FEDERAL COURT OF AUSTRALIA
Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft [2014] FCAFC 73
| IN THE FEDERAL COURT OF AUSTRALIA | |
| First Appellant LUPIN AUSTRALIA PTY LTD Second Appellant | |
| AND: | BAYER PHARMA AKTIENGESELLSCHAFT First Respondent BAYER AUSTRALIA LIMITED Second Respondent |
| DATE OF ORDER: | |
| WHERE MADE: |
THE COURT ORDERS THAT:
1. Leave to appeal be granted in terms of the Amended Draft Notice of appeal dated “2013”.
2. The appeal be dismissed.
3. The appellants pay the respondents’ costs of the application for leave to appeal and of the appeal.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
| IN THE FEDERAL COURT OF AUSTRALIA | |
| NEW SOUTH WALES DISTRICT REGISTRY | |
| GENERAL DIVISION | NSD 921 of 2013 |
| ON APPEAL FROM THE FEDERAL COURT OF AUSTRALIA |
| BETWEEN: | APOTEX PTY LTD Appellant |
| AND: | BAYER PHARMA AKTIENGESELLSCHAFT First Respondent BAYER AUSTRALIA LIMITED Second Respondent |
| JUDGES: | BESANKO, MIDDLETON and NICHOLAS JJ |
| DATE OF ORDER: | 19 June 2014 |
| WHERE MADE: | MELBOURNE VIA VIDEO LINK TO SYDNEY |
THE COURT ORDERS THAT:
1. Leave to appeal be granted in terms of the Amended Draft Notice of appeal dated “June 2013”.
2. The appeal be dismissed.
3. The appellant pay the respondents’ costs of the application for leave to appeal and of the appeal.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
| IN THE FEDERAL COURT OF AUSTRALIA | |
| NEW SOUTH WALES DISTRICT REGISTRY | |
| GENERAL DIVISION | NSD 984 of 2013 |
| ON APPEAL FROM THE FEDERAL COURT OF AUSTRALIA |
| BETWEEN: | GENERIC HEALTH PTY LTD First Appellant LUPIN AUSTRALIA PTY LTD Second Appellant |
| AND: | BAYER PHARMA AKTIENGESELLSCHAFT First Respondent BAYER AUSTRALIA LIMITED Second Respondent |
| JUDGES: | BESANKO, MIDDLETON and NICHOLAS JJ |
| DATE OF ORDER: | 19 June 2014 |
| WHERE MADE: | MELBOURNE VIA VIDEO LINK TO SYDNEY |
THE COURT ORDERS THAT:
1. The Application for an extension of time and leave to appeal dated 4 June 2013 be dismissed.
2. There be no order as to costs.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
| IN THE FEDERAL COURT OF AUSTRALIA | |
| NEW SOUTH WALES DISTRICT REGISTRY | |
| GENERAL DIVISION | NSD 1006 of 2013 |
| ON APPEAL FROM THE FEDERAL COURT OF AUSTRALIA |
| BETWEEN: | APOTEX PTY LTD Appellant |
| AND: | BAYER PHARMA AKTIENGESELLSCHAFT First Respondent BAYER AUSTRALIA LIMITED Second Respondent |
| JUDGES: | BESANKO, MIDDLETON and NICHOLAS JJ |
| DATE OF ORDER: | 19 June 2014 |
| WHERE MADE: | MELBOURNE VIA VIDEO LINK TO SYDNEY |
THE COURT ORDERS THAT:
1. The Application for an extension of time and leave to appeal dated 7 June 2013 be dismissed.
2. There be no order as to costs.
Note: Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.
| NEW SOUTH WALES DISTRICT REGISTRY | |
| GENERAL DIVISION | NSD 833 of 2013 NSD 984 of 2013 |
| ON APPEAL FROM THE FEDERAL COURT OF AUSTRALIA |
| BETWEEN: | GENERIC HEALTH PTY LTD First Appellant LUPIN AUSTRALIA PTY LTD Second Appellant |
| AND: | BAYER PHARMA AKTIENGESELLSCHAFT First Respondent BAYER AUSTRALIA LIMITED Second Respondent |
| JUDGES: | BESANKO, MIDDLETON and NICHOLAS JJ |
| DATE: | 19 June 2014 |
| PLACE: | MELBOURNE VIA VIDEO LINK TO SYDNEY |
| IN THE FEDERAL COURT OF AUSTRALIA | |
| NEW SOUTH WALES DISTRICT REGISTRY | |
| GENERAL DIVISION | NSD 921 of 2013 NSD 1006 of 2013 |
| ON APPEAL FROM THE FEDERAL COURT OF AUSTRALIA |
| BETWEEN: | APOTEX PTY LTD Appellant |
| AND: | BAYER PHARMA AKTIENGESELLSCHAFT First Respondent BAYER AUSTRALIA LIMITED Second Respondent |
| JUDGES: | BESANKO, MIDDLETON and NICHOLAS JJ |
| DATE: | 19 June 2014 |
| PLACE: | MELBOURNE VIA VIDEO LINK TO SYDNEY |
REASONS FOR JUDGMENT
THE COURT:
INTRODUCTION
1 There are four proceedings before the Court. Two of the applications are applications for leave to appeal from orders made by a judge of this Court. The other two applications are Applications for an extension of time and for leave to appeal from orders made by a judge of this Court. Two applications, one for leave to appeal, and the other for an extension of time and for leave to appeal, are brought by Generic Health Pty Ltd and Lupin Australia Pty Limited. For convenience, we will refer to these parties as the GH parties. The other two applications are brought by Apotex Pty Ltd (“Apotex”). The respondents to all four applications are Bayer Pharma Aktiengesellschaft and Bayer Australia Limited. For convenience, we will refer to these parties as the Bayer parties.
2 The Bayer parties manufacture and sell in Australia oral contraceptives under the brand-names Yasmin and Yas. They hold a patent (Australian Patent No. 780330) for a pharmaceutical combination of ethinylestradiol and drospirenone (“DRSP”) for use as an oral contraceptive (“the Patent”). Since February 2012, the GH parties have sold an oral contraceptive under the name, Isabelle, which the Bayer parties claim infringe their patent. They brought proceedings in this Court claiming various forms of relief for infringement of their patent. The GH parties defended the proceedings and they claimed that the Patent should be revoked for (among other things) lack of inventive step, lack of novelty and lack of fair basis.
3 On 4 April 2013, the primary judge delivered reasons in the proceeding (Bayer Pharma Aktiengesellschaft v Generic Health Pty Ltd (No 2) [2013] FCA 279). On 8 May 2013, she made declarations that each of the GH parties had infringed claims 3 and 11 of the Patent by selling or supplying the Isabelle product. She also granted injunctions restraining the selling or supplying of the product. Her Honour also ordered that a certificate be issued pursuant to s 19 of the Patents Act 1990 (Cth) (“the Act”) to certify that the validity of claims 3 and 11 of the Patent was questioned and each of claims 3 and 11 of the Patent were held to be valid in the proceeding. The primary judge made orders to facilitate an inquiry into damages or the taking of an account of profits. The primary judge stayed a number of her orders pending the determination of any application for leave to appeal and subsequent appeal.
4 Six days before the first day of the trial which commenced on 11 March 2013, the GH parties issued an interlocutory application dated 5 March 2013 in which they sought leave to rely on an affidavit of Mr Terrence Clive Burgess, sworn on 27 September 2012 and filed in the proceeding as part of their evidence-in-chief on invalidity. Mr Burgess’ affidavit was relevant to an experiment carried out by the GH parties. The Bayer parties contended that r 34.50 of the Federal Court Rules 2011 (Cth) applied and that the GH parties could not rely on Mr Burgess’ affidavit without the leave of the Court. In response, the GH parties contended that the evidence in Mr Burgess’ affidavit did not fall within the terms of r 34.50 and, in the event that they were wrong, they should be given leave to rely on the evidence in the affidavit. The primary judge heard submissions on the GH parties’ interlocutory application on 11 March 2013 before the Bayer parties opened their case at the trial. On that day, she made an order that the interlocutory application be dismissed. She decided that the evidence in Mr Burgess’ affidavit fell within the terms of r 34.50 and that leave should not be granted (Bayer Pharma Aktiengesellschaft v Generic Health Pty Ltd [2013] FCA 226). In the circumstances, the GH parties then elected not to present any evidence at the trial in relation to their challenge to the Patent on the ground that it was not novel.
5 The GH parties’ application for leave to appeal relates to the orders made by the primary judge on 8 May 2013, and their Application for an extension of time and for leave to appeal relates to the orders made by the primary judge on 11 March 2013.
6 The Bayer parties do not oppose leave being granted in relation to the orders made on 8 May 2013. It is plainly appropriate to grant leave (Decor Corporation Pty Ltd and Another v Dart Industries Inc (1991) 33 FCR 397, at 398-399) and we would do so. The Bayer parties oppose an extension of time and a grant of leave to appeal in relation to the orders made on 11 March 2013.
7 The other two applications before the Court are brought by Apotex and they relate to another proceeding before the primary judge. In that proceeding, the Bayer parties claimed that Apotex sold or supplied products which infringed the Patent and the issues in the proceeding were relevantly the same as the issues in the proceeding between the Bayer parties and the GH parties. On 20 December 2012, the primary judge noted an agreement of the parties to that proceeding as follows:
BY CONSENT THE COURT:
…
2. Notes the agreement of the parties as follows:
(a) The judicially determined result (as opposed to any consent orders) in the existing GH proceeding is to apply in this proceeding, such that if the Isabelle product (being the product of that name which is the subject matter of the existing GH proceeding) is restrained then the Respondent’s Products would be restrained and if the Isabelle product is not restrained, then the Respondent’s Products would not be restrained.
…
3. Orders that all evidence and submissions in the existing GH proceeding be and be taken to be evidence and submissions in this proceeding.
8 On 10 May 2013, the primary judge made orders in the proceeding between the Bayer parties and Apotex similar to the orders she made in the proceeding between the Bayer parties and the GH parties on 8 May 2013 (see [3] above).
9 Before this Court, Apotex in substance adopted the submissions made by the GH parties. The decision in the proceeding between the GH parties and the Bayer parties will resolve the proceeding between Apotex and the Bayer parties.
GLOSSARY OF TERMS
10 The primary judge included a glossary of terms in her reasons for judgment. We set out that glossary of terms, but only insofar as it includes terms relevant to the issues raised on the appeal:
Absolute bioavailability
A term used to compare the bioavailability of a test formulation by a specific route of administration to that of the drug when administered intravenously, i.e. when there is no barrier to absorption. Absolute bioavailability measures the amount of the drug that is absorbed into the systemic circulation and assesses the effect of the route of administration on drug absorption.
Acid Labile API
An API that is subject to chemical degradation in acidic conditions to some degree or other, also referred to as "acid sensitivity." Acidity is relative, for example a pH of 5 is less acidic than a pH of 1.
Active Pharmaceutical Ingredient ("API")
A substance in a drug formulation that is biologically active.
…
Binder
A binder (such as PVP) is an excipient that is the "glue" that holds the constituent powders together to form granules and ensures that a tablet remains intact until swallowed.
Bioavailability
The extent and the rate of absorption of a drug into the blood stream.
Bioequivalence study
Comparison of the plasma concentration and time profiles of two formulations normally conducted in humans.
Blister pack
A form of packaging in which unit doses are enclosed inside a blister or bubble formed between two layers of packaging material. The two layers may or may not be the same composition.
Bulkers or bulking agents
An excipient designed to give a tablet "bulk" (also known as fillers) (e.g. microcrystalline cellulose and lactose NF).
Buffering agent
An excipient added to stabilise pH in the local environment of the tablet including sodium bicarbonate, sodium citrate and disodium hydrogen phosphate.
C-17 epimerisation
The inversion of the stereochemical configuration at the C17 position of a molecule without any change to other parts of the molecule.
Capsule
Capsules contain powders or solutions which are encapsulated by a polymer shell, usually gelatin. Capsules can be hard gelatin capsules which are used to encapsulate powders or soft gelatin capsules which can be used to encapsulate solutions and suspensions of drugs.
Carrier
A synonym for “excipient”, sometimes specifically a bulking agent.
Cmax
The maximum plasma concentration of a drug after the onset of drug absorption.
Coating excipients
The purpose of the coating is partially cosmetic/aesthetic and can also be used to improve the friability (robustness) of a pharmaceutical product (see also: Enteric coatings).
Daily dosage unit
The term daily dosage units mean that one dosage unit should be administered daily, i.e. the frequency of dosage of the particular API (s) is once per day.
Delayed release preparation or dosage form
The most common example of which is enteric coated preparations which are formulated so that the API is not released in the stomach.
…
Dihydrospirorenone
Or 1,2-dihydrospirorenone, a synonym for drospirenone.
Direct compression
A method of tablet preparation whereby tablets are prepared by compression of dry mixtures in a tableting machine.
