PhotoCure ASA v Queen's University at Kingston
[2005] FCA 344
•6 APRIL 2005
FEDERAL COURT OF AUSTRALIA
PhotoCure ASA v Queen’s University at Kingston [2005] FCA 344
PATENTS – invention claimed for a method of detection and treatment of malignant and non-malignant lesions by photochemotherapy – whether patent invalid on grounds of obviousness, lack of novelty, lack of sufficiency and best method, lack of definition or lack of fair basis – whether the patent is infringed in substance by a variant that does not have a material effect on the way the invention works – consideration of the principles to be applied in determining a claim of infringement in substance when no claim is infringed on a textual approach to construction of the patent
Patents Act 1990 (Cth) ss 7, 40(2)(a), 40(2)(b), 117, 138(3)(b) and 234 and Sch 1
Patents Act 1952 (Cth) s 100(1)(e)Amadio Pty Ltd v Henderson (1998) 81 FCR 149
Minnesota Mining & Manufacturing Co v Tyco Electronics Pty Ltd (2002) 56 IPR 248
NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1993) 44 FCR 239
Aktiebolaget Hässle v Alphapharm Pty Limited (2002) 212 CLR 411
General Tire & Rubber Company v The Firestone Tyre and Rubber Company Ltd [1972] RPC 457
The Leonardis v Sartas No 1 Pty Ltd (1996) 67 FCR 126
ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc (1999) 45 IPR 577
Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253
Aktiebolaget Hässle v Alphapharm Pty Ltd (2000) 51 IPR 375
Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593
Williams Advanced Materials, Inc v Target Technology Company LLC [2004] FCA 1405
Nescor Industries Group Pty Ltd v Miba Pty Ltd (1997) 150 ALR 633
Chiron Corporation v Organon Teknika Ltd (No 3) [1994] FSR 202
ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc (2000) 106 FCR 214
Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228
R D Werner & Co Inc v Bailey Aluminium Products Pty Ltd (1989) 25 FCR 565
Bristol-Myers Squibb Company v FH Faulding & Co Ltd (2000) 97 FCR 524
Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513
Hills v Evans (1862) 31 LJ Ch 457
Olin Corporation v Super Cartridge Co. Pty Ltd (1977) 180 CLR 236
Arrow Pharmaceuticals Ltd v Merck & Co Inc (2004) 213 ALR 182
Rescare Ltd v Anaesthetic Supplies Pty Ltd (1992) 111 ALR 205
Kimberly-Clark Australia Pty Limited v Arico Trading International Pty Limited (2001) 207 CLR 1
Innovative Agriculture Products Pty Ltd v Cranshaw (1996) 35 IPR 643
Electric & Musical Industries Ltd v Lissen Ltd [1938] 4 All ER 221
Welch Perrin and Company Pty Ltd v Worrel (1961) 106 CLR 588
Kauzal v Lee (1936) 58 CLR 670
Raleigh Cycle Co Ltd v H Miller & Co Ltd [1948] 1 All ER 308
General Steel Industries Inc v State of New South Wales (1967) 40 ALJR 464
Windsurfing International Inc v Petit [1984] 2 NSWLR 196
Philpott v Hanbury (1885) 2 RPC 33
Rose Street Foundry and Engineering Company Ld v India Rubber Gutta Percha and Telegraph Works Company Ld (1929) 46 RPC 294
Cincinnati Grinders (Inc) v B.S.A. Tools Ld (1931) 48 RPC 33
Société des Usines Chimiques Rhône-Poulenc v Commissioner of Patents (1958) 100 CLR 5
F. Hoffman-La Roche & Co. Aktien-Gesellschaft v Commissioner of Patents (1971) 123 CLR 529
Rehm Pty Ltd v Websters SecuritySystems (International) Pty Ltd (1988) 81 ALR 79
CCOM Pty Ltd v Jiejing Pty Ltd (1994) 51 FCR 260
Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (2004) 212 ALR 1
Atlantis Corporation Pty Ltd v Schindler (1997) 39 IPR 29
Catnic Components Limited v Hill & Smith Limited [1982] RPC 183
Root Quality Pty Ltd v Root Control Technologies Pty Ltd (2000) 177 ALR 231
Improver Corporation v Remington Consumer Products Limited [1990] FSR 181
Nobel’s Explosives Company Limited v Anderson (1894) 11 RPC 519
Decor Corporation Pty Ltd v Dart Industries Inc (1988) 13 IPR 385
Populin v HB Nominees Pty Ltd (1982) 41 ALR 471
Flexible Steel Lacing Company v Beltreco Ltd (2000) 49 IPR 331
Gambro Pty Ltd v Fresenius Medical Care South East Asia Pty Ltd (2004) 61 IPR 442
Rhone-Poulenc Agrochimie SA v UIM Chemical Services Pty Ltd (1986) 12 FCR 477
Wheatley (Davina) v Drillsafe Ltd [2001] RPC 7
Patent Gesellschaft AG v Saudi Livestock Transport and Trading Company (1996) 33 IPR 426
Allsop Inc v Bintang Ltd (1989) 15 IPR 686
Sartas No 1 Pty Ltd v Koukourou & Partners Pty Ltd (1994) 30 IPR 479
Azuko Pty Ltd v Old Digger Pty Ltd (2001) 52 IPR 75
Commonwealth Industrial Gases Ltd v M.W.A. Holdings Pty Ltd (1970) 180 CLR 160
Doric Products Pty Ltd v Lockwood Security Products Pty Ltd (2001) 192 ALR 306
Nesbit Evans Group Australia Pty Ltd v Impro Ltd (1997) 39 IPR 56
Neurizon Pty Ltd v Jupiters Ltd (2004) 62 IPR 569
Sydney Cellulose Pty Ltd v Ceil Comfort Home Insulation Pty Ltd (2001) 53 IPR 359
Minnesota Mining & Manufacturing Company v Tyco Electronics Pty (2001) 53 IPR 32
Bartlem Pty Ltd v CMMC Pty Ltd (2001) 53 IPR 124
Great Western Corporation Pty Ltd v Grove Hill Pty Ltd [2001] FCA 423
Wimmera Industrial Minerals Pty Ltd v RGC Mineral Sands Ltd (No 3) (1997) AIPC 91-366
Hutt v Enig Pty Ltd (1998) 41 IPR 559
Cenefill Pty Ltd v Australian Sheetpiling Pty Ltd (1996) 35 IPR 64
Winner v Morey Haigh & Associates (A’Asia) Pty Ltd (1996) 33 IPR 215
Astra Lakemedel Aktiebolag v Commissioner of Patents (1995) 56 FCR 208
Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2005] 1 All ER 667
Union Carbide Corp v BP Chemicals Ltd [1999] RPC 409
Sundstrand Corporation v Safe Flight Instrument Corporation [1994] FSR 599
Insituform Technical Services Ltd v Inliner U.K. PLC [1992] RPC 83
Kastner v Rizla Ltd [1995] RPC 585
Beecham Group Limited v Bristol Laboratories Limited [1978] RPC 153PHOTOCURE ASA v QUEEN’S UNIVERSITY AT KINGSTON AND DUSA PHARMACEUTICALS, INC
AND BETWEEN DUSA PHARMACEUTICALS, INC v PHOTOCURE ASA, GALDERMA S.A., PHOTOCURE AUSTRALIA PTY LTD AND GALDERMA AUSTRALIA PTY LTD
V214 OF 2002
MERKEL J
6 APRIL 2005
MELBOURNE
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
V 214 OF 2002
BETWEEN:
PHOTOCURE ASA
APPLICANTAND:
AND BETWEEN:
AND:
QUEEN’S UNIVERSITY AT KINGSTON
FIRST RESPONDENTDUSA PHARMACEUTICALS, INC
SECOND RESPONDENTDUSA PHARMACEUTICALS, INC
CROSS-CLAIMANTPHOTOCURE ASA
FIRST CROSS-RESPONDENTGALDERMA S.A.
SECOND CROSS-RESPONDENTPHOTOCURE AUSTRALIA PTY LTD
THIRD CROSS-RESPONDENTGALDERMA AUSTRALIA PTY LTD
FOURTH CROSS-RESPONDENTJUDGE:
MERKEL J
DATE OF ORDER:
6 APRIL 2005
WHERE MADE:
MELBOURNE
THE COURT ORDERS THAT:
1.The application and the cross-claim be dismissed.
2.Each of the parties is to bear its own costs of and incidental to the application and cross-claim.
Note: Settlement and entry of orders is dealt with in Order 36 of the Federal Court Rules.
IN THE FEDERAL COURT OF AUSTRALIA
VICTORIA DISTRICT REGISTRY
V 214 OF 2002
BETWEEN:
PHOTOCURE ASA
APPLICANTAND:
AND BETWEEN:
AND:
QUEEN’S UNIVERSITY AT KINGSTON
FIRST RESPONDENTDUSA PHARMACEUTICALS, INC
SECOND RESPONDENTDUSA PHARMACEUTICALS, INC
CROSS-CLAIMANTPHOTOCURE ASA
FIRST CROSS-RESPONDENTGALDERMA S.A.
SECOND CROSS-RESPONDENTPHOTOCURE AUSTRALIA PTY LTD
THIRD CROSS-RESPONDENTGALDERMA AUSTRALIA PTY LTD
FOURTH CROSS-RESPONDENTJUDGE:
MERKEL J
DATE:
6 APRIL 2005
PLACE:
MELBOURNE
REASONS FOR JUDGMENT
INDEX PARA NUMBERS
1. Introduction 1 – 3
2. Background facts 4 - 13
3. The patent 14 – 18
4. Validity 19 – 151
(a) Obviousness 25 - 72
(b) Novelty 73 - 100
(c) Lack of sufficiency and best method 101 - 116
(d) Lack of definition 117 - 126
(e) Fair basis 127 - 151
5. Infringement 152 - 248
(a) The primary meaning of terms used in the claims 161 - 194
(i)“Administering to the patient” 176 - 182
(ii) “5-aminolevulinic acid” 183 - 194
(b) Infringement in substance 195 - 248
(i)Does the variant (or equivalent) have a material effect upon the way the invention works? 209 - 224
(ii)Would this (i.e. that the variant (or equivalent) had no material effect) have been obvious at the date of publication of the patent to a reader skilled in the art? 225 - 248
6. Conclusion 249
1. Introduction
As a result of a deed of assignment made between the first respondent (“Queen’s University”) and the second respondent (“DUSA”), DUSA became the registered proprietor of Australian Patent No 624985 (“the patent”). The patent is for an invention entitled “Method of Detection and Treatment of Malignant and Non-Malignant Lesions by Photochemotherapy”. A lesion is an injury, a hurt, a wound, any localised morbid structural change in the body or any pathological or traumatic discontinuity of tissue or loss of function of a part. The priority date for the patent is 28 July 1989, being the date of the United States application in respect of the invention.
The applicant (“PhotoCure”) has applied to the Court for the revocation of the patent on the ground of invalidity and DUSA has cross-claimed for declaratory and injunctive relief, claiming that the exploitation and supply by PhotoCure of its product “Metvix” in Australia and its proposed use in Australia of “Metvix Photodynamic Therapy” (“Metvix PDT”) infringes the patent. PhotoCure also claimed similar relief against the second cross-respondent (“Galderma”), which is an exclusive licensee of PhotoCure in Australia, and against the third and fourth cross-respondents, which are the wholly owned Australian subsidiaries of PhotoCure and Galderma respectively.
There were very few points or issues that were not contested. In order to prevent these reasons from being unacceptably long I have confined them to the significant and consequential issues that were both relied on in submissions and are capable of affecting the outcome of the dispute: see Amadio Pty Ltd v Henderson (1998) 81 FCR 149 at 175.
2. Background facts
The invention involves the use of photodetection and photodynamic therapy (“PDT”) for the detection and treatment of certain cancers and lesions or abnormalities (“lesions”). Photodetection and PDT are medical procedures involving the delivery to, or production in, the lesions of a photosensitive chemical compound. Photodetection involves exposing lesions to a certain wavelength of light thereby causing them to fluoresce and hence enable their detection. PDT involves exposing lesions to a wavelength of light that causes the photosensitised cells to be destroyed. One of the inventors, Professor Kennedy, describes the process as follows:
“PDT involves the interaction of photons of light of suitable (photoactivating) wavelengths with molecules of photosensitiser. When the energy of a photon of light is absorbed by a molecule of photosensitiser, that energy may be transferred by direct contact to a molecule of oxygen, thus producing an energized molecule of oxygen that is chemically quite reactive, called singlet oxygen. Singlet oxygen is capable of reacting with and destroying a wide variety of vital cellular structures. If the damage is severe enough, cell death follows. All else being equal, the higher the concentration of intracellular photosensitizer, the greater will be the production of activated oxygen in the presence of photoactivating light and the higher the probability that exposure of photosensitized tissues to light will lead to phototoxic cell death. However, very low concentrations of photosensitizer will have little or no effect on cell viability, since any minor cell damage that might be produced can quickly be repaired.”
