“an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”
“The present invention is the use of an analog of gammaaminobutyric acid (GABA) in pain therapy, as the compound exhibits analgesic/antihyperalgesic action. Advantages of the use of the compound includes the finding that repeated use does not lead to tolerance nor is there a cross-tolerance between morphine and the compound.”
“[0003] The instant invention is a method of using a compound identified 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. [0004] The compound is (S)-3-(aminomethyl)-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof.” [0004] The compound is (S)-3-(aminomethyl)-5-methylhexanoic acid or a pharmaceutically acceptable salt thereof.”
“[0006] The instant invention is a method of using (S)-3-(aminomethyl)-5methylhexanoic acid or a pharmaceutically acceptable salt thereof 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. [0007] The conditions listed above are known to be poorly treated by currently marketed analgesics such as narcotics or nonsteroidal antiinflammatory drugs (NSAID) due to insufficient efficacy or limiting side effects.”
“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 s.c. administration of gabapentin (10-300 mg/kg) or CI1008 (1-100 mg/kg) 1 hour before formalin dose-dependently blocked the licking/biting behaviour 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 [i.e. the racemate] produced only a modest blockade of the late phase at 100 mg/kg.”
“These data show that gabapentin and CI-1008 are effective in the treatment of inflammatory pain.”
“[0022] The assay of Bennett G.J. provides an animal model of a peripheral mononeuropathy in rat that produces disorder of pain sensation like those seen in man (Pain, 1988;33:87-107). [0023] The assay of Kim S.H., et al., provides one experimental model for peripheral neuropathy produced by segmented spinal nerve ligation in the rat (Pain, 1990;50:355-363).”
“1. Use of [pregabalin] or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treating pain. 2. Use according to Claim 1 wherein the pain is inflammatory pain, 3. Use according to Claim 1 wherein the pain is neuropathic pain.” pain.”
“Mr Burkill, in his skeleton argument, advanced an argument to the effect that where the skilled addressee was taken to be a team (because more than one skill was involved) then the law requires one member of the team to be the ‘head’ directing the others. Here the suggestion was that the head of the team would be a rock bit engineer who would be directing a computer model designer as some kind of assistant. That position was not pursued during the oral argument. And rightly so. If the addressee of a patent is a notional team of persons with differing skills, then it is a team with no boss. Each member of the team is assumed to play his/her own part.”
“101. A question arises as to whether it is sufficient to establish that a particular fact was known in the United Kingdom, or whether it is necessary to establish, where the art is an international one, that it was known more widely. 102. Mr Thorley maintained that the relevant common general knowledge was that in this country. Mr Birss was content to accept that proposition, whilst pointing out that where the art was an international one, it is relevant on the facts to take account of evidence that individuals abroad had not heard of it. Neither side showed any enthusiasm for arguing that common general knowledge had to be more extensive than the United Kingdom. 103. I am content to proceed on this legal basis, as I did not hear detailed argument on the point. It would seem to me to be an odd result if a patent for the United Kingdom could survive if it was obvious in the light of the common general knowledge in this country. A more difficult question may arise if a fact is only common general knowledge abroad. But that does not arise here.”
“Although the initial clinical experience with gabapentin in the management of reflex sympathetic dystrophy pain and a phobic disorder in this patient is encouraging, the authors recognise the need to subject this new drug therapy to randomized, blinded, prospective scrutiny.” ii) The Mellick prior art relied on by Mylan and Actavis. This is described in more detail below. For present purposes, it is sufficient to note that it is a letter to the editor published in The American Journal of Emergency Medicine in January 1995 describing the successful treatment of five patients with RSD (including the one described in Mellick and Seng) with gabapentin. iii) G.A. Mellick and L.B. Mellick, “Gabapentin in the management of reflex sympathetic dystrophy”, J. Pain and Symptom Management, 10, 265-266 (4 May 1995 ) (“Mellick and Mellick”). This is another letter to the editor, which is essentially an update of Mellick, reporting the treatment of nine patients with RSD (including the five previously reported) with gabapentin. The conclusion is expressed in very similar terms to that in Mellick and Seng quoted above. iv) B.S. Galer, “Neuropathic pain of peripheral origin: Advances in pharmacological treatment”, Neurology, 45 (Suppl 9), S17-S25 (December 1995). This is a review article by a respected author from the University of Washington in Seattle in a supplement to Neurology entitled “Chronic pain mechanisms and management”
“Several recently released antidepressant and anticonvulsant agents may prove useful for the treatment of neuropathic pain. Anecdotal evidence exists supporting use of several of these agents as pain relievers. None of these drugs has yet been established as a therapy for neuropathic pain (or for any other painful condition) through published double-blind placebocontrolled studies.”
“We haven’t seen such anticipation since spinal opiods were introduced. The field is awash with anecdotal accounts of the wonders of gapapentin (Neurontin) in treating both central and perhiperal neuropathic pain syndromes. It began with [Mellick and Mellick] reporting that a patient with refractory reflex sympathetic dystrophy responded nearly instantly to gabapentin, and it has avalanched ever since. Now the time has come to learn whether the claims ‘hold water’ …”
“There seems little doubt – including gratifying outcomes in our institution – that gabapentin is highly effective in managing neuropathic pain of central origin. Starting with the original report there have been numerous, albeit still anecdotal, testimonials of gabapentin efficacy, even in carbamazepineresistant subjects (see table). Several clinical trials are under way, or ‘tooling up’, to determine whether gabapentin is as powerful a neuropathic pain suppressant as we hope it to be. In fact, as this editorial goes to press, abstracts and posters addressing the issue should be flooding national pain medicine and neurology meetings.”
“At present, soft evidence that gabapentin looks promising is tantalizing, if not compelling. Let us hope that the reality of clinical trials matches our high expectations.”
“Gabapentin (Neurontin®) is a recently released anticonvulsant which appears to provide medical maintenance relief of the symptoms of reflex sympathetic dystrophy (RSD) and many forms of neuropathic pain including peripheral neuropathy. … I hope this new antiepileptic drug proves to be as useful in your pain practice as mine.”
“It would appear from the clinical reports analyzed herein that anticonvulsant drugs can provide relief of the paroxysmal lancinating pain that occurs in a number of clinical conditions. The explanation for this is not yet complete, but the clinical value is clear”. ii) R.K. Portenoy, “Pharmacologic management of chronic pain” in Pain Syndromes in Neurology, ed. H.L. Fields (Butterworths, 1990). In this chapter the author states (references omitted): “Despite the paucity of controlled clinical trials, anticonvulsant medications (Table 11.2) have become widely accepted in the management of chronic neuropathic pain, particularly those characterised as lancinating pains. Their mode of analgesic action in these syndromes is not known, but presumably relates to the variety of mechanisms underlying their anticonvulsant effects such suppression of paroxysmal discharges, neuronal hyperexcitability or spread of abnormal discharges.” iii) Chapter 46, “Central pain”, in the Textbook of Pain, contributed by J. Boivie. This states (references omitted): “The commonly used AEDs [anti-epileptic drugs] are listed in Table 46.9. Carbamazepine is probably the most widely used drug, but in recent years clonazepam has gained popularity. The rationale underlying the use of AEDs for central pain is their ability to suppress discharge in pathologically altered neurones, an effect that is also the basis for their use in epilepsy. Carbamazepine and phenytoin probably exert their effect by inactivation of sodium channels.” iv) H. McQuay et al, “Anticonvulsant drugs for management of pain: a systematic review”, B.M.J., 311, 1047-52 (21 October 1995 ). The authors stated in the introduction (footnote omitted): “Anticonvulsant drugs have been used in pain management since the 1960s, soon after they were first used to revolutionise the management of epilepsy. The clinical impression is that they are useful for neuropathic pain, especially when the pain is lancinating or burning”
“Anticonvulsants are used widely to control trigeminal neuralgia and other neuropathic pains”
“The excitable-membrane stabilizing properties of anticonvulsants probably account for their ability to diminish intrinsic neuronal hyperactivity/hyperexcitability in epileptic foci. As neuropathic pain arises, in part, from local neural hyperexcitability and self-sustaining ectopic discharges, membrane stabilizers such as anticonvulsants and local anaesthetics can be effective suppressants, with reduced pain the result.” vi) Rosner et al (cited above). The authors state: “Medications that reduce pathologically altered neurons from excessive discharge would seem to be good choices for management of [neuropathic pain] syndromes. Anticonvulsants have therefore been advocated in management of refractory neuropathic pain, by virtue of their pharmacological properties.” vii) Stacey et al (cited above). The authors state: “As the other anticonvulsants have been useful for a variety of neuropathic pain conditions, we utilized gabapentin in a series of patients with neuropathic pain who had failed previous treatment.”
