Effectiveness of pregabalin
186 In the present case claim 1 is directed to a method of treating pain in mammals including, in particular, humans. The skilled addressee would understand pain in this context in the way defined by the IASP (see [33] above). He or she would not read claim 1 as limited to pain states that involve central sensitisation. The term central sensitisation is not used anywhere in the Patent.
187 The skilled addressee would also understand claim 1 as covering pain conditions in humans that require medical treatment. The claimed invention is not directed to the treatment of minor ailments or irritations that the skilled addressee would not consider serious enough to warrant medical intervention.
188 All expert clinicians who gave evidence in this proceeding agreed that no drug will be effective in all patients. Thus, while they all agreed that pregabalin is an effective treatment for neuropathic pain, they all accepted that there will be some patients for whom it will provide no pain relief even from neuropathic pain.
189 As previously mentioned, the Patent does not convey any promise or representation as to the degree to which the claimed method of treatment will relieve pain. If the method of treatment defined in claim 1 is capable of providing some measure of pain relief to a substantial number of patients in need of treatment for pain then the claim is not invalid for lack of utility.
190 There are differences of opinion between the clinicians as to the effectiveness of pregabalin in the treatment of pain. At the Field 2 Expert Conference Professors Schug, Christie, Littlejohn and A/Prof. King agreed that "pregabalin is potentially effective in clinically relevant pain states in a mammal that involve a central sensitization component." Professor Gibson also agreed except if pregabalin is used as the sole pain relief therapy. This was a qualification frequently raised by Professor Gibson and for convenience I shall refer to it as his "sole therapy qualification". A/Prof. Lynden Roberts and Professor Harnett considered that pregabalin is a potentially effective treatment but only in those pain states in which central sensitisation is "clinically relevant".
191 In their oral evidence it became clear that A/Prof. Lynden Roberts and King and Professor Harnett considered that there are some pain states in which central sensitisation is not clinically relevant in the sense that it is not making any contribution to the pain state. In those circumstances they would not prescribe pregabalin either as a sole or an adjunctive therapy.
192 By way of example, A/Prof. King, a neurologist, referred to acute pain associated with disc disease involving no neuropathic component. In his opinion, central sensitisation is not clinically relevant to such cases. A/Prof. King said the pain in these cases is usually treated successfully with bed rest, anti-inflammatories and other therapies before it becomes chronic. There would be no point in prescribing pregabalin given the availability of these therapies.
193 Another example used to illustrate this way of thinking is acute gout. This is a condition that A/Prof. Lynden Roberts and Professor Littlejohn, both of whom are rheumatologists, are often required to treat. Acute gout pain refers to pain with a rapid, intense onset, which is associated with red, hot and swollen joints. It is caused by a build-up of uric acid in the joints, which become swollen and inflamed. Chronic gout pain is experienced by patients who generally have a history of acute attacks of gout pain. The pain experienced by patients with chronic gout is due to an ongoing inflammatory process. In some rare cases of chronic gout, a patient may also experience neuropathic pain. Pain associated with gout can be extreme.
194 A/Prof. Lynden Roberts and Professor Littlejohn agreed that most gout pain is acute and will resolve relatively quickly with treatment usually over a few hours or a couple of days. A/Prof. Lynden Roberts said that in practice he has never seen signs of central sensitisation in cases of acute gout pain. He said in the concurrent evidence (T 245):
… so in people who have acute gout in the knee, for example, they present with pain in the knee. And when I examine their knee, I can move their knee and it's very irritable. And I can see that it's acute gout and I treat them with anti-inflammatory tablets. When I see people with another condition in the knee that's persistent, I can find features of allodynia and hyperalgesia clinically that are very apparent clinically that would suggest that central sensitisation was the major component of their problem. And so clinically I can discriminate reasonably easily between people who have central sensitisation and people who don't.
195 A/Prof. Lynden Roberts was cross-examined with a view to suggesting that he had no basis for believing that central sensitisation was not playing any role in the pain experienced by patients with acute gout. It is clear from his evidence that many patients he treats for acute pain conditions, including acute gout, do not show any clinical signs of central sensitisation. He therefore considers that it would be pointless to prescribe pregabalin for the treatment of acute gout pain even as an adjunctive therapy.
