Alphapharm Pty Ltd v Cypress Bioscience, Inc
[2016] APO 58
•5 September 2016
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Alphapharm Pty Ltd v Cypress Bioscience, Inc. [2016] APO 58
Patent Application: 2012203789
Title:Milnacipran for the long-term treatment of fibromyalgia syndrome
Patent Applicant: Cypress Bioscience, Inc.
Opponent: Alphapharm Pty Limited
Delegate: Dr B. Akhurst
Decision Date: 5 September 2016
Hearing Date: 16 June 2016, in Sydney.
Catchwords: PATENTS – section 59 opposition to the grant of a patent – manner of manufacture – whether the claimed methods of treatment were obvious on the face of the specification – inventive step – whether the claimed methods are obvious in light of the common general knowledge or prior art documents – fair basis – real and reasonably clear disclosure – grounds of opposition not established.
Representation: Patent attorney for the applicant: Shelston IP.
Counsel for the opponent: Ben Fitzpatrick.
Patent attorneys for the opponent: Paul Whenman and Jess Gledhill of FB Rice.
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2012203789
Title:Milnacipran for the long-term treatment of fibromyalgia syndrome
Patent Applicant: Cypress Bioscience, Inc.
Date of Decision: 5 September 2016
DECISION
The opposition is unsuccessful. Costs are awarded according to Schedule 8 against Alphapharm Pty Limited.
REASONS FOR DECISION
Background
Cypress Bioscience, Inc. (Cypress) filed patent application 2012203789 on 27 June 2012 as a divisional of application 2006294645, claiming priority from application US 60/721,722 filed on 28 September 2005. Following examination, acceptance of the application was advertised on 11 December 2014.
Alphapharm Pty Limited (Alphapharm) filed a notice of opposition to the grant of a patent on 11 March 2015 and a statement of grounds and particulars (SGP) on 11 June 2015. Evidence in support, answer and reply was completed on 11 September 2015, 15 December 2015 and 16 February 2016, respectively.
Alphapharm appeared at the hearing, which took place on 16 June 2016 at FB Rice’s premises in Sydney. Cypress appeared by written submissions filed on 8 and 15 June 2016.
The Evidence
Evidence in support consisted of a declaration by:
- Peter Brooks dated 10 September 2015 (PB#1) with exhibits PB-1 to PB-22.
Evidence in answer consisted of declarations by:
- Geoffrey Littlejohn (GOL) dated 14 December 2015 with exhibits GOL-1 to GOL-8; and
- John Louis Quintner (JLQ) dated 14 December 2015 with exhibits JLQ-1 to JLQ-34.
Evidence in reply consisted of a declaration by:
- Peter Brooks dated 15 February (PB#2) with exhibits PB-23 to PB-30.
Grounds of opposition
The grounds of opposition pressed by the opponent at the hearing were manner of manufacture, inventive step and fair basis.
Onus of Proof
The request for examination in relation to the patent application was filed on 12 November 2012. As a consequence, the substantive amendments of the Patents Act 1990 brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present patent application. This includes the amendment to subsection 60(3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition has been made out. Instead, the onus of proof in this opposition proceeding lies with the opponent, who must establish that it is clear that a valid patent cannot be granted (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [29], [67]; 50 IPR 305; and Commissioner of Patents v Sherman [2008] FCAFC 182 at [18], [22]; 79 IPR 426).
The specification and claims
The principles for the construction of specifications are well established and were neatly summarised by Middleton J in Eli Lilly and Company Limited v Apotex Pty Ltd [2013] FCA 214, 100 IPR 451 at [139]:
“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.”
The construction of the specification was not in dispute. I will note here that the specification, the experts and the parties in their submissions variously refer to dosage or dosing regimen(s), regime(s) and/or schedule(s). It is my understanding that there is little difference in the meaning of these terms in the context of Cypress’s specification and claims. Therefore, for the purposes of this decision, these terms are used interchangeably.
The specification discloses that fibromyalgia, also known as fibromyalgia syndrome (FMS), is a common systemic rheumatologic disorder associated with a reduced threshold for pain, generally identified by an increased sensitivity to pressure all over the body, and is often accompanied by fatigue, sleep disturbance and morning stiffness (page 1a). Antidepressants are the cornerstone of many treatments paradigms, but other agents such as anti-convulsants, antispasticity agents, anxiolytics, sedatives and opiates have been used, in addition to non-steroidal anti-inflammatory drugs and acetaminophen (page 3). The majority of available antidepressants act by increasing the levels of the neurotransmitters serotonin and/or norepinephrine in the central nervous system (page 3).
The field of the invention relates to the long-term treatment of FMS and its symptoms by administration to a patient suffering from FMS a dual norepinephrine serotonin reuptake inhibitor (DRI) (page 1a). DRIs are a class of antidepressant compounds that increase the levels of norepinephrine and serotonin in the central nervous system by selectively inhibiting transporter-mediated reuptake of these transmitters from the synapse into the pre-synaptic neuron (page 3, last para; page 7a of the specification). The specification identifies and differentiates two subclasses of DRIs, which are those that preferentially block reuptake of norepinephrine, which it identifies as norepinephrine-serotonin reuptake inhibitors (NSRIs) and those that preferentially block serotonin reuptake, identified as serotonin-norepinephrine reuptake inhibitors (SNRIs) (page 6, para 5; page 7a, last para). The invention relates more particularly to the long term treatment of FMS with an NSRI (page 1a, para 1). It should be noted that the experts do not necessarily distinguish the DRI subclasses and/or use the same terminology as the specification. Therefore, I have interpreted their evidence in the context in which it is given and summarised it accordingly in this decision.
In summarising the invention, the specification states that no compound, even if it has benefits for the short-term treatment, has been shown to provide effective, long term treatment for FMS and its symptoms (page 6, para 3). The specification states that the double-blind, randomized, placebo-controlled clinical study using the NSRI milnacipran first reported in Example 1 of the specification, unexpectedly showed that a DRI may be used to provide effective long term treatment of FMS and its symptoms (page 6, para 4).
The accepted specification contains 19 claims, which are reproduced at Annex A to this decision.
Manner of Manufacture
Paragraph 18(1)(a) of the Act provides that an invention, so far as claimed in any claim, must be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. The question to be asked is:
“Is this a proper subject of letters patent according to the principles which have been developed for the application of s 6 of the Statute of Monopolies?”
(National Research Development Corporation (NRDC) [1959] HCA 67 at [14]; 102 CLR 252 at 269; D’Arcy v Myriad Genetics Inc [2015] HCA 35; (2015) 89 ALJR 924 (Myriad) at [18])
Alphapharm opposed claims 1-19 under the manner of manufacture ground relying primarily on the principles provided by the Courts in Merck & Co Inc v Arrow Pharmaceuticals Limited [2006] FCAFC 91; (2006) 154 FCR 31(Merck) and Arrow Pharmaceuticals Limited v Merck & Co., Inc. [2004] FCA 1282; (2004) 213 ALR 182 regarding the patentability of therapeutic methods. However, Cypress argued that the law relating to medical treatments had been superseded by Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd [2013] HCA 50; (2013) 253 CLR 284 (Apotex), in which the High Court considered whether a method of medical treatment of the human body is inherently patentable ([220]) and concluded at [286]:
“Assuming that all other requirements for patentability are met, a method (or process) for medical treatment of the human body which is capable of satisfying the NRDC Case test, namely that it is a contribution to a useful art having economic utility, can be a manner of manufacture and hence a patentable invention within the meaning of s 18(1)(a) of the 1990 Act.”
There was no dispute, and I agree, that the therapeutic methods encompassed by Cypress’s claims satisfy the requirement for an artificially-created state of affairs having economic utility. In the paragraph reproduced above, the High Court explicitly states that such a method can be patentable subject matter, which is permissive rather than mandatory language. Thus, it does not follow from Apotex that any claim to a method (or process) for medical treatment of the human body which is an artificially-created state of affairs having economic utility, must necessarily define a manner of manufacture. This conclusion is supported by the High Court’s statement in Myriad at [20]:
“The terminology of an “artificially created state of affairs of economic significance” is to be understood in the context in which it was used in NRDC. It was not intended as a formula exhaustive of the concept of manner of manufacture.”
