Merial Limited v Bayer Intellectual Property GmbH
[2016] APO 17
•1 April 2016
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Merial Limited v Bayer Intellectual Property GmbH [2016] APO 17
Patent Application: 2007341648
Title:Combination product for controlling parasites on animals
Patent Applicant: Bayer Intellectual Property GmbH
Opponent: Merial Limited
Delegate: Dr M-A. Fam
Decision Date: 1 April 2016
Hearing Date: 19 February 2016, in Canberra
Catchwords: PATENTS – section 59 – opposition to the grant of a patent – grounds of novelty and inventive step considered – novelty – citation does not disclose all the features of the claims – inventive step – determining the problem requires consideration of the common general knowledge and subsection 7(3) information – problem addressed is the provision of a topical ectoparasiticidal formulation that has a broad spectrum of activity, is safe to use on the target animal and reduces penetration of N-arylpyrazoles into the circulation – evidence does not establish that formulation of two active ingredients and three other components is a matter of routine – opposition fails
Representation: Patent applicant: Mr Julian Cooke of counsel instructed by Dr Mathew Lucas and Dr Althea Tsang of Davies Collison Cave
Opponent: Mr Tom Cordiner of counsel instructed by Dr Marcus Caulfield and Dr Toby Thompson of FB Rice
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2007341648
Title:Combination product for controlling parasites on animals
Patent Applicant: Bayer Intellectual Property GmbH
Date of Decision: 1 April 2016
DECISION
The opposition fails on all grounds. Subject to appeal, I direct the application proceed to grant. Costs according to Schedule 8 are awarded against Merial Limited.
REASONS FOR DECISION
1. Background
The present application was filed by Bayer Healthcare AG on 14 December 2007. Bayer Healthcare AG subsequently changed its name to Bayer Animal Health GmbH and the latter assigned its rights to Bayer Intellectual Property GmbH (Bayer). Following examination, the application was advertised accepted on 5 June 2014.
A notice of opposition was filed by Merial Limited (Merial) on 5 September 2014. A hearing was held in Canberra on 19 February 2016. Bayer was represented by Mr Julian Cooke of counsel instructed by Dr Mathew Lucas and Dr Althea Tsang of Davies Collison Cave. Merial was represented by Mr Tom Cordiner of counsel instructed by Dr Marcus Caulfield and Dr Toby Thompson of FB Rice.
The request for examination in relation to the application was filed on 22 September 2011. Consequently, substantive amendments of the Patents Act 1990 brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 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.
It is noted that the parties were heard in relation to the opposition to the grant of patent application 2007341647 on 18 February 2016. The present application and 2007341647 relate to similar subject matter. However, each case has its own evidence and the issues considered are not identical (for the decision on 2007341647 see Merial Limited v Bayer Intellectual Property GmbH [2016] APO 16).
2. Grounds of opposition
The original statement of grounds and particulars was filed on 5 December 2014. A request to amend the statement was filed on 5 March 2015 and subsequently allowed.
The statement of grounds and particulars specifies the following grounds of opposition:
- novelty
- inventive step
- manner of manufacture
- section 40 issues of clarity, fair basis and full description
- utility
- secret use.
The grounds pressed at the hearing were limited to novelty and inventive step.
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 at [67]; 50 IPR 305; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18]; 79 IPR 426).
4. Evidence
The evidence is summarised in the table below.
Evidence Declarant Exhibits Date Reference Leonore C. Witchey‑Lakshmanan
LCWL-1 to LCWL-32 3 March 2015 Witchey-Lakshmanan-1 Jeffrey N. Clark
JNC-1 to JNC-20 4 March 2015 Clark-1 In Support Joe R. Pippia JRP-1 to JRP-10 4 March 2015
Pippia-1 Toby Alexander Thompson
TAT-1 5 March 2015 Thompson Marcus Caulfield
D19 to D24, D27, D28, D30 to D36 and D39 to D41 5 March 2015 Caulfield In Answer
James S. Rowe
JSR-1 to JSR-2 21 May 2015 Rowe-1 Gavin Dean Recchia
GDR-1 to GDR-2 10 June 2015 Recchia James S. Rowe JSR-3 to JSR-10 10 June 2015 Rowe-2 Leonore C. Witchey‑Lakshmanan
LCWL-33 7 August 2015 Witchey-Lakshmanan-2 In Reply Jeffrey N. Clark
JNC-21 to JNC-30 6 August 2015 Clark-2 Joe R. Pippia
JRP-11 to JRP-12 6 August 2015 Pippia-2 5. Regulation 5.23
Two of the prior art documents relied on by Merial, AU 2002338201 (D13) and AU 2006201364 (D15), are in evidence as the B level publications which were published after the earliest priority date of the present claims (27 December 2006). During the hearing, I invoked regulation 5.23 in relation to the corresponding A level publications of these documents. A comparison of the A and B level publications indicates that the differences between the documents are only minor in nature.
6. The subject matter of the specification
6.1 Background of the invention
The specification relates to compositions for controlling parasites on animals. N-Arylpyrazoles are known for their insecticidal and acaricidal activity. In particular, the compound 1-[2, 6-dichloro-4-(trifluoromethyl)phenyl]-3-cyano-4-[(trifluoromethyl)sulphinyl]-5-aminopyrazole (fipronil) is regarded as being particularly effective for controlling most parasites (page 1).
When formulations containing N-arylpyrazoles are applied topically, the compounds accumulate in the sebaceous glands and are gradually released over a period of time. The specification states that in the case of customary formulations, penetration of the N‑arylpyrazoles into the circulation is also likely, and thus the availability of the active compound on the animal is limited both with respect to duration and concentration (pages 1 – 2). The specification further indicates that N‑arylpyrazoles are less effective against ticks from the genus Ixodes than those from other genera (page 2).
Pyrethroids are similarly known for their insecticidal and acaricidal activity. However, some pyrethroids are not tolerated by cats and, compared with N-arylpyrazoles, are less active against ticks of the genus Dermacentor (page 2).
The specification states that since most pyrethroids are detoxified via the p450 oxidase pathway, they have to be considered to be antagonists rather than synergists of N-arylpyrazoles (page 3). Whilst the prior art discloses that the treatment of ectoparasites with mixtures of N-arylpyrazoles and pyrethroids is possible when concentrated powder formulations are used, these are difficult to apply in practice (page 3).
6.2 Aim of the invention
The specification states (page 3, line 32 to page 4, line 3):
“…. it has to be the object to prepare a self-spreading liquid formulation having a good user safety profile which combines the positive activity properties of the pyrethroids with those of the N-arylpyrazoles and does not result in a reduction of the efficacy of the N-arylpyrazoles even in the presence of further synergists from the class of the p450 oxidase inhibitors.”
