Ranbaxy Laboratories Ltd v AstraZeneca AB
[2013] FCA 368
FEDERAL COURT OF AUSTRALIA
Ranbaxy Laboratories Limited v AstraZeneca AB [2013] FCA 368
Citation: Ranbaxy Laboratories Limited v AstraZeneca AB [2013] FCA 368 Parties: RANBAXY LABORATORIES LIMITED and RANBAXY AUSTRALIA PTY LTD v ASTRAZENECA AB and ASTRAZENECA PTY LIMITED; ASTRAZENECA AB and ASTRAZENECA PTY LIMITED; RANBAXY LABORATORIES LIMITED and RANBAXY AUSTRALIA PTY LTD File number: VID 1008 of 2011 Judge: MIDDLETON J Date of judgment: 23 April 2013 Catchwords: INTELLECTUAL PROPERTY – Patents – Construction of claims – Infringement of claims – Applicable principles – Section 116 Patents Act 1990 (Cth) – Amended patent – Whether reference to specification without amendment and other Patent Office documents permissible in construction – Skilled addressee and skilled team
INTELLECTUAL PROPERTY – Patents – Validity – Novelty – Prior art and common general knowledge
INTELLECTUAL PROPERTY – Patents – Validity – Inventive step – Common general knowledge and s 7(3) documents – Cripps question – Inventive journey of patentee – Secondary indicators – Commercial success – Conduct of competitors
INTELLECTUAL PROPERTY – Patents – Manner of new manufacture
Legislation: Patents Act 1952 (Cth)
Patents Act 1990 (Cth)
Patents Amendment Act 2001 (Cth)Cases cited: Aktiebolaget Hässle v Alphapharm Pty Limited (2002) 212 CLR 411
Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593; [1999] FCA 628
Albany Molecular Research Inc v Alphapharm Pty Ltd (2011) 90 IPR 457
Alcatel NV v Commissioner of Patents (1996) 68 FCR 8
Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618
Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162
Apotex Pty Ltd v Sanofi-Aventis (2008) 78 IPR 485; [2008] FCA 1194
Apotex Pty Ltd v Sanofi-Aventis (2009) 82 IPR 416; [2009] FCAFC 134
Baygol Pty Ltd v Foamex Polystyrene Pty Ltd (2005) 64 IPR 437; [2005] FCA 145
Britax Childcare Pty Ltd v Infa-Secure Pty Ltd (2012) 96 IPR 1; [2012] FCA 467
British Acoustic Films Ltd v Nettlefold Productions (1936) 53 RPC 221
Commissioner of Patents vMicrocellLimited (1959) 102 CLR 232
Danisco A/S v Novozymes A/S (No 2) (2011) 91 IPR 209; [2011] FCA 282
Dynamite Games Pty Ltd v Aruze Gaming Australia Pty Ltd [2013] FCA 163
EI Du Pont de Nemours & Co v ICI Chemicals & Polymers Ltd (2005) 66 IPR 462; [2005] FCA 892
Eli Lilly and Company Ltd v Apotex Pty Ltd [2013] FCA 214
General Tire & Rubber Company v Firestone Tyre and Rubber Company Ltd (1971) 1A IPR 121
H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151
ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc (2000) 106 FCR 214
Insta Image Pty Ltd v KD Kanopy Australasia Pty Ltd (2008) 78 IPR 20; [2008] FCAFC 139
Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461
Kimberly-Clark Australia Pty Limited v Arico Trading International Pty Limited (2001) 207 CLR 1
Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2005] 1 All ER 667
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173
Minnesota Mining and Manufacturing Co & 3M Australia Pty Ltd v Beiersdorf (Aust) Limited (1980) 144 CLR 253Nobel’s Explosives Company Ltd v Anderson (1894) 11 RPC 519
Novozymes A/S v Danisco A/S [2013] FCAFC 6
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1995) 183 CLR 655
Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157
PAC Mining Pty Ltd v Esco Corp (2009) 80 IPR 1; [2009] FCAFC 18
Pfizer Overseas Pharmaceuticals v Eli Lilly and Company (2005) 68 IPR 1; [2005] FCAFC 224
Populin v HB Nominees Pty Ltd (1982) 41 ALR 471
Prestige Group (Australia) Pty Ltd v Dart Industries Inc (1990) 26 FCR 197
SachtlerGmbH & Co KG v RE Miller Pty Ltd (2005) 65 IPR 605; [2005] FCA 788
Sigma Pharmaceuticals (Australia) Pty Ltd v Wyeth (2010) 88 IPR 459; [2010] FCA 1211
Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346
The Wellcome Foundation Limited v V R Laboratories (Aust) Pty Ltd (1981) 148 CLR 262
Wake Forest University Health Sciences v Smith & Nephew Pty Ltd (No 2) (2011) 92 IPR 496; [2011] FCA 1002
Welch Perrin and Company v Worrel (1961) 106 CLR 588Date of hearing: 19, 20, 21, 22, 25, 26, 27, 28 February 2013 and 1, 4, 7, 8, 12, 13, 14, 15, 18, 19, 20, 21, 24, 27, 28 March 2013 Date of last submissions: 12 April 2013 Place: Melbourne Division: GENERAL DIVISION Category: Catchwords Number of paragraphs: 1017 Counsel for the Applicants: Mr RC Macaw QC with Mr AJ Ryan SC and Ms SK Gatford Solicitor for the Applicants: King & Wood Mallesons Counsel for the Respondents: Mr A Bannon SC with Mr BJ Fitzpatrick and Mr B Gardiner Solicitor for the Respondents: Ashurst Australia
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION
VID 1008 of 2011
BETWEEN: RANBAXY LABORATORIES LIMITED
First ApplicantRANBAXY AUSTRALIA PTY LTD
Second ApplicantASTRAZENECA AB
First Cross-ClaimantASTRAZENECA PTY LIMITED
Second Cross-ClaimantAND: ASTRAZENECA AB
First RespondentASTRAZENECA PTY LIMITED
Second RespondentRANBAXY LABORATORIES LIMITED
First Cross-RespondentRANBAXY AUSTRALIA PTY LTD
Second Cross-Respondent
JUDGE:
MIDDLETON J
DATE OF ORDER:
23 APRIL 2013
WHERE MADE:
MELBOURNE
THE COURT ORDERS THAT:
1.Pursuant to s 37AF of the Federal Court of Australia Act 1976 (Cth), and on the ground that the order is necessary to prevent prejudice to the proper administration of justice, the reasons for judgment be marked “CONFIDENTIAL” and until further order are not permitted to be received by any person other than the Australian external legal solicitors and barristers of each of the parties and those permitted or previously agreed to be permitted to receive confidential information about the Ranbaxy Products pursuant to paragraphs 2 and 3 and Schedule 2 of the Court’s order of 21 October 2011
Note:Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
GENERAL DIVISION
VID 1008 of 2011
BETWEEN: RANBAXY LABORATORIES LIMITED
First ApplicantRANBAXY AUSTRALIA PTY LTD
Second ApplicantASTRAZENECA AB
First Cross-ClaimantASTRAZENECA PTY LIMITED
Second Cross-ClaimantAND: ASTRAZENECA AB
First RespondentASTRAZENECA PTY LIMITED
Second RespondentRANBAXY LABORATORIES LIMITED
First Cross-RespondentRANBAXY AUSTRALIA PTY LTD
Second Cross-Respondent
JUDGE:
MIDDLETON J
DATE:
23 APRIL 2013
PLACE:
MELBOURNE
REASONS FOR JUDGMENT
INTRODUCTION
This proceeding concerns an application for revocation of a number of patents registered in the name of AstraZeneca AB, being one of the respondents and cross-claimants in the proceeding (all of whom will be referred to collectively in these reasons as ‘AstraZeneca’), and claims of infringement of those patents.
Subject to the outcome of this proceeding, the applicants and cross-respondents (who will be collectively referred to as ‘Ranbaxy’) intend to market in Australia a drug in tablet form, the active ingredient of which is the magnesium salt of the (-)-enantiomer of omeprazole (esomeprazole magnesium) (the ‘Ranbaxy Product’).
AstraZeneca allege infringement of three Australian patents:
(a)Australian patent number 676,337 (the ‘Purity Patent’), claim 1 of which claims an optically pure salt of the (-)-enantiomer of omeprazole, including the magnesium salt;
(b)Australian patent number 695,966 (being the Multiple Unit Tableted Dosage Form Patent, which was referred to by the parties in this proceeding as the ‘MUPS Patent’), claim 1 of which claims, amongst other things, omeprazole or one of its single enantiomers or an alkaline salt thereof, in a tablet form with defined characteristics; and
(c)Australian patent number 695,774 (the ‘774 Patent’), claim 1 of which claims an oral pharmaceutical dosage form comprising, amongst other things, a proton pump inhibitor (‘PPI’), including omeprazole or the (-)-enantiomer of omeprazole.
Omeprazole was the subject of an Australian patent filed by AstraZeneca on 11 April 1979 (Australian patent number 529,654), now expired. That patent has been followed by a series of Australian patents, including Australian patent number 563,842 for different salts of omeprazole, Australian patent number 640,246 for a process for the preparation of omeprazole, and Australian patent number 601,974 for an oral preparation, the active ingredient of which is omeprazole.
The Purity Patent, the MUPS Patent and the 774 Patent can be collectively referred to as ‘the Patents’. I will be dealing separately with each of the Patents in these reasons.
This proceeding, as will become apparent, involved a large number of expert witnesses, and extensive disputation between the parties on a number of issues. The parties, for commercial reasons (particularly Ranbaxy), desire a determination preferably by no later than 23 April 2013. The actual hearing, covering some weeks, concluded on 28 March 2013. Final written submissions were filed on 12 April 2013.
To accommodate the parties’ request in this regard, it is impossible to set out and survey all the evidence led by the parties. But nor is it necessary to do so. The task undertaken by the Court has been to seek to address the major determinative issues, and the essential areas of disputation between the experts.
RELEVANT LEGISLATION
By way of overview:
(a)The application for the Purity Patent was filed on 27 May 1994, and the Purity Patent was granted on 25 June 1997. The priority date for this patent is 28 May 1993.
(b)The application for the MUPS Patent was filed on 7 June 1995, and the MUPS Patent was granted on 10 December 1998. The priority date for this patent is 8 July 1994.
(c)The application for the 774 Patent was filed on 9 February 1996, and the 774 Patent was granted on 3 December 1998. The priority date for this patent is 9 February 1995.
The issue of infringement in relation to each of the Patents is to be determined under the Patents Act 1990 (Cth) (‘the Act’).
As for the issues of validity, s 7 of the Act and the definition of “prior art base” was amended by items 1 to 6 and 12 of Sch 1, Pt 1 of the Patents Amendment Act 2001 (Cth) (‘the Amendment Act’), which took effect on 1 April 2002. However, the amendments made by the Amendment Act apply only in relation to patents for which the complete applications are made on or after 1 April 2002 (item 13 of Sch 1, Pt 1 of the Amendment Act).
Accordingly, the issues of validity in relation to each of the Patents is to be determined under the Act in the form in which it existed prior to the Amendment Act.
BACKGROUND
It is useful to commence with a summary of some of the key scientific concepts relevant to the Patents and the issues raised in this proceeding.
Stereochemistry
As will shortly become apparent, the Purity Patent invokes certain stereochemical concepts, such as the concept of enantiomers, which may require explanation. I understand that these basic principles are uncontroversial as between the parties.
At 28 May 1993 (being the priority date of the Purity Patent, which was the earliest priority date in issue in this proceeding), it was known that enantiomers are isomers (being compounds that have the same molecular formula, but which differ in the way in which their atoms are arranged) with identical structural connectivity and physical properties, except the direction in which they rotate a plane of polarised light. But another key aspect of the definition of enantiomers is that they are, at the molecular level, non-superimposable mirror images of each other. This property is known as ‘chirality’.
In a molecule, a carbon atom with four different functional groups attached to it is known as the ‘stereogenic’ or ‘chiral’ centre. However, any atom that can form four or more bonds to other atoms can demonstrate chirality. Accordingly, other atoms (such as sulphur) can also behave as chiral centres.
Diastereomers (also known as diastereoisomers) are molecules that contain two or more chiral centres (and can also exist as pairs of enantiomers).
Enantiomers rotate the plane of polarised light in either a clockwise or counter-clockwise direction. Compounds that rotate the plane of polarised light in a clockwise direction are described as dextro-rotatory and are represented with a “(+)” symbol. Compounds that rotate the plane of polarised light in a counter-clockwise direction are described as levo-rotatory and are represented with a “(-)” symbol. Omeprazole has two enantiomers: (-)-omeprazole and (+)-omeprazole.
The absolute configuration of an enantiomer is characterised as “(S)” or “(R)” depending on the spatial arrangement of atoms around the chiral atom. It is now known that the (-)-enantiomer of omeprazole is the (S)-enantiomer of omeprazole.
When both enantiomers are present in a mixture in equal proportions (ie 1:1), this is known as a ‘racemic mixture’, or a ‘racemate’. A racemate does not rotate the plane of polarised light (and is therefore not optically active) because, the rotation caused by the (-)-enantiomer is cancelled out by the equal and opposite rotation of the (+)-enantiomer.