“Studies utilizing the anticonvulsants carbamazepine, phenytoin and valproic acid for PHN have been either unimpressive or difficult to interpret because of the concomitant use of antidepressants. Although carbamazepine is a popular agent for the paroxysmal lancinating pain that commonly occurs, there is no conclusive evidence to justify its use in this fashion. … Although widely used, there is no good evidence of [sic – probably “for”] the use of anticonvulsants alone in this disorder.” ii) J.W. Scadding, “Neuralgia, post-herpetic” in Handbook of Current Diagnosis & Treatment, ed. R. Rounder and M. Hamilton (Current Medicine, 1995), in which Dr Scadding stated: “Anticonvulsants, e.g. phenytoin, carbamazepine, sodium valproate, and clonazepam, have not been shown to relieve postherpetic neuralgia; any effect will probably be short-lived and consistent with a placebo response”. iii) J.W. Scadding, “Pain management” in Concise Oxford Textbook of Medicine, ed. J.G.G. Ledingham and D.A. Warrell (OUP, 2000), based on an edition of the Oxford Textbook of Medicine from 1996, in which Dr Scadding stated: “Antiepileptic drugs have no effect on nociceptive pain. With the exception of the specific effect of carbamazepine in trigeminal neuralgia, antiepileptic drugs are also disappointingly ineffective in neuropathic pains. Although claims have been made for carbamazepine, phenytoin, valproate, and clonazepam in a variety of neuropathic pain, positive results have only emerged from poorly controlled short-term trials.”
“The last mode of the dorsal horn, Mode 4, differs from the first three in that it represents a potentially irreversible, or at the least prolonged, reorganization of the synaptic circuitry of the system. The first three modes reflect a system operating in a range of states of excitability, from suppressed to hypersensitive, determining the sensation produced by defined stimuli. Mode 4, in contrast, is that state which occurs when there is degeneration of elements of the system, or the formation of novel inputs. Such changes have been documented after injury to the nervous system, both peripheral and central, leading to a range of sensory abnormalities including neuropathic pain.”
“Mode 3, representing a state of hypersensitivity also has survival value in some circumstances. The state of central sensitization is triggered by certain types of nociceptor afferent input which will occur with tissue damage, peripheral inflammation and following nerve injury where injury discharge and spontaneous activity occur (Fig. 5.11). A state of excessive sensitivity, such that low-intensity stimuli begin to initiate pain, can help to protect injured body parts from further injury while recuperation or healing occurs. …. Sensitization is not always adaptive, however, and when it is produced in situations where the initial damage has healed or following nerve injury, it can result in pain with no apparent benefit to the sufferer.”
“Modes 1, 2 and 3 reflect the capacity of the nervous system for functional plasticity, the dynamic alteration in the performance of the system in response to changing situations. Mode 4 is qualitatively quite different. In this situation cells die, axon terminals degenerate or atrophy, new axon terminals may appear, and the structural contact between cells at the synapses may be considerably modified (Fig. 5.12). This mode represents true pathology and its contribution to neuropathic and central pain disorders is only just beginning to become apparent.”
“While it is now clear that during and immediately following inputs in nociceptors the excitability of a sizeable fraction of dorsal horn neuron increases and that this is almost certainly responsible for mechanical allodynia and secondary hyperalgesia (Torebjörk et al 1992), what is less certain is the extent to which such sensitization plays a role in the sensory abnormalities accompanying chronic pain states. Acute tissue damage and inflammatory states will directly and indirectly lead to the activation of nociceptors which will induce central sensitization. On recovery from the damage or inflammation, the source of the input during the central changes is removed and the hyperalgesia and allodynia commonly disappear within several hours or days. Neuropathic pain, in contrast, is typically persistent and intractable (Ch.10). One explanation may be that a constant drive of input from axotomized nociceptors is present (Devor 1991), which maintains the central sensitization. Another is that associated with peripheral nerve damage is the decrease in segmental inhibitory mechanisms (Wall & Devor 1981; Woolf & Wall 1982) which exaggerates the synaptic response to afferent input.”
“… Of particular interest is the finding that large myelinated afferent fibres which normally terminate in the deeper laminae of the dorsal horn, grow into lamina II, the site of C-fibre terminals (Woolf et al 1992). This may result in the formation of novel and inappropriate synapses which could dramatically alter the central processing of signals generated in the lowthreshold mechanoreceptors. Peripheral neuropathic pain may be an expression, therefore, of an alteration in the circuitry of the spinal cord as well as of changes due to the maintenance of central sensitization by a nociceptor drive (Ch.10) Central neuropathic pain resulting from spinal cord injury and a number of central lesions may also alter the spinal cord by removing some of the descending influences originating from the brainstem that control the gain of the system. If such changes resulted in a removal of a descending inhibitory input, the consequence might be a form of sustained central sensitization due to disinhibition.”
“There followed an intensive development of various animal models of this central sensitization to peripheral stimuli induced by various chemical stimulations of peripheral tissue and by lesions of soft tissue and peripheral nerves (see Table 1 and [8]). Interest was further stimulated by the demonstration that the widespread hyperalgesia in man that follows local intense cutaneous stimulation has to be attributed to central sensitization [9]. By analogy it is presumed that many of the pathological hyperpathic states in humans include central sensitization.”
“There are now many other experimental models of central sensitization associated with activation of peripheral C-fibres (see Table 1). Where central plasticity is triggered by irritant chemicals, soft tissue injury or nerve stimulation, the effects develop over minutes. The effects associated with tissue inflammation, however, have a slower onset, typically measured in hours, while nerve injury-associated central change may take days to develop. A striking feature of all these manifestation of central sensitization is that, where tested, they are blocked by NMDA receptor antagonists.”
