FEDERAL COURT OF AUSTRALIA

Boehringer Ingelheim Animal Health USA Inc. v Intervet International B.V. [2020] FCA 1333

ORDERS

THE COURT ORDERS THAT:

1.    By 4.00 pm on 21 September 2020, the parties provide minutes of proposed orders to give effect to the Court’s reasons.

Note:    Entry of orders is dealt with in Rule 39.32 of the Federal Court Rules 2011.

REASONS FOR JUDGMENT

MOSHINSKY J:

Introduction

1    On 23 June 2011, the respondent (Intervet) filed in Australia an application for a standard patent titled “Injectable formulation of a macrocyclic lactone and levamisole” (Application AU 2011268899 C1) (the Patent Application). The invention described in the application relates to injectable formulations comprising a macrocyclic lactone and levamisole for controlling parasites in animals, and the use of such formulations in the preparation of a medicament for controlling parasites.

2    The Patent Application claims priority from two earlier applications pursuant to the Paris Convention for the Protection of Industrial Property. The Patent Application’s entitlement to priority is not challenged in this proceeding. The priority date of the Patent Application is 24 June 2010 (the priority date).

3    Examination of the Patent Application was requested on 11 April 2013.

4    It is common ground that the amendments to the Patents Act 1990 (Cth) brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Cth) do not apply to the application. Any subsequent references to the Patents Act relate to the Patents Act prior to those amendments.

5    On 7 October 2016, the appellant, then called Merial Inc but now called Boehringer Ingelheim Animal Health USA Inc (Boehringer), filed a notice of opposition to the Patent Application. Following the filing of evidence and a hearing, on 17 August 2018 a delegate of the Commissioner of Patents decided to dismiss the opposition and directed the Patent Application proceed to grant.

6    Boehringer ‘appeals’ to this Court against the delegate’s decision pursuant to s 60(4) of the Patents Act. Although called an ‘appeal’, the proceeding is in the original jurisdiction of this Court and involves a hearing de novo on the grounds and evidence before the Court. On two occasions since the commencement of the proceeding, Intervet sought to amend the Patent Application. On 5 March 2019 and on 18 February 2020, orders were made by consent amending the Patent Application. Subsequent references in these reasons to the “Patent Application” are to the Patent Application as so amended.

7    By its amended notice of appeal, Boehringer relies on nine grounds, which can be summarised as follows:

(a)    Lack of novelty. Boehringer contends that the alleged invention claimed in each of claims 1, 2, 4, 5, 6, 7, 12, 13 and 15 of the Patent Application is not novel in light of Chinese patent application CN 1375291A (CN 291).

(b)    Lack of inventive step. Boehringer contends that the alleged invention claimed in each of the claims does not involve an inventive step because it was obvious in the light of the common general knowledge considered alone, or the common general knowledge combined with CN 291.

(c)    Lack of utility. Boehringer contends that the alleged invention claimed in each of the claims is not useful, in that the claims of the Patent Application include embodiments that do not achieve the promise of a physically and chemically stable suspension formulation of a macrocyclic lactone and levamisole.

8    Boehringer, as the opponent, bears the onus in relation to each ground of opposition. The authorities establish that, for an opposition to be upheld, it must be “clear” (or “practically certain”) that the patent, if granted, would not be valid.

9    For the reasons that follow, I have decided that none of the grounds relied on by Boehringer is made out. It follows that the appeal is to be dismissed.

The Patent Application

10    The introductory page of the Patent Application states that the “present invention relates to injectable formulations for controlling parasites and the use of such formulations in the preparation of a medicament for controlling parasites”.

11    It is further explained on the introductory page that:

Endoparasites commonly cause clinical disease in [sic] especially in livestock animals and have significant adverse economic effects on farming economies when present at subclinical levels. The most frequently encountered endoparasites are the group of worms referred to as nematodes. The nematodes are found in the intestinal tract, heart, lungs, blood vessels and other body tissues of animals and are a primary cause of anemia, weight loss and malnutrition in the infected animals. The nematodes most commonly found to be the infecting agents of ruminants include Haemonchus and Ostertagia generally found in abomasum; Cooperia, Trichostrongylus and Nematodirus generally found in the intestinal tract, and Dictyocaulus found in the lungs.

Treatment of animals to prevent infestation by any of the above-mentioned parasites, or to reduce or control the proliferation of these parasites in animals is thus important.

Meanwhile the problem has arisen that some parasites develop a resistance to antiparasitic drugs like ivermectin. The resistance occurs when a strain of a parasite is able to tolerate doses of an active ingredient that is efficacious against other populations of parasites of the same species. This characteristic is inheritable.

After the use of macrocyclic lactones (ML) for almost two decades in cattle in Brazil several reports on resistant endoparasites in sheep, cattle and goats were published.

The discovery of novel anti-parasitics with equal or better qualities than macrocyclic lactones seems to be a distant reality in the veterinary pharmaceutical industry.

Therefore, the chemical groups available nowadays must be used in a rational way, with a view to achieving high percentages of efficacy against endoparasites, especially in ruminants and delaying the occurrence of resistant strains.

Therefore a stable formulation for a combination of a macrocyclic lacone [sic] ad [sic] levamisole would be desirable[.] However, such combinations have been difficult to formulate.

Accordingly, there is a need for a stable suspension formulation capable of including macrocyclic lactone compounds together with levamisole.

(Emphasis added.)

12    As discussed later in these reasons, the problem identified in the above passage, namely that some parasites develop a resistance to anti-parasitic drugs, was common general knowledge as at the priority date. Further, it was common general knowledge that it would be desirable to develop an injectable formulation for a combination of a macrocyclic lactone and levamisole.

13    Parasiticides was an overarching term for products that treated parasites, and parasiticides that acted on helminths (a type of parasite) were referred to as anthelmintics. Common anthelmintics in use as at the priority date included macrocyclic lactones (such as ivermectin and abamectin) and imidazothiazoles (such as levamisole).

14    Under the heading “Statement of Invention” on page 2, it is stated that “[h]erein disclosed is a macrocyclic lactone solution formulation comprising levamisole in a particulate form in a non-aqueous solvent system”. It is stated that the non-aqueous solvent system may comprise oil and an organic solvent, and that the formulation may be suitable for injectable administration. A consistory clause for claim 1 is then set out:

According to a first aspect of the present invention, there is provided an injectable formulation of a macrocyclic lactone and levamisole in a non-aqueous solvent system comprising oil and an organic solvent, wherein the macrocyclic lactone is in solution and the levamisole is a salt in a particulate form, and wherein the levamisole salt is present in the range of between 10-35% w/v.

15    I note the following aspects of the invention claimed in claim 1, which will feature in the expert evidence discussed later in these reasons:

(a)    the formulation adopts a non-aqueous solvent system comprising oil and an organic solvent;

(b)    the macrocyclic lactone is in solution; and

(c)    the levamisole is a salt in a particulate form.

16    As discussed later in the reasons, it was common general knowledge as at the priority date that:

(a)    levamisole and macrocyclic lactones are chemically incompatible and tend to react with each other when combined;

(b)    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); and

(c)    levamisole salts are soluble in water, whereas macrocyclic lactones are not water soluble but are soluble in organic solvents, and are commonly formulated in oils and organic solvents.

17    The invention claimed in claim 1 addresses these issues by adopting a non-aqueous solvent system comprising oil and an organic solvent, in which the macrocyclic lactone is in solution, and the levamisole is a salt in particulate form (that is, in suspension). This type of formulation achieves a separation of the macrocyclic lactone and the levamisole, thus addressing the issue of chemical incompatibility.

18    Levamisole could be administered as levamisole base or as a salt. Two types of levamisole salt referred to in the evidence are levamisole hydrochloride (levamisole HCl) and levamisole phosphate.

19    There follows a series of consistory clauses for the other claims.

20    The detailed description commences on page 3. This includes the following statement (on page 3):

The macrocyclic lactone solution formulation comprising levamisole in a particulate form in a non-aqueous solvent system is advantageous as it provides stable formulations including an avermectin or milbemycin in combination with levamisole.

The complicated nature of prior art formulations is due in part to the different formulation requirements of the actives. Avermectins and milbemycins being substantially insoluble in water, whereas levamisole is water soluble. In addition, levamisole has previously been found to require a pH of less than about 4 for stability while avermectins and milbemycin require a pH of about 6.6.

The formulations of the present invention exhibit desirable properties which are useful characteristics for the administration of relatively high concentrations of levamisole. The formulations are physically and chemically stable. In addition, as the formulation excludes water, the issue of incompatible pH requirements is alleviated. Enabling the two actives to stability [sic] co-exist in a single phase.

The formulations of the present invention must be stable to be of commercial use. In this specification, a commercially acceptable anthelmintic formulation is one which is stable at room temperature for a period of at least 6 months. In conditions of accelerated testing, at 40°C., this requires the potency of the actives within the formulation to remain within specified and acceptable limits for 3 months.

21    In the last sentence of the third paragraph set out above, the word “stability” should presumably read “stably”. The fourth paragraph set out above is relevant to the lack of utility ground.

22    The following paragraphs of the detailed description refer to different types of macrocyclic lactones, that is, the avermectin and milbemycin series of compounds. One particularly contemplated macrocyclic lactone parasiticide is ivermectin. Other macrocyclic lactone parasiticides are listed on pages 3 to 4.

23    On page 4, it is stated that levamisole as used in the specification “includes levamisole base, levamisole hydrochloride, levamisole phosphate together with other salts and forms”. It is stated that, in one embodiment, levamisole HCl is used. It is stated:

Preferably levamisole is present in the range of between 0.1-40% w/v, 10-35% w/v, 12-30% w/v, 15-25% w/v[.]

Good results were obtained with a formulation comprising 1.6 - 4% w/v ivermectin and 15.04 - 18.8% w/v levamisole hydrochloride.

24    The following explanations are provided of terms used in the specification (on page 4):

By “particulate form” it is meant mobile, un-dissolved, solid matter suspended in a liquid. The liquid may be aqueous, oily, or both.

A solution is a mixture of two or more components that form a single phase that is homogeneous down to the molecular level.

A suspension consists of insoluble solid particles dispersed in a liquid medium, with the solid particles accounting for about 0.5% to about 30% of the suspension.

By “w/v” is meant weight/volume, i.e. “1% w/v” means 1 g in 100 ml of the formulation. “v/v” means volume per volume, and 1% v/v means 1 ml, in a total of 100 ml.

“Non-aqueous solvent system” means a solvent or a mixture of solvents that essentially consisting [sic] of liquid(s) other than water. The non-aqueous solvent system comprises at least one oil and at least one organic solvent.

25    There follows, on pages 4 to 5, a description relating to oils that can be used in the formulations. On page 5, reference is made to the organic solvent and to additional pharmaceutical excipients.

26    Preferred components and their concentration ranges are set out on page 6.

27    It is stated, on page 6, that in a preferred embodiment, the formulations according to the invention are used to treat a helminth infection, such as an infection caused by one or more of the helminths listed on that page. It is stated that, in cattle, the major production limiting parasite species is Ostertagia spp, and that another important cattle parasite is Cooperia spp.

28    The Patent Application provides some example formulations, including instructions for their manufacture, on pages 8 and 9. The example formulations are referred to as F1, F2, F3 and F4. Stability data in relation to these formulations is set out in Table 2 on page 10. I note that the heading to that table is inaccurate in that it refers only to “Formulation 3”, whereas the data presented in the table covers all four formulations. I also note that, somewhat confusingly, the data in the table is not presented in the numerical order of the four formulations, but rather presented in the following order: F1, F2, F4 and F3. As indicated in the sub-heading appearing immediately above the table, the data is based on accelerated stability studies, as distinct from studies conducted at room temperature, a matter that is relevant to the lack of utility ground.

29    Data from efficacy testing is set out in Table 3 on page 11.

30    The claims in the Patent Application are as follows:

1.    An injectable formulation of a macrocyclic lactone and levamisole in a non-aqueous solvent system comprising oil and an organic solvent, wherein the macrocyclic lactone is in solution and the levamisole is a salt in a particulate form, and wherein the levamisole salt is present in the range of between 10-35% w/v.

2.    The formulation as claimed in claim 1, wherein the levamisole is present in the range of between 12-25% w/v.

3.    The formulation as claimed in claim 1 or claim 2, wherein the oil comprises castor oil and a medium chain triglyceride or a mixture of medium chain triglycerides.

4.    The formulation as claimed in any one of claims 1 to 3, wherein the organic solvent is dimethylacetamide.

5.    The formulation as claimed in any one of claims 1 to 4, wherein the macrocyclic lactone compound is present in the range of between 0.01-10% w/v.

6.    The formulation as claimed in any one of claims 1 to 5, wherein the macrocyctic lactone compound is selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin and moxidectin.

7.    The formulation as claimed in any one of claims 1 to 6, wherein the levamisole is levamisole hydrochloride.

8.    The formulation as claimed in any one of claims 1 to 6, wherein the levamisole is levamisole phosphate.

9.    The formulation as claimed in any one of claims 1 to 8, wherein the non-aqueous solvent system comprises dimethylacetamide and an oil, wherein the oil comprises castor oil and a medium chain triglyceride or a mixture of medium chain triglycerides.

10.    The formulation as claimed in any one of claims 1 to 9, wherein the formulation additionally includes at least one further medicament selected from the group of anthelmintics, dietary supplements, vitamins, minerals.

 11.    The formulation as claimed in claim 1, comprising:

•    about 1.5-4% w/v ivermectin,

•    about 15-18.8% w/v levamisole salt, and

wherein the levamisole salt is particulate and the ivermectin is substantially dissolved in a non-aqueous solvent system comprising dimethylacetamide and an oil, wherein the oil comprises castor oil and a medium chain triglyceride or a mixture of medium chain triglycerides.

12.    A method for treating or preventing helminth infection of cattle with Cooperia or Ostertagia spp. by injecting an animal in need thereof with a formulation as claimed in any one of claims 1 to 11.

13.    Use of a formulation according to any one of claims 1 to 11 for the manufacture of a medicament for the treatment of parasitoses caused by helminth infestations.

14    A method of preparing an injectable formulation as claimed in any one of claims 1 to 11 comprising the steps of:

•    mixing an organic solvent with the macrocyclic lactone

•    mixing the macrocyclic lactone solution with an oil

•    add levamisole salt and mix until complete homogenisation

•    mill to get a homogeneous suspension of levamisole salt.

15.    The method as claimed in claim 12 or the use as claimed in claim 13, wherein the macrocyclic lactone compound is selected from the group comprising abamectin, doramectin, eprinomectin, ivermectin and moxidectin, and the levamisole is levamisole hydrochloride or levamisole phosphate.

16.    An injectable formulation of a macrocyclic lactone and levamisole salt as defined in claim 1, substantially as hereinbefore described with reference to the Example Formulations.

17.    The formulation according to claim 16, wherein said formulation is Formulation F3 as described in the Example Formulations.

18.    A method as defined in claim 14 of preparing an injectable formulation, said method being substantially as hereinbefore described with reference to the Example Formulations.

19.    The method according to claim 18, wherein said formulation is Formulation F3 as described in the Example Formulations.

I note that the above quotation of the claims takes into account the deletion of certain words from claim 11 effected by the orders dated 18 February 2020.

31    Claim 1 is the broadest claim, and defines an injectable formulation having the features there set out. Claims 2 to 11 are dependent claims that also define injectable formulations, adding various features relative to claim 1. Claim 12 relates to a method for treating or preventing helminth infection of cattle with Cooperia or Ostertagia spp, by injecting an animal in need with the injectable formulation of claims 1 to 11. Claim 13 is a so-called ‘Swiss type’ claim (see Commissioner of Patents v AbbVie Biotechnology Ltd (2017) 253 FCR 436 at [58]). Claim 14 is to a method of preparing an injectable formulation. Claim 15 depends on claims 12 and 13, and specifies a smaller group of macrocyclic lactones and levamisole. Claims 16 to 19 are limited by reference to the examples.

Applicable principles in relation to an appeal under s 60(4)

32    As noted by Heerey, Kenny and Middleton JJ in Commissioner of Patents v Sherman (2008) 172 FCR 394 at [18], the fundamental principles governing an appeal against a decision of the Commissioner of Patents on an opposition to a grant of a patent are well settled. Their Honours stated (at [18]-[22]):

18    … First, an appeal under s 60(4) of the Patents Act is not an appeal in the strict sense. Rather, it is a proceeding in the original jurisdiction of the Court and is conducted as a rehearing (sometimes referred to as a hearing de novo): see Jafferjee v Scarlett (1937) 57 CLR 115 at 119 per Latham CJ; and Kaiser Aluminum & Chemical Corporation v Reynolds Metal Company (1969) 120 CLR 136 at 142 per Kitto J. The Court upholds the opposition only if clearly satisfied that the patent, if granted, would be invalid: see Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232 at 251 per Dixon CJ, McTiernan, Fullagar, Taylor and Windeyer JJ; and Denison Manufacturing Company v Monarch Marking Systems Inc (1983) 76 FLR 200 at 201 per Smithers J and 215 per Franki J. An appeal under s 60(4) of the Patents Act is different from some other “appeals” (as referred to in some other enactments) against administrative decisions that may be brought to this Court, where the Court decides whether the decision was correct in law, having regard to the evidence that was before the decision-maker at the time of making the decision. In an appeal under s 60(4) of the Patents Act, the Court does not ask this question.