At the priority date, the photosensitising agents most commonly used in photodetection and PDT were substances called porphyrins. Porphyrins are naturally occurring chemical compounds in the human body which have fluorescent and photosensitive qualities. For PDT to function effectively a sufficient amount of porphyrins needs to accumulate in the targeted lesions with only minimal amounts accumulating in the surrounding normal tissue. The preferential accumulation of porphyrins in lesions is significant because it allows the precise area of the lesions to be identified when exposed to a light. The light then causes fluorescence of the porphyrins and allows those lesions to be destroyed while leaving the surrounding normal tissue undamaged. This accumulation of a photosensitising agent preferentially in abnormal tissue (as compared to the surrounding healthy tissue) is referred to in the art as “selectivity” or “specificity”.
When PDT and photodetection function effectively they can have significant advantages over other more established methods of cancer detection and treatment. Photodetection allows diagnosis before the cancer has grown to a size that would make its malignancy apparent in the normal course of events. It can also enable the identification of small secondary cancers, the presence of which might otherwise be overlooked. The ability of PDT to destroy malignant cells leaving healthy tissue unharmed gives it an advantage over traditional cancer treatments such as chemotherapy or radiotherapy, both of which can occasion significant damage to healthy tissue. The invasiveness and imprecision in the case of surgery are additional problems that are absent in PDT when it is effective.
However, the advantages of PDT are often not achieved in practice. Earlier forms of PDT usually involved intravenous administration of a mixture of porphyrins, known as hematoporphyrin derivative (“HpD”) or a related, but more purified, mixture known as Photofrin II (“PII”). Certain other porphyrin compounds and mixtures were also used. But the clinical use of these photosensitisers for PDT gave rise to some significant problems. Insufficient selectivity was achieved as a significant accumulation of porphyrins also occurred in normal cells. This meant that the photodetection was not able to achieve a precise detection of abnormal tissue since the surrounding normal tissue also showed significant fluorescence. It also meant that healthy tissue was photosensitised and harmed during PDT. Additionally, repeated administration of HpD or PII for multiple treatments can result in decreasing selectivity. A further problem was that high levels of porphyrins remained in patients’ systems for several weeks. Consequently, patients were required to avoid any exposure to light for some time after treatment in order to prevent severe burning from occurring.
In the light of these difficulties, attempts were made, including by Professor Kennedy as an employee of Queen’s University, to find alternative photosensitising agents which would demonstrate increased selectivity and more rapid clearance from the body. The outcome of that quest by Professor Kennedy was the use of 5-aminolevulinic acid (“ALA”) in PDT. 5-aminolevulinic acid and delta-aminolevulinic acid are the common names given to 5-amino-4-oxopentanoic acid, which is represented by the formula:
In order to appreciate the issues arising between the parties, it is necessary to outline the role played by ALA in the human body. ALA forms naturally in human cells as one step in the series of reactions leading to the creation of heme, which (along with globin) forms hemoglobin. The steps that lead to the creation of heme are referred to as the “biosynthetic pathway to heme”, which is an important basic metabolic pathway in living organisms in which biosynthesis occurs by the production of a chemical substance by a living organism. Heme is the primary respiratory agent in most organisms because it enables cells or molecules to transport or use oxygen. Within the biosynthetic pathway, ALA is created from other compounds, and it in turn reacts to create a sequence of porphyrins, the last of which ultimately combines with iron to form heme. A number of porphyrins follow ALA in the pathway to heme, one of which is protoporphyrin IX (“PpIX”), which functions as a photosensitising agent. ALA is a “rate-limiting step” in the biosynthetic pathway to heme. This means that the rate at which heme (and the other precursors to heme which follow ALA in the pathway) is created is controlled at the point in the pathway where ALA is created.
Because the creation and reaction of ALA precede the creation of PpIX, ALA is referred to as a “precursor” to PpIX and heme in the biosynthetic pathway. In general terms a “precursor” is a substance from which another substance is formed. The Oxford English Dictionary defines “precursor” in its chemical or biochemical sense as a “compound which precedes another in a metabolic pathway or a chemical synthesis, esp. a naturally occurring one”. This is consistent with the meaning advanced by PhotoCure that a precursor involves “a stage in the biosynthetic sequence for a metabolite which can be converted into another metabolite by one or more enzymatic reactions”. The common usage of the term “precursor” refers to a substance preceding another in a natural metabolic pathway, such as the biosynthetic pathway to heme. While the term might also refer to a compound from which another is formed, in a reaction not occurring in a natural metabolic pathway, I doubt that anything turns on that extended meaning in the present case. Clearly the context in which the term is used is of importance in ascertaining its meaning.
Professor Kennedy discovered that adding ALA can bypass the rate-limiting step and therefore treating a patient with ALA increased the generation and selective accumulation of PpIX in abnormal cells. The PpIX was then able to be employed as a photosensitising agent, which reacts with light to destroy those cells, and also fluoresces so as to enable photodetection. This selective process is different from the use of HpD, which is administered as a porphyrin-photosensitising agent to the patient. ALA is not itself a photosensitiser, but its administration has the consequence of bypassing the rate-limiting step and, as a consequence, inducing the production of photosensitising porphyrins within the targeted cell. DUSA claims that Professor Kennedy’s unique approach caused the very cell which PDT is intended to destroy to make its own photosensitiser.
The use of ALA in PDT and photodetection was found by Professor Kennedy to have a number of advantages over previous methods. In particular:
(1)in addition to systemic use, ALA can be applied topically (ie by administration to the skin or other epithelial layer), by localised injection or by infusion into a cavity such that the resulting photosensitivity affects only a small localised area;
(2)within the area treated with ALA (or the entire body where ALA is introduced systemically) PpIX accumulates preferentially in abnormal cells with the consequence that the administration of ALA results in selectivity even within the area to which it is applied;
(3)because ALA does not easily penetrate healthy skin, but can more easily penetrate through skin damaged by basal cell carcinomas, actinic keratoses or psoriasis, it may more readily reach those cells when it is applied topically to treat certain skin abnormalities;
(4)ALA-induced PpIX is highly susceptible to photobleaching (a process whereby the porphyrins are destroyed) in both normal and abnormal cells during treatment, but, since the levels of PpIX in normal cells are already low, photobleaching during treatment tends to reduce levels of PpIX in normal tissue to a sufficiently low level, such that photosensitivity in that tissue does not last after treatment;
(5)there is a rapid clearance of ALA-induced PpIX from normal cells, with the consequence that even if the photobleaching that occurs during treatment does not reduce PpIX levels in normal tissue to below that necessary for photosensitivity, this would occur rapidly by the normal clearance of the compound from the cells.
The advances able to be achieved by the use of ALA improved the precision of PDT (since abnormal cells could be targeted while not harming healthy cells), and reduced the problem of lasting photosensitivity and associated phototoxic skin reactions (since a smaller area of the body could be treated with ALA, healthy cells would not accumulate as much photosensitiser, and the levels of photosensitisers accumulated in healthy cells would be reduced through photobleaching and rapid clearance).
The use of ALA in PDT also presented several other benefits:
(1)ALA-based PDT can be effective against certain conditions which did not respond to the use of HpD and other photosensitisers;
(2)PpIX is strongly absorbent of red light, which passes through human tissue more readily than blue light, and therefore enables the use of PDT in relation to lesions that occur a greater distance below the surface of the skin;
(3)ALA-based PDT was shown to be particularly effective in treating basal and squamous cell carcinomas and some non-cancerous conditions such as psoriases.
3. The patent
The patent relates to “the detection and treatment of certain tissue abnormalities (both cancerous and non-malignant) by induced fluorescence and photochemotherapy respectively.” After explaining the background to the pre-existing forms of PDT, the specification sets out the object of the invention, the statement of the invention and a detailed description of the preferred embodiment as follows:
“Object of Invention
It is an object of the present invention to provide a method for the detection of certain types of malignant and non-malignant tissue abnormalities by induced fluorescence.
It is another object of the present invention to provide a photodynamic (photosensitizing) treatment method which can be administered either systemically or topically using an agent which is not in itself a photosensitizer but which induces the synthesis of protoporphyrin IX (PpIX) in vivo.
Statement of Invention
Thus, by one aspect of this invention there is provided a method for detecting malignant and non-malignant lesions in a patient comprising administering to said patient an effective amount of a precursor of protoporphyrin IX in the biosynthetic pathway for heme so as to induce an accumulation of protoporphyrin IX in said lesions and exposing said lesions to light having a wavelength within the absorbance spectrum of said protoporphyrin IX to thereby induce fluorescence in said lesions.
Thus, by another aspect of this invention there is provided a method for treating malignant and non-malignant hyperproliferative lesions of the skin, mucosa, endometrium and urothelium in a patient comprising administering to said patient an effective amount of a precursor of protoporphyrin IX in the biosynthetic pathway for heme so as to induce synthesis of protoporphyrin IX in said lesions, and exposing said lesions to light having a wavelength within the photoactivating action spectrum of said PpIX to thereby induce photoactivation in said lesions.
In preferred aspects of this invention the preferred precursor or protoporphyrin IX is 5-amino-4-oxo-pentanoic acid, otherwise known as 5-aminolevulinic acid, and a preferred wavelength of the photoactivating light is in the range 350-635 nm, more preferably a red light of about 635 nm.
Detailed Description of Preferred Embodiment
Protoporphyrin IX (PpIX), a naturally occurring photo sensitizer, is the immediate precursor of heme in the heme biosynthetic pathway. All nucleated cells have at least a minimal capacity to synthesize PpIX, since heme is necessary for the synthesis of various essential heme-containing enzymes. Certain types of cells and tissues can synthesize relatively large quantities of PpIX. Under normal conditions, the synthesis of PpIX in such tissues is under such tight feed-back control that the cells produce it at a rate just sufficient to match their need for heme. However, the usual rate-limiting step in the process, the synthesis of 5-aminolevulinic acid (ALA), can be bypassed by the provision of exogenous ALA, porphobilinogen, or other precursor of PpIX. Certain tissues and organs will then accumulate such a large excess of PpIX that they become both fluorescent and photosensitive. At least in the case of skin, the PpIX appears to be synthesized in situ. The ALA, which is commercially available from Sigma Chemical Company and which is water soluble, can be administered orally, topically or by injection. The oral and parenteral routes lead to the induction of clinically useful concentrations of PpIX in certain benign and malignant tissues throughout the body. Only certain types of tissue can synthesize clinically useful amounts of PpIX when provided with an excess of ALA, and the provision of ALA is only beneficial if the tissue affected is at a site that can be reached by photoactivating light. At the present time, treatment of basal cell, baso-squamous and squamous cell carcinomas and other lesions of the skin, mucosa (respiratory, digestive, and vaginal), endometrium and urothelium is contemplated. Treatment of non-malignant lesions such as genital warts and psoriasis is also contemplated. Sites could include lesions involving (i) skin and conjunctiva; (ii) the lining of the mouth, pharynx, esophagus, stomach, intestines and intestinal appendages, rectum, and anal canal; (iii) the lining of the nasal passages, nasal sinuses, nasopharynx, trachea, bronchi, and bronchioles; (iv) the lining of the ureters, urinary bladder, and urethra; (v) the lining of the vagina, uterine cervix and uterus; (vi) the parietal and visceral pleura; (vii) the lining of the peritoneal and pelvic cavities, and the surface of the organs contained within those cavities; (viii) the dura mater and meninges; (ix) any tumors in solid tissues that can be made accessible to photoactivating light either directly, at time of surgery, or via an optical fibre inserted through a needle.