“... we are now beginning to realise, as described in the first ten chapters of this book, that a peripheral event may trigger long lasting changes in the spinal cord and brain by way of nerve impulses and transported substances. This means that overt peripheral pathology is capable of initiating a cascade of changes which may persist in the central nervous system long after peripheral pathology has disappeared.” vi) Chapter 1 of the Textbook of Pain, “Peripheral neural mechanisms of nociception”, contributed by R.A. Mayer et al. This states under the heading “Central mechanism of secondary hyperalgesia”
“Substantial evidence favours this important tenet: the peripheral signal for pain does not reside exclusively with nociceptors. Under pathological circumstances, other receptor types, which are normally associated with the sensation of touch, acquire the capacity to evoke pain. This principle applies not only to secondary hyperalgesia but also to neuropathic pain states in general. This condition arises through augmentation of responsiveness of central painsignalling neurons to input from low-threshold mechanoreceptors, a phenomenon often termed central sensitization.” vii) S.W.N. Thompson et al, “Injury-induced plasticity of spinal reflex activity: NK1 neurokinin receptor activation and enhanced A- and C-fiber mediated responses in the rat spinal cord in vitro”, J. Neuroscience, 14, 3672-3687 (1994). Towards the end of the summary the authors conclude (at 3672): “The enhanced ventral root responses and changes in receptor sensitivity may contribute to the phenomenon of central sensitization and may be directly relevant to the behavioural hyperalgesia observed. Moreover these findings may be relevant to the mechanisms of enhanced excitability that occur in clinical conditions of inflammatory hyperalgesia and neuropathic pain.” viii) M. Koltzenburg et al, “Nociceptor modulated central sensitization causes mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain”, Brain, 117, 579-591 (1994). The title speaks for itself and clearly connects central sensitisation and neuropathic pain. ix) K.M. Park et al, “Effects of intravenous ketamine, alfentanil, or placebo on pain, pinprick hyperalgesia, and allodynia produced by intradermal capsaicin in human subjects”, Pain, 63, 163-172 (1995). The introduction states (at pages 163-164): “The phenomenon of sensitization of central nervous system (CNS) neurons is well established in animal models of acute and chronic pain (Woolf 1983; Dubner 1991; Woolf and Thompson 1991; Bennett 1994) and has been inferred from sensory studies in some patients with chronic neuropathic pain and post-traumatic pain syndromes (Campbell et al 1988; Price et al 1989, 1992; Gracely et al 1992; Koltzenburg et al 1994). Animal studies in many laboratories have shown that N-methylD-aspartate (NMDA) receptor-mediated processes play a role in central sensitization. For example, spinal administration of NMDA receptor antagonists blocks central sensitization caused by the repeated electrical stimulation of C-fiber nociceptors (Davis and Lodge 1987; Dickenson and Sullivan 1990) and by the peripheral injection of capsaicin (Ault and Hildebrand 1988; Nagy et al 1993) and diminishes hyperalgesia and allodynia in animal models of neuropathic pain (Yamamoto and Yaksh 1992; Mao et al 1993; Tal and Bennett 1993).” x) C.J. Woolf, “Somatic pain – pathogenesis and prevention”, B. J. Anaesthesia, 75, 1691-76 (1995). This is a short review article by Prof Woolf. Under the heading “Central sensitization”, Prof Woolf states (at page 171, references omitted): “Central sensitization has been documented in a large number of laboratories in a wide variety of species, including humans and is now accepted as a major contributor to post-injury pain hypersensitivity.”
“Neuropathic pain, the pain produced by damage to the central nervous system, is also characterised by central changes in sensitivity including A-mediated pain. This may be the consequence of three different kinds of pathological change produced by nerve lesions. First, a maintained state of central sensitization in response to ongoing ectopic C-fibre input either from the site of injury or the DRG (the generator model). Second, decreased inhibition due to impaired inhibitory transmission, as a result of either a decrease in GABA levels or an excitotoxic loss of inhibitory neurones (the disinhibition model). We have recently shown that disinhibition results in a central hypersensitivity phenomenon. Finally, A-mediated pain might be the consequence of a reorganization of synaptic connections in the spinal cord (the structural model).”
“It is likely that neuropathic pain in humans involves various combinations of these and other maladaptive changes that occur in response to nerve damage some of which may resemble inflammatory changes and others which will be quite different What will be critical now, is to establish what initiates which change and when, and to determine if the changes are reversible. It is particularly encouraging that neuropathic pain in laboratory animals can be prevented by some manipulations such as preventing an injury discharge with local anaesthetic block, NMDA-receptor antagonists or morphine and that this is also true for patients with intercostal neuralgia and phantom limb pain.”
“Although inflammatory and neuropathic pain are generally different in their presentation and natural history, related general pathophysiological mechanisms may be involved. These include alterations in chemical expression or phenotype and growth status of primary sensory neurons and increases in excitability or disinhibition of dorsal horn neurons. There are important differences though …”
“In summary, the most prominent feature in neuropathic pain patients is hyperalgesia to mechanical stimuli. Hyperalgesia to cold stimuli is often also observed. In contrast to primary hyperalgesia after tissue injury, hyperalgesia to heat stimuli is not prominent in neuropathic pain. The hyperalgesia in neuropathic pain bears a marked resemblance to secondary hyperalgesia, and may represent a form of chronic secondary hyperalgesia.”
“Substantial evidence points to central sensitisation as the principal mechanism in secondary hyperalgesia. ... Dorsal horn neurons exhibit both changes in stimulus-response functions and in receptive field size due to remote injury. In the case of mechanical stimuli, central sensitisation may be such that the response to a given nociceptor input is enhanced. On the other hand there is mounting evidence that the response to central pain-signalling neurons to input from low threshold mechanoreceptors is enhanced.”
“Based on the psychophysical characteristics, neuropathic pain may arise from neural mechanisms similar to those of secondary hyperalgesia … In neuropathic pain, as in secondary hyperalgesia, mechanical hyperalgesia is the hallmark sign. … Several lines of evidence have shown that mechanical hyperalgesia in neuropathic pain is mediated by low-threshold mechanoreceptors rather than nociceptors. … Since excitation of low-threshold mechanoreceptors does not normally cause pain, the responsiveness of central neurons must have changed in neuropathic pain, such that the hyperalgesia is mediated by these afferents …”
“Evidence is accumulating to support the notion that an ongoing discharge from hyperexcitable nociceptive afferents can change the impulse processing at central levels of the nervous system in such a way that normally nonpainful stimuli are now perceived as painful. This is termed central sensitization. The phenomenon has long been recognized clinically and can also be observed in normal subjects treated with chemical irritants to produce experimental pain. … It is concluded that the primary cause for neuropathic pain seems to be an abnormal excitability of primary nociceptive afferents. Sensitization of nociceptive afferents may express itself as mechanical hyperalgesia to pressure and hyperalgesia to heat. Secondary central changes in signal processing can aggravate these symptoms. The dynamic mechanical hyperalgesia to gentle stroking or vibration is regarded as a physiologic central consequence of ongoing activation of nociceptive fibers, regardless of the underlying pathophysiologic mechanism.” iii) Chapter 1 of the Textbook of Pain states (at page 13) that: “Once tissue is damaged, a cascade of events results in enhanced pain to natural stimuli termed hyperalgesia. A corresponding increase in the responsiveness of nociceptors called sensitisation occurs." As Dr Scadding accepted, this paragraph does not distinguish between neuropathic and inflammatory pain. The chapter continues (at page 19): “Hyperalgesia is a consistent feature of tissue injury and inflammation. … Hyperalgesia may be prominent in neuropathic conditions such as post-herpetic neuralgia, certain cases of diabetic neuropathy and certain cases of traumatic nerve injury.”
“As noted above, and as will be clarified further in this section, the distinction between primary and secondary hyperalgesia is to some extent artificial. The mechanisms that account for hyperalgesia to mechanical stimuli in the secondary zone may very well account for mechanical hyperalgesia in the primary zone.”
“Allodynia and hyperalgesia are very common symptoms. They may occur, singly or in various combinations, in any of the peripheral neuropathies and in patients with central pain. [...] The conceptual difference between allodynia and hyperalgesia is straightforward, but it must be admitted that in practice it is often difficult or impossible to differentiate the two.” v) Koltzenburg et al (cited above). The summary begins by saying that “Brushevoked pain (mechanical allodynia, dynamic mechanical hyperalgesia) is a hallmark of neuropathic and inflammatory pain states”
“The frequency of DMA in PHN is intriguing since in most of the clinical descriptions DMA is mentioned in at least 90% of patients [11,18].”
“At the time of the priority date, a lot of clinical conditions that were thought to be characterised by central sensitisation i.e. those that had hyperalgesia and allodynia had not actually been specifically shown to be the italicised version of central sensitisation. In fact, if you look at the class of drugs that were most commonly used to treat those conditions, whether it be neuropathic pain, fibromyalgia, any of the conditions that were characterised by the non-italicised version, central augmentation, amplification, the most commonly used class of drugs for all of those conditions were tricyclic drugs that were originally developed as anti-depressants. Amitriptyline is the one we have heard a lot about. That drug, although it binds very weakly to NMDA receptors, at the time and subsequent to the priority date, was really thought to be working more so by working on the inhibitory pathways. We have heard about disinhibition, those pathways that go from the brain areas, the peri-aqueductal grey – the Yunus chapter. We are just talking about those. So, compounds, which were the drugs most broadly used in clinical conditions, characterised by hyperalgesia, were probably not working on the italicised version of central sensitisation. They were working on the broader concept of central sensitisation. So that, clinically, in 1996, and even at present, the non-italicised version of central sensitisation is what we identify with hyperalgesia and allodynia and the classes of drugs that work in those conditions. Some may be working on the italicised version, but many are not working on the italicised version. They are treating hyperalgesia and allodynia via different mechanisms.”