196 A/Prof. Lynden Roberts' evidence on this topic may be contrasted with Professor Littlejohn's. It was put to Professor Littlejohn that there are some pain states in which central sensitisation is not clinically relevant. I understood him to accept that proposition as correct. However, he went on to qualify that answer as follows (T 288):
I think [central sensitisation] is always clinically relevant, but whether you target that process as your key strategy or whether you target the primary process causing the pain is a clinical decision based on the context and a lot of other factors, co-morbid factors, etcetera. […] We wouldn't use a drug to target central sensitisation for an acute attack of gout. We would treat that with high dose anti-inflammatories, but recognise the central sensitisation is playing a role in that patient's pain and their pain and allodynia and other clinical features, but you would treat the primary cause, and that would be the same as a lot of other clinical conditions.
197 Professor Littlejohn's position was made much clearer during cross-examination in which he gave the following evidence (T 626-627):
And […] acute gout is an example of a condition that you treat often, isn't it?---Yes, indeed.
And it's an example of a pain condition where central sensitisation does not manifest as the key pain that needs targeting?---I don't know about that. I think it's a major component of acute gout pain. It's just that we have other ways of targeting the acute gout mechanism through high dose anti-inflammatories, which are so effective that it just turns the whole process off very quickly.
But you don't use drugs specifically targeting central sensitisation for an acute attack of gout, do you?---No, they would take too long to work.
I see?---We - we want to work within, you know, hours to get relief.
I see. And I think you said [in] the concurrent session, you don't use pregabalin to treat acute gout?---No.
But you would accept, I think, that a patient presenting with acute gout will be in need of treatment for their pain?---Correct.
And I think you said that acute gout is the most intense inflammation that we can see within a joint?---Correct.
And so it's serious pain that a patient presents with acute gout?---A patient becomes sensitised to even someone walking into the room so it's extreme pain and extreme hyperalgesia.
You don't prescribe pregabalin in acute gout, because, in your professional opinion, it will not have any significant effect on that patient's pain experience?---Well, I don't know if we know that. I don't think trials or studies have been done to establish that. It's just that it hasn't been required, because we can put a cortisone injection into a gouty knee and the pain will be diminished within 30 minutes so there's no need to worry about other strategies that might be theoretically possibly [sic].
It would be possible, wouldn't it, to administer pregabalin in combination with other treatments, wouldn't it, in a case of acute gout?---You could certainly do that. It would be an interesting study.
And you don't do that?---No.
And you're not concerned that it might be beneficial to a patient to prescribe pregabalin to prevent a case of acute gout transitioning to a chronic disease?---I'm not concerned that would happen, no.
198 Professor Littlejohn went on to indicate that, in his view, central sensitisation is always present when a patient is experiencing pain but that sometimes there are other strategies that are better suited to a particular clinical situation that does not involve targeting central sensitisation. He later gave this evidence: (T 628):
But there are conditions where central sensitisation may not manifest as the key pain that needs targeting?---Yes, that is - that's true.
And I think you agreed with me that you wouldn't withhold a treatment from a patient you thought would provide a benefit to that patient?---No, I wouldn't.
And so it's your professional opinion, isn't it, that in a patient with a condition where there's no manifestation of central sensitisation that needs targeting, pregabalin will not provide a useful benefit to that patient?---That's probably correct.
199 Professor Schug was asked in the concurrent evidence to comment on the proposition that pregabalin is not effective in the treatment of pain conditions that do not involve central sensitisation. His response was that all clinically relevant pain states involve some degree of central sensitisation. Professor Christie was of the same opinion. Ultimately, Professor Gibson also agreed that processes of central sensitisation occur, to a greater or lesser extent, in all pathophysiological pain states. Although Professor Gibson questioned whether all nociceptive pain causes central sensitisation, he agreed that central sensitisation will be present to some degree in all pain states warranting medical intervention. He said that the process of central sensitisation is "not like an on-off switch" and added (T 296):
[I]t can be very minor in terms of the amount of central sensitisation […] that you have through to being extensive and prolonged and severe. And so my qualification really alludes to that process. There will be cases where you, yes, have central sensitisation, because it is part of the normal response pattern of the nociceptive system to any injury or disease, but that in some cases there will be a relatively minor component of central sensitisation. In other cases there could be a relatively major component of central sensitisation.