The wavelength of the photoactivating light is of some importance, as it has been shown that between 1 and 10 percent of incident red light (600-700 nm) can pass through a slab of human tissue 1 cm thick, whereas only 0.001 percent or less of blue light (about 400 nm) can pass through the same thickness of human tissue. The photosensitizer will, therefore, be more successful if it strongly absorbs red light. PpIX does strongly absorb red light. The present approach has several advantages over the prior art. First, PpIX has a much shorter half-life in normal tissues than does HpIX, HpD or Photofrin II. This greatly reduces the danger of accidental phototoxic skin reactions in the days following treatment. Second, the topical application of ALA to certain types of lesions can induce PpIX within those lesions, but nowhere else. This improves the specificity of the treatment, reduces the danger of accidental phototoxic reactions to a very low level, and greatly reduces the amount of both ALA and PpIX to which the entire body would be exposed if an equally effective dose of ALA were to be given systemically. Both ALA and PpIX are normal products of metabolism, and are handled quite readily by the biochemical machinery of the body. However, since very large doses of ALA (like large doses of HpIX or HpD) are associated with a transient decrease in motor nerve conduction velocity, it is desirable to reduce the dose of ALA to the minimum that is still effective. Topical application requires much less ALA than systemic administration. Third, PpIX is rapidly inactivated by the photoactivating light. Following exposure of tissues containing PpIX to a therapeutic dose of photoactivating light, there is a substantial decrease in photosensitization of the tissues within the treatment volume. Consequently, if PpIX is induced by the topical application of ALA to specific lesions, the patient can be exposed to sunlight immediately post-treatment without danger of serious phototoxicity. Fourth, ALA is an effective inducer of PpIX when given by mouth, by topical application, or by injection. In contrast, HpIX, HpD and Photofrin II are effective in most situations only when given by injection. This versatility of ALA enhances its acceptability for routine use by the medical profession, since the oral and topic routes of administration are much more convenient than the parenteral. Fifth, the normal and abnormal tissues that can be photosensitized by the administration of ALA are somewhat different from those that can be photosensitized by the administration of HpIX, HpD or Photofrin II. Consequently, ALA may be useful in clinical situations in which the other photosensitizers are not.
Thus present technique is not merely another way to do what can be done already but is, in fact, a significant advance in therapeutic capability.”
Four examples are then given of PDT involving the topical application of ALA to the skin of four patients for treatment of carcinomas. Example 5 relates to the systemic administration of ALA to mice. In that example it was found that the mouse endometrium showed strong protoporphyrin fluorescence while the underlying myometrium did not.
The claims defining the invention are as follows:
“1.A method for treating malignant and non-malignant tissue abnormalities and lesions of the skin; conjunctiva; respiratory, digestive and vaginal mucosa; endometrium; and urothelium in a patient in need of such treatment comprising administering to said patient an effective amount of 5-aminolevulinic acid so as to induce synthesis of protoporphyrin IX in said lesions, and exposing said lesions to light within the photoactivating action spectrum of said protoporphyrin IX.
2.A method as claimed in claim 1 wherein said malignant lesions are selected from basal, baso-squamous and squamous carcinomas.
3.A method as claimed in claim 1 wherein said non-malignant lesions are selected from psoriasis and genital warts.
4.A method as claimed in claim 1 wherein said photoactivating light is in the range of 350-365 nm.
5.A method for treating menorrhagia in a patient in need of such treatment comprising topically administering 5-aminolevulinic acid to the endometrium and exposing said endometrium to light having a wavelength within the photoactivating action spectrum of protoporphyrin IX.
6.A method as claimed in claim 1 where in said 5-aminolevulinic acid is administered parenterally.
7.A method as claimed in claim 1 wherein said 5-aminolevulinic acid is administered topically.
8.A method as claimed in claim 1 wherein said 5-aminolevulinic acid is administered orally.
9.A method for treating malignant and non-malignant hyperproliferative lesions of the skin, mucosa, endometrium and urothelium in a patient in need of such treatment comprising administering to said patient an effective amount of a precursor of protoporphyrin IX in the biosynthetic pathway for heme so as to induce synthesis of protoporphyrin IX in said lesions, and exposing said lesions to light within the photoactivating action spectrum of said protoporphyrin IX.
10.A method as claimed in claim 9 wherein said precursor is 5-aminolevulinic acid.
11.A method for detecting malignant and non-malignant tissue abnormalities and lesions of the skin, mucosa, endometrium and urothelium in a patient in need of such treatment, comprising administering to said patient an effective amount of a precursor of protoporphyrin IX in the biosynthetic pathway for heme so as to induce synthesis of protoporphyrin [IX] preferentially in said abnormalities and lesions, exposing said patient to light having a wavelength within the absorbance spectrum of said protoporphyrin IX to thereby induce fluorescence in said abnormalities or lesions, and detecting said fluorescence.
12.A method of treatment according to any one of claims 1, 5, 9 or 11 substantially as hereinbefore described with reference to the Examples.”
DUSA claims that PhotoCure’s use of Metvix PDT infringes claims 1, 2, 4, 7, 9, 10 and 12. PhotoCure’s riposte is that all of the claims are invalid and that the patent should be revoked.
At trial PhotoCure and DUSA adduced evidence from numerous expert witnesses who differed in their views on a number of critical factual issues. I accept that the expert evidence was carefully considered and was an honest expression of the witnesses’ opinions and views. The differences of opinion can be explained in part by the fact that each witness’s evidence was significantly influenced by the particular expertise, background and experience of that witness, which itself differed in significant respects from the particular expertise, background and experience of other witnesses. Where the witnesses differed in their views, I have tended to prefer the evidence of experts whose expertise, background and experience is most closely related to the subject matter of the invention. The evidence of the experts that I have preferred, or upon which I have relied, is set out in these reasons. I would add that I have not given significant weight to the expert evidence of Dr Hansson who is the President and Chief Executive Officer of PhotoCure. I regarded Dr Hansson’s evidence as having been influenced by his position, his belief in his company’s product, Metvix, and his advocacy of PhotoCure’s case.
4. Validity
The application for the patent was filed on 25 July 1990 and accepted on 25 June 1992. The Patents Act 1990 (Cth) (“the Act”) commenced on 30 April 1991. It was common ground between the parties that ss 234(2) and (5) of the Act apply to the patent with the result that the Act applies to the patent, subject to the proviso contained in s 234(5) that the validity of the patent cannot be impugned on any basis that would not have been available under the Patents Act 1952 (Cth) (“the 1952 Act”).
With respect to questions of obviousness and novelty, the effect of s 234 of the Act is that the patent will only be invalidated on those grounds by reference to things “known or used in Australia on or before the priority date” by virtue of s 100(1)(e) of the 1952 Act: see Minnesota Mining & Manufacturing Co v Tyco Electronics Pty Ltd (2002) 56 IPR 248 (“Minnesota Mining v Tyco”) at 250-251 [5]-[8] and 272 [98]; NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd (1993) 44 FCR 239 (“NV Philips”) at 251-254 and Aktiebolaget Hässle v Alphapharm Pty Limited (2002) 212 CLR 411 (“Alphapharm (HCA)”) at 421-422 [13]-[18].
It was common ground that for all other purposes the issues raised by the claim and cross-claim are governed by the Act.
Under s 138(3)(b) of the Act a patent may be revoked on the ground that is not for a patentable invention. Section 18 provides that:
“(1)Subject to subsection (2), an invention is a patentable invention for the purposes of a standard patent if the invention, so far as claimed in any claim:
(a)is a manner of manufacture within the meaning of section 6 of the Statute of Monopolies; and
(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
(c)is useful; and
(d)was not secretly used in the patent area before the priority date of that claim by, or on behalf of, or with the authority of, the patentee or nominated person or the patentee’s or nominated person’s predecessor in title to the invention.”
Section 138(3)(f) provides for revocation on the ground that a patent does not comply with ss 40(2) or (3) which, relevantly, provide:
“(2) A complete specification must:
a. describe the invention fully, including the best method known to the applicant of performing the invention; and
b. where it relates to an application for a standard patent – end with a claim or claims defining the invention…
(3)The claim or claims must be clear and succinct and fairly based on the matter described in the specification.”
PhotoCure relies upon the following grounds of invalidity:
(a)lack of inventive step (obviousness);
(b)lack of novelty;
(c)lack of sufficiency and best method;
(d)lack of definition;
(e)lack of fair basis.
(a) Obviousness
Section 7 of the Act, relevantly, provides that:
“(1) …
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 the information mentioned in subsection (3).
(3) The information for the purposes of subsection (2) is:
(a)any single piece of prior art information; or
(b)a combination of any 2 or more pieces of prior art 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, regarded as relevant and, in the case of information mentioned in paragraph (b), combined as mentioned in that paragraph.”
“Prior art base” is defined in Schedule 1 of the Act. However, as explained above, the effect of s 234 of the Act is that the validity of the patent cannot be impugned for obviousness other than by reference to things “known or used in Australia on or before the priority date”. Further, the requirement in s 7(2) that the question of obviousness be considered not only in the light of the common general knowledge existing at the priority date, but also taking account of the information mentioned in s 7(3), represents a change from the situation under the 1952 Act and the jurisprudence developed in relation to its application by the High Court: see Alphapharm (HCA) at 422 [16].
As the question of obviousness is to be assessed in the light of the common general knowledge as it existed in the patent area before the priority date, and by reference to the perspective of a person skilled in the art, it is first necessary to determine what the relevant art is, who the person skilled in that art would have been, and what would have constituted the common general knowledge available to such a person. DUSA contended that the relevant art or field is “PDT” and that the relevant person is someone “who was working in the area of PDT”, although it accepted that such a person would have a sound knowledge of PDT and biochemistry. PhotoCure’s contention was that the relevant person is “someone with a knowledge of porphyrin biochemistry, PDT and drug formulation”. DUSA has understated, and PhotoCure has overstated, the relevant area. At the priority date, PDT was a highly specialised and relatively recently developed area of research. Any person working in the area of PDT would have had a sound understanding of the role of porphyrins, as porphyrins were the main photosensitising agent used in PDT. In my view, the relevant person under s 7(2) of the Act was a person who was seeking to enhance the development of PDT using porphyrins as a photosensitising agent. Thus, the hypothetical skilled addressee would have a sound understanding of biochemistry and a detailed understanding and knowledge of PDT and of the role of porphyrins as a photosensitising agent in PDT.
The parties also differed as to whether the skilled addressee in this instance should be considered to consist of, or include, a team of persons working together. As a matter of law this may be the case where it is normal in the field for a team to work together: see General Tire & Rubber Company v The Firestone Tyre and Rubber Company Ltd [1972] RPC 457 (“General Tire & Rubber”) at 485; The Leonardis v Sartas No 1 Pty Ltd (1996) 67 FCR 126 (“Leonardis”) at 146; ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc (1999) 45 IPR 577 (“ICI Chemicals”) at 597 [100]). PhotoCure adduced some evidence to the effect that a team of persons with multidisciplinary expertise would be involved. However, that evidence was given by Professors Moore and Roberts, neither of whom had direct experience in the area of PDT research and development. In any event, while it is possible, and perhaps even likely, that a group of persons might have worked collaboratively in seeking to develop new methods of PDT, I do not consider that the evidence indicates that their skills would have been sufficiently multidisciplinary to materially expand the understanding and knowledge of the hypothetical skilled addressee as set out above.
It is next necessary to consider what constituted the common general knowledge in Australia at the priority date. In Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 (“Minnesota Mining v Beiersdorf”) at 292 Aickin J described the concept of common general knowledge as follows:
“The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.”
See also ICI Chemicals at 599 [111].
In the present context little turns on the issue of the availability of common general knowledge in Australia. PDT was being explored, developed and employed internationally with the consequence that what was generally known or used in Australia in relation to PDT did not differ in any material respect from what was generally known or used internationally.
The common general knowledge will encompass not only information that is retained in the memory of the skilled person, but also information that the person knows of, and to which he or she might refer as a matter of course, or habitually consult: see ICI Chemicals at 599 [112] and Aktiebolaget Hässle v Alphapharm Pty Ltd (2000) 51 IPR 375 at 391 [73]. However, common general knowledge does not include information merely because it would have been able to be found if a routine literature search was conducted: see Alphapharm (HCA) at 426 [31], 430 [44]-[45] and 434 [55]. Nor does it follow from the fact that a publication “may have been held in a library readily accessible to a particular formulator” that such a publication formed part of the common general knowledge: see Aktiebolaget Hässle v Alphapharm Pty Ltd (1999) 44 IPR 593 (“Alphapharm (FCA)”) per Lehane J at 625 [105].
