The Primary Judge's Reasons
13 The primary judge referred to the relevant principles governing an appeal against a decision of the Commissioner of Patents in an opposition to the grant of a patent. His Honour noted that, although the proceeding before him is referred to in the Act as an appeal, it is not an appeal in the strict sense, but rather a proceeding in the original jurisdiction by way of re-hearing. His Honour also noted that Boehringer bore the onus in relation to each ground of opposition and that, for an opposition to be upheld, it must be "clear" or "practically certain" that the patent, if granted, would not be valid.
14 His Honour made some observations concerning the witnesses who gave evidence including the three witnesses whose evidence was most relevant to inventive step. The first of these witnesses was Mr Lau, an expert witness called by Boehringer, who has qualifications in science and more than 30 years' experience in the field of pharmaceutical formulation, particularly the formulation of medicaments for animals. His Honour found that Mr Lau had specialised knowledge in the field of pharmaceutical formulation, in particular, the formulation and chemical and physical analysis of veterinary products. His Honour observed that Mr Lau demonstrated deep experience in matters of chemistry and the formulation aspects of the development of pharmaceutical products and, subject to some particular matters, he generally accepted Mr Lau's evidence.
15 The second witness relevant to inventive step was Dr Martin, also called by Boehringer, who his Honour found had specialist knowledge in the field of parasitology and the development of parasiticides for animals. Dr Martin's work appears to have focused on animal parasitology and the development of animal parasiticide products. His Honour generally accepted Dr Martin's evidence.
16 The third witness relevant to inventive step was Mr Vickers who was called by Intervet. Although Mr Vickers has a Bachelor of Veterinary Science, his Honour noted that Mr Vickers accepted that he had never been a formulation chemist. It is apparent that Mr Vickers' expertise was more in the area of product development and regulatory affairs management.
17 His Honour noted that he preferred Mr Lau's evidence in relation to matters of formulation chemistry to that of Mr Vickers, but that Mr Vickers impressed him as having considerable knowledge and experience in relation to the matters of safety and efficacy in the development of veterinary pharmaceutical products.
18 His Honour referred to joint expert reports that were in evidence. The first was a joint report of Mr Lau and Mr Vickers which largely focussed on issues of pharmaceutical formulation. The second was a joint report of Dr Martin and Mr Vickers which covered issues relating to the administration of veterinary pharmaceuticals, in particular, issues relating to the safety and efficacy of parasiticides.
19 His Honour referred to the description of the invention in the body of the specification and the claims including those matters to which we have previously drawn attention. His Honour noted at [29] of his reasons that "[d]ata from efficacy testing is set out in Table 3 on page 11" but did not refer again to Table 3 in his reasons.
20 His Honour found that the person skilled in the art to which the patent application was directed consisted of a team with experience in the field of animal health including a pharmaceutical formulator and parasitology expert. His Honour observed at [88]:
In Boehringer's outline of closing submissions, it submits that: the skilled person to whom the Patent Application is directed is a team with experience in the field of animal health, including the development of injectable dosage forms for drug delivery for use in the treatment of animals (including cattle); and the team consists of a pharmaceutical formulator, instructed by a parasitology expert or experts with knowledge of the possible modes of administration, active ingredients and their concentration and the dose volume. Intervet did not dispute that the person skilled in the art was a team comprising these persons, but also placed some emphasis in its evidence and submissions on the process of obtaining regulatory approval of new products. However, I am not persuaded that the notional team need include a person with such skills, which relate to processes after development of a product. I accept Boehringer's description of the notional skilled team.
21 His Honour found that it was common general knowledge at the priority date that it would be desirable to develop an injectable formulation for a combination of macrocyclic lactones and levamisole. The primary judge also noted that there was no suggestion that it was inventive to seek to combine macrocyclic lactones with levamisole at the priority date.
22 The findings made by the primary judge in relation to the common general knowledge at the priority date also included the following:
(1) Livestock including sheep and cattle were affected by endoparasites (which live inside the host) such as helminths or parasitic worms. Common parasites of this kind included Ostertagia (brown stomach worm) and Cooperia (small intestinal worm). Parasiticides is an overarching term for products that treated parasites, and parasiticides that acted on helminths were referred to as anthelmintics.
(2) Common anthelmintics for broad spectrum use include macrocyclic lactones (such as ivermectin, abamectin, avermectin, eprinomectin, moxidectin and doramectin) and imidazothiazoles such as levamisole.
(3) Macrocyclic lactones had been in use since the 1980s, and could be applied orally, topically and by injection. They were known to be effective against nematodes living in the stomach, small intestine and lungs of sheep and cattle. They tended to be longer acting, and to be effective for days or weeks.
(4) Levamisole had been in use since the 1970s and could be administered orally, by injection and by pour-on. Levamisole could be administered as levamisole base, or as a salt (such as levamisole HCl and levamisole phosphate). Levamisole was effective against nematodes such as Haemonchus, Ostertagia and Trichostrongylus, as well as lungworms, and it was also known to be effective against Cooperia. Levamisole tended to be short acting and rapidly excreted.
(5) The problem of resistance was well-known. Resistance occurs where anthelmintics become less effective after several years of usage, because ongoing use will eradicate parasites that do not have the genetic makeup to survive the anthelmintic, while parasites that do have the genetic make-up to survive become the main source of subsequent generations, and become the predominant population. The growing resistance of Cooperia populations to macrocyclic lactones was well-known.
(6) Although one strategy for dealing with resistance was to use new active ingredients, new active ingredients are very rare. A more common strategy was to combine two or three parasiticides from different classes, either separately or in combination products. From the mid-1990s, macrocyclic lactones were co-administered with levamisole to counter Cooperia resistance to macrocyclic lactones.
