Apotex Pty Ltd v Otsuka Pharmaceutical Co., Ltd
[2014] APO 28
•19 May 2014
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Apotex Pty Ltd v Otsuka Pharmaceutical Co., Ltd [2014] APO 28
Patent Application: 2009233591
Title:Substituted carbostyril derivatives as 5-HT1A receptor subtype agonists
Patent Applicant: Otsuka Pharmaceutical Co., Ltd
Opponent: Apotex Pty Ltd
Delegate: Karen Ayers
Decision Date: 19 May 2014
Hearing Date: 28 February 2014, in Melbourne
Catchwords: PATENTS – preferred construction of independent claim defined a broad population group of patients with treatment resistant schizophrenia –– claims inventive and a define a manner of manufacture –– knowledge of mechanism of drug increased possibility of success for certain patients–– this improved clinical outcomes for treatment-resistant schizophrenia as a whole even if success for an individual patient could not be predicted–– knowledge of drug mechanism therefore had practical implications and was not a mere discovery
Representation: Patent applicant: Cynthia L. Cochrane of counsel assisted by Dr Paula de Bruyn and Richard Jarvis of Davies Collison Cave, Melbourne
Opponent:Mr Neil Murray of counsel assisted by Dr Tom Gumley and Milena Dryza of Freehills Patent Attorneys, Melbourne
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2009233591
Title:Substituted carbostyril derivatives as 5-HT1A receptor subtype agonists
Patent Applicant: Otsuka Pharmaceutical Co., Ltd
Date of Decision: 19 May 2014
DECISION
The opposition is unsuccessful.
All the claims are inventive in light of the citations raised by the opponent. There are also no objections under manner of manufacture or section 40.
Absent an appeal being filed within 60 days of this decision, I direct the application proceed to grant.
REASONS FOR DECISION
Background
Patent application 2009233591 was filed on 29 October 2009 in the name of Otsuka Pharmaceutical Co., Ltd as part of a long chain of divisional applications. Its parent application (2007201701) is a divisional application of 2005201772 (grandparent) which in turn is a divisional application of 2002226752 (great grandparent). The great grandparent was filed on 29 January 2002 as a PCT application (PCT/JP02/00626) claiming priority from a US basic application (09/770210) filed on 29 January 2001.
Revocation-infringement proceedings are currently before the Federal Court in relation to the grandparent (‘772) and great-grandparent (‘752). The Full Court issued a decision on 6 March 2013 granting interlocutory injunctive relief on the supply of a particular pharmaceutical (see Generic Health Pty Ltd v Otsuka Pharmaceutical Co., Ltd [2013] FCAFC 17). The substantive hearing is expected to occur sometime this year. The parent application (‘701) was opposed but the opposition was withdrawn and the application proceeded to grant in March 2013.
The current application (‘591) was advertised accepted on 25 October 2011 and Apotex Pty Ltd filed a notice of opposition on 20 January 2012. The evidence stages were completed on 21 November 2013 and the matter was set for hearing in Melbourne on 28 February 2014.
Evidence
The following evidence was filed in this matter:
(a)Evidence in support
Statutory declarations by:
Jayashri Kulkarni dated 15 April 2013 (Kulkarni#1)
Jayashri Kulkarni dated 03 May 2013 (Kulkarni#2)
Sarah Catherine Hennebry dated 10 May 2013
Jayashri Kulkarni dated 17 May 2013 (Kulkarni#3)(b)Evidence in Answer
Bruce Sugriv Singh dated 21 August 2013
(c)Evidence in Reply
Jayashri Kulkarni dated 21 November 2013 (Kulkarni#4)
Onus of Proof
The request for examination in relation to this patent application was filed on 27 March 2009. As a consequence, substantive amendments of the Patents Act brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present application. This includes the amendment to subsection 60 (3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition exists.
Consequently the former standard for opposition proceedings applies and the opponent must establish that it is clear or practically certain that the patent is invalid (F Hoffman La Roche AG v New England Biolabs Inc [2000] FCA 283 at [29], [67]; 50 IPR 305 at 311, 319; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18], [22]; 79 IPR 426; Genetics Institute Inc v Kirin-Amgen Inc [1999] 92 FCR 106 at [17]).
Specification
The specification as accepted relates to a method of treating a patient suffering from schizophrenia. Schizophrenia is a serious mental disorder which generally manifests itself in early adulthood and affects 1% of the population worldwide. Its main features are a person’s disconnection with reality, lack of capacity to engage with others and disturbances in thinking, behaviour and emotional responses[1].