19    Secondly, on an appeal under s 60(4) of the Patents Act, subject to the Court’s direction, the parties may lead evidence-in-chief. The position of the opponent is relatively clear. As Emmett J said in F Hoffman-La Roche AG v New England Biolabs Inc (2000) 99 FCR 56 at [30], “[i]t would … be open to an opponent simply to tender the material that was before the Commissioner” and the “Court could, subject to all proper objections, admit that evidence”, although the opponent is not bound to this course.

20    Thirdly, the only evidence to be taken into account at the hearing of an appeal under s 60(4) will be the evidence tendered or admitted at the hearing: see Caroma Sales Pty Ltd v Philmac Pty Ltd (1972) 46 ALJR 324 at 324; [1972-73] ALR 427 at 428; Brickwood Holdings Pty Ltd v ACI Operations Pty Ltd [1983] 2 VR 587 at 588-589 per King J; European Community v Commissioner of Patents (2006) 68 IPR 539 at 543 per Young J; and Cadbury Schweppes plc v Effem Foods Pty Ltd (2006) 69 IPR 584 at 586 per Lindgren J. This is the evidence on which the Court acts. As Kitto J said in Kaiser Aluminum 120 CLR at 142-143, in relation to the same kind of proceeding under the former Patents Act 1952 (Cth), the outcome of a proceeding such as this “must be decided upon the evidence adduced before [the] Court”, even if a different case than that made before the Commissioner. We return to this proposition below, which is virtually decisive of the outcome of this appeal.

21    Fourthly, whilst the Court will make its own decision on the basis of the evidence before it, in deciding whether the applicant (here, Mr Sherman) has made out his case on the balance of probabilities, the Court will take into account the nature of the proceeding and the fact that the proceeding concerns the decision of an expert administrative decision-maker: see Commissioner of Patents v Emperor Sports Pty Ltd (2006) 149 FCR 386 at [24]; EI Du Pont de Nemours and Company v ICI Chemicals & Polymers Ltd (2003) 128 FCR 392 at [28] per Emmett J; EI Du Pont de Nemours and Company v ICI Chemical Industries plc (2002) 54 IPR 304 at [17] per Branson J; Neumann v Sons of the Desert SL [2008] FCA 1183 at [2] per Ryan J; and s 140 of the Evidence Act. The Full Court in Emperor Sports 149 FCR 386 at [24] explained that:

The Commissioner is an administrative decision-maker equipped with technical expertise. Subject to the rules of natural justice both common law and statutory … he or she is entitled to make use of that expertise, and draw inferences that may be rationally drawn from technical knowledge, including how skilled persons of various descriptions may act in their respective occupations … On an appeal by way of hearing de novo the judge would not be a person credited with technical expertise of his or her own. In such an event the judge may be able to take into account conclusions of the Commissioner based on his or her expertise, subject of course to the rights of other parties to call rebutting or supporting evidence.

Also in Emperor Sports 149 FCR 386 at [33], the Full Court noted that, when the identification of the relevant prior art is in dispute, “it is necessary to have either evidence or, which amounts to the same thing, reliance by an administrative decision-maker of expertise appropriate to the office”. Naturally enough, the weight given by the Court to the Commissioner’s findings will be affected by the extent to which the Court permits evidence to be adduced before it that was not before the Commissioner: see Du Pont 128 FCR 392 at [28] and Du Pont 54 IPR 304 at [17]. We return to these matters on the question of the admissibility of the evidence in question under the Evidence Act.

22    Fifthly, where a ground of opposition depends on proof of a fact, the onus of proof lies on the party seeking to make out the ground. Usually the party bearing this onus will be the opponent, but sometimes, as in the present case, it will be the Commissioner: see Titan Mining & Engineering Pty Ltd v Arnall’s Engineering Pty Ltd (1988) 12 NSWLR 73 at 75 per McLelland J.

(Emphasis in original.)

33    The grounds on which the grant of a standard patent may be opposed are set out in s 59 of the Patents Act. These in turn require consideration of other provisions of the Act, including s 7 (in relation to novelty and inventive step) and s 18 (in relation to novelty, inventive step and utility).

34    The opponent bears the onus in relation to each ground of opposition. The authorities establish that, for an opposition to be upheld, it must be “clear” (or “practically certain”) that the patent, if granted, would not be valid: Commissioner of Patents v Sherman at [18]; F Hoffman-La Roche AG v New England Biolabs Inc (2000) 99 FCR 56 (F Hoffman-La Roche) at [29], [67] per Emmett J; see also Commissioner of Patents v Microcell Ltd (1959) 102 CLR 232 at 244-245, 251 per Dixon CJ, McTiernan, Fullagar, Taylor and Windeyer JJ. In F Hoffman-La Roche, Emmett J stated at [67]:

The language employed in the cases to which I have referred suggests that it should appear clear to the Court that no patent granted in respect of the specification would be valid. I consider that, before the Court would uphold an opposition to the grant of a patent, the Court should clearly be satisfied that the patent, if granted, would not be valid.

See also Austal Ships Pty Ltd v Stena Rederi Aktiebolag (2005) 66 IPR 420 at [12] per Bennett J; Merial Inc v Intervet International BV (No 3) (2017) 122 IPR 128 (Merial) at [13]-[16]; and Meat & Livestock Australia Limited v Cargill, Inc (2018) 354 ALR 95 at [11] per Beach J.

The hearing

35    At the hearing, Boehringer led evidence from the following witnesses:

(a)    Mr Giuseppe (Joe) Robin Pippia (a chemist);

(b)    Mr Kai Kin Lau (a pharmaceutical expert, whose evidence focussed on pharmaceutical formulation);

(c)    Dr Paul John Martin (a pharmaceutical expert, whose evidence focussed on issues of parisitology);

(d)    Mr Rodney Ian Lindsay Cruise (a patent attorney);

(e)    Ms Melanie Kitchin (a solicitor); and

(f)    Mr Marmikkumar Mohanlal Patel (an analytical chemist).

36    Mr Cruise, Ms Kitchin and Mr Patel were not required to attend for cross-examination.

37    Intervet led evidence from the following witnesses:

(a)    Mr Mark Colin Vickers (a pharmaceutical expert); and

(b)    Mr Matthew Blair Stewart (a patent attorney).

38    Mr Stewart was not required to attend for cross-examination.

39    Joint reports were prepared as follows:

(a)    a joint report of Mr Lau and Mr Vickers addressing eight questions, which largely focussed on issues of pharmaceutical formulation (the Lau/Vickers Joint Report); and

(b)    a joint report of Dr Martin and Mr Vickers addressing seven further questions (numbered 9 to 15), which covered issues relating to the administration of veterinary pharmaceuticals, in particular issues relating to the safety and efficacy of parasiticides (the Martin/Vickers Joint Report).

40    The hearing of the proceeding took place over five days. Due to the COVID-19 pandemic, days 3, 4 and 5 of the hearing took place using video-conferencing software (Microsoft Teams), with counsel and witnesses appearing remotely. While there were occasional issues with the quality of the audio, the overall quality of the video and audio was good, and the hearing was able to proceed in a satisfactory manner. The parties were given the opportunity to review the transcript and provided an agreed list of corrections. In a small number of cases, a party requested that I review the recording of the hearing to check the transcript. The transcript was subsequently amended and re-issued to incorporate the corrections arising from those processes.

41    The oral evidence at the hearing was structured as follows. On day 1, Mr Pippia gave evidence and was cross-examined. Mr Lau and Mr Vickers gave evidence concurrently on days 2 and 3 of the hearing. The subject matter of their evidence reflected the subject matter of their joint report, namely pharmaceutical formulation issues. Dr Martin and Mr Vickers gave evidence concurrently on day 4. Their evidence also dealt with the subject matter of their joint report, in particular issues relating to the safety and efficacy of parasiticides.

42    In the period between day 4 and day 5, the parties filed written outlines of closing submissions. (I note for completeness that the page and line references to the transcript in those documents are based on the transcript as originally issued, rather than the re-issued versions.) The parties’ counsel presented oral closing submissions on day 5.

The witnesses

43    The principal evidence led by Boehringer was that of Mr Lau and Dr Martin. The principal evidence led by Intervet was that of Mr Vickers. I will make some observations about the evidence of these witnesses, and then refer to the other witness who gave oral evidence, Mr Pippia.

Mr Lau

44    Mr Lau is a technical consultant at Woodlink Consulting Services Pty Ltd, which is his own consultancy business and provides consulting services to animal health companies in relation to quality systems and formulation development. Mr Lau has qualifications in science and more than 30 years’ experience in the field of pharmaceutical formulation, particularly the formulation and chemical and physical analysis of medicaments for animals.

45    Between 1985 and 1993, Mr Lau held positions as a research chemist, a quality control manager and senior formulation scientist as detailed in his affidavit dated 24 May 2019 (Mr Lau’s first affidavit).

46    In 1993, Mr Lau joined Jurox Pty Ltd (Jurox) in New South Wales, as a quality manager. In 2003, he became the Head of Chemistry at Jurox. He remained in that position until mid-December 2014. While at Jurox, he carried out and supervised the formulation and development of more than 30 veterinary products, including a number of injectable anthelmintic products. Mr Lau is a (or the) named inventor for about 16 patent applications or patents relating to his work at Jurox. From 2006 to 2008, Mr Lau was a PhD supervisor for the Department of Pharmacy of the University of Newcastle.

47    Mr Lau’s qualifications and experience, as detailed in his first affidavit, establish that (as stated in that affidavit) he has developed specialised knowledge in the field of pharmaceutical formulation, in particular the formulation and chemical and physical analysis of veterinary products.

48    In his oral evidence, Mr Lau demonstrated his deep expertise in matters of chemistry and the formulation aspects of the development of pharmaceutical products. Subject to the matters discussed below, I generally accept his evidence.

49    In some instances, Mr Lau made concessions during his oral evidence. This bolstered his credibility as a witness whose evidence was directed to assisting the Court. To the extent that there were differences between his oral and written evidence, I prefer his oral evidence.

50    Mr Lau quite properly acknowledged the limits of his expertise during his oral evidence. For example, when asked to comment on certain oral evidence given by Mr Vickers concerning the relative speed at which macrocyclic lactones and levamisole act on parasites, Mr Lau indicated that this was not his area of expertise. Later in his oral evidence, he confirmed that issues of efficacy were outside his expertise.

51    In matters of formulation chemistry, Mr Lau has a greater level of expertise than Mr Vickers. I do not consider this to be controversial; I took Mr Vickers to accept that to be the case. Accordingly, to the extent that there were differences between Mr Lau and Mr Vickers regarding matters of formulation chemistry, I prefer the evidence of Mr Lau.

Dr Martin

52    Dr Martin is the director of PJM Scientific Pty Ltd, which is his own consultancy firm providing services to the Australian and New Zealand animal health industries. He has qualifications in science and more than 25 years’ experience in the field of animal health research and product development, including parasitology and the development of parasiticides for animals.

53    In 1968, Dr Martin began working as a lab technician with the Commonwealth Scientific and Industrial Research Organisation (CSIRO). In 1979, he completed a Bachelor of Science with Honours at the University of New England. Dr Martin worked as an experimental scientist and subsequently as a senior research scientist at CSIRO. Between 1983 and 1989, he undertook a PhD at the University of Melbourne. This focussed on understanding the genetics and population biology of parasite populations and their ability to become resistant to treatment.

54    In 1991, Dr Martin commenced employment at Pitman-Moore Australia Limited (later Mallinckrodt Veterinary Limited) as a senior research and development scientist. He progressed to the position of Product Development Manager (Australia and New Zealand).

55    In 1995, Dr Martin commenced employment as Director of Research and Development at Virbac (Australia) Pty Ltd (Virbac). In this role, he was involved in the formulation, chemistry, registration, clinical studies and quality control of products, as well as the development of parasiticides, antibiotics, dermatological products and vaccines for agricultural and companion animals. His responsibilities included oversight of the Research and Development teams in both Australia and New Zealand.

56    Virbac is part of a multinational group of companies. At Virbac, the development of large animal parasiticide products took place in Australia. Much of Dr Martin’s work at Virbac was on the development of products for cattle.

57    Dr Martin left Virbac in 2008 to start his own consultancy firm, PJM Scientific. PJM Scientific provides consulting services in relation to animal health research and development, product registrations, project management, animal parasitology, expert scientific writing, education and training. His work at PJM Scientific is focussed on the design and stability testing, as well as safety and efficacy testing, of products that his clients intend to have registered and put on the market.

58    In addition to authoring or co-authoring a large number of peer-reviewed journal articles, Dr Martin is named as an inventor in a number of patent applications and patents relating to parasitic treatment of animals.

59    Dr Martin’s qualifications and experience, as detailed in his affidavit dated 24 May 2019 (Dr Martin’s first affidavit), establish that he has developed specialised knowledge in the field of parasitology and the development of parasiticides for animals.

60    In his oral evidence, Dr Martin demonstrated his expertise in the matters about which he gave evidence. There were no substantial points of disagreement between Dr Martin and Mr Vickers, and I generally accept Dr Martin’s evidence.

Mr Vickers

61    Mr Vickers is the Managing Director of Seacrest Farms Limited, a New Zealand company. In this position, he works as a regulatory and product development consultant for a range of clients in veterinary medicines, in particular anthelmintics. His role includes the registering of animal health products in Australia and New Zealand, the on-farm investigation of adverse effects of registered products, including anthelmintics, and the management and development of new products, including veterinary anthelmintic products in the Australian and New Zealand markets.

62    Mr Vickers obtained a Bachelor of Veterinary Science in 1979 from Massey University in New Zealand. From 1979 to 1990, he worked as a Veterinary Investigation Officer within the Animal Health Laboratory network of the Ministry of Agriculture and Fisheries in New Zealand. Mr Vickers states in his affidavit, and I accept, that the New Zealand and Australian animal health laboratories worked closely together, including holding joint workshops, exchanging newsletters and sometimes staff to facilitate staff development and ongoing training, and to facilitate a greater trans-Tasman/Australasian understanding of disease and disease trends.

63    Mr Vickers states in his affidavit, and I accept, that in his role as a Veterinary Investigation Officer he was trained (including ongoing internal training) across all laboratory disciplines, including gross and microscopic pathology, chemistry and toxicology, biochemistry, haematology, virology and serology and parasitology, and in the on-farm investigation of diseases.

64    From 1990 to 1994, Mr Vickers was a consultant with Ruakura Animal Health Laboratory.

65    From 1994 to 1997, Mr Vickers held the position of Australasian Regulatory Affairs, Research and Development Manager with Bomac Laboratories Ltd (Bomac), a pharmaceutical company. At this time, two New Zealand companies – Bomac and Ancare Limited – emerged as large players within both the New Zealand and the Australian animal health markets; they also marketed their products internationally. Mr Vickers was based at Bomac’s manufacturing site in South Auckland, and had direct contact with those in production, as well as formulation and analytical chemists. Mr Vickers personally supervised the development of a range of products, including skin, nutritional, metabolic, antibiotic and anti-parasitic preparations for a range of animal species, including managing clinical trials conducted both in Australia and New Zealand.

66    From 1997 to 2001, Mr Vickers held the position of Australasian Regulatory Affairs and Development Manager with Nufarm Limited/Captec, located at the Nufarm manufacturing site in South Auckland. Mr Vickers’s role included, initially, the marketing and technical support of the sales staff for anthelmintic products, both in Australia and New Zealand. In his development role, he chaired the development meetings and was responsible for overseeing the entire development process, with formulation chemists, analytical chemists, product staff and regulatory affairs staff reporting directly to him. Mr Vickers routinely travelled to Australia around six times per year, often one to two weeks at a time. This included meeting with various business and technical staff in relation to the product development and trials.

67    Between 2001 and 2003, Mr Vickers was the Project Manager for Veterinary Medicines and Animal Health at AgriQuality, a State-owned enterprise, and also the national Manager of the animal health laboratories for AgriQuality. His role included responsibility for over 60 laboratory staff, including parasitology staff.

68    In 2003, Mr Vickers established his consultancy company, Seacrest. In this role, he acts as an independent consultant, working with a number of national and international clients to evaluate new products in animal health, pest control and environmental products. This work continues to the present day.