The common general knowledge in the relevant field at the priority date included the matters set out in [4] to [7] above and the role of ALA in the human body as set out in [8] above. In particular, it was uncontroversial between the parties, and clear from the evidence, that the following matters were within the common general knowledge in the relevant field as at the priority date:
(1)PDT involving the provision of exogenous porphyrins, such as HpD and PII, was known as a method of treatment for malignant and non-malignant lesions in various parts of the body;
(2)a characteristic of HpD and PII is their tendency to accumulate selectively, to some extent, in abnormal tissue;
(3)fluorescent diagnosis involving the provision of exogenous porphyrins was a method of detecting tissue abnormalities;
(4) PpIX was a fluorescent and photosensitive naturally-produced porphyrin;
(5)the nature of the biosynthetic pathway to heme was generally known, including the roles of PpIX and ALA in that pathway, and the fact that all nucleated cells have a capacity to synthesise PpIX;
(6)it was possible, and in some cases advantageous, to use a “prodrug” to achieve particular pharmacological results.
A prodrug is defined in the Oxford English Dictionary as any (usually biologically inactive) “compound which may be metabolized in vivo to produce a drug…”. Professor Roberts explained that a prodrug is a compound (which may or may not be active in its own right) which is converted once inside the body by metabolic activity into the drug whose biochemical effect is sought to be utilised. There was some disagreement as to whether ALA should be regarded as a “prodrug” of PpIX, but what is relevant for present purposes is that it was known in the relevant field that a compound may be given to a patient in order to induce in vivo the production of another, and more pharmacologically useful, compound.
PhotoCure claimed, and DUSA disputed, that the common general knowledge included the following matters:
(1)a detailed level of knowledge about porphyrias;
(2)knowledge that natural porphyrins, including PpIX, tended to accumulate selectively in malignant tissue, and therefore would be useful in PDT;
(3)knowledge that the provision of ALA, or any other precursor of PpIX in the biosynthetic pathway, to a cell caused an excess of PpIX in the cell, causing the cell to fluoresce and become photosensitive;
(4)The Peng paper.
(1)a detailed level of knowledge about porphyrias
Porphyrias are a number of related medical conditions. DUSA relied on the evidence of Professor Moore, whose background related more to biochemistry, including experience in relation to porphyrias, rather than PDT. Professor Moore explained porphyrias as follows:
“Some people have conditions which result from one of the enzymes having an altered activity so that the biosynthetic pathway to heme does not function properly. These conditions are called the porphyrias and have driven the study into the biosynthetic pathway to heme.
…The symptoms [of porphyrias] are acute neurological features (called an ‘acute attack’) or skin photosensitivity or both. …
Often in porphyria, there is a build up of porphyrinogens which are converted to porphyrins. The body cannot remove the porphyrins quickly enough and skin photosensitivity results. It was known before 1989 that the skin photosensitivity results from different porphyrins in different porphyrias. For example, in porphyria cutanea tarda and congenital porphyria, the skin photosensitivity arises from excess uroporphyrin. It was known in 1961 that the skin phototoxicity associated with PpIX is found in erythropoietic protoporphyria.”
Professor Moore’s evidence was that there was overlap at conferences and in research between the areas of “porphyrins, porphyria and PDT” and that:
“[PDT] was raised in various discussions amongst people interested in porphyria and in other areas for very very many years. The initial conceptualities behind porphyrin photosensitisation go back to 1913. You see even in more recent times that people with specific interests in these areas were talking about this in the late 1970s and right through to the present time.”
DUSA accepted that PDT researchers necessarily have some knowledge of porphyrin biochemistry, in the sense of the biological activity of pre-formed porphyrin photosensitisers. It also accepted that the researchers would have some understanding of porphyrias as a class of diseases arising from defects in the biosynthetic pathway. However, DUSA argued that there was a clear separation between what might constitute common general knowledge in relation to a person researching porphyrias and porphyrins per se, and a person doing so for the purpose of PDT research. Professor Oseroff and Professor Waner, DUSA’s expert witnesses, expressed the view that PDT researchers at the priority date did not draw an association between their work and the study of porphyrias. Both said that they had a familiarity with porphyrins as a result of their medical training, but before the priority date had not considered that their knowledge was relevant to their work in PDT, and that they did not recall consideration being given to porphyrias at the PDT conferences they had attended prior to 1989.
While it can be accepted that a person working in the area of porphrias might take a secondary interest in PDT, I prefer the evidence of Professors Oseroff and Waner, who were both involved in researching PDT, to the effect that the relevant area of interest of a person skilled in the art of researching PDT would be the photosensitising characteristics of porphyrins, rather than in porphyrias.
In any event, I do not consider that common general knowledge in relation to porphyrias on the part of the notional skilled addressee would have significantly advanced PhotoCure’s case on obviousness. A knowledge of porphyrias would not have indicated that natural porphyrins would be likely to be useful in PDT, the efficacy of which requires selective accumulation of a photosensitiser in abnormal, rather than in normal, tissue. As Professor Oseroff explained, “the symptoms of porphyria are inimical to the goals of PDT” in that:
“Porphyria involves circulating porphyrins which can cause injury to the vascular system, the skin, certain internal organs and the nervous system. One of the aims of PDT was to develop drugs which could be used in the human system to achieve selective and preferential accumulation of porphyrins in the target tissues, without causing injury to normal tissues in patients. In addition, the porphyrins that were being studied for use in PDT were generally not naturally occurring porphyrins, but rather were pre-formed photosensitisers. Accordingly, there was no particular emphasis on understanding porphyrin metabolism in the context of PDT.”
Professor Waner gave similar evidence, namely that his knowledge of porphyrias from his medical training led him to understand that patients suffering from those conditions suffered serious consequences as a result of an excess of porphyrins, whereas in his PDT research he sought to achieve the selective retention of a photosensitiser (which may or may not be a porphyrin) in tumour tissue. As a result, Professor Waner considered that
“A knowledge of porphyria and porphyrin metabolism did not lead to a better understanding of [the selective uptake of a photosensitiser by malignant tissue]. Rather, porphyria is associated with widespread tissue destruction, as a result of the accumulation of excess porphyrins. Accordingly, a knowledge of porphyrias would lead away from the choice of porphyrins as a photosensitiser.”
The skills and training which different researchers in the field of PDT would have brought to their work would vary depending, for example, on whether their background was in medical treatment or biochemistry. It is possible that some researchers in the field of PDT would have had detailed knowledge of porphyrias. However, the notional skilled addressee is “the person of ordinary skill in the art”: Williams Advanced Materials, Inc v Target Technology Company LLC [2004] FCA 1405 at [105], and I do not consider that such a person would have had more than a basic and general knowledge of porphyrias.
(2)knowledge that natural porphyrins, including PpIX, tended to accumulate selectively in malignant tissue, and therefore would be useful in PDT
PhotoCure relied on evidence from Professor Moore that well known publications indicated that natural porphyrins might be useful in PDT. He referred specifically to writings by Kessel and himself and the reference in the patent to the prior use of hematoporphyrin in PDT. However, even if the publications were part of, or reflected, the common general knowledge at the priority date, they would not assist PhotoCure’s case. The Kessel article (“Components of Hematoporphyrin Derivatives and Their Tumor-localizing Capacity” (1982) 42 Cancer Research 1703) is an investigation into the components of HpD, which is not a natural porphyrin. Although the article discusses the accumulation of protoporphyrin and hematoporphyrin in tumour cells, it does so in the context of the administration of HpD. The article does not teach that the use of those porphyrins when naturally occurring would be useful in PDT, and does not deal with PpIX. Professor Moore’s own text of 1987 (Moore et al, Disorders of Porphyrin Metabolism, Plenum Medical Book Company, New York) includes a chapter covering PDT. However it discusses only the use of HpD and hematoporphyrin. Similarly, in discussing the prior art, the patent refers only to the prior use of HpD, PII, and hematoporphyrin IX.
DUSA’s evidence was to the effect that, according to the existing knowledge in the field at the priority date, although commercially produced hematoporphyrin tended to localise in tumour cells, pure hematoporphyrin did not. DUSA also led evidence to demonstrate that the existing state of knowledge in the field prior to 1989 was that PpIX was not an effective agent for PDT. Experiments involving the injection of PpIX into mice had led to the conclusion that it would be unsuitable for use in PDT as it cleared too rapidly. Professor Batlle (at T 231) gave evidence that she was aware in 1989 that experiments involving the administration of PpIX had been viewed as unsuccessful. Professor Oseroff’s evidence was that there was little interest before the priority date in pursuing the use of natural porphyrins in PDT.
Having regard to the above evidence I do not accept that common general knowledge in the field at the priority date indicated that natural porphyrins in general, or PpIX specifically, would tend to accumulate selectively in malignant cells or lesions in such a way as to be potentially useful in PDT.
(3)knowledge that the provision of ALA or any other precursor of PpIX in the biosynthetic pathway to a cell caused an excess of PpIX in the cell, causing the cell to fluoresce and become photosensitive.
DUSA led evidence from Professor Waner and Professor Oseroff that this specific piece of information was not known, as well as evidence from experts working in PDT that they had no interest in ALA.
PhotoCure sought to demonstrate that this information was part of the common general knowledge at the priority date by reference to particular publications. The first of these, authored by JJ Scott in 1955, is titled “The metabolism of d-aminolaevulic acid” in Ciba Foundation Symposium on Porphyrin Biosynthesis and Metabolism (“the Scott paper”). The Scott paper considered experiments in which ALA was administered to rats and humans, and included the following paragraph (at 48):
“In all the human subjects tested, a dose of ALA has given rise to a transient but marked photosensitivity. There is an erythema of the exposed skin resembling a mild sunburn, reaching a maximum between nine and twelve hours (the experiments have always been begun in the early morning). In one subject the erythema was replaced one day later by a prolonged suntan.”
In the course of cross examining Professor Kennedy, PhotoCure produced a further article published in 1956 by NI Berlin, A Neuberger and JJ Scott, also titled “The Metabolism of d-aminolaevulic acid” in the journal Bioch. vol 64 at 80. It contained the following paragraph under the heading “Experimental photosensitivity in man induced by aminolaevulic acid” (at 89):
“The marked photosensitivity of human subjects who have been given aminolaevulic acid is of particular interest in view of the severe photogenic blistering which is the main clinical feature of congenital porphyria. The nature of the reaction in the experimentally induced condition is, however, different from that usually observed in the disease, where exposure to light will have occurred over long periods. In none of the human subjects was there any vesicular eruption. Only in the subject who received the largest dose was there any desquamation; in all subjects the condition in fact resembled most closely that of sunburn. The photosensitivity of congenital porphyria has long been assumed to be due to porphyrins, particularly uroporphyrin I, known to be present in the blood and tissues of patients with the disease. Preliminary experiments have shown that protoporphyrin is excreted in relatively large quantities in the bile of rats after administration of ALA (Scott, 1955). Circulating porphyrins may therefore be responsible for the experimentally induced sensitivity; the skin reaction is, however, very mild in the latter condition, compared with that in the disease, where exposure with porphyrinaemia has been prolonged.”
I am not satisfied that the articles formed a part of, or reflected, the common general knowledge of the notional skilled addressee. Very little evidence was led to that effect. Both articles were written in the 1950s in the context of the study of porphyrias, and the paragraphs in question formed minor, and not central, observations in those articles. In any event, even if the material formed part of the common general knowledge, I do not consider that it significantly advances PhotoCure’s case. The Scott paper does not indicate the biochemical process by which provision of ALA causes photosensitivity, nor does it identify PpIX as the specific porphyrin involved. Moreover, knowledge that the administration of ALA leads to a general photosensitivity in humans would not make the use of ALA in PDT obvious without the further knowledge that that photosensitivity can occur selectively in abnormal tissue. I do not consider that this additional information formed part of the common general knowledge at the priority date.
(4) The Peng paper
PhotoCure also sought to rely on an article authored by Peng Qian and others entitled “A Comparison of Different Photosensitizing Dyes with Respect to Uptake C3H-Tumors and Tissues of Mice” and published, in vol 36 of the journal Cancer Letters in 1987 (“the Peng paper”) at pp 1-10. In order to rely on that paper in support of its obviousness submissions it was necessary, in the light of the High Court’s decision in Alphapharm, for PhotoCure to demonstrate that the paper formed part of the common general knowledge at the priority date.
