Alphapharm Pty Ltd v Yeda Research & Development Co., Ltd - [2017] APO 41

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Alphapharm Pty Ltd v Yeda Research & Development Co., Ltd [2017] APO 41

Patent Application: 2013203367

Title:Low Frequency Glatiramer Acetate Therapy

Patent Applicant: Yeda Research & Development Co., Ltd

Opponent: Alphapharm Pty Ltd

Delegate: Dr Leslie F. McCaffery

Decision Date: 15 August 2017

Hearing Date: 3 May 2017, in Sydney

Catchwords: PATENTS – section 59 – opposition to the grant of a patent – grounds of clarity, fair basis, novelty, inventive step – section 40 – the claims are clear – some claims found to lack fair basis – novelty – the citation discloses the essential features of the claim but is not specific enough to provide clear and unmistakable directions – inventive step – lack of inventive step not established – further submissions sought from parties on inventive step and manner of manufacture – Claim 66 not for a manner of manufacture – costs awarded – applicant provided 2 months from the date of the decision to propose amendments.

Representation: Counsel for the applicant: Mr Tony Bannon SC
Patent Attorneys for the applicant: Mr Rob Clark, Mr Philip Kerr, Mr Andrew Wiseman and Ms Tracey Lu of Allens Patent and Trade Mark Attorneys
Counsel for the opponent: Mr Bruce Caine QC and Mr Benjamin Fitzpatrick
Patent Attorney for the opponent: Ms Lucy Hartland of DibbsBarker

IP AUSTRALIA

AUSTRALIAN PATENT OFFICE

Patent Application: 2013203367

Title:Low Frequency Glatiramer Acetate Therapy

Patent Applicant: Yeda Research & Development Co., Ltd.

Date of Decision: 15 August 2017

DECISION

The opposition by Alphapharm Pty Ltd is successful on the ground of fair basis.

Claims 1, 2, 7, 8, 10, 22, 23, 27, 28, 31 to 64 and 66 lack fair basis.

Claim 66 is not for a manner of manufacture.

The opposition is unsuccessful on the grounds of clarity, novelty and inventive step.

Yeda Research & Development Co., Ltd has 2 months from the date of this decision to propose amendments. Costs according to Schedule 8 awarded against Yeda Research & Development Co., Ltd.

REASONS FOR DECISION

Background

Application 2013203367 (the present application) was filed on 10 April 2013 by the applicant, Yeda Research & Development Co., Ltd (Yeda). It is a divisional application of 2013201328 which in turn is a divisional of 2010284666. While nothing turns on the point in this decision, certified innovation patents 2015101563, 2015101564 and 2016100455 and standard application 2016216657 are also divisionals of 2013201328. Parent application 20132012328 is currently also under opposition, while “grandparent” 2010284666 was withdrawn following the filing of a notice of opposition by Alphapharm Pty Ltd (Alphapharm).

The present application claims priority from two US Provisional applications: 61/274,687 (20 August 2009) and 61/337,612 (30 August 2010). The priority claim was not challenged and I therefore accept these as providing the priority dates for the present application.

The present application was advertised as accepted on 25 June 2015. A request for amendment of the claims was filed on 18 September 2015. This amendment was allowed on 1 March 2016. A notice of opposition under Section 59 of the Patents Act 1990 (the Act) was filed by Alphapharm on 25 September 2015, and a statement of grounds and particulars was subsequently filed on 23 December 2015. The statement of grounds and particulars was amended on 16 November 2016.

The statement of grounds and particulars sets out the following grounds of opposition: novelty, inventive step and section 40 (clarity and fair basis). These grounds were pressed at hearing. The hearing was held on 3 May 2017 at the offices of Allens Patent and Trade Mark Attorneys. Yeda was represented by Mr Tony Bannon and Alphapharm was represented by Mr Bruce Caine and Mr Ben Fitzpatrick.

Onus

The request for examination for the present application was filed on 10 April 2013. Accordingly substantive amendments of the Act brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act2012 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 Biolab Inc. (2000) 50 IPR 305 at [67]; Commissioner of Patents v Sherman (2008) 79 IPR at [18].

Evidence

The parties relied on the following evidence:

Evidence in support comprising declarations from Professor John Owen King (King 1); Dr Richard C Oppenheim (Oppenheim 1); and Ms Helen Grimes (Grimes 1).

Evidence in answer comprising a declaration from Professor Tjalf Ziemssen (Ziemssen).

Evidence in reply comprising declarations from Professor King (King 2); Dr Oppenheim (Oppenheim 2); and Ms Grimes (Grimes 2).

I will refer to the relevant parts of the evidence as required.

Construction: legal principles

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.”[2]
[2] Eli Lilly and Co Ltd v Apotex Pty Ltd [2013] FCA 214; 100 IPR 451 at 482 [139].
Middleton J went on to provide a useful summary of relevant principles:[3]
[3] 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.

10. 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.”[4]
[4] Ibid at [144].

11. These are the principles that I will apply in this determination.

The person skilled in the art

12. 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.[5] 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...”[6]
[5] General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd (1971) 1A IPR 121 at 134.
[6] Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70]-[71].

13. The person skilled in the art is assumed to be a skilled but unimaginative and non-inventive worker in the field of the invention.[7] One formulation describes them as “those likely to have a practical interest in the subject matter of [the] invention”.[8] 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”.[9]

[7] Minnesota Mining and Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253 at 293.

[8] Catnic Components v Hill & Smith Ltd [1982] RPC 183.

[9] Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59 at 153; (2002) 212 CLR 411 at 465.

14. As noted above, evidence was provided by several declarants:

Professor John Owen King: Professor King is an Associate Professor at the Centre for Neuroscience at the University of Melbourne, Chairman of the Royal Melbourne Hospital (RMH) Neuroscience Foundation and a Consultant Neurologist at RMH. He has specialised in Neurology since 1975 with particular focus on multiple sclerosis (MS). Alphapharm stated that he has authored many peer-reviewed journal articles and other publications on the topic of MS and been involved in a number of phase II and phase III clinical trials of therapeutic agents for the treatment of MS.

Dr Richard C Oppenheim: Dr Oppenheim is the Principal of a pharmaceutical consultancy firm. He was previously employed by R. P. Scherer Australia and the Victorian College of Pharmacy.

Professor Tjalf Ziemssen: Professor Ziemssen is the Director of the Centre of Neuroscience, Professor of Clinical Neuroscience and Vice Chair of the Department of Neurology at the Carl Gustav University Hospital in Dresden, Germany. He founded the Multiple Sclerosis Centre at the University Hospital, the largest MS teaching centre in Germany, in 2004.

15. There was some dispute between the parties as to the weight that each declarant’s evidence could be given. Yeda accepted that Professor King has relevant expertise to provide evidence, but submitted that the evidence of Dr Oppenheim was largely irrelevant. Alphapharm acknowledged that the art is international in nature but submitted that Professor Ziemssen had never treated patients suffering MS in Australia and therefore was not well-placed to provide evidence relating to patient compliance in Australia. Alphapharm also noted that Professor Ziemssen is a consultant to and received financial support from Teva, a company related to Yeda.

16. I have taken these submissions into account in my consideration of the evidence. Details have been provided where I have needed to consider circumstances such as these in order to determine the weight which certain evidence can be given.

Background

17. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). Typical symptoms include: motor weakness; partial paralysis of the limbs; tingling; prickling or burning sensations on the skin; blurred vision or loss of sight; loss of muscle coordination; and bladder dysfunction.

18. Diagnosis and tracking of MS can be carried out using one or more of magnetic resonance imaging (MRI), assessment of the accumulation of disability, and the rate and severity of relapses. Up until the early 2000s, the “Poser criteria” required evidence of two relapses of at least 24 hours’ duration and more than one month apart, together with clinical evidence of lesions in at least two different parts of the CNS in order for there to be a “clinically definite” diagnosis of MS.[10] From 2001 diagnosis used the “McDonald criteria”, which focussed on the dissemination of neurological lesions in both time and space.[11] MRI is typically used to monitor the number, location and volume of gadolinium-enhancing lesions on T1-weighted images, hyperintense lesions on T2-weighted images and hypointense lesions on T1-weighted images on MRI scans of the brain and spinal column repeated at regular intervals.[12] Formal measures of disability to monitor patient progress include the “Expanded Disability Status Scale” (EDSS), the Ambulation Index and the EuroQoL (EQSD) questionnaire.[13] I note that the claims use some of these measures in order to characterise the invention.

[10] King 1 at [63].

[11] Ibid at [64].

[12] Ibid at [74].

[13] Ibid at [76].

19. MS may present as several different types:[14] benign MS; relapsing-remitting MS (RRMS); secondary progressive MS (SPMS); primary progressive MS (PPMS); and progressive-relapsing MS (PRMS). RRMS is the most common form of MS, and is characterised by sporadic exacerbations or relapses, as well as periods of remission. Approximately 80% of people diagnosed with MS in Australia have RRMS at the time of diagnosis.[15] Patients experience intermittent, unpredictable relapses characterised by the appearance of new symptoms and/or increased severity of existing symptoms. Relapses last for various periods of time (days up to months) and are followed by partial or total remission. The time between relapses can vary, with the disease in some cases being inactive for months or years at a time.

[14] Specification at pages 1 to 3.

[15] King 1 at [55].

20. Many patients with RRMS will develop SPMS. Patients with SPMS experience sustained clinical manifestations of their disease, with functional disability becoming more severe over time. The distinction between relapsing and progressive forms of the disease is important as the drugs used for treatment of MS tend to be more effective with relapsing forms than progressive forms.[16]

[16] Ibid at [60].

