Merial New Zealand Limited v Jurox Pty Ltd
[2016] APO 63
•23 September 2016
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Merial New Zealand Limited v Jurox Pty Ltd [2016] APO 63
Patent Application: 2010249226
Title:Anthelmintic formulation
Patent Applicant: Jurox Pty Ltd
Opponent: Merial New Zealand Limited
Delegate: Dr M-A. Fam
Decision Date: 23 September 2016
Hearing Date: 17 August 2016, in Canberra
Catchwords: PATENTS – section 59 – opposition to the grant of a patent – grounds of novelty, inventive step, manner of manufacture, clarity, full description and utility considered – section 24 – two documents disregarded for the purposes of novelty and inventive step – novelty – citations do not disclose all the features of the claims – inventive step – claims 1 – 25 lack an inventive step in view of EP 0 045 655 and the common general knowledge – claims define a manner of manufacture – claims are clear – invention fully described – lack of utility not established – opposition succeeds
Representation: Patent attorney for the applicant: FB Rice
Counsel for the opponent: Mr Christian Dimitriadis SC
Patent attorneys for the opponent: Mr Denis Tuffery and Ms Helen Bellchambers of AJ Park
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2010249226
Title:Anthelmintic formulation
Patent Applicant: Jurox Pty Ltd
Date of Decision: 23 September 2016
DECISION
Claims 1 – 25 lack an inventive step in the light of EP 0 045 655 and the common general knowledge.
I allow Jurox Pty Ltd a period of two months from the date of this decision to file amendments to the specification.
Costs according to Schedule 8 are awarded against Jurox Pty Ltd.
REASONS FOR DECISION
1. Background
The present application was filed by Jurox Pty Ltd (Jurox) on 8 December 2010 and does not claim an earlier priority date. Following examination, the application was advertised accepted on 20 November 2014. A notice of opposition was filed by Merial New Zealand Limited (Merial) on 18 February 2015. A hearing was held in Canberra on 17 August 2016.
The request for examination in relation to the application was filed on 19 September 2012. Consequently, substantive amendments of the Patents Act 1990 brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 (Raising the Bar) do not apply to the present application. This includes the amendment to subsection 60 (3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition exists. Any subsequent references to sections of the Patents Act relate to the Patents Act 1990 prior to amendment by the Raising the Bar Act. A similar qualification applies to references to the Patents Regulations 1991.
2. Grounds of opposition
The statement of grounds and particulars was filed on 18 May 2015 and specifies the following grounds of opposition:
- novelty
- inventive step
- manner of manufacture
- section 40 issues of clarity, fair basis and full description
- utility.
All grounds, other than fair basis, were pressed at the hearing.
3. Standard of proof
The onus of proof in this opposition proceeding rests with the opponent, who must demonstrate that it is clear that a valid patent cannot be granted (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283; 50 IPR 305 at [67]; Commissioner of Patents v Sherman [2008] FCAFC 182; 79 IPR 426 at [18]).
4. Evidence
The evidence is summarised in the table below.
Evidence Declarant Exhibits Date Reference Gottfried Lichti
GL-1 to GL-7 18 August 2015 Lichti-1 Paul John Martin
18 August 2015 Martin-1 In Support Ray Simms
RS-1 to RS-3 18 August 2015 Simms-1 Edward Justin Hurst
18 August 2015 Hurst Helen Catherine Louise Bellchambers
HB-1 to HB-8 18 August 2015 Bellchambers-1 In Answer
Kai Kin Lau
KL-A to KL-B 22 November 2015 Lau Gottfried Lichti
GL(EIR)-1 22 January 2016 Lichti-2 In Reply
Paul John Martin
PJM(EIR)-1 to PJM(EIR)-5
20 January 2016 Martin-2 Ray Simms
22 January 2016 Simms-2 Helen Catherine Louise Bellchambers
HCLB(EIR)-1 22 January 2016 Bellchambers-2
Merial requested that its evidence in support filed on the opposition to the grant of patent application 2012200544 (also in the name of Jurox) be considered as evidence in support for the present proceedings. I will refer to this evidence where appropriate.
5. The subject matter of the specification
5.1 Background of the invention
The specification relates to compositions useful for treating parasites and in particular anthelmintic formulations comprising multiple active ingredients.
Parasites in farm animals are problematic, with further complications arising when parasites develop resistance to chemical treatments.
The specification indicates that “drench” is the common name for an anthelmintic, which is an agent designed to kill parasites such as worms. Classes of anthelmintics include macrocyclic lactones, benzimidazoles and imidothiazoles (page 2, lines 11 – 20). Drenches may be “broad spectrum”, i.e. suitable for treating a wide range of internal parasites or can target multiple stages of the parasite lifecycle, or “narrow spectrum”, i.e. suitable for treating a restricted range of internal parasites. “Combination drenches” are mixes of two or more of such classes (page 2, lines 12 – 16).
Combination drenches that contain multiple active ingredients may be formulated as emulsions. For example, Triton® is triple combination drench wherein a first active ingredient is contained in an oil phase and a second active ingredient is contained in an aqueous phase, wherein the first active ingredient is unstable in the conditions of the aqueous phase. A third active ingredient is suspended in the aqueous phase (page 2, line 31 – page 3, line 19).
Over time emulsions can become unstable and separate into the two phases. Once this occurs the active in the oil phase will contact the aqueous phase and vice versa, resulting in degradation. Although viscosity modifiers may be used to slow down the separation of the emulsion into its component phases, the resultant formulation is highly viscous and therefore difficult to administer and redisperse (page 3, lines 19 – 29).
As emulsion formulations will separate into the two phases over time, before administration it is important to shake the container in which the formulation is stored, in order to ensure that an animal receives sufficient amounts of each of the active ingredients (page 3, lines 29 – 32).
The specification indicates that AU 2010100349 discloses compositions that are in the form of a micellar solution. The compositions comprise at least three active ingredients selected from a macrocyclic lactone, a benzimidazole and an imidazothiazole (page 3, lines 34 – 36).
The specification at page 4, lines 8 – 10 states:
“… the inventors have surprisingly found that further effective anthelmintic compositions comprising two active ingredients may be prepared where the composition comprises a micellar solution.”
