Analysis
469 I begin with some general observations and a summary of the submissions of the parties.
470 The following points should be noted at the outset. First, a number of claims in the 666 Patent are combination claims. For example, claim 1 consists of three integers which interact to produce a new result. The integers are (1) tadalafil; (2) in free drug form; and (3) at least 90% of the particles of tadalafil have a particle size of less than about 40 microns. As the inventors of the 666 Patent state, the second integer interacts with the first integer to produce a more rapid absorption of tadalafil into the blood. The third integer interacts with the other two integers to improve the bioavailability of tadalafil by improving the rate and extent of its absorption (Welch Perrin & Co Pty Ltd v Worrel [1961] HCA 91; (1961) 106 CLR 588 at 612 per Dixon CJ, Kitto and Windeyer JJ). It is well-established that a court must be alert not to apply hindsight to questions of obviousness and the dangers of misusing hindsight can be particularly acute in the case of combination claims where some or all of the integers are old (Minnesota Mining at 266; AB Hässle v Alphapharm at [6], [21] and [41]). Secondly, to the extent that the inventive pathway is described in the 666 Patent, the pathway included, in one of the studies, the use of tablets involving a co-precipitate made in accordance with Butler. Thirdly, the 666 Patent states that a typical daily dose of tadalafil is from about 1 to about 20 mg per day and preferred daily doses generally are about 1 to about 20 mg per day, particularly 5 mg, 10 mg and 20 mg tablets administered as needed.
471 Apotex submits that the fact that tadalafil did not suffer from solubility-limited absorption at doses in the range of 1 - 20 mg would be established early in the drug development process and that the problem which would be identified would be that tadalafil suffered from dissolution rate-limited absorption. I will refer later in these reasons to Dr Mooney's evidence about the tests he considers would be conducted and lead to these conclusions. Apotex submits that the most obvious solution to a problem involving dissolution rate-limited absorption was micronisation and that would be well-known to the development team. Apotex submits that micronisation would be the first approach, or at least one of the first approaches, to be adopted to resolve that problem at the Priority Date of the 666 Patent. Apotex submits that ICOS's contention that on the information in Daugan 1997, it was plausible that tadalafil might be 20 to 50 times less soluble than the "practically insoluble" threshold of 1:10,000 in the BP and USP would be quickly disproved by routine solubility and in vitro dissolution tests such as the test carried out by the inventors of the alleged invention in the 666 Patent and referred to in Example 1 of the patent. The results of that study showed a near-complete dissolution of a 10 mg dose in 1L of the dissolution medium. Apotex submits that the pharmacologists and the clinicians in the development team would, in accordance with well-established criteria for pre-clinical studies and clinical trials, select doses of 1-20 mg. There are no solubility-limited absorption problems with tadalafil at those doses and there is no reason to think that they would arise prior to the selection of those doses.
472 In order to better appreciate the significance of the evidence to which I will refer, it is helpful to note at this point the three major ways in which Apotex put its case. First, Apotex submits that Daugan 1997 teaches that the free base form of tadalafil is the preferable form of tadalafil and that means that the formulation of a salt or the making of a solid dispersion, which are two of the possible solutions to the solubility problem identified by Professor Polli, would be excluded from consideration. Secondly, Apotex submits that the principal possible solutions to the solubility problem identified by Professor Polli, namely, the formulation of a salt of tadalafil, the preparation of a different polymorph or an amorphous form, or the use of a solid dispersion, including co-precipitates, are unrealistic solutions which would be quickly dismissed by the development team. Thirdly, Apotex submits that irrespective of possible solubility-limited absorption problems with tadalafil, a rapid onset of action is a desirable feature of a drug for the treatment of ED. Micronisation can improve the dissolution rate and, therefore, the onset of action, and in the circumstances the development team would be led, as a matter of course, to try micronisation with the required expectation of success.
473 Apotex submits that if micronisation does not involve an inventive step, then the claims which involve pharmacokinetic parameters (i.e., claims 10-12, 18 and later claims which include those parameters) do not involve an inventive step because the pharmacokinetic features inevitably flow from micronisation. I do not need to consider this submission for reasons which will become clear.