21. Patients may also have a single episode of symptoms consistent with MS, and a single neurological lesion consistent with MS, but do not fulfil the McDonald criteria necessary for a firm diagnosis to be made at the time. This patient group is described as presenting with a “clinically isolated syndrome” (CIS).[17] Patients presenting with CIS are likely to receive a formal diagnosis of MS at a later time. It was also expected that the treatments used for RRMS would provide them the same benefits.[18]

[17] Ibid at [79].

[18] Ibid at [81].

22. Prior to August 2009, glatiramer acetate (GA), which is marketed under the tradename Copaxone®, was used for treatment of RRMS, including patients who have experienced a first clinical episode and have MRI features consistent with MS.[19] The recommended dose was 20 mg administered by subcutaneous injection once daily.

[19] Ibid at [86].

Construction of the specification and claims

23. The invention relates to the treatment of MS using GA.

24. The specification states that existing GA therapies involving subcutaneous injection are inconvenient. Injection site reactions are the most frequent adverse reactions observed during GA therapy, and include erythema, pain, mass, puritus, edema, inflammation and hypersensitivity. Alternative strategies to address these drawbacks are said to be limited by the acceptable injectable volume (no more than 1-2 mL is permitted), drug degradation at the injection site resulting in lower bioavailability, entrapment in interstitial spaces resulting in localised irritation, precipitation of the drug, and concentration-dependent adverse effects. Variation of the frequency of administration is said to be unpredictable and require empirical testing.[20]

[20] Specification at pages 36 to 37.

25. The specification is said to disclose “an effective low frequency dosage regime of GA administration to patients suffering from a relapsing form of multiple sclerosis, including patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis”.[21]

[21] Ibid at page 4, lines 26 to 30.

26. Various embodiments of the invention are described and claimed. For reference a copy of the text of the independent claims is given in Appendix A. Specific issues relating to the construction of the claims are discussed in greater detail in the following section. In short the specific embodiments described and claimed include methods and uses of GA for:

alleviating a symptom of RRMS
reducing the frequency of relapses
treating RRMS
reducing the frequency and severity of post-injection reactions and injection site reactions of GA therapy
increasing the tolerability of GA treatment.

27. GA is administered as a 40 mg dose, wherein the various embodiments include one or more of the following characteristics:

A 1 mL dosage amount
A pH in the range of 5.5 to 8.5
Containing mannitol and having a pH of 5.5 to 7.0.

28. The patient groups include:

Patients suffering RRMS
Patients who have experienced a first clinical episode and are at high risk of developing clinically definite MS
Patients who have experienced a first clinical episode and have at least two MRI lesions suggestive of MS.

29. The claims also include a product consisting of prefilled syringes being “in a pattern of three unit dosages”. This is further discussed below.

30. Prima facie all of the features noted above in the methods, uses, dosage forms and patient groups are known in the art. The invention appears to lie in the dosage regime which is defined in different claims as indicated under the following dot points.

Three subcutaneous injections over a period of seven days with at least one day between every subcutaneous injection (independent Claims 1, 2, 40, 45 to 50, 52, 54 and 56 to 59)
Three subcutaneous injections every (or each) week with at least one day between every subcutaneous injection (independent Claims 3, 5, 6, 9, 11, 24, 25).

31. In effect, a dosage schedule of three injections in a seven day period with at least one day between injections would require that there be one period of two days between consecutive injections. For example if injections were administered on days 1, 3 and 5, then no injections would be administered on days 6 and 7.

Administering a subcutaneous injection on three days during each week (independent Claims 7, 8 and 10).

32. Claims 7, 8 and 10 define methods in which administration is performed three times each week. In contrast to other claims there is no specific definition of there being at least one day between injections. I take these claims to include, for example, dosage regimes including administration on consecutive days during the week.

Section 40 Issues

33. Subsection 40(3) requires that the claims must be clear and succinct and fairly based on the matter described in the specification.

34. The claims of a specification are construed according to the established rules of construction. 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.[22] However subsection 40(3) does not mandate the use of precise and absolute terms in the claims. Rather:

“Lack of precise definition in claims is not fatal to their validity, so long as they provide a workable standard suitable to their intended use. The consideration is whether, on any reasonable view, the claim has meaning. In determining this, the expression in question must be understood in a practical, common sense manner. Absurd constructions should be avoided and mere technicalities should not defeat the grant of protection.”[23]

[22] Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59.
[23] Flexible Steel Lacing Company v Beltreco Ltd [2000] FCA 890; (2000) IPR 331.

35. Subsection 40(3) also requires that the claim be fairly based. A claim will lack fair basis if the claims are not consistent with what the specification as a whole describes as the invention. The general principle for fair basis is set out in Kimberly-Clark v Arico as:

“where the issue is one under a 40(3) of ‘fair basing’ of a claim, what the 1990 Act requires is a comparison between the matter described in the specification and the claim which defines the scope of the monopoly”.[24]
[24] Kimberly-Clark Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at 15; (2001) 207 CLR 1.

36. The assessment requires a consideration of whether there is a “real and reasonable disclosure” of the invention as defined by the claim,[25] or whether the claims “travel beyond the subject matter of the invention”.[26]

[25] Société Des Usines Chimiques Rhône-Poulenc v Commissioner of Patents [1958] HCA 27; (1958) 100 CLR 5.

[26] Olin Corporation v Super Cartridge Co Pty Ltd (1977) 180 CLR 236.

37. Alphapharm made submissions under section 40 against Claims 7, 8, 10 and 66. I have also considered the fair basis of Claims 1, 2, 40, 45 to 50, 52, 54, 56 to 59 and 61 pursuant to the submissions made in relation to the construction of these claims.

Claims 7, 8 and 10 (and dependent claims)

38. Alphapharm submitted that Claims 7, 8 and 10 travelled beyond the disclosure of the specification, and were not fairly based, since it was evident from the specification that at least one day was required between every subcutaneous injection in order to achieve the stated aim of reducing the frequency of post-injection reactions. Yeda disputed this but did not provide detailed arguments in this response. I note that elsewhere in their submissions they appear to acknowledge that the subcutaneous administration injection of 40mg of GA three times a week with at least one day between each injection is central to the claims.

39. In the present case, the language of the Summary of the Invention mirrors the wording of Claim 7,[27] Claim 8,[28] and Claim 10.[29] However the consideration of fair basis is not “a superficial test based solely on the presence or absence of words”.[30]Rather, a consideration must be made as to what the specification read as a whole discloses as the invention.[31]

[27]Specification at page 5B, lines 15 to 19.

[28] Ibid at page 5B, lines 20 to 25.

[29] Ibid at page 5C, line 7 to 13.

[30] Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth [2011] FCAFC 132.

[31] Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at 87; (2004) 217 CLR 274.

40. Under the Detailed Description of the Invention, the invention is said to provide:

“a method of alleviating a symptom of relapsing-remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis comprising administering to the human patient three subcutaneous injections of a therapeutically effective dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection so as to thereby alleviate the symptom of the patient” [32] [emphasis added].
[32] Specification at page 8, lines 2 to 12.

41. The specification goes on to provide various injection schedules, all of which have at least one day between each injection during the seven day period.[33] All subsequent discussion of dosage schedules provided in the Detailed Description part specifically sets out that there is at least one day between injections.

[33] Ibid at page 8, lines 14 to 20.

42. The Experimental Details section describes a clinical trial “to assess the efficacy, safety and tolerability of Glatiramer Acetate (GA) injection 40mg/ml administered three times weekly by subcutaneous injection over placebo in a double-blind design”.[34] The study design sets out that the study compares 40 mg s.c. three times weekly against a matching placebo three times weekly. The description of the clinical trial does not give specific details of the schedule followed for the three weekly doses and whether there is at least one day between injections. However in the Discussion section, it is stated that:

“Based on the performance of the dosage regime in these studies, the administration of three s.c. injections over a period of seven days with at least one day between every injection is also expected to work in the treatment of patients who have experienced a clinically isolated syndrome (CIS)”[35] [emphasis added].
[34] Specification at page 20, lines 4 to 9.
[35] Ibid at page 37, lines 13 to 18.

43. I take this to mean that the clinical trial followed a dosage schedule in which three injections were administered over a seven day period with at least one day between each injection. Furthermore, the discussion section states that a significant drawback of the existing treatments is the need to administer daily injections, which can be inconvenient and result in adverse reactions including injection-site reactions.[36] While there is a broad disclosure of any schedule of administration of three injections over the period of a week in the summary of the invention, I consider that the only “real” disclosure that is said to overcome the obstacles and drawbacks of the existing GA treatments requires at least a day between injections.

[36] Ibid at page 36, lines 5 to 9.

44. Accordingly I consider that Claims 7, 8 and 10 lack fair basis. Claims 22, 23, 31 to 39, 42, 44, 51 and 60 to 64 also lack fair basis since these are appended to these claims but do not define a period of one or more days between injections.

45. I also note that Claim 7 defines the administration of three subcutaneous injections of a 40mg/ml dose of GA, but does not define a volume. This also travels beyond the invention described in that the concentration defined does not necessarily result in the administration of a 40mg dose.

Claim 66

46. Alphapharm submitted that Claim 66 was not clear and was not fairly based in that it was not limited by any particular means of administration, volume of formulation, use or dosage regime.