6.3 Nature of the invention
The specification indicates that certain formulations can improve the efficacy of N‑arylpyrazoles in combination with pyrethroids. Thus, in one aspect, the invention provides compositions comprising an N-arylpyrazole, one or more esters of a dihydric or trihydric alcohol having up to three carbon atoms with organic fatty acids having 6 to 18 carbon atoms (fatty acid ester), and a pyrethroid, in a formulation comprising:
·an aliphatic cyclic carbonate; and
·an aliphatic cyclic or acyclic polyether.
In a further aspect, the compositions may be used to control parasites on animals and in particular ectoparasites such as fleas and ticks.
6.4 The claims of the specification
The claims as accepted consist of composition claims 1 – 10, “Swiss” claim 11, method claim 12 and omnibus claim 13.
7. The person skilled in the art
The person skilled in the art was considered at the hearing. As stated in Root Quality Pty Ltd v Root Control Technologies Pty Ltd [2000] FCA 980 at [70] – [71]; 49 IPR 225:
“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.”
Dr Witchey-Lakshmanan has experience in the formulation and process development of pharmaceutical veterinary products, including topical and spot on formulations. Dr Rowe has experience in the formulation and testing of a range of veterinary products such as topical pour on formulations. Dr Clark has experience in animal health products with a focus on parasite control. Mr Pippia has experience in the development of spot on insecticidal formulations for animals. I consider that Dr Witchey-Lakshmanan, Dr Rowe, Dr Clark and Mr Pippia would all have a practical interest in the invention.
I will give regard to all of the evidence provided by the four declarants. Where there is conflicting evidence, I will use the normal practice of evaluating and weighing the evidence in order to resolve any conflict.
8. Claims construction
The approach to claims construction was considered by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [118]-[120]; 81 IPR 228:
“… 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 …”
8.1 Construction of claim 1
Claim 1 is the only independent claim and is as follows:
Composition for controlling parasites on an animal comprising an N-arylpyrazole, one or more esters of a dihydric or trihydric alcohol having up to three carbon atoms with organic fatty acids having 6 to 18 carbon atoms, and a pyrethroid, in a formulation comprising:
an aliphatic cyclic carbonate; and
an aliphatic cyclic or acyclic polyether.
(a)Composition for
The claim is directed to “A composition for controlling parasites on animals”. The term “for” is construed as merely indicating that the composition must be suitable for the intended purpose, but does not limit the composition only to that environment (Faberwerke Hoescht Aktiengesellschaft vormals Meister Lucius & Bruning’s Application (1964) AOJP 1483). Thus, the claim is considered to define a composition per se, wherein the composition is such that it is suitable for controlling parasites on animals.
(b)N-Arylpyrazole
Adopting the plain meaning, an N-arylpyrazole is understood to be a compound wherein an aromatic group, which may include one or more heteroatoms, is attached to one of the nitrogen atoms of the pyrazole ring. The parties confirmed that this is the intended meaning in the claims, and this is consistent with formula (I) depicted on page 5 of the specification, which allows for both phenyl and pyridyl rings to be attached to the pyrazole.
8.2 Construction of claim 11
Claim 11 reads as follows:
Use of a composition according to any one of claims 1 to 10 for preparing a medicament for controlling parasites on animals.
Claim 11 is a “Swiss” type claim, the construction of which was considered by Yates J in Otsuka Pharmaceutical Co., Ltd v Generic Health Pty Ltd (No 4) [2015] FCA 634; 113 IPR 191. It was held that a Swiss claim defines a method or process for making a medicament, wherein the intended therapeutic use of the medicament qualifies the scope of the claim.
Claim 11 is construed to define a method for making a medicament containing the composition of any one of claims 1 to 10, wherein the intended use of the medicament is to control parasites on animals.
9. 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 at [20]; 137 CLR 228:
“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 at [19]; 16 IPR 545). 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) (General Tire).
Merial submitted that claims 1 – 3, 5 – 8, 11 and 12 are not novel in view of US 2006/0252728 (D2).
9.1 US 2006/0252728 (D2)
D2 was published on 9 November 2006 and therefore forms part of the prior art base. D2 describes compositions comprising a pyrethrin or pyrethroid and the synergist MGK 264 and their use in controlling parasites on animals. D2 indicates that in a further embodiment other active ingredients may be included in the composition, of which N‑phenylpyrazoles are one of a range of possibilities ([0024], [0068]).
The compositions may contain other components, including cyclic carbonates (such as propylene carbonate), aliphatic cyclic or acyclic ethers [such as diethylene glycol monoethyl ether (DGME)] and triglycerides based on caprylic acid and caprinic acid (fatty acid ester) ([0088]).
The 17 preparative examples describe various formulations. Each formulation contains the pyrethroid flumethrin in combination with another active ingredient belonging to the neonicotinoid class of insecticides, i.e. no N-arylpyrazoles are exemplified. In relation to the other components of the formulation, 10 examples contain propylene carbonate, 3 examples contain Miglyol 812® (a mixture of caprylic/capric triglyceride fatty acid ester) and 1 example contains both propylene carbonate and Miglyol 812®. However, none of the examples contain the combination of an aliphatic cyclic carbonate, an aliphatic cyclic or acyclic polyether and an ester of a dihydric or trihydric alcohol (fatty acid ester).
D2 does not provide clear and unmistakeable directions to prepare a composition comprising an N-arylpyrazole, a pyrethroid, an aliphatic cyclic carbonate, an aliphatic cyclic or acyclic polyether and a fatty acid ester.
Merial further submitted that the claims do not represent a valid selection over the disclosure of D2. Thus, the claimed formulations are not associated with any particular advantage and arbitrarily singling out one suitable combination over others does not constitute a valid selection.
It is only necessary to consider the issue of a selection where a citation contains clear and unmistakeable directions and prima facie the claims lack novelty. As I have found that the claimed invention is novel according to the principles outlined in General Tire, the issue of a selection does not require further consideration.
It has not been demonstrated that the claims lack novelty.
10. 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 at [45]; 148 CLR 262)
In Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59 at [53]; 212 CLR 411 (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 (AstraZeneca), 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).
10.1 Determining the problem
Bayer submitted that the specification addresses the problems of:
·existing formulations containing N-arylpyrazoles penetrating into the circulation and therefore the availability of the active compound on the animal is limited both with respect to duration and concentration (the first problem).
·the efficacy of N-arylpyrazoles against representatives of the genus Ixodes being less than that against other genera of ticks (the second problem).
·pyrethroids having frequent incompatibilities and only particularly non-toxic representatives with limited efficacy can be used for cats (the third problem).
·compared to N-arylpyrazoles, pyrethroids are less active against ticks of the genus Dermacentor (the fourth problem).
·pyrethroids being antagonists of N-arylpyrazoles (the fifth problem).
·mixtures of N-arylpyrazoles and pyrethroids previously used to treat ectoparasites are concentrated powder formulations and are unsuitable for application on homeotherms (the sixth problem).
Merial stated that the problem addressed by the specification is the provision of an alternative topical ectoparasiticidal formulation.