The symptoms of the disorder are generally classified into three broad groups known as ‘dimensions’[2]:
·Positive symptoms (these include the psychotic symptoms most often associated with schizophrenia such as hallucinations and delusions);
·Negative symptoms (the absence of normal emotional responses); and
·Cognitive impairment (difficulty in concentration, inability to understand instructions and poor memory)
There is also a broad distinction made between ‘acute’ and ‘chronic’ schizophrenia. Acute schizophrenia lasts for more than 6 months but then the patient recovers[3]. These patients can however suffer intermittent relapses of the disease known as ‘acutely relapsing schizophrenia’. Chronic schizophrenia last for much longer. ‘Treatment-resistant’ schizophrenia is a particular form of chronic schizophrenia in which the patient’s positive symptoms (in addition to negative and cognitive symptoms) are at least partially unresponsive to antipsychotic medication[4].
[1] Singh at [5.1]
[2] Singh at [6.1]
[3] Singh notes at [8.3] that approximately 25-35% of patients who suffer from one or more episodes of schizophrenia will recover.
[4] Singh at [8.5]. He notes that that of all patients suffering from schizophrenia, approximately 20% are partially unresponsive and 5% are totally unresponsive to antipsychotic medication as far as their positive symptoms are concerned.
10.The broad range of symptoms in a patient suffering from schizophrenia reflects the complex nature of the neurobiology underlying the disease. The positive symptoms of schizophrenia are generally thought to be caused by hyperactivity in the brain dopaminergic system involving the dopamine (DA) receptors (D1, D2, D3, D4 and D5)[5]. However other receptors have also been implicated in the disorder particularly for serotonin (5-HT or 5-hydroxytryptamine). Serotonin receptors are currently designated from 5-HT1 up to 5-HT7 but a number of these also have sub-types (eg 5-HT1A)[6].
[5] Opposed specification at page 5, lines 21-24 and Singh at [5.4]
[6] Singh at [5.3]-[5.6]
11.There are two broad classes of drugs used to treat schizophrenia:
·‘typical’ (first generation) antipsychotic drugs which include chlorpromazine, fluphenazine, perphenazine, thioridazine, pimozide, and haloperidol; and
·‘atypical’ (second generation) antipsychotic drugs which include zotepine, clozapine, risperidone, olanzapine, sulpiride[7], amisulpride and quetiapine.
[7] The literature also sometimes classifies this drug as a “typical” anti-psychotic
12.The first generation drugs (which first appeared in the 1950s) are all strong D2 receptor antagonists (blockers) which control the positive symptoms of schizophrenia (ie: hallucinations and delusions) but are less effective against the negative and cognitive impairment dimensions associated with the disease. The typical drugs also often cause extrapyramidal (ie: movement disorders) side effects (EPS) such as Parkinsonism, akathisia, neuroleptic malignant syndrome and dystonias caused by a blockage of the dopamine receptors.
13.In contrast, the second generation drugs (which didn’t appear until the 1990s) are both D2 and 5-HT2A receptor antagonists (blockers)[8]. These produce less extrapyramidal side effects (EPS) and are more effective against the negative and cognitive impairment symptoms of the disease[9]. A characteristic of the atypical antipsychotics is their varying interactions with a range of other dopamine and serotonin receptors (eg D1, D3, D4, 5-HT1A, 5-HT1D, 5-HT2C, 5-HT3, 5-HT6 and 5-HT7) as well as receptors of other neurotransmitters. No two atypical antipsychotics have identical pharmacological profiles which helps explain their differing properties and clinical effects[10].
[8] Singh at [9.1]-[9.3]
[9] Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (2012) 291 ALR 763, [2012] FCA 239 at [59(d)-(e)]
[10] Singh at [9.4]
14.The first atypical antipsychotic was a drug known as clozapine and this is still considered the most effective (benchmark) treatment for schizophrenia. The specification noted that clozapine’s superior clinical efficacy may be related to its activity as a partial 5-HT1A agonist[11]. Despite this, the drug is not used on a wide spread basis because of its potential to cause agranulocytosis (a potentially lethal blood disorder). There is therefore a clear need to develop further drugs for the treatment of schizophrenia without the side effects of the current clinical options.
[11] Opposed specification at page 9, lines 20-22
15.The specification acknowledges that aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydro-carbostyril) was a known drug and had been previously used in the (first line) treatment of schizophrenia.[12] Professor Singh (in Evidence in answer) noted that he first became aware of aripiprazole as a potential treatment sometime in the 1990s. This compound was known to bind with high affinity to dopamine D2 receptors and with moderate affinity to dopamine D3 and 5-HT receptors[13]. Of particular note was that in addition to having D2/5-HT2A antagonist properties, it has the unusual property of also being a partial dopamine (D2) agonist. This meant it might be useful for treating the negative symptoms associated with schizophrenia[14].
[12] Opposed specification at page 1, lines 15-20 which references US patent 5,006,528, EP patent 367,141 and JP 7-304,740 (these patents have no AU equivalents)
[13] Opposed specification at page 2, lines 6-12
[14] Singh at [9.10]
16.The opposed specification was the first to recognise that the known drug aripiprazole also had 5-HT1A receptor agonist activity. The specification notes a possible link between the 5-HT1A receptor and the cognitive impairment symptoms observed in schizophrenia[15]. Based on this, the specification suggested that aripiprazole could treat the cognitive impairment symptoms of schizophrenia and be a useful alternative to clozapine in the treatment of treatment resistant schizophrenia.