47. Claim 66 defines:

A pharmaceutical product consisting of unit dosages in a pattern of three unit dosages each consisting of a prefilled syringe containing 40mg/ml glatiramer acetate and mannitol in a pharmaceutical composition having a pH in the range of 5.5 to 7.0.

48. The construction given to the claim is a key consideration in the determination of whether the claim meets the requirements of Section 40. None of the declarants provided evidence in relation to the meaning of Claim 66, so there is no evidence as to what the person skilled in art would understand the claim to define from the language the drafter used. Furthermore with the exception of the consistory statement corresponding to the claim there is no further clarification in the description as to the substance of the claim.

49. At first blush the claim appears to be directed to a product that consists of three prefilled syringes. However Yeda argued that the expression “unit dosages in a pattern of three unit dosages”, when read in light of the specification, would be understood by the skilled person to mean the application of doses three times in a seven day period with at least one day between each dose.[37] If this construction were to be followed the submission suggests to me that the term “in a pattern of three unit dosages” would import a temporal limitation akin to the claim defining the product when used in such a regime.

[37] Yeda’s written submissions for hearing at [108].

50. I do not find Yeda’s submissions on this point persuasive. Even reading the specification as a whole, there is nothing in the specification that would lead the skilled addressee to take the term “pattern of three unit dosages” as incorporating method steps into the claim, let alone the specific method steps suggested by Yeda. To limit the scope of the claim in such a manner would, in my opinion, require an impermissible gloss being given to the claim.[38]

[38] Eli Lilly and Co Ltd v Apotex Pty Ltd supra at [144].

51. I therefore construe the claim as defining prefilled syringes presented or associated in a group of three. The definition of a single “pharmaceutical product” suggests that there is a specific grouping of the three syringes, but I do not consider that this necessarily requires that they be associated in a single package or kit. For example three separate dosages associated as a weekly treatment would fall within the scope of the claim. Moreover as discussed above, I do not construe the claims to have any temporal requirement such as being limited to the dosages when used in a particular treatment regime. The formulation within the prefilled syringe is characterised by the particular components (GA and mannitol), the concentration of GA (40mg/ml) and by the pH (5.5 to 7.0).

52. As I have been able to give meaning to the claim I consider it does not lack clarity.

53. Turning now to the fair basis of the claim, I note that in the case of Claims 7, 8 and 10 the absence in these method claims of the specific dosage regime requirement of a day between injections resulted in the claims lacking fair basis. However in the case of Claim 66 I have construed the claim to define a product per se which comprises three prefilled syringes. There is no apparent dispute that prefilled syringes containing 40mg/ml glatiramer acetate and mannitol in a pharmaceutical composition having a pH in the range of 5.5 to 7.0 are known, and there is no suggestion in the specification that the invention lies in this specific dosage unit. One consideration is therefore whether the kit or pack of three prefilled syringes travels beyond the invention described and particularly whether this “product” claim must include the dosage regime and intended treatments in order to be fairly based.[39]

[39] Atlantis Corporation Pty Ltd v Schindler (1977) 39 IPR 29.

54. To this end the description does disclose a “pattern” of dosage – each of the methods described requires the administration of three 40 mg subcutaneous injections in a week. The presentation of the dosage forms in a pattern of three as defined in Claim 66 in essence equates to a weekly dosage that could be used in such a method. I consider that the method of administration requires a day between injections, but the claimed product per se comprising three doses in my opinion does not travel beyond the disclosure of three dosage units described in the specification.

55. However the claim also defines that the syringe contains 40mg/ml of GA, which is a measure of the concentration of GA in the formulation. There is otherwise no definition of the volume of the formulation held by the syringe. The claimed invention is defined as “consisting of unit dosages in a pattern of three unit dosages” (emphasis added). The invention as described lies in the administration of a 40mg dose by three subcutaneous injections over a period of a week with at least a day between injections. Each of these injections is a single unit dosage. As noted above the claim is characterised by the GA concentration (40mg/ml) but is not limited by a volume, and therefore is not limited to a 40mg unit dose. Therefore I consider that the claim lacks fair basis because it travels beyond the subject matter disclosed in the specification inasmuch as the unit dosages in the pattern of three are not limited to a 1ml volume.

Claims 1, 2, 40, 45 to 50, 52, 54, 56 to 59 and dependent claims

56. In addition to the specific Section 40 matters raised by Alphapharm, the construction of Claims 1, 2, 40, 45 to 50, 52, 54, 56 to 59 and dependent claims came into question under the ground of novelty. For example, Claim 1 defines:

A method of alleviating a symptom of relapsing-remitting multiple sclerosis in a human patient … said method comprising administering to the human patient three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection so as to thereby alleviate the symptom of the patient.

57. Alphapharm submitted that in context and accepting its plain meaning, the reference to the administration of three subcutaneous injections over a period of seven days with at least one day between each injection should be understood as encompassing injections that are administered over a single seven day period within the ongoing treatment regime. The key issue here appears to lie in whether the skilled person would construe the defined methods as:

A single one week period in which three subcutaneous injections are administered,
An on-going regime of three subcutaneous injections every week, or
An on-going regime in which three subcutaneous injections are administered in one or more week(s).

58. In this regard, Professor King stated that he understood the reference to refer to a single seven day period and noted the use of the indefinite article in “a period of seven days”. [40] He contrasted this with the reference in other parts of the application to the treatment being carried out over “at least 6 months”. At hearing Alphapharm also highlighted the references to “every week” and “each week” in other claims, which require all seven day periods to follow the defined regime. Professor King also noted (in his discussion of novelty) that an every other day (EOD) regime would result in three injections being administered on alternate weeks (that is a pattern of 4, 3, 4, 3 and so on).[41] On this point I note that I have been mindful to construe the claims independent of the teaching in the cited prior art, and having construed the claim to apply that construction consistently in all considerations.

[40] King 1 at [250].

[41] King 1 at [251].

59. Professor Ziemssen stated that the skilled person would not understand the reference to be a dosing schedule for one week only.[42] He noted that MS is a lifelong chronic disease, so treatment will always occur over a period far longer than a week. However his evidence did not address whether a skilled person would read these claims as being a dosage regime using three injections every week. At hearing Yeda submitted that the absence of any specific limitation on the length of treatment would not be read to limit those claims to a week or to only claim a specific week within the extended treatment period, but that those claims are unlimited in relation to the period of potential repetitions of the seven day long dosage cycle. Furthermore, Claim 1, for example, requires that the method “alleviate the symptoms” in patients. They submitted that a series of three doses would not be understood to, of itself, achieve such an outcome.

[42] Ziemssen at [80]-[81].

60. I agree with Yeda inasmuch as GA therapy appears from the evidence to be of a long-term nature, and indeed such a long-term treatment would be necessary in order to achieve the outcomes defined by the claim. A common sense approach to the interpretation would preclude a construction where the treatment is carried out for only one week and consists of only three doses and no more. On that basis I do not consider that these claims are defining treatment for only one week.

61. However, the claims in question define methods that comprise a three times weekly administration of three subcutaneous injections. The open-ended terminology does not preclude a long-term treatment regime where there is a different dosage frequency used in other weeks. In contrast to the terminology used in other claims there is no clear limitation that this is an on-going regime of only three times weekly injections.

62. On balance I read that Claim 1 defines a treatment regime in which at least one week within the regime consists of three subcutaneous injections within that week. I do not understand this to mean that the on-going regime is limited to three subcutaneous injections each or every week. It follows that the claim travels beyond the matter described in the specification. A similar consideration applies to other claims that do not include a clear limitation of the treatment regime being three times every week.

63. I therefore consider that Claims 1, 2, 40, 45 to 50, 52, 54, 56 to 59 lack fair basis. Claims 27, 28, 31 to 39, 41 to 44, 51, 53, 55 and 60 to 64 lack fair basis as these are dependent claims that are not limited to three subcutaneous injections every week.

Novelty

64. Under subsection 7(1), an invention is taken to be novel unless it is not novel in the light of the prior art base. Information in a document forms part of the prior art base for the purposes of novelty if it was published before the priority date of a claim. Alphapharm made submissions in relation to only one document, and specifically that claims 1, 2, 40, 45 to 50, 52, 54, 56 to 59 and 61 lack novelty in view of US2007/0161566 (Pinchasi).[43]

[43] Exhibit JK-8: US2007/0161566.

65. It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aicken J:

“The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement”.[44]

[44] Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228 at 235.

66. This test is satisfied if the alleged anticipation discloses all the essential features of the invention claimed.[45] Furthermore a prior publication may not explicitly disclose all of the features of the invention, but could still deprive the claimed invention of novelty if the missing information or feature is inherent:

“If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness.”[46]

[45] Nicaro Holdings Pty Ltd v Martin Engineering Company [1990] FCA 40; 16 IPR 545 at 549.

[46] The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited supra at 485 to 486.

67. Pinchasi discloses treatment of MS by “periodic” subcutaneous injection of a 40mg dose of GA. Two different periodic dosage regimes are disclosed: the first involves daily administration of a single dose of 40mg GA, while the second involves subcutaneous injection EOD (paragraphs [0021] and [0032] and Claim 3).

68. The dosage described by Pinchasi is presented as 40mg GA and 40mg mannitol in 1ml of water. The pH of the formulation used in the example is not specified but the general description states that it may be in the range of 5.5 to 8.5. The methods are said to alleviate symptoms of RRMS, including frequency of relapses and MRI-monitored disease activity such as reducing mean number of Gd-enhancing lesions and reducing the mean number of T2 lesions.

