3.1 Construction of the patent (grounds 1 to 4)
11 According to Apotex, the patent refers to a particular crystalline form, a polymorph. The patent claims the particular crystalline form, Crystals B. This is a compound in a particular crystalline form, not limited to any environment (a particular sample or batch) or to any process of manufacture. Hence, claim 12 refers to "Anhydrous Aripiprazole Crystals B wherein said crystals", and not an idiosyncratic sample of said crystals, possess or exhibit the defining properties specified. This, it is said, accords with the fact that the definitions at pp 23-24 of the patent characterise the crystals by saying:
"Anhydrous Aripiprazole Crystals B" of the present invention as used herein have the physicochemical properties given in (6) - (12) below.
12 The patent describes numerous ways of making Crystals B but, as Apotex put it, none of the methods claimed is limited to any method having an impact on hygroscopicity and the patent makes no mention of surface properties or adsorbed water. Hygroscopicity is a property of a polymorph and what the patent refers to as Crystals B is a single unique polymorph. Apotex thus submitted:
The proper construction of the Patent is that it describes "an improved form of aripiprazole having reduced hygroscopicity". That is the polymorph being Crystals B. There are numerous methods described and claimed - but not in suit. This improved form "has" the hygroscopicity of p24 lines 19-29 and claims 12 and 16. There is no suggestion that this is only possessed when it is made a certain way. ...
13 Apotex submitted that the primary judge accepted this construction is his amendment reasons at [17] where he said:
For present purposes I am satisfied on the evidence that a person skilled in organic chemistry in 2002 would have understood, on reading the specification as filed, that properties (7)-(11) are the essential physicochemical properties that define the crystalline form of Crystals B.
14 According to Apotex, the finding at [17] was plainly right as it accorded with the evidence and with the characterisation of anhydrous aripiprazole Crystals B in the specification. The primary judge, however, varied the finding in [17] of the amendment reasons by deleting the words "the crystalline form of" resulting in what Apotex described as a "significant change in the forensic landscape" and, more to the point, a "departure from the discourse of the patent". In Apotex's words:
… The patent is plainly about a new crystalline form, or polymorph. The result is that the primary Judge adopted a construction where "something happens that causes the crystals to have the low moisture content that is the characteristic of Crystals B as claimed in claim 12 of the patent". That "something" was held to overcome the holding that "Crystal B and type 1 crystals have the same crystalline form".
The "something" to which the primary Judge refers is independent of particle size. Indeed, the smaller particle size of claim 16 is a factor tending to increased hygroscopicity. The only possibility discernible from the primary Judge's reasons is that the "something" refers to the fact that hygroscopicity is influenced "in subtle ways, by the surface properties of the polymorph in question". See the surprising statement in [115] that "what that 'something' is, is neither here nor there".
To the contrary, the answer to "what that 'something' is", is highly significant. By his process of reasoning, the primary Judge departed entirely from the description in the specification. This says nothing about "surface properties". It defines or "characterizes" Crystals B by essential "physiochemical properties" including, uniquely, by its XRPD signature and its hygroscopicity. These properties indeed define its "crystalline form", as his Honour had originally held.
(Footnotes omitted, emphasis in original.)
15 It may be accepted that the primary judge varied the finding he made in [17] of the amendment reasons in the way Apotex has identified. Consideration of the primary judge's reasons discloses, however, that the issue at the heart of Apotex's complaint in this regard is the primary judge's conclusions about the weight of the evidence rather than any alleged misconstruction of the patent.
16 The primary judge (at [89]) recognised that:
An important aspect of Apotex's case is its contention that hygroscopicity is an inherent property of a given crystalline form of a given compound. Apotex contended that a given crystalline form of aripiprazole will have, inevitably, a given hygroscopicity so that the disclosure of a particular crystalline form of aripiprazole will also inevitably disclose certain of the physicochemical properties of that form, including its hygroscopicity. More specifically, Apotex contended that, if anhydrous aripiprazole crystals have an XRPD spectrum that is substantially the same as the XRPD spectrum shown in Figure 5 of the complete specification, those crystals will inevitably have low hygroscopicity, namely, a moisture content of 0.40% or less after being placed for 24 hours in a closed container maintained at a temperature of 60°C and a humidity level of 100%.
17 At [90] the primary judge also recognised that Apotex considered [17] of the amendment reasons to be consistent with these propositions. However, as he noted at [91] at the time he prepared the amendment reasons the evidence was far more limited than that now available. As the primary judge put it in [91]:
... had I had the benefit of the present evidence when dealing with the amendment application, I would have expressed myself differently when making my finding about what the person skilled in the art would have understood to be the physicochemical characteristics of Crystals B when reading the complete specification. That would not, however, have led me to reach any different conclusion on the fate of the amendment application.
