Arrow Pharmaceuticals Pty Ltd v Novartis AG - [2019] APO 22

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Arrow Pharmaceuticals Pty Ltd v Novartis AG [2019] APO 22

Patent Application: 2013204752

Title:Pharmaceutical compositions containing an S1P modulator

Patent Applicant: Novartis AG

Opponent: Arrow Pharmaceuticals Pty Ltd

Delegate: Dr Leslie F. McCaffery – Deputy Commissioner of Patents

Decision Date: 10 May 2019

Hearing Date: 21 November 2018, in Canberra

Catchwords: PATENTS – request for consideration of a document pursuant to regulation 5.23 – the balance of considerations lies with refusal of the request – section 59 – opposition to the grant of a patent – grounds of clarity, fair basis, manner of manufacture, inventive step – section 40 – the claims are clear – the claims are fairly based –– the claims define a manner of manufacture – utility – the promise of the invention has been met – inventive step – claims lack inventive step –– costs awarded – applicant provided 2 months from the date of the decision to propose amendments.

Representation: Counsel for the applicant: Christian Dimitriadis SC
Solicitor for the applicant: Clayton Utz
Patent attorney for the applicant: Davies Collison Cave
Counsel for the opponent: Claire Cunliffe
Patent attorney for the opponent: Jones Tulloch

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application: 2013204752

Title:Pharmaceutical compositions containing an S1P modulator

Patent Applicant: Novartis AG

Date of Decision: 10 May 2019

DECISION

The opposition by Arrow Pharmaceuticals Pty Ltd is successful on the ground of inventive step.

Claims 1 to 15 lack inventive step.

The opposition is unsuccessful on the grounds of utility, manner of manufacture, fair basis and clarity.

Costs are awarded against Novartis AG.

Novartis AG given 2 months from the date of this decision to propose amendments.

REASONS FOR DECISION

Patent Application 2013204752 (the Application) was filed by Novartis AG (the Applicant) on 12 April 2013. The application is a divisional of Australian application 2011235934, which lapsed without gaining acceptance. 2011235934 is itself a divisional of Australian application 2007302296, which also lapsed without gaining acceptance. The present application claims earliest priority of 26 September 2006. This was not in dispute so I do not need to go into any further detail on the priority of the present claims. There are also a number of other related applications, but nothing turns on this point so I will not consider these any further.

Examination was requested on 12 April 2013. The application was advertised accepted on 27 October 2016. A notice of opposition was filed by Arrow Pharmaceuticals Pty Ltd (the Opponent) on 27 January 2017.
The statement of grounds and particulars (SGP) was filed on 27 April 2017. This set out the following grounds of opposition: manner of manufacture, novelty, inventive step, usefulness, full description, fair basis and clarity. An amendment of the SGP was filed on 27 July 2017 and allowed on 17 August 2017. A further request for an amendment of the SGP was filed on 21 December 2017 to add bibliographic details of a document that the Opponent became aware of during the preparation of their Evidence in Reply (EIR). However, this amendment was not allowed since a Delegate of the Commissioner considered it was not properly in reply to the Evidence in Answer (EIA). The parties were advised that they could make submissions on this point and whether any of the material should be considered under Regulation 5.23 at the hearing. This issue is discussed in greater detail below.
The matter was heard on 21 November 2018 in Canberra. The grounds of manner of manufacture, utility, fair basis, clarity and inventive step were pressed at hearing. A request was also made pursuant to Regulation 5.23 for the consideration of additional evidence. The Opponent was represented by Ms Claire Cunliffe and the Applicant by Mr Christian Dimitriadis SC.

Standard of proof

The request for examination for the present application was filed on 12 April 2013. Substantive amendments of the Patents Act 1990 (the Act) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 therefore do not apply to the present application. This includes the amendment to subsection 60 (3A) that allows the Commissioner to refuse a patent if satisfied on the balance of probabilities that a ground of opposition exists. Any subsequent reference to sections of the Act relate to the Act prior to amendment by the Raising the Bar Act. The onus of proof in this opposition therefore lies with the opponent who must establish that it is clear that a valid patent cannot be granted.[1]
[1] F. Hoffmann-La Roche AG v New England Biolabs Inc. (2000) 50 IPR 305 at [67]; Commissioner of Patents v Sherman (2008) 79 IPR at [18].

Background

Sphingosine-1 phosphate (S1P) is a natural serum lipid. S1P receptor antagonists bind to S1P receptors in lymph nodes, leading to lymphopenia which in turn leads to a generalised immunosuppression. The specification states that there are 8 known S1P receptors, designated S1P1 to S1P8.

Fingolimod (1), which is otherwise referred to as FTY720 and marketed under the name of Gilenya, is an S1P receptor modulator. Fingolimod is an immunomodulator that was first synthesised in 1992 as a derivative of the immunosuppressive fungal metabolite myriocin. Fingolimod has found clinical use in the treatment of multiple sclerosis.

(1)

Evidence

Evidence in support (EIS) was completed on 27 July 2017 and consists of:

A declaration by James-Robert William Cram dated 27 July 2017 and exhibits JWC-1 to JWC-2.
A declaration by Desmond B. Williams dated 26 July 2017 and exhibits DBW-1 to DBW-13 (Williams 1).

Evidence in answer (EIA) was completed on 27 October 2017 and consists of a declaration by Peter James Stewart and exhibits PJS-1 to PJS-8 (Stewart).

10. Evidence in reply (EIR) was completed on 2 January 2018 and consists of:

A declaration by Ellen Frances Reid dated 20 December 2017 and exhibits EFR-1 to EFR-2 (Reid 1).
A declaration by Ellen Frances Reid dated 22 December 2017 and exhibit EFR-3 (Reid 2).
A declaration by Desmond B. Williams dated 19 December 2017 and exhibit DBW-14 (Williams 2).

11. As noted above, the Opponent requested an amendment to the SGP to include an additional document referred to in the EIR. This was not considered properly in reply to the EIA, but the Delegate advised the Opponent that they could make a request under the Patent Regulations 1991 (the Regulations) if they wished to pursue this matter. Before moving to the substantive matters in the opposition, I will deal with the request that was subsequently made for this material and an additional declaration that was filed before the hearing. The material in question relates to:

Paragraphs 52 to 58 of Williams 2.
Reid 1 and Reid 2.
A declaration by Dr John Mottershead dated 20 November 2018 and annexes thereto (Mottershead).

12. The material provided in Williams 2, Reid 1 and Reid 2 was considered by the Delegate who determined that Reid 1 was relevant to the evidence in answer since it could verify whether the key document DBW-8 (Chavez)[2] would be ascertained. However, paragraphs 52 to 58 of Dr Williams’ declaration were not considered to be specifically, or even generally, responsive to the evidence in answer. For similar reasons Reid 2 was not considered evidence in reply.

[2] Daniel Chavez, “FTY720 for relapsing Multiple Sclerosis – Phase II Data Shows Sustained Efficiency and Good Tolerability”, Medical News Today, 10 April 2006.

13. On the evening before the hearing, the Opponent filed the Mottershead declaration and requested that it be considered under regulation 5.23. My understanding is that the Opponent is not pressing the issue of whether paragraphs 52 to 58 of Williams 2 and Reid 2 are properly in reply, but instead is requesting that they be considered pursuant to regulation 5.23. I will limit my determination accordingly.

14. The relevant practice in relation to regulation 5.23 is given by Reflex v Minnovare,[3] which set out the following considerations in determining whether the provisions of regulation 5.23 should be enlivened:

[3] Reflex Instruments Asia Pty Ltd v Minnovare Ltd [2017] APO 8.

The circumstances leading up to the evidence not being filed earlier
What does the evidence show
Is the information likely to be crucial to the delegate’s decision
The public interest in having the information considered
The balance of convenience of the parties if the information is considered.

15. I will consider each of these in turn.

The circumstances leading up to the evidence not being filed earlier

16. The Opponent submitted that paragraphs 52 to 58 of Williams and the Reid declarations were intended to address statements by Professor Stewart in his evidence in answer.[4] This material was provided in evidence in reply, so I am satisfied that the Opponent sought to address the issue at a relatively early stage. However, Mottershead was also purported to address Professor Stewart’s statements, but was filed more than 12 months after evidence in answer was completed. On balance I do not consider that an adequate reason has been provided for the delay in filing this evidence.

What does the evidence show

[4] Opponent’s submissions to the Delegate dated 25 January 2018.

17. Dr Williams’ declaration provides a discussion of an article entered in evidence as DBW-14 (Thomson).[5] Dr Williams was asked to read and discuss what Thomson would have disclosed to him as at 25 September 2006. Reid 1 describes a prior art search for relevant prior art which is purportedly performed in the same manner as it would have been done in September 2006. Thomson was retrieved in this search. Reid 2 provides a confirmation of the publication date of Thomson.

[5] Andrew Thomson, “Emerging Therapy Review: FTY720 in multiple sclerosis: the emerging evidence”, Core Evidence, 2006: 1(3).

