Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (No 4)

[2015] FCA 634

FEDERAL COURT OF AUSTRALIA

Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (No 4) [2015] FCA 634

Citation:

Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (No 4) [2015] FCA 634

Parties:

OTSUKA PHARMACEUTICAL CO., LTD and BRISTOL-MYERS SQUIBB COMPANY v GENERIC HEALTH PTY LTD;

GENERIC HEALTH PTY LTD v OTSUKA PHARMACEUTICAL CO., LTD and BRISTOL-MYERS SQUIBB COMPANY 

File number(s):

NSD 121 of 2012

Judge(s):

YATES J

Date of judgment:

29 June 2015

Catchwords:

PATENTS – standard patent for the use of a carbostyril compound for the production of a medicament having certain features and a method for treating a patient involving the use of the carbostyril compound – where the carbostyril compound (aripiprazole) is claimed to be effective in treating disorders of the central nervous system associated with the 5‑HT_1A receptor subtype – treatment of cognitive impairment in schizophrenia

PATENTS – Swiss type claims – discussion of derivation of this form of claim – whether Swiss type claim should be characterised as a method or process

PATENTS – the person skilled in the art considered as a team – whether the team can be differently constituted depending on the patent question involved

PATENTS – infringement – Swiss type claim – whether claim can be infringed by exploitation in the patent area of a medicament manufactured outside the patent area – discussion of Saccharin doctrine

PATENTS – infringement – application of s 117(2)(b) of the Patents Act 1900 (Cth) to a method of treating the human body with a pharmaceutical product

PATENTS – validity – novelty

PATENTS – validity – manner of new manufacture – whether an invention is disclosed on the face of the specification

PATENTS – validity – inventive step – whether invention as claimed is obvious – whether person skilled in the art could be reasonably expected to have ascertained, understood and regarded as relevant certain prior art documents – whether certain sources of information would have been combined by the person skilled in the art  

PATENTS – validity – utility

PATENTS – validity – sufficiency and best method

PATENTS – validity – clarity and definition

PATENTS – validity – fair basis

PATENTS – standing to sue for infringement – whether second applicant an exclusive licensee

Legislation:

Act revising the Convention on the Grant of European Patents of 29 November 2000 (entered into force on 13 December 2007)
Convention on the Grant of European Patents, opened for signature 5 October 1973, 1065 UNTS 199 (entered into force 7 October 1977)
Patents Act 1990 (Cth) ss 7, 18, 40, 117
Patents Act 1977 (UK)

Cases cited:

ABBOTT RESPIRATORY/Dosage Regime (G02/08) [2010] EPOR 26
Actavis UK Ltd v Janssen Pharmaceutica NV [2008] FSR 35
Actavis UK Ltd v Merck & Co Inc [2009] 1 WLR 1186
Aktiebolaget Hässle v Alphapharm Pty Limited (2002) 212 CLR 411
Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618
AMERICAN CYANAMID/Melamine Derivatives (T279/93) [1999] EPOR 88
Apotex Pty Ltd v Sanofi-Aventis Australia Pty Ltd (No 2) (2012) 204 FCR 494
Apotex Pty Ltd v Sanofi-Aventis Australia Pty Limited (2013) 304 ALR 1
AstraZeneca AB v Apotex Pty Ltd (2014) 226 FCR 324
Bristol-Myers Squibb v Baker Norton Pharmaceuticals Inc [1999] RPC 253
Bristol-Myers Squibb Co v Apotex Pty Ltd (2015) 109 IPR 390
Bristol-Myers Squibb Company v Apotex Pty Ltd (No 5) (2013) 104 IPR 23
Bristol-Myers Squibb Company v FH Faulding & Company Ltd (2000) 97 FCR 524
British Thomson-Houston Company Ltd v Corona Lamp Works Ltd (1921) 39 RPC 49
Decor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385
DOW/Sequestering Agent (T958/90) [1994] EPOR 1
Dura-Post (Aust) Pty Ltd v Delnorth Pty Ltd (2009) 177 FCR 239
EISAI/Second Medical Indication (G05/83) [1979-85] EPOR B241
Elmslie v Boursier (1869) LR 9 Eq 217
Flexible Steel Lacing Company v Beltreco Ltd (2000) 49 IPR 331
Flower Oxidizing Company Ltd v Carr & Company Ltd (1908) 25 RPC 428
General Tire & Rubber Company v Firestone Tyre &  Rubber Company Ltd [1972] RPC 457
Generic Health Pty Ltd v Otsuka Pharmaceutical Co Ltd (2013) 296 ALR 50
John Wyeth & Brother Ltd’s Application; Schering AG’s Application [1985] RPC 545
Kinabalu Investments Pty Ltd v Barron & Rawson Pty Ltd [2008] FCAFC 178
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173
Merck & Co Inc v Arrow Pharmaceuticals Ltd (2006) 154 FCR 31
Meyers Taylor Pty Limited v Vicarr Industries Limited (1977) 137 CLR 228
MOBIL/Friction Reducing Additive (G02/88) [1990] EPOR 73
National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252
Northern Territory v Collins (2008) 235 CLR 619
Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157
Otsuka Pharmaceutical Co Ltd v Generic Health Pty Ltd (2012) 291 ALR 763
Pharmaceutical Management Agency Ltd v Commissioner of Patents [2000] 2 NZLR 529
Raychem Corp’s Patents [1998] RPC 31
Root Quality Pty Ltd v Root Control Technologies Pty Ltd (2000) 177 ALR 231
Saccharin Corporation Ltd v Anglo-Continental Works Ltd (1900) 17 RPC 307
Sanofi-Aventis Australia Pty Ltd v Apotex Pty Ltd (No 3) (2011) 196 FCR 1
Sopharma S.A’s Application [1983] RPC 195
Takeda Chemical Industries Ltd’s SPC Applications (No.3) [2004] RPC 3
Von Heyden v Neustadt (1880) 14 Ch D 230
Wright v Hitchcock (1870) LR 5 Ex 37

Legal Advice from the Swiss Federal Intellectual Property Office dated 30 May 1984 [1984] OJ EPO 581  

Date of hearing:

24-28 March 2014, 14, 16-17 April 2014

Place:

Sydney

Division:

GENERAL DIVISION

Category:

Catchwords

Number of paragraphs:

500

Counsel for the Applicants:

Mr B Caine QC with Ms C Cochrane

Solicitor for the Applicants:

Allens

Counsel for the Respondent:

Mr A Ryan SC with Mr A Fox

Solicitor for the Respondent:

Bird & Bird

Table of Corrections
10 July 2015	On the first page of the cover sheet in the heading “Parties”, the parties to the Notice of Cross-Claim filed in this matter on 10 February 2012 have been added
10 July 2015	On the orders page and the first page of the reasons for judgment, the parties to the Notice of Cross-Claim filed in this matter on 10 February 2012 have been added

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION	NSD 121 of 2012

BETWEEN:

OTSUKA PHARMACEUTICAL CO., LTD
First Applicant

BRISTOL-MYERS SQUIBB COMPANY
Second Applicant

AND:

GENERIC HEALTH PTY LTD
Respondent

AND BETWEEN:

GENERIC HEALTH PTY LTD
Cross-Claimant

AND:

OTSUKA PHARMACEUTICAL CO., LTD
First Cross-Respondent

BRISTOL-MYERS SQUIBB COMPANY
Second Cross-Respondent

JUDGE:	YATES J
DATE OF ORDER:	29 JUNE 2015
WHERE MADE:	SYDNEY

THE COURT ORDERS THAT:

1.The parties are to bring in draft orders giving effect to these reasons by 4.00 pm on 13 July 2015. 

2.If the parties are unable to agree on the question of costs, they are to provide short written submissions (not exceeding three pages) on that question, together with a draft of the order that is sought.

Note:Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

IN THE FEDERAL COURT OF AUSTRALIA
NEW SOUTH WALES DISTRICT REGISTRY
GENERAL DIVISION	NSD 121 of 2012

BETWEEN:

OTSUKA PHARMACEUTICAL CO., LTD
First Applicant

BRISTOL-MYERS SQUIBB COMPANY
Second Applicant

AND:

GENERIC HEALTH PTY LTD
Respondent

AND BETWEEN:

GENERIC HEALTH PTY LTD
Cross-Claimant

AND:

OTSUKA PHARMACEUTICAL CO., LTD
First Cross-Respondent

BRISTOL-MYERS SQUIBB COMPANY
Second Cross-Respondent

JUDGE:

YATES J

DATE:

29 JUNE 2015

PLACE:

SYDNEY

REASONS FOR JUDGMENT

INTRODUCTION........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......	[1]
THE WITNESSES........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[15]
BACKGROUND........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .	[27]
Schizophrenia and its symptoms........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[28]
Cognitive impairment and schizophrenia........ ........ ........ ........ ........ ........ ........ ........ ....	[33]
The course of the illness........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .	[40]
How is schizophrenia treated?........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......	[45]
The position at the priority date (29 January 2001)........ ........ ........ ........ ........ ........ ..	[57]
Neurotransmitters and receptors........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[64]
THE 772 PATENT........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[78]
Background........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[79]
The invention as summarised and described........ ........ ........ ........ ........ ........ ........ .......	[93]
Relevant claims........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .......	[96]
SWISS TYPE CLAIMS........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[100]
ISSUES OF CONSTRUCTION........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........	[122]
The person skilled in the art........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[123]
Disorders associated with the 5-HT1A receptor subtype........ ........ ........ ........ ........ .....	[130]
Cognitive impairment as a disorder caused by schizophrenia........ ........ ........ ........ ..	[149]
Failure to respond to antipsychotic drugs........ ........ ........ ........ ........ ........ ........ ........ ...	[157]
INFRINGEMENT........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......	[163]
Claim 1........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[163]
Claim 7........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[179]
Are the GH products staple commercial products?........ ........ ........ ........ ........ ........ ...	[182]
Reason to believe........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .	[192]
VALIDITY........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[250]
Introduction........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[250]
The prior art........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[252]
EP 141/US 528........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[252]
Serper........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[266]
Saha........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[273]
Petrie 1997........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[280]
Petrie 1998........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[285]
Keefe........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[288]
NOVELTY........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[293]
Introduction........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[293]
EP 141/US 528........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .	[308]
Serper........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ......	[330]
Saha........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .	[335]
MANNER OF NEW MANUFACTURE........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[351]
Introduction........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[351]
Consideration........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[355]
INVENTIVE STEP........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[371]
Introduction:  The respondent’s submissions........ ........ ........ ........ ........ ........ ........ ......	[371]
Introduction:  The applicants’ submissions........ ........ ........ ........ ........ ........ ........ ........ .	[389]
The requirements of s 7(3) in the present case........ ........ ........ ........ ........ ........ ........ ....	[399]
Are the requirements of s 7(3) satisfied in the present case?........ ........ ........ ........ .....	[409]
Is the invention as claimed obvious?........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[434]
Saha........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[438]
Serper/Keefe........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .	[455]
Petrie 1997........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[470]
Petrie 1998........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[479]
OTHER GROUNDS OF INVALIDITY........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[480]
Introduction........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[480]
Utility........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .......	[481]
Sufficiency and best method........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ..	[484]
Clarity and definition........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .....	[488]
Fair basis........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ .	[493]
EXCLUSIVE LICENCE........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ...	[499]
DISPOSITION........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ........ ....	[500]

INTRODUCTION

1. The first applicant, Otsuka Pharmaceutical Co., Ltd (Otsuka), is the patentee of Patent No. 2005201772, titled “Substituted carbostyril derivatives as 5‑HT_1A receptor subtype agonists” (the 772 patent). 