69. An EOD dosage regime results in a repeating dosage pattern of 4, 3, 4, 3 and so on and furthermore comprises at least one day between doses and therefore meets these limitations of the present claims. Yeda argued that Pinchasi required a dosage of 4 injections on alternating weeks, and therefore even if the consideration were limited to a single seven day period, it would be understood as directing either three- or four-times weekly dosage. They argued that the disclosure provided a direction that was capable of infringing the claim, but equally as likely to be carried out in a manner that would not. I consider this line of argument would be persuasive if the claims in question were construed as defining a one week only treatment and not as part of an on-going treatment. However I construe the present claims as defining (on-going) treatment regimes which include at least one week in which 40mg GA is administered three times during that week by subcutaneous injection, with at least one day between injections.

70. In my opinion the EOD regime described in Pinchasi meets this particular limitation – put simply the regime comprises a week of four doses followed by a week of three doses. However I do note here that the novelty consideration hinges on the construction I have given the claims. As a result of that construction I have determined that these claims lack fair basis. If the claims were to be clearly limited to a regime in which the three times weekly dose were administered every week, then the novelty consideration here would be moot. Pinchasi in no way discloses a regime consisting only of three times weekly injections.

71. As a consequence of my construction, Pinchasi discloses all of the essential features of the above claims. But in order to deprive a claim of novelty, Pinchasi must also:

“contain clear and unmistakeable directions to do what the patentee claims to have invented... A signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.”[47]
[47] The General Tire& Rubber Company v The Firestone Tyre and Rubber Company Limited supra at 486.

72. The only specific example of a dosage regime given by Pinchasi relates to a nine month trial of a daily dosage regime of 40mg GA. There is no specific example using an EOD dosage regime. The key consideration is whether the reference to EOD dosing in Pinchasi provides sufficiently clear and unmistakable directions to the claimed invention.

73. As highlighted by the full bench in AstraZeneca v Apotex:

“The metaphor of planting the flag has been taken up in this Court. For example, in ICI Chemicals, the Full Court at [51], after noting the metaphor, remarked that, in that case, the appellant’s argument involved the skilled addressee rummaging through a “flag locker” to find a flag which the prior art document possessed and could have planted. In Apotex Pty Ltd and Another v Sanofi-Aventisand Another [2008] FCA 1194; (2008) 78 IPR 485 (“Sanofi-Aventis (2008)”), Gyles J at [91] adopted a different metaphor, remarking that “anticipation is deadly but requires the accuracy of a sniper, not the firing of a 12 gauge shotgun”. Each metaphor underlines the importance of the specificity required in order for a prior art document to anticipate an invention as claimed.”[48]

[48] AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; 226 FCR 324; 312 ALR 1; 107 IPR 177.

74. Consistent with these principles a broad disclosure that encompasses the claimed invention may not necessarily anticipate a later, more specific claim.[49] A classic formulation of the level of disclosure required of a prior art document was given by Lord Westbury in Hill v Evans:

“The question then is, what must be the nature of the antecedent statement? I apprehend that the principle is correctly thus expressed; - the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand and be able practically to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful”.[50]
[49] Sanofi-Aventis AustraliaPty Ltd v Apotex Pty Ltd (No 3) [2011] FCA 846; 196 FCR 1 at [180]; 92 IPR 320.
[50] Hill v Evans (1862) 6 LT 90.

75. The extent to which further experimentation may be permissible in cases where there is less than a literal disclosure was interpreted by Lord Reid in Van der Lely v Bamfords as follows:

“Lord Westbury must have meant experiments with a view to discovering something not disclosed. He cannot have meant to refer to the ordinary methods of trial and error which involve no inventive step and are generally necessary in applying any discovery to produce a practical result.”[51]

[51] Van der Lely NV v Bamfords Ltd [1963] RPC 61.

76. These principles have been applied widely in Australian decisions. The requirement for specificity in the prior disclosure was noted in Eli Lilly v Apotex, which also touched on the permissible “addition” of missing information when approaching the disclosure:

“In the end, as accepted by Apotex, the question is one of clarity of disclosure. If the prior disclosure is clear and unmistakable enough in making directions and includes all the essential integers of the invention as claimed, then the invention will not be novel.
However there does not necessarily need to be a literal disclosure – see Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at 531 per Gummow. If there is not literal or exact disclosure, then if the skilled person would add the missing information as a matter of course (without the application of inventive ingenuity or undue experimentation), that would lead to anticipation.”[52]

[52] Eli Lilly v Apotex, supra at [290].

77. The Full Bench in Apotex v Sanofi provided a summary of some relevant principles as follows:[53]

[53] Apotex Pty Ltd v Sanofi-Aventis [2009] FCAFC 134 at [104].

Where the prior publication discloses exactly what is claimed, there is anticipation.
There is anticipation if the skilled addressee would add missing information to what is disclosed in the prior art as a matter of course and without the application of inventive ingenuity or undue experimentation. A disclosure is sufficient if it enables the skilled addressee, in the ordinary course and without invention, to add what is missing in the prior publication to obtain the claimed invention.
If the prior art discloses the very subject matter of the invention, the person skilled in the art is assumed to be willing to make trial and error experiments to get it to work. If the disclosure is of an invention which, if performed, would infringe the patent, there is anticipation.
The question is whether the disclosure is sufficient to enable the skilled addressee to perceive, understand and, where appropriate, apply the prior disclosure necessarily, but within the ordinary limits of trial and error, to obtain the invention.

78. However, while common general knowledge can be used to construe a document to determine the matter that it discloses, I am mindful that it should not be used in a manner that incorporates a feature that is otherwise absent in the disclosure when properly construed. As cautioned in AstraZeneca v Apotex:[54]

“Although the common general knowledge can be used in a limited way to construe a prior art document, s 7(1) does not permit the common general knowledge to be used as a resource that can be deployed complementarily to arrive at a disclosure which the document alone, properly construed, does not make. If it were otherwise, the separate requirement of an inventive step to support a patentable invention (see s 18(1)(b)(ii) of the Act) would be otiose. The test of novelty would encompass the test for inventive step, without the need to satisfy the threshold requirements of s 7(3) (as it then stood) that the information in the document be information that the person skilled in the art could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area. All that would be required is that the information in the prior art document be publicly available.”

[54] AstraZeneca AB v Apotex Pty Ltd, supra at [352].

79. I understand the above authorities as teaching that there does not need to be a specific example in order for a disclosure to provide clear and unmistakable directions. To the contrary that a degree of trial and error (provided the prior art discloses the very subject matter of the invention) or the addition of missing information as a matter of course (without the need for inventive ingenuity or undue experimentation) is permissible suggests to me that a lesser disclosure may be sufficient. The consideration here is whether the disclosure in Pinchasi of an EOD dosage regime is sufficiently specific to enable the skilled addressee to perceive, understand and apply the prior disclosure necessarily, but within the ordinary limits of trial and error, to obtain the invention.

80. A significant factor in this consideration is that the present claims define particular clinical outcomes including alleviation of symptoms and reduction in the frequency of relapse. In my opinion the prior art document must disclose and enable these features in particular in order for Pinchasi to anticipate the present claims.

81. The declarants differed as to their understanding of what was disclosed in Pinchasi in this respect. Professor Ziemssen noted that no data is provided as to the EOD regime or any other indication that such a regime had been attempted. He considered there was nothing that would indicate the EOD regime would be as effective or safe or tolerable as daily administration.[55] In contrast Professor King understood that the authors did not intend to limit their invention to the method described in Example 1.[56] He considered Pinchasi showed that the 40mg/d dose is more effective than the 20mg/d dose, and on that basis he would expect both of the described 40mg regimes to be effective in reducing symptoms and achieving the particular outcomes defined by the present claims.[57] He further stated that he would not have expected the authors of Pinchasi to have recommended an EOD regime if they did not think it safe and effective.[58]

[55] Ziemssen at [44].
[56] King 1 at [213].
[57] King 2 at [29] to [31].
[58] Ibid at [35].

82. I note that Pinchasi itself states that the efficacy shown by 40mg/d dosage regime is unexpected since a 30mg/d treatment regime (comprising two 15mg doses) showed no statistically significant difference over a placebo group even though the 20mg/day dosage is efficacious.[59] In my opinion there in insufficient evidence that the skilled person would read the document (on the face of the document itself or when read in light of the common general knowledge) as providing clear and unmistakable directions for a further change in the frequency of dosage while maintaining efficacy and safety. To this end, the language used by Professor King (to the extent he would expect both treatments to be effective) is couched in terms that seem to me to be more consistent with an obviousness consideration than with a disclosure for novelty purposes. An expectation that a treatment should be safe and effective based substantially on statements by the authors is not the same as an expectation based on a consideration of what is disclosed by the technical information in a paper.

[59] Pinchasi at [0072].

83. On balance I consider that Pinchasi does not provide the degree of specificity required for it to be considered clear and unmistakable directions. To the contrary the evidence before me suggests that the information required to be added by the skilled person to the disclosure in relation to whether the EOD regime is safe, effective and tolerable would require extensive trial and error, and indeed undue experimentation, in order for there to be enablement of the claimed invention. I therefore consider that Claims 1, 2, 40, 45 to 50, 52, 54, 56 to 59 and 61 are novel in view of Pinchasi.

Inventive Step

84. 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.[60]

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

85. 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.”[61]
[61] Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; 148 CLR 262 at 286.

86. In Alphapharm,[62] the High Court accepted the approach taken by Graham J in Olin Mathieson,[63] where he posed the reformulated Cripp’s 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]?”
[62] Aktiebolaget Hassle v Alphapharm Pty Ltd supra at [53].
[63] Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at [187].

