Apotex Pty Ltd v Warner-Lambert Company LLC (No 2)
[2016] FCA 1238
•21 October 2016
FEDERAL COURT OF AUSTRALIA
Apotex Pty Ltd v Warner-Lambert Company LLC (No 2) [2016] FCA 1238
File numbers: NSD 763 of 2013
NSD 251 of 2014Judge: NICHOLAS J Date of judgment: 21 October 2016 Catchwords: PATENTS – construction of patent specification describing methods for treating pain comprising administering a therapeutically effective amount of a compound to a mammal in need of said treatment – whether patent obtained by misrepresentation or false suggestion – whether misrepresentation or false suggestion made with respect to compound used in animal tests reported in complete specification – whether misrepresentation or false suggestion was a material inducing factor leading to grant of the patent – whether claims invalid and liable to be revoked on ground that the complete specification does not describe the invention fully – where complete specification does not include any reference to clinical trials involving humans – where complete specification refers only to experiments carried out on rats – whether complete specification provides notional skilled addressee with sufficient information to enable inventive method to be used in the treatment of humans – whether claims invalid and liable to be revoked on ground that the invention claimed is not useful – whether Swiss style claims infringed by importation and sale in Australia of a medicament made outside the patent area – meaning of “exploit” as defined in Schedule 1 of Patents Act 1990 (Cth) Legislation: Patents Act 1990 (Cth) ss 12, 13, 18(1), 22A, 40(2), (3), 120, 138(3), (4)
Patents Act 1952 (Cth) ss 70, 100(1)(k)
Patents Act 1949 (UK) s 32(l)(j)
Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth)
Evidence Act 1995 (Cth) s 136
Cases cited: Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd (1998) 194 CLR 171
Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618
Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd (2013) 253 CLR 284
Aristocrat Technologies Australia Pty Ltd v Konami Australia Pty Ltd (2015) 114 IPR 28
AstraZeneca AB v Apotex Pty Ltd (2014) 226 FCR 324
Biogen Inc v Medeva Plc [1997] RPC 1
British Liquid Air Co Ltd v British Oxygen Company Ltd (1908) 25 RPC 577
Electric & Musical Industries Ltd v Lissen Ltd (1938) 56 RPC 23
Eli Lilly and Company v Pfizer Overseas Pharmaceuticals (2005) 64 IPR 506
Eli Lilly & Company v Janssen Alzheimer Immunotherapy [2014] RPC 1
Fawcett v Homan (1896) 13 RPC 398
Generics (UK) Ltd v Daiichi Pharmaceutical Co Ltd [2009] RPC 23
Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1
ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc (1999) 45 IPR 577
Jupiters Ltd v Neurizon Pty Ltd (2005) 222 ALR 155
Lane Fox v Kensington and Knightsbridge Electric Lighting Co Ltd [1892] 3 Ch 424
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 217 CLR 274
Merck & Co Inc v Arrow Pharmaceuticals Ltd (2006) 154 FCR 31
Minnesota Mining and Manufacturing Company v Beiersdorf (Australia) Ltd (1980) 144 CLR 253
No-Fume Ltd v Frank Pitchford & Co Ltd (1935) 52 RPC 231
Norton and Gregory Ltd v Jacobs (1937) 54 RPC 271
Osram Lamp Works Ltd v Pope’s Electric Lamp Co Ltd (1917) 34 RPC 369
Otsuka Pharmaceutical Co Ltd v Generic Health Pty Ltd (No 4) (2015) 113 IPR 191
Pfizer Overseas Pharmaceuticals v Eli Lilly and Company (2005) 225 ALR 416
Prestige Group (Australia) Pty Ltd v Dart Industries Inc (1990) 26 FCR 197
Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79
Rescare Ltd v Anaesthetic Supplies Pty Ltd (1992) 25 IPR 119
Samuel Taylor Pty Ltd v SA Brush Co Ltd (1950) 83 CLR 617
Sanofi-Aventis Australia Pty Ltd v Apotex PtyLtd (No 3) (2011) 92 IPR 320
Tramanco Pty Ltd v BPW Transpec Pty Ltd (2014) 105 IPR 18
Valensi v British Radio Corporation [1973] 90 RPC 337
Washex Machinery Corporation v Roy Burton & Co Pty Ltd (1975) 49 ALJR 12
Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588
WM Wrigley Jr Co v Cadbury Schweppes Pty Ltd (2005) 66 IPR 298
Blanco White, Patents for Inventions, 5th ed, Stevens & Sons, London, 1983
Date of hearing: 16, 17, 20, 21, 22, 23, 27, 28, 30 and 31 July 2015 Registry: New South Wales Division: General Division National Practice Area: Intellectual Property Sub-area: Patents and associated Statutes Category: Catchwords Number of paragraphs: 306
Counsel for the Applicant/Cross-Respondent in NSD 763 of 2013:
Mr DK Catterns QC with Mr NR Murray and Mr MB Fleming Solicitor for the Applicant/Cross-Respondent in NSD 763 of 2013: Ashurst Australia Counsel for the Respondent/Cross-Claimants in NSD 763 of 2013 and Applicants/Cross-Respondents in NSD 251 of 2014: Mr AJL Bannon SC with Mr C Dimitriadis SC and Mr BA Mee Solicitor for the Respondent/Cross-Claimants in NSD 763 of 2013 and Applicants/Cross-Respondents in NSD 251 of 2014: Allens Linklaters Counsel for the Respondent/Cross-Claimant in NSD 251 of 2014: Ms AH Bowne SC Solicitor for the Respondent/Cross-Claimant in NSD 251 of 2014: Maddocks Lawyers
Table of Corrections 25 October 2016 Para [207], last sentence be amended to also refer to “A/Prof. King” 25 October 2016 Para [297], third sentence be amended to read “ the acts of importation and sale occur within the patent area.” 4 November 2016 Para [156], the word “based” deleted from the first sentence 4 November 2016 Para [174], first sentence amended to read “… that a pleading point was being taken.” ORDERS
NSD 763 of 2013 BETWEEN: APOTEX PTY LTD (ACN 096 916 148)
Applicant
AND: WARNER-LAMBERT COMPANY LLC
Respondent
AND BETWEEN: WARNER-LAMBERT COMPANY LLC
(and others named in the Schedule)First Cross-Claimant
AND: APOTEX PTY LTD (ACN 096 916 148)
Cross-Respondent
JUDGE:
NICHOLAS J
DATE OF ORDER:
21 October 2016
THE COURT ORDERS THAT:
1.The respondent and cross-claimants file and serve a draft minute of the final orders they seek in this proceeding within 7 days.
2.The proceeding stand over to a date to be fixed for the purpose of making final orders.
3.Up to and including 28 October 2016 or further order, the contents of paragraphs [275] to [281] (inclusive) and [283] of the reasons for judgment of Nicholas J dated today be kept confidential and not be made available for public inspection.
4.There be liberty to apply on 24 hours’ notice.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
ORDERS
NSD 251 of 2014 BETWEEN: WARNER-LAMBERT COMPANY LLC
First Applicant
PF PRISM CV
Second Applicant
PFIZER IRELAND PHARMACEUTICALS
(and others named in the Schedule)Third Applicant
AND: GENERIC PARTNERS PTY LTD (ACN 132 833 777)
Respondent
AND BETWEEN: GENERIC PARTNERS PTY LTD (ACN 132 833 777)
(ACN 132 833 777)
Cross-ClaimantAND: WARNER-LAMBERT COMPANY LLC
(and others named in the Schedule)First Cross-Respondent
JUDGE:
Nicholas J
DATE OF ORDER:
21 october 2016
THE COURT ORDERS THAT:
1.The applicants and cross-respondents file and serve a draft minute of the final orders they seek in this proceeding within 7 days.
2.The proceeding stand over to a date to be fixed for the purpose of making final orders.
3.Up to and including 28 October 2016 or further order, the contents of paragraphs [275] to [281] (inclusive) and [283] of the reasons for judgment of Nicholas J dated today be kept confidential and not be made available for public inspection.
4.There be liberty to apply on 24 hours’ notice.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
REASONS FOR JUDGMENT
NICHOLAS J:
INTRODUCTION
There are two proceedings now before me. The first proceeding (“the Pfizer proceeding”) is brought by Apotex Pty Ltd (“Apotex”) against Warner-Lambert Company LLC (“Warner-Lambert”) and various related entities that form part of the Pfizer group of companies (together “Pfizer”). The second proceeding (“the GPPL proceeding”) is brought by Pfizer against Generic Partners Pty Ltd (“GPPL”). In these proceedings Pfizer seek injunctive relief against Apotex and GPPL under s 120 of the Patents Act 1990 (Cth) (“the Act”).
Warner-Lambert is the registered owner of Australian Standard Patent 714980 (“the Patent”) entitled “Isobutylgaba and its Derivatives for the Treatment of Pain”. The Patent was applied for on 16 July 1997 (“the application date”) with a claimed priority date of 24 July 1996 (“the priority date”). There is no dispute as to the correctness of the priority date.
In general terms, the Patent relates to the use of certain compounds for the treatment of pain and in the manufacture of medicaments for the treatment of pain. These include the compound known as pregabalin which is marketed and sold in Australia by Pfizer Australia Pty Ltd under the brand name Lyrica.
In the Pfizer proceeding, Pfizer alleges that Apotex threatens to infringe each of the 32 claims of the Patent. Apotex seeks an order for the revocation of each of the claims upon which it is sued. Apotex admits that, if claims 1-15 and 31 are valid, then it threatens to infringe them. Apotex says that it does not threaten to infringe the various Swiss claims, claims 16-30, and 32 (if that is truly a Swiss claim), because the products it is proposing to market and sell in Australia will be manufactured overseas by a third party. There is a further infringement issue peculiar to claim 32 which I also need to consider.
Apotex alleges that the claims of the Patent are invalid because the complete specification does not describe the invention fully, as required by s 40(2)(a) of the Act. Apotex further alleges that the claims of the Patent are invalid because the invention claimed, contrary to s 18(1)(c) of the Act, is not useful. Apotex also alleges that the Patent should be revoked because the patentee, Warner-Lambert, was not entitled to the Patent (s 138(3)(a) of the Act) and also because the Patent was obtained by false suggestion or misrepresentation (s 138(3)(d) of the Act).
In the GPPL proceeding, Pfizer alleges that GPPL also threatens to infringe claims 1-30 of the Patent. GPPL admits that, assuming the claims of the Patent are valid, it threatens to infringe claims 1-15 but not claims 16-30 (the Swiss claims). GPPL contends that each of the claims upon which it is sued are invalid on the same grounds that are relied upon by Apotex and it also seeks an order for the revocation of all such claims. In final submissions, GPPL adopted Apotex’s submissions in relation to both infringement and validity in respect of claims 1-30. During the course of the trial Pfizer withdrew its allegations of infringement against GPPL in respect of claims 31 and 32 and GPPL withdrew its claims of invalidity in respect of those claims.