18. Dr Mottershead’s evidence relates to the skills and knowledge of clinical neurologists working in the field of diagnosis and treatment of multiple sclerosis (MS) patients as at 2006. Dr Mottershead is a Consultant Neurologist in the Department of Neurology, Dunedin Public Hospital, Dunedin, New Zealand. He is involved with MS treatment trials as a Principal Investigator.

19. Dr Mottershead stated that he was aware of several MS treatments in development by September 2006, and that prior to 2006 he was aware that FTY720 was being investigated in clinical trials:[6]

[6] Mottershead at [20].

“I remember that by September 2006, three potential new oral drugs to treat MS were in the development stage, and I was very interested in these drugs because they could be orally administered:
i. FTY720 (Fingolimod) later known as Gilenya. I was aware that Gilenya was going through clinical trials in MS. I remember that I first heard about FTY720 at a drug pipeline presentation at ECTRIMS prior to 2006. I followed the progress of FTY720 by looking out for presentations and publications. I was aware that Novartis was developing FTY720, and I followed the progress of clinical trials (including through press releases).
…

Given my particular interest in these three treatments for MS, I reviewed the literature for any reference to these treatments.

In following the progress of these drugs I referred to the resources mentioned above. The New England Journal of Medicine was of particular interest to me because it often published the results of clinical trials (including Phase III trials) of drugs in development that would be beneficial to keep up to date with. I also paid particular attention to any positive phase III data that was presented at the conferences I attended. I also did general internet searches and check for press releases (such as in Business Wire) from time to time to check the progress of development of these drugs.”

20. The Opponent sought to rely on this evidence to establish that Fingolimod and its use in the treatment of MS at the dosage levels used in the present invention were common general knowledge at the relevant time. However, they also submitted that if this could be inferred from the Williams declarations then there was no need for further consideration of the material which was the subject of the request under regulation 5.23.

Is the information likely to be crucial to the delegate’s decision

21. The Opponent submitted at hearing that Thomson establishes that Fingolimod was common general knowledge at the relevant time. Thomson was also relied upon to establish that the information contained in Chavez would have been ascertained by the skilled person at the relevant date. This was in reply to Professor Stewart’s statement that he would not have ascertained the Chavez citation.

22. As an initial point, I note that the Opponent’s submissions on this point are not in relation to whether the skilled person would have ascertained Chavez at the relevant time, but rather whether the information disclosed in Chavez was publicly available at that time. I also note that Chavez was the primary document argued at hearing, and that Thomson itself was not relied upon. The evidence provided in relation to Thomson does not adequately establish that Chavez would have been ascertained by the skilled person.

23. At best, Thomson may be indicative that the information provided by Chavez had become public knowledge. Although information may be public knowledge, it does not necessarily follow that it would be common general knowledge. There needs to be evidence of its assimilation and general acceptance in the art. I do not consider that the evidence provided has adequately established that either of Thomson or Chavez and the information provided therein could be considered to have met this requirement.

24. I therefore am not satisfied that Thomson is crucial to a determination of the matter. It follows that Reid 2 is also not crucial to the determination.

25. Reid 1 is relevant to the opposition in that it provides evidence as to whether documents would have been ascertained by the skilled person at the relevant date. However, during the hearing, the Opponent noted certain limitations on the search strategy used to retrieve the prior art document, and in particular the limitation on publication dates and document type (non-patent literature). The search provided in Reid 1 was used to support the assertion that the information in Chavez was common general knowledge (based on Thomson), and therefore was provided for a specific and limited purpose. Given my conclusion in relation to Thomson and Reid 2, I am also not satisfied that this material is crucial to the decision.

26. The gist of the Opponent’s submissions on Mottershead is that this evidence is important to establish that Fingolimod was common general knowledge for clinical neurologists at the relevant date. However, I am not satisfied that the evidence provided by Dr Mottershead achieves this outcome. While Dr Mottershead states that he was aware of FTY720 prior to 2006, there is nothing in the evidence that establishes that this public knowledge had developed to the point where it could be considered widely known and accepted. On balance I am not satisfied that this evidence is of a nature that is crucial to the outcome of the opposition.

The public interest in having the information considered

27. Regulation 5.23 is intended to provide the Commissioner with the discretion to rely on documents that are not formally in evidence. This helps ensure that matters before the Commissioner proceed in an efficient and orderly manner, while balancing the public interest that invalid patents are not granted.

28. In the present case, I have determined above that the evidence is unlikely to be determinative of a ground of opposition. As a consequence, I consider that there will be little impact on the public interest in not considering this information. On the other hand, the late introduction of Mottershead and the evidence that will be adduced in response by the Applicant is likely to result in a considerable delay and potentially result in new matters being raised. The public interest lies against me having regard to the material under regulation 5.23.

The balance of convenience of the parties if the information is considered.

29. Given my determinations above this is a moot point. However, if the evidence was to be considered under regulation 5.23 then the Applicant would be given the opportunity to respond.

Conclusion on the request under Regulation 5.23

30. The balance of considerations lies against the evidence being considered under regulation 5.23. I therefore refuse the Opponent’s request.

Construction

31. The principles of construction are well established. As Middleton J stated:

“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.”[7]
[7] Eli Lilly and Co Ltd v Apotex Pty Ltd [2013] FCA 214; 100 IPR 451 at 482 [139].

32. Middleton J went on to provide a useful summary of relevant principles:[8]

[8] Ibid at [143].

a patent is a public instrument which must, if it is to be statutorily valid, define a monopoly which is not reasonably capable of being misunderstood;
the Court, when reading the entire patent specification, must place itself in the position of a person who is skilled in the relevant art, given their general knowledge, and the common general knowledge and the state of the art that existed before the priority date of the patent;
the words used in a specification, including the claims, are to be construed from this standpoint in a “common sense” and not abstract manner;
what is disclosed in the body of the specification will also assist the skilled person in the art to understand the claims, bearing in mind that a patent is a unilateral document and the patentee has chosen particular words to describe the invention;
the claims define the monopoly claimed by the patent;
terms which are unclear in the claims may be defined or clarified by reference to the body of the specification;
language which has no positive meaning in the claims may become clear when the specification is used as a “dictionary” for the jargon in the claims; and
that said, given the special function of the claims, it is impermissible to read into a claim an additional integer, or otherwise vary the scope of the claim by reference to the body of the specification.

33. Middleton J also cautioned that:

“It is clear from the above propositions (particularly the latter three points) that the use the Court can make of the body of a specification will vary from case to case. As Apotex submitted, there is a fine line between using the specification to construe the claim, and using the specification in such a way that adds an impermissible gloss to the claims.”[9]
[9] Ibid at [144].

Person skilled in the art

34. The specification is construed through the eyes of the person skilled in the relevant art. This is the hypothetical person to whom the specification is addressed.[10] This determination plays a central role in determining the validity of the patent:

“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...”[11]
[10] General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1971) 1A IPR 121 at 134.
[11] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70]-[71].

35. The person skilled in the art is assumed to be a skilled but unimaginative and non-inventive worker in the field of the invention.[12] One formulation describes them as “those likely to have a practical interest in the subject matter of [the] invention.”[13] Notably:

“The identification of the relevant field will, in its turn, determine the characteristics of the notional worker skilled in the art who must provide the answer to the question of whether the invention was obvious. Such characteristics will include the qualifications of the notional worker, the setting in which he or she operates and the practices and techniques that he or she will regard as commonplace and known.”[14]
[12] Minnesota Mining and Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253 at 293.
[13] Catnic Components v Hill & Smith Ltd [1982] RPC 183.
[14] Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59 at [153]; (2002) 212 CLR 411 at 465.

36. The parties were largely in agreement as to the person skilled in the art in this case.[15] For example, the Applicant submitted that the specification was addressed to a pharmaceutical scientist who is skilled in formulating solid oral dosage forms. However, they noted that this is not the only relevant skilled person, and that pharmaceutical scientists conduct their work as a member of a skilled team that includes:

a)Physical and analytical chemists who are responsible for collecting pre-formulation data;
b)Pharmacists/pharmacologists who are responsible for bioavailability and dose selection; and
c)Clinicians with a knowledge of the relevant therapeutic area and who are responsible for the design of clinical trials.

[15] Williams 1 at [14]-[15], Stewart at [36].

37. I consider this a reasonable representation of the person skilled in the art for the present invention.

38. There were no significant differences between the parties on matters of construction. Expert evidence was provided by the following declarants:

Dr Williams is currently a Senior Lecturer of Pharmaceutical Science in the School of Pharmacy and Medical Sciences, University of South Australia. In addition to other faculty roles he has held in the University of South Australia, he has previously been the Group Manager, Research and Development at Sigma Pharmaceuticals, worked as a consultant in pharmaceutical and related sciences, and held various positions at F H Faulding & Co.

