7(b) The inventive step issue - consideration
266 In concurrent evidence, Dr Peppard observed that, unlike tolcapone which was administered in a flat dose three times daily, entacapone had to be taken each time with the levodopa/DDC medication and that a combination tablet "seemed just a small extra step to me". However Dr Peppard candidly, as he gave all of his evidence, acknowledged that he could not put a precise date on this thought. As he also acknowledged, he did not have any record made before 29 June 2000 that he had envisaged such a 3-in-one combination. And, despite his practice when attending international conferences, as he regularly did, of discussing important topics with a core group of 20 to 30 Australian colleagues, he did not discuss this subject with them before 29 June 2000.
267 While I have no doubt that Dr Peppard was giving his honest recollection, I do not consider that it is likely that he thought of a 3-in-one combination before 30 June 1999. First, he never expressed this idea to any of his colleagues, or anyone else, or recorded it, before 29 June 2000. Given that, as he said, it would relieve patients of a potentially significant extra burden of taking an additional tablet up to 10 times daily, I think that, had the idea of a combination occurred to him, he at least would have talked with colleagues about it at the time. Secondly, Dr Peppard, like all of the other experts, was dealing with long past events. He was seeking to recall his thought processes over 15 years earlier, where he had no contemporaneous record of his own to draw on and where the very idea (of a 3-in-one tablet) had been a reality in his daily practice for over a decade. The precision and dating of any recollection in those circumstances is highly likely to be a reconstruction that is inevitably affected by hindsight and experience. Indeed, as Dr Peppard said, "it's something I didn't give any great deal of thought to".
268 Thirdly, entacapone was a new medicine that had been in commercial use in England for eight months and only registered in Australia for about seven weeks by 30 June 1999. There had been a very recent significant setback in confidence in the use of COMT inhibitors because of the withdrawal of tolcapone from the market. There had been no foreshadowing of the potential of the fatal liver toxicity that three patients had suffered in 1998, after tolcapone had gone to market. Prof Jenner, Drs O'Neill and Peppard agreed in their joint report that, as at both June 1999 and June 2000, experience in Australia with tolcapone had raised concerns over the toxicity of COMT inhibitors and these concerns included entacapone. As Dr Peppard commented in the joint report, during this period neurologists were concerned that there "could be group toxicity between tolcapone and entacapone" and that they were looking "keenly at the characteristics and safety of entacapone, which was the only replacement COMT inhibitor on the horizon".
269 Having regard to all those factors, I am not satisfied that Dr Peppard's evidence as to his having had an idea about a 3-in-one combination using entacapone before 30 June 1999 is reliable. I think that he was honestly mistaken and thought of this idea much later, and only after entacapone had been in widespread, safe use for some time. As he said, first, he had not prescribed entacapone as at June 1999 and its approval by the TGA "wasn't enough for me" and, secondly, even on 1 February 2000, when entacapone received its PBS listing, he said "I would have been hesitant" about prescribing entacapone then. Given that this was his contemporaneous response in dealing with patients, I am not persuaded that he gave consideration before this time to a combination tablet of entacapone, levodopa and carbidopa.
270 Dr Peppard also said that his concern had been alleviated by June 2000. Even so, I am not satisfied that Dr Peppard's recollection of when he thought of the idea of a combination is sufficiently reliable to find that this occurred at any time before 29 June 2000.
271 Prof Stewart and Dr Morella agreed in the joint report that fixed dose combination prescription products were uncommon and that development of a formulation is an interactive process involving problem solving. They also agreed that the process was not a recipe that, if followed, inevitably would result in a suitable formulation.
