FEDERAL COURT OF AUSTRALIA

Apotex Pty Ltd v ICOS Corporation (No 3) [2018] FCA 1204

ORDERS

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

BESANKO J:

INTRODUCTION

1    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.

2    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.

3    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.

4    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).

5    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).

6    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.

7    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.

8    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.

9    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.

10    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.

11    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.

12    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.

13    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.

14    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.

15    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.

16    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

17    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.

18    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.

19    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.

20    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.

21    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.

22    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.

23    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

24    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.

25    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.

26    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.

27    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.

28    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.

29    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.

30    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).

31    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.

32    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.

33    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

34    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.

35    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.

36    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.

37    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.

38    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.

39    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.

40    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.

41    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

42    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.

43    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.

44    From 1993, Professor Brock was Assistant Professor at McGill University in Montreal, Quebec, before being promoted to Associate Professor and receiving tenure in 1998.

45    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.

46    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.

47    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.

48    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.

49    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.

50    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.

51    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.

52    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.

53    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.

54    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.

55    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.

56    Professor Brock gives lectures to physicians and pharmacists on behalf of various pharmaceutical companies, including Eli Lilly.

57    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.

58    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.

59    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

60    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.

61    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.

62    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.

63    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.

64    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).

65    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.

66    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.

67    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.

68    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).

69    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.

70    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.

71    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

72    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.

73    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).

74    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.

75    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).

76    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.

77    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.

78    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.

79    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.

80    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.

81    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.

82    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.

83    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.

84    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.

85    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.

86    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.

87    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.

88    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.

89    In all of his roles at Biota, Dr Reece was responsible for the company’s research and development activities.

90    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.

91    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

92    As mentioned above at [22], Professor Brock was also a part of the joint session of pharmacologists.

Professor Evans

93    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.

94    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.

95    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.

96    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.

97    Between 1985 and 1989, he was also involved in teaching undergraduate courses in pharmaceutics at the South Australian Institute of Technology.

98    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.

99    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.

100    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.

101    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.

102    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.

103    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.

104    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.

105    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.

106    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.

107    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.

108    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.

109    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.

110    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.

111    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.

112    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.

113    Professor Evans has also been named as an inventor on a number of international patent applications and Australian patents and patent applications.

114    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.

115    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

116    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.

117    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.

118    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.

119    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.

120    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.

121    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.

122    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).

123    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.

124    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.

125    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.

126    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.

127    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.

128    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.

129    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.

130    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.

131    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.

132    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.

133    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

134    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.

135    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.

136    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.

137    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.

138    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.

139    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.

140    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.

141    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.

142    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.

143    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.

144    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

145    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

146    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.

147    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.

148    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.

149    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.

150    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.

151    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.

152    The 946 Specification refers to Butler US Patent No 5,985,326 (Butler) which will be discussed later in these reasons in the context of the 666 Patent.

153    The 946 Specification states that the invention is based on detailed experiments and clinical trials and the unexpected observations that some side effects previously believed to be indicative of PDE5 inhibition can be reduced to clinically insignificant levels by the selection of a compound and unit dose. The unexpected observation enabled the development of a unit dosage form that incorporated tadalafil in about 1 to about 20 mg per unit dosage forms that, when orally administered, minimised some undesirable side effects previously believed unavoidable.

154    The 946 Specification set out IC50 values for tadalafil for PDE5 and PDE6. This is followed by examples showing the preparation of the claimed invention (Examples 1-4 inclusive).

155    Examples 5, 6 and 7 each contain a discussion of the results of studies carried out. Example 5 describes a study involving healthy male volunteers designed to evaluate the hemodynamic effects of the concomitant administration of tadalafil and short-acting nitrates. This Example will be particularly relevant when I come to consider the allegation of false suggestion. It is convenient to set out the discussion in Example 5 in full:

Example 5

This study was a randomized, double-blind, placebo-controlled, two-way crossover design clinical pharmacology drug interaction study that evaluated the hemodynamic effects of concomitant administration of a selective PDE5 inhibitor (i.e., Compound (I)) and short-acting nitrates on healthy male volunteers. In this study, the subjects received either Compound (I) at a dose of 10 mg or a placebo, daily for seven days. On the sixth or seventh day, the subjects received sublingual nitroglycerin (0.4 mg) while supine on a tilt table. The nitroglycerin was administered 3 hours after Compound (I) dosing, and all subjects kept the nitroglycerine tablet under their tongue until it completely dissolved. The subjects were tilted to 70° head-up every 5 minutes for a total of 30 minutes with measurement of blood pressure and heart rate. There were no discontinuations among the twenty-two healthy male subjects (ages 19 to 60 years old) that entered this study.

In a preliminary analysis of this study, Compound (I) was well tolerated and there were no serious adverse events. There were no Compound (I) changes in laboratory safety assessments or 12-lead ECGs. The most common adverse events were headache, dyspepsia, and back pain. Compound (I) demonstrated minimal effect on mean systolic blood pressure, and mean maximal nitroglycerin-induced decrease in systolic blood pressure.

156    Example 6 describes a study involving patients with ED designed to ascertain efficacy and to record side effects. The measurement tools used to determine efficacy were the International Index of Erectile Function (IIEF), diaries of sexual attempts and a global satisfaction question. These measurement tools are discussed below.

157    Example 7 describes a “third clinical study” and it involved “on demand” administration of tadalafil in the case of 212 men with mild to severe ED. Different doses were administered (2 mg, 5 mg, 10 mg and 25 mg). The measurement tools used were the IIEF, a Sexual Encounter Profile Diary and a global assessment question. These measurement tools are discussed later in these reasons (at [414]-[419]).

158    The two most important questions in the IIEF are said to be, first, the ability of the patient to penetrate his partner and, secondly, the ability of the patient to maintain an erection during intercourse. Those functions or abilities improved as the dose of tadalafil increased.

159    The Specification then sets out a Table showing combined results relating to efficacy and dose from clinical studies. It can be seen from the number of subjects which are referred to in this Table, that it is based on more studies than the third clinical study referred to in Example 7 which, as I have said, involved 212 male volunteers. The Table is as follows:

160    There is also a Table showing adverse events called “Treatment-Emergent Adverse Events” which illustrates the point made in the 946 Specification that treatment-emergent adverse events increase with an increasing unit dose of tadalafil. This Table also includes results in relation to doses of 50 mg and 100 mg. The Table is as follows:

161    Finally, Apotex relied on the following statement in the 946 Specification in connection with its novelty argument based on Stoner:

Throughout the specification, unless the context requires otherwise, the word “comprise” or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

THE 666 PATENT

162    As with the 946 Patent, I will address the 666 Patent in its amended form, that is to say, including claims 25-38.

163    As I have said, the filing date of the application for the 666 Patent was 3 August 2000. The 666 Patent claims a priority date of 3 August 1999 by reference to US 60/147048 (US 048).

164    The 666 Specification describes the invention as relating to the fields of pharmaceutical and organic chemistry and to a β-carboline compound which is useful for the treatment of various medical indications where the inhibition of type 5 cGMP-specific phosphodiesterase (PDE5) is desired. The invention is described as providing a free drug form of β-carboline particles in a size range allowing for the uniform formulation of stable pharmaceutical compositions, especially compositions providing desired bioavailability properties not provided previously.

165    The 666 Specification refers to Daugan 1995 and to Daugan 1997. It states that Daugan 1995 discloses a class of β-carboline compounds, and pharmaceutical compositions containing the β-carbolines, useful in the treatment of conditions wherein inhibition of PDE5 is desired and that Daugan 1997 discloses the use of the compounds in the treatment of sexual dysfunction.

166    The 666 Specification refers to the fact that the poor solubility of many β-carboline compounds useful in the inhibition of PDE5 led to the development of co-precipitate preparations as disclosed in, among others, Butler. Studies revealed that there were difficulties in generating precisely reproducible lots of co-precipitate product. Another problem with co-precipitate tablets is said to be that maximum blood concentration of the β-carboline compound was achieved in three to four hours. That was in a context where a more rapid achievement of maximum blood concentration and therapeutic effect was desired. The 666 Specification states that there was a need in the art for orally administrable beta-carboline compounds and beta-carboline-containing pharmaceutical compositions with the ability to provide a therapeutic effect within a desirable, or at least acceptable, timeframe.

167    The 666 Specification provides a summary of the invention. The invention is said to provide particulate preparations of a free drug form of a β-carboline compound having specific and defined particle size characteristics. The defined particle size is said to permit a uniform formulation of stable pharmaceutical compositions. In particular, it is said that the invention provides compositions that exhibit a rapid achievement of the maximum blood concentration of the PDE5 inhibitor or a rapid onset of a therapeutic PDE5 inhibitory effect or both.

168    The invention relates to tadalafil and pharmaceutically acceptable salts and solvates thereof.

169    The 666 Specification contains consistory clauses for claims 1–4 inclusive. There is a reference to particle size. It states that the invention provides for a free form of a β-carboline compound which can be used in an effective therapy for conditions where inhibition of PDE5 provides a benefit. The free form of tadalafil has a particle size such that the onset of beneficial effects of PDE5 inhibition are exhibited in a relatively short time after oral administration.

170    An aspect of the invention is a free drug form of tadalafil and pharmaceutically-acceptable carriers, diluents, or excipients with certain pharmacokinetic parameters, namely:

(1)    a Cmax of about 180 to about 280 micrograms/litre; or

(2)    an AUC (0-24) of about 2280 to about 3560 micrograms hour/litre

measured using a 10 mg dose of the compound.

171    Professor Boddy, whose evidence I accept, described the meaning of these terms. The term “Cmax” is a standard technical term that is used in pharmacokinetics to denote the observed or predicted maximum concentration of API in the plasma following a single dose of the API. AUC is an acronym for “area under curve” and the curve refers to a plot of the concentration of the API in the plasma over time. The AUCt represents the aggregate amount of API present in the plasma over a given amount of time. “AUC (0-24)” represents the amount of API present in the plasma in the 24 hour period following administration of the API.

172    The 666 Specification then states that Daugan 1995 teaches that processing tadalafil to bring the particle size within a particular narrow range enhances manufacturing capability and pharmaceutical compositions can be prepared that exhibit an improved bioavailability of the tadalafil. The Specification states that a typical daily dose of tadalafil is about 1 to about 20 mg per day. It states that preferred daily doses generally are about 1 to 20 mg per day, particularly 5 mg, 10 mg and 20 mg tablets administered as needed.

173    The 666 Specification contains definitions of various terms used in it and the following should be noted:

The term “free drug” refers to solid particles of compound (I) not intimately embedded in a polymeric coprecipitate.

…

The nomenclature describing the particle size of compound (I) is commonly referred to, and is herein, as the “d90”. For example, a d90 of 40 (or d90=40) means that at least 90% of the particles have a particle size of less than 40 microns.

174    The 666 Specification states that a co-precipitate, including tadalafil was manufactured in accordance with the method set out in Butler. The inventors found that on controlled dissolution, the co-precipitate contained a portion of the free drug form of tadalafil that was not embedded in the co-precipitate polymer and that the blood levels of tadalafil within 30 minutes of administration were attributable to the free drug present in the co-precipitate compositions. Those results are described as surprising in view of Butler, and that Butler was attempting to provide a solid dispersion of a poorly water-soluble drug which had enhanced bioavailability compared to free particles of the poorly water-soluble drug. Butler was attempting to avoid the free form of the drug. The 666 Specification states that, based on these observations, bimodal delivery of tadalafil could be achieved, that is, partly free drug in particulate form and partly embedded drug form.