Disintegrant
An excipient that promotes breakup of tablets when placed in an aqueous environment.
Dissolution rate
The rate that a drug dissolves in solution (either the API or the finished product).
Dissolution test
A test that measures the rate of dissolution of a drug under a standard set of equipment and conditions, such as in the United States Pharmacopeia (USP).
Dosage form
The pharmaceutical form in which an active pharmaceutical ingredient is presented in a suitable form for therapeutic administration, such as a tablet or cream.
DRSP
Means drospirenone.
Dry granulation
Also known as "slugging", involves the compression of a mixture into large and crude tablets that are subsequently ground (milled) into granules of a suitable size range for compression or where the mixture is squeezed between rollers to form a friable sheet that is milled into granules of a suitable size range for compression.
Elimination phase
The time period beyond Cmax during which a drug is eliminated through the processes of metabolism and excretion.
Enteric Coating
An acid resistant tablet coating designed to delay the release of the API in a tablet until the formulation passes from the acidic environment of the stomach to the less acidic environment of the small intestine. Enteric coats are used to protect an acid labile API, or if the API is an irritant to the gastric mucosa.
Epimer
The molecular product of epimerisation.
Epimerisation
The inversion of the stereochemistry of one sterically defined carbon atom centre in a molecule that contains more than one such centre.
Erythromycin
An acid labile macrolide antibiotic.
Estrogen
A type of steroidal endogenous hormone.
Ethinylestradiol (EE)
An estrogen commonly used in combined oral contraceptives.
Excipient
A non-active ingredient in a pharmaceutical product (also called adjuvants).
Extended Release preparation or dosage form
Prolonged or extended release preparations are designed so that release of the API is prolonged and is not immediate.
Formulation
The list of ingredients used in the manufacture of a dosage form and a statement of the quantity of each ingredient in a defined weight, volume, unit or batch.
Formulator
A member of the R&D team.
GAST
American Home Products Patent WO 98/04269.
Gastric Residence Time
The amount of time that contents (e.g. a drug) resides in the stomach.
Gastrointestinal permeability
The ability of an API to cross the human gut wall to be absorbed. Also referred to in shorthand as ‘permeability’.
Gastrointestinal tract (“GI Tract”)
The human GI tract comprises the oesophagus, stomach, duodenum, jejunum, small intestine, transverse colon, large intestine or colon, ascending colon, ileum and descending colon.
Gestagen
A hormone with progestational activity (see: progestogen, below).
Granulation
A method of tablet preparation in which an API is combined with other ingredients to form granules (relatively large particles) that have a diameter in the order of millimetres.
High Performance Liquid Chromatography ("HPLC")
HPLC is a process used to separate, identify and quantify individual compounds in a sample.
Immediate release preparation or dosage form
A dosage form which is designed to release an API upon ingestion with no means of slowing or delaying release and with minimum delay after ingestion.
In vitro tests
Pharmaceutical tests performed in a laboratory test tube as opposed to in a living body.
In vivo tests
Pharmaceutical tests performed in a living body, including animals.
Individually removable
A packaging system such that every dosage form or pharmaceutical preparation is able to be removed from the packaging individually without affecting the remainder of the dosage units or preparations in the packaging system.
Isomer
Each of two or more compounds with the same chemical formula but a different structural formula (i.e. spatial arrangement of atoms in the molecule).
Isomerization
Is the reaction by which a molecule changes into its isomer.
Krause I
Krause W & Jakobs U "Determination of plasma levels of spirorenone, a new aldosterone antagonist, and one of its metabolites by High Performance Liquid Chromatography (1982) 230(1) J Chromatog 37-45.
Krause II
Krause W & Kuhne G "Isolation & Identification of spirorenone metabolites from the monkey (Macaca fascicularis) (1982) 40(1) Steroids 81-90.
Krause III
Krause W et al., "Pharmacokinetics of a new aldosterone antagonist, spirorenone, in healthy volunteers after single and repeated daily doses" (1983) 25(2) European Journal of Clinical Pharmacology 231-236.
Krause IV
Krause W et al., “Determination of canrenone, the major metabolite of spironolactone, in plasma and urine by High Performance Liquid Chromatography” (1983) 277 J Chromatog 191-199.
Low dose formulation
A low dose formulation is generally understood to be a formulation with less than around 5mg of API.
Lubricant
An excipient which is designed to prevent the formulation from sticking to the tableting tool on compression during manufacture.
Macrocrystalline
A term used to describe an API that is in a crystalline form but is not microcrystalline.
Micronization
The process of reducing the particle size of a drug substance (API) providing a much higher surface area for dissolution.
MIMS
The MIMS annual published June 1999. Exhibit J in the proceedings.
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New Chemical Entity
A molecule that has not yet been marketed as a medicine.
Nickisch
Nickish et al., “Acid-catalysed rearrangements of 15Β, 16Β-methylene-17Α-pregnene-21, 17 carbolactone derivatives” (1986) 27(45) Tetrahedron Letters 5463-5466. Exhibit N in the proceedings.
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Oral dosage form
An oral dosage form is designed to be administered to the patient via the mouth including tablets, capsules, pills, solutions, suspensions and emulsions.
Oral contraceptive
Abbreviated to "OC".
pH
pH measures the acidity and basicity of a solution. The lower the pH value, the more acidic it is, the higher the pH value, the more basic (or "alkaline") it is. A pH value of 7 indicates a neutral solution (neither acid nor base).
Pharmaceutical composition
Is composed of an API and excipients.
Pharmaceutical development
The whole development process for a new medicine beginning with fundamental research and leading to a marketed product.
Pharmaceutical development studies
Studies carried out during the pharmaceutical development process including studies of the physicochemical properties of an API, assay development, stability of the API and of compressed tablets of varying formulations, compatibility of the API with common tablet excipients, powder flow and compression properties, and dissolution rate of test formulations (see also: preformulation studies, below).
Pharmacodynamic studies
Studies using clinical markers to assess the clinical effectiveness of a formulation. Volunteers are often administered with the formulation at different dosage levels, starting at the lowest and increasing towards the highest dose in the target range to assess the minimum dose required for clinical effectiveness.
Pharmacokinetics
The study of the rate of the processes involved in absorption, metabolism, distribution and excretion of a drug.
Phase I clinical trials
Trials involving a small number of healthy volunteers (usually between 5 and 15 individuals) and include pharmacodynamic studies (defined above) and pharmacokinetic studies.
Phase II clinical trials
Studies in which a formulation is administered to a large group of patients (typically several hundred patients) to determine whether the drug has a therapeutic effect against the targeted indication, at what dosage levels and tolerance to the medication (determining side-effects).
Phase III clinical trials
Studies in which a formulation is administered to a large population of patients (typically several thousand patients) to establish the safety of the drug and also the efficacy against existing medicines (if available).
Phase IV clinical trials
Trials conducted after a product is approved and on the market to determine long-term risks, benefits and optimal use, or to test the product in different populations (such as children).
Physicochemical properties
The physical and chemical properties of an API including:
solubility in water;
stability under the influence of moisture, acid, base light and heat;
crystalinity; and
lipophillicity(ability to dissolve in fats and oils)
Pilbrant
Pilbrant A. and Cederberg C., “Development of an oral formulation of omeprazole”, (1985) 20(108) Scandanvian Journal of Gastroentorology 113-120.
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Preformulation
The stage of drug development during which the physical pharmacist characterises the physico-chemical properties of the drug substance in question which are considered important in the formulation of a stable, effective and safe dosage form. Such parameters as crystal size and shape, pH solubility profile, pH stability profile, polymorphism, partitioning effect, drug permeability and dissolution behaviour are evaluated. During this evaluation possible interactions with various inert ingredients intended for use in the final dosage form are also considered.
Preformulation studies
A series of standard in vitro tests designed to provide a comprehensive understanding of the physical and chemical properties of a drug.
Progestogens
A group of steroid hormones which includes drospirenone. Also known as gestagens.
Progesterone
A steroid hormone involved in the female menstrual cycle.
Relative bioavailability
Where the bioavailability of a test formulation is compared to another formulation of the same dose and route of administration of the drug using AUC values.
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Residence Time
See: Gastric Residence Time.
Solubility
An intrinsic property of a drug that reflects how much of the drug can dissolve in a given volume of liquid under given conditions (such as temperature).
Spraying
In order to achieve suitable homogeneity in formulations where the drug is a small proportion of the total weight of the solid dosage form, the drug can be sprayed onto an inert carrier or filler.
Spironolactone (SPR)
Spironolactone is a potassium-sparing diuretic and an aldosterone antagonist.
Spirorenone
Spirorenone is an aldosterone antagonist with more than 5 times the potency of spironolactone. It metabolises to form drospirenone.
Surfactants, use of
A surfactant and other polymers may be used in a pharmaceutical formulation to improve the dissolution of a poorly soluble drug. These additives aid in "wetting" the drug surface by the gastro-intestinal fluid, so that there is more surface area available for dissolution.
Tablet
A tablet is a solid dosage form manufactured by compression or moulding.
Tmax
The time taken for a drug to reach Cmax (the time to maximum concentration)
USP
United States Pharmacopoeia.
the patent
11 The priority date of the Patent is 31 August 1999. The relevant parts of the Patent were identified by the primary judge and we set them out below:
FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising drospirenone and ethinylestradiol, a method of providing dissolution of drospirenone, methods of inhibiting ovulation by administration of drospirenone and the use of drospirenone and ethinylestradiol for inhibiting ovulation.
…
… (drospirenone) is known from DE 26 52 761 in which its use as a diuretic compound is disclosed.
In DE 30 22 337, the gestagen-like activity of the compound and its consequent utility as a contraceptive agent is described at dosage levels of 0.5-50 mg of drospirenone per day. It is also noted that the mechanism of action of the compound is very similar to that of the natural corpus luteum hormone progesterone, and that it does not give rise to increased blood pressure for which reason it may be administrated to women who have or are at risk of developing increased blood pressure. It is further described that drospirenone may be administered together with ethinylestradiol in amount of 0.03-0.05 mg per day.
DE 30 51 166 discloses the use of the drospirenone for the treatment of gynaecological irregularities and for contraception at a dosage level of 0.5-50 mg per day.
EP 398 460 discloses the use of drospirenone for the treatment of androgen-induced disorders, aldosterone-induced disorders and hormonal irregularities as well as for contraception at dosage levels of 0.5-50 mg, preferably 1-10 mg per day. Ethinylestradiol may be co-administered at a level of 0.02-0.04 mg per day.
US 5,756,490 discloses pharmaceutical combination preparations comprising 23 or 24 dosage units containing a combination of a gestagen and an estrogen and 4-10 dosage units containing estrogen alone. Drospirenone is mentioned as a possible, but not preferred, gestagenic compound and ethinylestradiol is mentioned as a possible, but not preferred, estrogenic compound.
Any discussion of documents, acts, materials, devices, articles or the like which has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed in Australia before the priority date of each claim of this application.
SUMMARY OF THE INVENTION
In the course of research leading to the present invention, it has surprisingly been found that a hitherto undisclosed minimum dosage level of drospirenone is required for reliable contraceptive activity. Similarly, a preferred maximum dosage has been identified at which unpleasant side effects, in particular excessive diuresis, may substantially be avoided.
Accordingly, in a first aspect, the present invention relates to a pharmaceutical composition comprising, as a first active agent, … (drospirenone) in an amount corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and, as a second active agent, … (ethinylestradiol) in an amount corresponding to a daily dosage of from about 0.01 mg to about 0.05 mg, together with one or more pharmaceutically acceptable carriers or excipients.
Apart form [sic] the active substances themselves, it is envisaged that an ester or prodrug of drospirenone may be employed in the present composition, e.g. an oxyiminopregnane carbolactone as disclosed in WO 98/24801. Likewise, it is envisaged that esters or ethers of ethinylestradiol may be included in the composition.
In a further aspect, the invention relates to a method of inhibiting ovulation in a mammal, in particular a human, comprising administering, to said mammal, drospirenone in an amount in the range of from about 2 mg to about 4 mg of per day, together with ethinylestradiol in an amount of from about 0.01 mg to about 0.05 mg per day, said amounts being effective to inhibit ovulation in said mammal.
In a still further aspect, the invention relates to the use of drospirenone combined with ethinylestradiol for preparing a pharmaceutical preparation for the inhibition of ovulation in a mammal, in particular a human, the composition comprising an amount of drospirenone corresponding to a daily dosage, on administration of the composition, of from about 2 mg to about 4 mg, and comprising an amount of ethinylestradiol corresponding to a daily dosage, on administration of the composition, of from about 0.01 to about 0.05 mg.
Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.
…
DETAILED DISCLOSURE OF THE INVENTION
Drospirenone, which may be prepared substantially as described in, e.g., US 4,129,564 or WO 98/06738, is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore, drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkaline conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof.