18 If the primary judge had had the present evidence available he concluded at [119] that the finding at [17] of the amendment reasons:
... would have been better expressed by saying that, at the relevant time, the person skilled in the art would have understood, on reading the complete specification as filed, that properties (7) to (11) are the essential physicochemical properties that define Crystals B.
19 The evidence presently available led the primary judge to this conclusion because, as he explained:
(1) "Professor Withers gave evidence that the hygroscopicity of a sample of crystals cannot be determined by the XRPD pattern of those crystals alone" (at [94]). He was not cross-examined.
(2) Dr Rowe, on reading Professor Withers' evidence, changed his opinion. Dr Rowe initially said that "if the XRPD analysis indicates that a compound is in a particular crystalline form, then the compound will have the physicochemical properties of that particular crystalline form" (at [92]). He subsequently accepted that XRPD data alone does not confirm the hygroscopicity of a sample but maintained that "if the hygroscopicity of a crystalline form identified by XRPD analysis is known, the "inherent hygroscopicity" of the sample will be the same". This, however, was qualified by his statement that he agreed that "particle size can affect the amount of water a sample adsorbs, because the surface area of a particle can vary with particle size" (at [96]).
(3) Professor Easton acknowledged that "the form of the material affects various of its properties, including its hygroscopicity" and "hygroscopicity is also determined by characteristics such as crystal size and surface area" (at [98]). Also, when a crystal structure takes up water, there may be a relationship between adsorption and absorption: "when a material converts from an anhydrous form to a hydrate, it generally goes through an adsorption phase first, which will be affected by the smoothness of the crystal surface, including whether there are fractures in it. He said that there has to be a localised restructuring to convert the anhydrous form to the hydrous form, 'which basically involves one [disassembling] and then another one re-assembling'" (at [99]).
(4) Professor Prestidge said that "[t]here are subtleties in this field, because you have a bulk crystal and the surface chemistry can be subtly different. So the techniques we use here to characterise the polymorphic form, as in the infrared spectroscopy and the XRPD, they measure bulk properties. Moisture uptake can be controlled by a surface phenomenon which is a little bit more subtle in some ways" (at [101]).
20 The primary judge concluded that this evidence shows that "the hygroscopicity of a crystalline compound is not just a function of its crystalline form, but may be influenced by particle size and, in subtle ways, by the surface properties of the polymorph in question". Further, that although "Professor Prestidge's evidence suggests that, as a general statement, water uptake by adsorption is likely to be significantly less than water uptake by absorption, when the particle size is in the tens of microns, such as the crystals claimed in claim 16", the primary judge did "not think that the possible influence of these factors can simply be ignored" (at [106]).
21 The disclosure in the specification that "type 1 crystals do not have the same hygroscopicity as Crystals B under certain conditions unless the type 1 crystals undergo heating at specific temperatures" caused the primary judge view to reject Apotex's fundamental contention that "a given crystalline form of aripiprazole will have, inevitably, a given hygroscopicity" (at [109]). On this basis, as the primary said, the specification teaches that "a particular heating step is … required as part of the process for obtaining Crystals B" (at [111]). The primary judge thus rejected Apotex's characterisation of the invention disclosed as "preventing the conversion of type 1 crystals to monohydrate by milling hydrous crystals to produce Hydrate A and then drying them". The primary judge described this characterisation as presenting "an incomplete picture of what is disclosed in the complete specification, [which] if not treated with care, serve to distract attention from the full description of the invention and the processes by which Crystals B can be obtained" (at [112]).
22 Accordingly, the primary judge's acceptance of the proposition that Crystals B and type 1 crystals had the same crystalline form (at [109], [115], [201], [289] and [308]) did not mean, as Apotex contended, that disclosure of type 1 crystals involved disclosure of the invention. Nor did it matter that the "complete specification 'makes no mention whatsoever of surface properties or adsorbed water'". The primary judge put it this way at [115]:
If, as Apotex contended, and as I accept, Crystals B and type 1 crystals have the same crystalline form, then the results of these experiments show that by suitable heating, as exemplified in the complete specification, something happens that causes the crystals to have the low moisture content that is characteristic of Crystals B as claimed in claim 12 of the patent. This conclusion is supported by the work disclosed in Otsuka's internal memoranda and experimental reports to which I have referred. What that "something" is, is neither here nor there. An inventor does not need to know why his or her invention is afforded utility in order for that invention to be patentable. Moreover, it does not matter that the invention can be achieved by various, indeed by many, means. All that a patentee in Otsuka's position is required to do is to describe the invention fully, including by giving the best method known to the patentee of performing the invention. Apotex has not challenged the validity of the patent on the basis that Otsuka has failed in that requirement.