It follows that Merck remains relevant to determining whether a claim is for a manner of manufacture. In Merck at [63], the Full Court summarised the principles for determining whether a claim is for a manner of manufacture for the purposes of s 6 of the Statute of Monopolies. Those relevant to Alphapharm’s submissions, are as follows:
The threshold requirement for a patentable invention is that it must not be apparent on the face of the specification that the subject matter of the claims is not new, or that it lacks the necessary quality of inventiveness for it to be a proper subject of letters patent under the Statute of Monopolies (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15 at [9]; (1995) 183 CLR 655 at 667).
A new use of an old substance is not an invention if its known properties make it suitable for that use – in such a case the new purpose is ‘no more than analogous to the purposes for which the utility of the substance is already known’ (NRDC [1959] HCA 67 at [7]; 102 CLR 252 at 262). However, there will be an invention if the new use consists in taking advantage of a hitherto unknown or unsuspected property of the substance (NRDC [1959] HCA 67 at [7]; 102 CLR 252 at 262).
The disclosure on the face of the specification
Cypress did not dispute Alphapharm’s submission that the following relevant propositions emerge from the opposed specification:
·FMS is a common systemic rheumatologic disorder (page 1a, lines 18-19). A broad array of medications have been used “off-label” in patients with FMS, and antidepressants of all varieties represent a common form of therapy for many chronic pain states including FMS (page 3, para 2).
·A significant body of literature supports the use of tricyclic antidepressants (TCAs) for FMS (page 3, para 2), which block the reuptake of serotonin and norepinephrine but favour norepinephrine reuptake blockade (page 3, para 2). However, additional activities of TCAs impart a wide assortment of undesirable side effects, which often compromise their tolerability and clinical acceptance (page 4, para 1).
·Results of clinical trials with the anti-depressant subtype, selective serotonin reuptake inhibitors (SSRIs) have been inconsistent (page 4, para 3). Two trials with the most serotonin-specific SSRI, citalopram, were convincingly negative (page 4, para 4). Based on the evidence, SSRIs as a class are generally less efficacious than TCAs in chronic pain states (page 5, para 1).
·DRIs are pharmacologically similar to TCAs inhibiting both serotonin and norepinephrine reuptake, but are generally devoid of significant activity at other receptor systems, resulting in diminished side effects and enhanced tolerability in comparison with TCAs. A number of DRIs are in clinical development; milnacipran is explicitly identified in the specification among 7 such compounds. (page 5, para 2)
On page 5, the opposed specification explicitly incorporates by reference the entire disclosure of US patent 6602911 (Kranzler et al.) 5 August 2003 (Kranzler), which is titled “Methods for treating fibromyalgia”. Kranzler is in evidence as Exhibit PB-17 and relevantly discloses the following information:
·Common DRIs include venlafaxine, duloxetine and milnacipran (column 3, lines 50-51). DRIs, and particularly milnacipran, can be used to treat FMS and pain generally (column 2, line 40 to column 3, line 5).
·Milnacipran has been used as an antidepressant in approximately 400,000 patients, and is known to be non-toxic in humans. In clinical trials treating depression at dosages of 100 mg/day or 200 mg/day, milnacipran was well tolerated and usually produced no more adverse effects than placebo. (Kranzler, column 6, lines 21-27)
·Under the heading “Effective Dosages” Kranzler teaches that suitable pharmaceutical compositions include those in which the active agent is contained in a therapeutically or prophylactically effective amount (column 11, lines 48-51). Furthermore:
“… the actual amount effective for a particular application will depend, inter alia, on the condition being treated and the route of administration. Determination of an effective amount is well within the capabilities of those skilled in the art, especially in light of the disclosure herein”. (column 11, lines 53-57)
In column 12, Kranzler provides further information regarding effective dosages:
“Effective amounts for use in humans can also be determined from human data for the NSRI compounds used to treat depression. The amount administered can be the same amount administered to treat depression or can be an amount lower than the amount administered to treat depression. For example, the amount of milnacipran administered to treat depression is in the range of about 50 mg-400 mg/day. Thus, either 50 mg-400 mg/day or a lower dose can be administered for practicing the present invention.
Patient doses for oral administration of the NSRI compounds typically range from about 1 mg-1 gm/day. For example, for the treatment of FMS … or pain with milnacipran the dosage range is typically from 25 mg-400 mg/day, more typically from 100 mg-250 mg/day. The dosage may be administered once per day or several or multiple times per day.”
·Example 3 of Kranzler, titled “Assessment of the efficacy of milnacipran in FMS patients”, describes the use of 100 mg daily, or 50 mg twice daily, for 6 weeks. Example 4 assesses the efficacy of milnacipran in patients with the condition “Painful Diabetic Neuropathy” and uses a dose escalation schedule that increases the dose of milnacipran by 25 mg/day every three days up to a maximum of 200 mg daily, unless the patient reports complete pain relief or significant side effects.
On page 10, the opposed specification explicitly incorporates by reference the entire contents of US Application No. 10/678,767. The corresponding US publication 2004/0106681 A1 (Rao et al.) 3 June 2004 (Rao) is in evidence as Exhibit PB-15. It is titled “Dose escalation and divided daily dose of anti-depressants to treat neurological disorders” and discloses the following information:
·Milnacipran is an NSRI which is approved and marketed in Europe for the treatment of depression (para 4).
·Rao describes a number of treatment protocols. In a preferred embodiment, the daily dose of active ingredient is escalated over a period of time to achieve a therapeutic amount of circulating active compound in the patient (para 116). The gradual escalation of daily dosage is intended to improve tolerance of the patient to the active agent in order to avoid or minimise adverse reactions (paras 117-118). Rao broadly discloses 2-4 step dose escalations (paras 119-123), in which the duration of each step can be 3 days or more up to 20 weeks or more (para 120). Most relevant to the opposed claims, Rao discloses milnacipran administered in 3-step or 4-step dose escalation regimes. A 3-step protocol at para 122 involves dose escalation of milnacipran as follows:
·initially between 10-50 mg/day for greater than 3 days;
·then escalating to about 25-75 mg/day for greater than 3 days;
·followed by greater than 100 mg for a sufficient period of time to effectively treat the symptoms of the neurological disorder.
A preferred 3-step regime for dosage escalation of milnacipran at para 131, involves:
“… 50 mg a day for about 3 days, followed by 25 mg [sic] to 75 mg for about 3 days and then followed by a dosage of greater than 100 mg for a sufficient period of time to effectively treat the symptoms of the neurological disorder.”
In the 4-step protocol (at paras 123 and 132), milnacipran is administered in the following manner:
· an initial daily dose between about 20-30 mg for 7 days;
· followed by about 40-60 mg for 7 days;
· about 75-125 mg for 7 days;
· then 175-225 mg for a sufficient period of time to treat the neurological disorder.
·Examples 1-2 of Rao relate to the use and effect of milnacipran for treating FMS. Example 1 discloses that in previous studies where patients were escalated over a short time period (typically 1 week or less) to their final daily dosage, the adverse event profile was substantially worse in patients given 200 mg of milnacipran, in comparison to those given 50 mg or 100 mg doses. Anticipating that higher doses would be more effective, the inventors sought to determine whether a gradual escalation of dosage could increase the tolerated dose of milnacipran. Providing the doses were tolerated, in the first week patients with FMS were given 25 mg milnacipran/day, which was increased to 50 mg/day for week 2, 100 mg/day for week 3, and 200 mg/day for week 4. Subjects took their maximum tolerated doses for an additional 8 weeks. Of approximately 70 patients treated with milnacipran only 9 failed to tolerate 200 mg/day. Side effects were worse in patients given an unescalated initial dose of 100 mg milnacipran, and the conclusion is drawn that the slower dose escalation was responsible for greater patient tolerance of a 200 mg daily dose of milnacipran.
In Example 2, FMS patients were escalated over a 4 week period in weekly steps from 25 mg/day, to 50, 100 and finally 200 mg/day or until dose-limiting toxicity was evident. Milnacipran was found to effectively treat the pain associated with FMS and improved mood in those with depression. The conclusions are drawn that twice-daily dosing was more effective than once-daily dosing in reducing pain and was better tolerated at the higher doses. Furthermore, that the relatively high 200 mg/day dose was important in alleviating pain.