272 Unlike Prof Stewart, Dr Morella considered that the development process to formulate a combination tablet comprised of the three APIs (entacapone, levodopa and carbidopa), even though much was known about their properties, was complex. He explained why he considered this development process not to be straightforward even with components with known properties saying, persuasively to my mind:
You just don't get answer A, B and C, plonk that into a development program and have it pop out the end. There are real issues that you encounter, unexpected issues that you encounter, during the development and you start to make compromises and choices. In the end, if the process was routine and simple and predictable, you should be able to come up with a formulation, very few experiments to satisfy the needs of the regulatory authorities. In my experience, unless you're producing a product that's … the same as what's on the market, that's unlikely to be the case. (emphasis added)
273 Prof Davies did not give evidence-in-chief on the obviousness of the invention. However, he had considerable experience in working with pharmaceutical companies on detailed analyses of various combination products that had included determining the structure, compatibility of each of APIs both with one another and with excipients used in a formulation, as well as the homogeneity of a drug product. I accept his evidence that, when placing one drug into a formulation with another, "you cannot predict what the release profile would be" and that:
it's rare that you have three drugs in a single product which is a prescription medicine, like this, and it would be extremely challenging to be able to reproduce and mimic the release profiles of those individual drugs. (emphasis added)
274 Professor Davies was also asked in cross-examination about formulating a combination tablet of the three APIs within a particular size range, in the following exchange:
And those challenges are ones that would involve you using the skills that you've developed as a formulator, to make selections of excipients that are compatible and appropriately sized to achieve a successful formulation? --- It's possible. It's a challenge, though, particularly in this context, where you have three drugs and you're trying to prepare formulations which are of a particular size for that target patient population. It can be extremely challenging. (emphasis added)
275 These difficulties in the formulation task are relevant to an overall assessment of whether a skilled addressee would have regarded the invention in each of claims 19, 20 and 21, as I have construed them, as obvious at either of the priority dates in issue.
276 Dr Reece gave evidence that:
So in terms of the logic of a triple dose regimen … if that concept is simply adding one pill to another is working, then one could think, well, [the] experiment pharmacokinetically has been done. Now, what I mean by that, pharmacokinetics is a study of the drug absorption, distribution, elimination, but … the simple experiment of putting those two pills together has been done pharmacokinetically, and so any discussion we've had about drugs in solution means that, putting formulation matters aside, and I don't portray myself as a formulator, but from a pharmacologist's perspective, we've learned a lot from this study about the pharmacokinetics of these two drugs and the context of the clinical effect. They're going in a solution and they're working. Whatever the obstacles, the outcome is there. We have a clinical effect. (emphasis added)
277 Dr Reece later asserted his perception that DDC and COMT inhibitors affected two separate enzymes and that it was "simple" science, from a pharmacological point of view, to develop a fixed dose 3-in-one combination. He again acknowledged his lack of formulation expertise. In the joint expert report he said that, as of June 1999, based on the Nomecomt report, he would reasonably expect that "without regard to stability or tablet size" the three APIs could be combined into a single composition that would provide a therapeutic effect comparable to the known separate formulations.
278 As Dr Reece acknowledged in oral evidence, his expectation was based on the unstated assumption that each of the three APIs had been released already into the gastrointestinal tract and were in solution:
I'm only considering the pharmacology component of it, and so that I'm interested in everything after the dissolution.
MR DIMITRIADIS: Yes.
DR REECE: So we're talking just about the, you know, potential effects of the biology on the system thereafter.
MR DIMITRIADIS: And so, the assumption does apply here as well; that's right, isn't it?
DR REECE: Yes. I'm just making the connection that this is a yes, that's a logical progression, so yes. (emphasis added)
279 Prof Jenner explained that while DDC inhibitors substantially blocked the enzyme activity to which they were directed, COMT inhibitors only inhibited about half of the enzyme activity for which they were introduced. As he and Dr Morella made clear, the formulation task required that any 3-in-one combination work inside the body in the way entacapone had done when administered separately (as COMTAN) with the levodopa/carbidopa dose administered (as SINEMET). Prof Jenner said that this required a triple combination to be "time locked" to achieve, as far as possible, the release into the gut of each of the three APIs in a way that enabled them to be absorbed into the bloodstream so as to act in a substantially similar way as the administration of two separate tablets had achieved.