In determining the problem it is necessary to have regard to the specification, and consider the common general knowledge and subsection 7(3) information as per AstraZeneca. Prima facie all of the documents in evidence (identified in the statement of grounds and particulars or presented as exhibits) relate to aspects of ectoparasiticidal formulations and are considered potential subsection 7(3) information.
I will consider each of the problems posed by Bayer in turn.
10.1.1 The first problem
The first problem relates to existing formulations containing N-arylpyrazoles penetrating into the circulation and therefore the availability of the active compound on the animal is limited both with respect to duration and concentration.
(a) What does the specification say?
The specification states at page 1 that existing formulations of N-arylpyrazoles (fipronil) have a high content of DEE (Transcutol) (DGME), which facilitates penetration into the sebaceous glands and epithelium. Reference is made to an article by Cochet et al., European Journal of Drug Metabolism and Pharmacokinetics, 1997, 22(3), 211 – 216 (Cochet), which demonstrates that fipronil accumulates in the sebaceous glands and epithelial layers. Cochet further confirms “the low percutaneous passage of fipronil” (Summary).
The specification indicates on page 2 that penetration of N-arylpyrazoles into the circulation is also likely, “since each hair follicle [which is associated with one or more sebaceous glands] is supplied by a blood vessel and the follicles are thus separated from the circulation by only a very thin barrier.” In this context reference is made to an article by Meidan et al., International Journal of Pharmaceutics, 2005, 306, 1 – 14 (Meidan). Meidan discusses exploiting the follicles as transport shunts for systemic drug delivery (Abstract).
(b) What was the common general knowledge and subsection 7(3) information?
I will now consider the common general knowledge and subsection 7(3) information insofar as they are relevant to determination of the problem(s). A more detailed discussion of the common general knowledge is provided in part 10.2.
Fipronil
The evidence indicates that it is commonly known that N-arylpyrazoles, and in particular fipronil, are broad spectrum ectoparasiticides.[1] Fipronil is the active ingredient in the Frontline® range of commercial products.[2] Dr Witchey-Lakshmanan and Dr Clark state that when fipronil is applied topically, it accumulates in the sebaceous glands and is then gradually released over a period of time.[3]
[1] Witchey-Lakshmanan-1 [34] – [35]; LCWL-5; Clark-1 [40].
[2] Witchey-Lakshmanan-1 [59]; Clark-1 [44]; Pippia-1 [24], [31] – [34].
[3] Witchey-Lakshmanan-1 [36]; Clark-1 [42].
Penetration of fipronil into the circulation
Dr Witchey-Lakshmanan indicates that fipronil is not thought to be systemically active, i.e. it is not effectively absorbed into the bloodstream.[4] With reference to Brayden, Irish Veterinary Journal, 2003, 56(6), 310 – 316 (LCWL-26) (Brayden), she states that the loss of fipronil to systemic delivery is no more than 5%. Therefore, even if a formulation could prevent the entire 5% from being delivered systemically, then any increase in duration of delivery would amount to at most 5%.[5] The loss of fipronil to systemic absorption is not significant and does not significantly reduce the effectiveness of fipronil.[6] Thus, Frontline® products are demonstrated to have a long duration of efficacy.[7] Dr Witchey-Lakshmanan considers that this problem posed by Bayer does not exist.[8]
[4] Witchey-Lakshmanan-1 [187] with reference to Cochet; Witchey-Lakshmanan-2 [26], [81] with reference to Cochet.
[5] Witchey-Lakshmanan-2 [27], [82].
[6] Witchey-Lakshmanan-2 [26] – [27].
[7] Witchey-Lakshmanan-1 [198] – [200]; Witchey-Lakshmanan-2 [27]; LCWL-29; LCWL-30; LCWL-31.
[8] Witchey-Lakshmanan-1 [188], [196]; Witchey-Lakshmanan-2 [24], [27], [28].
Dr Clark states that the Cochet study demonstrates that no fipronil passes into the bloodstream. Furthermore, it is very unlikely that there is significant accumulation of fipronil in the blood upon topical administration, as oral consumption of fipronil at or near the therapeutic dose for flea efficacy can lead to vomition in dogs.[9] Dr Clark agrees that fipronil has demonstrated long activity.[10] In relation to the problem posed by Bayer, he states “I do not think that there was any problem of significant systemic exposure to fipronil upon topical treatment such as that supposedly caused by the Frontline® products which needed to be addressed in the opposed specification.”[11]
[9] Clark-1 [42], [68] – [69]; Clark-2 [11] – [13]; JNC-24.
[10] Clark-1 [43]; JNC-5.
[11] Clark-2 [13].
Mr Pippia indicates that he is not aware of any problems associated with systemic exposure to fipronil and if there was any systemic absorption, it is not associated with a reduction in efficacy.[12] In his opinion this is not a problem requiring solution.[13]
[12] Pippia-2 [18] – [19] with reference to Brayden and Cochet.
[13] Pippia-2 [19].
Dr Rowe in response states, with reference to Cochet, that there is no data describing the analysis of the concentration of fipronil in the blood and no evidence that there is in fact no systemic delivery.[14]
[14] Rowe-2 [113], [115], [148].
Bayer made reference to several exhibits to demonstrate that fipronil (contained in various Frontline® products) is absorbed into the bloodstream. Two of these refer to the same product, Frontline® Combo Spot-on Cat (LCWL-14 and LCWL-15), and the third to Frontline® Spot-on Dog (D26). The relevant details are summarised in the table below.
Frontline® Product Amount of Systemic Absorption of Fipronil Document Date
(1. Date of First Authorisation/Renewal of the Authorisation
2. Date of Revision of the Text)Combo Spot-on Cat (LCWL-15) 18% (additional potential oral exposure from licking)
1. 29 January 2004
2. December 2014Spot-on Dog (D26) 15% 1. 17 October 2008
2. 13 November 2008
The document relating to Spot-on Dog is dated after the earliest priority date (27 December 2006) and there is no evidence that establishes when this information was first publicly available. It therefore follows that this exhibit is not part of the common general knowledge or subsection 7(3) information.
The Combo Spot-on Cat document is a Summary of Products Characteristics (SPC) accompanied by Post Authorisation Assessments (PAA). The PAA lists events that have occurred in relation to the product and the date of those events.[15] If any aspect of an SPC is changed, then this is listed in the PAA.[16] The PAA does not list any change relating to the amount of fipronil absorbed systemically. Thus, the figure of 18% systemic absorption of fipronil is information that was publicly available on 29 January 2004. It therefore follows that this information is part of the subsection 7(3) information and can be used when formulating the problem that the specification seeks to address.
[15] Thompson [8].
[16] Thompson [13].
(c) Conclusion on the first problem
LCWL-15 indicates that fipronil can penetrate into the circulation in amounts of up to 18%. This is considerably more than the 5% identified in the Brayden article relied on by Dr Witchey‑Lakshmanan, Dr Clark and Mr Pippia. I therefore conclude that one aspect of the problem to be solved is to address the issue of existing formulations containing N-arylpyrazoles penetrating into the circulation.