The validity of the Patent is to be determined by reference to the provisions of the Act as they stood as at 24 July 1996 which is, of course, before the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) (“the Raising the Bar Act”) took effect except for those provisions that relate to entitlement. So far as the latter issue is concerned, ss 22A and 138(4) of the Act in its current form apply in this case: see AstraZeneca AB v Apotex Pty Ltd (2014) 226 FCR 324 at [182]-[184].
THE WITNESSES
There were 14 witnesses who made affidavits that were read at the hearing, 12 of whom were experts who contributed to one or more Joint Expert Reports and who gave oral evidence during the concurrent sessions. The other two witnesses, Ms Smith and A/Prof. Miller, made affidavits, but were not required for cross-examination. There were five “fields” that were the subject of Expert Conferences that led to five Joint Expert Reports, covering the following fields:
Further details of the witnesses and, in the case of the expert witnesses, their field of expertise, are set out below. Witnesses called by Apotex are designated (A) and those called by Pfizer are designated (P). The only witnesses separately cross-examined after the completion of the concurrent sessions were Professors Christie, Easton, Littlejohn and Schug and A/Prof. Darren Roberts.
My assessment of the expert witnesses was mostly very favourable. Their oral evidence given in the concurrent sessions was particularly helpful. The concurrent sessions allowed the experts to engage in a candid and spontaneous exchange of views in relation to key issues relevant to their fields of expertise. The contributions of the clinicians and their approach to the task of giving evidence was in my opinion exemplary. This is also true of Professor Christie whose evidence, along with that of Professors Gibson and Schug, was particularly informative.
It is necessary to make the following observation in relation to Dr Oppenheim’s affidavit evidence concerning the difficulties that would be encountered by the skilled addressee in formulating a pharmaceutical composition with which to perform the claimed methods of treatment using the Patent and the common general knowledge. In light of evidence given by Dr Oppenheim in other proceedings (to which his attention was drawn in the concurrent session) I am satisfied that these difficulties were overstated in his affidavit evidence. In final submissions Apotex placed little (if any) reliance upon this evidence and it is therefore not necessary for me to say any more about it.
A/Prof. John King (A)
A/Prof. King is a consultant neurologist with the Royal Melbourne Hospital where he consults with patients on a range of neurological conditions. He also holds various other positions including that of Associate Professor at the University of Melbourne’s Centre for Neurosciences. He is a member of the Australia and New Zealand Association of Neurologists, the Royal Australasian College of Physicians and the American Academy of Neurology. A/Prof. King has worked in the field of neurology in Australia for 38 years. His evidence was directed toward Fields 1, 2 and 3.
A/Prof. Lynden Roberts (A)
A/Prof. Lynden Roberts is a practising consultant rheumatologist at the Monash Medical Centre. He is also a Member of the National Steering Committee Rheumatoid Arthritis Clinical Registry. A/Prof. Roberts is also a Member of the National Gout Group Steering Committee for Australia and New Zealand and is the Continuing Professional Development Lead of the Royal Australasian College of Physicians’ Rheumatology Specialist Training Committee. A/Prof. Roberts’ evidence was directed to Fields 1, 2 and 3.
Professor Paul Harnett (A)
Professor Paul Harnett is a medical oncologist who specialises in the management of breast cancer and gynaecological cancers. Professor Harnett holds the positions of Director, the Crown Princess Mary Cancer Centre, Westmead where he is a Senior Staff Specialist in Medical Oncology; Director, Sydney West Translational Cancer Research Centre and Director, Sydney West Cancer Network, Sydney West and Nepean Blue Mountains Local Health Districts. He also holds the positions of Consultant Medical Oncologist to the New South Wales Breast Cancer Institute, Consultant Medical Oncologist Westmead Centre for Gynaecologic Cancer and Clinical Professor of the University of Sydney. Professor Harnett’s evidence was directed to Fields 1, 2 and 3.
Professor Stephen Gibson (A)
Professor Stephen Gibson is a psychologist and research academic with a specialisation in pain. He is a Professor in the Department of Medicine at the University of Melbourne, the Director of Clinical Research at the National Ageing Research Institute and the Director of Research at the Caulfield Pain Management and Research Centre in Victoria. Professor Gibson has over 25 years’ experience in clinical pain research. He also works in clinical practice as a clinical psychologist at various multidisciplinary pain management clinics in Victoria. His evidence was directed to Fields 1, 2 and 3.
A/Prof. Darren Roberts (A)
A/Prof. Darren Roberts is a clinical pharmacologist, nephrologist and clinical researcher. He is a Fellow of the Royal Australasian College of Physicians with subspecialisation in clinical pharmacology and nephrology. He has expertise in clinical trials and clinical toxicology. He has participated in multiple investigator-initiated university-based and hospital-based clinical trials in Australia, the United Kingdom and Sri Lanka. This included working as a clinical sub-investigator in various Phase 3 clinical trials. Some of the clinical trials in which he has been involved have concerned treatments for iron deficiency and auto-immune disease. A/Prof Roberts’ evidence was directed to Fields 3, 4 and 5.
Dr Richard Oppenheim (A)
Dr Oppenheim is a formulation chemist and principal of his own consultancy. Dr Oppenheim provides consultancy services to the therapeutic goods and food industries. His work in this area is primarily with clients that market and manufacture prescription pharmaceutical products and over-the-counter products, complementary medicines, dietary supplements, therapeutic devices and foods. He has over 40 years’ experience in this field. Dr Oppenheim’s evidence was directed to Fields 4 and 5.
Dr Wayne Best (A)
Dr Best is an organic chemist who has worked in the field of chemistry in Australia for 26 years. He is the Managing Director of EpiChem Pty Ltd (“EpiChem”) which he founded in 2003. EpiChem supplies services in synthetic and medicinal chemistry to the drug discovery and pharmaceutical industries. EpiChem also undertakes in-house and collaborative drug discovery programs. Dr Best’s evidence was directed to Fields 4 and 5.
Ms Kellech Smith (A)
Ms Smith is a partner of Ashurst Australia, solicitors for Apotex. Her affidavit exhibited (inter alia) the product information documents published by Pfizer in relation to Lyrica and copies of correspondence between Pfizer and the United States Food and Drug Administration (“FDA”) relating to Lyrica.
Professor Stephan Schug (P)
Professor Schug is a pain specialist and the Director of Pain Medicine at the Royal Perth Hospital. Professor Schug is also Chair of Anaesthesia at the University of Western Australia. His academic appointments have had a significant clinical component, initially in anaesthesia, intensive care and pain medicine, with increasing emphasis on pain medicine. He has almost 30 years’ experience in the field of pain medicine. His evidence was directed toward Fields 1, 2 and 3.
Professor Macdonald Christie (P)
Professor Christie is a Professor of Pharmacology at the University of Sydney who also has expertise in pain. His research interests include the neurobiology of pain, analgesia, and pain-relieving drugs and therapies with a focus on neuroplasticity, neuropathic pain, visceral pain, analgesia and spinal-cord injury. Professor Christie’s research work includes a number of projects aimed at identifying neural and molecular mechanisms underlying the sensitisation responsible for chronic pain states in animal models, and at developing novel peptide drugs that target those mechanisms. Professor Christie’s evidence was directed to Fields 1, 2 and 3 . He also gave some oral evidence directed to Field 5.
Professor Geoffrey Littlejohn (P)
Professor Littlejohn is a rheumatologist. He is a Professor in the Department of Medicine at Monash University, Emeritus Director of Rheumatology at Monash Health and Adjunct Professor at Edith Cowan University, Perth. He also provides clinical and consulting services in the field of rheumatology. He has been the principal investigator in a large number of clinical trials at Monash Health using targeted pharmacological agents to treat rheumatoid arthritis, psoriatic arthritis, osteoarthritis, fibromyalgia and gout. Professor Littlejohn’s evidence was directed to Fields 1, 2 and 3.
Professor Christopher Easton (P)
Professor Easton is an organic chemist and a Professor at the Research School of Chemistry, Australian National University. He has been involved in various research projects undertaken in collaboration with various pharmaceutical and chemical companies. Professor Easton’s evidence directed to Fields 4 and 5.
Dr Angelo Morella (P)
Dr Morella is a chemist. He has extensive experience in the fields of drug delivery and pharmaceutics and has worked as both a biotechnology scientist and consultant to industry. Dr Morella has been a member of the various advisory groups at the University of South Australia including the Medical and Pharmaceutical Biotechnology Advisory Group, the Pharmaceutical Science Curriculum Development Advisory Group, the Centre for Drug Formulation and Delivery Advisory Group, and the Pharmaceutical Sciences Advisory Committee. His evidence was directed to Fields 4 and 5.
A/Prof. Graeme Miller (P)
A/Prof. Miller is an Associate Professor and Medical Director of the Family Medicine Research Centre (“FMRC”) at the University of Sydney. One of FMRC’s key research programs is the “Bettering the Evaluation And Care of Health” (“BEACH”) program which has been conducted since 1998 and collects data about the conduct of general practice in Australia. He provided an affidavit in which he exhibited a report (“the Beach Report”) that was relied upon by Pfizer to show that pregabalin is prescribed to treat pain associated with a wide variety of medical conditions.
THE SKILLED ADDRESSEE
There was no dispute between the parties as to the attributes of the skilled addressee. In the present case the subject matter of the Patent concerns the preparation and use of certain pharmaceutical compositions in the treatment of different types of pain (eg. neuropathic pain) including pain associated with different conditions (eg. cancer pain).
The skilled addressee is a notional person who may have an interest in using the products or methods of the invention, making the products of the invention, or making products used to carry out the methods of the invention either alone or in collaboration with others having such an interest: see Aristocrat Technologies Australia Pty Ltd v Konami Australia Pty Ltd (2015) 114 IPR 28 at [26].
In the present case people with a practical interest in the invention the subject of the Patent would include pharmacologists, clinicians (pain specialists and other clinicians who treat pain), pharmaceutical formulators and organic chemists. Thus, the relevant fields of expertise include pharmacology, pharmaceutical formulation, pain medicine, and organic chemistry.
SCIENTIFIC BACKGROUND
Common general knowledge
The notional skilled addressee will possess the common general knowledge in each of these fields in so far as they are relevant to the subject matter of the Patent. In the present case it will include the background knowledge and experience available to all those persons engaged in the particular fields that I have identified including publications to which they would refer as a matter of course: see Minnesota Mining and Manufacturing Company v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 at 292 per Aickin J; ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc (1999) 45 IPR 577 at [112] per Emmett J.