It has surprisingly been found that when drospirenone is provided in micronized form (so that particles of the active substance have a surface area of more than 10,000 cm2/g, and the following particle size distribution as determined under the microscope: not more than 2 particles in a given batch with a diameter of more than 30 Μm, and preferably ≤ 20 particles with a diameter of ≥ 10 Μm and ≤ 30 Μm) in a pharmaceutical composition, rapid dissolution of the active compound from the composition occurs in vitro (“rapid dissolution” is defined as the dissolution of at least 70% over about 30 minutes, in particular at least 80% over about 20 minutes, of drospirenone from a tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37ºC determined by the USP XXIII Paddle Method using a USP dissolution test apparatus 2 at 50 rpm). Instead of providing the drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the surface of inert carrier particles followed by incorporation of the particles containing drospirenone on their surface in the composition.
Without wishing to be limited to any particular theory, it appears that the in vitro dissolution rate of drospirenone is connected to the dissolution rate in vivo resulting in rapid absorption of drospirenone in vivo on oral administration of the compound. This is an advantage because isomerization of the compound in the gastric environment and/or hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound.
With respect to ethinylestradiol which is also a sparingly soluble substance, though less sensitive to degradation than drospirenone under conditions prevailing in the gastrointestinal tract, it is also an advantage to provide it in micronized form or sprayed from a solution, e.g. in ethanol, onto the surface of inert carrier particles. This has the added advantage of facilitating a more homogenous distribution of the ethinylestradiol throughout the composition which might otherwise be difficult to obtain because ethinylestradiol is incorporated in extremely small amounts. When ethinylestradiol is provided in micronized form, it preferably has the following particle size distribution as determined under the microscope: 100% of the particles have a diameter of ≤ 15.0 Μm, 99% of the particles have a diameter of ≤ 12.5Μm, 95% of the particles have a diameter of ≤ 10.0 Μm, and 50% of the particles have a diameter of ≤ 3.0 Μm. Furthermore, no particle is larger than 20 Μm, and ≤ 10 particles have a diameter of ≥ 15 Μm and ≤ 20.0 Μm.
To obtain a more rapid rate of dissolution, it is preferred to include carriers or excipients which act to promote dissolution of both active substances. Examples of such carriers and excipients include substances that are readily soluble in water such as cellulose derivatives, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it appears as though polyvinylpyrrolidone might be particularly helpful to promote dissolution.
The composition of the invention preferably comprises drospirenone in an amount corresponding to a daily dosage of from about 2.5 mg to about 3.5 mg, in particular about 3 mg. The amount of ethinylestradiol preferably corresponds to a daily dosage of from about 0.015 mg to about 0.04 mg, in particular from about 0.015 mg to about 0.03 mg. More particularly, the present composition comprises an amount of drospirenone corresponding to a daily dosage of from about 3.0 to about 3.5 mg and ethinylestradiol in an amount corresponding to from about 0.015 to about 0.03 mg.
Apart from its ability to inhibit ovulation, the composition of the invention has been found to possess pronounced anti-androgenic properties and may therefore be used in the prevention or treatment of androgen-induced disorders, in particular acne. Such use may be independent from or concomitant with the use as a contraceptive disclosed above. Furthermore, since drospirenone is an aldosterone antagonist, it has diuretic properties and is therefore suitable for counteracting the water-retentive properties of ethinylestradiol.
In a particular embodiment, the invention relates to a pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein each of said daily dosage units comprises a combination of drospirenone in an amount of from about 2 mg to about 4 mg and ethinylestradiol in an amount from about 0.01 to about 0.05 mg.
…
The composition of the invention may be formulated in any manner known in the pharmaceutical art. In particular, as indicated above, the composition may be formulated by a method comprising providing drospirenone and, if desired, ethinylestradiol in micronized form in said unit dosage form, or sprayed from a solution onto particles of an inert carrier in admixture with one or more pharmaceutically acceptable excipients that promote dissolution of the drospirenone and ethinylestradiol so as to promote rapid dissolution of drospirenone and preferably ethinylestradiol on oral administration. Examples of suitable excipients include fillers, e.g. sugars such as lactose, glucose or sucrose, sugar alcohols such as mannitol, sorbitol or xylitol, starch such as wheat, corn or potato starch, modified starch or sodium starch glycolate, lubricants such as talc, magnesium stearate, calcium stearate, colloidal silica or stearic acid, and binders such as polyvinylpyrrolidone, cellulose derivatives, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, methyl cellulose or gelatin, for making oral dosage forms such as tablets, pills or capsules.
Tablets may conveniently be coated with a suitable film-forming agent, e.g. hydroxypropylmethyl cellulose, hydroxypropyl cellulose or ethyl cellulose, to which a suitable excipient may optionally be added, e.g. a softener such as glycerol, propylene glycol, diethylphthalate or glycerol triacetate, filler such as sucrose, sorbitol, xylitol, glucose or lactose, a colorant such as titanium hydroxide, etc.
…
The present invention is further described in the following examples which are not in any way intended to limit the scope of the invention as claimed.
EXPERIMENTAL
Example 1
Preparation of tablets containing drospirenone ad ethinylestradiol
Tablet cores of the following composition
| micronized drospirenone | 3.00 mg |
| micronized ethinylestradiol | 0.03 mg |
| lactose monohydrate | 48.17 mg |
| corn starch | 14.40 mg |
| modified starch | 9.60 mg |
| polyvinylpyrrolidone 25,000 | 4.00 mg |
| magnesium stearate | 0.80 mg |
were prepared by charging a fluidized bed granulator with 31.68 kg corn starch, 21.12 kg modified starch, 6.60 micronized drospirenone, 0.066 kg micronized ethinylestradiol and 105.974 kg lactose monohydrate and activating the fluidized bed. An aqueous solution of 8.80 kg polyvinylpyrrolidone 25,000 in 46.20 kg purified water was sprayed continuously onto the fluidized bed while drying by heating the air stream of the fluidized bed. At the end of the process 1.76 kg magnesium stearate was sucked into the granulator and mixed with the granules by maintaining the fluidized bed. The resulting granulate was pressed into tablet cores by compression using a rotary tablet press.
…
Example 2
Dissolution of drospirenone from tablets
The rate of dissolution of drospirenone from the tablets prepared in Example 1 was determined by the USP XXIII Paddle Method using a USP Dissolution Test Apparatus 2 including 6 covered glass vessels and 6 paddles. Tablets were placed in 900 ml water at a temperature of 37ºC (± 0.5ºC) and stirred at 50 rpm.
The results appear from Figs. 1, 2 and 4. From Fig. 1, it appears that the batch numbered V8 containing macrocrystalline drospirenone (but otherwise identical to the tablets prepared in Example 1) exhibited an extremely slow dissolution of drospirenone, whereas all batches containing micronized drospirenone exhibited a dissolution rate of more than 70% within 30 minutes.
Fig. 2 and Fig. 4 shows the results of dissolution of drospirenone from tablet cores and film-coated tablets, respectively. In both cases more than 70% of the active agent is dissolved within 30 minutes. Thus, the film coating did not significantly influence the rate of dissolution.
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Example 4
Bioavailability of drospirenone and ethinylestradiol from tablets containing 3 mg of drospirenone and 0.03 mg ethinylestradiol
42 healthy women between 18 and 35 years of age were included in an open-label crossover study after their informed consent had been obtained. The aim of the study was to investigate the relative bioavailability of drospirenone and ethinylestradiol from a tablet formulation containing 3 mg drospirenone and 0.03 mg ethinylestradiol with reference to an oral suspension containing 6 mg of drospirenone and 0.06 mg ethinylestradiol per vial.
The bioavailability was determined using serum concentrations of each active agent as parameters. Compared to the oral suspension, the relative bioavailability of drospirenone and ethinylestradiol from the tablets is 107% and 117%, respectively. It was therefore concluded that both drospirenone and ethinylestradiol are completely released from the tablets in vivo.
The absolute bioavailability of drospirenone was determined in two studies to be 76%±13% after oral administration of 2 mg drospirenone to 8 young healthy women and 85%±24% after oral administration of a microcrystalline suspension containing 3.13 mg drospirenone to 6 postmenopausal women.
The oral bioavailability of ethinylestradiol was determined in several studies, and mean values of from 36% to 59% were reported in the literature indicating a first-pass effect.
…
The results of the study showed that both LH and FSH were clearly suppressed with both trial preparations. Accordingly, the secretion of estradiol and progesterone were greatly reduced over all three treatment cycles with the exception of 3 volunteers receiving the 2 mg drospirenone preparation. This result was, in principle, confirmed by the accompanying ultrasound examinations. Follicular ripening occurred in several cases with both trial preparations. Athough three ovulations were diagnosed with the preparation containing 2 mg drospirenone (one of which was described as “equivocal” and the other as a “tablet-taking error”), no differences were demonstrable statistically (p > 0.05) between the two trial preparations as regards the hormones LH, FSH, estradiol and progesterone, and the parameter “ovulation during the treatment cycles”. In keeping with the hormones, cervical function was greatly limited and the “spinnbarkeit” and crystallisability of the cervical mucus was greatly reduced with both trial preparations. Prolactin increased minimally and SHBG and CBG distinctly with both preparations. Triglycerides and HDL levels increased with both trial preparations, while LDL levels decreased. Total cholesterol was largely unchanged in both treatment groups. Oral glucose tolerance remained virtually unchanged or was slightly decreased. Testoserone, androstenedione and DHEA-S decreased minimally.
The subjective and objective tolerance was good with both treatments. This was also the case for cycle control with the exception of the first cycle with 2 mg drospirenone. Blood pressure, heart rate and body weight remained constant in the majority of cases or showed a slight tendency to decrease.
After three months’ treatment, it was concluded:
The two trial preparations were equally good as regards the subjective and objective tolerance.
No negative metabolic effects were observed with either preparation. HDL was influenced positively in the sense of an increase.
The results confirmed the results of earlier studies that the 2 mg drospirenone preparation was in the threshold region of ovulation inhibition, whereas the 3 mg drospirenone preparation had a demonstrable ovulation-inhibiting effect in all cases examined.
The claims defining the invention are as follows:
…
3. A pharmaceutical composition in oral dosage form comprising:
3 mg of drospirenone and 0.01 mg to 0.05 mg of ethinylestradiol, together with one or more pharmaceutically acceptable carriers or excipients, wherein the oral dosage form is a tablet, and
wherein at least 70% of said drospirenone is dissolved from said composition within 30 minutes, as determined by USP XXIII Paddle Method II using 900 ml of water at 37ºC as the dissolution media and 50 rpm as the stirring rate.
…
11. A pharmaceutical preparation consisting of a number of separately packaged and individually removable daily dosage units placed in a packaging unit and intended for oral administration for a period of at least 21 consecutive days, wherein said daily dosage units are in tablet form and comprise a combination of 3 mg of drospirenone and ethinylestradiol in an amount from 0.01 to 0.05 mg, wherein at least 70% of said drospirenone is dissolved from said dosage units within 30 minutes, as determined by USP XXIII Paddle Method II using 900 ml of water at 37°C as the dissolution media and 50 rpm as the stirring rate.
12 It is convenient at this point to mention her Honour’s characterisation of the invention. Although there was a dispute about the appropriate characterisation of the invention at trial, it was made clear at the hearing of the appeal that her Honour’s characterisation of the invention was not challenged.
13 Her Honour rejected the suggestion that the invention was no more than finding the means to ensure that DRSP dissolved rapidly. She found that the invention was the finding of a suitable formulation by which DRSP is bioavailable and not degraded in the stomach. The problem which would have confronted the hypothetical formulator was that DRSP was both poorly soluble and acid labile. The invention lay in the creation of a rapidly dissolving formulation of DRSP which substantially reduced isomerization of the DRSP in the stomach leading to high bioavailability.
grounds of appeal
14 The Amended Draft Notice of appeal contains 12 grounds of appeal. Grounds 1 and 2 relate to a fair basis issue and allege that the primary judge erred in concluding that claims 3 and 11 of the Patent were fairly based on the matter described in the specification. At the relevant time, s 40(3) of the Act was in the following terms:
40 Specifications
…
(3) The claim or claims must be clear and succinct and fairly based on the matter described in the specification.
15 Grounds 3 to 10 inclusive relate to inventive step and allege that the primary judge erred in not concluding that the invention described in the Patent lacked an inventive step. At the relevant time, ss 18 and 7 of the Act were in the following terms:
18 Patentable inventions
(1) Subject to subsection (2), an invention is a patentable invention for the purpose of a standard patent if the invention, so far as claimed in any claim:
…
(b) when compared with the prior art base as it existed before the priority date of that claim:
(i) is novel; and
(ii) involves an inventive step; and
…
7 Novelty and inventive step
…
(2) For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with either of the kinds of information mentioned in subsection (3), each of which must be considered separately.
