The cOmplete Patent specification
11 The entitlement of the complete specification is set out in paragraph 1 above. The body of the Patent specification describes the product, process and method of treatment which are defined in the claims thus:
'The present invention relates to a stable intravenously injectable ready-to-use solution of an antitumour anthracycline glycoside, e.g. doxorubicin, to a process for preparing such a solution, and provide the same in a sealed container, and to a method for treating tumours by the use of the said ready-to-use solution.'
12 Then follows a description of relevant prior art and the problems which the invention seeks to overcome as set out in paragraphs 9 and 10 above.
13 The complete specification then sets out the consistory clause for the product, which underlines Claim 1, as follows:
'According to the present invention, there is provided a sterile, pyrogen-free, anthracycline glycoside solution which comprise a physiologically acceptable salt of an anthracycline glycoside dissolved in a physiologically acceptable aqueous solvent therefor at an anthracycline glycoside concentration of from 0.1 to 50 mg/ml, which has not been reconstituted from a lyophilizate, and the pH of which has been adjusted from 2.5 to 5.0 solely with a physiologically acceptable acid. Preferably the solution of the invention is provided in a sealed container.'
14 The language of the consistory clause for the product is then reflected in a preferred embodiment as follows:
'According to a particularly preferred embodiment of the invention, there is provided a sterile, pryogen-free, doxorubicin solution which consists essentially of a physiologically acceptable salt of doxorubicin dissolved in a physiologically acceptable solvent therefor at a doxorubicin concentration of from 0.1 to 50 mg/ml, which has not been reconstituted from a lyophilizate and the pH of which has been adjusted from 2.5 to 5.0 solely with a physiologically acceptable acid.'
15 The complete specification then sets out the consistory clause for the process as follows:
'The invention also provides a process for producing a sterile, pyrogen-free anthracycline glycoside solution with a pH of from 2.5 to 5.0, which process comprises dissolving the physiologically acceptable salt of the anthracycline glycoside, which salt is not in the form of a lyophilizate, in the physiologically acceptable solvent therefor; adding solely a physiologically acceptable acid to adjust the pH within the said range as desired; passing the resulting solution through a sterilising filter and, optionally, adding an additional component selected from a co-solubilizing agent, a tonicity adjustment agent and a preservative, for instance of the kind previously specified, to the solution prior to passing the solution through the sterilising filter.'
16 The complete specification then proceeds:
'With the solutions of the invention it is possible to obtain compositions having a very high concentration of the anthracycline glycoside active substance even at 50 mg/ml and more. This constitutes a great advantage over the presently available lyophilized preparates wherein high concentrations of anthracycline glycoside can only be obtained with difficulty because of solubilization problems encountered in reconstitution, mainly with saline. The presence of the excipient, e.g. lactose in the lyophilized cake, and its generally high proportion in respect of the active substance, even up to 5 parts of excipient per part of active substance, has a negative effect on solubilization so that difficulties may arise in obtaining dissolution of the lyophilized cake.'
17 Then the complete specification sets out the consistory clause for the method as follows:
'… according to the invention there is also provided a method of inhibiting the growth of a tumour, in particular one of those indicated above, which comprises administering to a host suffering from said tumour an injectable solution according to the invention containing the active drug substance in an amount sufficient to inhibit the growth of said tumour. The injectable solutions of the invention are administered by rapid intravenous injection or infusion according to a variety of possible dose schedules.'
18 Further, in terms of preferred embodiments, the complete specification then provides 12 examples which 'illustrate but do not limit in any way the invention' and they include the dissolution of doxorubicin, and the adjustment of the solution's pH, followed by the filtration and containment of the solution in sealed vials. The stability of the 12 solutions is then described over various periods of time.
19 The invention is the subject of 26 claims. The pharmaceutical product (solution) claims are claims 1 to 19 and 22. The process claims are claims 20, 21, 23 and 24 and the claims relating to a method of treatment using the product are claims 25 and 26.
20 The applicants allege the respondents have infringed:
(a) product claims 1 to 3, 5 to 10, 14 and 15; and
(b) method claims 25 and 26.
21 Claim 1 is the only independent claim relating to a solution of the invention and the only claim that refers to the invention as a solution 'which has not been reconstituted from a lyophilizate' and 'the pH of which has been adjusted from 2.5 to 5.0 solely with a physiologically acceptable acid.'