DUSA sought to rely in its closing submissions on PhotoCure’s failure to plead that the Peng paper was part of common general knowledge. However, from the outset of the hearing PhotoCure made it clear that it intended to rely on the Peng paper in that way. No objection was raised at that time by DUSA in relation to PhotoCure’s failure to plead the Peng paper as part of common general knowledge. I am satisfied that this question was “in the ring” at trial and that DUSA is not disadvantaged by PhotoCure’s reliance on it: see Nescor Industries Group Pty Ltd v Miba Pty Ltd (1997) 150 ALR 633 at 640, 647 and 650.
In support of its contention that the Peng paper was part of the common general knowledge at the priority date, PhotoCure relied on the following evidence:
· The evidence of Professor Moore that he had read the Peng paper before the priority date; the evidence of Professor Oseroff that it was very likely that he had read the Peng paper around the time of its publication; and the evidence of Dr Ward that the Peng paper was part of his collection of “articles by significant researchers in the field”;
· the response of Professor Kennedy when asked whether he had read the Peng paper around the time of its publication (“No. It’s a bit embarrassing to admit, but I am not a very organised researcher and I do not do all the reading that I should do…”) which was said to imply that an organised researcher who engaged in the appropriate reading would have read the article;
· the evidence of Professor Moore that Cancer Letters, the journal in which the Peng paper was published is “a well known publication by a well known science publisher” and is “commonly read by medical and biological scientists”; and the evidence of Dr Waner that Cancer Letters is a well known publication; and
· evidence indicating that of the authors of the Peng article, Dr Moan, and possibly Professor Rimington, were well known in the field.
DUSA, in arguing that the Peng paper was not part of the common general knowledge at the priority date, relied on the following evidence:
· evidence from Dr Ward that, although he had the paper as part of his collection of articles, he did not recall its contents before revisiting it for the purposes of this case;
· evidence from Professor Oseroff that, although it was very likely that he read the Peng paper around the time of its publication, he “had no specific recollection of the article prior to reading it for the purposes of making this affidavit”;
· the following evidence from Dr Waner:
“MACAW: I think you said this is a paper that you have not read?
WANER: That’s correct.
MACAW: But did I correctly understand your earlier evidence to be that you were not attempting prior to 1989 to keep up to date with all relevant literature on the subject?
WANER: Please repeat that?
MACAW: Did I correctly understand an earlier answer to me that you were not attempting to keep up to date with all relevant literature on the subject?
WANER: No, I – prior to 1989 I was attempting to keep up to date with what I considered to be all of the relevant literature, which does not necessarily mean that I read every single article. You know, there’s a tremendous amount of stuff being put out there and I may well have missed this and several other articles. I could possibly or I may possibly have read this and did not recall at the time of – few years ago or at least a year ago I may not have recalled that I had in fact read this article.
MACAW: The publication, Cancer Letters?
WANER: Yes.
MACAW: Is a well-known publication?
WANER: Yes, but, you know, prior to the age of computers it was very difficult to keep up with every single article that was published. One would go to Index Medicus and pick out as many of the articles as appeared to be relevant. One would go to the meetings and listen to what was being spoken about and thereby pick out the articles. This article did not come into my radar or at least I do not recall it coming into my radar.
MACAW: Have you ascertained whether the use of Index Medicus would have identified it?
WANER: No, I have not gone back and checked that.
MACAW: Would you accept that Cancer Letters is a journal which is commonly read by medical and biological scientists?
WANER: It’s a journal read by oncologists.
MACAW: Including those whose interest in oncology involves PDT?
WANER: I guess so. You know, there are more interesting and more pertinent journals. There is a wide range of publications which are used by certain individuals. One attempts to get an article published wherever one can and an ever increasing number of articles are being used as [a] vehicle to publish literature.
MACAW: You don’t mean by that, do you professor, to demean the status of Cancer Letters?
WANER: No, I don’t mean to demean the status of this. I just mean that someone such as myself interested in photodynamic therapy would tend to read other journals before I would read Cancer Letters.
MACAW: Do you in fact retain a collection of the articles that you read from time to time?
WANER: Yes, I do, and this is not one of them.
MACAW: Not one in the retained collection?
WANER: Yes, that’s correct.
…”
I find that the evidence relied upon by PhotoCure is sufficient to establish that the Peng paper formed part of the common general knowledge of the hypothetical skilled addressee at the priority date. While the witnesses may not all have instantly recalled the paper, it satisfies the requirement in Alphapharm (HCA) (at [31] and [55]) that it has been “generally accepted and assimilated” by the relevant community. However, as I later explain, my finding that the Peng paper was part of the common general knowledge, does not make out PhotoCure’s case on obviousness.
Finally, in his opening submissions at trial, senior counsel for PhotoCure indicated that he would also be relying on a paper by Nora M Navone and others (including Alcira M. del C. Batlle, a PhotoCure witness) titled “Porphyrin biosynthesis in human breast cancer. Preliminary mimetic in vitro studies” and published in Medical Science Research (1988) vol. 16 no.2, 61-62 (“the Navone paper”). However, the reliance was not pressed in closing submissions and PhotoCure did not challenge DUSA’s submission that the Navone paper was not part of the common general knowledge. Nor did PhotoCure plead that the Navone paper was part of the common general knowledge. Irrespective of whether or not it is open to PhotoCure to rely on the Navone paper as part of common general knowledge, I am satisfied in any event that the evidence does not support a conclusion that it was part of the common general knowledge.
Having determined the main contested issues in relation to common general knowledge, it is necessary then to consider whether, in the light of common general knowledge, the invention would have been obvious to the skilled addressee. For this purpose the invention can be characterised as a new form of PDT and photodetection which administers to the patient an effective amount of ALA or another precursor of PpIX in the biosynthetic pathway for heme so as to induce an accumulation of PpIX in lesions and expose the lesions to light having a wavelength which induces fluorescence in the lesions. In the preferred embodiment of the invention the precursor administered to the patient is ALA.
DUSA agreed with Professor Moore’s definition of an “effective amount” in the present context as meaning “effective to induce synthesis of a sufficient amount of PpIX to enable the treatment of the malignant and non-malignant tissue abnormalities and lesions”. Professor Moore explained his preference for that meaning by stating that it relies on the abnormality or lesion to accumulate sufficient amounts of PpIX after application of ALA, which would be photoactivated by exposure to an appropriate wavelength of light and thus provide the desired result of cell death. Professor Moore’s definition accords with the meaning that would be attributed to the phrase “an effective amount” in claims 1 and 9 of the patent by the hypothetical person skilled in the art. However, as explained earlier, it was a requirement for PDT to be effective that the accumulation of the photoactive agent be selective and that would have been known and understood by a person skilled in the art at the priority date.
The most recent explanation of when an invention will be “obvious” in the context of the 1952 Act is found in the majority judgment of Gleeson CJ, Gaudron, Gummow and Hayne JJ in Alphapharm (HCA) at 427-428 [33]-[38]. Their Honours cautioned against purported formulas or definitions of what is “obvious”, citing Diplock LJ in Johns-Manville Corporation’s Patent [1967] RPC 479 at 493-494 and emphasised that obviousness is a classic question of fact (at 447-449 [94]-[99]). However, their Honours also observed, in determining whether an invention is “obvious”, it is wrong to equate that concept with what is “worth a try” or “obvious to try”.
I consider that in the light of the common general knowledge existing at the priority date, the highest that one could put the evidence in support of obviousness is that it could be said by the relevant hypothetical person skilled in the art that administering to a patient a precursor of PpIX, including ALA, was worth trying. This is because there was nothing in the common general knowledge at that date which indicated that the administration of ALA would cause a sufficiently selective accumulation of PpIX in lesions or tumours to enable PDT treatment of the malignant and non-malignant tissue abnormalities and lesions. As stated above, it is clear from the evidence that this quality of selectivity is, and was considered at the priority date to be, a requirement for an effective PDT agent. Without the knowledge that the use of ALA would result in selectivity, its use could not have been obvious. Indeed, the requisite quality of selectivity for particular tumours or lesions could only be established with any degree of scientific reliability after appropriate in vivo clinical experimentation. For example, when asked about the usefulness of the in vitro tests carried out by Navone and Batlle using ALA on breast adenocarcinoma tumours, Professor Waner gave the following evidence:
“MACAW: Do you say that one may not extrapolate to any degree from the result in adenocarcinoma to, for example, the prospective results in other epithelial issues?
WANER: No, one cannot extrapolate - I think extrapolation is sceptical. I wouldn’t like to use the word ‘dangerous’ but one should not extrapolate, certainly not in science, not in these circumstances.
MACAW: Is it true to say that one cannot extrapolate with confidence in the sense that one could never extrapolate without doing confirmatory testing but one can extrapolate to some extent subject to confirmatory testing?
WANER: One can merely speculate but one cannot extrapolate and there is a distinct difference in the scientific field between the two. I have an article in front of me which simply describes that adenocarcinoma appeared to concentrate protoporphyrin IX and that the tumour to background ratio was very favourable. However, the experiment was done in vitro, it was done in tissue culture and that’s all we can say. We can speculate that this could or may well be interesting and that further work needs to be done but we cannot extrapolate into our tumour lines based on this.”
That evidence is in conformity with the evidence that was given by various witnesses in the context of the question of whether it was obvious in March 1991 that the methyl ester of ALA (“methyl-ALA”) would work in the same way as ALA. Indeed, the need for human in vivo testing was made clear by the discouraging results arising from Professor Kennedy’s experiments using ALA-based PDT on rats and mice over a period of more than seven years. Professor Kennedy’s breakthrough in relation to skin tumours came about when he obtained ethics approval to conduct clinical trials on human patients after he applied ALA to normal and abnormal areas of his own skin. After those trials had been conducted, the clinical efficacy of ALA-induced PpIX as a photosensitiser for use in PDT on humans was able to be established. Professor Kennedy stated in his affidavit that as a result of the clinical trials:
“… we found that ALA-induced photosensitisation in fact produced beneficial results in the treatment of cancer patients, even though models involving transplantable tumours in mice did not support such a finding and did not give a basis for predicting such benefit.”
I am satisfied that the evidence establishes that in order to ascertain whether ALA was effective for use in PDT in respect of particular tumours or lesions in humans, clinical testing
on human subjects was required. Prior to such testing occurring, the most that might have been said is that the use of ALA, or some other precursor to PpIX, was worth trying.
I am able to reach this conclusion without relying on the direct hindsight evidence given by DUSA’s witnesses – in particular Professors Oseroff and Waner, who were both involved in researching new PDT agents – that they had not considered the use of ALA in PDT before the priority date. However, that evidence, and the evidence that numerous researchers were working towards new drugs for use in PDT, reinforces the view that I have reached. Such evidence is admissible, though not always helpful on its own, in ascertaining whether an invention is obvious: see Chiron Corporation v Organon Teknika Ltd (No 3) [1994] FSR 202 at 229 and ICI Chemicals & Polymers Ltd v The Lubrizol Corporation Inc (2000) 106 FCR 214 at 239-240 [78].
In any event, the contents of the Peng paper fall short of establishing PhotoCure’s case on obviousness. The summary contained in the Peng paper explains the experiment outlined in the paper as follows:
“Nine dyes, all potential sensitizers for photodynamic cancer therapy (PDT), were injected in mice with C3H mammary carcinomas. Twenty-four hours later the animals were sacrificed and the dye concentrations in tumors and 9 other tissues were measured by means of spectrofluorimetry. … The porphyrin precursor d-aminolevulinic acid was also tested and found to induce porphyrin fluorescence in tumors and some other tissues.
The best tumorlocalizer of those tested was 3THPP. This drug also showed a favorable tissue distribution. The following dyes showed lower skin/tumor concentration ratios than PII (the most widely used dye for PDT): Chl e6’ PSD-007, HP-di-hexyl-ether and 3THPP. Low brain/tumor ratios were found for: PSD-007, HP-di-hexyl-ether, 3THPP, TPPS4 and A1PCTS.”
The article explained that two of the nine dyes tested, HpD and PII, were the only photosensitisers being used in clinical trials of PDT. It states (at 2) that:
“Hematoporphyrin derivative (HPD) and Photofrin II (PII), a more purified product, are the only photosensitizers being used in clinical studies of photodynamic cancer therapy (PDT) outside China. So far, promising results have been obtained both in the clinical studies and in the experimental animal investigations. However, these drugs are not ideal: they contain several chemically different components, they have a low absorbance in the red part of the spectrum (which is best transmitted through tissue) and they induce skin photosensitivity in patients for several weeks after an injection. For these reasons several other dyes have been proposed to replace HPD and PII. For a comparison with PII we have chosen 9 such dyes and studied their uptake in C3H mouse mammary carcinomas and other tissues of tumorbearing mice. A good PDT-sensitizer should be efficiently taken up by tumors and show tissue/tumor concentration ratios as low as possible.”
