Apotex Pty Ltd v ICOS Corporation (No 3)
[2018] FCA 1204
•14 August 2018
FEDERAL COURT OF AUSTRALIA
Apotex Pty Ltd v ICOS Corporation (No 3) [2018] FCA 1204
File number: VID 280 of 2016 Judge: BESANKO J Date of judgment: 14 August 2018 Catchwords: PATENTS – where applicant seeks relief by way of declarations of invalidity and orders for revocation of claims in two patents (the 946 Patent and the 666 Patent) – where respondent is the registered owner of the two patents and denies that the claims are invalid – whether, in respect of the 946 Patent, there is a lack of inventive step, lack of novelty, the patent was obtained by false suggestion and the invention is not useful – whether, in respect of the 666 Patent, there is a lack of inventive step and a lack of novelty
PATENTS – where respondent brings a cross-claim against the applicant in which it seeks declarations to the effect that the applicant has threatened to infringe claims in the two patents – whether applicant has threatened to infringe claims in the two patents – where claims in respect of which the respondent alleges threatened infringement are the same claims which the applicant alleges are invalid – where, in respect of the two patents, the applicant admits, subject to its case on invalidity, threatened infringement in respect of certain claims – where applicant denies infringement in respect of certain claims in the two patents – where, in respect of the 666 Patent, the applicant does not admit threatened infringement of certain claims, but accepts that expert evidence establishes threatened infringement, subject to its case on invalidity
PRACTICE AND PROCEDURE – where respondent seeks injunctions, damages or an account of profits, additional damages or other relief – where issues of quantum arising from the respondent’s cross-claim be heard and determined separately from, and after, all other issues in the proceeding
Legislation: Patents Act 1952 (Cth) s 100
Patents Act 1990 (Cth) ss 7, 12, 13, 18, 102, 105, 138
Federal Court Rules 2011 (Cth) r 30.01
Patents Regulations 1991 (Cth) reg 3.12
Cases cited: Actavis Group Ptc EHF v ICOS Corporation [2016] EWHC 1955 (Pat)
Actavis Pty Ltd v Orion Corporation [2016] FCAFC 121
Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411
Alcatel NV v Commissioner of Patents (1996) AIPC 91-260; (1996) 68 FCR 8
Alphapharm Pty Ltd v H Lundbeck A/S [2008] FCA 559; (2008) 76 IPR 618
Anaesthetic Supplies Pty Ltd v Rescare Ltd (1994) AIPC 91-076; (1994) 50 FCR 1
Apotex Pty Ltd v ICOS Corporation [2017] FCA 466
Apotex Pty Ltd v Warner‑Lambert Company LLC (No 2) [2016] FCA 1238; (2016) 122 IPR 17
AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; (2014) 226 FCR 324
AstraZeneca AB v Apotex Pty Ltd [2015] HCA 30; (2015) 257 CLR 356
Beecham Group Limited v Bristol Laboratories Limited and Another (1978) RPC 153
Beecham Group Ltd’s (Amoxycillin) Application (1980) 97 RCP 261
CCOM Pty Ltd v Jiejing Pty Ltd (1994) AIPC 91-079; (1994) 51 FCR 260
Coopers Animal Health Australia Ltd v Western Stock Distributors Pty Ltd (1988) AIPC 90-491; (1987) 15 FCR 382
Danisco A/S v Novozymes A/S (No 2) [2011] FCA 282; (2011) IPR 209
Delnorth Pty Ltd v Dura-Post (Aust) Pty Ltd [2008] FCA 1225; (2008) 78 IPR 463
DSI Australia (Holdings) Pty Ltd v Garford Pty Ltd [2013] FCA 132; (2013) IPR 19
E I Du Pont de Nemours & Co v ICI Chemicals & Polymers Ltd [2005] FCA 892; (2005) 66 IPR 462
E I Du Pont de Nemours & Company v Imperial Chemical Industries plc [2007] FCAFC 163; (2007) 163 FCR 381
Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73; (2014) 222 FCR 336
Graham v John Deere Co of Kansas City (1966) 383 US 1
Hill v Evans (1862) 45 ER 1195; (1862) IPR 1A 1
ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc [2000] FCA 1349; (2000) 106 FCR 214
IG Farbenindustrie AG’s Patents (1930) 47 RPC 289
IGT (Australia) Pty Ltd v Aristocrat Technologies Australia Ltd [2008] FCAFC 131; (2008) 77 IPR 482
Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; (2001) 207 CLR 1
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58; (2004) 217 CLR 274
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) [2007] HCA 21; (2007) 235 CLR 173
Minnesota Mining & Manufacturing Company v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253
Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; (1977) 137 CLR 228
Novozymes A/S v Danisco A/S [2013] FCAFC 6; (2013) 99 IPR 417
Otsuka Pharmaceutical Co Ltd v Generic Health Pty Ltd (No 4) [2015] FCA 634; (2015) 113 IPR 191
Pracdes Pty Ltd v Stanilite Electronics Pty Ltd (1995) 35 IPR 259
Pracdes Pty Ltd v Stanilite Electronics Pty Ltd (1995) 35 IPR 277
Prestige Group (Aust) Pty Ltd v Dart Industries Inc (1990) AIPC 90-715; (1990) 26 FCR 197
Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368; (2013) 101 IPR 11
Ranbaxy Australia v Warner-Lambert Co LLC [2008] FCAFC 82; (2008) 77 IPR 449
R D Werner & Co Inc v Bailey Aluminium Products Pty Ltd (1989) 13 IPR 513; (1989) 25 FCR 565
Re Alsop’s Patent (1907) 24 RPC 733
Re Stauffer Chemical Company’s Application [1977] RPC 33
Saccharin Corporation Ltd v Anglo-Continental Chemical Works Ltd (1900) 17 RPC 307
Samsung Electronics Co Ltd v Apple Inc [2011] FCAFC 156; (2013) 217 FCR 238
Sigma Pharmaceuticals (Aust) Pty Ltd v Wyeth [2011] FCAFC 132; (2011) 119 IPR 194
The General Tire and Rubber Company v The Firestone Tyre and Rubber Company Limited and Others [1972] RPC 457
Vehicle Monitoring Systems Pty Limited v Sarb Management Group Pty Ltd (t/as Database Consultants Australia) (No 2) [2013] FCA 395; (2013) 101 IPR 496
Warner-Lambert Co LLC v Apotex Pty Ltd (No 2) [2018] FCAFC 26; (2018) 355 ALR 44
Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91; (1961) 106 CLR 588
Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; (1981) 148 CLR 262
Date of hearing: 1, 2, 5-9, 13, 15, 16 June 2017 Registry: Victoria Division: General Division National Practice Area: Intellectual Property Sub-area: Patents and associated Statutes Category: Catchwords Number of paragraphs: 777 Counsel for the Applicant/Cross-Respondent: Mr D Catterns QC with Mr M Fleming and Mr N Murray Solicitor for the Applicant/Cross-Respondent: Herbert Smith Freehills Counsel for the Respondent/Cross-Claimant: Mr B Caine QC with Mr J Cooke and Mr C Burgess Solicitor for the Respondent/Cross-Claimant: Wrays Lawyers ORDERS
VID 280 of 2016 BETWEEN: APOTEX PTY LTD (ACN 096 916 148)
Applicant
AND: ICOS CORPORATION
Respondent
AND BETWEEN: ICOS CORPORATION
Cross-Claimant
AND: APOTEX PTY LTD (ACN 096 916 148)
Cross-Respondent
JUDGE:
BESANKO J
DATE OF ORDER:
14 August 2018
THE COURT ORDERS THAT:
1.The respondent bring in draft minutes of order reflecting the conclusions in these reasons.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
REASONS FOR JUDGMENT
INTRODUCTION
[1]
WITNESSES
[17]
The Clinicians
[24]
Dr Cherry
[24]
Dr McMahon
[34]
Professor Brock
[42]
Dr Mitchell
[60]
The Pharmacologists
[72]
Dr Reece
[72]
Professor Brock
[92]
Professor Evans
[93]
The Formulators
[116]
Dr Mooney
[116]
Professor Polli
[134]
Professor Boddy
[145]
THE 946 PATENT
[146]
THE 666 PATENT
[162]
THE COMMON GENERAL KNOWLEDGE RELEVANT TO THE ISSUES IN THIS CASE
[181]
INVENTIVE STEP AND THE 946 PATENT
[307]
Daugan 1997
[308]
Relevant Principles
[334]
Analysis
[353]
The general submissions of the parties
[354]
The information available to the development team
[359]
The choice of Compound A
[378]
Difficulties associated with the development of Compound A, both generally and as to the appropriate doses
[391]
Other important matters
[434]
Conclusion
[465]
INVENTIVE STEP AND THE 666 PATENT
[467]
Daugan 1997
[467]
Relevant Principles
[468]
Analysis
[469]
Conclusion
[532]
NOVELTY AND THE 946 PATENT
[533]
Introduction
[533]
The Contents of the Stoner Specification
[537]
Relevant Principles
[550]
Analysis
[563]
Monotherapy as against a Combination and Synergistic Effect
[567]
The Choice of PDE5 Inhibitors
[579]
The Range of Unit Doses
[582]
The Range of Maximum Daily Doses
[585]
Example 5
[589]
Conclusion
[592]
NOVELTY AND THE 666 PATENT
[593]
Introduction
[593]
The Submissions of the Parties
[595]
Relevant Principles
[616]
Analysis
[623]
Conclusion
[631]
FALSE SUGGESTION – THE 946 PATENT
[632]
The Pleaded Case
[632]
Relevant Principles
[653]
Analysis
[664]
Was the Pleaded Representation Made?
[675]
Has the composite representation been shown to be false?
[690]
Facial flushing
[690]
The side effects following the co-administration of tadalafil and a nitrate
[701]
A material cause?
[747]
Discretion
[749]
Conclusion
[750]
INFRINGEMENT
[751]
Claims 10-12 and 18 in the 666 Patent and Professor Boddy’s Evidence
[753]
Manufacturing Process and Swiss Claims
[763]
CONCLUSION
[776]
ANNEXURE A
ANNEXURE B
ANNEXURE C
ANNEXURE D
ANNEXURE E
BESANKO J:
INTRODUCTION
In this proceeding, Apotex Pty Ltd (Apotex) seeks relief by way of declarations of invalidity and orders for revocation of claims in two patents, being Australian Patent No 769946 (the 946 Patent) and Australian Patent No 773666 (the 666 Patent). The claims in suit are claims 1-6, 8-17, 19-29 and 31-35 in the 946 Patent, and claims 1-3, 5-8, 10-12, 14-18 and 24-38 in the 666 Patent. ICOS Corporation (ICOS) is the registered owner of the two patents and it denies that the claims are invalid.
ICOS brings a cross-claim against Apotex in which it seeks declarations to the effect that Apotex has threatened to infringe claims in the 946 Patent and claims in the 666 Patent. The claims in respect of which ICOS alleges threatened infringement are the same claims which Apotex alleges are invalid. In addition to its claim for declarations of threatened infringement, ICOS seeks injunctions, damages or an account of profits, additional damages and other relief. On 17 May 2017, I made an order under r 30.01 of the Federal Court Rules 2011 (Cth) that the question of issues of quantum arising from ICOS’s cross-claim be heard and determined separately from, and after all other issues in the proceeding.