There was no issue between the parties as to the state of the common general knowledge at the priority date. Some of the relevant scientific and medical knowledge referred to in the evidence was first acquired by the experts after the priority date (particularly in relation to “central sensitisation”) and the following account of the relevant science indicates if this is so. Subject to that qualification, the matters set out in this section of my reasons (which is mostly drawn from Professor Christie’s and Professor Easton’s affidavit evidence) were matters of common general knowledge as at the priority date.
Pain
Pain classification
Pain is a complex phenomenon that reflects a blend of sensory, cognitive, emotional, and social components. It occurs in the context of fundamental biological events taking place at multiple levels of the “somatosensory system”.
The somatosensory system is the part of the nervous system (including the brain) that conveys sensory stimuli, such as sensations of touch, pressure, temperature, proprioception (position) and vibration, arising from the muscles, joints, internal organs, skin and fascia to the brain where it is interpreted.
Pain has been defined as “[a]n unpleasant sensory and emotional experience associated with actual and potential tissue damage, or described in terms of such damage” (see International Association for the Study of Pain (“IASP”), Classification of Chronic Pain, IASP Press, 2nd Edition, 1994 at p 210).
Descriptions of the underlying biological mechanisms associated with pain are particularly relevant in the preclinical environment where an understanding of pain mechanisms is central to the research and the development of new pain therapies and drug indications.
In the clinical setting there is limited availability of diagnostic tools to definitively identify the involvement or contribution of a biological mechanism in a patient presenting with pain and in this setting pain is usually categorised in other ways. Pain may be described in terms of its etiology (ie. the cause or set of causes of a disease or condition), pathology or disease-base (eg. osteoarthritis), duration (eg. acute or chronic), or by the location of the pain (eg. headache, lower back pain).
There are various pain mechanisms that are intimately interlinked and more than one mechanism is commonly implicated in the pain experience at any point in time.
Nociceptive pain
Nociception is the neural process by which noxious stimuli generate neural signals, the outcome of which can be a range of autonomic responses (such as altered blood pressure and heart rate), reflex withdrawal, and the perception and experience of pain. Nociceptive pain is part of the normal response to threatened or actual physical trauma or injury, and induces a response to the noxious stimulus which is aimed at preventing or minimising injury and/or protecting or healing existing injury.
“Nociceptive pain” is a pain sensation initiated by a noxious stimulus and typically subsides when the noxious stimulus ceases or the threat of injury is removed. However, some diseases can generate recurrent noxious stimuli, leading to ongoing nociceptive pain (eg. osteoarthritis). The neurobiological process of nociception commences with the activation of specialised receptors called “nociceptors”.
Neurons are electronically excitable cells that process and transmit electrical and chemical signals. Nociceptors are located on the peripheral terminals of specialised neurons called “primary sensory neurons” (or “primary afferent neurons”) that innervate peripheral tissue.
There are two main classes of primary sensory neurons responsive to intense noxious stimuli: medium diameter, myelinated “Aδ-fibres” and small diameter, unmyelinated “C-fibres”. Related classes of sensory neurons are the myelinated “Aβ-fibres”, responsible for the detection of low threshold, innocuous stimuli such as touch, and “Aα-fibres” which are largely responsible for proprioception.
Myelin is a material formed of lipid and protein that acts as an insulating sheath, which allows faster rates of signal transmission along the length of the neuron. Myelinated Aδ-fibres are responsible for the first sharp sensation of pain and reflex withdrawal. Unmyelinated C-fibres are responsible for the subsequent sensation of pain experienced over the following seconds, and provide the brain with further information about the tissue damage, including information about its location, type and severity.
The cell bodies of primary sensory neurons are located in the dorsal root ganglia (“DRG”) for neurons that innervate the body, and the trigeminal neural ganglion (“TNG”) for neurons that innervate the face and head. They have both a peripheral and central axonal branch that innervates their target organ/tissue and the spinal cord or brain stem, respectively.
Nociceptor peripheral axonal terminals are characterised by specialised, high threshold transducer receptor/ion channel complexes which respond to (or are “gated” by) intense or prolonged noxious stimuli, such as elevated temperature (eg. a burn from a hot iron), chemicals (eg. an acid burn) or mechanical forces such as pressure or shearing (eg. a hammer strike or surgical incision). Some nociceptors respond to different types of noxious stimuli while others respond only to a specific type.
Nociceptors convert (or “transduce”) noxious stimuli into electrical signals. When activation by a noxious stimulus causes nociceptor ion channels to open, allowing sodium and calcium cations to enter the peripheral terminal of the sensory neuron, the influx of sodium and calcium cations produce an electrical current which depolarises the terminal membrane. If the noxious stimulation produces a sufficiently strong depolarising current, specialised voltage-gated sodium channels will also open. The opening of these voltage-gated sodium channels increases the flow of sodium ions into the peripheral terminal, causing further depolarisation of the terminal membrane and resulting in the generation of “action potentials”. Action potentials are a brief fluctuation in membrane electrical potential resulting from the rapid opening and closing of voltage-gated sodium ion channels. The intensity and duration of the initiating noxious stimulus is reflected in the frequency of the action potentials.
Action potentials generated in the nociceptor peripheral terminals are conducted along the axon of the sensory neuron by successive firing (opening and closing) of voltage-gated sodium channels to the cell body located in the DRG and to the central terminal of the primary sensory neuron located in the dorsal horn of the spinal cord. The dorsal horn of the spinal cord is organised into distinct laminae (layers). Aδ-fibres project to lamina I and the deeper lamina II of the dorsal horn, C-fibres project more superficially to lamina I and II, and Aβ-fibres and Aα-fibres project to deep laminae III, IV and V of the dorsal horn.
Transfer of input from peripheral nociceptors to secondary neurons located in the dorsal horn of the spinal cord is mediated through direct synaptic contact between the central terminals of the primary (pre-synaptic) and secondary (post-synaptic) neurons. A “synapse” is the specialised junction at which action potentials are transmitted by chemical transmission from the axon terminal of one neuron (the pre-synaptic terminal) and received by the terminal of one or more target neurons (post-synaptic terminal).
Depolarisation of the pre-synaptic terminal by incoming action potentials leads to the opening of voltage-gated calcium channels (“VGCCs”, principally neural “N-type” VGCCs) located in the pre-synaptic membrane and triggers an influx of calcium ions into the pre-synaptic terminal. This in turn leads to the release of the excitatory neurotransmitter “glutamate”, the neuropeptides “substance P” and calcitonin gene-related peptide (“CGRP”), from vesicles located within the pre-synaptic terminal. The neurotransmitters and neuropeptides cross the synaptic cleft (the space separating the pre-synaptic and post-synaptic neurons) and bind to receptors located on the post-synaptic membrane of the secondary neuron.
Glutamate binds at post-synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (“AMPA”) receptors, N-methyl-D-aspartate (“NMDA”) receptors, and kainate receptors, which are all “ionotropic” receptor ion channels. Ionotropic receptors directly gate ion channels when a ligand binds to the receptor located on the ion channel. There are also various “metabotropic” glutamate receptors. Metabotropic receptors indirectly gate ion channels.
Substance P binds at post-synaptic, metabotropic neurokinin-1 (“NK-1”) receptors. CGRP binds to a metabotropic calcitonin receptor-like receptor (“CRL”) and a receptor activity-modifying protein (“RAMP”) complex located on the post-synaptic terminal.
Secondary neurons are responsible for localising, integrating and distributing signals from peripheral neurons. The majority of sensory inputs are distributed directly from secondary neurons in the spinal cord dorsal horn to the periphery and are responsible for (inter alia) muscle reflexes. Only a small percentage (about 10%) of all sensory input is transmitted from secondary neurons to the higher regions of the brain where ultimately it may be perceived as pain. Not all nociceptive sensory input is transmitted to the brain. The central nervous system (“CNS”) contains mechanisms that can block or modify the transmission of signals before they ascend to the brain. One way this is achieved is by the mechanism called “descending modulation”.
During normal nociceptive transmission, binding by glutamate to AMPA ionotropic receptor ion channels located on the post-synaptic central terminal of secondary neurons leads to an influx of sodium ions, and a lesser efflux of potassium ions. This has the effect of depolarising the secondary neuron, leading to the generation of a new action potential in the secondary neuron.
In the basal, or normal resting state, ionotropic NMDA receptor ion channels located on post-synaptic terminals of secondary neurons are each blocked by an extracellular magnesium ion. This means that in most neurons in their normal resting state glutamate binding to the NMDA receptor does not result in significant influx of calcium ions across the post-synaptic membrane.
However, if depolarisation of the postsynaptic terminal is sufficiently strong (eg. in response to the influx of calcium ions and sodium ions through activation of ionotropic AMPA receptor ion channels) sodium ions and calcium ions will flow in through the NMDA receptor ion channels. This further depolarises the post-synaptic terminal.
“Neuroplasticity” refers to the capacity of the nervous system to adapt and reorganise itself. Increased depolarisation of the post-synaptic terminal results in increased excitability, and calcium-dependent neuroplasticity associated with activation of intracellular protein kinases, that can produce a persistent increase in postsynaptic excitability and synaptic responses in the secondary neuron.
The activity-dependent effects of NMDA receptor activation are a major component of the underlying mechanisms associated with the phenomenon of central sensitisation.
Inflammatory pain
Inflammation can give rise to pain when a stimulus (usually noxious), infection, or disease results in tissue damage that triggers the body’s inflammatory response. The inflammatory response involves the initiation of a complex series of biochemical and cellular events aimed at repairing the damaged tissue.
(Source: Extracted from CJ Woolf “What is this thing called pain?” (2010) 120(11) Journal of Clinical Investigation (“Woolf (2010)”).
Tissue injury results in the release of numerous chemical mediators from peripheral nerve terminals, ruptured cells, and immune cells that are recruited to the site of injury. Some inflammatory mediators (eg. protons, bradykinin, adenosine triphosphate) can directly activate nociceptors, leading to spontaneous nociceptive pain. Other mediators modify the response properties of primary afferent neurons to subsequent stimuli. For example, this can occur by increasing the sensitivity of transducer receptors located in the nociceptor peripheral terminals so that they are activated by lower intensity noxious stimuli, and increasing the intensity of the response by altering the activation threshold of voltage-gated ion channels. The phenomenon of increased responsiveness and reduced nociceptive threshold in the peripheral terminal of primary sensory neurons is known as “peripheral sensitisation” and is responsible for the increased sensitivity and tenderness of injured tissue that promotes protective behaviour toward the injured site.
Inflammatory pain typically resolves when the underlying injury has healed. However, some inflammatory pain conditions (eg. rheumatoid arthritis) can give rise to an ongoing inflammatory response associated with chronic pain.
Nociceptive pain and inflammatory pain are part of the normal function of the body’s protective and healing response.