175    The 666 Specification then states that the pharmacokinetic parameters of Cmax and AUC (0-24) in plasma are dose dependent and that there should be a linear relationship between the parameters for a 10 mg dose and the parameters of a 20 mg dose such that the parameters of a 20 mg dose should be about twice that of a 10 mg dose. A 5 mg dose will produce parameters about half that of a 10 mg dose.

176    There are five examples in the 666 Specification.

177    Example 1 involved in vitro dissolution tests where the raw state particulate form of tadalafil (d90 = 75–200 microns) were processed to sizes of d90 = 4, d90 = 22, d90 = 55, d90 = 65, d90 = 73 and d90 = 116. The results illustrated in Figure 1 to the 666 Specification show improved in vitro dissolution occurs with smaller particle sizes of tadalafil.

178    Example 2 states that the pharmaceutical composition with which it deals was prepared as in Examples 4 and 5. It sets out results in terms of Tmax, of a comparison between a particulate free drug form of tadalafil having a d90 of 8.4 microns and a compound incorporating the co-precipitate of tadalafil. Tmax is said to be a measure of the time to achieve peak blood levels of a drug and to be indicative of an improved onset of action.

179    Example 3 was a particle size comparison of tadalafil in terms of its pharmacokinetic properties and involved particle sizes of d90 = 8.4 microns, d90 = 20 microns and d90 = 52 microns. Unlike Example 2, Example 3 does not state that the pharmaceutical compositions used were prepared as in Examples 4 and 5. The study which was carried out and which is the subject of the report in Example 3 shows, according to the Specification, that reducing the particle size of tadalafil improved the in vivo absorption of the drug from a solid dosage form and hence the bioavailability of the drug. The significance of Example 3 and the results referred to in it will become apparent when I address Apotex’s novelty challenge to claims in the 666 Patent based on Oren.

180    Example 4 sets out the formula used to prepare the finished dosage form of a tablet providing 10 mg of tadalafil, and Example 5 does the same in relation to a tablet providing 5 mg and 20 mg respectively of tadalafil.

THE COMMON GENERAL KNOWLEDGE RELEVANT TO THE ISSUES IN THIS CASE

181    In Minnesota Mining & Manufacturing Company v Beiersdorf (Aust) Ltd [1980] HCA 9; (1980) 144 CLR 253 (Minnesota Mining), Aickin J described common general knowledge in the following terms (at 292):

…The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge…

182    In Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59; (2002) 212 CLR 411 (AB Hässle v Alphapharm), Gleeson CJ, Gaudron, Gummow and Hayne JJ said (at [31]) that information that was not shown by evidence to be generally accepted and assimilated by, in that case the formulating community, was not part of common general knowledge.

183    In ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc [2000] FCA 1349; (2000) 106 FCR 214 (ICI Chemicals) at [57], the Full Court of this Court endorsed observations of the trial judge in that case to the effect that common general knowledge is not limited to material which might be memorised and retained at the front of the skilled worker’s mind, but also includes material in the field in which he is working which he knows exists and to which he would refer to as a matter of course.

184    In Alphapharm Pty Ltd v H Lundbeck A/S [2008] FCA 559; (2008) 76 IPR 618 (Alphapharm v H Lundbeck A/S), Lindgren J, after referring to Minnesota Mining, said (at [221]):

… The question is whether it is “generally accepted without question” or “generally regarded as a good basis for further action” by the bulk of those in the art: Minnesota Mining and Manufacturing Co v Tyco Electronics Pty Ltd (2002) 56 IPR 248 at [100], quoting Blanco White TA, Patents for Inventions and the Protection of Industrial Design (5th ed, Stephens, London, 1983) at [4-207].

(See also Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368; (2013) 101 IPR 11 (Ranbaxy v AstraZeneca) at [214]-[218] per Middleton J.)

185    There is no dispute that in this case the skilled person in the relevant art for the purposes of s 7(2) of the Act would comprise a multidisciplinary team of professionals with different fields of expertise who were typically involved in the drug discovery and development process. I describe the composition of the team later in these reasons (at [334]).

186    The subject matter of the two patents in suit is the formulation and use of a PDE5 inhibitor for the treatment of ED. The asserted priority dates are 30 April 1999 in the case of the 946 Patent, and 3 August 1999 in the case of the 666 Patent. The alternative dates (i.e., the filing dates) of 26 April 2000 and 1 August 2000 respectively were also the subject of evidence. The experts did not give any evidence which suggested that there was any material difference in the relevant common general knowledge between the dates in 1999 and the dates in 2000.

187    There was a good deal of common ground between the experts as to the knowledge and information which comprised the common general knowledge. I set out below my findings as to common general knowledge. Where there was a dispute, I will identify it and the way in which I resolve it.

188    ED is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. It is a condition that is particularly common among males over 50 years of age. It is also referred to as impotence and that term was used more frequently prior to April 1999 than it is today.

189    It was understood prior to April 1999, and this understanding continues to the present day, that ED can be caused by patho-physiological diseases and conditions (organic ED) or by psychological problems (psychogenic ED) and sometimes by a combination of both. It was understood that depending on the underlying causes, certain treatment options would be more suitable than others. Furthermore, it was understood that the condition itself can have psychological effects, such as strong feelings of inadequacy. A clinical guide referred to by Dr Cherry in his evidence stated that almost all men with ED will be affected psychologically even if the cause is organic (Erectile Dysfunction European Society for Impotence Research, Physicians Guide (Annexure DJC-6)).

190    Sildenafil, or Viagra as it is commonly known, was released in Australia in September 1998. It revolutionised the treatment of ED and was effective and resulted in manageable side effects for most patients. In addition, sildenafil was far more convenient to administer than the other ED treatment options that were available prior to its release. However, there were disadvantages associated with sildenafil. The first was that it did not have spontaneous effects. Typically, a patient would need to wait about 30 minutes to one hour after ingestion of the tablet before the drug took effect and longer if the tablet was ingested with food. The second disadvantage was that it was a relatively expensive drug that was also relatively short acting. Sildenafil had a short half-life, that is to say, it was cleared and excreted from the body quickly. The third disadvantage was that sildenafil had known side effects, which include the risk of cardiovascular events, facial flushing, reflux and vision abnormalities.

191    The clinicians were persons skilled in the field of the treatment of ED before 30 April 1999. In their joint experts’ report, they said that a person skilled in the field would have known and understood the following matters about sildenafil or Viagra:

(1)    it was the first approved oral treatment for ED;

(2)    it is a PDE5;

(3)    it is effective, well tolerated and safe;

(4)    the commonest side effects of Viagra are facial flushing, headache and dyspepsia;

(5)    vision abnormalities resulted from PDE6 inhibition; and

(6)    the co-administration of Viagra and a nitrate is contraindicated.

192    PDEs are enzymes that are diffusely found in many parts of the body.

193    One of the clinical guides referred to by Dr Cherry provides the following relatively simple explanation of how sildenafil or Viagra works:

Viagra works by inhibiting an enzyme called phosphodiesterase (PDE), in particular, one member of this class of enzymes called PDE5. This enzyme is found within the penis and this accounts for the relatively selective action of Viagra on ED. By inhibiting PDE5, Viagra increases the level of cyclic guanosine monophosphate (cGMP). Elevated cGMP levels result in relaxation of the cavernosal smooth muscle, which in turn results in engorgement of the tissue and erection. In patients with ED, cGMP levels may be low and would therefore be raised by Viagra.

    (Erectile Dysfunction: A Clinical Guide (Annexure DJC-6))

194    The potency of a drug is an important feature of the drug and may be is measured by an IC50 value which is the amount of the drug needed to reduce the enzymes’ activity by 50%. I have already referred to the description of an IC50 value in the 946 Patent. The lower the IC value, the more potent the drug. If a lot of the drug is needed to be effective, then its potency is not very good.

195    The selectivity of a drug is also important. There are a number of PDEs in the body and it is important that the drug be as selective as possible for PDE5 in order to avoid undesirable side effects. One difficulty in the area of selectivity is that, as at 30 April 1999, scientists were not aware of all the PDEs in the body. Those skilled in the field were aware of approximately six different subtypes of PDEs. Furthermore, those skilled in the field were not aware of which PDEs were responsible for the side effects associated with a PDE5 inhibitor.

196    Potency and selectivity may point in opposite directions in terms of the usefulness of a drug. A potent drug may not be selective and may cause side effects that patients are not prepared to tolerate. Selectivity can be measured as a ratio between the IC50 for a given PDE and the IC50 for PDE5. In order to establish the selectivity of a PDE inhibitor to the extent it could be done, it was necessary to determine the IC50 for a given PDE and the IC50 for PDE5.

197    A Product Information (PI) Statement for Viagra was issued when the drug came onto the market and such a statement has been reissued from time to time. The PI Statements for Viagra for 1998, 1999 and 2016 respectively, were tendered in evidence. A PI Statement contains information about the product and that will include a description of the product, its pharmacodynamics properties, details of clinical trials of the product, its pharmacokinetic properties, indications, contraindications, precautions, details of adverse reactions and details of dosage, administration and presentation. The purpose of contraindications is identified later in these reasons (at [703]-[707]).

198    The clinicians were asked to consider the 1999 Viagra PI Statement and identify the information in the Statement which was part of the generally accepted background knowledge and understanding of a person skilled in their field. As I understand it, that was done simply because it was a convenient way for them to proceed. They agreed that the following information fell into that category:

(1)    Sildenafil is an orally active selective inhibitor of a cGMP-specific PDE5.

(2)    Nitrates and sildenafil (Viagra) must not be used concomitantly and Viagra is contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors.

(3)    Viagra is an oral therapy for ED which restores blood flow to the penis resulting in a natural response to sexual stimulation.

(4)    Sildenafil is a potent and selective inhibitor of PDE5 which is responsible for degradation of cGMP in the corpus cavernosum. Inhibition of PDE5 by sildenafil results in increased corpus cavernosum levels of cGMP. Therefore, sexual stimulation is required in order for Viagra to produce its beneficial pharmacological effects.

(5)    Mild and transient differences in colour discrimination (blue/green) are detected in some patients following a 100 mg dose and at lower doses. The postulated mechanism for this change in colour discrimination is related to inhibition of PDE6. In vitro studies show that sildenafil is 10-fold less potent against PDE6 than PDE5.

(6)    The IIEF can be used to measure efficacy of an ED treatment.

(7)    A 100 mg dose of Viagra provides better therapeutic efficacy than a 50 mg dose, a 50 mg dose provides better therapeutic efficacy than a 25 mg dose. All three doses provide better therapeutic efficacy than placebo.

(8)    Viagra improves erectile function, orgasm, satisfaction with intercourse and overall satisfaction.

(9)    A therapeutic effect is ordinarily observed within about an hour after administration of Viagra.

(10)    Viagra is indicated for the treatment of ED in adult males.

(11)    Use of Viagra is contraindicated in patients with known hypersensitivity to any component of the tablet.

(12)    Viagra potentiates the hypotensive effects of organic nitrates and its co-administration with nitric oxide (NO) donors or organic nitrates in any form is therefore contraindicated. Drugs which must not be used concomitantly include glyceryl trinitrate (injection, tablets, sprays or patches), isosorbide salts, sodium nitroprusside, amyl nitrite or organic nitrates in any form.