The Patents Act 1990 (Cth) (the Act) which is relevant for the purposes of this proceeding is the version of the Act prior to the amendments made in 2001, particularly the amendments made to s 7(3) by the Patents Amendment Act 2001, No. 160, 2001.
After Apotex had commenced this proceeding, but before the trial, ICOS made an application under s 105 of the Act to amend the two patents. The amendments to the 946 Patent involved various deletions from, and amendments to, statements which appeared in the body of the Specification. There was no application to amend any of the claims in the patent. By contrast, the amendments to the 666 Patent involved no amendments to the body of the Specification, but did involve the addition of 15 claims to the existing 23 claims. I allowed the amendments (Apotex Pty Ltd v ICOS Corporation [2017] FCA 466) (the Amendment Reasons).
With respect to the claims in suit in the 946 Patent, Apotex advances the following grounds of invalidity:
(1)The lack of an inventive step in light of the common general knowledge and the information contained in WO 97/03675 published on 6 February 1997 (Daugan 1997), either alone or in combination with one or both of WO 95/19978 published on 27 July 1995 (Daugan 1995), and GB9514464.8 published on 6 February 1997 (GB 464) (s 18(1)(b)(ii) of the Act);
(2)A lack of novelty in light of WO 00/53148 published on 14 September 2000 (Stoner) (s 18(1)(b)(i) of the Act);
(3)The patent was obtained by false suggestion (see s 138(3)(d) of the Act); and
(4)The invention is not useful (s 18(1)(c) of the Act).
Apotex submitted that the claims in suit in the 946 Patent focus on doses of the relevant compound of up to 20 mg, the use of such doses to treat conditions where the inhibition of PDE5 is desirable, or erectile dysfunction (ED) which is such a condition, and Swiss-style claims for their manufacture. Some claims are further limited to daily administration. Because other claims are limited to a dose per day, the daily administration claims add nothing significant. Apotex submitted that the alleged inventive concept claimed in the 946 Patent is the selection of lower dosages of the relevant compound. It submitted that this was reflected in, inter alia, the passages which were deleted from the body of the Specification by the amendment. It submitted that it was relevant to its case on obviousness that much of the “nitrate” rationale for the claimed invention has been removed. In broad terms, one of Apotex’s principal submissions in its obviousness case with respect to the 946 Patent, is that the patent is now for a range of doses that would be determined by the notional skilled team following a conventional Phase II dose ranging study, informed by the usual in vitro pre‑clinical and Phase I work.
The 946 Patent claims a priority date of 30 April 1999. The filing date of the application is 26 April 2000. The claims in suit in the 946 Patent are set out in Annexure A to these reasons.
Apotex no longer pursues one of the validity challenges raised in its Particulars of Invalidity. The challenge started with an allegation that the earliest priority date for claims 4, 15 and 27 in the 946 Patent is 26 April 2000 and that those claims are anticipated by WO 01/08686 (Oren). Apotex now accepts that the better view is that both Oren and the 946 Patent are entitled to the earlier priority date in respect of dosage claims. In those circumstances, Apotex does not press its novelty challenge to claims 4, 15 and 27 based on Oren.
Apotex maintains its claim that the invention claimed in the 946 Patent lacks utility in order to preserve the right to challenge the decision to allow the amendments to the 946 Patent, to the extent that that decision bears on the final determination of Apotex’s claim at trial.
Apotex claims that the 666 Patent is invalid on the following grounds:
(1)The lack of an inventive step in light of common general knowledge and the information contained in Daugan 1997 either alone, or in combination with one or both of Daugan 1995 and GB 464 (s 18(1)(b)(ii) of the Act);
(2)With respect to claims 10-12 and 18 (and claims 24-28 and claims 34-38 insofar as those claims are dependent on claims 10-12 and 18), a lack of novelty in light of Oren (s 18(1)(b)(i) of the Act). The novelty challenge based on Oren depends on a challenge to the asserted earliest priority date of those claims.
The claims in the 666 Patent which were originally in suit effectively, fell into two classes. First, claims 1-3, 5-8 and 14-17 are claims for free drug forms, compositions, methods of treatment or methods of manufacturing the free drug forms or compositions, all limited by particle sizes where 90% of the particles have a particle size of less than 40, 25 or 15 microns respectively (i.e., a d90 of less than those sizes). Secondly, claims 10-12 and 18 are claims which are limited to one or both of two pharmacokinetic parameters, being Cmax and AUC (0‑24), which are terms I will explain later in these reasons. Apotex submitted that the 666 Patent demonstrates that these pharmacokinetic parameters flow from particle size, in a given formulation. The amendments to the 666 patent introduced claims 24-38. Apotex submitted, correctly in my opinion, that these claims add limitations as to doses and dosage forms to the preceding claims, and that the result is a hybrid of the 946 and the 666 Patents. Apotex submitted that evidence that was previously relevant to these aspects of the 946 Patent is now also relevant to the 666 Patent. The submissions as to the obviousness of the claimed range of doses is also relevant.
The 666 Patent claims a priority date of 3 August 1999. The filing date of the application is 1 August 2000. The claims in suit in the 666 Patent are set out in Annexure B to these reasons.
In connection with its lack of novelty case, Apotex submitted that the priority document for the 666 Patent does not contain the relevant example, that is, Example 3, and does not otherwise mention the relevant pharmacokinetic parameters.
With respect to ICOS’s allegation of threatened infringement of the claims in suit in the 946 Patent, Apotex admits, subject to its case on invalidity, threatened infringement of claims 1-6, 8-11, 12-17 and 19-23. In addition to its case on invalidity, Apotex denies threatened infringement of claims 24-29 and 31-35 on the basis that the Apotex products will be manufactured by third party entities located outside of Australia, with different entities (located in different countries) approved for the manufacture of the active ingredient in the drug and the manufacture of the finished dosage form.
With respect to ICOS’s allegation of threatened infringement of the claims in suit in the 666 Patent, Apotex admits, subject to its case on invalidity, threatened infringement of claims 1-3, 5, 6 and 16, 7-8, 24-28 and 29-33. It does not admit threatened infringement of claims 10-12, 14‑15, 17-18 and 34-38. As I have already said, claims 10-12 and 18 in the 666 Patent refer to two pharmacokinetic properties, Cmax and AUC (0‑24). ICOS adduced evidence at the trial from a Professor Alan Boddy about the pharmacokinetic properties of the Apotex products. In its closing written submissions, Apotex said that it accepted that the Court “will find” that Professor Boddy’s evidence demonstrates infringement of claims 10-12 and 18 in the 666 Patent by the Apotex products. In other words, while not formally admitting threatened infringement, Apotex accepts that Professor Boddy’s evidence establishes threatened infringement, subject to its case on invalidity. Apotex denies that it has threatened to infringe claims 14-15, 17-18 and 34-38 in the 666 Patent on the same ground upon which it denies threatened infringement of claims 24-29 and 31-36 in the 946 Patent, that is to say, the Apotex products will be manufactured by third party entities located outside of Australia, with different entities (located in different countries) approved for the manufacture of the active ingredient in the drug and the manufacture of the finished dosage form.
For the assistance of the reader, a short glossary of terms used in these reasons is Annexure C. The compound which is the subject of the patents is tadalafil which is sold under the brand name of Cialis. The compound on the market at the respective priority dates of the two patents was sildenafil which was sold under the brand name of Viagra. I will refer to this drug as sildenafil or Viagra depending on the context.
WITNESSES
Apotex adduced evidence (both written and oral) from Dr Denis Cherry, Dr Phillip Reece and Dr Brett Mooney. In addition, it tendered affidavits of Mr Rodney Cruise and Ms Catherine Halmagyi respectively. Neither Mr Cruise nor Ms Halmagyi were required for cross‑examination. It is convenient to refer to the evidence of those witnesses first.
Mr Cruise is a patent attorney. He is a partner of Phillip Ormonde Fitzpatrick, an intellectual property services firm. He was engaged by Apotex to carry out a search of material available on 29 April 1999. Mr Cruise affirmed two affidavits in this proceeding. Those affidavits were tendered in evidence. Mr Cruise’s evidence establishes (and ICOS does not dispute) that Daugan 1997 satisfies the requirements of s 7(3) of the Act.
Ms Halmagyi is an employee of Apotex. She is a Regulatory Affairs Team Leader and has held this position since June 2015. She joined the Regulatory Affairs Department of Apotex in June 2013. Her evidence establishes that the Apotex products will be manufactured by third party entities located outside of Australia, with different entities (located in different countries) approved for the manufacture of the active ingredient in the drug and the manufacture of the finished dosage form.
ICOS adduced evidence (both written and oral) from Professor Boddy, Dr Christopher McMahon, Professor Gerald Brock, Dr Malcolm Mitchell, Professor Allan Evans and Professor James Polli. It tendered an affidavit of Dr Alan Robertson. Dr Robertson was not required for cross-examination. Again, it is convenient to refer to his evidence first.
Dr Robertson described his technical expertise as being in medicinal chemistry. A medicinal chemist is a scientist with expertise in chemistry who conceives new molecules with a view to achieving a given therapeutic effect. Dr Robertson’s qualifications are set out in his affidavit and I will not repeat them. I am satisfied that he has specialised knowledge and experience in the field of medicinal chemistry. Dr Robertson expresses the opinion that, as at 3 August 1999 and 1 August 2000, the relevant compound or active pharmaceutical ingredient (API) (tadalafil) was capable of forming salts and it would not necessarily be difficult to form a salt of tadalafil. I will return to his evidence later in these reasons.
With respect to three of the relevant scientific disciplines in this case, the experts conferred before the trial and prepared a joint experts’ report. They then gave evidence in a joint session. The joint sessions were as follows:
(1)Dr Cherry, Dr McMahon and Professor Brock. Dr Mitchell was involved in part of the joint experts’ report and in part of the joint session. These experts were referred to as the clinicians;
(2)Dr Reece, Professor Evans and Professor Brock. These experts were referred to as the pharmacologists; and
(3)Dr Mooney and Professor Polli. These experts were referred to as the formulators.
A summary of the qualifications and experience of each of the experts is set out below. Generally speaking, I find that each expert was well qualified to give evidence on the matters which they addressed and I find that each did his best to assist the Court. There was one area where I thought that Professor Brock gave more emphasis to a point than was warranted, and this is discussed below. Otherwise, he was well-qualified and his evidence was satisfactory. Dr Reece gave some evidence relevant to obviousness which was based on information which went beyond common general knowledge. Apotex did not rely on this aspect of his evidence and I do not think that it affected the balance of his evidence. Of the most significance was Dr Mooney’s lack of experience in formulating new chemical entities (NCEs) and, in my opinion, that lack of experience does affect the weight to be accorded to his evidence.
The Clinicians
Dr Cherry
Dr Cherry is a consultant and, formerly, he was the Medical Director of the Perth Human Sexuality Centre (PHSC). The PHSC was, and remains, an organisation that specialises in the assessment and management of all areas of male and female sexuality, with a special interest in the treatment of male ED. Dr Cherry graduated in 1970 with a Bachelor of Medicine and Surgery from the University of Western Australia.