Neuropathic pain
The IASP currently defines “neuropathic pain” as “pain caused by a lesion or disease of the somatosensory nervous system” (see Jensen et al, “Commentary: A new definition of neuropathic pain” (2011) 152 Pain at 131). However, at the priority date, the IASP defined neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.”: see IASP, op. cit at p 212. The deletion of the reference to “dysfunction” has led many experts in the field to treat dysfunctional pain as a pain classification different from neuropathic pain.
(Source: Extracted from Woolf (2010))
Neuropathic pain is considered to be a pathological condition as it provides no protective or healing benefit. It can be caused by a range of different diseases and lesions to the nervous system. Peripheral neuropathic pain results from damage to the primary sensory neurons (eg. as a result of a surgical incision), or from neuropathies such as postherpetic neuralgia, diabetic peripheral neuropathy and trigeminal neuralgia. In contrast, central neuropathic pain results from nerve damage within the spinal cord or brain and commonly arises due to spinal cord injury, brain trauma, stroke or multiple sclerosis.
There was some evidence given by A/Prof. Lynden Roberts to suggest that neuropathic pain will always be a chronic pain condition. Ultimately however, he accepted that this may reflect too narrow a view of neuropathic pain, which can describe both acute and chronic pain conditions.
Dysfunctional pain
Dysfunctional pain is a maladaptive condition caused by the abnormal functioning of the nervous system in the absence of any identifiable damage to the CNS, disease or condition which may account for the pain. Dysfunctional pain is an example of pain as a disease condition in itself requiring treatment in its own right. Fibromyalgia is an example of dysfunctional pain syndrome. Fibromyalgia is a maladaptive pain syndrome which manifests as diffuse pain throughout the body with widespread tenderness over discrete areas of the body, but with no identifiable precipitating pathological or physical condition.
(Source: Extracted from Woolf (2010))
Pain modulation
The perception of pain is not limited to the brain’s processing of ascending signals received from the peripheral sensory apparatus (nociceptors) in response to noxious stimulation. Peripheral and central changes which affect pain thresholds and responses, referred to as “peripheral sensitisation” and “central sensitisation” respectively, can modify the way in which stimuli are detected and pain is experienced. In addition, pain perception can be modulated by regulation of the transmission of signals from the spinal cord to the brain, and also within the brain itself. This enables the brain to amplify or reduce the sensation of pain. This is a complex process that is in turn strongly influenced by psychological and social factors. The mechanism by which the brain regulates the transmission of pain signals from the spinal cord to the brain is referred to as “descending modulation”.
The brain can directly modulate (amplify or depress) incoming sensory signals and thus influence pain perception. The descending pain modulatory circuit takes inputs from multiple areas of the brain (including, but not limited to, the hypothalamus, the amygdala and the rostral anterior cingulate cortex), feeds them into the midbrain periaqueductal gray (“PAG”) region, which in turn sends outputs to the rostral ventromedial medulla (“RVM”). In essence, the action of descending modulation can be characterised as a complex feedback control system in which neurons within the RVM project to the spinal or medullary dorsal horns to directly or indirectly enhance or diminish nociceptive signals and thereby facilitate, as well as inhibit, pain.
Peripheral sensitisation
Peripheral sensitisation refers to the reduced activation threshold and amplified responsiveness of nociceptors to stimulation of their receptive fields which occurs after initiation of the inflammatory response following tissue injury. Peripheral sensitisation is characterised by primary hyperalgesia localised at the site of injury or trauma. The term “hyperalgesia” refers to the amplification of the pain sensation following stimulation by a stimulus which is normally painful. “Primary hyperalgesia” is characterised by enhanced pain in response to heat and mechanical stimuli at the site of injury. “Secondary hyperalgesia” refers to an amplified pain response evoked outside the receptive field of the nerve or nerves directly stimulated at the point of injury.
Peripheral sensitisation is an adaptive process and is part of the body’s normal protective response to physical trauma or injury which induces protective behaviour toward the site of injury that promotes healing. Peripheral sensitisation typically arises during inflammation, and is fundamentally associated with increased peripheral sensitivity of the nociceptive system. There must usually be some ongoing peripheral stimulation by inflammatory mediators for it to persist.
At a cellular level, peripheral sensitisation involves increased nociceptor sensitivity arising from a decrease in the activation threshold of normally high-threshold nociceptors by inflammatory mediators (eg. bradykinin, prostaglandins and NGF). As a result, normally high threshold nociceptors, which normally would respond only to intense noxious stimuli, can be activated by lower intensity stimuli. Peripheral sensitisation also results in increased excitability of voltage gated ion channels at nociceptor terminals which in turn modifies the activation threshold of the ion channel, resulting in an increased number of action potentials being generated. The net result of these adaptive changes to the nociceptive system is primary hyperalgesia.
Central sensitisation
Central sensitisation is a phenomenon that was discovered in 1983 by a neurophysiologist named Clifford Woolf. Central sensitisation is a form of neuroplasticity leading to dynamic changes in the properties and function of neurons in the CNS, and amplified pain processing in the CNS, which ultimately manifests as pain hypersensitivity and/or spontaneous pain in the absence of sensory input. It is an important component of inflammatory, neuropathic and dysfunctional pain.
As at the priority date, the term central sensitisation referred to so-called “activity dependent neuronal plasticity” triggered by the increased activity evoked in secondary neurons in the spinal cord dorsal horn in response to intense, repeated or sustained noxious stimulus. Activity dependent neuronal plasticity or central sensitisation is characterised by increased sensitivity manifesting as enhanced responsiveness to noxious stimuli (hyperalgesia) and a reduction in sensory threshold such that non-noxious stimuli evoke pain (allodynia). Activity dependent central sensitisation can arise very quickly (within seconds to minutes) following intense, sustained or recurring nociceptive input.
An important consequence of central sensitisation is that the sensation of pain is no longer reflective of the presence, duration or intensity of noxious peripheral stimuli. The level of central sensitisation elicited in any individual subjected to a particular noxious stimulus is variable. However, in activity dependent (adaptive) central sensitisation the level of sensitisation is commonly linked to the severity and duration of the stimulus, so that the more severe and prolonged the stimulus, the greater the central sensitisation.
Two of the key mechanisms by which activity dependent central sensitisation arises are shown in simplified form in Figure 4. An increase in N-type VGCC activity (N-type VGCC hyperactivity) in the primary afferent synaptic transmitting terminals of Aδ-fibres and C-fibres (circled in Figure 4) amplifies signals transmitted from those fibres to the secondary neuron which transmits sensory signals to the brain, where ultimately they may be interpreted as pain. This central amplification enhances the pain response to noxious stimuli in amplitude, duration and spatial extent and causes a normally painful stimulus to be perceived as more painful. This condition is known as hyperalgesia.
(Source: Affidavit of Professor Macdonald James Christie dated 7 November 2014)
As a result of central sensitisation, signals from low threshold myelinated Aβ-fibres (which are normally involved in the sensation of touch) may also be transmitted to the secondary pain transmitting neurons via excitatory neurons, as depicted in Figure 4. This transmission is usually prevented by inhibitory neurons. An increase in N-type VGCC activity in the pre-synaptic terminals of the Aβ-fibres stimulates the excitatory neurons, and at the same time down-regulates the inhibitory neurons, causing the excitatory neurons to transmit signals to the secondary neurons in the dorsal horn. An increase in N-type VGCC activity in pre-synaptic terminals of the excitatory neurons can further amplify this effect. The consequence is that a normally innocuous stimulus such as ordinary touch can give rise to stimulation of the secondary neurons, which transmit such sensory signals to the brain where it is interpreted as pain. This mechanism causes a normally non-painful stimulus to be interpreted as painful. This condition is known as allodynia.
Central sensitisation can be viewed as an “adaptive” phenomenon in the sense that it contributes to the normal protective and healing responses by increasing sensitivity to both noxious and non-noxious stimuli at the site of injury (primary hyperalgesia and allodynia) and the surrounding body area (secondary hyperalgesia and allodynia). While primary hyperalgesia and allodynia can be caused by peripheral sensitisation or central sensitisation, secondary hyperalgesia and allodynia are the result only of central sensitisation.
An example of adaptive central sensitisation is the transient central sensitisation that occurs during inflammation, which enhances the body’s protective behaviours to promote healing, but which subsides when the underlying pathological condition has resolved.
Central sensitisation is a complex phenomenon that is still not fully understood. Since the priority date, the body of knowledge surrounding the phenomenon of central sensitisation has expanded and it is now apparent that there are other complex pathways and mechanisms that can heighten the sensitivity of the CNS. These forms of central sensitisation can be long-lasting, or in some cases permanent, and are reflective of maladaptive central sensitisation associated with pathological pain conditions common in neuropathic and dysfunctional conditions. Maladaptive central sensitisation can occur in the absence of a noxious stimulus, or may develop after an initial stimulus has resolved.
Although the mechanisms involved in central sensitisation are complex, N-type VGCC hyperactivity is a common feature of central sensitisation. The reduction in hyperactivity in N-type VGCC is therefore a potential way to reduce central sensitisation.
Pregabalin
Mechanism of action
Pregabalin has the chemical name (S)-3-(aminomethyl)-5-methylhexanoic acid and the following chemical structure:
Pregabalin was originally developed as a gamma-aminobutyric acid (“GABA”) agonist to activate GABA receptors. However, it was established after the priority date that pregabalin does not bind to GABA receptors.
Whilst the mechanisms of action of pregabalin were not fully understood at the priority date, it was known that pregabalin binds with high affinity to alpha-2-delta (α2δ) auxiliary protein subunits of pre-synaptic VGCCs, particularly N-type VGCCs, located on the central terminals of primary sensory neurons in the dorsal horn of the spinal cord.
It is now understood that by binding to α2δ subunits pregabalin acts as a “calcium channel modulator” that produces analgesic effects by the modulation of VGCCs and relieving pain associated with central sensitisation.
VGCCs are comprised of combinations of subunits as depicted in Figure 6. The α1 subunit spans the cellular membrane and forms a channel through which calcium ions may pass. The α1 subunit is associated with three auxiliary (accessory) subunits: the cytosolic (intracellular) β subunit; the transmembrane γ subunit; and the transmembrane α2δ subunit. The α2δ subunit stabilises the location of the α1 subunit within the membrane and also modulates its function.
(Source: Extracted with adaptations from Wall & Melzack’s Textbook of Pain, 6th Edition, 2013 at p 496)
As previously explained, release of excitatory neurotransmitters from the presynaptic terminal is mediated by calcium ion influx through VGCCs. Thus, in response to cell membrane depolarisation, resulting from incoming action potentials, the channel-forming α1 subunit allows calcium ions to enter the cell. This calcium ion influx triggers the pre-synaptic release of the excitatory neurotransmitter glutamate, as well as substance P and CGRP, particularly under conditions of intense nociceptive stimulation. When glutamate is released by this mechanism, it is available to bind to post-synaptic receptors (including AMPA and NMDA receptors) and activate secondary neurons within the spinal cord dorsal horn.