(13)    Viagra is contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors (e.g., patients with severe cardiovascular disease such as established cardiac failure and unstable angina pectoris). The possibility of undiagnosed cardiovascular disorders in men with ED should be considered before prescribing Viagra.

(14)    The use of sildenafil is contraindicated in patients with severe hepatic impairment, hypotension, uncontrolled hypertension (at higher risk of heart attack or stroke), recent history of stroke or myocardial infarction and known hereditary degenerative retinal disorders such as retinitis pigmentosa.

(15)    A thorough medical history and physical examination should be undertaken to diagnose ED, determine potential underlying causes and identify appropriate treatment.

(16)    Prior to initiating any treatment for ED, physicians should consider the cardiovascular status of their patients, including those with recent onset angina, since there is a degree of cardiovascular risk associated with sexual intercourse.

(17)    Viagra has vasodilator properties, resulting in mild transient decreases in blood pressure and, as such, potentiates the hypotensive effect of nitrates.

(18)    The incidents of adverse events may be greater in those patients who require the maximum recommended dose of 100 mg (e.g., some diabetic and spinal cord injury patients).

(19)    Patients with cardiovascular disease who have not engaged in sexual intercourse for a number of years should have their cardiovascular status carefully assessed prior to initiating treatment with Viagra.

(20)    Viagra is not indicated for use in women.

(21)    As transient visual disturbances have been reported in some patients taking Viagra, particularly at the 100 mg dose, patients should be aware of how they react to Viagra before driving or operating machinery, and the doctor should advise accordingly (visual disturbances are also reported in some patients taking 50 mg doses).

(22)    When Viagra is taken as recommended (on an as needed basis in flexible dose placebo controlled clinical trials) the following adverse events were reported: headache, flushing, dyspepsia and abnormal vision.

(23)    In fixed dose studies, the incidents of adverse events increased with dose.

(24)    In fixed dose studies, dyspepsia and abnormal vision were more common at 100 mg than at lower doses. Priapism is rare with sildenafil. Single doses of more than 100 mg cause adverse events similar to those seen at lower doses, but incidents are increased.

(25)    Viagra tablets are for oral administration.

(26)    The recommended dose of Viagra is 50 mg taken as needed approximately one hour before sexual activity. Based on the efficacy and toleration, the dose may be increased to 100 mg or decreased to 25 mg, although the most commonly prescribed dose was 100 mg, with the 25 mg dose only prescribed in limited cases.

(27)    The maximum recommended dose is 100 mg. The maximum recommended dosing frequency is once per day. Since sildenafil clearance is reduced in elderly patients, a first dose of 25 mg should be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and 100 mg.

(28)    The dosing recommendations for use in adults should be followed for patients with mild to moderate renal impairment. Since sildenafil clearance is reduced in patients with severe renal impairment, a 25 mg starting dose may be considered. Based on efficacy and toleration, the dose may be increased to 50 mg and 100 mg.

(29)    Viagra is not indicated for use in children.

199    The clinicians also addressed the issue of the extent to which, in their clinical practice, they would consult the 1999 Viagra PI Statement. Dr McMahon and Professor Brock said that they would have read the 1999 Viagra PI Statement at about the time Viagra received regulatory approval, but would rarely consult the Statement and it would have little or no role as a source of information in their clinical practice. Dr Cherry, on the other hand, said he read it initially and thereafter regularly consulted the Viagra PI Statement in his clinical practice. After discussion between the clinicians, they agreed that in the vast majority of cases, the Viagra PI Statement was rarely reviewed by physicians. In an addendum to the joint experts’ report, Dr Cherry corrected his answer by saying that he was uncertain about the use of the specific Viagra and Cialis PI Statements by doctors (i.e., specialists and general practitioners). He provided some information about the availability of PI Statements on MIMS digital platforms and by way of printed versions. However, as ICOS pointed out, Dr Cherry’s research as to those matters was carried out on 1 and 2 June 2017.

200    Dr Cherry gave evidence that his ongoing use of PI Statements was mainly for drug interactions, impact upon the elderly, impact upon diabetics and, say, kidney and liver failure. He said:

Those sort of clinical situations rather than the actual pharmacological situations.

201    He said that he did not consult the 1999 Viagra PI Statement in respect of the molar mass of sildenafil or plasma concentrations of sildenafil associated with any dose or the pharmacokinetics of sildenafil being absorption (bioavailability), distribution, metabolism and excretion (clearance). Dr Cherry said he rarely consulted the Viagra PI Statement for pharmacological information, including information about PDE potency. The significance of whether this type of information was part of common general knowledge will become clear when I come to consider the evidence of the pharmacologists and, in particular, Dr Reece.

202    I am not satisfied on the evidence that information in the 1999 Viagra PI Statement (other than that agreed between the clinicians and set out above) was generally accepted and assimilated by the skilled person in the field in the sense identified in the authorities to which I have referred. It is therefore not part of the common general knowledge.

203    The contraindication of Viagra with the concomitant use of nitrates which are a common ingredient in medications to treat angina, limited in a not insignificant way, the number of patients who were able to take Viagra. That was the case because the primary group of males with ED were males over 50 years old and many of that group suffered from heart disease and needed to take medications to treat angina.

204    Viagra was available in 25 mg, 50 mg and 100 mg tablet doses. Although not all patients responded in the same way, it was generally the case that efficacy and the severity of side effects increased with dose.

205    The clinicians were asked to describe their dosing practices in relation to Viagra.

206    Dr Cherry’s dosing practice with respect to Viagra as at 30 April 1999 was to start at a low dose and titrate up to minimise side effects, but eventually achieve a successful dose. His practice was to start with a dose of 25 mg and raise the dose until a satisfactory outcome for the patient had been achieved. He gave evidence that he had done a small survey in relation to patients in his practice which indicated that within a week, or two at most, he had settled on a dose for his patients. Almost three-quarters of his patients were taking doses of 100 mg.

207    In contrast to the dosing practice of Dr Cherry, the dosing practice of Dr McMahon and Professor Brock was to start the vast majority of patients seeking treatment for ED on doses of 100 mg of Viagra. Their dosing practice differed from the recommended 50 mg dose in the 1999 Viagra PI Statement. They explained their reasons for their practice in the following way:

The rationale for our dosing practice was predominantly based upon the fact that the majority of patients seeking treatment for erectile dysfunction are aged ˃50 years and have vasculogenic erectile dysfunction. Many of these men have vascular risk factors including diabetes, hypertension, hyperlipidaemia, a history of coronary artery disease or peripheral vascular disease or smoke cigarettes. This population of men is a more challenging population to treat and the majority will require a dose of 100 mg. Furthermore, there are recognised links between erectile dysfunction, depression and a reduced quality of life. Many of these men have suffered erectile dysfunction for several years and or may have failed to respond to previous treatments. The psychological burden of erectile dysfunction is substantial and many men who fail to respond to treatment made [sic] choose to suspend treatment-seeking, further reducing the quality of life. On this basis we regard that it is vital to achieve the best possible outcome from treatment and regard a 100 mg dose of Viagra as most likely to achieve that outcome.

In Goldstein’s 1998 landmark article published in the New England Journal of Medicine only 2% of patients selected 25 mg of Viagra at the end of dose titration. We would occasionally vary this dosing practice in younger men with psychogenic erectile dysfunction and use a commencing dose of 50 mg. Although the prescribed information recommends a commencing dose of 25 mg in men with impaired renal or hepatic function and in men prescribed CYP 3A4 inhibitor drugs, these are uncommon clinical scenarios which were only occasionally seen in our practices.

208    The Goldstein article to which this evidence refers stated the following:

In the flexible dose-escalation study, 329 different men were randomly assigned to take placebo or 50 mg of sildenafil approximately one hour before sexual activity for 12 weeks. At each follow-up visit, the dose could be doubled or reduced by 50 percent on the basis of the therapeutic response and adverse effects. Each man completed the International Index of Erectile Function at 0 and 12 weeks and was asked about global efficacy at week 12. The event logs were reviewed at 0, 2, 4 8 and 12 weeks. The men who completed the study and who did not have any serious adverse effects were eligible to receive open-label sildenafil for an additional 32 weeks.

    (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 (Goldstein et al (1998) (Annexure GBB-9).)

209    As I have said, the clinicians agree that, as at 30 April 1999, the most efficacious dose of Viagra was 100 mg and that was the most commonly prescribed dose (see [198](7) and (26)).

210    Although Dr Cherry was an impressive witness, I find that his dosing practice did not represent the norm. I find that the dosing practice of Dr McMahon and Professor Brock represented the norm among clinicians. I reach that conclusion for the following reasons.

211    First, most of those patients taking Viagra as at 30 April 1999 were taking doses of 100 mg and doses in that quantity were known to have the greatest therapeutic effect. Secondly, it is likely that the majority of Dr Cherry’s patients were, after a short period of time, taking doses of 100 mg. Thirdly, Dr Cherry conceded that his dosing practice was influenced by his experience with intracavernosal injections which could cause priapism. Priapism is a prolonged, rock-hard, painful erection lasting for greater than four hours. The clinicians agree that priapism is rare with sildenafil (see [198](24)). Finally, various scientific publications provide strong support for the reasons which Dr McMahon and Professor Brock gave for their dosing practices.

212    Professor Brock said, and I accept, that his clinical experience at and since 30 April 1999 is consistent with findings reported in Tomlinson & Wright, “Impact of erectile dysfunction and its subsequent treatment with sildenafil: qualitative study”; British Medical Journal, doi.org/10.1136/bmj.38044.662176.EE (published 29 March 2004) (Annexure GBB-12) concerning the following matters: the psychological effects of ED, the psychological effects of treatment for ED, treatment failure even the first time and the high expectations generated by Viagra. I will not set out all of the details. It is sufficient to say that patient interviews revealed that ED had a significant effect on a patient’s confidence, morale and relationship with their partner, that most patients had high expectations of sildenafil and that an initial failure, and certainly a second failure, could have devastating consequences.

213    Professor Brock’s approach (and that of Dr McMahon) aligns with the findings set out in Ströberg P, Kaminetsky JC, Park NC, Goldfischer ER, Creanga DL and Stecher VJ, “Hardness, Function, Emotional Well-being, Satisfaction and the Overall Sexual Experience in Men using 100-mg Fixed-dose or Flexible-dose Sildenafil Nitrate” (2010) 22 International Journal of Impotence Research 284 (Annexure GBB-11). The following appears in that article:

Given that almost 90% of the men who initiated treatment with flexible-dose sildenafil titrated to a dose of 100 mg after 2 weeks, initiating treatment with 100-mg sildenafil should greatly decrease the need for dose titration and, in those men for whom a dose of 50 mg might prove ineffective, may decrease the risk of discouragement and treatment abandonment because of inadequate dosing. The high proportion of men titrating to a dose of 100 mg supports earlier results, which showed that 100-mg sildenafil produced optimal erection hardness (fully hard and rigid) in a substantial proportion of men with ED and that 100 mg was the dose used by most men in dose-optimization studies. Several studies reported that titration to the highest well-tolerated approved dose and/or early dose optimization contributed to treatment success.

…

In conclusion, sildenafil in doses of 50 and 100 mg is effective for the treatment of ED, and both doses are generally well tolerated. An initial dose of sildenafil 100 mg appears to be at least as efficacious and well tolerated as an initial dose of 50 mg with the option to titrate to the optimal dose. Furthermore, an initial dose of 100 mg may reduce the need for dose titration and may prevent discouragement and treatment abandonment in men for whom a dose of 50 mg is insufficient. This suggests prescription of an initial dose of 100 mg, except in those for whom it is inappropriate.