[15] Opposed specification at page 8, line 22-page 9, line 7
17.The applicant noted a number of other potential benefits of aripiprazole in treating schizophrenia[16]:
(a) it is not an anticholinergic agent and therefore not sedating nor does it have antihistamine activity which means it has little propensity to cause weight gain; and
(b) It leads to increased energy and movement compared to other antipsychotic drugs.
[16] Singh at [9.16]- Kulkarni#4 at [22] agrees that aripiprazole was less sedating, had less propensity to cause weight gain, had less side effects and may have more cognitive enhancing properties because of its activity at the 5-HT1A receptor
18.The specification ends with 24 claims of which two are independent (claims 1 and 13). Claim 13 is the key method of treatment claim which is outlined as follows:
A method for treating a patient suffering from disorders of the central nervous system associated with 5-HT1A receptor subtype, wherein the disorders are selected from treatment resistant schizophrenia, inveterate schizophrenia or chronic schizophrenia, each with or without cognitive impairment, which fails to respond to anti-psychotic drugs selected from chlorpromazine, haloperidol, sulpiride, fluphenazine, perphenazine, thioridazine, pimozide, zotepine, risperidone, olanzapine, quetiapine or amisulpride which comprises administering a therapeutically effective amount of a carbostyril compound of formula (1):
wherein the carbon-carbon bond between 3- and 4- positions in the carbostyril skeleton is a single or double bond; or a pharmaceutically acceptable salt or solvate thereof.:
19.Formula I is a class of compounds which includes the specific compound aripiprazole (7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydocarbostyril). Although only dependent claims 12 and 24 are limited to the use of this specific compound, I’ll refer to formula I as if it were limited to aripiprazole for the purpose of this decision (and note that this was how the parties presented their arguments).
20.The other independent claim (claim 1) is a ‘Swiss style’ claim which defines the use of the carbostyril compound of formula I for the manufacture of a medicament for the treatment of the same disorders[17]. The opponent did not raise any objection regarding this style of drafting. I will therefore consider this claim as if it were a method of treatment claim (similar to claim 13).
[17] The history and meaning of the “Swiss-style claim” is explained in Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd [2012] FCA 239 at [66]-[67]
Construction of claim 13
21.The claimed method of treatment (claim 13) relates to patients with disorders of the central nervous system associated with 5-HT1A receptor subtype, “wherein the disorders are selected from treatment resistant schizophrenia, inveterate schizophrenia or chronic schizophrenia……which fails to respond to certain anti-psychotic drugs”. While the phrase “treatment resistant schizophrenia, inveterate schizophrenia or chronic schizophrenia” implies that there are three separate disorders, the conditions are interrelated. Thus, inveterate schizophrenia is a synonym for chronic schizophrenia and treatment resistant schizophrenia is a type of chronic schizophrenia[18]. The three selected disorders are also defined by their failure to respond to particular drugs. In other words, each of the disorders is also treatment resistant. This means that each of the disorders defines the same (broad) treatment group (ie: patients with treatment resistant schizophrenia which fails to respond to a specific list of anti-psychotic drugs).
[18] Although the term “inveterate schizophrenia” is not a recognised term in the art, both parties agreed at the hearing that its only reasonable meaning term was “chronic schizophrenia”
22.The applicant suggested that the introductory phrase “disorders of the central nervous system associated with the 5-HT1A sub-type receptor” limited the broad treatment group to a particular sub-population within the group whose condition is linked to that receptor. However the art doesn’t recognise different schizophrenic sub-populations based on their ‘association’ with different receptors. The specification also fails to provide any directions which might enable a skilled worker to identify such sub-populations. Aripiprazole targets a number of receptors and has different activities at each receptor (agonist, partial agonist or antagonist). A clinician would therefore be unable to determine whether a particular clinical effect of aripiprazole is associated with the 5- HT1A sub-type receptor (and which is not) and if the applicant’s construction is correct, the clinician would not be able to work the invention or determine whether they were infringing the claim. As a consequence, the applicant’s construction leads to serious validity concerns under section 40 (sufficiency and clarity).
23.The more reasonable construction (and one which would obviate these validity concerns) is that the phrase provides an introductory preamble for the specific treatment group defined later in the claims. This construction is consistent with the specification as a whole which acknowledges that there is a broad range of disorders of the central nervous system associated with the 5-HT1A sub-type receptor including depression, migraine, Alzheimer’s disease, Parkinson’s disease and schizophrenia[19]. Given that context, the phrase simply refers to this broad group with the specific form of schizophrenia defined later in the claim as a specific treatment group within that broader list.
[19] Opposed specification at pages 3-4. for example
24.As a consequence, I accept the opponent’s construction of the phrase and find that the phrase “disorders of the central nervous system associated with the 5-HT1A sub-type receptor” is merely descriptive of the single treatment group defined later in the claim.