2. The 772 patent claims the use of a carbostyril compound (relevantly, aripiprazole) for the production of a medicament having certain features and a method for treating a patient involving, relevantly, the use of aripiprazole.

3. The complete application for the 772 patent was a divisional application of the complete application for Patent No. 2002226752, also titled “Substituted carbostyril derivatives as 5‑HT_1A receptor subtype agonists” (the 752 patent). 

4. The second applicant, Bristol-Myers Squibb Company (BMS), is a licensee of the 772 patent and the 752 patent.  It says that it is the “exclusive licensee” of each patent for the purposes of the Patents Act 1990 (Cth) (the Act).

5. The respondent is a pharmaceutical company that supplies generic pharmaceuticals and other products.  It has obtained registration of a number of aripiprazole products on the Australian Register of Therapeutic Goods (the ARTG).  These products are registered under either the ARIPIPRAZOLE GENERICHEALTH label or the ARIPIPRAZOLE GH label (respectively, the GENERICHEALTH products and the GH products). 

6. The GENERICHEALTH products are registered for:

   ·the treatment of schizophrenia including maintenance of clinical improvement during continuation therapy;

   ·the acute treatment of manic or mixed episodes associated with Bipolar I Disorder in adults in monotherapy and in combination with lithium or valproate; and

   ·maintenance treatment of manic or mixed episodes in Bipolar I Disorder in adults as monotherapy.

7. The GH products are registered for:

   ·the treatment of schizophrenia including maintenance of clinical improvement during continuation therapy. 

8. The applicants have alleged that, by engaging or threatening to engage in certain acts in respect of the GENERICHEALTH products and the GH products, the respondent has infringed or threatened to infringe claims 1 and 7 of the 772 patent.  The respondent has denied these allegations.  It has also challenged the validity of these claims.

9. The applicants have also alleged that, by engaging or threatening to engage in certain acts in respect of the GENERICHEALTH products and the GH products, the respondent has infringed or threatened to infringe claims 1, 2 and 3, and claims 8, 9 and 10, of the 752 patent.  The respondent has denied these allegations.  It has also challenged the validity of these claims.

10. At the outset, it is necessary to refer to two events that have changed the landscape of the case that falls for decision. 

11. The first is that, when opening its case, the respondent gave certain undertakings to the Court, without admissions of liability:  see Exhibit 3.    As a consequence, the applicants did not pursue their case in respect of the GENERICHEALTH products or their case on infringement of the 752 patent in relation to the GH products.  That left the applicants’ case on infringement of the 772 patent in respect of the GH products. I will return to discuss more fully the effect of those undertakings when considering that case.

12. The second is that, shortly before the commencement of closing submissions, the respondent advised the applicants that it no longer pursued its case for revocation of the relevant claims of the 752 patent.

1. Thus, by the time of closing submissions, the issues for determination were limited to the applicants’ case on infringement of claims 1 and 7 of the 772 patent, to the extent that that case concerned acts done or threatened to be done in respect of the GH products, and the respondent’s case on the invalidity of those claims.

2. For the reasons that follow, I am of the view that claims 1 and 7 of the 772 patent are invalid and should be revoked.  But for that finding, I would have found that the applicants’ final case in respect of the threatened infringement of claims 1 and 7 had been established.  However, only Otsuka has standing to sue for infringement.  BMS is not an exclusive licensee of the patent.

   THE WITNESSES

3. The applicants read affidavits made by the following expert witnesses:

   ·Bruce Sugriv Singh (19 January 2012, 29 October 2012, 8 March 2013 and 13 June 2013);

   ·Jonathan Phillips (13 June 2013); and

   ·Trevor Ronald Norman (2 November 2012; 5 March 2013 and 13 June 2013)

4. These witnesses were cross-examined.

5. Professor Singh is a consultant psychiatrist in private practice at The Melbourne Clinic and a senior consultant psychiatrist at the Royal Melbourne Hospital.  He was Deputy Dean of the Faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne, where he has been a Professor of Psychiatry since 1991.  He has been a Fellow of the Royal Australian and New Zealand College of Psychiatrists (RANZCP) since 1979.

6. Associate Professor Phillips is a consultant psychiatrist in private practice.  He is an Associate Professor at the University of New South Wales, the University of Adelaide and James Cook University.  He is a Fellow of the RANZCP and was President from 1998 to 2000.

7. Associate Professor Norman is an Associate Professor in the Department of Psychiatry at the University of Melbourne.  He was an Adjunct Professor in the School of Behavioural Sciences at La Trobe University and President of the International Society for the Investigation of Stress from 2002 to 2004.

8. The applicants read affidavits made by the following lay witnesses:

   ·Phillip John Kerr (8 February 2012); and

   ·Robert Dwyer McQuade (16 April 2013).

9. The respondent read affidavits made by the following expert witnesses:

   ·Patrick Dennistoun McGorry (2 November 2012, 2 March 2013, 12 June 2013 and 10 September 2013);

   ·Jeremy Francis O’Dea (17 October 2012, 31 October 2012, 2 November 2012, 5 March 2013, 12 June 2013 and 11 September 2013); and

   ·Iain Stewart McGregor (4 April 2013).

10. These witnesses were cross-examined.

11. Professor McGorry is a consultant psychiatrist and Professor of Youth Mental Health at the University of Melbourne.  He is an Executive Director of the Orygen Youth Health Research Centre (Orygen) and has been a Fellow of the RANZCP since 1986.

12. Dr O’Dea is a consultant psychiatrist in public and private practice and a Conjoint Lecturer in the School of Psychiatry at the University of New South Wales.  He has been a been a Fellow of the RANZCP since 1991. 

13. Professor McGregor is Professor of Pharmacology at the University of Sydney.  He is a Professorial Fellow of the Australian Research Council.

14. The respondent read affidavits made by the following lay witnesses:

    ·Elmo De Alwis (22 February 2012 and 5 March 2012); and

    ·Timothy Cameron Francis (22 February 2012).

    BACKGROUND

15. The parties provided an agreed primer of the medical and scientific background relevant to this case:  Administrative Exhibit 1.  The primer was prepared from the affidavit evidence given by the expert witnesses.  The following summary is based substantially on the primer. 

    Schizophrenia and its symptoms

16. Schizophrenia is a serious mental disorder affecting 1% of the population worldwide.  It generally comes on in early adulthood.  Its main features are disturbances in the ability to experience reality, a lack of capacity to engage with others in the outside world, and disturbances in thinking, behaviour and emotional responses.  The disorder may run a number of courses, but standard definitions of schizophrenia state that the symptoms must last for at least six months for the diagnosis to be made.  In the majority of cases, the condition is chronic.  The cause of schizophrenia is not known, but both genetic factors and environmental stressors operating prenatally and in childhood may play a part.

17. The symptoms of schizophrenia can be classified according to separate dimensions.  Positive symptoms and negative symptoms are two of those dimensions.  The positive symptoms include hallucinations (the perception of a sensory experience in the absence of a source), delusions (fixed false beliefs not shared by others), and disorganised speech.  Negative symptoms include blunting of emotional response, apathy, amotivation and poverty of thought.

18. The Positive and Negative Syndrome Scale (PANSS) is an internationally recognised medical scale used for measuring symptom severity in schizophrenia patients.  The PANSS Positive Subscale is used for measuring the positive symptom dimensions of schizophrenia.  The PANSS Negative Subscale is used for measuring the negative symptom dimensions of schizophrenia.  A reference to, for example, a “PANSS-Negative score” is a reference to a score on the PANSS Negative Subscale.

19. There appears to be universal recognition that the range of symptoms associated with schizophrenia can be categorized around positive symptoms and negative symptoms.  This certainly seems to have been the case historically.  However, since the 1990s, some have classified the symptoms of schizophrenia by reference to two additional dimensions, namely cognitive symptoms and mood symptoms (including, anxiety and depression).  Others have continued to treat cognitive impairment as co-related to the negative symptoms of schizophrenia: cognitive impairment tends to occur together with a patient’s negative symptoms.

20. The diagnosis of schizophrenia is made on the basis of the criteria set out in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM IV).  The diagnosis is made by conducting clinical interviews with the patient, with the aim of eliciting the recognised signs and symptoms of the disorder.  The diagnosis may also take into consideration information from collateral sources, such as information from the patient’s relatives and friends, police, and other health care professionals.  There are no independent diagnostic tests that would confirm a diagnosis of schizophrenia.  However, when a patient presents and is first diagnosed with the disorder, the patient is, by the current definition set out in DSM IV, inevitably suffering positive symptoms.

    Cognitive impairment and schizophrenia

21. Cognitive impairment is a term referable to a range of impaired higher cognitive functions.  These functions include problems with attention, long-term memory, and abstraction and planning.  These impairments are also referred to as cognitive defects and cognitive symptoms.

22. Cognitive impairment also occurs in other serious psychiatric disorders, such as severe mood disorders.  It is not, therefore, diagnostically specific to schizophrenia.  However, compared to other psychiatric disorders, the pattern of cognitive impairment in some schizophrenia patients may be somewhat different.

23. The main manifestations of cognitive symptoms of schizophrenia are disturbances in attention, memory and executive function (such as the ability to generate and implement plans).  A patient suffering from cognitive impairment will generally exhibit difficulty in thinking and in articulating thoughts.  These problems include slow speech and thinking, memory problems, problem-solving, rationalising, being able to handle different mental activities at once, poverty of thought, poverty of content of thought, and problems relating to others.  The term can also be used to cover problems with general thinking.

24. There is disagreement between the expert witnesses as to whether psychiatrists are able to measure and assess the response of cognitive impairment in schizophrenia to medication, and whether specific neuropsychological tests are used by psychiatrists in clinical practice to assess cognitive impairment in schizophrenia.

25. For example, Professor Singh gave evidence that the disturbances that manifest cognitive impairment in schizophrenia patients can be demonstrated by a range of neuropsychological tests, such as:

    ·the Wechsler Memory Scale (a standard test of visual and verbal memory);

    ·the Wisconsin Card Sorting Test (in which the subject is expected to follow instructions as to how a series of cards are to be sorted); and

    ·a full scale IQ test.

26. On the other hand, Dr O’Dea, for example, gave evidence, based on his experience, that formal neuropsychological tests are not routinely used by clinical psychiatrists to assess the response of a schizophrenia patient’s cognitive impairment symptoms and signs to antipsychotic drugs.  He said, for example, that, although the Wechsler Memory Scale is a well-respected, detailed psychometric test, it is usually administered by psychologists and not used by psychiatrists clinically to assess cognitive impairment in schizophrenia.  Indeed, he said that he was not aware of any psychiatrist who employs the Wechsler Memory Scale, the Wisconsin Card Sorting Test, or Standard IQ tests to assess cognition in schizophrenia.