23 The primary judge also rejected a distinction drawn by Apotex between "the properties of a given crystalline compound, specifically, aripiprazole as Crystals B, and the properties of samples of that compound", the end point of the distinction being the proposition that the "specification refers to and claims a particular crystalline form of aripiprazole - Crystals B" and not samples of that compound (at [116], emphasis in original). The primary judge responded to this submission at [117] and [118] as follows:
I do not accept that reasoning. In my view, the distinction which Apotex sought to draw is not meaningful in the present context. The complete specification is a practical document giving practical information about the manufacture and use of aripiprazole as a pharmaceutical product. It necessarily refers to the problem of hygroscopicity associated with conventional anhydrous aripiprazole crystals that have been prepared on an industrial scale for pharmaceutical processing and formulation. The complete specification's description of the invention by reference to examples necessarily involves a consideration of, and comparison between, samples of anhydrous aripiprazole crystals.
More importantly, I do not accept that the complete specification merely refers to and claims a particular crystalline form, or crystalline forms, of aripiprazole. It describes and claims crystalline aripiprazole having certain characteristics. When the complete specification refers to the form of aripiprazole crystals, it is not referring only to their crystalline form but more generally to their form as crystals defined by cumulative characteristics. In the case of Crystals B, one of these characteristics is that the crystals have an XRPD spectrum that is substantially the same as the spectrum disclosed in Figure 5; that is, they have a particular crystalline form. Another characteristic is that, in that crystalline form, the crystals must have low hygroscopicity in a specific sense: their moisture content is 0.40% or less after being placed for 24 hours in a closed container maintained at a temperature of 60°C and a humidity level of 100%.
24 The key to this reasoning is that the patent, properly construed, is not claiming as the invention "a particular crystalline form of aripiprazole - Crystals B" (Apotex's characterisation) but is claiming "crystalline aripiprazole having certain characteristics" including low hygroscopicity in the specific sense identified. It is this reasoning which explains the primary judge's observation that, with the evidence now available, he would vary the terms of [17] of the amendment reasons to say "the person skilled in the art would have understood, on reading the complete specification as filed, that properties (7) to (11) are the essential physicochemical properties that define Crystals B" rather than "a person skilled in organic chemistry in 2002 would have understood, on reading the specification as filed, that properties (7)-(11) are the essential physicochemical properties that define the crystalline form of Crystals B".
25 The real issue, accordingly, is whether the claimed invention is "a particular crystalline form of aripiprazole - Crystals B" (Apotex's case) or "crystalline aripiprazole having certain characteristics" including low hygroscopicity in the specific sense identified (the primary judge's conclusion). That question cannot be answered by rhetorical appeals. It must be answered by reference to the terms of the complete specification. It does not matter that the primary judge said one thing in the amendment reasons and another in the principal reasons. He did so because the evidence had changed. It does not matter that the primary judge accepted that Crystals B and type 1 crystals have the same crystalline form. The invention, as characterised by the primary judge, is not the crystalline form of aripiprazole - Crystals B but "crystalline aripiprazole having certain characteristics". What matters is whether, as Apotex contends, this characterisation meant the primary judge "departed entirely from the description in the specification".
26 This proposition should not be accepted. The terms of the complete specification support the primary judge's characterisation of the invention. The invention relates to a form of aripiprazole having reduced hygroscopicity. The form is not just a crystalline substance. Crystals B is a crystalline substance having certain characteristics which result from suitable heating. So much is clear from the summary of the invention quoted at [49] of the primary judge's reasons, the characterisation of Crystals B at [54], and the processes by which Crystals B can be manufactured at [55]. As BMS and Otsuka submitted, the patent does not teach an inherent hygroscopicity of a crystalline form of aripiprazole; it teaches to the contrary. Claim 12 does not support any contrary characterisation. It claims as Crystals B anhydrous aripiprazole crystals having the specified characteristics which, the specification demonstrates, will result from the preparation processes described including the suitable heating. The fact that the claims are not limited to Crystals B where "something happens" is immaterial. What the specification demonstrates is that something does happen when suitable heating is involved - namely, the creation of Crystals B being anhydrous aripiprazole crystals having the specified characteristics.