Grounds of Opposition
25.The opponent relied on the following grounds of opposition in relation to this hearing:
(a) Inventive step;
(b) Manner of Manufacture; and
(c) Section 40
Inventive step
Relevant Law
26.Section 7(2) provides that an invention is taken to involve an inventive step when compared to the prior art base unless it would have been obvious to a person skilled in the relevant art in the light of common general knowledge within Australia either considered alone or together with information made publicly available anywhere in the world. Section 7(3) restricts the information to that which could be reasonably expected to have been ascertained, understood and regarded as relevant by the person skilled in the relevant art.
27.Inventive step may be assessed having regard to the reformulated so-called ‘Cripps question’ set out in Aktiebolaget Hassle v Alphapharm Pty Limited [2002] HCA 59; 212 CLR 411 at [53]:
“Would the notional research group at the relevant date in all the circumstances … directly be led as a matter of course to try [the claimed invention] in the expectation that it might well produce [the desired result]?”
28.To provide some context to that question, the Courts commonly determine the ‘starting point’ for consideration of inventive step in terms of an existing problem for which the inventor found a solution. As noted by High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (no. 2) [2007] HCA 21 at [105]:
“While not every invention constitutes a solution to a problem, it is commonplace so to describe an invention where is appropriate to do so”
29.Recent Federal Court decisions have followed this approach. Thus in Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368 (23 April 2013) ([203]-[218]), Justice Middleton cited Jagot J’s comments in Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162 with approval:
“In assessing obviousness, it is necessary first to determine the nature of the claimed invention and the inventive step described in the Patent. This may involve ascertaining the “starting point” of the inventive step, sometimes described in terms of an existing problem for which the inventor found a solution. The obviousness of the invention as claimed is then assessed by reference to common general knowledge in Australia at the priority date.”
Starting point of the invention
30.The problem to be solved in the current case is to improve drug therapy treatments for schizophrenia patients. The person skilled in the art is a treating clinician (a psychiatrist).
Common General Knowledge
Clinical approach to treating schizophrenia
31.Both Professors Singh and Kulkarni acknowledged that schizophrenia was a complex disease and that individuals responded differently to drug therapy treatments. Treatment of first-time patients involves administering an antipsychotic to the patient as soon as possible and the choice of a drug tended to vary depending on the experience of the clinician. By January 2001, the typical (first generation) antipsychotics were gradually being phased out of clinical use as first line treatments and replaced with the more effective atypical (second generation) therapies. Both Professors Kulkarni and Singh identified Risperidone and Olanzapine as the preferred first drug therapy treatments in 2001 (because these drugs had fewer side effects and more rapid antipsychotic effects)[20]. Professor Singh also suggested Quetiapine as a possible option[21].
[20] Kulkarni#1 at [31] and Singh at [9.7]-[9.9]
[21] Singh at [9.7]-[9.9]
32.Professor Singh noted that certain patients do not respond well to their first line treatment either because their positive symptoms were not brought under control (or if the positive symptoms had been addressed, negative or cognitive symptoms persisted) or because the patients experienced unacceptable side effects. For such patients, he would have switched to a second atypical antipsychotic (second line treatment) or a third medication if the first and second treatments were unsuccessful. He referred to this approach as ‘switching therapy’. The selection of the second (and later) drugs is based on the patient’s response to the earlier treatments and the known clinical properties of the other available drug options. For example, if a patient is aggressive, the clinician might prescribe a sedating antipsychotic such as Olanzapine (rather than Risperidone).
33.Aripiprazole was identified as a potential new antipsychotic drug for the treatment of schizophrenia sometime in the 1990s. Both Professors Singh and Kulkarni were aware of the drug before 2001 which by then had been in worldwide phase 3 clinical trials (including Australia[22]). However the drug did not obtain ARTG marketing approval until 2003[23] and was therefore not an actual treatment option in Australia. As a consequence, the only actual clinical experience of the drugs in Australia was in the phase 3 (double-blind, controlled) trial environment. As the chief investigator for these trials in Victoria, the opponent’s expert (Professor Kulkarni) was able to provide some insight into her experience prior to 2001[24] but there is no real evidence which establishes (nor would it be expected) that this (inside) knowledge about aripiprazole was also part of the CGK[25].
[22] Kulkarni#4 at [4]-[7]
[23] De Bruyn’s evidence establishes that aripirazole had an ARTG start date of 21 May 2003
[24] Kulkarni#4 at [6]-[7]
[25] Kullkarni#4 at [4] suggests that the clinical trials prior to 2001 were used as forward marketing and recruitment tools for clinicians who were more likely to prescribe a drug with seen benefits. However there is no evidence from a clinician to confirm this was the case for aripiprazole.