‘Racemisation’ is a process whereby enantiomers interconvert to create a racemate (ie a 1:1 mixture of the two enantiomers just discussed), resulting in a complete loss of optical activity.
Omeprazole and acid secretion
Humans produce hydrochloric acid in the stomach, secreted by specialised cells known as ‘parietal cells’. These are generally located in the proximal two-thirds of the stomach lining, namely, in the part of the stomach lining that is closer to the mouth.
Acid secretion is regulated by a combination of hormones and nerves, working via three major pathways known as the paracrine, neurocrine and hormonal pathways. Stimulation of gastric acid secretion by all three pathways is primarily catalysed by a highly specialised enzyme located in the parietal cells known as hydrogen potassium adenosine triphosphatase (or H+/K+ ATPase). Its mechanism of action involves the transport (or ‘pumping’) of a hydrogen ion (ie a proton) out of the parietal cell and into the cavity of the stomach, in exchange for a potassium ion (which enters the parietal cell). Because it pumps protons out of the parietal cell, H+/K+ ATPase is known as a ‘proton pump’.
Omeprazole is a gastric proton pump inhibitor. It suppresses the secretion of gastric acid by binding to and inhibiting the H+/K+ ATPase enzyme in the parietal cell secretory membrane. For this reason, omeprazole has been used to treat gastrointestinal conditions (about which more will be said in due course).
Omeprazole is a chiral sulphoxide that exists as two enantiomers. Its chemical structure is as follows:
Omeprazole is described as being ‘acid labile’, meaning that it is sensitive to acid.
Pharmacodynamics
The field of pharmacodynamics examines the effect of a drug on a biological target or receptor. The therapeutic effect of a drug can result from the action of the unaltered drug molecule, or from one or more of its metabolites, or both.
Drugs taken orally are generally absorbed through the wall of the small intestine (the upper gastrointestinal tract) and then carried to the liver in the bloodstream. A significant fraction of a drug can be metabolised by enzymes in the wall of the small intestine and the liver. This is referred to as “first pass metabolism”. The remaining drug is then distributed to the ‘active site’ in the body by the systemic circulation.
In the case of omeprazole, the proportion of the drug that escapes first pass metabolism and reaches the systemic circulation unchanged is then available to act at the parietal cells of the stomach, where it is converted to the active species responsible for inhibiting the proton pumps responsible for gastric acid secretion. “Prodrugs” are drugs that are therapeutically inactive when introduced to the body, but that upon metabolism, produce a therapeutically active metabolite. They are designed with the goal of ensuring the delivery of the drug to the liver, plasma or other site where conversion to the active species occurs. Omeprazole is a prodrug. Both of its enantiomers are converted to the same achiral active species.
Interindividual variability (also referred to as ‘interindividual variation’) is the variability between different people in response to the same dose of a drug. In terms of pharmacokinetic properties, interindividual variability refers to differences in absorption, distribution and elimination of a drug between different people. This concept reflects the fact that there may be differences in the extent of metabolism of the same dosage of a drug between different people.
To this end, genetic differences in drug metabolism may manifest as different phenotypes (being the observable characteristics resulting from an individual’s genetic makeup), whereby individuals can be classified as “rapid”, “extensive” or “fast” metabolisers of a drug; or “poor” or “slow” metabolisers of a drug. That difference in metabolism is caused by genetic differences between individuals in the level of enzyme activity at the site of metabolism of a drug, resulting in variability in the metabolism of that drug by different individuals. This is an example of a genetic polymorphism (being the occurrence of two or more genetically determined phenotypes in a population in such proportions that the rarest phenotype cannot be maintained by mutation or migration alone).
Accordingly, the acknowledged desirability of a compound with improved metabolic properties is related to the objective of reducing interindividual variability. Assume, for example, a significant amount of a drug is converted by first pass metabolism into inactive metabolites, and the extent of that conversion varies between those who metabolise the drug more extensively and those who metabolise it less extensively. A modification which causes less first pass metabolism would increase the amount of drug available for its intended useful activity. The increase in the available amount of the drug would be greater for the more extensive metabolisers than the less extensive metabolisers. Hence, the amount of interindividual variability would be reduced.
WITNESSES
Ranbaxy relied on the following witnesses:
(a)Dr Phillip Reece, who swore affidavits dated 25 January 2012 and 12 October 2012. Dr Reece participated in the concurrent evidence session on pharmacology. Dr Reece holds a Bachelor of Science (Hons) Degree (1973) from the University of Adelaide, majoring in Organic Chemistry, and a PhD in Medical Chemistry (1976) from the John Curtin School of Medical Research at the Australian National University. Dr Reece worked as a hospital scientist, including as Chief Hospital Scientist, at the Queen Elizabeth Hospital in Adelaide between 1975 and 1986. Dr Reece then worked at AstraZeneca in Sydney as a Clinical Trials Manager in 1987 and 1988 before joining Parke-Davis in late 1988. From 1990 to 1993, Dr Reece was Director of Clinical Pharmacology at Parke-Davis’ research facility in Michigan, United States where he managed the transition of new pharmaceuticals from pre-clinical studies to clinical trials. He prepared the clinical pharmacology section of applications for certain types of new Parke-Davis drugs and liaised with regulatory authorities. Dr Reece currently works as a consultant to the biotechnology and pharmaceutical industries, advising on pharmaceutical drug development issues and clinical trials.
(b)Dr Graeme Irvine Stevenson, who swore an affidavit dated 12 October 2012. Dr Stevenson participated in the concurrent evidence session on organic chemistry. Dr Stevenson holds a Bachelor of Science Degree with First Class Honours in Chemistry (1984) and a PhD in Synthetic Organic Chemistry (1988) from the University of Edinburgh. At the time of swearing his affidavit, Dr Stevenson was Group Leader of Drug Discovery and Design at the Eskitis Institute for Cell and Molecular Therapies at Griffith University in Queensland. Between 1987 and 2001 Dr Stevenson worked in drug synthesis, medicinal chemistry and drug design in the United Kingdom for Merck & Co. Dr Stevenson commenced his employment at Merck as a research chemist and was promoted to Senior Research Chemist in 1989 and Research Fellow in 1996. His main responsibilities involved undertaking drug design and synthesis activities at an early stage of the drug discovery process.
(c)Dr Richard Allen Pyter, who swore affidavits dated 27 January 2012, 3 April 2012, 6 June 2012, 12 July 2012, 12 October 2012, 1 November 2012 and 5 February 2013. Dr Pyter participated in the concurrent evidence sessions on salts, non-TOF-SIMS experiments (being experiments not related to Time of Flight Secondary Ion Mass Spectrometry (‘TOF-SIMS’)), construction of the 774 Patent and infringement of the 774 Patent. Dr Pyter holds a Bachelor of Science Degree in Pharmacy (1973), a Masters of Science Degree in Pharmaceutics (1977) and a PhD in Pharmaceutics (1980) from the University of Wisconsin. Dr Pyter was employed at Abbott Laboratories in the United States from 1980 to 2007. Between 1992 and 1994 and also between 1998 and 2001, Dr Pyter was the Manager of Solid Products Development where he worked on the development of solid dosage forms for newly discovered and on-market molecules and provided technical support for manufacturing operations. In the intervening four years he was in different roles within Abbott Laboratories, including having responsibility for the conduct of stability studies and good management practice compliant excipient and drug storage facilities. Dr Pyter is currently a Pharmaceutical Product Development Consultant and he is the Adjunct Professor of Pharmaceutical Sciences at the University of Wisconsin.
(d)Dr Peter John Prichard, who swore an affidavit dated 11 October 2012. Dr Prichard participated in the concurrent evidence session on gastroenterology. Dr Prichard holds a Bachelor of Medicine, Bachelor of Surgery from Monash University (1977). Dr Prichard began his specialist training in gastroenterology in 1982 and qualified as a specialist in gastroenterology in 1985. Between 1987 and 1995, Dr Prichard worked at the Flinders Medical Centre in South Australia where he provided clinical treatment, attended outpatient clinics and undertook endoscopy sessions. Dr Prichard has been employed as a Senior Visiting Medical Specialist in Gastroenterology at the Royal Melbourne Hospital since 1997. He was the Acting Director of Gastroenterology at the Royal Melbourne Hospital from June 2001 until February 2002. Dr Prichard has also worked as a private medical consultant at the Epworth Hospital in Melbourne since 1997.
(e)Mr Rodney Ian Lindsay Cruise, who swore affidavits dated 30 January 2012 and 12 October 2012. Mr Cruise was not cross-examined. Mr Cruise is a patent attorney from Melbourne. In relation to the Purity Patent, Mr Cruise gave evidence as to the searches he completed which replicated searches that Dr Stevenson said he would have done on omeprazole in 1993 if he had been asked to prepare the enantiomers of omeprazole.
(f)Dr Walter Joseph Herzberg, who swore an affidavit dated 25 January 2012. Dr Herzberg was not cross-examined. Dr Herzberg is a translator from New Jersey, United States, who translated the document which is referred to in these reasons as “DE 455”, and related documents.
(g)Ms Janine Lois Krochmal, who swore an affidavit dated 4 April 2012. Ms Krochmal was not cross-examined. Ms Krochmal is a librarian from Monash University and gave evidence that certain publications were available in Australia at 28 May 1993.
(h)Dr Thomas Leo Reiland, who swore affidavits dated 27 January 2012, 22 March 2012, 16 July 2012, 10 October 2012 and 26 November 2012. Dr Reiland participated in the concurrent evidence session on the MUPS Patent. Dr Reiland holds a Bachelor of Science Degree in Pharmacy (1972) and a PhD in Pharmaceutical Chemistry (1981) from the College of Pharmacy at the University of Iowa. Dr Reiland worked for five years as a registered pharmacist in Iowa from 1972. Dr Reiland worked at Abbott Laboratories between 1981 and 2005 on drug delivery and drug formulation projects. Dr Reiland was the Manager of Preformulation and Drug Delivery at Abbott Laboratories between 1991 and 1994. This group was responsible for the detection of physical and chemical properties of potential pharmaceutical compounds. From 1994 to 1996, Dr Reiland managed the Liquid Products Development division at Abbott Laboratories and from 1996 to 1999 worked as the manager of the Formulation Development Centre. Since April 2005, Dr Reiland has worked as a consultant providing drug delivery and formulation development advice to clients.
(i)Mr Gilbert Siu-Chung Tsang, who swore an affidavit dated 30 January 2012. Mr Tsang was not cross-examined. Mr Tsang is a lawyer from King & Wood Mallesons, solicitors for Ranbaxy, in Melbourne. He gave evidence as to AU 222 and the identity of the Japanese priority document that it refers to.
(j)Dr Birgit Hagenhoff, who swore affidavits dated 6 June 2012, 25 June 2012 and 1 February 2013. Dr Hagenhoff participated in the concurrent evidence session on TOF-SIMS experiments. Dr Hagenhoff holds a Diploma in Physics (1987) from the University of Münster in Germany. During her studies she concurrently took courses at the University’s medical school as well as in mathematics at the University itself. Dr Hagenhoff also holds a PhD in Physics (1993) from the same University. Dr Hagenhoff was employed as a Project Scientist at that University in 1993 where she conducted and coordinated research into organic surface mass spectrometry. Dr Hagenhoff was a Senior Scientist and Deputy Group Leader of the Surface Analysis Group at the Philips Center for Manufacturing Technology in Eindhoven, The Netherlands between 1994 and 1997. She was responsible for conducting analytical services using techniques like TOF-SIMS. She founded and has operated a specialist TOF-SIMS analytical service since 1997, and has 27 years’ experience in conducting TOF-SIMS analysis.
(k)Mr Danish Bhutani, who swore an affidavit dated 28 June 2012. Mr Bhutani was not cross-examined. Mr Bhutani is a Senior Research Scientist employed by Ranbaxy in India. Mr Bhutani gave evidence of the pH of the Ranbaxy esomeprazole magnesium, which is the active pharmaceutical ingredient (‘API’) in the Ranbaxy Product.
(l)Mr Kiran Vasantrao Bachhav, who swore an affidavit dated 9 November 2012. Mr Bachhav was cross-examined. Mr Bachhav is a Pharmaceutical Scientist employed by Ranbaxy in India. He holds a Bachelor of Pharmacy and a Master of Pharmacy from the University of Pune, India.
AstraZeneca relied on the following witnesses:
(a)Mr Per Oskar Sverker von Unge, who swore an affidavit dated 5 June 2012. Mr von Unge was cross-examined. Mr von Unge, a Principal Scientist in the Medicinal Chemistry Department of AstraZeneca R&D Mölndal, Sweden, holds a Master of Science in Engineering, specialising in Organic Chemistry (1983), and a Licentiate of Engineering, specialising in Organic Chemistry (1988) from Chalmers University of Technology in Göteborg, Sweden. Mr von Unge commenced employment at AstraZeneca as an organic chemist in 1988 and has worked on PPIs since that time. Mr von Unge was promoted to Principal Scientist in 2007. In his time at AstraZeneca Mr von Unge has worked on numerous drug discovery projects, mainly in the gastrointestinal therapy area. Mr von Unge and his supervisor Dr Per Lindberg are the named inventors of the Purity Patent.