280 Prof Jenner explained in his affidavit that carbidopa was absorbed into the blood (technically, systemic circulation) from a significant portion of the small intestine. However, because both levodopa and entacapone were only absorbed from the upper small intestine, those two APIs had a smaller window of opportunity to be absorbed into the blood. And each API used a different bodily transport mechanism to convey the API towards the blood brain barrier. Carbidopa is probably absorbed by simple passive diffusion. Levopoda is a naturally occurring amino acid and utilises what Prof Jenner described as "a capacity limited active transport mechanism that exists to take large neutral amino acids from ingested food in to the body". Entacapone uses another active transport process the nature of which, Prof Jenner said, is not fully understood. He said that he knew, before June 1999, both levodopa and entacapone were only partially absorbed in a way that was erratic, with large inter-subject and intra-subject variations. Prof Jenner continued:
This is an important issue as small differences in the amounts of the two drugs entering the systemic circulation can have a major effect on the clinical response achieved.
Levodopa and entacapone have short half-lives in plasma, while the half-life of carbidopa is longer and the duration of inhibition of DDC is maintained. By half-life, I refer to the time over which a 50% fall in plasma concentrations of the drug will occur following the absorption phase and after peak concentrations have been achieved. The inhibition of COMT produced by entacapone is transient, reflecting its short half-life. As a result, it is essential that the plasma exposure to levodopa and entacapone is "time locked" as differences in peaks and troughs of plasma concentrations of the drugs will negate the enhanced clinical effect that is sought. By "time locked", I refer to the need to ensure that both DDC and COMT are adequately inhibited peripherally to prevent levodopa metabolism by ensuring that both carbidopa and entacapone are absorbed and reach effective concentrations in plasma simultaneously.
I would not have expected that this could have been achieved in a combined formulation. Instead I would have expected that:
(a) the release of drug from the combined preparation would be different from that of individual immediate release formulations; and
(b) the subsequent absorption of one or the other of these drugs would have been altered such that the concentrations in plasma required to inhibit enzyme activity would not be achieved at the same time. (emphasis added)
281 I accept Prof Jenner's pharmacological explanation. It is cogently reasoned. That explanation was supported by Dr Morella whose expertise included both pharmacology and formulation.
282 As both Drs O'Neill and Peppard said, few Australian doctors would have prescribed COMTAN until its PBS listing on 1 February 2000, and neither clinician thought he had done so. And, the PBS records show that only 31 prescriptions for COMTAN were filled in February 2000. I accept Dr Peppard's evidence as reflective of the general attitude of treating doctors dealing with patients suffering from Parkinson's disease. As I noted above he said that before 30 June 1999, he "would have been hesitant" about COMTAN in light of what had happened with tolcapone.
283 Accordingly, I am satisfied that the use of entacapone as a part of treatment for Parkinson's disease was not part of the common general knowledge before 30 June 1999.
284 The skilled addressee, for present purposes, is a hypothetical construct of one person who has the background and skills of a non-inventive worker in each of the four presently relevant fields relating to therapy for Parkinson's disease (clinical, pharmacological, pharmaceutical and formulatory); he or she makes an assessment of obviousness in light of the common general knowledge having regard to the interaction of each of those three fields together. Just as, in the case of a skilled addressee in one field or discipline, the hypothetical amalgam must approach the issue of obviousness through one set of eyes, not three. If an addressee in one discipline would scotch a suggestion from their discipline as impractical or not worth thinking about because of known or perceived impediments, where both disciplines had to work together to achieve a result, then the invention will not be obvious to an amalgam skilled addressee, anymore than it would be to one in a single discipline who would not see it as obvious.
285 In Otsuka Pharmaceutical Co Ltd v Generic Health Pty Ltd (No 4) (2015) 113 IPR 191 at 213 [124] Yates J adopted the following passage from General Tire [1972] RPC at 485 to explain how the Court places itself into the position of the skilled addressee, including in cases where that person is taken to have the composite skills of a team of persons namely, in the words of Sachs LJ:
The earlier publication and the patentee's claim must each be construed as they would be at the respective relevant dates by a reader skilled in the art to which they relate having regard to the state of knowledge in such art at the relevant date. The construction of these documents is a function of the court, being a matter of law, but, since documents of this nature are almost certain to contain technical material, the court must, by evidence, be put in the position of a person of the kind to whom the document is addressed, that is to say, a person skilled in the relevant art at the relevant date. If the art is one having a highly developed technology, the notional skilled reader to whom the document is addressed may not be a single person but a team, whose combined skill would normally be employed in that art in interpreting and carrying into effect instructions such as those which are contained in the document to be construed. (emphasis added)
286 This is why, whatever characteristics the skilled addressee has in any particular case, if the prior art discloses only some, but not all, of the integers of the claimed invention, it would only be obvious, or anticipated by the prior art, if the skilled addressee would add the missing information as a matter of course and without the application of inventive ingenuity or undue experimentation.