From 1970 to 1981, Dr Cherry worked in various positions across public hospitals in Western Australia, including as a resident medical officer, senior resident medical officer and registrar. Between 1974 and 1980, he worked as a registrar in the Department of Clinical Biochemistry at the Royal Perth Hospital, and later, the Princess Margaret Hospital. During that time, he became interested in many aspects of endocrinology, human biochemistry and the fundamental role of pharmacology in developing new treatments in the management of human disease. He also became a member of the Australian Association of Clinical Biochemistry.
From 1981 to 1989, Dr Cherry worked as a general medical practitioner in Western Australia and maintained a large clinical practice. He also held the position of chief medical officer for the Shires of Donnybrook and Capel, and was responsible for local hospital management and public health issues. During this time, Dr Cherry developed an interest in sexual medicine, particularly treatments for ED. He would regularly refer patients to the late Professor Ted Keogh, who specialised in the treatment of ED. Dr Cherry would generally be responsible for the patients’ treatment.
In 1989, Dr Cherry was offered a part-time position as a clinical fellow at the Reproductive Medicine Research Institute (RMRI) that had been set up by Professor Keogh (now known as the Keogh Institute for Reproductive Medicine). RMRI was, and remains, a clinical institute with specialised expertise in the field of sexual medicine. As a clinical fellow, Dr Cherry was responsible for the assessment, management and treatment of male patients with ED.
In 1992, Dr Cherry set up the PHSC, together with Dr Alistair Tulloch (a urologist who had also previously worked with Professor Keogh at RMRI). From 1992 to 2011, Dr Cherry was the medical director of the PHSC.
At the PHSC, the treatment of ED constituted about 75% of the male sexual disorders that were treated by the practice. The majority of those patients were males aged over 50 years old. The remainder of the PHSC’s practice involved the treatment of ejaculatory and libido disorders, and, more rarely, transgender cases. During his time at PHSC, Dr Cherry would treat upwards of around 15 to 20 patients per day.
During his time as Medical Director of PHSC, Dr Cherry also served as a member of the Australian Advisory Boards of Pfizer (in relation to Viagra), Eli Lilly (in relation to Cialis), and GSK-Bayer (in relation to Levitra). As I will explain later in these reasons, all of these drugs are used in the treatment of ED. As I have said, tadalafil is the compound which is the subject of the two patents in suit in this proceeding. He also undertook clinical research on behalf of Pfizer, Eli Lilly and GSK-Bayer in relation to each of those drugs, which was part of the clinical trials for obtaining regulatory approval for those drugs from the Therapeutic Goods Administration (TGA).
While the Medical Director of PHSC, Dr Cherry was also a lecturer at a number of institutions. From 1997 to 2011, he was a lecturer in the Royal Australian College of General Practitioners Training Program in Western Australia, where he delivered a series of lectures to general practitioners concerning the management and treatment of ED. From 2005 to present, he has held the position of visiting lecturer at the Notre Dame University, where he lectures year one to three students in the Medical Faculty.
Between 1995 and 2014, Dr Cherry was also a consultant with the Urology Out Patient Sexual Dysfunction Clinic at the Royal Perth Rehabilitation Hospital, where he advised on the sexual issues associated with spinal cord injuries.
Over the course of his career, Dr Cherry has been a member of the following professional organisations: Australian Urological Association, Australian Society for Impotence Medicine and European Society for Impotence Research. He has also served as a board or committee member for the following organisations at various dates: Centre for Sexual Health (Curtin University of Technology), Impotence Australia, Asian EDACT (Advisory Council), Pfizer (Australian Advisory Board), Eli Lilly (Australian Advisory Board), GSK-Bayer (Australian Advisory Board), and the Men’s Health Journal Asia Pacific (Editorial Board).
Dr McMahon
Dr McMahon is an Australian physician, who has specialised in sexual medicine since 1982. In 1976, he was awarded a Bachelor of Medicine and Bachelor of Surgery from Monash University.
Between 1976 and 1981, Dr McMahon held positions in Melbourne hospitals as an intern, then a junior resident, before becoming a surgical registrar. In 1981, he commenced working as a general practitioner. Later in 1981, he commenced his genito-urinary/sexual health practice in Sydney.
Since 1991, Dr McMahon has been the Director of the Australian Centre for Sexual Health. He is the founding and past president of the Australasian Society of Impotence Medicine, which he himself founded in 1995. He is the current committee chairman of the World Health Organisation (WHO) Consultation on ED, and a committee member of the International Society of Impotence Research.
He is a member of the Australian ED medical advisory boards for various pharmaceutical companies, including Eli Lilly, Bayer and Pfizer. He gave evidence as an independent expert witness in relation to Pfizer’s application to have Viagra listed on the Australian Schedule of Pharmaceutical Benefits. He has also conducted clinical trials for new drug companies, including Eli Lilly, Pfizer, Bayer, and Pharmacia & Upjohn.
Dr McMahon has also been a clinical investigator on multiple clinical trials in Australia, including trials conducted with respect to Viagra, Cialis and Levitra for each of Pfizer Australia, Eli Lilly Australia and Bayer Australia/GSK Singapore respectively, which were, in each case, the sponsor of trials in Australia. Those trials were run in 1996, 1998 and 2000, respectively.
Between 2001 and 2006, Dr McMahon was the chairman of Eli Lilly’s Australian Medical Advisory Board for Cialis. During that time, in 2002, Cialis was approved in Australia by the TGA.
Dr McMahon is a member of the editorial board of the Journal of Sexual Medicine and Sexual Medicine Reviews, and he has acted as a referee for multiple international peer-reviewed medical journals. He is a member of several local, regional and international medical associations, and he is the past international president of the International Society of Sexual Medicine. He is the vice chairman of the WHO Second and Third International Consultation on Erectile and Sexual Dysfunction.
Dr McMahon has been invited to lecture on sexual medicine worldwide, and has published extensively on sexual health. He has published over 90 articles in peer reviewed international medical journals and 22 book chapters. His current research focuses on drug treatment for patients with refractory ED and drug treatment of premature ejaculation.
Professor Brock
Professor Brock is a Professor of Urology at the University of Western Ontario, Canada, where he manages a research team in ED. He was awarded a Bachelor of Science in physiology in 1981 and a Doctor of Medicine (MD) in 1986, both from McGill University. From 1986 to 1991, he trained as a urology resident at McGill University. In 1991, he passed his Urology Royal College board exams.
From 1991 to 1993, Professor Brock was a research fellow at the University of California in San Francisco. His research was conducted under the direction of Drs Tom Lue and Emil Tanagho, both of whom are leading researchers in the area of ED, focussing on neuro-urology.
From 1993, Professor Brock was Assistant Professor at McGill University in Montreal, Quebec, before being promoted to Associate Professor and receiving tenure in 1998.
In 1998, he left McGill University to join the Division of Urology at the Schulich School of Medicine and Dentistry at the University of Western Ontario as an Associate Professor. In 2000, he also joined the Obstetrics and Gynaecology Department of the Schulich School of Medicine and Dentistry. Since 2006, he has held the title of Professor of Urology at the University of Western Ontario. In 2009, he became the Program Director of the Division of Urology at the University of Western Ontario.
Professor Brock is also a practising clinical urologist Ontario where he treats patients with urological issues, including ED. Since 1991, he has practised as a clinical urologist at the various institutions at which he was employed. In 1999, on average, he treated approximately 50 new patients, and in the range of approximately 100 patients in total, per week, who were suffering from ED. Today, he continues to treat the same number of patients suffering from ED.
Since 1991, Professor Brock has both taught and carried out research in relation to the cause of ED and its treatments. Since 1993, he has also managed his own research team. He is widely published and has written over 200 peer-reviewed publications, of which at least 150 concern the field of male sexual dysfunction. His research from 1991 until present continues to focus on the causes and treatments of ED.
Professor Brock has also had significant experience with various animal models for ED, performing such work in his various laboratories since 1993. He has published over 30 peer reviewed articles and many more abstracts concerning the use or development of animal models.
Professor Brock has extensive experience in the role of principal or lead investigator in clinical trials that are directed to ED treatments. For example, in 1997, he was the principal investigator in at least five clinical studies concerning sildenafil. He was also principal investigator of other studies that investigated the effect of sildenafil in patients with mild ED and patients who were hypersensitive.
Professor Brock was also the chair of the Viagra Advisory Board for Canada from about 1997. In the period from around 1997 and 1998, he served on Eli Lilly/ICOS’s international and Canadian Advisory Boards for the development of tadalafil, noting that once Eli Lilly purchased ICOS, the advisory boards became an Eli Lilly Advisory Board.
In around 1998, Professor Brock was the principal investigator for a ten site multi-centre Phase II study for tadalafil in Canada. His involvement with tadalafil has continued until the present day through his role as an investigator in various clinical trials as well as in his practice as a clinical urologist.
At the same time as conducting the Cialis Phase II study, he was the lead investigator in one of Bayer’s clinical trials for vardenafil. The brand name for vardenafil is Levitra. In around 2009 and 2010, Professor Brock was chair of Johnson & Johnson’s Drug Safety Monitoring Board for their clinical trials relating to dapoxetine (marketed as Priligy), a treatment for premature ejaculation.
Professor Brock has received multiple awards for his research in the field of urology, and in particular, relating to investigations into ED. He is currently the president‑elect and a member of the Canadian Urology Association, chair of the Canadian Male Sexual Health Council and secretary-general of the International Society for Sexual Medicine. He was previously the secretary of the Sexual Medicine Society of North America, and is also a member of various other associations relating to the field of urology.
Professor Brock has also held seats on national and international committees relating to ED and its treatments, including as chair of the Canadian Urological Association’s Office of Education, the Heart and Stroke Foundation’s Cariovascular Safety – Viagra Panel, and the WHO Consensus Panel on Impotence. In 2003, at the Second WHO Consensus Conference on Impotence in Paris, he served as a member on the pharmacologic therapeutics committee that evaluated inhibitors. In 2009, he was co-chair of the Penile Rehabilitation Committee at the Third WHO meeting, and meeting chair of the 2015 Fourth ISSM Consensus Meeting on Sexual Medicine, held in Madrid, where more than 200 of the world’s experts met to arrive at a consensus on current and future therapies in the field.
Professor Brock consults with and sits on the medical advisory boards of a number of pharmaceutical companies and routinely advises these companies about various issues relating to the causes and clinical treatments of urological conditions, including ED. These companies include Pfizer, Eli Lilly/ICOS, Bayer, Janssen-Ortho, Pharmacia and American Medical Systems.
Professor Brock gives lectures to physicians and pharmacists on behalf of various pharmaceutical companies, including Eli Lilly.
Since 1993, Professor Brock has also taught and supervised undergraduate and graduate medical students, post-doctoral research fellows, and urology residents. His teaching has focused on infertility and ED, including the causes, known and established treatments, and research regarding new theories of treatment. Between 2009 and 2014, he was the urology residency Program Director at Western University. From 2000 to 2004, he was a corresponding member of the test committee for the Royal College of Physicians and Surgeons of Canada for urology and, from 2005 to 2010, he served as a core examiner for the test committee.