87. Where the invention involves a combination of integers, obviousness is to be determined by reference to the combination as a whole and not each integer individually. As stated in Alphapharm at [41]:

“The claim is for a combination, the interaction between the integers of which is the essential requirement for the presence of an inventive step. It is the selection of the integers out of ‘perhaps many possibilities’ which must be shown by Alphapharm to be obvious, bearing in mind that the selection of the integers in which the invention lies can be expected to be a process necessarily involving rejection of other possible integers.”

88. Alphapharm made submissions on two aspects:

Obviousness in view of the common general knowledge alone
Obviousness in view of a prior art document under subsection 7(3).

Common general knowledge

89. 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.”[64]

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

90. There was no apparent contention between the parties on many aspects of the common general knowledge, including:

RRMS and CIS could be treated with daily subcutaneous injections of 20mg GA.[65]

[65] King 1 at [99].

A common side effect of GA treatment is injection site reaction.[66]

GA was well tolerated and has a good safety profile.[67]

GA has an indirect mode of action and initiates its action in the periphery rather than directly in the CNS.[68]

Patient compliance was an issue with GA treatment.

Strategies that had been trialled prior to 2009 included the use of alternative syringe designs, placement of ice on the injection site before administration and providing nurse support.

[66] King 1 at [100].

[67] King 2 at [18].

[68] Ziemssen at [52] to [54].

91. As noted above the parties agreed that problems with patient compliance were part of the common general knowledge, but there was some dispute between the parties as to the extent of the problem. Professor King stated that patient compliance was as low as 60%,[69] while Professor Ziemssen stated that this was not his understanding or experience, and that if he had observed such low compliance he would have addressed it by education or nursing assistance, or by seeking an alternative treatment.[70] The dispute appears to lie in whether compliance would be understood to mean that 40% of patients had discontinued treatment or whether patients did not administer their injection in 40% of scheduled times. This does not impact significantly on my determination and therefore I do not consider it necessary to consider the issue in great depth. Both parties acknowledge that patient compliance with GA therapy is a problem – the precise extent of compliance is not determinative.

[69] King 1 at [130] and King 2 at [13].

[70] Ziemssen at [31].

92. The parties also disputed whether the results of the “Forte trial” were also common general knowledge. [71] Professor Ziemssen had referred to this document as being common general knowledge in his submissions.[72] The trial was the subject of a press release by Teva,[73] was presented at a conference (Comi),[74] and was reported in a news article on Medscape Medical News.[75] Yeda also submitted that the Forte trial is referenced by Caon,[76] which they said indicated that the Forte trial was widely accepted in the art and therefore common general knowledge, but I note the reference in Caon is fairly general and does not specifically name the Forte trial.

[71] King 2 at [9].

[72] Ziemssen at [67].

[73] Exhibit TZ-11: Retrieved at Exhibit TZ-4: Comi G et al., Multiple Sclerosis (2008) 14 S299-S301.

[75] Exhibit TZ-13: Retrieved at Exhibit JK-13: Caon C et al., (2009) 72 (11; Supp 3) Neurology A317 (Abstract No. P06.141).

93. Guidance on this consideration was provided in British Acoustic Films v Nettlefold:

“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.”[77]

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

94. I acknowledge that the Forte trial was certainly public knowledge at the relevant time, and maybe even had gained general interest in being reported and referenced, but I do not consider that there is sufficient corroborative evidence that the Forte trial had become part of the common stock of knowledge for those skilled in the art at the relevant time. As a consequence I do not consider the Forte trial can be considered common general knowledge.

The problem to be solved

95. The problem to be solved was framed in different ways by the parties, but there is no real difference in substance. Alphapharm referred to “improving compliance with GA therapy, but accepted the problem (as I will) framed by Yeda as follows:

(a)Improving the compliance and tolerability of GA therapy;
(b)Reducing the frequency and severity of post injection and post injection site reactions; and
(c)At the same time maintaining the efficacy of the therapy.

96. For sake of brevity I will refer to the problem as being related to improving patient compliance.

97. While the parties were in agreement as to the nature of the problem, they disagreed as to the composition of the hypothetical team who would be tasked with addressing the problem. In particular while they agreed that the team would comprise a clinician with experience in treatment of MS, they differed as to whether a pharmaceutical formulator would be a member of the team.

98. Professor Ziemssen did not specifically address whether there was a need for a formulator in the hypothetical team, but neither of the solutions he set out to the above problem would require such a team member.[78]

[78] Ziemssen at [38].

99. Dr Oppenheim was asked what his steps would be if he was tasked with the problem of developing a new formulation assuming that:

he is a member of a multi-disciplinary team tasked with developing a new dosage regime for a known drug, glatiramer acetate (GA), used in the treatment of a known medical condition, multiple sclerosis;

the team also includes a clinician who has expertise in treating multiple sclerosis, including by administration of GA;

the clinician has advised that, since approximately 1999, GA has been administered once daily by subcutaneous injection at a dose of 20 mg;

the clinician has recommended that GA be administered according to a new dosage regime, whereby 40mg of GA is to be administered three times per week;

as the member of the team with expertise in pharmaceutical formulation, have been tasked with providing a formulation suitable for administration of GA at a dose of 40 mg three times per week (the new formulation).[79]

[79] Oppenheim 1 at [28].

Dr Oppenheim’s Evidence in Support is clearly based on a pre-determined course of action aimed at providing a new formulation, and is framed around the solution given in the present application. Regardless of whether or not the hypothetical team would comprise a formulator, I consider that little weight could be given to this particular evidence in relation to the steps that the skilled person would take when faced with the problem of improving patient compliance.

In his Evidence in Reply, Dr Oppenheim stated that he considered a pharmaceutical formulator would be included in a multi-disciplinary team tasked with developing a new subcutaneous dosage regime for a known drug, GA, when used in the treatment of MS in order to improve patient compliance. As an initial observation I note here that the question has been asked in terms of the development of a new dosage regime to improve patient compliance, rather than in the context of improving patient compliance per se.[80] Moreover it is not clear whether his team was formulated based on the specific task set for him in Evidence in Support. He was also asked to provide further comments as to the literature searches he would have undertaken in this task, but in this case he was asked to assume that no decision as to an alternate dosage had been made.[81] To some extent his evidence in relation to the composition of the team appears to presuppose a particular solution.
[80] Oppenheim 2 at [3].
[81] Ibid at [7].

Professor King was also asked to explain the approach he would take if he was tasked with improving compliance with GA therapy,[82] and his suggested solutions (alternate dosage regimes including lower frequency dosage) were not said to require a pharmaceutical formulator. However in his subsequent declaration, and purportedly in response to paragraphs 7 and 8 of Professor Ziemssen’s evidence, Professor King stated that if assembling a team he would include a pharmaceutical formulator in order to consider any changes to the dosage regimes that would provide useful alternatives to the existing dosage regime.[83] This statement is prima facie not strictly in response to any evidence given by Professor Ziemssen, particularly since paragraphs 7 and 8 of his evidence appear to be general statements of his relevant skills and experience.
[82] King 1 at [28].
[83] King 2 at [5].
I also note that in his first declaration, Professor King was asked to explain the approach that he would have taken if tasked with improving compliance with GA therapy. However this appears to differ from his subsequent declaration in which he stated:
“If I had been asked to assemble a team for the purpose of developing alternative dosage regimes for the administration of GA for the treatment of MS, including addressing the problem of patient compliance with GA therapy, I would include in that team, in addition to a person with expertise in the clinical treatment of MS, a pharmaceutical formulator in order to consider any changes to the dosage regimes that would provide useful alternatives to the existing dosage regime” [emphasis added].
This appears to be a different problem than the one initially posed to Professor King – that is, rather than the original task of improving compliance with GA therapy, the task is the development of alternative dosage regimes including the problem of patient compliance. The inclusion of a formulator in the hypothetical team does not appear to be suggested by any of Professor King’s statements in his first declaration and there appears to be an inconsistency in the evidence as a consequence of the different formulation of the problem in his second declaration. As a result of this inconsistency I feel that this evidence can be given lesser weight.

However I think that some guidance on the composition of the team may be taken from Professor King’s Evidence in Support, wherein after being tasked with improving patient compliance and provided with Cohen and Kahn, Professor King stated that he would have recommended a clinical trial to compare daily, EOD and three times weekly dosage regimes.[84] A consideration stemming from this approach is: what would be the composition of a team who would develop and undertake a trial of this nature? An indication of this is provided by Professor King, who stated that his previous experience had included clinical trials where as Principal Investigator he supervised and coordinated a team of researchers including treating neurologists, examining neurologists, nurse coordinators, neuro-radiologists and radiographers.[85] It seems reasonable to me that this would be the type of team he would form for his proposed clinical trial.
[84] King 1 at [195].
[85] Ibid at [47].

In short I consider that the hypothetical team tasked with the problem as set out above would comprise a clinical neurologist. However I am not satisfied that the evidence before me establishes that if faced with the problem of improving patient compliance the hypothetical team would include a pharmaceutical formulator.

Obviousness in view of the common general knowledge alone

Alphapharm submitted that the skilled person would be aware that the approved weekly dose of GA is 140mg (7x20mg) and that GA had a good safety profile, injection site reactions aside. This being the case, they submitted that the skilled person would not have been concerned at the prospect of doubling the dose of GA from 20 mg per day to 40 mg/day,[86] and they would be directly led to try a three times weekly regime as it would enable patients to inject on the same day each week. There would be a high expectation of success because of the indirect mode of action, the tolerance and safety profile and the therapeutic equivalence between 120mg and 140 mg weekly.
[86] King 2 at [18].

