point as gleaned from the specification.[122] I therefore consider that I can give Dr Oppenheim’s evidence lesser weight on this point.
[121] Oppenheim 1 at [98].
[122] AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99 at [203].
124. But in any case, I am not satisfied that the evidence establishes that the invention as claimed is obvious in view of the common general knowledge alone. Claims 1, 5 and 19 are drafted in terms of desired dissolution characteristics and the consideration is therefore linked to particular in-vitro controlled-release characteristics of the formulation (IVIVC). This in vitro dissolution pattern is purported to provide in vivo blood levels of melatonin that are consistent with the endogenous melatonin levels. These dissolution profiles are not part of the common general knowledge, and there is otherwise nothing in the common general knowledge that would directly lead the skilled person to seek or otherwise arrive at a formulation having these specific characteristics, including a mini-tablet.
125. The opponent’s reduction of the inventive step consideration to one of only two choices, micro-particulates or mini-tablets, in my opinion over-simplifies the determination. The common general knowledge above certainly includes these options, and the preference for a solid oral dosage form would appear to lend itself to the use of one of these types of formulations when dealing with patients having difficulty in swallowing. However, beyond what was suggested to be a simple choice of two, there are a multitude of different ways by which a controlled-release formulation may be obtained.
126. To this end, Prof Davies stated that in his experience mini-tablets were difficult to work with, and he would be most likely to attempt to formulate a new drug delivery system using micro-particulates first.[123] He then outlined various ways of approaching the manufacture of micro-particulates having controlled-release properties, including extrusion, spheronisation, spraying onto beads and mixing granules with different dissolution properties.[124] In the case of mini-tablets, a coating may be used but uniformity of the core would be difficult to control depending on the amount of excipient used. The surface area to volume ratio can be problematic and it may not be possible to achieve the same results for a mini-tablet as for a standard sized tablet with the same excipients.[125] The approach to providing a solution to the problem of providing a controlled-release formulation of melatonin for patients with difficulty swallowing clearly does not come down to a simple, or obvious, choice of two solutions, even if a standard tablet formulation is known.
[123] Davies at [114] to [115].
[124] Davies at [116] to [117].
[125] Davies at [111] to [113].
127. I acknowledge that there does not need to be only one solution to the problem, or that the skilled person must be led only to one solution in order to prove obviousness. However, absent the knowledge of Circadin® and its properties as a starting point, and based on the evidence before me, I consider there is no obvious course that could reasonably be expected to provide the specific dissolution properties of the formulations defined in Claims 1 to 20 without inventive effort.
128. The opponent did not press obviousness in relation to Claim 21 in view of the common general knowledge alone, but pressed obviousness in view of D6 combined with the common general knowledge. I have dealt with this claim in more detail below.
129. In summary I consider that the invention defined by the claims as a whole is not obvious in view of the common general knowledge alone.
Common general knowledge in view of the common general knowledge together with D6
130. D6 discloses the preparation and use of melatonin for the treatment or prevention of a dependence, tolerance or addiction to a benzodiazepine. In addition to such treatments, D6 states that:
“The invention further relates to a pharmaceutical controlled release formulation comprising melatonin in combination with at least one carrier, diluent or coating. Wherein, upon administration to a human, the formulation releases melatonin over such time that the person’s melatonin plasma substantially simulates the melatonin plasma profile of a human having a normal endogenous melatonin profile.”
131. Figure 1 of D6 is said to illustrate the nocturnal plasma profile of melatonin concentration in a healthy adult human – this shows the manner in which melatonin blood plasma levels rise to around 60 pg/ml where they are maintained for around 4 hours, before dropping again.
132. The citation discloses two sets of controlled-release tablets containing 2 mg melatonin. The first, designated SR-A, comprises 1.2% melatonin, 48.8% Eudragit RS100, and 50% lactose. The second, SR-B comprises 1.3% melatonin, 35.3 Eudragit RSPO, 16.7% lactose, 41.4% calcium hydrogen phosphate, 1.3% talc and 4% magnesium stearate. Eudragit RS100 and RSPO are both type B AMC.[126] The release rates of SR-A and SR-B are compared to an immediate release formulation in Table A. A third formulation is used in the trial described in Example 3. This tablet comprises 1 mg of melatonin per tablet and is said to be prepared similar to SR-A. A general description of various other dosage forms is provided,[127] but the only reference to controlled-release formulations (besides the three examples) is in relation to a preferred embodiment comprising coated particles.
[126] Davies at [151].
[127] D6, column 4, lines 29 to 52.
133. Release is measured in distilled water at 37° C. As indicated in the table, both SR-A and SR-B release less than 50% melatonin within 1 hour and greater than 70% within 6 hours. These are within the range defined by present Claim 1, even though the specific dissolution figures defined in Claim 1 are not used in D6.