Professor Stewart is an Emeritus Professor in the Faculty of Pharmacy and Pharmaceutical Sciences at Monash University. Prior to his retirement and appointment as an Emeritus Professor in 2014 he held faculty positions including the Deputy Dean of the Faculty of Pharmacy and Pharmaceutical Sciences and Head of the Department of Pharmaceutics. He has also held various faculty positions at the University of Queensland, including Head of the Department of Pharmacy, and has worked as a consultant to companies such as Sigma Pharmaceuticals, Aventis and GlaxoSmithKline.

39. There was no dispute that Dr Williams and Professor Stewart are qualified to provide evidence on the present matter. However, there was some dispute as to the weight that their evidence should be given. The Opponent noted that Professor Stewart’s evidence relied heavily on input from other members of the team, which they considered reflected Professor Stewart’s academic background,[16] as opposed to the pragmatic approach taken by formulation scientists working in industry. The Applicant countered this submission noting that Professor Stewart had worked as a consultant for several pharmaceutical companies, teaching students in design and manufacture of solid oral dosage forms and his appointment as Chair of the Continuing Education Program of the Australian Pharmaceutical Manufacturers Association.[17]

[16] Opponent’s submissions for hearing at [22] and references therein.

[17] Applicant’s submissions for hearing at [96].

40. The key consideration in my opinion is that the hypothetical skilled person may be an individual or a team consisting of different members with different skills. Where the skilled person is a team, it is the knowledge and the skill set of the team as a whole, rather than the skills of any particular person within the team, that is relevant. Dr Williams appears to have experience and knowledge that extends to areas that would ordinarily sit with a separate expert within the team. This was also reflected in his description of his experience in industry and his core qualifications, which he considered were the same or similar to others in the field.[18] He stated that:

“It was usual prior to 26 September 2006 for a team of people like this to be involved in pharmaceutical development. For example, the most successful groups would most likely have had at least one person with a good overview of the different elements of drug product development and assessment through to scale-up to manufacture, then a number of others with narrower focus, say on the physical properties of the drug, pharmacokinetics and regulatory affairs. In my time at Faulding I was a pharmacist in one such team and I worked with synthetic chemists and physical chemists, for example, including those with proficiencies in formulation and pharmacokinetics. So while there was some specialisation, there was enough overlap in knowledge among these people that all the essential elements were picked up and appropriately applied.”[19]

[18] Williams 1 at [14].

[19] Williams 1 at [15].

41. I do not consider it necessary for me to determine that I should prefer the evidence of one expert over the other. Both experts have provided relevant evidence on the knowledge and skills of a formulation chemist within the team. Dr Williams’ experience perhaps allows him to provide evidence on other skills and knowledge within the hypothetical team. The difference appears to lie in the roles they have played and the nature of the teams in which they worked. This of course does not lessen the relevance of Professor Stewart’s evidence on matters which he has (appropriately) stated he is not able to comment on. Where necessary I will indicate that the determination has taken such matters into account.

The Claims

42. The specification broadly describes various S1P receptor modulators and various pharmaceutical compositions, but the claims are limited to compositions comprising fingolimod, and in which a sugar alcohol is absent. Claim 1 defines:

A solid pharmaceutical composition suitable for oral administration in the form of a tablet or a capsule, comprising:

(a)0.1 to 10% by weight of the S1P receptor modulator 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form; and
(b)75 to 99.99% by weight microcrystalline cellulose (MCC)

in the absence of a sugar alcohol.

43. Claim 15 is an independent claim and also defines a pharmaceutical composition:

A solid pharmaceutical composition suitable for oral administration in the form of a tablet or capsule, comprising:

(a)0.1 to 10% by weight of the S1P receptor modulator 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form; and
(b)a microcrystalline cellulose (MCC)

in the absence of both a sugar and a sugar alcohol.

44. Notably Claim 15 defines the absence of both a sugar alcohol and a sugar, and furthermore places no specific limitation on the amount of MCC in the composition. I take this to mean that in contrast to Claim 1, where the quantity of MCC defined is consistent with its use as a diluent, filler or carrier, the compositions defined by Claim 15 include MCC in lesser quantities which would be consistent with its use as a binder (see for example page 5, lines 16 to 21).

45. Other claims define the use of the compositions in the treatment or prevention of multiple sclerosis and neurodegenerative brain inflammation in multiple sclerosis sufferers, as well as the treatment of other autoimmune diseases. The claims also include methods of preparing the formulations of the invention. The claims are provided in their entirety in the attached Annex.

Inventive Step

46. 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 the prior art. The prior art is information that the skilled person could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant.[20]

[20] Subsections 7(2) and 7(3), Patents Act 1990.

47. The test for whether an invention is obvious is whether it would have been a matter of routine to proceed to the claimed invention:

“The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.”[21]
[21] Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; 148 CLR 262 at 286.

48. In Alphapharm,[22] the High Court accepted the approach taken by Graham J in Olin Mathieson,[23] 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]?”
[22] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [53].
[23] Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at [187].

49. The Opponent in this case argued that the Cripps question as re-stated in Alphapharm is not always appropriate. They noted that the Full Court in Generic Health v Bayer[24] held that Alphapharm does not stand for the proposition that the Cripps question must be applied in every case and the question whether experiments were of a routine character to be tried as a matter of course remains relevant.

[24] Generic Health Pty Ltd v Bayer Pharma AG (2014) 222 FCR 336 at [71].

50. The Opponent made submissions on obviousness in view of the common general knowledge and in view of the common general knowledge combined with subsection 7(3) information. I will deal with these in turn.

The common general knowledge

51. 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.”[25]
[25] Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd [1980] HCA 9; 144 CLR 253 at 292.

52. 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.[26] This was expressed in the following way by Luxmoore J in British Acoustic v Nettlefold:[27]

“In my judgement it is not sufficient to prove common general knowledge that a particular disclosure is made in an article, or a series of articles, in a scientific journal, no matter how wide the circulation of that journal may be, in the absence of any evidence that the disclosure is accepted generally by those who are engaged in the art to which the disclosure relates. A piece of particular knowledge as disclosed in a scientific paper does not become common general knowledge merely because it is widely read, and still less merely because it is widely circulated. Such a piece of knowledge only becomes common general knowledge when it is generally known and accepted without question by the bulk of those who are engaged in the particular art; in other words, when it becomes part of their common stock of knowledge relating to the art.”

[26] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [31].

[27] British Acoustic Films Ld v Nettlefold Productions (1936) RPC 221 at 250.

53. 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:

· The most common route of administration was the oral route unless there were compelling reasons why the oral route was unsuitable, such as the active agent being a peptide.[28]
[28] Williams 1 at [27].

·     Tablets and capsules are the most commonly used oral dosage forms, and these have a number of advantageous qualities: they are relatively easy to manufacture, they are generally more stable than dosage forms such as liquids, they are acceptable to most patients, and they are generally a reliable and safe method of drug administration.[29]
[29] Stewart at [28].
·     Various excipients were routinely used when preparing oral dosage forms. These included diluents/fillers/carriers, binders, disintegrants, glidants, lubricants, colours, polymers and complexing agents.[30]
[30] Stewart at [51], Williams 1 at [30].
·     Diluents are used to increase the bulk of a composition, particularly if the dose is relatively small and the drug without the diluent would be too small both for manufacture and patient handling.[31] Diluents could also be used to alter and improve the flow properties and compatibility of mixtures of powdered materials.[32]
[31] Williams 1 at [30(i)].
[32] Stewart at [51(a)(iii)].
·     Binders act to bind particles together during manufacture and are commonly used in wet granulation.[33]
[33] Stewart at [51(b)].
·     Lubricants prevent ingredients from sticking to tableting equipment,[34] as well as acting to reduce friction between particles and a tablet die, making compression easier and minimising heat build-up which can cause instability or other undesirable characteristics.[35]
[34] Stewart at [51(c)ii].
[35] Williams 1 at [30(iii)].
·     Disintegrants cause the tablet to break up and increase the surface area of drug particles exposed to the gastrointestinal tract fluids and allows for greater dissolution and release of the active agent.[36]
[36] Stewart at [51(d)(i)].
·     Glidants help compositions to mix for flow through tabletting and encapsulation machinery.[37]
·     Tablets can be made by wet granulation, dry granulation and direct compression.[38]
·     Wet granulation involves the addition of a liquid to a powder comprising the ingredients. In general, the active, diluent and disintegrant are mixed in powder form to which a solution of the binder is added. The resulting wet mass is milled and/or sieved to form granules which are dried before milling and sieving again to form granules that are suitable for filling capsules. For tabletting, a lubricant is added before the final mixture is compressed to form tablets.[39]
·     Dry granulation involves the aggregation of particles to form granules through compression without the addition of a liquid. The blended powder is compressed to form a “slug” which is then subjected to a size reduction process to form a granulate. Like wet granulation the granules are milled and sieved to a size that is suitable for preparing capsules and tablets.[40]
·     Direct compression, as indicated by its name, involves blending of the excipients and the active as a dry powder, and direct compression of the powder to form the tablets. One or more excipients known as direct compression vehicles are required which result in adequate binding, compactability and disintegrant properties.[41]

[37] Williams 1 at [30(v)].