It is now known that expression of the α2δ subunit is increased (or upregulated) in models of pain that involve central sensitisation. This increase in α2δ expression is thought to increase VGCC activity in nerve terminals, leading to hyperexcitability. Under these conditions, pregabalin may normalise VGCC activity and reduce central sensitisation by inhibiting or reducing the release of glutamate and other excitatory neurotransmitters which modulates the transmission of pain signals to the cortex. There is also some evidence to suggest that pregabalin may act in other ways that might inhibit excessive synapse formation that contributes to sensitisation, and also activate descending pain modulation which produces analgesia. It has been observed that the regions of the highest concentration of α2δ expression in the CNS (in particular the PAG region) are known to be implicated in the descending modulation of pain.
Organic Chemistry
“Organic chemistry” is the chemistry of carbon compounds. The smallest unit of any compound is known as a molecule. A molecule is in turn made up of atoms. The complexities of organic chemistry derive from the ability of carbon atoms to form molecules in which chains or rings of carbon atoms form the “skeleton” of a three dimensional molecular structure.
The compounds of organic chemistry are generally compounds of carbon (“C”) and hydrogen (“H”), but may also include a range of other elements such as oxygen (“O”), nitrogen (“N”) and fluorine (“F”). These elements can be linked together by covalent bonds to form molecules. Covalent bonds result from the sharing of electrons between atoms. Organic molecules are generally made up by covalent bonds between carbon atoms, although oxygen and nitrogen atoms can also be involved in forming linking parts of molecular structures. Carbon is able to form up to four covalent bonds with other atoms. The ability to form multiple covalent bonds enables these elements to form linking parts of molecular structures.
A molecule can have the same chemical formula (representing the number and types of the atoms of the compound) but different structures. This means they have different chemical and physical properties. This is because the linkages in the compounds are different. Compounds which have the same chemical formula but different structures are referred to as “structural isomers”.
Where compounds of the same chemical formula have the same sequence of bonded atoms but differ in the orientation of atoms in space, they are referred to as “stereoisomers”. Stereoisomers can occur when the four atoms (or groups of atoms) to which a carbon is bonded in a molecule are different. In that case, there are two ways in which the atoms or groups arrange around the carbon atom. These arrangements are non-superimposable mirror images of each other in the same way that a left and right hand are non-superimposable mirror images. The carbon atom in this type of arrangement is called “chiral” (which derives from the Greek for “hand”). Each chiral carbon atom is called a “chiral centre”. Figure 3 is a diagram that represents chiral carbon atoms in compounds which are non-superimposable mirror images of each other, shown as Figure 3(a) and Figure 3(b).
(Source: Affidavit of Professor Christopher John Easton dated 6 November 2014)
When representing a chiral structure, a third dimension is required to fully represent the structure. Conventionally two of the bonds are represented in the plane of the page by using plain lines (ie. the bonds with the “H” and “X” groups in Figures 3(a) and 3(b)). Bonds represented using a wedge-shaped symbol indicate that the bond projects above the plane of the page (ie. the bond to the “Z” group in Figures 3(a) and 3(b)). Bonds represented using dashes or broken lines indicate that the bond projects below the plane of the page (ie. the bond to the “Y” group in Figures 3(a) and 3(b)). In a compound that includes a single chiral centre there are only two possible stereoisomers. Both of these stereoisomers are non-superimposable mirror images of each other, as shown in Figures 3(a) and 3(b).
Stereoisomers which are non-superimposable mirror images are called “enantiomers”. Enantiomers have many of the same chemical and physical properties, such as chemical reactivity, melting point, boiling point, density and solubility. An exception is when polarised light is passed through a solution containing only one of the two enantiomers, the plane of polarised light is rotated either in a clockwise or anticlockwise direction. When two enantiomers have been separated from each other it is therefore possible to distinguish between them by their respective effect on the rotation of polarised light.
The enantiomer that causes the plane of polarised light to rotate in a clockwise direction is referred to as the “(+)” enantiomer. The enantiomer that causes anticlockwise rotation is referred to as the “(-)” enantiomer. Where a sample containing an equal mixture of two enantiomers of a particular compound is tested in this way, there will be no rotation of the plane of polarised light because the rotation caused by one enantiomer is cancelled by the rotation caused by the opposite enantiomer. An equal mixture of the two enantiomers is called a “racemic” mixture or a “racemate”. A racemic mixture is typically denoted “(±)”.
The usual system of assigning absolute stereochemistry about chiral centres involves designating each chiral carbon atom “(R)” (from the Latin “rectus”) or “(S)” (from the Latin “sinister”) as follows. An order of priority is assigned to the four atoms or groups bonded to the chiral carbon (based on rules that rank each of the atoms or groups bonded to the carbon). The arrangement of atoms or groups will be right-handed or left-handed depending on how the priority of the atoms or groups works out. The designation of “(R)” or “(S)” denotes the absolute stereochemistry at the chiral centre in the compound in accordance with these rules. Whether an enantiomer is (R) or (S) cannot be determined merely from knowing whether it is (+) or (-).
Racemic mixtures may be denoted as “(RS)” indicating that the compound contains equal amounts of the (R) and (S) enantiomers, “(±)” indicating that the compound contains equal amounts of the (+) and (-) enantiomers, or with the prefix “rae” as an abbreviation for “racemic”. If a chemical compound is described by its chemical name alone (ie. the stereochemistry is not specified), the term, by definition, includes all compounds of that chemical without being limited by particular stereochemistry.
When a molecule has two chiral centres, there are usually four possible stereoisomers. In the normal case, when the stereoisomers are assigned their absolute stereochemistry, the possibilities are as follows: (RR), (RS), (SR) and (SS). Among these four stereoisomers, the (RR) and (SS) isomers are non-superimposable mirror images of each other and are enantiomers in the same way that the (R) and (S) stereoisomers are enantiomers in the case of a molecule with a single chiral centre. Likewise, the (RS) and the (SR) stereoisomers are a pair of non-superimposable mirror image forms and thus they are also enantiomers. Again, the enantiomers have identical chemical and physical properties other than in relation to the rotation of polarised light and interaction with chiral systems.
Stereoisomers that are not enantiomers are referred to as “diastereomers”. Each diastereomer will generally have different chemical and physical properties.
THE PRINCIPLES OF CONSTRUCTION
There was no dispute between the parties as to the relevant principles of construction. These were summarised by the Full Court (Hill, Finn and Gyles JJ) in Jupiters Ltd v Neurizon Pty Ltd (2005) 222 ALR 155 at [67]:
There is no real dispute between the parties as to the principles of construction to be applied in this matter although there is some difference in emphasis. It suffices for present purposes to refer to the following:
(i)the proper construction of a specification is a matter of law: Décor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 at 400;
(ii)a patent specification should be given a purposive, not a purely literal, construction: Flexible Steel Lacing Co v Beltreco Ltd (2000) 49 IPR 331; [2000] FCA 890 at [81] (Flexible Steel Lacing); and it is not to be read in the abstract but is to be construed in the light of the common general knowledge and the art before the priority date: Kimberley-Clark Australia Pty Ltd v Arico Trading International Pty Ltd (2001) 207 CLR 1; 177 ALR 460; 50 IPR 513; [2001] HCA 8 at [24];
(iii)the words used in a specification are to be given the meaning which the normal person skilled in the art would attach to them, having regard to his or her own general knowledge and to what is disclosed in the body of the specification: Décor Corporation Pty Ltd at 391;
(iv)while the claims are to be construed in the context of the specification as a whole, it is not legitimate to narrow or expand the boundaries of monopoly as fixed by the words of a claim by adding to those words glosses drawn from other parts of the specification, although terms in the claim which are unclear may be defined by reference to the body of the specification: Kimberley-Clark v Arico at [15]; Welch Perrin & Co Pty Ltd v Worrel (1961) 106 CLR 588 at 610; Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 at 478; the body of a specification cannot be used to change a clear claim for one subject matter into a claim for another and different subject matter: Electric & Musical Industries Ltd v Lissen Ltd [1938] 4 All ER 221 at 224–5; (1938) 56 RPC 23 at 39;
(v)experts can give evidence on the meaning which those skilled in the art would give to technical or scientific terms and phrases and on unusual or special meanings to be given by skilled addressees to words which might otherwise bear their ordinary meaning: Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd (1994) 30 IPR 479 at 485–6 (Sartas No 1 Pty Ltd); the court is to place itself in the position of some person acquainted with the surrounding circumstances as to the state of the art and manufacture at the time (Kimberley-Clark v Arico at [24]); and
(vi)it is for the court, not for any witness however expert, to construe the specification; Sartas No 1 Pty Ltd at 485–6.
THE PATENT
The Patent commences with a description of the background to the invention. Relevantly, the Patent states at page 1, lines 4 to 13:
The present invention is the use of analogs of glutamic acid and gamma- aminobutyric acid (GABA) in pain therapy, as the compounds exhibit analgesic/antihyperalgesic action. Advantages of the use of the compounds includes the finding that repeated use does not lead to tolerance nor is there a cross-tolerance between morphine and the compounds.
The compounds of the invention are known agents useful in antiseizure therapy for central nervous system disorders such as epilepsy, Huntington’s chorea, cerebral ischemia, Parkinson’s disease, tardive dyskinesia, and spasticity. It has also been suggested that the compounds can be used as antidepressants, anxiolytics, and antipsychotics.
There is then a reference to two prior patent specifications, WO 92/09560 (“the 92 Specification”) and WP 93/23383 (“the 93 Specification”). In closing submissions Apotex accepted that these specifications were “incorporated by reference”.
The Patent includes a summary of the invention which relevantly states at page 1, line 17 – page 2, line 13:
The instant invention is a method of using a compound of Formula I below in the treatment of pain, especially for treatment of chronic pain disorders. Such disorders include, but are not limited to, inflammatory pain, postoperative pain, osteoarthritis pain associated with metastatic cancer, trigeminal neuralgia, acute herpetic and postherpetic neuralgia, diabetic neuropathy, causalgia, brachial plexus avulsion, occipital neuralgia, reflex sympathetic dystrophy, fibromyalgia, gout, phantom limb pain, burn pain, and other forms of neuralgic, neuropathic, and idiopathic pain syndromes.
According to a first aspect, the invention provides a method for treating pain comprising administering a therapeutically effective amount of a compound of Formula I:
or a pharmaceutically acceptable salt diastereomer or an enantiomer thereof wherein
R1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl
to a mammal in need of said treatment.