134. The results of an in vivo study of SR-A (measured by urine levels of 6-sulfoxymelatonin, which apparently reflect melatonin blood levels) are shown in Table B:
135. The in vitro release shown in Table B is said to only approximate the in vivo release, apparently because of a known phenomenon of the active ingredient being absorbed by tissues in the early stages of release.
136. The opponent submitted that the invention is obvious in view of D6, save for Claim 9.[128] The key consideration is whether, faced with the problem of providing a prolonged release formulation of melatonin for patients with difficulty swallowing, the skilled person would have taken as a matter of routine the steps from the prior art to the claimed invention.
[128] Oppenheim 1 at [214].
137. Dr Oppenheim provided little specific information on the steps he would have taken in view of the disclosure provided by D6, but stated that it “would have buttressed my conclusions that I would have done what is claimed in those claims based on the common general knowledge alone”.[129] In this respect he stated that it is usual to have two key components in the matrix that will be involved in the erosion process. The first will dissolve in the stomach and intestinal fluids, while the second holds the matrix together as erosion occurs, before slowly splitting off. That is, the first component has greater water solubility, and the second lower water solubility.[130] Various different pairs of components can be used, and Dr Oppenheim stated the choice of pairs will depend on the personal experience of the formulator modified by any expected chemical interaction between the API and any possible excipient. He stated that he had a good understanding of and familiarity in using the Eudragit range of materials, and this would be an “excellent” starting range of materials to control the rate of release of an API from a solid dose formulation.[131]
[129] Oppenheim 1 at [214].
[130] Oppenheim 1 at [62].
[131] Oppenheim 1 at [63].
138. A mixture of RL (high permeability) and RS grades (low permeability) of Eudragit, which I understand to be types A and B respectively, were commonly Dr Oppenheim’s first choice for the required blend of high and low permeable polymers.[132] Apparently, while this approach works well with longer release periods (dosage at 24, 12 or 8 hourly intervals), it is generally not fast enough for immediate release or release over shorter periods such as 3-5 hours. A water-soluble excipient such as lactose would be added to the Eudragit copolymer with high permeability to form pores in the matrix. This would have to have a very small particle size to avoid formation of large channels. A water insoluble excipient would also be added to assist diffusion of the lactose throughout the matrix of the Eudragit RL matrix.[133]
[132] Oppenheim at [64].
[133] Oppenheim 1 at [65].
139. Dr Oppenheim stated that since a mini-tablet is still a tablet, the techniques and methodologies involved in its manufacture would be the same in principle as those used for a standard tablet.[134] He stated that since mini-tablets have a much smaller volume than the original tablet, the concentration of the API is much higher. This means that the relative proportion of the two eroding components in the matrix needs to change so that the rate of erosion is decreased.[135] He stated that:
“Hence to achieve the same rate of release of the API from the mini-tablet as occurred from the original Oral Dosage Form, the rate of penetration of the liquids within the gastrointestinal tract into the bulk of the mini-tablet will have to be slower than that occurring in the original Oral Dosage Form. A different proportion of the more hydrophilic excipient is likely to be needed. Dependent on the outcomes of these changes, other excipients may be needed to be added to the original excipients. If this proved unsuccessful, a different set of excipients would be needed. All this formulation development work is common in such programs and the way they are conducted is quite routine.”[136]
[134] Oppenheim 1 at [85].
[135] Oppenheim 1 at [89].
[136] Oppenheim 1 at [92].
140. D6 discloses the use of the excipients used in the present examples: a type B AMC, CHPD, lactose and melatonin. In response to a question concerning the use of CHPD, AMC and lactose monohydrate as suitable excipients in the manufacture of a solid dosage form of any prolonged release API, Dr Oppenheim stated that he was well aware of their use in any API.[137] Prof Davies disagreed to the extent that Dr Oppenheim was suggesting that these excipients could be used for any API, and certainly not for melatonin (which Dr Oppenheim had acknowledged he had no experience in formulating). He also did not understand Dr Oppenheim to be saying that these excipients could be used in all prolonged release formulations to achieve the desired in vivo release profile.[138] He stated more generally that:
“Dr Oppenheim characterises the steps involved in the formulation of “any new tablet form” as simply “standard and routine”. I fundamentally disagree with this characterisation of the formulation process. If that were the case, one would be able to formulate absolutely any type of tablet, using any type drug, to meet any therapeutic target, with a complete expectation of success. That is not the case. Dr Oppenheim does not seem to contemplate that the process of pharmaceutical development could lead to inventive output in any case, given that he considers the steps to be standard and routine for any new tablet form…”[139]
[137] Oppenheim 1 at [123].
[138] Davies at [326].
[139] Davies at [313].