(3) For the purposes of subsection (2), the kinds of information are:
(a) prior art information made publicly available in a single document or through doing a single act; or
(b) prior art information made publicly available in 2 or more related documents or, or though doing 2 or more related acts, if the relationship between the documents or acts is such that a person skilled in the relevant art in the patent area would treat them as a single source of that information;
being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area.
16 Under s 138(3) of the Act, the Patent could be revoked either on the ground that the invention described in the Patent lacked an inventive step or on the ground of lack of fair basis. The primary judge rejected both of those grounds. She went on to find that the GH parties’ product infringed claims 3 and 11 of the Patent. There is no appeal by the GH parties against her Honour’s finding of infringement.
17 As we have said, once her Honour made her decision to refuse leave under r 34.50(2) for the GH parties to rely on the evidence in the affidavit of Mr Burgess, those parties abandoned their case that the invention lacked novelty. In grounds 11 and 12 of the Amended Draft Notice of appeal, the GH parties contend that the primary judge should have found that Mr Burgess’ evidence did not fall within the terms of r 34.50(1). Alternatively, they contend that leave should have been granted under r 34.50(2). The GH parties contend that they can challenge the primary judge’s decision under r 34.50 as part of their challenge to the orders made on 8 May 2013. If they are correct about that, we would grant leave to appeal because we think that there is sufficient doubt about the decision, and sufficient prejudice to the GH parties if the decision be wrong, to warrant a grant of leave. If they are not correct about that, then it will be necessary to consider the separate application brought by the GH parties for an extension of time and leave to appeal.
THE PRIMARY JUDGE’S REASONS
18 After setting out a glossary of terms and the relevant parts of the Patent, the primary judge referred to the expert witnesses who gave evidence before her. The GH parties called Dr James Rowe and Dr Susan Walters. The primary judge described their qualifications and summarised the evidence that each of them gave. The Bayer parties called Professor Martyn Davies. Again, the primary judge described his qualifications and summarised his evidence. It is unnecessary for us to summarise this part of her Honour’s reasons.
19 The primary judge then turned to consider the grounds upon which the GH parties claimed the Patent should be revoked and she dealt with them, relevantly for the purposes of the appeal, in the order of lack of novelty, lack of inventive step, and lack of fair basis.
20 As far as the alleged lack of novelty was concerned, the primary judge noted that the GH parties’ case depended on a single document being Gast (PCT Publication WO 98/04269) “Monophasic contraceptive method and kit comprising a combination of a progestin and estrogen”, published on 5 February 1998. She said that, on 11 March 2013, before the hearing commenced, the GH parties sought leave to rely on the affidavit of Mr Burgess. She noted that she refused leave and dismissed the interlocutory application. She noted that, at the commencement of the hearing, the GH parties advised that, as a consequence of her ruling, they would not be pressing their claim for invalidity based on the alleged lack of novelty. No evidence was sought to be tendered relevant to this issue, and it followed that the claim could not succeed. Her Honour said that it did not need to be considered further.
21 As far as lack of inventive step or obviousness is concerned, the primary judge noted that there were two issues of principle between the parties. However, she also noted that, given the factual findings that she subsequently made, the resolution of the issues of principle was unnecessary.
22 The GH parties alleged that the invention was obvious and they relied on the evidence of Dr Rowe and Dr Walters. They claimed that the hypothetical formulator at the priority date, if confronted by DRSP – an acid labile and poorly soluble API – as a matter of course and routine, would carry out a limited or pilot bioavailability test in vivo for the purpose of determining whether there was any bioavailability with the DRSP, and whether an immediate release formulation of DRSP would be sufficiently bioavailable. On this thesis, the hypothetical formulator would not respond to the acid lability and poor solubility of DRSP by immediately proceeding to develop an enteric coated formulation as Professor Davies suggested. If these contentions were correct, then claims 3 and 11 of the Patent were invalid on the ground of the lack of an inventive step or obviousness.
23 The Bayer parties responded to these contentions by contending that a hypothetical formulator would not respond to an acid labile and poorly soluble API such as DRSP by carrying out a pilot bioavailability test, and that, even if the formulator did, they would have no expectation of success. They also contended that the invention, which the GH parties asserted was obvious, was not any immediate release form of any version of DRSP, but included the particular dissolution rate specified in claim 3.
24 The primary judge said that the two issues of principle to which the dispute gave rise were both “founded” on the reasoning of the High Court in Aktiebolaget HÄssle and Another v Alphapharm Pty Ltd (2002) 212 CLR 411 (“Alphapharm”). The first issue of principle was whether the expectation of the hypothetical formulator was a necessary part of the resolution of the issue of obviousness. The Bayer parties submitted that it was, whereas the GH parties submitted that it was not. The GH parties submitted that the only question was whether the hypothetical addressee of the Patent, faced with the same problem, would have taken, as a matter of routine, whatever steps might have led from the prior art to the invention. The primary judge considered the reasoning of the High Court in Alphapharm and of this Court in Pfizer Overseas Pharmaceuticals and Others v Eli Lilly and Co and Others (2005) 225 ALR 416 (“Pfizer”) and concluded that, in determining the question of obviousness, it was necessary to consider the expectation of the hypothetical skilled addressee of the Patent.
25 The second issue of principle was whether the expectation of the hypothetical formulator (assuming it to be relevant) must be an expectation of the production of the invention or an expectation relating to “some other useful result” (Alphapharm Pty Ltd v H Lundbeck A/S and Another (2008) 76 IPR 618, at [180]), and if so, what is meant by the words “some other useful result”. The primary judge rejected the suggestion that “some other useful result” could be the obtaining of information to ascertain whether there was any bioavailability problem with an immediate release formulation of DRSP. The primary judge rejected the GH parties’ contention, and held that “some other useful result” in the context of obviousness must be understood as the claimed invention or at least something very like the claimed invention.
26 On the appeal, the GH parties challenged the primary judge’s conclusion with respect to the first issue of principle. They did not challenge her conclusion with respect to the second issue of principle. As senior counsel for the GH parties put it, “we accept – we’re trying to get bioavailable drospirenone”.
27 The primary judge’s approach to lack of inventive step or obviousness was to first consider whether the GH parties had established that the invention would have been obvious to the hypothetical formulator in the light of the common general knowledge which she assumed without deciding included the article referred to as Pilbrant. She identified matters which led her to accept the evidence of Professor Davies in preference to that of Dr Rowe and Dr Walters.
28 First, she referred to the qualifications and experience of the experts who gave evidence before her. She said that, in weighing up the competing expert opinions, it was relevant to have regard to the fact that Professor Davies’ experience involved extensive direct engagement with the formulation process as a member of a research drug development team which, according to his oral evidence, extended to new APIs. By contrast, Dr Walters had not been involved in the task of formulating any drug, let alone a new API, since the early 1970s, and her formulation experience from her period of work in industry was limited. Her main experience was as a regulator. Dr Rowe, while having experience as a formulator, did not have experience as to the identification of the appropriate dosage form for a new API.
29 Secondly, her Honour found Professor Davies’ evidence cogent and compelling. His evidence did not disclose any inconsistencies, and was measured, thoughtful and precise. By contrast, Dr Rowe’s evidence was internally inconsistent and his explanation for the inconsistency was not particularly persuasive. As far as Dr Walters’ evidence was concerned, her Honour found that it was not as cogent and compelling as that of Professor Davies.
30 Thirdly, the primary judge said that Professor Davies’ evidence was that a hypothetical formulator would perceive it as critical that the DRSP be formulated in such a way that it would be protected from stomach acid, and that the obvious answer in 1999 was that it be enteric coated. This was in a context where, although DRSP, as an oral contraceptive taken on a long term basis, need only be delivered to a patient throughout a 24 hour period, the whole dose of the drug must be effectively delivered in order to obtain the desired therapeutic effects. Her Honour found that neither Dr Rowe nor Dr Walters adequately explained the reasons, in those circumstances, the hypothetical formulator would not perceive it as critical that DRSP be formulated in such a way that it would be protected from stomach acid.
31 Fourthly, the primary judge accepted Professor Davies’ evidence that the hypothetical formulator or drug development team in 1999 would not perceive any technical, therapeutic or marketing issue with the enteric coating of an oral contraceptive. The primary judge said that she did not accept the evidence of Dr Rowe and Dr Walters to the extent that it depended on some form of difficulty with enteric coatings and she found that it did so depend “to a considerable extent”. She found that by 1999, and indeed well before that date, enteric coatings were routinely used for the purpose of protecting drugs from the acid environment of the stomach and for protecting the stomach from the effects of certain drugs. She found that enteric coatings were seen as a simple and reliable technology to achieve these purposes and that it was well known by 1999 that any fear of dose-dumping could be addressed by enteric coating granules or pellets of the API which could then be made in tablet or capsule form.
32 Fifthly, the primary judge said that Professor Davies had, in reaching his view that the obvious course that the hypothetical formulator would have taken if confronted by all the relevant circumstances as at the priority date was to develop an enteric coated formulation of DRSP, taken into account the circumstances that the drug was an acid labile, poorly soluble drug intended to be used for oral contraceptive purposes. By contrast, the evidence of Dr Rowe and Dr Walters was not, as her Honour said, “persuasively related” to those matters.
33 Sixthly, the primary judge found Professor Davies’ evidence of the predictive relevance of in vitro test results clear and more compelling than that of Dr Rowe and Dr Walters. She accepted that a rapid rate of dissolution in vitro was not necessarily predictive of good bioavailability because of the many other factors at play, whereas a poor dissolution rate in vitro is predictive of a poor dissolution rate in vivo and hence poor bioavailability. Her Honour said that Dr Rowe and Dr Walters never adequately explained the reasons, if a dissolution rate in vitro was poor, a hypothetical formulator would have any expectation that DRSP would be bioavailable to a sufficient extent in vivo.
34 Seventhly, and, in our opinion, to some extent echoing the third point, the primary judge said that Dr Rowe and Dr Walters never adequately explained why a more rapid dissolution rate of DRSP (which both accepted was necessary), would not heighten concern about the likelihood of degradation of the API in the stomach.
35 Finally, her Honour considered that Professor Davies gave proper weight, whereas Dr Rowe and Dr Walters did not, to the realities of the process of formulation, including the fact that resources are limited, there is a need to make hard decisions, and there is an aim to reduce the number of human patients required during the drug development process.
36 These eight matters led her Honour to conclude that she should accept Professor Davies’ evidence that the hypothetical skilled addressee would not, at the priority date, have carried out the type of bioavailability study described by Dr Rowe and Dr Walters as a matter of routine and thereby be led, as a matter of course, to the invention.
37 Her Honour did not think that the Pilbrant article was “to the contrary”. She accepted Professor Davies’ evidence that the Pilbrant article confirmed what the hypothetical formulator would already know and expect, that is, that acid labile drugs degrade in the stomach. In that sense, there would not be any expectation of success and, in fact, there was no success for omeprazole in a conventional form, so that the only formulation option would be an enteric coated formulation. As we have said, her Honour did not make a finding as to whether Pilbrant and the results expressed therein about omeprazole were part of the common general knowledge at the priority date. She said that, if it was, what the hypothetical formulator would take from the Pilbrant article is that “the API would degrade in the stomach and needed to be protected by an enteric coating just as Pilbrant says was required for omeprazole”. Before this Court, the appeal was argued on the basis that the Pilbrant article and the results therein concerning omeprazole were part of the common general knowledge at the priority date.
38 As we have said, the primary judge found that the hypothetical skilled addressee would not have carried out the type of bioavailability study described by Dr Rowe and Dr Walters as a matter of routine and thereby be led, as a matter of course, to the invention.
39 Her Honour went on to say that, at best, there was a possibility that the hypothetical formulator and drug development team might have carried out a bioavailability study of the type described by Dr Rowe and Dr Walters, but that, even if they did, it would have been with the expectation of failure, not success. She found that that was the effect of Professor Davies’ evidence, and she found the effect of the evidence of Dr Rowe and Dr Walters was that the bioavailability study was needed to exclude the possibility, albeit unlikely, that DRSP would prove to be bioavailable in an immediate release form.
40 The primary judge also said that the invention as claimed included the dissolution rate and it is the invention as claimed which must be obvious. She said that there was no evidence to explain why it would have been obvious to the hypothetical formulator as at the priority date to have improved the dissolution of DRSP to the standard specified in claims 3 and 11 as a requirement of the pharmaceutical composition in the oral dosage form as described in those claims.
41 The primary judge then turned to consider prior art information said to be relevant by reason of s 7(3) of Act. For the purposes of the appeal, the only documents that need be considered are Krause I and Krause III.