“The second phase of the formalin test does model elements of inflammatory and neuropathic pain, specifically the phenomenon of central sensitisation which is present in both. It is therefore fair to say that the formalin model is a model of inflammatory pain in so far as inflammatory pain has a mechanistic central component (as does neuropathic pain)”
“The linkage was not exclusively inflammatory pain, but obviously inflammatory pain has a central sensitisation component and that was certainly what I was attempting to say there, that the late phase of the formalin model was recognised to reflect the presence of central sensitisation, that certainly could be present in inflammatory pain, but equally could be present in other conditions, including neuropathic pain.”
“In the years in the run up to the Priority Date there were many publications that made it clear that an inflammatory response could not alone be responsible for the second (late) phase of the formalin test and that a central sensitisation component must play a role or even the dominant role.”
“I think the disagreement was, was phase 2 exclusively central sensitisation? I think that some people interpret[ed] the Coderre work as such and there were others who said it was exclusively peripheral and driven only by primary activity. As is common in most cases, it is a mixture of both. There is some peripheral drive which continues to contribute to the phenomenon, but it is acting on a facilitated state. That was clear at the priority date.”
“In the last 5 years, it has become increasingly appreciated that in addition to the acute component, protracted afferent drive for periods lasting minutes can evoke pronounced changes in pain behaviour, suggesting an augmented processing of the nociceptive response, i.e. a hyperalgesic state. Thus, the injection of an irritant, such as formalin, into the skin will lead to an acute barrage followed by a protracted ongoing low level of C fibre activity. In the animal so treated, one observes a multiphase component of behaviour in which the first phase reflects the acute afferent barrage, followed, after a brief period of quiescence, in a powerful second phase of agitation. ”
“Tests, such as the hot plate or paw pressure, define substrates which are activated by an acute high-intensity stimulus. On the other hand as noted above, protracted afferent input, as generated by an injury state, may lead to a prominent hyperalgesia. Models, such as the formalin test, appear to define systems which are brought into play by such ongoing afferent input.”
“The injection of an irritant such as formalin into the paw will result in an initial burst of small afferent activity, followed by a prolonged low level of afferent discharge (Heapy et al 1987). Behaviourally, the animal displays an initial transient phase of flinching and licking of the infected paw (phase 1), followed after a brief period of quiescence by a second prolonged phase of licking and flinching of the injected paw. Significantly, the spinal delivery of NMDA and NK-1 antagonists have little effect upon the first phase, but will significantly diminish the magnitude of the second phase response (Yamamoto & Yaksh 1991, 1992; Coderre & Melzack 1992). … Of equal importance, delivery of NMDA and NK-1 antagonists after the first phase of the formalin test results in a loss of their ability to alter the second phase response (Yamamoto & Yaksh 1991, 1992; Coderre & Melzack 1992). These observations indicate that the magnitude of the second phase response is dependent upon processes which were initiated by the activation of NMDA and NK-1 sites during the first minutes after the injection of the formalin, but these sites are not required for the sustenance of the second phase activity and occur independently of these sites. The mechanisms of this augmented responsiveness induced by repetitive C-fibre input and the activation of NMDA and sP are not completely understood. …”
“As noted above, the generation of a modestly protracted afferent barrage by the injection of an irritant into the skin or the generation of a state of inflammation will evoke an acute pain state, followed by a profound hyperalgesia. Models such as the formalin test in the rat have been shown to be associated with a two-phased response, with the magnitude of the secondphase behaviour being in excess of that anticipated on the basis of the afferent activity measured in the peripheral afferent at the corresponding time points (Heapy et al 1987; Wheeler Aceto et al 1990). Similarly, other models of hyperalgesia involving chronic inflammatory states may well be involved in such states of facilitated processing (though if the increased pain behaviour reflects upon a greater sensitivity of the peripheral nerve to the stimulus, then this hyperalgesia might reflect a model mediated by a peripheral mechanism). The spinal delivery of certain afferent transmitters, such as sP or NMDA will evoke a prominent decrease in the thermal nociceptive threshold of the unanaesthetized rat, corresponding to the presumed mechanisms set into play by repetitive afferent input. In man, the focal activation of cutaneous C-fibres by the subcutaneous injection of capsaicin results in a prominent acute pain behaviour followed by a profound hyperalgesia over an area of skin that greatly exceeds the focal site of the original stimulus. Importantly, this secondary hyperalgesia appears centrally mediated, for (as with the formalin test) if the acute afferent barrage is blocked by local anaesthetic, the secondary phase does not occur (Torebjörk et al 1992).”
“The observation that NK-l and NMDA antagonists given between phase I and phase 2 have little effect upon phase 2 supports the argument that these receptors systems serve to initiate, but not sustain the facilitated component of the second phase (Coderre & Melzack 1991, 1992; Yamamoto & Yaksh l99l, 1992). These agents, as described, thus serve as antihyperalgesics and, to the degree that a pain state is augmented by these processes, those classes of agents will serve to normalize the facilitated pain state. In contrast, agents such as the opioids on the formalin test serve as analgesics by blocking the afferent input responsible for evoking behaviour (as in phase 1 of the formalin test and the acute response on the hot-plate or tail-flick test).”
“… intrathecal agents such as the NMDA antagonists have no effect upon the normal paw latency, but will result in a dosedependent increase in the latency of the hyperalgesia paw to normal (nonhyperalgesic) response latencies. In this sense, as with those agents which block in a limited, but dose-dependent fashion, phase 2 of the formalin test, such agents might also be classified as being antihyperalgesic.”
“While there are certain parallels between the systems which underlie the mechanisms of the hyperalgesia observed in the formalin test and that in nerve injury, consideration of Table 9.7 emphasizes that the pharmacology of these two measured end-points are not the same. Thus, for the nerve injury evoked hyperalgesia, NK-l antagonists and cyclooxygenase inhibitors are not active. Moreover, it is not known if the spinal substrates through which the NMDA antagonists act to alter the two hyperalgesia states are the same. Thus heterogeneous spinal mechanisms may be involved in the different pain states. Still, at present it is not clear that all agents which block the hyperalgesia component observed following nerve lesion will block the facilitated component of phase 2 of the formalin test.”
“If you are exploring secondary hyperalgesia, you need to test it outside the zone of the injury. So, that logic is irrefutable, by definition.”
“Gabapentin (Fig. 6) has been shown to prevent seizures in several animal models and in clinical studies. It has a mechanism of action that appears to be different from the AEDs described above. … Originally, gabapentin was synthesized as a structural analogue of GABA …. … gabapentin cannot be described as ‘GABA-mimetic’ and, despite activity in a variety of in vivo and in vitro models, its molecular site of action remains to be clearly defined. There has, however, been some study of a newly-discovered specific gabapentin binding site in neuronal tissues (see … below). Gabapentin has several properties in animals and humans that give it a desirable profile. It has a very low degree of toxicological effects …. It is readily absorbed from the gastrointestinal tract but is not significantly metabolized … ; Gabapentin does not bind significantly to plasma proteins ... Thus gabapentin is unusually easy to administer because of its simple pharmacokinetics, and it has few of the dose-related side effects that are common with other AEDs. … In vitro, gabapentin does not interact with neuronal sodium channels or L-type calcium channels, thus distinguishing it from phenytoin, carbamazepine and lamotrigine as well as from the dihydropyridine calcium-channel blockers. It is also inactive in standardized receptor-binding assays. …. These negative results support the idea of a novel mechanism of anticonvulsant action for gabapentin.”