141. I agree with the applicant on this point. While Dr Oppenheim suggests that the development of mini-tablet formulations would be expected to follow standard procedures and activities, I do not take this to mean that there is no invention in such activities. Indeed, Dr Oppenheim refers to the work being common in these areas, and the way they are conducted as being routine. I do not consider this necessarily means that inventive activity does not involve some degree of routine work. The extent to which it does will be based on the facts of the case, noting that the consideration of inventiveness is a reasonable expectation of success, not a guarantee of success.
142. On balance I do not consider that the evidence establishes that the skilled person would be led with a reasonable expectation of success in view of D6 to prepare the melatonin mini-tablets defined by the present claims. As noted above, there is little evidence specific to the steps that would have been taken in view of D6. My understanding is that the closest formulation to those described in the present application is SR-B, which comprises lactose, AMC and CPHD. Give my determination in relation to support and sufficiency I will concentrate on this formulation in my consideration of inventive step.
143. D6 provides in vitro dissolution properties for SR-B but does not provide in vivo results. While the formulations provided in D6 provide release of melatonin at a rate that meets the definition of 50% within 1 hour and 70% within 6 hours, there is no indication in D6 that these figures have any significance (and particularly in relation to the IVIVC). As shown in Table A above, SR-B has a faster in vitro release rate than SR-A, which is used in in vivo testing to “correct for the deficiency and distortion of the melatonin rhythm”.[140]
[140] D6, Example 3.
144. Based on the disclosure provided in the present specification,[141] mini-tablets would probably be expected to have an increased rate of dissolution than a corresponding “normal” tablet due to the greater surface area to volume ratio. To that end the evidence suggests that the rate of erosion in a mini-tablet could be controlled by changing the proportion of the high permeability and low permeability excipients. However, while the evidence suggests that this presumably require a decrease in the high permeability excipient (lactose) and/or an increase in the proportion of the low permeability excipient (AMC), the first example of the present application appears to contain a higher proportion of lactose and a lower proportion of AMC compared to SR-B in D6.
[141] Specification at page 14, lines 4 to 6.
145. Furthermore, my understanding of Dr Oppenheim’s evidence is that formulations comprising type A AMC together with lactose are suited for intermediate or immediate release formulations, but the present examples (Ex.6 and Ex.7) include formulations comprising type A AMC which are said to provide acceptable prolonged release rates in comparison to similar compositions containing type B AMC (Ex.1 and Ex.2 differ in the type of AMC). Use of a finer particle size of lactose did not influence the dissolution of melatonin (Ex.5 compared to Ex.6). These observations appear inconsistent with the general approach described by Dr Oppenheim, and indeed suggest a lack of predictability when it comes to the formulation of the present mini-tablets based on the disclosure in D6. This appears consistent with the statements in the specification that it was not possible to make a priori assumptions or predictions about the resultant flowability, dissolution and release characteristics of mini-tablet formulations based on another formulation. It also appears consistent with Prof Davies’ evidence that it is difficult to know how changes to the surface area to volume ratio will affect the release profile of the drug and if the same excipients will be effective in the smaller size.[142] On that basis, and in view of the evidence before me, I am satisfied that the claims are not obvious.
Conclusion on inventive step
[142] Davies at [113].
146. The claims are inventive in view of the common general knowledge alone, and in view of D6 when read in light of the common general knowledge.
Conclusion
147. The opposition is successful.
148. Claims 1 to 21 lack support. The specification does not provide a clear enough or complete enough disclosure across the full scope of the invention as presently claimed in Claims 1 to 21.
149. Despite my determination I consider that the specification includes patentable subject matter. I therefore allow the applicant two (2) months from the date of this decision to propose amendments to overcome the issues identified.
Costs
150. Costs generally follow the event. I see no reason to depart from that approach. I award costs according to Schedule 8 against the applicant, Neurim Pharmaceuticals Limited.
Dr Leslie F. McCaffery
Delegate of the Commissioner of Patents
ANNEX A (Figure 1 of the specification)
ANNEX B (The claims)
1. A controlled-release melatonin mini-tablet comprising:
a therapeutically effective amount of melatonin; and
one or more pharmaceutically acceptable carriers;wherein the mini-tablet has a diameter of less than or equal to 4 mm and has a release profile of less than 50% melatonin release within 1 hour, and about greater than 70% melatonin release within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C.
2. The controlled-release melatonin mini-tablet of claim 1, wherein the mini-tablet is formulated such that it produces a minimal blood level of about 60 to about 200 picograms melatonin per milliliter over at least four hours after oral ingestion of the controlled release melatonin mini-tablet by a human patient.
3. The controlled-release melatonin mini-tablet of claim 1, wherein the mini-tablet is formulated such that it produces a minimal blood level of about 100 to about 200 picograms melatonin per milliliter over at least four hours after oral ingestion of the controlled-release melatonin mini-tablet by a human patient.