5.2 The aim of the invention
The specification does not explicitly state a particular problem to be solved or addressed by the invention. However, the specification discusses the escalating dilemma of resistance in animals to drenches (page 2, lines 6 – 9). Reference is made to combination drenches containing multiple active ingredients, including Triton®, which is in the form of an emulsion, and a micellar solution disclosed in AU 2010100349 (page 2, line 31 – page 3, line 36). Certain stability issues associated with emulsion formulations are also noted.
Given this context of parasite resistance, I consider that the aim of the invention is to provide an anthelmintic composition comprising multiple active ingredients.
This is consistent with statements made by Dr Lichti[1] and Dr Martin[2] regarding the emergence of parasite resistance as a contributing factor in the development of new anthelmintic agents or strategies for parasite control, including the use of combinations of two or more active ingredients.
[1] Lichti-1 [32] – [33].
[2] Martin-1 [22] – [29], [32], [49].
5.3 Nature of the invention
The specification indicates that anthelmintic compositions comprising only two anthelmintic agents may be prepared in the form of a micellar solution. One agent is a macrocyclic lactone, such as abamectin, and the other is an imidazothiazole, such as levamisole. The composition is in the form of a single phase wherein the two agents are protected from interacting (page 6, lines 4 ‑ 12).
The specification states that the compositions are stable and less prone to separation. The increased stability means that less thickening agent is required to maintain an adequate shelf life for the product. Consequently, this results in a decrease in the viscosity of the composition, which has advantages during manufacture and administration (page 6, lines 12 – 19).
5.4 The claims of the specification
The specification contains 25 claims and these are reproduced in Annex A. Claims 1 – 17 are directed to compositions, claims 18 – 24 are method, use or Swiss style claims and claim 25 is an omnibus claim.
6. The person skilled in the art
The person skilled in the art was considered in Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980; 49 IPR 225 at [70] – [71]:
“He is the person to whom the patent is addressed and who must construe it. He is the person whose knowledge will determine whether a patent is novel. He is the person who will judge whether a patent is obvious. ….
In Catnic Lord Diplock said (at 242) that skilled addressees are ‘those likely to have a practical interest in the subject matter of [the] invention’. A variety of people may have that interest. There are those who might wish to make or construct the invention, those who may wish to compound the invention and those who may wish to use the invention. The skilled addressee seems to me to be a relative expression which does not identify any specific person.”
Mr Lau has experience in the formulation and development of veterinary products, and is the inventor of the present application. Dr Lichti has experience in the development and formulation of anthelmintic compositions. Dr Martin has experience in researching and developing anthelmintic agents. I consider that Mr Lau, Dr Lichti and Dr Martin would all have a practical interest in the invention.
Merial submitted that Mr Lau, as the inventor, has a personal interest in supporting the grant of a patent on the present application, and that his evidence is not independent and not corroborated by any independent expert.
I will give regard to all of the evidence provided by the declarants. Where there is conflicting evidence, I will use the normal practice of evaluating and weighing the evidence in order to resolve any conflict.
7. Claims construction
The approach to claims construction was considered by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70; 81 IPR 228 at [118] – [120]:
“… the end point is that the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear. … While the claims define the monopoly claimed in the words of the patentee’s choosing, the specification should be read as a whole … It is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification … However, terms in the claim which are unclear may be defined or clarified by reference to the body of the specification …”
7.1 Construction of claim 1
Claims 1 is as follows:
A stable anthelmintic composition in the form of a micellar solution, comprising only two anthelmintic agents in an anthelmintically effective amount, wherein one anthelmintic agent is a macrocyclic lactone selected from the group consisting of: abamectin, ivermectin, doramectin, moxidectin, milbemycin and avermectin; and the other anthelmintic agent is an imidazothiazole selected from the group consisting of: levamisole, pyrantel pamoate and butamisole;
the composition further comprising a therapeutically acceptable carrier comprising water; at least one surfactant; one or more water miscible solvent(s) selected from the group consisting of one or more polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol; and a buffering system to adjust the pH of the composition to a range of about 5 to 5.5.
(a)Stable
The specification states (page 7, lines 2 – 4):
“As used herein the term ‘stable’ refers to a composition which is chemically and physically stable to a commercially acceptable level for a period of at least 6 months and preferably at least 12 months.”
The specification has therefore set up a dictionary, such that “stable” has a special meaning in this context. The nature of the dictionary principle was discussed by Viscount Haldane in British Thomson-Houston Company Ld. v Corona Lamp Works Ld. (1922) 39 RPC 49 at 67:
“We have to scan the Specification with the closeness which is required in the case of any instrument conferring a monopoly, but, subject to this, all we can legitimately do is apply the ordinary rules for the construction of written instruments. One of these, which is relevant in the case before us, is that the instrument must be read as a whole. The Claiming Clauses, for example, are not to be taken as standing in complete isolation. For if the Patentee has used in these clauses expressions which he has already adequately interpreted in the body of his Specification, he is entitled to refer to the Specification as a dictionary in which the meaning of the words he uses has been defined.”
(b)Micellar solution
The specification states at page 6, lines 31 – 32:
“As used herein the term ‘micellar solution’ refers to a thermodynamically stable single phase system.”
Similar to “stable” discussed above, the specification has established a dictionary for the term “micellar solution.”
Merial submitted that this term lacks clarity and this is considered further in part 8.
(c)Comprising only two anthelmintic agents
The specification states (page 5, lines 7 – 11):
“Throughout this specification, and unless it is stated to the contrary, the word ‘comprise’, or variations such as ‘comprises’ or ‘comprising’, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.”
The plain meaning of the word “only” is “exclusively” (Macquarie Dictionary).
Thus, although the anthelmintic composition may contain components in addition to those specifically listed in the claim, in the case of the anthelmintic agent there is the qualification that only two agents are present, i.e. the macrocyclic lactone and the imidazothiazole, with other agents excluded.
8. Clarity
Subsection 40(3) requires that the claims must be clear. A claim will lack clarity if a third party could not ascertain whether a proposed action would fall within the ambit of the claim (Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59).