Relevant art
34.The opponent relied on the following documents for the purposes of inventive step:
Saha, A.R et al (1999) “Safety and efficacy profile of aripiprazole, a novel antipsychotic” Schizophrenia Research 36(1-3): 295 (Abstract) published 22 March 1999 (‘Saha’)
Lieberman, J.A (1996) “Atypical antipsychotic drugs as a first line treatment of schizophrenia: a rationale and hypothesis” Journal of Clinical Psychiatry 57(Suppl. 1): 68-71 published 7 May 1996 (‘Lieberman’)
Saha
35.Saha is a short abstract published in 1999 by the applicant company which outlines results from their (worldwide) phase 3 clinical trials of aripiprazole. Saha discloses the results of a study in which acutely relapsing hospitalised schizophrenic patients were treated with fixed doses of aripiprazole of 2 mg, 10mg and 30 mg per day. In phase 2 trials of acutely relapsing hospitalised schizophrenic patients, it improved patient’s symptoms in each dimension (excitement, depression and cognitive function).
36.Saha notes that a unique feature of aripiprazole is its agonistic effect at presynaptic dopamine receptors and a postsynaptic dopamine D2 antagonistic effect. The phase 3 trials compared the efficacy of aripiprazole with haloperidol[26]. Saha also highlights a number of useful properties of the drug in particular noting its effectiveness in preventing weight gain and improving cognitive function compared to haloperidol. The abstract concludes that the drug is both safe and “impressively effective” and that it should be a substantial addition to the new generation antipsychotics.
[26] Kulkarni#1 at [44] and Kulkarni#4 at [4]
37.The opponent argued that Saha was part of the CGK but I disagree. While the article identifies the drug as having some promise, there is no evidence that the article (or the drug itself) would have been referred to as a “matter of course”[27]. In addition, the journal is not the type of general publication that a skilled worker would routinely refer to solve a particular problem[28].
[27] As per Emmett J in ICI Chemicals & Polymers Ltd v Lubrizol Corp 45 IPR 577 (at [112])
[28] As per Full court decision in Aktiebolaget Hassle and Astra Pharmaceuticals Pty Ltd v Alphapharm Pty Ltd 51 IPR 375; [2000] FCA 1303 (at [73])
38.Nevertheless I accept the skilled worker would have ascertained, understood and regarded the document as relevant before the priority date. Both experts acknowledged that they were aware of the drug aripiprazole prior to the priority date. The applicant’s expert (Professor Singh) mentioned he became aware of the drug in the 1990s because of a medical conference[29]. The article is an abstract presented from such a medical conference and published in the journal “Schizophrenia Research” (a high profile medical journal specifically focussed on schizophrenia research). The opponent’s expert (Professor Kulkarni) also acknowledged that she would have regularly consulted this journal prior to the priority date[30]. In addition, because the article relates to a promisingly new drug treatment for schizophrenia, it would have been of immediate interest to the skilled worker who would also have understood it and regarded it as relevant. Therefore, my view is that this document is part of the prior art base for inventive step under section 7(3).
[29] Singh at [9.10]
[30]Kulkarni#2 at [6]
Federal Court’s preliminary view on the relevance of Saha in the grandparent patent
39.In his primary interlocutory judgement[31], Yates J considered whether the ‘Gillette defence’[32] was applicable. As part of that consideration, he provided some preliminary views on the asserted invalidity of the grandparent (’772) application based on the Saha citation. Neither party suggested that this preliminary view was binding on the Commissioner but nonetheless it is important background to the current case and could be highly relevant given that the citation is the same and the claims under consideration are very similar. As a consequence, I need to discuss this related decision in some detail.
[31] Otsuka v Generic Health (2012) 291 ALR 763, [2012] FCA 239
[32] As explained in Otsuka v Generic Health (2012) 291 ALR 763 at [113], the “Gillette defence” is where an alleged infringer establishes that its impugned acts were merely those disclosed in a publication which can be relied upon to establish invalidity
40.The Court decision sets out the relevant ‘772 claim (claim 7) as follows:
A method of treating a patient suffering disorders of the central nervous system associated with the 5-HT1A receptor sub-type, which disorder
(i)Selected from cognitive impairment caused by treatment-resistant schizophrenia, cognitive impairment caused by inveterate schizophrenia or cognitive impairment caused by chronic schizophrenia, and
(ii)Fails [to respond] to antipsychotic drugs selected from chlorpromazine, haloperidol, sulpiride, fluphenazine, perphenazine, thioridazine, pimozide, zotepine, risperidone, olanzapine, quetiapine or amisulpride
Comprising administering a therapeutically effective amount of a carbostyril compound of [a particular formula] or a pharmaceutically acceptable salt, or solvate thereof.
41.The difference between the methods defined in the grandparent (‘772) and current claims is that the earlier claims are limited to treatment of a patient group with cognitive impairment where the current claims include patients with or without cognitive impairment.
