(b) Factual background
91 The specification in the arginine patent described perindopril as being intrinsically fragile (p 1 line 24). It noted that perindopril and its non-salt compounds had previously been described in European patent EPO 049 658 (the compound patent) and that this had given examples of addition salts, with a pharmaceutically acceptable salt, that had both good bioavailability and adequate stability to be suitable for the preparation and storage of pharmaceutical compositions. The specification identified the earlier conclusion that perindopril erbumine had adequate qualities for the development of the product and was currently being marketed (p 1 lines 12-17). Then the specification explained that the tert-butylamine salt had not been capable of providing a complete solution to the problems of the product's stability to heat and humidity. That was because of the constraints that required perindopril erbumine to use additional and more costly packaging, and that limited its shelf-life (p 1 line 24-p 2 line 7).
92 A substance is hygroscopic if it physically absorbs water. It may do so without changing its chemical structure. In that case, the substance will gain weight, being a reflection of the amount of water absorbed, thus affecting its physical stability. On the other hand, if the substance is hygroscopic and reacts with water so that its chemical structure changes, it also will gain weight but will not be chemically stable.
93 Apotex and Servier are at odds over what was the starting point identified in the specification identified for the purpose of evaluating, under s 7(2) of the Act, whether the invention involved an inventive step. Apotex said that the skilled addressee would have proceeded, as the patent explained, namely by immediately considering whether a new salt could be developed to meet the issues created by the problems with perindopril erbumine's stability to heat and humidity. Thus, Apotex' expert witnesses (Drs Spargo, Williams and Prof Perkins) were instructed to address what they would do, as Dr Spargo explained: "… if I was tasked with developing a new salt of perindopril which was more stable to heat and humidity than the tert-butylamine salt of perindopril." Servier contended that the skilled addressee would see the starting point, or problem, as addressing the problems with the more general issues of perindopril's stability to heat and humidity, including those problems experienced with the tert-butylamine salt. I will consider the correct characterisation of what the skilled addressee would have taken as the starting point later in these reasons.
94 I do not accept as reliable Prof Perkins' evidence that, prior to the priority date, he would have considered using arginine as a counter-ion to make a salt with perindopril. His discussions with Apotex' lawyers prompted his thought process, that led to his including arginine in his considerations. Servier did not suggest that that prompting occurred in any improper way. Rather, Prof Perkins' cross-examination revealed how his identification of arginine as a potential counter-ion in his affidavit came about as:
"ASSOC PROF PERKINS: It was a natural progression of the discussions of the basic basicity and acidity strengths of the various functional groups and the ideas behind salt formation.
MR BANNON: And the natural progression, the progression of the discussions was prompted by the lawyers, I take it?
ASSOC PROF PERKINS: The series of questions were set by the lawyers, yes."
95 I did not find of assistance his evidence as to how the skilled addressee, prior to 18 April 2002, would have approached dealing with making improvements to perindopril erbumine or creating a new salt. That is because I think that he approached the issue affected by the apparently accidental prompting and, once having thought of arginine in this context he, not unnaturally, continued to be influenced by this. Prof Perkins did not do any research into what information a skilled addressee may have found about salt forms that were used in other ACE inhibitors at or before 18 April 2002. He accepted that the results he could have discovered in such research may have led him down one research path rather than others. Moreover, Prof Perkins accepted that he had no expertise in 2002 as to whether a salt was suitable in a pharmaceutical context.
96 Only Prof Evans, Drs Morella and Spargo were familiar in 2002 with the pain relief substance, ibuprofen. It was marketed in a lysine salt formulation. Prof Evans had written his thesis on that substance and was aware that some research was being conducted at around that time as to whether the active moiety could also make a salt with arginine to speed up its absorption in patients. He said that this was illustrative of how the choice of the counter-ion could have pharmacokinetic and or pharmacological effects on the active moiety that would require appropriate studies to satisfy regulatory authorities as to the properties of the API. I am not satisfied that ibuprofen or its formulation as a salt with lysine, or any research involving it in salt formulation with arginine, was general common knowledge at the priority date.
97 The person skilled in the art would have recognised that perindopril erbumine was unstable in higher temperatures and humidity levels, as the experts agreed. They all suggested, in no particular order, that a number of options could be explored including development of more stable forms of perindopril such as new salts, polymorphs (i.e. crystal structures, solvates or complexes, reformulating perindopril erbumine compositions using a range of excipients or new formulations, improving the packaging or tablet manufacturing processes, developing derivatives of perindoprilat, including new prodrugs or analogues, or changing the chemical structure of the active moiety, for example, by identifying another "pril" with a more stable chemical structure than the compounds based on the active moiety, being perindoprilat.