(7) There was a strong market demand to formulate combination products for ease of administration.
(8) Levamisole and macrocyclic lactones are chemically incompatible and tend to react with each other when combined.
(9) Levamisole and macrocyclic lactones are stable under different pH conditions (levamisole requires a pH of about 3.0-4.0 to be stable, while macrocyclic lactones require a pH of around 6.0-7.0).
(10) Levamisole salts are soluble in water. Macrocyclic lactones are not water soluble but are soluble in organic solvents, and are commonly formulated in oils and organic solvents.
(11) Macrocyclic lactones were routinely administered to cattle by injection at a dose of 0.2 mg per kg of cow.
(12) A safe and effective dose of levamisole HCl routinely administered to cattle by injection was 7.5 mg per kg (equivalent to 6.35 mg of levamisole base and 9.4 mg of levamisole phosphate).
(13) For a 500 kg cow, a preferred dose volume would be no more than 20 mL overall, and preferably 10-15 mL; this equates to a dose volume rate of 1 mL/25 kg to 1 mL/50 kg of cow; where necessary, a dose volume may be divided and injected at more than one site.
(14) The concentration of active ingredient was calculated based on the desired dose of that active ingredient, and the desired dose volume rate. Thus, for example, for an injectable combination product with a dose volume rate of 1 mL/25 kg of cow, the required concentration of levamisole and ivermectin to ensure a safe and effective dose of each of these active ingredients would be 15.9% w/v, 18.8% w/v or 23.5% w/v of levamisole (depending on whether the base, hydrochloride or phosphate form was used), and 0.5% w/v of ivermectin.
(15) In addition to the active ingredients, there was a range of common ingredients available for use in formulating an injectable combination product. These included organic or non-aqueous solvents such as benzyl alcohol and dimethylacetamide, and oils such as castor oil and medium chain triglycerides, as well as the other ingredients disclosed in the patent application.
23 There was also expert evidence, accepted by his Honour, as to the mode of operation of levamisole in the animal. His Honour said at [178]:
In oral evidence, Dr Martin agreed with the following propositions regarding the mode of operation of levamisole: one requires a sufficient dose level and concentration within the animal to achieve paralysis of the relevant worms; the intention of the particular mode of operation of levamisole is that the worms stay paralysed for long enough that they are excreted; one typically aims to achieve a rapid, high blood level of levamisole if levamisole is being administered by injection; the nature of levamisole is that it is rapidly metabolised by the animal; the effect of this is to rapidly reduce the concentration of levamisole within the animal; in terms of the speed of excretion, typically more than 90% is excreted within 24 hours for cattle. Mr Vickers agreed with these matters and added that levamisole usually peaks very quickly, usually about two to three hours after administration by an oral or injectable; it peaks very quickly and then it is excreted very quickly. Dr Martin agreed with this. I take these matters to form part of the common general knowledge as at the priority date.
24 There are several observations to make in relation to his Honour's common general knowledge findings.
25 First, an injectable formulation including as active ingredients a macrocyclic lactone, ivermectin at 0.5% w/v and the levamisole salt, levamisole HCl at 18.8% w/v would be within the concentrations specified in claim 1.
26 Secondly, since macrocyclic lactones are not water soluble, they were commonly formulated in oils and organic solvents. Claim 1 requires that the macrocyclic lactone be present in solution (ie. dissolved) in such a system.
27 Thirdly, there were no known oily formulations in which levamisole was present in particulate form (or at least none that were common general knowledge). This is presumably because levamisole is water soluble and can only be dissolved in an aqueous solution.
28 Fourthly, since macrocyclic lactone and levamisole salt are chemically incompatible, requiring different pH conditions if they are to remain stable, a formulation that combined these ingredients would need to address these issues.
29 The primary judge also made a number of significant findings concerning the way in which the hypothetical team, including the formulation chemist, would develop a new formulation including, in particular, an injectable combination product with a macrocyclic lactone and levamisole as the two active ingredients. His Honour found at [196]-[199]:
[196] There were a range of routine or conventional tests or trials available to the skilled team to evaluate and assess the stability, safety and efficacy of a formulation. These would be carried out as a matter of course. Such tests or trials included dose titration or confirmation studies to identify preferred concentrations of the active ingredients, and routine preliminary tests to assess the occurrence and extent of potential issues with injection site irritation, the blood/release profile of the active ingredient, any impact of using an oil-based formulation, and any impact of the active ingredient being in particulate form. Where appropriate, the tests or trials would be carried out in parallel on multiple variants of a proposed formulation.
[197] More particularly, the formulation chemist would develop preliminary formulations, which would be assessed for chemical stability using [high performance liquid chromatography] under normal and accelerated testing conditions. Formulators would also assess the physical characteristics and physical stability of each formulation. The preliminary formulations would be refined until there was a lead formulation or formulations that could be progressed to preliminary efficacy trials in the field and further stability testing. Lead formulations that proved effective and stable in preliminary trials would then be submitted to full-scale efficacy and safety trials and stability testing for the purpose of obtaining regulatory approval. The formulation chemist would understand that the regulator would require full-scale efficacy and stability testing irrespective of whether or [sic] the formulation was based on a registered single-active product, or formulated as a suspension rather than another type of formulation.