69    Between 2008 and 2009, in addition to performing his role at Seacrest, Mr Vickers was employed as the Quality Assurance Manager of Alpha Laboratories (NZ) Limited (Alpha), a large contract manufacturing company of human health products/complementary medicines. Its product range spanned animal, plant, bee and marine products. Mr Vickers’s role included management of both Quality Assurance and Quality Control aspects, as well as overseeing areas including Australian and New Zealand regulatory affairs, formulation, production and technical staff. His role included developing new products and manufacturing processes and maintaining commercial relationships in Australia and New Zealand. From 2009 to 2010, Mr Vickers was the Technical and Regulatory Affairs, New Product Development Manager for Alpha. In this role, his focus was on the formulation, production and regulatory affairs of new products, including overseeing 10 to 12 technical staff.

70    During the period of time up to and including June 2010, a focus of Mr Vickers’s consulting work for Seacrest was investigating the benefit of combining levamisole and macrocyclic lactones in cattle, and in developing a formulation of combination injectable anthelmintics, particularly combinations of levamisole phosphate and ivermectin or abamectin.

71    Mr Vickers is named as an inventor for a number of patents and patent applications, including patents and patent applications relating to anthelmintics.

72    Over the course of Mr Vickers’s career, including as set out above, he had worked in Australia and New Zealand and with organisations and regulatory bodies in Australia, New Zealand and other countries around the world. Based on his experience in interacting with colleagues in Australia, he considered that what was known in the field in New Zealand as at June 2010 was also known in Australia at that time. International journals, particularly veterinary journals, often contained articles on, and also product advertisements, that related to anthelmintic products. There was also movement of veterinarians in practice between the USA, UK, Australia and New Zealand.

73    Subject to what I say below, I accept that, as a result of his training, study and experience, Mr Vickers has developed specialised knowledge of:

(a)    the interpretation of laboratory results including pathology and parasitology results and a knowledge of various disease control programs;

(b)    veterinary pharmaceuticals, and the development and manufacture of such pharmaceuticals (including antibiotics and anti-parasitic preparations) for a variety of animal species;

(c)    designing, planning and conducting farm trials;

(d)    formulation, production (manufacture) and regulatory affairs in Australia and New Zealand of new veterinary pharmaceutical products;

(e)    the benefits of combining levamisole and macrocyclic lactones in agricultural animals such as cattle and sheep, and in developing a formulation of combination injectable anthelmintics; and

(f)    common parasites, their effects on agricultural production animals and the resistance prevalent in these parasites.

74    During his oral evidence, Mr Vickers accepted that he had never been a formulation chemist. He said that, while he might have input into formulations, and might also have evaluated formulations, he did not do the day-to-day formulating. Mr Vickers accepted that Mr Lau had done more formulation chemistry work than him. In response to a question as to how he would describe himself, if not a formulation chemist, Mr Vickers said that product development manager or regulatory affairs were the areas in which he worked.

75    In the Lau/Vickers Joint Report, Mr Vickers referred to US patent 4096271 to support his view that the levamisole HCl in Example 3 of CN 291 existed as a solution. However, in oral evidence he accepted that the patent was teaching that it was a levamisole base and other bases of formula 1 that were soluble in the benzyl benzoate solvent, and that the corresponding salts, including levamisole HCl, were not soluble because they would precipitate out. This portion of the oral evidence tends to support the approach that I am taking, that is, to prefer the evidence of Mr Lau on matters of formulation chemistry.

76    Notwithstanding the preceding paragraph, Mr Vickers impressed me as having considerable knowledge and experience in relation to the development of veterinary pharmaceutical products, in particular in relation to safety and efficacy issues. Thus, while I prefer Mr Lau’s evidence in relation to matters of formulation chemistry, I otherwise generally accept Mr Vickers’s evidence. To the extent that there were differences between Mr Vickers’s written and oral evidence, I prefer his oral evidence.

Mr Pippia

77    Mr Pippia is the Managing Director of Pia Pharma Pty Ltd, which provides analytical, manufacturing, regulatory and consulting services to the pharmaceutical, animal health and agrochemical industries. He has 28 years’ experience in laboratory-based research and analysis of veterinary pharmaceutical products. Mr Pippia’s qualifications and experience are set out at [7]-[17] of his affidavit. I accept that he has expertise in relation to the analytical and formulation aspects of the development of veterinary pharmaceuticals.

78    Mr Pippia’s evidence concerned the design, conduct and results of a study that he undertook to prepare and determine the properties of the formulation described in Example 3 in CN 291. I accept Mr Pippia’s evidence.

The lack of novelty ground

The issue

79    Boehringer contends that the alleged invention claimed in each of claims 1, 2, 4, 5, 6, 7, 12, 13 and 15 of the Patent Application is not novel in the light of CN 291, being a Chinese patent application. This ground is set out in grounds 2 and 3 of Boehringer’s amended notice of appeal:

2.    The Delegate erred in finding that the invention as claimed in the [Patent] Application is a patentable invention within the meaning of s 18(1)(b)(i) of the Act and that the alleged invention was novel in light of [CN 291] as published on 23 October 2002.

3.    In making the finding referred to in paragraph 2 above, the Delegate erred in:

(a)    finding that [CN 291] does not provide clear and unmistakable directions to use levamisole in a range of 10-25% (w/v) ([78] to [81] of the Decision); and

(b)     further or in the alternative, finding that the range of 10-35% levamisole as claimed in claim 1 of [CN 291] was not arbitrary ([57] and [78] of the Decision).

80    In brief summary, Boehringer submits that Example 3 of CN 291 discloses a formulation with macrocyclic lactone in solution and levamisole HCl in particulate form. Boehringer submits that, although Example 3 does not describe the levamisole HCl as being in particulate form (or in a suspension), the experimental evidence of Mr Lau and Mr Pippia, which is consistent with Mr Lau’s understanding, based on his common general knowledge, demonstrates that the levamisole HCl is in particulate form in a suspension. Accordingly, Boehringer submits, CN 291 anticipates at least claim 1 of the Patent Application. Boehringer also submits that a number of the other claims are anticipated by CN 291.

Applicable principles

81    Section 18(1)(b)(i) of the Patents Act requires that an invention be novel when compared with the prior art base as it existed before the priority date of each claim. Novelty is to be assessed in accordance with s 7(1) of the Act, which provides that an invention is to be taken to be novel when compared with the prior art base unless it is not novel in the light of any one of the kinds of information identified in s 7(1). Relevantly, these include information made publicly available in a single document.

82    The principles for the assessment of novelty are well established. The key decisions include: Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513, Bristol-Myers Squibb Co v FH Faulding & Co Ltd (2000) 97 FCR 524 (Bristol-Myers), H Lundbeck A/S v Alphapharm Pty Ltd (2009) 177 FCR 151 (Lundbeck) and AstraZeneca AB v Apotex Pty Ltd (2014) 226 FCR 324 (AstraZeneca FC).

83    In Lundbeck, Bennett J (with whom Middleton J agreed) set out, at [173], a series of general propositions relating to novelty that emerge from the cases, including:

•    Commonly the only question may be whether the prior publication describes the claimed invention with sufficient clarity (Bristol-Myers 97 FCR 524 at [67]).

•    The disclosure is assessed by reference to the skilled addressee, a person of ordinary skill in the art.

•    The question is whether the prior publication is sufficient to make the claimed invention apparent to the skilled addressee (Nicaro Holdings Pty Ltd v Martin Engineering Company (1990) 91 ALR 513 at 529).

•    A prior publication does not invalidate a patent unless it supplies sufficient information to enable a person of ordinary skill to produce the product subsequently claimed (Acme Bedstead Company Ltd v Newlands Brothers Ltd (1937) 58 CLR 689 at 707). A specification is not to be read as in a vacuum but by the reader having at least the common knowledge of the art (Acme Bedstead 58 CLR at 701; Nicaro 91 ALR at 530).

•    The requirement is that a person of ordinary knowledge of the relevant subject would be able practically to apply the prior published discovery without the necessity of making further experiments (Hill v Evans 1A IPR at 6-7).

•    The further experiments do not include those that formed part of standard procedure or common general knowledge. They are experiments with a view to discovering something not disclosed (Van der Lely 1A IPR at 90).

•    The further experiments do not mean ordinary methods of trial and error (Van der Lely 1A IPR at 90).

…

•    Something less than a full description of the invention allegedly anticipated may be sufficient to invalidate it for want of novelty (Nicaro 91 ALR at 529).

…

•    A direction, recommendation or suggestion may be implicit in what is described (Bristol-Myers 97 FCR 524 at [67]).

•    A disclosure that describes an effective means by which a claimed invention may be produced falls short of anticipation if it requires the exercise of inventive ingenuity or the taking of any inventive steps (Nicaro 91 ALR at 531).

84    Further, at [181], Bennett J stated:

If the prior art discloses some but not all integers of a claimed patent to a product, such as a combination, there is anticipation if the skilled addressee would add the missing information as a matter of course and without the application of inventive ingenuity or undue experimentation (Nicaro 91 ALR at 530-531).

85    In AstraZeneca FC, Besanko, Foster, Nicholas and Yates JJ stated at [293] that the touchstone for determining whether a prior publication, such as the patent relied on in that case, anticipates a claimed invention, was stated in General Tire & Rubber Company v Firestone Tyre & Rubber Company Ltd (1971) 1A IPR 121 (General Tire) at 138 as follows:

When the prior inventor’s publication and the patentee’s claim have respectively been construed by the Court in the light of all properly admissible evidence … the question whether the patentee’s claim is new … falls to be decided as a question of fact. If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publications will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated.

If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee’s claim, but would be at least as likely to be carried out in a way which would not do so, the patentee’s claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee’s claim the prior publication must contain clear and unmistakable directions to do what the patentee claims to have invented … [a] signpost, however clear, upon the road to the patentee’s invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee.

86    After setting out that passage, Besanko, Foster, Nicholas and Yates JJ continued:

294    The metaphor of planting the flag has been taken up in this Court. For example, in ICI Chemicals, the Full Court at [51], after noting the metaphor, remarked that, in that case, the appellant’s argument involved the skilled addressee rummaging through a “flag locker” to find a flag which the prior art document possessed and could have planted. In Apotex Pty Ltd v Sanofi-Aventis (2008) 78 IPR 485 (Sanofi-Aventis (2008)), Gyles J at [91] adopted a different metaphor, remarking that “[a]nticipation is deadly but requires the accuracy of a sniper, not the firing of a 12 gauge shotgun”. Each metaphor underlines the importance of the specificity required in order for a prior art document to anticipate an invention as claimed.

…

298    Here, relying only on the disclosures of the 471 patent, and not imputed common general knowledge concerning the administration of prior art statins, the person skilled in the art might seek to use one or any number of different dosages and dosage regimens for administering a pharmaceutical composition containing either the sodium salt or the calcium salt of rosuvastatin to treat hypercholesterolemia. It is possible that, out of a very large number of possibilities, the person skilled in the art might, based only on the disclosures of the 471 patent, use the dosage and dosage regimen of claim 1 or claim 2 of the 051 or low dose patent. But it is at least equally possible that such a dosage and dosage regimen might not be used. It cannot be said, therefore, that, by following the directions — such as they are — in the 471 patent, the person skilled in the art would inevitably do something that would inevitably infringe either claim 1 or claim 2 of the 051 or low dose patent.

299    It is here that the true setting for using the notion of reverse infringement in assessing anticipatory disclosure must be recognised. In Meyers Taylor Pty Ltd v Vicarr Industries Ltd (1977) 137 CLR 228 Aickin J (at 235) said:

The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement.

300    But it is important to note that the reverse infringement test is not applied by simply asking whether something within the prior art document would, if carried out after the grant of the patent, infringe the invention as claimed. In Flour Oxidizing Company Ltd v Carr & Company Ltd (1908) 25 RPC 428, Parker J (at 457) observed:

… where the question is solely a question of prior publication, it is not, in my opinion, enough to prove that an apparatus described in an earlier Specification could have been used to produce this or that result. It must also be shown that the Specification contains clear and unmistakable directions so to use it.

301    These observations are the wellspring of a long line of cases that recognise that, in order for a prior art document to be anticipatory, there must be (to adopt the language in General Tire) a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent. In Bristol-Myers Squibb Company v FH Faulding & Company Ltd (2000) 97 FCR 524 (Bristol-Myers), Black CJ and Lehane J reviewed the relevant authorities and concluded (at [67]):

What all of those authorities contemplate, in our view, is that a prior publication, if it is to destroy novelty, must give a direction or make a recommendation or suggestion which will result, if the skilled reader follows it, in the claimed invention. A direction, recommendation or suggestion may often, of course, be implicit in what is described and commonly the only question may be whether the publication describes with sufficient clarity the claimed invention or, in the case of a combination, each integer of it. But in this case medical practitioners hardly needed to be told that it was possible to infuse a particular dose of taxol over three hours, or how to do it. Nor, equally obviously, is that the point of the claims. The claims of the earlier of the petty patents are for a method for administration of taxol to a patient suffering from cancer; the claims of the later one are for a method of treating cancer. In each case the method involves a particular regimen for the infusion of taxol. The context was that great difficulties had been encountered in using taxol, despite its known anti-carcinogenic properties, in the treatment of cancer, because of the drug’s side effects. Each of the trials reported in the articles referred to was an investigation directed towards finding a solution of the difficulties: directed, particularly, to ascertaining safe dosage levels. But, though methods falling within the claims of the patents were used in each trial, none of the reports can be said to teach (a word which in this context encompasses direct, recommend and suggest) that which the petty patents claim.

302    Sufficiency of disclosure is a cardinal anterior requirement in the analysis of whether a prior art document anticipates a claimed invention. It is only after the stage of assessing the sufficiency of disclosure — which involves a determination about whether a prior document has “planted the flag” as opposed to having provided merely “a signpost, however clear, upon the road” or, perhaps, something less — that the notion of reverse infringement comes into play as the final and resolving step of the required analysis. It is not the first step of the required analysis; nor is it the only step.

87    See also the discussion of the principles in AstraZeneca FC at [345]-[352].

The person skilled in the art

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.

CN 291

89    No issue has been raised as to the publication and public availability of CN 291 before the priority date. Further, Intervet admits that the English translation in the Court Book is accurate.

90    CN 291 is a patent application published on 23 October 2002 for an invention titled “Veterinary Compound Injection Containing Levamisole or Salts thereof”. The abstract set out on the first page is as follows:

The present invention relates to a veterinary compound injection containing levamisole or salts thereof, which comprises the following formula components: 1-25% (W/V) of levamisole or salts thereof and 0.1-20% (W/V) of other anthelmintic. The compound preparation has the following prominent features: 1) the compound preparation has a remarkable synergistic action of repelling and killing nematodes in bodies of pigs, cattle and sheep, and can repel ectozoic parasites, therefore expanding the parasite controlling spectrum and overcoming the defect that levamisole cannot repel and kill ectozoic parasites; 2) the compound injection is extremely effective to nematodes which have single drug-resistance; 3) a compound oil injection has both quick-acting and long-acting efficacies, is good in absorbability and small in irritation, and is a very excellent injection.

I note that the last part of the above passage refers to a “compound oil injection”. Of the three examples set out later in the patent application, only Example 3 has an oil component. It may be, therefore, that the last part of the abstract is referring to Example 3. Mr Vickers in oral evidence said that he thought this was the case.

91    The claims, which are set out on the next two pages of the application, are as follows:

1.    A veterinary compound injection containing levamisole or salts thereof, characterized in that the veterinary compound injection 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;

(d)    other adjuvants (such as suspending agent, surfactant and antioxidant) which can be added if necessary.

2.    The compound injection according to claim 1, characterized in that the dispersion media include water, vegetable oil, mineral oil or other organic liquid media; preferred organic media include ethanol, 1,2-propylene glycol, glycerol, isobutanol, isopropanol, polyethylene glycol, benzyl alcohol, glycerol formal, dimethylacetamide, benzyl benzoate, ethyl oleate, oleic acid, Miglyol 840 (dicaprylate/dicaprate of propylene glycol), sorbitan fatty acid esters, glyceryl dicaprylate/dicaprate, and pentaerythritol dioleate; in a formula, two or more of the liquid dispersion media above can be combined to form composite media for use; the vegetable oil includes corn oil, peanut oil, soybean oil, castor oil, rapeseed oil, sesame oil, cottonseed oil, apricot kernel oil, peach kernel oil, coconut oil, tea-seed oil and olive oil; two or more of the vegetable oils added into the formula can be combined for use, and the vegetable oil can also be combined with other dispersion media to form a co-solvent for use; the suspending agent added if necessary is medicinal suspending agent; preferred suspending agent includes xanthan gum, carboxymethyl cellulose (sodium), ethylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone, sodium alginate, aluminum stearate and hydrogenated vegetable oil; the surfactant added if necessary is medicinal surfactant, including anionic surfactant, cationic surfactant, non-ionic surfactant and ampholytic surfactant; preferred surfactant is non-ionic surfactant, including polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, alkylphenol ethoxylates, polyoxyethylene castor oil and ester compounds synthesized from glycerol. One kind of the surfactant can be used for forming the preparation, and two or more of the surfactants can also be mixed for use.