(b)Professor Allan Mark Evans, who swore affidavits dated 8 June 2012 and 1 February 2013. Professor Evans participated in the concurrent evidence session on pharmacology. Professor Evans is Pro Vice Chancellor and Professor of Pharmaceutics at the University of South Australia. Professor Evans holds a Bachelor of Pharmacy Degree (1982) from the South Australian Institute of Technology and a PhD from the department of Clinical and Experimental Pharmacology (1989) at the University of Adelaide. Professor Evans’ PhD research investigated the pharmacokinetics of the enantiomers of ibuprofen. He completed post-doctoral research as a research associate at the School of Pharmacy and Pharmaceutical Sciences at the University of Manchester (1989-91) and at the Department of Clinical & Experimental Pharmacology at the University of Adelaide (1992). In 1992 he began lecturing at the School of Pharmacy and Medical Sciences at the University of South Australia and, in 1993, was lecturing in pharmacokinetics, biopharmaceutics, clinical pharmacology and pharmacy practice. Professor Evans specialises in pharmaceutical science, particularly pharmacology, pharmacokinetics and formulation science.
(c)Professor Stephen Graham Davies, who swore affidavits dated 6 June 2012, 28 June 2012 and 1 February 2013. Professor Davies participated in the concurrent evidence sessions on organic chemistry and salts. Professor Davies is the Waynflete Professor of Chemistry at the University of Oxford. He holds a B.A. Degree (1973) and a D.Phil. Degree (1975), both in Chemistry, from the University of Oxford. He also holds a D.Sc in Chemistry (1980) from the University of Paris. Following his D.Sc., Professor Davies accepted a lectureship at the Dyson Perrins Laboratory at the University of Oxford where he remained until 2004 after becoming a Professor of Chemistry in 1996. In the late 1980s and early 1990s, Professor Davies consulted for scientists and pharmaceutical companies who sought his assistance in obtaining diastereomerically pure compounds of interest. In 1992, Professor Davies founded Oxford Asymmetry Ltd, which aimed to provide pharmaceutical companies with homochiral compounds of interest, and which focused on the preparation of compounds with high enantiomeric purities. In 1995, Professor Davies founded Oxford Diversity Ltd, which used combinatorial chemistry to produce large numbers of organic compounds for screening. Since 2004, he has continued to teach in the Department of Chemistry at the University of Oxford. In 2006, he became the Waynflete Professor of Chemistry and from 2006 to 2011 he was also the Chairman of the Department of Chemistry at Oxford.
(d)Professor John Dent, who swore affidavits dated 6 June 2012 and 30 January 2013. Professor Dent participated in the concurrent evidence session on gastroenterology. Professor Dent is a Clinical Professor of Medicine at the University of Adelaide. He holds a medical degree from the University of Cambridge (1968) and completed the clinical component of his degree at St Thomas’ Hospital in London (1965-68). Professor Dent migrated to Australia in 1972 and completed a PhD at Monash University (1978). Professor Dent was appointed Director of the Gastroenterology Unit at the Royal Adelaide Hospital in 1986 where he remained until 2004. He was involved in AstraZeneca’s clinical trials of omeprazole in the 1980s. In 1990, Professor Dent established a nerve-gut research laboratory at the Royal Adelaide Hospital, a facility of which he remains a member today. Professor Dent maintains broad expertise across the field of gastroenterology.
(e)Dr Louisa King, who swore an affidavit dated 20 April 2012. Dr King was not cross-examined. Dr King is a patent, design and literature searcher at KingSearch Pty Ltd and has been a patent, design and literature searcher since 2003. Dr King gave evidence as to the availability of a particular publication (which is referred to in these reasons as ‘Andersson 1992 Conference Abstract’) before 28 May 1993.
(f)Mr Mike James Henry Bull, who swore affidavits dated 30 January 2012 and 24 April 2012. Mr Bull was cross-examined. Mr Bull is Director of Primary Care (Gastrointestinal/Rheumatology, Cardiovascular and Respiratory Products) at AstraZeneca Pty Ltd and has been an employee of AstraZeneca since 1994. Mr Bull holds a Bachelor of Science (Honours) degree (1982) from Otago University. Mr Bull has held a number of sales and marketing roles within AstraZeneca since 1994. At the time of swearing his affidavits, Mr Bull had strategic and management control of AstraZeneca Australia’s Primary Care marketing and sales. Mr Bull gave evidence as to the sale of various AstraZeneca products in Australia.
(g)Mr Mark Donald Fladrich, who swore affidavits dated 30 January 2012 and 24 April 2012. Mr Fladrich was cross-examined. Mr Fladrich is the Managing Director of AstraZeneca Australia, a position he has held since 2011. Mr Fladrich was first employed by AstraZeneca in April 1993. He holds a degree in pharmacy from the South Australian Institute of Technology (1980) and a Master of Business Administration from Macquarie University (1995). He gave evidence as to worldwide sales figures of certain AstraZeneca products.
(h)Professor Roland Bodmeier, who swore affidavits dated 28 March 2012, 5 July 2012, 20 September 2012 and 20 December 2012. Professor Bodmeier participated in the concurrent evidence sessions on the MUPS Patent and construction and infringement of the 774 Patent. Professor Bodmeier holds a Bachelor of Science Degree in Pharmacy (1982) from the Ludwig-Maximilians-Universität in Munich, a PhD in Pharmaceutics from the University of Texas and an additional doctorate degree (habilitation - the highest academic qualification in Germany) (1993) from the Universität Regensburg in Germany. From 1986 to 1994, Professor Bodmeier worked first as an Assistant Professor and then as an Associate Professor at the University of Texas in Austin. His research focussed on controlled release polymeric drug delivery systems for oral use, microencapsulation, multiparticulate drug delivery systems and coating technology. Since June 1994, Professor Bodmeier has worked as a Professor at the College of Pharmacy, Freie Universität Berlin. The focus of Professor Bodmeier’s research has continued to be on polymeric drug delivery systems and, in particular, on the preparation of coated multiparticulate dosage forms. This research has received significant funding from public agencies and industrial partners, including major pharmaceutical companies and excipient suppliers.
(i)Dr Angelo Mario Morella, who swore affidavits dated 22 June 2012, 4 July 2012, 11 September 2012 and 21 September 2012. Dr Morella participated in the concurrent evidence sessions on the MUPS Patent and construction of the 774 Patent. Dr Morella holds a Bachelor of Science Degree with Honours in Organic Chemistry (1979) and a PhD in Organic Chemistry (1985) from the University of Adelaide. Dr Morella commenced work as a chemist at F.H. Faulding & Co. Limited in 1985 and later that year became an analytical scientist. The following year, Dr Morella took up a position as a formulator in Faulding’s Pellet Product Development Group. From 1988 to 1994, Dr Morella managed as well as actively participated as a formulator in Faulding’s research efforts in respect of the development of microencapsulated products, from initial concepts through to commercial products (“microencapsulated products” are coated particles that are less than 2mm in size and include pellets and powders). Dr Morella’s work at Faulding also involved the testing of pharmaceutical formulations using analytical and pharmacopoeial techniques. Dr Morella retired from Faulding in March 2012 and since that time has been a self-employed independent consultant to the pharmaceutical industry.
(j)Mr Mark Lee Nicholas, who swore affidavits dated 6 March 2012 and 4 December 2012. Mr Nicholas participated in the concurrent evidence sessions on TOF-SIMS and non-TOF-SIMS experiments. Mr Nicholas holds a Bachelor of Arts Degree in Chemistry (1975) from The College of Wooster in Ohio, United States. Mr Nicholas undertook a number of graduate chemistry and physics courses between 1978 and 1983. Between 1977 and 1992, he worked for The Standard Oil Company, in various research roles including one role involving the direct commercial precursor to TOF-SIMS. Mr Nicholas then held positions at the Chemistry Department of the University of North Carolina Chapel Hill as a researcher in TOF-SIMS of polymers and a researcher in Surface Mass Spectrometry of Combinatorial Libraries. From 1995 to 1999, Mr Nicholas worked for a contract surface laboratory in New Jersey as an analyst conducting TOF-SIMS analyses of polymer, metal, semiconductor, drug and biological surfaces. Since 1999, Mr Nicholas has been employed by AstraZeneca in various roles focussing on surface analysis techniques. He has been heavily involved in the analysis of drug substances and solid dosage formulations using a range of microanalytical and chemical imaging techniques, in particular TOF-SIMS. He has in total 19 years’ experience in conducting TOF-SIMS analysis (subsequent to earlier use since 1985 of other forms of time-of-flight mass spectrometry) and has specifically 14 years’ experience in conducting TOF-SIMS analysis of pharmaceutical samples.
(k)Dr Hanna Erika Matic, who swore affidavits dated 6 March 2012 and 30 November 2012. Dr Matic participated in the concurrent evidence session on non-TOF-SIMS experiments. Dr Matic holds a Master of Science Degree in Chemical Engineering (1996) and a PhD in Materials Science (2002) from Chalmers University of Technology, Gothenburg. At the time of swearing her affidavits, Dr Matic worked at AstraZeneca in Physical Science, Pharmaceutical Development. Dr Matic has worked at AstraZeneca since 2004. Dr Matic analyses pharmaceutical formulations for the development of new products and the improvement of existing products.
(l)Dr Thomas Nils Wännman, who swore an affidavit dated 7 March 2012. Dr Wännman was not cross-examined. Dr Wännman holds a Bachelor of Science Degree (1977) and a PhD in Analytical Chemistry (1985) from the University of Stockholm. At the time of swearing his affidavit, Dr Wännman was an analytical chemist in the Process Research and Development Department at AstraZeneca. He was employed by AstraZeneca from 1995 to 2012. Dr Wännman previously worked for IBM and has experience in the use of ICP-OES analysis (being Inductively-Coupled Plasma Optical Emissions Spectrometer analysis, which is intended to identify the presence of a specific element in a substance). He gave evidence as to the sodium content of the pharmaceutical excipient hydroxypropyl cellulose.
(m)Dr Shen Yung Luk, who swore affidavits dated 6 March 2012, 20 September 2012, and 20 December 2012. Dr Luk participated in the concurrent evidence sessions on TOF-SIMS and non-TOF-SIMS experiments. Dr Luk holds a Bachelor of Science Degree (1984) and a PhD in Physical Chemistry (1987) from the Institute of Science and Technology at the University of Manchester. After completing his PhD, Dr Luk worked as a Research Fellow at the same university, investigating the non-linear optical properties of ordered asymmetric bilayer films. From 1999 to 2000, he worked as a Research Scientist at Courtaulds Corporate Research in Coventry, where he was involved in optimising the manufacture of hydroxypropyl cellulose and other polymers. In 2000, Dr Luk began working for Molecular Profiles in Nottingham, United Kingdom, first as a Technical Director (from 2000 to 2005) and then as Chief Scientific Officer, the position that he held at the time of swearing his affidavits. As the Chief Scientific Officer, Dr Luk is responsible for the scientific and research divisions of the company. Dr Luk has experience in polymer synthesis, the characterisation of cellulosic polymers and understanding the concepts underpinning acid and base chemistry and its use in, among other, things, pharmaceutical product development.
The experts produced the following joint expert reports:
(a)“Joint Expert Report: Gastroenterology” dated 13 February 2013 (authors: Dr Dent and Dr Prichard);
(b)“Joint Expert Report: Pharmacology” dated 12 February 2013 (authors: Professor Evans and Dr Reece);
(c)“Joint Expert Report: Organic Chemistry” dated 12 February 2013 (authors: Professor Davies and Dr Stevenson);
(d)“Joint Expert Report: Salts” dated 13 February 2013 (authors: Professor Davies and Dr Pyter);
(e)“Joint Expert Report on AU 966 (MUPS)” dated 28 February 2013 (authors: Professor Bodmeier, Dr Morella and Dr Reiland);
(f)“Joint Expert Report: AU 774 – TOF-SIMS Analysis” dated 14 February 2013 (authors: Dr Luk, Dr Hagenhoff and Mr Nicholas);
(g)“Joint Expert Report: AU 774 – Non TOF-SIMS Experiments” dated 20 February 2013 (authors: Dr Luk, Dr Matic and Mr Levay);
(h)“Joint Expert Report: AU 774 – Construction” dated 5 March 2013 (authors: Professor Bodmeier, Dr Morella and Dr Pyter); and
(i)“Joint Expert Report: AU 774 – Infringement” dated 14 March 2013 (authors: Professor Bodmeier and Dr Pyter).
In addition to these reports, a document was produced by Dr Stevenson entitled “ORGANIC CHEMISTRY: Second meeting” (dated 22 February 2013). This document records the answers of Dr Stevenson to a number of additional questions that were put to both him and Professor Davies. AstraZeneca submitted that the document is neither an affidavit, a joint expert report nor an expert report that meets the requirements of r 23.13 of the Federal Court Rules 2011 (Cth). Accordingly, it was submitted, I should give it no weight. As will become apparent later in these reasons for judgment I do not accept this submission. However, I have not accepted the views expressed by Dr Stevenson in this document to the extent that they are inconsistent with his prior evidence and that of the other experts.
I will now make a number of general observations about the evidence of the various expert witnesses, and the comparative weight to be accorded to their evidence.