42.In the Court matter, the applicant had argued that Saha did not disclose the use of aripiprazole in the treatment of cognitive impairment disorders of schizophrenia which had failed to respond to certain anti-psychotic drugs. The judge accepted that these claims were novel and this has not been raised as a ground of opposition in the current case. While the judge did not specifically address inventive step, his discussion on manner of manufacture (threshold of invention) is nevertheless relevant to this ground.
43.The respondent had argued that the claims were directed to the use of a known formulation for treatment of a known symptom. Their view was that the realisation that aripiprazole could assist cognitive impairment was a ‘mere discovery’ about the inherent effect of a known compound for a known condition[33].
[33] Otsuka v Generic Health (2012) 291 ALR 763 at [135]
44.In rejecting this argument, Yates J noted at [136] that:
“My own reading of the complete specification of the ‘772 patent suggests that those submissions may be advanced at a level of generality that might mask the importance to be attached to the teaching concerning the action of aripiprazole at the 5-HT1A receptor and the implications that that action has for the treatment of patients who suffer from cognitive impairment caused by treatment-resistant, inveterate or chronic schizophrenia and who have failed to respond to the administration of other antipsychotic drugs. I am satisfied that at least, prima facie claim 7 of the ‘772 patent claims patentable subject matter on the face of the specification.”
45.In his conclusion, Yates J found there was no prima facie case of invalidity on the grandparent claims. However in expressing this view, he noted that this was not a final determination as the respondent’s case could be considerably more developed at the time of trial.
Saha
46.The applicant argued that Saha could be distinguished from the current claims because their results were obtained from acutely relapsing schizophrenic patients rather than the chronic schizophrenic patients defined in the current claims[34]. I note that the focus of treatment for the 2 types of patients was different in clinical practice because of the different time periods involved in the illness. For (short-term) acute patients, the focus was to get the positive symptoms under control. For (longer-term) chronic patients, the emphasis was maintaining control of the positive symptoms as well as trying to counter the negative and cognitive symptoms[35].
[34] Opponent’s submissions at [51]-[52]
[35] Opponent’s submissions at [21]
47.However despite this, the symptoms in the two disorders are the same and a treatment which targets these symptoms would be expected to work in both. In fact, phase 3 (clinical) trials are designed to test the efficacy of drug treatment for both forms of schizophrenia. Acutely relapsing patients are generally used for such trials because they have no residual anti-psychotic drugs in their system (which might affect the clinical results). Saha clearly understood this because they studied negative and cognitive functions which are critical for chronic (but not acute) schizophrenia.
48.As a consequence, I do not believe that there is invention in treating chronic schizophrenia compared with the acute schizophrenia of the prior art. This means that the key difference between Saha and the current claims is that Saha doesn’t specifically recommend aripiprazole as a second line treatment when the patient is treatment resistant to certain other drugs.
49.I note that aripiprazole’s clinical outcomes are not dependent on its use as a first or second line treatment or whether the patient is already resistant to another drug. As Professor Kulkarni noted, prior treatment with another drug does not modify the pathophysiology of the condition and would not affect an individual’s (later) response to aripiprazole[36]. At first glance, the decision to use aripiprazole as either a first or second line treatment therefore appears to be a simple matter of choice from a limited range of known options (the ‘armoury of options’).
[36] Kulkarni#4 at [46]
50.The applicant argued that the skilled worker would not have used aripiprazole as a treatment option at the priority date because the drug did not have marketing approval until 2003. However, as noted by the Full Court in Novozymes v Danisco [2013] FCAFC 6 @ [177]), “it is not the doing of [an act], nor even the ability to do it, that amounts to anticipation: it is the content of the information. If the information contains directions which if carried out, would constitute an infringement of the patent in suit, the invention under the latter is not novel”. While the Novozymes discussion concerned novelty, the same comments are equally applicable to inventive step which under section 7(3) is also based on prior art information.
51.In the current case, Saha’s results are clearly very promising and the drug being in phase 3 clinical trials is strong evidence of its efficacy (especially for a condition as serious as schizophrenia). Based on the ‘impressively effective’ results in Saha, the skilled worker is directed to use aripipazole as a specific treatment option for schizophrenia with the reasonable expectation that it would work even if the drug was not actually commercially available at that time.
52.Saha doesn’t teach (and the skilled worker wouldn’t otherwise know) that aripirazole was a partial agonist of the 5-HT1A receptor. However (as both parties acknowledged), psychiatrists diagnose and treat schizophrenia patients based on their presenting symptoms without fully understanding how a particular drug works. Thus, unless there was a practical benefit in determining a drug’s underlying mechanism of action, this knowledge could be considered a ‘mere discovery’ (rather than an invention).
53.Yates J alludes to this in his discussion on manner of manufacture when he commented on the importance of the 5-HT1A receptor agonist activity and the implications that that this [mechanism of] action has in in the treatment of patients who suffer from cognitive impairment caused by treatment-resistant schizophrenia. This link is less relevant in this case because firstly the opposed claims are not limited to the treatment of cognitive impairment and secondly the judge was not specifically considering the Saha citation. Nonetheless, the key inventive step question is very similar – Is there an advantage taken from the discovery of aripiprazole’s underlying mechanism of action which provides an inventive step over and above the teaching in Saha?