3.    The compound injection according to claim l, characterized in that preferred formula components include:

(a)    levamisole or hydrochloride thereof    10-20% (W/V);

(b)    abamectin or ivermectin                      0.5-2% (W/V);

(c)    dispersion media added to                   100% (V/V);

(d)    other adjuvants which can be added if necessary.

4.    The compound injection according to claim 3, characterized in that further preferred formula components include:

(a)    levamisole or hydrochloride thereof    10% (W/V);

(b)    abamectin or ivermectin                      1% (W/V);

(c)    1,2-propylene glycol                            50-80% (V/V);

(d)    glycerol formal                                    20-50% (V/V).

5.    The compound injection according to claim 3, characterized in that further preferred formula components include:

(a)    levamisole or hydrochloride thereof    12% (W/V);

(b)    abamectin or ivermectin                      1% (W/V);

(c)    dimethylacetamide                              10% (V/V);

(d)    Tween-80                                           10% (V/V);

(e)    1,2-propylene glycol                           20% (V/V);

(f)    water for injection                              added to 100% (V/V).

6.    The compound injection according to claims 4 and 5, characterized in that the injection is used for prevention and treatment of nematodes and ectozoic parasites in animal body, and is administered orally or by injection, with a dosage of 1-2ml per 20kg of weight for pigs, cattle or sheep.

92    I note that it is common ground that the reference to a “macrolide anthelmintic” in paragraph (b) of claim 1 is to a macrocyclic lactone.

93    The detailed description in the specification commences with a description of the properties of levamisole, followed by a description of macrolide anthelmintics (macrocyclic lactones). It is then stated (specification, page 1):

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.

94    The specification then sets out certain formula components and a description of the dispersion media. On page 2 of the specification, there is a table headed “Parasite controlling spectra of levamisole, ivermectin and compound preparations thereof”.

95    On page 3 of the specification, in a passage that corresponds with claim 3, it is stated:

Preferred formula components of the present invention include:

(a)    levamisole or hydrochloride thereof        10-20% (W/V);

(b)    abamectin or ivermectin                          0.5-2% (W/V);

(c)    dispersion media added to 100% (V/V);

(d)    other adjuvants which can be added if necessary.

96    On pages 4 and 5, three examples are set out. Boehringer relies on Example 3, which 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)

97    It is convenient to note at this point that, while the concentration of levamisole HCl in Example 3 is 5% w/v, the concentration of levamisole salt in claim 1 in the Patent Application is in the range 10-35% w/v. Thus, on its face, Example 3 does not fall within claim 1 of the Patent Application.

98    In oral evidence, Mr Lau accepted that CN 291 makes no reference to chemical degradation issues between levamisole and macrocyclic lactones. He also accepted that CN 291 makes no mention of the issue of stability or of stability tests having been conducted.

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.

100    Thus Mr Lau conceded in oral evidence that, if he had been given the task of formulating a combination injectable comprising a combination of a macrocyclic lactone and levamisole, CN 291 would not have provided him with assistance.

The experimental evidence

101    Mr Lau was asked to design and conduct experiments to demonstrate how he would prepare an injectable combination formulation containing a macrocyclic lactone and levamisole based on:

(a)    Example 3 in CN 291, assuming he had been directed to include levamisole HCl at 15% w/v and ivermectin at 0.4% w/v (Formulation 1); and

(b)    Mr Lau’s optimised version of Example 3 of CN 291, following the approach described in his first affidavit at [114]-[118], also assuming he had been directed to include levamisole HCl at 15% w/v and ivermectin at 0.4% w/v (Formulation 2).

102    In each case he was instructed to use only his knowledge as at June 2010.

103    The concentrations of levamisole HCl and ivermectin that Mr Lau was instructed to incorporate in his experiments reflected the adjustments that Dr Martin would have made to the concentrations of each active ingredient in Example 3 of CN 291 in order to produce a formulation with an effective dose of each active ingredient for cattle (see below).

104    The final experimental protocol for Mr Lau’s experiments, a copy of which was included in the Court Book, reflects the approach that Mr Lau would have taken based on the information in CN 291, in light of his knowledge before June 2010, having regard to the instructions given to him.

105    The Experimental Protocol describes:

(a)    Mr Lau’s preparation of Formulations 1 and 2 at bench scale (referred to in Mr Lau’s first affidavit as Experiments 1 and 4, respectively);

(b)    Mr Lau’s pre-formulation tests for Formulation 2, which involved:

(i)    determining the solubility of levamisole HCl in medium chain triglycerides (MCTs) (referred to in Mr Lau’s first affidavit as Experiment 2); and

(ii)    determining a suitable matrix of MCTs and aluminium stearate (referred to in Mr Lau’s first affidavit as Experiment 3); and

(c)    the stability tests conducted on Formulations 1 and 2 over a three month period, as well as the conditions under which samples of Formulations 1 and 2 were stored.

106    Experiments 1 to 4, which include the making of Formulations 1 and 2, took place on 4 and 5 April 2019. The experiments are described in Mr Lau’s first affidavit. In relation to Experiment 1 (Formulation 1), the steps taken by Mr Lau were described at [153] of his first affidavit:

(a)    I weighed out 4.4046 grams of ivermectin on an analytical balance using a weighing dish. I tared a 600 mL beaker on the balance and transferred the sample of ivermectin into that beaker. 4.3947 grams of the ivermectin was transferred into the beaker.

(b)    I measured out 100 mL of benzyl alcohol using a measuring cylinder, ensuring that the bottom of the meniscus was at the 100 mL mark. I waited until the bubbles reached the surface and left the solution before I measured the meniscus. I transferred the benzyl alcohol into the beaker containing the ivermectin. I placed the beaker onto a magnetic stirrer plate. I added a magnetic stirrer bar, and began stirring the mixture until the ivermectin dissolved.

(c)    I measured out 400 mL of benzyl benzoate using a measuring cylinder, waiting until the bubbles reached the surface and left the solution before I measured the meniscus. I poured the benzyl benzoate into the ivermectin-benzyl alcohol solution while the mixture was being stirred.

(d)    I weighed out 150.6 grams of levamisole HCl and transferred it into the precalibrated 2 L beaker. In transferring the levamisole HCl, I dropped an insignificant amount on the analytical scale (I estimated would have been less than 0.5 grams, and so less than 0.5% of the overall levamisole HCl content), I do not consider the small amount would have reduced the amount of levamisole HCl present in any meaningful way.

(e)    I measured out 300 mL of soybean oil using a measuring cylinder. I waited until the bubbles reached the surface and left the solution before I measured the meniscus. I poured the soybean oil into the pre-calibrated 2 L beaker containing the levamisole HCl.

(f)    I mixed the soybean oil-levamisole HCl solution using an IKA homogenizer, in order to break up any agglomerated particles of levamisole HCl and to produce a uniform suspension. I inserted an electronic thermometer into the formulation so that I could measure the temperature and ensure that it did not increase above 35°C during homogenisation. I chose 35°C as the limit of an acceptable temperature rise, because ivermectin is not stable at high temperatures.

(g)    As the blade was stirring, I used a spatula to ensure that the soybean oil could reach any compacted levamisole HCl and incorporate it into the suspension. I also occasionally moved the beaker around on the homogeniser base to ensure that the homogeniser blade was reaching all of the levamisole HCl.

(h)    I began homogenising the dispersion at 9:33am, and stopped homogenising the dispersion at 9:42am. I set the homogeniser at a speed of 11,440 RPM, which I considered to be sufficient to homogenise the dispersion without generating excessive heat. At the end of the homogenising period, the temperature of the dispersion was 30.4°C.

(i)    Once I was satisfied that all of the levamisole HCl was uniformly dispersed, I added the ivermectin-benzyl alcohol-benzyl benzoate solution into the levamisole HCl suspension. I made the formulation up to volume with more soybean oil, until the meniscus of the formulation was at the mark.

(j)    I strapped the 2 L beaker back into the homogeniser. I inserted an electronic thermometer into the formulation so that I could measure the temperature and ensure that it did not increase above 35°C.

(k)    I set the homogeniser at a speed of 14,000 RPM, which I considered to be sufficient to homogenise the dispersion without generating excessive heat. I began homogenising at 10:55am, and stopped the homogeniser at 11:06am. During this time, the temperature did not reach or exceed 35°C. At this stage, the formulation appeared as a smooth, white suspension.

(l)    I unstrapped the 2 L beaker from the homogeniser. I moved the beaker of Formulation 1 to the side, and placed foil over the top to prevent any contamination or evaporation whilst I ran other experiments.

(m)    I washed the homogeniser in MCT, in preparation for its use in preparing Formulation 2.

107    As noted above, Experiment 4 (Formulation 2) involved Mr Lau following the approach described in [114]-[118] of his first affidavit. In those paragraphs he explained that, in order to formulate the combination injectable using the information contained in Example 3 of CN 291, he would optimise the formulation by swapping out the soybean oil and benzyl benzoate for MCT (for the reasons given in his affidavit). He stated that he would also swap the benzyl benzoate for more MCT because he was more familiar with the use of MCTs in injectable products than benzyl benzoate. Mr Lau stated that he would also add a suspending agent to a sample of MCT, to create a matrix that had a viscosity suitable for the suspended levamisole HCl (it being Mr Lau’s expectation that the levamisole HCl would be present in suspension). He stated that he would run some preliminary tests to confirm his expectation that the levamisole HCl would be present in suspension. Mr Lau summarised the steps he would take at [118] of his first affidavit:

 (a)    I would begin by dissolving the ivermectin in benzyl alcohol.

 (b)    I would sterilise the solution through a 0.22 micron filter.

(c)    In a separate vessel, I would make up a matrix using pre-sterilised suspending agent and some of the MCT, which I would have pre-sterilised. The amount of suspending agent I would use would be dictated by the preliminary tests I describe in paragraph 117 above.

(d)    I would mix pre-sterilised, micronised levamisole HCl with the MCT-suspending agent matrix.

(e)    I could either purchase pre-micronised levamisole HCl, or I could micronise sterilised levamisole HCl in some MCT using a ball mill. If I were micronising the levamisole HCl myself, I would run some preliminary validation tests to determine the duration and speed at which the levamisole HCl would need to be milled for a given canister with a given number of balls. If I were using pre-micronised levamisole HCl, I would homogenise the levamisole HCl-MCT suspension in order to break up and disperse any agglomerated particles.

(f)    I would add the ivermectin solution to the levamisole HCl suspension, and top it up with the remaining sterilised MCT.

(g)    Unlike the Example 1 formulation, in relation to the Example 3 formulation I would not add a preservative, because benzyl alcohol is a very good preservative and fulfils that role. I also would not add a buffer, given that the formulation is non-aqueous.

(h)    I would homogenise the formulation as a final step in order to break up and disperse any agglomerated particles, and to evenly disperse the suspension.

108    Later in his first affidavit, at [158], Mr Lau described the steps he undertook in conducting Experiment 4 (Formulation 2).

109    Stability tests were carried out on the following dates: 5 April, 6 May, 5 June and 3 July 2019.

110    The results of the stability tests (contained in Mr Lau’s second affidavit) can be summarised as follows:

(a)    in both Formulations 1 and 2, the levamisole HCl was present in suspension in particulate form;

(b)    the experimental results confirmed Mr Lau’s expectation that the formulation set out in Example 3 of CN 291 contained levamisole HCl in particulate form;

(c)    the experimental results confirmed the validity of Mr Lau’s approach of optimising Example 3 of CN 291, to produce Formulation 2; and

(d)    Formulations 1 and 2 fell within the scope of claim 1 of the Patent Application.

111    In addition to the experiments conducted by Mr Lau, Boehringer relies on experiments conducted by Mr Pippia for the purposes of the opposition proceeding below. This evidence did not originally form part of Boehringer’s evidence-in-chief. However, after the filing of Mr Vickers’s affidavit, Boehringer sought and was granted leave to rely on evidence of the experiments conducted by Mr Pippia in the opposition proceeding. Boehringer then filed Mr Pippia’s affidavit, which set out details of his earlier experiments.

112    As explained in Mr Pippia’s affidavit, the goal of the study he undertook was to determine whether the anthelmintic formulation referred to Example 3 in CN 291 was a solution formulation or whether it contained solid (that is, particulate) matter. If the formulation contained particulate matter, an additional goal was to determine whether the ivermectin and levamisole HCl were present in the liquid and/or solid fractions.

113    The study involved the preparation, in duplicate batches, of the formulation described in Example 3 of CN 291 (with the same concentrations as specified in the example). The method was described in Mr Pippia’s affidavit at [25]:

Each of the two batches was to be prepared by combining benzyl alcohol and benzyl benzoate by stirring, then adding ivermectin to the solvents and mixing by stirring for 30 minutes, then adding levamisole HCl and mixing by stirring for 30 minutes, then adding the soybean oil and mixing by stirring for 40 minutes. The appearance of the batches was to be assessed by visual observation (e.g. whether a solution resulted or whether solid material was present). In the event that solid material was present following the addition of soybean oil and stirring for 40 minutes, the batches were then to be heated at 40°C for 30 minutes with stirring, to encourage dissolution of the solid, and the appearance of the formulation then assessed again.

114    The results of the study are set out in Mr Pippia’s affidavit. In summary, Mr Pippia’s formulations comprised a combination of the two active ingredients in which the ivermectin was present in solution and the levamisole HCl was present in particulate form.

115    During cross-examination, Mr Pippia was asked whether he made a decision about the particular steps he undertook to make the formulation (given that Example 3 does not set out any manufacturing steps). Mr Pippia said that he was provided with instructions as to the steps to undertake. He accepted that he did not turn his mind to what steps he could have taken to try to dissolve the levamisole HCl within something having the components listed in Example 3. Mr Pippia accepted that one option that he could have tried, consistently with the information presented in Example 3, would have been to dissolve the levamisole HCl in the benzyl benzoate by itself.

116    In relation to the experiments conducted by Mr Lau and Mr Pippia, Mr Vickers stated in the Lau/Vickers Joint Report that he agreed that the experiments produced formulations that had levamisole HCl in particulate form. Mr Vickers considered that this outcome was because of the manufacturing processes used by Mr Lau and Mr Pippia.

117    I accept, on the basis of the evidence set out above, that the experiments conducted by Mr Lau and the experiments conducted by Mr Pippia produced formulations that had the levamisole HCl in particulate form. However, I note that the manufacturing steps adopted by Mr Lau and Mr Pippia were not set out in Example 3, which has no manufacturing steps.

Adjusting the concentrations in Example 3 of CN 291

118    As noted above, Example 3 of CN 291 specifies a concentration of levamisole HCl of 5% w/v. The evidence of both Dr Martin and Mr Vickers is that that is too low a dose rate to be effective.

119    In the Martin/Vickers Joint Report, Dr Martin and Mr Vickers agreed that calculations could be made to correct the concentration of the active ingredients in Example 3 of CN 291 to reflect currently known dose rates. Dr Martin’s evidence was that he would increase the concentration of levamisole HCl from 5% or 15% and reduce the concentration of ivermectin from 0.5% to 0.4%, to achieve an appropriate dose rate and ratio as between the two active ingredients. These adjusted concentrations of the active ingredients were the ones used by Mr Lau in his experiments, described above.

120    Mr Vickers’s view was that, while it would be possible to calculate hypothetical levels of a macrocyclic lactone and levamisole HCl for such a formulation based on known formulation types, as the formulation type was unknown it would be necessary to prove the dose rates by way of dose confirmation (dose titration) studies. In oral evidence, he accepted that this was a conventional technique for identifying or confirming an appropriate dose when looking at a new formulation.

Consideration

121    Having regard to the principles discussed in AstraZeneca FC as set out above, the issue to be determined may be stated as: whether CN 291, in particular Example 3, contains a clear description of, or clear instructions to do or make, something that would infringe claim 1 of the Patent Application if carried out after the grant of the application, picking up the words of General Tire quoted above. Alternatively, again picking up the words of General Tire, if carrying out the directions contained in CN 291 (in particular Example 3) will inevitably result in something being made or done which, if the application were granted, would constitute an infringement of claim 1, this will demonstrate that the claim has been anticipated.

122    Boehringer submits that:

(a)    CN 291 discloses an injectable composition containing levamisole, or levamisole salt, and a macrocyclic lactone in a dispersion media or carrier.

(b)    In particular, CN 291 discloses formulations containing 1-25% w/v levamisole or levamisole salt, 0.1-10% w/v macrolide anthelmintic (that is, a macrocyclic lactone), a balance of dispersion media (that is, carrier or solvent) and other adjuvants as necessary. CN 291 discloses that, preferably, the formulation comprises levamisole or levamisole HCl in an amount of 10-20% w/v, and abamectin or ivermectin in an amount of 0.5-2% w/v.