[198] A formulation chemist asked to formulate an injectable combination product as at June 2010 would seek to develop a product that was effective, stable, safe, sterile and syringeable. The formulation chemist would depend on other members of the skilled team to provide the effective dose of the product, as well as other relevant information. The formulation chemist would receive a briefing from a colleague with biological training as to issues relating to the biological properties of the active ingredients. The formulation chemist would have some knowledge of each ingredient, based on his or her experience in developing anthelmintic products, including other injectable formulations and other dosage forms.
[199] In the case of a combination of a macrocyclic lactone and levamisole or its salts, the formulation chemist would know that levamisole HCl or levamisole phosphate were preferred over levamisole base because they are more chemically stable, with a longer shelf life. The formulation chemist would know that levamisole HCl was commonly used in anthelmintic products and readily available. The formulation chemist would prefer to use ivermectin and abamectin over other macrocyclic lactones, since these were widely available from suppliers.
30 The primary judge referred to Mr Lau's evidence in which he was instructed to assume that, as at the priority date, he was given the task of formulating a combination injectable product containing a macrocyclic lactone and levamisole for cattle that was effective, stable, safe, sterile and syringeable. According to Mr Lau, he would have selected levamisole HCl together with ivermectin or abamectin. Due to the chemical incompatibility of these ingredients Mr Lau would have explored strategies for formulating the combination injectable which kept the levamisole and macrocyclic lactone separated.
31 The two main strategies Mr Lau would have considered involved the use of either a micellar formulation or a suspension formulation with the aim of keeping the two active ingredients physically separated.
32 Using the micellar approach proposed by Mr Lau, a micellar solution would form when the concentration of surfactant in water reached the concentration at which micelles formed. In a micellar solution, each micelle has a hydrophilic exterior, where the polar hydrophilic ends of the surfactant molecules are in contact with water molecules, and a hydrophobic interior, where the fatty ends of the surfactant are located. The abamectin or ivermectin would be dissolved in an organic co-solvent and reside in the hydrophobic environment inside the micelles. The levamisole HCl would be dissolved in the aqueous environment outside the micelles. It may be noted that in such a system both the macrocyclic lactone (ie. abamectin or ivermectin) and the levamisole HCl are dissolved in solution. Such a system would be outside claim 1.
33 If Mr Lau was to have used the suspension approach, he would have dissolved the abamectin or ivermectin in a carrier made using an oil or organic carrier as the base. He would also use a co-solvent, such as benzyl alcohol, to assist in solubilizing the abamectin or ivermectin. He might use more than two organic carriers depending on the viscosity of his preliminary formulation and whether it was suitable for holding the levamisole HCl in suspension. He would, if necessary, adjust the viscosity of his formulations through the selection of different solvents or the use of a suspending agent to increase the viscosity of the carrier. Mr Lau expected that, if he were to formulate the combination of abamectin or ivermectin and levamisole HCl as a suspension, it would be stable. A formulation such as that described by Mr Lau in which the macrocyclic lactone is in solution, and the levamisole HCl is in particulate form, would be within claim 1 subject to it meeting the relevant concentration requirements.
34 The primary judge referred to the evidence of Mr Vickers who expressed concern that the use of a suspension could affect the release profile of the levamisole in the formulation making it different from the known release profile of the drug. We note that his Honour's reasons do not indicate what the release profile of levamisole was when used in solution or to what extent this would also be affected by the mode of administration, its concentration, or whether it was used in combination with other active ingredients. However, Mr Vickers' evidence was that use of a suspension in which the levamisole was in particulate form could affect its release profile.
35 Mr Lau accepted that the use of a suspension in which the levamisole was in particulate form could affect its release profile. His response to Mr Vickers' evidence on this topic was referred to by the primary judge as follows at [227]-[229]:
[227] Mr Lau also stated in his third affidavit that he did not agree with Mr Vickers that a potential change in the release profile or absorption rate of levamisole salt was a reason not to formulate the combination injectable with the levamisole salt in suspension. Mr Lau stated that an active ingredient could be formulated so as to have a different release profile and a different absorption rate from an existing formulation and still be effective. He stated that the efficacy of the levamisole salt as part of the combination injectable would be tested in the ordinary course of product development.
[228] In oral evidence, Mr Lau was questioned about the statement in [60] of his first affidavit (summarised in [212(a)] above) regarding the risk that an active ingredient formulated as a suspension will not be dispersed evenly throughout the formulation. Mr Lau had stated in his affidavit that this risk was greater if the active ingredient was present at a low concentration. It was put to Mr Lau that the same would be true where there was a high concentration of the active ingredient. Mr Lau accepted that, theoretically, this was the case, but said that he did not think it was an issue practically. In response to a question whether he had conducted any tests to establish that it was not an issue practically, Mr Lau said that he had not. I am not persuaded that there was a relevant difference in relation to the risk that an active ingredient may not be evenly dispersed as between a low concentration and a high concentration of the active ingredient. Accordingly, I find that this is a risk in both scenarios (and this formed part of the common general knowledge as at the priority date).
[229] Mr Lau was asked during oral evidence about issues regarding agglomeration of particles (that is, the formation of larger particles). Mr Lau accepted that if there are more solid particles present, there is a higher chance of agglomeration; he said agglomeration was possible. Mr Lau was asked whether, all other things being equal, for an injectable formulation, it is preferable to have a solution rather than a suspension. Mr Lau responded: "If you take away the compatibility problem and you take away things like - you might want an extended release product, yes." On the basis of this evidence, I find that, all other things being equal, for an injectable formulation, a solution is preferable to a suspension (and this formed part of the common general knowledge as at the priority date).
36 It is apparent that Mr Lau did not accept that a potential change in the release profile of levamisole was a reason not to use the suspension and the fact that the release profile might be different from an existing formulation did not mean that the drug would not be effective. He acknowledged that there was a risk that levamisole might not be evenly dispersed in a suspension, which was a risk his Honour found existed irrespective of whether the concentration used was high or low.