214    Viagra was the only oral drug treatment for ED on the market prior to 30 April 1999 where the active ingredient, sildenafil, acted as a PDE5 inhibitor. As at 30 April 1999, it was expected by those skilled in the field that Viagra would eventually be followed by other oral drug treatments for ED which acted in the same way as sildenafil. The person skilled in the field expected that other pharmaceutical companies would have been keen to develop other oral drug treatments for ED to compete with Viagra. Viagra was a first generation drug because it acted in a unique way that was different to all previous drugs for the treatment of a particular condition, that is, it was the first oral drug treatment for ED where the active ingredient (sildenafil) acted as a PDE5 inhibitor. Drugs which follow a first generation drug and act in the same way to treat the same condition are referred to as second generation drugs. The first and second generation drugs are part of the same therapeutic class. Typically, each new drug in a therapeutic class has improved features which distinguish it from the existing drugs in that class on the market, such as better efficacy or reduced side effects.

215    The clinicians agreed that as at 30 April 1999, the desirable properties of a treatment for ED were as follows:

(1)    oral administration;

(2)    on-demand prior to sexual activity;

(3)    rapid onset;

(4)    effective;

(5)    minimal side effects;

(6)    safe;

(7)    tolerable; and

(8)    low cost.

216    There was evidence directed to the form of administration. Viagra was a tablet and Daugan 1997 referred to tablets and capsules. Generally speaking, tablets and capsules were the preferred form of administration. Dr Reece described tablets and capsules as the most common and convenient form of administration of drugs, and Professor Boddy said that it was the most common route of administration. On the other hand, Dr Cherry (with the concurrence of Dr McMahon and Professor Brock) said that forms of administration, other than oral administration, such as nasal, buccal and sublingual, would be avenues to be explored by a skilled team developing an ED treatment in April 1999. In fact, Dr Cherry said that in his practice he would often advise his patients to grind their Viagra tablet into a powder in order to aid absorption. I will return to the issue of the form of administration later in these reasons.

217    ICOS submitted that in giving his opinion in his affidavit affirmed on 18 November 2016 as to how he would proceed with drug development in light of Daugan 1997, Dr Reece has relied on information in the 1999 Viagra PI Statement which was not part of common general knowledge First, Dr Reece has given an opinion as to the increased selectivity of Compound A (tadalafil) over sildenafil (see paragraphs 318(b) and (c) of his first affidavit) and, in doing so, has used the selectivity figures in the 1999 Viagra PI Statement in relation to PDE6 and in relation to PDE1, PDE2, PDE3 and PDE4 (see paragraph 306 of his first affidavit). Secondly, Dr Reece has used information in the 1999 Viagra PI Statement as to the absorption and half-life of sildenafil when expressing opinions concerning Compound A (see paragraphs 309, 318(d) and 325 of his first affidavit). Thirdly, Dr Reece has expressed opinions about the relative potency of Compounds A and B compared with sildenafil based on (among other things) the molecular weight of sildenafil contained in the 1999 Viagra PI Statement (see paragraphs 312, 314, 316-318 of his first affidavit). He uses that information to express an opinion as to the range of doses at which he would expect efficacy would be observed for Compound A (see paragraph 322 of his first affidavit). The matters which have been taken from the 1999 Viagra PI Statement were not part of common general knowledge. I address Dr Reece’s evidence and the extent to which I accept it later in these reasons.

218    With an eye to Apotex’s obviousness challenge, ICOS emphasised two matters about common general knowledge as at 30 April 1999 and 3 August 1999 which it is convenient to identify at this point.

219    First, ICOS emphasised the fact that on-demand treatment was desired, not chronic dosing. Chronic dosing means lower dosing and the fact that it was not desired supports (so ICOS’s submission goes) the inventiveness of the lower doses of less than 10 mg. Professor Brock said, and I accept, that patients and physicians expected on-demand treatment. In 1999/2000, he had recommended against a daily dosing regimen for tadalafil. He could not be more precise about the date. Professor Brock had taken this view for two reasons. First, the paradigm of on-demand treatment had been set by Viagra. Secondly, there was also the consideration that, in light of the likely limited sexual activity of the target group, the risk of chronic exposure to side effects was not justified. Dr Cherry had given advice as to chronic dosing, but he could not recall whether that was before or after the priority dates in 1999. ICOS submitted, and I accept, that, in any event, to investigate chronic dosing was not a matter of routine. I will return to this issue.

220    Secondly, ICOS emphasised that the nature of ED and the way in which any improvement is measured means that identifying a minimum clinically relevant dose is difficult. There are difficulties and complexities in interpreting the data produced by the measurement tools which are available and judgment calls have to be made. I will return to this issue. The identification of the minimum clinically relevant dose does not mean that it will be used in Phase III trials where a balance must be struck between safety and efficacy. I accept that, unlike some other drugs, most of the patients with ED have a combination of organic and psychogenic ED and it is important that a treatment for ED succeed on the first occasion, otherwise there could be further psychological harm or the patient will not return for further treatment.

221    It is not in dispute that tadalafil and its physiochemical, pharmacokinetic and pharmacodynamics properties were not part of common general knowledge at the priority dates in 1999.

222    I turn now to summarise common general knowledge at the priority dates in 1999 as to the process of drug discovery and drug development. This summary is given at a high level of generality and is not specific to developing a new drug for the treatment of ED.

223    The pharmacologists described the steps involved in drug discovery and drug development prior to April 1999. They are not in dispute. Dr Reece said that drug discovery covers the period from the first identification of a target, the identification of compounds that are active against the target, and then the identification of a compound to take into development. He said that drug development covers the processes of pre-clinical and clinical development of a drug candidate, the object of which is to establish the safety and efficacy of the drug for approval by a regulator. The process includes determining the doses intended to be marketed. Dr Reece said that drug development also includes formulation development, both for the purposes of early human studies and also for use in late stage clinical trials. Professor Evans gave evidence to similar effect. More particularly, the drug development process involves the following. First, there are pre-clinical trials involving in vitro tests and tests with animal models and these trials may include an assessment of efficacy if one or more appropriate and validated animal models are available. Secondly, Phase I clinical trials will be conducted and these trials will involve healthy volunteers. The primary purpose of the Phase I clinical trials is to identify and characterise the pharmacokinetics and safety of the API. Thirdly, Phase II clinical trials will be conducted and these will involve patients (i.e., persons with the condition to be treated). The primary purpose of Phase II clinical trials is to obtain an indication of whether certain doses show efficacy and safety in patients. Pharmacokinetics are also measured in Phase II clinical trials. Phase II clinical trials may be divided into Phase IIA and Phase IIB, with Phase IIA involving fewer patients and a shorter time to complete, for example, up to 20 patients over a few weeks, and Phase IIB involving a larger number of patients and longer time to complete, for example, up to a few hundred patients for up to several months, depending on the indication. Phase III clinical trials are conducted over a longer period of time than Phase II clinical trials and involve a larger number of patients. Such trials can involve hundreds or thousands of patients over many months. The primary purpose of Phase III clinical trials is to demonstrate the clinical efficacy and safety of the API. Phase IV clinical development occurs after marketing approval has been given and involves the surveillance of patients who are taking the commercial product. Phase IV clinical development commonly involves thousands of patients.

224    The pharmacologists were agreed as to the type of pre-clinical tests which would be carried out in the course of developing a new drug for the treatment of ED. The in vitro and animal studies that would be carried out and the significance of the data that would be obtained from such studies was summarised by the pharmacologists in the following table:

“GB” is Professor Brock.

225    The design and conduct of clinical trials are established in accordance with well-established protocols and procedures. The conduct of clinical trials is governed by the Declaration of Helsinki which can be considered as a general set of principles for the conduct of clinical trials in order to respect the human rights of the subjects participating. The objective of clinical trials is to establish the safety and efficacy of a drug. The doses, dose regimes and dosage forms are determined during the clinical trials.

226    At the in vitro stage when testing for the IC50 result, the question of the doses to be tried in the Phase II clinical trials has not yet arisen.

227    Professor Evans gave evidence about how the doses for use in clinical trials are formulated. I accept this evidence which may be summarised as follows. First, the tests for the IC50 value are carried out at the very start of the in vitro tests. The result is not particularly useful in determining the dose to be used in humans. Secondly, the first Phase I study is carried out primarily to assess the safety and tolerability of the drug in humans in most cases, and generally, the drug development team would start at doses well below the doses which caused dangerous effects in the animal models. In Phase I studies, the development team is working towards determining the maximum tolerated dose and proceeds by increasing the dose having regard to previous results. In Phase I studies, the development team is not only observing side effects, but (usually) conducting pharmacokinetic studies. Thirdly, the results of the Phase I studies will inform the doses the development team will experiment with in the Phase II study. The development team do not go above what has been determined as the maximum tolerated dose. Fourthly, it may be that a Phase IIA study is used to test safety because the drug is for the first time administered to patients suffering from the condition to be treated. One might then progress to efficacy studies in Phase II. Fifthly, Professor Evans considered that the study which is described in Example 7 in the 946 Patent “looks like” a “Phase 2B type study”. I will return to this issue. Sixthly, Professor Evans said that even in the case of a Phase II efficacy study, the team would be cautious and often start off with a low dose. Finally, as each study informs the next, the team may start with quite a wide range which is then narrowed down or refined as the studies progress.

228    Dr Reece said that, where possible, efficacy is also determined in animal models. However, there are cases where there are no predicative animal models for determining the dose at which a drug will achieve efficacy in humans. An example is a drug to treat Alzheimer’s disease. In such a case, the in vitro potency and selectivity may provide a guide to predicting efficacy in human studies.

229    The pharmacologists were asked to comment on the extent of judgment involved in the selection of an API(s) and dosage(s) in the course of a drug discovery and drug development process and its different stages, including any specific issues that arise in relation to a new drug to be used for the treatment of ED. In their joint experts’ report, they provided the following answer:

Judgement is needed at all stages of drug development from preclinical through Phase 4. The selection of the API and dosage form requires a series of judgements early in the discovery process. The degree of uncertainty or certainty (in other words the extent of judgement) will be determined by the extent and quality of the data at hand and the clarity of the signals it sends in terms of the judgements or the decisions that need to be made.

At one extreme the in vitro and animal data collected (refer to our previous table) might signal a standout candidate from a group of possibilities (it may be most potent and safe and has suitable chemical properties) and tested animal models of efficacy point to the compound being an obvious choice. In this case, the degree of uncertainty at each judgement point would be relatively low. At the other extreme, data may be lacking or unreliable, experience with previous similar compounds in that therapeutic class may be limited and what data is available suggests there will be problems during development (ie. early signs of toxicity, stability problems). In this case, the degree of uncertainty at each judgement point will be relatively high.

230    Professors Brock and Evans also pointed out that as at 30 April 1999, the dosage forms that existed for the treatment of ED include intracavernosal, topical, nasal, oral dispersible and oral.

231    The pharmacologists were also asked to comment on the extent of judgment involved in the design and conduct of clinical trials in the course of a drug discovery and drug development process, including any specific issues that arise in relation to a new drug to be used for the treatment of ED in relation to the following:

(1)    plasma concentrations;

(2)    the selection of doses and dosage regimens;

(3)    the relevance of the minimum clinically relevant dose;

(4)    the methods of measuring efficacy;

(5)    an acceptable side effect profile; and

(6)    the relevance of information about a first generation drug when the NCE is a second generation drug, including in respect of the issues referred to in (1) to (5) above.