Merial submitted that certain terms in the claims do not meet the requirements of both subsection 40(3) and paragraph 40(2)(b), which requires that the claims define the invention. At the hearing, the opponent indicated that if the claims were found to lack clarity under subsection 40(3), then non-compliance with paragraph 40(2)(b) would follow as a consequence. I will therefore only consider the ground of clarity.
(a)Micellar solution
Merial submitted that the term “micellar solution” is not clearly defined. In particular, the claim refers to the composition being in the form of a micellar solution, suggesting that the two anthelmintic agents are present in the micelles. Merial stated that this is incorrect, as only the macrocyclic lactone is contained within the micelle[3] and the imidazothiazole is present in the aqueous solution.
[3] Lichti-1 [27].
The specification states (page 8, lines 14 – 15):
“The micellar solution is thermodynamically stable and the macrocyclic lactone inside the micelles is well protected from reacting with the other actives in the formulation.”
Therefore, considering the specification as a whole, it is clear that the macrocyclic lactone is inside the micelles and the other active, specifically the imidazothiazole, is in the aqueous solution. I further note that Dr Lichti understands the present application to relate to formulations wherein only the lactone is contained within the micelle.[4]
[4] Lichti-2 [40] – [41], [43].
Merial also stated that the use of the term “micellar solution” to describe the whole composition is inaccurate. A micellar solution is one in which there are no solid particles present.[5] Dependent claims 13 and 17 define compositions comprising colloidal silicon dioxide, which is a suspended particle.
[5] Evidence in support for 2012200544, further declaration of Lichti dated 12 August 2015, [14].
Dr Martin, in discussing AU 2010201490 (D3), notes:
“that this three-way product contains abamectin, levamisole and a benzimidazole and is a micellar solution.”[6]
wherein the benzimidazole (BZ) is in suspension.[7]
[6] Martin-2 [32].
[7] Martin-2 [22] – [23].
Thus, Dr Martin refers to the formulations of D3 as “micellar solutions”, despite the presence of the suspended benzimidazole.
Therefore, although describing the compositions of claims 13 and 17 as “micellar solutions” may not be strictly technically correct due to the presence of solid particles such as colloidal silicon dioxide, I consider that this does not present any difficulty for the skilled addressee in determining the scope of the claims.
(b)Benzyl alcohol
Claim 1 lists benzyl alcohol as a water miscible solvent. Merial submitted that benzyl alcohol only partially mixes with water, whereas “miscible” requires that a substance mix with water in all proportions. Therefore the use of the term “water miscible” without qualification is not correct.[8]
[8] Evidence in support for 2012200544, further declaration of Lichti dated 12 August 2015, [45] – [47].
The specification states at page 10, lines 4 – 8:
“In a preferred embodiment of the composition, the macrocyclic lactone is in a solvent system. The solvent system is preferably miscible with water to form a single phase. In one embodiment the solvent system includes one or more solvents selected from the group comprising one or more liquid polyethylene glycols, tetraglycol, ethanol, benzyl alcohol and propylene glycol.”
It is therefore clear that the specification includes benzyl alcohol in the class of a “water miscible” solvent. I also note that “miscible”, in addition to the meanings “capable of mixing in any ratio without separation of two phases” and “capable of being mixed in all proportions” provided by Dr Lichti,[9] may also mean “capable of being mixed” (Macquarie Dictionary).
[9] ibid., [46].
I consider that when reading claim 1 it is clear that benzyl alcohol is categorised as a “water miscible” solvent, regardless of its physical properties. I further note that defining benzyl alcohol in this manner did not present any difficulties for Dr Martin when considering the components of the composition.[10] Thus, Exhibit PJM(EIR)-5 lists benzyl alcohol as a component defined by the present claims.
[10] Martin-2 [33].
8.1 Conclusion on clarity
It has not been established that the claims lack clarity.
9. Sufficiency and best method
Paragraph 40(2)(a) requires that a complete specification must describe the invention fully, including the best method of performing the invention. The High Court in Kimberly Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8; 207 CLR 1 at [25] stated that the question to consider is:
“will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty?”
Merial submitted that the specification is insufficient as it does not provide adequate teaching as to how to formulate micellar solutions across the whole range of amounts of the components claimed.
The specification describes methods for formulating the anthelmintic compositions (page 11, line 27 – page 12, line 9). Examples 1 to 3 on pages 12 – 13 disclose the preparation of specific formulations. This information is considered sufficient to enable the person skilled in the art to produce compositions that fall within the scope of the claims.
Merial made additional submissions relating to the inclusion of benzyl alcohol in the class of “water miscible” solvents. Merial stated that benzyl alcohol is the only specific solvent in that category that is exemplified. However, as benzyl alcohol is only partially soluble in water (40 g/L at room temperature), there is no information provided on how to use a water miscible solvent.
Furthermore, “water miscible” means a substance that mixes with water in all proportions. The specification states that the amount of benzyl alcohol can be 1 – 50 g/L (page 10, line 16), however this is in excess of its solubility in water (40 g/L).
I have previously found that the specification categorises benzyl alcohol as a “water miscible” solvent, notwithstanding its physical properties, and that the plain meaning of “miscible” allows for some variation in the amount of the substance that is mixed. Therefore, the use of a water miscible solvent, i.e. benzyl alcohol, is exemplified. I further note that Examples 1 to 3 all contain propylene glycol, which claim 1 also defines as a water miscible solvent.
In relation to the use of quantities of benzyl alcohol that exceed its solubility in water, I note that the reference in the specification to the use of more than 40 g/L of benzyl alcohol is in the context of a solvent system which also comprises propylene glycol (page 10, lines 15 – 17). In such systems, based on the quantities stated (5 – 250 g/L), propylene glycol is the primary solvent. I consider that the disclosure of the specification is sufficient to enable the skilled addressee to prepare a formulation comprising 1 – 50 g/L of benzyl alcohol, with the use of propylene glycol as the primary solvent, without difficulty.
9.1 Conclusion on sufficiency and best method
It has not been demonstrated that the specification fails to describe the invention fully.