Comparative weight to be given to the testimony of expert witnesses
No issue of credit arises in respect of any expert witness being untruthful or not attempting to assist the Court in accordance with their obligations, although issues of advocacy or lack of expertise or practical experience arise. No party contended that any of the experts were incompetent or dishonest, but they did contend that the evidence of some witnesses should be preferred.
I do not consider I can say that I generally prefer any one expert in any given field in respect of all topics relevant to that field, although in certain respects I have adopted the evidence of a particular expert over another expert. In some instances, for instance, a witness would give positive and thoughtful answers, consistent with their own and other testimony, whilst on other matters the same witness would be uncertain or inconsistent. In some instances, an element of hindsight intruded, which affected the relative weight to be given to that witness’s evidence.
Expert evidence was presented by way of concurrent evidence, involving joint reports and oral “hot tub” testimony. This approach to the receiving of expert evidence proved effective, efficient and time-saving. It focussed on the real scientific issues, and enabled the expert witnesses to express their views openly and without inhibition. Discussion between the experts themselves and cross-examination in most instances assisted in the process of developing the position of each expert, particularly in areas of disagreement or qualification. Whilst I accept that over the course of giving evidence (including the preparation undertaken therefore), an expert becomes more informed, I do place significant weight on any agreement reached in a joint expert report. After all, such agreement was reached after discussion amongst the experts, in circumstances where proper reflection could be had outside an unfamiliar forensic setting, and where there was little or no influence of a third party. Nevertheless, in a contest such as that found in this proceeding, the Court must rely heavily on the expert testimony, and adjudicate on any differences of expert opinion based upon a consideration of the evidence as a whole, including the oral testimony provided during the hearing.
In light of these observations, the preferable approach is to consider the evidence of each witness on a topic by topic basis to the extent necessary, and consider the impact of each expert witness’s testimony in that context.
THE PURITY PATENT
I turn first to the Purity Patent.
Title of the Purity Patent and Field of Invention
The specification of the Purity Patent is entitled “Optically pure salts of pyridinylmethyl sulfinyl-IH-benzimidazole compounds”.
The field of the invention is described at p 1, line 5 as:
The present invention is directed to new compounds with high optical purity, their use in medicine, a process for their preparation and their use in the manufacture of pharmaceutical preparation. The invention also relates to novel intermediates in the preparation of the compounds of the invention.
Background to the invention
The Purity Patent begins at p 1, lines 15 to 18 by explaining that omeprazole and its alkaline salts are effective gastric acid secretion inhibitors that are useful as antiulcer agents, and that those compounds exist as two optical isomers (enantiomers).
At lines 18 to 22, it is said that:
It is desirable to obtain compounds with improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of interindividual variation. The present invention provides such compounds, which are novel salts of the (-)-enantiomer of omeprazole.
The pharmacokinetic properties of a drug explain what happens to it once it is introduced into the body, generally according to three criteria: absorption, distribution and elimination. Elimination is the removal of a drug from the body via metabolism and excretion.
As noted above, the specification in its current form says that “novel salts of the (-)-enantiomer of omeprazole” are compounds with improved pharmacokinetic and metabolic properties which will give an improved therapeutic profile such as a lower degree of interindividual variation.
However, in the specification as filed, the invention was said to be “novel salts of single enantiomers of omeprazole”, that is, both the (-)-enantiomer and the (+)-enantiomer of omeprazole. Both enantiomers were said to have the improved pharmacokinetic and metabolic properties referred to in the specification. The specification was amended on 21 June 2000 to refer to the (-)-enantiomer of omeprazole only. This may explain why a number of the Examples in the Purity Patent do not relate to the compounds of the invention, but instead relate to the opposite enantiomer.
The specification acknowledges that the separation of the enantiomers of omeprazole has previously been described on both an analytical and preparative scale: p 1, lines 24 to 26.
The first publication referred to in the specification – “J. Chromatography, 532 (1990) 305-19” – is Erlandsson et al, “Resolution of the enantiomers of omeprazole and some of its analogues by liquid chromatography on a trisphenylcarbamoylcellulose-based stationary phase: The effect of the enantiomers of omeprazole on gastric glands”, 532 (1990) Journal of Chromatography 305-319 (‘Erlandsson 1990’). One author of Erlandsson 1990, Mr Per Lindberg, is an inventor of the Purity Patent. The specification identifies Erlandsson 1990 as a document describing the separation of the enantiomers of omeprazole on an “analytical” scale. More will be said about the scale on which separation of enantiomers is carried out in due course.
The second publication referred to in the specification – “DE 4035455” – is German patent application number DE 40 35 455 A1 (‘DE 455’). DE 455 describes, in terms, “optically pure compounds... or their salts with bases” including the (-)-enantiomer of omeprazole.
At p 2, lines 6 to 7 of the Purity Patent specification, it is said:
The present invention in a further aspect provides a novel method for preparing the novel compounds of the invention in large scale.
It is not contended by any party that any of the claims relating to the method or process for preparing the compounds of the invention is infringed or invalid.
At p 2, lines 11 to 13 the specification states:
There is no example known in the prior art of any isolated or characterized salt of optically pure omeprazole, i.e. single enantiomers of omeprazole, neither of any isolated or characterized salt of any optically pure omeprazole analogue.
Description of invention
A detailed description of the invention commences at p 2 of the specification. In one aspect, the invention is said, at lines 17 to 18, to provide Na+, Mg2+, Li+, K+, Ca2+ and N+(R)4 salts of the (-)-enantiomer of omeprazole, where R is an alkyl with 1-4 carbon atoms. The chemical name for the (-)-enantiomer of omeprazole is “(-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole”.
The most preferred salts according to the invention are said to be the optically pure Na+ salt of the (-)-enantiomer of omeprazole and the optically pure Mg2+ salt of the (-)-enantiomer of omeprazole: see p 3, lines 1 to 6.
Page 3, line 7 to p 4, line 8, describes a further aspect of the invention, being “a process for the preparation of compounds of the invention, ie, the salt of the (-)-enantiomer of omeprazole”. That process involves the separation of a diastereomeric mixture, followed by dissolving the separated diastereomer (comprising the (-)-enantiomer of omeprazole) in alkaline solution to give the “optically pure” (-)-enantiomer of omeprazole, which is then converted to the intended salt. That separation of diastereomeric mixture is exemplified in Examples 7 and 9. That dissolving of the separated diastereomer comprising the (-)-enantiomer of omeprazole in alkaline solution to give the (-)-enantiomer of omeprazole is exemplified in Example 10. The product of Example 10 has an enantiomeric excess of 94%.
At p 4, lines 10 to 21, it is said that in a further aspect the invention provides a process for the preparation of the (+)-enantiomer of omeprazole or the (-)-enantiomer of omeprazole, “to give the optically pure compound after neutralization with a neutralizing agent which can be an acid or an ester”. That step is described in Example 10 (as above) for the (-)-enantiomer of omeprazole and Example 11 for the (+)-enantiomer of omeprazole.
At p 4, lines 23 to 27, it is stated:
Thus, as indicated below, the direction of optical rotation of the enantiomers of omeprazole will change from (-) to (+) optical rotation and vice versa, from (+) to (-) optical rotation, when preparing the sodium salt from the neutral form (non-salt form) of omeprazole and when preparing the magnesium salt from the sodium salt of omeprazole.
The “(-)” rotation in the claims describes the rotation of the neutral (non-salt) form of the enantiomer of omeprazole. The invention is a salt of the neutral compound which has that (-) (namely, counter-clockwise) rotation, notwithstanding that the salt form may actually have a different rotation. For example, Example 1 describes the preparation of “(+)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole sodium salt”. That compound is the sodium salt of the (-)-enantiomer of omeprazole.
At p 5, lines 1 to 11, the specification states:
With the expression “optically pure Na+ salts of omeprazole” is meant the Na-salt of the (-)-enantiomer of omeprazole essentially free of the Na-salt of (+)-enantiomer of omeprazole. Single enantiomers of omeprazole have hitherto only been obtained as syrups and not as crystalline products. By means of the novel specific method according to one aspect of the invention of preparing the single enantiomers of omeprazole, the salts defined by the present invention are easy to obtain. In addition, the salts, however not the neutral forms, are obtained as crystalline products. Because it is possible to purify optically impure salts of the enantiomers of omeprazole by crystallisation, they can be obtained in very high optical purity, namely ≥ 99.8% enantiomeric excess (e.e.) even from an optically contaminated preparation.
I interpolate to observe that the optical purity (or enantiomeric purity) of a mixture describes the relative proportion of each enantiomer present in the mixture. Optical purity can be expressed as enantiomeric excess (e.e.). Enantiomeric excess is the difference between the percentage amounts of two enantiomers in a mixture. For example, a mixture with an optical purity of 95% of the (S)-enantiomer and 5% of the (R)-enantiomer has a 90% enantiomeric excess (ie 90% e.e.).
The specification continues, at p 5, lines 11 to 16:
Moreover, the optically pure salts are stable towards racemization both in neutral pH and basic pH, which was surprising since the known deprotonation at the carbon atom between the pyridine ring and the chiral sulphur atom was expected to cause racemization under alkaline conditions. This high stability towards racemization makes it possible to use a salt of the (-)-enantiomer of omeprazole in therapy.
It is to be recalled that racemisation is a process where the enantiomers in an enantiomerically-enriched compound interconvert, creating a racemate (a 1:1 mixture of the two enantiomers) and thereby resulting in a loss of optical activity.
At p 5, line 21 to p 6, line 7, the specification states that the compounds according to the invention may (like omeprazole) be used for, amongst other things, inhibiting gastric acid secretion in mammals and man and the treatment of gastric acid-related diseases, gastrointestinal inflammatory diseases and other gastrointestinal disorders. One of those disorders is gastro-oesophageal reflux disease, sometimes referred to as ‘GORD’.
Page 6, lines 9 to 20 identifies an intermediate compound, said to be a further aspect of the invention, used in the method of preparation.
A process for the preparation of “optically pure compounds of the invention, ie the salts of the (-)-enantiomer” is then described from p 6, line 24.
This process first involves isolation of the (-)-enantiomer by resolution of the diastereomeric mixture. Examples 7 and 10 exemplify the process.
The specification goes on, at p 7, line 29 to p 8 line 6, to describe the preparation of the “optically pure Na+ salts of the invention, ie the Na+ salt of the (-)-enantiomer of omeprazole”. This is done, for example, by treating the (-)-enantiomer “with a base, such as NaOH, [being sodium hydroxide] in an aqueous or nonaqueous medium”. It is said that in order to obtain the crystalline form of the Na+ salt, “addition of NaOH in a non-aqueous medium such as a mixture of 2-butanone and toluene, is preferred”. That preparation is exemplified in Example 1.
The specification then describes (p 8, lines 8 to 16) the preparation of the Mg2+ (magnesium) salt of the (-)-enantiomer.
The compounds of the invention include “salts with Li+, K+, Ca2+ and N+(R)4, where R is an alkyl with 1-4 C-atoms”. The salts referred to are lithium, potassium, calcium and tetra alkyl ammonium salts: see p 8, lines 18 to 21, and claim 1. The preparation of those salts is not exemplified in the Purity Patent.
At p 8, lines 23 to 25, it is said that optically pure compounds of the invention are formulated into pharmaceutical formulations for oral, rectal, parenteral or other modes of administration. Such pharmaceutical formulations are described at p 8, line 25 to p 10, line 24.
At p 10, line 30, the specification states:
The invention is illustrated by the following examples, which describe processes in which optically pure salts of omeprazole are prepared.
In fact, only Examples 1, 5 and A exemplify the preparation of an “optically pure salt” of the (-)-enantiomer of omeprazole. Examples 2, 3 and 4 relate to preparations of salts of the (+)-enantiomer. Examples 6 and 8 describe the preparation of synthetic intermediates (diastereomers) used in the preparation of the compounds of the invention. As noted above, Examples 7 and 9 describe the chromatographic separation of the diastereomers. Example 10 describes the preparation, from one of those diastereomers, of the (-)-enantiomer of omeprazole as a colourless syrup, with an enantiomeric excess of 94%. Example 11 describes the preparation, from one of those diastereomers, of the (+)-enantiomer of omeprazole as a colourless syrup, with an enantiomeric excess of 98%.
The best mode of carrying out the invention is said to be the use of the compounds described in Example 1 and 2, being “the sodium salts of the optically pure compounds of the invention”: p 20, lines 15 to 17 (although it is noted that the compound prepared in accordance with Example 2 is not a compound of the invention – it is the opposite (namely, (+)) enantiomer of omeprazole).
The pharmaceutical formulations “containing the compounds of the invention as active ingredient” are illustrated by the formulations described at p 20, line 21 to p 24, line 4, which in each case involve an active ingredient “according to the invention”: p 20, line 26; p 21, lines 15 and 30; p 22, lines 18 and 30; and p 23, line 29.
The stability of “optically pure compounds of the invention towards racemization” is described by reference to two racemisation experiments at p 24, lines 6 to 24. In the first, the optically pure compound of the invention is the (-)-enantiomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole. Example 10 describes the preparation of that compound. The second refers to optically pure “(+)-isomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole sodium salt”, which is the sodium salt of the (-)-enantiomer of omeprazole. Example 1 describes the preparation of that compound.