232    The answers they gave, including additional comments made by one of the clinicians were as follows:

PR & AE

(i)    plasma concentrations;

Judgement related to plasma concentrations will depend on having a thorough knowledge of the relationship between plasma concentration and efficacy, safety and tolerability. To obtain this information, plasma concentrations and end points that relate efficacy, safety and tolerability need to be simultaneously measured. If a suitable animal model is available, this relationship might be defined ahead of a Phase 1 study. For safety and tolerability, this is usually the case. In terms of efficacy related to erectile dysfunction, GB makes a comment below. If a drug is second in class, it may be possible to use learnings from the first in class compound to make some judgements about a new compound. For example, if the plasma concentrations for the new compound in Phase 1 exceed the IC-50 for that compound and if this had been shown for sildenafil to be efficacious, then this may make for an easier or earlier judgement in deciding on whether to proceed to Phase 2.

GB

In the case of erectile dysfunction, reliable animal models do not exist to predict efficacy in humans. Furthermore, Phase 1 pharmacokinetic studies will not allow assessment of erectile efficacy given the lack of sexual stimulation.

(ii)    the selection of doses and dosage regimens;

PR, GB & AE

Judgements concerning the selection of doses and dosage regimes in any phase of clinical development will be determined by evidence collected in the preceding phases. This evidence would be used to select the optimal dose range that achieves a chosen balance between efficacy and side effect.

GB

In the case of erectile dysfunction with a new PDE-5 inhibitor, information from the clinical use of sildenafil would also be of use in some aspects. However, sildenafil had been used exclusively as on-demand therapy, which defined the treatment paradigm at that time. This would have needed to be taken into account in the selection of doses and dosage regimens, as would issues around patient preferences.

(iii)    the relevance of the minimum clinically relevant dose;

PR & AE

During Phase 2 of drug development you may determine a dose that may produce a partial or full clinical response in a proportion of patients and this might be considered to be a minimum clinically relevant dose at that time. More information collected in Phase 3 and in special populations might refine what is considered to be the minimum clinically relevant dose. In terms of its relevance for clinical study design it would depend on tolerability as well as efficacy. If the drug was well tolerated at higher doses where efficacy was better, we believe that a Phase 3 study would not necessarily utilise a minimum clinically relevant dose. However, up and until the point of drug registration a company might decide, or be called upon by the regulatory body, to lower the dose range.

GB

Specifically with respect to defining a minimum clinically relevant dose in erectile dysfunction, researchers would face challenges in terms of reproducibility of their efficacy measures, the intra-individual variation, the effect of the partner on efficacy measures and given that questions 3 and 4 of the IIEF were used as primary efficacy measures. Recall bias may further dilute the veracity of the findings, as this questionnaire captures erectile function that occurred over the previous four weeks.

(iv)    the methods of measuring efficacy;

PR, GB & AE

The extent of a judgement in the design of a trial is improved when researchers have access to a reliable method of measuring efficacy (eg. that is objective rather than subjective, it is reproducible and shows minimal bias).

GB informs us that there was a range of efficacy measures that were available at the priority date (30 April 1999) that provided an insight into the dose-response relationships. Included in this list are the IIEF, GAQ, EDITS, Rigiscan, EHS and SEP period. All of these efficacy measures have strengths and weaknesses with variable reliability.

(v)    an acceptable side effect profile; and

PR, GB & AE

In general terms a compound that shows an acceptable side effect profile (that might mean side effects are primarily tolerated by individuals, that they are not serious and they are predictable from the known pharmacological profile of the drug) allows for more certainty in terms of the judgements required for the design and conduct of clinical trials. Patients are less likely to tolerate side effects when the therapeutic area involves a lifestyle or non-life threatening condition, and this needs to be taken into account when making judgements around what is an acceptable side effect profile for any new drug.

GB

Specifically when dealing with erectile dysfunction treatments, a wide variability in toleration of side effects between individuals is frequently encountered. Some side effects may be interpreted as being ominous whereas others may simply negatively impact treatment efficacy.

(vi)    the relevance of information about a first generation drug when the new chemical entity is a second generation drug, including in respect of each of the issues referred to in paragraphs (i)-(v) above.

PR, GB & AE

Some of the judgements involved in the design and conduct of clinical trials are assisted by knowledge of, and learnings from, the process that was undertaken for development and registration of the first generation drug.

“PR” is Dr Reece and “AE” is Professor Evans.

233    I turn now to the evidence of common general knowledge which was directly relevant to issues of drug formulation. Most of the evidence on this topic was given by Dr Mooney and Professor Polli.

234    The process for formulating NCEs was well-established before August 1999, being the earliest priority date for the 666 Patent. An NCE is a compound that has not been approved by a recognised health regulatory body, such as the FDA, TGA or Medicines and Healthcare Products Regulatory Agency (MHRA) for use for medicinal purposes.

235    In their joint experts’ report, Dr Mooney and Professor Polli said that a common requirement for a generic product and an NCE in terms of developing and formulating a product for commercial approval by the regulatory authorities was that they have to meet the same quality control standards for the raw material and the finished product as detailed in various guidances and pharmacopeia, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidances, FDA guidances, United States Pharmacopeia (USP), European Pharmacopeia (Ph Eur) and British Pharmacopeia (BP). The quality standards for NCE formulations and generic formulations are the same in terms of the chemistry and manufacturing control requirements.

236    The formulators agreed that there were differences between the formulation development process for a generic product and that for an NCE.

237    As to the former, they said:

Generics:

1.    The dose is known, including the form of the API (at least salt form), route of administration, target pharmacokinetic profile in terms of bioequivalence requirements, qualitative composition of the reference formulation and the fact that the reference formulation is safe and effective.

2.    The method of manufacture of the referenced drug product is unknown, but a qualitative composition will provide guidance as to compatible excipients with the active and possibly method of manufacture such as direct compression but no details further than that.

3.    For the API not all of its physico-chemical characteristics used in the formulation would be known (for example: polymorph or particle size of the material).

4.    In the case of the raw material the unknown physico-chemical characteristics that are not already disclosed in the drug master file/technical package can be established through experimental studies.

5.    The method of manufacture is dependent on the experience of the formulator and the equipment at their disposal and may be very different to what can be surmised from what’s in the public domain. The qualitative composition of the reference product may have limited application for selection of the excipients with the alternative method of manufacture.

238    As to the latter, they said:

New Chemical Entity (NCE)

NCE: a compound that has not been approved by a recognised health regulatory body (such as FDA, MHRA, TGA) for use for medicinal purposes.

1.    Dose is unknown

2.    Route of administration is unknown

3.    Excipients are unknown and dependent on the final dosage form

4.    Method of manufacture is unknown and there is further uncertainty on the grounds that the method or route of administration are unknown

5.    There is no target pharmacokinetic profile at least initially. A target pharmacokinetic profile evolves during drug discovery (eg. from in-vitro and animal studies) and drug development (eg. clinical study phases 1- 3).

6.    There is a larger volume of information available prior to generic drug development compared to NCE development. This information is relevant to the likelihood of being able to successfully develop a formulation of the API that produces a pharmacokinetic profile that is safe and effective.

239    Dr Mooney described the development brief he would expect to receive had he been asked on 3 August 1999 to develop a formulation for an NCE for which there is no reference product. Dr Mooney was provided with a development brief by Apotex’s solicitors. The development brief identified certain matters which were known about the treatment of ED by August 1999, patient considerations and identified the task which Dr Mooney was asked to perform. Dr Mooney agreed that he did not have any actual experience before 3 August 1999 of formulating any product for administration to a patient or a volunteer with so little information as was set out in his development brief. Apotex submitted that, to the extent that information was missing, Dr Mooney would obtain that information by conducting routine tests or from other members of the drug development team.

240    One of the most important chemical properties of a drug is its solubility. This is particularly important for immediate release oral formulations where rapid absorption of the drug into the blood stream is desired. One of the responsibilities of the formulator is to optimise the drug’s absorption characteristics to achieve the desired therapeutic effect.

241    Apotex submitted that both of the formulators acknowledged that solubility can be defined quantitatively, as describing its absolute (or saturation) solubility and that used in this way the absolute solubility is distinct from its dissolution rate. The formulators also referred to qualitative descriptions of solubility that provide semi-quantitative characteristics, for example, the solubility tables in the BP and the USP.

242    Professor Polli gave evidence of common general knowledge relevant to the formulation of a solid dosage form for oral administration of an API as at 3 August 1999. I accept that evidence, and the following is largely a summary of Professor Polli’s evidence.

243    An API is rarely administered to a patient alone. It is typically combined with other compounds, known as excipients, in a “dosage form”. The combination is also known as a “formulation”.

244    Dosage forms may be administered by various “routes”, such as oral or intravenous. Dosage forms for oral administration include solid oral dosage forms, such as tablets and capsules, and non-solid dosage forms, such as solutions and suspensions.

245    An excipient is a compound that is not directly responsible for the pharmaceutical activity of the dosage form. Some excipients do influence the therapeutic effect of the API by affecting the manner in which the API is absorbed from the dosage form into the patient. Other excipients may be used to assist in the manufacture of the API, or to enhance the stability of the API, or the palatability of the dosage form.

246    The gastrointestinal tract is 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 (GI tract). Orally administered APIs are typically absorbed into the body from the GI tract.

247    Upon the oral dosage form reaching the stomach, it disintegrates unless protected by “enteric coating”, thereby exposing particles of the API in the tablet to the gastric fluid. The stomach empties into the small intestine periodically and this is known as gastric emptying. There is considerable variation in gastric emptying times between individuals. Furthermore, the gastric emptying times vary according to whether the person has ingested a meal and the nature of the meal (solid or liquid).

248    The pH of the small intestine is substantially higher than that of the stomach. The stomach is very acidic (the pH varies between about 1.5 and 3.5), whereas the small intestine is closer to neutral. Some compounds that are soluble in the much lower pH of the gastric fluid of the stomach are less soluble in the higher pH of the small intestine. This can cause re-precipitation in the small intestine. Other compounds may be soluble in the higher pH of the small intestine and poorly soluble in the stomach.

249    Most orally administered APIs are intended to be absorbed from the small intestine. The features of the stomach are that it has a relatively small surface area and absorption is limited by its thick mucus layer and short transit time. On the other hand, the small intestine has the largest surface area for drug absorption in the GI tract and its membranes are more permeable than those of the stomach. The residence time in the small intestine is approximately three to five hours.

250    The process of absorption of the API from the GI tract involves two steps. First, the API must be solubilised into the fluid in the GI tract. Secondly, the solubilised API must permeate through the epithelial cells that line the GI tract into the bloodstream. Thus, absorption from the GI tract is affected by both the solubility characteristics of the API into the fluid in the GI tract and the permeability of the dissolved API across the epithelial cells of the GI tract into the hepatic portal vein which carries it to the liver, from which it enters the systemic circulation. An illustration of this process is set out in the evidence of Professor Polli and is reproduced below.

(Chan OH and Stewart BH, “Physicochemical and Drug-delivery Considerations for Oral Drug Bioavailability” (1996) 1 Drug Discovery Today 461, Figure 2, p 462.)