98 As Prof Byrn said, there were at least five methods of crystallisation that a person skilled in the art could use and these involved potentially many different variables such as the choice of one or more solvents, heating rate, maximum temperature, whether, and how long, to cool the mixture, the time allowed for crystals to form, type of crystallisation vessel, its surface volume and the mixing rate, to name only some. Each variable can affect the result.
99 Thus, the selection and development of a new salt of perindopril was one of a range of reasonably open choices that the person skilled in the art would have considered. As Prof Byrn explained, if one tries to create new hydrates, polymorphs or other crystal structures in which a salt exists, each crystal structure can affect the salt's stability characteristics in a way that is not predictable. Prof Byrn said that when the patent used the concept of "perindopril arginine" and its hydrates it was referring to a solid material (the salt) that can be in a solvent and that the solvent could be water (and then it would be a hydrate - i.e. it would contain, but not be chemically bonded to, water). He explained that differences in the form of polymorphs or hydrates can also affect the stability of the substance. He illustrated how the form can affect stability by the example of the minerals, diamond and graphite, each of which is different solid form of carbon and has very distinct properties from the other. He said that a person skilled in the art could try to make a new polymorph of perindopril erbumine to solve the then stability problem with its correct form. He pointed out that one would need to do empirical studies of whatever new form or forms of polymorph or hydrate came about in order to determine what, if any, difference(s) in their properties had occurred.
100 As I have explained above, there is no certainty that, first, any particular counter-ion will be able to make a salt with an API and, secondly, if it does what the properties of that salt will be.
101 If, and it is not certain that this would necessarily occur, a person skilled in the art decided before or after trying other alternatives, to experiment with creating a new salt, it would be necessary to do one or more salt-screens. The person skilled in the art would have selected a number of counter-ions for a first salt-screen from Table 1 in the Berge paper. That is because the counter-ions in Table 1 have been used to make salts that the FDA previously had approval for pharmaceutical use. The source of the common general knowledge for counter-ions in that table in Australia for persons skilled in the art was, as Prof Evans explained, the standard text, Remington and, on the evidence, they would not have known of, or gone to, the Berge paper itself.
102 If the first salt-screen failed to identify a suitable counter-ion, the person skilled in the art would be likely to have undertaken a second salt-screen. That is the more likely because of the significant commercial value promised by a successful and patentable improvement that a more stable composition of perindopril offered. Dr Williams, who knew of the Berge paper from his Kansas education, said that it was hard to say if he would have tried arginine at all. All the experts agreed that, as a natural substance, a salt made with arginine was likely not to have toxicity issues. Prof Evans and Dr Morella considered that the lack of commercial precedents for arginine as a counter-ion in a pharmaceutical salt would discourage and make unlikely its selection as a candidate in a salt-screen. Drs Morella and Williams also made the significant point that the economics of the selection process would affect its comprehensiveness and duration.
103 One of the difficulties in evaluating the "jury" question of whether an alleged invention involves an inventive step, is that the expert witnesses, in a case like this, will often not be the ordinary, non-inventive person skilled in the art. Here, each expert was distinguished and accomplished in his field. Nonetheless, the evidence of Prof Evans, Drs Morella and Williams left me with the firm impression that none of them would have included arginine in a second salt-screen.
104 Both Prof Byrn and Dr Spargo had much more extensive practical experience of salt-screens than the Australian expert witnesses. Prof Byrn said that he would not have tried arginine since it is complex and could catalyse reactions. He illustrated this on a whiteboard as I explain below at [113]-[115]. Only Dr Spargo said that he would have tried arginine if his first salt-screen failed to produce a suitable salt. He said that he had not treated Table 1 in the Berge paper as prescriptive during his professional career. He said that he would not go through all of the counter-ions listed in it before branching outside to try other ones and would look at other literature for a potential candidate. However, he acknowledged that Prof Byrn had a different, and acceptable, perspective on this issue. Dr Spargo had used arginine, unsuccessfully, once in a salt-screen in the mid-1990s. He was aware of, and used, the Berge paper at that time.
105 In his affidavit evidence, Dr Spargo hypothesised that he would have tried both basic and acidic counter-ions from Table 1 in his first salt-screen to take account of zwitterionic nature of perindopril. He said that he would have assumed that Servier had tried these and failed to make a salt before it had succeeded with tert-butylamine since the latter was an unusual choice of counter-ion and not in Table 1. His first 12 screen selections would have been simple metal (basic) cations such as sodium, potassium, magnesium and calcium, and the most common (acidic) anions such as hydrochloride, maleate, citrate and mesylate. He could not say whether any of those counter-ions could have made a salt with perindopril, including the ones that Servier had unsuccessfully tried: sodium, hydrochloride and maleate. That was because different techniques in salt making can produce different results and, as all the experts agreed, successful salt making is sometimes dependent on the maker's intuitions and interventions with stirring or leaving the mixture. Dr Spargo accepted the description that salt making was "something of a dark art and you can do it at different times and get different results".