27. The current view, as reflected in the literature, is that the majority of all patients with schizophrenia suffer from some degree of cognitive impairment.  In some cases, this impairment is identifiable when the patient first presents with the illness.  That said, in the early stages of the illness, cognitive impairment may be masked by the more florid positive symptoms of schizophrenia and become more evident and pronounced as the illness progresses and as the more florid positive symptoms and signs subside.  Cognitive impairment can fluctuate and present at any time through the course of the illness.

    The course of the illness

28. The course of schizophrenia can be very variable.  Generally speaking, a broad distinction is usually made between “acute” schizophrenia and “chronic” schizophrenia.  In addition, chronic schizophrenia includes a particularly severe form of schizophrenia known as “treatment-resistant” schizophrenia.  Professor McGorry gave evidence that chronic and treatment-resistant schizophrenia are descriptions of the duration and responsiveness to treatment of the same disorder, namely schizophrenia.  Chronic and treatment-resistant schizophrenia are terms that simply describe people with schizophrenia who have not made a full recovery.

29. Acute schizophrenia is schizophrenia that lasts for more than six months and then remits (meaning that the patient recovers).  Approximately 25% to 35% of patients who suffer from one or more episodes of schizophrenia will recover.  If acute schizophrenia is remitted, it may relapse from time to time.  Where a patient periodically recovers and relapses, that patient would not be seen as “deteriorating” but rather as experiencing intermittent episodes of acute schizophrenia.  Such a patient would be described as suffering from “recurring acute” schizophrenia or “intermittent” schizophrenia.  Recovery from such a condition may occur even after a number of years.

30. Chronic schizophrenia is schizophrenia which lasts significantly longer than six months and usually for many years.  A patient suffering from chronic schizophrenia may have his or her positive symptoms under control, but the negative symptoms persist, and the illness has not been eliminated.  Generally speaking, the symptoms of chronic schizophrenia are the negative symptoms and cognitive impairment, but there may also be a relapse in positive symptoms from time to time.  The nature and extent of the residual symptoms and/or signs of schizophrenia vary widely between patients.  Chronic schizophrenia is the outcome for the majority of those who suffer from the illness.

31. Treatment-resistant schizophrenia (sometimes referred to as treatment-refractory schizophrenia) is a particular form of chronic schizophrenia.  Treatment-resistant schizophrenia is schizophrenia in which the patient’s positive symptoms, in addition to negative and cognitive symptoms, are unresponsive to antipsychotic medication.  Of all patients suffering from schizophrenia, 20% are partially unresponsive and 5% are totally unresponsive to antipsychotic medication so far as their positive symptoms are concerned.  The key to a diagnosis of treatment-resistant schizophrenia is the non-remission of positive symptoms.

32. Treatment-resistant schizophrenia is defined in the RANZCP Clinical Practice Guidelines (the RANZCP guidelines) as schizophrenia in which there have been two six to eight week trials of two separate antipsychotics, where the patient’s positive symptoms do not respond with full remission to those drugs.

    How is schizophrenia treated?

33. Schizophrenia is treated with antipsychotic medications described as being either “typical” (also known as “first generation”) antipsychotics, and “atypical” (also known as “second generation”) antipsychotics.

34. Typical antipsychotics were developed in the 1950s and 1960s.  They include: chlorpromazine; haloperidol; sulpiride; fluphenazine; perphenazine; thiroidazine; pimozide; and, zotepine.  However, sulpiride, perphenazine, thiroidazine, pimozide and zotepine were never available in Australia or, if originally available, are no longer available for prescription or no longer prescribed in practice.

35. Atypical antipsychotics block serotonin as well as dopamine receptors.  They are also known as “SDAs” (serotonin dopamine antagonists).  Atypical antipsychotics include: risperidone; olanzapine; quetiapine; and, amisulpride.

36. Atypical antipsychotics have fewer side effects than typical antipsychotics, particularly in terms of causing movement disorders in the form of unwanted and uncontrolled movements of arms, legs and facial muscles (such as twitching, restlessness and grimacing).  Agents, known as anticholinergics, are often used with typical antipsychotics in order to control these movement disorders.

37. Currently, in Australia, atypical antipsychotics are more widely used than typical antipsychotics.  The most widely used atypical antipsychotics are: olanzapine; risperidone; and, quetiapine.  It would now be very rare for a new patient presenting with schizophrenia to be commenced on a typical antipsychotic.  This has been the case since the mid to late 1990s.

38. The treatment of schizophrenia with antipsychotic medications is complemented by:

    ·case management (active involvement of mental health staff with individual patients);

    ·assertive community treatment (assertively following up patients in the community by visiting them);

    ·cognitive behavioural therapy, cognitive remediation and various other psychotherapies (which teach patients psychological techniques to manage their symptoms);

    ·rehabilitation social skills therapies (retraining people in social skills);

    ·vocational rehabilitation (retraining people for work); and

    ·supportive psychotherapy.

39. Certain patients may not respond well to a particular medication that is first prescribed.  They may also experience unacceptable side effects (such as movement side effects).  It is common, in clinical practice, to then try prescribing a different medication for those patients.  This change to a different medication is known as “switching”.

40. Switching antipsychotics is done in an effort to optimise response.  It can lead to a worsening, as well as an improvement, of symptoms due to non-response or delayed response to the new drug.  Other problems can occur with the adverse effects of the medication being enhanced.

41. The patient’s response rate diminishes with the more drugs that are tried.  Thus, the chance of responding to the second or third antipsychotic drug is much less than responding to the first drug.

42. Practising psychiatrists tend to distinguish between two types of treatment for schizophrenia.  The first is “acute” treatment, in which the emphasis is placed on getting the patient’s positive symptoms under control.  The second is longer-term treatment, in which the aims are to maintain control of the positive symptoms and to try to counter the negative symptoms and cognitive impairment.

43. Acute treatment involves low dose atypical antipsychotic medication and psychosocial interventions.  The psychosocial interventions (interventions involving social or psychological interventions or blends of these) become more central as the patient recovers from the acute phase of the illness.

44. The RANZCP guidelines state that switching is advised for patients “in whom there are persistent positive or negative symptoms, or who are experiencing distressing side-effects.”  The guidelines emphasise that there is a need to try clozapine early in the treatment-resistant stage, where there has been “the failure of full remission of positive symptoms or the lack of satisfactory clinical improvement despite sequential use of recommended doses of two or more antipsychotic medications for 6-8 weeks.”  In other words, there is recommendation in the guidelines to use clozapine when third line treatment is required (ie when two previous drug treatments have been used).

    The position at the priority date (29 January 2001)

45. The prescription of antipsychotic medications was the cornerstone of the treatment of schizophrenia.  An antipsychotic was used to begin the treatment of a patient presenting in the acute phase of schizophrenia, and was used to maintain control of the positive symptoms of schizophrenia during the period of recovery (known as “continuation therapy”).  The use of antipsychotic medicines in this way had been in practice since the 1950s.  Antipsychotic medications were prescribed in the hope that they might treat a whole range of symptoms—positive, negative and cognitive.

46. Switching to try different antipsychotics, where the response of the patient’s positive symptoms to his or her current medication was not satisfactory, was common.  Switching to improve the patient’s cognitive symptoms associated with schizophrenia was also practised.  If the patient’s cognitive impairment improved but there were other factors at play (such as extrapyramidal or metabolic issues, or weight gain), there could be a reason to switch from one antipsychotic to another.

47. The atypical antipsychotic medications available in Australia (and the time at which they became available) were:  risperidone (1993); clozapine (1994); olanzapine (1996); quetiapine (2000); and amisulpride (2000).  Depot preparations of risperidone and olanzapine, and further atypical antipsychotics (aripiprazole, ziprasidone and asenapine), became available in Australia after that time.

48. There were no blood tests or other tests that could identify which antipsychotic would be the most effective to treat a particular patient with schizophrenia.  It was therefore a process of trial and error to discover the most effective antipsychotic to use to treat the individual schizophrenia patient.

49. By the mid to late 1990s and early 2000s, there was an increased recognition among researchers and clinicians, as well as in the academic literature, that cognitive impairment, at least in established schizophrenia, was a key correlate of vocational and functional impairment.  From about the late 1990s/early 2000s, there was an emphasis in the research community to find drug and psychosocial treatments to assist with remediation of cognitive impairment.  A program—called “Measurement and Treatment Research to Improve Cognition in Schizophrenia” (MATRICS)—was commenced in 2003.  It was initiated by the National Institute of Mental Health (NIMH) in the United States of America in order to identify and remedy barriers to the development and evaluation of drugs targeting the treatment of cognitive impairment in schizophrenia.  A contract was awarded to the University of California, Los Angeles and a number of other centres to develop the MATRICS battery (ie a collection of tests) and to conduct research in neurocognition and interventions to ameliorate cognitive deficits.

1. At the priority date, there was no clear consensus among psychiatrists as to:

   ·how to best conceptualise and measure cognitive impairment in schizophrenia; and

   ·whether cognitive impairment could be effectively treated with the presently available antipsychotic medications. 

2. Further, at the priority date, there was significant overlap between the negative and cognitive symptoms of schizophrenia.  They were not treated as two distinctly different domains in clinical practice.

   Neurotransmitters and receptors

3. In humans and other species, the transmission of nerve impulses in the brain and peripheral nervous system takes place by means of specific chemical agents called neurotransmitters.  Transmission within the peripheral nervous system is important not only for everyday processes without which an organism cannot survive (such as breathing, heartbeat, movement and so on), but also for functions such as thinking (cognition) and feeling (emotion).

4. Neurotransmission is the process by which neurotransmitters transmit signals (electrical impulses) from one neuron to the next.  This takes place at a synapse, where two neurons are in close proximity to, but do not touch, one another.  Neurotransmission usually occurs when an electrical impulse is initiated in a neuron—the pre-synaptic neuron.  The impulse arrives at the nerve terminal and causes the release of neurotransmitters.  The neurotransmitters bind with receptors on a post-synaptic neuron.  This may cause changes to the electrical charge contained by the post-synaptic neuron or may activate certain complex second messenger systems.  Neurotransmission takes place only in one direction: from the pre-synaptic cell to the post-synaptic cell.

5. A receptor is a protein molecule consisting of chains of amino acids.  Typically, these chains comprise 500 to 700 amino acids connected in a specific order to make unique molecules.  Such receptors are located partially within neuronal cell membranes and generally consist of three parts. 

6. The first part is an extra-cellular portion which protrudes above the cell membrane, such that it may receive signals from nearby cells. 

7. The second part is a transmembrane-spanning domain located within the cell membrane, arranged as a series of helical shapes which give the receptor its shape.  For some receptors, a neurotransmitter will act as a ligand at this part of the receptor. The term “ligand” refers to a molecule that will bind to a receptor to induce a conformational change (ie a change in shape) and bring about an alteration in the function of the receptor.  Neurotransmitters and hormones are endogenous ligands (ie they are present in the body).  Drugs are exogenous ligands (ie they are introduced to the body).

8. The third part is an intracellular domain which interacts with intracellular elements to produce changes in second messenger systems.