10.1.2 The second problem
The second problem relates to the efficacy of N-arylpyrazoles against representatives of the genus Ixodes being less than that against other genera of ticks.
(a) What does the specification say?
The specification states at page 2 that the efficacy of N-arylpyrazoles against representatives of the genus Ixodes is less than that against other genera of ticks. In this context reference is made to Endris et al., Veterinary Therapeutics, 2000, 1(3), 159 – 168 (Endris-1) and Endris et al., Veterinary Therapeutics, 2002, 3(1), 64 – 71 (Endris-2).
Endris-2 does not mention N-arylpyrazoles and I will not consider it further. Endris-1 describes the treatment of dogs with permethrin (a pyrethroid) or fipronil. It states that the efficacy of permethrin against Ixodes ticks was significant when compared to the controls, whereas the efficacy of fipronil was not significant as compared to the controls (Abstract). Endris-1 does not describe the use of N-arylpyrazoles to treat other genera of ticks.
(b) What was the common general knowledge and subsection 7(3) information?
Dr Witchey-Lakshmanan states that fipronil is known to be effective against ticks of the Ixodes species.[17] In support of this, reference is made to the SPC for Frontline® Spot-on Cat (LCWL‑12). However, the Date of the First Authorisation/Renewal of the Authorisation of this document is 17 October 2008 which is after the earliest priority date (27 December 2006).
[17] Witchey-Lakshmanan-2 [16], [80].
Mr Pippia states that to his knowledge the Frontline® range of products has always been indicated for controlling Ixodes infestations.[18] He refers to the SPC for Frontline® Spot-on Dog (JRP-4). This has a Date of First Authorisation/Renewal of the Authorisation of 27 November 2006 and a Date of Revision of the Text of March 2010. There is no accompanying PAA and therefore it is not clear whether the information relating to Ixodes ticks was publicly available before the earliest priority date.
[18] Pippia-2 [20].
Dr Clark comments that the results reported in Endris-1 are not surprising, as permethrin has rapid knockdown activity whereas fipronil is slower acting.[19] In support of his conclusion that there is no problem with the efficacy of fipronil against Ixodes ticks, he refers to two studies reported in the literature, JNC-17 and JNC-19. However, both of these documents were published in 2007, i.e. after the earliest priority date. Dr Clark also refers to the SPC for Frontline® Spot-on Cat (JNC-25)[20] which indicates that fipronil is active against Ixodes. This document has a Date of First Authorisation/Renewal of the Authorisation of 27 November 2006 and a Date of Revision of the Text of March 2010. The accompanying PAA does not list any change in the information relating to Ixodes ticks after 27 November 2006. Thus, the activity of fipronil against Ixodes ticks is information that was publicly available on this date.
[19] Clark-2 [14].
[20] Clark-2 [15].
(c) Conclusion on the second problem
Dr Witchey-Lakshmanan, Dr Clark and Mr Pippia are of the view that fipronil is effective against ticks of the genus Ixodes. This efficacy is documented in JNC-25. The article Endris-1 reports the results of a study where the efficacy of fipronil against Ixodes ticks was not significant as compared to the controls.
The key issue here is one of efficacy and whether a formulation will be effective against a range of ectoparasites including ticks of the genus Ixodes, i.e. a formulation having a broad spectrum of activity.
Dr Rowe, when considering the section of the specification that discusses antagonism (the fifth problem), states:
“… I read this section as requiring a broader spectrum acting formulation that will be active against other species genus, like the genus Ixodes as mentioned on page 2 of the opposed specification.”[21]
[21] Rowe-2 [20].
As noted by Dr Witchey-Lakshmanan:
“It was well known that the most useful ectoparasiticide products were those having a broad spectrum of activity, that is, they remove a wide range of parasite species and life cycle stages with a single administration, high potency, and long duration of activity (4+ weeks).”[22]
[22] Witchey-Lakshmanan-1 [31].
I consider that one aspect of the problem to be solved is to provide an ectoparasiticidal formulation having a broad spectrum of activity.
10.1.3 The third problem
The third problem relates to pyrethroids having frequent incompatibilities and only particularly non-toxic representatives with limited efficacy can be used for cats.
(a) What does the specification say?
The specification states at page 2 that:
“Pyrethroids do likewise have a relatively broad insecticidal action, and some representatives also show good acaricidal effects; however, with these compounds there are frequently incompatibilities, and only particularly non-toxic representatives with limited efficacy can be used for cats”.
(b) What was the common general knowledge and subsection 7(3) information?
The evidence indicates that it was commonly known that certain pyrethroids are less well tolerated in cats, with some being highly toxic.[23]
[23] Clark-1 [52], [57]; Rowe-2 [146]; Pippia-2 [21]; LCWL-5.
(c) Conclusion on the third problem
The issue here is one of safety and whether a formulation will be suitable for use on the target animal. I consider that one aspect of the problem to be solved is to provide a formulation that is safe to use on the target animal.
10.1.4 The fourth problem
The fourth problem relates to the issue that compared to N-arylpyrazoles, pyrethroids are less active against ticks of the genus Dermacentor.
(a) What does the specification say?
The specification states at page 2 that compared to N-arylpyrazoles, pyrethroids are less active against ticks of the genus Dermacentor.
(b) What was the common general knowledge and subsection 7(3) information?
None of the declarants commented on the efficacy of pyrethroids against Dermacentor ticks. I note that US 2002/0103233 (D24) compares the efficacy of permethrin and fipronil against Dermacentor ticks (Table 2, [0068]). The study concludes that permethrin alone required 7 days to approach a 100% killing of ticks, whereas fipronil produced an early kill ([0071] – [0072]).
(c) Conclusion on the fourth problem
Similar to the second problem discussed above, the issue here is one of efficacy and whether a formulation will be effective against a range of ectoparasites including ticks of the genus Dermacentor, i.e. a formulation having a broad spectrum of activity.
As I concluded above, one aspect of the problem to be solved is to provide an ectoparasiticidal formulation having a broad spectrum of activity.
10.1.5 The fifth problem
The fifth problem relates to pyrethroids being antagonists of N-arylpyrazoles.
(a) What does the specification say?
The specification on page 3 refers to an article by Valles et al., Journal of Economic Entomology, 1997, 90(5), 1254 – 1258 (Valles) and states:
“However, [Valles] indicates that inhibitors of the oxidative metabolism (P450 oxidase inhibitors) have an antagonistic effect in cockroaches on the action of N‑arylpyrazoles. Since most pyrethroids are detoxified via the p450 oxidase path, they, like MGK264 or piperonyl butoxide, have to be considered to be antagonists rather than synergists of the N-arylpyrazoles.”
(b) What was the common general knowledge and subsection 7(3) information?