10. Section 24
Jurox submitted that two of the prior art documents relied on by Merial, AU 2010201490 (D3) and AU 2010100349 (D4), must be disregarded for the purposes of determining novelty and inventive step under the provisions of subsection 24(1) (the “grace period”). Jurox and Mr Lau are the applicant (nominated person) and inventor, respectively, for both documents.
Subsection 24(1) provides:
“24 Validity not affected by certain publication or use
(1) For the purpose of deciding whether an invention is novel or involves an inventive step or an innovative step, the person making the decision must disregard:
(a) any information made publicly available, through any publication or use of the invention in the prescribed circumstances, by or with the consent of the nominated person or patentee, or the predecessor in title of the nominated person or patentee; and
(b) any information made publicly available without the consent of the nominated person or patentee, through any publication or use of the invention by another person who derived the information from the nominated person or patentee or from the predecessor in title of the nominated person or patentee;
but only if a patent application for the invention is made within the prescribed period.”
The “grace period” is a beneficial provision intended to cover circumstances where an inventor has inadvertently disclosed their invention prior to making a patent application for the invention.
Merial submitted that the grace period provisions do not apply. Merial stated that in order for the grace period to apply, it is necessary that the earlier document be a “publication … of the invention.” D3 and D4 are directed to anthelmintic compositions comprising at least three anthelmintic agents, whereas “the invention” of the present application is an anthelmintic composition containing two agents. Merial acknowledged that if this means that D3 and D4 each fall short of a novelty destroying disclosure, these documents nevertheless require consideration under the ground of lack of inventive step.
If the invention that is published in D3 and D4 must be “the same” as the present invention, as alleged by Merial, this would effectively mean that the grace period provisions are only relevant for information considered for novelty purposes and not inventive (or innovative) step. This is clearly not the case given the wording of section 24. Furthermore, such a narrow interpretation of “the invention” would not reflect the intent of the grace period.
The intention of section 24 was put beyond doubt by amendments introduced by the Raising the Bar Act.[11] These replaced the reference to “information made publicly available, through any publication … of the invention” in paragraph 24(1)(a) (the relevant paragraph in the present circumstances, as discussed below) with “information made publicly available”.
[11] The Explanatory Memorandum, Intellectual Property Laws Amendment (Raising the Bar) Bill 2011, items 32 and 33.
As stated in the Explanatory Memorandum:
“The grace period allows for public disclosure of information relating to an invention (under certain conditions) without that information affecting the tests for novelty, inventive step (for a standard patent) or innovative step (for an innovation patent) of a patent claiming the invention.
…
The purpose of the grace period is to cover circumstances where an inventor has inadvertently disclosed their invention prior to seeking patent protection.
…
The first problem with the current provision is that it only applies to publication or use of the invention. This means that the grace period could be taken only to apply to information that could deprive an invention of novelty, not to information that could deprive an invention of an inventive or innovative step. For example, the grace period would not apply in a circumstance where the patentee disclosed the work they had done, or a prototype that led directly to their invention.” (emphasis added)
From this statement it is clear that the grace period was always intended to apply to the ground of inventive step. I consider that the use of the term “could” indicates that although it was possible to interpret the grace period as only applying to information that deprived an invention of novelty, this was not the intention, and therefore the grace period also applied to information that deprived an invention of inventive step. Consequently, I do not consider there is any requirement that D3 and D4 disclose “the same” invention as the present invention.
Having established that D3 and D4 need not disclose “the same” invention, I will now consider whether the other requirements of section 24 are satisfied. In filing the applications for D3 and D4 with the Patent Office, it is reasonable to assume that Jurox consented to the subsequent publication of these documents in accordance with the requirements of the Patents Act and Patents Regulations. I therefore consider that in the present circumstances the relevant provision is paragraph 24(1)(a).
In relation to paragraph 24(1)(a), subregulation 2.2(1A) states that a prescribed circumstance is that there was a publication of the invention within 12 months before the filing date of the complete application. Subregulation 2.3(1A) further provides that the prescribed period is the period of 12 months after the information was first made publicly available.
The present application was filed on 8 December 2010. D3 was published on 4 November 2010, whilst D4 was published on 13 May 2010. Consequently, the requirements of subregulations 2.2(1A) and 2.3(1A) are met.
10.1 Conclusion on section 24
The requirements of section 24 have been met. Consequently, D3 and D4 must be disregarded for novelty and inventive step purposes.
11. Novelty
Under subsection 7(1), an invention is taken to be novel unless it is not novel in the light of the prior art base. Information in a document forms part of the prior art base for the purposes of novelty if it was published before the priority date of a claim.
It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aicken J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19; 137 CLR 228 at 235:
“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”.
This test is satisfied if the alleged anticipation discloses all the essential features of the invention claimed (Nicaro Holdings Pty Limited v Martin Engineering Company [1990] FCA 40; 16 IPR 545 at 549). In order to meet this requirement, the prior art “must contain clear and unmistakeable directions to do what the patentee claims to have invented” (The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 486).
Merial submitted that certain claims are not novel in view of the Q-drench® label (D1), AU 2010201490 (D3), AU 2010100349 (D4) and the “launch” or use of Q-drench® (A1).
As discussed previously, D3 and D4 must be disregarded for novelty purposes. D1 and A1 both relate to Q-drench® and therefore will be considered together.
11.1 Q-drench® label (D1) and use of Q-drench® (A1)
The label D1 in evidence is dated 31 July 2008 and therefore forms part of the prior art base. D1 indicates that Q-drench® contains four anthelmintic agents, namely abamectin (macrocyclic lactone), levamisole hydrochloride (imidazothiazole), albendazole (benzimidazole) and closantel.
Merial acknowledged that D1 and A1 only arise as lack of novelty citations if claim 1 is construed so as to encompass compositions that include more than two anthelmintic agents. As I have found that claim 1 defines a composition containing only two agents and no more, D1 and A1 do not provide clear and unmistakeable directions to prepare such a composition.
11.2 Conclusion on novelty
It has not been demonstrated that the claims lack novelty.
12. Inventive step
Under subsections 7(2) and 7(3), an invention is taken to involve an inventive step unless it would have been obvious to the person skilled in the art in the light of the common general knowledge, either considered alone or together with the prior art. The prior art is information that the skilled person could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant.