37 His Honour found that if levamisole was present in particulate form in a formulation, an issue requiring investigation would be whether this affected the rate of absorption of the levamisole. His Honour found that was a matter of common general knowledge at the priority date.
38 As to the risk of agglomeration, Mr Lau acknowledged that agglomeration was possible and that, all other things being equal, this risk could be avoided by using a solution rather than a suspension. His Honour found that due to the risk of agglomeration occurring in a suspension, it would be preferable to employ a solution rather than a suspension. We should say it is not clear to us whether his Honour is referring here to a single phase solution, which would not be capable of carrying two incompatible active ingredients, or a micellar solution which, as explained in Mr Lau's evidence, would be able to provide the physical separation necessary to carry two incompatible active ingredients.
39 There was other evidence given by Mr Vickers and summarised by the primary judge which indicated that use of levamisole in particulate form and with an oil based solvent system had the potential to affect the release rate. According to Mr Vickers it would therefore be necessary to test the formulation to prove that it was effective and safe. There was other evidence given by Mr Lau, also referred to by the primary judge, which indicated that because micellar solutions contain large amounts of surfactants, they can suffer from foaming problems during manufacture and use in the field.
40 His Honour also referred to oral evidence given by Mr Vickers and Dr Martin in relation to the concentration of active ingredients to be included in an injectable formulation of macrocyclic lactone and levamisole and the impact that the use of an oil based solvent system with levamisole in particulate form might have on the release rate. His Honour referred to this evidence as follows at [237]-[238]:
[237] During the oral evidence, Mr Vickers was taken to [21]-[24] of the Martin/Vickers Joint Report, which sets out the concentrations of macrocyclic lactone and levamisole salt that the experts would include in an injectable veterinary pharmaceutical product for cattle, comprising a combination of (a) a macrocyclic lactone; and (b) a levamisole salt. Dr Martin and Mr Vickers agreed on certain concentrations, which are summarised in [195] above. In that context, the following exchange took place:
[COUNSEL FOR BOEHRINGER]: And so if [sic] this right? If you were considering a formulation, an injectable veterinary pharmaceutical formulation as at June 2010 that comprised those two ingredients, the macrocyclic lactone and the levamisole salt, the amounts that you've set out in your answers are the amounts or concentrations of those ingredients that you would include in that formulation?
MR VICKERS: Correct.
[COUNSEL FOR BOEHRINGER]: And you would do that based on the standard dose rates that you've previously referred to and the desirable dose volume rates for cattle; correct?
MR VICKERS: Correct.
[COUNSEL FOR BOEHRINGER]: And in adopting that approach, you would expect, based on the knowledge that you had as at June 2010, that those concentrations of those two active ingredients in that formulation may well produce an acceptable formulation in terms of its efficacy and the action of the two active ingredients.
MR VICKERS: Yes.
[COUNSEL FOR BOEHRINGER]: Doctor - sorry.
MR VICKERS: My only comment about that is that we're using desired dose rates which are actually known dose rates.
[COUNSEL FOR BOEHRINGER]: Yes.
MR VICKERS: So they're not based on solutions of levamisole salt.
[COUNSEL FOR BOEHRINGER]: Yes. But you're using the information that was known to derive a concentration that you would use, and then seek to take it forward; correct?
MR VICKERS: Correct, yes.
[COUNSEL FOR BOEHRINGER]: Dr Martin, do you agree with that?
DR MARTIN: Yes, I would agree with that.
[238] The following exchange also occurred:
[COUNSEL FOR BOEHRINGER]: Yes. I think I asked you this before, but just to come back to it, just based on what you knew as at June 2010, you wouldn't know whether or not these issues that you've raised, having the levamisole in an oil-based organic solvent system and being in a particular [sic] form, would have an impact on the release rate ..... of it, correct?
MR VICKERS: I actually believe I would have considered it possible and quite probable that it could change the release of the levamisole hydrochloride, but I wouldn't know the extent or the duration.
[COUNSEL FOR BOEHRINGER]: And in light of the fact that you wouldn't know the extent or the duration, your expectation, if you were asked to consider a formulation of this kind, as at June 2010 would be that it may well produce an acceptable release rate of levamisole hydrochloride, but you wouldn't know? You would have to go and test it; is that correct?
MR VICKERS: Correct.
[COUNSEL FOR BOEHRINGER]: And, Dr Martin, do you agree with that?
DR MARTIN: Yes. I would agree with that.
41 His Honour also referred to other evidence by Mr Lau concerning work he undertook while he was the Head of Chemistry at Jurox relating to the formulation of a stable parasiticide composition comprising a mixture of tetramisole (a class of active ingredients that includes levamisole and levamisole salts) and macrocyclic lactone. His Honour noted that this project led to the filing on 20 December 2005 of a patent application in respect of which Mr Lau was the named inventor. His Honour referred to this patent application and oral evidence given by Mr Lau in relation to it as follows at [241]-[243]:
[241] The title of the patent application is "Stable Parasiticide Composition" and the abstract commences: "The invention provides a stable preparation containing a mixture of tetramisole and macrocyclic lactone in an alkaline medium without the need for formation of an emulsion or micelle solution." The "Background art" section of the application included:
It has been difficult to formulate liquid formulations which contain a mixture of some classes of actives due to chemical incompatibility between active compounds, hydrolysis, low solubility of the active compounds and instability at alkali pH.