474 ICOS made a general submission to the effect that Apotex's approach is flawed because the 1 - 20 mg doses to which Apotex referred are not part of the common general knowledge and they are not part of the teachings in Daugan 1997. The submission was that the formulation issues will be addressed before the doses, which are found to be safe and efficious following multiple clinical studies, have been conducted. The formulator must formulate the dosage forms for use in clinical trials, including Phase I and Phase II clinical trials. The dose escalation studies would include studies to determine the maximum tolerable dose.
475 ICOS submits that Daugan 1997 reveals a clear solubility problem which a development team would address as a priority. There were various possible solutions at the Priority Date, including the formation of a salt of tadalafil, different polymorphs and amorphous forms and solid dispersions, including co-precipitates. Micronisation is not a solution and would not be tried by the development team. Even if that be wrong, micronisation would not be tried with the required expectation of success.
476 ICOS also made particular submissions directed to particular classes of claims: ((1) Claims 7, 8 and 17 Method of Treatment and Swiss Style claims; (2) Claims 10-12 and 18 Pharmacokinetic parameter claims; and (3) Claims 24-38 Incorporating Dosage Regimen Integers). Again, I do not need to consider these submissions for reasons which will become clear.
477 I turn to address the expertise and experience of the formulators.
478 As far as the expert formulators are concerned, I formed a clear preference for the evidence of Professor Polli over that of Dr Mooney. Dr Mooney had a high level of expertise in the formulation of generic drugs and was doing his best to assist the Court. However, he had virtually no experience in the formulation of NCEs. There is an important difference between generic drugs and NCEs when considering "solubility" problems. In my opinion, the development team would include a formulator with knowledge and experience in the formulation of NCEs. If I may put it this way, Professor Polli meets that description.
479 Prior to August 1999, the vast majority of Dr Mooney's experience in the field of pharmaceutical formulation related to formulating generic versions of an existing drug. Dr Mooney said that he did not consider that the underlying scientific principles and product development principles associated with formulation changed because the drug substance is an NCE. He said that the main difference between a generic formulation and a formulation for an NCE is the volume of pre-existing information about the drug substance and the need, in the case of a generic formulation, for certain features to match those of the existing drug. Dr Mooney said that he would expect that in the case of an NCE less would be known about the drug substance, and as a result, some additional basic testing may need to be performed by either himself or others in the team to identify its basic physical and chemical properties. Dr Mooney said that in the defined period of time (i.e., 3 August 1999 - 1 August 2000), he was not familiar with solubility-limited absorption. He was asked to bring his own knowledge and experience to the development brief and that knowledge and experience was limited. Dr Mooney had only ever addressed "solubility" issues by reducing particle size and he had no experience (nor the need) to solve solubility issues by any other means. Dr Mooney agreed that a formulator of a generic pharmaceutical product already knows that the amount of the drug needed to produce the desired therapeutic effect can be absorbed. There may be dissolution rate-limited absorption problems to confront, but not solubility-limited absorption problems.
480 Put another way, Dr Mooney's experience was limited to the formulation of generic or copy drugs where absolute solubility problems do not arise. It is known from the original drug that the marketed doses will be absorbed. Dissolution rate problems did arise in the course of formulating generic drugs and Dr Mooney's first choice in terms of a solution, was micronisation. Dr Mooney used the term "solubility" to include both, what might be called, absolute solubility and dissolution rate.
481 Dr Mooney said that he would recognise at the outset of the formulation process that tadalafil had solubility problems. He said that he would conclude from Daugan 1997 that the free base form of tadalafil was the preferable form. He said that he would undertake two steps or tests involving micronisation. First, he would arrange for a sample of tadalafil at the lowest micron range to be prepared and tested in vitro. He would thereby discover (so he said) that the problem was dissolution rate, not absolute solubility. Secondly, Dr Mooney would then arrange for a study to be undertaken of the compound at different particle sizes to determine the best particle size, or range of sizes. This second study was referred to in the evidence as Dr Mooney's particle evaluation study.