Professor Brock sits on the editorial boards of the Canadian Journal of Urology, Journal of Andrology, and Asian Journal of Urology and Translational Urology and Andrology. He is also a peer reviewer for the Journal of Urology, Urology, American Journal of Physiology, American Society of Hospital Medicine, Pharmacists AHFS Drug Information, Canadian Medical Association Journal and the Journal of Sexual Medicine. He has authored over 200 peer-reviewed publications and book chapters and hundreds of additional presentation abstracts, most relating to ED. He has also been an invited speaker at many institutions around the world, again mostly relating to ED.
Finally, he has presented expert advice to the Health Protection Branch (the Canadian pharmaceutical regulatory authority) on behalf of Johnson & Johnson for a premature ejaculation treatment and Sanofi-Aventis for an over-the-counter ED treatment containing tadalafil (on licence from Eli Lilly).
Dr Mitchell
Dr Mitchell is a former clinical pharmacologist, who has now retired. He was previously the Medical Director at Eli Lilly. In that role, he was responsible for overseeing the clinical pharmacology studies that were brought into existence and deployed to support the registration of Cialis. He was also one of the co-authors of the “Kloner Papers” which were the subject of evidence from the clinicians and which are referred to later in these reasons.
In 1973, Dr Mitchell graduated from Newcastle Medical School in the United Kingdom with a Bachelor of Medicine and Bachelor of Surgery. Between 1973 and 1977, he undertook junior doctor medical rotations. Between 1978 and 1979, he held the position of research registrar at various hospitals.
In 1979, Dr Mitchell moved to Glasgow and commenced practising in the area of radiotherapy and oncology, which involved working with cancer patients receiving treatment for their disease. Between 1979 and 1982, he was the radiotherapy registrar at two hospitals in Glasgow.
In 1982, Dr Mitchell joined Pfizer UK as a medical advisor. In that role, he took on responsibility for a compound called prazosin, which is an “alpha-blocker” used to treat high blood pressure (amongst other diseases). He was also responsible for Phase III clinical trial work relating to follow-up alpha-blocker compounds.
Under the supervision of the Medical Director at Pfizer UK, Dr Mitchell also explored the use of alpha-blockers in diseases such as asthma and prostatic hyperplasia (enlargement of the prostate). During that time, Dr Mitchell also worked on high-dose cytarabine (a chemotherapy medication used for the treatment of certain blood cancers).
Between 1986 and 1987, Dr Mitchell then moved to Napp Pharmaceutical Holdings Limited in Cambridge, where he held the position of Medical Director. During that time, he worked on the development of slow-release compounds, and in particular, morphine.
In 1987, Dr Mitchell moved to Eli Lilly. He was initially involved in Phase II and Phase III clinical trial work, relating to respiratory compounds, as well as the H2 blocker, nizatidine. In 1990, Dr Mitchell then moved to Cardiac Pacemakers Inc, which was then a part of Eli Lilly, for around three years. In that role, he was involved in applying pharmaceutical development strategies to cardiac implantation devices.
In 1993, Dr Mitchell moved to Eli Lilly’s clinical pharmacology group, where he was involved in ongoing drug development work for all aspects of clinical pharmacology across Eli Lilly’s portfolio, including conducting many first in human studies, through to bioequivalence studies for formulation changes. A large part of that work included developing clinical pharmacology regulatory packages for compounds (small molecules and biologics) that Eli Lilly was intending to register as medicines. This process involved designing the package of clinical pharmacology studies that would need to be conducted and included in the regulatory dossier in order to obtain marketing approval for the compound, as well as overseeing the implementation of the study protocols, discussing them with investigators, and analysing the resulting data (on a study-by-study basis as well as across multiple studies). For example, Dr Mitchell was responsible for developing the clinical pharmacology regulatory package for tadalafil, in all the indications registered to date, with the largest pharmacology package being for the original ED indication. I will refer to his work in relation to tadalafil again later in these reasons.
Dr Mitchell was also in charge of the clinical pharmacology package for olanzapine (an atypical antipsychotic medication used in the treatment of schizophrenia and other psychoses) for all formulations registered after the original launch of that product (namely, the oral rapidly dissolving formulation and both intramuscular preparations).
In around 2006, Dr Mitchell became Medical Director for Eli Lilly for late phase compounds. While this was more of a managerial role, given his extensive experience in clinical pharmacology at Eli Lilly, the clinical pharmacologists continued to consult him in relation to the regulatory packages they were designing. As such, he has advised in relation to clinical pharmacology packages for almost all the approvals obtained by Eli Lilly in the last twenty years.
In addition to his experience in creating pharmacology packages for small and large molecules, Dr Mitchell also has particular knowledge of the Thorough QT (TQT) study, which is designed to assess whether new drugs have the potential to cause cardiac arrhythmia. Since 2002, he has conducted TQT studies, and became a member of the Eli Lilly cardiovascular safety committee at around the same time. That committee had responsibility for reviewing all molecules in development from a cardiovascular safety perspective.
Since his retirement in 2016, Dr Mitchell has acted as a consultant for Eli Lilly in relation to its ongoing application (made in conjunction with its licensee, Sanofi) for regulatory approval to supply Cialis without a prescription, as well as in connection with patent litigation relating to tadalafil.
The Pharmacologists
Dr Reece
Dr Reece has been an independent consultant to the biotechnology and pharmaceutical industries, both in Australia and overseas, since May 2003. In 1971, he was awarded a Bachelor of Science from the University of Adelaide, and, in 1973, First Class Honours in organic chemistry also from the University of Adelaide. In 1976, he was awarded his PhD in medical chemistry from the Australian National University.
Immediately after completing his doctoral studies, Dr Reece was employed initially as a hospital scientist, and later, as a principal hospital scientist, in the Department of Clinical Pharmacology at the Queen Elizabeth Hospital in Adelaide (QEH).
Dr Reece worked at the QEH for a number of years and he was promoted to various positions. In February 1983, he was promoted to Chief Hospital Scientist, and in 1985, to the ‘excellence’ category of Chief Hospital Scientist. He remained in that position until September 1987. In these roles, Dr Reece had both service-related and research-related duties.
In 1977, Dr Reece completed a postgraduate course in pharmacokinetics presented by Dr William O’Reilly in the School of Pharmacy at the South Australian Institute of Technology in Adelaide (now part of the University of South Australia).
In 1978, Dr Reece took three months’ study leave from the QEH to train under the guidance of Professor Sidney Riegelman at the School of Pharmacy, Medical Centre at the University of California in San Francisco. During this time, he undertook a three-month intensive postgraduate course in advanced pharmacokinetics at the University of California.
Following Professor Riegelman’s death in 1982, Dr Reece attended and presented at a symposium held in his honour. This symposium covered a broad range of drugs, pharmacokinetic principles and delivery mechanisms. It involved a number of presentations given by Professor Riegelman’s former colleagues and students. Dr Reece attended each of these lectures and also presented a lecture on his work on hydrallazine and endralazine pharmacokinetics.
Dr Reece’s research interests at the QEH evolved to include oncology research, in which he specialised after he was awarded a Churchill Fellowship in 1983. The Churchill Fellowship provided support for Dr Reece to undertake a six month project with Dr Garth Powis at the prestigious Mayo Clinic in Rochester, Minnesota in the United States, to study the pharmacokinetics of anticancer drugs.
On his return to the QEH, Dr Reece applied for and was awarded Anticancer Foundation and National Health & Medical Research Council grants to support his research projects.
By the time Dr Reece left the QEH, he had completed several clinical research projects with various groups both within and outside the hospital. The projects were mainly focused on oncology, but also included other therapeutic areas, such as neurology, cardiology and renal disease. Dr Reece had a small team of researchers working on these different projects. In general terms, that work related to investigating the relationship between the plasma concentrations of the drug or drug dosage and pharmacological effect.
In addition to his duties as Chief Hospital Scientist at the QEH, between January 1986 and September 1987, Dr Reece was also an evaluator for the Australian Department of Health. In this capacity, he evaluated the pharmacokinetic component of applications for the regulatory approval of drugs. He reviewed approximately six different approval applications over that time.
The Department of Clinical Pharmacology at the QEH was part of what was known as the Adelaide Pharmacology Group (APG), which was a group that also included the Departments of Clinical Pharmacology of the University of Adelaide and Flinders University and the Pharmacy School of the South Australian Institute of Technology. At that time, the APG was considered the pre-eminent group in Australia for its expertise in clinical pharmacology and pharmacokinetics.
In September 1987, Dr Reece moved to Sydney to become the Clinical Trials Manager at Astra Pharmaceuticals (Astra). As Clinical Trials Manager, he was responsible for six clinical research associates, each of whom had responsibility for conducting and monitoring human clinical trials of Astra’s new pharmaceuticals in Australia and New Zealand for the purpose of obtaining regulatory approval of those products. These trials were generally Phase III trials. Dr Reece’s group had responsibility for ensuring that the clinical trial data that was generated met international regulatory requirements suitable for submission in support of a new drug application.
After 12 months, Dr Reece left Astra to take up the position of Associate Regional Director of Clinical Research at Parke Davis Ltd (Parke Davis) in Sydney. In this role, he was responsible for the clinical trial research activities of the international group in the Asia Pacific region.
In August 1990, Dr Reece transferred to the United States office of Parke Davis in Ann Arbor, Michigan, as Director of Clinical Pharmacology. In that role, he served as the clinical pharmacology representative on several multi-disciplinary project teams, each of which was responsible for the development of a new pharmaceutical product. Each of the drug development project teams of which he was a member included representatives from multiple departments across Parke Davis. In general, those teams included personnel with expertise in medicinal chemistry, toxicology and non-clinical pharmacology, formulation chemistry, clinical pharmacology, clinical medicine, regulatory affairs and marketing. In a majority of the drug development projects that he was involved in at Parke Davis, Dr Reece participated in the transition from pre-clinical studies (involving studies conducted in vitro and in laboratory animals) to Phase I clinical trials in human subjects. He remained a member of the team as the drug proceeded through clinical development. As the clinical pharmacology representative on those teams, Dr Reece was responsible for designing and monitoring studies of each new drug in human subjects (primarily healthy volunteers, and occasionally patients) and analysing and interpreting the results obtained in those studies, including all of the associated pharmacokinetic and toxicology data.
In his role at Parke Davis, Dr Reece was also responsible for designing the protocols for Phase I trials of new pharmaceutical products and for conducting the trials which he designed with the assistance of medical practitioners in the clinical pharmacology group at Parke Davis. He also provided advice on the design and conduct of Phase II and Phase III trials.
Dr Reece was also responsible for preparing the clinical pharmacology reports for investigational new drugs (IND) and new drug applications, and reviewed pre-clinical data for suitability for IND applications and Phase I trials.
In October 1993, Dr Reece returned to Australia to take up the position of Director of Research and Development at Biota Holdings (Biota) in Melbourne. He worked for Biota in a number of different roles for the next nine years, including, between July 1994 and May 1995, acting as Biota’s Chief Executive Officer, and, between May 2001 and March 2002, as a non-executive director of Biota’s United States subsidiary, Biota Inc. In December 2001, Dr Reece was promoted to general manager of the Australian operations of Biota.