42 The primary judge found, we think, that the hypothetical formulator would have ascertained Krause I and Krause III and he or she would have treated those documents as a single source of information. However, she appears to have found that the hypothetical formulator would not have regarded Krause I and Krause III “as of any real relevance”, or as making any difference, or as making “any material difference to the position of the hypothetical formulator at the priority date”. In other words, the hypothetical formulator would not have regarded them as relevant or, if relevant, nevertheless insufficient to satisfy the test of obviousness.
43 Her reasons for reaching that conclusion were as follows. First, Dr Rowe said that Krause I would not have made any difference to the way in which he proceeded, and each of the experts said that they would have carried out their own preformulation studies. Secondly, her Honour noted that Krause I showed that DRSP is acid labile, with 50% or thereabouts of the DRSP degrading over 90 minutes, compared to a 50% degradation of spirorenone in 150 minutes. Thirdly, her Honour accepted Professor Davies’ opinion that the in vitro experiments in Krause I were likely to have been carried out at room temperature (25oC), rather than at body temperature (37oC). Finally, her Honour said that the evidence of Dr Walters as to the relevance of Krause I and Krause III was not persuasive. She gave two reasons for reaching that conclusion. The first reason was said by the GH parties, and accepted by the Bayer parties, to be erroneous. Her Honour said that ultimately Dr Walters came to the view that there were key differences between DRSP and spirorenone and that literature about spirorenone was unhelpful in relation to DRSP. Her Honour erred because Dr Walters did not come to that view about spirorenone, but rather about spironolactone, which is a different molecule. The second reason for her Honour’s conclusion that Dr Walters’ evidence about the relevance and importance of Krause I and Krause III was unpersuasive related to a hypothesis Dr Walters advanced as to the reasons the invention worked. Her Honour said (at [90]):
… When this is considered with Dr Walters’ evidence about the stomach it tends to lend even greater weight to the contrary opinions of Professor Davies. Dr Walters attempted to provide a hypothesis as to why the invention claiming the patent [sic] in fact works by reference to the processes of the stomach which depended upon the notion of a limited or fixed amount of hydrochloric acid being present in the stomach for dissolution purposes. Professor Davies’ contrary evidence to the effect that the processes of the stomach are dynamic with gastric acid being created by hormonal responses, there being an ongoing process of gastro intestinal transit, was readily able to be understood and far more cogent on this issue than that of Dr Walters.
44 The primary judge concluded her reasons on obviousness with the following observations (at [93]):
However, and as the applicants put it, at the time the formulator would have been making these decisions all the preformulation data that would have been obtained would indicate that an immediate release version would degrade in the stomach and thus not be bioavailable. In the context of an oral contraceptive the idea that the hypothetical formulator would carry out an in vivo study on a formulation that they expected to fail rather than moving forward with an enteric coated formulation they would have been confident would work is unrealistic. The respondents have, as the applicants put it, succumbed to the “seductive clarity of hindsight” (Alphapharm at [21]).
45 With respect to the lack of fair basis, the primary judge referred to the GH parties’ submission to the effect that, whilst claims 3 and 11 of the Patent claimed any type of formulation that achieved the specified rapid dissolution parameters, there was no real and reasonably clear disclosure in the specification of what was claimed because the specification was limited to a pharmaceutical composition prepared by micronizing DRSP or spraying from a solution onto particles of an inert carrier. The primary judge found as follows (at [100]):
As the applicants submitted it is clear from the specification when read as a whole that the invention is not limited to compositions created by micronizing and spraying DRSP onto inert carrier particles, these being mere examples of how the required rapid dissolution might be achieved.
46 On that basis, she rejected the GH parties’ submission of invalidity due to a lack of fair basis.
47 We turn now to summarise the primary judge’s reasons for dismissing the GH parties’ interlocutory application dated 5 March 2013.
48 Her Honour said that the first issue for determination was whether r 34.50 was engaged. She noted the context in which that question arose. On 3 August 2012, the GH parties filed evidence from Dr Rowe. Dr Rowe considered Gast and her Honour noted that Gast contained an invention and the disclosure of information which the GH parties maintained anticipated, and thus destroyed, the novelty of the Patent. Her Honour noted that Gast, insofar as relevant for the interlocutory application before her, identified a range of dosage units for an oral contraceptive and noted that the various dosage units which it disclosed could be prepared by conventional methodology that is well known to one skilled in the art. Gast provided an example of what was said to be an acceptable composition of a contraceptive progesterone/oestrogen combination of the invention, being Example 1. Dr Rowe’s evidence consisted of a description of the formulation that he would develop based upon this example in Gast. Mr Burgess was subsequently provided with the affidavit of Dr Rowe and he was asked by the GH parties to observe a process undertaken by Lupin Ltd in Pune, India, on 20 September 2012 involving the manufacture of tablets said to be in accordance with Dr Rowe’s formulation. Those tablets were then subsequently used in dissolution tests upon which the GH parties also relied in the proceeding. Those dissolution tests were the subject of directions and orders made by the Court on 31 August 2012.
49 The primary judge noted that the submission of the GH parties was that the experimental proof was limited to the experiment consisting of the dissolution of the tablets which were manufactured in accordance with, in effect, the recipe prepared by Dr Rowe, and that Mr Burgess’ evidence was a form of confirmation that the manufacturing process by Lupin Ltd was carried out in accordance with that recipe. The GH parties referred her Honour to the decision of Emmett J in Lexmark International Inc and Another v Boomerang Imaging Supplies Pty Ltd and Others (2001) 112 FCR 331 (“Lexmark”).
50 The primary judge rejected the submission of the GH parties. She said (at [5]):
I do not agree with the respondents’ characterisation of what constitutes the experimental proof of a fact. In this case, the tablets were manufactured for the purpose of carrying out subsequent dissolution tests. It seems to me that the manufacture of the tablets is plainly part of the experimental proof of the fact which the respondents wish to establish in these proceedings. I am unable to see how the manufacture of the tablets does not constitute part of the relevant experimental proof. Accordingly, I consider that r 34.50 is plainly engaged on the facts of the present case.
51 The primary judge went on to consider whether leave to rely on the affidavit of Mr Burgess should be granted under r 34.50(2). She considered a number of matters to be relevant.
52 The first matter was the fact that “the issue of engagement of r 34.50” had been alive between the parties since at least 26 July 2012. The primary judge noted that, in March 2012, the GH parties had raised the possibility of carrying out an experiment based on Gast before the then docket judge. On 23 July 2012, the GH parties in correspondence with the Bayer parties noted that it was their view that the actual tablet preparation from the formulation did not fall within the experimental proof of a fact. The GH parties said that they welcomed the Bayer parties’ comments on the issue. By letter dated 26 July 2012, the Bayer parties made it clear to the GH parties that they considered that the manufacture of the tablets themselves was part of the relevant experimental proof. By letter dated 1 August 2012, the GH parties rejected this contention. Correspondence followed in early August 2012. The proceeding came before a judge of the Court on 10 August 2012. At that time the GH parties, through their counsel, made it clear that there had been a hold up in relation to the manufacture of the tablets according to Dr Rowe’s formulation and that such a manufacture could be done very easily and very cheaply at the GH parties’ parent premises in India. The judge was informed that, whilst this had been offered to the Bayer parties with the ability for them to observe the manufacture over there, they had not concurred with that approach.
53 The Bayer parties advised the judge that the issue, although raised some time previously, had not been resolved. The Bayer parties contended that the GH parties’ position that the manufacture of the tablets was not an experiment was “completely untenable”.
54 The primary judge noted that an exchange occurred between the judge and counsel for the Bayer parties at the hearing on 10 August 2012. Her Honour said (at [10]-[12]):
Yates J, having heard this complaint from the applicants said, “[n]ow, Mr Shavin, surely the risk is with the respondents on this. If, in fact, there’s an obligation – there is an obligation to comply with r 34.50, if it’s not complied with, then the risk is with the respondent, is it not?” His Honour then said, “[n]ow, you’re in the process of articulating those objections now and, no doubt, they have been articulated in correspondence, or will be.” His Honour also said:
“It seems to me – I mean, I can’t force the respondent to put its evidence on in a particular form. It may be, for the sake of argument, that the evidence is deficient in many ways, and it may fail to comply with the rules. If it does, then r 34.50 provides the consequence and, really, it’s at the time of determining the admissibility of that evidence that these decisions are to be made. But I don’t have any application before me at the moment. The only application that I have before me at the moment is one for an extension of time for the filing of evidence, which has been identified in general terms.”
His Honour then said, again, “[b]ut it seems to me that the risk is with the respondent on that, not with your client.”
His Honour also said:
“The point that I understand is that you say that, so far as the tablet creation, or the oral formulation, the manner in which it’s created is part of the experimental proof and a vitally indispensible part of that proof, and that if, in fact, the court has not given approval or leave in relation to that particular aspect, then, on your submission, if accepted, the likelihood is that evidence will not be accepted at trial.”
55 The primary judge concluded from these matters that the GH parties were on notice that the Bayer parties’ position was that manufacture of the tablets formed not only a part of, but a vitally indispensable part of, the experimental proof.
56 The primary judge observed that the GH parties could have taken a number of actions at that point. They could have filed an interlocutory application seeking to bring to a head the question of which it was fully aware, namely, the question of whether the manufacture of the tablets was a part of the experimental proof of a fact. They chose not to do so.
57 The primary judge said that, in July and August 2012, the GH parties made a forensic decision not to bring the issue to a head, or failed to make a forensic decision to bring the issue to a head, in circumstances in which they now claimed that they would be seriously prejudiced by the exclusion of Mr Burgess’ evidence.
58 The primary judge said that the subsequent course of events was “even more disturbing”, as disclosed by the affidavit material. She noted that the GH parties were having considerable difficulty in arranging for the Australian manufacturer to manufacture the tablets within the timetable which had been fixed by the Court. After the directions hearing before a judge of the Court on 10 August 2012, it was apparent that, as at 24 August 2012, they were still trying to arrange for the manufacture of the tablets by the Australian manufacturer. However, on 19 September 2012, the GH parties forwarded a letter containing a range of information. They advised the Bayer parties that they had not been able to arrange for the Australian manufacturer to make the tablets within the required time frame due to that company’s conflicting manufacturing requirements. They said that it might be possible to engage an independent laboratory in India to conduct the manufacturing more quickly than the Australian manufacturer. They said:
We understand that your clients have a substantial operation in India, and therefore available persons to observe any such manufacture. If this approach facilitates a faster completion of this stage of this stage of our evidence [sic], please indicate if you would be amenable to this process.
59 They also said:
Given the delay in manufacture at IDT Australia Ltd, and in order to in part meet the timetable ordered 31 August 2012, so that any prejudice to your clients’ preparation of evidence in answer on invalidity is minimised, a batch of tablets manufactured in accordance with Dr Rowe’s evidence is to be manufactured at Lupin Ltd’s research laboratories under the supervision of an independent expert. It is these tablets that will be the subject of next week’s dissolution experiment.
60 Mr Burgess attended Lupin Ltd’s research park in Pune on Thursday, 20 September 2012, and, on that day and the following day, 21 September 2012, observed the manufacture of tablets. As the primary judge noted, in other words, the day after the letter of 19 September 2012, the manufacture at Lupin Ltd’s research laboratories was undertaken, and the letter of 19 September 2012 did not disclose that the manufacture was to be undertaken the following day. The primary judge said that the GH parties could not have reasonably expected that the Bayer parties would have responded to this information by the following day, nor could they reasonably have expected that the Bayer parties would have been able to arrange for anyone to attend in Pune in India to observe the manufacture the following day, even if they had made arrangements for a person from their operations in India to be available for that purpose. The primary judge noted that, in any event, this was all moot because the letter from the GH parties did not identify the fact that the manufacture was to occur the following day. The primary judge said that, whether intentional or not, the position in which the GH parties left the Bayer parties was to effectively deny them any opportunity to be present during that manufacturing process and to observe what Mr Burgess had the opportunity of observing. The primary judge considered that the above circumstances were “completely unsatisfactory”. She said that, in terms of discretionary considerations, it could hardly be more clear that, whether deliberate or not, the GH parties’ actions effectively denied the Bayer parties an opportunity to be present to observe the experiment involving the manufacture of the tablets.
61 The primary judge considered the prejudice which would be suffered by the GH parties if leave was not granted. In that context, she found that they would be prejudiced by the exclusion of Mr Burgess’ evidence. However, she said that was insufficient for her to conclude that a grant of leave was appropriate for a number of reasons and leaving aside all of the discretionary factors to which she had already referred.
62 The first matter the primary judge identified was the fact that the people who had carried out the experiments, or essentially did so, being the formulation scientist, Ketan Bhasale, and a supervisor, Subhasis Das, had not given any evidence to explain the experiments. Secondly, although Mr Burgess had given a fairly detailed explanation of what he had observed, his affidavit was limited to his observations only and there was something “distinctly inscrutable” about his evidence. By “inscrutable” her Honour meant that it would simply not be possible for there to be any meaningful cross-examination of what was actually done in the manufacturing process which, as Mr Burgess himself said, was essentially undertaken by two other people. Her Honour said (at [26]):
Accordingly, in circumstances where Mr Burgess’s evidence has this quality of conclusiveness which cannot be effectively tested by cross-examination there is, as the applicants submitted, a real issue not only in terms of r 34.50 but also unfair prejudice to the applicants under s 135 of the Evidence Act 1995 (Cth).