27 The primary judge's acceptance at [115] that knowing what happened was unnecessary is orthodox. Apotex accepts this is so. As such, it is not to the point that the patent does not mention surface properties or adsorbed water as explaining the invention. Equally, no significance can be attached to the fact that when identifying the meaning of a polymorph the primary judge omitted that part which said that polymorphic forms may be hygroscopic (meaning they absorb moisture from the atmosphere). The weight of the evidence before the primary judge was that hygroscopicity is determined not just by the crystalline form but also by characteristics such as crystal size and surface area and subtle surface phenomena.
28 Apotex characterised the primary judge's conclusions about the weight of the evidence as "magical thinking" coming perilously close to a characterisation of the invention as the product of a process contrary to the observations in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd [2005] RPC 9 at [87]-[101]. According to Apotex, the vague and tentative opinions expressed by the experts about surface properties and the like leading to "something" happening as a result of drying were insufficient to displace the clear evidence, including that of Professor Easton on the amendment application, that hygroscopicity is an inherent property of a particular crystalline form. Apotex also submitted that the primary judge's treatment of Reference Example 1 in the specification (for example, at [113]) was wrong as there was no data available about the amount of residual ethanol in the example which would itself affect hygroscopicity and it was not apparent from the specification that the product was type 1 crystals. Accordingly, the finding that there was a difference between type 1 crystals and Crystals B at [115] could not be sustained. Apotex also said the primary judge was wrong in [114] and [115] of his reasons to use Otsuka's internal documents to shore up this conclusion.
29 Insofar as the Otsuka internal documents are concerned it is apparent from [114] and [115] of the primary judge's reasons that Apotex in fact raised those documents as supporting its case, said to relate to the construction of the patent but in fact constituting its fundamental factual assertion that hygroscopicity is a property of a crystalline form and that surface properties and the like are immaterial. The primary judge dealt with those documents principally in order to reject Apotex's submission and otherwise for the proper purpose of assessing the facts, specifically relating to the impact of heating on hygroscopicity. Despite the alleged error by the primary judge in improperly using the Otsuka internal documents as an aid to construction, Apotex again effectively invited this Court to undertake the same exercise. The invitation should be declined, at least to the extent that the issue in the appeal is said to be one of construction.
30 Otherwise, it is apparent that Apotex's complaints do not concern the construction of the claims of the patent. They are complaints about factual findings based on the primary judge's assessment of the weight of the evidence, in particular the finding at [109] rejecting the contention that a given crystalline form of aripiprazole will have an inherent hygroscopicity. However, Apotex's challenge to the primary judge's factual findings was based upon an unduly selective analysis of the evidence.
31 The primary judge was correct to weigh the evidence and reach the conclusions he did. Whatever the state of the evidence at the time of the amendment application, the evidence before the primary judge included the opinions of Professor Withers (at [94]), the revised opinions of Dr Rowe (at [96]), the further opinions of Professor Easton (at [97]-[99]) and the opinions of Professor Prestidge (at [100]-[105]). The primary judge was right to conclude that this evidence could not "simply be ignored" (at [106]). Apotex's fundamental contention about hygroscopicity was disclosed by this evidence to be an inaccurate over-simplification of a complex, not easily explained, and perhaps not that well understood, kinetic process.
32 Insofar as Reference Example 1 is concerned, three points can be made. First, that evidence was admitted as evidence of an experiment (Bristol-Myers Squibb Company v Apotex Pty Ltd (No 4) [2012] FCA 1433). Second, Apotex always contended that Otsuka had used type 1 since January 1996. Apotex's contention was not that Reference Example 1 did not involve type 1. It was only that type 1 and Crystals B were the same including in terms of hygroscopicity. On this basis Apotex's criticism of the primary judge having erred by equating Reference Example 1 and type 1 is unfounded. Third, Apotex's possible residual ethanol argument is mere speculation. Ethanol, an impurity, is not mentioned in the specification. Apotex's case on the 141 application (see below at [35]) was that a person skilled in the art would remove ethanol as a matter of routine. Otsuka's internal documents show it was aware of the need to remove ethanol and to test to ensure that impurity did not remain. Reference Example 1 was dried at 80°C for 40 hours, well within the ranges the experts said would remove ethanol which has a boiling point of 78°C.
33 Insofar as the product of a process submission went, it is apparent that this was founded only upon the primary judge's ultimate finding rejecting Apotex's inherent hygroscopicity contention, said to constitute "magical thinking" because the explanation by reference to surface properties and the like was somewhat vague and, according to Apotex, "dwarfed" by the inherent hygroscopic properties of the crystalline form. Again, these submissions cannot be accepted given the evidence which was before the primary judge. No error in principle, reasoning or outcome has been demonstrated.
34 For these reasons appeal grounds 1 to 4 should not be accepted.