[38] Stewart at [43].

[39] Stewart at [47].

[40] Stewart at [48].

[41] Stewart at [49].

54. Dr Williams also stated that certain textbooks were widely used in the art,[42] including Remington[43] and Goodman & Gilman.[44] Professor Stewart stated that textbooks are of limited utility when attempting to formulate a specific active pharmaceutical ingredient, but they may be of assistance for providing a refresher on the general principles of formulation and well-known examples of formulations.[45]

[42] Williams 1 at [26].

[43] Gennaro, A. R., Remington: The Science and Practice of Pharmacy, Vols. 1-2, Easton: Mack Publishing Company, 18th Ed. 1990, 19th Ed. 1995, 20th Ed. 2000.

[44] Brunton, L. L., Goodman & Gilman’s the Pharmacological Basis of Therapeutics, 2006, McGraw-Hill, 11th Ed.

[45] Stewart at [173].

55. Professor Stewart did not identify any specific textbooks that would have been referred to in this manner but did comment on the availability of some of the named textbooks when he responded to specific documents raised in evidence. He stated that Remington was a common textbook used in the training and education of pharmacy and pharmaceutical science students and it would also have been present in the libraries of many industrial pharmaceutical companies as of September 2006. But Professor Stewart considered that a formulation scientist would have been unlikely to have even be aware of Goodman & Gilman, and even if aware of it would have been unlikely to have referred to a chapter relating to fingolimod when considering formulation of a drug.[46]

[46] Stewart at [89].

56. The difference in opinion on this point may derive from the difference in experience between the two experts as noted above. I agree that Goodman & Gilman would not have been referred to by a formulation scientist. However Dr Williams appears to have knowledge and experience consistent with other members of the skilled team. He stated that Goodman & Gilman was a basic pharmaceutics/pharmacology textbook.[47] I am therefore satisfied that a pharmacologist in the team would have regard to Goodman & Gilman.

[47] Williams 2 at [32].

The problem

57. At 26 September 2006, subsection 7(2) of the Act set out that:

For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with the information mentioned in subsection (3).

The problem articulated by the Opponent was how to formulate fingolimod in an oral formulation.[48] The Applicant submitted that this was not an appropriate starting point since it is not permissible to incorporate information that is not available to the person skilled in the art as either common general knowledge or information available under section 7(3).[49] To this end the Applicant argued that fingolimod, its structure, properties and uses were not common general knowledge at the relevant time.[50]
[48] Opponent’s submissions for hearing at [99].
[49] AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99.
[50] Applicant’s submissions for hearing at [58].

59. The present starting point could potentially be framed in several alternative ways. A consideration of the specification is helpful to determine the problem, as opposed to the “inventive journey” undertaken by the applicant to arrive at the claimed invention.

60. The invention is said to relate to pharmaceutical compositions comprising sphingosine-1 phosphate (S1P) receptor modulators. The specification indicates that S1P receptor modulators have structural similarities which result in related problems in providing a suitable formulation. The specification states that:[51]

There is a need for an S1P receptor modulator which is well-adapted for oral administration.
Many patients have difficulties in swallowing because of an unpleasant taste or there being no water available at the time of ingestion, so there is a need for a formulation that can be easily swallowed.

There is a need for formulations providing a variety of dosage strengths.
[51] Specification at page 1, paragraph 5.

61. The invention is said to provide various pharmaceutical compositions which are aimed at addressing these needs. These are said to provide a convenient means of systemic administration, do not suffer from the disadvantages of liquid formulations for injection or oral use and have good physicochemical and storage properties. The specification goes on to describe various types of formulations: compositions comprising a coating, compositions comprising a disintegration agent, compositions comprising a freeze-dried dosage form, compositions in which a sugar alcohol is absent, and compositions comprising a coating which contains an S1P receptor agonist.

62. The specification also states that the various compositions can comprise various S1P receptor modulators. Fingolimod is given as a preferred compound. The specification then sets out 40 examples of formulations of the different types. Each of the formulation examples uses fingolimod, but only examples 13 to 38 and 39 (second formulation given) contain microcrystalline cellulose and fall within the scope of the claims.

63. There is no suggestion that any new treatments or dosage regimens were discovered. The specification does indicate that the formulations are suitable for treatment of particular autoimmune diseases, and clearly the dosage forms are intended to be used in treatment of patients. The specific treatment does not appear integral to the starting point or problem. The only implications for such treatments appear to be that the dosage form needs to have certain desirable (or convenient) properties. This aspect of the starting point is clearly common general knowledge.

64. The broadest statement of the background of the invention is perhaps that it relates to the stability of S1P receptor modulators and the need to provide a convenient solid oral dosage form for administration to patients. I consider this a reasonable expression of the starting point. The problem can therefore be expressed as the provision of a stable oral dosage form of an S1P receptor modulator.

Matters of routine

65. A key area in which the experts disagreed was the approach that a formulator would take if seeking to provide a new formulation. The arguments related to this point applied across most of the submissions, so to avoid duplication I will deal with these before moving to the specific inventive step considerations.

66. Both experts stated that pre-formulation information was desirable when developing a new formulation. Pre-formulation data include information such as the bioavailability, dose amount, the intended purpose of the drug and the clinical condition that is to be treated.

67. Professor Stewart stated that it would have been “impossible” for him to formulate or predict a formulation without pre-formulation data.[52] It was not his role to determine such information and he would rely on other team members to provide this data.[53] If a compound had been formulated before then the pre-formulation information would be provided by the supplier. If any pre-formulation information was not available he would look for other reliable sources of information such as commonly used textbooks, reference books and peer reviewed journals.[54] Professor Stewart stated that it was not a case of trial and error in selecting appropriate excipients, and noted that a formulator would have required the complete pre-formulation data.[55] Ignoring or proceeding in the absence of the complete pre-formulation data is likely to lead to a formulation that is unsuitable.[56]

[52] Stewart at [99].

[53] Stewart at [37].

[54] Stewart at [30].

[55] Stewart at [176].

[56] Stewart at [175(c)].

68. In contrast Dr Williams considered that the amount of pre-formulation information is “a question of need vs want”[57] and that while it was preferable to have as much knowledge as possible about key physical and chemical properties it was common practice in the generic pharmaceutical industry to proceed with only minimal information available.[58]

[57] Williams 2 at [25].
[58] Williams 2 at [31].

69. I do not consider that the differences between the experts as to the need for pre-formulation data impacts significantly on the determination of what would be considered routine in the art. Given sufficient pre-formulation information, either from an external source or from experimentation within the team, the formulator would seek to develop the new formulation. It appears reasonable to me that a formulator would proceed on the basis of the important physical and chemical properties of the active ingredient. But even if I accept that a formulator would not proceed unless they had a more “complete” set of pre-formulation data, the evidence suggests the work required of other members of the team to provide this data involved routine experimentation.[59]

[59] Williams 2 at [22].

70. The experts also provided evidence in relation to the steps in developing a new formulation once they had sufficient pre-formulation data. Professor Stewart stated that he would use various excipients and methods of manufacturing to try and achieve a suitable formulation.[60] Key considerations included the need for the dosage form to have sufficient stability, having a dosage form that is a convenient size for patients to handle and administer, and achieving adequate bioavailability of the active ingredient.[61] He noted that not every excipient in a class is appropriate for each active ingredient, and there was no way of telling whether an excipient may cause a problem without testing the formulation.[62] Notably Professor Stewart stated that pre-formulation data informed both the composition of the formulation and the method of manufacture.[63]

[60] Stewart at [35].
[61] Stewart at [31].
[62] Stewart at [52].
[63] Stewart at [175(d)].

71. Dr Williams described his approach in the following way:

“…absent any specific requirements or suggestions as to otherwise e.g. from the literature, and without any testing, in initial formulations for a tablet a formulator would include a diluent, probably a glidant, a binder, a lubricant and a disintegrant as a first pass. Small-scale formulations would then be made up in a development laboratory and tested, e.g. in stability trials. That said, however, the approach would be to keep a formulation as simple as possible; a formulator generally would not include an excipient if it were not necessary to do so. For example, for a capsule, at first pass a formulator may include no more than a diluent. Additionally, a formulator would not conduct an exhaustive search for different or uncommon excipients unless there was a clear requirement to do so, even if it were known that there was a potential stability problem. The formulator would identify any stability problem, determine where possible the mechanism involved in the decomposition of the drug, and then choose some potential excipients that may help to achieve an acceptable shelf-life, for example based on rate of decomposition as a function of pH data and accelerated stability trials.”[64]

[64] Williams 1 at [33].

72. My understanding of the evidence from the experts is that they have described two different approaches. Professor Stewart utilises a complete set of pre-formulation data to base his choice of excipients and then tests the resulting formulations to determine whether they are suitable. Dr Williams proceeds on a lesser amount of pre-formulation data, prepares a series of “test” formulations based on common excipients, and if necessary, after testing extends his tests to other less common excipients. As noted above, Dr Williams stated that it was common in the generic industry to proceed on a minimum of pre-formulation data, so their different backgrounds may be the basis of the differences in the approach of the two experts. I conclude that both approaches were routine in the art as there is no evidence that clearly establishes otherwise.