287 I summarised the principles applicable to a consideration of obviousness in relation to a product claim, such as claims 19, 20 and 21, in Apotex Pty Ltd v Les Laboratoires Servier [2013] FCA 1426 at [83]-[90] as follows:
83 The word "obvious" in s 7(2) of the Act means "very plain". It is a question of fact whether an invention is "obvious". However, that assessment involves a question of degree and this often will be by no means easy: Lockwood [No 2] 235 CLR at 195 [51]. The parties agreed that no question arises under s 7(3) in these proceedings. In Aktiebolaget HÄssle v Alphapharm Pty Ltd (2002) 212 CLR 411 at 427-433 [33]-[53] Gleeson CJ, Gaudron, Gummow and Hayne JJ discussed the law in respect of obviousness and the requirement of an inventive step as it had developed up to the Patents Act 1952 (Cth) (the 1952 Act). Subsequently, the Court said that that discussion was relevant and applicable to the current Act: Lockwood [No 2] 235 CLR at 193 [46]. The Court observed that (at 195 [52]):
"obviousness and inventiveness are antitheses and the question is always "is the step taken over the prior art an 'obvious step' or 'an inventive step'?" ... A "scintilla of invention" remains sufficient in Australian law to support the validity of a patent." (citations omitted, emphasis added)
84 There is no unique approach to ascertaining whether any invention claimed involves "an inventive step" for the purposes of s 18(1)(b)(ii). Sometimes, the question of whether an invention is obvious when compared to the prior art base, in light of common general knowledge, can be approached by a "problem and solution" analysis. But, this has its limitations, as the Court explained in Lockwood [No 2] 235 CLR at 200-201 [65]-[66]. They held that such an approach could be unfair to an inventor of a simple solution adding (at [65]):
"… especially as a small amount of ingenuity can sustain a patent in Australia. Ingenuity may lie in an idea for overcoming a practical difficulty in circumstances where a difficulty with a product consisting of a known set of integers is common general knowledge. This is a narrow but critical point if, as here, the circumstances are that no skilled person in the art called to give evidence had thought of a general idea or general method of solving a known difficulty with respect to a known product, as at the priority date." (citations omitted, emphasis added)
85 The Court cautioned against treating a specification that described a problem and solution as a conclusive admission by the patentee. That was because the patentee makes such statements from the vantage point of knowing the solution. Their Honours said that statements of this type must be weighed with any evidence given by persons skilled in the art of their perception, before the priority date, of any problem: i.e. before those witnesses had been exposed to the solution contained in, or provided by, the invention (235 CLR at 211 [105]). The concept of whether a step is inventive (235 CLR at 213-214 [111]):
"… will turn on what a person skilled in the relevant art, possessed with that person's knowledge, would have regarded, at the time, as technically possible in terms of mechanics, and also as practical. That is the sense in which an idea can involve an inventive insight about a known product. A court cannot substitute its own deduction or proposition for that objective touchstone, except in the rarest of circumstances, such as where an expressly admitted matter of common general knowledge is the precise matter in respect of which a monopoly is claimed. Even if an idea of combining integers, which individually may be considered mere design choices, is simple, its simplicity does not necessarily make it obvious. Older cases concerning simple mechanical combinations illustrate this point. Common general knowledge has negative as well as positive aspects. Practical and technical issues can affect the means by which a concept may be implemented in respect of an already known vendible product, and scepticism can inhibit recognition of the utility of applying a concept or idea to a known set of integers. These are matters within the knowledge of relevant witnesses." (citations omitted, emphasis added)
86 Thus, the practical considerations that a person skilled in the art would take into account in seeking to address a problem may affect the characterisation of a step as inventive or not. In Alphapharm 212 CLR at 432-433 [50]-[53] Gleeson CJ, Gaudron, Gummow and Hayne JJ discussed the difference between what a person skilled in the relevant art, in light of common general knowledge, might do to lead to the alleged invention by way of a series of steps or experiments that were routine as opposed to doing something that amounted to an inventive step. They drew on what Aickin J had said, with the agreement of Gibbs ACJ, Stephen, Mason and Wilson JJ, in The Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 at 280-281 and 286. Aickin J referred to evidence of what the inventor did, for example by way of experiment, as one means of establishing or negating the involvement of an inventive step. He said (212 CLR at 432-433 [51]):