When formulating a preparation containing tetramisoles and macrocyclic lactones, traditional formulations require micelles or emulsions to stabilise the macrocyclic lactones at alkaline pH or the use of a salt of tetramisole in an acidic medium. Emulsions and micelle solutions contain large amounts of surfactants and tend to create foaming problems during manufacturing and use in the field. Emulsions and micelle solutions tend to foam when agitated during transport or shaking. Foaming traps air bubbles in the product and therefore a 30 ml dose may be altered to contain for example, 25 mL liquid and 5 mL air. This may cause non-uniformity in dose volume. Emulsions may also suffer from emulsion breakdown at high or low storage temperature, which causes break down of the formulation.
(Emphasis added.)
[242] In oral evidence, Mr Lau was taken to the passage set out above and the following exchange occurred:
[COUNSEL FOR INTERVET]: If I could then just direct your attention down to about line 16, is this the case, that - so this is from around 2005. At that time - this is reflective of your understanding, that it had been:
… difficult to formulate liquid formulations which contain a mixture of some classes of actives, due to chemical incompatibility between active compounds, hydrolysis, low solubility of the active compounds and instability at alkali pH.
MR LAU: Yes.
[COUNSEL FOR INTERVET]: And that related specifically to the tetramisoles, including levamisole and to - with macrocyclic lactones?
MR LAU: Yes.
[COUNSEL FOR INTERVET]: And is this a document - did you help draft this or review it at the time?
MR LAU: Yes, I helped draft and review it, yes.
[COUNSEL FOR INTERVET]: And if you go down a few more lines, it says here:
Emulsions and micelle solutions contain large amounts of surfactants and tend to create foaming problems during manufacturing and use in the field.
And down a couple more lines, it states that that can cause non-uniformity in dose volume. So that was a potential issue with having a micellar formulation; is that the case?
MR LAU: Yes.
[243] Mr Lau accepted that the approach taken in the 2005 patent application involved a co-solvent approach, and that the patent application was an example of a co-solvent approach being used to achieve a stable formulation of a macrocyclic lactone and levamisole; in other words, the approach taken did not involve the use of a suspension. After further discussion of the patent application, the following exchange took place:
[COUNSEL FOR INTERVET]: So what this patent shows - or patent application, rather, shows, back in 2005, you were working on the very same issue - at least at the level of achieving a stable liquid formulation of levamisole and a macrocyclic lactone; is that correct?
MR LAU: Yes.
[COUNSEL FOR INTERVET]: It doesn't relate - the approach that you took doesn't relate to either of the two approaches that you describe in your affidavit, does it?
MR LAU: Yes, that's right.
42 With regard to Boehringer's case that the invention, as claimed, did not involve an inventive step, the primary judge described two available approaches to the question of inventive step. His Honour said at [257]:
[257] If the matter is approached by reference to the modified "Cripps question", the question is whether, in light of the common general knowledge as at June 2010, the notional skilled team would be directly led as a matter of course to try a formulation as claimed in claim 1 of the Patent Application in the expectation that it might well produce a useful alternative to or better alternative than known products. Alternatively, the matter may be approached by asking whether, in light of the common general knowledge as at June 2010, the task of formulating a composition as claimed in claim 1 involves steps of a routine character that would be tried by the skilled team as a matter of course.
We will refer to the authorities that inform these approaches to inventive step later in these reasons.
43 His Honour next referred to the submissions made by Boehringer which his Honour recorded as follows at [258]-[259]:
[258] Boehringer submits that the evidence discloses that it would have been obvious to the notional skilled person or team to make a suspension formulation using an oil or organic carrier as a base and a co-solvent such as benzyl alcohol (an organic solvent), in which the macrocyclic lactone was in solution and the levamisole salt was in suspension. It is submitted that the skilled person would appreciate that, in such a composition, the levamisole salt would be in particulate form, and would know to use a concentration of levamisole salt of 18.8% w/v (for levamisole HCl) or 23.5% w/v (for levamisole phosphate) to achieve the desired dose in a product for cattle having a dose volume rate of 1 mL/25 kg. Boehringer submits that that results in a formulation in accordance with claim 1 of the Patent Application, and that a conclusion of obviousness similarly follows in relation to the dependent claims (for the reasons set out in a schedule to Boehringer's closing submissions).
[259] Boehringer relies heavily on Mr Lau's evidence that he would have adopted either of two routine formulation approaches, namely a micellar solution approach or a suspension formulation approach. Boehringer submits that the fact that two such options were available does not undermine the conclusion that the suspension formulation approach was obvious; this is a case where there were two obvious pathways available, one of which directly led to the claimed invention.
44 His Honour then enumerated eight reasons why he considered that the lack of inventive step case was not made out. These eight reasons were the focus of Boehringer's submissions in this Court. We now summarise his Honour's eight reasons, and will refer to them in greater detail when considering the parties' submissions.
45 First, his Honour referred to "the extent of departure from existing known formulations". His Honour regarded it as important that there were no commercially available injectable formulations of levamisole in particulate form including, injectable formulations of levamisole in particulate form in an oily formulation.
46 Second, his Honour referred to his previous findings in relation to the common general knowledge which included the fact that levamisole and macrocyclic lactones are chemically incompatible and have different pH requirements, that levamisole salts are soluble in water, whereas macrocyclic lactones are not soluble in water and are commonly formulated in oils and organic solvents.
47 These first two matters were said by his Honour to be important. His Honour also said at [263]:
[263] These matters presented, at the least, challenges in developing a satisfactory formulation for a combination injectable comprising a macrocyclic lactone and levamisole. As noted at [242] above, Mr Lau accepted that the statement in the 2005 patent application (Exhibit R6) that "[i]t has been difficult to formulate liquid formulations which contain a mixture of some classes of actives due to chemical incompatibility between active compounds, hydrolysis, low solubility of the active compounds and instability at alkali pH" reflected his understanding.