The test for whether an invention is obvious is whether it would have been a matter of routine to proceed to the claimed invention.
“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.” (Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12; 148 CLR 262 at 286)
In Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59; 212 CLR 411 at [53] (Alphapharm), the High Court accepted the approach taken in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at [187] where Graham J posed the reformulated Cripp’s question:
“Would the notional research group at the relevant date, in all the circumstances, …. directly be led as a matter of course to try [the claimed combination] in the expectation that it might well produce a [useful or better result]?” (emphasis in original)
Where the invention is a combination of integers (as in the present case), obviousness is to be determined by reference to the combination as a whole and not each integer individually. As stated in Alphapharm at [41]:
“The claim is for a combination, the interaction between the integers of which is the essential requirement for the presence of an inventive step. It is the selection of the integers out of ‘perhaps many possibilities’ which must be shown by Alphapharm to be obvious, bearing in mind that the selection of the integers in which the invention lies can be expected to be a process necessarily involving rejection of other possible integers.”
In AstraZeneca AB v Apotex Pty Ltd [2014] FCAFC 99; 107 IPR 177, the court held that in formulating the problem it is not permissible to incorporate information that is not available to the person skilled in the art either as common general knowledge or information available under subsection 7(3).
12.1 Determining the problem
At the hearing Merial submitted that the problem solution approach is not applicable in the present case, as there is no specific need for further anthelmintic compositions. Jurox in its submissions[12] refers to the broader question of “How would I produce a new anthelmintic formulation?”
[12] Jurox submissions [368].
The aim of the invention was previously considered in part 5.2. Consistent with this, the problem to be addressed is the provision of an anthelmintic composition comprising multiple active ingredients.
12.2 Common general knowledge
The common general knowledge was considered by Emmett J in ICI Chemicals & Polymers Ltd v Lubrizol Corporation Inc [1999] FCA 345; 45 IPR 577 at [112]:
“The common general knowledge is the technical background to the hypothetical skilled worker in the relevant art. It is not limited to material which might be memorised and retained at the front of the skilled workers mind but also includes material in the field in which he is working which he knows exists and to which he would refer as a matter of course. It might, for example, include:
·standard texts and handbooks;
·standard English dictionaries;
·technical dictionaries relevant to the field;
·magazines and other publications specific to the field.”
12.2.1 Common general knowledge – anthelmintic compositions
(a) Anthelmintic agents
The evidence indicates that the following matters are all part of the common general knowledge.
Common classes of anthelmintic agents are the benzimidazoles, the imidazothiazoles and the macrocyclic lactones.
Benzimidazoles have a broad spectrum of activity and include albendazole, oxfendazole and fenbendazole.[13] They are relatively chemically inert and insoluble in most biologically acceptable solvents.[14] They are generally used in the form of finely divided (micronised) powders and are easy to formulate.[15]
[13] Lichti-1 [22].
[14] Lichti-1 [23].
[15] Lichti-1 [23] – [24].
Levamisole is a commonly used anthelmintic agent belonging to the imidazothiazole class. The free base is soluble in oil, whereas the hydrochloride salt is highly soluble in water.[16] The hydrochloride is widely used in aqueous formulations.[17]
[16] Lichti-1 [25].
[17] ibid.
Macrocyclic lactones include ivermectin, abamectin, doramectin and moxidectin.[18] They are soluble in a range of common solvents, however have limited solubility in aqueous solutions.[19] Macrocyclic lactones are susceptible to hydrolysis and this may be enhanced in acidic or basic aqueous solutions.[20]
[18] Lichti-1 [26].
[19] Lichti-1 [27].
[20] ibid.
(b) Other ingredients
Common excipients used in anthelmintic compositions include surfactants, thickening agents, dispersing agents and suspending agents.[21]
[21] Lichti-1 [45], [48].
(c) Combining anthelmintic agents
It is common general knowledge that combining anthelmintic agents with different modes of action is an effective strategy for addressing the issue of parasite resistance.[22]
[22] Lichti-1 [32] – [33]; Martin-1 [22] – [32], [49].
12.3 Lack of inventive step in light of the prior art
Merial submitted that claims 1 – 25 are not inventive in the light of any one of the Q-drench® label (D1), AU 2010201490 (D3), AU 2010100349 (D4), EP 0 045 655 (D8) and its equivalents, WO 98/18463 (D10) and the “launch” or use of Q-drench® (A1) when considered together with the common general knowledge.
As discussed previously, D3 and D4 must be disregarded for inventive step purposes. Therefore the first question to consider is whether D1, D8, D10 and A1 would have been ascertained, understood and regarded as relevant.
Dr Lichti states that if he was asked to develop a multi-anthelmintic formulation, he would have searched patent databases.[23] Dr Martin indicates that by conducting patent and literature searches, a prudent research team would be able to glean much information from other commercial products.[24] Therefore I consider that D8 and D10 would have been ascertained.
[23] Lichti-1 [54].
[24] Martin-2 [39].
D1 is a label for the product Q-drench®. As noted above, Dr Martin states that he would obtain information on commercial products and it is not unreasonable that this would include product labels.
Dr Lichti indicates that he would seek information on commercially available products.[25] I note this statement is made in the context of finding information when developing a product including abamectin and levamisole hydrochloride, and with the aim of producing a micellar formulation.[26] Notwithstanding this, I nevertheless consider the approach of obtaining information on commercial products would generally apply.
[25] Lichti-1 [49] – [51].
[26] See question above Lichti-1 [49].
Dr Lichti states that possible sources of information include data disclosed to regulatory authorities,[27] such as the Australian Pesticides and Veterinary Medicines Authority (APVMA).[28] D1 in evidence indicates that it is from an APVMA file.
[27] Lichti-1 [51].
[28] Lichti-1 [17].
Based on the evidence of Dr Lichti and Dr Martin I consider it reasonable that D1 would be ascertained.
A1 is the “launch” or use of the product Q-drench®. Dr Lichti states that he is aware of the production and sale of Q-drench® and that this apparently started in January 2004.[29] Dr Martin believes Q-drench® was definitely marketed in Australia well before 2010.[30] I therefore consider it reasonable that A1 would be ascertained.