“Gabapentin-receptor binding is displaced by unlabelled gabapentin and by several structural analogues of gabapentin, including 3-isobutyl GABA (Fig 6). The two enantiomers of 3isobutyl GABA have different potencies for binding at the gabapentin site, and the same difference in potency is seen in seizure models with whole animals (Fig. 11) [89] Several other compounds that are potent inhibitors of gabapentin binding in vitro [84] also prevent seizures in animal models [90]. Together these findings strongly suggest that the gabapentin-binding site is novel in comparison to commonly studied neurotransmitter and drug receptor sites of brain. These findings also indicated that the anti-convulsant actions of gabapentin and related compounds are correlated with binding at the gabapentin site, even though the physiological function of the binding site remains to be discovered. Future biochemical studies may lead to the purification and identification of a protein receptor for gabapentin, such as a functionally characterized membrane-bound receptor, uptake transporter, or enzyme.”
“These results indicate that gabapentin is unlikely to have direct pharmacological actions on the GABAergic synapses or calcium channels that are responsible for glutamate or GABA neurotransmitter release.” 272. It goes on to say (at page 30): “ … gabapentin (100μmol) failed to reduce or otherwise alter long-term potentiation in rat hippocampal slices in vitro, a response that is known to depend on activation of NMDA receptors [88]. … …. Depolarizing responses of cultured spinal cord neurons to the iontophoretic of GABA were not altered by the addition of gabapentin. Gabapentin is also inactive in other electrophysiological tests sensitive to antagonism or modulation of glutamate receptors. In addition, gabapentin had no effect on sustained repetitive firing of sodium-dependent action potentials in cultured spinal cord neurons. …. Considered together, biochemical and electrophysiological studies suggest that gabapentin interacts with a novel receptor or enzyme in neurons and thereby causes a biochemical change (poorly defined at present) to cause an anti-convulsant effect. Although gabapentin slightly reduces the release of monoamines, the relevance for anti-convulsant action is not clear.”
“Studies of gabapentin in tests for various anti-epileptics mechanisms are compared with results for prototype AEDS in Table 3. The results indicate that gabapentin does not interact with voltage-sensitive sodium channels, which may be the major site of action of phenytoin, carbamazepine and lamotrigine. … … Finally, unlabelled gabapentin and several structural analogues of gabapentin with anti-convulsant properties displace binding of tritiated gabapentin at a novel receptor site of brain membranes, and other AEDs do not displace binding. Stereospecific binding activity of 3-isobutyl GABA is related to stereospecific anti-convulsant activity in whole animals. Together, these data indicate that gabapentin prevents seizure by a mechanism different from those of other AEDS and related to a novel drug-binding site.”
“To date, we have had no treatment failures. More extensive descriptions of these case studies are pending publication in the pain management literature. We look forward to future controlled investigations in order to confirm our recent discovery of successful pain control with gabapentin in patients with RSD.”
“A single high affinity (KD = 38 + 2.8 nM) binding site for [3H] gabapentin in rat brain has been described (7). Radioligand binding to brain membranes was potently inhibited by a range of gabapentin analogues and by several 3-alkyl-substituted analogues of GABA, although GABA itself was only weakly active. Other antiepileptic drugs including phenytoin, diazepam, carbamazepine, valproate, and phenobarbitone were inactive. Gabapentin (IC 50 = 80 nM) and (RS)-3-isobutylGABA (IC 50 = 80 nM) were the most active compounds identified (7). The (S+)-enantiomer of 3-isobutyl-GABA was significantly more active than the (R-)-enantiomer both in displacing [3H] gabapentin binding and in preventing maximal electroshock seizures in mice (8). These data strongly suggest that the protein defined by [3H] gabapentin plays an important role in controlling the excitability of neurons.”
“Unlike GABA, gabapentin passes the blood-brain barrier. However, gabapentin itself is not active at GABAA or GABAB receptors, nor is it an inhibitor of GABA uptake. Numerous pharmacological studies have failed to pinpoint gabapentin’s mechanism of action (6.7), but recent studies suggest that gabapentin increases the nonsynaptic release of GABA, perhaps by altering cellular GABA metabolism. In any case, the anticonvulsant activity of gabapentin has been demonstrated in numerous models (see below) and in clinical trials (8-10).”
“Gabapentin was not active in several models of analgesia in response to acute painful stimuli. … However results in a model of neuropathic pain due to constriction of rat sciatic nerve or nerve roots (19, 20) indicated that gabapentin reduces behavioural responses of heightened sensitivity to painful stimuli when administered either systematically or intrathecally. These results suggested that gabapentin alters spinal neuronal circuitry involved in the perception of pain from peripheral neuropathy.”
“Biochemical and electrophysiological studies in vitro with gabapentin are summarized in Table II. Although a constellation of effects were observed, it is not clear which of these are most relevant for the anticonvulsant and/or other pharmacological actions of gabapentin. … Although there are still questions to be answered about the molecular and cellular mechanisms involved and how they might contribute to the prevention of seizures, alteration of nonsynaptic GABA in neuronal tissues is a reasonable explanation for the anticonvulsive effect of gabapentin. … Gabapentin has other actions that are less clearly associated with its anticonvulsant actions. …”
“Gabapentin did not affect ligand binding at a wide variety of commonly studied drug and neurotransmitter binding sites and voltage-activated ion channels, including GABA, glutamate and glycine receptors of several types. However, experiments with [3H]-gabapentin revealed gabapentin binding sites in mouse brain, but not in several peripheral organs (37).”
“The binding of gabapentin to its receptor was characterised in studies using rat, mouse and pig brain homogenates (37, 39). Unlabelled gabapentin displaced [3H]-gabapentin from rat brain membranes (KD = 0.08 µM). [3H]-gabapentin was also displaced by the neutral branched-chain amino acids …, as well as by L-glutamine (39). Gabapentin was not displaced from its receptor by other anticonvulsants such as valproate or phenytoin, but it was displaced by several chemically related compounds (37, 40). The displacement of gabapentin from its binding site by various neutral branched-chain amino acids led to the proposal that the gabapentin binding site is related to the membrane transported for these amino acids (39). Recently, gabapentin was used to isolate and identify a protein from mammalian brain that binds with high affinity to gabapentin molecules (41). These studies indicated that the high-affinity gabapentin binding protein is identical with the α 2δ subunit of voltage-sensitive calcium channels. However, since the function of α 2δ subunits of calcium channels is not clear, the functional significance of the high-affinity gabapentin binding site remains to be established.”
“Gabapentin did not alter voltage-clamped sodium currents in the same manner as phenytoin, carbamazepine or lamotrigine (43), but with longer in vitro incubation periods it did alter sustained firing of Na-dependent action potentials (44). In addition, a recent study suggested that gabapentin has other electrophysiological actions that may account for reduced excitability (45). It is not yet clear whether these in vitro findings are relevant to its anticonvulsant and/or other pharmacological actions in in vivo.”
“(1)(a) Identify the notional ‘person skilled in the art’; (b) Identify the relevant common general knowledge of that person; (2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it; (3) Identify what, if any, differences exist between the matter cited as forming part of the ‘state of the art’ and the inventive concept of the claim or the claim as construed; (4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?”
“The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these: (i) the first step is to identify the invention and that is to be done by reading and construing the claims; (ii) in the case of a product claim that means making or otherwise obtaining the product; (iii) in the case of a process claim, it means working the process; (iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims; (v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification; (vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim; (vii) the specification must be sufficient to allow the invention to be so performed without undue burden.”
“100. It must therefore be possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods within the claim are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then it cannot be said the claim is insufficient simply because the patentee has not demonstrated the invention works in every case. 101. On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient. It may also be invalid for obviousness, there being no invention in simply providing a class of products or methods which have no technically useful properties or purpose.”
“I would not quarrel with Jacob L.J.’s comment, after consulting the Shorter Oxford English Dictionary, that the sense [the word ‘plausibly’] conveys is that there must be some real reason for supposing that the statement is true: para. 111. The important point, however, is that the standard is not any higher than that.”
“Misuse, abuse potential or dependence Cases of misuse, abuse and dependence have been reported. Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of pregabalin misuse, abuse or dependence (development of tolerance, dose escalation, drug-seeking behaviour have been reported).”