48 His Honour then referred to a statement by Dr Martin made in 2007 that "[d]ifferent classes of actives are difficult to formulate together, and some combinations are incompatible, and degrade if held in the same solvent formulation". His Honour noted that Dr Martin accepted that statement applied to a combination of macrocyclic lactone and levamisole, with Dr Martin adding that "I'd have to be careful of combining anthelmintics to achieve the stability that's required, and I think that's also the case for macrocyclic lactone and levamisole."
49 Thirdly, the primary judge referred to the fact that Mr Lau's second approach, which broadly corresponded with claim 1 of the patent application, was proposed by Mr Lau without knowledge of the mode of action and desired release profile of levamisole. His Honour observed at [265] that "… [t]he fact that Mr Lau, a formulation chemist, came up with his two main approaches without the benefit of input from the biology team and thus without relevant knowledge regarding the mode of action and release profile of levamisole, calls into question whether his approach to the hypothetical formulation task is representative of that of the notional skilled team".
50 In relation to Mr Lau's evidence concerning the significance of the release profile and absorption rate of levamisole salt, and evidence given by Dr Martin concerning those matters, his Honour said at [266]-[267]:
[266] I note for completeness that Mr Lau in [33] of his third affidavit stated that he did not agree with Mr Vickers that a potential change to the release profile or absorption rate of levamisole salt was a reason not to formulate the combination injectable with the levamisole salt in suspension. However, that needs to be read with Mr Lau's oral evidence in relation to that paragraph. In response to questions by counsel for Intervet, Mr Lau accepted that the release profile and absorption rate of levamisole were relevant considerations. He also said that a formulation with a different release profile may nevertheless prove to be effective upon testing. The difficulty with the evidence at [33] of Mr Lau's third affidavit is that it comes after the event, that is, after he had already developed his two main approaches without the benefit of input from the biology team and thus without relevant information.
[267] I also note for completeness the evidence given by Dr Martin quoted at [235] above. With reference to the proposition that the fact that the levamisole salts were in particulate form could potentially affect the release rate of the levamisole, Dr Martin was asked by senior counsel for Boehringer: "Is it the case, then, that that proposition wouldn't have dissuaded you from trying and considering a formulation that had levamisole salts in particulate form?" Dr Martin answered: "I think the answer is yes. I would think that could be tried. I didn't at the time do that, but if it had have been suggested to me, then perhaps yes, you could undertake that process." In relation to that evidence, and the other evidence quoted in [235] above, I note that several of Dr Martin's answers were couched in tentative terms. Thus, I do not consider this evidence to detract substantially from the point that Mr Lau developed his two main approaches without the benefit of input from the biology team and thus without relevant information, and that this is relevant in considering whether his approach is representative of that of the notional skilled team.
51 Thus, his Honour appears to have regarded the persuasiveness of Mr Lau's evidence on this point was diminished because Mr Lau's two main approaches were developed without the benefit of relevant information which would have been provided to him by the biology team. As to Dr Martin's evidence, his Honour characterised this as "tentative" and that it did not overcome the difficulty with Mr Lau's evidence.
52 Fourth, his Honour made an important finding regarding uncertainty as to the efficacy of levamisole when delivered in a combination product as a particulate form and in an oily formulation. His Honour found at [268] that "… this uncertainty would have pointed the notional skilled team away from adopting this type of formulation with the expectation that it might well produce a useful alternative to or better alternative than the known products".
53 His Honour developed this proposition as follows at [269]-[274]:
[269] As set out at [178] above, one requires a sufficient dose level and concentration of levamisole within the animal to achieve paralysis of the relevant worms; the intention of the particular mode of operation of levamisole is that the worms stay paralysed for long enough that they are excreted; one typically aims to achieve a rapid, high blood level of levamisole if levamisole is being administered by injection; levamisole usually peaks very quickly, usually about two to three hours after administration by an oral or injectable; it is then excreted very quickly.
[270] All commercially available injectable formulations of levamisole had the levamisole dissolved in an aqueous solution, which allowed for sufficiently quick absorption to achieve the above concentration peak. The effect of shifting to an oily formulation involved significant unknowns. Oily formulations were used to delay the absorption of active ingredients, for long-acting active ingredients such as macrocyclic lactones. An oily formulation for levamisole was a significant departure from known formulations, and its impact could only be known by conducting testing. There was clear potential for such a formulation to prevent the necessary peak concentration from being reached.
[271] Further, a particulate formulation of levamisole was also a significant departure from known injectable formulations, all of which had levamisole in dissolved form. Before the particulate levamisole became effective it would need to reach the animal's gut, where the relevant helminths are located. Dr Martin said in oral evidence that that could happen by it being dissolved, or being absorbed by some other process. He explained that one possibility was that it would "simply dissolve in the aqueous environment in the subcutaneous area of the animal", and then said: "And I don't know, but I would be interested to ask the question as a researched [sic] or how that did impact on its absorption and the blood levels in the animal. I don't know the answer. I would want to explore it."
[272] In his written and oral evidence, Mr Vickers identified using levamisole as a particulate and in an oily formulation as areas of uncertainty. In particular, as noted above, in oral evidence Mr Vickers was asked about the issue of the slowing down of the release rate in the context of an approach that had the levamisole present in an oily formulation as particles. Mr Vickers stated that he thought the issue "arises even more so" in such a case. He stated that if the levamisole was present in particles, his concern was: "would that even slow it down further and slow the release rate?"