"It might show that the experiments devised for the purpose were part of an inventive step. Alternatively it might show that the experiments were of a routine character which the uninventive worker in the field would try as a matter of course. The latter could be relevant though not decisive in every case. It may be that the perception of the true nature of the problem was the inventive step which, once taken, revealed that straightforward experiments will provide the solution. It will always be necessary to distinguish between experiments leading to an invention and subsequent experiments for checking and testing the product or process the subject of the invention. The latter would not be material to obviousness but might be material to the question of utility." (original emphasis)
Aickin J also said (148 CLR at 286):
"It is still correct to say that a valid patent may be obtained for something stumbled upon by accident, remembered from a dream or imported from abroad, if it otherwise satisfies the requirements of the legislation. What is important is that the patent itself should involve an inventive step, whether or not it was consciously taken by the patentee and whether or not it appeared obvious to the patentee himself. The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not." (emphasis added)
87 Thus, steps that lead to the alleged invention that a hypothetical non-inventive worker in the field would have taken as a matter of routine negate the involvement of an inventive step. That is because steps of a routine character that the worker would try as a matter of course would demonstrate obviousness: Alphapharm 212 CLR at 433 [52]. In the modern context of large pharmaceutical companies, the correct approach is to ask a question along the lines of that described as the reformulated "Cripps question" (which was in an early example of the use of a written submission by Stafford Cripps KC of counsel, as Sargant LJ explained in Sharp & Dohme Inc v Boots Pure Drug Company (1928) 45 RPC 153 at 176 and see at 173 per Lord Hanworth MR; cf Blanco White, op cit at [4-211]): (I have adapted and added emphasis to this question below.)
"Would the notional research group at the relevant date, in all the circumstances, (including a knowledge of all relevant prior art and of the facts of the nature and success of the existing drug or formulation [here, the tert-butylamine salt of perindopril]) be led directly, as a matter of course, to try the new or substituted drug or formulation [here, the arginine salt] in substitution in the expectation that it might well produce a useful alternative to or a better drug than [perindopril erbumine] or a body useful for any other purpose?"
88 If a hypothetical formulator or skilled addressee must pursue a complex, detailed and laborious course of action, involving a good deal of trial and error, dead ends and retracing of steps, he or she will not have taken routine steps leading to an invention as a matter of course: Alphapharm 212 CLR at 436 [58]. There Gleeson CJ, Gaudron, Gummow and Hayne JJ accepted what Maugham J had said in In re IG Farbenindustrie AG's Patents (1930) 47 RPC 289 at 322 that mere verification was not invention. They approved his analogy advertising to the capture of the citadel in the passage below. The latter case concerned a selection patent i.e. one where, like here, a putative inventor selects, from one or more candidate substances or compounds, something to use as a substitute or derivative for an earlier component or ingredient of an original compound. There can be many possible candidates for such combinations (47 RPC at 321). His Lordship propounded a corollary to the Cripps' question, namely, that if for practical purposes it is not obvious to skilled chemists, in the state of chemical knowledge existing at the (priority) date, that the selected components possess a special property then there is, or may be, a sufficient "inventive step" to support the patent. He said that in this respect the workings of the inventor's mind were not usually material. Rather, the Court was "concerned, so far as subject-matter is concerned, only with the results. The invention must, of course, add something of a substantial character to existing knowledge; but the Courts do not inquire into the way in which the conquest achieved. If the language of metaphor may be used, the citadel may be captured either by a brilliant coup-de-main or by a slow and laborious approach by sap and mine according to the rules of the art; the reward is the same.
