Merial Ltd v Evultis - [2013] APO 18

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Merial Ltd v Evultis [2013] APO 18

Patent Application: 2004230326

Title:Method for synthesising 5-chloro-1-aryl-4-(4, 5-dicyano-1H-imidazol-2-yl)-3-alkyl-1H-pyrazole derivatives

Patent Applicant:                   Evultis
Opponent:  Merial Ltd
Delegate:  Dr S.D.Barker
Decision Date:  15 February 2013
Hearing Date:  28 November 2012, in Canberra
Catchwords:  PATENTS – opposition to the grant of a patent – improved synthesis of known compounds – novelty established due to differences in process – inventive step found as it would not have been a matter of routine to use hypochlorite as oxidant – opposition unsuccessful

Representation: Patent applicant: Houlihan²
Opponent:F B Rice & Co

IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2004230326

Title:Method for synthesising 5-chloro-1-aryl-4-(4, 5-dicyano-1H-imidazol-2-yl)-3-alkyl-1H-pyrazole derivatives

Patent Applicant: Evultis
Date of Decision: 15 February 2013
DECISION
Opposition unsuccessful on all grounds.
Costs according to Schedule 8 awarded against the opponent, Merial Ltd.
Subject to appeal, the application is to proceed to grant.
REASONS FOR DECISION