[29] Lichti-1 [67].
[30] Evidence in support for 2012200544, fifth declaration of Martin dated 13 August 2015, [11].
In determining the relevance of a document, it was stated in Beecham Group Limited’s (Amoxycillin) Application [1980] RPC 261 at 282 that:
“The test in my judgment is whether it can be expected that the skilled man will be likely to recognise the document in question as being particularly pertinent to, though it may not specifically solve the problem before him.”
I consider that the skilled addressee would regard as relevant those documents relating to anthelmintic compositions.
D1 indicates that Q-drench® is a multi-combination drench for sheep and therefore would be regarded as relevant. Although the exact information disclosed by the use of Q-drench®, namely A1, is less clear, it is nevertheless not unreasonable that A1 is relevant.
D8 was published on 10 February 1982 and therefore forms part of the prior art base. Its family members, AU 551280 (D8A) and US 4389397 (D8B), are also in evidence, however for the present purposes it is only necessary to refer to D8. D8 discloses liquid formulations containing the macrocyclic lactone ivermectin and their use in treating parasitic infections. D8 would therefore be regarded as relevant.
D10 was published on 7 May 1998 and thus forms part of the prior art base. It is directed to compositions comprising an anthelmintic compound, a selenium salt and other ingredients. D10 would therefore be regarded as relevant.
I will consider D1, A1, D8 and D10 in turn.
12.3.1 Q-drench® label (D1)
D1 indicates that Q-drench® contains the anthelmintic agents levamisole hydrochloride, abamectin, closantel and albendazole. No further information is disclosed about the composition in terms of its form or additional ingredients.
Merial submitted it was common knowledge that Q-drench® existed in the form of a micellar solution. Further, the two additional anthelmintic agents, closantel and albendazole, could simply have been removed or not added in order to obtain a composition containing two agents as claimed, and that it would have been obvious to do so. Consequently, on this basis, Merial stated that claims 1 – 25 lack an inventive step.
I will firstly consider the issue of whether it was common knowledge that Q-drench® existed in the form of a micellar solution. Merial submitted it was common knowledge at least following the Federal Court proceedings involving Jurox and Nufarm Pty Ltd, in which that issue was addressed in detail.
In Nufarm Ltd v Jurox Pty Ltd [2008] FCA 178; 75 IPR 341[31] (Nufarm) the Federal Court found that Q‑drench® is in the form of a micellar solution. This finding was upheld by the Full Court of the Federal Court in Nufarm Limited v Jurox Pty Limited [2008] FCAFC 180.[32]
[31] Exhibit GL-4.
[32] Exhibit HCLB(EIR)-1, see Exhibit SS.1 referred to therein.
Dr Lichti states that he was an expert witness in Nufarm:
“I note that I was involved as an expert witness in the Nufarm vs Jurox proceedings. On this basis I knew before 2010 that public-domain records from this litigation existed and would have been relevant to the formulation of multi-active anthelmintics, and especially to the formulation of liquid formulations which included a micellar solution. The subject of these proceedings was Q-drench marketed by Jurox from January 2004. The case was I understand reported as Nufarm Ltd v Jurox Pty Ltd 75 IPR 341, a copy of which is now produced and shown to me marked GL-4.”[33]
[33] Lichti-1 [55].
He further states:
“It was well known in Australia in 2009 that Q-drench formulation was based on the use of a micellar system to protect the ML [macrocyclic lactone]. In particular published material from the Nufarm v Jurox litigation contains this information.”[34]
[34] Lichti-1 [67].
One would expect Dr Lichti to be aware that Q-drench® is in the form of a micellar solution, given his role as an expert witness in the Nufarm proceedings. However, I am not satisfied that this was common general knowledge. Although Dr Lichti states it was well known in 2009 that the Q-drench® formulation was based on a micellar system, this statement is further qualified by reference to the publication of the Nufarm proceedings. I do not consider that material published from Federal Court proceedings falls into the category of information that the skilled addressee would refer to as a matter of course.
I also note that none of the other declarants has stated that they consider it was well known or common general knowledge that Q-drench® existed in the form of a micellar solution.
Consequently, it has not been established that it was common general knowledge that Q-drench® existed in the form of a micellar solution. Furthermore, there is no evidence to suggest that the person skilled in the art would combine D1 with the Federal Court publication of the Nufarm proceedings.
Therefore, the question to consider is whether based solely on the information on D1 that Q‑drench® contains four active ingredients, it would have been a matter of routine to prepare an anthelmintic composition in the form of a micellar solution that contains only two active ingredients.
Merial’s submissions rely on the premise that D1 is in the form of a micellar solution. In the absence of this information, I am not satisfied that the evidence demonstrates it would be a matter of routine to prepare an anthelmintic composition in the form of a micellar solution based merely on the disclosure of the label. It has not been shown that there is a lack of inventive step in the light of D1.
Given this finding, it is not necessary to consider whether it would have been a matter of routine to omit two anthelmintic agents from D1.
12.3.2 “Launch” (use) of Q-drench® (A1)
A1 relates to the “launch” or use of the product Q-drench®. The exact nature of the information disclosed by the use of the product is less clear, however I consider it can be no more than that disclosed by the label D1. I have previously found that it has not been established that the claims lack an inventive step in the light of D1. It necessarily follows that it has not been demonstrated that there is a lack of inventive step in view of A1.
12.3.3 EP 0 045 655 (D8)
Merial submitted that claims 1 – 25 are not inventive in view of D8 and the common general knowledge.
D8 discloses anthelmintic formulations wherein the macrocyclic lactone ivermectin is located within micelles (abstract). The document indicates that the ivermectin is solubilised and stabilised through the use of surfactants to dissolve the anthelmintic agent, and certain cosolvents and substrates to stabilise the thus formed micelle solution (page 2, lines 14 – 23). The resultant anthelmintic formulations possess increased stability, losing less than 5% of ivermectin activity over a 2 to 3 year period (page 4, lines 10 – 22).