73. Dr Williams went on to describe how he would use such an approach to develop a new formulation of fingolimod. He performed a literature search to identify its structure,[65] some pharmacokinetic information[66] and clinical uses.[67] He considered the hydrochloride salt preferable to the free base because salts are generally easier to handle and formulate.[68] He proposed the following initial capsule formulation as follows:[69]

[65] Williams 1 at [41].

[66] Williams 1 at [43].

[67] Williams 1 at [37].

[68] Williams 1 at [45].

[69] Williams 1 at [46].

Ingredient	Weight (mg)
Fingolimod HCl	1.112
Diluent	100
Glidant	1
Total	102.112

74. He noted that doses of 0.5 up to 2.5 mg were employed prior to the end of 2005, and arbitrarily chose a 1 mg dose in his initial formulation. Such small dose amounts apparently necessitate the use of a diluent in the capsule and a glidant ensures good flow properties.[70] He proposed an initial tablet formulation as shown below:

[70] Williams 1 at [47].

Ingredient	Weight (mg)
Fingolimod HCl	1.112
Diluent	100
Disintegrant	10
Lubricant	1
Glidant	1
Total	113.112

75. His specific choice of diluents was explained as follows:[71]

“The diluents I considered include lactose, mannitol, sorbitol, sucrose, calcium phosphate, pharmaceutical grade sugars and microcrystalline cellulose (MCC). I would make up a few formulations, each with a single different diluent, and pick the best one based on dissolution, cost and general performance. In this case, I hesitate over calcium phosphate as the metal ion may have an interaction with the drug molecule or possibly promote micelle formation in the gastro-intestinal tract. With the use of lactose and sugar diluents, there is also the possibility of interaction with the drug molecule by way of the Maillard reaction with the drug amino group, which may steer one away from these diluents… Mannitol and sorbitol are compounds commonly referred to as sugar alcohols which find particular utility in chewable tablets.”
[71] Williams 1 at [48].

76. Professor Stewart questioned why Dr Williams did not consider a broader range of potential diluents or mixtures of diluents, and in particular various calcium salts.[72] He acknowledged that MCC was suitable as a direct compression vehicle because it has good compatibility, it can act as a disintegrant in the gastrointestinal tract and it can be used as a diluent, filler or carrier with granulation methods.[73] However, it also has poor flow properties and if it was used it was necessary to also use a glidant to achieve acceptable flow properties.[74] MCC has the disadvantage of being expensive in comparison with other excipients, and Professor Stewart stated that an important consideration in the formulation process was how to avoid or reduce the use of MCC to decrease the overall cost of the formulation.[75]

[72] Stewart at [185(c)].

[73] Stewart at [54].

[74] Stewart at [56].

[75] Ibid.

77. Professor Stewart agreed that the use of lactose is likely to be problematic, but did not share Dr Williams’ concerns in relation to the use of calcium salts and the formation of complexes because it is insoluble in water and he was not aware that complexes would form.[76] He noted that calcium phosphate and calcium sulfate are relatively cheap and if required to choose he would have chosen these or used them in combination with MCC, which as an aside would prima facie fall within the scope of Claim 15.[77]

[76] Ibid.
[77] Stewart at [185(f)].

78. However, I note that Dr Williams’ concerns related to the properties of the excipient in the gastrointestinal tract rather than the solubility in water. Given the apparent difference in the acidity of these two environments, I consider Professor Stewart’s evidence carries less weight on this point. Moreover, Exhibit DBW-4 (Remington) at page 1635 provides an example of a drug interaction with calcium salts. I also acknowledge that cost may be a consideration in the choice of carrier, but an invention may be obvious for technical or practical reasons even if it is not obvious commercially.[78] Exhibit DBW-4 also indicates MCC has been studied extensively as a direct compression agent because of its favourable properties for this purpose (see page 1646).

[78] Hallen Co. v Brabantia (UK) Ltd [2989] 307.

79. On balance I am satisfied that the choice of excipients provided by Dr Williams in his initial formulations would have been considered routine in the art. This is relevant to the consideration of inventive step in view of the common general knowledge and information under subsection 7(3).

Inventive step in light of the common general knowledge alone

80. As noted above I have determined the problem to be the provision of a stable oral dosage form of an S1P receptor modulator. The Opponent submitted that the claimed invention was obvious in view of the common general knowledge. However, fingolimod is not part of the starting point or the problem that I have identified. The key consideration in this regard is therefore whether fingolimod formed part of the common general knowledge at the relevant time and therefore can be taken to be part of the starting point.

81. To this end, fingolimod is certainly an S1P receptor modulator. Dr Williams stated that fingolimod appeared in several hundred peer-reviewed literature and patent documents prior to 26 September 2006.[79] He also noted that it was mentioned in Goodman & Gilman, which he suggested showed that the molecule was “rising in prominence”. He went on to say that:

“Based on this, and the publication frequency elsewhere, I would not go so far as to say that the drug would have been generally known among the pharmaceutical community as a whole, but I would say that it would have been known to those working in the field of immunosuppressant drugs and the fields of the relevant clinical indications.”
[79] Williams 1 at [37].

82. The Applicant submitted that information may only be considered part of the common general knowledge when it has been generally accepted and assimilated by the bulk of the relevant skilled persons working in the art.[80] They also argued that the Goodman & Gilman entry for fingolimod was only made publicly available on 9 September 2006, about 17 days before the priority date, and therefore there was insufficient time for the fingolimod entry to have been generally accepted and assimilated.

[80] Applicant’s submissions for hearing at [69].

83. I consider the entry in Goodman & Gilman certainly suggests that at the time the compound was of interest as an immunosuppressant and that it was undergoing clinical trials. But my understanding is that the information essentially confirms Dr Williams’ statement that fingolimod was rising in prominence, and while the skilled person may have taken more than just an ephemeral interest in the disclosure, it does not rise to the level where I could conclude that fingolimod was common general knowledge. Dr Williams’ evidence also draws inferences from separate pieces of public information, but no direct evidence has been adduced that establishes that fingolimod had indeed become part of the common general knowledge.

84. Based on the evidence provided I cannot consider fingolimod was common general knowledge. It follows that the invention as claimed is inventive in view of the common general knowledge alone.

Inventive step in view of common general knowledge and information under subsection 7(3)

85. For the purposes of determining whether a claimed invention involves an inventive step, the common general knowledge may be considered together with information set out in subsection 7(3) as follows:

The information for the purposes of subsection (2) is:
(a) any single piece of prior art information; or
(b) a combination of any 2 or more pieces of prior art information;

being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant and, in the case of information mentioned in paragraph (b), combined as mentioned in that paragraph.

86. The Opponent made submissions on obviousness in view of the common general knowledge combined with the following documents:

Chavez

US 6004565 A (Chiba)

WO 2004/089341 (Oomura)

EP 1201236 (Matsumori)

87. I will deal with each of these in turn. Before turning to these, as an initial point I note that the problem relates to the provision of a stable oral dosage form of an S1P receptor modulator, but the evidence provided by Dr Williams and Professor Stewart was predicated on the choice of fingolimod as active ingredient. There is therefore a threshold question of whether, in view of the problem, the skilled person would ascertain and have regard to documents relating to fingolimod. In this regard the entry in Goodman & Gilman indicates that this was the lead S1P modulator, and I therefore consider it reasonable that the skilled person seeking to provide a stable oral dosage form of an S1P receptor modulator would have regard to material relating to this compound.

Chavez

88. Chavez is a media release summarising the results of a completed Phase II study of fingolimod for the treatment of relapsing multiple sclerosis and provides an overview of a Phase III trial which was underway at that time. The document shows that patients taking once-daily oral fingolimod at dosages of 1.25 and 5 mg experienced a 50% reduction in their relapse rate, and that this low relapse rate was maintained during the subsequent 12-month extension. The 5 mg dose was associated with a higher incidence of adverse events and during the extension patients on the higher dose were transferred to the lower dose. The Phase III trial is said to involve a larger patient group at doses of 1.25 or 0.5 mg for a period of up to 2 years. Chavez does not provide any specific detail of the formulations used in the study other than the dosage amount and oral administration once daily.

89. The Applicant argued that the evidence does not establish that Chavez could reasonably be expected to be ascertained by the skilled person.[81] They noted that when Dr Williams was asked to “go through” the searches he would have conducted before the priority date he did not ascertain Chavez. They highlighted that Dr Williams had not addressed whether he would have ascertained Chavez until evidence in reply, where he stated that:

“I expect that, had I not located it myself, it would have been brought to my attention by the marketing department. In fact, certainly in my experience at Sigma, more often than not it was the marketing people who got a new project started, by approaching the research and development group for a particular product, possibly triggered by an article such as Chavez…”[82]

[81] Applicant’s submissions for hearing at [112].

[82] Williams 2 at [36].

