RHONE-POULENC RORER S.A.
[1995] APO 50
•25 August 1995
official notice
decision of a delegate of the commissioner of patents
Application : No. 12264/92 in the name of RHONE-POULENC RORER S.A.
Title: Optically active 5H-pyrrolo[3,4-b]pyrazine derivative, its preparation and pharmaceutical compositions containing same
Action: Hearing in relation to objections during examination
Decision: Issued
Abstract: 1. The invention related to a single isomer isolated from a known racemic mixture. It was found that the claims which did not refer to the degree of purity of the isomer did not define the invention.
2. The problem-solution approach to inventive step is applicable if a problem can reasonably be inferred on the basis of the specification as a whole and the surrounding facts.
3. The invention was found to lack an inventive step by application of the problem-solution approach as it would have been considered worthwhile to separate the isomers to determine whether one isomer embodied the two desirable properties.
patents act 1990
decision of a delegate of the commissioner of patents
Re:Patent Application No. 12264/92 by Rhone-Poulenc Rorer S.A., and objections raised by the Commissioner during examination.
background
Patent application PCT/FR92/00031, which is entitled "Optically active 5H-pyrrolo[3,4-b]pyrazine derivative, its preparation and pharmaceutical compositions containing same" was filed (in the French language) as an international application on 16 January 1992. The application designated Australia, and the Australian application was accorded the number 12264/92. The applicant and nominated person is Rhone-Poulenc Rorer S.A. The application claims priority from a French application (number 91/00490) filed on 17 January 1991.
A first examination report was issued on 30 November 1993. This report raised only two issues: a notice of entitlement had not been filed, and an objection of lack of inventive step was taken against the claims. The objection of lack of inventive step was maintained through a further three reports in the light of argument from the patent attorney for the applicant.
On 7 August 1995 the applicant filed a facsimile correspondence requesting a hearing on the inventive step objection. The hearing was set down for 15 August. [This date was determined in consultation with the patent attorney for the applicant. The normal period of notice required under regulation 22.23 was not observed due to the imminence of the final date for acceptance of the application i.e. 30 August 1995]
The hearing was conducted by telephone. The applicant was represented by Mr J.Slattery (patent attorney of Davies Collision Cave, Melbourne).
THE SPECIFICATION
By virtue of section 89, the verified translation of the international application is taken to be the specification.
The specification relates to the known sedative compound zopiclone. The molecular structure of zopiclone is:
The molecular structure of zopiclone has an asymmetrical carbon atom (at position 5 of the pyrrolopyrazine ring), so the compound exists in different isomeric forms. The specification identifies the invention as the dextrorotatory isomer of zopiclone, which had not previously been separated from the racemic mixture. The dextrorotatory isomer is more active as a sedative, and less toxic, than the racemic mixture.
The specification contains an example of the separation of the dextrorotatory isomer by fractional crystallisation, and an example of a tablet compounded using the dextrorotatory isomer.
The specification ends with four claims directed to the isomer, a process for preparing the isomer, a pharmaceutical composition containing the isomer, and a method of improving sleep using the isomer. The claims are:
"1. The dextrorotatory isomer of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, as well as its pharmaceutically acceptable salts.
2. Process for preparing the product according to claim 1, characterised in that racemic 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine is resolved by means of D(+)-O,O'-dibenzoyltartaric acid, working in an organic solvent, the salt of the dextrorotatory isomer of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)-carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]-pyrazine is displaced from its salt, then isolated and optionally converted to a pharmaceutically acceptable salt.
3. Pharmaceutical composition, characterised in that it contains the product according to claim 1 in combination with one or more pharmaceutically acceptable diluents or adjuvants.
4. Method for improving sleep quality and time, characterised in that a sufficient quantity of the dextrorotatory isomer of zopiclone is administered to humans."
THE EXAMINER'S OBJECTION
The examiner's objection as taken in the first adverse report is as follows:
"The invention as claimed does not contain an inventive step. The problem that the invention solves is to find a more effective sleep disorder agent. The person skilled in the art is suitably a pharmaceutical chemist.
It is respectfully submitted that it is well-established in the pharmaceutical field that where a particular racemic mixture of a compound possesses certain pharmaceutical properties, normally it would not be unexpected that a specific enantiomer shows enhanced activity compared with one of the other enantiomers in the mixture. Therefore, it is "common general knowledge" that one particular enantiomer would almost certainly show greater activity than the mixture (see, for example, "Comprehensive Heterocyclic Chemistry", volume 1, published 1986, pages 146-149). As acknowledged by the applicant in present application, the compound per se, as claimed in the present invention is known as a racemic mixture. (See also, Merck Index, 11th Edition, abstract No. 10095, published 1989).