Professor King stated that he understood a primary factor in poor compliance as being the need for patients to receive a daily injection and the associated injection site reactions.[87] His experience with various alternative MS treatments having a reduced frequency of administration suggested that “all things being equal”, a reduction in the number of injections that a patient was required to take each week would be expected to improve compliance.[88] He stated that he was aware of clinical trials that had already been conducted examining the safety and efficacy of alternate dosage regimes for GA, including less frequent administration.[89] In this regard Professor Ziemssen stated that:

“Although patients might prefer to have less frequent injections, in my experience, doctors will not generally sacrifice efficacy for convenience. A doctor would not normally purposefully treat a patient with a sub-efficacious dose of a drug, and thus increase the risk that the patient would suffer increased injury from their disease, in order to make the drug more tolerable. Instead, a doctor would attempt to find a way to make the effective dose of the drug more tolerable to the patient or switch the patient to a drug that could be tolerated by the patient as an effective dose.”[90]

[87] King 1 at [138].

[88] Ibid at [139].

[89] Ibid at [141].

[90] Ziemssen at [40].

I accept that it was well known in the art that GA has a good safety profile, but in my opinion there is nothing in the common general knowledge that would lead the skilled person to double the dose to 40mg, even with a concomitant reduction in frequency, if seeking to increase tolerability and reduce the injection site reactions. The clinical trials referred to by Professor King which administer GA using an EOD regime are not common general knowledge, and therefore are not relevant in this consideration.

Even if it was known in the art that other MS treatments could be administered at a reduced frequency, the drugs referred to by Professor King have a different mode of action and therefore different properties. Other than Professor King’s statements as to the convenience of a reduced frequency of administration, I have no evidence before me of it being common general knowledge that GA would be more efficacious and have fewer adverse effects if administered at a lower frequency and different dose than 20mg/day.

Finally, Professor King stated that the total weekly dose approved by the TGA (and FDA) was 140mg and he would expect a 120mg/week dosage to be therapeutically equivalent based on what was known in August 2009.[91] There is no dispute as to the common general knowledge being that GA was approved for administration at an amount of 20mg/day. However this is expressed as a daily dosage amount and there is no corroborating evidence that a weekly “approved” dosage was common general knowledge as of August 2009, nor that it would be considered therapeutically equivalent to a 120mg/week dosage.
[91] King 2 at [25].
On this point I do note that the GALA study[92] was provided to Professor King in his first declaration and he considered its disclosure in detail.[93] This document describes a double-blind, placebo-controlled study involving around 1400 patients with RRMS aimed at assessing the efficacy and safety of a 40mg GA three-times weekly dosage regime. The paper states that the three times weekly schedule providing a cumulative amount of 120mg was selected for its similarity to the 140mg cumulative weekly dose. However the GALA paper was published in 2013, well after the priority date of the present application and the fact that Professor King provided his statements following his consideration of the document suggests to me that his evidence may have been tainted by hindsight on this issue.
[92] Exhibit JK-9: Khan O et al., Ann. Neurol. (2013) 73, pp. 708-713.
[93] King 1 at [216]-[231].

I therefore consider the claims are inventive in view of the common general knowledge alone.

Obviousness in view of a document under subsection 7(3)

Alphapharm made submissions under this ground in relation to the following documents:

Pinchasi[94]
Cohen[95]
Khan[96]
Caon[97]
Flechter A[98] and Flechter B.[99]

[94] Exhibit JK-8, supra.

[95] Exhibit JK-6: supra.

[96] Exhibit JK-7: Khan O et al., Multiple Sclerosis, 14 (Supp. 1), (2008), S296, Abstract No. P902.

[97] Exhibit JK-13, supra.

[98] Exhibit JK-12: Flechter S, Clinical Neuropharmacology (2002) 25(1), pp. 11-15.

[99] Journal of the Neurological Sciences 197 (2002), pp. 51– 55.

In order for a document to meet the requirements of subsection 7(3) it must be one which the skilled person could be reasonably expected to have ascertained, understood and regarded as relevant. A threshold question is therefore whether the skilled person would have ascertained the prior art raised by Alphapharm.

Yeda disputed whether Pinchasi, being a patent document, would have been ascertained by the skilled person. Professors King and Ziemssen were accepted by both parties as being persons skilled in the art, so their evidence is key in this determination.
Professor King stated that he regularly reviewed a variety of literature published by MS researchers in Australia and overseas. If seeking to address the issue of compliance with GA therapy he would consult leading journals in the field of general neurology and MS (for example, Neurology, Annals of Neurology and the Multiple Sclerosis Journal) and would review the proceedings of leading international conferences (AAN and ECTRIMS). In the event that those searches did not identify sufficient information concerning alternative dosage regimes for GA he stated that he would have expanded his search to include alternative journals and the proceedings of other conferences using, for example, Pubmed.[100]
[100] King 1 at [141] to [144].
Professor Ziemssen stated that he refers to similar journals and conferences in order to keep up to date with developments in the field.[101] He also stated that it was not his practice to refer to patent literature to gain knowledge about MS or to keep up to date with developments in the field.[102]
[101] Ziemssen at [32] to [33].
[102] Ziemssen at [34].
Neither declarant stated that they would have regard to patent literature if tasked with the problem of improving patient compliance. However Alphapharm drew my attention to the decision of the Full Court in Emperor Sports[103] and particularly their acceptance of the correctness of the Australian Patent Office Manual of Practice and Procedure where it stated:

“Examiners should generally proceed on the basis that it would be reasonably expected that the person skilled in the art would conduct a search of patent literature, including the patent specifications of major countries, and that [subject to certain exceptions not relevant for present purposes] any patent document located in a patentability search would reasonably be expected to be ascertained by the person skilled in the art.”

[103] Commissioner of Patents v Emperor Sports Pty Ltd [2006] FCAFC 26 at [34]; 67 IPR 488.

They submitted that as an administrative decision maker equipped with technical expertise, the Commissioner is entitled to make use of that expertise and to draw inferences that may be rationally drawn from technical knowledge, including how skilled persons may act in their respective occupations. I acknowledge this approach is suitable in the context of examination where the examiner may not have evidence as to the approach taken by the skilled person. However as also noted in Emperor Sports:

“In Minnesota Mining Aikin J said at 294-295 (citations omitted):

‘There may be some fields of endeavour in which those who work therein study and make themselves familiar with all patent specifications as they become available for inspection in one or in many countries so that what was contained therein becomes less common general knowledge in that particular trade or field of manufacture in the country in question. But this is not so in all fields or in all countries. There was no evidence in the present case that those working in Australia in the field of adhesives or of surgical tapes followed such a practice or that any of the specifications relied upon was part of the common general knowledge of those working in those fields in Australia.

The respondent relied upon a number of prior art specifications which had been available in Australia for public inspection before the priority date as providing a basis for the argument that the invention claimed was obvious. For the reasons which I have set out above I do not regard such specifications as capable of sustaining that argument without evidence that they were part of the common general knowledge at that time.’

Of course, that case was decided under the pre-1990 law which did not make provision for documents which only became part of the prior art information as a result of s 7(3) ascertainment. Nevertheless the statement confirms that when identification of the relevant prior art is in dispute it is necessary to have either evidence or, which amounts to the same thing, reliance by an administrative decision-maker of expertise appropriate to the office.”[104]

[104] Commissioner of Patents v Emperor Sports Pty Ltd ibid at [33].

In the present case I have evidence before me on which to make a determination of whether a document could be reasonably expected to have been ascertained by the skilled person. To some extent this is an unusual situation given the nature of medical research and the expectation that researchers would consider patent documents. But neither of the declarants suggested that they would have regard to patent documents in the ordinary course of their work, nor if they were tasked with addressing the problem of patient compliance with GA therapy. There is otherwise no other evidence that would establish that they would have ascertained Pinchasi. I therefore consider the opponent has not discharged its onus to show that Pinchasi represents relevant prior art according to subsection 7(3).

Alphapharm also disputed whether there was evidence that Caon and Flechter A and B meet the requirements of subsection 7(3), and noted that there was no evidence that they would have been ascertained, even though they may be in recognised journals. They argued that Professor King referred to these documents in his Evidence in Reply only in the context of his statements as to patient compliance being well known, as evidenced by the number of studies investigating alternate dosing regimes.[105] However, I note that Professor King refers to Caon and Flechter A in the context of alternative dosage regimes.[106] I am satisfied that these documents may be considered under subsection 7(3), but no evidence was provided by any of the declarants in relation to Flechter B. This has little bearing on the determination since it appears to provide much the same information as Flechter A.

Cohen

[105] King 2 at [12].

[106] Ibid at [17].

Cohen describes a comparative study of a 40mg/day dosage regime against the standard 20mg/day dosage regime in order to evaluate the safety, tolerability and efficacy of the increased dosage. The formulations were essentially identical other than for the GA concentration which Professor King understood to mean that each was presented for self administration in a 1ml syringe containing GA and mannitol at a pH of 5.5 to 7.0.

The gist of Alphapharm’s arguments in relation to Cohen was that the skilled person would:

Understand that a 40mg/day dose provides faster onset of therapeutic action.
There is only a minimal difference in adverse effects between the 20mg/day and 40mg/day regimes.
That the risk of adverse effects of an EOD or three days per week regime would effectively halve the risk of adverse effects and have a positive effect on patient compliance.