Consideration
Alphapharm submitted that it is sufficient to deprive the claimed invention of the necessary quality of inventiveness if the claims of the patent are analogous to the use of the drug as taught in the opposed specification, including information in documents incorporated by reference into the specification. In this regard, Alphapharm’s submissions are essentially that once a potential new indication has been proposed for a pharmaceutical drug, routine clinical trials will lead to the identification of particular dosing schedules. Relying on Merck, Alphapharm argued that these schedules will not be patentable subject matter and alterations to these schedules will not be patentable subject matter if they are not based on some newly discovered characteristic or property of the drug, or “newly discovered technical effect” or “hitherto unknown or unsuspected property” of the drug.
In Merck, the Full Federal Court considered claims that can relevantly be summarised as methods of treating or preventing osteoporosis in a human comprising once weekly oral administration of an amount of an alendronate salt, which the description taught would minimise the gastrointestinal side affects of the drug. Consideration was given to the disclosure of two documents incorporated by reference into the specification. The first did not disclose continual administration on a weekly basis, but it taught weekly, oral administration of an effective amount of alendronate as a way of minimising the adverse gastrointestinal side effects of the treatment and to provide improved convenience to the patient (Merck at [50]-[51], [72]). The second document disclosed methods for the prevention and treatment of a bone-related disorder other than osteoporosis but did not address the adverse gastrointestinal side effects of alendronate. Nevertheless, the second document disclosed dosage levels of alendronate appropriate for the alternative disorder and asserted they are the same as those used to treat osteoporosis. It also disclosed (among other things) weekly oral administration of alendronate and the individual single doses encompassed by Merck’s claims. (Merck at [57]-[60], [62]) In Merck at [75], the Full Court described these matters as “an existing substance and practice” and “well-known and well-understood things”, and concluded that Merck’s claims were analogous to the use of alendronate as taught in those documents. As a consequence, the Full Court found at [75] that Merck’s patent specification disclosed no new substance, no new characteristic of a known substance, no new use and no new method, and, therefore, no new manner of manufacture.
Alphapharm submitted that by the explicit incorporation by reference of Kranzler and Rao, the opposed specification discloses that milnacipran can be administered to FMS patients between 25-400 mg/day, and that escalating dosages minimises side effects. While Alphapharm accepted that the specific dosage regimes in Cypress’s claims were just outside those disclosed in the specification (including Kranzler and Rao), it argued that the disclosure in the specification need not be all encompassing, rather that it must be “analogous enough”. Alphapharm submitted that there was nothing new, surprising or technically advantageous in Cypress’s claims; they simply avoid the prior art only, for no technical reason and no technical effect. Alphapharm argued that since the dosing schedules in Cypress’s claims do not depend on any newly discovered characteristic, property or technical effect, or hitherto unknown or unsuspected property of the drug, they demonstrate no necessary quality of newness or inventiveness and consequently are not to patentable subject matter.
In contrast, Cypress submitted that its claims relate to dose escalation regimes that require specific doses to be administered at each stage, and that these dosing schedules are not obvious on the face of the specification. I agree. In Merck, all of the features of the claims were disclosed in the complete specification either directly or by way of documents the disclosure of which was explicitly incorporated into the specification by reference. The opposed specification is distinguished in that the particular combination of features in each of Cypress’s claims is not disclosed in the opposed specification, either directly or by way of the Kranzler and Rao disclosures.
Relevant to the present circumstances, in Merck at [64], the Full Court acknowledged the need to avoid incursion into areas correctly addressed under other sections of the Act. In Bristol-MyersSquibb Company v F H Faulding & Co Ltd [2000] FCA 316; (2000) 97 FCR 524, in considering whether a claimed invention has the necessary quality of inventiveness in the light of the prior body of knowledge discussed in the specification, the Full Bench of the Federal Court stated at [45]:
“Where the Court has evidence on the basis of which it can make a finding about common general knowledge, and the other information referred to in s 7(2) and s7(3), and about what would or would not have been obvious to persons skilled in relevant art, it must be only rarely that it will be appropriate to find (by resort to a “threshold test”) lack of inventiveness on the face of a specification.”
With this in mind, I believe Alphapharm’s submissions that routine clinical trials will identify particular dosing schedules are best considered under the ground of inventive step.
I find the claimed invention is a manner of manufacture.
Inventive Step
Paragraph 18(1)(b)(ii) of the Act provides that an invention, so far as claimed in any claim, must involve an inventive step when compared with the prior art base. Under the provisions of subsections 7(2) and 7(3) of the Patents Act 1990, an invention is taken to involve an inventive step when compared with the prior art base unless it would have been obvious to a person skilled in the art. “Obvious” means “very plain” (Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; (2007) 72 IPR 447 (Lockwood No 2) at [51]-[52]). The invention must be obvious in the light of the common general knowledge as it existed in the patent area before the priority date, either on its own or together with information in a document, or combination of documents, 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 and, where necessary, combined.
The test for obviousness was provided by Justice Aicken in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12 at [45]; 148 CLR 262 at 286 as follows:
“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.”
The High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; 212 CLR 411 (AB Hässle) at [51]-[53] approved that approach, in addition to that taken by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187 in which he posed a reformulated “Cripp’s question” as follows:
“Would the notional research group at the relevant date, in all the circumstances, directly be led as a matter of course to try [the invention claimed] in the expectation that it might well produce a useful [result or alternative]?”
Both approaches require that the person skilled in the art has a reasonable expectation of success, which is explicit in the expectation that an approach “might well” succeed and implicit in steps characterised as routine and to be tried as a matter of course (Generic Health Pty Ltd v Bayer Pharma Aktiengessellschaft [2014] FCAFC 73 at [71]; (2014) FCR 336 at 364 [71]). The reasonable expectation does not require a guarantee of success and includes some possibility that the steps taken will not achieve the intended result (AB Hässle at [74], [76]). A test for obviousness formulated in terms of “worthwhile to try” was rejected by the High Court in AB Hässle at [72].
The usual approach to determining inventive step is the problem-solution approach. Once the problem has been formulated and the common general knowledge and the prior art base has been determined, the question of whether the claimed solution is obvious can be addressed.
The problem
At the hearing, Alphapharm accepted Cypress’s characterisation of the problem as the need to develop new methods for the treatment of FMS using antidepressants, and in particular DRIs. This approach is reasonable in the circumstances.
The person skilled in the art
The notional “person skilled in the art” is an artificial construct that is used as a tool of analysis “which guides the court in determining, by reference to expert and other evidence, whether an invention as claimed does not involve an inventive step” (AstraZeneca AB v Apotex Pty Ltdand Ors [2015] HCA 30; (2015) 89 ALJR 798 (AstraZeneca HCA) at [23]). In general, the skilled person or addressee is the person who works in the art or science with which the invention is connected. He or she is a person, or team, likely to have a practical interest in the subject matter of the invention. While the skilled person may be assumed to be well-versed in the relevant art, such a person must be taken to be non-inventive. (Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 [71]-[72]; 49 IPR 225 [71]-[72] referring to Catnic Components Ltd v Hill & Smith Ltd [1982] RPC 183 at 242; The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 485; and Minnesota Mining and Manufacturing Company and Another v Beiersdorf (Australia) Limited (Minnesota Mining) [1980] HCA 9 at [115]; 144 CLR 253 at 293).
The parties’ submissions were consistent with the notional person skilled in the art in this case being a team of people, including a rheumatology physician (a rheumatologist) and a clinical researcher, each having a practical interest in FMS. The inclusion of a rheumatologist in the team is consistent with the information at page 2, para 1 of the opposed specification that FMS patients are managed by a range of care providers, including rheumatologists; it is also supported by the evidence (Exhibit PB-8: Goldenberg, D. L. et al. (2004) JAMA 292(19): 2388-2395 “Management of Fibromyalgia Syndrome”, page 2388, para 2). The parties were in agreement, and I accept, that since the field of the invention is complex, the person skilled in the art is likely to be highly skilled and even capable of some novel thought or original research.