9. Several receptor types may be found within a cell.  Each type will be coupled to a particular biochemical pathway.  The various receptors recognise and only bind with certain ligands.  The binding of a selective ligand to its receptor either activates or inhibits a specific biochemical pathway. 

10. An agonist is a drug that mimics the effects of an endogenous neurotransmitter by bringing about a similar conformational change—and thus a similar biological response—in the receptor as that brought about by the endogenous ligand. 

11. An antagonist is a drug that binds to the receptor but does not bring about a biological response.  Its effect is to block the action of the endogenous ligand (neurotransmitter).

12. The differences in efficacy of agonists and antagonists at the receptor (ie the nature of their biological effect elicited by binding) is independent of their affinity for the receptor (ie their binding strength) and their potency for the receptor (ie the amount of a drug required to produce an effect of a given intensity).

13. A drug may be a partial agonist.  Such drugs bind to and activate a given receptor but have only partial efficacy at the receptor in that they elicit less than the maximal response from the receptor.  Partial agonists may exert both agonist and antagonist effects under certain conditions.  At high doses, a partial agonist may antagonise the effects of a full agonist if its affinity for the receptor is greater than that of the full agonist.  This is sometimes referred to as mixed agonist-antagonist actions.

14. Serotonin (5-hydroxytryptamine or “5‑HT”) is a neurotransmitter intimately connected to neuropharmacology because of certain chemical structural resemblances to that of the hallucinogenic compound LSD.  Serotonin is found throughout the body, including in many cells that are not neurons.  Only a small percentage of total body serotonin is synthesised in serotonergic neurons of the central nervous system.  Indeed, 90% of serotonin is made in the gut.

15. The serotonin system in the brain is perhaps one of the most complex due to the multiplicity of receptors with which serotonin can interact.  To date, at least 14 unique receptor subtypes have been identified which use serotonin as their neurotransmitter.  These are denoted by the numeral and letters “5‑HT”.  The function of all these receptors is not certain because drugs which act specifically at the various subtypes have not been synthesised.  Nevertheless, the roles of some subtypes in various physiological processes have, to some extent, been delineated.

16. 5‑HT_1A  receptors are the best characterised of the 5-HT₁ family of receptors.  They have high affinity for serotonin.  Studies in several species, including humans, show the presence of these receptors in significant levels in almost all parts of the brain.  5‑HT_1A  receptors function as both pre-synaptic auto-receptors (ie they control their own firing rate and, therefore, the release of serotonin) and as post-synaptic receptors (ie they receive the neurotransmitter released and, as a consequence of the changes in receptor conformation, they alter biochemical processes within the post-synaptic neuron).  The major electrical effect brought about by interaction with 5‑HT_1A receptors on neurons involves attenuation of the firing of neurons, thus resulting in decreased release of neurotransmitters from the synaptic ends of the neurons.  Thus, 5‑HT_1A  receptors have an inhibitory effect on neurotransmission when an agonist binds to them.

    THE 772 PATENT

17. The complete specification of the 772 patent (more specifically identified as AU 2005201772 C1) (the 772 specification) is organised in a conventional way.  It makes a number of disclosures, in this case supported by extensive citations, by way of background before proceeding to summarise and then describe the invention more fully.  It is necessary to refer to the background section of the 772 specification in some detail.

    Background

18. The 772 specification describes the invention as relating to a method of treating a patient suffering from a disorder of the central nervous system associated with the 5‑HT_1A receptor subtype.

19. The 772 specification identifies US Patent No. 5,006,528 (US 528), European Patent No. 367,141 (EP 141) and another patent, as related art containing “the same chemical structural formula as the carbostyril derivatives in the present invention”.  In this proceeding, it has been accepted that the disclosures of US 528 and EP 141 are materially the same.  I will return to consider these patents in more detail when dealing with the respondent’s challenge to the validity of claims 1 and 7 of the 772 patent.  For present purposes, it is important to note that the 772 specification states that these carbostyril derivatives have pharmacological properties that are beneficial drug treatments for schizophrenia.  Claim 27 of EP 141 and claim 17 of US 528 claim a pharmaceutical composition for treating schizophrenia in which aripiprazole or its salt is the active ingredient.  Unlike US 528, EP 141 specifically claims the use of aripiprazole for the preparation of a drug useful in the treatment of schizophrenia.  This claim is a Swiss type claim.   

20. Otsuka does not hold an Australian patent for the compound aripiprazole or for its use in treating schizophrenia generally.    

21. The 772 specification records that it has been reported that aripiprazole binds with high affinity to D₂ receptors and with moderate affinity to D₃ and 5‑HT₇ receptors.  The notation “D” refers to dopamine.  Further, the 772 specification records that it has been reported that aripiprazole possesses:

    ·presynaptic dopaminergic autoreceptor agonistic activity;

    ·postsynaptic D₂ receptor antagonistic activity; and

    ·D₂ receptor partial agonistic activity. 

22. However, the 772 specification notes that it has not been reported that “compounds in the present invention”, which include aripiprazole, have agonistic activity at the 5‑HT_1A receptor subtype. 

23. The 772 specification then records that the following matters concerning the 5-HT_1A receptor subtype have been reported (citations omitted):

    ·Therapeutic interventions using 5‑HT_1A receptor ligands may be useful drug treatments for alcohol abuse.

    ·5‑HT_1A agonist drugs may be useful for the treatment and/or prophylaxis of disorders associated with neuronal degeneration resulting from ischemic events in mammals.

    ·5‑HT_1A receptor hypersensitivity could be the biological basis for the increased frequency of migraine attack “in stressful and anxious conditions”.

    ·A particular 5‑HT_1A receptor agonist has neuroprotective, anxiolytic and anti-depressant-like effects in animal models.

    ·5‑HT_1A receptor agonists appear to be broad spectrum antiemetic agents.

    ·Serotonin plays a role in several neurological and psychiatric disorders, including Alzheimer’s disease, depression, nausea and vomiting, eating disorders, and migraine.

    ·Buspirone, a 5‑HT_1A receptor agonist, is efficacious in treating a variety of symptoms associated with attention deficit hyperactivity disorder (ADHD), and that combined use of a D₂ receptor agonist and 5‑HT_1A agonist provides effective treatments for ADHD and Parkinson’s disease.

    ·5‑HT_1A agonists are effective in the treatment of cognitive impairment in Alzheimer’s disease, Parkinson’s disease or senile dementia.

    ·Ipsapirone, a 5‑HT_1A agonist, is effective in treating Alzheimer’s disease by improving memory.

    ·Buspirone is useful for improving short-term memory in patients “in need of treatment.”

    ·Use of 5‑HT_1A partial agonists have been used for the treatment or prevention of cognitive disorders associated with Alzheimer’s disease, Parkinson’s disease or senile dementia.

    ·5-HT_1A agonists are effective in the treatment of depression.

    ·Gepirone, a 5-HT_1A receptor partial agonist, is useful in alleviating certain primary depressive disorders, such as severe depression, endogenous depression, major depression with melancholia, and atypical depression.

    ·The combined use of gepirone with an antidepressant can effectively treat depression.

    ·Buspirone alleviates motor disorders such as neuroleptic-induced Parkinsonism and extrapyramidal symptoms.

    ·5-HT_1A agonists reverse neuroleptic-induced catalepsy in rodents, which mimic movement impairments observed in Parkinson’s disease.

    ·Aripiprazole can be used to manage psychosis in geriatric patients, Alzheimer’s disease, Parkinson’s disease or senile dementia, because it possesses potent, partial agonistic activities at D₂ and 5‑HT_1A receptors.  These patients might not experience extrapyramidal symptoms due to this property of aripiprazole. 

24. The 772 specification turns to consider the treatment of schizophrenia.  It makes the following disclosures in that regard (citations omitted):

    ·Heretofore, schizophrenia has been understood to be caused by hyperactivity in the brain dopaminergic system.  For this reason, some drugs were developed with strong dopaminergic receptor blocking activity.  These typical antipsychotic drugs are effective in treatments for the positive symptoms of schizophrenia. 

    ·A variety of atypical anti-psychotic drugs have been developed, which include clozapine, risperidone, olanzapine and quetiapine.  These drugs have less extrapyramidal side effects and have other activities in addition to their dopaminergic receptor blocking activity.

    ·In contrast to typical antipsychotic drugs, such as chlorpromazine and haloperidol, it is reported that atypical antipsychotic drugs are more effective against “the negative symptoms and cognitive impairments associated with schizophrenia than typical antipsychotic drugs”, and atypical antipsychotic drugs have less extrapyramidal side effects.

    ·Certain patients are resistant to the therapy provided by atypical antipsychotic drugs.  These patients may either not respond to the therapy or may become refractory (that is, “may feel more anxious, depressed or [suffer from] cognitive dysfunction”) in response to that therapy.  These treatment-resistant patients pose a problem for how a physician may provide an appropriate therapy.

    ·A number of treatment-resistant and treatment-refractory schizophrenic patients display symptoms that do not respond adequately to a variety of known effective classes and doses of typical or atypical antipsychotic drugs.  Further, these patients may also be “inveterate” schizophrenics or chronic schizophrenics, who are often repeatedly admitted to and discharged from hospitals.

    ·The symptoms of patients corresponding to treatment-resistant and treatment-refractory schizophrenics involve not only the positive symptoms, but also the negative symptoms and emotional disorders, as well as cognitive impairments. 

    ·Cognitive impairment exists separately from the psychic symptoms in a schizophrenic individual.  Medical treatment is quite important because cognitive impairment may disturb the socially adaptable behaviour of these individuals.

25. The 772 specification gives particular attention to the role of clozapine, an atypical antipsychotic drug, in the treatment of schizophrenia, and the role played by the 5-HT_1A receptor subtype in the therapeutic efficacy of clozapine and other drugs (citations omitted):

    ·Clozapine is effective against treatment-resistant schizophrenia.  It has been reported to be “effective against cognitive impairments in treatment-resistant schizophrenics”. 

    ·It is reported that clozapine “improves cognitive impairments in attention, response time, fluent-speech, etc.” in treatment-resistant schizophrenics. 

    ·It has also been reported that clozapine provides “effective improvements in cognitive impairments in an objective evaluation scale of the Wechsler Adult Intelligence Scale-Revised Full Scale”.

    ·The 5-HT_1A receptor has been demonstrated to play a role in the therapeutic efficacy of clozapine against “treatment-resistant schizophrenia and cognitive impairments.”  This relationship was revealed by a binding experiment using human 5‑HT_1A receptors.

    ·It is clearly understood that 5‑HT_1A receptor agonistic activity or 5‑HT_1A receptor partial agonistic activity plays an important role in treatment-resistant schizophrenia and cognitive impairments.

    ·It has been reported that the number of 5‑HT_1A receptors is increased in the prefrontal cortex of chronic schizophrenics classified as treatment-resistant.  This observation was explained as a compensatory process mediated by hypofunctional 5‑HT_1A receptors.  Therefore, a lowering in neuronal transmission mediated through 5‑HT_1A receptors is expected in treatment-resistant schizophrenics.

    ·The clinical efficacy of clozapine may be related to its partial agonist efficacy at 5‑HT_1A receptors.  This hypothesis is supported by a positron emission tomography study in primates which showed that clozapine interacts with brain 5‑HT_1A receptors at a therapeutically effective dose.