In all of his roles at Biota, Dr Reece was responsible for the company’s research and development activities.
In March 2002, Dr Reece left Biota to become Chief Executive Officer and Managing Director of Boron Molecular Ltd in Melbourne. In May 2003, Dr Reece left Boron Molecular Ltd and became an independent consultant.
Since 2003, Dr Reece has been an Honorary Senior Fellow in the Department of Pharmacology, University of Melbourne and each year he has presented a series of lectures on drug discovery and development. He has also held the following positions: from December 2000 to February 2009, non-executive director of EnGeneiC Pty Ltd in Sydney; from December 2003 to April 2008, non-executive chairman of Cryptopharma Pty Ltd in Melbourne; and from February 2004 to November 2008, consultant to Biota.
Professor Brock
As mentioned above at [22], Professor Brock was also a part of the joint session of pharmacologists.
Professor Evans
Professor Evans is the Provost and Chief Academic Officer at the University of South Australia. His expertise is in the areas of pharmacology, pharmacokinetics and formulation science of medicines. Professor Evans also has extensive experience in the design, conduct and analysis of clinical trials in the context of drug development projects.
Apart from his academic duties at the University of South Australia, he has conducted training programs for Australian members of the pharmaceutical industry and the TGA on the process of drug development spanning pre-clinical through to the point where the drug is marketed. He also has extensive experience working with pharmaceutical companies in developing new drug treatments spanning a 10 year period. Professor Evans has also acted as a primary investigator or consultant in at least 50 clinical trials studying the pharmacokinetics and efficacy of APIs.
In 1982, Professor Evans was awarded a Bachelor of Pharmacy from the South Australian Institute of Technology. From 1983 to 1984, he worked full time as a pharmacist in community pharmacies and in a hospital pharmacy. He continued to work part time in community pharmacies until 1989.
Between 1985 and 1989, Professor Evans also completed his PhD at the Department of Clinical & Experimental Pharmacology at the University of Adelaide. His PhD research investigated the pharmacokinetics of enantiomers of ibuprofen.
Between 1985 and 1989, he was also involved in teaching undergraduate courses in pharmaceutics at the South Australian Institute of Technology.
From 1989 and 1991, Professor Evans lived in Manchester in the United Kingdom, where he worked as a postdoctoral research associate under the supervision of Professor Malcolm Rowland at the School of Pharmacy and Pharmaceutical Sciences at the University of Manchester. In 1990, he attended a residential Advanced Course in Pharmacokinetics and Pharmacodynamics in Switzerland.
In 1991, Professor Evans returned to Australia and spent a brief period as a research associate at the Department of Clinical & Experimental Pharmacology at the University of Adelaide. In August 1992, he joined the School of Pharmacy and Medical Sciences at the University of South Australia as a lecturer. In January 1995, he became a senior lecturer and associate professor in January 2000. He was promoted to Professor of Pharmaceutics in January 2003, and then Head of School in September 2004.
In August 2009, Professor Evans became Pro Vice Chancellor & Vice-President of the Division of Health Sciences of the University of South Australia. He held this position until June 2013. As Pro Vice Chancellor, he had responsibility for the teaching, research, human resources, financial and engagement activity of all health science activity at the University. He was also responsible for the management of the University’s City East campus. He continued to teach undergraduate and postgraduate students in the Division of Health Sciences, although to a far lesser extent than in the 1990s through to 2004.
In 2013, Professor Evans became Provost and Chief Academic Officer at the University of South Australia; a position that he currently holds. He has lectured in pharmacokinetics, biopharmaceutics, clinical pharmacology, and pharmacy practice. In particular, he taught students how drugs were discovered, how they were developed and the process of taking a drug from discovery through to marketing, which required him to keep up-to-date with new developments within the pharmacology and pharmaceutical field.
From 1992 to 2001, Professor Evans was also a faculty member of the APG Drug Disposition Workshop Faculty (Workshop Faculty), which ran intensive five-day training programs for Australian members of the pharmaceutical industry and the TGA. In 1996, Professor Evans became convenor of the Workshop Faculty and was the main organiser of the 1998 program, held in Canberra.
Professor Evans has also held a variety of consulting roles. During his time living in Manchester in the early 1990s, he consulted for an Italian pharmaceutical company, Zambon Company S. p. A, providing it with advice on pharmacological issues and, in particular, pharmacokinetics.
In 1992, after returning to Australia, Professor Evans also began consulting for FH Faulding & Co Ltd (Faulding), advising it in relation to new drug delivery systems and formulations. In around 1995, Faulding set up a clinical trial facility conducted at the Royal Adelaide Hospital. At the time, Faulding employed Professor Evans as their main consultant, so he was responsible for liaising with industry representatives, providing advice around the design and conduct of clinical trials and assisting with the quality control and analytical systems. He held this role for nearly ten years and only stopped consulting in 2004, when he was promoted to Head of School.
From 1994 until 2009, Professor Evans also worked extensively with Gebro Pharma during which time he assisted with (among other things) investigating whether or not there were any advantages of (S)-ibuprofen over racemic ibuprofen, for the purposes of European regulatory approval of (S)-ibuprofen. This product was successfully registered and is currently marketed as Seractil.
Beginning in 1993, Professor Evans also worked (and still currently works) with the Italian company Sigma Tau S. p. A and its United States subsidiary Sigma Tau Pharmaceuticals, based in Washington (Sigma Tau). His role at this company with respect to clinical trials was similar to the role held for Faulding, which included responsibility for work concerning propionyl-L-carnitine. Propionyl-L-carnitine is an endogenous compound (meaning that it is already naturally present in the body), which shows some evidence that it is a useful energy source.
In 1997, Professor Evans moved to Italy for approximately six months, so that he could assist Sigma Tau in preparing the dossier that was to be submitted for regulatory approval across Europe. He worked primarily with the pharmacokinetics and metabolism team (which comprised three or four other scientists), but was required to integrate the reports we drafted into the dossier as a whole.
In 1993, Professor Evans became involved with the Drug Metabolism and Disposition Group (later to become the Centre for Pharmaceutical Research) at the University of South Australia, and was the Director of the Centre between 2001 and 2004. He remains a non‑executive director of this company, now known as CPR Pharma Services, which is one of Australia’s largest contract research organisations.
Between 1993 and up to 30 April 1999 (the priority date for the 946 Patent), Professor Evans provided consultancy for 10 to 20 pharmaceutical companies through the Centre. After that priority date, he consulted directly with at least 20 to 30 pharmaceutical companies. His consultancy work involved assisting these companies with evaluating the pharmacological properties of dosage forms and with designing new dosage forms. In this role, he consulted extensively with Faulding to design novel drug delivery systems and improve existing drugs. In particular, he assisted with formulation work by analysing the results of various pre‑clinical and clinical trials and advising Faulding about how to modify their formulations to obtain improved plasma drug concentration versus time profiles.
Throughout his career, Professor Evans has acted as a primary investigator, investigator or consultant in what he estimates to be at least 50 clinical trials studying the pharmacokinetics and efficacy of APIs.
Professor Evans has also been involved, both before and after the priority date of the 946 Patent, in designing and analysing the results of pre-clinical studies. His work before that priority date in this area included designing animal models (primarily in rats) to address absorption, distribution (including protein binding modelling), metabolism and excretion. After that priority date he formed a company called PharmaQuest to commercialise intellectual property in the cancer prevention area.
Between 1998 and 2001, Professor Evans was a member of the Human Research Ethics Committee and chair of the Divisional Human Research Ethics Committee, Division of Health Sciences (Divisional), at the University of South Australia. During the same period, he assisted the National Health and Medical Research Council in reviewing grant proposals for both human and non-human research. His role as a reviewer was to consider matters such as scientific rationale, statistical factors, human ethics issues, researcher track record and project feasibility.
Professor Evans has also been named as an inventor on a number of international patent applications and Australian patents and patent applications.
Between 1995 and 2004, Professor Evans worked for the TGA evaluating pharmacokinetic studies and advising on the accuracy of the results and indications set out in the product information. In this role, he considered approximately 25 submissions for entry onto the Australian Register of Therapeutic Goods, including submissions dealing with antidepressant, immune-suppressant, cardiovascular and non-steroidal anti-inflammatory drugs. This work, combined with his teaching roles, allowed him to gain experience in a wide range of drugs and keep up-to-date with developments in relation to both specific drugs as well as the general therapeutic markets. In 1999, he became the Assistant Editor for Sansom Lloyd N (ed), Australian Pharmaceutical Formulary and Handbook (17th ed, Pharmaceutical Society of Australia, 2000). This reference source was mandatory for all pharmacies in Australia.
During the period leading up to the priority date of the 946 Patent, Professor Evans attended various academic conferences in his field, including the Australian Pharmaceutical Science Association. Between 1998 and 2002, he was the president of that body, and has been involved in various organising committees for these conferences.
The Formulators
Dr Mooney
Dr Mooney is a consultant and director at BM Pharma Consulting Pty Ltd, and has been in this position since 14 December 2012. His expertise is in pharmaceutical sciences, including in the areas of pharmaceutics and pharmaceutical formulation (including oral formulations). He holds a Bachelor of Science (Honours) in organic chemistry, which was awarded to him in 1976 by the University of Adelaide, and a PhD in synthetic organic chemistry, which was awarded to him in 1980 by the University of Adelaide.
Dr Mooney is the co-inventor of about 27 Australian patent applications, including in relation to composition, processes for manufacture and formulation of solid dosage forms. The majority of those patent applications have lapsed, and Alphapharm is the applicant on 25 of them. Two of the patent applications have joint applicants, being Alphapharm and Generics (UK) Limited.
Over the course of Dr Mooney’s career he has been involved in the formulation of about 140 oral solid dosage forms involving about 160 drug substances. This work includes drug substances used in immediate and modified-release tablets and capsules, formulations with cosmetic and functional coatings, orally dispersible tablets and oral contraceptives manufactured under current good manufacturing practice.The majority of this experience occurred throughout the course of his employment with Alphapharm.
Between 1985 and 2009, during Dr Mooney’s employment with Alphapharm, the company grew in size from about 50 to about 500 local employees and became one of Australia’s leading generic pharmaceutical companies. Alphapharm also went through a number of corporate restructures during his employment. Throughout Dr Mooney’s employment, Alphapharm had a focus on developing, manufacturing and registering solid oral dosage forms for domestic and foreign export markets.
From 1985 to 1988, Dr Mooney was employed as a research and development chemist at Alphapharm. During this period he was engaged in, and responsible for the supervision of about 12 employees involved in product formulation and manufacture, analytical method development and method validation, finished product and stability testing and process validation.
Between 1988 and 1999, Dr Mooney was employed as Manager of Research and Development at Alphapharm. In this role, he was responsible for supervising approximately 50 employees working in Alphapharm’s research and development program and managing the associated budget for the research and development program. His role included responsibility for overseeing the research and development product formulation team, the research and development laboratory team and the research and development regulatory affairs team.