Dr Clark states that he has not seen it suggested that N-arylpyrazoles and pyrethroids might be antagonistic. On reviewing Valles, he comments that the document relates to the treatment of cockroaches with fipronil and either piperonyl butoxide (PBO) or S, S, S-tributyl phosphorotrithioate and notes that no experiments were carried out using pyrethroids alone. Based on Valles and three other documents (JNC-13, JNC-14 and JNC-15) he states that it would appear that PBO actually enhances (e.g. agonist rather than antagonist) the activity of fipronil.[24]
[24] Clark-1 [70] – [72]; Clark-2 [21].
Dr Witchey-Lakshmanan states that no evidence of this problem is directly cited by the specification, only speculation is provided.[25]
[25] Witchey-Lakshmanan-2 [19].
As discussed previously, Dr Rowe, when considering the part of the specification that discusses antagonism, indicates that he reads this section as requiring a broader spectrum acting formulation.[26]
[26] Rowe-2 [20].
(c) Conclusion on the fifth problem
When asked at the hearing to clarify the fifth problem, Bayer submitted that the specification raises the concern that pyrethroids could antagonise fipronil in particular pests (emphasis added).
If antagonism of N-arylpyrazoles by pyrethroids is expected, but not observed, then this unexpected result may be relevant in determining whether combining these two active ingredients is a matter of routine. However, based on the evidence, I am not satisfied that the issue of antagonism is relevant to formulating the problem.
The Valles article shows that PBO (a cytochrome P450 monooxygenase inhibitor) antagonised fipronil toxicity in German cockroaches and synergised it in house flies (page 1257). Neither of these pests is an ectoparasite. I am not satisfied that the teachings of Valle can be used to draw any meaningful conclusion on the possible effects that pyrethroids may have on the toxicity of N‑arylpyrazoles in ectoparasites.
The fifth problem posed by Bayer is not a relevant consideration in formulating the problem that the specification seeks to address.
10.1.6 The sixth problem
The sixth problem relates to mixtures of N-arylpyrazoles and pyrethroids previously used to treat ectoparasites are concentrated powder formulations and are therefore unsuitable for application on homeotherms.
(a) What does the specification say?
The specification states on page 3 that GB 2396577 teaches that the treatment of ectoparasites with mixtures of N-arylpyrazoles and pyrethroids is possible when concentrated powder formulations are used. However, such formulations are difficult to apply in practice and, owing to the particles, involve additional toxicological risks.
(b) What was the common general knowledge and subsection 7(3) information?
Dr Witchey-Lakshmanan states that the idea of a liquid composition containing an N-arylpyrazole and a pyrethroid is not new.[27] In support of this, reference is made to AU 2006201364 (D15) and in particular the emulsifiable concentrates exemplified on page 67.
[27] Witchey-Lakshmanan-2 [20].
Dr Rowe, on reviewing this section of the specification, comments that it suggests that a self‑spreading liquid formulation with a good safety profile is favoured.[28]
[28] Rowe-2 [13].
On reviewing GB 2396577 (D18), I note that whilst pyrethroids and N-arylpyrazoles are listed as possible ingredients, there are no preparative examples of any powder formulations that contain both of these compounds.
(c) Conclusion on the sixth problem
The issue to be addressed is one of providing a formulation that is readily applied to the target animal. Merial submitted that the specification has a clear preference for topical formulations. On considering the specification as a whole, I agree that the emphasis is on this type of formulation.
I conclude that one aspect of the problem to be solved is the provision of a topical ectoparasiticidal formulation.
10.1.7 Conclusion on the problem
I consider that the six problems posed by Bayer may be summarised as relating to the provision of a topical ectoparasiticidal formulation that has a broad spectrum of activity, is safe to use on the target animal and reduces penetration of N-arylpyrazoles into the circulation.
I will now turn to Merial’s problem, namely to provide an alternative topical ectoparasiticidal formulation. As discussed previously, those skilled in the art are aware of formulations having a broad spectrum of activity as part of their common general knowledge, such as the Frontline® range containing fipronil. In seeking to provide an alternative formulation, it seems reasonable that the person skilled in the art would consider a broad spectrum formulation. Similarly, I consider it reasonable that the person skilled in the art would as a matter of course seek to provide an alternative formulation that is safe to use on the target animal.
In regard to the formulation reducing penetration of N-arylpyrazoles into the circulation, this is not part of the problem posed by Merial. However, as I have previously found, this aspect (of Bayer’s problem) incorporates information available to the skilled addressee as part of the subsection 7(3) information, as per AstraZeneca.
I therefore consider it reasonable to conclude that the problem to be solved is the provision of a topical ectoparasiticidal formulation that has a broad spectrum of activity, is safe to use on the target animal and reduces penetration of N-arylpyrazoles into the circulation.
I note that Dr Witchey-Lakshmanan states that she does not agree that the problems posed by Bayer exist and considers the problem addressed is the provision of an alternative formulation.[29] Dr Clark disagrees that the problems posed by the specification have been addressed and considers that the specification just describes a formulation with no advantage over existing formulations.[30] Mr Pippia’s view is that Bayer’s problems either did not require addressing or have not been adequately addressed.[31]
[29] Witchey-Lakshmanan-2 [12], [28], [30].
[30] Clark-2 [31] – [32].
[31] Pippia-2 [22].
Notwithstanding the declarants’ opinions on the problem to be solved, I am nevertheless of the view that their evidence is of assistance in the consideration of inventive step.
10.2 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.”
10.2.1 Sources of common general knowledge
Merial submitted that sources of information that would be part of the common general knowledge include:
·Material Safety Data Sheets (MSDS) which inform about hazardous components of commercial products.
·Regulatory Databases. Authorities such as the Australian Pesticides and Veterinary Medicines Authority (APVMA) and the Health Products Regulatory Authority (HPRA, formerly the Irish Medicines Board) have databases that provide details about authorised veterinary products.
·Summary of Product Characteristics (SPC) which include a summary of the active substances and a list of excipients for a veterinary product.
·Patent publications directed to commercial formulations.
Dr Witchey-Lakshmanan, Dr Clark and Mr Pippia indicate that they would consult the patent literature as a source of information.[32] However, there is no evidence that the contents of any particular patent documents form part of the common general knowledge and I do not regard these documents as such.
[32] Witchey-Lakshmanan-1 [23]; Clark-1 [38]; Pippia-1 [26].
In relation to the regulatory databases, SPC and MSDS, Dr Witchey-Lakshmanan, Dr Clark and Mr Pippia state that they would consult these sources to locate information about a particular product.[33] Dr Rowe states that it is his understanding that regulatory bodies usually only publish details of the actives of veterinary products. He does not consider such databases as an informative source as to the formulation ingredients included in any given product, nor consider that the contents of such databases would be commonly known in the field.[34]
[33] Witchey-Lakshmanan-1 [23], [28] – [30], [66], [69]; Witchey-Lakshmanan-2 [37]; Clark-1 [38]; Pippia‑1 [26] ‑ [27], [29] – [30]; Pippia-2 [7] – [8].
[34] Rowe-2 [30], [38].