I accept the evidence of Professor Gibson on this topic which is consistent with that of Professors Christie and Schug.
200 There are some types of pain which there may be no reason to treat with pregabalin. The pain associated with acute gout provides a very good example of this. As Professor Schug explains in his affidavit evidence, there may be various reasons why a clinician might not prescribe pregabalin to treat a particular type of pain. As he explained:
Because pain is complex and responses to treatment are variable, my experience is that a useful benefit from the use of pregabalin is obtained in only some patients. Some patients can suffer side effects like somnolence or dizziness. There are many cases of pain for which pregabalin is usually not used. For example, other analgesic options may be efficacious for particular conditions, they may be cheaper or may not have the same side effect profile. However, this does not mean that pregabalin would not be effective to treat those conditions in at least some patients, if it were administered to them. There are a range of reasons, including particularly side effect profile and cost, why pregabalin would not be prescribed in a given situation, particularly when pain is not difficult to treat and cheaper alternatives are likely to be effective.
In all cases of clinically relevant pain I assume, and I consider that most pain specialists would assume, that central sensitisation contributes to some degree which may be large or small, to the pain experience. As a result, pregabalin could be administered to any patient suffering any pain condition with the expectation that the patient may receive a benefit due to the reduction in the central sensitisation component of the pain. Whether pregabalin is the analgesic of choice in a given situation, or a benefit is actually obtained by a particular patient, are different matters for the reasons I have explained.
201 As part of the Field 2 Expert Conference, the clinicians were also asked to comment on the proposition that when central sensitisation is a clinically relevant component of a patient's pain condition, pregabalin could be an effective treatment for various pain conditions including acute gout pain. As part of the same question they were also asked about other pain conditions although for present purposes I will focus on the one that I have mentioned. Professors Littlejohn, Schug and Christie's collective response was as follows:
Prof Littlejohn, Prof Schug and Prof Christie agree but consider the definition of 'clinically relevant' central sensitization to be ambiguous because central sensitization […] might occur but not always be obvious as defined by some clinicians but is nonetheless expected to contribute to a greater or less [sic] extent to all pain types involving intense or prolonged nociceptive stimulation, or nerve injury whether or not other mechanisms (e.g. ongoing nociceptor stimulation) or pain drug targets dominate. In cases wherein other mechanisms and drug targets dominate, pregabalin could still be an effective treatment, alone or in combination with other treatments, even if the pain type is likely to respond fully or in part to other preferred treatments. Many conditions have pain contributed to by different mechanisms, particularly central sensitization.
202 Professor Gibson agreed that, leaving aside pain of entirely neuropathic origin, pregabalin could be used as an effective pain relief therapy, but not on its own. Professor Schug accepted that there would be many pain conditions for which pregabalin alone would not be an effective treatment. Mr Catterns QC, who appeared for Apotex, asked Professor Schug whether there are some pains which would be treated with pregabalin alone or in combination with other drugs. Professor Schug's answer was as follows (T 428):
I mean as already discussed many times, pregabalin addresses not pain itself, but the central sensitisation which follows an initial painful insult, and therefore pregabalin is not qualifying as an analgesic, and I think even the patent makes clear that it is not an analgesic but an antihyperalgesic drug. And for that reason there is nearly no condition except neuropathic pain and fibromyalgia, and as a pathological pain states [sic] where the only mechanism is central sensitisation, where pregabalin on its own is effective.