482 Dr Mooney said that there were a number of options to improve solubility. First, particle size reduction could improve solubility. There would be no raw material chemistry change. However, the impact on stability with increased surface area and manufacturing would be addressed as part of the development. Secondly, solubility could be improved by the use of a different polymorph. The chemistry remains the same, but to find a suitable polymorph that is stable in the dosage form and complies with the c-GMP quality requirements would be time impacting. Thirdly, solubility could be improved by the use of solid dispersions. Dr Mooney said that this task requires identification of the appropriate polymer, establishing the active to polymer ratio, establishing that the level of polymer is appropriate from a permitted daily ingestion exposure level and then product development time. Additionally, with a high polymer to active ratio, this could lead to a very large dosage presentation, which may limit patient acceptance. Fourthly, solubility could be improved if the salt of tadalafil could be made. Dr Mooney said that this would involve an NCE. He said that significant time would be taken to develop and manufacture appropriate c-GMP material, then formulation commences. In those circumstances, there is an extensive time lag to human clinical trials. He said the synthesis to make the salt at the purity level required for clinical trials would take longer than micronising the existing material. He also said that new salts still require formulation development and have their own inherent issues. Fifthly, solubility could be improved by the use of pro-drugs. This involves an NCE which requires full NCE development and subsequent evaluation. Dr Mooney did not consider that pro-drugs would be considered as a means of improving the dissolution rate.
483 The difficulty with Dr Mooney's analysis is that micronisation does not improve solubility-limited absorption and the problem revealed by Daugan 1997, which would be apparent to the skilled formulator on the development team considering an NCE, was solubility-limited absorption. Dr Mooney's lack of experience with NCEs would have led to him adopting a dissolution rate-limited absorption problem (i.e., micronisation) to what appeared to be a solubility-limited absorption problem. It is now known that the problem with tadalafil at doses of 1 - 20 mg is a dissolution rate-limited absorption problem.
484 By contrast, Professor Polli had researched, taught and published the science relating to the task of formulating NCEs before the Priority Date. He had worked on between six and 12 projects involving the formulation of NCEs before the Priority Date and that work included formulating poorly soluble drugs and, in one case, overcoming a solubility-limited absorption problem by developing a more soluble polymorph. He has had experience working with poorly soluble NCEs since the Priority Date. He was an impressive witness.
485 Professor Polli said that the approach he would take if he was developing the first formulation of an API would be very different to the approach he would take if he was developing a generic version of a registered formulation of the API. He said that that was so because in the case of the first formulation of an API, he would not have a proven pharmacokinetic target to aim for.
486 Professor Polli said that solubility could not be improved by reducing the particle size of the API by micronising to the "low micron range". He said that he was not familiar with the practice of grinding an API to below 100 microns for pre-formulation testing and that, in his experience, it was not generally accepted by other pharmaceutical scientists before the relevant date (i.e., 3 August 1999 - 1 August 2000). In other words, he was not familiar with Dr Mooney's first step or test involving micronisation. He explained that IVIVC was not common for at least two reasons. First, particle size may not impact on in vivo pharmacokinetics, including situation when not expected. Secondly, clinical development resources are not often applied to investigate the in vivo effects of particle size. Clinical development resources typically prioritise the demonstration of safety and efficacy over investigating potential particle size effects.
487 I turn to state my key conclusions and the reasons I have reached those conclusions.
488 The key conclusions I have reached are as follows. It is of the utmost importance that the formulation of a compound is such as to achieve appropriate absorption at various doses. The evidence supports the conclusion that the formulation task would proceed by reference to doses of 25 mg, 50 mg and 100 mg, and the same formulation technique would be used for each of these doses. I accept Professor Polli's evidence that the skilled non-inventive formulator would detect from Daugan 1997 a solubility-limited absorption problem for which there were various possible solutions. Micronisation was not one of them. Having regard to the whole of the evidence, I accept that some of the solutions identified by Professor Polli were realistic solutions.
489 There is no dispute that the first and most important priority of a formulator faced with an NCE is to ensure absorption into the blood stream of a sufficient quantity of the drug to achieve the desired therapeutic effect. The formulators were agreed that for the purposes of a dose escalation study (or studies), the formulation strategy must ensure that higher doses involve greater absorption of the drug than the lower doses. Dr Mooney agreed that the formulators need to ensure that each dose which is tested is absorbed. Dr Mooney also agreed that the relationship between the size of the dose and measured solubility needed to be considered by the formulator as a matter of priority in developing the oral formulation because of the risk that the desired dose for therapeutic effect will not be absorbed. He also agreed that although dissolution rate was a relevant consideration, it was of no use addressing that issue if the dose for the desired therapeutic effect could not be absorbed. Professor Polli said that he would be concerned if the maximum absorbable dose was less than the dose required to achieve the desired therapeutic effect. He also said that solubility and whether poor solubility may result in the necessary dose being unable to be absorbed must be addressed first and foremost.