The object of the experiments reported in the Peng paper was to find a drug that provides a high uptake of the photosensitiser in tumours, but with low levels of concentration in healthy tissue. The paper explains the reasons for choosing each of the nine tested substances and includes the statement (at 2) that “d-aminolevulinic acid (d-ALA) was chosen because it is a precursor in the biosynthesis of porphyrins.”
The results of the experiment were discussed and set out in a number of graphs, including Fig 1 under the heading “Tumor uptake”:
The article observes (at 5) that:
“…injection of the porphyrin precursor d-ALA gave rise to some porphyrin fluorescence in the tumor samples. This fluorescence is most likely to be due to protoporphyrins as can be suggested from the biosynthetic pathways leading to heme but no chemical analysis was attempted.”
The evidence at the hearing established that the tumour uptake for ALA was too low for any practical judgment to be made on its effectiveness. It seemed to be common ground that, with the benefit of hindsight, the reason for the poor result in respect of ALA was the fact that the tumour and tissue concentrations were tested 24 hours after the injection, by which time the ALA uptake had been significantly dissipated because of its “short half-life”.
Under the heading “Tissue distribution” (at 7-8) the paper states:
“Porphyrin fluorescence is clearly induced by injection of d-ALA (Figs. 1 and 6). The tissue distribution of the porphyrin fluorescence obtained in this way was on several points different from that obtained by injection of porphyrins. One should particularly note that practically no fluorescence was found in muscle and heart tissue (Fig. 6) and relatively low amounts were found in lung, kidney spleen and liver. This indicates that one should investigate further the possibility to use porphyrin precursors in PDT.”
Figure 6 was as follows:
The hatched bars in the graph compare PII with ALA. They show some promising selectivity outcomes for tumours over some normal tissues, but poor selectivity outcomes in the important practical areas of the skin and the brain.
Although the Peng paper investigated the use of ALA and other photosensitising dyes as drugs for use in PDT, despite some of the potentially positive results demonstrated by figure 6, the overall results were seen by the authors as only warranting the observation that “one should investigate further the possibility to use porphyrin precursors in PDT”. The Peng paper stops short of indicating that the use of ALA in PDT is obvious. All that may reasonably be taken from the paper in respect of ALA or other porphyrin precursors is the authors’ conclusion that the use of such precursors in PDT is worth investigating. As is clear from the High Court’s decision in Alphapharm, that is not sufficient to invalidate a patent on the ground of obviousness.
Accordingly, the patent is not invalid by reason of lack of an inventive step.
(b) Novelty
Section 7(1) of the Act, relevantly, provides that:
“an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the following kinds of information, each of which must be considered separately:
(a) prior art information … made publicly available in a single document or through doing a single act;
…”As explained above, the prior art base relates only to information and documents available in Australia at the priority date.
It is well established in Australia that generally the test for want of novelty is that of “reverse infringement”:
“The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement.”
See Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228 per Aickin J at 235; R D Werner & Co Inc v Bailey Aluminium Products Pty Ltd (1989) 25 FCR 565 (“RD Werner & Co”) at 568-569; Bristol-Myers Squibb Company v FH Faulding & Co Ltd (2000) 97 FCR 524 (“Bristol-Myers”) at 546.
The test is only “generally” applicable because further issues may arise in cases, such as the present, where the anticipation sought to be relied upon is a published paper: see Bristol-Myers at 546 and R D Werner & Co at 569. In cases involving a claimed “paper anticipation” there are two questions: whether the extent or scope of the information in the document is sufficient to cover all of the essential integers of the patent; and additionally, whether the quality of the disclosure in the paper is sufficient to adequately disclose those integers. In Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 (“Nicaro”) at 528 Gummow J explained:
“Where the alleged anticipation is a paper publication, particularly a prior patent specification, there may be ground for debate in a comparison with the specification in suit as to the presence of inessential integers and mechanical equivalents…There may also be a dispute whether what has been disclosed sufficiently reveals an essential integer, in the light of the principles in Hill v Evans …”
His Honour there referred to the often cited statement by Lord Westbury LC in Hills v Evans (1862) 31 LJ Ch 457 at 463:
“[in order to invalidate the subsequent patent] the antecedent statement must be such that a person of ordinary knowledge of the subject would at once perceive, understand, and be able practically to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful… the information as to the alleged invention given by the prior publication must, for the purposes of practical utility, be equal to that given by the subsequent patent.”
That approach has been adopted in Australia: see Olin Corporation v Super Cartridge Co. Pty Ltd (1977) 180 CLR 236 (“Olin”) at 261.
In claiming that the patent is invalid for lack of novelty, PhotoCure relies, in particular, on a paper by Professor Kennedy entitled “Photochemotherapy – clinical aspects”, which was presented at the NATO Conference on Photosensitisation held in July 1987 and published in written form on 30 November 1988 as part of the proceedings of the conference: Photosensitisation: Molecular, Cellular and Medical Aspects, eds G Moreno, RH Pottier, TG Truscott, Springer-Verlag, Berlin, 1998 (“the Kennedy paper”), at 453. It was common ground that the publication of that paper in Australia preceded the priority date of the patent.
The Kennedy paper covers some ten pages and provides an overview of PDT and discusses some of the chief difficulties with, and recent promising developments relating to, this type of treatment. In a number of sections it emphasises the need to improve tissue selectivity of PDT agents. For example, Kennedy states (at 455-456):
“Hematoporphyrin derivative (HpD), the photosensitizing agent in common clinical use at present, shows a useful degree of specificity for many different types of malignant tissue. Of the several normal tissues that retain a clinically significant amount of HpD, the skin is the most important in clinical practice. We often see previously irradiated breast cancer patients who have developed hundreds of tiny cutaneous or subcutaneous secondaries in a restricted area of skin. Curative surgery is impossible, additional radiotherapy is inadvisable, and often the cancer has demonstrated resistance to all of the usual forms of chemotherapy. Since we must assume that the involved area contains many other clusters of malignant cells too small to identify by palpation, we must treat the whole area via a broad external beam. However, since HpD is retained to a significant extent by normal skin, we may find it impossible to eradicate the malignant tissue without causing serious damage to the overlying skin. In principle, there would be no such problem if our photosensitizer showed a greater concentration differential between the malignant tissues and the skin. We could then use doses of photoactivating light sufficiently large to ensure complete eradication of all of the subcutaneous tumors within the treatment field without seriously damaging the overlying skin. A related problem, the retention of HpD by the skin for several weeks or even several months followings its injection, results in a serious risk of phototoxic skin reactions following accidental exposure to sunlight. This hazard would be reduced if HpD showed greater specificity for malignant tissues.
Obviously, a major goal of research should be to improve the tissue specificity of our photochemotherapeutic agents. How might this be done? Four basically different strategies appear to be feasible: (i) combine photodynamic therapy with some other therapeutic procedure that shows similar tissue specificity; (ii) selectively protect non-target normal tissues from phototoxic damage, or selectively decrease the amount of oxygen scavenger normally present in some malignant tissues; (iii) improve the tissue specificity of the photosensitizing drugs; (iv) improve the tissue specificity of the delivery system for the photoactivating light.”
At the conclusion of his paper Kennedy discusses protoporphyrin IX (at 462):
“Protoporphyrin IX (PPIX), a naturally-occurring photosensitizer, is the immediate precursor of heme in the heme biosynthetic pathway. All nucleated cells have at least a minimal capacity to synthesize PPIX, since heme is necessary for the synthesis of various essential heme-containing enzymes. Certain tissues can synthesize relatively large quantities of PPIX. Under normal conditions, the synthesis of PPIX in such tissues is under such tight feedback control that the cells produce it at a rate just sufficient to match their need for heme. However, the usual rate-limiting step in the process, the synthesis of 5-aminolevulinic acid (ALA), can be bypassed by the provision of exogenous ALA. Certain tissues and organs will then accumulate such a large excess of PPIX that they become both fluorescent and photosensitive. At least in the case of skin, the PPIX appears to be synthesized in situ (Sima et al, 1981). Also, several years ago we reported that certain hepatomas and rhabdomyosarcomas retain the ability of their tissue of origin to accumulate large amounts of PPIX if their host is given sufficient ALA. Such tumors become photosensitized, and can be destroyed if exposed to appropriate doses of photoactivating light. On the other hand, certain squamous cell carcinomas lose the ability of their tissue of origin to accumulate PPIX, presumably as a result of a malignancy-induced change in their enzyme profile such that a new rate-limiting step appears in the heme biosynthesis pathway at some stage before the synthesis of PPIX. The main attraction of ALA-induced PPIX as a photosensitizing agent is its short half-life (Pottier et al, 1986). Its main disadvantages are its high concentration in normal skin and its failure to accumulate in certain malignant tissues.”
Accordingly, I propose to consider the Improver questions within the framework outlined by Lord Hoffmann in Kirin-Amgen.
(i)Does the variant (or equivalent) have a material effect upon the way the invention works?
In the present case, the variant (or the equivalent) may be described as the administration to the patient of the methyl ester of ALA which is later transformed into ALA by hydrolysis. Whether or not the variant has a material effect on the way the invention is claimed to work was a matter of some dispute at the trial. However, it appeared to be common ground that this question is to be determined on the basis of the information that is presently available and is to be answered by reference to how the patent claims the invention works. In Improver at 191 Hoffmann J observed that the answer to this question will depend on the level of generality at which one describes the way the invention works. The correct level of generality is that at which the invention is defined in the claims in the patent: see Wheatley at 143 [26] and 144 [34], Union Carbide Corp v BP Chemicals Ltd [1999] RPC 409 at 421, Sundstrand Corporation v Safe Flight Instrument Corporation [1994] FSR 599 at 615 and Kirin-Amgen at [70].
PhotoCure argued that Metvix PDT works in a materially different way to the invention. It sought to demonstrate that Metvix PDT involves:
(a) deeper penetration in a shorter time period;
(b) greater selectivity;
(c) a different cellular uptake;
(d) less pain;
(e) lower systemic absorption; and
(f) a faster clearance rate
than PDT using ALA as described in claim 1.
However, the question as set out in Catnic, Improver and subsequent cases is whether the variant has a material effect on the way the invention works. It is not, as PhotoCure submitted, necessary for DUSA to demonstrate that Metvix PDT “is equivalent in every sense to the administration of ALA”. In Improver, Hoffmann J held that differences between the commercial embodiment of the patented invention and the alleged infringing device, including that the latter was said to work more slowly and cause less pain, were not material differences as to the way the invention worked (at 191-192). In Insituform Technical Services Ltd v Inliner U.K. PLC [1992] RPC 83 at 92-93 Aldous J considered an infringement action in relation to a patented invention for the lining of pipes. He said:
“…[Counsel for the defendant] submitted that the eversion process [used by the defendant] had advantages as compared with the method described in the patent, namely, it was possible to dispense with the outer membrane, no pulling was needed, it was quicker, air was excluded, and it was easier to heat the water during thermal cure. There is no dispute that an eversion process has advantages, but that does not mean that carrying out eversion has a material effect upon the working of the invention.
The invention … is the making of a pipe within a pipe by urging an impregnated flexible laminate against the surface of the pipe until the resin is cured. The actual way that the laminate is inserted or formed is not the essence of the invention as claimed or described in the complete specification. I cannot see any reason why the skilled reader would believe that insertion of the laminate by eversion was intended to be excluded from the monopoly claimed. Further, if he realised that eversion had advantages over pulling a preformed laminate through the pipe, he would realise that it would have no material effect upon the way the inventive concept of the patent worked.” [emphasis added]
In Kastner v Rizla Ltd [1995] RPC 585 Aldous LJ noted at 599 that the variant was mechanically different from the patented invention, but found that it produced the same effect.
In the present matter the specification states that an object of the invention is “to provide a method for the detection of certain types of malignant and non-malignant tissue abnormalities by induced fluorescence”, and that another object is:
“to provide a photodynamic (photosensitizing) treatment method which can be [administered] either systemically or topically using an agent which is not in itself a photosensitizer but which induces the synthesis of protoporphyrin IX (PpIX) in vivo.” [emphasis original]
The “Statement of Invention” refers to administering to the patient a precursor of PpIX in the biosynthetic pathway to heme in order to induce an accumulation of PpIX in lesions (and mentions the use of ALA as a preferred embodiment of the invention). The Objects and the Statement of Invention are set out in claim 1, which describes the way in which the invention works as the administration to the patient of an effective amount of ALA, so as to induce synthesis of PpIX in the targeted lesions and expose those lesions to light within the photoactivating action spectrum of PpIX. Claim 9, relevantly, describes the invention in the same terms, save that the administration is of a precursor of PpIX in the biosynthetic pathway.