22 The parties are agreed that resolution of the construction of Claim 1, in respect of those parts emphasised below, will resolve the controversy between them. Claim 1 is now set out with numbers (1) to (6) interpolated to identify its six integers:
'1. (1) A sterile,
(2) pyrogen‑free
(3) anthracycline glycoside solution
(4) which comprises
(i) a physiologically acceptable salt of an anthracycline glycoside
(ii) dissolved
(a) in a physiologically acceptable aqueous solvent therefor
(b) at an anthracycline glycoside concentration of from 0.1 to 50 mg/ml,
(5) which has not been reconstituted from a lyophilizate
(6) and the pH of which
(i) has been adjusted from 2.5 to 5.0
(ii) solely with a physiologically acceptable acid.'
23 It is also necessary to set out Claim 20, the process claim, relied on by the respondents as an aid to construing Claim 1:
'20. A process for producing a sterile, pyrogen-free, anthracycline glycoside solution with a pH of from 2.5 to 5.0, according to any one of the preceding claims; which process comprises dissolving a physiologically acceptable salt of the anthracycline glycoside, which salt is not in the form of a lyophilizate, in a physiologically acceptable aqueous solvent therefore; adding solely a physiologically acceptable acid to adjust the pH within the said range as desired; passing the resulting solution through a sterilising filter; and, optionally, adding an additional component selected from a cosolubilizing agent, a tonicity adjustment agent and a preservative to the solution prior to passing the solution through the sterilising filter.'
24 The invention is for a new combination. Accordingly, to establish infringement, the applicants must demonstrate that the respondents have taken 'each and every one of the essential integers': Populin v H.B. Nominees Pty Ltd (1982) 41 ALR 471 at 475. The respondents have admitted their product has the features of the new combination in Claim 1 except those covered by integer (5) and the emphasised part of integer (6)(ii).
25 Each of the respondents is involved in one of the manufacture, distribution or sale of the respondents' product. In a written outline of submissions, the respondents' product is described as:
'. . . a sterile, pyrogen-free anthracycline glycoside solution which comprises a physiologically acceptable salt of an anthracycline glycoside dissolved in a physiologically acceptable aqueous solvent therefor at an anthracycline glycoside concentration of from 0.1 to 50 mg/ml. The pH of the solution has been adjusted to a figure within the range of 2.5 to 5.0.'
26 The respondents assert that their product does not infringe the Patent because, at an early stage in the manufacturing process, the dissolution of bulk lyophilizate takes place, and that therefore their solution has been 'reconstituted from a lyophilizate', a feature of production which it asserts is expressly excluded by Claim 1 of the Patent. It can be noted in this context that the applicant conceded that the bulk powder used in the manufacture of the respondents' product is a lyophilizate.
27 The applicants assert that the Patent is to be construed such that the words 'which has not been reconstituted from a lyophilizate' in Claim 1 are limited to mean the process that takes place just prior to administration of the solution to a patient. They submit that the expression means (and thereby excludes from the monopoly claimed) solutions made up shortly before administration to a patient, which were known at the priority date and does not mean the dissolution of the lyophilizate in the respondents' method of manufacture. Therefore, it is submitted, the respondents' product is within the scope of Claim 1.
28 Thus the two questions to be resolved by the court are whether (i) the respondents' product has been 'reconstructed from a lyophilizate' as the phrase is used in Claim 1 and (ii) the pH of the respondents' product has been adjusted solely with a physiologically acceptable acid.
29 The claims in a complete specification define the invention: s 40(2)(b) of the Patents Act. They mark out the monopoly operating to disclaim what is not specifically and definitely claimed: Walker v Alemite Corp (1933) 49 CLR 643 at 656. This is to ensure that the public and specifically a manufacturer will not have difficulty being satisfied that a claim is not infringed: General Tire & Rubber Co. v Firestone Tyre & Rubber Co Ltd (No. 1) [1972] RPC 457 at 515 ('General Tire & Rubber Co.'). There are no special rules for the interpretation of patent specifications: Décor Corporation Pty Ltd v Dart Industries Inc (1998) 13 IPR 385 at 391 (per Lockhart J) ('Décor'). The approach to be taken is discussed by the High Court in Kimberly‑Clark Australia Pty Limited v Arico Trading International Pty Limited and Others (2001) 207 CLR 1 at [24] ('Kimberly-Clark'):
'It is well settled that the complete specification is not to be read in the abstract; here it is to be construed in the light of the common general knowledge and the art before 2 July 1984, the priority date; the court is to place itself "in the position of some person acquainted with the surrounding circumstances as to the state of [the] art and manufacture at the time".'