251    The solubility of an API refers to the maximum amount of API that will dissolve in a given volume of solvent at a certain temperature. A solution that contains the maximum amount of API that can dissolve is a “saturated” solution. There was debate between the experts as to whether solubility could include dissolution rate. Dr Mooney considered that it did, whereas Professor Polli considered that it did not. Professor Polli said that pharmaceutical scientists are very aware of the difference between the concepts of solubility on the one hand, and dissolution rate on the other. He teaches the difference to his students. The difference is reflected in the standard texts. The following appears in Smith BT, Remington Education: Physical Pharmacy (Pharmaceutical Press, 2015) (Smith (2015) at pp 31-32:

Solubility and dissolution are different concepts, but are related. Solubility is the capacity of a solute to dissolve in a pure solvent. This means the maximum amount of solute that the pure solvent can hold in solution, at specified environmental conditions. Beyond this saturation concentration, a solute cannot further dissolve in the amount of solvent provided. It can exist tenuously in a supersaturated condition but will eventually revert to the solvent’s true capacity. But what occurs between solutes and solvents that bestows the variability observed in solubilities in a given solvent? Solubility is a thermodynamic process: the system will tend to arrive at a point of lowest potential energy (PE) (Gibbs free energy), which is most thermodynamically stable. When we speak of solubility, it is understood to mean the ultimate outcome, without regard to how fast it occurs. Solubility provides us with important information, but it only tells us the endpoint, not how long it takes to get there.

Solutes vary not only in the extent to which they will dissolve, but also how quickly they will reach their respective solubility limits. Solubility and dissolution rate are two distinct phenomena. Dissolution rate is a kinetic process. A solute may have poor solubility in a solvent, yet its dissolution rate may be rapid. Conversely, a solute can be very soluble, yet require a protracted amount of time to arrive at the final, saturation concentration. Some solutes dissolve very rapidly in appropriate solvents, while others can take an inordinate amount of time to reach a desired concentration, or saturation.

252    Dr Mooney, on the other hand, referred to “solubility” as the tendency of a drug substance to go from a solid phase into solution in a specific aqueous and organic media (e.g., water). Apotex submitted that Dr Mooney’s approach encompassed both the amount of a drug that is capable of being dissolved, that is to say, its absolute solubility as well as the rate at which it dissolves in a particular solvent, that is to say, its rate of dissolution. As I will explain, absolute solubility and the rate of dissolution of a drug are distinct concepts.

253    ICOS submitted that, in the end, the so-called dispute was one of form rather than substance. Apotex took a similar approach and it submitted that nothing turned on the difference. Apotex submitted that what was important was that the experts agreed that both absolute solubility and dissolution would be measured as part of routine in vitro pre-formulation tests, and the methods for determining absolute solubility and dissolution were well-established as at August 1999.

254    Compounds are generally more soluble in solvents at higher temperatures. The solubility of an API in a given solvent is generally expressed in terms of mass of API per unit volume of the solution. Professor Polli gave the following example. At a temperature of 37 degrees centigrade, 1 g of aspirin dissolves in 100 mL of water. This corresponds to 10 g of aspirin per litre of water (10 g/L or 10 gL-1) or, using units commonly used in the pharmaceutical field, 10 mg per millilitre (mg/mL) or 10,000 micrograms per millilitre (ug/mL). Upon the maximum amount of API being dissolved in a given amount of solvent at a given temperature, any further API present will remain in a solid state. In the aspirin example, if 50 g of aspirin is present in a litre of water, 10 g will be dissolved in the water and 40 g will remain in a solid state.

255    The solubility of compounds, including APIs, can be vastly different in different solvents. The solubility of an API in a solvent may be altered by adding other compounds to the solvent. The GI tract contains two solvents, being gastric fluid and intestinal fluid. Both are described as aqueous solvents, although both contain other compounds which may affect the solubility of the API relative to pure water. Another factor which may affect the solubility of some compounds, including APIs in aqueous solutions, is the pH of the solvent. For example, a compound that is basic will be more soluble in aqueous solutions with a low (acidic) pH than in neutral solutions or solutions with high (basic) pH. Gastric fluid has a much lower (more acidic) pH than intestinal fluid. As a result, some APIs are more soluble in gastric fluid than intestinal fluid, and vice versa.

256    The process by which a solid dissolves into a solvent involves breaking the intermolecular forces which hold the molecules of solute together and the intermolecular forces that hold the molecules of solvent together, and the forming of forces between the solute and the solvent.

257    It is and was well-known that high melting points are a useful indicator of poor solubility in aqueous solutions because they correspond with strong bonds between the molecules within a solid which must be overcome for the solid to dissolve. Dr Mooney expressly agreed with Professor Polli on this issue.

258    Solubility refers to “equilibrium solubility”, that is to say, the solubility that is observed after the solute/solvent system has had sufficient time to reach thermodynamic equilibrium. A given solute has a given equilibrium solubility in a given solvent at a given temperature. Professor Polli referred to the fact that it may be possible to exceed that equilibrium solubility (“apparent solubility”), but this is temporary only and the solubility will return to equilibrium solubility.

259    Whilst solubility refers to the amount of API that is able to be dissolved in a given amount of solvent, such as GI fluid, dissolution rate refers to something different. It refers to the speed at which the API dissolves in that fluid. It does not affect the API’s solubility. Irrespective of any increase or decrease in the rate at which the API dissolves, the amount of API that is able to be dissolved in a given volume at a given temperature will remain constant. By contrast, the solubility of an API does affect the dissolution rate.

260    The Noyes-Whitney equation is as follows:

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).

261    As shown by the Noyes-Whitney equation, the dissolution rate of an API is a function of the following: the difference between the saturation concentration of API at the surface of the API particles and the concentration of the API in the bulk solution of API in the solvent; the surface area of the API particles which is exposed to the solvent; and the dissolution rate constant for the API. The variables within the Noyes-Whitney equation which may be modified by the pharmaceutical scientists are the surface area of the API exposed to the solvent and/or the solubility of the API. A higher surface area of API exposed to the solvent means a higher dissolution rate. A higher solubility of the API (Cs) means the difference between the solubility and the API concentration in the bulk solution is higher, meaning a higher dissolution rate. As I have said, solubility cannot be improved by increasing the dissolution rate, but the dissolution rate can be increased by modifying an API’s solubility.

262    The dissolution rate can also be improved by altering the surface area of the API that is exposed to the solvent. As at 3 August 1999, a technique that could be used to achieve this result was called “micronisation”. Professor Polli described this as a process where the mean particle size of the API is reduced to, at the smallest, single digit micron sizes. I accept that description of “micronisation”. It was generally accepted among pharmaceutical scientists as at 3 August 1999 that solubility was independent of surface area and particle size. It was also understood that the Noyes-Whitney equation did not mean that a drug with a low solubility reached that low solubility slowly. The rate of dissolution defined by the Noyes-Whitney equation relates to the absolute amount of API that dissolves per unit time (for example, milligrams per second), not the amount of API relative to the total solubility. In other words, as Professor Polli put it, “all else being equal, although a poorly soluble drug may have a small dissolution rate measured in mg s -1, it will nevertheless reach its Cs just as quickly as a highly soluble drug”. The other matter demonstrated by the Noyes-Whitney equation is that the rate of dissolution slows as the concentration of the API in the bulk solution (Ct) increases (as the difference between Cs and Ct becomes smaller).

263    The dissolution rate and the solubility of an API are dependent on the identity of the API itself and are very likely to be dependent on the dosage form into which the API has been formulated and from which the API dissolves. Formulating an API into a dosage form may affect the apparent solubility and thus (as expressed in the Noyes-Whitney equation), the dissolution rate. The dissolution rate may be affected by the apparent surface area of the API exposed to the solvent, even though this will not impact the apparent solubility of micron sizes. Frequently, the purpose of formulating the API is to affect the apparent solubility of the API, the dissolution rate of the API, or both.

264    Permeation of dissolved API from the GI tract may occur by one or more different mechanisms. This is shown by a diagram which was part of Professor Polli’s evidence and which is reproduced below.

(Boroujerdi M, Pharmacokinetics: Principles and Applications (McGraw-Hill/Appleton & Lange, 2001) p 61.)

265    Most APIs pass through the epithelial lining of the GI tract by passive diffusion from an area of high concentration of API, such as the fluid in the small intestine, to an area of low concentration of API, such as the intestinal cell membrane.

266    The rate at which the dissolved API will permeate across the epithelial lining of the GI tract depends on the following factors:

(1)    the surface area of the GI tract exposed to the API;

(2)    the concentration “gradient” being the difference between the concentration of the API in the gastrointestinal fluid and the concentration of the API across the cell membranes. Drugs diffuse across the cell membrane from a region of high concentration (e.g., GI fluids) to one of low concentration (e.g., across the cell membranes and into the hepatic portal vein). Drugs having higher solubility in the gastrointestinal fluid are capable of existing at higher concentration in the gastrointestinal fluid;

(3)    the epithelial cells lining the gastrointestinal tract comprises a cell wall that is formed from a layer of lipids. Accordingly, solubility of the API and lipids will affect the rate at which the dissolved API will permeate. Lipids are fatty compounds and, generally speaking, a compound that is highly soluble in aqueous solvents, such as the fluids of the GI tract, will be poorly soluble in lipids. Highly lipid-soluble drugs tend to diffuse more rapidly through the cell walls;

(4)    the size of the API. Smaller molecules tend to permeate membranes more rapidly than larger ones; and

(5)    where the drug is a weak acid or weak base, the proportion of unionised API present. Many drugs are weak organic acids or bases, capable of existing in charged (ionised) and neutral (unionised) forms in an aqueous environment, depending on the pH of that environment. The neutral form is usually more lipid-soluble and thus more capable of permeating into the lipid bi-layer of cell walls than the charged form.

267    Permeable compounds are simply not those that are lipophilic. A compound must be lipophilic enough to partition into the lipid bi-layer, but not so lipophilic (i.e., not so hydrophobic) that it will not partition out again, which it must do to be absorbed into the bloodstream.

268    The following matters affect the total amount of API that may be absorbed from the GI tract into the hepatic portal vein from a given dosage form of an API:

(1)    the amount of API in the dosage form;

(2)    the apparent solubility of the API from the dosage form;

(3)    the volume of the gastrointestinal fluid into which the API may dissolve;

(4)    the rate at which the API dissolves from the dosage form into the gastrointestinal fluid;

(5)    the rate at which the dissolved API permeates through the membranes of the GI tract into the hepatic portal vein;

(6)    the time for which the API remains in the region of the GI tract from which it may be absorbed, usually the small intestine; and

(7)    the stability (including metabolism) of the API in the gastrointestinal fluids prior to the hepatic portal vein.

269    The volume of the gastrointestinal fluid and the time for which the API remains in the region of the GI from which it may be absorbed (i.e., (3) and (6) directly above) are independent of the identity of the API and the dose form in which it is formulated.

270    The amount of API in the dosage form provides an upper limit to the amount of API than can be absorbed. However, more often, because the API only remains in the relevant region of the GI tract for a limited time, a portion of the API in the dosage form is absorbed. If there was an infinite amount of time available, then all API would be absorbed from any dosage form, although that API would be subject to metabolism.

271    The total amount of API that is absorbed from a given dosage form of the API is limited by one of the following three mechanisms:

(1)    the rate at which the API dissolves (“dissolution rate-limited absorption”);

(2)    the rate at which the dissolved API permeates from the solution through the relevant gastrointestinal membrane, into the hepatic portal vein (“permeability-limited absorption”); and

(3)    the apparent solubility of the API (“solubility-limited absorption”).

272    Apotex accepts the absorption of a drug may be limited by the dissolution rate, the permeation and absolute solubility. It is clear that as at 3 August 1999, Dr Mooney had not come across an absolute solubility limitation.