Based on the evidence, I consider it more likely than not that the skilled addressee would routinely consult regulatory databases, SPC and MSDS. In terms of whether the contents of such information sources are part of the common general knowledge, it seems reasonable that where a particular product is common general knowledge, e.g. Frontline® as discussed above, then the information contained in the databases, MSDS and SPC as it relates to the product ingredients forms part of the common general knowledge. Such information falls into the category of that not necessarily memorised by the skilled worker, but which is known to exist and would be referred to as a matter of course.
10.2.2 Common general knowledge – individual ingredients
(a)Fipronil
As discussed previously, it is commonly known that fipronil is the active ingredient in the Frontline® range of products. These include the Frontline® Plus range which contains fipronil and the insect growth regulator (S)-methoprene.[35]
[35] Witchey-Lakshmanan-1 [59], [72]; LCWL-15; Clark-1 [53]; Clark-2 [17]; Pippia-1 [33] – [34]; JRP-5.
(b)Aliphatic cyclic or acyclic polyether – DGME
DGME (also known as Transcutol) is commonly used in topical formulations as a solvent, spreading agent and/or penetration enhancer.[36] The MSDS for Frontline® Top Spot lists DGME as an ingredient in the product[37] and this is considered to be part of the common general knowledge.
[36] Witchey-Lakshmanan-1 [75]; Rowe-2 [52].
[37] Witchey-Lakshmanan-1 [67]; LCWL-10; JSR-4; JNC-22; Pippia-1 [31] – [32]; JRP-4.
(c)Aliphatic cyclic carbonate – propylene carbonate
Propylene carbonate is a common solvent[38]. Dr Witchey-Lakshmanan indicates that propylene carbonate is used in the Advantage® range of commercial topical formulations (which contain the neonicotinoid imidacloprid).[39] In support of this, reference is made to the SPC (LCWL‑17) which lists propylene carbonate as an excipient in Advantage 100 Spot-on solution for Dogs. The Date of First Authorisation/Renewal of the Authorisation for this document is 17 March 1997 and the accompanying PAA establishes that the components of the formulation have remained constant over time.[40]
[38] Witchey-Lakshmanan-1 [81]; Rowe-2 [95].
[39] Witchey-Lakshmanan-1 [80].
[40] Thompson [9] – [15]. Note: At the hearing I confirmed that paragraphs [4] and [9] of the Thompson declaration should refer to exhibits LCWL-13, LCWL-15, LCWL-16 and LCWL-17, i.e. the reference to LCWL-14 is an error.
(d)Fatty acid esters – Miglyol® products
The esters are known for their function as solvents, spreading agents, penetration enhancers and emollients.[41] Triglyceride fatty acid esters, such as Miglyol 812® (a mixture of caprylic/capric triglyceride fatty acid ester), are used in veterinary formulations.[42] Dr Witchey-Lakshmanan states that Miglyol 812® is an ingredient in the Advantix® product, which also contains imidacloprid and permethrin.[43] In support of this, reference is made to the SPC (LCWL‑16) which lists Miglyol 812® as an excipient in Advantix® Spot-on solution for Dogs. The Date of First Authorisation for this document is 23 December 2003 and the accompanying PAA establishes that the components of the formulation have remained constant over time.[44]
[41] Witchey-Lakshmanan-1 [48], [79], [161]; Rowe-2 [36].
[42] Witchey-Lakshmanan-1 [176].
[43] Witchey-Lakshmanan-1 [77] – [78]
[44] Thompson [9] – [15].
(e)Pyrethroids
Pyrethroids are known for their activity against ectoparasites. They provide excellent knockdown (rapid kill), but poor residual activity due to their instability.[45] As discussed previously, certain pyrethroids are highly toxic to cats. Commercial products that contain pyrethroids include Advantix® discussed above and Defend EXspot® for Dogs which contains permethrin.[46]
[45] Witchey-Lakshmanan-1 [42]; LCWL-5; Clark-1 [52], [57]; Clark-2 [14].
[46] Witchey-Lakshmanan-1 [61], [68]; LCWL-11; Clark-1 [59]; Clark-2 [17].
10.3 Lack of inventive step in the light of the common general knowledge
Merial submitted that claims 1 – 13 lack an inventive step in the light of the common general knowledge alone. In particular, in looking to provide a topical ectoparasiticidal formulation, the skilled addressee would have tried to make a composition containing an N-arylpyrazole (e.g. fipronil), a pyrethroid (e.g. permethrin), an aliphatic acyclic polyether (e.g. DGME), a fatty acid ester (e.g. Miglyol 812®) and an aliphatic cyclic carbonate (e.g. propylene carbonate), since in the light of the common general knowledge it would be expected that those ingredients would be suitable to combine into such a formulation.
As the claimed invention is a composition comprising a combination of ingredients, Merial must demonstrate that it would be a matter of routine to combine the ingredients in order to solve the problem.
10.3.1 Matter of routine – individual ingredients
The common general knowledge indicates that the selection of N-arylpyrazoles (e.g. fipronil), pyrethroids (e.g. permethrin), polyethers (e.g. DGME), cyclic carbonates (e.g. propylene carbonate) or fatty acid esters (e.g. Miglyol 812®) as individual ingredients in a topical formulation is a matter of routine. However, preparing an ectoparasiticidal composition necessarily involves combining those individual ingredients into a suitable formulation. This requirement must also be a matter of routine and is discussed below.
10.3.2 Matter of routine – combining individual ingredients into a formulation
Dr Clark considers that pyrethroids would be good agents to use in a combination product if one was trying to broaden or enhance the spectrum and duration of activity achieved by fipronil.[47] Dr Clark states:
“I see no reason why developing a combination product containing an N‑arylpyrazole such as fipronil, and a pyrethroid such as permethrin, would not be achievable. I would expect that such a combination would achieve a fast and sustained knockdown of parasites such as fleas and ticks, with the pyrethroid being responsible for fast knockdown, and the fipronil being responsible for the sustained effects.”[48]
[47] Clark-1 [52]; Clark-2 [16] – [17].
[48] Clarke-1 [62].
Dr Witchey-Lakshmanan states that as fipronil and permethrin have been shown to be chemically compatible with other active ingredients in commercial products (Frontline® Plus and Advantix® discussed above), this would give her some confidence that fipronil and permethrin were likely to be compatible with each other.[49]
[49] Witchey-Lakshmanan-2 [32].
Dr Rowe submits:
“There are many different features that need to be taken into consideration when developing a new purpose specific formulation of an existing active ingredient. This is also somewhat further complicated if the formulation contains two active ingredients. The two active ingredients may have different solubilities in a given solvent, have different stability profiles at a given pH and different interactions with excipients.”[50]
[50] Rowe-1 [8].