490 It is important to recognise that the formulator in the development team in this case would approach the formulation issues by reference to doses of 25 mg, 50 mg and 100 mg for the following reasons. First, a commonly used yardstick for appropriate doses is 1 mg for every kilogram of body weight and this was part of common general knowledge at the Priority Date. This yardstick leads to a 70 mg dose in the case of a normal adult male. Secondly, the example pharmacy formulations in Daugan 1997 used doses of 50 mg. Dr Mooney said that, in addition to doses of 50 mg, different doses would be required for the drug to be provided across the population and therefore, he expected that a dose higher and lower than 50 mg would also be developed. Thirdly, Dr Mooney's development brief contained an instruction that he prepare an immediate-release solid oral dosage form in unit doses of 25 mg, 50 mg and 100 mg for use in clinical trials in humans and Dr Mooney said that he could not detect anything in Daugan 1997 that suggested that that was not an appropriate instruction.
491 The related point to the doses the formulator would use is that it was not suggested that different formulation techniques would be applied to different doses. The same technique would be used whether the dose was 25 mg, 50 mg or 100 mg.
492 I accept ICOS's submission that Daugan 1997 raises a clear and pressing solubility-limited absorption problem at 50 mg and 100 mg doses. It suggests that there is a real risk that tadalafil is so poorly soluble that the amount of drug necessary to achieve a therapeutic effect or escalating doses in Phase I and Phase II trials will not be absorbed. Furthermore, the formulator working in the development team would recognise a likely solubility-limited absorption problem, having regard to common general knowledge and Daugan 1997. There is no dispute that Daugan 1997 indicates that tadalafil will be poorly water soluble, perhaps very poorly water soluble. The high melting point and materials used in the Example pharmacy formulations establish this matter. It follows that doses of 25 mg, 50 mg and 100 mg are likely to be very poorly water soluble, particularly if tadalafil is 20 times less soluble than the BP threshold point, or worse still, is 50 times less soluble.
493 A compound (solute) that is "practically insolvent" requires at least 10,000 parts of solvent for each part of the compound. An allowance of 10 times is made for the fact that part of the compound is absorbed over time and further dissolution then occurs. The volume of solvate in the gastrointestinal tract is 250 mL. This means that if a compound had a solubility that required more than 10 times the volume of gastrointestinal fluid, then permeation will not overcome the poor solubility and not all of the dose will be absorbed. Whether all of the dose is absorbed will depend on dose size. If a compound is at the threshold of 1:10,000, a 25 mg dose will dissolve in 250 mL of fluid. If it is significantly above the threshold, then solubility issues arise. The formulators agreed that it was plausible that the correct ratio in the case of tadalafil was 1:200,000 or even 1:500,000 and those levels would require (for a 50 mg dose) quantities of solvent of 10 L and 25 L respectively compared with 2.5 L available (250 mL x 10).
494 I accept Professor Polli's evidence to the effect that one of the very first properties of a compound which is tested is its melting point and that high melting points are a well-known indicator of poor solubility in aqueous solutions because they correspond to strong bonds between the molecules within the solid that must be overcome for the solid to dissolve. I accept that this was part of common general knowledge at the Priority Date. I also accept Professor Polli's evidence that melting points over 300°C were strongly indicative of very poor solubility. As I have said earlier, the melting point for tadalafil shown in Daugan 1997 is 302-303°C.
495 The formulator reading Daugan 1997 in the context of a project to develop an NCE would have recognised the problem of solubility-limited absorption that Daugan 1997 raises for the exemplified 50 mg dose and other doses that may be tested in Phases I and II. The formulator would seek to improve the solubility of tadalafil. This can be done by formulating the API in a way that increases the amount of tadalafil that is able to dissolve in the gastric fluid at thermodynamic equilibrium, that is, raising equilibrium solubility or enables a "super-saturated" state to be achieved, where the amount of tadalafil that is able to dissolve in the gastric fluid temporarily exceeds thermodynamic equilibrium.
496 Professor Polli said that he expected solubility-limited absorption problems at doses of 25 mg and especially at 50 mg and 100 mg. Although having read the 666 Patent, Professor Polli now recognises that tadalafil in doses of 1-20 mg does not raise solubility-limited absorption problems, he maintains his view that tadalafil at doses of 25 mg and (especially) 50 mg and 100 mg were likely to raise solubility-limited absorption problems. This is because of the relationship between the amount of the dose and measured solubility as the BCS previously discussed makes clear. That has a classification for drugs in terms of solubility and permeability and the solubility is calculated by reference to the highest unit dose in a given volume of fluid. Of course, in the case of an NCE in drug development, such as tadalafil, the highest unit dose is not known.
497 There is one other matter to be identified in this context. The formulator could not assume from Daugan 1997 that there would not be permeability-limited absorption problems with tadalafil. There is simply no information in Daugan 1997 from which one could predict or assume permeability. I accept Professor Polli's evidence that if permeability is poor, the solubility-limited absorption problem is likely to be worse and his evidence that improving the rate, whether by reducing the particle size or increasing solubility, will have no effect on the rate at which the API is absorbed, and thus no effect on the onset of action. I accept ICOS's submission that the absence of information about permeability is a further reason that the skilled person reading Daugan and having regard to common general knowledge could not reasonably expect that micronising tadalafil would result in a successful outcome.
498 Professor Polli said that the first option which he would consider to deal with his concerns about the solubility of Compound A and Compound B would be to use salt and solvate forms, particularly salt forms. There is support for this view in the following passage in Lieberman et al (1989) at p 17:
When the drug substance under consideration is not an acidic or basic compound, or where the acidic or basic character of the compound is not amenable to the formation of a stable salt, other means of enhancing the solubility may be explored.
499 There is repeated reference in Daugan 1997 to the compounds of the invention including different salt forms and it broadly describes a process for synthesising salts.
500 Professor Polli gave evidence that his second and third choices to improve the solubility of tadalafil would be to try and make a different solvate, polymorph or amorphous forms. The passage from Lieberman et al (1989) proceeds as follows:
The use of a more soluble metastable polymorph to enhance bioavailability of orally administered solids is one way to approach the problem. Other approaches to improve solubility or rate of dissolution include use of complexation and high-energy coprecipitates that are mixtures of solid solutions and dispersions.
501 Professor Polli said that the most common solvate is a hydrate and he described the interactions within the crystalline structure. Daugan 1997 refers to solvates and, in particular (by way of example), hydrates.
502 Professor Polli gave evidence that polymorphic forms are alternative crystalline structures of the same API and that the use of different polymorphic forms was a common technique to improve solubility at the Priority Date. Dr Mooney acknowledged that trying to find a polymorph that had a better solubility value is an option that is worth a try in resolving a solubility problem.
503 The fourth choice that the formulation scientist was likely to try was to formulate tadalafil in the form of a co-precipitate or solid dispersion. Professor Polli described how this works: when the polymer dissolves, the drug will be molecularly dispersed to render it more soluble. The formulators identified particular difficulties with the formulation of co-precipitates. It is clear from the formulators' evidence that all of the techniques have disadvantages in terms of time, cost, difficulty and uncertainty.
504 Micronisation cannot solve the solubility-limited absorption problem that appears in Daugan 1997. Dr Mooney agreed in his evidence that increasing the surface area of a particle to a low micron range does not alter the quantitative definition of solubility as distinct from the rate of dissolution. It seemed to me that he agreed that micronisation will not change the character of the drug as "practically insoluble" under the BP and USP. In the course of his evidence, he said:
MR BURGESS: And then in paragraph 131, you say the first approach you would have considered to improve the solubility of a poorly water-soluble drug would be to reduce the particle size of the drug substance.
DR MOONEY: Yes.
MR BURGESS: So is this right: when you say micronizing is a technique that can be employed to improve the solubility of a poorly water-soluble drug, in both your affidavit and in the joint expert report, what you mean is that micronizing is a step that can be taken to improve the dissolution rate; correct?
DR MOONEY: Yes.
MR BURGESS: And that's what you refer to in paragraph 132; correct?
DR MOONEY: Yes.
MR BURGESS: And you do not mean to say that micronizing can be used to improve the measured solubility value.
DR MOONEY: Well, as I said, when I wrote this my solubility wasn't defined based on saturation. The solubility was referring to my original characteristic.
505 I turn to address the significance of Daugan 1997 containing formulations of tadalafil in free base form.
506 The formulators were asked the "inventive step" question, if I may use that expression, in another way. They were asked whether, having regard to Daugan 1997, they would consider formulating the compounds in other than their free base form. In one sense, this is really doing no more than asking them to comment on the extent to which Daugan 1997 advocates or teaches the use of tadalafil in its free base form.
507 Professor Polli was not dissuaded from his central thesis and he said that he would turn to salts and solvates as his first choice, especially salts. He did note that an alternative polymorph with higher apparent solubility could be in free base form. Professor Polli said that he would first use salt and solvate forms, particularly salt forms, to increase the solubility of Compounds A and B. Even if it was known or discovered that the problem was one of the dissolution rate as distinct from solubility, he would turn to solubility solutions which improve dissolution rate, or failing that, if he was to consider micronisation, not micronisation to the smallest possible size.
508 Dr Mooney considered that Daugan 1997 supported the use of tadalafil in its free base form.
509 It is true that Daugan 1997 describes pharmacy formulations of tadalafil in its free base form, but there is no real indication that that is the preferred form. Furthermore, there are a number of references in the specification to the formation of salts or solvates of tadalafil. In any event, the overriding problem suggested by Daugan 1997 is one of absolute solubility which the formulators skilled in the formulation of NCEs would know could not be solved by micronisation.
510 I turn to address whether Professor Polli's suggested solutions were realistic.
511 Apotex submits that none of the possible solutions identified by Professor Polli were realistic solutions and that they would be quickly dismissed by the development team.
512 Apotex submitted that making a salt of tadalafil was unlikely to be considered a realistic solution to the solubility problem. Daugan 1997 contains information about the preparation of a salt of tadalafil, both an acid addition salt and a base addition salt. As I have said, Professor Polli's first option to solve the solubility problem was the formation of a salt of tadalafil, although he did not give evidence about the extent to which that would be possible or how the development team would go about it. That was because those matters were not within his expertise. The first option of Dr Mooney (who had a PhD in organic chemistry) to solve the solubility problem - in reality, from his point of view, a dissolution rate problem - was micronisation, but if that did not work, the formation of a salt was one of his other options. Dr Robertson is an experienced medicinal chemist and his evidence (which is discussed below) is that the formation of an effective salt of tadalafil is possible. Having regard to Dr Robertson's expertise, his evidence is decisive.
513 Dr Reece gave evidence in relation to the alleged invention in the 946 Patent. In addition, he gave evidence about whether the formation of a salt of tadalafil was possible. He said that he considered that it would be difficult to form an acid addition salt. Dr Reece agreed that he had only considered an acid addition salt and, even as to that opinion, he acknowledged that he would need to consult a medicinal chemist on the point. He seemed to acknowledge that it would be possible to form a base addition salt, but then qualified his opinion by saying that the formation of a salt would present some challenges because the reagents necessary to do so were "explosive agents to use…". There was also reference in the evidence of the pharmacologists to the possibility of re-precipitation of tadalafil in the low pH environment of the stomach. Professor Evans said that the formation of a salt would not be his first option because of the "extreme conditions", but that it is a matter he would take advice on from a medicinal chemist.
514 Dr Robertson explained that a salt is formed by reacting an acid and base. A salt formed by adding an acid to the API is called an acid addition salt. In an acid addition salt, the API behaves as a base and accepts a proton from the acid. A base addition salt is formed by adding a base to the API. Dr Robertson said that it may be that Compound A was insufficiently basic to form an acid addition salt, even with a strong acid. However, he expected that the indole nitrogen in the structure would be capable of forming a base addition salt of the compound represented by the structure (i.e., the chemical structure of tadalafil) and he said that he was confident that he could make such a salt applying his skills as a medicinal chemist. Dr Robertson's opinion was supported by the standard textbook to which he referred (Smith LR, "Indoles, Part Two", in Houlihan WJ, The Chemistry of Heterocyclic Compounds, (Wiley-Interscience, 1972) (Annexure ADR-4)). Dr Robertson said, and I accept, that Dr Reece did not give consideration to base addition salts. I accept Dr Robertson's opinion that, in the event that an acid addition salt of tadalafil could not be made, there was a good expectation that a base addition salt could be made and, furthermore, other medicinal chemists would have recognised that to be the case at the Priority Date of the 666 Patent.
515 Apotex sought to gain assistance from the decision of Birss J in the counterpart UK proceedings in the Patents Court, Actavis Group Ptc EHF v ICOS Corporation [2016] EWHC 1955 (Pat) (Actavis Group v ICOS) (at [418]) where his Lordship said that the alternative of a salt formation would be ruled out early and that there was nothing suggesting that finding a different polymorph was realistic. I have noted those observations, but clearly I am required to proceed having regard to the evidence before this Court.
516 Apotex submitted that making a different polymorph was unlikely to be considered a realistic solution to the solubility problem. It pointed to the fact that the formulators agreed that all polymorphs and amorphous forms achieve the same absolute solubility. However, Professor Polli considered that a different polymorph was an option and, although his experience with different polymorphs was limited as Apotex submitted, his opinion is supported by the standard texts (Lieberman et al (1989) Vol 1 p 34 (JEP-27)). Furthermore, the formulators agreed that equilibrium solubility may be exceeded on a temporary basis and that this may happen with amorphous and more soluble polymorphs. The period of time over which equilibrium solubility may be exceeded can be minutes or hours. In addition, a process of polymorphism, which can improve solubility, involves lyophilisation of a solution of the compound in p-dioxane to produce a dioxane solvate. Elimination of the dioxane by exhaustive drying can produce a polymorphic form with significantly increased solubility (Lieberman et al (1989) Vol 1 p 60 (BAM-32)).
517 I should make it clear that I have not overlooked the point made in one of the articles tendered in evidence (Curatolo W, "Physical Chemical Properties of Oral Drug Candidates in the Discovery and Exploratory Development Settings" (1998) 1 Pharmaceutical Science & Technology Today 387 (JEP-15)) that the formation of salts and different polymorphs does have the disadvantage that earlier pre-clinical work needs to be repeated.
518 With respect to solid dispersions such as the formulation of co-precipitates, Apotex submitted that this was not a realistic possible solution because of the challenges associated with the formation of solid dispersions and, or because of these challenges, solid dispersions were not commonly used at the Priority Date. Professor Polli agreed that solid dispersions were not commonly used at the Priority Date. The force of these points may be acknowledged, but the development team was facing a pressing and significant solubility-limited absorption problem. It may be noted in this context that the inventors of the alleged invention in the 666 Patent started with a co-precipitate.
519 I find that a salt form of tadalafil was a realistic possible solution to solve the solubility problem as were, albeit less attractive, a different polymorph or amorphous forms and a solid dispersion.
520 Even if the possible solutions involved multiple challenges, this is not a reason to think that the development team would adopt a dissolution rate solution (micronisation) for what presents as a solubility-limited absorption problem. Even if the team considered micronisation, which I note raises its own challenges, was worth a try, it would not undertake micronisation with the required expectation of success. There is another matter. Whilst it is now known that the problem with tadalafil of doses at 1-20 mg is the dissolution rate, there is no evidence about the problem at the doses Dr Mooney was asked to consider (i.e., 25 mg, 50 mg and 100 mg). There is, therefore, no evidence that testing at those doses would have led, as a matter of course, to micronisation.
521 Finally, I turn to address whether the development team would have adopted micronisation, in any event, to improve the onset of action.
522 Apotex submitted that even if absolute solubility as distinct from dissolution rate was seen as a problem, a rapid onset of action was seen as a desirable feature of a drug for the treatment of ED, and therefore, micronisation would be easily recognised as a means of improving the onset of action.
523 I reject this submission. For the reasons I have already given, the development team would focus on solving the solubility-limited absorption problem. The development team would know that improving solubility was also likely to improve the dissolution rate. In any event, a dissolution rate problem is not apparent on the face of Daugan 1997. Finally, it is relevant that there are challenges and disadvantages associated with micronisation, including ongoing manufacturing costs. I turn now to expand on these points.
524 It is correct (as ICOS submitted) that no rate of onset problem appears on the face of Daugan 1997. It is clear from the evidence that a drug substance with poor solubility may nevertheless reach its saturated concentration quickly and a highly soluble drug substance can reach its saturated concentration very slowly. Smith (2015) contains the following passage:
Solubility and dissolution are different concepts but are related…
Solutes vary not only in the extent to which they dissolve, but also how quickly they will reach their respective solubility limits. Solubility and dissolution rate are two distinct phenomena. Dissolution rate is a kinetic process. A solute may have poor solubility in a solvent, yet its dissolution rate may be rapid. Conversely, a solute can be very soluble, yet require a protracted amount of time to arrive at the final, saturated concentration…
525 Dissolution is not mentioned in Daugan 1997, nor is there any pharmacokinetic data in Daugan 1997 and without that data, no skilled person would reasonably expect any problem with the rate of onset of therapeutic effect. The pharmacokinetic data would indicate the therapeutic window for tadalafil, including the minimum effective plasma concentration at which efficacy is first observed, and the time required to reach that minimum plasma concentration.
526 Furthermore, even if the dissolution rate was thought to be a potential problem, this would not be the priority for the formulator. The priority for the formulator would be to address the solubility-limited absorption problem.
527 Dr Mooney agreed that improving solubility will also improve the dissolution rate. In the course of his evidence he said:
MR BURGESS: Thank you. Now, you would accept as well that if more soluble forms of compound were identified they may improve not only the measured solubility, but also the dissolution rate; correct?
DR MOONEY: Yes.
MR BURGESS: And any such improvement in measured solubility of compound A or B may have remedied any problem that might otherwise have existed with the dissolution rate of the freebase form of Compound A; correct?
DR MOONEY: I accept that, yes.
MR BURGESS: And the same could be said of the other 13 suitable compounds; correct?
DR MOONEY: Yes.
528 While taking steps to improve the solubility of the selected compound, the formulator would have no reason to expect the dissolution rate and, still less, the time of onset, was problematic.
529 Dr Mooney accepted that his particle size evaluation study could not have occurred until after Phase I dose escalation studies had been conducted to find the maximum tolerable dose and, in the absence of good efficacy models in animals, "perhaps" would not have occurred until after Phase II studies had been conducted investigating safety and efficacy in patients. I accept ICOS's contention that at that point there would be no reason to consider micronisation. Starting with Daugan 1997 and the common general knowledge only, any need to conduct Dr Mooney's study could not be expected to arise until after Phase I testing and, at the earliest, during Phase II or after, wherein formulations were used in which solubility has been increased to address the problem of solubility-limited absorption and yet Phase II (or potentially Phase I) testing showed that despite such steps being taken to increase solubility, there is a dissolution rate problem. If there was no rate of absorption or rate of onset problem observed as a result of these studies, there would be no motivation to reduce the particle size to micron levels or investigate the benefits of doing so. Micronisation is not carried out as a matter of course and I accept the evidence of both experts that there are disadvantages with micronisation and that a formulator or drug development team will not engage in a process of micronisation unless it is necessary to do so. Dr Mooney made a reference to the fact that the findings of his particle evaluation study could be used "to set appropriate quality control particle limits of the raw material for ensuring batch to batch consistency for future clinical trial batches in terms of the extent and rate of absorption of the drug where differences were seen for different particle sizes". The problem with that approach was identified by Professor Polli. A study carried out for that purpose is quite different from a study carried out to address a dissolution rate-limited absorption problem.
530 Even if the development team considered that micronisation was "worth a try" and it was carried out, it would not be done with any expectation of success, either at all or at particular sizes. Before one carried out micronisation, one would need the pharmacokinetic data for safety and efficacy and that was not part of either common general knowledge or in Daugan 1997. Nor was there any way of knowing the appropriate micron range and there may be some inventiveness in perceiving the best particle size range for a particular drug substance.
531 I am not satisfied that the development team would be directly led, as a matter of course, to try micronisation with the required expectation of success.