90. The Applicant argued that this evidence was “speculative, given in the glare of hindsight, and based on his own peculiar experience formulating generic products at Sigma”.[83]

[83] Applicant’s submissions for hearing at [112(f)].

91. I acknowledge the Applicant’s submissions on this point but note that the searches that Dr Williams carried out were in relation to obtaining pre-formulation data for fingolimod. These appear to be specific searches aimed at obtaining particular information for the formulator. In this regard, Professor Stewart stated that as a first step in developing a new formulation he would see whether anyone had attempted to make such a dosage form previously.[84] This suggests to me that he would have regard to disclosures specifically related to formulation of the active, but that his considerations might also extend to disclosures involving the use of the active compound. However, he stated that:

“I doubt I would have ascertained this document in my role as a formulator as (a) it was not my usual practice to search or review media release documents and (b) it contains little or no formulation data or examples. I do not know whether the team that I was working with would have found this document; this would have depended on the particular search and review practices of other members of the team.”[85]

[84] Stewart at [41].

[85] Stewart at [97].

92. Dr Williams described a similar approach to obtaining relevant information. He considered that most information would be sourced from the commercial originator through commercial literature, industry reports and pharmaceutical science conferences. He would have regard to published journal articles, and he considered it prudent to look at the patent literature. He stated that it was common practice when formulating generic products to avoid transgressing existing patents and “at least as a first pass, I would be looking at journal articles and the patent literature to get some hints as to what formulation approach might be feasible”. His preferred source of technical data was SciFinder.[86] This approach is consistent with the evidence he gave in relation to how he would have set about sourcing pre-formulation data. While he did not ascertain Chavez, this “first pass” does not appear to be an exhaustive search, particularly in view of the other sources of information he listed such as industry reports and the like from the originator.

[86] Williams 1 at [22].

93. The key consideration here is whether another member of the team, such as a pharmacologist, would reasonably be expected to have ascertained Chavez. Professor Stewart did not know whether another member of his team would have found Chavez, but he did not rule it out, stating that it would depend on their search and review practices. Dr Williams stated that while at Fauldings and Sigma his own searches were complemented by those with specialist training in the area of information retrieval from databases. He believed this was the standard practice amongst his colleagues.[87]

[87] Williams 2 at [35].

94. I note that the evidence shows that fingolimod was one of the first S1P agonists and that Phase II and Phase III trials were being undertaken at the time.[88] I have no direct evidence from a pharmacologist on this point, but I have accepted above that Goodman & Gilman is a standard textbook for pharmacologists. I can therefore infer from the entry in Goodman & Gilman that information concerning clinical trials is relevant and of interest to pharmacologists, and they would therefore have regard to such disclosures in their work. Chavez is a media release from the innovator company Novartis, relating to clinical trial data presented at a significant scientific conference (American Association of Neurology). This is consistent with the sources of information set out by Dr Williams. On balance I am satisfied that the nature and content of this disclosure would reasonably be expected to have been ascertained, understood and considered as relevant by the skilled person if they were seeking to solve the problem of providing a stable oral dosage form of an S1P modulator.

[88] Exhibit DBW-6.

The question is then what would the skilled person have done as a matter of routine in view of Chavez. Dr Williams stated that in view of Chavez he would make up the following capsule and tablet formulations shown in Table 1 and Table 2 below. This followed the general approach that he followed as discussed in the section above on “Matters of routine”. This provides various compositions, including one in which MCC is a diluent. The “binary” use of excipients results in a composition also meeting the defined limitation in Claim 1 of sugar alcohols being absent, and the defined limitation in Claim 15 of both sugar alcohol and sugar being absent.
Dr Williams acknowledged that Chavez does not give much information as to the formulation per se, but it does provide the dose amount. He chose a 0.5 mg dose on the basis that this dosage was to be used in the Phase III trial, and it “would be prudent to go to the lower dose to minimise the incidence and severity of any adverse effects.”[89]
[89] Williams 1 at [69].

Table 1 – capsule formulation

Weight (mg)
Ingredient	A	B	C	D	E	F	G
Fingolimod HCl		0.556	0.556	0.556	0.556	0.556	0.556	0.556
Diluent	Lactose	100
Mannitol	100
Sorbitol	100
Sucrose	100
CaHPO4	100
Sugar	100
MCC	100
Glidant	1	1	1	1	1	1	1
Total	101.556	101.556	101.556	101.556	101.556	101.556	101.556

Table 2 – tablet formulation

Weight (mg)
Ingredient	A	B	C	D	E	F	G
Fingolimod HCl		0.556	0.556	0.556	0.556	0.556	0.556	0.556
Diluent	Lactose	100
Mannitol	100
Sorbitol	100
Sucrose	100
CaHPO4	100
Sugar	100
MCC	100
Disintegrant		10	10	10	10	10	10	10
Lubricant	1	1	1	1	1	1	1
Glidant	1	1	1	1	1	1	1
Total	112.556	112.556	112.556	112.556	112.556	112.556	112.556

The Applicant argued that there is a level of unpredictability about how an active agent will interact with an excipient. They noted that Dr Williams identified several excipients as having “the most potential”, rather than having a reasonable expectation of success, and in addition to the ones he considered most promising he would still make and test other formulations that he considered had less potential.[90]
[90] Applicant’s submissions for hearing at [81] – [83].

I do not find these submissions persuasive. Admittedly several results were considered feasible, but obviousness does not require that only one possible solution be arrived at.[91] I am satisfied that the evidence establishes that it would be a matter of routine for the skilled person to arrive at a limited number of feasible formulations in view of the information provided by Chavez and their common general knowledge, one of which uses MCC. I am also satisfied that the reference to several formulations having the most potential equates to a reasonable expectation of success, noting that a reasonable expectation is not a guarantee. Moreover, while testing would be required to confirm the stability of the resulting formulations, as indicated by Professor Stewart, this is required for a formulation regardless of the approach taken to its development. The testing by Dr Williams of additional formulations does not detract from his identification of several formulations with a greater level of potential than others, but rather reflects a real-world approach that would be taken in an empirical approach of this type.
[91] Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 [91] - [92].

Claims 1 and 15 also require that fingolimod be present in an amount of 0.1 to 10% by weight of fingolimod. I note that the claims define the constituents in terms of their percentage weights rather than specific quantities. Dr Williams selected the dosage of 0.5 mg as it is good practice to use the lowest possible dosage, but I do not consider this to mean that only this dosage would be used. Chavez discloses as much as 5 mg being used in the treatment. It seems reasonable to me that the skilled person would choose any dosage amount between the lower and upper levels in the expectation that it would be useful for the stated purpose. Chavez indicates that 5 mg dosages have an increased occurrence of adverse events, but I do not consider that dosages in this, or indeed in larger amounts would be non-obvious on that basis. Defining an amount merely based on a recognised disadvantage does not constitute an inventive step.
The evidence establishes that small dosages require a diluent,[92] whereas in the case of a larger dosage such as 100 mg no filler may be necessary.[93] Dr Williams used 100 mg of the diluent in his initial formulations which arrived at a formulation meeting the limitations set out in the claims. However, the evidence also suggests that having a convenient tablet size is a consideration,[94] and where there is a relatively small amount of the active ingredient then diluents are added to achieve a dosage form size that is convenient for patients to handle and administer and can be processed effectively.[95] Clearly the percentage weight content of fingolimod will change in proportion to changes in the amount of diluent. There is consequently no inventiveness in the defined range of 0.1 to 10% by weight fingolimod or the defined range of MCC.
[92] Williams 1 at [30(i)].
[93] Williams 1 at [40].
[94] Stewart at [31(b)].
[95] Stewart at [33].

I therefore consider independent Claims 1 and 15 lacking in inventive step. The routine approach described by Dr Williams resulted in formulations having the features defined in Claims 2 to 5, and these similarly lack inventive step in view of Chavez. Claims 12 and 13 define methods of preparing the formulations of Claims 1 to 4. This involves steps of mixing MCC and fingolimod, milling the mixture and the mixing it with a lubricant. The process defined in these claims appears to be routine.[96]
[96] Williams 1 at [54].
Claims 6 to 11 define methods of using fingolimod in the treatment or prevention of multiple sclerosis, diseases resulting from multiple sclerosis and autoimmune disease (noting that multiple sclerosis is an autoimmune disease). Chavez discloses the treatment of multiple sclerosis with fingolimod and hence there is no apparent inventiveness in these claims.

Claim 14 is an omnibus claim that defines the composition of Claim 1 with reference to the examples. I note that the exemplified formulations contain various additional excipients that are set out in the discussion of the common general knowledge above. The only apparent difference lies in the specific amounts selected for each component, noting that most are between the lower and upper dosage amounts described in Chavez. On balance I can see no combination that would be clearly considered non-obvious in view of the determination above, and therefore consider that Claim 14 lacks inventive step.
In summary Claims 1 to 15 lack inventive step in view of Chavez.