54.The specification notes that the 5-HT1A receptor is an important receptor linked to a range of neurological disorders including depression and Parkinson’s disease[37] where the symptoms are similar to the negative and cognitive dimensions of schizophrenia. Antipsychotic drugs having 5-HT1A agonist activity (in addition to their D2 blocking activity) were also uncommon (or “surprising”) at the priority date. In fact, the only other available antipsychotic drug at that time known to have this property[38] was the benchmark drug clozapine which was (and still is) the most effective available schizophrenic treatment.
[37] Opposed specification at page 4, lines 13 et seq
[38] A 2008 (post-priority date) Review [Meltzer and Sumiyoshi: Does stimulation of the 5-HT1A receptors improve cognition in schizophrenia? Behavioural Brain Research 195 (2009) 98-102 [BSS-5] suggests that olanzapine, perospirone, quetiapine, risperidone and ziprasidone have now been shown to be direct or indirect 5-HT1A agonists (see abstract)
55.The specification considered that the therapeutic efficacy of clozapine was related to its 5-HT1A agonist activity[39]. There is no evidence in this opposition to suggest that aripiprazole is as effective as clozapine (or more effective than other available drugs) as a first line treatment. Despite this, aripiprazole’s activity at a key receptor (5-HT1A) might allow aripiprazole to successfully treat certain patients where another drug (with a different profile) had failed[40]. In other words, the knowledge of the underlying mechanism of the drug increases the possibility of success for certain patients who had failed to respond to other treatments.
[39] Opposed specification at page 8, lines 22-25
[40] Singh at [9.12]-[9.13]
56.The clinician normally uses a ‘trial and error’ to work out which treatment option to use for an individual patient. There are no predictors for individual drug response and apart from their clinical experience, the skilled worker has no guidance as to which drugs should be tried and in which order. Evidence referred to by Yates J in the interlocutory matter suggests that this could be a significant problem because the response rate to medication diminishes with the more drugs that are tried[41]. In practice, this means that there are a limited number of different drug treatments that can be used before prescribing the benchmark drug clozapine (with all its unwanted side effects). In this context, understanding that aripiprazole has a similar mechanism of action to clozapine allows the clinician to better target their treatment choices with an increased probability of success.
[41] Otsuka v Generic Health 291 ALR 763 at [38]
57.I accept that it is not possible to predict whether any given patient will respond to treatment with aripiprazole[42] nor is there any suggestion that this drug is a ‘wonder drug’ that works for all patients. However this is an unpredictable field with a high treatment failure rate[43]. Increasing the prospect of success even for a certain proportion of patients would still improve clinical outcomes in the population as a whole even if success for an individual patient could not be predicted. This would motivate the skilled worker to choose aripiprazole over other options and provide a practical benefit to the knowledge of the mechanism of action beyond ‘mere discovery’.
[42] Kulkarni#4 at [14]-[15], also note Yates J comments in Otsuka v Generic Health 291 ALR 763 at [38]
[43] Lieberman estimates that 30-60% of patients have only a partial or no therapeutic response to treatment
58.Professor Kulkarni suggested that despite the lack of teaching of its 5-HT1A agonist activity, aripiprazole would have still been considered a ‘leading candidate’ in the treatment of chronic schizophrenia based on the Saha disclosure. She notes that Saha mentions aripiprazole’s pre- and post-synaptic activity at dopamine receptors which would lead to less unwanted extrapyramidal side effects. The article also discloses that the drug had no effect on prolactin or weight gain. According to Professor Kulkarni, this would have motivated her to use this drug in treatment resistant schizophrenic patients especially if these relevant side effects were a particular concern in these patients[44].
[44] Kulkarni#4 at [8] and [17]
59.However I am not convinced that the skilled worker reading Saha at the priority date would necessarily have come to the same conclusion without the benefit of hindsight. As Professor Kulkarni conceded, the Saha experiments had a number of deficiencies (eg: the duration was too short, it was not conducted by an independent group and the statistical method used (LOCF) was not ideal)[45]. As a highly trained scientific professional, the skilled worker is unlikely to accept broad assertions about a drug from the actual manufacturer without proper clinical data.
[45]Kulkarni#2 at [7]
60.Saha also only compared their drug to haloperidol. This is a typical anti-psychotic drug[46] which would not be expected to control the negative and cognition dimensions in schizophrenia and neither expert said they would have prescribed haloperidol in practice as a first line treatment at the priority date[47]. While Saha concludes that the drug improves ‘cognitive function’ compared to haloperidol, it is not clear how significant this improvement was or even whether it was an improvement in ‘cognitive impairment’ (ie: cognitive dysfunction or cognitive disturbances)[48] as opposed to other symptoms associated with ‘cognition’ (disorientation, poor attention, difficulties in judgement and insight and difficulties in abstract thinking)[49].