    ·Tandospirone, which is a known selective 5‑HT_1A receptor agonist, improved cognitive impairments in chronic schizophrenic patients.

    ·

    In animal tests, the reports do not always suggest that 5‑HT_1A receptor agonist activity may be related to cognitive impairment.   However, a known selective 5‑HT_1A receptor agonist (8-OH-DPAT), improves learning and memory impairments induced by scopolamine, known as a muscarinic receptor antagonist. 

    
    

    This suggests a relationship between 5‑HT_1A receptor agonistic activity and improvements in cognitive impairments.

26. The 772 specification also records that it has been reported that later atypical antipsychotic drugs, such as risperidone and olanzapine, improve treatment-resistant schizophrenia or cognitive impairments in treatment-resistant schizophrenics.  However, these drugs were not shown to be consistently superior to typical antipsychotic drugs in their effectiveness against treatment-resistant schizophrenia.  The 772 specification discloses that risperidone and olanzapine bind with lower affinity to human 5‑HT_1A receptors and thus “cannot clearly perform activities through human 5‑HT_1A receptors at clinical effective doses.”

27. The 772 specification also discloses that, while it is understood that clozapine is effective against treatment-resistant schizophrenia, its use is limited due to its severe

    
    

    side- effect of producing agranulocytosis. 

28. The 772 specification reasons that, under these circumstances, the development of a safe antipsychotic drug with potent, full or partial agonist activity at 5‑HT_1A receptors is “earnestly desired.”

29. The 772 specification continues:

    The carbostyril compound in the present invention binds with high affinity and displays a potent, partial agonist activity at the 5‑HT_1A receptors and it has higher intrinsic activity (about 68%) as compared with that of clozapine. Therefore, the compound in the present invention has a 5‑HT_1A receptor agonistic activity that is more potent than the agonistic activity of clozapine.  Thus, the present carbostyril compound may represent a more potent and highly safe drug for curing
    treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairments caused by inveterate schizophrenia, chronic schizophrenia, cognitive impairments caused by chronic schizophrenia and the like, as compared with other currently available pharmacotherapeutic treatments.  That is, the compound in the present invention may prove to be a potent and safer drug therapy for treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairments caused by inveterate schizophrenia, chronic schizophrenia, or cognitive impairments caused by chronic schizophrenia, etc., which fail to respond adequately to currently available antipsychotic drugs such as chlorpromazine, haloperidol, sulpiride, fluphenazine, perphenazine, thioridazine, pimozide, zotepine, risperidone, olanzapine, quetiapine, amisulpride, etc.

    
    

    (Emphasis added.)

30. This passage of the 772 specification speaks of the carbostyril compound providing an alternative drug therapy for the identified disorders where patients have failed to respond or to respond adequately to other available antipsychotic drugs.  The 772 specification exemplifies the use of the invention as drug therapy “against treatment-resistant schizophrenia, cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia, cognitive impairments caused by inveterate schizophrenia, chronic schizophrenia or cognitive impairments caused by chronic schizophrenia” which fail to respond adequately to:

    ·“both of 1 to 3 typical antipsychotic drugs selected from the group consisting of chlorpromazine, haloperidol and perphenazine, and one atypical antipsychotic drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride”;

    ·“both of 2 typical antipsychotic drugs selected from the group consisting of chlorpromazine, haloperidol and perphenazine, and one atypical antipsychotic drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride”;

    ·“both of 1 to 2 typical antipsychotic drugs selected from the group consisting of chlorpromazine and haloperidol, and one atypical drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride”; and

    ·“both of 2 typical antipsychotic drugs selected from the group consisting of chlorpromazine and haloperidol, and one atypical antipsychotic drug selected from the group consisting of risperidone, olanzapine, quetiapine and amisulpride”.

1. It can be seen that these four examples teach the use of, relevantly, aripiprazole in relation to these conditions where the patient has failed to respond adequately to the previous administration of at least two of the specified antipsychotic drugs.  In short, these particular examples are directed, unequivocally, to the use of, relevantly, aripiprazole as third line or later line treatment.  That said, the 772 specification does not teach that aripiprazole can only be used as third line or later line treatment.

   The invention as summarised and described

2. After setting out the extensive background to the invention that I have summarised above, the 772 specification summarises the invention by reference to two consistory statements, which find later expression in claims 1 and 7 of the 772 specification:  see below.

3. The 772 specification makes clear that the compounds of the invention may be suitably prepared into pharmaceutically acceptable formulations, with reference to, amongst other things, US 528 and EP 141.

4. The 772 specification describes the utility of the invention as follows:

   The potent, partial 5‑HT_1A receptor agonist in the present invention is useful for various disorders of the central nervous system associated with the 5‑HT_1A receptor subtype that induces bipolar disorders, such as bipolar I disorder with most recent hypomanic, manic, mixed, depressed or unspecified episode;  bipolar II disorder with recurrent major depressive episodes with hypomanic episodes, and cyclothymic disorder; depression, such as endogenous depression, major depression, melancholia, and treatment-resistant depression; panic disorder; obsessive compulsive disorder (OCD);  sleep disorders;  sexual dysfunction;  alcohol abuse and drug addiction; cognitive impairment;  neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and the like, cognitive impairments caused by neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease and related disorders;  emesis;  motion sickness;  obesity;  migraine;  autism;  Down’s syndrome; 
   attention-deficit hyperactivity disorder (ADHD);  treatment-resistant, inveterate or chronic schizophrenia, (which fail to respond adequately to currently available antipsychotic drugs);  cognitive impairments caused by treatment-resistant schizophrenia, inveterate schizophrenia or chronic schizophrenia and the like.

   
   

   (Emphasis added.)

   Relevant claims

5. Claim 1 of the 772 specification is:

   Use of a carbostyril compound of [a given structural formula] … or a pharmaceutically acceptable salt or solvate thereof, for the production of a medicament, effective in the treatment of disorders of the central nervous system associated with [the] 5‑HT_1A receptor subtype, which disorder

   (i)is 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.

6. This is a Swiss type claim.

7. Claim 7 of the 772 specification is:     

   A method for treating a patient suffering from disorders of the central nervous system associated with [the] 5‑HT_1A receptor sub-type, which disorder

   (i)[is] 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 to said patient a therapeutically effective amount of a carbostyril compound of [the given structural formula] …  or a pharmaceutically acceptable salt or solvate thereof.

8. It is not in dispute that, in one form, the carbostyril compound, referred to in each claim, is aripiprazole.

   SWISS TYPE CLAIMS

9. It is convenient at this point to deal with a question of characterisation concerning claim 1 of the 772 patent.  As I have noted, this is a Swiss type claim.  Such claims are also referred to in the cases and in the literature as, variously, “Swiss form” or “Swiss style” or, simply, “Swiss” claims.  I will use the expression Swiss type claim in deference to the use of that expression by Crennan and Kiefel JJ in Apotex Pty Ltd v Sanofi-Aventis Australia Pty Limited (2013) 304 ALR 1.

10. The generalised form of such a claim is “the use of compound X in the manufacture of a medicament for a specified (and new) therapeutic use”:  Bristol-Myers Squibb v Baker Norton Pharmaceuticals Inc [1999] RPC 253 at [44]; Actavis UK Ltd v Merck & Co Inc [2009] 1 WLR 1186 at [7]; see also Apotex 304 ALR 1 at [248]. In the discussion that follows, my reference to Swiss type claims is to claims which, as a matter of substance, accord with this generalised form.

11. The appellation “Swiss” derives from a statement of legal advice from the Swiss Federal Intellectual Property Office dated 30 May 1984, which was published in [1984] OJ EPO 581. The headnote to that statement is as follows:

    A claim for the “use of compound X to treat … (indication) …” is inadmissible under Swiss Law.  Limited claims directed to the “use of a compound … to produce agents against …” are admissible even where they relate to a second (or subsequent) medical use of a known medicament.  Details concerning the formulation of a medicament (e.g. labelling, packaging or dosage) may be included in a patent application’s description.

12. The validity of such claims under the Convention on the Grant of European Patents, opened for signature 5 October 1973, 1065 UNTS 199 (entered into force 7 October 1977) (the EPC) was considered and accepted by the Enlarged Board of Appeal of the European Patent Office (the Enlarged Board and the EPO, respectively) in EISAI/Second Medical Indication (G05/83) [1979-85] EPOR B241 (Eisai).  The Enlarged Board was there considering the EPC before revisions introduced in 2000:  see the Act revising the Convention on the Grant of European Patents of 29 November 2000 (entered into force on 13 December 2007).

13. It is important to understand the particular legal setting in which Eisai was decided.  The first particular matter to note is that, under (then) Art 52(4) of the EPC, methods for, amongst other things, treatment of the human body by surgery or therapy were not patentable as European patents, on the fiction that such methods were not susceptible of industrial application, as understood by Art 57—one of the requirements for patentability of an alleged invention.  Article 53(c) of the EPC now provides for the same exclusion from patentability but removes the rationale of non-industrial application.  Importantly, the exclusion from patentability of such methods of treatment did not (and, at the present time, does not) include products for use in those methods. 

14. The second particular matter to note is that, when dealing with the requirement for novelty, (then) Art 54(5) provided that any substance or composition comprised in the state of the art (and hence not itself new) for use in a (then) Art 52(4) method was not denied patentability for lack of novelty, provided that the use of the substance or composition for “any method” referred to in (then) Art 52(4) was not comprised in the state of the art.  As interpreted, the proviso meant that a product claim directed to the substance or composition for a first medical indication—in other words, a purpose-limited product claim—was allowable under the EPC.  However, a claim directed to the substance or composition for a second or later medical indication was not allowable:  see Sopharma SA’s Application [1983] RPC 195 at 197-198.

15. Eisai was one of seven cases which came before the Enlarged Board to determine whether, by means of a Swiss type claim, patent protection could be obtained for an invention where the substance or composition was to be used for a second medical indication.

16. The Enlarged Board held that it was “legitimate in principle” to allow Swiss type claims where the medicament was for a specified new and inventive therapeutic application, even where the process of manufacture did not differ from known processes using the same active ingredient.

17. The Enlarged Board’s conclusion was based on the following reasoning:

    ·Claims directed to substances or compositions for use in any method for treatment of the human body are directed to inventions that are susceptible of industrial application.

    ·Even though a substance or composition is known, an inventor can obtain a purpose-limited product claim for that substance or composition in respect of a first medical indication.  The requirement for novelty is derived from the new pharmaceutical use.

    ·Claims directed to the use of a substance or composition for the preparation of a pharmaceutical product (ie, Swiss type claims) are equally directed to inventions that are susceptible of industrial application.

    ·The required novelty for the process which forms the subject matter of such claims is also derived from the new therapeutic use of the medicament.  This is so, irrespective of whether any pharmaceutical use of the medicament is already known. 

    ·The special provision of (then) Art 54(5) is directed to a purpose-limited product claim.  It did not exclude second (and further) medical indications from patent protection other than by a purpose-limited product claim.