89 It is not appropriate to analyse whether a claimed invention, at least in the cases of selection or combination patents, involves an inventive step on the basis that it will not if the selected answer was "worth a try" or "obvious to try" or resulted from an exercise in trying out various known possibilities until a correct solution emerged: Alphapharm 212 CLR at 441-443 [72]-[76], [78]. Secondary evidence such as commercial success, the satisfaction of a long felt but unsolved want or need and the failure of others to find a solution to the problem is also relevant, but not necessarily determinative, of the question whether the invention is obvious: Lockwood [No 2] 235 CLR at 215-216 [115]-[116], [119].
90 The purpose of considering the prior art base, in assessing whether the invention involves an inventive step, is to look forward to see from it what a skilled addressee "is likely to have done when faced with a similar problem which the patentee claims to have solved with the invention" (235 CLR at 218 [127]). Each claim in a patent must be examined independently of the others in assessing whether an alleged invention involves an inventive step. Also in addressing the "jury" question of whether the claimed invention involves an inventive step, a judge must be very careful to avoid the wisdom of hindsight: Alphapharm 212 CLR at 443 [78].
288 Here the reformulated "Cripps' question" is: Would the skilled (composite) addressee at the relevant date (here 30 June 1999), in all the circumstances (including a knowledge of the prior art, here, the Nomecomt report) and of the facts of the nature and success of the existing drugs or formulations (here, the combination levodopa/DDC inhibitor formulations and COMTAN) be led directly, and as a matter of course, to try the new or substituted drug or formulation [here, an oral solid composition comprising levodopa, carbidopa and entacapone], in the expectation that it might well produce a useful alternative to, or a better drug than [here, the known separate formulations] or a product useful for any other purpose?
289 The evaluative process in that reformulated question will involve considering whether the alternative or better drug could be expected to have the characteristics of, in the case of claims 19 and 20, being of a size that persons being treated for Parkinson's disease would be able to swallow the new combination tablet.
290 The Nomecomt report revealed that entacapone produced beneficial therapeutic effects when concurrently administered with a combination levodopa/DDC inhibitor. That report did not identify or even suggest how the three APIs could be formulated into a combination tablet that was small enough to be swallowed by patients suffering Parkinson's disease, within any of the integers in claims 19 or 20. I accept Prof Jenner's evidence about the uncertainties in the way in which entacapone is both absorbed and transported once ingested, and the real potential for difficulty that these factors posed for incorporating it into a combination with levodopa and a DDC inhibitor that would then be "an oral pharmaceutical tablet" as I have construed that expression as used in claims 19 and 20 (see [123] above). The pathway through those difficulties was not spelt out in the Nomecomt report and would not have been obvious to a skilled addressee in June 1999 in light of the common general knowledge. The skilled addressee would not find that pathway as a matter of course without the application of inventive ingenuity or undue experimentation. That is so from the perspectives of both a formulator, as Dr Morella explained, and a pharmacologist, as Prof Jenner explained.
291 In any event, I am quite unpersuaded that, before 30 June 1999, a skilled addressee would have thought that the idea of a 3-in-one combination tablet, in light of the Nomecomt report and the common general knowledge, was obvious or that the addressee would have been led directly, as a matter of course, to try to make it in the expectation that it might well produce a useful alternative, better drug or something useful. Prof Jenner was himself working in the field of researching the use of entacapone in combination with levodopa/DDDC inhibitors and knew of the Nomecomt report. He said (OIS 301):
Despite knowledge of entacapone and my research work with it, it never occurred to me to even consider whether a 3-in-1 formulation of levodopa/carbidopa/entacapone might be a research avenue worth pursuing before June 1999 or June 2000. Indeed, it never occurred to me to consider more generally whether a 3-in-1 formulation of levodopa, a DDC inhibitor (carbidopa or benserazide) and a COMT inhibitor (tolcapone or entacapone) might be a research avenue worth pursuing before June 1999 or June 2000. I was also not aware of any attempt made to combine levodopa with any other DDC inhibitor and a COMT inhibitor in such a 3-in-1 formulation before June 1999 or June 2000.