106 In contrast, Prof Perkins said that he was not aware of the Berge paper before the priority date. He said that he would only have tried arginine if there was (and he was not aware before the priority date of any) a scientific reason in literature evidence that one or more potentially pharmaceutically acceptable arginine salts had been prepared previously.
107 I prefer the more convincing evidence of Prof Byrn, Drs Evans and Morella to that of Dr Spargo on this issue. I find that the skilled addressee at the priority date would not have tried to make a salt with arginine because it was outside the field of candidates that he or she would have considered for this purpose for the reasons given by Prof Byrn, Drs Evans and Morella that I have referred to above. I am not satisfied that, before the priority date, the skilled addressee, in Australia could be reasonably expected to have ascertained, understood and regarded the Berge paper and, in particular the contents of Table III, as relevant to work in relation to creating a pharmaceutically acceptable salt of perindopril. That paper was not part of the common general knowledge: Firebelt Pty Ltd v Brambles Australia Ltd (t/as Cleanaway) (2002) 188 ALR 280 at 289 [36] per Gleeson CJ, McHugh, Gummow, Hayne and Callinan JJ.
108 Once a salt has been made, the maker then must subject it to stability studies that usually (and for perindopril would) include exposing it to extreme conditions of temperature and humidity. Those studies potentially could be significant in order to assess whether the new salt offered the promise of improved stability over that of perindopril erbumine. If, on the initial stability studies, the new salt performed similarly to, or its results were ambiguous in comparison to, the existing one, Dr Spargo thought that it would probably not be worthwhile subjecting it to longer term stability studies. That was because the aim of the search was to obtain a new salt that was clearly better. Dr Spargo said in one affidavit that, having reviewed Servier's internal study reports for the stability testing of the tert-butylamine and arginine salts:
"I do not consider that one is clearly better than the other based on these data. These data do not suggest to me that there are insurmountable problems with perindopril tert-butylamine or perindopril arginine with respect to heat and humidity. Accordingly, these data would not discourage me from selecting either salt." (emphasis added)
109 He said that a skilled addressee considering those results would "say it's a tough call" as to whether to subject the arginine salt to more extensive testing. He said that the arginine salt was more hygroscopic than the tert-butylamine. He said that this might be balanced against arginine being a natural substance and probably less toxic. Dr Spargo observed that based on those initial results:
"these things are a balance and there would not necessarily be a clear view. In the end somebody has to make a decision. And that's a business decision. It would not be purely a scientific decision ..."
110 Dr Spargo said that even if there were a decision to proceed with further tests, until tested in tablets one would not know if the new salt would be an improvement on the existing one. Moreover, he agreed that changes in formulation in the salt formation process or of the tablets could produce different results and considerations of both time and money would affect whether such changes would be exposed. Dr Spargo said that in arriving at the selection of counter-ions for a second salt-screen he, or a person skilled in the art, might, or might not, have selected arginine. In his career he had only done so once in a salt-screen and that had not resulted in a successful salt. He said that he could not say that he, or a skilled addressee, would have actually tested arginine, because some other counter-ion might have produced success earlier. He gave this evidence that I accept:
"MR BANNON: But you would accept, would you not, that there would be others of ordinary skill who would quite reasonably, in the circumstances, not choose arginine.
DR SPARGO: Well, clearly. Professor Byrn said he wouldn't, Dr Evans and Dr Morella have said they wouldn't.
MR BANNON: And you would accept that they were reasonable views as to what a skilled addressee would do, albeit not the one you would prefer; correct?
DR SPARGO: Well, I respect their views because they are their views and I respect these gentlemen."
111 However, I do not accept his evidence immediately after he said this that sought to qualify the last answer in which he seemed to disagree with the proposition that the views of Prof Byrn, Dr Evans and Dr Morella were reasonable. Dr Spargo, in trying to justify his disagreement with the three other experts, gave this evidence:
"I wouldn't talk myself out of doing it and, in fact, that's one of the things that you know, the poorer scientists talk themselves out of doing experiments because they think they're clever enough to know and actually you don't know until you try, as we've said.
MR BANNON: Just to make it clear, to make sure I understand your position on this, what I'm suggesting to you is: Do you agree, notwithstanding what you say that you think you would have done, that an ordinary skilled worker in similar circumstances could quite reasonably have chosen not to take the arginine route?
DR SPARGO: What, given that all of the more common counter-ions have failed, I don't think I can answer that question with a yes or no answer because I actually think the context and the circumstances are very, very important and they influence what level of risk and the new ground you break when you're doing this." (emphasis added)
112 I prefer Prof Byrn's evidence that in a real world study only 6 to 12 salts would be tested and the skilled addressee would use counter-ions in Table 1 of the Berge paper. He had never encountered or heard of a salt-screen that worked through all or most of the counter-ions in the three Tables in that paper. As he said:
"It's so unpredictable that I'm not sure it helps you to go to unusual salts. I didn't say I would never, ever. I think what I said was if I had unlimited money and time I might go on to Berge 2 and 3, but in a practical sense I don't think I really would."