Cosolvents include propylene glycol and polyethylene glycol, whilst the substrate may be benzyl alcohol (page 3, lines 22 – 36). Other formulation components are buffering agents and water and the pH range of 6.0 to 6.5 is preferred for optimum stability (page 4, lines 1 – 7).
Examples 2 and 3 describe formulations comprising MK-933 (ivermectin[35]), TWEEN 80 (surfactant), benzyl alcohol, monobasic and dibasic sodium phosphate (buffer) and water. Example 3 additionally contains propylene glycol. The formulations of D8 differ from the claimed invention in that there is no imidazothiazole present and the preferred pH range is 6.0 to 6.5.
[35] Lichti-1 [82].
The problem to be addressed in the present application is the provision of an anthelmintic composition comprising multiple active ingredients. As discussed previously, it is common general knowledge that combining anthelmintic agents with different modes of action is an effective strategy for addressing the issue of parasite resistance. However, it is necessary to consider whether it would be a matter of routine for the person skilled in the art to prepare an anthelmintic composition by combining an imidazothiazole with the formulation of D8 and thereby arrive at a composition with a pH of about 5 to 5.5 as defined by the present claims.
(a)Combining ivermectin with another anthelmintic agent
Dr Martin states that resistance to ivermectin was reported in both Australia and New Zealand.[36] He indicates that a 2006 report showed that ivermectin resistance was evident in New Zealand beef cattle farms and the parasite most prevalent in resistant populations was Cooperia spp. However, none of these populations showed resistance to levamisole.[37] He further submits:
“It had been noted back in 1997 that resistance to levamisole was relatively rare in H. contortus while it was common in Ostertagia and Trichostrongylus colubriformis.
These reports of LEV [levamisole] being potentially an effective anthelmintic against ML [macrocyclic lactone] resistant H. contortus in sheep and Cooperia in cattle, stimulated interest in using LEV in these specific situations to control the parasites and delay any increase in resistance. Hence, the logical extension was to include LEV in a combination anthelmintic with IVM [ivermectin] or another ML.”[38]
[36] Martin-1 [30] – [31].
[37] Martin-1 [36].
[38] Martin-1 [37] – [38].
He later concludes:
“Following the reports of H. contortus and Cooperia showing resistance to the ML class but susceptibility to LEV, interest was in combining an ML with LEV.”[39]
[39] Martin-1 [50].
Dr Martin indicates that as a result of the resistance problems, various dual, triple and quad active products were developed.[40]
[40] Martin-1 [39] – [44].
Dr Martin comments on the relative merits of triple and dual active products. He states that:
“The triple active compounds had the same level of activity against all of the parasites that resulted from the presence of an ML [macrocyclic lactone] and levamisole as would be achieved by a dual active formulation that had the same concentration of an ML and levamisole. The perception in the industry was that a triple active was more desirable because it increased the efficacy which may prevent or delay the development of future resistance.”[41]
[41] Martin-1 [47].
He also indicates that in some areas of Australia resistance had developed to each of the three families [i.e. macrocyclic lactones, imidazothiazoles (levamisole) and benzimidazoles] and thus a desirable product would be a formulation with an active from all three families.[42]
[42] Martin-2 [35], point (2).
In relation to dual active products, Dr Martin states that a dual active combination of a macrocyclic lactone and levamisole would be a desired commercial product in areas of Australia where the resistance to one anthelmintic class, for example benzimidazoles, was greater than in others.[43] Dual active component formulations would also be cheaper to manufacture than triple or four active formulations.[44]
[43] ibid., point (3).
[44] ibid., point (4).
Based on the evidence, the skilled addressee would, as a matter of routine, consider combining an imidazothiazole (such as levamisole) with a macrocyclic lactone (such as ivermectin) in order to produce a dual active or triple active anthelmintic composition. For the present purposes, it is only necessary to consider the production of a dual active anthelmintic composition.
(b)Combining anthelmintic agents – general formulation considerations
Mr Lau indicates that veterinary formulations generally require certain physical and chemical properties.[45] In regard to combinations of active ingredients, he states:
[45] Lau [24].
“… if two actives are to be included in a formulation the formulator is clearly faced with a challenge of getting all of the actives into the formulation. The formulator must consider the following additional issues:
(a) pH requirements for each active;
(b) interactions between the actives;
(c) interactions between the actives and excipients;
(d) solvent type – aqueous or organic;
(e) flowability;
(f) effect of temperature on the physiochemical properties of the formulation;
(g) viscosity; and
(h) stability.”[46]
[46] Lau [30].
He additionally comments that devising a successful formulation is not straightforward and generally requires some ingenuity on the part of the formulator.[47]
[47] Lau [27].
Dr Lichti states:
“There are several issues that would need to be considered when formulating a multi-active combination product:
·Compatibility and stability of each active agent in a practical common formulation medium,
·pH compatibility,
·possible reactivity issue between components (including various active agents, water, and formulation adjuvants),
·physical stability of the complete formulations which will generally contain more types of components and more phases/microenvironments than a formulation comprising only one active agent. This means ensuring the final formulation remains homogeneous under typical storage conditions.
The last of the above mentioned characteristics (physical stability of a more complex system) can be particularly challenging to achieve because the number of possible instability mechanisms is greater than in formulations made with only one type of active agent. Having said that, however, the preparation of stable multiple active combination products which incorporate active agents from more than one class has been well known and such products have been routinely prepared since before the priority date of 8 December 2010. This is evidenced by the large number of products on the market which contained multiple actives in the one dosage form.”[48]
[48] Lichti-1 [34] – [35].
Dr Martin indicates that in his experience, the issues raised by Mr Lau “are the normal considerations of a formulator.”[49]
[49] Martin-2 [15].
The evidence indicates that there are various issues that arise when formulating an anthelmintic composition containing multiple active ingredients. These issues are considered to be those that the skilled addressee would routinely expect to encounter in the course of formulating such a composition. However, it does not necessarily follow that overcoming these issues is a matter of routine.
I will now consider whether the addition of an imidazothiazole, such as levamisole, to the composition of D8 would be a matter of routine.