On 13 January 1997, AstraZeneca lodged amendments to the specification to include the following passage, which now appears at p 24, line 24 and p 25:
Some evidence of the improved pharmacokinetic and metabolic properties of the optically pure salts of pyridinylmethyl sulfinyl-1H-benzimidazole compounds according to the invention, is presented in the data set out in the accompanying drawings, which shows the advantageous effects for a single enantiomer of omeprazole, a well known pyridinylmethyl-sulfinyl-1H-benzimidazole, i.e. the sodium salt of (-)-omeprazole (identified as neutral (-)-omeprazole), over the sodium salt of the racemic omeprazole (EPO 124 495), in being the closest prior art herein.
The accompanying drawings, Fig 1 and Fig 2, are at p 1/1 of the specification.
Figure 1 is described, at p 25, lines 6 to 15, as showing the mean plasma levels of omeprazole (the racemate) in “rapid metabolisers” (also known as ‘fast’ or ‘extensive’ metabolisers) compared to the mean plasma levels of the (-)-enantiomer of omeprazole in rapid metabolisers. At p 25 lines 9 to 11, it is said that in rapid metabolisers, the “mean AUC at steady state of (-)-omeprazole was almost 90% higher than that of omeprazole”.
The “AUC” or ‘area under curve’ is the area bound by the curve created by plotting plasma concentration of a drug against time (this is referred to as a “plasma concentration time profile”). The AUC represents the total amount of the drug that a patient is exposed to. The AUC for omeprazole (the racemate) is smaller in Fig 1 than the AUC for the (-)-enantiomer of omeprazole. This means that when the (-)-enantiomer of omeprazole is administered (as opposed to the racemate of omeprazole), the patient is exposed to more of the drug.
Figure 2 is described, at p 25, lines 17 to 21, as showing the mean plasma levels of omeprazole (the racemate) in slow metabolisers compared to the mean plasma levels of the (-)-enantiomer of omeprazole in slow metabolisers.
The specification then states, at p 25, lines 21 to 24:
Thus, after correction for different dose levels, the resulting difference in AUC between slow and rapid metabolisers was almost 9-fold for racemic omeprazole and only 3-fold for (-)-omeprazole.
That is, a comparison of the AUC in Figs 1 and 2 for both omeprazole (racemate) and the (-)-enantiomer of omeprazole in both slow and rapid metabolisers shows that there was less variability in the metabolism of the (-)-enantiomer of omeprazole between slow and rapid metabolisers (ie less ‘interindividual variability’).
The specification then says, at lines 25 to 28:
Thus, the present invention provides salts of the single enantiomers of specific pyridinylmethyl sulfinyl-1H-benzimidazole compounds, having improved antisecretory effect suitable for use in the treatment of gastric acid related diseases.
As already noted, although the specification refers to the “single enantiomers”, the invention as now claimed relates only to the (-)-enantiomer of omeprazole.
The invention claimed in the Purity Patent
The specification concludes at p 26 with 37 claims. Relevantly, for the purpose of infringement and validity:
(a)Claim 1 is an independent claim for an optically pure salt of the (-)-enantiomer of omeprazole, “said compound having improved pharmacokinetic and metabolic properties with respect to antisecretory effect in the treatment of gastric acid related diseases” (emphasis added). This compound is characterised in being selected from Na+, Mg2+, Li+, K+, Ca2+ and N+(R)4 salts of the (-)-enantiomer of omeprazole, wherein R is an alkyl with 1-4 carbon atoms. The italicised words were added to claim 1 by the 1997 amendments.
(b)Claims 2 and 3 are dependent claims to particular alkaline salts.
(c)Claim 18 is a claim to a pharmaceutical preparation comprising an optically pure compound according to, inter alia, any of claims 1 to 3 as an active ingredient, in combination with a pharmaceutically acceptable carrier. Claim 19 and 20 are dependent claims thereon.
(d)Claim 21 is a claim to use of an optically pure compound according to, inter alia, any of claims 1 to 3, in formulating a pharmaceutical preparation suitable for inhibiting gastric acid secretion or for the treatment of gastrointestinal inflammatory diseases.
(e)Claims 22 to 24 are claims to a method of treatment for inhibition of gastric acid secretion, comprising administration of an effective amount of an optically pure compound according to, inter alia, any of claims 1 to 3 or an effective amount of a preparation of any one of claims 18 to 20.
(f)Claims 25 to 27 are claims to a method for the treatment of gastrointestinal inflammatory diseases comprising administration of an effective amount of an optically pure compound according to, inter alia, any of claims 1 to 3, or an effective amount of a preparation of any one of claims 18 to 20.
Ranbaxy has made certain admissions to the effect that claims 1 to 3 and 18 to 27 of the Purity Patent are infringed, subject to the Court’s determination of the validity of those claims. As will be explored further in due course, Ranbaxy seeks to revoke those claims on the grounds of lack of novelty, lack of inventive step and lack of manner of manufacture.
It is necessary, before going to these specific grounds, to deal with the issue of the skilled addressee and the proper construction of the Purity Patent.
The skilled team and the evidence
Relevant principles and their application to this case
The parties accepted that the relevant principles regarding the identity of the skilled addressee in the context of the construction inquiry are as set out in my decision in Britax Childcare Pty Ltd v Infa-Secure Pty Ltd (2012) 96 IPR 1; [2012] FCA 467 at 43 to 45, [238]-[250]; and more generally in Eli Lilly and Company Ltd v Apotex Pty Ltd [2013] FCA 214 at [167] and following.
The following recent statement from Jagot J in Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162 usefully summarises the position (at [94]):
… [I]t is important to understand that the skilled addressee is not a reference to a specific person but is a legal construct (Root Quality Pty Ltd v Root Control Technologies Pty Ltd (2000) 177 ALR 231; [2000] FCA 980 at [71]). The legal construct may not be a single person but may be a team of persons “whose combined skills 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” (General Tire & Rubber Co v Firestone Tyre & Rubber Co Ltd [1972] RPC 457 at 485) (General Tire). And as Watson and Ascent also said:
A patent specification is addressed to those likely to have a practical interest in the subject matter of the invention, and such persons are those with practical knowledge and experience of the kind of work in which the invention is intended to be used. The addressee comes to a reading of the specification with the common general knowledge of persons skilled in the relevant art, and they read it knowing that its purpose is to describe and demarcate an invention. The person skilled in the art is unimaginative without inventive capacity.
It is well-established that the hypothetical skilled addressee may be a team whose combined skills 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. It is accepted that the combined skills of a team would be required for the purposes of this proceeding.
The first step in identifying the membership of the skilled team is to identify the field of knowledge to which the invention relates.
In this proceeding, the relevant field is pharmaceuticals – specifically, those related to gastric acid-related diseases. The impugned claims of the Purity Patent are directed to certain identified optically pure salts of a single compound, and pharmaceutical preparations and treatment methods relating to those salts.
The skilled team for the Purity Patent is therefore a team of scientists working in the field of gastrointestinal disorders with a particular interest in the treatment of gastric acid-related diseases, involved in a research project to find a new pharmaceutical compound as at 28 May 1993, which (it will be recalled) is the priority date for the Purity Patent.
It seemed to be uncontroversial that the team would include:
(a)a medicinal chemist (ie an organic chemist);
(b)a pharmacologist; and
(c)a person familiar with the preparation of pharmaceutically acceptable salts.
Ranbaxy contended that the medicinal chemist would “normally be involved in the resolution of enantiomers and the testing of their properties”. Whether a medicinal chemist would “normally be involved” in such activity as at May 1993 is one of the many issues in contest in the proceeding. In AstraZeneca’s submission, the evidence does not support the proposition that a medicinal chemist on such a team would normally have had such involvement as at May 1993. In fact, it was submitted that the evidence shows that the standard approach to drug development was by the investigation of structure-activity relationships (described by Senior Counsel for Ranbaxy as the “analogue route”), and not by investigation of enantiomers. However, since the organic chemistry experts both have experience in the resolution and testing of enantiomers, this issue has no bearing on their capacity to give evidence as expert medicinal chemists, and their ability to assist on construction.
Ranbaxy also contended that the team would have included “a gastroenterologist (who would have clinical experience in the use of omeprazole)”. While AstraZeneca did not accept that the team would have included a gastroenterologist, they accepted that the team would have taken advice from gastroenterologists with clinical experience in the use of omeprazole from time to time. I think that very little rests on this distinction, although it may be significant insofar as it relates to “motivation” in the context of inventive step. I would include a gastroenterologist in the team. The extent of and timing of the contribution of this team member is a matter which may impact upon the team’s ultimate deliberations and its motivation to proceed in any particular direction. I will return to this issue later.
Construction
I now turn to the construction issues.
Summary of issues for the Court to determine
The key Purity Patent construction issue for determination is the meaning of the expression “optically pure salt of [(-)-omeprazole]” in claim 1. AstraZeneca contended that “optically pure” means greater than or equal to 98% enantiomeric excess (e.e.). That is to say, to be considered to be “optically pure” in this context, the preparations must contain at least 99% of the salt of the (-)-enantiomer of omeprazole, with no more than 1% of the (+)-enantiomer. In contrast, Ranbaxy contended that “optically pure” has its “ordinary meaning” – namely, it means greater than or equal to 90% e.e. (with the consequence that a salt of the (-)-enantiomer of omeprazole containing 5% of the (+) enantiomer would be “optically pure” for the purpose of this patent).
The issue is not relevant to infringement. Ranbaxy accepts that if the Purity Patent is held to be valid, then their products will infringe regardless of the outcome of this construction issue. No party contended that the claims lack clarity. Rather, the determination of the construction issue impacts only on the question of validity.
A further construction issue is the meaning to be given to the words “said compound having improved pharmacokinetic and metabolic properties with respect to antisecretory effect in the treatment of gastric acid related diseases” in claim 1.
Legal principles
The parties accepted the principles of construction reviewed and summarised in Eli Lilly [2013] FCA 214 at [139] to [144]. Nevertheless, certain points should be repeated, all of which are well settled.
The words of the patent should be read through the eyes of the skilled addressee in the context in which they appear. That is, the words are to be given the meaning which the person skilled in the art would attach to them, having regard to his or her own general knowledge and to what is disclosed in the body of the specification. The notional skilled addressee “is expected to read the specification on the assumption that its purpose is both to describe and to demarcate an invention”: see Dynamite Games Pty Ltd v Aruze Gaming Australia Pty Ltd [2013] FCA 163 at [192].
Of course, the Court has the ultimate responsibility for interpreting the patent: no one witness’s view however ‘skilled’ that witness may be, is to dictate the Court’s conclusion as to the proper interpretation of a patent.
In the case of terms with a scientific or industry meaning, evidence as to the meaning of such terms ought be received by the Court. If there is no such special meaning, then the Court can rely upon the ordinary meaning of the term or terms, albeit in the context of the science of the patent. A patent, of course, may provide its own dictionary of particular terms used in the patent and the claims.
Patents are to be given a purposive construction and the subject matter of a patent is not confined to the literal meaning of the claim.
Above all, the Court should approach the task of patent construction with a generous measure of common sense.
It is useful to set out the contentions of Ranbaxy on the first construction issue.
Ranbaxy’s submissions on construction
Ranbaxy contended that the Purity Patent does not describe the invention by reference to any specific level of optical purity. In particular, there was said to be “no indication in the Purity Patent that any level of optical purity is required to achieve the practical function of the invention”, namely, providing patients with a compound having improved pharmacokinetic and metabolic properties. As a result, it was submitted, “optically pure” should be given its ‘conventional meaning’.
Ranbaxy then contended that the accepted, conventional meaning of “optically pure” is 90% e.e. (which equates to 95% enantiomeric purity). In the abstract, Professor Davies and Dr Pyter were prepared to accept 90% e.e. as a ‘conventional’ meaning of “optically pure”. That level of purity was one which was said to permit statistically meaningful tests to be performed to determine the properties of enantiomers. In contrast, Dr Stevenson did not agree that there was any “conventional” meaning of this term at the priority date. However, despite these conclusions about what may constitute a conventional meaning of optically pure, the experts agreed that absent any indication of how optical purity is measured in a particular case, the expression has no meaning. I will return to this point later in these reasons for judgment.
The experts disagreed on the level of optical purity required by claim 1 of the Purity Patent. I consider there was a difference of approach: some of the experts seemed to proceed on the basis that “optically pure” must be defined with respect to a specific number in the patent specification. For example, Dr Stevenson said that the only number he could find for this purpose was 99.8%, which was found on p 5 at line 10. Professor Davies reviewed the Purity Patent and focused on the language at p 10 and the Examples, and ultimately adopted a figure of 98% e.e.. In contrast, Dr Pyter did not consider there to be a need to find a number in the patent specification, and interpreted claim 1 by reference to what he deemed to be the ‘conventional’ meaning of “optically pure”.
It was submitted by Ranbaxy that AstraZeneca’s construction of “optically pure”, namely, 98% e.e., should not be accepted because it represents the high or very high optical purity value that is shown to be achievable in examples of only two of the claimed salts. Although the expression “optically pure” is apt to include such a high e.e. value, Ranbaxy contended that it is used in the specification in such a way that makes it clear that the meaning is not limited to that high value.