“Pregabalin and gabapentin misuse widespread among drug users and prisoners Most of the 17 areas covered by the survey highlighted the significant increase in misuse of two prescription drugs, pregabalin and gabapentin, chiefly among Britain’s opiateusing and prison populations. These anticonvulsant medications are increasingly prescribed to treat epilepsy, neuropathic pain and anxiety. People who misuse the drugs do so because of the feelings of euphoria they can create; they are commonly used alongside - and as enhancers to - other drugs, such as alcohol, opiates such as heroin or methadone, and diazepam. Pregabalin and gabapentin are easily available on the illicit market in 25mg to 800mg capsules, changing hands for between 50p and£2 . Drug workers reported users displaying extreme intoxication and uninhibited, risky behaviours while on the drugs. Mixing these medications with other central nervous system depressants such as opiates and alcohol significantly increases the risk of overdose. Deaths involving pregabalin and gabapentin are on the rise and the Office for National Statistics told DrugScope that pregabalin and gabapentin were mentioned on 41 death certificates in 2013 (pregabalin on 33 and gabapentin on 9).”
“[The product in question] is also authorised to treat other conditions which are not mentioned in this leaflet. Ask your doctor or pharmacist if you have further questions.”
“Lecaent may be prescribed to treat other conditions not listed in this leaflet. If you have any questions, ask your doctor or pharmacist.”
“Actavis is therefore preparing to launch a pregabalin product in the UK with a summary of product characteristics (‘SmPC’) limited to the treatment of epilepsy and general anxiety disorders (a so-called ‘skinny label’) in December 2014 or January 2015. Actavis also wishes to launch a pregabalin product with a full label in the UK, including for the treatment of neuropathic pain, as soon as possible, but wishes to clear the way first by seeking revocation of EP(UK) 0 934 061. Such a full label launch will therefore not take place until after the hearing [of] Actavis’s revocation proceedings.”
“Our client’s product will be marketed in conjunction with the attached Product Information Leaflet, which you will note does not include indication for the treatment of neuropathic pain. On launch our client also intends to notify superintendent pharmacists specifically that its product is not indicated for the treatment of neuropathic pain.”
“We are of the opinion that, if your client intends to launch a generic product, it is required to take appropriate steps to ensure that it is not dispensed for the treatment of pain, including by ensuring that all pharmacists are aware that its generic product is not authorised for and should not be dispensed for the treatment of pain. As a starting point, this would seem to require an appropriate notice being placed on the outside of the packet of your client’s product to ensure that this matter is brought to the attention of the pharmacist handling the product.”
“Given your client’s approach, there is an urgent need to take steps that will prevent infringement of our client’s patent, whilst allowing your client to market its product in respect of its authorised indications.”
“You have our client’s position that in its view its planned launch of the Skinny Label Product will not infringe your client’s patent. However, we remain in the dark as to your client’s position on what would or would not constitute patent infringement beyond the piecemeal raising of late objections to aspects of our client’s launch. Please provide us with the steps which your client considers to be sufficient to prevent infringement of your client’s patent by our client’s Skinny Label Product.”
“… certain players in the prescription, dispensing and reimbursement chain may, albeit potentially unwittingly, be involved in such infringing activities”
“… you said that the Department of Health was not able to issue guidance under the new NHS structure. However, you believed the issuing of guidance was important for Pfizer in achieving a solution, and that the PAG/Nick Beavon’s communication was clear and gave those healthcare professionals who received it what they needed to act within the law. Your view is that getting prescribers to act appropriately, since it is they who hold the discretion as to whether to prescribe by reference to INN or brand, is key.”
“… at present I do not think that the correct formulation of prescriptions for pregabalin is an issue on which we should express a view on behalf of NHS England, at least on a timescale that is likely to be material to the litigation under way.”
“… we share the Hon Mr Justice Arnold’s view that issuing guidance to prescribers that pregabalin should be prescribed by brand name (ie LYRICA) when pregabalin is being prescribed for pain is the simple fix to this problem.”
“In addition, the Lyrica (Pfizer) brand of pregabalin has patent protection until July 2017 for its licensed indication of peripheral and central neuropathic pain; until such time as this patent expires generic pregabalin products will not be licensed for this indication and their condition would be off-label and may infringe patent.”
“In view of the above, Pfizer requests that you issue appropriate guidance prescribing clinicians within your CCG [or Health Board] to help ensure that our pain patent is respected and that all prescribing clinicians are aware of the pain patent situation. There are a number of ways in which this might be achieve but the simplest solution, we believe, is for clinicians to be advised to prescribe Lyrica® by brand when prescribing pregabalin to treat neuropathic pain. Pharmacists will then be able to dispense Lyrica® against such prescriptions and this will ensure that they do no infringe the pain patent.”
“It is my view that when prescribing for neuropathic pain within licence, the only appropriate action at this point in time is to prescribe by Lyrica brand to avoid confusion and infringement of patent law.”
“1. Pregabalin should only be prescribed for the treatment of neuropathic pain under the brand name Lyrica® (unless there are clinical contra-indications or other special clinical needs e.g. patient allergic to an excipient, branded product unavailable etc which apply to Lyrica®, when you should not prescribe Lyrica® or pregabalin). … 4. When dispensing pregabalin, if you have been told that it is for the treatment of pain, you should ensure, so far as reasonably possible, that Lyrica®, the branded form of pregabalin, is dispensed. However, when dispensing pregabalin for the treatment of anything other than pain, you are not restricted to dispensing Lyrica®.”
“Alert If treating neuropathic pain, prescribe Lyrica (brand) due to patent protection. For all other indications, prescribe generically”
“If treating neuropathic pain, prescribe Lyrica (brand) due to patent protection”. ii) In the case of OptimiseRx: “Consider prescribing as Lyrica (by brand) if for the treatment of pain. NHS England advise that, due to licensing and patent protection, all prescribing of pregabalin for pain should be with explicit reference to the brand Lyrica. For all other indications, continue to prescribe generically.”
“Only one authorisation may be granted to an applicant for a specific medicinal product. However, the Commission shall authorise the same applicant to submit more than one application to the Agency for that medicinal product when there are objective verifiable reasons relating to public health regarding the availability of medicinal products to healthcare professionals and/or patients, or for co-marketing reasons.”
“- correspondence, possibly accompanied by material of a nonpromotional nature, needed to answer a specific question about a particular medicinal product, - factual, informative announcements and reference material relating, for example, to pack changes, adverse-reaction warnings as part of general drug precautions, trade catalogues and price lists, provide they include no product claims.”
“There is a critical difference, not always recognised in the authorities, between imputing the existence of an intention as a matter of law and inferring the existence of an intention as a matter of fact. Imputation of an intention by operation of a rule of law is a vestige of a previous age and has no proper role in the modern law of tort. It is unsound in principle. It was abolished in the criminal law nearly 50 years ago and its continued survival in the tort of wilful infringement of the right to personal safety is unjustifiable. It required the intervention of Parliament to expunge it from the criminal law, but that was only because of the retrograde decision in Director of Public Prosecutions v Smith[1961] AC 290 . The doctrine was created by the courts and it is high time now for this court to declare its demise.”
“… socio-ethical and public health considerations. In fact physicians should be free to take all actions they considered suitable to prevent or to cure a disease, and in this exercise they should remain uninhibited by patents.”
“118. … The skilled person would understand that the technical features of the present claim extend beyond making pregabalin, yet fall short of including the step of actually using pregabalin for treating pain. Instead it includes a feature concerned with the ultimate purpose of the product manufactured, namely the intentional treatment of pain. I would describe the subject matter of the claim, therefore, as making pregabalin for patients to whom it will be intentionally administered for treating pain. Making pregabalin for patients to whom it is to be administered for the non-patented indications is not within the technical subject matter of the claim. Only the former category of manufacture makes use of the technical contribution of the patentee. 119. I think the skilled person would understand the technical subject matter of the claim in the way I have indicated because he or she would first understand that it was necessary for the claim to include a manufacturing step to ensure that the claim does not touch the doctor, and fall foul of the method of treatment exclusion. However the skilled person would understand that any manufacturing step is adequate for this purpose, as the doctor does not manufacture the medicament. 120. The skilled person would understand that the claim in question owes its novelty to the discovery of the new therapeutic use of the medicament. … 121. Thus the skilled person would understand that the technical subject matter of the claim was concerned with the ultimate end use of the medicament, from which it derived its novelty. The therapeutic treatment is of course new because, and only because, it is carried out with the intention of producing the new therapeutic effect. The prior use of the compound may have in fact produced the effect, for example if a patient taking it for GAD or epilepsy was at the time experiencing pain as well. This demonstrates, to my mind, that it is the intention for which the compound is administered which is at the heart of the invention.” end use of the medicament, from which it derived its novelty. The therapeutic treatment is of course new because, and only because, it is carried out with the intention of producing the new therapeutic effect. The prior use of the compound may have in fact produced the effect, for example if a patient taking it for GAD or epilepsy was at the time experiencing pain as well. This demonstrates, to my mind, that it is the intention for which the compound is administered which is at the heart of the invention.”