In the present context, the issue is whether the administration of methyl-ALA results in an effective amount of ALA, thereby inducing synthesis of PpIX in the targeted lesions.
While some of the matters relied upon by PhotoCure can be relevant to demonstrating how methyl-ALA (or Metvix) works (in particular, by a different cellular uptake or greater selectivity) they involve quantitative questions, or questions of degree, in relation to the efficacy of methyl-ALA or Metvix PDT, rather than to any qualitative difference in the biological sequence by which the selective accumulation of PpIX in the targeted lesions is achieved. In those circumstances I am not satisfied that the matters relied upon by PhotoCure establish that the use of methyl-ALA or Metvix PDT has a materially different effect on the way the invention works.
PhotoCure’s case on this issue sits uncomfortably with its “Expert Report on the Toxico-Pharmacological (Preclinical) Documentation for Metvix” dated 23 March 2000, which formed part of PhotoCure’s Therapeutic Goods Administration application. The report states that methyl-ALA is a precursor in the cellular synthesis of heme and PpIX and that methyl-ALA and ALA “are both metabolised to the photoreactive protoporphyrin PpIX through the same or similar metabolic pathways”. At p 7 of the Report reference is made to PpIX as an endogenous photosensitiser which is “the last intermediate in the synthesis of heme…” and that “[w]hen adding precursors of PpIX e.g. ALA or esters of ALA, the negative feedback mechanism controlling the production of heme is by-passed and PpIX accumulates”. At p 10 of the report there is a reference to the identity of PpIX formed from ALA and methyl-ALA in certain in vitro studies. The Report is consistent with the evidence that, in so far as the inventive concept is concerned (ie using ALA, as a non-sensitising agent, to induce synthesis of PpIX in the targeted cells), ALA and methyl-ALA are not materially different in relation to how the invention works.
Of course, the report refers to in vitro, rather than in vivo, studies, but similar statements were made in the Norwegian Radium Hospital Research Foundation patent for methyl-ALA, which treated methyl-ALA’s metabolic conversion to ALA as making the use of methyl-ALA “essentially equivalent” to the use of ALA. PhotoCure’s Australian patent for methyl-ALA referred to methyl-ALA as acting “like ALA” by exerting its effect by enhancing production of PpIX. The patent states that upon delivery of the methyl-ALA “to the desired site of action hydrolytic enzymes such as esterases present in the target cells break down the esters into the parent ALA, which then enters the [heme] synthesis pathway and leads to a build-up of Pp[IX]”. While both patents also refer to the claimed advantages of methyl-ALA over ALA, I regard those advantages as relating to the quantitative aspects of methyl-ALA referred to above, rather than to the way the invention works.
Further, Professor Moore (at T 203) accepted that methyl-ALA is a precursor of ALA because, although it is a different compound with differences in its pharmokinetics, its ultimate “manner of action” is equivalent to ALA.
An unpublished report written after 1992, which lists Professor Kennedy as one of the authors, revealed that research had been conducted into “ALA derivatives in order to see if other non-natural amino acids could also be used for PDT”. The preliminary finding on the use of methyl-ALA was that it “mimics the in vivo reactivity of ALA”.
Finally, numerous papers published since 1991 (a number of which are referred to in Schedule A of DUSA’s reply submissions on infringement) also treat the way in which methyl-ALA and ALA work as essentially equivalent. One of the more recent papers, “New 5-Aminolevulinic Acid Esters – Efficient Protoporphyrin Precursors for Photodetection and Photodynamic Therapy” by H Brunner et al (Exhibit A6), which was published in 2003 in
vol 78(5) of the journal Photochemistry and Photobiology at 481-486 (“the Brunner et al article”), states:
“…ALA esters have been used as prodrugs instead of ALA itself. Within the cells the ALA esters are hydrolyzed by unspecific esterases to give the parent compound ALA.”
In the 1998 paper by J Kloek et al titled “Derivatives of 5-Aminolevulinic Acid for Photodynamic Therapy: Enzymatic Conversion into Protoporphyrin” published in vol 67(1) of Photochemistry and Photobiology at 150-154 (“the Kloek et al 1998 article”) the authors state:
“One of the solutions to the bioavailability problem of ALA is provided by the prodrug concept. A prodrug is a chemical derivative of a drug that shows more favorable pharmacological properties than its parent compound. The prodrug itself is pharmaceutically inactive, but it is converted into the active parent compound by enzymes at the site of action. In the case of ALA prodrugs, conversion into original ALA will cause the onset of PpIX synthesis in the same way as administration of ALA itself. Hence, in photochemical terms, there is no difference between administration of ALA prodrugs and ALA itself.”
JM Gaullier et al wrote (in their article “Use of 5-Aminolevulinic Acid Esters to Improve Photodynamic Therapy on Cells in Culture” published in vol 57 of the journal Cancer Research at 1481-1486) that “… the esterification of ALA has no detectable effects on the pathway leading to PpIX formation or on the intracellular distribution of PpIX”. I would add that there was other evidence, to which I refer in relation to the second Improver question, to the same effect.
PhotoCure also claimed that Metvix PDT involves the production and use of different porphyrins than those involved in ALA PDT. The production of PpIX is clearly central to the way in which the invention described in the patent works. In this context, PhotoCure relied on the results of studies by Menon and Haberman commissioned by DUSA’s predecessor, Deprenyl Research, which compared the functioning of ALA with that of methyl-ALA. Those studies, which DUSA sought to discredit, show that different porphyrins were produced through the administration of methyl-ALA than were produced when ALA was used. While the studies go some way in supporting PhotoCure’s case on this issue, there are several reasons why I am not satisfied that they establish that methyl-ALA works in a different way. First, the studies are not sufficiently detailed or comprehensive to overcome the substantial body of expert opinion, and the papers upon which I have relied to conclude that methyl-ALA and ALA are not materially different in the way they induce the synthesis of PpIX in the targeted lesions. Second, the studies do not justify a conclusion that protoporphyrin (PpIX) is not the active moiety in Metvix PDT. Third, the results were not based on any in vivo tests. Finally, the studies were not conclusive on the utility of the additional porphyrins. Rather, they referred to the different porphyrins produced from ALA and methyl-ALA as showing “…the possibility that different derivatives of ALA would be useful for [PDT] of a variety of conditions.”
For the above reasons the first Improver question is to be answered in the negative.
(ii)Would this (i.e. that the variant (or equivalent) had no material effect) have been obvious at the date of publication of the patent to a reader skilled in the art?
The relevant date for the making of this assessment is the date of the publication of the patent (Improver at 189), namely 11 March 1991. The assessment was framed by Hoffmann J in Improver at 192 as presupposing that the reader skilled in the art is told of both the invention and the variant (or equivalent) and asked whether it will obviously work in the same way.
As stated earlier in these reasons, the reader skilled in the art is a researcher in the field of PDT who is working on improving PDT methods of treatment. That reader is to be treated as equipped with the common general knowledge available at the publication date. The evidence did not indicate that there would have been any material difference between the common general knowledge that existed at the priority date and that existing at the publication date. I therefore do not consider it to be of significance that some of the evidence led on this question related to the priority date (in 1989), rather than to the publication date (in 1991).
PhotoCure adduced a significant body of evidence to the general effect that it would not have been possible to determine in 1989 what would happen if methyl-ALA was used in PDT. It also relied on Professor Oseroff’s agreement (at T 556) with the proposition put to him by senior counsel for PhotoCure that “If one were considering in 1989 the possibility of using an esterified form of ALA for some particular supposed advantage over ALA, it’s … true … that the outcome would be impossible to predict”.
However, evidence of that kind is not necessarily helpful to PhotoCure’s case without more. The specific question that needs to be considered is whether, at the relevant date, it would have been obvious that the use of methyl-ALA, instead of ALA, would have had no material effect on the way that the patented invention works. As I have indicated above, this does not include considerations such as whether the variant would have worked more or less rapidly, or whether it would have had more or fewer side effects or what their nature would be. It is necessary to ask whether it would have been obvious that the use of methyl-ALA would induce synthesis of a sufficient amount of PpIX in the targeted lesions to enable the PDT treatment of those lesions. There was evidence that was directly relevant to this specific question.
In the Kloek et al 1998 article the authors observed that:
“The improvement of the bioavailability of ALA by use of an ALA-prodrug is determined by two processes: the rate of diffusion of the prodrug through biological barriers and its rate of enzymatic conversion into the parent ALA.”
I am satisfied that there was expert evidence, upon which I am prepared to rely, to the effect that in March 1991 it would not have been possible to predict the rate or extent of hydrolysis of the methyl-ALA. Without this knowledge it would not have been possible to know whether a sufficient amount of ALA would be produced so as to induce the synthesis of the requisite amount of PpIX to enable PDT treatment of the targeted lesions.
Professor Roberts gave evidence (at T 284-285) that it would not have been possible to predict the rate of hydrolysis and that this would have been crucial in determining whether methyl-ALA would work in the same way as ALA:
“CATTERNS: Then so far as selectivity goes, whether or not one was able to predict how selective one would be versus the other, again that’s a matter of setting up experiments of a conventional type?
ROBERTS: Except that you always have 100 per cent vision in hindsight and I have to be honest with you. I didn’t understand, and I’ve only just started to understand now, the relevant importance of this metabolism, you know, of the actual prodrug going to the whatever in tumours compared to normal tissue. The amount of work that has been done in terms of tumours and normal tissue in terms of metabolism isn’t that great.
CATTERNS: When you say ‘metabolism’ are you referring about the hydrolysis of the - - -?
ROBERTS: Hydrolysis of the ester.
CATTERNS: The rate at which it does and doesn’t hydrolyse?
ROBERTS: Yes, and as it applies to different sorts of esters. That information I can’t find too easily.
CATTERNS: So far as – is that the matter so far as selectivity goes that you would have had difficulty predicting back in 1989?
ROBERTS: Correct.
CATTERNS: So far – sorry?
ROBERTS: I was going to say selectivity depends upon both getting it in and then having the material converted if you assume that the conversion of ALA is active moiety. It also depends on that rate of conversion.
CATTERNS: Having perceived various differences of that type, it’s a matter for the experimenter and then the clinician, isn’t it, to adjust your time, doses and other pharmacokinetic variables?
ROBERTS: It is, but for instance which ester do you choose? Do you choose a methyl ester or do you choose a hexyl ester or do you choose a propyl ester? That you have to establish by experiment.
CATTERNS: Of the type you and I have been talking about? If you wouldn’t mind just saying yes for the transcript?
ROBERTS: Yes.”
When asked about a 2001 publication which compared the use of ALA with methyl-ALA, Professor Roberts said (at T 276) that the outcomes of that study would not have been foreseen:
“…because we don’t – as I said, the problem with esterase activity is in the fact that we have different esters in the – different esterases in the body. So we have different esterases for long chain fatty acids compared to short chain ones. So I’m not sure we would have foreseen exactly how the ALA-ME was going to be – how fast it can be metabolised. I can’t find any literature around at all on ALA-ME metabolism, how fast it is. So I couldn’t have foreseen that.”
Professor Roberts then indicated that he would have had to experiment in order to ascertain the rate at which ALA-ME would be metabolised.Later (at T 289) he explained more specifically the state of knowledge in 1989 regarding the metabolism of esters of ALA:
“MACAW: You said a short time ago that one of the differences between esters of ALA was their rate of hydrolysis?
ROBERTS: Yes.
MACAW: Could you in 1989, in selecting a particular ester of ALA, have predicted then the rate of hydrolysis for the esters you were concerned to select from?
ROBERTS: In some cases yes, in some cases no. So if we were playing around with acetylcholine and trying to make a sort of a range of acetylcholine derivatives, we knew exactly what the enzyme was, acetylcholinesterase, which would be metabolising that series of compounds. For other compounds we didn’t know where the actual metabolism was occurring, so that – I was doing work at that time on aspirin hydrolysis, and we only found in, I think it was 1989 in fact, that albumen was one of the things which hydrolysed it. So there’s a range of both specific and non-specific esterases involved.