To this end, it was contended by Ranbaxy that the specification distinguishes between “optically pure” compounds and compounds with “high optical purity” or “very high optical purity”: see, for example, p 1, line 5 and p 5, line 9 of the specification. The “very high” optical purity at p 5, line 9 is the product of crystallisation. The “optically pure” salts of claim 1 are not limited to salts in crystalline form. Rather, that limitation is introduced by dependent claims.
Ranbaxy then drew attention to the fact that the compounds of the invention are said to be “novel salts of the (-)-enantiomer of omeprazole”: at p 1, lines 20 to 22. Ranbaxy submitted that at p 2 lines 11 to 12, the specification refers to a:
salt of optically pure omeprazole, i.e. single enantiomers of omeprazole” (emphasis added) and at page 6, line 24 to “The optically pure compounds of the invention, i.e. the salts of the (-)-enantiomer…” (emphasis added)
It was argued that there was no suggestion here that the specification uses the term “optically pure” to mean high optical purity or very high optical purity, or in any way other than its ordinary meaning.
Ranbaxy then referred to the unamended specification, which at p 5 line 24 read: “The optically pure compounds of the invention, i.e. the single enantiomers…”. It was submitted that the expression “optically pure” had a broader meaning than the particular level of optical purity achieved in the examples of two of the salts of the single enantiomers set out elsewhere in the specification.
Ranbaxy further contended that the specification acknowledges that the separation of the enantiomers of omeprazole is described in the prior art, for example, in Erlandsson 1990 and DE 455. Erlandsson 1990 reports the separation of the (-)-enantiomer of omeprazole with an enantiomeric excess of 91.2%. DE 455 discloses, in terms, “optically pure compounds of Formula I… or their salts with bases”, including the (-)-enantiomer of omeprazole.
Ranbaxy argued that the specification distinguishes the invention in the Purity Patent by asserting, “[t]here is no example known in the prior art of any isolated or characterized salt of optically pure omeprazole…” (emphasis added): p 2, lines 11 to 14. It was then contended that this is not suggesting that the compounds obtained in Erlandsson 1990 (91.2% e.e.) and DE 455 (“optically pure”) were not optically pure in accordance with the way that term is used in the Purity Patent; just that those compounds were not in salt form.
Ranbaxy then went to the Examples. The invention is said to be “illustrated by” the Examples: see p 10, line 30. The Examples show a variety of measurements of optical purity ranging from 94% to 99.9% e.e.. As already alluded to, only three of those Examples (Examples 1, 5 and A) actually relate to the invention as claimed in claim 1 (namely, optically pure salts of the (-)-enantiomer of omeprazole).
Ranbaxy reminded the Court that it is not legitimate to read down the ordinary meaning of the term “optically pure” in the claims by drawing an impermissible gloss from particular Examples in the specification, or to use those Examples to introduce into the words of claim 1 a numerical qualification: Welch Perrin and Company v Worrel (1961) 106 CLR 588 at 610; Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 at 478; Kimberly-Clark Australia Pty Limited v Arico Trading International Pty Limited (2001) 207 CLR 1 at 12 [15]; Pfizer Overseas Pharmaceuticals v Eli Lilly and Company (2005) 68 IPR 1; [2005] FCAFC 224 at 52 [247]; PAC Mining Pty Ltd v Esco Corp (2009) 80 IPR 1; [2009] FCAFC 18 at 14 [28]; and Britax Childcare (2012) 96 IPR 1; [2012] FCA 467 at 49 [272].
Ranbaxy then contended that the specification refers to “optically pure” compounds which are not the subject of any of the Examples in the Purity Patent. For example, “salts with Li+, K+, Ca2+ and N+(R)4 salts of the (-)-enantiomer of omeprazole, where R is an alkyl with 1-4 C-atoms” (p 8, lines 18 to 21 and claim 1), and the “optically pure Mg2+ salt... prepared by treating the (-)-enantiomer of omeprazole with a base… in a non-aqueous solvent”(at p 8, lines 11 to 13). There is no Example relating to the preparation of these compounds or, in the case of the “optically pure Mg2+ salt”, the preparation of this compound in this manner. These salts are, however, claimed in, inter alia, claims 1 and 15 as “optically pure” salts. It was then contended that there was no reason to suppose these salts of the invention have a particular optical purity greater than (as ordinarily understood) 90% e.e.. Therefore, Ranbaxy submitted, in the context of at least these salts, the skilled addressee can only sensibly assume that “optically pure” has its conventional meaning and is not to be limited to a particular numerical limit in a particular Example.
Ranbaxy further submitted that the pharmaceutical formulations referred to at pp 20 to 21 of the specification that contain “the compounds of the invention as active ingredient” are not fixed to the product of any Example, or otherwise limited to the (-)-enantiomer of omeprazole with a particular enantiomeric excess greater than “optically pure”.
Further, it was noted by Ranbaxy that the “evidence of the improved pharmacokinetic and metabolic properties of the optically pure salts of pyridinylmethyl sulfinyl-1H-benzimidazole compounds according to the invention” is not said to be limited to the salts of any particular (or indeed any) Example: see p 24.
Reference was also made by Ranbaxy to Example 10. It was submitted that “optically pure” is used to describe the product of Example 10, which has an enantiomeric excess of 94%. That description was contended to be consistent with the ordinary meaning of “optically pure”. The following examples in support were given (emphases as per Ranbaxy’s submissions):
(a)The process at p 4, lines 6 to 7 for the preparation of “optically pure (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole compound” (the (-)-enantiomer) is exemplified in Example 10.
(b)The process at p 4, lines 19 to 20 for the preparation of the (+)-enantiomer of omeprazole or the (-)-enantiomer of omeprazole to give the “optically pure compound after neutralization with a neutralizing agent” is also exemplified in Example 10 (where that compound is the (-)-enantiomer of omeprazole).
(c)The stability of “optically pure compounds of the invention towards racemisation” is described by reference to an experiment with the (-)-isomer of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl]sulfinyl]-1H-benzimidazole. Example 10 describes the preparation of that compound.
(d)Claim 6 claims a process for the preparation of an optically pure compound according to claim 1, characterised in that a diastereomeric mixture of an ester is separated to obtain separated diastereomers, whereafter one of the diastereomers is dissolved in an alkaline solution to give “the optically pure (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)-methyl] sulfinyl]-1H-benzimidazole compound”. This is the product of Example 10.
(e)Claim 28 claims a process for the preparation of the (+)-enantiomer of omeprazole or the (-)-enantiomer of omeprazole to give the “optically pure compound after neutralization with a neutralizing agent”. That process, as it relates to the (-)-enantiomer of omeprazole, is exemplified in Example 10.
(f)Claim 35 claims as the invention the compound obtained by, inter alia, the process exemplified in claim 28, and thus claims the product of Example 10.
Construction – Analysis
First Issue: “Optically Pure”
As previously foreshadowed, Professor Davies, Dr Stevenson and Dr Pyter agreed that “optically pure” will normally take its meaning from the context in which it is used, including, in part, the nature and extent of identified measuring standards used to ascertain a particular level of optical purity.
Therefore, the Court, guided by evidence concerning the approach of the skilled addressee, will look for the context in which the term “optically pure” is used in the Purity Patent.
In my view, the Purity Patent has provided its own context or “internal dictionary” for the expression “optically pure”. At p 5, lines 1 to 11, it states:
With the expression “optically pure Na+ salts of omeprazole” is meant the Na-salt of the (-)-enantiomer of omeprazole essentially free of the Na-salt of (+)-enantiomer of omeprazole. Single enantiomers of omeprazole have hitherto only been obtained as syrups and not as crystalline products. By means of the novel specific method according to one aspect of the invention of preparing the single enantiomers of omeprazole, the salts defined by the present invention are easy to obtain. In addition, the salts, however not the neutral forms, are obtained as crystalline products. Because it is possible to purify optically impure salts of the enantiomers of omeprazole by crystallisation, they can be obtained in very high optical purity, namely ≥99.8% enantiomeric excess (e.e.) even from an optically contaminated preparation. Moreover, the optically pure salts are stable towards racemization both in neutral pH and basic pH, which was surprising since the known deprotonation at the carbon atom between the pyridine ring and the chiral sulphur atom was expected to cause racemization under alkaline conditions. This high stability towards racemization makes it possible to use a salt of the (-)-enantiomer of omeprazole in therapy.
I accept this as the “internal dictionary”, and I further accept that the passage draws a distinction between three levels of optical purity: first, “optically pure salts”, which are “essentially free” of the (+)-enantiomer; secondly, salts of a “very high optical purity”, namely ≥ 99.8% e.e.; and thirdly, an “optically contaminated” preparation. On this basis, and for the reasons that follow, I consider that the construction put forward by AstraZeneca is to be preferred – namely, that “optically pure” means ≥ 98% e.e..
The Examples in the Purity Patent are introduced by the words: “The invention is illustrated by the following examples, which describe processes in which optically pure salts of omeprazole are prepared” (p 10, lines 30 to 32; emphasis added). The only “salts of omeprazole” identified in the subsequent examples are those described in Examples 1 to 5, A and B. It follows that each of those salts of omeprazole may be characterised as “an optically pure salt”.
Further, each of the optically pure salts exemplified in Examples 1 to 5 and A and B has an enantiomeric excess of at least 98%. I find this fact to be very significant in determining this construction point.
Example 1 (p 11, line 7) refers to a preparation “contaminated with 3% of the (+)-isomer”, and Example 2 (p 11, line 20) refers to a preparation “contaminated with 3% of the (-)-isomer”. From each of those preparations, a sodium salt of an enantiomer of omeprazole with an optical purity greater than or equal to 99.8% e.e. is derived. A preparation “contaminated with 3%” of the other enantiomer has an enantiomeric excess of 94% (calculated by deducting 3% from 97%).
The preparations “contaminated with 3%” of the other enantiomer identified in Examples 1 and 2 are the preparations to which reference is made by the expression “an optically contaminated preparation” appearing on p 5, lines 10 to 11 of the Purity Patent. The use of this expression is in contradistinction to the “optically pure” salts of the invention also referred to in that passage on p 5.
Accordingly, the Purity Patent draws a distinction between:
(a)an “optically pure salt” of one enantiomer of omeprazole, being a salt (specifically a sodium salt, in the context of p 5 of the specification) which is “essentially free” of the other enantiomer; and
(b)a salt of an enantiomer that is “contaminated with 3%” of the other enantiomer.
Further, the proposition that an “optically pure salt of (-)-[omeprazole]” as referred to in claim 1 means a salt of 98% e.e. or more is supported by the following:
(a)the distinction drawn on p 5 between an “optically pure salt” that is “essentially free” of the (+)-enantiomer and a salt of “very high optical purity” (namely, ≥ 99.8% e.e.); and
(b)the inclusion, in the descriptive expression “[t]he invention is illustrated by the following examples, which describe processes in which optically pure salts of omeprazole are prepared” at p 10 at lines 30 to 31, of salts in the Examples with an optical purity of between 98% e.e. and 99.8% e.e..
None of the Examples expressly describes any salt of any enantiomer of omeprazole with an optical purity lower than 98% e.e. as being “optically pure”. Nor does any other part of the Purity Patent.
Even though only Examples 1, 5 and A exemplify the preparation of an optically pure salt of (-)-omeprazole, I accept that all of Examples 1 to 5, A and B are relevant to construing the meaning of the phrase “optically pure salt” in claim 1.
The “optically pure salts” of Examples 1 to 5, A and B are clearly differentiated from the compounds of Examples 6 to 11. First, Examples 6 to 11 are not salts. Secondly, Examples 6 to 11 are introduced by the words “[p]reparation of the synthetic intermediates according to the invention will be described in the following examples” (at p 15, lines 31 to 32). These are non-salt intermediate compounds, and I accept that their optical purities, to the extent they are reported, cannot be determinative or informative of the meaning of “optically pure salt” in the claims.
The principles of construction have been referred to earlier in this judgment, in the context of the Purity Patent.
AstraZeneca, in the context of the construction debate relating to the 774 Patent, submitted that the Court should not adopt a narrow, non-purposive interpretation of the key integers, or impose limitations on those integers. This was the way they described the approach taken by Ranbaxy to the construction issues.
It was also said that Ranbaxy’s approach to the construction of the claims of the 774 Patent was misconceived and contrary to the accepted principle explained by Bennett J in SachtlerGmbH & Co KG v RE Miller Pty Ltd (2005) 65 IPR 605; [2005] FCA 788 at 613 [42] that:
Although the claims are construed in the context of the specification as a whole, it is not legitimate to narrow or expand the boundaries of monopoly, as fixed by the words of a claim, by adding to those words glosses drawn from other parts of the specification. If a claim is clear and unambiguous, it is not to be varied, qualified or made obscure by statements found in other parts of the document.
In guiding the Court as to the proper approach to construction, Ranbaxy also referred to the comments made in Populin v HB Nominees Pty Ltd (1982) 41 ALR 471, where the Full Court of the Federal Court (Bowen CJ, Deane and Ellicott JJ), said at p 476:
The essential features of the product or process for which it claims a monopoly are to be determined not as a matter of abstract uninformed construction but by a common sense assessment of what the words used convey in the context of then-existing published knowledge.