The research and development product formulation team was responsible for formulation development and manufacture from small scale trials (involving batch sizes of about 0.5 to 1 kilogram) through scale-up (involving batch sizes of about 3 to 8 kilograms) to pilot batch manufacture (involving at least 100,000 tablets or 10% of the proposed commercial batch size, whichever was greater). The team was also involved in technology transfer (manufacturing) for commercialisation (i.e., the passing on of know-how relating to manufacturing processes for production on a commercial scale).
The research and development laboratory team was responsible for the evaluation and testing of the drug substance (physical and chemical properties), testing of in-process products and final formulations of trial batches including small scale batches to pilot batches and bioequivalence batches and stability testing of development batches. The team was also engaged in analytical method development and validation, cleaning validation and the analytical work required for process validation.
The research and development regulatory affairs team coordinated the distribution of chemistry and manufacturing documentation of new products to overseas and local affiliates for dossier compilation and the filing of necessary documentation for new product registration with the relevant regulatory bodies in Australia and overseas. The team supervised by Dr Mooney was responsible for preparing the relevant dossiers. The team was also involved with post-approval product compliance. In his work with this team he regularly liaised with colleagues regarding bioequivalence study (also referred to as biostudy) requirements for filing product applications in Australia, Europe, Canada and the United States, supervised the preparation of chemistry manufacturing controls for foreign regulatory filings and was involved in pre and post approval of regulatory files and responses to questions for product registrations into Europe, Australia, Canada, New Zealand and the United States.
As Manager of Research and Development Dr Mooney was also responsible for provision of relevant information and product samples to overseas and local biostudy teams. Each biostudy team in a particular jurisdiction was responsible for designing and supervising the bioequivalence studies that were included in the regulatory materials submitted to the relevant authorities in Australia or overseas for product approval.
In addition to having direct contact with the members of the teams described in the preceding paragraphs which included chemists, formulators and pharmacokineticists, as Manager of Research and Development, Dr Mooney also had regular contact with Alphapharm’s patents group. The patents group was responsible for obtaining and providing information on existing patents in relation to a particular molecule to help guide product development work within Alphapharm. The patents group was also responsible for monitoring patent activities of products of interest.
Between 1999 and 2005, Dr Mooney was employed as Senior Manager of Research and Development at Alphapharm. In this role, he was responsible for supervising approximately 70 employees and managing the associated budget. He also continued to have responsibility for, and supervise, the research and development program covering the research and development product formulation team, the research and development laboratory team and the research and development regulatory affairs team. His responsibilities during this period included being involved in decisions regarding bioequivalence studies and in particular, making decisions whether or not to conduct pilot studies or full clinical bioequivalence trials. Pilot studies involve a reduced number of subjects compared to a full study, which have an increased number of participants as necessary to meet statistical needs of the regulatory requirements. He also continued to coordinate with related Alphapharm Group companies on bioequivalence studies for their markets.
From 2005 to 2009, Dr Mooney was employed as Director of Research and Development for the Asia Pacific Region at Alphapharm. In this role, he was responsible for the coordination of Alphapharm’s research and development programs in Australia and at Merck Seiyaku in Japan. The research and development programs involved product development steps from formulation through to registration of a product. This role included managing the budget for and supervision of approximately 80 employees in Australia and approximately 40 employees in Japan engaged in the research and development product formulation, research and development laboratory and research and development regulatory affairs teams.
As Director of Research and Development for the Asia Pacific Region Dr Mooney continued to be involved in decisions regarding the conduct of bioequivalence studies. He also reviewed regulatory submission documents for various global markets and supported the research and development regulatory affairs team in response to any questions from those regulatory bodies regarding the registration of products.
During his time as Director of Research and Development for the Asia Pacific Region Dr Mooney was responsible for the successful integration of the Merck Seiyaku research and development team (of approximately 40 employees) into the global Merck Generics research and development group through regular visits to Japan, coordination of staff exchange and the conduct of intra-company training programs on formulation and analytics for senior research and development people.
From September 2009 to October 2010, Dr Mooney was a Senior Manager at KPMG in the research and development tax group. His role included developing new business opportunities across various disciplines including biotechnology, oil and gas, electrical, manufacturing, construction engineering and mining.
From November 2010 to November 2012, Dr Mooney was employed by CHEMO at their Leon Farma pharmaceutical manufacturing facility in Spain, initially as a private consultant and, from March 2011 onwards, as Research and Development Manager of women’s health care. In both roles, he provided advice and guidance to the Leon Farma research and development team on the development of solid dosage oral contraceptives, including formulation, analytics and regulatory affairs in Europe, the United States and Canada. He was also involved in project management of the development of a medical device. The Leon Farma research and development team consisted of approximately 35 employees.
In December 2012, Dr Mooney started his own consulting firm, BM Pharma Consulting. He has been providing consultancy services to companies in Bangladesh, China, Australia, New Zealand, Europe, the United States and South Africa concerning solid oral dosage formulation of tablets and capsules (both immediate-release and modified release) and the analytical development, validation and testing of drug substances and finished dosage forms. As part of his consulting, Dr Mooney also provides pharmaceutical expertise on drug substance evaluation in terms of its drug master file and physical property characterisation, processes to optimise the efficiencies in product development, bioequivalence studies, regulatory guidance with review of dossiers and expertise on manufacturing scale up of oral dosage forms from small scale through pilot to commercial scale production with accompanying validation protocol review.
Professor Polli
Professor Polli is a Professor of Pharmaceutical Sciences and the Ralph F Shangraw/Noxell Endowed Chair in Industrial Pharmacy and Pharmaceutics at the University of Maryland in Baltimore. He has been a member of the Department of Pharmaceutical Sciences at the University of Maryland since 1993. He has over 25 years of academic industry experience in the field of pharmaceuticals, including formulation, oral absorption and biopharmaceutics. Professor Polli has had an extensive engagement with industry which I will explain below.
In 1989, Professor Polli was awarded a Bachelor of Science in pharmacy from the Philadelphia College of Pharmacy and Science. In 1993, he was awarded his PhD in pharmaceutics from the University of Michigan. On completion of his PhD, he joined the Department of Pharmaceutical Sciences at the University of Maryland, where he has remained since.
Professor Polli’s primary interest, and the continued focus of his research, is the study of orally administered drugs, including the improvement of oral bioavailability through formulation and chemical approaches. He has published widely in peer-reviewed journals in his field, having published approximately 100 articles in the areas of dissolution, drug intestinal permeability, transporter substrate requirements, prodrug design, oral bioavailability, in vitro-in vivo correlation and bioequivalence.
Since 2008 Professor Polli has been a Fellow (and from 2012 and 2013 was a member‑at‑large) of the American Association of Pharmaceutical Scientists. From 2005 to 2010, he was the Vice Chair of the USP Expert Committee on Biopharmaceutics. From 2011, he has been a member of the FDA Advisory Committee on Pharmaceutical Sciences and Clinical Pharmacology.
From 1989 to 2016, Professor Polli was also a licensed pharmacist. Since 1993, he has taught professional pharmacy students and graduate students at the University of Maryland.
Since 2011, he has been the co-director of the University of Maryland Centre of Excellence in Regulatory Science and Innovation and since 2013, he has been the director of the University of Maryland MS in Regulatory Science degree program.
Professor Polli is on the editorial boards of several academic journals in the field of pharmaceutical sciences. In particular, he is associate editor of Pharmaceutical Research.
Professor Polli’s collaboration with industry began in the late 1980s during his undergraduate studies. He was invited to join an industrial pharmaceutical laboratory operated by Dr Joseph Schwartz, a renowned pharmaceutical scientist. The purpose of this laboratory was to solve problems associated with the formulation and dissolution of drugs identified by the pharmaceutical industry. During that time, one of the projects Professor Polli was involved in was a project concerning the formulation of an immediate release oral dosage form for a poorly‑soluble API.
During his undergraduate studies, Professor Polli also had the opportunity to work in the manufacturing group at Merck & Company Inc. The role of the manufacturing group was to translate the drug formulations developed in a laboratory environment to manufacturing on a large scale.
In 2004, Professor Polli worked with Sanofi-Aventis in relation to formulation, in vitro dissolution and in vitro-in vivo correlation work. More recently, in 2010, he worked with Novartis to develop a formulation approach to increase the bioavailability of a poorly soluble, weakly basic drug.
One of Professor Polli’s current research projects, funded by the United States Food and Drug Administration (FDA), involves the poorly soluble, weakly basic drug, itraconazole. Given the low solubility of itraconazole, the project involves making spray-dried amorphous solid dispersions of the drug, resulting in a more soluble form of the drug in order to increase drug dissolution and absorption. The project also aims to develop a clinically-relevant in vitro dissolution test for itraconazole spray-dried amorphous solid dispersions.
Professor Boddy
Professor Boddy gave evidence in the usual way. He is a Professor of Pharmacy at the University of Sydney. His expertise is in the fields of pharmacology and pharmacokinetics. Pharmacokinetics is a branch of pharmacology dedicated to determining the fate of substances administered to a living organism. Professor Boddy’s primary area of expertise is in the application of pharmacokinetic principles to the dosing of anti-cancer drugs, in the context of both adult and paediatric cancers. Professor Boddy’s qualifications are set out in his affidavit. They were not challenged and there is no need for me to set them out. I am satisfied that he has specialised knowledge and experience in the fields of pharmacology and pharmacokinetics.
THE 946 PATENT
I will address the 946 Patent in its amended form. I will discuss the patent in its original form and the amendments made to it in the section of these reasons dealing with Apotex’s claim of false suggestion.
The 946 Specification describes the “Field of the Invention” as follows:
The present invention relates to a highly selective phosphodiesterase (PDE) enzyme inhibitor and to its use in a pharmaceutical unit dosage form. In particular, the present invention relates to a potent inhibitor of cyclic guanosine 3ꞌ ,5ꞌ – mono-phosphate specific phosphodiesterase type 5 (PDE5) that when incorporated into a pharmaceutical product is useful for the treatment of sexual dysfunction. The unit dosage form described herein is characterized by selective PDE5 inhibition, and accordingly, provides a benefit in therapeutic areas where inhibition of PDE5 is desired, with minimization or elimination of adverse side effects resulting from inhibition of other phosphodiesterase enzymes.
The 946 Specification then refers to a pharmaceutical product, which was currently on the market and which is a PDE5 inhibitor, namely, VIAGRA® (Viagra) and states that the active ingredient in Viagra is sildenafil. The 946 Specification contains statements as to the potency and selectivity of sildenafil, as well as its potential to cause side effects, such as vision abnormalities and facial flushing. It also refers to the risks involved in taking sildenafil and organic nitrates at the same time. There is then a reference to the disclosures in Daugan 1995 about the selectivity, dosages and side effects of tadalafil.
The 946 Specification states that the applicants have discovered that one of the compounds disclosed in Daugan 1995 (i.e., tadalafil) can be administered in a unit dose which is effective and without all the side effects associated with sildenafil. There is then a discussion of the benefits of tadalafil in terms of reduced or lessened side effects and, in that context, the side effects which are discussed are facial flushing and vision abnormalities.