(c)    Claim 2 of CN 291 discloses injectable formulations of a macrocyclic lactone and levamisole, including in non-aqueous solvent systems comprising oil and an organic solvent. Claim 3 is to 10-20% w/v levamisole or levamisole HCl and 0.5-2% w/v abamectin or ivermectin.

(d)    Example 3 of CN 291 discloses an oil based formulation with 5% w/v levamisole HCl, 0.5% w/v ivermectin, 10% v/v benzyl alcohol, 40% v/v benzyl benzoate and soybean oil to 100%. Mr Lau’s evidence is that the ivermectin (a macrocyclic lactone) would be present in solution, and the levamisole HCl would be present in suspension.

(e)    The oil injection disclosed in Example 3 is also described in the Abstract in the following terms: “has both quick acting and long acting efficacies, is good in absorbability and small in irritation, and is a very excellent injection”. The expert evidence is that this refers to the formulation in Example 3.

(f)    Example 3 of CN 291 is to be read in conjunction with claim 3 of CN 291, which discloses levamisole HCl in the amount of 10-20% w/v, and with page 3 of the specification, which discloses that preferably the levamisole HCl is present in the amount of 10-20% w/v. CN 291 teaches on page 4 of the specification that the formulations disclosed are administered by injection with a dosage of 1mL per 20 kg for pigs, cattle or sheep. A skilled person reading CN 291 as a whole would understand that CN 291 contained a direction, recommendation or suggestion to make the Example 3 formulation using 10-20% w/v levamisole HCl. Based on Dr Martin’s evidence, a skilled person would consider the 5% w/v concentration of levamisole HCl stated in Example 3 to be far too low for cattle, particularly in light of this teaching. Mr Vickers accepted that the preferred range of 10-20% w/v of levamisole HCl disclosed by CN 291 is one that “looks more right”.

(g)    This is consistent with the common general knowledge of the skilled person regarding the concentration of levamisole HCl in an injectable product for cattle, including a product comprising a combination of a macrocyclic lactone and levamisole salt. Having regard to the disclosure in CN 291 that the formulations are administered at a dose volume of 1 mL/20 kg, the skilled person would adjust the dose of levamisole HCl in Example 3 to give a concentration of 15% w/v for a product for cattle. (I interpolate that the dose volume disclosed on page 4 of CN 291 is in fact 1-2 mL/20 kg rather than 1 mL/20 kg.)

(h)    The skilled person would expect the levamisole HCl in Example 3 to be suspended in the solvent system and to be present in particulate form. This is because, reading CN 291 with their common general knowledge:

(i)    the skilled person would recognise that levamisole HCl is an ionic salt, and a highly polar ionic compound;

(ii)    the skilled person would recognise the solvent system comprising soybean oil, benzyl alcohol and benzyl benzoate, to be non-polar; and

(iii)    the skilled person would expect, based on these relative polarities, that levamisole HCl will not dissolve in the solvent system of Example 3.

(i)    The above matters are sufficient to anticipate at least claim 1 of the Patent Application. All of the integers of claim 1 are apparent to the skilled person from the disclosure of CN 291.

123    Boehringer submits that if there is any doubt in the skilled person’s mind that Example 3 of CN 291 discloses a formulation containing levamisole HCl in particulate form, the experiments undertaken by Mr Lau and Mr Pippia confirm the skilled person’s expectation that the levamisole HCl is present in particulate form.

124    In my view, Boehringer has not established that claim 1 of the Patent Application is anticipated by CN 291 (in particular, Example 3).

125    First, Boehringer’s lack of novelty case is based on combining an unexplained, generalised recommendation to use 10 to 20% levamisole or hydrochloride thereof that is located on page 3 (and also in claim 3) and using that to vary Example 3, which clearly, and inconsistently, specifies using 5% levamisole HCl. There is no sufficiently clear and unambiguous direction to modify Example 3 by applying the concentration level referred to on page 3 instead of the concentration level specified in Example 3.

126    CN 291 describes a broad range of potential formulations. Claims 1 to 4 are directed to formulations of levamisole, a macrocyclic lactone, and one or more dispersion media. “Dispersion media” is defined broadly in claim 2 and includes water, vegetable oil, mineral oil and other organic liquid media. Each of those latter three classes is extremely broad. Claim 2, moreover, lists 28 specific examples within the above classes. Claim 2 also explains that various combinations of dispersion media may be used.

127    It is in this context that there is disclosure of the use of 10 to 20% levamisole or hydrochloride thereof, both in claim 3 and on page 3 of the specification as part of the “[p]referred formula”. No explanation is given in CN 291 as to the reason for the generalised recommendation, or in what circumstances it would be appropriate to apply that recommendation. There is nothing in the generalised recommendation that clearly and unambiguously refers to Example 3. It follows that no reason is given as to why that recommendation should be read as relating to Example 3, which expressly – and inconsistently – requires the use of a lower percentage of levamisole HCl.

128    Secondly, Example 3 does not set out any manufacturing steps or any description of the formulation that is intended to be made. In particular, Example 3 of CN 291 does not describe the intended formulation as one in which the levamisole HCl is in particulate form.

129    Although Mr Lau’s written evidence was that he would understand or expect Example 3 to be a suspension formulation containing ivermectin in solution and levamisole HCl in particulate form in suspension, this was qualified to some extent in his oral evidence. Mr Lau was taken to parts of CN 291 that emphasise the desirability of having higher amounts of levamisole present, and Example 1, which has levamisole present at 12% w/v. In that context, the following exchange took place in relation to Example 3, which has levamisole HCl present at 5% w/v:

[COUNSEL FOR INTERVET]: So, here, when you see that they’ve only included it at a level of five per cent, that again is at least an indication that the authors may have been intending for this to be a solution formulation, rather than a suspension formulation; is that correct?

MR LAU: I think it could be both. It could be a suspension or solution.

I take that passage as indicating that, although Mr Lau’s understanding or expectation was that Example 3 would produce a formulation in which the levamisole HCl was in particulate form in suspension, reading the example in context it may be that the authors of the document intended a solution. In other words, it is not clear from the document whether the authors intended a suspension or a solution formulation.

130    Mr Lau was also asked a question about the ability of benzyl benzoate to dissolve levamisole HCl. He accepted that, while he would be able to make a prediction about the solubility of that particular combination, he would need to confirm this one way or the other by experiment.

131    It is convenient at this point to refer to Mr Vickers’s evidence in relation to CN 291. Mr Vickers considered CN 291 to present three different and known ways of formulating macrocyclic lactones with levamisole added, without suitable data to show the true nature of the formulations or to demonstrate that the formulations were stable, effective, safe and suitable as injectable formulations. Mr Vickers also stated in the Lau/Vickers Joint Report that he did not envisage Example 3 of CN 291 as a suspension, but rather levamisole in solution. Mr Vickers stated that he saw Example 3 as a variant of well-known abamectin/soybean oil/benzyl alcohol formulations such as the Genesis injection.

132    Mr Vickers considered the nature of Example 3 to be dependent on the manufacturing process. He accepted that ivermectin is non-polar and therefore will be soluble in non-polar solvents. He also accepted that levamisole HCl is a highly polar ionic compound and that the dispersion media was non-polar. However, he did not accept that it followed that the levamisole HCl would exist in particulate form. He said that the levamisole HCl may or may not exist in particulate form. Mr Vickers’s view was summarised in the following exchange:

[COUNSEL FOR BOEHRINGER]: Would it fair to put it in this way: based on the consideration of the polarity of the components – at that point, your expectation would be that the levamisole would exist in particulate form. But in your view, because you need to consider the manufacturing process, it may be that it does or doesn’t exist in particulate form, depending on the nature of the manufacturing process.

MR VICKERS: Correct.

133    The views of Mr Vickers on the nature of the formulation in Example 3 depended to a considerable extent on matters of formulation chemistry. On these matters, as indicated above, I prefer the views of Mr Lau.

134    Nevertheless, as discussed above, the oral evidence of Mr Lau was that, reading Example 3 in the context of the patent application as a whole, the authors may have intended a suspension formulation or a solution formulation. In light of this evidence, I am not satisfied that the formulation chemist forming part of the notional skilled team would understand or expect Example 3 to contain a clear direction to make or description of a formulation in which the levamisole HCl was in particulate form.

135    Thirdly, insofar as Boehringer relies on the experiments conducted by Mr Lau and Mr Pippia to establish that a formulation containing levamisole HCl in particulate form was an inevitable result of making the formulation in Example 3 of CN 291, I am not satisfied that the experimental evidence establishes this.

136    Both of the formulations prepared by Mr Lau modified the concentration of levamisole HCl from 5% w/v to 15% w/v. Further, Formulation 2 prepared by Mr Lau involved a number of additional departures from Example 3. Also, in respect of both Formulation 1 and Formulation 2, Mr Lau adopted a series of manufacturing steps that are not set out in Example 3, which contains no such steps.

137    In relation to Mr Pippia’s experiments, while the concentration level reflected that in Example 3, the manufacturing steps he undertook were based on his instructions. Mr Pippia did not turn his mind to what manufacturing steps would be reasonable to use.

138    Boehringer’s experimental evidence was therefore limited to proving that one particular manufacturing method (or two such methods) for the ingredients of Example 3 resulted in levamisole being present as particulates. It did not conduct experiments that were designed to prove that any steps used to manufacture a formulation having the composition of Example 3 would inevitably contain levamisole HCl in particulate form. To prove such an outcome Boehringer would logically have needed to conduct experiments that were designed to favour the dissolution of levamisole HCl, and then establish that those formulations still had the levamisole HCl in particulate form. Boehringer bore the onus of establishing the inevitability of the outcome that it contended for, not merely that this was one possible result, or even a likely result.

139    Accordingly, Boehringer’s experimental evidence does not establish that a formulation containing levamisole HCl in particulate form was an inevitable result of making the formulation in Example 3 of CN 291.

140    For these reasons, I am not satisfied (let alone clearly satisfied) that claim 1 of the Patent Application is anticipated by CN 291 (in particular, Example 3).

141    Boehringer also contends that claims 2, 4, 5, 6, 7, 12, 13 and 15 of the Patent Application are anticipated by CN 291. For the same reasons as for claim 1, I am not satisfied (let alone clearly satisfied) that these claims are anticipated by CN 291. Further, in relation to claim 4 of the Patent Application, this uses dimethylacetamide as the organic solvent. Example 3 in CN 291 does not refer to dimethylacetamide; while it is true that dimethylacetamide is referred to elsewhere in CN 291, there is no sufficiently clear and direct recommendation to vary Example 3 so as to include it as the organic solvent in the formulation. For this additional reason, I am not satisfied that claim 4 is anticipated.

142    Accordingly, grounds 2 and 3 of the amended notice of appeal fail.

The lack of inventive step ground

The issue

143    In the alternative to the lack of novelty ground, Boehringer contends that the alleged invention claimed in each of the claims does not involve an inventive step because it was obvious in the light of the common general knowledge considered alone, or the common general knowledge combined with CN 291. This ground is set out in grounds 4 and 5 in the amended notice of appeal:

4.    The Delegate erred in finding that invention as claimed in the [Patent] Application is a patentable invention within the meaning of s 18(1)(b)(ii) of the Act and that the alleged invention involved an inventive step in light of the common general knowledge considered alone or together with [CN 291].

5.    In making the finding referred to in paragraph 4 above, the Delegate erred in:

(a)    finding that the skilled addressee would find Example 3 of [CN 291] a less than optimal formulation in terms of physical stability, and would use either Example 1 or 2 of [CN 291] to create a more concentrated formulation rather than combining Example 3 with claim 3 ([121] of the Decision); and

(b)    concluding that the skilled addressee would not be directly led as a matter of routine to increase the concentration of levamisole in Example 3 of [CN 291] with the expectation of success ([122] of the Decision).

Applicable principles

144    Section 18(1)(b)(ii) of the Patents Act requires that the invention, so far as claimed in any claim, involves an inventive step when compared with the prior art base as it stood before the priority date. I discussed the applicable principles in Merial at [133]-[155]. For ease of reference, I incorporate the substance of those paragraphs into these reasons in the following paragraphs.

145    The concept of inventive step is the subject of provision in s 7(2) and (3) of the Act. There have been three iterations of these provisions: as originally enacted in the 1990 Act; as they stood following the Patents Amendment Act 2001 (Cth); and as they currently stand following the Intellectual Property Laws Amendment (Raising the Bar) Act 2012. The relevant version for present purposes is the second iteration. Section 7(2) and (3) provided as follows:

(2)    For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with the information mentioned in subsection (3).

(3)    The information for the purposes of subsection (2) is:

(a)    any single piece of prior art information; or

(b)    a combination of any 2 or more pieces of prior art information;

being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, regarded as relevant and, in the case of information mentioned in paragraph (b), combined as mentioned in that paragraph.

146    The expression “prior art base” was relevantly defined in the Dictionary in Sch 1 to the Act as meaning:

(a)    in relation to deciding whether an invention does or does not involve an inventive step or an innovative step:

(i)    information in a document that is publicly available, whether in or out of the patent area; and

(ii)    information made publicly available through doing an act, whether in or out of the patent area.

147    The expression “prior art information” was defined in the Dictionary as meaning, for the purposes of s 7(3), information that is part of the prior art base in relation to deciding whether an invention does or does not involve an inventive step.

148    The person skilled in the relevant art is a person to whom the patent specification is addressed, or a person with a practical interest in the subject-matter of the alleged invention. It is well established that the person skilled in the art is a notional construct, and is a tool of analysis rather than an actual person or an expert witness in the case. It is also well established that it may be a skilled team, or a notional person with skills from multiple fields.

149    Section 7(2) as set out above referred to the common general knowledge in the patent area. In simple terms this referred to the common general knowledge in Australia. The common general knowledge constitutes “the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old”: Minnesota Mining and Manufacturing Co v Beiersdorf (Australia) Ltd (1980) 144 CLR 253 at 292 per Aickin J (Minnesota Mining).

150    The principles relating to inventive step were considered by the High Court in Aktiebolaget Hässle v Alphapharm Pty Ltd (2002) 212 CLR 411 (Alphapharm); Lockwood Security Products Pty Ltd v Doric Products Pty Ltd (No 2) (2007) 235 CLR 173 (Lockwood No 2); and AstraZeneca AB v Apotex Pty Ltd (2015) 257 CLR 356 (AstraZeneca HC).

151    Alphapharm was concerned with the provisions of the Patents Act 1952 (Cth). While that Act contained a provision (s 100(1)(e)) that was comparable to part of s 7(2), it did not contain an equivalent to s 7(3), which was introduced when the Patents Act 1990 was enacted. Subject to that difference in the applicable legislation, the statements of principle regarding inventive step in Alphapharm are relevant to the issues to be determined in the present case.

152    In Alphapharm, Gleeson CJ, Gaudron, Gummow and Hayne JJ introduced the topic of obviousness or lack of inventive step at [19]. At [21], their Honours referred to the warnings in the authorities about the misuse of hindsight and stated that the danger of such misuse will be particularly acute where what is claimed is a new and inventive combination for the interaction of integers, some or all of which are known. Their Honours considered a number of authorities concerning obviousness at [33]-[41] and discussed the divergence between Australian and United Kingdom law at [42]-[49]. Their Honours then dealt with the expression “matter of routine” at [50]-[53]. First, their Honours quoted the following passage from the judgment of Aickin J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 (Wellcome Foundation) at 286:

The test is whether the hypothetical addressee faced with the same problem would have taken as a matter of routine whatever steps might have led from the prior art to the invention, whether they be the steps of the inventor or not.

(Emphasis added by the majority in Alphapharm.)

153    Chief Justice Gleeson and Gaudron, Gummow and Hayne JJ said at [51] that what Aickin J had in mind as “routine” appears from an earlier passage in his judgment in which he was discussing the question whether evidence of the steps taken by the patentee was relevant and therefore admissible in a revocation action. Justice Aickin had said (at 280-281):

Evidence of what he did by way of experiment may be another matter. It might show that the experiments devised for the purpose were part of an inventive step. Alternatively it might show that the experiments were of a routine character which the uninventive worker in the field would try as a matter of course. The latter could be relevant though not decisive in every case. It may be that the perception of the true nature of the problem was the inventive step which, once taken, revealed that straightforward experiments will provide the solution. It will always be necessary to distinguish between experiments leading to an invention and subsequent experiments for checking and testing the product or process the subject of the invention. The latter would not be material to obviousness but might be material to the question of utility.

(Emphasis added by the majority in Alphapharm.)

154    Chief Justice Gleeson and Gaudron, Gummow and Hayne JJ discussed the above passage in connection with the issues in Alphapharm, stating that the relevant question in a case such as the one before the Court was that posed in the first part of the passage, namely, were the experiments “part of” the inventive step claimed in the patent or were they “of a routine character” to be tried “as a matter of course”? Their Honours then said (at [53]):

That way of approaching the matter has an affinity with the reformulation of the “Cripps question” by Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd. This Court had been referred to Olin in the argument in Wellcome Foundation. Graham J had posed the question:

“Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and of the facts of the nature and success of chlorpromazine, directly be led as a matter of course to try the –CF3 substitution in the ‘2’ position in place of the –C1 atom in chlorpromazine or in any other body which, apart from the –CF3 substitution, has the other characteristics of the formula of claim 1, in the expectation that it might well produce a useful alternative to or better drug than chlorpromazine or a body useful for any other purpose?” (Emphasis added.)