273    Professor Polli produced a diagram which illustrates the three absorption limiting factors. The diagram is reproduced below:

Scenario (A) represents dissolution rate-limited absorption and the top tank represents the amount of API in solid form, the middle tank represents the amount of API dissolved in the fluid of the GI tract and the bottom tank represents the amount of dissolved API absorbed in the hepatic portal vein. Scenario (B) represents permeability-limited absorption and Scenario (C) represents solubility-limited absorption.

274    Professor Polli explained that dissolution rate-limited absorption occurs where the in vivo dissolution rate of the API is slower than its permeation through the intestinal membrane, such that the limiting step is represented by the top tank. If the absorption of API from the dosage form is dissolution rate-limited, increasing the surface area of the API exposed to the gastrointestinal fluid, for example, by decreasing the size of the API particles, can increase the amount of API absorbed, as can increasing the dose. The dissolution rate of an API is related to the solubility (as I described in the context of discussing the Noyes-Whitney equation), so improving the solubility will also increase the amount of API absorbed if the absorption is dissolution rate-limited.

275    Permeability-limited absorption occurs where the API dissolves rapidly from the dosage form, but the dissolved API permeates slowly across the GI tract into the hepatic portal vein. Since the API is only present in the GI tract for a finite period of time (approximately three to five hours), permeation rate can limit the amount of API absorbed. If absorption is permeability-limited, then modifying solubility may increase absorption by increasing the concentration gradient (the difference between the concentration of the API in the gastrointestinal fluid and the concentration of the API in the blood).

276    Solubility-limited absorption occurs when the total dose of the API exceeds the amount of API that is able to be dissolved in the GI fluids, limiting overall absorption of the API. In this scenario, the API may dissolve quickly, and therefore reach the maximum (saturated) concentration quickly. It may also permeate quickly. However, the saturated concentration at the site of drug absorption is low relative to the total dose of the API. This limits the amount of API that can be absorbed in the time frame when the API is in the small intestine. This is reflected in the drawing by the smaller tank in Scenario C relative to the other scenarios. If absorption is solubility-limited, the extent of absorption of the API can only be improved by improving the solubility of the API. Increasing the rate of dissolution will have no effect on the amount of API that is absorbed.

277    The key to understanding solubility-limited absorption is to appreciate that it depends entirely on the relationship between the measured solubility and the size of the dose. The problem of solubility-limited absorption is that even if permeability is good and the dissolution rate is instant, the measured solubility value is so low relative to the dose size that the full amount of drug will never dissolve in the limited amount of gastric fluid that is available for the purpose. This is because the gastric fluid will become saturated at a concentration that is too low for even good permeation to result in the full dose dissolving in the limited 3-5 hour period for absorption. This is a basic application of a fundamental principle, being that for every solute there is a maximum amount that is capable of dissolving in a given volume of solvent in particular environmental conditions.

278    The Cialis 2002 PI Statement describes tadalafil as a crystalline solid that is practically insoluble in water. The BP and USP contain a threshold point of “practically insoluble” as meaning above 1:10,000. In that circumstance, a 50 mg dose of API would require more than 10 L of solvent to dissolve. Dr Mooney accepted in his evidence that it would have been apparent to him that a 50 mg dose would not have been capable of dissolving in the gastric fluid, even assuming instant dissolution and good permeability. He accepted that other pharmaceutical scientists would have recognised the problem immediately. At the same time, it would not have deterred Dr Mooney from trying to find a way around it. Nevertheless, Dr Mooney accepted in his oral evidence that micronising could not solve this particular problem. The BP and USP provide a calculation for practically insoluble or insoluble of 10,000 and over parts of a solvent required for one part of the solute. ICOS put a series of examples to Dr Mooney, including this formula, an assumption that tadalafil was 20 times less soluble than the BP threshold point, and an assumption that tadalafil was 50 times less soluble than the BP threshold point. The USP sets out the meaning of various terms used to describe the solubility of a compound. It is as follows:

The BP is in similar terms.

279    Professor Polli said that in drug development, the BP and USP solubility classification has very limited relevance because any one descriptor encompasses a broad range of solubilities and does not factor in anticipated dose, so cannot even contribute to differentiating permeability-limited absorption from either solubility-limited absorption or dissolution rate-limited absorption. The BP and USP solubility classifications which do not consider dose is less useful than the Biopharmaceutical Classification System (BCS) solubility classification which does consider dose. This difference is dramatically accentuated when doses are known. Professor Polli considered that the BP and USP solubility classifications are of little practical assistance. By contrast, actual solubility and permeability values are the most relevant and can be applied to calculations of the maximum absorbable dose.

280    Dr Mooney described the BP and USP solubility classifications as a semi-quantitative value, which classifies qualitatively the tendency of a drug to dissolve in different media, but particularly water. Where the drug substance is very slightly soluble or practically insoluble or insoluble, it is classified as poorly soluble. Development proceeds assuming the drug substance is a poorly soluble drug and ways are considered to improve its solubility and thus dissolution rate.

281    Professor Polli referred to a paper by Amidon GL, Lennernäs H, Shah VP, Crison JR, “A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of in Vitro Drug Product Dissolution and in Vivo Bioavailability” (1995) 12 Pharmaceutical Research 413 (Annexure JEP-17). The paper acknowledged that “sink” (i.e., non saturated) conditions will not prevail if the dose is very high relative to measured solubility. In that case, the gastric fluid will be saturated. This does not necessarily mean the dose must be high.

282    The following passage also appears in this paper:

…If the drug is a case 2 drug (high permeability, low solubility) then absorption from solution is faster than dissolution and sink conditions are likely to prevail in vivo. As a general rule one should maintain sink conditions in the dissolution media if possible, such that the drug dissolves in less than 20-30% of the dissolution media.

Other factors which need to be considered, especially for case 2 drugs, are particle aggregation and the effective particle size in vivo. Quite often the first approach to increasing the dissolution rate of drugs in this class is micronization. This, however, also increases the surface energy and hence potential for particle aggregation…

283    The Amidon paper led to the adoption by the FDA by no later than 1997 of the BCS. The classification system takes into account the size of the highest unit dose for a drug which has been approved by the relevant regulator. Both the solubility and permeability determinations are made with reference to the dose of the API in the dosage form. As a result, two drugs with equivalent solubility can be classified as having either “high” or “low” solubility under the BCS depending on the size of the highest marketed dose for the drug. The BCS classification system is a further recognition of the relevance of the relationship between solubility and dose size. Professor Polli states that depending on the relationship between the dose of the API and the dosage form, and the solubility of the API from the dosage form, for BCS Class II dosage forms, dissolution rate may be the absorption limiting step, or where the solubility is low and the dose is high, solubility may be the absorption limiting step. If absorption of the intended dose of API is solubility-limited, micronising the API will not assist to increase the amount of drug absorbed.

284    The BCS is set out in the United States “Guidance for Industry, Dissolution Testing of Immediate Release Solid Oral Dosage Forms, August 1997”. The following classes are identified based on drug solubility and permeability:

Case 1:        High solubility – high permeability drugs

Case 2:        Low solubility – high permeability drugs

Case 3:        High solubility – low permeability drugs

Case 4:        Low solubility – low permeability drugs

285    The Guidance provides that the classification can be used as a basis for setting in vivo dissolution specifications and can also provide a basis for predicting the likelihood of achieving a successful in vivo in vitro correlation (IVIVC). The Guidance states that the solubility of a drug is determined by dissolving the highest unit dose of the drug in 250 mL of buffer adjusted between pH 1.0 and 8.0. The Guidance states that a drug substance is considered highly soluble when the dose/solubility volume of solution are less than or equal to 250 mL.

286    Dr Mooney and Professor Polli agreed that if a poorly water soluble drug had a high permeability across the GI membranes, as with BCS class 2 drugs, the rate of dissolution of the drug in the aqueous environment of the GI tract is likely to be the rate-limiting step in drug absorption and so attempting to improve the aqueous solubility of the drug is likely to lead to an increase in the rate of absorption. BCS class 3 drugs, that is, drugs with high solubility and low permeability, with very rapid dissolution are expected to have permeability-limited absorption.

287    Professor Polli said that a poorly water soluble drug with a high permeability as with BCS class 2 drugs, can exhibit solubility-limited absorption or dissolution rate-limited absorption. He said that he would want to understand both the aqueous solubility of the drug substance and the permeability of the drug substance across the GI membranes. If a poorly water soluble drug had poor permeability across the GI membranes, as with BCS class 4 drugs, attempting to improve the aqueous solubility of the drug may not lead to an increase in the rate of absorption.

288    Professor Polli considered that the BCS categories have “some relevance”. Solubility and permeability values will contribute to the maximum absorbable dose calculation and they will also contribute to assessing if the compound is poorly soluble or not. In addition, they will contribute to assessing if absorption can be expected to be permeability-limited absorption. Professor Polli said that although solubility and permeability allow for an API to be categorised into one of the four BCS classes, the BCS is primarily a regulatory framework for biowaivers. BCS categories themselves do not differentiate between solubility limited absorption and dissolution rate-limited absorption as low solubility drugs are not eligible for biowaivers. I accept his evidence.

289    Dr Mooney said that he had been developing products since 1985 and his decisions in terms of the influence of solubility was based on the Pharmacopeia characteristic definition. The BCS provides a definition of highly soluble to which I have already referred. The limiting feature in initial product development is that the dose is not known and further, there is no indication of how long you use to establish whether the material dissolves in that volume. In those circumstances, there is no characteristic to base development decisions on.

290    Lieberman H, Lachman L and Schwartz JB (eds) Pharmaceutical Dosage Forms: Tablets (2nd ed revised and expanded, Taylor & Francis, 1989) (Lieberman et al (1989)) is a standard pharmaceutical textbook well-known in this field. The following appears in the edition available as at 3 August 1999:

When dissolution is considered to be slow, a means of enhancing it may be sought. In the absence of a more soluble, physical or chemical form of the drug, particle size reduction is the most commonly employed practice. Enhanced surface area, with a concomitant increase in the dissolution, can also be accomplished by adsorbing the drug on an inert excipient with a high surface area, such as a fumed silicone dioxide. …

(at p 23) (Annexure BAM-4)

… It is now generally recognized that poorly soluble drugs showing a dissolution rate-limiting step in the absorption process will be more readily bioavailable when administered in a finely subdivided state than as a coarse material.

…

Because of these significant roles, it is important to decide on a desired size range, and thence to maintain and control it. It is probably safest to grind most new drugs having particles that are above approximately 100 µm in diameter. If the material consists of particles 30 µm or less in diameter, then grinding is unnecessary except if the material exists as needles – where grinding may improve flow and handling properties or if the material is poorly water-soluble where grinding increases dissolution rate. Grinding should reduce coarse material to, preferably, the 10–40 µm range. Once this is accomplished, controlled testing can be performed both for subsequent in vivo studies and for in depth preformulation studies. As the studies proceed, it may become apparent that grinding is not required and that coarser materials are acceptable. At that time, it is conceptually simpler to omit that step without jeopardizing the information already developed. The governing concept is to stage the material so that challenges are maximised.

    (at p 5) (Annexure BAM-18)

291    Dr Mooney said that he understood that the above textbook was widely read and routinely consulted by other people in his profession in Australia and overseas prior to 3 August 1999. He said that he himself routinely consulted Lieberman et al (1989) before 3 August 1999 when developing pharmaceutical formulations. There is a dispute between the parties as to the proper interpretation of the above passage. Professor Polli said that the passage quoted was limited to poorly soluble drugs. Apotex submitted that, read in context, that is not the case.