Cohen is silent as to whether the dosage frequency could be decreased but Alphapharm argued, based on the evidence of Professor King,[107] that Cohen clearly indicated that there was scope to increase the dosage amount and reduce the frequency of administration in the expectation of improving patient compliance without loss of efficacy.
[107] Ibid at [22]-[23].

Cohen does indeed disclose that there is a more rapid onset of action, and indications are that the safety of the 20 and 40mg/day doses was similar, but it was acknowledged that the 40mg dose was associated with a higher incidence of adverse effects. Injections were said to be more painful, and injection site reactions were said to be more common and severe. Professor King stated that he saw little difference in the results in terms of adverse effects, but noted that reducing the frequency of administration to an EOD or three times weekly regime would effectively halve the risk of adverse effects.[108]
[108] King 2 at [23].
I do not dispute that a reduction in the frequency of administration would reduce the incidence of adverse effects, but the problem also related to maintaining the efficacy of GA treatment. In my opinion the key issue here is what the skilled person would be led to do in view of the information provided in Cohen. Professor Ziemssen acknowledged that Cohen indicated a general trend favouring the 40mg dosage, but noted that there was no statistically significant difference between the 20 and 40 mg dosages with respect to the primary endpoint (a reduction in the cumulative numbers of Gd-enhancing lesions at 7, 8 and 9 months). The only statistically significant differences with respect to efficacy between the two regimes were for exploratory endpoints (endpoints for which the trial may not be powered to assess or that may be analysed post hoc), which he considers are far less probative and reliable. In particular:
“Success in clinical trials is defined by statistical significance of disproving a null hypothesis. In ordinary language, what this means is that if statistics do not prove a difference, then one cannot conclude that there is a difference between cohorts. In this case, the reduction of Gd-enhancing lesions at 7, 8, and 9 months had a p-value – the key statistical measure – which did not achieve success (p-value is p=0.0898 which is greater than the pre-determined value for success of 0.05). Thus, the Cohen Paper does not demonstrate any statistically significant difference between administration of 20 mg GA as compared to administration of 40 mg GA with respect to the primary endpoint though a positive trend was observed in the data.”
He stated that the failure of the primary endpoint means that the skilled person would generally not consider any lower-tiered endpoints. He noted that the Cohen Paper concludes that “[a] larger, longer study will be necessary to confirm the sustainability of the efficacy advantage of the higher dose”.[109]
[109] Ziemssen at [42].

Professor King also acknowledged the importance of the primary endpoint, but responded that:

“While I agree that achieving the primary end point is of high value, valuable information can nevertheless be obtained from the exploratory end points and from trends shown in the results. Exploratory endpoints and trends provide encouragement that further research in those areas would be worthwhile. Accordingly, I do not consider it reasonable to suggest that the teachings in Cohen would be ignored simply because a larger, longer study is suggested in Cohen.”[110]

[110] King 2 at [19].

I agree that the teachings of Cohen cannot be ignored because of the failure of the primary endpoint. But my understanding from the evidence before me is that Cohen does not provide a definitive conclusion that the 40mg/day dosage regime is safe and efficacious, and instead suggests that a further more detailed study would be required in order to determine this. In my view, and contrary to the submissions by Alphapharm, Cohen does not clearly indicate that the dosage amount could be increased and the frequency reduced, but rather invites further research as to whether the efficacy of the 40mg/day dosage regime is sustainable.

I am therefore not satisfied, in view of the evidence before me, that the skilled person would embark on a line of research (or indeed clinical trials) based on, and further varying, the 40mg/day dose unless the safety, efficacy and tolerability of that dosage had been clearly established. Indeed, my understanding is that a three times weekly dosage regime includes about 48 hours between doses, with up to 72 hours between two of the doses. While Professor King stated that he would expect a three times weekly dosage regime to be effective based on the safety profile and the indirect mode of action there was little corroborative evidence based on specific data for GA that would support such statements and that would, as of August 2009, have provided a reasonable expectation of success if you were to try.

Accordingly I consider that the claims are inventive in view of Cohen.
For sake of completeness, even if (contrary to my previous determination) Pinchasi was relevant prior art for the purposes of subsection 7(3), I consider that it would not render the present claims obvious for similar reasons to Cohen. These documents describe much the same results and similarly to Cohen, there was no statistically significant difference between the 20 and 40mg doses with respect to the primary end point (the results on this point were the same). The obviousness argument would therefore likely fail for the same reasons I have outlined above. The argument in relation to Pinchasi suggesting an EOD regime is perhaps stronger in this regard, but I consider that the conflict between what is suggested by the inventors and what the data would suggest to the skilled person would give little expectation of success. Furthermore as noted under Novelty, the claims which include an EOD dosage regime have been found to lack fair basis, and if they were to be limited to the three times weekly regime the obviousness of the EOD would be a moot point.

Khan, Caon, Flechter A and Flechter B

These citations disclose similar subject matter and Alphapharm made the same submissions in relation to each, so I will deal with them together. Alphapharm submitted that each of these documents would suggest to the skilled person that:

A 20mg EOD dosage regime is as effective as a 20mg/day dosage regime. [111]
GA does not need to be administered daily since its indirect mode of action would result in it persisting for some time after administration.[112]
Administering GA less frequently would result in fewer adverse reactions.[113]
It would be desirable to ensure that the weekly dose of GA was as close as possible to 140mg (the weekly dose approved by the FDA). A regime of 40mg three times weekly would be preferable to a 20mg EOD regime because it would be closer to the total dose administered under the 20mg/daily regime.

[111] King 1 at [180].

[112] Ibid at [181].

[113] Ibid at [198].

I have already addressed the last dot point above in my consideration of inventive step in view of the common general knowledge alone. The comments I made in that regard are applicable here as well. However I do note the submission that a 20mg EOD regime is equally as effective as a 20mg/day regime. This being the case, and no evidence was adduced to the contrary, then presumably the cumulative dose under a 20mg EOD regime would be equally desirable (that is an average of 70mg per week – made up of alternating 4x20mg and 3x20mg). Under such circumstances why would the skilled person pursue a dosage of 140mg/week (or the purportedly therapeutically equivalent 120mg/week) when the evidence relied upon by Alphapharm suggests that half that amount is equally as effective? No clear evidence was provided on this point.

Furthermore, Alphapharm did not otherwise identify any particular shortcoming in the 20mg EOD regime that would require addressing by a change in the dosage amount. It is arguable that the skilled person might be motivated to further reduce the frequency of injections from an EOD regime to, say, a three times weekly dosage regime. In this respect, Professor King stated that prior to August 2009 patients found it easier to comply with a “three times per week” dosage regime than with an “alternate day” dosage regime, particularly since this enabled them to take their medication on the same day every week.[114] He went on to articulate a hypothetical comparative clinical trial in which patient groups would be dosed either once daily, on alternate days (“EOD”) or three-times per week, on the same days each week.[115] Moreover, in his evidence in reply he stated that:

“A three day per week regime is preferable to an alternate day regime, because the latter… requires the patient to remember whether they have taken the dose the previous day. A three times per week regime is generally preferable, because this allows the dose to be taken on the same days per week (eg every Monday, Wednesday and Friday)…”[116]

[114] Ibid at [194].

[115] Ibid at [195].

[116] Ibid at [39].

In my view, and based on the disclosure of Kahn, Caon, Flechter A and Flechter B and the submissions by Alphapharm, if a skilled person were to undertake such a clinical trial they would most likely be motivated to use a 20mg dosage. There is nothing in the evidence before me that would clearly motivate them to use a 40mg dose based on Kahn, Caon, Flechter A and Flechter B.

I therefore find that the present claims are inventive in view of Khan, Caon, Flechter A and Flechter B.

Claim 66: Additional considerations.

Subsection 60(3) of the Act permits the Delegate to take into account any of the grounds of opposition set out in section 59 when deciding a case, regardless of whether the ground is relied upon by the opponent.

It is a long-standing practice of the Commissioner to raise an objection in relation to “kit” claims under the grounds of manner of manufacture and/or inventive step.[117] A classic formulation of this approach is given in British Celanese v Courtaulds:

“It is accepted as sound law that the mere placing side by side of old integers so that each performs its own proper function independently of the others is not a patentable combination, but where the old integers when placed together have some working inter-relationship producing a new or improved result is patentable subject matter in the idea of working brought about by the collocation of integers.”[118]

[117] Patent Manual of Practice and Procedure at 2.9.2.16.2.

[118] British Celanese Ltd v Courtaulds Ltd [1935] 52 RPC 171 at 194.

My initial consideration of Claim 66 suggested that the claim could be interpreted to define a “kit” or collocation of known components. I considered that it was appropriate to seek submissions from the parties on this point. Alphapharm provided submissions on these additional points on 7 June 2017, while Yeda responded by relying on their existing written submissions while noting that Claim 66 is not dependent on any of the other claims under opposition.

As previously discussed, I construe Claim 66 as defining prefilled syringes presented or associated in a group of three – there is no requirement that they be associated in a single package or kit. The formulation within each prefilled syringe is characterised by the particular components (GA and mannitol), the concentration of GA (40mg/ml) and by the pH (5.5 to 7.0). Such prefilled syringes are disclosed in Pinchasi and Cohen.

The claim is essentially to a kit of separate and known integers having no working interrelationship (or potential working interrelationship) between those integers. In this regard I do not consider that the phrase “in a pattern of three” provides an actual or potential working relationship. There may be a clinical outcome provided by the administration of three dosages according to the three times weekly dosage regime described in the specification, but this is not brought about as a result of the manner in which the kit is arranged – that is there is nothing in the defined pattern that requires it to be used according to the method of the invention, within the same week, or indeed with the same patient. Each part (unit dosage) performs its normal function and is not functionally dependent on any other part. On that basis the claim does not define a manner of manufacture.