That approach should be accepted.

(Footnotes omitted.)

155    Their Honours then discussed the approach taken at first instance and in the Full Court of the Federal Court. After setting out a particular passage from the judgment at first instance, their Honours said (at [58]):

The tracing of a course of action which was complex and detailed, as well as laborious, with a good deal of trial and error, with dead ends and the retracing of steps is not the taking of routine steps to which the hypothetical formulator was taken as a matter of course.

156    In connection with the reasoning of the Full Court of the Federal Court, the majority in the High Court said at [65] that the focus upon each integer rather than the interaction between them in combination went against the teaching in authorities such as Minnesota Mining. The majority in Alphapharm also said (at [72]) that the statute does not ask whether a particular avenue of research was obvious to try so that the result claimed is obvious; the adoption of a criterion of validity expressed in terms of “worth a try” or “obvious to try” begs the question presented by the statute. Their Honours emphasised that s 100(1)(e) of the Patents Act 1952, as applied to the facts of the case before the Court, asked whether the combination claimed in claim 1 was obvious; the provision did not direct an inquiry respecting each integer of the claimed combination (at [72]).

157    In Lockwood No 2, the applicable version of s 7(2) and (3) of the Patents Act 1990 was the first iteration, set out at [33] of the reasons of Gummow, Hayne, Callinan, Heydon and Crennan JJ. The critical difference between the relevant provisions of the Patents Act 1952 and those of the Patents Act 1990 was that, under the latter, certain kinds of publicly available information (namely those described in s 7(3)) were also to be taken into account. This was explained by Gummow, Hayne, Callinan, Heydon and Crennan JJ at [49]:

Previously, only common general knowledge was taken into account when assessing an inventive step. Now, additional information which was publicly available as at the priority date must also be taken into account. Broadly speaking, s 7(3) has as its purpose the specification of the additional publicly available information (s 7(3) information) which must be added to common general knowledge for the purposes of deciding whether an alleged invention is obvious when compared with the prior art base.

158    Although these observations were made in the context of the first iteration of s 7(2) and (3), they would appear to apply also to the second iteration (which is applicable in the present case).

159    Justices Gummow, Hayne, Callinan, Heydon and Crennan set out some general principles concerning inventive step at [50]-[58]. Their Honours said at [51]-[52]:

51    In Alphapharm, this Court reiterated that “obvious” means “very plain”, as stated by the English Court of Appeal in General Tire & Rubber Co v Firestone Tyre and Rubber Co Ltd. The majority in Alphapharm also confirmed that the question of whether an invention is obvious is a question of fact, that is, it is what was once a “jury question”. Broadly speaking, the question is not a question of what is obvious to a court. As well as being a question of fact, the question of determining whether a patent involves an inventive step is also “one of degree and often it is by no means easy”, because ingenuity is relative, depending as it does on relevant states of common general knowledge. This difficulty is further complicated now by the need, in some circumstances, to consider s 7(3) information as well as common general knowledge.

52    Further, as recognised in Beecham Group Ltd’s (Amoxycillin) Application, as a basic premise, obviousness and inventiveness are antitheses and the question is always “is the step taken over the prior art an ‘obvious step’ or ‘an inventive step’”? An inventive step is often an issue “borne out by the evidence of the experts”. There is no distinction between obviousness and a lack of inventive step. A “scintilla of invention” remains sufficient in Australian law to support the validity of a patent. In RD Werner Lockhart J stated that there must be “some difficulty overcome, some barrier crossed”. This is consonant with older authorities in the United Kingdom which recognised that some inventiveness was required to distinguish patentable advances over the prior art from advances which “any fool” could devise. It also accords with the requirement in the United States that for an invention to be “non-obvious” it must be “beyond the skill of the calling”.

(Footnotes omitted.)

160    In a section headed “Patentability of ideas”, their Honours referred to developments in a number of English cases and said at [65]:

Such developments were considered and distinguished in Alphapharm. This Court rejected confining the question of obviousness to a “problem and solution” approach, particularly with a combination patent. This should not be misconstrued. The “problem and solution” approach may overcome the difficulties of an ex post facto analysis of an invention, which may be unhelpful in resolving the question of obviousness. However, it is worth repeating that the “problem and solution” approach may be particularly unfair to an inventor of a combination, or to an inventor of a simple solution, especially as a small amount of ingenuity can sustain a patent in Australia. Ingenuity may lie in an idea for overcoming a practical difficulty in circumstances where a difficulty with a product consisting of a known set of integers is common general knowledge. This is a narrow but critical point if, as here, the circumstances are that no skilled person in the art called to give evidence had thought of a general idea or general method of solving a known difficulty with respect to a known product, as at the priority date.

161    In a section dealing with admissions in a specification, Gummow, Hayne, Callinan, Heydon and Crennan JJ noted at [105] that, while not every invention constitutes a solution to a problem, it is commonplace so to describe an invention where it is appropriate to do so.

162    The High Court in Lockwood No 2 also held (at [132]) that “ascertained” in s 7(3) simply means discovered or found out, and “understood” in the subsection means that, having discovered the information, the skilled addressee would have comprehended it or appreciated its meaning or import.

163    In AstraZeneca HC, the High Court considered the first iteration of s 7(2) and (3). Chief Justice French (with whom Gageler, Keane and Nettle JJ agreed) set out the legislative history at [10]-[17]. After referring to the purpose of s 7(3), his Honour stated: “While the range of disclosures that would support a finding of obviousness was widened, the content of the ‘inventive step’ requirement was not changed. The test was still that posed under the Patents Act 1952 by Aickin J in Wellcome Foundation in terms of the hypothetical addressee taking, as a matter of routine, steps which might lead from the prior art to the invention” (at [17]). Chief Justice French referred at [40] to the approach to the question of inventive step taken by Jessup J in the Full Court, which adopted as the correct approach to “obviousness” that approved in Alphapharm and derived from the judgment of Graham J in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187-188 (Olin Mathieson). Chief Justice French (at [42]) approved the approach adopted by Jessup J, stating that no error was involved in his Honour’s reasoning.

164    Justice Kiefel (as her Honour then was) (with whom Gageler, Keane and Nettle JJ agreed) referred (at [66]) to Alphapharm, noting that that case had stated the question to be answered to determine obviousness under the Patents Act 1952. Her Honour noted that s 100(1)(e) was in relevantly the same terms as s 7(2) of the Patents Act 1990 except for the latter’s addition of the prior art information referred to in s 7(3) to the matters to be considered. Her Honour then set out (at [67]) how the question stated in Alphapharm was to be modified to allow for that further information. The terms of the question reflected the reformulation of the “Cripps question” by Graham J in Olin Mathieson endorsed by the majority in Alphapharm, as set out above.

165    Justice Kiefel also stated (at [70]) that, in addressing s 7(2), it is to be borne in mind that the skilled person is an artificial construct, intended as an aid to the courts in addressing the hypothetical question of whether a person, with the same knowledge in the field and aware of the problem to which the patent was directed, would be led directly to the claimed invention. Her Honour stated (at [70]):

The statute’s creation of the skilled person construct for this purpose is not to be taken as an invitation to deal with the question posed by s 7(2) entirely in the abstract. Whilst the question remains one for the courts to determine, the courts do so by reference to the available evidence including that of persons who might be representative of the skilled person.

(Footnote omitted.)

166    Although AstraZeneca HC concerned the first iteration of s 7(2) and (3), the observations and holdings referred to above would appear to apply also to the second iteration of s 7(2) and (3) (which is applicable to the present case).

167    In addition to the above summary of the applicable principles, which is based on my judgment in Merial, I note the following matters. The modified “Cripps question” does not require certainty of outcome; it requires that the skilled person be directly led as a matter of course to try the claimed invention, in the expectation that a particular research path “might well produce” a useful result: Alphapharm at [53]; see also Nichia Corporation v Arrow Electronics Australia Pty Ltd [2019] FCAFC 2 (Nichia Corporation) at [89], [99] per Jagot J (with whom Besanko and Nicholas JJ agreed). On the other hand, the question of obviousness is not determined by asking whether a given step or given steps were “worth a try” or “well worth trying out”: Alphapharm at [66]-[76]; see also Mylan Health Pty Ltd v Sun Pharma ANZ Pty Ltd (2020) 380 ALR 582 at [147].

168    The formulation given in Alphapharm at [53] is not the only test for assessing obviousness. One only need review the various formulations subsequently given in Lockwood No 2 in order to appreciate this: see Lockwood No 2 at [50]-[58]. Another way of approaching the issue is the oft-cited test in Wellcome Foundation at 286, which asks whether the claimed invention is of a routine character, to be tried as a matter of course. See also Generic Health Pty Ltd v Bayer Pharma Aktiengesellschaft (2014) 222 FCR 336 at [71] per Besanko, Middleton and Nicholas JJ.

169    Relatedly, it is also clear that more than one thing can be obvious. Thus, the claimed invention need not be the only path that might be followed by the notional skilled person in addressing a particular problem, in order for a finding of obviousness to be made. This was recently confirmed by the Full Court in Nichia Corporation at [65]-[66], [79], [80], [87]-[89], [90]-[94], [98]-[100].

170    Further, the cases demonstrate that, in technical fields such as the present involving pharmaceutical products, the fact that a formulation would need to be tested or trialled in order to confirm that it would work, does not undermine a conclusion of obviousness. It is enough that the relevant expectation of success is present, if the tests or trials that would be required are routine or conventional in nature and would be carried out as a matter of course: see, eg, AstraZeneca HC at [44], [80], [95], [123].

The person skilled in the art

171    This matter has been dealt with at [88] above, in the context of the lack of novelty ground. I adopt the same approach for the purposes of the lack of inventive step ground.

Common general knowledge

172    The following statement of the common general knowledge as at the priority date (24 June 2010) is based in large part on the summary in Boehringer’s closing outline of submissions at [102]-[132], with modifications having regard to supplementary submissions filed by Intervet and responding submissions filed by Boehringer. I have also drawn on the written and oral evidence in some respects.

Macrocyclic lactones and levamisole

173    Before June 2010, it was well known that 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 was an overarching term for products that treated parasites, and parasiticides that acted on helminths were referred to as anthelmintics.

174    Common anthelmintics in use included macrocyclic lactones (such as ivermectin, abamectin, avermectin, eprinomectin, moxidectin and doramectin) for broad spectrum use, and imidazothiazoles such as levamisole, also for broad spectrum use. Active ingredients with broad spectrum use were known to be effective in killing a number of species.

175    Macrocyclic lactones had been in use since the 1980s, and could be applied orally, topically and by injection. As at June 2010, 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.

176    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). As at June 2010, levamisole was effective against nematodes such as Haemonchus, Ostertagia and Trichostrongylus, as well as lungworms. As at June 2010, it was also known to be effective against Cooperia. Levamisole tended to be short acting and rapidly excreted.

177    Levamisole salts were known to be highly polar ionic compounds soluble in water.

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.

Resistance and combination products

179    The problem of resistance was well-known before June 2010. 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 before June 2010.

180    Although one strategy for dealing with resistance was new active ingredients, new active ingredients are very rare. A more common strategy was the combination of two or three parasiticides from different classes, either separately or in combination products (because parasites would generally be cross-resistant to other anthelmintics in a single class, but may not have genes for resistance to a different class). From the mid-1990s, macrocyclic lactones were co-administered with levamisole to counter Cooperia resistance to macrocyclic lactones.

181    Thus there was a strong market demand to formulate combination products for ease of administration. There is no suggestion that it was inventive to seek to combine macrocyclic lactones with levamisole at the priority date.

Modes of administration

182    There were a number of ways to administer parasiticides to cattle, including:

(a)    pour-on drenches;

(b)    oral drenches; and

(c)    injectables.

183    However, pour-on drenches involved the risk of incorrect dosing, and required higher dosages because of the need for transdermal penetration. Oral drenches were less commonly used for cattle because of the difficulties in administering the required dosage. Injectable products were common because they ensure the delivery of the correct dosage.

184    Injectable products included subcutaneous injectable products and intramuscular injectable products. Desirable properties of an injectable product were that it be effective, safe, not cause unacceptable adverse reactions (over and above transient swelling), easy to administer (easily syringeable), sterile, cost effective and stable (chemically and physically). However, it was not always possible to develop an acceptable formulation.

Commercially available products

185    There were multiple injectable products on the market in Australia before June 2010 that contained macrocyclic lactones. These included products in which the macrocyclic lactones were formulated in organic solvent systems, including organic solvent systems together with oil. An example of the latter was the Genesis injectable product, which Mr Vickers described as using a well-known formulation approach for macrocyclic lactones.

186    As at the priority date, there were long-acting formulations of macrocyclic lactones that used an oily formulation to slow down the rate of absorption within the animal.

187    Combination products with more than one active ingredient from different families of anthelmintic agents were available as at the priority date. These products included the following (which were oral drench or pour-on products):

(a)    Triton, an aqueous oral drench containing levamisole HCl, ivermectin and albendazole (for sheep);

(b)    Q-drench, an aqueous oral drench containing levamisole HCl, abamectin, albendazole and closantel (for sheep);

(c)    Arrest C, an aqueous oral drench containing albendazole and levamisole HCl (for cattle and deer);

(d)    Scanda, an aqueous oral drench containing oxfendazole and levamisole HCl (for cattle and sheep);

(e)    Switch oral for sheep and Switch C for cattle, both aqueous oral drenches, containing levamisole HCl, and abamectin at two different concentrations;

(f)    Ivomec plus a non-aqueous injection, containing ivermectin and clorsulon (for cattle);

(g)    Matrix, an aqueous oral drench containing abamectin, oxfendazole and levamisole HCl (for sheep);

(h)    Eclipse, a non-aqueous clear pour-on containing abamectin and levamisole base (for cattle);

(i)    Saturn, a non-aqueous clear pour-on containing abamectin and levamisole base (for cattle); and

(j)    Ambex tablet, an oral tablet containing levamisole HCl and niclosamide (for dogs and cats).

188    There was no evidence of any injectable combination products containing levamisole and another active anthelmintic agent before June 2010. In particular, there were no injectable combination products on the market before June 2010 containing a macrocyclic lactone and levamisole.

189    Levamisole was formulated in an injectable combination product with a vaccine (as distinct from an anthelmintic) before June 2010, namely Nilvax. This was a combination of a vaccine (5 clostridial toxoids, which were suspended) with levamisole phosphate in solution of an aqueous formulation.

190    All commercially available injectable formulations of levamisole as at June 2010 had the levamisole dissolved in an aqueous solution. There was no evidence of any commercially available injectable formulations of levamisole in particulate form as at June 2010. There was no evidence of any commercially available injectable formulations of levamisole in an oily formulation as at June 2010.

191    Although no combination macrocyclic lactone and levamisole injectable product existed as at June 2010, separate macrocyclic lactone and levamisole injectable products were used in combination with each other. The two active ingredients were also formulated in combination with each other for oral and pour-on administration.

192    In the course of oral evidence in reference to CN 291, Mr Lau accepted that, as at 2002 (the date of CN 291), it would have been well appreciated that it would be desirable to have an injectable product that combined levamisole and a macrocyclic lactone. I therefore take it to be common general knowledge as at the priority date that it would be desirable to develop an injectable formulation for a combination of a macrocyclic lactone and levamisole. I understood this to be common ground between the parties.

193    As to the characteristics of the formulations in commercially available anthelmintic products, these included, in relation to products for oral administration: solutions of active ingredients in appropriate solvents or solvent systems; suspensions of active ingredients in particulate form in liquid carriers; micellar solutions or emulsions containing active ingredients in separate liquid phases; and combinations of the foregoing approaches.

Determination of dosage

194    In relation to dosage, the skilled team would be concerned to identify a dose (amount of active ingredient, usually identified in milligrams per kg of animal) that was high enough to be effective as an anthelmintic but not too high to be unsafe, and an appropriate dose volume. If the team did not have experience with the active ingredient, they could consult the Australian Pesticides and Veterinary Medicines Authority (APVMA) register and scientific publications, existing products and reference textbooks to identify an effective and acceptable dose. The evidence establishes that (in relation to the present context):

(a)    macrocyclic lactones were routinely administered to cattle by injection at a dose of 0.2 mg per kg of cow;

(b)    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); and

(c)    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.

195    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.

Routine tests or trials

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 HPLC 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 the formulation was based on a registered single-active product, or formulated as a suspension rather than another type of formulation.

The process of formulating an injectable combination product

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.