63 Her Honour went on to say (at [27]):
But the circumstances are such that the applicants have been prevented from viewing the manufacturing process by the respondents’ conduct when it would always have been in the power of the respondents to give the applicants that opportunity. The applicants have also been presented with a form of evidence which is effectively not capable of meaningful cross-examination about essential decisions, not being decisions made by Mr Burgess and not being matters about which he can give any meaningful evidence.
lack of inventive step/obviousness
64 The GH parties submit that the primary judge erred in her application of the relevant principles, that she erred in various ways in relation to the eight matters which she identified, that she misunderstood Krause I and Krause III, and that she made a number of associated factual errors.
65 The thrust of the first challenge is not just in the application of the relevant principles, but also in the identification of the principles to be applied in a case such as the present. The GH parties submitted that the primary judge erred in concluding that it is an element of the test of obviousness that the party alleging the lack of an inventive step show that the experiment or test which would have led to the invention was undertaken with an expectation of success. The primary judge held by reference to Alphapharm that the expectation of the hypothetical formulator is a necessary part of the resolution of the issue of obviousness and the expectation is that the experiment might well produce the invention. Nowhere did she suggest that the expectation need be any higher than that.
66 The GH parties did not argue that there were not passages in Alphapharm that supported the primary judge’s approach. Their argument was that Alphapharm did not lay down a test of universal application. It did not lay down a test to be applied in all cases and, in particular, in a case such as this where the choices are both limited and simple. There were two choices, being a preformulation study and an enteric coating on the one hand, or a preformulation study and a limited or pilot bioavailability test or study on the other. Both these choices involve (it was submitted) relatively simple exercises and, in fact, they could be carried out at the same time. The GH parties submit that in such a case the reformulated Cripps question is not the appropriate test. When addressing the expert evidence, the GH parties identified the test the primary judge ought to have applied in a variety of ways, including whether a person skilled in the art would be led to try an immediate release formulation in a pilot bioavailability study, whether it was obvious to do a routine test on an immediate release formulation to see whether it did absorb before degradation, whether the idea of an immediate release formulation and of a pilot bioavailability study was beyond the skill of the calling or represented some barrier crossed and, finally, whether an immediate release formulation lies in the way.
67 In Alphapharm, the plurality said (at [52] and [53]):
Thirdly, in a case such as the present, the relevant question was that posed in the first part of the passage. Were the experiments “part of” that inventive step claimed in the Patent or were they “of a routine character” to be tried “as a matter of course”? If the latter be attributable to the hypothetical addressee of the Patent, such a finding would support a holding of obviousness.
That way of approaching the matter has an affinity with the reformulation of the “Cripps question” by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd. This Court had been referred to Olin in the argument in Wellcome Foundation. Graham J had posed the question:
“Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and of the facts of the nature and success of chlorpromazine, directly be led as a matter of course to try the –CF3 substitution in the ‘2’ position in place of the –C1 atom in chlorpromazine or in any other body which, apart from the –CF3 substitution, has the other characteristics of the formula of claim 1, in the expectation that it might well produce a useful alternative to or better drug than chlorpromazine or a body useful for any other purpose?” (Emphasis added.)
That approach should be accepted.
(Citations in original omitted.)
68 In support of their contention that in a case such as the present the reformulated Cripps question was not the appropriate test, the GH parties relied on the following matters. First, they submitted that the plurality in Alphapharm approved Diplock LJ’s statement in Johns-Manville Corporation’s Patent [1967] RPC 479, at 493-494, that it is doubtful whether there is a verbal formula appropriate to determine obviousness in all classes of claim (Alphapharm at 428, [37]). Secondly, they pointed out that the facts in Alphapharm, unlike the facts in this case, involved a course of action which was complex and detailed, as well as laborious, with a good deal of trial and error, with dead ends and the retracing of steps (Alphapharm at 436, [58]). Thirdly, they pointed out that, although the fact that the “worthwhile to try” or “obvious to try” tests were rejected by the plurality in Alphapharm by reference to United States authorities such as In re O’Farrell (1988) 853 F 2d 849, that rejection must be considered in light of more recent United States authority. They referred to KSR International Co v Teleflex Inc and Another (2007) 75 IPR 434, where Kennedy J said (at 444, [41]):
The same constricted analysis led the Court of Appeals to conclude, in error, that a patent claim cannot be proved obvious merely by showing that the combination of elements was “obvious to try”: Teleflex (2005) at 289 (internal quotation marks omitted). When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.
69 Fourthly, they submitted that the plurality in Alphapharm did not qualify the test of steps of a routine character to be tried as a matter of course and said no more than that the test had an affinity to the reformulated Cripps question. Fifthly, they pointed out that, in Olin Mathieson Chemical Corporation and Others v Biorex Laboratories Limited and Another [1970] RPC 157 itself, Graham J did not suggest that the reformulated Cripps question was the sole test or sole determination of the question of obviousness. His Lordship said (at 188):
I do not think it matters very much whether the question is put in the form I have suggested or in the Cripps form as long as one has clearly in mind what is meant by the word “obvious”, which the Cripps question does not define. Sir Lionel rightly pointed out, however, that in fact the Cripps question does not seem to have been applied in the judgments in the Sharpe & Dohme case, and that its application and form must depend on the form of the claim. Here, for example, claim 1 makes no reference to therapeutic qualities and covers any body within the formula whatever its use may be. It would not, therefore, be right to include a limitation to therapeutic qualities in the question, at any rate then applied to claim 1. Though the Cripps question has been approved from time to time, some of the difficulties which occur in framing it are pointed out in Mr. Blanco White’s book, Patents for Inventions at page 127.
In this case, in my judgment, provided one is quite clear as to the sense of the word “obvious”, one arrives at the same result whether the appropriate question is put in the Cripps form or in the form which I have formulated. I prefer the latter because it incorporates in effect a definition of “obvious” and makes it clear that there is no limitation in the claim to therapeutic qualities. The word “obvious”, as Sir Lionel agreed, and as its derivation implies, means something which lies in the way, and in the context of the Act is used in its normal sense of something which is plain or open to the eye or mind, something which is perfectly evident to the person thinking on the subject.
70 Finally, the GH parties submitted that, in the later case of Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [No 2] (2007) 235 CLR 173, at 195-196, [52], the High Court did not suggest that the obviousness question was always to be determined by reference to the reformulated Cripps question. Their Honours referred to “some difficulty overcome, some barrier crossed” (R D Werner & Co Inc v Bailey Aluminium Products Pty Ltd (1989) 25 FCR 565, at 574 per Lockhart J) or “beyond the skill of the calling” (Graham v John Deere Co of Kansas City (1966) 383 US 1, at 15; Leonardis v Sartas No 1 Pty Ltd (1996) 67 FCR 126, at 146).
71 We do not think that the plurality in Alphapharm were saying that the reformulated Cripps question was the test to be applied in every case. Rather, it is a formulation of the test which will be of assistance in cases, particularly those of a similar nature to Alphapharm. The plurality did not reject as an alternative expression of the test the question whether experiments were of a routine character to be tried as a matter of course (The Wellcome Foundation Limited v VR Laboratories (Aust) Proprietary Limited (1981) 148 CLR 262, at 280-281, 286, per Aickin J). We do not think there is a divide here in terms of whether an expectation of success is relevant between a test which refers to routine steps to be tried as a matter of course and the reformulated Cripps question. It is difficult to think of a case where an expectation that an experiment might well succeed is not implicit in the characterisation of steps as routine and to be tried as a matter of course. On the other hand, we think a test formulated in terms of worthwhile to try was firmly rejected by the High Court in Alphapharm (see also Pfizer, at 476, [287], per French and Lindgren JJ). The fact (if it be the fact) that the position in the United States may have shifted does not affect the binding nature of what the plurality said in Alphapharm.
72 In any event, the difficulty the GH parties face with their submission is in showing that, even if accepted, it makes any difference. The primary judge said that strictly it was not necessary to address the issues of principle because of her factual findings. One of the findings she made was that a hypothetical skilled addressee would not have carried out the type of bioavailability study described by Dr Rowe and Dr Walters as a matter of routine and thereby be led, as a matter of course, to the invention. Furthermore, even when her Honour did consider the matter having regard to an expectation of success, she found that there would be an expectation in the hypothetical formulator of failure, in that failure was very likely.
73 The GH parties attacked her Honour’s conclusions on obviousness primarily by reference to common general knowledge and Krause I and Krause III. However, they also challenged her Honour’s conclusions on obviousness by reference to common general knowledge alone and that involved a challenge to the eight matters identified by her Honour. It is convenient to consider that challenge first.
74 As to the first matter, her Honour was clearly entitled to consider the qualifications and experience of the experts in order to assess the weight to be placed on their evidence. There was a suggestion that Professor Davies had not himself formulated an enteric coating and that thereby his evidence should be discounted in some way. We reject that submission because the evidence establishes that Professor Davies was sufficiently familiar with enteric coating to express the opinions he did. There was a submission that the primary judge simply picked a preferred witness and used that witness as an “avatar” for the person skilled in the art. We are not sure we understand that submission, but in any event, her Honour identified the factual issues and the statutory question. She assessed the evidence carefully, made findings, and then applied those findings to the statutory question.
75 As to the second matter, the GH parties submitted that the primary judge erred in finding aspects of Dr Rowe’s evidence internally inconsistent and his explanation for the inconsistency not particularly persuasive.
76 Dr Rowe was asked in another proceeding in 1998 to provide his opinion about the steps he would have taken before 30 April 1986 to formulate omeprazole using only the knowledge and materials that he had, or to which he would have had access to, before that date. He swore an affidavit setting out his opinions and he was cross-examined on that affidavit in the proceeding before her Honour. It was suggested to him that his previous evidence about an enteric coating being the simplest solution and the ideal approach in the case of a poorly soluble drug which degraded rapidly in acidic solutions was inconsistent with the evidence he gave before her Honour. Dr Rowe’s response was that he knew omeprazole was poorly absorbed, whereas he did not know the same of DRSP.
77 Her Honour did not find that response an adequate explanation of the inconsistency. In reaching that conclusion, she relied on a number of matters, each of which she was entitled to rely on. First, she found that Dr Rowe’s evidence before her was that erythromycin was usually not enteric coated, whereas his evidence in 1998 was that erythromycin was usually enteric coated. Secondly, he either under-emphasised the problems and complexities associated with enteric coating in 1998, or over-emphasised the difficulties in the evidence before her. As her Honour noted, this was all in a context where Dr Rowe could have predicted from the structure of DRSP that it would have been poorly soluble and acid labile. We reject the challenge to her Honour’s conclusions about Dr Rowe’s evidence.
78 Dr Walters offered two theories as to why, despite the acid lability and poor solubility of DRSP, the immediate release formulation worked. One of these theories related to the processes of the stomach and a saturation point. Her Honour found that this theory was disproved by the more cogent evidence of Professor Davies as to the processes of the stomach. The GH parties submitted that this was the basis upon which the primary judge found Professor Davies’ evidence more cogent than that of Dr Walters and that it was irrelevant to the question of obviousness. There are two answers to that submission. First, in referring to the cogency of Professor Davies’ evidence, we think the primary judge was referring to all of the evidence given by Professor Davies and Dr Walters. Secondly, in any event, the cogency or otherwise of Dr Walters’ evidence as to the processes of the stomach was relevant to whether her opinion evidence should be accepted.
79 As to the third matter, the GH parties submitted that the primary judge erred in that Dr Rowe and Dr Walters were aware of the risk of degradation in the stomach and that the solution was to do a routine test on an immediate release formulation to see whether it did absorb before degradation. We do not think that her Honour was saying that Dr Rowe and Dr Walters were not aware that there was a risk of degradation in the stomach. We think she was saying that, on the evidence, a hypothetical formulator would be so acutely aware of the risk of degradation that the obvious answer would be for the drug to be enteric coated. She could not understand why, in those circumstances, a hypothetical formulator would consider a pilot bioavailability study on an immediate release formulation.
80 As to the fourth matter, the GH parties submitted that the primary judge overlooked the fact that, in cross-examination, Professor Davies accepted potential difficulties with enteric coating. The Court was referred to a lengthy passage in the cross-examination of Professor Davies. We have considered that passage carefully and we reject the criticism. Professor Davies did acknowledge potential difficulties with enteric coating, but not in the context of this case, where the drug is to be used for oral contraception purposes and the “key point”, as Professor Davies puts it, is that the patient gets their dose in the day.