The 946 Specification contains a detailed summary of the invention and a diagram showing the structural formula for tadalafil. The invention is said to provide for a pharmaceutical dosage form for human pharmaceutical use, comprising 1 to about 20 mg of tadalafil in a unit dosage form suitable for oral administration. Further, the invention is said to provide a method of treating conditions where inhibition of PDE5 is desired, which comprises administering to a patient in need thereof, an oral dosage form containing about 1 to about 20 mg of a selective PDE5 inhibitor, as needed, up to a total dose of 20 mg per day. Conditions that can be treated include male ED. The invention is also said to provide the use of a unit dose containing about 1 to about 20 mg of a compound having the structure set out for the manufacture of a medicament for administration up to a total maximum dose of 20 mg of the compound per day for the treatment of sexual dysfunction in a patient in need thereof.
There is then a detailed description of the invention. Certain terms are defined in this section of the 946 Specification and it is important to note the following definitions:
The term “IC5o” is the measure of potency of a compound to inhibit a particular PDE enzyme (e.g., PDE1c, PDE5, or PDE6). The IC50 is the concentration of a compound that results in 50% enzyme inhibition in a single dose-response experiment. Determining the IC50 value for a compound is readily carried out by a known in vitro methodology generally described in Y. Cheng et al., Biochem. Pharmacol., 22, pp. 3099-3108 (1973).
…
The term “oral dosage form” is used in a general sense to reference pharmaceutical products administered orally. Oral dosage forms are recognized by those skilled in the art to include such forms as liquid formulations, tablets, capsules, and gelcaps.
The term “vision abnormalities” means abnormal vision characterized by blue-green vision believed to be caused by PDE6 inhibition.
The term “flushing” means an episodic redness of the face and neck attributed to vaso-dilation caused by ingestion of a drug, usually accompanied by a feeling of warmth over the face and neck and sometimes accompanied by perspiration.
The term “free drug” means solid particles of drug not intimately embedded in a polymeric coprecipitate.
Apotex submits that the particle size manufacturing process claims in the 666 Patent (claims 14 and 15) rise no higher than the Swiss claims. They are claims 14 and 15. Apotex submits that the Apotex products are manufactured in accordance with a method that includes each of the features of claims 14 and 15 of the 666 Patent. However, Apotex does not, itself, manufacture the Apotex products. They will be manufactured by third party entities which are located outside Australia. Apotex does not, itself, use the processes claimed in claims 14 and 15 of the 666 Patent.
Apotex submits that patent law is territorial. Infringements occur by acts done in the patent area with respect to patented products or to products resulting from the use in the patent area of patented methods. The reasoning of Lindgren J in Alphapharm v H Lundbeck A/S should no longer be followed. It follows that none of the Swiss and manufacturing process claims in suit is infringed.
ICOS submits that the decision of Nicholas J in Apotex v Warner-Lambert is correct. Section 13 and the definition of “exploit” operate in tandem to delineate the limits of a patentee’s exclusive rights and, pursuant to this legislative scheme, the question of territorial limits only arises when one is determining whether an act of exploitation has infringed a patent, not whether an act amounts to an exploitation. It submits that it is clear from the definition of “exploit” that an Australian patent may be “exploited” anywhere in the world. The question of whether a party is exploiting a patent does not depend on where the relevant act took place. It is only if that exploitation occurs within the patent area that the patentee’s legal rights may be infringed. ICOS submits that to place “territorial limitations” into the definition of “exploit” would render the territorial limitation in s 13 superfluous. Accordingly, the exploitation in Australia of the Apotex products will infringe Swiss-style claims irrespective of where the products are manufactured. Apotex threatens to infringe the relevant claims in both patents.
After I had reserved my decision, the Full Court of this Court delivered its decision in an appeal from the decision of Nicholas J in Warner-Lambert Co LLC v Apotex Pty Ltd (No 2) [2018] FCAFC 26; (2018) 355 ALR 44 (at [156]‑[169]). The Full Court held that Nicholas J’s construction of s 13 and the definition of “exploit” is correct. I am bound to follow that decision. I would, in any event, have followed the decision because I respectfully consider that the reasoning of Nicholas J is correct.
For the above reasons, I conclude that Apotex threatens to infringe all of the claims in suit in the 946 Patent and in the 666 Patent.
CONCLUSION
Apotex’s challenge to the validity of the 946 Patent and the 666 Patent must be rejected. ICOS has established that Apotex threatens to infringe the claims in suit in the case of each patent.
I will hear the parties as to the appropriate orders in light of these reasons.
I certify that the preceding seven hundred and seventy-seven (777) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Besanko. Associate:
Dated: 14 August 2018
ANNEXURE A
Claims in suit in the 946 Patent
1.A pharmaceutical unit dosage composition comprising about 1 to 20 mg of a compound having the structural formula:
said dosage unit form suitable for oral administration up to a maximum total dose of 20 mg per day.
2.The dosage form of claim 1 comprising about 2 to 20 mg of the compound in unit dosage form.
3.The dosage form of claim 1 comprising about 5 to 20 mg of the compound in unit dosage form.
4.The dosage form of claim 2 comprising about 2.5 mg of the compound in unit dosage form.
5.The dosage form of claim 3 comprising about 5 mg of the compound in unit dosage form.
6.The dosage form of claim 3 comprising about 10 mg of the compound in unit dosage form.
8.The dosage form of any one of claims 1 through 7 wherein the unit dose is in a form selected from the group consisting of a liquid, a tablet, a capsule, and a gelcap.
9.The dosage form of any one of claims 1 through 7 wherein the unit dose is in the form of a tablet.
10.The dosage form of any one of claims 1 through 7 when used to treat a condition where inhibition of PDE5 is desirable.
11 The dosage form of claim 10 wherein the condition is male erectile dysfunction.
12.A method of treating male erectile dysfunction in a patient in need thereof comprising orally administering one or more unit dose containing about 1 to 20 mg, up to a maximum total dose of 20 mg per day, of a compound having the structure:
13.The method of claim 12 wherein the unit dose contains about 2 to 20 mg of the compound.
14.The method of claim 12 wherein the unit dose contains about 5 to 20 mg of the compound.
15.The method of claim 13 wherein the unit dose contains about 2.5 mg of the compound.
16. The method of claim 14 wherein the unit dose contains about 5 mg of the compound.
17. The method of claim 14 wherein the unit dose contains about 10 mg of the compound.
19.The method of claim 14 wherein the unit dose contains about 10 mg of the compound and is administered once per day.
20.The method of any one of claims 12 to 19 wherein the unit dose is in a form selected from the group consisting of a liquid, a tablet, a capsule, and a gelcap.
21.The method of any one of claims 12 to 19 wherein the unit dose is in the form of a tablet.
22.The method of any one of claims 12 to 19 when used to treat a condition where inhibition of PDE5 is desirable.
23. The method of claim 22 wherein the condition is male erectile dysfunction.
24. Use of a unit dose containing about 1 to 20 mg of a compound having the structure:
for the manufacture of a medicament for administration up to a maximum total dose of 20 mg of said compound per day for the treatment of male erectile dysfunction in a patient in need thereof.
25.The use of claim 24, wherein the unit dose contains about 2 to 20 mg of the compound.
26.The use of claim 24, wherein the unit dose contains about 5 to 20 mg of the compound.
27. The use of claim 25, wherein the unit dose contains about 2.5 mg of the compound.
28. The use of claim 26, wherein the unit dose contains about 5 mg of the compound.
29. The use of claim 26, wherein the unit dose contains about 10 mg of the compound.
31.The use of claim 26, wherein the unit dose contains about 10 mg of the compound and is for administration once per day.
32The use of any one of claims 24 to 31, wherein the unit dose is in a form selected from a liquid, a tablet, a capsule, or a gelcap.
33.The use of any one of claims 24 to 31, wherein the unit dose is in the form of a tablet.
34.A use according to any one of claims 24 to 31 when used to treat a condition wherein inhibition of PDE5 is desirable.
35. A use according to claim 34 wherein the condition is male erectile dysfunction.
ANNEXURE B
Claims in suit in the 666 Patent
1. A free drug particulate form of a compound having a formula
and pharmaceutically acceptable salts and solvates thereof, comprising particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns.
2.The free drug particulate form of claim 1 wherein at least 90% of the particles have a particle size of less than about 25 microns.
3.The free drug particulate form of claim 1 wherein at least 90% of the particles have a particle size of less than about 15 microns
5.A pharmaceutical composition comprising the free drug particulate form of claim 1 and one or more pharmaceutically-acceptable carriers, diluents, or excipients.
6.The pharmaceutical composition of claim 5 wherein the free drug is entirely in particulate form.
7.A method of treating sexual dysfunction in a patient in need thereof, which comprises administering to the patient a therapeutically effective amount of a composition comprising the free drug particulate form of claim 1 and one or more pharmaceutically-acceptable carriers, diluents, or excipients.
8. The method of claim 7 wherein the sexual dysfunction is male erectile dysfunction.
10. A pharmaceutical composition comprising:
(a) a free drug form of a compound having the formula
and pharmaceutically-acceptable salts and solvates thereof, and
(b)one or more pharmaceutically-acceptable carriers, diluents, or excipients, wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/liter on an AUC (0-24) of about 2280 to about 3560 microgram hour/liter, measured using a 10 milligram dose of the compound.
11.The composition of claim 10 wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/liter and an AUC (0-24) of about 2280 to about 3560 microgram hour/liter.
12.A pharmaceutical composition comprising:
(a)a compound having the formula
and pharmaceutically-acceptable salts and solvates thereof, and
(b)one or more pharmaceutically-acceptable carriers, diluents, or excipients, wherein the composition exhibits a Cmax of about 180 to about 280 micrograms/liter and an AUC (0-24) of about 2280 to about 3560 micrograms hour/liter, measured using a 10 milligram dose of the compound.
14. A method of manufacturing the free drug particulate form of claim 1 comprising:
(a) providing a solid, free form of the compound, and(b)comminuting the solid free form of the compound to provide particles of the compound wherein at least 90% of the particles have a particle size of less than about 40 microns.
15.The method of claim 14 further comprising the step of admixing the particles of step (b) with one or more pharmaceutically-acceptable carriers, diluents, or excipients.
16.A pharmaceutical composition prepared by admixing particles of a compound having a formula
or a pharmaceutically-acceptable salt or solvate thereof, with one or more pharmaceutically-acceptable carrier, diluent, or excipient, wherein the particles of the compound have a d90=40 or less.
17. Use of particles of a free form of a compound having a formula
wherein at least 90% of the particles have a particle size of less than about 40 microns, for the manufacture of a medicament for the treatment of male erectile dysfunction or female sexual arousal disorder.
18. The use of particles of a free form of a compound having a formula
which exhibits a Cmax of about 180 to about 280 micrograms/liter and an AUC (0‑24) of about 2280 to about 3560 micrograms hour/liter, measured using an 10 milligram dose of the compound, for the manufacture of a medicament for the treatment of male erectile dysfunction or female arousal disorder.
24.A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises about 1 to about 20 mg of the compound.
25.A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises 20 mg of the compound.
26.A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises 10 mg of the compound.
27.A pharmaceutical composition according to any one of claims 5, 6, 10 to 13 and 16, wherein the pharmaceutical composition comprises 5 mg of the compound.