Given this determination the question of whether the claim also lacks inventive step is largely moot, but I do make the observation that the mere collocation of known integers in a group of three, having no working interaction and each performing its normal function appears unlikely to be inventive. However I do not intend to make a further determination in this regard.

In summary Claim 66, inasmuch as it defines a collocation of known components with no apparent interworking relationship, is not a manner of manufacture within the meaning of s 18(1)(a) of the Act.

Conclusion

The claims as a whole are clear, novel and inventive.

However, the opposition is successful on the ground of fair basis.
Claims 1, 2, 7, 8, 10, 22, 23, 27, 28, 31 to 64 and 66 lack fair basis.

Claim 66 is not for a manner of manufacture.

I consider that these issues may be overcome by amendment and allow Yeda 2 months from the date of this decision to propose appropriate amendments.

Costs

The parties submitted that costs should follow the event. The opposition argued by Alphapharm in relation to fair basis has been successful. I therefore award costs according to Schedule 8 against Yeda.

Dr Leslie F. McCaffery
Deputy Commissioner of Patents

Appendix A: Text of Independent Claims.

A method of alleviating a symptom of relapsing-remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, said method comprising administering to the human patient three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection so as to thereby alleviate the symptom of the patient.

A method of reducing the frequency of relapses in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and has MRI features consistent with multiple sclerosis comprising administering to the human patient a therapeutically effective dosage regime of three subcutaneous injections of 1 ml of a pharmaceutical composition comprising 40mg of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection, the regime being sufficient to reduce the frequency of relapses in the patient.

Use of a medicament comprising glatiramer acetate in treating a human patient who is suffering from relapsing remitting multiple sclerosis or who has experienced a first clinical episode and is at high risk of developing clinically definite multiple sclerosis, wherein the medicament is to be administered in a regime of three subcutaneous injections of a 40mg dose of glatiramer acetate every seven days with at least one day between each subcutaneous injection.

Use of glatiramer acetate in a regime of three subcutaneous injections of a 40mg dose of glatiramer acetate every seven days with at least one day between each subcutaneous injection for treatment of a human patient who is suffering from relapsing-remitting multiple sclerosis or who has experienced a first clinical episode and is at high risk of developing clinically definite multiple sclerosis.

Use of a medicament comprising glatiramer acetate in treating a human patient who is suffering from relapsing remitting multiple sclerosis or who has experienced a first clinical episode and is at high risk of developing clinically definite multiple sclerosis, wherein the medicament comprises a 40mg dose of glatiramer acetate and wherein the medicament is to be administered by subcutaneous injection in a regime of subcutaneous injections three times every week with at least one day between each subcutaneous injection, and wherein the medicament is a pharmaceutical composition having a pH in the range of 5.5 to 8.5.

Use of glatiramer acetate in a regime of administration, the regime comprising a 40mg dose of glatiramer acetate administered by subcutaneous injection three times every week with at least one day between each subcutaneous injection for use in treatment of a human patient who is suffering from relapsing-remitting multiple sclerosis or who has experienced a first clinical episode and is at high risk of developing clinically definite sclerosis, and wherein the glatiramer acetate is administered in a pharmaceutical composition having a pH in the range of 5.5 to 8.5.

A method of treatment of a human patient suffering from a relapsing form of multiple sclerosis comprising administration to the human patient of three subcutaneous injections of a 40 mg/ml dose of glatiramer acetate each week so as to treat the human patient.

A method of treatment of a human patient suffering from a relapsing form of multiple sclerosis which consists of administering weekly to the human patient on only three days during each week a single subcutaneous injection of a 40mg dose of glatiramer acetate so as to treat the human patient.

A method of treatment of a human patient suffering from a relapsing form of multiple sclerosis consisting of subcutaneous injections for at least 6 months with lml of a pharmaceutical composition comprising 40mg of glatiramer acetate on only three days during each week with at least one day without a subcutaneous injection of the pharmaceutical composition between each day on which there is a subcutaneous injection, wherein the pharmaceutical composition is in a prefilled syringe, and wherein the pharmaceutical composition further comprises mannitol and has a pH in the range 5.5 to 7.0.

A method of treatment of a human patient who has experienced a first clinical episode suggestive of multiple sclerosis and has at least two MRI lesions suggestive of multiple sclerosis which consists of administering weekly to the human patient on only three days during each week a single subcutaneous injection of a 40mg dose of glatiramer acetate so as to treat the human patient.

A method of treatment of a human patient who has experienced a first clinical episode suggestive of multiple sclerosis and has at least two MRI lesions suggestive of multiple sclerosis consisting of subcutaneous injections for at least 6 months with lml of a pharmaceutical composition comprising 40mg of glatiramer acetate on only three days during each week with at least one day without a subcutaneous injection of the pharmaceutical composition between each day on which there is a subcutaneous injection, wherein the pharmaceutical composition is in a prefilled syringe, and wherein the pharmaceutical composition further comprises mannitol and has a pH in the range 5.5 to 7.0.

A method of treatment of a human patient suffering from a relapsing form of multiple sclerosis which method is more tolerable than and as effective as administration of 20mg of glatiramer acetate s. c. daily, the method consisting of subcutaneous injections for at least 6 months with lml of a pharmaceutical composition comprising 40mg of glatiramer acetate on only three days during each week with at least one day without a subcutaneous injection of the pharmaceutical composition between each day on which there is a subcutaneous injection, wherein the pharmaceutical composition is in a prefilled syringe, and wherein the pharmaceutical composition further comprises mannitol and has a pH in the range 5.5 to 7.0, so as to treat the human patient as effectively as, but more tolerably than, administration of 20mg of glatiramer acetate s. c. daily, wherein the effect is reduction of relapses.

A method of reducing the frequency and severity of post injection reactions and of injection site reactions of glatiramer acetate therapy in a human patient suffering from a relapsing form of multiple sclerosis, the method consisting of subcutaneous injections for at least 4 months with lml of a pharmaceutical composition comprising 40mg of glatiramer acetate on only three days during each week with at least one day without a subcutaneous injection of the pharmaceutical composition between each day on which there is a subcutaneous injection, wherein the pharmaceutical composition is in a prefilled syringe, and wherein the pharmaceutical composition further comprises mannitol and has a pH in the range 5. 5 to 7. 0, so as to reduce the frequency and severity of post injection reactions and of injection site reactions in the human patient relative to administration of 20mg of glatiramer acetate s.c. daily.

A method of increasing the tolerability of Glatiramer acetate (GA) treatment in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, said method comprising reducing a frequency of subcutaneous injections from daily subcutaneous injections of a pharmaceutical composition comprising a 20 mg dose of glatiramer acetate to three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every injection.

Use of glatiramer acetate medicament for treating in the preparation of a relapsing-remitting multiple sclerosis in a human patient suffering from relapsing remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis wherein the administration pattern of the medicament is three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

Use of glatiramer acetate in the preparation of a medicament for treating relapsing-remitting multiple sclerosis in a human patient suffering from relapsing remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, wherein the medicament is prepared for an administration pattern of three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

Use of glatiramer acetate in the preparation of a medicament for increasing the tolerability of Glatiramer acetate (GA) treatment in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, wherein the administration pattern of the medicament is three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

Use of glatiramer acetate in the preparation of a medicament for increasing the tolerability of Glatiramer acetate (GA) treatment in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, wherein the medicament is prepared for an administration pattern of three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

Glatiramer acetate when used in treating relapsing remitting multiple sclerosis in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis by three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

Glatiramer acetate when used in increasing the tolerability of GA treatment in a human patient suffering from relapsing-remitting multiple sclerosis or a patient who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis by three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

A method of reducing frequency of relapses in a human patient suffering from relapsing-remitting multiple sclerosis, said method comprising administering to the human patient three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

A method of treating a human patient with at least two MRI lesions suggestive of multiple sclerosis who has experienced a first clinical episode and is determined to be at high risk of developing clinically definite multiple sclerosis, said method comprising administering to the human patient three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection.

A medicament comprising a 40mg dose of glatiramer acetate when used in reducing frequency of relapses in a human patient suffering from relapsing-remitting multiple sclerosis, wherein the medicament is to be administered in three subcutaneous injections over a period of seven days with at least one day between each subcutaneous injection.

Use of glatiramer acetate in a treatment regime to reduce frequency of relapse in a human patient suffering from relapsing-remitting multiple sclerosis, wherein the treatment regime comprises three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between each subcutaneous injection.

A medicament comprising a 40mg dose of glatiramer acetate when used in treating a human patient with at least two MRI lesions suggestive of multiple sclerosis who has experienced a first clinical episode, wherein the medicament is to be administered in three subcutaneous injections over a period of seven days with at least one day between each subcutaneous injection.

Use of glatiramer acetate in a treatment regime to treat a human patient with at least two MRI lesions suggestive of multiple sclerosis who has experienced a first clinical episode, wherein the treatment regime comprises three subcutaneous injections of a 40mg dose of glatiramer acetate over a period of seven days with at least one day between each subcutaneous injection.

A pharmaceutical product consisting of unit dosages in a pattern of three unit dosages each consisting of a prefilled syringe containing 40mg/ml glatiramer acetate and mannitol in a pharmaceutical composition having a pH in the range of 5.5 to 7.0.