30 The parties were substantially in agreement that the skilled addressee for the purposes of this case was a 'team' as is appropriate with highly developed technology: General Tire & Rubber Co. at 485. The team included not only a pharmacist working in a hospital but also persons involved in the manufacture of cytotoxic drugs for hospital pharmacists, as at the priority date 2 April 1985.
31 Speaking broadly, it was contended for the applicants that the word 'reconstituted' as it occurs in the phrase 'has not been reconstituted from a lyophilizate' in Claim 1 was a term of art. It was conceded that the word had an ordinary English meaning in pharmaceutical science but it was contended that it also had a specialist meaning in pharmaceutical science. Thus the word 'reconstitution' was capable of having more than one meaning. It was submitted that ambiguity or lack of clarity could be dispelled by resort to the body of the specification.
32 Alternatively, if 'reconstituted' as used in Claim 1 is not a term of art, it was contended that the complete specification, ie. the context showed the expression was used in a special and narrow sense. Either way the exclusionary integer would indicate to the skilled addressee that the invention did not cover known prior art.
33 It was contended for the respondents that the word 'reconstituted' as used in Claim 1 is not a term of art. Next, it was submitted it was a word of ordinary English meaning, which as a matter of principle precluded resort to the body of the specification to qualify Claim 1. Further, the express terms of Claim 1 were relied on as not limiting the phrase in contention, to solutions in a vial or to injectable solutions. It was submitted that the applicants' attempts to construe the exclusionary integer narrowly should fail.
34 Numerous experts gave evidence about the meaning of the term 'reconstituted' which is unexceptional given the terms of the dispute: Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd [1979‑1980] 144 CLR 253 at 270 ('Minnesota Mining'); Leonardis v Sartas No. 1 Pty Ltd (1996) 35 IPR 23 at 36.
35 The applicants' experts did not dispute the fact that 'reconstitution' has a usual, or as they put it, general meaning, perhaps best exemplified by the relevant entry in the 1982 Supplement to the Oxford English Dictionary:
'reconstituted, that has been constituted or formed anew; applied spec. to food which has been dehydrated and subsequently made ready for use by adding liquid.'
36 It was also conceded by the applicants that the word 'reconstituted' was used in the pharmaceutical sciences with a usual but narrower meaning of describing the step of putting lyophilized material into solution. This is exemplified in an entry after the priority date in the Dictionary of Pharmacy, Pharmaceutical Products Press, 2004:
'reconstitution process of adding a solvent or suspending liquid (usually purified water) to a previously prepared spray‑dried or freeze‑dried drug formulation intended to be used in a short period of time (usually within two weeks) after the addition (generally refrigerated following reconstitution); example: reconstitution of an antibiotic suspension'
37 Professor Stella, an American Professor of Pharmaceutical Chemistry, gave evidence on behalf of the applicants that as at the priority date, in 1985, all anthracycline glycosides were supplied for use as lyophilizates prepared in a particular way to produce an intravenously injectable solution.
38 Dr Williams, a specialist pharmacist in manufacturing from Westmead Teaching Hospital in New South Wales, gave evidence on behalf of the applicants of his experience also as at the relevant date. He gave evidence that anthracycline glycosides were provided to pharmacists in single dose sealed vials:
'. . . which had to be prepared by the pharmacist for administration to the patient by a reconstitution. A reconstitution was carried out as part of the general dispensing process in response to receipt of a prescription. The doses were reconstituted immediately prior to the administration to a patient, either on the day of administration or no more than one day before administration.'
He also gave evidence he performed many such reconstitutions and trained many others in the procedure:
'Pharmacists used the term "reconstitution" to describe the act of adding a sterile diluent to a sterile solid drug in a vial (or, rarely, in an ampoule) to dissolve or suspend the drug in order to prepare an injection, installation or irrigation, and a product which is reconstituted has been prepared in this way.