Preferred compounds of the invention are those according to claim 1 wherein R3 and R2 are hydrogen, and R1 is -(CH2)0-2-iC4H9 as an (R), (S), or (R,S) isomer.
The more preferred compounds of the invention are (S)-3-(aminomethyl)-5- methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid.
A second aspect of the invention is then described which also refers to Formula I but “for the manufacture of a medicament for the treatment of pain” rather than a method of treatment.
It is convenient at this point to refer to the claims. The Patent contains 32 claims. Claims 1 to 15 define methods of treatment. Claim 1 is to:
A method for treating pain comprising administering a therapeutically effective amount of a compound of Formula I
or a pharmaceutically acceptable salt, diastereomer, or enantiomer thereof wherein
R1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl to a mammal in need of said treatment.
There is an issue between the parties as to how the words “a method for treating pain” in claim 1 should be interpreted (“Construction Issue 1”). There is also an issue between the parties as to how the reference to “a mammal” in claim 1 and other claims should be interpreted (“Construction Issue 2”). Apotex contends that when the claims are read in the context of the Patent as a whole, the reference to a mammal means a human, and would not encompass a rat. This issue is said by the parties to be relevant to the sufficiency case.
Claims 2 to 15 are dependent on claim 1. It is important to note that each of the dependent claims 2 to 15 is expressed to be dependent on claim 1 rather than any other preceding claim.
Claims 2 and 3 narrow the class of compound claimed. Claim 2 is for:
2.A method according to Claim 1 wherein the compound administered is a compound of Formula I wherein R3 and R2 are hydrogen, and R1 is
-(CH2)0-2-i C4H9 as an (R), (S), or (R,S) isomer.
Thus, claim 2 is limited to a method of treatment that uses a compound of Formula I in which R1, R2 and R3 consist of particular molecules and in which the compound is in the form of an (R), (S) or (R,S) isomer.
Claim 3 is for:
3.A method according to Claim 1 wherein the compound administered is named (S)-3-(aminomethyl)-5-methylhexanoic acid and 3-aminomethyl-5-methyl-hexanoic acid.
The reference to “(S)-3-(aminomethyl)-5-methylhexanoic acid” is the (S)-enantiomer of “3-(aminomethyl)-5-methyl-hexanoic acid” which I shall for convenience refer to simply as “the 3-amino compound”. The presence of the (S) immediately before the reference to the 3-amino compound indicates that claim 3 is here referring to the (S)-enantiomer of the 3-amino compound. For convenience I will refer to this as “the (S) 3-amino compound” or simply as “the (S)-enantiomer”. In some parts of the Patent the 3-amino compound is also referred to as 3-Isobutylgaba and the (S)-enantiomer as S-(+)-3-Isobutylgaba or occasionally abbreviated to “(S)-(+)-IBG”. It is common ground that pregabalin, the active pharmaceutical ingredient in Lyrica, is the (S) 3-amino compound.
There is an issue between the parties as to how the second reference to the 3-amino compound in claim 3 should be interpreted (“Construction Issue 3”). Apotex contends that it refers to the racemate of the 3-amino compound. Pfizer contends that, read in context, it is a reference to the (S)-enantiomer, since it is the only compound in “(S)-3-(aminomethyl)-5-methylhexanoic acid and 3-(aminomethyl)-5-methyl-hexanoic acid”. Alternatively, Pfizer contends that it refers to any mixture of the (S)-enantiomer and the (R)-enantiomer including both racemic and non-racemic mixtures. Construction Issue 3 is relevant to both false suggestion and utility.
Claims 4 to 15 identify particular types of pain that may be treated with the relevant compounds. For example, claim 4 is to “[a] method according to Claim 1 wherein the pain treated is inflammatory pain.” The other types of pain that are specified in claims 5 to 15 are neuropathic pain; cancer pain, postoperative pain; phantom limb pain; burn pain; gout pain; osteoarthritic pain; trigeminal neuralgia pain; acute herpetic and postherpetic pain; causalgia pain; and idiopathic pain.
Claims 16 to 18 are Swiss claims that are for the use of the same compounds as are identified in claim 1 to 3 in a medicament for the treatment of pain. Claims 19 to 30 are for uses according to claim 16 for the same pain types that are identified in claims 5 to 15. Claims 31 and 32 resemble omnibus claims. They claim a method of treating pain and the use of a relevant compound by reference to one or more of the examples and accompanying figures as follows:
31.A method for treating pain, substantially as herein described with reference to one or more of the examples but excluding comparative examples.
32.Use of a compound of formula I or a pharmaceutically acceptable salt diastereomer or an enantiomer thereof wherein
R1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl, substantially as herein described with reference to one or more of the examples and the accompanying figures.
The Patent includes a detailed description of the invention. The Patent states at page 5, lines 9 to 22:
The instant invention is a method of using a compound of Formula I above as an analgesic in the treatment of pain as listed above. Pain such as inflammatory pain, neuropathic pain, cancer pain, postoperative pain, and idiopathic pain which is pain of unknown origin, for example, phantom limb pain are included especially. Neuropathic pain is caused by injury or infection of peripheral sensory nerves. It includes, but is not limited to pain from peripheral nerve trauma, herpes virus infection, diabetes mellitus, causalgia, plexus avulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain is also caused by nerve damage from chronic alcoholism, human immunodeficiency virus infection, hypothyroidism, uremia, or vitamin deficiencies. Neuropathic pain includes, but is not limited to pain caused by nerve injury such as, for example, the pain diabetics suffer from.
The conditions listed above are known to be poorly treated by currently marketed analgesics such as narcotics or nonsteroidal anti-inflammatory drugs (NSAID) due to insufficient efficacy or limiting side effects.
The Patent also states at page 6, lines 6 to 10:
The compounds of the present invention can contain one or several asymmetric carbon atoms. The invention includes the individual diastereomers or enantiomers, and the mixtures thereof. The individual diastereomers or enantiomers may be prepared or isolated by methods already well-known in the art.
Some further information relevant to formation of the compounds of the invention is then provided. It was not contended by Apotex that this information was insufficient to enable the notional skilled addressee to prepare compounds of the invention. As I mentioned, Apotex accepted that the 92 Specification and the 93 Specification were “incorporated by reference” and that these provide sufficient information to enable the skilled addressee to make the (S)-enantiomer (pregabalin). Though it is questionable whether or not these documents are properly described as incorporated by reference, I am satisfied that they would be read and understood by the skilled addressee as relevant background material and that the information contained in them would enable the skilled addressee to manufacture the (S)-enantiomer (by resolution of the racemate) without undue difficulty.
The Patent states at page 7 lines 4 to 27:
The compounds made by the synthetic methods can be used as pharmaceutical compositions as agent in the treatment of pain when an effective amount of a compound of the Formula I, together with a pharmaceutically acceptable carrier is used. The pharmaceutical can be used in a method for treating such disorders in mammals, including human, suffering therefrom by administering to such mammals an effective amount of the compound as described above in unit dosage form.
The pharmaceutical compound, made in accordance with the present invention, can be prepared and administered in a wide variety of dosage forms by either oral or parenteral routes of administration. For example, these pharmaceutical compositions can be made in inert, pharmaceutically acceptable carriers which are either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories. Other solid and liquid form preparations could be made in accordance with known methods of the art and administered by the oral route in an appropriate formulation, or by a parenteral route such as intravenous, intramuscular, or subcutaneous injection as a liquid formulation.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from 1 mg to about 300 mg/kg daily, based on an average 70-kg patient. A daily dose range of about 1 mg to about 50 mg/kg is preferred. The dosages, however, may be varied depending upon the requirement with a patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for particular situations is within the skill of the art.
There is an issue between the parties as to whether the reference to “1 mg” in the first and second sentences of this last paragraph (page 7, lines 22 to 23) should be interpreted as to mean “1 mg” or “1 mg per kilo” (ie. 1mg/kg) (“Construction Issue 4”). The issue is relevant to Apotex’s sufficiency case and, in particular, the amount of work that must be carried out by the skilled addressee to ascertain a safe and effective dose of the compounds of the invention for use as a treatment for pain.
THE RAT TESTS
The Patent describes tests performed on rats to demonstrate the comparative efficacy of various compounds in treating pain. The test results are presented in graphs that are reproduced in the six sets of Figures that are entitled as follows:
The reference to “CI-1008” in the Figures is a reference to the (S)-enantiomer (pregabalin). Some of the Figures (Figures 1e and 1f) also refer to “PD-144550” which is in turn referred to in the description of the Figures as “3-aminomethyl-5-methyl-hexanoic acid”, that is to say, the 3-amino compound. There is a significant issue that is relevant to the false suggestion case as to how those references should be interpreted or, more particularly, how they are likely to have been interpreted by the Commissioner when considering whether or not to grant the Patent.
It is common ground that PD-144550 is actually the (R)-enantiomer of the 3-amino compound. However, Apotex contends that the skilled addressee would have understood the term “PD-144550” to refer to the racemate of the 3-amino compound rather than (R)-enantiomer, and that this is how the Commissioner would have interpreted the reference to PD-144550 when considering whether or not to grant the Patent. I will return to this topic later in these reasons.
Figure 1 describes the results of the “Rat Paw Formalin Test”. In this test, formalin, a chemical irritant, is injected into the rat paw which triggers behavioural responses (licking or biting of the paw) which are measured over two phases, an early phase (0-10 minute period) followed by a late phase (10-45 minute period). Both gabapentin (Figure 1b) and the (S)-enantiomer (Figure 1d), administered 1 hour before the injection of formalin, demonstrated significant late phase effects. However, the (S)-enantiomer showed the strongest effect, particularly at lower doses.
The Patent includes some discussion of the results of the Rat Formalin Paw Test. The Patent states at page 8, lines 7 to 13:
The s.c. administration of gabapentin (10-300 mg/kg) or CI-1008 (1-100 mg/kg) 1 hour before formalin dose-dependently blocked the licking/biting behavior during the late phase of the formalin response with respective minimum effective doses (MED) of 30 and 10 mg/kg (Figure 1). However, neither of the compounds affected the early phase at any of the doses tested. Similar administration of 3-aminomethyl-5-methyl-hexanoic acid produced only a modest blockade of the late phase at 100 mg/kg.
Apotex contends that this last sentence would have most likely been understood by the Commissioner to refer to the racemate of the 3-amino compound.
Figures 2 and 3 describe a number of tests which show the effect of (inter alia) gabapentin and pregabalin on carrageenin-induced mechanical hyperalgesia (Figure 2) and thermal hyperalgesia (Figure 3). Carrageenin (or carrageenan) is an irritant which is injected into the paw that produces prolonged irritation and hyperalgesia. A device is used to apply and measure pressure applied to the paw until it is withdrawn from the device by the animal. A lower measure is indicative of mechanical hypersensitivity and hyperalgesia. The results for the (S)-enantiomer (Figure 2a) show a dose dependent increase in the pain threshold. The results for pregabalin (Figure 2b) show a similar dose-dependent response but at lower doses (1-100 mg/kg) than for gabapentin (3-300 mg/kg). Morphine, which was also tested, completely blocked hyperalgesia (also shown in Figure 2b).