[46] See for example Meltzer and Sumiyoshi: Does stimulation of the 5-HT1A receptors improve cognition in schizophrenia? Behavioural Brain Research 195 (2009) 98-102 at page 98 column 2 [BSS-5]
[47] See discussion above at [31]
[48] Opposed specification at page 7, lines 10-13
[49] Singh at [10.9(c)]
61.In my view, without proper clinical data (or some knowledge of the underlying mechanism of the drug), the skilled worker would not realise that aripiprazole was particularly effective in improving cognitive impairment or in treating treatment-resistant schizophrenia from the Saha dislosure. At best, they would have understood that there could be a promising new atypical antipsychotic drug in phase 3 trials rather than the ‘leading candidate’ at the priority date as Professor Kulkarni argued.
62.As a consequence, I am not convinced that the skilled worker would have been directly led to use aripiprazole as a second line treatment from the limited disclosure in Saha. In my view, there is an inventive (selective) advantage in recognising that aripiprazole has 5-HT1A agonist activity because of its potential to improve clinical outcomes in the population of treatment-resistant schizophrenics. As each of the claims is limited by this feature, they all contain an inventive step in light of Saha.
Lieberman
63.The second document relied on by the opponent was an article by Professor Lieberman who both parties acknowledged to be a world expert on schizophrenia, Both experts also agreed that his article would have been widely read and part of the CGK at the priority date[50]. Lieberman provides some useful background about treatment options available for schizophrenia prior to 2001. In particular, he notes that 30-60% of patients have only a partial or no therapeutic response to treatment and acknowledged the need for better drug treatments. He also showed an awareness of atypical anti-psychotic drugs currently under development.
[50] Singh at [10.10]
64.Lieberman notes that the first atypical antipsychotic (clozapine) had set a new therapeutic standard but had limiting side effects. However other atypical drugs were becoming available or under development. At that time risperidone was available and olanzapine, sertindole, quetiapine and ziprasidone were ‘imminent prospects’. There were also a number of putative atypical antipsychotic drugs being trialled including the drug OPC-14597 (which was later identified as aripiprazole)[51].
[51] Opposed specification page 2, lines 7-8
65.Lieberman notes there had been a tendency to only use atypical anti-psychotic drugs with the most severely-ill and treatment-resistant patients. He suggested that because these drugs had superior efficacy and reduced side effects compared to the typical anti-psychotics, they should be the drugs of choice as a first line treatment arguing that early effective intervention might be able to prevent the progression of schizophrenia and reduce the deterioration and persistent morbidity associated with the disease.
66.The key difference between Lieberman and claim 1 is the use of aripiprazole to treat treatment-resistant schizophrenia as a first or second line treatment. While Lieberman lists aripiprazole as the potential drug OPC-14597, there was no evidence that a skilled worker would have recognised this at the priority date or that they knew how effective the drug was likely to be. As a consequence, there is no motivation in Lieberman to use aripirazole in either the first or second line treatment of schizophrenia. Therefore this document does not deprive any of the claims of an inventive step.
Section 40
67.The opponent raised some sufficiency and clarity issues based on the applicant’s construction of claim 1. These issues disappear once the applicant’s construction was rejected.
68.The remaining issue relates to claim 2 which the opponent argued was unclear because it was completely redundant on claim 1. Claim 2 simply restates all the listed disorders in claim 1 (ie: the use of claim 1 wherein the disorder is treatment resistant schizophrenia, inveterate schizophrenia or chronic schizophrenia) and I accept this doesn’t change the scope of claim 1.
69.The applicant argued that because claims have to be construed against redundancy, the claim necessarily imports the feature ‘without cognitive impairment’ based on the feature ‘with cognitive impairment’ being present in claim 3. While this might have been the applicant’s intention, the feature is clearly not in the claim and no rule of claim construction allows it to be imported based on a subsequent claim. I therefore agree with the opponent that claim 2 is redundant on claim 1. Despite this problem, I have no difficulties in understanding claim 2 which on its own is still perfectly clear. The redundancy issue therefore does not create a clarity problem under section 40 which affects the validity of the claims.
Manner of Manufacture
70.I note that there is a potential manner of manufacture objection because the nature of the invention relates to the ‘discovery’ of the mechanism of action of aripiprazole. However this argument is the same as the inventive step argument which was discussed in detail above. For the same reasons as inventive step, the claims do not relate to a ‘mere discovery” and therefore define a manner of manufacture.
Conclusion
71.All the claims are inventive in light of the citations raised by the opponent. There are also no objections under manner of manufacture or section 40. In my view, the case is in order for sealing. Absent an appeal being filed within 60 days of this decision, I direct the application proceed to sealing.
Costs
72.The opposition is unsuccessful. I therefore award costs against the opponent in accordance with schedule 8.
Karen Ayers
Delegate of the Commissioner of Patents
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