[273] I note that Dr Martin gave evidence (quoted at [235] above) that his expectation, without more than the knowledge he had then, would be that levamisole in particulate form "would be absorbed not too differently to the aqueous solutions". However, elsewhere in Dr Martin's evidence he seemed to accept that this was an area of uncertainty. To the extent that there is a difference between Mr Vickers's evidence and that of Dr Martin on this point, I prefer Mr Vickers's evidence, which I found persuasive.
[274] In closing submissions, Boehringer drew attention to the fact that there were commercially available products with the anthelmintic in suspension products as at the priority date. One example given was the Triton product. However, as described in [61] and [69] of Mr Vickers's affidavit, this was an oral drench product rather than an injectable, and the anthelmintic present as suspended particles was albendazole. Further, it was a predominantly aqueous formulation in which the levamisole was dissolved in the aqueous phase.
54 His Honour concluded at [275] that the possibility of an oily formulation with levamisole present as a particulate was a substantial departure from known formulations, particularly in relation to levamisole and that the resultant "uncertainties as to efficacy" would point the notional skilled team away from the adoption of Mr Lau's second approach.
55 Fifth, his Honour referred to the risk that an active ingredient formulated as a suspension would not be dispersed evenly throughout the formulation, which would also give rise to the risk of agglomeration. It followed, according to his Honour, that, all other things being equal, it was preferable to use a solution rather than a suspension for an injectable formulation.
56 Sixth, his Honour referred to secondary evidence that he found supported the existence of an inventive step. He found at [277] that there was a long-standing need for combination treatments of levamisole and macrocyclic lactone which could be administered as a combination in injectable form. His Honour considered that the fact that no one had suggested or made an oily injectable formulation with levamisole salt in particulate form before the priority date was some evidence that such a formulation was not obvious. In this context his Honour referred to Mr Lau's work at Jurox aimed at developing a stable liquid formulation of levamisole and a macrocyclic lactone. Importantly, his Honour noted that the approach in the patent application did not reflect either of the two main approaches identified in Mr Lau's first affidavit. His Honour also referred to Dr Martin's involvement in the Virbac project which was focused on a combined treatment of macrocyclic lactone and levamisole. However, as his Honour's reasons recognise, the Virbac project related to the use of two different formulations rather than a single combined formulation.
57 Seventh, his Honour did not regard the uncertainties associated with Mr Lau's second approach as merely issues to be resolved by way of routine testing. His Honour reiterated that the uncertainties he had identified would point the notional research team away from the second approach proposed by Mr Lau. His Honour added (without elaboration) that "… while the uncertainties could be the subject of testing, I would not characterise such tests as routine".
58 The eighth and final reason given by his Honour for rejecting Boehringer's lack of inventive step case based on the common general knowledge alone concerned the evidence given by Dr Martin and Mr Vickers which concerned matters such as efficacy, release rate and absorption (rather than formulation chemistry). His Honour referred here to Dr Martin's evidence (set out above) concerning his willingness to consider a formulation that had levamisole salts in particulate form. As to Mr Vickers' evidence, his Honour observed that, while Mr Vickers accepted certain propositions as to his expectation of achieving an acceptable result "… this was qualified by the need for testing … not merely routine testing but testing of a more fundamental nature". His Honour said this evidence of Dr Martin and Mr Vickers was evidence that "does not go very far".
59 In the result, with regard to Boehringer's case based on the common general knowledge alone, his Honour said that he was not satisfied (let alone clearly satisfied) that the notional skilled team would be directly led as a matter of course to try a formulation as claimed in claim 1 of the patent application in the expectation that it might well produce a useful alternative to or better alternative than known products or that the task of formulating a composition as claimed in claim 1 involved steps of a routine character that would be tried by the skilled team as a matter of course.
60 His Honour then turned to the lack of inventive step case which relied on both the common general knowledge and a patent application ("CN 291") entitled "Veterinary Compound Injection Containing Levamisole or Salts thereof" published on 23 October 2002. His Honour noted that there was no issue that CN 291 is a document falling within s 7(3) of the Act and that it was prior art information that the skilled person or team could, before the priority date, be reasonably expected to have ascertained, understood and regarded as relevant.
61 It is necessary to refer to CN 291 in a little detail before explaining why it was that his Honour rejected Boehringer's lack of inventive step case based on the common general knowledge together with the information contained in that document.
62 CN 291 states at p 1 of the specification:
The present invention relates to a veterinary anthelmintic compound injection prepared by using levamisole or salts thereof and macrolide anthelmintic.
Levamisole is a levo form of tetramisole and a broad-spectrum nematode-repelling drug, and has a repelling and killing effect for various nematodes which parasitize in animal body. However, the repelling and killing activities to nematodes of different species are different. For example, the repelling and killing activity to several nematodes which parasitize in stomach and lung tissues of animals (such as pigs, cattle and sheep) can reach 95-100% (see Table 1), while the repelling and killing activity to some nematodes which parasitize in small intestine and large intestine is lower, and levamisole does not have repelling and killing activities to trematodes, tapeworms and ectozoic parasites.