Further, routine experiments allows a person skilled in the art to resolve the racemic mixture of a compound into specific enantiomers. (See, for example, "Organic Chemistry" by T W G Solomons, published 1986, page 343).
Thus, a person skilled in the art searching for an answer to the problem identified above would readily locate compounds containing the "pyrrolo-pyrazine" fused system (e.g., using the IPC system), particularly zopiclone, as this compound is already known in the literature (see, e.g., US 4220646, US 3862149 and Merck). Moreover, zopiclone is used for treating sleep disorders and hypnosis. These documents would have been readily found by a person skilled in the art who would also regard these US patents and the article in the Merck Index as relevant in the art.
The person skilled in the art, therefore, knowing that the racemic mixture of zopiclone is active against sleep disorders would consider the step involving the isolation and testing of a specific enantiomer for a similar pharmaceutical purpose "to be worthwhile" or "worth trying". [Johns-Manville Corporation's Patent [1967] RPC 479, cited with approval in Asahi and Grace [1992] AIPC 90-847 and Grace and Asahi 25 IPR 481].
Furthermore, it is respectfully submitted that the applicant in carrying out the test finds that the new step has the sort of consequence he/she had hoped but in an unexpectedly high degree, this does not necessarily mean that the new step was inventive or other than obvious; it might merely mean that the new and obvious step has solved the problem or met the need unexpectedly well."
On 11 August 1995 I notified the patent attorney for the applicant that in preparing for the hearing I had become aware of an additional issue that I considered needed to be included in the hearing. This issue is whether the claims define the invention, in that they do not contain a limitation as to the degree of purity of the dextrorotatory isomer with respect to the other isomer.
SUBMISSIONS
Mr Slattery made submissions on the subjects of whether the claims define the invention and whether there is an inventive step. In essence, the submissions on inventive step were that the problem-solution approach is not appropriate in the present case. Mr Slattery reminded me that the benefit of any doubt should be given to the applicant.
Details of the submissions and the written responses to the examiner's objections are given where appropriate in my decision.
DECISION
Before considering the objection raised by the examiner, I will consider the issue of whether the claims define the invention. The claims are drawn to aspects of the isomer without any limitation on the purity of the isomer. The invention as it is described is the dextrorotatory isomer in its purified form (that is, substantially free of the laevorotatory isomer). The applicant argued that when the claims are read in the light of the disclosure, it is clear that they are limited to the dextrorotatory isomer free of the laevorotatory isomer. I do not agree. As the claims are silent as to the degree of purity of the isomer, I consider that they do not define the invention. The applicant undertook to limit the claims in any event.
I will turn now to the question of inventive step. In what follows I will consider the claims as if they were limited to the dextrorotatory isomer substantially free of the laevorotatory isomer.
The starting point for any analysis of the requirements of inventive step must be the words of the Patents Act. The relevant provision is section 7, which states in part:
"(2) For the purposes of this Act, an invention is to be taken to involve an inventive step when compared with the prior art base unless the invention would have been obvious to a person skilled in the relevant art in the light of the common general knowledge as it existed in the patent area before the priority date of the relevant claim, whether that knowledge is considered separately or together with either of the kinds of information mentioned in subsection (3), each of which must be considered separately.
(3) For the purposes of subsection (2), the kinds of information are:
(a)prior art information made publicly available in a single document ...
being information that the skilled person mentioned in subsection (2) could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant to work in the relevant art in the patent area."
The interpretation of this provision was considered by the Delegate of the Commissioner in Application by American Home Products Corporation, Patent Office decision, 28 September 1994, patent application number 16397/92, unreported. The Delegate concluded:
"The approach to the question of what is obvious must involve the concept of the relevant art (which is recurrent in section 7). The reported cases under the 1952 Act establish that obviousness can be determined by considering whether the invention as claimed provides an obvious solution to a problem in the light of the relevant prior art (for example, see Winner v Ammar Holdings Pty Ltd, supra). However, in other cases the problem-solution approach has not been followed (for instance, Elconnex Pty Ltd v Gerard Industries Pty Ltd, (1992) AIPC 90-848). It is not clear whether only one approach is permitted under the 1990 Act, or whether one approach is more suited to chemical inventions. I will use the problem-solution approach because it is clearly consistent with the Act (the problem-solution approach incorporates a consideration of the relevant art), and provides a structured approach for tackling the question of obviousness."