200    The evidence makes it clear that the formulation chemist tasked with formulating a combination injectable comprising a macrocyclic lactone and levamisole would be aware that:

(a)    levamisole and macrocyclic lactones are chemically incompatible and tend to react with each other when combined;

(b)    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); and

(c)    levamisole salts are soluble in water, whereas macrocyclic lactones are not water soluble but are soluble in organic solvents, and are commonly formulated in oils and organic solvents.

201    Mr Vickers stated in [77] of his affidavit that in developing a combination injectable formulation, relevant considerations include safety, efficacy and an acceptable residue profile. Mr Vickers stated:

(a)    In relation to safety, this concerns safety both at the injection site (that is, there should be no excessive swelling, irritation, tissue damage or sterile abscess formation), and in the animal as a whole (that is, it should not cause any adverse systemic effects). An injectable formulation must be sterile, free from endotoxins or pyrogens, and typically have antimicrobial excipients that prevent microbial growth and allow the continued use over the shelf life (broached stability) to meet regulatory requirements.

(b)    The product should meet the required effectiveness. To obtain regulatory approval for a product containing a new active ingredient, efficacy must be established by animal trials to demonstrate suitable worm treatment or worm control. Alternatively, where a product with the same active ingredient already has regulatory approval, a later product may sometimes be able to establish efficacy and obtain regulatory approval by presenting results of a bioequivalence study. The bioequivalence study compares the amount of the active ingredient in the blood over time (blood profile) for the new product compared with the existing registered product.

(c)    In relation to an acceptable residue profile (and meat withholding times), this includes at the injection site and within the target tissues, being muscle, fat, liver and kidney (the so-called “edible” tissues). Residues can include the active ingredient and some of its metabolites. These levels need to be below the maximum residue limits for these tissues, which are based on acceptable daily intake levels for humans. When these levels are sufficiently below the maximum residue limits, the tissues are considered to be safe for human consumption. This determines the withhold time after treatment, being the period of time after treatment that an animal should not be slaughtered for consumption, or that an animal product (such as milk) should not be collected for human consumption.

202    In [78] of his affidavit, Mr Vickers stated that: a formulation, including a combination formulation, that is developed will need to address each of the above three issues, in addition to stability and sterility; adjustments to a formulation to address one issue, for example stability, may also have an impact (positive or negative) on another issue, such as product efficacy; and sometimes it may not be possible to develop an acceptable formulation for an active ingredient for a particular route of administration.

203    There was no cross-examination on [77]-[78] of Mr Vickers’s affidavit, and I accept these statements as correct and as forming part of the common general knowledge as at the priority date.

204    In his second affidavit, Dr Martin stated that he agreed with Mr Vickers that changes to a formulation can potentially change the release profile, rate of absorption and blood profile of the active ingredient. However, he stated, this does not necessarily decrease the efficacy of the active ingredient. In oral evidence, Dr Martin stated that formulations have the potential to change the behaviour of an anthelmintic, and studies are needed to test whether a formulation is having the effect for which it was designed. Dr Martin stated that one would undertake a two-step process: first, assessing if the formulation changed the available profile of the anthelmintic in the host; secondly, asking whether it was still functioning effectively as a parasiticide. I accept this evidence and find that it formed part of the common general knowledge as at the priority date.

Ingredients available for formulation

205    The evidence indicates that a range of common ingredients and excipients were known and available for use in formulating an injectable combination product.

206    In addition to the active ingredients, these included organic or non-aqueous solvents such as benzyl alcohol and dimethylacetamide, and oils such as castor oil and MCTs, as well as the other ingredients disclosed in the Patent Application and CN 291. These included ingredients such as preservatives and stabilising agents. There was nothing special in the use of any of these ingredients in such a formulation, and the choice between them was a matter for the formulation chemist.

The approaches of Mr Lau and Mr Vickers to formulating a combination injectable

207    In his first affidavit, Mr Lau stated that he was instructed to assume that in June 2010, he was given the task of formulating a combination injectable product containing: (a) a macrocyclic lactone; and (b) levamisole. It is apparent from the heading to the relevant section of the affidavit that the product was for cattle. He stated that he, together with his Chemistry and Quality teams, would work with the Biology, Regulatory Affairs, Marketing and Sales, and Technical teams to develop a product that was effective, stable, safe, sterile and syringeable.

208    Mr Lau stated that for the combination injectable, he would select levamisole HCl rather than levamisole base or levamisole phosphate (for the reasons set out at [199] above). In relation to the macrocyclic lactone in the combination injectable, Mr Lau stated that he would prefer to use ivermectin or abamectin (for the reasons set out at [199] above).

209    Mr Lau stated in his first affidavit that, due to the chemical incompatibility of levamisole and macrocyclic lactones (see [200] above), he would have explored strategies for formulating the combination injectable wherein the levamisole and the macrocyclic lactone were separated. Two main strategies for formulating the combination injectable that he would have considered would have been:

(a)    micellar formulations; and

(b)    suspension formulations.

210    In each of these types of formulations, Mr Lau explained, the two active ingredients would be physically separated. Mr Lau stated that he would have also considered it possible to try formulating the combination injectable as an emulsion formulation, but this would be a less attractive option.

211    In relation to the micellar formulation approach, Mr Lau stated that a micellar solution forms when the concentration of a surfactant in water reaches the critical micellar concentration, resulting in the formulation of micelles. He stated that a micellar solution is a common way to stabilise macrocyclic lactones in an aqueous environment. He stated that, on this approach, the abamectin or ivermectin would be dissolved in an organic co-solvent and reside in the hydrophobic interior of the micelle; the levamisole HCl would be dissolved in the aqueous environment outside the micelles.

212    In relation to the suspension formulation approach, Mr Lau stated that a suspension formulation is one that contains solid particulates suspended in an aqueous or organic carrier. Mr Lau provided the following description and explanation of the approach he would take:

(a)    If he formulated the combination injectable as a suspension, he would dissolve the abamectin or ivermectin in the carrier, and keep the levamisole HCl in suspension. This is because, compared with levamisole HCl, macrocyclic lactones such as abamectin and ivermectin are generally administered at very low doses and are therefore present in the formulation at low concentrations. If an active ingredient is present at a low concentration, it is preferable to formulate it as a solution so that the active ingredient is uniform throughout the formulation. If an active ingredient is present at a low concentration and it is formulated as a suspension, there is a greater risk that it will not be dispersed evenly throughout the formulation, which means that each injection may not deliver the required amount of that active ingredient.

(b)    Because he would be dissolving the abamectin or ivermectin, due to the chemical instability of macrocyclic lactones in aqueous environments, he would use an oil or organic carrier as the base, rather than an aqueous base. He would also use a co-solvent, such as benzyl alcohol, which he knew to be a very good solubiliser of macrocyclic lactones, in order to speed up the rate of dissolution of the macrocyclic lactone. The benzyl alcohol would also act as a preservative. He might use more than two organic carriers, depending on the viscosity of the preliminary formulations he made and whether the viscosity was suitable for accommodating the suspended levamisole HCl. If necessary, he would adjust the viscosity of the formulation. This could be done by adjusting the amounts of lower-viscosity and higher-viscosity solvents and/or by using a suspending agent.

(c)    A suspending agent is a type of viscosity modifier that can increase the viscosity of a carrier solvent. When included in a suspension formulation, suspending agents can help to maintain the suspendability and reduce the rate of settling of the solid particles. By “suspendability”, he meant the ability of a carrier media to suspend any solid particles, and to minimise sedimentation of those particles. The suspendability of a carrier is affected by the density and the viscosity of the media that makes up the carrier, as well as the density and the size of the solid particles. Aluminium stearate is an example of a suspending agent that he and his team commonly used for an oil-based or an organic carrier-based suspension formulation.

(d)    If he formulated the combination injectable as a suspension, he would expect the macrocyclic lactone and the levamisole HCl to be chemically stable. This is because having the different active ingredients in different physical states minimises the interaction between them. pH incompatibility is also not an issue when oils or organic carriers are used as a formulation base. This is because the concept of pH refers to the hydrogen ion concentration of an aqueous solution, and oils and organic solvents do not dissociate in the same way that water does.

213    Although Mr Lau’s evidence was that, in developing a new formulation, he would usually receive relevant information from his biology colleagues about issues of dose and efficacy, it does not appear that this occurred in relation to the hypothetical development project described in his first affidavit. Mr Lau said in oral evidence that he was not provided with the affidavits of Dr Martin.

214    In his affidavit, Mr Vickers also described the approach he would have undertaken if given the task of trying to formulate a new combination injectable product containing levamisole and a macrocyclic lactone as at the priority date. He stated that his preferred starting point would have been to base a proposed formulation on the commercially available injectable products, although (to his knowledge) there were no injectable products as at June 2010 that combined levamisole and a macrocyclic lactone. The basis for Mr Vickers’s preference was that the commercially available injectable products were known to contain excipients suitable for injectable products, and their properties, including efficacy, safety, residues and tolerance at the injection site, were known.

215    For reasons set out in his affidavit, Mr Vickers would prefer levamisole phosphate as the form of levamisole that he would use if formulating a combination injectable as described above.

216    Mr Vickers stated that his preferred option in developing a combination formulation would have been to have the levamisole dissolved in an aqueous phase, to try to have its release profile match as closely as possible the release profile of the existing levamisole injectable products. He stated that he would have tried having the macrocyclic lactone present in an organic solvent as a micellar or micro-emulsion formulation, and investigated stability at different pH levels. Only if that were unsuccessful, Mr Vickers stated, would he have considered using a different carrier system for the levamisole that did not involve water.

217    Mr Vickers stated that, using a partition formulation, which physically separates the solubilised active ingredients, was how the problem was addressed in the Switch oral drench product, although this was an oral liquid drench and not an injectable product. For the reasons set out in his affidavit, Mr Vickers stated that it would not be straightforward to adjust an oral formulation to a formulation for injection administration.

218    Mr Vickers stated that, as at the priority date, he was unaware of any levamisole injectables that did not contain water, and so developing a non-aqueous formulation would involve trialling different solvents or solvent systems (mixtures of different solvents).

219    Mr Vickers referred in his affidavit to exploring possible non-aqueous formulations. He stated that, in that regard, he would need to conduct tests as to the stability of the two active ingredients over time and the efficacy of the product. He stated that he would be concerned at the impact of changing the levamisole from an aqueous formulation to a non-aqueous formulation, as he considered this to be likely to affect the rate of absorption from the injection site into the animal, and hence the product’s efficacy. Mr Vickers stated that:

(a)    levamisole is quick acting, with peak blood levels within about two hours and total elimination within about 24 hours;

(b)    if an insufficient dose is delivered or absorbed, it may not sufficiently paralyse the worms to result in them being killed and expelled; and

(c)    he would have been less concerned at the impact on the abamectin or other macrocyclic lactone, as macrocyclic lactones are longer acting, and a variety of short and long acting formulations containing abamectin and other macrocyclic lactones were known and registered.

220    In his affidavit, Mr Vickers responded to the evidence in Mr Lau’s first affidavit as to the approach he would have taken to the formulation task. Mr Vickers stated that, in general, suspensions are not good for injectable products because of the difficulty of injection and because the solid particles can settle in either or both of the container or the syringe and so require resuspension. For this reason, in Mr Vickers’s opinion, for an injectable product, a solution is preferable. Mr Vickers stated that, by “solution”, he was referring to a clear liquid, typically with lower viscosity, and where the actives remain homogenous and evenly distributed or dispersed through the formulation; this could include a solution where all components are fully dissolved, but also a solution that included micelles.

221    In response to Mr Lau’s two main strategies for formulating levamisole and a macrocyclic lactone, Mr Vickers stated that he would not have considered a suspension for an injection. This was because, for an injectable product, either he would have wanted something solubilised or a clear solution that was easily injectable; these formulations also typically remain homogenous and do not require shaking and resuspension. Mr Vickers stated that he was not aware of any liquid product for any administration route that included levamisole as a suspension.

222    Mr Vickers also stated that he would have concerns about the use of a suspension because of the high loading of levamisole that would be needed to achieve the required dose rate. He stated that he would also have concerns that Mr Lau’s second approach could change the release profile of the levamisole, making it different from the known release profile. Mr Vickers stated that he had no knowledge of how a levamisole particle would be tolerated as an injection as at June 2010.

223    Mr Vickers stated in [131] of his affidavit that, normally, when levamisole HCl is in an injectable formulation, it is a solution; in this form, once injected, it is freely absorbed into the animals’ system. Mr Vickers stated that a particle will take longer to be absorbed and this is problematic for the following reasons:

(a)    When an aqueous levamisole solution is injected into an animal, the rapid absorption allows for the rapid onset and high peak of levamisole, which is important in its mode of action; the injected levamisole would also be rapidly excreted. By contrast, a particulate form of levamisole, having a slower rate of absorption, could make the levamisole less effective. The required peak blood levels may not be achieved, leading to a failure to kill the parasites, and it may also be less rapidly excreted. While micronisation of the levamisole particles may possibly assist with the rate of absorption, the rate of absorption may still be limited by the use of an oil or organic carrier. This could only be determined by testing.

(b)    Levamisole HCl is an irritant at the injection site. Given the severity of injection site reactions encountered when delivered as a solution, which is rapidly absorbed from the injection site, he would expect injection site reactions to be much worse where the injection involves levamisole HCI in particulate form, because the levamisole is less rapidly dispersed from the site. Further, given that levamisole is immunostimulatory, this may further promote injection site reactions.

(c)    The use of levamisole HCI as a particle may also adversely affect syringeability.

224    In oral evidence, Dr Martin accepted that it would necessary to investigate whether having the levamisole present as a particulate affected the efficacy, bio-availability and safety of a formulation. He said that he did not know whether having an active ingredient present as a particulate could potentially slow the rate of absorption, and that he had not seen evidence to that effect. Dr Martin was asked whether, for an active ingredient to be transported from the injection site to the animal’s gut would require the active ingredient first to be dissolved in some appropriate media within the animal. He said that it would need to be absorbed, either by being dissolved or by some other process. In response to a question whether having the levamisole present in particulate form meant that an extra step was required compared with levamisole that is dissolved in water. Dr Martin stated that, if the levamisole salt was in particulate form, it could be possible that it would simply dissolve in the aqueous environment in the subcutaneous area of the animal. He added:

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.

225    On the basis of the evidence in [131] of Mr Vickers’s affidavit and the oral evidence of Dr Martin summarised in the preceding paragraph, I find 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 (and this formed part of the common general knowledge at the priority date).

226    In his third affidavit, Mr Lau responded to Mr Vickers’s affidavit. Mr Lau stated that, to the extent that Mr Vickers was proposing to solubilise both active ingredients in the same solvent (aqueous or non-aqueous), Mr Lau did not agree that this was a viable approach. This was because levamisole and macrocyclic lactones are chemically incompatible, and when solubilised in the same solvent they tend to react with each other. Mr Lau stated that a further reason not to solubilise both active ingredients in an aqueous solution was their pH incompatibility.

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).

230    In oral evidence, Mr Vickers accepted that he recognised, as at June 2010, that if he were to adopt a formulation approach that involved including a macrocyclic lactone and levamisole together in an aqueous solution, two issues that would arise were potential instability and the different pH requirements. He accepted that the issue of instability would not arise to the same degree if he adopted a formulation approach where the macrocyclic lactone and levamisole were separated in some way in the formulation.

231    Mr Vickers accepted in oral evidence that whether an impact on the release rate of levamisole was sufficient to indicate that he should not proceed with the formulation would depend on the extent of the impact. He accepted that the release rate may be acceptable, and this was something he would assess through preliminary tests.

232    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?” Mr Vickers accepted that he would conduct preliminary tests to evaluate such an approach.

233    In oral evidence, Mr Vickers referred to a suspension of levamisole being “very much unknown” and to the potential for toxicity if the particles were not evenly distributed. Mr Vickers stated that these were reasons why he would not initially consider suspension of either of the actives as particles. He accepted, however, that they were approaches he may have considered in the formulation process, having first considered other options.

Evidence relating to expectation of an acceptable result

234    During the concurrent evidence of Dr Martin and Mr Vickers, senior counsel for Boehringer asked a number of questions relating to the witnesses’ expectation of achieving an acceptable result in respect of the matters covered in their joint evidence (such as efficacy, release rate and absorption). It is convenient to set out these passages, which are relied on by Boehringer in its written submissions.

235    In response to a question whether having the levamisole present as a particulate could potentially slow down the rate of absorption, Dr Martin stated that he was not aware of evidence to support that statement. The following exchange then took place between senior counsel for Boehringer and Dr Martin (called by Boehringer), in reference to the proposition that the fact that the levamisole salts were in particulate form could potentially affect the release rate of the levamisole:

[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: 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.

[COUNSEL FOR BOEHRINGER]: And in undertaking that process, would it be the case that you would have expected, based on your knowledge at the time, that the release rate of the levamisole may well be acceptable in that formulation?

DR MARTIN: That would be the objective, of course.

[COUNSEL FOR BOEHRINGER]: And would that be your expectation, that it may well be accepted?