Macrolide anthelmintic includes abamectin, ivermectin, eprinomectin, moxidectin and doramectin. They are a kind of high-efficacy broad-spectrum anthelmintic and have activities to nematodes and ectozoic parasites which widely parasitize in animal body. However, the repelling and killing activities to nematodes of different species which parasitize at different parts of organisms are different (see Table 1). Recent investigation and clinical tests indicate that, since ivermectin or levamisole single-component preparation has been used for many years (approximately 20 years), some nematodes have resistance to these two kinds of drugs in different degree. For example, the repelling rate of ivermectin to haemonchus is 100% at the beginning of use but the current repelling rate is 78-85%. When the compound preparation (containing 5mg of abamectin or ivermectin and 50-60mg of levamisole) provided by the present invention is injected into castle and sheep according to a dosage of 0.5ml per 10kg of weight, the repelling rate thereof to haemonchus and other various nematodes can still reach 95-100% (see Table 1), and after abamectin or ivermectin is added into the formula, ectozoic parasites can be controlled at the same time.
Therefore, the preparation provided by the present invention has the feature that levamisole and the macrolide anthelmintic such as abamectin are combined to form a compound preparation which can be used for controlling drug-resistant nematodes. In addition, the compound injection provided by the present invention not only has a fast-acting efficacy, but also has a long-acting efficacy, therefore not only reducing both dosing times and dosing cost but also thoroughly repelling parasites.
The veterinary compound injection containing levamisole or salts thereof provided by the present invention comprises the following formula components:
(a) 1-25% (W/V) of levamisole or salts thereof;
(b) 0.1-10% (W/V) of macrolide anthelmintic (abamectin, ivermectin, eprinomectin, moxidectin and doramectin);
(c) balance of dispersion media;
63 CN 291 includes three examples. Example 1 on p 4 of the specification is an example of what we would understand to be a micellar solution containing the surfactant Tween-80 (10% w/v) and the two active ingredients levamisole HCl (12% w/v) and abamectin (1% w/v). Example 3 on p 5 of the specification is as follows:
Example 3
This example is used for preparing an oil injection containing 0.5% of ivermectin and 5% of levamisole hydrochloride
Levamisole hydrochloride 5% (W/V)
Ivermectin 0.5% (W/V)
Benzyl alcohol 10% (V/V)
Benzyl benzoate 40% (V/V)
Soybean oil added to 100% (V/V)
64 We will return to consider evidence given in relation to CN 291 later in these reasons. For present purposes we merely note that Mr Lau gave evidence that Example 3 was a suspension formulation. We also note that Example 3 includes the two relevant active ingredients, levamisole HCl and ivermectin, but that the concentration of levamisole HCl is below that specified in claim 1 of the patent application in suit.
65 Having referred to evidence given by Mr Lau and Mr Vickers in relation to CN 291 and Boehringer's submissions in relation to that document, his Honour provided three reasons why Boehringer's case of lack of inventive step based on the common general knowledge and CN 291 was not made out.
66 First, his Honour observed at [292] that there was no discussion in CN 291 of stability issues or stability tests. His Honour said that the authors of CN 291 appear to have been unaware of the chemical incompatibility of levamisole and macrocyclic lactones. It followed, according to his Honour, that CN 291 did not provide any direct assistance to the notional skilled team in addressing the known chemical incompatibility of levamisole and macrocyclic lactones.
67 Secondly, his Honour noted at [293] that Example 3 of CN 291 does not set out any manufacturing steps or any description of the formulation that is intended to be made including whether it was intended that the levamisole HCl be in particulate form.
68 Thirdly, his Honour also noted at [294] that, after being taken through the detail of CN 291, Mr Lau accepted that it would not provide any additional assistance to the task of solving the relevant problem. In this regard his Honour referred to evidence he previously set out in connection with his consideration of novelty. His Honour said at [99]:
[99] Mr Lau accepted during oral evidence that CN 291 does not state whether any of the Examples had been made or tested. Mr Lau accepted that none of the Examples sets out any manufacturing steps, or any description of what is intended to be made. The following exchange took place during the oral evidence, with reference to Mr Lau undertaking the task of formulating a combination injectable comprising a combination of a macrocyclic lactone and levamisole:
[COUNSEL FOR INTERVET]: In practical terms, though, if you were actually undertaking this task in 2010, there is nothing in CN291 that would have provided you with any practical assistance, is there?
MR LAU: Could you repeat your question?
[COUNSEL FOR INTERVET]: Yes. So as a practical matter, had you actually been undertaking that task in June 2010? There's nothing in CN291 that would have provided you with any practical assistance.
MR LAU: Okay. I would be using my experience to make up those formulations.
[COUNSEL FOR INTERVET]: But you could have used your experience based on the description you have already given in your affidavit. You don't get any additional assistance from anything that's in CN291, do you?
MR LAU: Sorry, I didn't quite understand your question.
[COUNSEL FOR INTERVET]: So you had a set of knowledge as at June - - -
MR LAU: Yes.
[COUNSEL FOR INTERVET]: - - - 2010, as you've - - -
MR LAU: Yes.
[COUNSEL FOR INTERVET]: - - - described previously, in earlier parts of this affidavit.
MR LAU: Yes.
[COUNSEL FOR INTERVET]: And what I am saying - suggesting to you that in approaching this combination [injectable] exercise at that time, there is nothing in CN291 that would provide you with any additional assistance.
MR LAU: Correct.
[COUNSEL FOR INTERVET]: Sorry?
MR LAU: Yes, there is not.
69 His Honour concluded at [295] that, in light of those matters, he was not satisfied (let alone clearly satisfied) that, equipped with the common general knowledge and CN 291, the notional skilled team would be directly led as a matter of course to try a formulation as claimed in claim 1 of the patent application in the expectation that it might well produce a useful alternative to or better alternative than known products or that the task of formulating a composition as claimed in claim 1 involves steps of a routine character that would be tried by the skilled team as a matter of course. His Honour therefore rejected Boehringer's case based on the common general knowledge and CN 291.