He further states:
“Selecting co-actives to provide a functional and beneficial formulation where incompatibility is not observed is not a trivial exercise. If there is only one active then all the physiochemical factors would have to be determined to select the vehicle in which the drug was soluble and stable by undertaking a pH vs stability profile & chemically compatible. Other factors such as sensitivity to light, water, oxidation, hydrolysis would need to be considered. When there are two actives the problem is more complex as the pH of maximum stability for one active may not be the same as for the other. Other considerations are that one drug may react with another in the presence of one of the excipients etc. or the two drugs may be chemically or pharmacologically incompatible. It is thus a complex process which requires considerable time to select the right excipients for a given combination of drugs.”[51]
[51] Rowe-2 [25].
In relation to the excipients used in a formulation, Dr Witchey-Lakshmanan states that “the formulator would check what excipients were present in similar commercial veterinary and other products, since those had already been shown as suitable for producing a stable and efficacious formulation.”[52]
[52] Witchey-Lakshmanan-2 [10].
Dr Rowe submits:
“While in some instances it may be quite straight forward to solve a formulating problem by exchanging, for instance, one solvent for another, it is invariably the case that, especially when dealing with different active ingredients, one cannot predict whether a variation in the formulation would solve any given problem from the outset. In relation to the opposed specification, which teaches a combination of three specific classes of formulation excipients (with two actives) this does not represent a straightforward or routine formulation task (i.e., to choose the particular combination of excipients that would give a viable formulation of an N‑arylpyrazole and a pyrethroid to be applied to a companion animal as a liquid formulation) to address the problem(s) posed in the opposed specification.”[53]
[53] Rowe-2 [61].
As stated by Dr Witchey-Lakshmanan:
“Moreover, if improperly formulated, fipronil may crystallize out of solution, resulting in white residue on the skin or coat of the animal that may rub or flake off into the environment. This loss of drug is not desirable for efficacy nor for the safety of the environment.”[54]
[54] Witchey-Lakshmanan-1 [47].
The evidence does not establish that it would have been a matter of routine to formulate the combination of an N-arylpyrazole (e.g. fipronil), a pyrethroid, a polyether (e.g. DGME), a cyclic carbonate (e.g. propylene carbonate) and a fatty acid ester (e.g. Miglyol 812®). In particular, the improper choice of formulation ingredients may result in crystallisation of fipronil and consequential loss of efficacy. Furthermore, the formulation of two different active ingredients is not a straightforward process. It has not been established that the claimed invention lacks an inventive step in the light of the common general knowledge alone.
10.4 Lack of inventive step in light of the prior art
Merial submitted that claims 1 – 13 are not inventive in the light of any one of US 2006/0252728 (D2), AU 2002338201 (D13), AU 2006201364 (D15), GB 2334888 (D19) and D13 when combined with D19, when considered together with the common general knowledge.
The first question to consider is whether these documents would have been ascertained, understood and regarded as relevant. Dr Witchey-Lakshmanan, Dr Clark and Mr Pippia indicate that they consult the patent literature.[55] Dr Rowe, when presented with a patent document, states that if he had been asked to search for it he probably would have found it.[56] Therefore D2, D13, D15 and D19 would have been ascertained.
[55] Witchey-Lakshmanan-1 [23]; Clark-1 [38]; Pippia-1 [26].
[56] Rowe-2 [7].
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 therefore consider that the skilled addressee would regard as relevant those documents relating to topical ectoparasiticidal formulations.
As discussed previously, D2 describes compositions comprising a pyrethrin or pyrethroid and the synergist MGK 264 and their use in controlling parasites on animals. In a further embodiment other active ingredients may be included in the composition, such as N-phenylpyrazoles. D2 would therefore be regarded as relevant.
D13 (A level publication) was published on 6 May 2003 and thus forms part of the prior art base. The document describes macrocyclic lactones (milbemycins) that are used together with another active ingredient, such as fipronil, to treat parasites. Topical formulations are also disclosed. D13 would therefore be regarded as relevant.
D15 (A level publication) was published on 27 April 2006 and therefore forms part of the prior art base. The document describes compositions comprising an N-arylpyrazole and a pyrethroid and their use in treating and controlling insects that damage crops. Insects treated include yellow rice stem borers, leafhoppers and turnip moths. I am not satisfied that the skilled addressee, in seeking to address the problem of providing a topical ectoparasiticidal formulation that has a broad spectrum of activity, is safe to use on the target animal and reduces penetration of N-arylpyrazoles into the circulation, would regard D15 as relevant. This document will therefore not be considered further.
D19 was published on 8 September 1999 and thus forms part of the prior art base. This document discloses topical ectoparasiticidal formulations comprising an N-arylpyrazole and a macrocyclic lactone. D19 would therefore be regarded as relevant.
I will consider D2, D13 and D19 in turn.
10.4.1 US 2006/0252728 (D2)
Merial submitted that the skilled addressee would have been motivated to produce a formulation containing an N‑arylpyrazole (e.g. fipronil), a pyrethroid, an aliphatic acyclic polyether (e.g. DGME), a fatty acid ester (e.g. Miglyol 812®) and an aliphatic cyclic carbonate (e.g. propylene carbonate), since having considered D2 in light of the common general knowledge, there would have been a reasonable expectation that such a composition would be effective.
The disclosure of D2 is discussed above. Thus, D2 describes compositions comprising a pyrethroid or pyrethrin, the synergist MGK 264 and another active ingredient, such as N‑phenylpyrazoles. The compositions may also contain other components. These are listed at paragraph [0088] and include DGME, propylene carbonate and fatty acid esters.
Turning to the examples, Example 3 is a topical formulation that most closely represents that defined by the present claim 1. This formulation comprises the active ingredients flumethrin (pyrethroid) and imidacloprid (neonicotinoid), propylene carbonate and Miglyol 812®. The differences between D2 and the claimed invention are that the prior art formulation does not contain an N-arylpyrazole (fipronil) and a polyether (DGME), although these are possible ingredients (paragraph [0068] and paragraph [0088] respectively).
I have previously determined that it is a matter of routine to select fipronil and DGME as individual ingredients in a topical formulation. Therefore the skilled addressee would consider adding these components to the prior art formulation. However, as stated above, the incorporation of fipronil into a formulation is not a matter of routine, as improper formulation may result in the active crystallising out of solution. It has not been demonstrated that the claims lack an inventive step in the light of D2.
10.4.2 AU 2002338201 (D13)
Merial further submitted that the claimed invention is not inventive in view of D13 taken together with the common general knowledge.
D13 discloses compositions comprising milbemycin derivatives and another active ingredient, which may be an N-arylpyrazole such as fipronil (page 1 and pages 6 – 7). The compositions may further comprise a solvent such as propylene carbonate (page 17, lines 5 – 15). There is no disclosure of the use of a pyrethroid, a polyether or a fatty acid ester.