Chiba

Chiba describes the use of fingolimod as an immunosuppressive agent, including in the treatment of multiple sclerosis and other autoimmune diseases. The treatment is said to be associated with accelerated lymphocyte homing immunosuppression (or ALH-suppression) in a dosage range of 0.1 to 10 mg. Chiba describes various animal-based treatments, including by oral administration. Chiba also purports to describe compositions, but no specific excipients are disclosed. A general description of admixture with “carrier, excipient, diluent, and so on” and formulation into “powders, capsules, tablets, injections, topical administration, or the like” is provided. The only other description of the excipients is as follows:[97]

“In many cases, these compositions can be administered orally. The examples below detail the use of FTY720 by oral administration. One skilled in the art is familiar with numerous methods and tests for determining the effectiveness of a selected route of administration. Furthermore, pharmaceutically or physiologically acceptable carriers or excipients for use with the 2-aminopropane-1,3-diol compounds or benzene compounds noted herein are known in the art or can be readily found by methods and tests known in the art. And, pharmaceutically and physiologically acceptable salts of these compounds can also be determined and used by one skilled in the art.”

[97] Chiba, column 11.

The initial consideration is whether the skilled person would have ascertained Chiba in view of the problem. Professor Stewart stated that in general very little information in journals and patents is of use to a formulator as they need to rely on pre-formulation data which is almost never given in its entirety in journals or patent literature.[98] Dr Williams similarly recognised that patents do not provide highly detailed pre-formulation data. However, he considered they do contain useful information such as the dosage amount and clinical uses.[99]
[98] Stewart at [170].
[99] Williams 1 at [22].
Professor Stewart doubted that he would have ascertained Chiba because it contains little formulation data but acknowledged that another team member may have found it.[100] I note that his evidence here prima facie goes to the point of whether Chiba would be considered relevant rather than whether it would have been ascertained. Arguably whether the document contains relevant formulation would require an in-depth consideration of the content of the document once found. I consider it reasonable that based on the title (“Compositions and methods of using compositions with accelerated lymphocyte homing immunosuppressive properties”), that the skilled person would ascertain the document if they were seeking documents relevant to formulation of fingolimod.
[100] Stewart at [100].

The question of whether the skilled person would have understood Chiba was not disputed. The subsequent consideration is whether the skilled person would consider the document to be relevant. As indicated above, Professor Stewart considered that Chiba contains little formulation data and therefore it would have been of little relevance to a formulator. Dr Williams stated that Chiba was relevant in that it disclosed information about the biological activity, and the indication that standard formulations could be used to formulate fingolimod would be of interest to a formulator.[101] On balance I am satisfied that the skilled person would consider the document relevant.
[101] Williams 2 at [38].
The remaining consideration is what the person skilled in the art would do as a matter of routine in view of Chiba. Similarly to the approach given in relation to Chavez above, Dr Williams arrived at formulations comprising mannitol, sorbitol and MCC.[102] The Applicant noted that Dr Williams employed a dosage of 0.5 mg based on this being the lowest possible dosage provided in Chavez, and argued that this was importing information from Chavez into Chiba.[103] I agree with this observation, but note that the quantity is in essence an arbitrary amount within the disclosure of Chiba. On that basis I do not consider this is fatal to the evidence provided by Dr Williams on this point.
[102] Williams 1 at [82] referencing earlier statements at [49], [53] - [54].
[103] Williams 1 at [83].
The Applicant also argued that while a general dosage range (0.01-10 mg) and combinations with other immunosuppressants are described, no information is given about the carriers that are used in the treatments. The Applicant submitted that there was no evidence that the skilled person would formulate fingolimod in small dose sizes that would result in a composition having less than 10% by weight of fingolimod.[104] However I consider the evidence establishes that such dosage amounts would require the use of a diluent, and the initial formulations proposed by Dr Williams result in formulations within the defined range. I therefore do not find this particular submission persuasive.
[104] Applicant’s submissions for hearing at [120(c)].
On balance I acknowledge that Chiba provides no specific information about the ingredients in the formulations, but it does indicate that they may be administered orally and that they can be prepared by routine techniques. A dosage range is also provided for use in the treatments in humans. Given this information, I am satisfied that the skilled person would, as a matter of routine, prepare formulations comprising fingolimod and MCC.
As discussed above for Chavez, there also appears to be nothing inventive in the dependent claims, or in the specific dosage amounts and additional excipients as set out in the examples. The claims therefore lack inventive step in view of Chiba.

Oomura

Oomura describes formulations comprising S1P modulators for oral administration. The carrier is a sugar alcohol such as mannitol, and the preferred modulator is fingolimod. The compositions are said to be useful in the treatment of various diseases requiring immunomodulation, including autoimmune diseases. The S1P modulator makes up 0.01 to 20% by weight of the composition and is preferably 0.5 to 5% by weight. The formulations contain sugar alcohols and therefore fall outside of the scope of the present claims.

There was no apparent dispute that the skilled person would have ascertained, understood and regarded the document as relevant. I will proceed on that basis.

Professor Stewart’s evidence was similar to that for Chiba. I note that like the other documents raised by the Opponent, Oomura does not provide any specific pre-formulation data. However, this does not appear to have presented any issue for Professor Stewart who considered that he would be able to formulate the claimed sugar alcohol formulations, even though Oomura only provides examples comprising mannitol as a sugar alcohol carrier. He stated he would not be able to make any formulation using an alternative carrier without the necessary pre-formulation data because of lack of information on the stability of the active in the solid state, in the presence of light, moisture or air.[105]
[105] Stewart at [105].

Dr Williams stated that:

“Having read the Oomura document, had I wanted to produce a generic fingolimod formulation as at 25 September 2006, so as to avoid impinging on the claims of this patent specification, then my immediate suggestion would be to exclude mannitol or any other sugar alcohol, e.g. from any of the formulations given in the examples.”[106]

[106] Williams 1 at [92].

The Applicant noted Dr Williams’ reference to working around a patent and submitted that this results in a different consideration to that required under inventive step. They argued that working around a patent essentially requires doing the opposite of what the patent teaches to avoid infringement, while obviousness is a consideration of what the skilled person would be directly led to do in view of the disclosure. The former consideration is a legal one, which they considered a matter for legal or commercial persons rather than the notional person skilled in the art.[107]
[107] Applicant’s submissions for hearing at [128] – [129].

I consider this submission has merit. Thus, while the evidence provided by Dr Williams may broadly describe how he would go about formulating alternative dosage forms, I do not consider this a true reflection of how the skilled person would approach the problem of providing a stable oral dosage form comprising fingolimod. In particular, the approach does not represent what the skilled person would do based on the disclosure given by Oomura, but rather what they would do to avoid the disclosure. I consider that the skilled person would be more likely to start with mannitol as the carrier since this appears to provide a solution to the problem of obtaining a stable formulation of fingolimod. There is no clear evidence that they would be led to replace mannitol as a carrier. The Opponent therefore has not made out an obviousness case on Oomura.

Matsumori

Matsumori describes treatment of viral disease using fingolimod. A solid tablet formulation is described which comprises fingolimod (1 mg), lactose (90 mg), crystalline cellulose (25 mg) and magnesium stearate (4 mg). I note that the amount of MCC used is lower than required by Claim 1, and that the inclusion of lactose falls outside of the formulations defined by Claim 15.

Professor Stewart stated that if he had been tasked with formulating a solid oral dosage of fingolimod, he may have ascertained Matsumori.[108] However he would not have regarded it as relevant because it contains no pre-formulation data and the information provided is “very formulaic and broad”. Professor Stewart stated that the examples did not strike him as examples of real formulations, and that they were more likely to be hypothetical examples that appeared to be written by someone who does not understand formulation science. For example, he noted the examples used the term “crystalline cellulose” which he had never used or heard other formulators use to refer to MCC.[109] He considered that Matsumori contained no useful information for a formulation scientist.
[108] Stewart at [107].
[109] Stewart at [108].

Dr Williams stated that if he wanted to reproduce a dosage form of fingolimod he would first have simply reproduced the formulations given by Matsumori.[110] However he went on to say that:

“the tablet formulation includes lactose, which would remain in my mind as a potential problem, as I have explained above for reasons of the potential for the Maillard reaction. I would therefore be wary of using it and I would consider the possibility that I may have to remove lactose from the formulation, and replace it with an alternative. To be clear, this would not cause me to exclude lactose from the outset, but it would be enough for me to make up and test a small number of alternative formulations for performance comparison. Of course, if indeed my tests showed that the Maillard reaction was a significant problem with lactose, then I would exclude it, and all excipients capable of the same interaction, from the formulation altogether.”[111]

[110] Williams 1 at [110].

[111] Williams 1 at [111].

Dr Williams proceeded to consider the body of the specification for a suitable alternative diluent. A number of alternatives are disclosed, but some of these were not traditionally known and used as diluents and he was wary of at least two because of their potential to form gels. He then noted that if he excluded lactose from the formulation that he arrived at a mixture of fingolimod, MCC and magnesium stearate. He stated that as a first cut and keeping things as simple as possible that it would be a simple matter to increase the MCC to bulk out the composition to obtain the present invention.[112]
[112] Williams 1 at [112] - [115].