Brooks
Cypress disputed that Prof Brooks had the relevant skills, submitting that it is not sufficient to merely be a rheumatologist since FMS is not a conventional rheumatic disorder, and conventional therapies for treating rhematic disorders are ineffective in FMS. Cypress argued that unless a rheumatologist had a practical interest in FMS, evidenced by actively practicing the diagnosis, treatment or research of FMS, they cannot be considered an appropriate person skilled in the art. In this regard Cypress, noted that the word “fibromyalgia” does not appear in Prof Brooks’s CV, which Cypress concluded does not establish that he belongs to any associations specific to FMS, or that Prof Brooks has published articles or delivered presentations specific to FMS.
In my view, the evidence supports a conclusion that rheumatologists in general, and Prof Brooks in particular, would have had a practical interest in FMS at the relevant time. There are over 150 rheumatic disorders (PB#1 [18]). However, before the priority date, FMS was the second most common rheumatic disorder after osteoarthritis, affecting at least 2-4% of the population (the specification page 1a, para 4; supported by Exhibit JLQ-3, Crofford, L. J. (2004) Current Rheumatology Reports 6: 274-280, page 274; Exhibit JLQ-6, Guymer, E. K. and Littlejohn, G. O. (2002) Australiasian Chiropractic & Osteopathy 10(2): 81-84, page 81). The specification states on page 2 that 16% of visits by FMS patients to care providers are to rheumatologists. Fibromyalgia accounted for 15% of outpatient rheumatology visits before the priority date (Exhibit PB-9, O’Malley, P. G. (2000) Journal of General Internal Medicine 15: 659-666). Prof Quintner confirms that before the priority date the diagnosis, treatment and research associated with conditions and disorders classified as FMS were the domain of rheumatologists and specialist physicians in this field (JLQ [22]). This is consistent with Prof Littlejohn’s evidence at [11] that he had been invited to speak about FMS at a number of national and international rheumatology meetings before the priority date. In my view, it is reasonable to expect rheumatologists in general to have a practical interest in a condition that they regularly see and treat, and which is the subject of presentations at the rheumatology meetings they attend.
Prof Brooks’ evidence establishes that before the priority date, he had extensive experience in the field of rheumatology as a practicing clinician and in teaching, and clinical and laboratory research roles (PB#1 [2]-[4], [6]). Between 1988 and 1990 Prof Brooks was the Foundation Professor of Rheumatology at the Royal North Shore Hospital (PB#1 [6]). Between 1994 and 2003, he was section editor and contributor for three editions of the textbook “Rheumatology” (PB#1 [6]). Prof Brooks’ evidence confirms his familiarity with FMS (#1 [20]-[23]) and that he treats FMS patients (PB#1 [34]; PB#2 at [16], [18] and [29] at least).
Littlejohn and Quintner
Alphapharm submitted at the hearing that Prof Littlejohn’s CV establishes that he has a professional relationship with the sponsor of milnacipran in Australia, Pierre Fabre Medicament. However, it is often the case in matters before the Commissioner that evidence is provided by persons associated with a party to the matter. Therefore, I do not consider this circumstance necessarily disqualifies Prof Littlejohn’s evidence from consideration in determining this opposition, although it may affect the weight it is given.
Before the priority date Prof Littlejohn and Dr Quintner both had extensive experience in the field of rheumatology, working as consultant physicians in public hospitals and private practice (GOL [3]-[5] and Exhibit GOL-1; JLQ [1]-[5] and Exhibit JLQ-1). Although Prof Littlejohn states at [7] that he has been a principle investigator for over 40 rheumatology clinical trials, including those involving FMS, it is not clear from his evidence whether any relevant trial preceded the priority date.
Summary
I am satisfied that before the priority date, each of the experts worked in the art or science with which the invention is connected and had a practical interest in the subject matter of the invention. Therefore, their evidence is relevant to establishing the skills and knowledge of the notional person skilled in the art relevant to this opposition.
The common general knowledge in the art
A definition of common general knowledge was provided by Aitken J in Minnesota Mining [1980] HCA 9 at [115]; 144 CLR 253 at 292:
“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.”
Cypress submitted that little weight should be given to Prof Brooks’ assessment of the common general knowledge, firstly because he has insufficient practical knowledge in the field of FMS, and secondly because his evidence was provided after he was given with a number of prior art documents, including the opposed patent application (consistent with PB#1 [13]). However, I have found above that Prof Brooks’ evidence is relevant in this opposition. Furthermore, I am not satisfied that Prof Brooks’ evidence with respect to the common general knowledge is tainted by hindsight as Cypress has inferred. In his first declaration, under the heading “Common Knowledge Prior to 28 September 2005” Prof Brooks states:
“15.I was informed by FB Rice that preliminary questions would be posed to me in order to set out what I believe was generally known in the field which relates to the opposed application. FB Rice informed me that this is referred to as the “common general knowledge” of a skilled but non-inventive worker in the relevant field in Australia immediately before 28 September 2005 … . FB Rice asked me to comment on the position as it stood immediately prior to 28 September 2005. As such, unless expressly stated otherwise, the information I provide in this declaration is based on the position as it stood immediately prior to 28 September 2005.
16.I note that at the time when I was providing my opinion with respect to this, I had not seen a copy of the opposed application and nor was I aware of the subject matter that the opposed application addressed.
17.In view of my qualifications and experiences in Australia before the priority date, I believe I am qualified to comment on what was the state of the common general knowledge of skilled workers in the field of rheumatology in Australia immediately before that priority date.”
It is clear from those paragraphs that when Prof Brooks provided his evidence on the common general knowledge, he had not seen a copy of the opposed application, and nor was he aware of its subject matter. It is also clear that Prof Brooks understood that he was to provide evidence of what he understood was generally known in the rheumatology field, and I understand his evidence to have been given in this context. Prof Littlejohn and Dr Quintner both explicitly confirm that unless stated otherwise, their comments in the “Background” section of their evidence relate to matters that were commonly known and routinely practiced in the field of rheumatology and particularly FMS before 28 September 2005 (GOL [16]; JLQ [12]). The expert evidence of what was generally or commonly known or routinely practiced in the art is relevant to the common general knowledge in the art.
Prof Littlejohn does not mention Prof Brooks’ evidence and it is not apparent that he saw it. However, Dr Quintner was provided with Prof Brook’s declaration and he explicitly states at [106] that he comments on Prof Brooks’ statements where he disagrees. Therefore, where Dr Quintner does not disagree with Prof Brooks’ evidence as to the common general knowledge, I take this as an implicit agreement.
Considered as a whole, the evidence establishes that the following matters were common general knowledge in the art at the priority date:
·The field of rheumatology relates to clinical problems of the musculoskeletal system involving joints, soft tissues, bones and muscles and encompasses what are referred to as rheumatic diseases or disorders. The most important and most common symptom of rheumatic disorders is that of pain. (PB#1 [18])
·FMS is a chronic rheumatic disorder that causes widespread pain and tenderness, which is frequently associated with psychiatric conditions (e.g. depression, anxiety and stress) and other symptoms such as sleep problems, fatigue, memory loss, disturbed cognition, headaches, digestive or bladder problems, and weakness. Not all patients with FMS experience all associated symptoms and each patient manifests the symptoms in a unique way. The symptoms of FMS persist for many years, although phases of recurrence and remission may occur. Accordingly, treatment is generally over a time period of months to years. The classification criteria for FMS were established in 1990, which guide diagnosis of the condition. (PB#1 [20]-[22]; JLQ [21])
·By the 1990s, there was a lot of interest by physicians (including rheumatologists) and pharmaceutical companies, in understanding the causes of FMS and, as a result, there was extensive research being conducted (PB#1 [23]). One subject receiving significant attention was the role neurotransmitters, particularly norepinephrine and serotonin, might play in the pathogenesis of FMS (PB#1 [24]). It was known that the levels of norepinephrine and serotonin are decreased in FMS patients, resulting in heightened pain perception and increased sensitivity to particular stimuli (PB#1 [24]). Before the priority date, it was known that inhibition of both norepinephrine and serotonin reuptake contributes to reduction of fibromyalgia pain, and these neurotransmitters and their biological receptors were being investigated with regard to new or improved treatments for FMS. (PB#1 [23], [30])
·Conventional treatments for FMS included regular exercise and good sleep (JLQ [24]). Analgesics such as tramadol, non-steroidal anti-inflammatory drugs and anti-anxiety drugs were known to be used to treat FMS (PB#1 [25]; JLQ [24]). Antidepressants were widely used to treat FMS symptoms including pain (PB#1 [25], [27]) with TCAs being most commonly prescribed and deemed quite effective (PB#1 [25]-[27]; GOL [24]; JLQ [24], [29]; PB#2 [6]). TCAs were known to act by modulating norepinephrine and serotonin reuptake (PB#2 [6]).