81 As to the fifth matter, the GH parties submitted that they did not understand this reason because both Dr Rowe and Dr Walters were aware that DRSP was poorly soluble, that its solubility would need to be improved, and that it was acid labile. We reject this criticism because we think that at least one of the matters her Honour considered important was the use of the drug for oral contraceptive purposes and that was a matter Professor Davies had taken into account in his reasoning.
82 As to the sixth matter, the GH parties submitted that this was something of a “red herring” because it was agreed between the experts that DRSP was poorly soluble. We think there is force in the criticism, but we do not think that her Honour misunderstood the evidence. It is plain from reading her reasons that she understood that the difficulties with an immediate release formulation were poor solubility or, if the solubility was improved, the risk of degradation in the stomach.
83 As to the seventh matter, we think, as we have said, it echoes the third matter and the conclusions we have expressed in relation to that matter apply.
84 As to the eighth matter, the GH parties submitted that to consider the realities of the process of formulation is to distract attention from the statutory question. They submitted that one does not postulate a particular team with a particular budget. It is true that one does not postulate a particular team with a particular budget, but we do not think that is what Professor Davies was doing. All he was doing was making the point that the hypothetical formulator makes decisions in a particular context and identifying that context. The context is not irrelevant, although it can only be taken into account in a general sort of way. As we read the relevant passages of Professor Davies’ evidence, that was all he was doing.
85 The GH parties submitted that her Honour erred in her treatment of the Pilbrant article. As we have said, before this Court, the appeal was argued on the basis that the information in the Pilbrant article was part of common general knowledge. The GH parties submitted that her Honour should have held that Pilbrant confirmed the evidence of Dr Rowe and Dr Walters to the effect that there were two options, an immediate release formulation or an enteric coating, and that the hypothetical formulator would test. The submission was that, as happened in the case of omeprazole, a hypothetical formulator would undertake a pilot bioavailability study. We reject this submission. The pilot bioavailability study carried out in relation to omeprazole was unsuccessful and, if anything, the Pilbrant article confirmed Professor Davies’ evidence that a pilot bioavailability study of an immediate release formulation of DRSP would be carried out without any expectation of success.
86 Returning then to the eight matters, although the third and seventh matters are probably the same matter, and although her Honour may have over-emphasised the sixth matter, the challenges of the GH parties are otherwise rejected. We think they support her Honour’s conclusion that, in all the circumstances apparent at the priority date, the hypothetical skilled addressee of the Patent would not have carried out the type of bioavailability study described by Dr Rowe and Dr Walters as a matter of routine and thereby be led, as a matter of course, to the invention.
87 It is not necessary for us to consider the alternative basis for her Honour’s conclusion that the invention lacked obviousness based on common general knowledge at the priority date because a pilot bioavailability study, which her Honour found was a possibility not a probability, would be carried out with an expectation of failure not success. It is not clear to us on what precise basis her Honour considered this matter, but it matters not because, if it was relevant, it was open to her Honour to accept Professor Davies’ evidence that the expectation would be of failure not success, and that is an answer to the GH parties’ case on obviousness by reference to common general knowledge.
88 Her Honour went on to reject the GH parties’ obviousness case on a further ground which the GH parties challenged. She said that the invention included a particular dissolution rate and it was not obvious or routine to try at the priority date, let alone to try with an expectation of success, an immediate release formulation of DRSP that would produce the claimed dissolution rate. Her Honour referred to Dr Walters’ evidence that micronization is a relative concept with a potentially wide range of meanings. The GH parties submitted that her Honour erroneously adopted an approach akin to a novelty analysis and that there is no inventiveness in choosing “a typical dissolution rate or the degree of micronization required to achieve it, in combination, of course”. There is a good deal of force in the submission of the GH parties if it is correct to say that the dissolution rate is typical. Professor Davies said that it was a typical dissolution rate for an immediate release formulation. Dr Walters said that the dissolution rate specified is typical and she goes on to say:
The default acceptance criterion that was specified by the British Pharmacopoeia in 1999 was 75% in 45 minutes, unless otherwise specified in the monograph, so a limit of 70% in 30 minutes is a little tighter.
89 On this evidence, and given her Honour’s general preference for Professor Davies’ evidence, we think the appropriate finding is that the dissolution specified is typical. If one adds to that finding the fact that in August 1999 there were, according to Professor Davies, a number of well known techniques for increasing the rate of dissolution of a drug substance which is otherwise poorly soluble, then we would conclude that her Honour erred in deciding that it was not obvious to arrive at the dissolution rate claimed.
90 This brings us to the principal submission of the GH parties on the issue of obviousness. It was that her Honour erred in not concluding that the invention was obvious in light of common general knowledge and Krause I and Krause III.
91 Krause I deals with a compound known as spirorenone. DRSP is one of spirorenone’s metabolites. The paper discusses a method of determining the plasma concentrations (i.e., the rate or degree of absorption) of spirorenone. Spirorenone and DRSP are chemically similar and both are subject to degradation or reduction to an inactive form by a process described in the paper as acid-catalysed rearrangement. The paper reports the results of in vitro testing of spirorenone and DRSP and in vivo testing of spirorenone.
92 The tests conducted in vitro measured the time course of the acid-catalysed rearrangement of spirorenone and DRSP and the results were shown in Figure 4 in the Krause I paper. The tests showed that DRSP is acid labile, with 50% or thereabouts of it degrading over 90 minutes, compared to a 50% degradation of spirorenone in 150 minutes. The Krause I paper did not expressly state whether the in vitro tests were conducted at room temperature (25oC) or at body temperature (37oC). In the commentary on the in vitro results, and in the context of the in vivo test results, the authors of the Krause I paper state that “the process of rearrangement was relatively slow compared to possible absorption rates in the stomach (cf. below)”.
93 The tests conducted in vivo involved a small group of two healthy males who were given oral doses of 10mg and 40mg of spirorenone. It seems likely from a passage in the Krause III paper that the doses were in a macrocrystalline not micronized form. One of the results of the in vivo tests reported in the Krause I paper was that the “lactone rearrangement product of spirorenone was not detectable in the plasma, suggesting that the absorption process was much faster than the acid-catalysed isomerization of the drug”.
94 The Krause III paper reports that tests conducted in vivo involving a larger group of subjects were conducted with similar results, with the qualification that there was incomplete absorption of the 40mg dose, a problem the authors considered might be overcome by introducing micronized material.
95 Professor Davies did not think the Krause papers would alter the views that a hypothetical formulator would hold by reference to common general knowledge. He gave a number of reasons for this opinion and many of them related to the information to be gleaned from Figure 4 in the Krause I paper. Dr Walters took a different view. She considered that the reference in the Krause I paper to a suggestion that the absorption process was much faster than the acid-catalysed isomerization of spirorenone was particularly significant. In her evidence-in-chief she said:
I concluded that, because the absorption process was much faster than the acid-catalysed isomerization of the drug, it would not be necessary to develop an enteric coated tablet formulation of spirorenone. In my opinion, it is highly unlikely that the small difference in chemical structures between spirorenone and DRSP, and the nature of the difference, would lead to a different conclusion in relation to whether to develop an immediate release, enteric coated or prolonged release tablet of DRSP. Whilst this latter sentence is not scientifically conclusive, it is sufficient evidence for me to discount the necessity of developing an enteric-coated tablet form of DRSP (even though DRSP has a degree of acid lability) and I would proceed to develop an immediate release tablet. A prolonged release dosage form would also be unnecessary, would add to possible problems in development and manufacture, and would require extensive supporting documentation for regulatory purposes, including new pharmacokinetic studies in humans.
96 The primary judge preferred the evidence of Professor Davies and concluded that the Krause papers would not have made any difference to the position of the hypothetical formulator at the priority date. We have summarised her reasons above (at [42]-[44]).
97 As we have said, it is common ground that the primary judge made an error in her statement of one of the reasons for rejecting Dr Walters’ evidence in that, although Dr Walters did put aside the literature concerning spironolactone, that was not to the point, because the relevant comparison was between DRSP and spirorenone. The GH parties submitted that the primary judge also erred in the other reason she gave for rejecting Dr Walters’ evidence. They submitted that the lack of cogency in Dr Walters’ evidence about the processes of the stomach related to her explanation as to why the invention works and not the relevance and importance of the Krause papers. To a point this is true, although the lack of cogency of one aspect of an expert’s evidence is relevant to whether their evidence is accepted on other matters.
98 The primary judge’s error in relation to spirorenone and spironolactone means that this Court must consider for itself the relevance and importance of the Krause papers.
99 The other reasons her Honour gave for concluding that the Krause papers would have made no material difference to the hypothetical formulator are sound. Dr Rowe did say that the information in Krause I would have made no difference to the way he would have proceeded, although, in fairness, he also said that the Krause papers would have confirmed what he would otherwise have expected, that is, that DRSP may have been well absorbed. All of the experts did say that they would have carried out their own preformulation studies notwithstanding Krause I. These preformulation studies would have confirmed that DRSP is poorly soluble and acid labile. Figure 4 does show a 50% degradation of DRSP over 90 minutes, whereas it takes 150 minutes for 50% of spirorenone to degrade. The particular significance of these facts is that the average time food and drink stays in the stomach is 90 minutes. That can vary by reason of other factors, but that is the average time, and during that time the contents are exposed to stomach acid. The temperature at which the in vitro tests referred to in Krause I is significant because the higher the temperature, the faster the rate of reaction (i.e., degradation). All of the experts agreed on that. We think it was open to the primary judge to conclude that it was “far more likely” that the in vitro tests were carried out at room temperature. That was the evidence of Professor Davies and was supported by the fact that similar results were obtained by other researchers (Nickisch) carrying out tests at room temperature. Professor Davies said that carrying out the in vitro tests at body temperature might see the rate of reaction shown in Figure 4 of Krause I increase by two or three times. Adjusted for that fact would mean that 50% of the DRSP would have been degraded after 30 minutes exposure to the acid in the stomach. That type of result would confirm, not bring into question, the views of Professor Davies based on common general knowledge.
100 Professor Davies gave other reasons for concluding that the Krause papers were of no real relevance, although they were not referred to by the primary judge in the context of her discussion of the significance of the Krause papers. They ranged from the fact that the subjects of the in vivo tests were given spirorenone not DRSP and, although the chemical structures of those compounds are similar, one cannot generalise about similarities in how they will react, to the small size of the group subject to in vivo tests reported in Krause I, and to the hypothesis that the lack of degradation was due to the form – macrocrystalline as distinct from micronized – in which the spirorenone was administered. The GH parties submitted that these other reasons illustrated that Professor Davies’ approach was too “black and white”. We reject this criticism. Professor Davies put forward a number of reasons for his opinions about the Krause papers which were of varying degrees of cogency and persuasiveness. None of the matters he put forward was so untenable or lacking in cogency as to reflect generally on his evidence.
101 The primary judge generally preferred the evidence of Professor Davies to that of Dr Rowe and Dr Walters. There was a proper basis for her to do that. There were persuasive reasons for her Honour to conclude that the Krause papers would have made no material difference to the hypothetical formulator at the priority date.
102 In our opinion, the invention was not obvious in light of common general knowledge at the priority date and the Krause papers.
FAIR BASIs
103 The appellants submitted that claims 3 and 11 were not fairly based on matter described in the body of the specification because the invention described in the body of the specification was restricted to the delivery of the DRSP in micronized form or by way of a spray onto the surface of inert carrier particles, whereas claims 3 and 11 were not so restricted. Claims 3 and 11 are not limited to the delivery of the DRSP in micronized form or by way of spraying onto the surface of inert carrier particles, so the question is whether the invention as described in the body of the specification is so limited.
104 The primary judge rejected the appellants’ submission, holding that from reading the specification as a whole the invention was not restricted to compositions involving DRSP in micronized form or by way of a spray onto inert carrier particles, and she said that these forms of delivering DRSP were mere examples of how the required rapid dissolution might be achieved.
105 The appellants raised an alternative argument in oral submissions on the appeal, which, so far as we can see, is not raised in either their Amended Draft Notice of appeal or their outline of submissions. It was that even if the Bayer parties were correct and the relevant limit in the body of the specification was a form of DRSP that promoted rapid dissolution (i.e., not limited to micronization or spraying onto inert carrier particles), claims 3 and 11 were not limited to a form that promoted rapid dissolution. The Bayer parties submitted that the GH parties should not be permitted to raise this argument for the first time on appeal and that they may have called evidence on the issue had it been raised at trial. We accept that submission because we accept that the Bayer parties may have called evidence at the trial to deal with the issue (Coulton & Others v Holcombe & Others (1986) 162 CLR 1, at 7-8 per Gibbs CJ, Wilson, Brennan and Dawson JJ).