Similar tests were performed using the carrageenan inflammatory pain model as an indicator of thermal hyperalgesia. In this test each animal was placed on a glass plate and a heat source was directed at its inflamed paw. The results show that gabapentin (Figure 3a) and the (S)-enantiomer (Figure 3b) dose-dependently reduced the time taken for the animal to remove its paw from the heat source. This is indicative of their antihyperalgesic effect.
Figure 4 describes the results of tests that apply a rat model of postoperative pain which involves making a standard incision of the skin, facia and muscle at a particular part of the hind paw which is then sutured. The Patent states at page 9, lines 23 to 26:
It has been suggested that this model displays some similarities to the human postoperative pain state. In the present study we have examined and compared the activities of gabapentin and S-(+)-3-isobutylgaba with morphine in this model of postoperative pain.
Figure 4 shows results for pre-treatments with gabapentin, the (S)-enantiomer or morphine before the surgery. Gabapentin (30 mg/kg) is shown (Figure 4b) to have a significant effect inhibiting thermal hyperalgesia 2 hours and 24 hours after surgery. The (S)-enantiomer is shown (Figure 4c) to have a much more sustained reversal of hyperalgesia than gabapentin when used at the same dose.
Animals with tactile allodynia will have a painful reaction to an innocuous force. Figure 5 shows the results of tests for the effect of gabapentin, pregabalin and morphine administered before surgery on the development of tactile allodynia using the same model used in Figures 3 and 4 but also using thin nylon filaments (Frey filaments) that are used to apply a force to a particular area of skin, allowing the force at which a response is elicited to be measured. The results for morphine (Figure 5a), gabapentin (Figure 5b) and the (S)-enantiomer (Figure 5c) show that pregabalin was most effective at reducing tactile allodynia, and that this effect was maintained for 3 days.
Figure 6 describes tests on rats for tactile allodynia and thermal hyperalgesia after surgery followed by administration of pregabalin one hour later. The results for both tactile allodynia (Figure 6a) and thermal hyperalgesia (Figure 6b) are shown. An analgesic effect was observed over a five hour period at a dosage of 6 mg/kg.
The Patent states at page 13, lines 10 to 16:
The results presented here show that incision of the rat plantaris muscle induces thermal hyperalgesia and tactile allodynia lasting at least 3 days. The major findings of the present study are that gabapentin and S-(+)-3-isobutylgaba are equally effective at blocking both nociceptive responses. In contrast, morphine was found to be more effective against thermal hyperalgesia than tactile allodynia. Furthermore, S-(+)-3-isobutylgaba completely blocked induction and maintenance of allodynia and hyperalgesia.
This passage is followed by the claims.
At no point does the Patent refer to any safety or efficacy testing of the compounds of the invention in humans. The tests summarised in the Patent were, as I have explained, all conducted on rats.
CONSTRUCTION ISSUES
Construction Issue 1: “method of treating pain”
In its written submission Apotex submitted that there was an issue to be determined as to the meaning of the words “a method of treating pain” (claims 1 to 15 and 31) and “for the treatment of pain” (claims 16 to 30 and 32). In the present case I do not think there can be much doubt about what those words mean. The scope of the claim is limited by purpose and not by result: see Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd (2013) 253 CLR 284 at [174], [177] and [289] per Crennan and Kiefel JJ when referring to the claim for “[a] method of preventing or treating a skin disorder which comprises administering to the recipient an effective amount of [leflunomide]”. The claim will be infringed if a person administers a therapeutically effective amount of the relevant compound to a patient in need of treatment for pain for the purpose of providing such treatment even though the treatment may not be effective in that patient.
This construction of the claim is supported by the expert evidence. A/Prof. King, with whom the other clinicians who gave evidence agreed, accepted that a clinician would consider themselves to be engaging in the medical treatment of pain in the event that they prescribed a drug for the purpose of providing treatment and in the expectation that the treatment would be effective. He also agreed that pain treatments do not always work, either at all or to the same extent, in every patient suffering from pain.
Claim 1 is not limited to a method of treating neuropathic pain or pain associated with central sensitisation. The notional skilled addressee would have understood claim 1 as defining a method of treatment for any type of pain. The language of the claim is exceedingly broad and does not limit the types of pain that may be treated with the relevant compounds. It covers all those pain types specifically referred to in dependent claims 4 to 15 and more. Nor is claim 1 limited to the use of the relevant compounds as an adjuvant (or adjunctive) therapy. Use of a relevant compound as an adjuvant therapy is within the claims, but so too is use of such a compound as the sole treatment for pain.
Construction Issue 2: “mammals”
Mr Catterns QC relied upon the words “inventive matters may arise at any stage” in the last sentence of the experts’ answer to question 3.6. However, as I read those words, they do no more than recognise that there is a possibility in the case of any new drug that is being evaluated for the purposes of obtaining regulatory approval, that the notional skilled team might be confronted at one or more stages of the process with a problem that cannot be solved without invention.
In cross-examination of Professor Christie, Mr Catterns QC referred to extracts from a textbook entitled “Drug Safety Assessment in Clinical Trials” (Ex 6) that included some observations concerning data analysis and interpretation in pre-clinical drug safety evaluations. Referring to the database of information that must be collected the authors stated (at p 17):
… the database created in a routine preclinical toxicology package is enormous by any standards. The organization, interpretation, integration, and summation of these data are the responsibility of the toxicologist. To adequately review all of the information collected, the toxicologist draws on a working understanding of pharmacology, physiology, biochemistry, pathology, pharmacokinetics, and other fields within the medical sciences.
Professor Christie was not familiar with the textbook but he did agree with this statement. He was then asked some questions concerning certain challenges referred to by the authors faced by the toxicologist that required the exercise of skill and judgment. He agreed that these included the integration of data into a single comprehensive statement on toxicity and the extrapolation of safety data between different test species. However, it was not suggested to him that this work would be anything other than routine to a person with relevant expertise. Nor was it suggested that, in making such judgments, the notional skilled team would be exercising skills or making judgments that involve creative or inventive reasoning or problem solving beyond the competence of the highly skilled, but unimaginative, expert working in the field.
Exhibit 1
Apotex relied upon various reports of studies (reproduced in Ex 1) conducted by or for Pfizer. These reports record the research and experimental work undertaken between July 1992 and December 2000 in relation to the use of CI-1008 (pregabalin) as a possible treatment for seizures or pain. There was almost no written or oral evidence specifically directed to these reports with the exception of Document 17 (which is a reproduction of the Field paper) and Apotex appears to have assumed that they would speak for themselves.
It is apparent from a reading of the documents in Ex 1 that they broadly reflect the course of research work that is usually undertaken for the purpose of obtaining regulatory approval from the FDA for the clinical use of a new drug.
The vast majority of the documents in Ex 1 record the results of pre-clinical evaluations of the toxicological and pharmacokinetic properties of CI-1008: see Documents 2-14, 20, 23-28, 30-31 and 38. In particular, these documents record the results of laboratory testing in mice, rats, monkeys, dogs and rabbits in relation to a wide range of matters including:
·the bioavailability of CI-1008 as determined using mice, rats, monkeys and human plasma;
·the stability of CI-1008 including the potential for degradation or racemization using mouse, rat, monkey and human plasma;
·toxicity studies using rats, dogs and monkeys to determine metabolic profile and route of excretion of CI-1008;
·toxicity tests using oral or intravenous administration of CI-1008 in rats and monkeys including escalating and continuous dosing with the compound;
·toxicity studies using monkeys to determine effects of CI-1008 on (inter alia) blood pressure, heart rate and cardiac rhythm.
The other documents, excluding some summaries and memoranda prepared by or for the FDA, are reports of Phase 1, Phase 2/3 and Phase 3 clinical trials.
The first Phase 1 study in which CI-1008 was administered to healthy volunteers appears to have been conducted between February and June 1996: see Document 15. Doses administered were initially very small, but were slowly escalated in the absence of any significant adverse events. Some mild to moderate side effects were observed (eg. dizziness, headache, drowsiness and nausea). The drug was reported to be generally well tolerated at the doses tested. Other Phase 1 studies were conducted in 1996, 1997, 1999, 2000 and early 2001: see Documents 16, 18, 19, 32-33, 36 and 37.
Exhibit 1 contains two reports relating to what are described as Phase 2/3 studies: see Documents 22 and 29. The first of these was conducted between March 1998 and March 1999 and involved several hundred patients. The second report relates to another Phase 2/3 study conducted between October 1998 and July 1999 involving several hundred patients. Both studies appear to show that treatment with pregabalin was safe and well tolerated. Exhibit 1 also contains a report of a large Phase 3 multi-centre study of pregabalin that took place between September 1999 and December 2000. The study concluded (inter alia) that pregabalin was well-tolerated with no unexpected side effects.
The Ex 1 documents were relied by Apotex in support of two submissions. First, they were relied upon in support of the submission, previously discussed, that the notional skilled team would be confronted with an “undue burden” or, in the language of Kimberly-Clark, a need for “… new inventions or additions or prolonged study of matters presenting initial difficulty” when performing the invention. Secondly, the Ex 1 documents were relied upon to show that prior to the application date, Pfizer had engaged in a substantial amount of pre-clinical work and that it had by then already completed at least one Phase 1 study. Apotex submitted that it would not impose any “undue burden” on Pfizer to require it to include in the complete specification as originally filed some of the safety information thereby obtained. It is convenient to deal with this latter submission first.
The law of sufficiency is concerned with the “enablement” of the invention. In the United Kingdom what is sometimes referred to as “classical insufficiency” arises when the specification fails to provide the skilled addressee with the information required to enable the invention to be performed without “undue burden”. The term “undue burden” is used to describe the extent of the burden imposed upon the skilled addressee. Leaving aside the issue of “best method” (which is not relevant in this case) the question raised by a challenge to the sufficiency of the description of a claimed invention is not whether the patentee could have supplied the skilled addressee with more information than it did, but whether the skilled addressee has been supplied with enough information to enable the working of the invention.
During his opening Mr Catterns QC drew my attention to Document 9 which is a report entitled “Oral Toxicity Study of CI-1008 in Cynomolgus Monkeys” dated 14 November 1994. This report indicates that CI-1008 caused mortality (death), ataxia (loss of control of bodily movements) and hypoactivity (drop in activity) in a number of monkeys after doses of 1000 or 2000 mg/kg. The experiment was apparently terminated early because four moneys died after the first dose. The suggestion seemed to be, though it was never put in these terms, that I should conclude from this report and a few other animal studies in which some adverse events were noted, that the pre-clinical work undertaken by Pfizer would have presented the skilled addressee with problems that would be difficult for the notional skilled team to resolve and that would be beyond the competence of the notional skilled team engaged in routine testing. However, no such proposition was put to any expert witness and any submission to that effect based upon those particular reports, or any others included in Ex 1, cannot be sustained on the evidence.