292    As at April 1999, particle size distribution and size distributions by mass and by volume were well understood by pharmaceutical scientists.

293    ICOS’s contention is that the fact that a marketed product is classified BCS Class II, indicating that absorption is likely to be dissolution rate-limited, does not mean that the absorption of a higher dose of the very same API will not be solubility-limited. A marketed dose is unlikely to be affected by solubility-limited absorption as, by definition, an effective amount of the drug can be absorbed. Any issue of solubility-limited absorption has already been solved.

294    The distinction between solubility-limited absorption and dissolution rate-limited absorption is of little consequence to the purpose for which the BCS is used by the FDA, as no BCS Class II formulations are eligible for a waiver of the need to perform a human bioequivalence experiment. Professor Polli’s evidence is that Daugan 1997 does not contain information concerning the permeability of the claimed compounds. It is not possible to categorise tadalafil into a BCS class without conducting experiments to determine the permeability classification of the compound.

295    Dr Mooney did not give consideration to the issue of solubility-limited absorption in his affidavit or in the joint experts’ report. Dr Mooney was a formulator of generic drugs before the priority date. He had no knowledge or experience with the problem of solubility-limited absorption because it never arose (or arises) in the context of generic drug formulation. He did agree that the relationship between the measured solubility value and dose size was a potential limitation to absorption that was relevant to the development of NCEs before August 1999. He also agreed that the concept of solubility-limited absorption was documented in the literature and readily recognisable having regard only to the general background knowledge that was available to all pharmaceutical scientists interested in formulation as at August 1999.

296    The relationship between the three scenarios (i.e., those illustrated by the tanks diagram prepared by Professor Polli) is as follows. Where absorption is dissolution rate-limited and where absorption is permeability-limited absorption, the rate at which API dissolves or permeates determines the amount of API in the dosage form that is absorbed. Where absorption is solubility-limited, it is the extent to which the API in the dosage form is able to dissolve that determines the amount of API in the dosage form that is absorbed. Where absorption of the API from the dosage form is permeability-limited, increasing the amount of API in the dosage form (the dose) proportionately increases the concentration of dissolved API and proportionately increases the amount of API absorbed. However, where the extent of the absorption of the API from the dosage form is solubility-limited, increasing the dose of API will simply result in more undissolved API in the gastrointestinal tract, and it will not increase the extent of absorption. The only mechanism by which the extent of absorption can be increased is by increasing the solubility of the API.

297    Which of the three mechanisms limits absorption of the API from the dosage form may depend on either the API or the dosage form within which the API is formulated. For example, for a given formulation of a given API, the dissolution of the API may be slow and limit the amount of API absorbed within the available time. The dissolution rate of the API from the dosage form may be improved by changing the formulation, for example, by adding excipients such as disintegrants, or by increasing the effective surface area of the API such as by reducing particle size. The improvement may be such that dissolution rate no longer limits the amount of API absorbed. If dissolution rate does not limit the extent of absorption, then either permeability or solubility will. If permeability or solubility limits the extent of absorption, further improvements to the dissolution rate will not improve the extent of absorption. The dissolution rate may be improved to the point that it is practically instantaneous. However, if the saturated concentration of the API in the gastrointestinal fluid is too low relative to the size of the dose for the entire amount of the API to be absorbed within the limited time available, the extent of absorption from that dosage will be solubility-limited. As the Noyse-Whitney equation shows, increasing the solubility (the saturated condition of the API) in the solution (Cs) will also increase the dissolution rate of the API. It is possible to improve the extent of absorption of API from a dosage form from which absorption of the API is dissolution rate-limited by improving the solubility of the API from the dosage form. However, improvements to the dissolution rate of the API will not affect the solubility of the API so will not improve the extent of absorption from a dosage form from which the absorption of the API is solubility-limited.

298    The distinction between solubility and dissolution rate is of real practical importance because different formulation techniques may be used to address the problem. A drug development team is able to use calculations to assess whether or not there might be a solubility-limited absorption problem, including the maximum absorbable dose (MAD calculation). Professor Polli said that the maximum absorbable dose can be calculated using the following formula:

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).

299    The amount of fluid available in the small intestine to dissolve the API is effectively constant at 250 mL. The residence time in the small intestine is also effectively constant and for the purpose of the calculation is assumed to be 4.5 hours. The solubility and permeability can be measured enabling the calculation of the maximum absorbable dose. The maximum absorbable dose is the maximum amount of the compound that could be absorbed if the small intestine was saturated with a compound for the entire period of time in which the compound transited through the small intestine. It assumes that the dissolution rate of the API in the intestinal fluid is instant because the purpose of the calculation is to test whether, even if dissolution is perfect, there will still be a problem with absorbing the anticipated dose due to solubility. The maximum absorbable dose describes the maximum amount of drug that can be absorbed into the hepatic portal blood. The oral bioavailability of an API is a function of the amount of drug absorbed into the hepatic portal blood, and of the amount of that API that survives first pass metabolism by the liver and thus enters the systemic circulation. The maximum absorbable dose model takes no account of first pass metabolism which can result in still less API being absorbed in plasma concentration. If the maximum absorbable dose is lower than the anticipated dose, the pharmaceutical scientists would be concerned that the anticipated dose would not be absorbed (and therefore the target pharmacokinetic profile could not be attained) without improving the solubility of the API. This is a simple way of ascertaining, early in a drug development project, whether or not solubility-limited absorption is likely to be a problem.

300    Another available approach is to consider the volume of gastrointestinal fluid required to dissolve a full dose of the API. If the volume required to deliver a full dose is much higher than the volume of gastrointestinal fluid in the small intestine (250 mL), then it is unlikely that the dose will be absorbed. This approach allows for the fact that permeation of dissolved API from the GI tract will mean that more API can be dissolved by considering multiples of the actual volume of GI fluid. At the priority date, if an API had a solubility that required more than 10 times the volume of gastrointestinal fluid (10 x 250 mL = 2.5 L) to dissolve a full dose that would be an API where permeation would not be adequate to overcome the poor solubility and the full dose would not be absorbed.

301    Professor Polli said, and I accept, that as at August 1999, it was common general knowledge that the following techniques could be adopted to improve the solubility of an API:

(1)    the formation of salts of acidic or basic APIs;

(2)    the formation of polymorphs (different crystalline forms) of the API;

(3)    the formation of amorphous forms of the API (where the API is solid, but not crystalline);

(4)    the use of co-precipitates (solid dispersions), where the solid API is dispersed through another solid compound;

(5)    the use of solvates (and other co-crystals), where the API is crystallised together with a fixed ratio of the solvent, such as water,

(6)    the use of lipid-based formulations where the API is dissolved in a lipid;

(7)    the use of liposomes where the API is dissolved in a lipid bi-layer;

(8)    the use of surfactants and pH modifiers; and

(9)    the use of pro-drugs, where a different API is produced, the different API being metabolised into the original API after absorption has occurred.

302    Dr Mooney said that there were a number of well-known approaches employed by formulators to improve the solubility of a poorly water soluble drug, including particle size reduction or micronisation, use of different polymorphs, use of different salts, use of a solid dispersion and use of pro-drugs. He did accept that the choice may depend on whether absolute solubility or dissolution rate is the rate-limiting step in drug absorption. Dr Mooney accepted that micronisation is not a technique that can improve the solubility (absolute solubility) of an API.

303    The experts were agreed that the formulator uses the same formulation strategy for all doses tested. When formulating for a study of a range of doses, such as a Phase II study by which the dose is established, the formulator must formulate the drug so as to ensure that none of the doses tested will be solubility-limited.

304    Micronising can increase the surface area of the API exposed to the GI fluid and may therefore increase dissolution rate. However, there are certain disadvantages associated with micronising. They are as follows:

(1)    a reduction in particle size can also cause a decrease in drug stability by increasing the total particle surface area exposed to the external environment. Formulations with the micronised drug substance (i.e., reduced particle size) may therefore be more susceptible to degradation caused by heat, light, oxygen and moisture as compared to formulations with the unmicronised drug substance (i.e., unreduced particle size);

(2)    micronisation can also affect the compressibility and flow properties of the drug substance. Compressibility refers to the ability of the blend to be subjected to a compressional force so that the blend compressed volume can be decreased to provide a tablet or capsule with appropriate physical characteristics. Flowability refers to the ability of the blend to flow through the compression or encapsulation process and afford consistent tablet and capsule weight respectively;

(3)    where the drug particle size is very fine, this can cause drug substance particles to aggregate due to electrostatic changes. Particle aggregation can occur during manufacture of the dosage form when blending the drug substance with excipients to create a blend for direct compression, or when mixing prior to dry/wet granulation. This can lead to poor tablet (capsule drug substance) uniformity of content (especially for low dose formulations) and poor compressibility and flowability of the blend (especially for high dose formulations); and

(4)    powder segregation can occur. This is a process where particles of different sizes that are mixed together (such as a mixture of API and excipient particles intended for tableting) will separate based on size under agitation (such as during transport). This is undesirable as it is important that tablets are homogenous.

305    A further disadvantage is that making increasingly smaller particles is likely to be associated with increased cost.

306    Professor Polli said, and I accept, that the extent of any improvement in in vitro dissolution rate in any given solvent produced by a given reduction in particle size was not predictable. As a result, any effect on in vivo absorption is even more unpredictable in the sense that correlations between in vitro dissolution rate and in vivo absorption are difficult to establish.

INVENTIVE STEP AND THE 946 PATENT

307    As I have said, it is not in dispute that Daugan falls within the terms of s 7(3) of the Act. GB 464 is the priority document for Daugan 1997 and it and Daugan 1995, which was said to be unpublished at the time of the application for Daugan 1997, are both referred to in Daugan 1997. Daugan 1997 refers to GB 464 as describing the synthesis of the compounds of the invention and their utility in the treatment of impotence, and Daugan 1995 as describing the synthesis of the compounds of the invention and their utility in the treatment of other diseases associated with inhibition of cGMP PDEs. ICOS did not dispute that the development team could also have reference to GB 464 and Daugan 1995 to the extent that they may be relevant.

Daugan 1997

308    It is convenient to deal with all of the teachings in Daugan at the same time and, in the analysis which follows, I will also identify matters that are particularly relevant to the inventive step challenge to the claims in suit in the 666 Patent.

309    The Daugan 1997 Specification describes the invention as relating to the use of tetracyclic derivatives which are potent and selective inhibitors of cyclic guanosine 3ꞌ,5ꞌ–monophosphate specific phosphodiesterase (cGMP-specific PDE) in the treatment of impotence. A description of impotence and its prevalence in the community is set out. The existing treatments for impotence are described, including direct injections of vasoactive substances into the penis, or patches applied to the penis, or the use of a penile prosthesis.

310    The Daugan 1997 Specification provides the general formula for the compounds which are the subject of the invention and “salts and solvates (e.g. hydrates) thereof” and then it identifies by chemical formula what it describes as 13 suitable individual compounds of the invention for use in the treatment of ED and “physiologically acceptable salts and solvates (e.g. hydrates) thereof”. The list of compounds includes Compound A which is tadalafil, but it does not include what is later described as Compound B.

311    The Daugan 1997 Specification then refers to Compound A and Compound B and “physiologically acceptable salts and solvates (hydrates) thereof” as the specific compounds of the invention.