“Against that background the skilled person would understand the word ‘for’ in the claim to be providing a link between the act of manufacture using pregabalin and the ultimate intentional use of the drug by the end user to treat pain. The critical issue for me to decide is what is sufficient to constitute that link. An extreme view might be that if the drug is in fact used for the patented indication then it has been made ‘for’ that indication, whatever the manufacturer's intention might be. [Counsel for Pfizer] did not contend for that construction. I think he was right not to do so. It would mean that a manufacturer could not tell whether he had made use of the subject matter until after, and perhaps a long time after, he had disposed of the product. The realistic candidates are therefore (a) foreseeability that the drug will intentionally be used for the patented indication and (b) a subjective intention to that effect.”
“123. [Counsel for Actavis] is right that the skilled person would understand the purpose of the Swiss form of claim to be that of avoiding the twin perils of lack of novelty and lack of patentable subject matter. However, as this court made clear in Actavis v Merck, the objection of lack of patentable subject matter is overcome by the fact that the claim is a manufacturing process claim. The skilled person would thus appreciate that there is no reason to imply a narrow or strict mental element in order ensure that this peril is avoided. 124. If [counsel for Actavis] were correct that a subjective mental element on the part of the manufacturer were necessary in order to provide the claim with novelty, there would be powerful reasons for adopting it. However, I do not see how that can in fact be so. If a product is ‘for’ a particular therapeutic indication if it is reasonably foreseeable that it will be used intentionally for the treatment of pain, then it will not be rendered lacking in novelty by showing that products in the prior art had been manufactured in circumstances when it was not possible to foresee such a result. 125. Mr Speck’s point is a slightly different one, namely that no-one should be prevented by the grant of a patent from doing that which they did, or could have done, before. He called this the ‘golden thread’ of English patent law. That principle is not, however, an entirely reliable one. It was relied on in Merrell Dow … to suggest that the patent was invalid because it would have the effect of restraining the continuance of the prior use. The principle was ineffective there because the old use itself was ‘uninformative’. At pages 86-87 Lord Hoffmann recognised that a gap had opened up under the 1977 Act between anticipation and infringement. The present case is another situation in which one cannot rely on the principle, because the subject matter of the invention is concerned with the purpose of acts which are in themselves no different from those which were done before. In any case it is not correct that the patent can prevent that which was done before. It was not possible before the patent was granted to foresee that the product would intentionally be used for treating pain.”
“127. I can therefore see no reason why the skilled person would conclude that the word ‘for’ implied subjective intent. He would understand that the manufacturer who knows (and for this purpose constructive knowledge is enough) or could reasonably foresee that some of his drug will intentionally be used for pain is making use of the patentee's inventive contribution, in the same way as a manufacturer who actively desires that result. In my judgment, therefore, the skilled person would understand that the patentee was using the word ‘for’ in the claim to require that the manufacturer knows (in the above sense) or can reasonably foresee the ultimate intentional use for pain, not that he have that specific intention or desire himself. 128. In reaching his conclusion that it was the manufacturer’s intention that was determinative, the judge relied on what Jacob LJ said in Actavis v Merck at [75], namely that claims in Swiss form were aimed at the manufacturer and did not touch the doctor. I think the judge may have read too much in to this passage. Jacob LJ was there considering whether the claim was a disguised claim to a method of treatment. The inclusion of a manufacturing step ensures that it is not. Jacob LJ was not addressing the nature of the mental element in the claim. It is, I think, important to bear in mind that there are two mental elements involved: the question is what the manufacturer knows or foresees about the intentional use of the drug by the end user which counts.”
“How does one tell whether a manufacturer is using the manufacturing process of the claim, and therefore rendering himself liable for patent infringement? The answer must be when he manufactures pregabalin when he knows or foresees that users will intentionally administer it for pain.”
“Another hard case is that in which a defendant has taken all the steps open to him to avoid his medicine being prescribed for the new use, yet those steps are, due to the structure of the marketplace, insufficient to stop it happening. Actavis’ test would provide a defence in those circumstances, because the defendant could credibly say that he did not target those sales which he was striving manfully to prevent. The hard case arises because of the peculiarities of the UK's market place for drugs. Normally a vendor of a product can control by contract the uses to which his product is put and require any intermediary to include similar terms. I do not think we should allow the regulatory environment to dictate the scope of the claim in this way.”
“110. Both parties are agreed that the issues of law which arise on both types of infringement are ones which are capable of being decided on the materials before us. The Secretary of State for Health … indicated to us … that he would prefer us not to decide those issues, but to leave them over to trial where the Secretary of State intended to make a formal application to intervene. 111. I do not consider that the course advocated by the Secretary of State for Health is a sensible one for us to follow for a number of reasons. Given the parties’ agreement that the issue is capable of resolution now, it is plainly desirable that we should decide it so the parties know where they stand. …”
“Intention in the law of tort is commonly relevant as a control mechanism limiting the ambit of a person’s obligation to safeguard the rights of others, where this would constrict his freedom to engage in activities which are otherwise lawful. The economic torts are a classic illustration of this.”
“It might be suggested … that the court should modify the injunction so as to try to spell out what it is that the defendant can do. We would not have thought that normally appropriate: it will be up to the defendant to work out how to ensure that there is no ultimate infringement.” infringement.”
“… if, as I have held, there is a case of threatened or actual infringement of the process claim under section 60(1)(b), then it follows that dealings downstream in the direct product of the process are also infringements under section 60(1)(c). Although this may not add anything to the direct infringement case, it is wrong to strike it out as a viable additional cause of action.”
“… it is arguable … that when section 60(2) speaks of ‘putting the invention into effect’, it may be legitimate to look not just at whether any one person is carrying out the invention in a sense which would give rise to liability of that person for an act of infringement. It may be that the invention is put into effect if pregabalin is manufactured by one person and supplied to another who intentionally uses it for the treatment of pain.”
“Where a person (whether or not the proprietor of, or entitled to any right in, a patent) by circulars, advertisements or otherwise threatens another person with proceedings for any infringement of a patent, a person aggrieved by the threats (whether or not he is person to whom the threats are made) may, subject to subsection (4) below, bring proceedings in the court against the person making the threats, claiming any relief mentioned in subsection (3) below.”
“As discussed, Pfizer believes that the current prescription, dispensing and reimbursement framework is likely to contribute to infringement of the pain patent. This may occur if generic pregabalin products are prescribed, dispensed and used to treat Neuropathic pain — as opposed to epilepsy or generalised anxiety disorder. Therefore we believe that certain players in the prescription, dispensing and reimbursement chain may albeit potentially unwittingly, be involved in such infringing activities. Pfizer is ready to work with the relevant stakeholders to achieve the most practical solution to this issue … You disagreed with Pfizer that an individual prescriber would be infringing Lyrica’s pain patent if generic pregabalin were to be prescribed for pain. However, you agreed that it would be inappropriate for CCGs (or other NHS bodies) to instruct as to generic pregabalin usage in pain on the basis of cost, and you confirmed that you would not endorse such guidance.”