28.A pharmaceutical composition according to any one of claims 24 to 27, wherein the pharmaceutical composition comprises a tablet.
29.A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises about 1 to about 20 mg of the free drug particulate form of claim 1.
30.A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises 20 mg of the free drug particulate form of claim 1.
31.A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises 10 mg of the free drug particulate form of claim 1.
32.A method of treating male erectile dysfunction in a patient in need thereof according to claim 8, wherein the composition comprises 5 mg of the free drug particulate form of claim 1.
33.A method of treating male erectile dysfunction in a patient in need thereof according to any one of claims 29 to 32, wherein the composition comprises a tablet.
34.A use according to any one of claims 17 and 18, wherein the medicament comprises about 1 to about 20 mg of the compound.
35.A use according to any one of claims 17 and 18, wherein the medicament comprises 20 mg of the compound.
36.A use according to any one of claims 17 and 18, wherein the medicament comprises 10 mg of the compound.
37.A use according to any one of claims 17 and 18, wherein the medicament comprises 5 mg of the compound.
38.A use according to any one of claims 17 and 18, wherein the medicament comprises a tablet.
ANNEXURE C
Glossary of terms
Term
Description
666 Patent
Australian Patent No 773666
946 Patent
Australian Patent No 769946
Act
Patents Act 1990 (Cth)
Amendment Reasons
Apotex Pty Ltd v ICOS Corporation [2017] FCA 466
APG
Adelaide Pharmacology Group
API
Active pharmaceutical ingredient
Apotex
Apotex Pty Ltd
Astra
Astra Pharmaceuticals
AUCt
Area under curve, where the curve refers to a plot of the concentration of the API in the plasma over time, which represents the aggregate amount of API present in the plasma over a given amount of time
BCS
Biopharmaceutical Classification System
Biota
Biota Holdings
BP
British Pharmacopeia
Butler
Butler US Patent No 5,985,326
cGMP
Cyclic guanosine monophosphate, noting that Viagra increases the level of cGMP and elevated cGMP levels result in relaxation of the cavernosal smooth muscle, which, in turn, results in engorgement of the tissue and erection
cGMP-specific PDE
Cyclic guanosine 3’,5’-monophosphate specific phosphodiesterase
Cialis®
Brand name for tadalafil, which is the compound that is the subject of the two patents in suit in this proceeding
Cmax
Pharmacokinetic parameter used to denote the observed or predicted maximum concentration of API in the plasma following a single dose of the API
cytarabine
Chemotherapy medication used for the treatment of certain blood cancers
Daugan 1995
WO 95/19978, published on 27 July 1995
Daugan 1997
WO 97/03675, published on 6 February 1997
DBP
Diastolic blood pressure, which is the pressure in the arteries between beats
Declaration of Helsinki
General set of principles for the conduct of clinical trials in order to respect the human rights of the subject participating
dissolution rate
Speed at which the API dissolves in a given amount of solvent
ED
Erectile dysfunction (also referred to as impotence), which is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance and is a condition that is particularly common among males over 50 years of age
EDITS
Erectile Dysfunction Inventory of Treatment of Satisfaction, which is a questionnaire consisting of two parts, one to be completed by the patient and the other by the patient’s partner
equilibrium solubility
Solubility that is observed after the solute/solvent system has had sufficient time to reach thermodynamic equilibrium
Faulding
FH Faulding & Co Ltd
FDA
United States Food and Drug Administration
flushing
Defined in the 946 Patent as “… means an episodic redness of the face and neck attributed to vasodilation caused by an ingestion of a drug, usually accompanied by a feeling of warmth over the face and neck and sometimes accompanied by perspiration”
free drug
Defined in the 946 Patent as “… means solid particles of drug not intimately embedded in a polymeric coprecipitate”
GAQ
Global Assessment Question, which is a single question to be answered “yes” or “no” four weeks after the administration of the drug and which asked whether the drug had improved their erections
GB 464
GB9514464.8, published on 6 February 1997
GI tract
A continuous passageway between the mouth and the anus that includes the main organs of digestion, being the stomach which feeds into the small intestine which, in turn, feeds into the large intestine
Goldstein et al (1998)
Goldstein I, Lue TF, Padma-Nathan H, Rosen RC, Steers WD and Wicker PA, “Oral Sildenafil in the Treatment of Erectile Dysfunction” (1998) 338 The New England Journal of Medicine 1397
HSF
Herbert Smith Freehills (Apotex’s solicitors)
IC50
Measure of potency of a compound to inhibit a particular PDE enzyme
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
ICOS
ICOS Corporation
IIEF
International Index of Erectile Dysfunction
IND
Investigational new drugs
IVIVC
In vitro in vivo correlation
Kloner Papers
A collection of three papers that were the subject of evidence from the clinicians in this proceeding, and which include the following: Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J and Jackson G, “Time Course of the Interaction Between Tadalafil and Nitrates” (2003) 42 Journal of the American College of Cardiology 1855 (Kloner et al (2003)); Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J and Jackson G, “Reply” (2004) 43 Journal of the American College of Cardiology 2150 (Kloner et al Reply); and Kloner RA, Mitchell MI and Emmick JT, “Cardiovascular Effects of Tadalafil” (2003) 92 The American Journal of Cardiology 37M (Kloner et al Review)
Levitra®
Brand name for vardenafil, which is a PDE5 inhibitor
Lieberman et al (1989)
Lieberman H, Lachman L and Schwartz JB (eds), Pharmaceutical Dosage Forms: Tablets (2nd ed revised and expanded, Taylor & Francis, 1989)
Lilly ICOS
A new company formed for the purpose of the joint development of tadalafil
Lilly Nitrate Studies
Five pharmacology studies conducted by Lilly ICOS during the period 1999 to 2002 to investigate the potential interaction between tadalafil and nitrates, being LVAB, LVBY, LVCM, LVCP and LVCN, which are discussed in detail in Annexure E
MAD calculation
Maximum absorbable dose calculation, being MAD = S x Ka x SIWV x SITT, where:
S is the solubility of the API at pH6.5 (in mg mL-1)
Ka is the transintestinal absorption rate constant (in min-1)
SIWV is the volume of fluid in the small intestine (in mL); and
SITT is the small intestine transit time (in minutes)
MC-4R
Melanocortin-4 receptor
MD
Doctor of Medicine
MEC
Minimum effective concentration
MHRA
Medicines and Healthcare Products Regulatory Agency, which regulates medicines, medical devices and blood components for transfusion in the United Kingdom
micronisation
A process where the mean particle size of the API is reduced to, at the smallest, single digit micron sizes
mmHg
Millimetre of mercury, which is a manometric unit of pressure, formerly defined as the extra pressure generated by a column of mercury one millimetre high and now defined as precisely 133.322387415 pascals
NCE
New chemical entity, which is a compound that has not been approved by a recognised health regulatory body for use for medicinal purposes
NO
Nitric oxide
Noyes-Whitney equation
dm/dt – kA (Cs – Ct), in which:
A = the effective surface area of the undissolved API, which is the surface area available for contact with the surrounding dissolution medium, being the GI tract fluid (solvent);
Cs = the saturated concentration (i.e. solubility) of the API at the interface of the solid particle surface and the liquid dissolution medium (i.e. the diffusion layer which surrounds the undissolved drug);
Ct = the concentration of the dissolved API in the bulk of the dissolution fluid (where convectional mixing occurs) at time t; and
K = the dissolution rate constant, calculated by dividing the API diffusion coefficient by the thickness of the “diffusion layer” around the particle (being the stagnant liquid layer adjacent to the solid-liquid interface into which the particle’s molecules dissolve)
olanzapine
Atypical antipsychotic medication used in the treatment of schizophrenia and other psychoses
oral dosage form
Defined in the 946 Patent as “… used in a general sense to reference pharmaceutical products administered orally. Oral dosage forms are recognised by those skilled in the art to include such forms as liquid formulations, tablets, capsules and gelcaps”
Oren
WO 01/08686, published on 8 February 2001
Oren Priority Document
US 60/146,924, filed on 3 August 1999
organic ED
ED caused by patho-physiological diseases and conditions
Parke Davis
Parke Davis Ltd
PDE
Phosphodiesterase, which are enzymes that are diffusely found in many parts of the body
PDE5
Phosphodiesterase type 5, which is an enzyme found within the penis
pH
A figure expressing the acidity or alkalinity of a solution on a logarithmic scale on which 7 is neutral, lower values are more acid and higher values more alkaline
Ph Eur
European Pharmacopeia
PhD
Doctor of Philosophy
PHSC
Perth Human Sexuality Centre
PI Statement
Product Information Statement
prostatic hyperplasia
Enlargement of the prostate
psychogenic ED
ED caused by psychological problems
QEH
Queen Elizabeth Hospital, which is a teaching hospital affiliated with the University of Adelaide
Regulations
Patents Regulations 1991 (Cth)
RMRI
Reproductive Medicine Research Institute (now known as the Keogh Institute for Reproductive Medicine)
SBP
Systolic blood pressure, which is the pressure in the arteries when the heart beats
Sexual Encounter Profile Diaries
Diaries containing the patient’s answer to questions formulated by the drug development company
Smith (2015)
Smith BT, Remington Education: Physical Pharmacy (Pharmaceutical Press, 2015)
solubility
The amount of the API that is able to be dissolved in a given amount of solvent
Stoner
WO 00/53148 published on 14 September 2000 (noting that Stoner and US 244 are, in all material respects, the same)
TGA
Australian Therapeutic Goods Association
The clinicians
Dr Denis Cherry, Dr Christopher McMahon, Professor Gerald Brock and Dr Malcolm Mitchell
The formulators
Dr Brett Mooney and Professor James Polli
The pharmacologists
Dr Phillip Reece, Professor Allan Evans and Professor Gerald Brock
Tmax
Measure of the time to achieve peak blood levels of a drug and to be indicative of an improved onset of action
TQT study
Thorough QT study, which is designed to assess whether new drugs have the potential to cause cardiac arrhythmia
US 048
US 60/147048 (also referred to in the reasons as the “666 Priority Document”)
US 244
US 60/123,244, filed on 8 March 1999 (noting that US 244 and Stoner are, in all material respects, the same)
USP
United States Pharmacopeia
VIAGRA®
Brand name for sildenafil, which is a PDE5 inhibitor
vision abnormalities
Defined in the 946 Patent as “… means abnormal vision characterised by blue-green vision believed to be caused by PDE6 inhibition”
Webb et al (1999)
Webb DJ, Freestone S, Allen MJ and Muirhead GJ, “Sildenafil Citrate and Blood-pressure-lowering Drugs: Results of Drug Interaction Studies with an Organic Nitrate and Calcium Antagonist” (1999) 83 American Journal of Cardiology 21C
WHO
World Health Organisation
Workshop Faculty
APG Drug Disposition Workshop Faculty
Wrays
Wrays and Associates (ICOS’s patent and trade mark attorneys)
β-carboline compound
Compound useful for the treatment of various medical indications where the inhibition of PDE5 is desired
Annexure D
ANNEXURE E
CONFIDENTIAL
4