18. To summarise:  Prior to Eisai, it was possible under the EPC to obtain patent protection for a known substance or composition for a medical use by means of a purpose-limited product claim, provided no medical use of the substance or composition was previously known.  It was not possible, by means of a purpose-limited product claim, to obtain patent protection for the known substance or composition for a second or later medical use; after Eisai, it was possible, by employing the Swiss type claim, to obtain patent protection in respect of the known substance or composition for a second or later medical use, even though such protection could not be obtained by a purpose-limited product claim. 

19. It is apparent, therefore, that the Swiss type claim derives from the need to accommodate and satisfy the particular requirements for patentability that, at the time of Eisai, existed under the EPC.  In Baker Norton at [44], Jacob J explained the rationale for Swiss type claims as the need to steer clear of two obstacles to patentability—the requirement of novelty (by which Jacob J must have meant the particular requirement of novelty in respect of substances and compositions for therapeutic use under (then) Art 54(5)) and the ban on methods of treatment of the human body by therapy.

20. Dealing with the requirement for novelty, Jacob J explained that such claims are unnecessary when the substance or composition (used in the manufacture of the medicament) is new, because the substance or composition itself can be patented.  However, when the substance or composition is old, the Swiss type claim is accepted as satisfying the requirement for novelty because the specified therapeutic use of the medicament, as opposed to the specified therapeutic use of the substance or composition (used in the manufacture of the medicament), is new.  As Jacob J put it, “the manufacture of an old pill for use in a new treatment” is considered to be novel.  In a later case (Takeda Chemical Industries Ltd’s SPC Applications (No.3) [2004] RPC 3 at [3]), Jacob J described the Swiss type claim as “intellectually questionable”.

21. Nevertheless, it can readily be seen how the Swiss type claim avoids the prohibition under the EPC on patents for methods for treatment of the human body.  The manufacture of a medicament for use in particular treatment is not itself use of the medicament for that treatment:  see Actavis [2009] 1 WLR 1186 at [21]. Swiss type claims are directed to the manufacturer of the medicament, not the physician who prescribes the medicament for use by a patient.

22. I should add that the revisions to the EPC in 2000 included a provision that now specifically allows purpose-limited product claims that are directed to substances or compositions for second (or later) medical uses, removing at least the novelty justification for permitting Swiss type claims:  see (current) Art 54(5).  Following those revisions, the Enlarged Board in ABBOTT RESPIRATORY/Dosage Regime (G02/08) [2010] EPOR 26 declared that, as this reason for Swiss type claims had ceased, applications for such claims should also cease.  Now, Swiss type claims are no longer permitted for European patents.  This is also the position in the United Kingdom for patents granted under the Patents Act 1977 (UK).

23. The rationale for Swiss type claims, as explained by Jacob J in Baker Norton, is not one that applies to Australian patents.  The legal position in Australia is different.  Methods for treating the human body with pharmaceutical products are patentable:  Apotex 304 ALR 1 at [50], [286] and [314]. In Australia, such methods are accommodated by the general principles outlined in National Research Development Corporation v Commissioner of Patents (1959) 102 CLR 252. The particular impediment presented by the EPC in respect of methods for treatment does not exist for the applicant for an Australian patent.

24. Nevertheless, under Australian law, an invention which is a method for treating the human body with a pharmaceutical product must still satisfy the other requirements for a patentable invention specified in s 18 of the Act, including the requirement for novelty. But, unlike the requirements of the EPC considered in Eisai, no special novelty requirements exist under Australian law in relation to inventions involving substances or compositions for medical uses. 

25. It is convenient to note here that, in its written submissions, the respondent stated that it “put in issue” whether Swiss type claims are “a valid form of claiming”.  This submission seems to have been advanced merely formally.  The respondent did not develop that fundamental question.  Rather, it directed its submissions to a subsidiary question, with specific reference to the facts of the present case.  In that connection, the respondent relied on the (then) generally-stated proposition in European patent law that novelty of purpose for use will confer novelty that is sufficient to support a Swiss type claim.  In so doing, the respondent must be taken as having accepted, for the purposes of its submission, the general proposition that a new therapeutic use for a known medicament can provide the element of novelty required to support an invention claimed in the form of a Swiss type claim. However, the respondent submitted that no “new use” is in fact disclosed in claim 1 of the 772 patent because aripiprazole, as a product, was claimed for all uses in the treatment of schizophrenia in EP 141/US 528, and the selection of a sub-set from those uses in claim 1 does not involve a “new use”. It developed that submission in the context of certain grounds of invalidity referable to s 18(1) of the Act. I leave for later consideration in these reasons the question of whether claim 1 of the 772 patent, as a Swiss type claim, satisfies the requirement of “a patentable invention”, having regard to the particular arguments raised by the respondent in its case on invalidity. I will not address the fundamental question raised by the respondent because the respondent has not itself addressed that question.

26. The question for consideration in this section of my reasons is, as I have stated, one of characterisation.  Should an invention defined by a Swiss type claim be characterised as a product or as a method or process?  Are these characterisations apt for a Swiss type claim?  The importance of determining the proper characterisation of the invention lies in determining how the question of infringement of claim 1 of the 772 patent is to be approached.

27. The applicants submitted that Swiss type claims are process claims.  The respondent submitted that they are neither method or process claims, nor product claims.

28. The Enlarged Board in Eisai plainly considered (at [21] and [23]) Swiss type claims to be directed to a process of manufacture.  In John Wyeth & Brother Ltd’s Application; Schering AG’s Application [1985] RPC 545, Whitford and Falconer JJ, siting in banc in two appeals to the Patents Court, held that Swiss type claims are claims directed to a method of manufacture. Whitford and Falconer JJ reasoned that a claim in the form of “[t]he use of substance A in the manufacture of a medicament to treat disease B” is, in reality, a claim to the method of manufacture of such a medicament by using substance A in its manufacture: see at 563. The New Zealand Court of Appeal in Pharmaceutical Management Agency Ltd v Commissioner of Patents [2000] 2 NZLR 529 reached a similar conclusion. Their Honours said that Swiss type claims are not product claims. They reasoned that such claims are akin to method claims: see at [47] and [60].

29. In my view, an invention defined by a Swiss type claim is appropriately characterised as method or process. For the purpose of this analysis, no useful distinction exists between the words “method” and “process”. In the Act, the words “method” and “process” are not defined. In my view, neither word has a meaning that is different from its ordinary English signification. My conclusion reflects, therefore, what I consider to be an apt use of the words “method” and “process” when applied as ordinary English words to describe the content and subject matter of the generalised form of the claim to which I have referred.

30. My conclusion on the question of characterisation also accords with the cases noted above which, whilst not binding, stand as persuasive authorities on the question.  I propose to follow them.

    ISSUES OF CONSTRUCTION

31. The parties are at issue in relation to a number of questions of construction that are common to both claims 1 and 7 of the 772 specification.

    The person skilled in the art

32. It is trite law that, whilst construction is ultimately a question for the court, a patent specification, and relevant prior art documents, are to be construed through the eyes of the hypothetical person skilled in the art.  The words are to be given the meaning which the person skilled in the art would attach to them in light of the common general knowledge and what is disclosed in the document itself:  see, for example, Decor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385 at 391; Root Quality Pty Ltd v Root Control Technologies Pty Ltd (2000) 177 ALR 231 at [49]; Flexible Steel Lacing Company v Beltreco Ltd (2000) 49 IPR 331 at [81]; Kinabalu Investments Pty Ltd v Barron & Rawson Pty Ltd [2008] FCAFC 178 at [45].

33. It is also trite law that the person skilled in the art may be taken, in an appropriate case, as having the composite skills of a team of persons.  In General Tire & Rubber Company v Firestone Tyre & Rubber Company Ltd [1972] RPC 457, Sachs LJ, who delivered the judgment of the Court of Appeal, said (at 485):

    The earlier publication and the patentee’s claim must each be construed as they would be at the respective relevant dates by a reader skilled in the art to which they relate having regard to the state of knowledge in such art at the relevant date.  The construction of these documents is a function of the court, being a matter of law, but, since documents of this nature are almost certain to contain technical material, the court must, by evidence, be put in the position of a person of the kind to whom the document is addressed, that is to say, a person skilled in the relevant art at the relevant date.  If the art is one having a highly developed technology, the notional skilled reader to whom the document is addressed may not be a single person but a team, whose combined skill would normally be employed in that art in interpreting and carrying into effect instructions such as those which are contained in the document to be construed.

1. The applicants advanced a number of specific submissions with respect to Saha.  They submitted that Saha was merely an abstract.  They submitted that there is nothing in the evidence to suggest that it had been followed by a more detailed account published in a peer-reviewed journal.  Secondly, they reiterated their submissions that Saha only reports on results that were said to be statistically significant (not clinically significant) and that it is unclear what the authors meant by cognitive function and how they actually measured an improvement in cognitive function when aripiprazole had been administered in the Phase 2 study. 

2. Further, as with their submissions on novelty, the applicants pointed to Professor Singh’s evidence in cross-examination that he was unsure of the particular aspects of cognition that were covered by Saha’s use of the expression “cognitive function”.  They also pointed to certain evidence given by Professor McGorry in cross-examination in relation to the PANSS cognitive function measure referred to in Saha, although not in the context of the disclosures actually made in Saha. 

3. Relatedly, the applicants submitted that, although Saha states that “[a]n impressive effectiveness and a favorable safety profile indicate that aripiprazole should be a substantial addition to the new generation antipsychotics”, the authors do not discriminate between positive and negative symptoms and cognitive function.

4. All these submissions were directed to an argument that there is a limit to what one can conclude from Saha.  I accept that Saha has its limitations and that it is an abstract that contains somewhat limited information.  The person skilled in the art might well be unsure about the specific aspects of cognitive function that were tested in the Phase 2 studies and the nature of the testing that was undertaken in that regard.  But, as I have stated, none of this detracts from the fact that Saha discloses that there was an improvement in cognitive function, in the circumstances it describes.  Further, as I have sought to emphasise, claims 1 and 7 do not themselves descend to the detail which the applicants say Saha fails to disclose, or promise an improvement in the patient’s cognition that is measurable to any particular level or standard.

5. Professor McGorry noted that Saha reports that aripiprazole improves cognitive impairment in schizophrenia over placebo.  He said that, if someone was of a mind to prescribe an antipsychotic to treat cognitive impairment in a patient with schizophrenia (including chronic or treatment-resistant schizophrenia), Saha supports the view that that person should try aripiprazole to see if the patient’s cognitive impairment responds accordingly. 

6. Professor McGorry went on to say that, based on his professional opinion, he would not expect a specific benefit on cognition separate from aripiprazole’s effect on the patient’s positive symptoms.  This last observation reflects Professor McGorry’s view that antipsychotic medication is a key part of the patient’s treatment to maintain response or remission from the positive symptoms of schizophrenia and that if this treatment resulted in any other benefit in effect on the negative symptoms or other domains of schizophrenia, which was not uncommonly the case, then this benefit was viewed by him as “a bonus”.

7. I do not consider that Professor McGorry’s evidence about his expectations of when the patient’s cognitive impairment might improve detracts from his acceptance that, at the priority date, Saha would suggest to the clinician that he or she should try aripiprazole to see if the patient’s cognitive impairment responds to the medication in the way reported.