First principal construction issue
Of the principal construction issues, the central debate is about the term “core material”. Of course, the term must be read in context of claim 1, and the specification as a whole.
There is no scientific or industry meaning of “core material”. It is an expression of ordinary English, although it may be used in various ways in the context of the 774 Patent.
It is necessary to look at the whole specification in some detail to assist in determining the meaning of the term “core material” in claim 1. As I go through the specification, I will emphasise the word “core”, and the relevant phrases which include the words “core” or “core material”. This will help the reader follow the various ways in which the word “core” is used. In each context, the various references I make support the conclusion I have reached as to the meaning of “core material” in claim 1.
The conclusion I have reached is as follows.
In essence, in the context of claim 1, the dosage form comprises “a core material”, with “said core material” “having” a water soluble separating layer “thereon”. There is a specific reference to core material, specifically defined as having a specific water soluble separating layer thereon. The dosage form is then “characterized” as referring to the “core material” being alkaline reacting, with the separating layer described as to its composition and formation. There is a very clear distinction drawn between core material and coating layers (enteric or separating). Therefore, the reference to core material does not include a coating layer.
This clear description in claim 1 has no ambiguity, and is consistent with the concept of the invention.
Claim 1 of the 774 Patent does not describe an oral pharmaceutical dosage form with an applied separating layer being part of the core material. In the context of the 774 Patent, “core material” is defined in claim 1 according to what it actually contains. In this sense, it means the material in the centre of the dosage form (containing the API, alkaline reacting compound and any pharmaceutically acceptable excipients), on which the functioning layers may be subsequently formed. This definition of “core material” necessarily excludes any layers applied to the core material as defined, including coating layers that do not contain API.
I now go to the specification, upon which both sides relied for their own interpretation of claim 1.
The invention as described in the patent
The 774 Patent begins on pp 1 to 6 by identifying certain PPIs. The specification states, at p 6, lines 5 to 10:
The proton pump inhibitors used in the dosage forms of the invention may be used in neutral form or in the form of an alkaline salt, such as for instance the Mg2+, Ca2+, Na+, K+ or Li+ salts, preferably the Mg2+ salts. Further where applicable, the compounds listed above may be used in racemic form or in the form of a substantially pure enantiomer thereof, or alkaline salts of the racemates or the single enantiomers.
At p 7, lines 9 to 11 it is recorded that these PPIs are susceptible to degradation or transformation in acidic reacting and neutral media:
The degradation is catalyzed by acidic reacting compounds and the proton pump inhibitors are usually stabilized in mixtures with alkaline reacting compounds.
It follows, it is said, at lines 13 to 15, that “it is obvious that a proton pump inhibitor in an oral solid dosage form must be protected from contact with the acidic reacting gastric juice”. The skilled addressee would understand that, otherwise, the PPI will be degraded in the acidic environment in the stomach before it reaches the part of the gastrointestinal tract where absorption of the PPI can occur.
The specification records that a pharmaceutical dosage form of such PPIs is best protected from contact with acidic gastric juice by an enteric coating layer: see p 7, lines 20 to 21. An example is given of such “enteric coated preparations” at lines 21 to 22, and it is then stated that (emphasis added):
Said preparations contain an alkaline core material comprising the active substance, a separating layer and an enteric coating layer.
Three separate items are addressed here, as emphasised (namely, the alkaline core material, the separating layer, and the enteric coating layer).
However, the problem is that the PPI might also react with some acidic compound in the enteric coating layer itself. At p 7, lines 26 to 31, the specification states (emphasis added):
Ordinary enteric coating layers, however, comprise compounds which contain acidic groups. If covered with such an enteric coating layer, the acid labile substance may rapidly decompose by direct or indirect contact with the acidic groups resulting in discoloration of the content and loss in content of the active compound with the passage of time. The discoloration can be avoided by applying some type of separating layer between the core material comprising the susceptible proton pump inhibitor and the enteric coating layer.
Three separate items are again addressed here, as emphasised.
The specification states that the prior art pharmaceutical dosage forms included a separating layer between “a core material” and an enteric coating layer: p 8, lines 1 to 3 (emphasis added):
Thus, there are a lot of patent applications describing such a separating layer between a core material comprising the pharmaceutically active substance and an enteric coating layer. See for instance, US-A 4,786,505, EP 0,277,741 and EP 0,342,522.
Again, three separate items are referred to here.
“US-A 4,786,505” is a reference to US 505 (being AstraZeneca’s patent dated 22 November 1988, that has already been the subject of discussion in these reasons).
The specification further states, at p 8, lines 3 to 7 (emphasis added):
The prior art techniques to apply at least two different layers on a pellet core or a tablet comprising an acid labile compound is rather complicated and there is a demand for finding new processes and formulations to simplify the manufacturing of such enteric coated articles comprising acid labile substances.
This passage indicates that the terms “pellet core” and “tablet” are interchangeable. The reference here to “pellet core” as a tablet is only in the context of discussing techniques to apply at least two different layers, and the complications involved. This obviously follows on from the earlier reference in the very same paragraph to the prior art patent applications, which I have already noted draws a clear distinction between the separating layer, core material, and enteric coating layer.
Aspects of the invention
There are said to be two aspects of the invention. Under the heading “Summary of the Invention” at p 8, the first aspect of the invention is said to be (at p 8, lines 9 to 16; emphasis added):
…an oral pharmaceutical dosage form comprising a core material that contains a proton pump inhibitor, one or more alkaline reacting compound(s) and optionally pharmaceutically acceptable excipients, said core material having a water soluble separating layer thereon, with an enteric coating layer thereupon, characterized in that the core material is alkaline reacting and that the separating layer comprises a water soluble salt of an enteric coating polymer(s) and is formed in situ during the enteric coating.
It is said, at p 8, lines 17 to 20, “[t]he separating layer between the alkaline reacting core material comprising the indicated pharmaceutically active acid labile substance and the enteric coating layer, importantly comprises a water soluble salt of an enteric coating polymer”.
In relation to the second aspect of the invention, it is said at p 8, lines 24 to 27:
…the present invention provides a process for the manufacture of two functionally different layers in one manufacturing step. By such a process a separating layer comprising a water soluble salt of an enteric coating polymer is obtained, as well as the enteric coating layer itself.
As previously noted, the complete specification describes the invention as simplifying the preparation of enteric coated pharmaceutical dosage forms by providing a process for the manufacture of two functionally different layers in one manufacturing step: p 8, lines 28 to 30.
By this process, it would appear that the core or core material is the base upon which to work and build up on in the preparation of the invention.
Importantly, the 774 Patent goes on to say (emphasis added):
Thus, the present invention simplifies the preparation of enteric coated articles comprising a separating layer between a core material and an enteric coating layer by providing a new process for the manufacture of such dosage forms. According to said process the separating layer is formed by an in situ reaction between the enteric coating polymer and the alkaline core material comprising the pharmaceutically active substance.
Again, the distinction between the three separate items (core material, separating layer and enteric coating layer) is clear. The in situ reaction occurs between a specifically defined core material, and the enteric coating polymer.
As recorded on p 9, lines 1 to 2, Fig 1 in the 77 Patent is a photograph showing a cross-section of a tablet manufactured according to the invention. Then (again of some significance), the 774 Patent describes Fig 2 (being a schematic drawing of the photograph disclosed in Fig 1) as follows (emphasis added):
The tablet has an enteric coating layer (3), which has been applied on an alkaline core material (1) comprising the pharmaceutically active substance. Between the enteric coating layer (3) and the core material (1) there is a separating layer (2) shown.
The distinction is again clear: there is an enteric coating layer “which has been applied on an alkaline core material”, which comprises the active substance. Then there is the separating layer. Figures 1 and 2 of the 774 Patent are set out in “Annexure A” to these reasons.
A detailed description of the invention commences at p 9 of the specification.
At p 9, line 28 to p 10, line 5, it is said that (emphasis added):
Compacted tablets or individual cores (in the form of small tablets, small beads, granules or pellets) contain the proton pump inhibitor in the form of a racemate or one of its single enantiomers or an alkaline salt of said compound or one of its single enantiomers. The tablets or individual cores, that also comprise one or more alkaline reacting compound(s) which is in the position to form a water soluble salt by a reaction with an enteric coating material, are coated with one or more enteric coating layers.
This is introduced as the further characterisation of the new dosage form, and is not meant to change any of the basic tenets of the invention.
In fact, the 774 Patent goes on to say immediately after this reference, at p 10, lines 6 to 8 (emphasis added):
The separating layer is formed in situ by a reaction between the enteric coating polymer(s) and the alkaline reacting compound(s) in the core material during the enteric coating process.
The “core material” (so specifically mentioned) can be prepared according to two main processes, set out at p 10, lines 12 to 15 (emphasis added):
Firstly, seeds can be layered with the proton pump inhibitor, alkaline reacting compound(s) and necessary excipients to give an alkaline reacting core material, or the alkaline reacting core material can be prepared as substantially homogeneous cores or tablets comprising the proton pump inhibitor and the alkaline reacting compound(s).
Layered seeds are a particle or substrate (eg a sugar sphere) upon which one or more layers of active substances are applied. Homogeneous cores involve the preparation of the core material by mixing the active substance with alkaline compounds and suitable constituents (without a seed).
Then the 774 Patent continues at p 10, lines 16 to 18 (emphasis added):
The alkaline reacting compound(s) in the core material or tablet cores, necessary for an in situ reaction with the enteric coating polymer, is a substance in the position to form a water soluble salt with an enteric coating polymer.
This shows that in this patent, core material and tablet cores are treated for all practical purposes as the same thing.
Then in the same context, it is also said, at p 10, lines 29 to 31, that (emphasis added):
The core material as such should be an alkaline reacting core material, i.e. the amount of alkaline reacting compound(s) available in the core material should be enough to form a salt between the enteric coating polymer(s) and the alkaline reacting compound(s).
That is, there must be enough alkaline reacting compound(s) in the core material to form the claimed separating layer in situ by a reaction between the enteric coating polymer(s) on the one hand, and the alkaline reacting compounds of the core material on the other.
The concentration of alkaline reacting compounds in the core material is described at p 11, lines 1 to 16. It is said (emphasis added):
Thus, the concentration of alkaline reacting compound(s) in the core material (before applying the enteric coating polymer) is from approximately 0.1 mmol/g dry ingredients in the alkali containing part of the core material up to approximately 15 mmol/g, preferably the concentration shall be more than 0.3 mmol/g dry ingredients in the alkaline part of the core material.
It is then said, at lines 8 to 13 (emphasis added):
The upper limit range is only restricted by the need to include a pharmaceutically active ingredient and excipients such as binders etc in the alkaline core material. The concentration of alkaline reacting compound(s) may be illustrated as follows. For a core material where, for instance, 10% w/w of a proton pump inhibitor and 5% w/w of excipients (binders, surfactants etc) are to be included, 85% w/w remains to possible disposition to the alkaline reacting compound(s)…
It is then said, at p 11, line 18, that “[o]ne or more enteric coating layers are applied onto the prepared core material or tablets…” (emphasis added).
The preparation of the core material is described at p 12 line 6 to p 13 line 25 of the specification (emphasis added):
The preparation of the core material containing the proton pump inhibitor and alkaline reacting compound(s) is described more in detail below. The individually enteric coated cores can be constituted according to different principles.
The active substance, the proton pump inhibitor, used as a racemate or one of its single enantiomers or an alkaline salt of said compound or one of its single enantiomers, mixed with the alkaline reacting compound(s) is applied on seeds and are used for further processing.
The seeds, which are to be layered with the active substances, can be water insoluble seeds comprising different oxides, celluloses, organic polymers and other materials, alone or in mixtures or water soluble seeds comprising different inorganic salts, sugars, non-pareils and other materials, alone or in mixtures. Further, the seeds may comprise active substance in the form of crystals, agglomerates, compacts etc. The size of the seeds is not essential for the present invention but may vary between approximately 0.1 and 2 mm. The seeds layered with active substance are produced either by power or solution/suspension layering using for instance granulating or spray coating/layering equipment.
Before the seeds are layered, the active substance is mixed with alkaline reacting compound(s) and further components to obtain preferred handling and processing properties and suitable concentration of the active substance. Pharmaceutical constituents such as fillers, binders, lubricants, disintegrating agents, surfactants and other pharmaceutically acceptable additives, can be used. Binders are for example celluloses such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and carboxymethylcellulose sodium, polyvinylpyrrolidone, sugars, starches and other pharmaceutically acceptable substances with cohesive properties. Suitable surfactants are found in the groups of pharmaceutically acceptable non-ionic or ionic surfactants such as a for instance sodium lauryl sulphate or polysorbates.
Alternatively, the active substance mixed with alkaline compound(s) and further mixed with suitable constituents can be formulated into tablets or individual cores. Said tablets or cores may be produced by compression/extrusion/spheronization or balling utilizing different processing equipments. The manufactured tablets or cores can further be layered with additional ingredients comprising active substance and alkaline reacting compound(s) and/or be used for further processing.