Patent application 2004230326 in the name of Evultis has a filing date of 9 April 2004, and an earliest priority date of 17 April 2003. An opposition to the grant of a patent was filed by Merial Ltd. A hearing of the opposition was held in Canberra on 28 November 2012. The applicant filed written submissions only. The opponent was represented by Damian Slizys, patent attorney of FB Rice.
The specification
The specification discusses a known class of organic compounds (the generic name for the compounds is 1-aryl-4-(imidazol-2-yl)-3-alkyl-1H-pryrazoles). A method of preparation of the compounds is already known (in EP 412849). The specification relates to a method of preparation having fewer steps than the previous method, requiring the use of fewer purification steps and giving a better overall yield.
In order to understand the process that is the subject of the specification, it is necessary to lay out the process used in the prior art, and the process in the present application. Figure 1 of the specification is a representation of the prior art method:
The specification then represents the process of the invention in Figure 2:
The specification notes the differences in the following terms:
"Steps (a1) and (a2) according to figure 1 are advantageously replaced with a single step (a) as illustrated in figure 2." (page 7)
"Step (b) according to figure 2 is improved compared with step (b) according to figure 1 … The formation of the imine according to general formula (V) is usually carried out in a solvent medium such as aromatic solvents, and more specifically benzene or toluene, in a chlorinated solvent medium or aliphatic alcohols, such as methanol or ethanol, at a temperature of between 0 and 70°C. According to the method of the invention, the reaction is preferably carried out in a methanolic medium with acid catalysis" (page 8)
"Step ( c) as illustrated in figure 2 is carried out by treatment of the compound corresponding to formula (V) with a hypochlorite … According to the methods of the prior art, the oxidative cyclization of the imine of formula (V) was carried out (EP-0 412 849) by treatment with the N-chlorosuccinimide, nicotinamide couple" (page 9)
The specification ends with 17 claims. The single independent claim is claim 1:
A method for synthesising 5-chloro-1-aryl-4-(4,5-dicyano-1H- imidazol-2-yl)-3-alkyl-1H-pyrazol derivatives of the general formula (I):
in which formula:
- R₁ to R₅, which maybe identical or different, represent a group chosen from:
*a hydrogen atom,
*a halogen atom,
*a radical corresponding to the formula –(X)n-R₇ in which X represents a group chosen from oxygen, sulphur, a sulfinyl radical and a sulfonyl radical, n is equal to 0 or to 1, and R₇ represents a linear or branched, saturated or unsaturated alkyl radical optionally substituted with one or more halogen atoms, which may be identical or different, this alkyl radical comprising 1 to 4 carbon atoms,
- R₆ represents a linear or branched, saturated or unsaturated alkyl radical comprising from 1 to 6 carbon atoms, optionally substituted with one or more halogen atoms, which may be identical or different, in which method a 1-aryl-3-alkyl-1H-pyrazolin-5-one derivative of formula (II) is used as starting product, this method being characterised in that:
(a)in a first step, the pyrazolin-5-one derivative (II) is converted to the 1‑aryl-3-alkyl-4-carboxaldehyde-5-chloropyrazol derivative of formula (IV) in one step by Vilsmeier treatment in the presence of POCl₃ and DMF,
(b)in a second step, the aldehyde (IV) is converted to the 1-aryl-3-alkyl-4-[(2-amino-1,2-dicyanoethenylimino)methyl]-5-chloropyrazole corresponding to general formula (V) by condensation of the aldehyde (IV) with diaminomaleonitrile,
(c)in a third step, the imine (V) gives the derivative according to general formula (I) via oxidative cyclization, which is carried out by treatment with a hypochlorite,
according to the scheme represented in figure 2:
In summary, the steps of the process as claimed are (a) a one step Vilsmeier reaction, (b) a condensation with diaminomaleonitrile (without a limitation on the solvent), and (c) a cyclisation using a hypochlorite.
The grounds of opposition
The hearing proceeded on the basis of the grounds of
Inventive step
Novelty
Manner of manufacture
The evidence
The opponent's evidence consists of two declarations by Professor Margaret Brimble. Professor Brimble is the Chair of Organic and Medicinal Chemistry at the University of Auckland. The applicant's evidence consists of a declaration by Dr Jason Alfred Smith. Dr Smith is a Senior Lecturer in the School of Chemistry at the University of Tasmania. I accept that both declarants are in a position to provide relevant evidence.
Novelty
Section 7(1) states that an invention is taken to be novel unless it is not novel in the light of the prior art base. A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim (see definition of "prior art base" in Schedule 1 of the Act).
The basic test for lack of novelty is the reverse infringement test. The classic formulation of this test is that given by Aickin 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 as claimed (see Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at 517). It is well established that 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).
The citation raised is EP 412 849 (hereafter referred to as D1). D1 states on its face that it was published many years before the earliest priority date of the present application, and there was no objection that the citation is not part of the prior art base. D1 differs from the claimed invention in two significant respects: the Vilsmeier process is completed in one step rather than two, and a different oxidant is used for the final cyclisation. Professor Brimble notes these differences in paragraph 40 of her first declaration. The opponent submitted these are immaterial variations, and D1 would be regarded as effectively disclosing the same process. I do not agree. Looking particularly at the use of hypochlorite as the oxidant, there is nothing in D1 to suggest this as a possible reagent. Neither declarant says they would have regarded D1 as disclosing that hypochlorite could be used for the cyclisation.
It follows that D1 does not disclose all essential features of the invention, and there is no lack of novelty. The more significant question is whether there is a lack of inventive step in the light of D1.
Inventive step
Section 7(2) states that an invention is taken to involve an inventive step, when compared with the prior art base, unless the invention would have been obvious to a person skilled in the art in the light of the common general knowledge. It is well established that the obviousness question can be formulated as follows:
"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 (Aickin J)
The High Court in Aktiebolaget Hassle v Alpharpharm Pty Ltd [2002] HCA 59, 212 CLR 411 at 433 [53] stated that it is also permissible to use the "Cripps question":
Would the notional research group at the relevant date, in all the circumstances, which include a knowledge of all the relevant prior art and the facts, directly be led as a matter of course to try the invention as claimed in the expectation that it might well produce a solution to the problem
It is clear that any potential solution to a problem will not be obvious unless it would have been a matter of routine to try that solution, but with the significant caveat that there must be an expectation that the potential solution "might well" solve the problem. It is not necessary that success is guaranteed.
The problem addressed by the present application relates to the preparation of certain pyrazoles. The opponent sought to characterise the problem as modifying the method of preparation so that it is more suitable for industrial scale synthesis. I think that the problem is more accurately described as a process giving higher yield and having fewer steps. This is apparent from the passage spanning pages 3 and 4 of the specification:
"A subject of the present application is a novel method for the conversion of the products corresponding to general formula (II) to products according to the general formula (I), in which formulae the variables R1 to R6 have the same definition as above, this method having fewer steps compared with the methods of the prior art and requiring the use of fewer purifications. In addition, the method has better yields."
The only prior art method of preparation described is that in European application EP 412 849, which is represented in Figure 1 of the present specification. It is clear that the improvement sought is over the process in EP 412 849.
The citation raised is D1, which is part of the prior art base. Given that the problem relates to improving the process in D1, there can be no doubt that D1 would have been ascertained, understood and regarded as relevant. D1 differs from the claimed invention in two significant respects: the Vilsmeier process is completed in one step rather than two, and a different oxidant is used for the final cyclisation. Thus the issue in the present opposition is whether it would have been a matter of routine to carry out the Vilsmeier reaction in one step (without isolating the intermediate), and whether it would have been a mater of routine to carry out the cyclisation with hypochlorite rather than NCS/nicotinamide. The parties also referred to the condensation step, but the claim places no limit on the solvent used. Consequently the claimed method does not differ from D1 in this aspect.
The Vilsmeier reaction
The claimed process performs the Vilsmeier reaction in one step, whereas in the citation the intermediate adduct is isolated. Professor Brimble stated at paragraph 41 of her first declaration that isolating the intermediate in the Vilsmeier reaction is unusual:
"the experimenter in D1 took the unusual step of isolating the Vilsmeier adduct"
Dr Smith responded at paragraph 71 of his declaration:
"I agree with Professor Brimble that it is unusual to isolate this compound. However, as this does seem unusual, I would consider and expect that isolation of the intermediate before chlorination is the best route by which to synthesise the compound."
At paragraph 72 he further stated:
"It is not stated why the compound is isolated. However, one reason that I can see why a compound might be isolated before use in the next reaction is to remove by‑products which may interfere with the reagents or reactants in the next reaction step and therefore reduce the yield of the products obtained."
Both declarants agree it is unusual to isolate the Vilsmeier intermediate, and Dr Smith provided a reasonable speculation of why this might have been done. Professor Brimble declared that it would be routine to "telescope" the steps, i.e. to combine the two (paragraph 42 of her first declaration). Dr Smith asked rhetorically if it is routine to do this, why wasn't it done in the citation (paragraph 73)?
The evidence shows that it was unusual to isolate the Vilsmeier intermediate, and that it would have been routine to investigate carrying out the Vilsmeier reaction without isolating the intermediate. It is not necessary to speculate why this was not done by the authors of the D1.
Change of oxidant
The final step in the claimed process is performed with hypochlorite. In the citation N‑chlorosuccinimide and nicotinamide is used. The evidence that this change would be a matter of routine is slim. Professor Brimble stated at paragraph 47 of her first declaration:
"The second requirement is the use of hypochlorite as the oxidant in the oxidative cyclisation. There is nothing exotic about choosing to use hypochlorite in an oxidative cyclisation. Hypochlorite is well known oxidant and would readily be regarded as a suitable reagent for ring closures of this type. It is cheap, readily available and better environmentally than the reagents described in D1"
Dr Smith responded at paragraph 77 of his declaration as follows:
"In relation to Professor Brimble's comments in paragraph 47 that hypochlorite is a common oxidant, I agree that using it would have advantages over using other known oxidants, such as DDQ and NCS, as these reagents generate significant by-products as well as being contaminants in their own right. However, hypochlorite is more commonly known as a reagent for epoxidation, chlorination or as a co‑oxidant with a catalyst."
While it is undoubtedly correct that hypochlorite is a known oxidant, it is less clear that it was known to be capable of the kind of oxidative cyclisation in the present application. The opponent referred to an article in the Journal of Organic Chemistry at 52(12), 2355-61 (1987) in which t‑butyl hypochlorite is used for the cyclisation of imidazoles (hereafter referred to as D2). D2 is mentioned in the specification at page 11 as follows:
"It has been reported, by J.P.Ferris, J. Org. Chem., 52(12), 2355-61, (1987), that tert-butyl hypochlorite can, in an ethyl acetate medium and under relatively mild conditions, contribute to the conversion of an acyclic ribose derivative incorporating an iminoamino-maleonitrile residue to a 2‑substituted‑4,5‑dicyanoimidazol derivative, with a yield of 66%."
Professor Brimble stated at paragraph 87 of her first declaration:
"My view of this statement and of the results given in the paper is that tert-butyl hypochlorite, ie hypochlorite as the active component, would be suitable for use as an oxidant in an oxidative cyclisation and it would be routine to test it as one of a number of possible alternative oxidants when scaling up a reaction."
Dr Smith responded at paragraph 119:
"I agree that from the results of J. Org. Chem., 52(12), 2355-61 (1987) (Exhibit MB-6), the use of tert-butyl hypochlorite would be part of investigations to improve yield and ease of work-up when compared to DDQ or NCS/nicotinamide … the use of aqueous solutions of sodium hypochlorite that introduce water to a potentially hydrolysable imine would not be routine route to select when optimising a reaction"
Professor Brimble replied at paragraph 61 of her second declaration:
"in my view, the skilled process development chemist would have considered hypochlorite would work as an oxidant in the preparation of an imidazole substituent … In addition, although the skilled process development chemist would look for more accessible, safer and cheaper hypochlorites that they could use, since tert-butyl hypochlorite is expensive, highly flammable, light sensitive, and unstable"
The evidence establishes that hypochlorite is a known oxidant. However, it is not apparent that hypochlorites were generally known for oxidative cyclisation to produce imidazoles. The evidence indicates that the only source of this knowledge was in D2. There is evidence that suggests that if a person was aware of D2 it would have been routine to investigate t-butyl hypochlorite for the cyclisation step. However, D2 was not part of the common general knowledge, and there is no reason to believe that a worker in the field would have been aware of the information that it contained. Additionally, it is not apparent that a person would have combined D2 with D1. Consequently, I am not satisfied that it would have been a matter of routine to investigate using t-butyl hypochlorite for the cyclisation. It is not necessary to consider whether it would have been routine to replace t-butyl hypochlorite with sodium hypochlorite.
I conclude that it has not been established that claim 1 lacks inventive step in the light of D1.
Manner of manufacture
The opponent argued that D1 and D2 are disclosed on the face of the specification, and consequently there is a lack of invention on the face of the specification. Even if it were accepted that it were possible to mosaic the information in these documents, that does not address the issue of carrying out the Vilsmeier reaction in one step. I am not satisfied that there is a lack of manner of manufacture on the face of the specification.
Conclusion
I have found that all grounds of opposition are unsuccessful.
Costs
It is normal for costs to follow the event unless there are significant reasons to do otherwise. In the present case there are no significant reasons to depart from the norm.
Dr S.D.Barker
Delegate of the Commissioner of Patents