In the specific context of reconstituting cytotoxic drugs for intravenous injection, other important aspects of a reconstitution include the fact the resulting product must be fully dissolved and that the reconstituted solution must be free of pyrogens.
Reconstitution technique is an important element of pharmacy training and practice. Hospital pharmacists, in particular, may perform reconstitutions many times a day; larger hospitals including Westmead have dedicated reconstitution units including cytotoxic reconstitution units, as I have mentioned. Accordingly, reconstitution is a well known procedure and the term "reconstituted" is well understood by pharmacists.'
He did not accept that 'reconstitution' was a synonym for 'dissolution' in the context of hospital pharmacy practice.
39 The applicants also relied on the evidence of Dr Marshall, a Consulting Pharmaceutical Scientist from South Australia who gave the following evidence:
'I have been asked . . . to consider what term or expression would be used by pharmaceutical formulation chemists to describe the step where a lyophilizate is put into solution as part of a manufacturing process. The words I would use are "dissolve" or "dissolution". The words "dissolve" and "dissolution" are in my experience frequently used both orally and in writing (such as in operating manuals or manufacturing instructions) in describing processes involving putting solid pharmaceutical compounds into solution. I cannot recall (before or after 1985) seeing the words "reconstitute" or "reconstitution" used in a technical document (of which I have seen hundreds) relating to the process of dissolving pharmaceutical compounds in the manufacturing of pharmaceuticals or formulations of such pharmaceuticals.
The word "reconstitution" is, however, used in the pharmaceutical industry in relation to finished product powders, whether lyophilized or not, which are dissolved or suspended before administration to a patient . . .'
40 Dr Marshall referred to the text Modern Pharmaceutics by Gilbert S. Banker and Christopher T. Rhodes (1979) which states:
'Several ophthalmic drugs are prepared as sterile powders for reconstitution by the pharmacist before dispensing to the patient… The sterile powder is usually manufactured by lyophilization and is packaged separately from the diluent, and a sterile dropper assembly is provided. In powder form these drugs have a much longer shelf life than that of their solution forms. The pharmacist should use only the diluent provided with the product since it has been developed to maintain the optimum potency and preservation of the reconstituted solution. The pharmacists should use great care in performing the reconstitution to prevent microbial contamination of the sterile product and dropper. Each product has an expiration date for the reconstituted solution which should be explained to the patient along with the proper storage conditions and method of usage.'
41 Professor Peter Stewart, Head of the Department of Pharmaceutics, Victorian College of Pharmacy, upon whom the applicants also rely, echoed the evidence of Dr Marshall as follows:
'Reconstitution has a particular meaning in the context of pharmacy. It refers to the following fundamental steps taken shortly before administration of the drug to the patient.
(a) Taking a solid form of an active pharmaceutical compound (plus any excipients).
(b) Adding a solvent to the solid to make an acceptable delivery system.
The delivery system produced by reconstitution is referred to as "reconstituted".'
Dr Stewart also gave evidence that:
'For injectable delivery systems reconstitution is usually a matter of hours before administration.'
42 Dr Richard Oppenheim, a chemist with some 30 years experience in the area of 'human pharmaceuticals', was at the relevant time a member of the Pharmaceutics faculty of the Victorian College of Pharmacy in Melbourne. He gave clear evidence on behalf of the respondents that:
'The term "reconstitution" refers to the process of adding a suitable and appropriate liquid or liquid system to a solid that has previously been associated with that liquid or some other liquid system, to form a solution, dispersion or suspension suitable for its intended use. If a solid has undergone the process of reconstitution by the addition of a suitable liquid or liquid system, the resultant solution, dispersion or suspension is said to have been "reconstituted".'
He also gave evidence of an instance of doxorubicin being available as bulk lyophilizate for research purposes only, as at the priority date. In this respect, his knowledge and experience differed from that of the other experts.
43 Dr Kenneth Brown, Consultant Pharmaceutical Scientist in Pharmaceutics, from New South Wales, provided a similar assessment as follows:
'The process of reconstitution does not necessarily involve bringing the solution back to exactly the same form as the previous solution. The practical essence of reconstitution is the re-association of the lyophilizate with solvent.