8. Dr O’Dea gave evidence that, if he had read Saha at the priority date, he would have understood the authors to be suggesting that aripiprazole could be beneficial for the treatment of excitement, depression and cognitive impairment in schizophrenia.  Further, he said that Saha suggests to him that aripiprazole may be effective in treating the positive, negative and cognitive symptoms and signs of schizophrenia.

9. Associate Professor Norman gave evidence that Saha’s “take home” message included the message that, at higher doses, aripiprazole has effects on the negative symptoms of schizophrenia, which might include some improvement in cognition, although Saha is not specific about which domains of cognition are likely to improve. Associate Professor Norman elaborated on these views in his cross-examination. I have already quoted part of his evidence in that regard: see [341]. Associate Professor Norman went on to accept that, in an hypothetical search for a new antipsychotic at the priority date, Saha indicated that aripiprazole was a drug candidate that he might well wish to pursue. He said that:

   … you would be keen to get a hold of some and have a go at it really.  As soon as it became available you would perhaps think “Well, have I got a couple of patients here?  I will try it and see how it goes.” …

10. I have already referred to Professor Singh’s evidence (at [343]) concerning the reliability or validity of the authors using their own “subscales”.  Professor Singh said that, in order to conclude anything about cognition, the authors of Saha would have had to look at the General Psychopathology Scale.  He observed that the abstract does not say anything about that scale.

11. Recognising Professor Singh’s criticism of Saha, I think that it is nevertheless important to bear in mind that Saha conveys that related items of the PANSS were clustered and analysed to determine the effect of aripiprazole on excitement, depression and cognitive impairment.  The symptom or sign of “excitement” is found in the Positive Scale.  The symptom or sign of “depression” is found in the General Psychopathology Scale.  There is no item in the PANSS for “cognitive function”, but there is no reason to think that the authors did not cluster related items in PANSS (including from the Negative Scale and the General Psychopathology Scale) in order to assess aripiprazole’s effect on cognition:  see, in this regard, [276].

12. Having regard to the totality of the evidence, I am satisfied that, with the benefit of Saha at the priority date, the person skilled in the art would have been directly led as a matter of course to try aripiprazole as a method of treating a patient’s symptoms of schizophrenia, including the patient’s symptoms of cognitive impairment where the patient was suffering from chronic schizophrenia.  Such a method of treatment would have included one where the patient’s symptoms had failed to respond to two or more of the medications identified in claim 7.

13. Based on Saha’s teaching, the person skilled in the art would have tried aripiprazole with the expectation that it might well be useful in treating that patient’s cognitive impairment.  The person skilled in the art would have understood Saha to be teaching that aripiprazole holds the promise of being “a substantial addition to the new generation antipsychotics” because of the matters on which it reports, including the observed improvement in cognitive function.  Even though the evidence reveals that, for some of the witnesses, there was uncertainty about the specific aspects of cognitive function that were tested in the Phase 2 studies reported in Saha, and the nature of the testing that was undertaken in that regard, it is important to bear in mind that this aspect of the reformulated “Cripps question” does not require the person skilled in the art to have known, before the event, that the method (or the medicament) to be investigated will in fact prove to be useful.  As Jessup J emphasised in AstraZeneca 226 FCR 324 at [542], the requirement is that it “might well” be useful. I am satisfied that this standard has been reached and that the invention as claimed in claim 7 is obvious and, therefore, does not involve an inventive step.

14. As I have noted, no different analysis is required in assessing whether the invention claimed in claim 1 involves an inventive step.  The same conclusion follows. 

    Serper/Keefe

15. I have summarised the disclosures in Serper at [266]-[272].  As I have stated at [330], I am satisfied that, at the priority date, the person skilled in the art would have understood Serper to be disclosing that aripiprazole is a drug that is used to treat schizophrenia, including in patients suffering from cognitive impairment associated with chronic schizophrenia.  I am satisfied that the person skilled in the art would have understood Serper to be disclosing that, on the basis of the study on which it reports, patients taking aripiprazole showed a greater improvement in their cognitive performance compared to patients taking typical antipsychotic medication.  Necessarily, the person skilled in the art would have also understood that aripiprazole had been used to produce a medicament for use in the study to which it refers.

16. I have summarised the disclosures in Keefe at [288]-[292].  Keefe’s authors said that their review and analysis of the 15 studies, including Serper, suggests that atypical antipsychotics (aripiprazole among them), when compared with typical antipsychotics, improve cognitive function in patients with schizophrenia.

17. As with Saha, my reasons at [330]-[334] for concluding that the invention as claimed in claims 1 and 7 is not novel in light of the information made publicly available by Serper lead me also to conclude that, at the priority date, the person skilled in the art, with the benefit of the prior art information in Serper, would also have regarded the invention as obvious.  However, once again, even if I am wrong in my legal conclusion on lack of novelty, I am satisfied that the person skilled in the art would still have regarded the invention as obvious in light of the common general knowledge and Serper’s teachings.  I am reinforced in that view by the fact that the person skilled in the art would also have had the benefit of Keefe’s teachings.

18. As with Saha, Serper does not disclose that aripiprazole is a partial agonist at the 5-HT_1A receptor or that aripiprazole’s 5-HT_1A partial agonism is useful in the treatment of cognitive impairment in schizophrenia patients.  Similarly, Serper does not disclose, in terms, the failure of patients to respond to previous treatment with two or more of the antipsychotic drugs identified in the claims.  Nevertheless, this does not mean that the person skilled in the art, when armed with the common general knowledge and the prior art information in Serper/Keefe, would not have regarded the invention as obvious.  Once again, the discovery of aripiprazole’s action at the 5-HT_1A receptor is no more than an elucidation of why aripiprazole is useful and, perhaps, an explanation of why it had the beneficial effects reported in Serper and reviewed in Keefe.  Further, the person skilled in the art would not have understood Serper to be disclosing that aripiprazole had a limited utility based on either the patient’s previous medication or the number of times the patient’s previous medication had been switched.  Once again, no witness suggested that Serper or, indeed, Keefe should be read otherwise.  The person skilled in the art would have understood from Serper that aripiprazole could be used in a method such as that claimed in claim 7 or the production of a medicament such as that claimed in claim 1.

19. The applicants advanced a number of specific submissions with respect to Serper and Keefe.  They submitted, based on Professor McGorry’s evidence in cross-examination, that Serper was “a very limited paper”.  They pointed to the small sample size involved in the study.  They also pointed to Keefe’s finding that the neurocognitive test batteries used in Serper were not appropriate and that the study was also wanting in relation to other test criteria.  Finally, they noted that Serper does not disclose the effectiveness of aripiprazole in circumstances where an earlier drug had failed to adequately treat the patient’s cognitive impairment (a matter with which I have dealt).

20. I accept the submission that Serper is a limited paper and that its findings are based on a small sample size.  I also accept that, according to Keefe, the Serper study suffered from certain other methodological deficiencies.  However, Keefe’s criticisms in that regard were not confined to Serper.  Keefe’s authors concluded that none of the 15 studies they reviewed met all of the (then) recently developed standards for the assessment of cognitive change in schizophrenia.  Nevertheless, they said:

    However, these studies have served an important function by lending initial support for the relatively recent notion that cognitive impairment can be improved in patients with schizophrenia.  As a result of these initial studies, several large-scale comprehensive investigations of the effect of atypical antipsychotics on cognitive impairment in schizophrenia are under way.

21. These observations are important.  On reading Keefe at the priority date, the person skilled in the art would have understood its authors to have formed the view that, despite the various methodological shortcomings in the studies that were reviewed, those studies nevertheless provided at least initial support for the notion that cognitive improvement in schizophrenic patients could be improved by medication, such as those medications reviewed (including aripiprazole).  Further, the results showed enough promise to warrant several large-scale comprehensive investigations. These facts are relevant to a consideration of both aspects of the reformulated “Cripps question” and stand as some evidence that the person skilled in the art would have would have been directly led as a matter of course to try aripiprazole with an expectation that it might well be useful in treating cognitive impairment in patients with chronic schizophrenia.

22. Professor Singh gave evidence that he understood Serper to be teaching that the novel antipsychotics to which it refers improve attentional functioning in schizophrenic patients.  Although criticising the sample size and methodology of Serper, Professor Singh nevertheless volunteered in cross-examination that the results that Serper reported were “interesting and useful”.

23. Associate Professor Norman gave evidence that he understood Serper to be teaching that there appears to be some improvement in neuropsychology tests with “atypical agents” which is not the case for “typical agents”.  By his use of “atypical agents”, I understand Associate Professor Norman to be at least referring to aripiprazole, since this was one of the atypical antipsychotics which Serper studied.  Associate Professor Norman also said that, due to the methodological limitations, in particular the small sample size involved, further work would be needed “to evaluate this possible effect”.  He also saw this to be one of Keefe’s teachings.  Nevertheless, in cross-examination, Associate Professor Norman saw the results reported in Serper to be “promising”, “interesting”, “indicative” and “encouraging”, such that one would go ahead and design another study.

24. Professor McGorry gave evidence that, if a clinician was minded to prescribe an antipsychotic for the purpose of treating cognitive impairment in schizophrenia, Serper would support the decision to use aripiprazole to treat both the positive and cognitive symptoms of schizophrenia.

25. Dr O’Dea gave evidence that he read Serper as supporting the likelihood that aripiprazole could be used to cause improvement of cognitive impairment in people with chronic schizophrenia.

26. Having regard to the totality of the evidence, I am satisfied that, with the benefit of Serper and Keefe at the priority date, the person skilled in the art would have been directly led as a matter of course to try aripiprazole as a method of treating a patient’s symptoms of schizophrenia, including the patient’s symptoms of cognitive impairment where the patient was suffering from chronic schizophrenia.  Such a method of treatment would have included one where the patient’s symptoms had failed to respond to two or more of the medications identified in claim 7. 

27. The applicants submitted that the person skilled in the art would not choose aripiprazole over any other atypical antipsychotic, such as ziprasidone which was also disclosed in Serper.  Relatedly, they said Professor McGorry’s evidence was that Serper does not disclose that aripiprazole will be superior to other atypical antipsychotics in treating cognitive impairment in schizophrenia.  These considerations are irrelevant to the question of whether the person skilled in the art would be directly led as a matter of course to try aripiprazole as a method of treatment.  It does not matter that the person skilled in the art might be led by Serper to try other atypical antipsychotics as well.  The only question is whether the person skilled in the art would be directly led as a matter of course to try aripiprazole.

28. I am also persuaded that the person skilled in the art would have been directly led as a matter of course to try aripiprazole in such a method of treatment with the expectation that it might well be useful.  In this connection, I accept that, on considering the study reported in Serper with the benefit of the review and analysis provided by Keefe, the person skilled in the art would have viewed Serper’s results with respect to aripiprazole as tentative results.  However, I am also persuaded that the person skilled in the art would have seen those results as a promising line of inquiry that might well provide a useful method of treating cognitive impairment in patients suffering from chronic schizophrenia.  This is all that the second aspect of the reformulated “Cripps question” requires.  I am satisfied that the invention as claimed in claim 7 is obvious and, therefore, does not involve an inventive step.