(c)Addition of anthelmintic agent to a composition comprising a micellar solution
In discussing D8, Dr Martin states:
“This taught how to solubilise IVM [ivermectin] in a micelle using a surfactant, a co-solvent and a water miscible organic solvent. The relatively small amount of IVM in these water based formulations allowed the opportunity to add additional anthelmintics in combination with the IVM micelle. This was in my view a well recognised formulation strategy by November 2010. Adding levamisole hydrochloride to the IVM micellar system would have been one option that a formulator in a development team would have considered. Adjustment of the pH to reach the level at which the two actives were as stable as possible would have been a routine step.”[50]
[50] Martin-1 [48].
He further states:
“I believe a formulator wanting to produce a combination product of an ML [macrocyclic lactone] and an imidazothiazole (such as levamisole hydrochloride) would be aware of the original Merck patent EP 045655 [D8] and therefore know that a formulation utilising a micelle to protect the ML from degradation would be a good vehicle for dissolving the levamisole hydrochloride and then adjusting the pH to provide the most stable environment.
I believe therefore the formulations claimed in ‘226 [the present application] are the result of routine formulation techniques.”[51]
[51] Martin-1 [51] – [52].
Dr Lichti comments on D8 as follows:
“To any formulator engaged with the development of the formulations containing both an ML [macrocyclic lactone] and water, a natural strategy would have been to utilise the protective effect of a suitable micelle on the ML.
I believe it would have been apparent to a formulator in Australia prior to December 2010 that adding soluble materials into the aqueous micellar system described in EP 45655 [D8] would have been a useful strategy.”[52]
[52] Lichti-1 [68] – [69].
In relation to micellar solutions, Mr Lau comments on the effect other components may have. Thus:
“In a micellar solution, the amount of surfactant is critical to micelle formation and micellar stabilization which could also be affected by other components in a complicated matrix formulation.”[53]
[53] Lau [20].
In considering D8, he states:
“It neither provides any information on formulating a composition containing a mixture of macrocyclic lactone and imidazothiazole nor discloses how to overcome the stability problem for such a liquid combination micellar solution.”[54]
[54] Lau [78].
Mr Lau indicates that formulation of a macrocyclic lactone and an imidazothiazole presents particular difficulties, as they are chemically incompatible and therefore the interaction between the two actives must be minimised.[55] He further states that the lactone is only stable in a pH environment close to neutral, while imidazothiazoles are generally only stable in an acidic environment.[56]
[55] Lau [36].
[56] Lau [35], [38] – [39].
In response to Mr Lau’s comments on D8, Dr Lichti states:
“KKL [Lau] in this assertion is correct in the very narrow sense that prior art D8 does not disclose a full solution to the stability problem. However the formulations of D8 have a lot in common with the formulations of the opposed application ie,
(i) there is an aqueous micellar formulation with ML [macrocyclic lactone] inside the micelles, and
(ii) the de-stabilising agent for ML (water) is outside the micelles.
Compare this with the formulations of the opposed patent, where
(i) there is also an aqueous micellar formulation with ML inside the micelles, and
(ii) the de-stabilising agent (aqueous levamisole hydrochloride) is outside the micelles.
The key micellar components in D8 are very close to the key micellar components in the formulations of the opposed application (see table). In D8 there is an abundantly clear teaching that the de-stabilising agent for ML can be separated from ML by having the ML inside a micelle, and the de-stabilising agent outside the micelle. There is only a small step from this teaching to the formulation of the opposed patent.”[57]
[57] Lichti-2 [40] – [42].
Dr Martin states:
“Kai Lau appears to maintain that formulating an ML [macrocyclic lactone] and levamisole (Lev) together presented a formidable challenge in December 2010. I do not agree. All the difficulties he outlines are, in my experience, standard formulation work.
….
Starting from the micellar system described in EP 045655 [D8] was a further option that would have led to a successful formulation even if some trial and error might be involved.”[58]
[58] Martin-2 [19], [21].
Dr Lichti and Dr Martin indicate that they would consider adding levamisole to the composition of D8. This would necessarily require reformulation of the composition as noted by Mr Lau. The question to consider is whether the reformulation required in order to produce a composition that falls within the scope of the present claims would be a matter of routine. For reasons discussed below, this question reduces to whether it would have been a matter of routine to adjust the pH to a range of about 5 to 5.5, rather than the preferred range of 6.0 to 6.5 in D8.
D8 teaches that micelles may be used to solubilise and stabilise macrocyclic lactones. Dr Lichti and Dr Martin indicate that the micelle protects the macrocyclic lactone from degradation. This overcomes many of the problems alluded to by Mr Lau, such as the need to minimise the interaction between the macrocyclic lactone and the imidazothiazole Therefore, the solution to the stability issue seems to lie solely in adjusting the pH to a range of about 5 to 5.5.
The specification states that preferably the pH of the composition is about 5 to 5.5 (page 10, lines 26 – 27) and that the pH is preferably adjusted before adding the imidazothiazole to ensure that it is buffered to remain as an acidic water soluble salt (page 12, lines 3 – 5).
Mr Lau states:
“To formulate the invention I chose a buffer solution close to neutral pH. As an example, Example 4 of the present invention formulation uses phosphate buffers and is buffered to a pH of about 5.5. Surprisingly the pH successfully balances the stability of avermectin and levamisole. This is an achievement because a neutral pH is desirable for administration to animals as it makes the formulation more palatable.”[59]
[59] Lau [48].
It is not clear which example Mr Lau is referring to, as the specification only contains Examples 1 to 3 and the macrocyclic lactone exemplified is either abamectin or moxidectin. Consequently, I give Mr Lau’s evidence on this point low weight.
Dr Martin states that adjusting the pH to reach the level at which the two actives are as stable as possible would have been a routine step. In response to Mr Lau’s comments, he indicates that the pH of Q-drench® is similar, 5.5 – 6.5 in 2008; 5.0 – 5.5 in 2012 and 2014.[60] I note that Dr Martin also refers to a pH range for Q-drench® of 5.3 – 5.5.[61] He further states that the pH for different products ranges from very acidic (about 2) to alkaline (9.5) and that all of these would meet the requirement of a stable anthelmintic and be acceptable to an animal.[62]
[60] Martin-2 [29].
[61] Martin-2 [4].
[62] Martin-2 [30].
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