Test Example 2 describes a spot on formulation comprising fipronil, benzyl alcohol and propylene carbonate, either with or without a milbemycin derivative. This formulation differs from the claimed invention in that there is no pyrethroid, no fatty acid ester and no polyether (DGME) present. As discussed previously, pyrethroids, fatty acid esters (e.g. Miglyol 812 ®) and polyethers (DGME) are known individually for their use in topical formulations. The evidence also indicates that the skilled addressee would consider combining a pyrethroid with fipronil in order to produce a formulation having a broad spectrum of activity. The question to therefore consider is whether it would be a matter of routine for the person skilled in the art to prepare a formulation by combining a pyrethroid, a fatty acid ester and a polyether (DGME) with the formulation of D13.
Dr Witchey-Lakshmanan states:
“As a formulator looking to develop an N-arylpyrazole and pyrethroid formulation, I would have been particularly interested in Test Example 2 since it contained the solvents from the Advantage® product, solvents which have been accepted by regulatory authorities for topical spot-on use. Secondly, from D13 I would also know that propylene carbonate and benzyl alcohol are suitable solvents for formulating fipronil.”[57]
[57] Witchey-Lakshmanan-2 [63].
However, Dr Witchey-Lakshmanan does not state whether, based on the teachings of D13 and the common general knowledge, it would be a matter of routine for the skilled addressee to formulate a pyrethroid, a fatty acid ester and DGME with an existing formulation containing fipronil and propylene carbonate. In this regard I note that in considering D13, Dr Witchey-Lakshmanan additionally relies on the disclosure of D2 to support her arguments that D13 provides guidance as to how to formulate an N-arylpyrazole and a pyrethroid.[58]
[58] Witchey-Lakshmanan-2 [66].
As I have found previously, formulating two different active ingredients is not a straightforward process. Although it may be possible to combine the active ingredients with various excipients, the assertion that the skilled addressee would do so as a matter of routine appears to be made with the benefit of hindsight.
I am not satisfied that the evidence demonstrates it would be a matter of routine to prepare a formulation by formulating a pyrethroid, a fatty acid ester and DGME with an existing formulation comprising fipronil and propylene carbonate.
It has not been shown that there is a lack of inventive step in the light of D13.
10.4.3 GB 2334888 (D19)
Merial similarly submitted that the claimed invention lacks an inventive step in view of D19 and the common general knowledge.
D19 discloses topical ectoparasiticidal formulations comprising N-arylpyrazoles (preferably fipronil) and a macrocyclic lactone (pages 3 – 5). Other possible components include DGME (Transcutol) and caprylic/capric triglycerides (Estasan or Miglyol 812®) (page 10, line 32 to page 11, line 2). There is no disclosure of the use of a pyrethroid or a cyclic carbonate (propylene carbonate).
Turning to the examples, Example 3 and Example 5 describe formulations that most closely represent those defined by the present claim 1. The formulations comprise fipronil, Transcutol (DGME) and Estasan (Miglyol 812®). The formulations differ from the claimed invention in that there is no pyrethroid and no cyclic carbonate present. As discussed previously, pyrethroids and cyclic carbonates (propylene carbonate) are known individually for their use in topical formulations. The evidence also indicates that the skilled addressee would consider combining a pyrethroid with fipronil in order to produce a formulation having a broad spectrum of activity. The question to therefore consider is whether it would be a matter of routine for the person skilled in the art to prepare a formulation by combining a pyrethroid and a cyclic carbonate (propylene carbonate) with the formulation of D19.
Dr Rowe submits:
“Although D19 suggests of compatibility between N-arylpyrazoles and avermectins in a particular formulation, there is no indication that a combination of N-arylpyrazoles and pyrethroids would also be compatible in the same formulation.”[59]
[59] Rowe-2 [98].
Dr Witchey-Lakshmanan states:
“D19 also provides guidance that fipronil is not inherently incompatible with other active ingredients, and gives me some confidence that I can achieve my task of developing a topical formulation of an N-arylpyrazole and a pyrethroid.”[60]
[60] Witchey-Lakshmanan-2 [68].
However, Dr Witchey-Lakshmanan does not state whether, based on the teachings of D19 and the common general knowledge, it would be a matter of routine for the skilled addressee to formulate a pyrethroid and a cyclic carbonate with an existing formulation containing fipronil, DGME and Miglyol 812®. In this regard I note that in considering D19, Dr Witchey-Lakshmanan additionally relies on the disclosure of D2 and D13 to support her arguments that D19 provides guidance as to how to formulate an N-arylpyrazole and a pyrethroid.[61]
[61] Witchey-Lakshmanan-2 [68], [71].
As I have found previously, formulating two different active ingredients is not a straightforward process. Although it may be possible to combine the active ingredients with various excipients, the assertion that the skilled addressee would do so as a matter of routine appears to be made with the benefit of hindsight.
I am not satisfied that the evidence demonstrates it would be a matter of routine to prepare a formulation by formulating a pyrethroid and a cyclic carbonate with an existing formulation comprising fipronil, a fatty acid ester and DGME.
It has not been shown that there is a lack of inventive step in the light of D19.
10.4.4 Combination of D13 and D19
Merial further submitted that the claimed invention is not inventive over the combination of D13 and D19 in view of the common general knowledge. Merial stated that D13 demonstrates that propylene carbonate is a suitable solvent for the topical formulation of fipronil, whilst D19 provides confirmation that polyethers (DGME) and fatty acid esters (Miglyol 812®) are suitable topical carriers for fipronil. It was submitted that the skilled addressee would combine the teachings in D13 and D19 and would have been motivated to produce a composition containing an N-arylpyrazole, a pyrethroid, a polyether, a fatty acid ester and a cyclic carbonate, since there would be a reasonable expectation that it would be an effective topical ectoparasiticide.
In considering whether there is any motivation to combine D13 and D19, I note that neither document makes reference to the other. However, Dr Witchey-Lakshmanan when considering D19 states:
“D19 and D2 guide the formulator to use a narrow group of solvents which have been demonstrated to be safe by their use in commercial topical ectoparasiticidal products, and which have been shown to be compatible with N-arylpyrazoles and pyrethroids. This is similar to the guidance provided by D13, as discussed above at paragraph 66. Looking across to D2, D19 and D13 again guide the formulator back to the same narrow group of solvents used in the commercial topical ectoparasiticidal products.”[62]
[62] Witchey-Lakshmanan-2 [71].
If the teachings of D13 and D19 are combined as suggested by Merial, the resulting formulation still lacks a pyrethroid. As I have found previously, formulating two different active ingredients is not a straightforward process. Furthermore, the preparation of a formulation by selecting specific ingredients from D13, and then combining these with specific ingredients from D19, appears to be made with the benefit of hindsight. I am not satisfied that the evidence demonstrates it would be a matter of routine to prepare a formulation by formulating a pyrethroid with a formulation derived from the combined disclosures of D13 and D19.
It has not been shown that there is a lack of inventive step in the light of D13 when combined with D19.
11. Conclusion
The opposition fails on all grounds.
12. Costs
Both parties submitted that costs should follow the event. I award costs in accordance with Schedule 8 against Merial Limited.
Dr M-A. Fam
Delegate of the Commissioner of Patents
10
0