“Pfizer believes that the current prescription, dispensing and reimbursement framework could contribute to infringement of the pain patent This may occur if generic pregabalin products are prescribed, dispensed and used to treat Neuropathic pain — as opposed to epilepsy or generalised anxiety disorder. Therefore certain players in the prescription, dispensing and reimbursement chain may, albeit potentially unwittingly, be involved in such infringing activities.”
“First of all let me say that making allegations of infringement against pharmacists (who are in most cases also our customers) is not something that Pfizer would engage in lightly. I also take your point that, as a general matter, patentees have not tended to assert patent infringement against pharmacists for dispensing generic product, although it certainly has happened on occasion. … The key issue is whether there is any relevant patent in place — if there is, then subject to the fairly narrow exception insection 60(5)(c) of the Patents Act 1977 , it is indeed possible for retail pharmacists to be liable for infringement. The facts we are dealing with here are different from the usual generic launch scenario, but the bottom line is that Pfizer has in place a patent that it believes is valid and which it believes could be infringed. … … there are various ways in which a retail pharmacist could be said to be liable for infringement, for example if they started taking more than their non-pain demand for pregabalin supplies from generic companies with the inevitable result that neuropathic pain prescriptions were not being filled with Lyrica. In direct response to your query we do believe that retail pharmacists would be infringing if they receive prescriptions for ‘pregabalin’ and dispense the generic, knowing it to be for treating neuropathic pain. …”
“Whilst Pfizer’s pain patent remains in effect, we expect that generic manufacturers will generally only seek authorisation of their pregabalin products for use in epilepsy and generalised anxiety disorder, i.e. the two indications for which Pfizer has no patent protection. It is likely that the generic companies will initiate discussions with you about their products and we therefore think it is important for you to understand that we believe the supply of generic pregabalin for use in the treatment of pain, whilst the pain patent remains in force in the UK, would be infringing Pfizer’s patent protection and would constitute an unlawful act.”
“In the circumstances described above, Pfizer believes the supply of generic pregabalin for use in the treatment of pain whilst the pain patent remains in force in the UK would infringe Pfizer’s patent rights. This would not be the case with supply or dispensing of generic pregabalin for the non-pain indications, but we believe it is incumbent on those involved to ensure that skinny labelled generic products are not dispensed and used for pain. In this regard, we believe the patent may be infringed, even potentially unwitting, by pharmacists and others in the supply chain, if they supply generic pregabalin for the pain indication. Without information, guidance and practical solutions from the authorities, Pfizer believes that multiple stakeholders, possibly without realising, may contribute to patent infringement which would be an unlawful act. This runs contrary to the government’s established policy of rewarding additional research by the granting of a second of a second medical use patent. We also note that, by issuing guidance, your CCG is able to influence patterns of prescribing and dispensing in your area. We believe these powers must be exercised responsibly and a with a view to avoiding the infringement of Pfizer’s pain patent. … We should also note that, in our view, (i) CCG guidance instructing or encouraging the usage of generic pregabalin in pain would amount to procurement of patent infringement ( an unlawful act); and (ii) your CCG is under an obligation to address the risk of wide scale infringement of Pfizer’s patent rights. Pfizer therefore formally reserves all of its legal rights in this regard.”
“We understand that a conversation took place between Neville Fitzgerald of Pfizer and Fiona Murray of Murrays Pharmacy on4 February 2015 during which Ms Murray made it clear that Murrays Pharmacy would take a position with regard to the dispensing of pregabalin which is one that threatens to infringe Pfizer’s Lyrica pain patent, and we are therefore very concerned. We appreciate that the situation is unusual, and so we wanted to write in confidence to you to ensure that you were made aware of the issues, which in turn we hope will allow us to reach an amicable agreement with you on the way forward. … Pfizer believes that the current prescription, dispensing and reimbursement framework could contribute to infringement of the pain patent. Patent infringement will occur if generic pregabalin products are dispensed and used to treat pain – as opposed to epilepsy or GAD. Potential liability for pharmacists In relation to the impact on pharmacists (and pharmacy technicians), the relevant legislation is taken from the acts of patent infringement that are set out insection 60(1)(c) of the Patents Act 1977 . In this case, we believe infringing acts would include: * Disposing of or offering to dispose of generic pregabalin for use in the treatment of pain (it is our view that dispensing is the same as disposing for the purposes of the legislation); … … Pfizer believes that pharmacists (and pharmacy technicians) could be liable for patent infringement under thePatents Act 1977 , even potentially unwittingly, if they receive prescriptions for ‘pregabalin’ and dispense a generic pregabalin for pain. Therefore we believe that the best and simplest solution lies with prescribing doctors ensuring that only Lyrica is prescribed for pain. … Our understanding of your position As we mention at the beginning of this letter, we have become aware of a conversation that took place on4 February 2015 between Pfizer’s Neville Fitzgerald and your Fiona Murray, during this conversation, despite acknowledging the pain patent, Ms Murray stated your view that you do not accept any responsibility for what dispensing practices your pharmacy branches engage in when they are presented with prescriptions from prescribers for either ‘Lyrica’ or ‘pregabalin’. Our understanding is that Ms Murray’s current view is that she will not be informing your pharmacists that they should be checking the indication / condition for which the pregabalin has been prescribed. This indicates that you, perhaps unwittingly, would be committing acts which we believe infringe our pain patent if you were to pursue this strategy then you would be threatening to infringe the pain patent. Next steps We would like to emphasise again that this matter is a legal one, not a clinical one. … We request that you agree to change your current position and to ensure until after the trial in June 2015 that: 1. you do not inform pharmacists in your company that generic pregabalin should be dispensed for pain or neuropathic pain or conditions including pain or neuropathic pain or in any other way procure pharmacists in your company to dispense generic pregabalin for pain; and 2. you inform all pharmacists in your company, that until the judgment in the trial referred to above, only Lyrica should be dispensed for the treatment of pain. We request that you provide us with a copy of your advice to your pharmacists in draft form before it is disseminated. Finally, we recognise that your current position may have resulted from you not being fully appraised of the unusual legal situation concerning Lyrica pain patent. We would simply ask that you respond to this letter by close of business on Friday13 February 2015 to confirm that you will agree to the steps set out above and the requested notifications to your pharmacists, to enable us to bring this matter to an amicable conclusion. …”
“… we wanted to make you aware of the issues and to discuss how we may work together to ensure that doctors are property informed and that they respect the patent when using Lyrica to treat patients with pain. … … Pfizer believes that the current prescription, dispensing and reimbursement framework could contribute to infringement of the pain patent. Patent infringement will occur if generic pregabalin products are prescribed, dispensed and used to treat pain - as opposed to epilepsy or GAD. For your reference, we received the enclosed letter from NHS England dated10 February 2015 from Sir Bruce Keogh … The letter specifically refers to BMA (and professional bodies) and its potential role in assisting clinicians to avoid unlawful behaviour. … We also would like to emphasise that this matter is different to general off-label prescribing in unlicensed situations where there is no patent in force in respect of the off-label/unlicensed indication. In the patent situation any guidance to encourage prescribing of unlicensed generic pregabalin for pain cannot be for clinical reasons and would infringe the patent. We would like to emphasise again that this is a legal matter, not a clinical one. ...”
“When presented with a generic prescription for pregabalin, you will therefore need to take steps to ensure that the appropriate product is dispensed. This might involve, amongst other things, contacting the prescriber to establish the indication, or making a similar enquiry of the patient. … … it is necessary for pharmacists to take steps to avoid dispensing generic pregabalin for pain (as set out above). We would like to emphasise that this is a legal matter, not a clinical one. However, given the imminent launch of generic pregabalin and the crucial role pharmacists will play, we believe it is important that pharmacists are fully informed of the situation.”
“To avoid possible patent infringement by pharmacists, steps will need to be taken to ensure that where generic pregabalin is requested on a prescription the correctly licensed product is supplied. This may mean contacting the prescriber and establishing the indication and requesting that the prescription is amended and ordered by brand as Lyrica if necessary. … Using generic pregabalin for neuropathic pain may be deemed by Pfizer to be a patent infringement by all parties concerned, including the prescriber and the supplying pharmacist.”