The challenge to the validity of the Patent based upon any alleged insufficiency of description fails.
ENTITLEMENT
Section 138 of the Act relevantly provides:
138 Revocation of patents in other circumstances
(1)Subject to subsection (1A), the Minister or any other person may apply to a prescribed court for an order revoking a patent.
[…]
(3)After hearing the application, the court may, by order, revoke the patent, either wholly or so far as it relates to a claim, on one or more of the following grounds, but on no other ground:
(a) that the patentee is not entitled to the patent;
[…]
(4)A court must not make an order under subsection (3) on the ground that the patentee is not entitled to the patent unless the court is satisfied that, in all the circumstances, it is just and equitable to do so.
As to s 138(3)(a), Apotex’s pleaded case is that Warner-Lambert is not entitled to the Patent, because the inventor, Mr Singh, from whom Warner-Lambert purports to derive its title, did not invent the use of the racemate to treat pain. I do not think there is any substance to this contention.
A person may be the inventor of a patentable invention without reducing it to practice or proving that it actually works. Mr Singh will be the inventor of the invention described in the Patent by virtue of him having conceived that the compounds of Formula I (which include the racemate of the 3-amino compound) might be used in the manner described in the Patent in the treatment of pain. There is no evidence to suggest that he was not the person who conceived this invention. His status as the inventor does not depend upon him having used or tested any particular compound.
As to s 138(4), Apotex did not plead or submit (either in writing or orally) that in the circumstances of this case, if the Court was to hold that Warner-Lambert is not entitled to the Patent, it would be just and equitable to revoke the Patent or any one or more of its claims. As I pointed out at the commencement of these reasons, s 138(4) of the Act (in its current form) applies to the claims for relief made in these proceedings pursuant to s 138(3)(a) of the Act.
INFRINGEMENT
Apotex contends that it does not threaten to infringe any of the Swiss claims (claims 16-30 and 32) because the medicaments it threatens to import and supply in Australia will be made outside the “patent area” by a third party. It submits that the importation and sale in Australia of medicaments made outside the patent area cannot infringe a Swiss claim. GPPL relies on the same argument in relation to each of the Swiss claims relied upon against it (claims 16-30). For the following reasons I do not accept Apotex’s submission.
To understand Apotex’s argument it is necessary to refer to the relevant statutory provisions. Sections 12 and 13 of the Act provide:
12 Application of Act
This Act extends to:
(a) each external Territory; and
(b) the Australian continental shelf; and
(c) the waters above the Australian continental shelf; and
(d)the airspace above Australia, each external Territory and the Australian continental shelf.
13 Exclusive rights given by patent
(1)Subject to this Act, a patent gives the patentee the exclusive rights, during the term of the patent, to exploit the invention and to authorise another person to exploit the invention.
(2)The exclusive rights are personal property and are capable of assignment and of devolution by law.
(3)A patent has effect throughout the patent area.
The definition of “patent area” includes Australia and the other areas referred to in s 12. The term “exploit” is defined in Schedule 1 to mean:
exploit, in relation to an invention, includes:
(a)where the invention is a product–make, hire, sell or otherwise dispose of the product, offer to make, sell, hire or otherwise dispose of it, use or import it, or keep it for the purpose of doing any of those things; or
(b)where the invention is a method or process–use the method or process or do any act mentioned in paragraph (a) in respect of a product resulting from such use.
There are two points to note about the definition of exploit: first, it is inclusive; second, it does not include any express territorial limitation. Relevant express territorial limitations are found in s 12 and s 13. In particular, s 13 makes clear that the exclusive rights conferred on a patentee by the grant of a patent apply throughout the “patent area” and, by implication, not outside the “patent area”.
All parties approached the present question on the assumption that a Swiss claim is properly characterised as a method or process claim. This view of the Swiss claims accords with that expressed by Yates J in Otsuka Pharmaceutical Co Ltd v Generic Health Pty Ltd (No 4) (2015) 113 IPR 191 and the authorities referred to by his Honour at [117]-[121]. All parties accepted that it is appropriate to consider the question of infringement of the Swiss claims through the prism of para (b) of the definition of “exploit”.
Apotex submitted that para (a) of the definition should be interpreted as though it referred to a product made in the patent area and that para (b) should be given a corresponding interpretation so that “any act mentioned in paragraph (a)” will be taken to refer to an act that is done in respect of a product resulting from the use of a patented method in the patent area.
On Apotex’s construction, para (b) would include a sale of a product made by a patented method in Australia but not a sale of a product made by the patented method in another country. In support of this construction, Apotex relied upon some (but certainly not all) of Lindgren J’s reasoning in Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618 (“Alphapharm”) at [691]-[694]. In that case Lindgren J held at [694] that the definition of “exploit” should be interpreted as follows:
exploit, in relation to an invention includes:
(a)where the invention is a product — [in Australia, or more accurately, in the patent area] make, hire, sell or otherwise dispose of the product, offer to make, sell, hire or otherwise dispose of it, use or import it, or keep it for the purpose of doing any of those things; or
(b)where the invention is a method or process — [in Australia, or more accurately, in the patent area] use the method or process or do any act mentioned in paragraph (a) in respect of a product resulting from [the use, anywhere, of the method or process].
(Emphasis added)
Apotex submits that Lindgren J should also have read into para (b) of the definition a further territorial limitation requiring that the product resulting from the use of the relevant method be one that results from the use of the method in the patent area.
The definition of “exploit” makes no reference to the patent area. As I have said, the express territorial limitation upon the patentee’s exclusive rights is found in s 12 and s 13. In my respectful view, there is therefore no reason to read down the words of either para (a) or para (b) of the definition of “exploit” to found any territorial limitation. This is because the Act expressly provides that a patent only has effect in the patent area: see also s 70 of the Patents Act 1952 (Cth).
Paragraph (b) of the definition of “exploit” refers to the doing of an act referred to in para (a) which includes to make or import a product. The patentee’s exclusive rights are infringed (subject to available defences) if another person does any such act within the patent area. The fact that the patented method is performed outside the patent area does not avoid infringement of a method claim (including a Swiss claim) if the product imported and sold in Australia was made using the patented method because the acts of importation and sale occur within the patent area. The relevant act of infringement is not the use of the method outside the patent area but the exploitation (by importation and sale) in Australia of a product made using the patented method.
In my respectful opinion, contrary to the approach taken by Lindgren J, the relevant territorial limitation is reflected in the language of s 12 and s 13(3) and there is therefore no justification for importing words of territorial limitation into the definition of “exploit”. It follows that I take a somewhat different approach to the construction of the definition of “exploit” to that taken by Lindgren J in Alphapharm, though I do not think the difference has any impact on whether or not Apotex threatens to infringe the Swiss claims in this case.
In opening Apotex also contended that it did not threaten to infringe claims 31 and 32 “because there were no relevant methods of treatment exemplified in the Patent.” This contention was not developed by Apotex in its closing submissions. In any event, so far as claim 31 is concerned, the point is not open to Apotex on the pleadings. As to claim 32, it seems to reflect a particularly poor attempt by the patentee to draft what was probably intended to be a claim for the use of a relevant compound as a medicament for the treatment of pain. Since the examples and accompanying figures referred to in claim 32 shows the use of a relevant compound in experiments on rats, I do not think it can be said that Apotex threatens to infringe claim 32.
RULINGS ON EVIDENCE
I have already dealt with the relevance objection made by Pfizer based upon Apotex’s pleading at [171] to [185].
I admitted into evidence provisionally a bundle of copies of patent specifications (Ex 11) tendered by Apotex that relate to the use of various pharmaceutical compositions in the treatment of different medical conditions. These were said by Apotex to be relevant to the issue of sufficiency in that they revealed that other patentees included in their patent specification details of clinical trials in humans that were conducted prior to filing. In my view what other patentees may disclose in their patent specifications or at what point in their research and development they may choose to file for patent protection are not relevant to any fact in issue in these proceedings. Exhibit 11 is excluded from evidence on that basis.
I also admitted into evidence provisionally the Beach Report on the basis that it may be relevant to the issue of utility. Although I have not derived any assistance from the Beach Report, I consider that it is relevant and it is admitted into evidence unconditionally.
During the course of Professor Christie’s and Professor Easton’s cross-examinations Mr Bannon SC sought various orders pursuant to s 136 of the Evidence Act 1995 (Cth) on the basis that aspects of their evidence relating to the Carlton paper and the Jun paper might be unfairly prejudicial to Pfizer or misleading or confusing. Having considered their evidence in relation to those matters I am not satisfied that the requirements of s 136 have been satisfied. I therefore do not propose to make the orders sought.
The parties agreed on various other exclusions and limitations in relation to the evidence that are recorded in the transcript and documents marked for identification. It is not necessary for me to say anything more about those agreed rulings.
DISPOSITION
The challenges to the validity of claims 1 to 32 are rejected. Pfizer is entitled to quia timet injunctive relief against Apotex for threatened infringement of claims 1 to 31 and against GPPL for threatened infringement of claims 1 to 30.
Pfizer will be directed to file and serve a minute of the orders it seeks within 7 days. Both proceedings will be relisted on a date to be fixed for the purpose of making final orders.
I certify that the preceding three hundred and six (306) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Nicholas.
Associate:
Dated: 21 October 2016
SCHEDULE OF PARTIES
NSD 763 of 2013 Cross-Claimants
Second Cross-Claimant:
PF PRISM CV
Third Cross-Claimant:
PFIZER IRELAND PHARMACEUTICALS
Fourth Cross-Claimant:
PFIZER ASIA PACIFIC PTE LTD
Fifth Cross-Claimant:
PFIZER AUSTRALIA PTY LTD (ACN 008 422 348)
NSD 251 of 2014 Applicants
Fourth Applicant:
PFIZER ASIA PACIFIC PTE LTE
Fifth Applicant:
PFIZER AUSTRALIA PTY LTD (ACN 008 422 348)
Sixth Applicant:
GENERIC PARTNERS PTY LTD (ACN 132 833 777)
Cross-Respondents
Second Cross-Respondent
PF PRISM CV
Third Cross-Respondent
PFIZER IRELAND PHARMACEUTICALS
Fourth Cross-Respondent
PFIZER ASIA PACIFIC PTE LTD
Fifth Cross-Respondent
PFIZER AUSTRALIA PTY LTD (ACN 008 422 348)
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