·Other antidepressants were being investigated for their effectiveness in treating the pain associated with FMS, including SSRIs and DRIs (PB#1 [31]; GOL [24]; consistent with JLQ [109]). The SSRIs had shown reduced efficacy compared with TCAs (PB#1 [31]; consistent with GOL [24]). The DRIs had shown mixed results (GOL [26]; consistent with PB#1 [31]). However, the DRI duloxetine had demonstrated some efficacy in treating FMS (GOL [26]) and preliminary studies had shown that milnacipran may have the potential to alleviate symptoms associated with FMS (PB#1 [31]; GOL [26]).
·In prescribing a drug, it was typical to look to previously described dosage schedules, but consideration must be given to whether these would be appropriate for the particular patient, or whether the dosage schedule should be adjusted (PB#1 [32]). Reasons for varying a dosage schedule include:
·any additional medical condition the patient may have or other drugs they may be taking;
·the availability of:
(i) new information that indicates or suggests that a different schedule would be more effective in treating the condition; or
(ii) new or more relevant information specific to a disease or disorder;
·knowledge of side effects of the drug; and
·the age of the patient. (PB#1 [32]; JLQ [112])
·Determining optimal patient dosage schedules for a particular drug, including antidepressants, was a standard aspect of everyday practice (PB#1 [33]). If a dosage schedule was not providing the desired outcome or was not tolerated in the individual patient, it would be reconsidered, adjusted and re-trialled in that patient until an optimal or improved dosage schedule was identified and/or acceptable tolerability was achieved, balancing the need for an efficacious dose, with the need to minimise side effects (PB#1 [33]).
·Typically, and particularly for antidepressants, the drug would be started at a low dose and increased (escalated) over time to prevent unwanted reactions or side effects in a patient (PB#1 [32], [34]; GOL [30], [33]; and by inference from JLQ [113]). The frequency of dosing was a routine consideration and, before the priority date, it was commonly known for antidepressants to be administered in multiple daily doses in order to maintain sufficiently high circulating levels of the drug while minimising side-effects (PB#1 [37]).
Obviousness in the light of the common general knowledge in the art alone
To establish that the claimed methods of treatment lacked an inventive step, Alphapharm’s submissions relied on AstraZeneca HCA, in which the High Court upheld the Full Federal Court’s findings on inventive step in AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; (2014) 226 FCR 324 (AstraZeneca FCAFC). Alphapharm submitted that the person skilled in the art would have known that the DRI milnacipran had shown promising results in clinical trials for treating FMS, and that in seeking to solve the problem they would directly be led as a matter of course to use it as a new therapeutic option to replace TCAs, with a reasonable expectation of success. Alphapharm argued that dose optimisation would necessarily take place in clinical trials focusing on the shortest time to arrive at an effective dose, making any specific dosage regime obvious. Alphapharm’s extensive submissions with respect to dosage optimisation are essentially that the person skilled in the art, either in clinical practice or as part of a research team, would directly be led to test all the range of possibilities for administering milnacipran, and the direct and inevitable consequence of these trials would be the identification of the range of safe and efficacious dosage schedules for treating FMS.
In AstraZeneca FCAFC and AstraZeneca HCA, the Courts relevantly considered the obviousness of a claim to a method of treating a patient suffering from a specified medical condition, the method comprising administration as a starting dose, a single, once daily 5 to 10 mg oral dose of the compound rosuvastatin or a pharmaceutically acceptable salt thereof, in the form of a pharmaceutical composition (AstraZeneca FCAFC at [28]). No further doses were specified in the claim. Rosuvastatin itself was known from s 7(3) information, as was its potential to treat the specified medical condition (AstraZeneca FCAFC at [256]-[259], [316]-[322]). Based on the evidence of two experts that they would trial 5 mg and 10 mg doses of the compound (AstraZeneca FCAFC at [544]), Jessup J at [545] (with Besanko, Foster, Nicholas and Yates JJ agreeing at [228]-[229]) confirmed the primary judge’s finding that the person skilled in the art would directly be led as a matter of course to try these doses and, it follows, the claimed method, with a reasonable expectation of success. This finding was subsequently affirmed by the Full Bench of the High Court in AstraZeneca HCA (at [48], [95], [97] and [118]).
Cypress’s claims encompass methods of treating FMS involving a dose escalation schedule involving particular doses of milnacipran administered for specified periods of time. The circumstances in this opposition are distinguished from those before the Courts in the AstraZeneca cases in that the prior art does not teach the more detailed dosage schedules specified in Cypress’s claims. I agree with Cypress that it is not sufficient under Australian law for the opponent to show that a particular aspect of the invention would have been routine had the person skilled in the art chosen to include it. To establish its case for lack of inventive step, Alphapharm must show that in seeking to solve the problem the person skilled in the art would be led as a matter of course or a matter of routine to try the precise combination of features in each of the opposed claims, with a reasonable expectation that it would result in a useful alternative treatment for FMS.
In its submissions, Cypress referred to AB Hässle, in which the High Court found that the primary judge had erred in his consideration of “routine” for inventive step purposes, in not adequately considering the expert evidence. In this regard, the High Court explained at [54]:
“What his Honour did was in line with the position which now apparently obtains in England, that “all of the courses of action which present themselves without the exercise of invention are obvious”. His Honour did not assess what was said by the expert witnesses concerning the procedures they would have followed by making findings whether they would have been led directly as a matter of course to pursue one avenue in the expectation that it might well produce the claimed compound.”
For the reasons that follow, I am not satisfied that the expert evidence establishes to the level of practical certainty that in seeking to solve the problem and without the benefit of hindsight, the person skilled in the art would be led, as a matter of course or as a matter of routine, to try administering milnacipran in the precise manner required by the opposed claims.
In order to treat FMS before the priority date, Dr Quintner would have considered using, in order of preference, at least one of a TCA, an SSRI or a DRI (JLQ [28]). However, he would only use an SSRI or DRI where the patient also presented with a major depressive disorder or an anxiety disorder, respectively (JLQ [29]-[31]). Dr Quintner was unaware before the priority date that milnacipran could be used to treat FMS (JLQ [36]).
Prof Littlejohn states that if using antidepressants to treat FMS before the priority date, he would have considered low dose TCAs, and possibly the DRI duloxetine (GOL [27]-[28]). Despite preliminary studies showing that the DRI milnacipran had the potential to alleviate the symptoms of FMS (GOL [26]), Prof Littlejohn would not have used it to treat FMS before the priority date because there was only limited information indicating that it was well tolerated and effective for treating of FMS-associated pain (GOL [37]). Relevant to the dosing regime, when introducing FMS patients to new drugs, Prof Littlejohn would use a start low/go slow dose escalation regime increasing the dose over several weeks since these patients have a general tendency to be more sensitive to external stimuli and commonly do not tolerate new drugs well (GOL [33]).
In his first declaration, Prof Brooks states that clinical trials had taken place for up to 12 weeks using TCAs, SSRIs and DRIs, including milnacipran (#1 [31]). SSRIs were shown to have a reduced efficacy profile compared to TCAs, while trials of DRIs, including milnacipran, had demonstrated that these compounds can be effective for treating FMS (PB#1 [31]). For antidepressants generally, Prof Brooks confirms that the use of an increasing dosage schedule was typical practice immediately prior to September 2005, for both depression and FMS (#1 [34]). Furthermore, Prof Brooks states:
“In prescribing an anti-depressant of any of the classes that I have described above [i.e. TCAs, tetracyclic antidepressants, monoamine oxidase inhibitors, SSRIs, DRIs serotonin antagonists and reuptake inhibitors and norepinephrine reuptake inhibitors (PB#1 [26])], in nearly all instances, I would prescribe that the patient starts on a low dose which increases to the maximum dose over a period of days to weeks. Typically, I would prescribe that the increase in dose occurs every few days, e.g., 2 to 4 days.” (PB#1 [34], consistent with PB#2 [18], [26])
In his reply evidence at [13], Prof Brooks notes that milnacipran had demonstrated a good safety profile with low to minimal side effects and, subject to any patient-specific issues, there would be little reason to think a protracted dosage escalation such as that suggested by Prof Littlejohn would be necessary. However, at no stage in his evidence does Prof Brooks indicate the doses that he would have administered in a dose escalation regime to a patient with FMS before the priority date.