The active substance may optionally be mixed with alkaline pharmaceutically acceptable substance (or substances) for further stabilisation. Such substances can be chosen among, but are not restricted to, substances such as for instance the above mentioned alkaline reacting compounds or other alkaline reacting substances known by the skilled person in the art to be useful as stablizers for acidic susceptible substances.
Alternatively, the aforementioned alkaline reacting core material can be prepared by the use of spray drying or spray congealing technique.
The prepared alkaline reacting core material in the form of tablets or pellets are spray coated with an aqueous enteric coating polymer dispersion/solution. The process parameters such as inlet air temperature, air flow, atomizer air flow and spraying rate are adjusted with respect to the equipment used for the process as well as the specific enteric coating polymer(s). The inlet air temperature must not be such that the enteric coating polymer(s) will block in the spraying nozzles.
This demonstrates the nature of the process. The reference to “tablets or individual cores” relates to the preparation of the “core material”. In one instance, the tablets or pellets are the form of the prepared alkaline reacting core material before they are spray coated.
The invention as described in the examples set out in the specification describes the formulation of the “core material”. Undoubtedly, there are a variety of words or terms used in these examples, such as “cores”, “core formation”, “sugar cores”. But these terms are all used in the context of referring to the formation of the “core material”.
The layered seeds referred to in the 774 Patent involve the application of a layer or even layers of active substance – that is, material containing the PPI. Some pharmaceutically acceptable excipients are exemplified at p 12, line 28 to p 13, line 2, including (at p 12 line 29) binders such as hydroxypropyl cellulose (‘HPC’). The layered seeds described in the specification do not in and of themselves include any layers that do not include the active substance.
Further, the homogeneous core material referred to at p 13, lines 4 to 9, may be layered with additional “active substance and alkaline reacting compound(s)”. That is, further active drug layers are added to the homogeneous cores containing the active substance. Again, the homogeneous cores as described in the specification do not in and of themselves include any layers that do not include the active substance.
Therefore, as is evident from a reading of the 774 Patent, but as was also stated by Dr Pyter (whose evidence on this aspect I accept), the specification does not describe core material that is “layered” or “further layered” with an applied separating layer or any layer not including an active substance.
The invention claimed
The specification concludes at p 28 with 25 claims. Claim 1 is an independent claim for an oral pharmaceutical dosage form. Claims 2 to 20 are dependent claims. Claim 21 is an independent claim to a process for the preparation of an oral, enteric coated, pharmaceutical dosage form. Claim 21 refers specifically to a core material in a similar manner to claim 1. Claim 22 is a ‘product by process’ claim. Claim 23 is a claim to a method for inhibiting gastric acid secretion by administering a dosage form as claimed in any one of claims 1 to 20 and 22. Claims 24 and 25 are claims to use of the claimed oral pharmaceutical dosage form.
I make specific mention of claim 9, as it (like claim 21 and claim 1) specifically refers to “core material”, as follows (emphasis added):
9.A dosage form according to any one of claims 1 to 8, wherein the alkaline reacting compounds are present in a concentration of more than 0.1 mmol/g dry ingredients in the alkaline part of the core material.
The person skilled in the art
Before going any further in analysing the construction of the 774 Patent, I should briefly discuss the skilled addressee and the evidence of the experts. The 774 Patent relates to solid oral dosage formulation and design. It appears to be common ground that the hypothetical person to whom the 774 Patent specification is addressed is a pharmaceutical formulation scientist working in the field of solid oral dosage formulation and design. Dr Pyter, Dr Morella and Professor Bodmeier were put forward by the parties as being representative of the notional skilled addressee.
I have already described each of these witnesses.
Ranbaxy’s expert was Dr Pyter as a formulation scientist with experience in this role in a pharmaceutical company. AstraZeneca’s witnesses were Dr Morella as a formulation scientist with experience in this role in a pharmaceutical company, and Professor Bodmeier as an academic who has experience interacting with the pharmaceutical industry.
The evidence of the other expert witnesses relevant to the 774 Patent (Dr Hagenhoff, Dr Luk, Dr Matic, Mr Nicholas and Dr Wännman) was not evidence of the skilled addressee of the 774 Patent, or put forward as being evidence of persons who could assist the Court on construction. Their role was properly confined to assisting the Court in interpreting the experimental results.
I should say something more about the evidence led on construction and its relevance to the Court’s task. It was necessary for the Court to be informed as to the invention of the 774 Patent and the science relating to it. The concept underpinning the 774 Patent is relatively straight-forward as described previously – namely, a process by which two functionally different layers form in one manufacturing step. However, the terms “core”, “core material”, “separating layer” and “thereon” are not technical terms, and will be read as expressions of ordinary English, albeit in the scientific context of the 774 Patent.
Both sides attacked the evidence of the opposing experts, and sought to support their own.
I have not found this debate helpful on the question of construction. Each witness gave his view as to the interpretation of claim 1, and referred to different parts of the 774 Patent in support of that view. They referred also to the main purpose of the invention and to the relevant content of the prior art. The Court has now been informed of each of these matters, and can use that information to interpret claim 1. There was no dispute as to the purpose of the invention, nor relating to the reference to and content of the prior art in this regard. As I have said, the invention simplifies the preparation of the enteric coating by forming two layers in the one step. The question then is not what “core material” or “core” may mean in a general sense, but what it means in the context of claim 1.
AstraZeneca’s submissions and analysis
Apart from stressing the principles of construction referred to above, AstraZeneca’s position was as follows.
In the context of the claim, “core material” is to be understood by reference to the dynamic process by which the claimed in situ layer forms. The manner in which the dynamic process informs the construction of the integer is illustrated by the fact that the enteric coating is applied to the alkaline reacting core material, but due to the formation of the in situ separating layer, the enteric coat is not adjacent to the alkaline reacting core material. The integer “core material” means material that is beneath the water soluble separating layer (which layer forms during the enteric coating process). This meaning is informed by the nature of the invention claimed, which involves an alkaline reacting compound(s) from the core material reacting with the enteric coating polymer, by which process the water soluble separating layer (comprising a water soluble salt of the enteric coating polymer) is formed in situ during the enteric coating.
It is then submitted by AstraZeneca that the term “core material” must take its meaning from the claims which define the separating layer forming on the core material. In the context of the invention, the skilled addressee would understand this to mean that the core material is everything beneath the separating layer once it has formed. What is required is that the alkaline reacting compounds react with the enteric coating polymers to form the separating layer. When this occurs, everything beneath the separating layer is core material.
AstraZeneca submitted that the 774 Patent refers to, and exemplifies, multi-layered cores. For example, it is contended, in discussing the prior art, it refers to “at least two different layers” (emphasis added), which – it was said – clearly contemplates multi-layered cores.
AstraZeneca further submitted that the expression “core” can only be understood by reference to something which surrounds or is intended to surround that “core”. It takes its meaning from the functional layer being considered.
Put another way, AstraZeneca submitted that the phrase “core material” is used in two interrelated senses. First, in a functional sense to refer to material that is capable of participating in a reaction whereby two functional layers are formed in one step. To this end, AstraZeneca pointed to p 10, lines 8 to 29, and p 13, line 20. Secondly, in a situational sense to refer to “the relation of the core material to the separating layer”. In support of this contention, AstraZeneca pointed to p 7, line 30, and p 8, lines 1 to 2.
In my view, this is a distinction of no significance in the task of interpreting claim 1. By looking at the references in the 774 Patent that I have already emphasised in these reasons, it is clear that the reference to “core material” is a separate distinct concept to any subsequent layers. Take one of the examples given by AstraZeneca, located at p 10 line 8 of the 774 Patent. The subject matter is the defined “core material”. There is a reaction between the alkaline reacting compound(s) and the enteric coating polymer(s) so that the separating layer is formed.
To take another example relied upon by AstraZeneca, at p 8 lines 28 to 32 (emphasis added):
Thus, the present invention simplifies the preparation of enteric coated articles comprising a separating layer between a core material and an enteric coating layer by providing a new process for the manufacture of such dosage forms. According to said process the separating layer is formed by an in situ reaction between the enteric coating polymer and the alkaline core material comprising the pharmaceutically active substance.
Here one of the specifically identified reference points in both the prior art techniques and the new process is the core material. Figure 2 referred to at p 9 makes this clear insofar as it differentiates between the alkaline core material and the separating layer, as do the examples referred to in the specification.
Therefore, I do not accept AstraZeneca’s argument that the expression “core” or “core material” can only be understood by reference to something which surrounds or is intended to support the “core”.
In my view, “a core material” means just that – the material specifically described in claim 1 and throughout the specification of the 774 Patent. This interpretation will exclude any applied sub-coats on the core material. But contrary to what was submitted by AstraZeneca, this is not a “limitation” imposed other than as a consequence of the proper reading of the phrase “core material” in the context of claim 1 and the specification as a whole.
Of course, it is impermissible to look to the allegedly infringing article to determine the scope of the claim. This has been made clear in a number of cases. In Nobel’s Explosives Company Ltd v Anderson (1894) 11 RPC 519, Lord Esher MR observed (at 523):
...in construing this patent, one has no right to ... construe the patent by considering what the Defendant has done. I adjure that altogether, and I say we are bound to construe the patent as if we had to construe it before the Defendant was born, if the patent was before that time.
His Lordship’s comments are apposite in this proceeding.
However, in many ways, this appears to have been the approach of AstraZeneca to the construction of the 774 Patent. AstraZeneca attempted to formulate the so-called “functional” approach to overcome the fact that Ranbaxy’s allegedly infringing product has an applied barrier coating.
The foregoing discussion has focussed a great deal on the specification, and not the wording of claim 1. It is claim 1 that must be interpreted. Focussing on the terms of claim 1 the conclusion I have reached seems equally clear. You have an oral pharmaceutical dosage form. It comprises “a core material”. For present purposes, it does not matter whether “comprises” means “includes”; or whether it is exhaustive. “A core material” contains (a term which I take to be exhaustive, but again, this does not matter) a PPI and one or more alkaline reacting compound(s), and optionally pharmaceutically acceptable excipients. This is the “core material”. The claim then goes on to refer to “said” core material having thereon a separating layer, with the enteric coating layer thereupon. Claim 1 goes on to say that “the core material” (previously defined) is alkaline reacting.
Recalling that the expression “core material” is not a technical or scientific term, and is one which must be read in the context of the 774 Patent, and keeping in mind the purpose of the invention claimed, the term “core material” as defined in claim 1 should be interpreted as I have concluded above. This is consistent with the aim and purpose of the invention, and the way in which the term is used in the specification.
It is also important to remember that the phrase “a core material” and “thereon” inter-relate, and when read together in context, support the view that I have taken as to the interpretation and ambit of claim 1.
If one returns to the experts called by AstraZeneca, they had no answer to the contention put by Senior Counsel for Ranbaxy that the expression “core material” has its own separate and contained meaning. Both experts seemed to have some difficulty in considering the issue other than by returning to the so-called “functional” point of view. Their evidence, like AstraZeneca’s submissions, was infected by construing claim 1 with the Ranbaxy Product (and its separately applied barrier coating) in mind. The full exchange between the experts and Senior Counsel is instructive, and for this reason, the relevant parts of the transcript are set out in “Annexure B” to these reasons.
The question of construction, as I have said, is one for the Court. However, the debate between Senior Counsel for Ranbaxy and the experts exposed, in my mind, that both witnesses failed to properly consider the actual wording of claim 1 and the context in which the term “core material” is used throughout the specification.
I do not accept that the fact that the nature of the invention claimed (which involves an alkaline reacting compound from the core material reacting with the enteric coating polymer, by which process the separating layer is formed in situ during the enteric coating) means that Dr Morella and Professor Bodmeier are correct in their approach to the construction of claim 1 (exemplified by the exchange set out in Annexure B). The “core material” is as defined, and the invention is still of utility adopting such an interpretation. There is no limitation introduced upon claim 1, unless one views the construction of claim 1 by reference to the allegedly infringing Ranbaxy Product. This, of course, cannot be done.
Second Principal Construction Issue
The second principal construction issue, which was dependent on the construction of “core material”, was the term “thereon”. As I have alluded to, this term must be read in the context of the use of the phrase “a core material”, as that phrase also must be read in the context of the term “thereon”.
I do not think there was any real debate that “thereon” means directly thereon.
The word “thereon” is not a term of art. Its ordinary meaning would indicate a direct relationship. The invention is characterised in that the enteric coating is applied onto the core material to form the separating layer. The claimed separating layer formed by a reaction between the enteric coating layer and the core material must be directly on the core material. The photo in Fig 1 and the schematic drawing in Fig 2 (both set out in Annexure A) confirm this understanding.
Therefore, I accept the arguments put forward by Ranbaxy on the two principal construction issues, which means that there is no infringement of the 774 Patent by the Ranbaxy Product.
OVERALL DISPOSITION OF THIS PROCEEDING
The parties are provided with these reasons for decision on a confidential basis as contemplated by the Orders of the Court made on 23 February 2012.
The parties should now confer and draft minutes of orders reflecting the outcome of the proceedings, and provide them to the Court no later than 4:00pm on Monday 29 April 2013.
I certify that the preceding one thousand and seventeen (1017) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Middleton. Associate:
Dated: 23 April 2013
ANNEXURE ‘A’
ANNEXURE ‘B’
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