113 Profs Byrn and Perkins together with Dr Spargo drew, and commented on, a whiteboard illustration of how a perindopril molecule could form a salt with alternately the guanidino group in a side chain of arginine as part of a (positively charged) cation, or acid, on the one hand, or a (negatively charged) carboxylic acid anion or base, on the other hand. Potentially, two amino acids with acidic side chains, aspartic acid and glutamate acid, could form a salt with perindopril, and there are three amino acids with basic side chains that could do so, namely in lysine, histidine and arginine. Another amino acid, glycine, is a zwitterion. Arginine is the strongest of those bases with the best chance of making a salt in solution. Though as Prof Byrn noted, there is no certainty that a crystalline salt will form from that solution. Dr Spargo considered that glycine could be a candidate although he considered that it was a more complex question whether it would be successful in making a salt.
114 Prof Byrn considered that the anion, or acid, would be likely to form a stronger iconic bond with perindopril because it had two ionisable groups with which to form a resonance structure (or ionic bond). He said that perindopril also had three ionisable groups with which it could form a resonance structure with a cation, like arginine, but that this was likely to make a more complex and weaker bond and, thus it was less likely to form a crystalline salt. Prof Evans agreed.
115 Drs Spargo, Williams and Prof Perkins disagreed that those differences in the ionic bonding characteristics affected the predictability of whether a crystalline salt would form. Dr Morella observed that the theoretical discussion on this point emphasised the unpredictability of salt formation and of the characteristics of any salt that did form, including whether it would crystallise.
116 These matters would be known to a skilled addressee. However, he or she would only give consideration to them if, and when, he or she had moved beyond the routine salt-screen candidate selection process.
117 Apotex criticised Prof Byrn's evidence that he would not have screened arginine because, it contended, he had been aware of a paper by Kenneth R Morris and others entitled: "An integrated approach to the selection of optimal salt form for a new drug candidate" published in the International Journal of Pharmaceutics in 1994 (the Morris article). Dr Morris became, and has remained, a colleague of Prof Byrn's at Purdue University and SSCI since about 1996. Another co-author of the paper, Dr Ann W Newman, worked for SSCI for about 10 or so years before leaving in around 2012.
118 The Morris paper discussed a general method that the authors had employed to select an optimal salt for a carboxylic acid, HMG-CoA reductase inhibitor. As Prof Byrn explained, however, that substance is quite a different molecule to that of the zwitterionic structure of perindopril. Perindopril has a carboxylic acid limb that can be used as a base to form a salt. The Morris paper referred to the Berge paper and discussed the (Morris) authors' development of a three tiered procedure for salt selection. The authors chose to study five bases from Table 1 of the Berge paper together with two bases from Table III, arginine and lysine. The first tier of the study considered the hygroscopicity of each of the seven salts which led to the rejection of four (sodium, potassium, calcium and zinc) because they took up too much moisture in the range of anticipated humidity present in pharmaceutical manufacturing plants. The remaining three salts were tested in tier 2 for changes in their crystalline structure in respect of humidity and for their aqueous solubility in the gastrointestinal pH range. This led to the exclusion of the magnesium salt. The authors found that the crystalline structures of the arginine and lysine salts were resistant to change under extremes of humidity conditions and had high aqueous solubility. They were tested in tier 3 of the screen to assess their chemical stability in respect of temperature, humidity and the presence of excipients. Following this, the authors chose the arginine salt for development. They said that the process could be completed within four to six weeks. However, that salt was never taken to the market. Prof Byrn explained that even if a compound or a salt appeared to perform well in experiments it may not be able to be successfully made on a larger scale for commercial use. Pros Evans and Perkins, and Drs Morella and Williams were not aware of the Morris paper before the priority date.
119 In or after 2009, Prof Byrn used the three tier study described in the Morris paper in a presentation he gave to the Boston Solubility Conference. Prof Byrn accepted that the Morris study described an intelligent and tenable salt selection process. Although he was aware of that study from around the time it was published, he never tried arginine in any salt-screens he conducted, preferring instead to work with counter-ions in Table 1 of the Berge paper that he considered appropriate for the particular compounds with which he was trying to make salts. He also had used a tiered approach when screening salts from about 1993 but with different criteria at different stages. He had developed the protocols for his method while he was working extensively in dealings with the FDA. Usually, he looked for crystallinity in the first tier, solubility in the second and hygroscopicity in the third, but his could vary depending on what requirements SSCIs customer had.