MACAW: What about the range of esters themselves?
ROBERTS: There’s a range of those as well, as, as I said earlier, we talk about acetylcholinesterases, we talk about arylesterases, and I think I’ve mentioned in my affidavit there’s about five or more of them. So there are some esterases meant to break down the lipids that you – you know, the very – the fatty acids that you swallow in your food. You have to sort of convert those lipids into fatty acids that the body can then use for energy, and they are different sorts of esterases to, say, acetylcholinesterase, which is meant to break down acetylcholine, which is a natural transmitter.”
Professor Robert’s views were consistent with those of DUSA’s witness, Professor Oseroff, whose evidence (at T 546-547) was as follows:
“MACAW: Professor, an esterified form of an active compound would have to hydrolyse to the active compound before it would have the activity of the active compound?
OSEROFF: That’s correct.
MACAW: You couldn’t tell, could you, in advance what would be the rate or extent of hydrolysis of any particular esterified form?
OSEROFF: My understanding of the esterases, at least in the skin, is that they’re not particularly selective as to which ester it is. So I don’t know of data that says that an ethyl ester, for example, would be hydrolysed at a different rate than a methyl ester. So I wouldn’t necessarily believe that different esters would be hydrolysed at different rates but I certainly would believe that they all need to be hydrolysed.
MACAW: Let me ask you though about different tissues. The biochemistry of the body means that you might get a different rate or extent of hydrolysis of any particular esterified form for any particular given tissue?
OSEROFF: Yes.
MACAW: The rate and extent of hydrolysis might vary according to whether one adopted the oral or parenteral or topical route of administration?
OSEROFF: Yes, though I can’t conceive of why one would use a[n] ester form for other than topical application, actually. That may be my bias as a dermatologist but the issue is to get it through this barrier, biological barrier, that would otherwise keep out the drug. If one is administering it into a vein then you’ve – there is no barrier and I’m not sure I would see any immediate reason to use an ester.
MACAW: Does the same observation apply in the case of oral administration?
OSEROFF: I have little experience – in fact, I have no experience with oral administration of ALA. So I’m not certain I really can give an informed opinion on the oral issues.
…MACAW: Professor, would this be a correct proposition, that because one couldn’t tell with any certainty in advance what the pharmacological activity would be of an esterified form, because one couldn’t tell with any certainty in advance that there may be toxic side effects, because one couldn’t tell in advance what the rate or extent of hydrolysis was for any particular tissue, and because one couldn’t tell in advance what the rate or extent of hydrolysis would be for any particular mode of application, one would necessarily have to experiment in order to work out whether an esterified form would produce a useful outcome of otherwise?
OSEROFF: Yes. That’s a very broad question and I really can only – I’d like to confine my answer to the skin, which is really where my focus has been. In the skin there is – one knows of the existence of the esterases because of other esterified drugs that have been administered and one knows that there have been no cases of toxicity, at least to my knowledge, of using esterified forms. The amount of drug that gets into the body through the skin is so small that the – I mean that’s the virtue of topical application – that systemic effects are usually not a significant concern. So I guess my – what you say is true in theory but in terms of – it’s I think far simpler for topical drugs and the skin.
MACAW: Do you mean that in the case of topical application you might have a higher degree of assurance in advance that some predicted advantage of using any particular esterified form might be achieved?
OSEROFF: That is correct.
MACAW: But you would always need to test?
OSEROFF: Of course, of course.”
Professor Kennedy (at T 683) agreed that the enzymatic profiles of particular tissues were of significance in determining “… whether they can or cannot generate and accumulate an abnormally large amount” of PpIX. Professor Oseroff (at T 551) also stated that clinical testing was necessary before being confident that any particular derivative of ALA would be a useful one.
PhotoCure’s evidence included the Brunner et al article, which set out results from in vitro testing of various esters of ALA as agents in PDT and photodetection. The authors remark (at 486) that:
“It is well known that in vitro properties of ALA esters are quite different from their in vivo properties. Therefore, esters poorly performing in this study might show better performance in in vivo studies.”
When cross-examined on this question Professor Oseroff agreed with the authors’ remark and confirmed (at T 556) that “the studies of the sort in this paper are not highly predictive for the ultimate outcome in practical applications.” Professor Kennedy stated in his affidavit that:
“The use of methyl ALA requires conversion by an esterase into the active pro-drug ALA. In this process, animal models have limited predictive value for human treatment because so much depends on the details of human biochemistry.”
The minutes of the PDT Steering Committee of the Norwegian Radium Hospital of 19 December 1994 make the same point. The minutes state:
“Esters
It was agreed to intensify the work on esters. Peng had performed testing in mice that indicates similar properties as 5-ALA. The model used has limited precision with respect to human effect. TW will perform some biopsies on patients that will remove basaliomas with surgery.”Professor Waner also commented on the difficulties of extrapolating from the results of in vitro experiments without confirmatory in vivo testing. He regarded (at T 341) such extrapolations without confirmatory testing as justifying no more than speculation on the outcome.
There are a number of reasons why in March 1991 it would have been accepted by persons skilled in the art that the efficacy of an ester of ALA, including methyl-ALA, which, unlike ALA, is a synthetic compound, could only be ascertained with any degree of confidence after in vivo testing. However, the main reason is the need to determine whether the esters of ALA have hydrolysed to a sufficient extent and at a sufficient rate to induce the required synthesis of PpIX in the targeted human cells.
Professor Kennedy’s evidence (at T 659 and T 710), concerning the unpublished research by Menon and Haberman from about 1991-1992, which was commissioned by DUSA’s predecessor, Deprenyl Research, also suggests that methyl-ALA needed to be tested in order to ascertain whether the methyl alcohol in methyl-ALA might result in a different enzyme activity and intra-cellular response than would occur with ALA.
Another reason why testing was necessary was that in March 1991 little was known by the reader skilled in the art as to why the exogenously administered ALA caused the by-passing of the rate-limiting step to induce the synthesis of PpIX in situ in the targeted cells. Thus, it would have been difficult to predict with any confidence whether methyl-ALA would work in the same way as ALA. It is relevant in that regard that, as at 1991, only two articles had been published on ALA-based PDT. By 1995, 55 articles had been published on ALA or methyl-ALA based PDT (Peng et al “5-Aminolevulinic Acid-Based Photodynamic Therapy: Principles and Experimental Research” 65(2) Photochemistry and Photobiology (1997) at 235-251). The fact is that most of the studies that might be relevant to this question only became available to the hypothetical reader skilled in the art after 1991.
DUSA relied upon a number of publications in support of its case on the second Improver question. The publications, which were annexed as Schedule A to DUSA’s reply submissions, all post-date the 1991 publication date. However, several of the papers are to the effect that during the 1990s those engaged in researching the subject held expectations or theoretical views that ALA and methyl-ALA would be likely to work in the same way, but those expectations and views fall short of it having been obvious to the authors that the two compounds would work in the same way. I am not satisfied that the publications justify the affirmative answer, as at March 1991, to the second Improver question that DUSA is contending for.
In the result, I am satisfied that the reasonable reader skilled in the art would not answer the second Improver question in the affirmative unless satisfied that some in vivo tests had been carried out to justify that answer. It is clear that the results of such testing did not become known until well after 1991.
Ultimately, DUSA submitted that the present case cannot, relevantly, be distinguished from Beecham Group Limited v Bristol Laboratories Limited [1978] RPC 153 (“Bristol Laboratories”). In Bristol Laboratories the House of Lords held that the “pith and marrow” approach resulted in the marketing of hetacillin, which was a reproduction of the substance ampicillin, albeit temporarily masked, constituting an infringement of the ampicillin patent. DUSA claimed that methyl-ALA was developed for the sole purpose of producing ALA and contended that the reversible reaction of esterifying ALA to methyl-ALA and hydrolysing methyl-ALA to ALA plus alcohol is comparable to hetacillin. The answer to that contention is to be found in the following passage of Lord Diplock in Catnic at 243-244:
“My Lords, upon analysis of the speeches in this House in Van der Lely v. Bamfords the division of opinion between Lord Reid and the remainder of their Lordships appears to have been due to his thinking that it would be obvious to the informed reader that dismounting the ‘foremost’ rather than the ‘hindmost’ wheels was an immaterial variant, whereas the majority were not satisfied that this was even the fact, let alone that it was obviously so. In the bracelet case, Rodi and Weinenberger A.G. v. Harry Showell Ltd. (ubi sup.) where this House was more evenly divided, the difference between the majority and the minority appears to have turned upon their respective views as to whether the particular variant alleged to be an infringement, had a material effect upon what were claimed to be the advantages obtained by the patented invention - as to which they differed. In the third of the trilogy of leading cases in this House upon this topic, the ampicillin case, Beecham Group Ltd. v. Bristol Laboratories Ltd. [1977] F.S.R. 215; [1978] R.P.C. 153, the descriptive phrase was ‘an amino group in the alpha position’. In the alleged infringing antibiotic, hetacillin, this amino group had been temporarily converted by a further chemical reaction into a molecular structure that was no longer an amino group, but the reaction was reversible and upon being put to use as an antibiotic, (which necessitated contact with water) it reverted to its original form as an amino group and in that form produced its prophylactic effects. This House unanimously held that this temporary masking of the amino group amounted to an immaterial variant. It would be obvious to anyone skilled in the specialised art of selecting and synthesising polymers for use as antibiotics that the essential feature of the invention was that when put to use for its intended purpose, the product should have an amino group in the alpha position; and that, accordingly, the patentee's reference to this feature of his claim cannot have been intended by him to exclude products in which the amino group in that position was temporarily displaced during a period before the product was put to any prophylactic use.” [emphasis added]
Infringement was established in Bristol Laboratories because of the conclusion that it was obvious to a person skilled in the art that the temporary masking of the ampicillin was an immaterial variant which did not result in the variant falling outside the claims. Thus, the variant, hetacillin, did not have a material effect upon the way the invention worked (the first Improver question) and that would have been obvious at the relevant time to the reader skilled in the art (the second Improver question). Accordingly, the variant was not intended to fall outside the claim (the outcome of the third Improver question).
As explained above, the present case is one in which I have determined that, as at the publication date, it was not obvious to the reader skilled in the art that the variant (methyl-ALA) would have no material effect upon the way the invention (ALA) worked. Thus, the present case is clearly distinguishable from Bristol Laboratories. I would add that, in any event, as was explained in Root Quality (at 242 [44]-[45]), the “pith and marrow” approach has been overtaken by the purposive approach enunciated in Catnic, Improver, and Kirin-Amgen.
It may not be strictly necessary to address the third Improver question as the answer to the second question has the consequence that, applying a purposive approach to the construction of the claims, there is no proper basis for concluding that the primary meanings of “administering to the patient” and “5-aminolevulinic acid” in the claims were not the intended meanings. However, it is also clear that the answer to the third Improver question is that the reader skilled in the art would have understood that compliance with the primary meaning of those phrases was an essential requirement of the invention. I would add that it was not, and could not be, disputed that “administering to the patient” and “5-aminolevulinic acid” were essential integers. Thus, DUSA has not made out its case on infringement.
6. Conclusion
In the result, PhotoCure’s application for revocation of the patent is to be dismissed and DUSA’s cross-claim for infringement must also be dismissed. Because so many of the issues raised on the application and the cross-claim were closely related, it would be an almost impossible task to separate the substantial costs incurred in relation to the application from the substantive costs incurred in relation to the cross-claim. For example, a great deal of the extensive evidence relating to obviousness was relevant to both the application and the cross-claim. In the circumstances, which include DUSA’s success on the application and PhotoCure’s success on the cross-claim, I am of the view that the fair and reasonable outcome is for each of the parties to bear its own costs of and incidental to the application and the cross-claim.
I certify that the preceding two hundred and forty-nine (249) numbered paragraphs are a true copy of the Reasons for Judgment herein of the Honourable Justice Merkel. Associate:
Dated: 5 April 2005
Counsel for the Applicant and Cross-Respondents: Mr RC Macaw QC with
Mr AJ RyanSolicitors for the Applicant and Cross-Respondents: Mallesons Stephen Jaques Counsel for the Respondents and Cross-Claimant: Mr DK Catterns QC with
Ms SJ GoddardSolicitors for the Respondents and Cross-Claimant: Freehills Dates of Hearing: 1, 2, 5, 6, 7, 8, 13, 14, 15, 16, 19, 28, 29 and 30 April and 23 September 2004 Date of Judgment: 6 April 2005
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