4. The controlled-release melatonin mini-tablet of any one of claims 1-3, wherein the mini-tablet is coated with a pharmaceutically acceptable coating.
5. A method of manufacturing a controlled-release melatonin mini-tablet, the method
comprising:
combining a therapeutically effective amount of melatonin and one or more pharmaceutically acceptable carriers to produce a mixture; and
compressing the mixture into mini-tablets that each have a diameter of less than or equal to 4 mm such that the mini-tablet has a controlled-release profile of less than 50% melatonin released within 1 hour of dissolution, and about greater than 70% melatonin released within 6 hours of dissolution measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C.
6. The method of claim 5, further comprising a step of coating the tablets with a pharmaceutically acceptable coating.
7. The method of claim 5 or 6, wherein the combining step comprises dry blending the therapeutically effective amount of melatonin and the one or more pharmaceutically acceptable carriers.
8. A controlled-release melatonin mini-tablet of any one of claims 1-4 produced by the method of any one of claims 5-7.
9. The controlled-release melatonin mini-tablet of any one of claims 1-4 or 8 and the method of any one of claims 5-7, wherein the one or more pharmaceutically acceptable carriers comprise a fast dissolving sugar or alcohol that is not lactose.
10. Use of the controlled-release melatonin mini-tablet of any one of claims 1-4, 8 or 9:
a) in a method of inducing sleep in a patient in need thereof, the method comprising orally administering the mini-tablet to the patient, wherein sleep is induced in the patient,
b) in a method of orally administering melatonin to a patient who has difficulty swallowing tablets or capsules, the method comprising orally administering the controlled release mini-tablet to the patient, or
c) in a method of inducing a phase shift of the circadian rhythm of a patient in need thereof, the method comprising orally administering the controlled-release mini-tablet to the patient, wherein a phase shift in the patient’s circadian rhythm is induced.
11. The use of claim 10, wherein the patient is a pediatric patient.
12. The use of claim 10, wherein the patient is a geriatric patient.
13. The use of any one of claims 10-12, wherein the mini-tablet is administered before sleep.
14. The use of any one of claims 10-12, wherein the mini-tablet is administered between a first sleep period and a second sleep period.
15. The controlled-release melatonin mini-tablet of any one of claims 1-4, 8, the method of any one of claims 5-7 or the use of any one of claims 10-14, wherein the therapeutically effective amount of melatonin is 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg.
16. The controlled-release melatonin mini-tablet of any one of claims 1-4, 8, 9, 14 or 15 the method of any one of claims 5-7, 14 or 15 or the use of any one of claims 10-15, wherein the mini-tablet or the pharmaceutically acceptable carriers comprise one or more of calcium hydrogen phosphate dihydrate, ammonio methacrylate copolymer, and lactose monohydrate.
17. The controlled-release melatonin mini-tablet, method or use of claim 15, wherein the ammonio methacrylate copolymer is ammonio methacrylate copolymer type A or ammonio methacrylate copolymer type B.
18. The controlled-release melatonin mini-tablet, method or use of claim 15 or 16, wherein the ratio between melatonin, ammonio methacrylate copolymer, calcium hydrogen phosphate dihydrate and lactose monohydrate by weight is 1 : 1.1-5.9 : 0.8-8.3 : 1.8-8.8.
19. A method of safely inducing and maintaining sleep in a patient in need thereof, the
method comprising:
providing a pharmaceutical product comprising one or more melatonin mini-tablets capable of inducing sleep in a patient and achieving a minimal blood level of about 60 to about 200 picograms melatonin per milliliter over at least four hours following the administration without inducing unacceptable side effects in a human, wherein said pharmaceutical product is manufactured by combining a therapeutically effective amount of melatonin and one or more pharmaceutically acceptable carriers to produce a mixture,
compressing the mixture into one or more mini-tablets that each have a diameter of less than or equal to 4 mm such that the mini-tablet has a release profile of less than 50% melatonin release within 1 hour, and about greater than 70% melatonin release within 6 hours measured by in vitro dissolution of melatonin therefrom in distilled water at 37° C,
and optionally filling a plurality of the mini-tablets into a capsule;
and orally administering the one or more mini-tablets to the patient.
20. Use of a controlled-release melatonin mini-tablet according to any one of claims 1-4, 8 or 9 in the manufacture of a medicament for safely inducing and maintaining sleep in a patient in need thereof.
21. A pharmaceutical mini-tablet formulation comprising melatonin in combination with at least one pharmaceutical carrier, diluent or coating, wherein, upon administration to a patient, the mini-tablet formulation releases melatonin over time such that the patient's melatonin plasma profile substantially simulates the melatonin plasma profile of a human having a normal endogenous melatonin profile.
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