If I had considered the matter before June 1999 or June 2000, I would not have regarded a 3-in-1 formulation of levodopa/carbidopa/entacapone to be a research avenue that was worth pursuing. In my opinion, research of this kind was not worth pursuing, because it would have involved complex and difficult work of the kind discussed below, the outcome of which could not have been predicted in advance. Further, I was not aware of any clinical or treatment need that I would have expected a 3-in-1 formulation to address. (emphasis added)
292 Of course, successful combinations of two APIs, and sometimes more, had been achieved as at 30 June 1999, including that of levodopa with DDC inhibitors. However, the skilled addressee would have been aware of the complexities in achieving a successful formulation of a 3-in-one tablet that both had about the same or a better therapeutic effect as the two separately administered tablets (COMTAN and SINEMET or MADOPAR) and was of a size that patients could swallow, particularly having regard to the then existing size of the COMTAN tablet.
293 Moreover, the skilled addressee as at 30 June 1999, in light of the common general knowledge of the recent, very significant problems with tolcapone as a COMT inhibitor, is unlikely to have considered, in the circumstances, the subsequent, very newly released alternative COMT inhibitor, entacapone, as a substance that at that time should be incorporated into a 3-in-one combination. At that time, a skilled addressee is more likely to have considered entacapone as a new form of treatment that was to be approached with considerable caution, as each of Drs O'Neill and Peppard said.
294 The use of entacapone was not part of the common general knowledge in Australia at 30 June 1999. It had been registered for only seven weeks and was an expensive form of treatment; it was not yet subsidised by the PBS. Few doctors were then prescribing entacapone and practical experience of its administration was not extensive. The adverse side effects of tolcapone on a limited class of patients had only emerged after it had been widely prescribed and on the market for some time. These factors are further indicators that, in the context of the time and uncertainties as at 30 June 1999, it is unlikely that a skilled addressee, apprised of the Nomecomt report and the common general knowledge, would be thinking about a 3-in-one combination as worthy of investigation.
295 Having regard to these matters, I am of opinion that a skilled addressee with the combined insight of a clinician, a pharmacologist, a pharmacist and a formulator, who knew of the Nomecomt report and in light of the common general knowledge, would not have been led directly, as a matter of course, to try a formulation of a combination of the three APIs in the expectation that it might well produce a useful alternative to, or a better, drug than the existing separate formulations or anything useful for another purpose. This is because of:
the recency of entacapone's availability as a prescription medicine;
the significant concerns as to the safety of COMT inhibitors as a class, as a result of the experience with tolcapone;
the non-routine difficulties of achieving a suitable formulation that would enable each of the three APIs to be incorporated into a single combination, so that they would achieve a comparable therapeutic effect to the existing separate formulations, as explained by Prof Jenner and Dr Morella and having regard to the significant formulation, pharmacodynamic and pharmacokinetic difficulties to which they adverted;
Prof Jenner's evidence that the idea of a 3-in-one combination never occurred to him at the time, and my finding that I was not satisfied that the idea had occurred to Dr Peppard.
296 There were too many practical and technical difficulties at that time, a lack of widespread experience of entacapone and a significant cautionary approach to its use as a result of the problems with tolcapone, to warrant a conclusion that invention claimed in any of claims 19, 20 and 21 lacked an inventive step.
297 Further, the complete specification gave several examples of the inventors finding disappointment when they began their pursuit of a combination product, such as the discovery that the bioavailability of carbidopa was reduced when all three APIs were wet granulated together (page 7) and how that difficulty had to be addressed, as well as the apparently non-routine formulation problems with incompatibilities, with long term storage issues from use of MCC and some other excipients (pages 10-11). Those matters suggest that what the inventors pursued as routine steps, or matters of course, failed to achieve the desired result: cf Wellcome 148 CLR at 280-281. That eventuality is not decisive, but lends objective support to the pharmacological and formulation difficulties to which Profs Jenner, Davies and Dr Morella referred.
298 For these reasons, I am not satisfied that Actavis has proved that, as at 30 June 1999, claims 19, 20 and 21 did not involve an inventive step.