DR MARTIN: My expectation would have been that it – we’re talking, I think, of a particulate salt in an oily formulation being injected. My expectation, without more than the knowledge I had then, would be that it would be absorbed not too differently to the aqueous solutions.

[COUNSEL FOR BOEHRINGER]: And would that be an acceptable result?

DR MARTIN: That would be an acceptable result.

[COUNSEL FOR BOEHRINGER]: And if I asked you the same questions relating to whether there would be any issue of having levamisole in an oily-based organic solvent system, would you have the same expectation as at June 2010 that it may well produce an acceptable result?

DR MARTIN: Yes.

236    Also during the oral evidence, Mr Vickers confirmed his view that, having the levamisole in particulate form had the potential to affect the release rate of the levamisole. He also confirmed his view that having the levamisole salts in an oily-based organic solvent system had the potential to affect the release rate. He accepted that, in each of these cases, this potential could not be known in advance. He stated that testing would be needed to prove that the formulation was effective and safe, and that this testing could be considerably more than that required if one were using a known formulation. In this context, the following exchange took place:

[COUNSEL FOR BOEHRINGER]: … would you agree with Dr Martin’s view that, knowing what you did in June 2010, if you were considering a formulation that had levamisole in particulate form or levamisole in an oily-based organic solvent system, you would expect that it may be the case that you could achieve an acceptable release rate of the levamisole, you would need to test it?

MR VICKERS: Correct.

In Boehringer’s closing submissions, the words “[but that]” are inserted before the words “you would need to test it?” in the last line of the above question. The addition of those words was not one of the corrections made to the transcript. Even if they are read in to the question, it is unclear what part or parts of the question Mr Vickers was accepting. It may be that he was accepting that you would expect that it may achieve an acceptable release rate, or that you would need to test it, or both.

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 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.

Projects before the priority date

239    In the course of the oral evidence, Intervet adduced evidence from Mr Lau and Dr Martin regarding projects with which they were involved before the priority date relating to macrocyclic lactones and levamisole. I summarise that evidence in this section of these reasons.

240    In or about 2005, while Mr Lau was the Head of Chemistry at Jurox, he worked on a project relating to a stable parasiticide composition containing a mixture of tetramisole (a class of active ingredients that includes levamisole and levamisole salts) and a macrocyclic lactone. This project culminated in Jurox filing, on 20 December 2005, patent application AU 2005101039 A4 (Exhibit R6), in respect of which Mr Lau was the named inventor.

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.

244    In or about 2005-2007, in his role as Director of Research and Development at Virbac, Dr Martin was involved with a project relating to a combined treatment comprising a macrocyclic lactone and levamisole. This culminated in New Zealand patent 601082 (annexure “PJM-11” to Dr Martin’s first affidavit).

245    The title to the patent, which was dated 20 November 2007, was “Anthelmintic Formulations and Treatments”. The patentee was Virbac New Zealand Ltd. Dr Martin said in oral evidence that he remembered the document from his time at Virbac and that he believed he was initially named as an inventor, but he did not think he was so named in the final version. Dr Martin said that the work in relation to the patent involved people in Virbac as well as external people, including a veterinarian at Virbac, an external person with skills in parasitology, and people with knowledge of chemistry.

246    Dr Martin was taken to the second page of the patent, which includes the following statement:

Different classes of actives are difficult to formulate together, and some combinations are incompatible, and degrade if held in the same solvent formulation.

247    The following exchange then took place:

[COUNSEL FOR INTERVET]: So you see there, at lines – starting at line 14 and going through to line 20, there’s a description of the fact that some actives are difficult to formulate together. Some combinations are incompatible and will degrade if held in the same solvent formulation. In relation to that statement, did you understand that to be applicable to a combination of a macrocyclic lactone and levamisole?

DR MARTIN: Yes. I think – the general statement is very true and, more often than not, 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.

While the passage to which Dr Martin was responding referred to the actives being held in “the same solvent formulation”, as distinct from, for example, a formulation in which one active is in solution and another is suspension, I do not consider Dr Martin’s response to be so confined; I take him to be making a more general point about the care needed when combining anthelmintics to achieve the required stability.

248    Under the heading “Statement of the invention”, the specification for the 2007 patent describes an aspect of the invention as follows:

In a first aspect the invention provides a method of controlling parasites in ruminants by treating the animal with separate formulations A and B, wherein formulation A is orally administered to the animal as an oral formulation, or is injected into the animal as an injectable formulation, or is administered to the animal as an implantable formulation, and formulation B is either orally administered to the animal as an oral formulation, or is administered by injecting it into the animal as an injectable formulation, and wherein formulation A is a long acting anthelmintic formulation containing a macrocyclic lactone, and wherein formulation B is a short acting anthelmintic formulation containing levamisole.

Thus, in this aspect, the invention involved the administration of two separate formulations, one containing a macrocyclic lactone and the other containing levamisole, rather than the administration of a single formulation comprising both a macrocyclic lactone and levamisole.

249    On page 8 of the specification, it states:

These two treatments may be separate formulations, and it is more likely that they will be separate formulations because of the incompatibility of a macrocyclic lactone formulation, and a levamisole formulation.

250    The following exchange took place with reference to that passage:

[COUNSEL FOR INTERVET]: And so, here – at Virbac, this particular project is looking further at that issue of a combination treatment of levamisole with a macrocyclic lactone.

DR MARTIN: That’s correct.

[COUNSEL FOR INTERVET]: And my question in relation to that first sentence is that at that time, you understood that there would be difficulty in formulating a macrocyclic lactone with a levamisole in a single formulation?

DR MARTIN: As a general concept, formulating two products would always present some challenges for a formulation chemist.

[COUNSEL FOR INTERVET]: And that’s why you thought that more likely than not, that administering both active ingredients to an animal would involve separate formulations?

DR MARTIN: I wouldn’t see the concept of using two separate formulations and the possibility of formulating a combination product as being mutually exclusive. I would see them more as being – first instance would demonstrate the concept, and then likely the follow-on .... happened previously in combining anthelmintics going back to the 1980s was to demonstrate the concept using single active compounds, and then that proved to be successful. Then it was usually followed on by companies formulating combination products.

[COUNSEL FOR INTERVET]: So back in the mid-1990s, it was a known approach to apply – administer to an animal a combination of levamisole and a macrocyclic lactone, correct?

DR MARTIN: Correct.

[COUNSEL FOR INTERVET]: And then this project that you’re involved in; you say at paragraph 51 of your first affidavit that the work commenced in either 2004 or 2005, correct?

DR MARTIN: I think that’s correct as I remember it, yes.

[COUNSEL FOR INTERVET]: So this is a project that has lasted for some two to three years; is that the case?

DR MARTIN: That’s correct.

[COUNSEL FOR INTERVET]: And at this point, that statement is saying, isn’t it, at the top of page 8, that the view that was taken by you and your colleagues within Virbac was that administering the macrocyclic lactone with levamisole would likely require separate formulations for each active ingredient.

DR MARTIN: In the context and the concept of demonstrating – using those two compounds in field situations that we were exploring, yes, we were using it in two separate compounds. And, as I’ve said, it didn’t preclude the long-term objective of doing a combination product. The other thing I believe we were exploring here was the timing of treatment as well, and that was something that could only be achieved if you had two compounds – two separate compounds.

251    The next sentence on page 8 of the specification states:

Moreover they need to have completely different release profiles, and thus it is possible that the method of this invention may involve two separate injections of these two formulations, preferably at about the same time, although the timing could be staggered, as in one version of the invention it may be preferable to provide the short acting anthelmintic (such as levamisole) by way of an injection, 4-8 hours before the introduction of the long acting macrocyclic lactone anthelmintic.

252    In oral evidence, Dr Martin confirmed that this passage was referring to a quick-acting release profile for the levamisole and a slower acting release profile for the macrocyclic lactones. He accepted that that was something that would be an additional challenge in relation to having a single formulation that administered those two active ingredients.

253    Dr Martin accepted that there was no suggestion in the 2007 patent of an approach that involved combining in an injectable formulation levamisole and the macrocyclic lactone. It was put to him that this was because it would not have been straightforward to do so. Dr Martin responded:

In the context of normal formulation chemistry, there would be challenges. That wouldn’t have precluded going down that pathway, but it wasn’t part of this particular document.

254    In follow-up questions by senior counsel for Boehringer, Dr Martin stated that: he did not think there was a formulation chemist actively involved in the project; the project was not a formulation project, but more of a conceptual project about the administration of products in combination; and in cases where he did work on projects that were formulation projects, there would be a formulation chemist on the team.

255    Mr Vickers stated in his affidavit that he was actively working in the area of co-administering levamisole (as an injection) and abamectin (as a pour-on) to animals in the time leading up to the priority date, with the intent of creating a combined injectable formulation.

Consideration

256    Consistently with the structure of Boehringer’s submissions, I will first address the lack of inventive step ground on the basis of the common general knowledge alone; I will then address this ground on the basis of the common general knowledge together with CN 291.

Common general knowledge alone

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.

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.

260    In my view, for the reasons that follow, the lack of inventive step ground is not made out.

261    First, it is important to recognise the extent of departure from existing known formulations:

(a)    there were no commercially available injectable formulations of levamisole in particulate form;

(b)    there were no commercially available injectable formulations of levamisole in an oily formulation; and

(c)    it follows that there were no known injectable formulations of levamisole in particulate form in an oily formulation.

262    Secondly, it is also important to recognise that, as was common general knowledge:

(a)    levamisole and macrocyclic lactones are chemically incompatible and tend to react with each other when combined;

(b)    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); and

(c)    levamisole salts are soluble in water, whereas macrocyclic lactones are not water soluble but are soluble in organic solvents, and are commonly formulated in oils and organic solvents.

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.

264    Further, as noted at [247] above, Dr Martin accepted that the statement in the 2007 patent 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” was applicable to a combination of a macrocyclic lactone and levamisole. He added: “I think – the general statement is very true and, more often than not, 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.”

265    Thirdly, while Mr Lau’s second main approach corresponds with claim 1 of the Patent Application, this approach was proposed by Mr Lau without knowledge of the mode of action and desired release profile of levamisole. As noted above, although Mr Lau’s evidence was that, in developing a new formulation, he would usually receive relevant information from his biology colleagues about issues of dose and efficacy, it does not appear that this occurred in relation to the hypothetical development project described in his first affidavit. Thus, Mr Lau was not provided with the information that he would require from a biology colleague as to the dosage and efficacy considerations for the relevant active ingredients. When asked to comment on evidence given by Mr Vickers about the respective modes of operation of levamisole and macrocyclic lactones, Mr Lau (quite properly) explained that this was not his area of expertise and he would not like to make a comment. Thus, in undertaking the hypothetical formulation task, Mr Lau did not have available to him relevant information about efficacy considerations, including considerations that pointed away from using levamisole as a particulate in an oily formulation (discussed below). The 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.

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.

268    Fourthly, in seeking to develop a combination injectable containing a macrocyclic lactone and levamisole for cattle, there would be considerable uncertainty as to efficacy in using levamisole as a particulate and in an oily formulation. I consider 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.

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.

275    In summary, the possibility of an oily formulation with levamisole present as a particulate was a substantial departure from known formulations, particularly (and most significantly) in respect of levamisole. The uncertainties as to efficacy, discussed above, would point away from the adoption of such an approach.

276    Fifthly, other uncertainties may also have pointed away from using levamisole as a particulate and in an oily formulation in seeking to develop a combination injectable containing a macrocyclic lactone and levamisole for cattle. As discussed at [228] above, there is a risk that an active ingredient formulated as a suspension will not be dispersed evenly throughout the formulation. Further, as noted in [229] above, if there are more solid particles present, there is a higher chance of agglomeration. Thus, all other things being equal, for an injectable formulation, a solution is preferable to a suspension.

277    Sixthly, there is secondary evidence that supports the existence of an inventive step: see Lockwood No 2 at [115]-[116]. The need for combination treatments of levamisole and a macrocyclic lactone was long-standing, as was the desirability of having such a combination in injectable form. Issues of resistance to macrocyclic lactones were well-known before June 2010. The use of combination treatments to address issues of resistance was well-known. From the mid-1990s, macrocyclic lactones were co-administered with levamisole to counter Cooperia resistance to macrocyclic lactones. The incompatibility of levamisole and macrocyclic lactones was also well-known prior to June 2010. Injectable products were common because they ensure the delivery of the correct dosage.

278    In light of the above, the fact that by June 2010 no-one had suggested, let alone made, an oily injectable formulation with levamisole salt in particulate form provides some evidence that such an invention was not obvious.

279    In addition to the above, there is evidence of projects being undertaken in this area before the priority date: see [239]-[255] above. While it is true that the project undertaken by Mr Lau at Jurox (which culminated in the 2005 patent application, Exhibit R6) was not focussed on producing an injectable combination product, it was nevertheless concerned with achieving a stable liquid formulation of levamisole and a macrocyclic lactone. In that context, it is noteworthy that the approach in the patent application did not relate to either of the two main approaches in Mr Lau’s first affidavit. In relation to the 2005-2007 Virbac project with which Dr Martin was involved, while this relates to a combined treatment of a macrocyclic lactone and levamisole (that is, two formulations being administered), the fact that the project was focussed on a combined treatment tends to underline the difficulty of producing a combined injectable product (particularly where a combination injectable product was desirable as at the priority date for the reasons given at [181] and [183] above).

280    Seventhly, contrary to Boehringer’s submissions, the uncertainties attending Mr Lau’s second main approach were not merely issues to be resolved by way of routine tests. The testing of any new pharmaceutical product, no matter how inventive, will involve routine testing. This does not demonstrate, however, that the uncertainties were merely issues to be resolved by way of routine tests. As discussed, above, the uncertainties pointed away from adopting the formulation approach proposed by Mr Lau. Further, while the uncertainties could be the subject of testing, I would not characterise such tests as routine.

281    Eighthly, insofar as Boehringer relies on the evidence discussed at [234]-[238] above regarding an expectation of achieving an acceptable outcome, that evidence does not go very far. The passages from the transcript there set out are from the concurrent evidence of Dr Martin and Mr Vickers, which concerned matters such as efficacy, release rate and absorption (rather than formulation chemistry). Insofar as Dr Martin’s evidence is concerned, there was some hesitation in the acceptance of the propositions put to him by senior counsel for Boehringer. (I refer to the discussion at [267] above.) In relation to Mr Vickers’s evidence, while he acceded to certain propositions as to expectation of achieving an acceptable result, this was qualified by the need for testing, and he made clear in his evidence that this was not merely routine testing but testing of a more fundamental nature.

282    In light of the above, I am 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. Nor am I satisfied (let alone clearly satisfied) 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.

283    For these reasons, I conclude that the ground of lack of inventive step (having regard to the common general knowledge alone) is not made out in relation to claim 1 in the Patent Application. For the same reasons, the ground is not made out in relation to the other claims in the Patent Application.

Common general knowledge and CN 291

284    I now turn to consider the lack of inventive step ground based on the common general knowledge and CN 291, being the patent application discussed above, in the context of the lack of novelty ground. There is no issue that CN 291 is a document falling within s 7(3) of the Patents Act, that is, it is 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.

285    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 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. Alternatively, the matter may be approached by asking whether, in light of the common general knowledge as at June 2010 and CN 291, 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.

286    Boehringer submits that: Mr Lau’s evidence was that CN 291 was a source of information that might help him to formulate an injectable product containing a macrocyclic lactone and levamisole in combination; he explained that it was a source of useful information that would help him develop formulations based on his preferred approaches, namely a micellar solution or a suspension formulation, given that Example 1 of CN 291 discloses a micellar solution and Example 3 discloses a suspension.

287    Boehringer refers to Mr Vickers’s oral evidence that the authors of CN 291 appeared to have looked to the known ways of formulating macrocyclic lactones, taken those as a base for making a formulation, and added in the levamisole as the second component. Boehringer notes that Mr Vickers accepted that this was, in principle, a reasonable formulation approach that one might take, and that it “makes sense”.

288    Boehringer submits that, although Mr Vickers had concerns around the dose rates used in Examples 2 and 3 of CN 291, he agreed that he would have been able to substitute (or “correct”) an appropriate dose rate (particularly given the dose rate in Example 1 and the preferred dose rates given). It is submitted that he agreed that if he was considering an injectable formulation, using standard dose rates may well produce an acceptable formulation in terms of its efficacy and the action of the two active ingredients.

289    Thus, Boehringer submits, the skilled person reading CN 291 would see that it disclosed a formulation approach of taking the existing known formulations of macrocyclic lactones and adding levamisole into those formulations; they would appreciate that that approach was a reasonable formulation approach.

290    CN 291 has been discussed in some detail in the context of the lack of novelty ground. I refer to that discussion of the patent application and the evidence in relation to the application.

291    In my view, the ground of lack of inventive step, based on the common general knowledge and CN 291, is not made out.