The opposed claims each define a method for treating FMS with milnacipran consisting of a detailed dosing regime. Prof Littlejohn’s and Dr Quintner evidence reproduced above leads me to conclude that they would not have used milnacipran to treat FMS before the priority date. At best, Prof Brooks’ evidence establishes that he would have administered milnacipran by increasing the dose every two to four days from an unspecified starting dose to an unspecified maximum dose (PB#1 [34]; PB#2 [18], [26]).
Where, as in this case, the invention lies in a combination of features, the question is whether the combination, not each individual feature, is obvious when compared to the prior art base (AB Hässle at [41], [72]; Minnesota Mining [1980] HCA 9 at [116]; (1980) 144 CLR 253 at 293). In this regard, in AB Hässle the High Court cautioned at [41]:
“It is the selection of the integers out of “perhaps many possibilities’ which must be shown by [the opponent] 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.”
In this case, Prof Brooks’s strategy encompasses a wide range of possible dosing regimes, including those in the opposed claims. There is no evidence that establishes that in seeking to solve the problem, the person skilled in the art would be led as a matter of course, or as a matter of routine, to try milnacipran in any one of the dosage regimes specified in Cypress’s claims. Regarding Alphapharm’s submission that the person skilled in the art would directly be led to test all the range of possibilities for administering milnacipran, the expert evidence does not support this conclusion.
Alphapharm has not established that any claim lacks an inventive step in light of the common general knowledge in the art.
Obviousness in the light of prior art documents
The 28 September 2005 priority date was not in dispute. To establish the claimed invention is obvious in light of s 7(3) information in combination with the common general knowledge, Alphapharm relied on the following prior art documents:
Rao
Kranzler
Vitton et al. (2004) Human Psychopharmacology 19: s27-s35 (Vitton)
Gendreau et al. (2003) Arthritis and Rheumatism 48 Suppl 9: S616 (Gendreau)
Ansseau, et al. (1989) Psychopharmacology 98: 163-168 (Ansseau I)
Ansseau et al. (1989) Human Psychopharmacology 4: 221-227 (Ansseau II)
US 2004/012010 (Hirsh, J. et al.) 24 June 2004 (Hirsh)
Tignol et al. (1998) Acta Psychiatria Scandanavia 97: 157-165 (Tignol)
Ascertained, understood and regarded as relevant
“Ascertained” means discovered or found out (Commissioner of Patents v Emperor Sports Pty Ltd [2006] FCAFC 26 [29]-[30], (2006) 67 IPR 488). “Understood” means that the person would have “comprehended” the information or “appreciated its meaning or import” (Lockwood (No 2) at [132]). The person skilled in the art could be expected to have regarded a prior disclosure as relevant if it is directed to solving a particular problem or meeting a long-felt want or need as the patentee claims to have done (Lockwood (No 2) at [152]). The question of what a person skilled in the relevant art would regard as relevant, when faced with the same problem as the patentee, is to be determined on the evidence (Lockwood (No 2) at [153]).
There was no dispute that it was known before the before the priority date that DRIs, including milnacipran, were being investigated for the treatment of FMS and this is supported by the evidence (PB#1 [26], [31]; GOL [26]; JLQ [28]). Since Vitton and Gendreau relate to those clinical trials (JLQ [37]; GOL [41]), Cypress accepted that that the person skilled in the art would ascertain these documents, understand them and regard them as relevant. It remains to be determined whether this is the case for the additional documents.
Search strategy
Prof Littlejohn used databases such as PubMed and Medline to research relevant information and would have monitored TGA and FDA approvals of drugs relevant to the rheumatology field (GOL [20]). Prof Littlejohn also gained knowledge of relevant emerging drugs and technologies at national and international conferences (GOL [21]). Dr Quintner used PubMed, Medline and The Cochrane Library to locate information relevant to his field of research (JLQ [16]). None of these search engines access patent literature and Prof Littlejohn and Dr Quintner identically state in their evidence:
“As at September 2005, I had no knowledge of patents and had never searched for patent documents nor was I aware of any of my colleagues working in my field searching patent documents.” (GOL [22]; JLQ [19]).
I find it a little surprising that Prof Littlejohn has “no knowledge of patents” since his CV has him on the advisory boards of a number of pharmaceutical companies (Exhibit GOL-1 section (7) on page 3). Nevertheless, I conclude from their evidence that neither Prof Littlejohn and Dr Quintner routinely seek out patent documents specifically when seeking information in order to solve a problem.
Prof Brooks kept up to date with developments by reading high impact journals in the rheumatology field and by attending rheumatology conferences in Australia and overseas (PB#1 at [7]-[8]). He also regularly reads, among other things, results of clinical trials and patents relevant to the field of rheumatology (PB#1 [8]). On being asked what type of documents he would have searched for and read immediately prior to September 2005, when considering a new treatment for FMS, Prof Brooks states that he would have searched the scientific literature using PubMed, Web of Science and SciFinder databases, and would have read at least the abstracts of relevant articles (PB#1 [38]). Consistent with Prof Brooks’ evidence that he knew at the time that a preliminary search of the patent literature could be performed using publicly available search engines (PB#1 [38]), Web of Science and SciFinder both provide access to the patent literature. If there were commercial aspects to a potential new treatment for FMS, Prof Brooks, or a member of his team, would deliberately search the patent literature for relevant documents (PB#1 [8], [38]).
I conclude that before the priority date, persons working in the rheumatology field searched for information in the scientific literature and some conducted their search in a manner that would identify patent documents. On this basis, I consider it reasonable to conclude that the notional person skilled in the art could, before the priority date, be reasonably expected to ascertain and have regard to patent literature when seeking information with which to develop new methods for the treatment of FMS using antidepressants, and in particular DRIs. Furthermore, that in screening the documents, they would at least have regard to the abstracts.
Rao, Kranzler, Hirsh, Ansseau I, Ansseau II and Tignol
Prof Brooks was provided with each of these documents by Alphapharm’s attorneys (PB#1 [39]) and he states that he would have expected to identify these types of documents during routine searches if he were tasked with developing a new treatment for FMS (PB#1 [40]). Dr Quintner and Prof Littlejohn address the documents in the context of the treatment of FMS with milnacipran in particular. In considering the question of whether these documents would have been ascertained, understood and regarded as relevant, I have borne in mind that none of the declarants explicitly address this question without the benefit of hindsight.
Rao (Exhibit PB-15) is titled “Dosage escalation and divided daily dose of anti-depressants to treat neurological disorders”. The abstract reveals that such methods include a number of advantages, in particular that high daily dosages of antidepressant can be administered without adverse reactions by escalating the dosages over time, achieving more efficacious amounts than would otherwise be permitted. At para 3 of the specification, the neurological disorders include FMS. On reviewing Rao, Prof Brooks and Dr Quintner understand it to describe potential dosage regimes for the treatment of FMS with DRIs and in particular milnacipran (PB#1 [42]-[43]; JLQ [58]). On this basis, I am satisfied that Rao could be reasonably expected to have been ascertained, understood and regarded as relevant to solving the problem.
Kranzler (Exhibit PB-17) is titled “Methods of treating Fibromyalgia”. The abstract relevantly states that the invention provides a method of treating FMS and pain in an animal by administering a DRI. On this basis I am satisfied that the skilled addressee seeking information with which to solve the problem, could be reasonably expected to have ascertained, understood and regarded Kranzler as relevant.
Hirsh (Exhibit PB-18) is titled “Pulsatile release compositions of milnacipran”. The Hirsh abstract discloses that this patent application relates to once-a-day oral pulsatile release compositions of milnacipran, which reduce the incidence or intensity of the common side effects of the drug (consistent with PB#1 [56]; JLQ [74]). As indicated above, Prof Brooks identifies Hirsh as a type of document he would expect to identify when seeking information in a routine search for treatment for FMS (PB#1 [40]). Dr Quintner does not contradict this. On balance, the evidence supports a view that when seeking information with which to solve the problem, Hirsh could reasonably be expected to have been ascertained, understood and regarded as relevant.