106 The High Court considered the scope of s 40(3) of the Act in Lockwood Security Products Pty Limited v Doric Products Pty Limited (2004) 217 CLR 274. The Court overturned a holding of the Full Court of this Court that the patentee’s claims were not fairly based on the matter described in the specification. The Court said that the test for fair basis was not analogous to the test for a claim and an alleged anticipation or infringement. It is wrong to isolate in the body of the specification the essential integers or features of a claim. The test is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed. The Court said that a consistory clause, whilst relevant, was not decisive. It was necessary to consider the consistory clause with the specification read as a whole. If when that is done the invention is found to be limited, then the wider remarks are put to one side as loose or stray in nature (see also CCOM Pty Ltd and Another v Jiejing Pty Ltd and Others (1994) 51 FCR 260; Atlantis Corporation Pty Ltd and Another v Schindler and Others (1997) 39 IPR 29).
107 The Bayer parties submitted that the decision of the Court of Appeal in England in Gedeon Richter plc v Bayer Pharma AG [2012] EWCA Civ 235 was relevant because the Court in that case considered and rejected a similar argument in the case of patent in materially identical terms. Kitchin LJ and Sir Robin Jacob (with whom Mummery LJ agreed) said (at [38]):
It is true that the only methods of producing a rapid dissolution form of DSP specifically disclosed in the parent application are micronisation and the spraying of inert carrier particles. But that does not mean to say that the skilled person would understand the parent application to be teaching that these are the only ways that rapid dissolution may be achieved. To the contrary, we believe that the skilled person would understand these particular methods are described by way of example together with a method by which rapid dissolution may be tested, that is to say the USP test. It was common ground he would know there were other ways by which rapid dissolution could be achieved, and we have no doubt that he would understand that he could use these too.
108 With respect, we would place no weight on the decision because it is a decision on a matter of construction made in a different statutory context.
109 Both parties relied on the whole body of the specification, but emphasised different parts of it.
110 The GH parties emphasised the following passages on page 4 of the Patent:
Drospirenone, which may be prepared substantially as described in, e.g., US 4,129,564 or WO 98/06738, is a sparingly soluble substance in water and aqueous buffers at various pH values. Furthermore, drospirenone is rearranged to an inactive isomer under acid conditions and hydrolysed under alkaline conditions. To ensure good bioavailability of the compound, it is therefore advantageously provided in a form that promotes rapid dissolution thereof.
It has surprisingly been found that when drospirenone is provided in micronized form (so that particles of the active substance have a surface area of more than 10,000 cm2/g, and the following particle size distribution as determined under the microscope: not more than 2 particles in a given batch with a diameter of more than 30 Μm, and preferably ≤ 20 particles with a diameter of ≥ 10 Μm and ≤ 30 Μm) in a pharmaceutical composition, rapid dissolution of the active compound from the composition occurs in vitro (“rapid dissolution” is defined as the dissolution of at least 70% over about 30 minutes, in particular at least 80% over about 20 minutes, of drospirenone from a tablet preparation containing 3 mg of drospirenone in 900 ml of water at 37ºC determined by the USP XXIII Paddle Method using a USP dissolution test apparatus 2 at 50 rpm). Instead of providing the drospirenone in micronized form, it is possible to dissolve it in a suitable solvent, e.g. methanol or ethyl acetate, and spray it onto the surface of inert carrier particles followed by incorporation of the particles containing drospirenone on their surface in the composition.
Without wishing to be limited to any particular theory, it appears that the in vitro dissolution rate of drospirenone is connected to the dissolution rate in vivo resulting in rapid absorption of drospirenone in vivo on oral administration of the compound. This is an advantage because isomerization of the compound in the gastric environment and/or hydrolysis in the intestine is substantially reduced, leading to a high bioavailability of the compound.
111 The Bayer parties emphasised the following passages on pages 5 and 9 of the Patent:
To obtain a more rapid rate of dissolution, it is preferred to include carriers or excipients which act to promote dissolution of both active substances. Examples of such carriers and excipients include substances that are readily soluble in water such as cellulose derivatives, carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, gelled starch, gelatin or polyvinylpyrrolidone. In particular, it appears as though polyvinylpyrrolidone might be particularly helpful to promote dissolution.
…
The composition of the invention may be formulated in any manner known in the pharmaceutical art. In particular, as indicated above, the composition may be formulated by a method comprising providing drospirenone and, if desired, ethinylestradiol in micronized form in said unit dosage form, or sprayed from a solution onto particles of an inert carrier in admixture with one or more pharmaceutically acceptable excipients that promote dissolution of the drospirenone and ethinylestradiol so as to promote rapid dissolution of drospirenone and preferably ethinylestradiol on oral administration.
…
The present composition may also be formulated in liquid form, e.g. as a solution, suspension or emulsion, together with conventional diluents or excipients in a manner known per se in the pharmaceutical art.
112 In our opinion, the primary judge was correct. The last sentence of the first passage on page 4 and the first passage on page 9 set out above make it clear that the invention was not limited to compositions created by micronizing or spraying DRSP onto inert carrier particles, and that these were examples of how the required rapid dissolution might be achieved. As the evidence of Professor Davies makes clear, the hypothetical skilled addressee would have been aware of at least seven methods whereby the rate of dissolution of DRSP could be increased.
lack of novelty
113 As we have said, the GH parties did not pursue a lack of novelty case after her Honour had made her decision with respect to Mr Burgess’ affidavit.
114 The Bayer parties submitted that her Honour’s decision was an interlocutory decision made on an interlocutory application heard before the trial commenced, albeit on the first day of trial. They submit that the GH parties’ application for leave is out of time and that they should not be granted an extension of time because of the prejudice the Bayer parties would suffer and because they have not explained why they brought within time but then abandoned an application for leave.
115 In response, the GH parties submitted that they do not need an extension of time because her Honour’s interlocutory decision is sufficiently connected with the orders made on 8 May 2013 that time began to run from that date. In the alternative, they submitted that they should be granted an extension of time.
116 In Gerlach v Clifton Bricks Pty Limited (2002) 209 CLR 478, at 482-486, [4]-[6], [8] and [13] per Gaudron, McHugh and Hayne JJ, the High Court said that the correctness of a final judgment may be challenged on the ground that an interlocutory decision was wrong in the case of certain interlocutory decisions. A ruling on the evidence to be admitted in the course of a trial was an obvious example (see also Michael Wilson & Partners Limited v Nicholls and Others (2011) 244 CLR 427, at 449, [78] per Gummow A-CJ, Hayne, Crennan and Bell JJ).
117 We think her Honour’s decision on 11 March 2013 is sufficiently analogous to a ruling on evidence to be treated in that way. The GH parties could have made another application at the trial to tender the evidence of Mr Burgess and we note that, significantly, r 34.50(2) is framed in terms of the admissibility of evidence.
118 It follows that we do not think the GH parties need an extension of time and, as we have already said, we would grant leave to appeal. We would add that, if we are wrong, we would grant an extension of time. The Bayer parties spoke eloquently of the prejudice they will suffer if a challenge to her Honour’s decision of 11 March 2013 is successful, but the question is what prejudice they have suffered as a result of delay. We are not satisfied that there is any prejudice.
119 Rule 34.50 is in the following terms:
34.50 Experimental proof as evidence
(1) If a party (the proponent) proposes to tender, as evidence in a proceeding, experimental proof of a fact, the proponent must apply for orders in relation to the experimental proof, including orders about any of the following:
(a) the service on other parties of particulars of the experiment and of each fact that the proponent asserts is, will or may be proved by the experiment;
(b) any persons who must be permitted to attend the conduct of the experiment;
(c) the time when, and the place where, the experiment must be conducted;
(d) the means by which the conduct and results of the experiment must be recorded;
(e) the time by which any other party (the opponent) must notify the proponent of any grounds on which the opponent will contend that the experiment does not prove a fact that the proponent asserts is, will or may be proved by the experiment.
(2) Evidence of the conduct and results of the experiment is admissible in the proceeding, only:
(a) if the proponent has complied with subrule (1) and any orders given under that subrule; or
(b) with the leave of the Court.
120 The first question is whether the evidence in Mr Burgess’ affidavit is experimental proof of a fact or part of experimental proof of a fact. Mr Burgess was provided with an affidavit of Dr Rowe wherein Dr Rowe had set out his method of preparation of the formulation set out in Example 1 on page 10 of Gast (the alleged anticipation using drospirenone instead of another compound (trimegestone)), and Dr Rowe’s evidence included the process to be followed in the manufacturing of the formulation. Lupin Ltd (Lupin Australia Pty Limited’s parent company) was to manufacture the formulation in accordance with the process and Mr Burgess’ task was to observe the process and confirm whether the specified steps were undertaken. A batch of 6,000 tablets were produced and they were subsequently used in the dissolution testing which was the subject of directions under r 34.50.
121 The purpose of r 34.50 is to ensure the other party has an adequate opportunity to challenge the validity of the experiment or test and to avoid wasteful duplication by that party of an experiment that can be seen to be valid: Lucent Technologies Inc v Krone Aktiengesellschaft (No 2) (1999) 94 FCR 124.
122 In Lexmark, Emmett J said (at 334, [10]):
I consider that both categories of procedure are experiments within the meaning of the Rule. An experiment may be defined as follows:
“1. The action of trying anything; a test, trial ... 3. An action or operation undertaken in order to discover something unknown, to test a hypothesis, or establish or illustrate some known truth.”
- New Shorter Oxford English Dictionary.
“1. A test or trial; a tentative procedure; an act or operation for the purpose of discovering something unknown or testing a principle.”
- Macquarie Dictionary.
It seems to me that both categories of test referred to by Mr Villanueva fit those definitions.
123 The GH parties relied heavily on these observations. They submitted that the manufacture of a piece of equipment or a standard product used in the course of an experiment was not part of the experiment. They submitted that the manufacture of the tablets by Lupin Ltd was in no different position. The manufacture was not undertaken to discover something unknown or to test a hypothesis or to illustrate some known truth.
124 We do not accept the submission of the GH parties. The 6,000 tablets were manufactured for the purpose of the proposed dissolution testing. They were not a standard product used in the course of an experiment. They were to be manufactured in accordance with instructions of an expert as to the formulation and the process to be undertaken. We think the manufacture of the tablets was part of the experiment. Emmett J was not confronted with the particular situation that arises in this case and we do not think that his Honour was purporting to lay down a universal test.
125 With respect, the primary judge was correct to hold that leave to rely on the evidence in Mr Burgess’ affidavit was required.
126 The primary judge’s decision to refuse leave was made in the exercise of a discretion and the GH parties must show an error of the type identified in House v The King (1936) 55 CLR 499 before this Court will interfere with the decision.
127 The GH parties claimed that the primary judge erred in two respects. First, her Honour erred by assessing and then taking into account the level or degree of fault on the part of the GH parties. Secondly, her Honour erred in finding that Mr Burgess’ affidavit was inscrutable and then in taking that matter into account.
128 The primary judge said that the GH parties made a forensic decision not to bring matters to a head in July and August 2012 and that events after August 2012 were “even more disturbing”. Her Honour said that, whether intentional or not, the GH parties decided to proceed to have the tablets manufactured in circumstances and at a time when their conduct effectively made it impossible for the Bayer parties to attend. The GH parties submitted that the suggestion that there was something sinister or untoward in their conduct overlooked the fact that, throughout this time, they were maintaining their efforts to have the tablets manufactured in Australia. The manufacturing of the tablets in India was to be additional to tablets manufactured in Australia by IDT Australia Ltd. We do not think her Honour either mischaracterised the conduct of the GH parties or placed too much weight on it. When she came to weigh the relevant factors against the prejudice the GH parties would suffer if leave was refused, she did no more than find what was clearly open to her to find, that is, that the Bayer parties had been prevented from viewing the manufacturing process by the conduct of the GH parties when it would always have been in the power of those parties to give the Bayer parties that opportunity.
129 The primary judge placed weight on what she described as the inscrutable nature of Mr Burgess’ evidence and the fact that the two persons actually involved in the manufacturing of the tablets did not give evidence. In those circumstances, there could be no cross-examination by the Bayer parties about essential decisions. The GH parties submitted that this was an error because the manufacturing process was a step-by-step process which could be and was observed by Mr Burgess, and the significant issue was whether the steps were undertaken. We think her Honour was correct to take into account the fact that the best witnesses as to the manufacturing process were not to be called.
130 The matters her Honour took into account were relevant and we do not think that there was a relevant matter which she failed to take into account. There is no basis for interfering with her Honour’s exercise of the discretion.
conclusions
131 For these reasons, we would grant leave to appeal to the GH parties. However, we would dismiss the appeal. The GH parties must pay the costs of the application for leave to appeal and of the appeal. The Application for an extension of time and leave to appeal by the GH parties should be dismissed with no order as to costs. Similar orders will be made in the proceedings between Apotex and the Bayer parties.
| I certify that the preceding one hundred and thirty-one (131) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justices Besanko, Middleton and Nicholas. |
Associate:
