7.9.2 Consideration of the evidence
354 Dr Robertson's evidence is that Jain discusses the administration of 20 mg and 40 mg doses of parecoxib in a Phase III double-blind placebo-controlled randomised study. Whilst it does not provide the administration volume for intravenous administration in the case of post-surgical pain, generally, his view is that a small volume is preferred when being administered by a medical professional, and volumes such as 1-2 mL can be administered conveniently using a syringe. He notes that in Talley, parecoxib sodium is described as having a solubility of 22 mg/mL which, in his experience, is sufficient for formulating an intravenous formulation of 1 or 2 mL. He would accordingly formulate parecoxib with injection volumes of 1 mL for 20 mg of parecoxib, and 2 mL for 40 mg of parecoxib.
355 Dr Robertson gave evidence that his preferred formulation would include parecoxib sodium and a phosphate buffer in a solution of around 20 mg/mL at a pH of 7.4 before lyophilisation. He said that in doing so he would ensure that the majority of the composition was comprised of the active ingredient and that the amount of buffer and any other excipients was kept low because, in his view, excipients are only included in any given formulation if they are required to solve a particular problem. He gave evidence that his preference for reconstituting the lyophilised powder was to use a diluent of 0.9% w/w solution sodium chloride, to ensure that the reconstituted solution was isotonic.
356 Professor Winter challenged that approach. Whilst he accepted as a matter of principle that unnecessary excipients would not be added to a formulation, his evidence was to the effect that an experienced formulator would typically consider how to formulate the pre-lyophilised solution by having regard to a well-known consideration in the field that it is desirable for the dried product resulting from lyophilisation to occupy the same volume as the original solution. He referred to the text book Alphonso R. Gennaro et al, Remington: The Science and Practice of Pharmacy (19th ed, Mack Publishing, Easton, 1995), which is quoted in the patent (page 2 lines 29 - 32) as saying that in order to achieve this volume "the solids content of the original product must be between approximately 5 and 25%" of the total original solution.
357 Professor Winter gave evidence that a formulator with experience in lyophilisation would also consider:
(a) limiting the amount of excipient salts, as products which contain salts are difficult to dry;
(b) the potential need to add a bulking agent such as mannitol, which was the most common bulking agent before April 2001, to achieve an elegant cake;
(c) the need to ensure that the reconstituted solution would be isotonic, which is commonly achieved with a bulking agent;
(d) the need to form a cake which is porous and dissolves quickly and completely, which is commonly achieved by adding a bulking agent; and
(e) the need to add stabilisers, such as mannitol (the most common stabiliser used at the time) to ensure that the active ingredient could be stored in a stable condition while dry.
358 The disagreement between Dr Robertson and Professor Winter was explored in the joint expert report and in their oral evidence. Much apparent disagreement was resolved.
359 In their joint report, the experts considered the passage in Remington. They agreed in answer to question 17 as follows:
Bulking agents were very common and were immensely popular in 2001. A person seeking to make a lyophilised product would likely add a bulking agent at some stage in the development of the freeze dried product; an experienced formulator would make the decision on a rule of thumb that ca. 10% solid material would likely be appropriate. The experience formulator would not necessarily need to read Remington.
(emphasis added)
360 The experts also discussed the use of mannitol. In the joint expert report they agreed:
Mannitol was very popular in the pharmaceutical industry as a bulking agent for freeze dried products. It wasn't the only carbohydrate used for that purpose but the one most often used. A lyophilisate (cake) containing mannitol mostly had particularly good appearance, but not always. One had to consider the risk of re-crystallization in different modifications and vial cracking…One key feature of mannitol was the belief that it was a non-reactive, inert excipient.
(emphasis added)
361 Furthermore, the oral and written evidence supports a finding that it was known by formulators before April 2001 that the addition of mannitol may have been useful for at least the following purposes:
(a) to increase the mass of the lyophilised product and to disburse the active ingredient, reducing the likelihood of any residual water, for example from the rubber stoppers used to close the vial, coming into contact with the active ingredient;
(b) to aid in the drying of the active ingredient by providing a matrix together with the active ingredient and other excipients that is porous and stable and allows moisture to be removed;
(c) to guard against the risk of collapse of the cake;
(d) to guard against the risk of the cake being blown out of the vial by water vapour convection;
(e) to reduce the risk of poor dissolution upon reconstitution; and
(f) to assist in ensuring that the reconstituted solution is isotonic.
362 The experts agreed that the formulations of the patent fell outside the rule of thumb because the content of solids in the pre-lyophilisation solution as a percentage of the amount of water added before lyophilisation is less than about 10%. Accordingly, were the rule of thumb to be applied, the use of bulking agent would normally be required.
363 Both experts were skilfully cross-examined about the approaches that they would take. In answer to a general question, without parecoxib sodium as the target active ingredient, they said:
MR COOKE: I will ask another question, then. Professor, you would agree, wouldn't you, that when formulating a lyophilised pharmaceutical before April 2001, if you used no excipients, you would not be certain that you would produce a useful result. But you might just, might well just do that, mightn't you? And that would justify you, first, trying to lyophilise the formulation with no excipients?
…
PROF WINTER: Yes. I understand the question in a way that this hypothetical formulation without excipients would be one of the first to start with. And I totally disagree with. The ones I would start, first, with is those that give me the - let's say, "highest probability of success". I think, this is the term you're familiar with, and this is also a term that the formulator, let's say, uses in the back of his head. And from there, he might walk into several directions and variations, and one of them could also be to try a formulation without an excipient, and therefore it is one of many choices, but surely not the starting one or the preferred one for theoretical reasons.
364 Asked to comment on Professor Winter's answer, Dr Robertson said:
DR ROBERTSON: Yes. Well, I say from - you know, for APIs of a - of a suitable bulk, I suppose. When we - when we started off, you know, with an API that we knew nothing about, first of all, you've got to gather a lot of information, and certainly can you - can it be freeze-dried at all is the very first question that we ask. So - so generally while - this is not, maybe - this is on the way to a formulation. We would generally attempt to freeze-dry the API on its own, so that we could at least understand that, and then - that would not - that would [not] necessarily be the final formulation, but part of our understanding on the way to a final formulation. And then we would add, if that was the - if that didn't work out, then we might add other excipients; if that did work out, we would feel gratified, and then add excipients as we felt the need. But this is, you know - I don't know. Simplest is always the best and we - we start - we used to start from no excipients and then add them as required, if that - if that makes sense, rather than use a standard formulation and take them away as required. So that may be two different ways of doing things, but as I've described, it is the way that we did it.
(emphasis added; the word "not" in brackets is a correction added after reviewing the video file)
365 It is notable here that Professor Winter made clear that he would not attempt a formulation that he did not consider had a probability of success and, consequently, he would not try a formulation that did not involve using bulking agent.
366 I understand from his reference to "for API's of a suitable bulk" that Dr Robertson agreed that where the active ingredient was of a suitable bulk he might try formulating the pre-lyophilisation solution with no excipients. It is a little unclear in the latter part of his answer whether, and in what circumstances, freeze-drying the active ingredient on its own would be simply part of a development path alone, or whether it may be the solution and represent a potential final formulation. Later, Dr Robertson sought to clarify his evidence. He said that where he was starting with a parecoxib sodium formulation with a solids content of considerably lower than 10%, being about 3% (as in the patent):
I think I said earlier that, you know, when you're starting out in the formulation you would determine whether the API could be freeze-dried at all. Then you would see whether it could be freeze-dried with an excipient which was of interest if you're to get the formulation, and if you failed in all of these, then you might consider - in fact, you would consider adding a bulking agent, but, you know, I think it's a different approach that I have, whereas I would start with an understanding of how the API could be lyophilised on its own, and add bulking agents or excipients as required.
…. My approach would not be to add a bulking agent just to get up to 10 per cent because that's the rule of thumb, and then subtract bulking agents as necessary ..... the other way around.
(emphasis added)
367 However, Dr Robertson subsequently accepted that, having regard to the rule of thumb, his approach would not likely be the approach taken by other formulators in the field:
MR DIMITRIADIS: …Dr Robertson, I suggest that having regard to your agreement in question 17 of the joint report, you would accept that an experienced formulator seeking to make a lyophilised product would add a bulking agent in order to increase the solids content up to about 10 per cent solid material in the circumstances that I was putting to you. Do you accept that?
DR ROBERTSON: I think what we agreed was that it would likely be appropriate. That doesn't mean that it's essential.
MR DIMITRIADIS: And if the experienced formulator applied the rule of thumb, that's what they would do. Correct?
DR ROBERTSON: If they were to apply the rule of thumb, but an experienced formulator would not necessarily take the rule of thumb as gospel.
(emphasis added)
368 Returning to Professor Winter, later in his oral evidence, a more concrete proposition was put to him. He was asked to assume that he was endeavouring to make a lyophilised form of parecoxib sodium for injection, and had formulated a pre-lyophilisation formulation consisting of parecoxib sodium with a phosphate buffer at a pH of 8.1. It was suggested to him that "a logical approach" would be to prepare the lyophilised formulation without a bulking agent. He responded:
MR COOKE: Now, you would agree, wouldn't you, that although the formulator would not be certain that the formulation would produce a suitable cake, a logical approach to prepare the lyophilised formulation would be without a bulking agent because it may well produce a useful result.
PROF WINTER: Well, you asked me a similar question earlier and I said no. The standard approach would be to go with a bulking agent. I agreed and I still agree that trying it out without a bulking agent would be one of a number of, let's say, experiments I would conduct. I cannot deny that. I cannot exclude that.
MR COOKE: Okay. And you would run that at the same time as your experiment with the bulking agent if you're in a pharmaceutical company, you're pressed for time. You would run the experiments together.
PROF WINTER: This is a matter of other circumstances like how much material you have, how - are the freeze dryers booked out and so on. Maybe not at exactly same time, but in the course of a formulation package or a set of experiments, this could be done. Whether it's done immediately, this is a matter of, let's say, organisation, logistics and - - -
369 Professor Winter was pressed on his evidence about trying a formulation without bulking agent. He was asked to assume formulations without bulking agents containing 20 mg or 100 mg of parecoxib sodium, a disodium sodium phosphate buffer, water for injection and with or without a pH adjuster. It was suggested to him that after these formulations were lyophilised the next step would be to test the lyophilised cakes to see whether they had sufficient structure:
PROF WINTER: Yes, that would include this - analysing the quality of what you have achieved, which is, as for that structure, it is residual water, it is quality of the drug, of course. Yes, that's true. And if this is not what you like to see, then you have to do it again, and eventually again, and again. This is then always taking one more cycle, until you are satisfied, or do you not reach the target. And this is, in a way, also the reason why I say, well, let us go with a bulking agent first, because then, the probability of success to reach a good cake that is dissolves fast, is very high. And leaving that out, I might need to go in several circles that may take time, and - to block the machine, and so on, and so on.
370 Having regard to this evidence, I am not persuaded that the skilled formulator would take the path proposed by Dr Robertson in his oral evidence. In my view, the evidence of the common general knowledge both as to the use of bulking agents in lyophilised formulations and the frequent use of mannitol is compelling. Dr Robertson's frank acceptance that other formulators would be likely to consider it appropriate to apply the rule of thumb provides support to the evidence of Professor Winter as to the likely approach.
371 The evidence set out above makes plain that the use of bulking agents in the course of lyophilising active ingredients where they fell outside of the rule of thumb formed part of the common general knowledge. As Dr Robertson accepted, whilst adding a bulking agent was not the course that he would have taken, it is the course that he would expect other formulators to have taken before April 2001. Furthermore, it was common general knowledge that mannitol would likely be used as the bulking agent.
372 Having regard to the whole of the evidence, I am not satisfied that hypothetical skilled formulator would have approached the formulation of parecoxib sodium in the manner described by Dr Robertson. I consider that his approach is idiosyncratic having regard to the common general knowledge as at the priority date. I consider that the most likely path that the skilled team would take would be to use a bulking agent, most likely mannitol, to produce a lyophilised formulation of parecoxib sodium. The common general knowledge points to this path as being the one with a reasonable prospect of success.
373 I accept that at times in his oral evidence Professor Winter accepted after some prompting that he might try to lyophilise a buffered solution containing the active ingredient without a bulking agent, but he was resolute that this was not his preference. His preference was to choose a formulation that he considered was likely to succeed and that would involve applying the rule of thumb such that a bulking agent would be included to bulk out the solid content. Moreover, Professor Winter's expectation was that if he deviated from that rule he would simply be reiteratively experimenting and going round in circles. I do not accept that this evidence amounts to an acceptance that he would have an expectation of success had he resorted to trying a formulation that did not include a bulking agent.
374 A debate emerged between the experts as to whether a predicted interaction between mannitol and parecoxib would deter a formulator from taking Professor Winter's approach of adding mannitol as a bulking agent. I do not consider that the hypothetical skilled formulator would have foreseen in advance that the use of mannitol as a bulking agent (capable of providing the other benefits to which I have referred in [361] above) would have caused difficulties or diminished the likely success of the preferred formulation.
375 Dr Robertson gave evidence that he would not use mannitol in a pre-lyophilisation solution because mannitol appeared to accelerate the decomposition of parecoxib to valdecoxib. However, as he explained in his oral evidence, that view was expressed on the basis of the results set out in example 2 of the patent. Dr Robertson noted from those results that the inventors backtracked from the use of mannitol and considered that there had to be a reason why mannitol facilitates the accelerated decomposition of parecoxib to valdecoxib. Although he noted that "it may not be that the…formulator thought of this up front", he hypothesised that mannitol, as a weak acid, may deprotonate in the presence of a base and become unstable such that it reacts with parecoxib. In this way he opined that it would catalyse the undesirable conversion of parecoxib to valdecoxib. He and Professor Winter agreed that substantial deprotonation of mannitol would not occur except at a very high pH (in the joint expert report, they considered a pH of above 12). Professor Winter thought that any deprotonation would be negligible at a pH of 8 and would not affect the stability of parecoxib sodium. Dr Robertson thought that there would be minimal deprotonation at a lower pH but that this would nonetheless be sufficient to affect the stability of the parecoxib sodium.
376 The explanation offered by Dr Robertson was plainly given in hindsight, he having had the benefit of the results of the experiments reported in the patent. Furthermore, Professor Winter disagreed with Dr Robertson's theory that deprotonation would be likely to cause instability at a pH of about 8 and disagreed that other formulators would perceive this to be a cause for instability. Having regard to the hindsight built into Dr Robertson's analysis, in this regard I prefer the evidence of Professor Winter.
377 Nor am I persuaded by the three remaining arguments advanced by the respondents to the effect that the rule of thumb would not arise.
378 The first is a submission that, armed with knowledge: (a) that a lyphophilised powder formulation of parecoxib sodium does not collapse; (b) that there was found to be no need to add a bulking agent to aid in the dissolution of parecoxib sodium given its solubility; and (c) that there was no information to give reason to believe that water is unevenly distributed throughout the freeze-dried parecoxib sodium formulation; it is apparent that the skilled formulator would not have encountered any of the risks that would motivate the addition of a bulking agent. This argument is based wholly on hindsight and must for that reason be rejected.
379 Secondly, the respondents contend that the evidence supports the proposition that excipients should only be used where appropriate and where they are "inert" and "safe". They contend that Dr Robertson explained that mannitol is neither.
380 However, in my view, this argument cannot go far in light of the agreement of the experts that mannitol was very popular in the pharmaceutical industry as a bulking agent for freeze-dried products. It is plain that the skilled formulator, who will have significant scientific qualifications and experience, would be aware that they must be familiar with the properties of excipients used in formulating pharmaceutical products and account for likely chemical and other interactions with the other components in a formulation. One example acknowledged by the experts is the likely effect (mostly beneficial) of mannitol on the crystal structure of the "cake". Another is mannitol's ability to affect the tonicity of the powder composition. I consider that the accepted popularity of mannitol amongst those in the field may be taken to indicate a general positive disposition towards its use in formulating freeze-dried products. In this context, in my view, the debate between the experts as to whether mannitol is "inert" was largely a side wind.
381 The third involves the somewhat convoluted proposition that one of the dosage amounts proposed by Professor Winter in his written evidence (being 100 mg parecoxib for intravenous use) falls outside the rule of thumb, and inside the scope of the asserted claims in the patent. Accordingly, the respondents submit that, taking the applicants' case at its highest, the skilled worker would not add a bulking agent and that therefore there is no inventive step.
382 This submission falls at the first hurdle. The evidence given by Professor Winter did not propose a dosage amount for a lyophilised solution. Nor did Dr Robertson. Rather, the amounts proposed were for a ready to use dosage form. As noted above, Professor Winter's evidence was that it was commonly necessary to change the formulation if a product previously being prepared as a ready to use formulation is instead formulated as a lyophilised product. For example, as I have discussed above, it may be necessary to add a bulking agent to a lyophilised formulation in order to achieve certain objectives not relevant to ready to use formulations.