203 Mr Catterns QC relied heavily on this answer as evidence that pregabalin will have no effect upon a patient's pain where pregabalin is used as the sole treatment except in cases of neuropathic pain or fibromyalgia. However, I do not think this answer goes that far. Professor Schug, as I understood him, did not accept that when answering Mr Catterns' question that pregabalin would have no effect on pain if used alone except in cases of neuropathic pain or fibromyalgia. The question and answer were directed to how a clinician would treat such pain conditions given that, except in cases of neuropathic pain and fibromyalgia, central sensitisation is not the only pain mechanism involved.
204 The evidence established that central sensitisation plays a role in all pain conditions but that in some cases it plays a minor role only. What this indicates is that for some pain conditions pregabalin may provide a patient with little in the way of pain relief especially when compared with other treatment options. But it does not follow that the use of pregabalin would provide such a patient with no pain relief.
205 The best example of pain that is least likely to be relieved by treatment with pregabalin is acute gout. One reason why pregabalin is not used to treat pain associated with acute gout is that there are more effective, quick-fire treatments available that resolve the underlying condition and with it the accompanying pain. Another reason is that, because acute gout is an inflammatory condition, central sensitisation will only play a minor role in the patient's pain and, therefore, the scope for pregabalin to reduce the patient's pain will be quite limited. But if acute gout were treated with pregabalin alone, can it be said that this would not provide a substantial number of patients with some measure of pain relief? The fact that the pain relief achieved might be quite small, because central sensitisation was contributing to the patient's pain in a minor way, does not mean that pregabalin does not provide a useful treatment option for patients suffering from pain associated with acute gout. The fact that there may be far simpler, cheaper and more effective ways of treating pain in patients suffering from acute gout explains why clinicians do not prescribe pregabalin as a treatment for acute gout but it does not establish that pregabalin would not be useful in the treatment of that condition either alone or in combination with other therapies.
206 I am not persuaded that pregabalin would not reduce the patient's pain to some degree in cases of acute gout. Put in slightly different terms, I am not persuaded that in cases of acute gout, treatment with pregabalin would provide no greater reduction in the patient's pain state than would treatment with placebo. In those circumstances, Apotex's inutility case, in so far as it is based upon the usefulness of pregablin as a treatment for acute gout or, for that matter, any other condition in which central sensitisation plays a minor role, must fail.
207 Apotex advanced the same arguments in relation to various other pain conditions including cancer pain, postoperative pain and burn pain. I do not propose to refer to the evidence in relation to each of these particular conditions because what I have said in relation to gout pain also applies to all other pain conditions in which central sensitisation plays a minor role and for which pregabalin is likely to be much less effective than other treatments. However, in deference to Professor Harnett, who like Professors Schug, Christie, Gibson, Littlejohn, A/Prof. Lynden Roberts and King, was an exemplary witness, I propose to say a little more about his evidence.
208 Professor Harnett, an oncologist, said that he would not expect pregabalin to have a therapeutic effect in treating the pain experienced by a patient with cancer if the patient's pain condition did not involve neuropathic pain.
209 Professor Harnett said that he does not need to target central sensitisation as the mechanism causing pain in the majority of cases. I accept this evidence. It reflects the approach of a highly experienced clinician who is providing his cancer patients with the best pain relief available. There are no doubt other pain treatments (eg. analgesics) that will be of much greater benefit to patients whose pain does not have a neuropathic component. However, I do not think Professor Harnett's evidence provides a sound basis for concluding that pregabalin would not have any therapeutic effect in the treatment of pain that does not include a neuropathic component. As with gout pain, central sensitisation is likely to play some role in cancer pain lacking any neuropathic component, even though its role might be quite minor.
210 I accept that the extent of any therapeutic effect that will be achieved using pregabalin in cases where central sensitisation plays a minor role is likely to be slight. However, in my view, it is not possible to determine in the absence of more specific evidence whether the effect is likely to be merely slight or, as Apotex contends, non-existent. The positon would be different were I able to conclude that central sensitisation does not play any role in pain that does not involve a neuropathic component. However, each of Professors Schug, Christie and Gibson, all of whom have great expertise in the mechanisms of pain, agree that this is not the case.