29. Once again, no different analysis is required in assessing whether the invention claimed in claim 1 involves an inventive step.  The same conclusion follows. 

    Petrie 1997

30. I have summarised the disclosures in Petrie 1997 at [280]-[284]. At the priority date, the person skilled in the art would have understood Petrie 1997 to be referring to patients with chronic schizophrenia having regard to the authors’ use of the description “acutely relapsing hospitalised schizophrenic patients”.

31. Petrie 1997 discloses that in Phase II studies, aripiprazole was superior to placebo in treating schizophrenia.  It suggests that aripiprazole may represent an important advance in the management of psychotic disorders in light of its favourable safety profile and the existence of data supporting its efficacy in treating the positive and negative symptoms of schizophrenia.

32. All the witnesses who gave evidence on Petrie 1997 were in agreement that it made no specific disclosure concerning aripiprazole’s effect on cognitive impairment.  Petrie 1997 does disclose aripiprazole’s effect in treating negative symptoms, but the meaning of “negative symptoms” in this context must be understood in the light of the measurements that were used to support that conclusion. 

33. In this connection, Petrie 1997 refers to a PANSS total score and a PANSS negative score, once again expressed as a total.  The latter must be taken as a reference to the total score on the Negative Scale.  Petrie 1997 does not descend to an evaluation of the efficacy of aripiprazole in relation to the treatment of the discrete symptoms or signs comprising the Negative Scale.  Moreover, Professor Singh’s and Associate Professor Norman’s evidence, but not Dr O’Dea’s evidence, is that only one symptom or sign of schizophrenia on the Negative Scale has a possible relationship to impaired cognition in any event.  Thus, although Petrie 1997 suggests that aripiprazole may be an important advance in the treatment of schizophrenia, it falls far short of stating that aripiprazole will be useful for treating cognitive impairment associated with schizophrenia.

1. This is a significant point of difference between Petrie 1997 and Saha.  Although Petrie 1997 reports on one of the Phase 2 studies (referred to as Phase II studies in Petrie 1997), Saha goes much further than Petrie 1997 to state that related items of PANSS were clustered and analysed to determine the effect of aripiprazole on excitement, depression and cognitive function.  On each of these dimensions, the aripiprazole doses showed improvement over baseline.  Saha further states that, for cognition, the aripiprazole 30 mg dose showed statistically significant improvement over placebo.  Thus, Saha contains an explicit disclosure of aripiprazole’s efficacy in treating cognitive impairment, whereas Petrie 1997’s reference to the PANSS makes, at best, a doubtful disclosure in that regard.

2. Petrie 1997 also refers to a BPRS total score.  Associate Professor Norman said that the BPRS gave a measure of total psychopathology.  So understood, Petrie 1997’s reference to the BPRS does not advance the question of whether improvement in cognitive impairment is disclosed.

3. Perhaps recognising this difficulty, the respondent pointed to the disclosure in Petrie 1997 that aripiprazole demonstrated affinity for the 5-HT₂ receptor.  Professor Singh gave evidence that action on the 5-HT₂ receptor signifies that the antipsychotic is an atypical or “second generation” antipsychotic.  Professor Singh said that all second generation antipsychotics are better for treating the negative and neurocognitive symptoms of schizophrenia.  It is not at all clear to me that, when making this last statement, Professor Singh was giving evidence of the common general knowledge at the priority date.

4. The respondent also pointed to general evidence from Professor Singh and Associate Professor Norman to the effect that Petrie 1997 suggested that aripiprazole might well be an effective or useful treatment for schizophrenia.  However, this is not the question.  The reformulated “Cripps question” is directed to the invention as claimed.

5. On the whole, I am not persuaded that, armed with the common general knowledge and Petrie 1997 at the priority date, the person skilled in the art would have been directly led as a matter of course to try aripiprazole as a method of treatment as claimed, or to use aripiprazole to produce a medicament as claimed, or that the person skilled in the art would have been led to do so with an expectation that aripiprazole might well be useful for those purposes.     

   Petrie 1998

6. I have summarised the disclosures in Petrie 1998 at [285]-[287].  The disclosures are very similar to those in Petrie 1997.  Professor Singh referred to Petrie 1997 and Petrie 1998 as “the same story.”  Associate Professor Norman saw Petrie 1997 and Petrie 1998 as “more or less the same thing.”  My analysis of Petrie 1997 in relation to the reformulated “Cripps question” is also applicable to Petrie 1998.  My conclusion on whether the person skilled in the art would regard the invention as obvious is the same. 

   OTHER GROUNDS OF INVALIDITY

   Introduction

7. The respondent advanced a number of additional grounds on which it contended that claims 1 and 7 of the 772 patent were invalid.  However, in both opening its case, and in closing submissions, the respondent only dealt with these grounds briefly, saying that its challenge with respect to lack of utility, lack of clarity and lack of definition were intended to complement its earlier contentions on claim construction, non-infringement and manner of manufacture.  The respondent did not seek to elaborate these grounds, or indeed its challenge on lack of fair basis, in oral address in closing submissions.  The respondent was content to rely on the very brief statements made in its written submissions.  I will deal with these submissions commensurately. 

   Utility

8. The respondent’s challenge that the invention as claimed is not useful was based on its contention that there is no disorder of cognitive impairment caused by the forms of schizophrenia identified in the claims.  On the respondent’s argument, if there is no such disorder, the invention, as claimed, cannot be useful.

9. At [149]-[156], I have set out my reasons for concluding that, when the claims speak of cognitive impairment “caused by” these forms of schizophrenia, they are simply referring to cognitive impairment as a symptom of schizophrenia.  This finding on construction removes the basis of the respondent’s challenge on this ground. 

10. For this reason, I am not persuaded that the invention as claimed is not useful.

    Sufficiency and best method

11. The respondent contended that the 772 specification does not comply with s 40(2)(a) of the Act because it does not describe the invention fully and does not describe or enable the person skilled in the art to determine what constitutes the methods of treatment claimed, including the best method known to the patent applicant by which the invention is to be performed.

12. Although the respondent particularised a number of grounds in support of this overall contention, its case at hearing was confined to the single proposition that the association between the 5‑HT_1A receptor and cognitive impairment in schizophrenia is “so uncertain and nebulous that it leads to a lack of clarity and lack of definition in the claim[s].”  Although, as framed, that submission focuses on the claims, rather than on the description of the invention in the 772 specification, I understood the respondent to be contending that the association between the 5‑HT_1A receptor and cognitive impairment in schizophrenia was so “uncertain and nebulous” that the invention is not fully described.

13. I reject that challenge.  It lacks a proper foundation in light of my conclusion that the 772 specification teaches that the forms of cognitive impairment identified in the claims are disorders of the central nervous system associated with the 5‑HT_1A receptor.  I refer to my reasons at [130]-[148].  I also refer to my summary of the 772 specification at [78]-[99]. 

14. I am not persuaded that the 772 specification does not fully describe the invention, including the best method of performing it. 

    Clarity and definition

15. The respondent contended that the invention as claimed does not comply with s 40(3) of the Act in that they are not clear and succinct.

16. The respondent particularised a number of terms and phrases in each of claims 1 and 7 as not being clear.  It also particularised a ground that claims 1 and 7 do not properly define the invention because cognitive impairment is not: a disorder; a disorder of the central nervous system associated with the 5‑HT_1A receptor; or, caused by schizophrenia.

17. In the end, however, the respondent confined its challenge on “lack of clarity” to the argument identified above, namely that the association between the 5‑HT_1A receptor and cognitive impairment in schizophrenia is so “uncertain and nebulous” that the invention is not properly defined.

18. Once again, I reject that challenge on the basis of the reasons I have given at [130]-[148].

19. In light of the confined argument advanced, I am not persuaded that the claims are not clear and succinct.

    Fair basis

20. The respondent contended that claims 1 and 7 of the 772 patent do not comply with s 40(3) of the Act in that they are not fairly based on the matter described in the 772 specification.

21. At the time of closing submissions, the respondent wished only to advance the following paragraph of its written submissions in support of this challenge:

    As to fair basis, the complaint made is that the claims are not fairly based on the matter disclosed in the body of the specification.  To the extent the method claim claims any manner of performing the invented method, the body of the specification provides no support.  For example, it does not disclose how to determine failure of the disorders to respond to other antipsychotic drugs, and there is no clear disclosure of the basis for use of aripiprazole or any manner of performing the inventions, or of how aripiprazole achieves the effect claimed.  The presence of consistory clauses which provides a “coincidence of language” with the claims do not provide proper fair basis for claims which are unsupported by the body of the specification:  Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No. 1) (2004) 217 CLR 274 at 306 [87].

22. I reject those submissions.  They appear to be directed more to a challenge that the invention is not fully described and that the best method of performing the invention is not given, rather than the invention, as claimed in each claim, is not fairly based.  In any event, the respondent’s submission that the 772 specification does not disclose how to determine the failure of the disorders to respond to other antipsychotic drugs is without substance.  There is no need for the specification to disclose what the person skilled in the art already knows as a matter of clinical practice.  In this connection, it can be taken that the 772 specification proceeds, quite justifiably, on the basis that the person skilled in the art knows how to diagnose schizophrenia and knows how the prior art medication is used.  I have no doubt from the evidence I have heard from the expert witnesses that a competent psychiatrist in clinical practice would be able to tell whether a patient’s cognitive impairment associated with schizophrenia has adequately responded to medication.

23. Further, I simply do not accept the respondent’s submissions that the specification does not describe the basis for using aripiprazole or how the invention is to be performed or how aripiprazole achieves its desired effects.  The 772 specification is explicit on all these matters.  I refer, once again, to my summary at [78]-[99].  I also refer to [27]-[63] dealing with background matters concerning the diagnosis and treatment of schizophrenia, including in particular [57]-[63] dealing with the position at the priority date.

24. Further, contrary to the respondent’s submission, I do not accept that the consistory clauses stand in the 772 specification as a mere “coincidence of language”.

25. For these reasons, I am not persuaded that the invention claimed in claims 1 and 7 is not fairly based on the matter described in the 772 specification.

    EXCLUSIVE LICENCE

26. BMS sues as an exclusive licensee of the 772 patent based on a grant of rights under an agreement titled “Restated Development and Commercialization Collaboration Agreement” that was made on 23 October 2001.  I considered the effect of that agreement in another proceeding and rejected the submission that, by dint of the agreement, BMS is an exclusive licensee:  Bristol-Myers Squibb Company v Apotex Pty Ltd (No 5) (2013) 104 IPR 23 at [413]-[440]. My conclusion was upheld on appeal: Bristol-Myers Squibb Co v Apotex Pty Ltd (2015) 109 IPR 390 at [83]-[105]. The applicants did not contend that BMS is in any different position in the present case. It follows that BMS is not an exclusive licensee of the 772 patent and does not have standing to sue for infringement.

    DISPOSITION

27. The parties are to bring in draft orders giving effect to these reasons.  If the parties are unable to agree on the question of costs, they are to provide short written submissions (not exceeding three pages) on that question, together with a draft of the order that is sought.

I certify that the preceding five hundred (500) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Yates.

Associate:

Dated:       29 June 2015