Ansseau I (Exhibit PB-16), Ansseau II (Exhibit PB-19) and Tignol (Exhibit PB-20) each disclose milnacipran for the treatment of depression. Ansseau I is titled “Controlled comparison of two doses of milnacipran (F 2207) and amitriptyline in major depressive inpatients” and the abstract reveals that this multicentre study involves assessment of the antidepressant efficacy and tolerance of milnacipran doses (PB#1 [48]). Ansseau II is titled “Controlled comparison of milnacipran (F2207) 200 mg and amitriptyline in endogenous depressive patients”. The Ansseau II abstract indicates that it relates to a multicentre study involving an assessment of the antidepressant efficacy and the tolerance of a milnacipran dose over 4 weeks in groups of patients with endogenous major depression. Tignol is titled “Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major depressive episode” and the abstract reveals that it involves assessing the efficacy and safety of milnacipran in elderly patients with major depression.
In commenting on Ansseau I and II and Tignol, Prof Brooks states that administering an anti-depressant for the treatment of FMS would involve trial and optimisation of the dosage schedules, and in this regard he would start by considering the dosage schedules used to treat depression (PB#1 [52], [66], [71]). Dr Quintner would not have considered the Ansseau documents or Tignol particularly relevant since they are only short-term studies that are not directed towards the alleviation of pain, the most important presenting symptom of fibromyalgia (JLQ [69], [76] and [81]). Prof Brooks disputes this arguing that it does not matter that these documents do not specifically address pain symptoms, since it was known that milnacipran alleviates pain (PB#2 [41]).
In my view, in giving his evidence Dr Quintner approaches the relevance of the prior art on the basis of whether he would apply its teaching in his everyday clinical practice (JLQ [70], [79]). However, both parties acknowledge in their submissions that an important part of bringing a new treatment into routine clinical practice, are the clinical trials required to identify the optimal doses and treatment regimes. Consistent with this, I have found above that the person skilled in the art includes the skills of a clinical researcher. In this broader context, Prof Brooks’ evidence supports a conclusion that documents such as Ansseau I and II and Tignol, which relate to patient tolerance, safety and efficacy of DRI doses albeit in disorders other than FMS, would be ascertained by the skilled person and regarded as relevant to the problem. On this basis I am satisfied that Ansseau I and II and Tignol could be reasonably expected to have been ascertained, understood and regarded as relevant to solving the problem.
Summary
I am satisfied that the documents relied on by Alphapharm for inventive step purposes could be reasonably expected to have been ascertained, understood and regarded as relevant by the person skilled in the art seeking information with which to solve the problem.
Nothing turns on whether the person skilled in the art could be reasonably expected to have combined any two or more of the documents that Alphapharm relies on to establish that the claimed invention lacks an inventive step. Consequently, for the purpose of this deciding this ground of opposition, I will proceed on the basis that there was such a reasonable expectation.
Consideration
Alphapharm submitted that the person skilled in the art would know from any of Rao, Vitton, Gendreau, Kranzler and/or Hirsch that milnacipran could be used to treat FMS. Alphapharm submitted that having identified milnacipran as a promising candidate and knowing that it was already registered for the treatment of depression, the person skilled in the art would search the literature to find dosing schedules previously used to treat depression. This search would have found the two Ansseau documents and Tignol, which each teach dose escalation protocols, which the person skilled in the art would then use as a starting point for routine clinical trials or routine clinical practice optimisation. Consistent with its submissions regarding obviousness in light of the common general knowledge, Alphapharm concluded that dose optimisation would have led directly as a matter of course to all of the effective dosage schedules including those in the opposed claims.
I have summarised the relevant disclosure of Rao and Kranzler above in this decision. Neither discloses the particular dosing regimes for milnacipran specified in the opposed claims. Like Rao and Kranzler, Vitton and Gendreau also originate with Cypress’s research team and all refer to the same clinical trial in which 125 patients with FMS were treated with milnacipran with the primary endpoint being the improvement of pain (Vitton, page S59). Vitton and Gendreau both describe a dosage regimen in which FMS patients received either single or twice daily doses of milnacipran escalated over 4 weeks followed by 8 weeks on a stable dose. Dose escalation took place in weekly steps from 25 mg/day, to 50, 100 and finally 200 mg/day or until dose-limiting toxicity was evident, in which case the dose would be dropped to the previous week’s dose and maintained at that level for the remainder of the study. Patients continued to take their maximum tolerated dose for an additional 8 weeks. (Vitton, page S28 right column, last full para; Gendreau, page 1976 under the heading “Study design and procedures” and Figure 1) Both Vitton and Gendreau reported significant symptomatic improvement in the FMS patients treated with milnacipran (the Abstracts). (Consistent with JLQ [44-]-[45]; GOL [41], [45])
Hirsh describes a once-a-day oral milnacipran pulsatile release composition (Abstract) and at paras 36-40 summarises Cypress’s clinical trial including its dose escalation regime. At para 97, Hirsh states that milnacipran can be administered for the treatment of FMS. (Consistent with PB#1 [57]-[58]; JLQ [74])
Ansseau I reports a 4-week study comparing the antidepressant efficacy of 50 mg and 100 mg of milnacipran with that of another drug (PB#1 [47]). In the 50 mg study group the milnacipran dose was escalated from 12.5 mg on day 1, to 25 mg on days 2-3, followed by 50 mg/day for the remainder of the treatment period. In the 100 mg study group milnacipran was escalated from 25 mg on day 1, to 50 mg on day 2, 75 mg on days 4-5, followed by 100 mg/day from day 5 through to the end of the study. (Ansseau I para bridging pages 163-164; consistent with PB#1 [51]) Subsequently, Ansseau II reported a 4-week study comparing the antidepressant efficacy and tolerance of 200 mg milnacipran with that of another drug (PB#1 [60]). In this study, the daily milnacipran dose was escalated over 5 days from 50 mg to 100 mg, 150 mg, then 200 mg for the remainder of the study (Ansseau II page 222, first full para; PB#1 at [64]).
Tignol discloses an 8-week study of the efficacy and safety of milnacipran and another drug in elderly patients with major depressive episode (Abstract). During the first week, patients were treated with a stepwise dosage increase to 100 mg daily. The dosage was titrated during the second week to a final dosage of 75 mg/day or 100 mg/day. This dosage was then maintained until the end of the trial period. (Tignol page 158, under the heading “Study design”; consistent with PB#1 [70]; JLQ [83])
None of the documents relied on by Alphapharm for inventive step purposes disclose a precise dosing schedule that falls within Cypress’s claims. Moreover, the expert evidence does not establish that in seeking to develop new methods for the treatment of FMS using DRIs, the person skilled in the art would try milnacipran in the particular dosing schedules in the opposed claims. Prof Littlejohn and Dr Quintner would have referred to Vitton for guidance (GOL [45]; JLQ [44]-[47]), which discloses milnacipran dose escalation to 100 or 200 mg/day over 4 weeks. Prof Brooks would have regard to the known doses and dosage schedules for milnacipran in the treatment of depression and used these as a starting point for developing treatments for FMS, from which he would optimise the dose as necessary by reconsidering, adjustment and re-trialling to achieve the final effective dosage regime (PB#1 [30], [52], [54], [59], [66]; PB#2 [20], [22]).
As it did for its obviousness submissions in light of the common general knowledge, Alphapharm relied on the AstraZeneca cases to support its submission that dose optimisation would have led directly as a matter of course to all of the effective dosage schedules including those in the opposed claims. However, for the reasons provided above, the claims considered in the AstraZeneca cases which referred simply to a “starting dose” of the compound are distinguished from Cypress’s claims which encompass a more detailed dosage regimen. Furthermore, in contrast to the situation in the AstraZeneca cases, there is no expert evidence that supports a conclusion that, based on the disclosure of one or more of the cited documents, the person skilled in the art seeking to solve the problem, would be led as a matter of course or a matter of routine to try milnacipran in any one or more of the particular dosage regimes specified in Cypress’s claims.