In the pharmaceutical sciences "reconstitution" includes the reconstitution of a lyophilized product by a pharmacist immediately prior to administration. However, this is not the only meaning of the term. "Reconstitution" is a broad and non-specific term which applies at any time a lyophilizate is redissolved into a solvent or passes into solution.'
44 The respondents' experts did not disagree that 'reconstitution' has a meaning, in the pharmaceutical sciences, of 'reconstitution of a lyophilized product prior to administration to a patient'. However, they did not accept that reconstitution in that pharmacy context can only occur shortly before administration to a patient. When cross-examined about the references to 'lyophilized cake' and the reconstitution of 'a lyophilized preparate' which occur in the passages extracted respectively in paragraphs 9 and 10 above describing the prior art, Dr Oppenheim agreed these reference were to material in a vial, that is, they were references to the drug as it was available in a hospital environment. Dr Brown also agreed that the reference to 'lyophilizate preparate' extracted in paragraph 10 above is a reference to the product available in the hospital environment.
45 I now turn to consider submissions in more detail. Mr Caine, of senior counsel, appearing for the applicants conceded that the term 'reconstituted' has a general meaning in the context of pharmaceutical sciences to describe the step of putting lyophilized material into solution. However, he submitted that 'reconstituted' was used also as a term of art in the context of cytotoxic drugs which meant the process of preparing a liquid dosage form of a cytotoxic drug before administration to a patient. He submitted that the essence of the invention is a reformulation of a known drug in a ready-to-use solution which was something that had never before been achieved. I agree with that description of the essence of the invention. He then submitted the context of the specification makes it clear that the phrase in contention in Claim 1 was a disclaimer in respect of the prior art. It was a reference to the lyophilised preparation, known at the priority date, which needed to be made up before administration.
46 It was further submitted that the process undertaken by the respondents is one in which a manufacturer produces a lyophilized material, in bulk, and supplies it to one of the Mayne entities, which then takes that freeze-dried, raw material and makes it into a ready‑to‑use solution. The applicants assert that the bulk lyophilization from the supplier entity is different from the prior art disclaimed and dealt with by the inventors in the Patent specification. Mr Caine's submissions are that the reconstitution referred to in the complete specification is reconstitution which involves a lyophilized cake in a vial; and that it is this specific reconstitution which is carved out from the definition of the monopoly of Claim 1.
47 The applicants submit that the complete specification refers to the dangers involved in the systems, as they were in 1985, being risks to the staff who had to reconstitute the lyophilized preparations shortly before administration because the preparations were unstable in solution over a longer period of time. This was the problem sought to be overcome through the invention of the ready-to-use solution. The invention did not involve the problematic process of reconstitution just prior to administration. Therefore, the applicants submit that the act of reconstitution just prior to administration is that which is sought to be disclaimed in Claim 1 through use of the phrase 'which has not been reconstituted from a lyophilizate.'
48 Mr Macaw, of senior counsel for the respondents, submitted that the words 'reconstituted from a lyophilizate' as occurring in Claim 1 bear an ordinary meaning and no special sense for them exists in the pharmaceutical industry, which would confine the meaning to a subset of their usual or ordinary meaning. It was contended that the meaning of the exclusionary integer of the claim including the word 'reconstituted' is plain and unambiguous, and in accordance with well‑settled principle, the meaning of the exclusionary integer could not be qualified by resort to the body of the specification.
49 It was next submitted that even if resort were had to the body of the specification to clarify the expression in contention, such resort supports the ordinary meaning. Reliance was placed on the inventor's failure in the body of the specification to expressly state that 'lyophilized preparates' referred to in the body of the specification (about which Drs Brown and Oppenheim were cross‑examined) were confined to what was known as at the priority date. Reliance was also placed on the fact that Claim 1 was not confined to a solution in a sealed container, as occurs in dependent Claim 2, and also placed on the fact that there was a broad reference to containers in the body of the specification which was arguably not confined to vials or ampoules.
50 Further, the respondents relied on the consistory clause for the process in the body of the specification and the definition of the process in Claim 20 as it referred to 'anthracycline glycoside, which salt is not in the form of a lyophilizate' to support an argument that the dissolution of a salt was synonymous with 'reconstitution from a lyophilizate'.