I do not find this evidence persuasive. The approach described by Dr Williams in this case is based largely on knowing the desired formulation, and essentially removing or adding ingredients to arrive at the present invention defined by Claims 1 and 15. I consider such an approach to be tainted by hindsight. I therefore consider that the claims do not lack inventive step in view of Matsumori.

Conclusion on Inventive Step

The claims lack inventive step in view of each of Chavez and Chiba.

Utility

Section 18(1)(c) requires that the invention is useful. The approach used in deciding whether the claimed invention is useful is to firstly determine what is the promise of the invention derived from the whole of the specification, and secondly, by following the teaching of the invention, to establish whether the invention, as claimed in the patent, attains the result promised for it by the patentee. Everything that is within the scope of a claim must be useful, that is, it must attain the result promised for the invention by the patentee.[113]
[113] Artcraft Urban Group Pty Ltd v Streetworx Pty Ltd [2016] FCAFC 29 at [120] – [121].

The Opponent submitted that the promise of the invention is stable compositions, but it has not been met since the compositions of the invention are less stable than other formulations of fingolimod. They noted that Dr Williams considered that the exclusion of a sugar alcohol actually appeared to be detrimental based on the experimental results given in the “Rane declaration” (DBW-13), a document that was filed during the prosecution of US patent application 12/189323 which relates to fingolimod formulations containing sugar alcohols. The results indicated that mannitol, a sugar alcohol, provides a more stable formulation than both MCC and lactose.

I do not find this submission persuasive. The specification indicates that there is a need for formulations comprising “an S1P receptor modulator that is well-adapted for oral administration in a solid form”, which can be easily swallowed and that can provide dosage forms of various dosage strengths.[114] The specification goes on to state:
“The present invention provides various pharmaceutical compositions containing an S1P receptor modulator which addresses these needs. The compositions provide a convenient means of systemic administration of S1P receptor agonists and other modulators, do not suffer from the disadvantages of liquid formulations for injection or oral use, and have good physicochemical and storage properties. In particular, the compositions of the present invention may show a high level of uniformity in the distribution of the S1P receptor modulator throughout the composition, as well as high stability.”
[114] Specification at page 1, paragraph 5.
I do not understand these statements as promising any better or improved formulations of fingolimod compared to any other formulation(s). The above statement indicates a high level of uniformity and stability is provided by MCC, but I have no evidence to suggest that the claimed formulations are not considered to have a “high” level of stability. The evidence merely shows that the claimed formulations are not as stable as others. This is not inconsistent with the promises made in the specification.

I consider that the Opponent has not made out their case that the claimed invention has failed to attain the promise of the invention.

Manner of manufacture

Section 18(1)(a) requires that the invention is a manner manufacture within the meaning of section 6 of the Statute of Monopolies. The gist of the Opponent’s submissions was that on the face of the specification the claimed invention lacked the necessary quality of newness and inventiveness. At most, they argued, the invention is a mere collocation. To this end they argued that there is no evidence of synergy and the claimed invention works no better than the sum of its parts.

While I have determined that the claims lack inventive step, this determination was made based on information made available under subsection 7(3). There is nothing on the face of the specification that would establish that the invention is not a manner of manufacture. I do not find the Opponent’s submission that the invention is a mere collocation persuasive.
While the formulation using MCC is less stable than those using mannitol, this is not a basis for concluding that it is not an invention. There is no requirement that the qualities of newness and inventiveness in an invention be an improvement or that the invention be better. Inventiveness is a question of whether the matter is obvious – a claimed invention need not be “better” for it to be considered inventive.
In any case, I do not consider that the claims define a mere collocation of integers. Such a collocation would require that there is no working interrelationship between the individual integers. In this case MCC acts as a carrier for the active ingredient. The process of formulation results in an intimate mixture of the ingredients that enables the relatively low dosage amount to be administered to the patient in a convenient manner and for it to remain relatively inert during storage. Upon administration the formulation works to release the drug in the body. I consider that the mixture and the manner it works when administered is a sufficient working inter-relationship to satisfy the requirement that it be an invention under section 18(1)(a).
I am satisfied that the claims are for a manner of manufacture.

Fair basis

Subsection 40(3) requires that the claims are fairly based on the matter described in the specification. For fair basis the claims must be consistent with what the specification as a whole describes as the invention.[115]
[115] Kimberley Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; 207 CLR 1.

The Opponent submitted that Claim 15 is not fairly based in that it defines a solid pharmaceutical composition comprising fingolimod and MCC in the absence of both a sugar alcohol and a sugar, but the specification is completely silent in relation to the omission of sugar. To the contrary any reference to sugar in the specification suggests it is an inclusion in the formulations of the invention rather than an omission and there is no suggestion of any disadvantage in including sugar in the composition.
I acknowledge that the specification makes no specific reference to formulations omitting sugars. However, the specification describes formulations comprising a sugar alcohol. There is no specific exclusion of sugars. Therefore, the broadest definition includes both a formulation comprising a sugar, and the alternative embodiment in which the sugar is absent. Claim 15 is therefore not inconsistent with the invention described in the specification. I consider Claim 15 is therefore fairly based.

Clarity

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.[116]
[116] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59.

The Opponent submitted that Claim 14 lacks clarity since it is appended to Claim 1 which requires the absence of a sugar alcohol but defines a composition substantially with reference to any one of the examples. Some examples include sugar alcohols which they argued makes the claim fundamentally unclear.
I disagree. The claim is an omnibus claim, which was allowable prior to the Raising the Bar Act. I consider it clear that the reference to the examples is limited only to those that meet the definition provided in Claim 1. The Opponent has not made out this ground.

Conclusion

The claims lack inventive step. The opposition is successful on that ground. None of the other grounds of opposition are successful.

Given my determinations above, I see no basis on which a valid patent could be granted. Nevertheless, I allow the Applicant the opportunity to propose amendments within 2 months from the date of this decision.

Costs

The parties submitted that costs should follow the event. The opposition argued by Arrow Pharmaceuticals Pty Ltd in relation to inventive step has been successful. I therefore award costs according to Schedule 8 against the Applicant, Novartis AG.

Dr Leslie F. McCaffery

Deputy Commissioner of Patents

Annex: Claims

1. A solid pharmaceutical composition suitable for oral administration in the form of a tablet or a capsule, comprising:

(a) 0.1 to 10% by weight of the S1P receptor modulator 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form; and

(b) 75 to 99.99% by weight microcrystalline cellulose (MCC)

in the absence of a sugar alcohol.

2. A composition according to claim 1, comprising 90 to 99.5% by weight MCC.

3. A composition according claim 1 or claim 2, comprising 0.5 to 5% by weight of the S1P receptor modulator 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form.

4. A composition according to any one of claims 1 to 3, wherein the S1P receptor modulator is 2-amino-2-[2-(4-octylphenylethyl)]propane-1,3-diol hydrochloride.

5. A composition according to any one of the preceding claims for the treatment and prevention of multiple sclerosis.

6. A method of treating or preventing multiple sclerosis comprising administering to a subject in need thereof a composition according to any one of claims 1 to 4.

7. A method of treating or preventing an autoimmune disease comprising administering to a subject in need thereof a composition according to any one of claims 1 to 4.

8. A method of protecting multiple sclerosis subjects against neurodegenerative brain inflammation, comprising administering to a subject in need thereof a composition according to any one of claims 1 to 4.

9. The use of a composition according to any one of claims 1 to 4 in the preparation of a medicament for the treatment or prevention of multiple sclerosis.

10. The use of a composition according to any one of claims 1 to 4, in the preparation of a medicament for the prevention or treatment of an autoimmune disease.

11. The use of a composition according to any one of claims 1 to 4 in the preparation of a medicament for protecting multiple sclerosis subjects against neurodegenerative brain inflammation.

12. A process for producing a pharmaceutical composition of any one of claims 1 to 4, comprising the steps:
(a) mixing S1P receptor modulator with a microcrystalline cellulose,
(b) milling the mixture obtained in (a); and
(c) mixing the milled mixture obtained in (b) with a lubricant.

13. A pharmaceutical composition prepared by the process of claim 12.

14. A solid pharmaceutical composition according to claim 1, substantially as hereinbefore described with reference to any one of the Examples.

15. A solid pharmaceutical composition suitable for oral administration in the form of a tablet or a capsule, comprising:

(a) 0.1 to 10% by weight of the S1P receptor modulator 2-amino-2-[2-(4- octylphenylethyl)]propane-1,3-diol, in free form or in a pharmaceutically acceptable salt form; and

(b) a microcrystalline cellulose (MCC)

in the absence of both a sugar and a sugar alcohol.

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Citations

Arrow Pharmaceuticals Pty Ltd v Novartis AG [2019] APO 22

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Metso Sweden AB v Outotec Pty Ltd [2019] APO 25

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Novartis AG v Arrow Pharmaceuticals Pty Ltd (No 2) [2020] FCA 1475

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