Alphapharm has not established that any claim lacks an inventive step in light of one or a combination of the cited prior art.
Fair basis
Subsection 40(3) requires that the claim or claims in a patent specification be fairly based on the matter described in the specification. As the test for fair basis, the High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274 (Lockwood) at [69] approved the words of Gummow J in Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95:
“... the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification.”
Alphapharm submitted that the body of the specification provides no real and reasonably clear disclosure of the dosing schedules as presently claimed. Specifically, it noted that Example 1 describes dose escalation over 3 weeks to maintenance levels of 100 or 200 mg, and neither appears in the claims other than the omnibus claim. On this basis Alphapharm argued that when the body of the specification is read as a whole, no particular dosage schedule is disclosed “as part of the invention”, or if dosing schedules are disclosed, it is the two dosage schedules in Example 1, not those actually claimed in the independent claims.
Relevant to Alphapharm’s submissions, the High Court in Lockwood provided the following principles:
“the requirement in s 40(3) that the claims be fairly based on the matter described in the specification is a requirement that they be fairly based on the matter in it that discusses the “invention” (an expression which includes the “alleged invention”)”. (Lockwood at [53])
“Even if s 40(3) did not impliedly refer to an invention, the language points to a comparison between the claims and what is described in the specification only, and again it does not call for any inquiry into an ‘‘inventive step’’, or inventive “merit” or a “technical contribution to the art”. (Lockwood at [54])
“It is wrong to seek to isolate in the body of the specification ‘‘essential integers’’ or ‘‘essential features’’ of an alleged invention and to ask whether they correspond with the essential integers of the claim in question” (Lockwood at [68])
The field of the invention is broadly described in the opposed specification as the long-term treatment of fibromyalgia by administering a DRI (page 1a). The summary of the invention on page 6 includes that the invention provides methods of long-term treatment of FMS comprising administering a DRI to the patient for at least 3 months. This is relevantly followed by the statement that in exemplary embodiments the compound is milnacipran (page 6, para 5). References to “milnacipran” can include pharmaceutically acceptable salts thereof (page 8, para 1). Between pages 6-7, the specification discloses that “long-term treatment of FMS and its symptoms may be provided to a patient suffering from FMS by administering 25 mg per day to 400 mg per day of milnacipran”. Between pages 7-8, consistory clauses reflect the words of the independent claims.
On page 10, the specification describes a trial of milnacipran monotherapy for the treatment of FMS patients, in which “milnacipran was administered once or twice daily in a dosage escalation regimen to a maximum dose of 200 mg/day”. In Example 1, the specification discloses the use of dose escalation regimes in a study undertaken to demonstrate the safety and efficacy of milnacipran for treating FMS. On page 13, the specification discloses the nature of the trial:
“Patients were randomized to receive placebo, 100 mg/day milnacipran, or 200 mg/day milnacipran in a ratio of a 1:1:2. All randomized medications (placebo and milnacipran) were administered in a split-dose (BID [i.e. twice daily]) fashion. The doses were administered in a dose escalation regimen as outlined below:
Step 1: 12.5 mg 1 day (12.5 mg pm)
Step 2: 25 mg 2 days (12.5 mg am, 12.5 mg pm)
Step 3: 50 mg 4 days (25 mg am, 25 mg pm)
Step 4: 100 mg 7 days (50 mg am, 50 mg pm)
Step 5: 200 mg 7 days (100 mg am, 100 mg pm).
All patients were scheduled to receive a total of 24 weeks of milnacipran or placebo after the 3 weeks of dose escalation steps, for a total of 27 weeks of milnacipran or placebo exposure.”
In the passages summarised above, the specification provides a real and reasonably clear disclosure of the use of milnacipran for the treatment of fibromyalgia, the method comprising administering a composition comprising milnacipran to a subject in need thereof according to a dose escalation schedule up to a maximum dose of 100 mg or 200 mg per day, in the manner required by the opposed claims. It follows that the claims are fairly based.
Conclusion
The opposition fails.
Costs
Both parties claimed costs in the opposition. It is usual in oppositions before the Commissioner that costs should follow the event and I see no reason to depart from the normal practice. Alphapharm has been unsuccessful in its opposition. Therefore, it is appropriate to award costs according to Schedule 8 against Alphapharm.
Barbara Akhurst
Delegate of the Commissioner of PatentsAnnex A: The claims.
1. A method for the treatment of fibromyalgia comprising administering a composition comprising milnacipran or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the composition is administered according to the following schedule:
a) administering up to 25mg of milnacipran or a pharmaceutically acceptable salt thereof per day for up to 3 days; then
b) administering 50mg of milnacipran or a pharmaceutically acceptable salt thereof per day for up to 5 days; then
c) administering 100mg of milnacipran or a pharmaceutically acceptable salt thereof per day.
2. The method of claim 1 wherein the milnacipran or a pharmaceutically acceptable salt thereof of step (a) is administered as a 12.5mg dosage twice daily.
3. The method of any one of the preceding claims wherein the milnacipran or a pharmaceutically acceptable salt thereof of step (b) is administered as a 25mg dosage twice daily.
4. The method of any one of the preceding claims wherein the milnacipran or a pharmaceutically acceptable salt thereof of step (c) is administered as a 50mg dosage twice daily.
5. The method of any one of the preceding claims wherein the milnacipran or a pharmaceutically acceptable salt thereof is administered in a tablet dosage form.
6. The method of claim 5 wherein the tablet dosage form comprises an amount of 25 milnacipran or a pharmaceutically acceptable salt thereof selected from 12.5mg, 25mg, 50mg or l00mg.
7. The method of any one of the preceding claims wherein in step (a) 25mg of milnacipran or a pharmaceutically acceptable salt thereof is administered for 2 days.
8. The method of any one of the preceding claims wherein the composition comprises milnacipran hydrochloride.
9. A method for the treatment of fibromyalgia comprising administering a composition comprising milnacipran or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the composition is administered according to a schedule comprising the following steps:
a) administering the same amount of milnacipran or a pharmaceutically acceptable salt thereof per day for up to 3 days; and
b) administering 100mg of milnacipran or a pharmaceutically acceptable salt thereof per day by the eighth day of treatment.
10. The method of claim 9 wherein the amount of milnacipran or a pharmaceutically acceptable salt thereof of step (a) is 25mg.
11. The method of claim 10 wherein the 25mg of milnacipran or a pharmaceutically acceptable salt thereof is administered as a 12.5mg dosage twice daily.
12. The method of any one of claims 9 to 11 wherein the milnacipran or a pharmaceutically acceptable salt thereof of step (b) is administered as a 50mg dosage twice daily.
13. The method of any one of claims 9 to 12 wherein the milnacipran or a pharmaceutically acceptable salt thereof is administered in a tablet dosage form.
14. The method of claim 13 wherein the tablet dosage form comprises an amount of milnacipran or a pharmaceutically acceptable salt thereof selected from 12.5mg, 25mg, 50mg or 100mg.
15. The method of any one of claims 9 to 14 wherein in step (a) 25mg of milnacipran or a pharmaceutically acceptable salt thereof is administered for 2 days.
16. The method of any one of claims 9 to 15 wherein the composition comprises milnacipran hydrochloride.
17. A method for the treatment of fibromyalgia comprising administering a composition comprising milnacipran or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the composition is administered according to the following steps:
a) administering milnacipran or a pharmaceutically acceptable salt thereof in an escalating dosage for up to 7 days, wherein the initial dosage is 12.5 mg per day and the final dosage is 100 mg per day; and
b) administering 100 mg of milnacipran or a pharmaceutically acceptable salt thereof per day thereafter.
18. A method for the treatment of fibromyalgia comprising administering a composition comprising milnacipran or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the composition is administered according to the following steps:
a) administering milnacipran or a pharmaceutically acceptable salt thereof in an escalating dosage for up to 7 days, wherein the initial dosage is 12.5 mg per day and the final dosage is 100 mg per day; and
b) administering 200 mg of milnacipran or a pharmaceutically acceptable salt thereof per day thereafter.
19. A method according to any one of claims 1, 9, 17 or 18, substantially as herein described with reference to any one or more the examples but excluding comparative examples.
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