As the Delegate stated, the Act does not explicitly require a problem-solution approach, although the problem-solution approach is clearly consistent with the Act. The Act lays down an approach which requires only three steps:
i)identify the art in which the invention lies;
ii)identify a citation which could have been ascertained, understood and regarded as relevant to work in the art; and
iii)ask whether the claimed invention is obvious in the light of the citation (and any common general knowledge in the art).
The value of the problem-solution approach is that it provides a framework for considering step iii), and answering the question of "is it obvious?". Clearly, it may be possible to consider the obviousness question in different ways.
The applicant accepted that the problem-solution approach is a test for obviousness, but argued that it is not the appropriate test to use in the present case. I note that this submission was first included in the applicant's response dated 31 July 1995. (Both previous responses were framed in terms of the problem-solution approach.) It is regrettable that the applicant's case was not disclosed until such a late stage in the examination process. The applicant suggested that the problem-solution approach is only appropriate when there is a previously recognised problem in the art. I was referred to the comments of Heerey J in the Asahi case (Asahi Kasei Kogyo Kabushiki Kaisha v W R Grace & Co (1991) 22 IPR 491) in which he quoted from the decision of Wilcox J in Coopers Animal Health Australia Ltd v Western Stock Distributors Ltd (1986) 6 IPR 545 at 565, who in turn was quoting from Beecham Group Ltd's (Amoxycillin) Application [1980] RPC 261 at 290-1. I will quote from the relevant passage from Beecham's Application (at page 290):
"It is clearly established that, for a particular step or process to be obvious for the purpose of either section, it is not necessary to establish that its success is clearly predictable: Johns-Manville Corporation's Patent [1967] RPC 479 at 494. It will suffice if it is shown that it would appear to anyone skilled in the art but lacking in inventive capacity that to try the step or process would be worthwhile: Technograph Printed Circuits Ltd v Mills & Rockley (Electronics) Ltd [1972] RPC 346, per Lord Reid at 355 and 356; Johns-Manville, supra, per Diplock LJ at 493 and 494; Tetra Molectric Ltd v Japan Imports Ltd [1976] RPC 541 at 581, 583-4. Worthwhile to what end? It must, in my opinion, be shown to be worth trying in order to solve some recognised problem or meet some recognised need."
[emphasis added]
The emphasised portion indicates that the problem or need must be recognised, and Mr Slattery argued that this means recognised in the art before the date of the invention. As a consequence, Mr Slattery stated that if there is no previously recognised problem with the prior art, then there is no problem, and the problem-solution approach cannot be applicable. I do not agree.
In Beecham's Application, two lines after the passage quoted above, Lord Justice Buckley goes on to say (in relation to the notional uninventive expert against whom obviousness is assessed):
"Having been shown what was disclosed by the prior art, he must be supposed to be attempting to solve some problem or fulfill some need which has not been resolved or satisfied by the prior art but which appears to his uninventive mind to be possibly capable of solution or satisfaction by taking the step or doing the thing under consideration."
[emphasis added]
This does not suggest that the problem that is considered for the obviousness analysis must have been previously recognised. This passage suggests to me merely that some problem is to be imputed to the skilled addressee. The facts of the Beecham case bear out this conclusion.
The Beecham case involved an improved penicillin called Amoxycillin. Although there was no evidence of a previously recognised problem with the known penicillins, a problem was recognised for the purposes of the obviousness analysis. Interestingly, the formulation of the problem as "finding a better penicillin for the treatment of humans than Ampicillin" (page 296; Ampicillin was a known penicillin) seems to have been rejected in favour of a problem that recognises "the particular characteristics of Amoxycillin and its suitability for treating humans", even though these properties could not have been ascertained until Amoxycillin had been made. I think that in the end the Beecham case supports an approach where a problem must be recognised in the sense of discovered by the court.
I note in support of the above conclusion that in Winner v Ammar Holdings Pty Ltd (1992) AIPC 90-916 it was explicitly noted that a problem can be recognised even if it was not known to anyone other than the inventor (see page 38,634). Additionally, formulation of the problem based on an inferred problem also occurred in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157, see pages 187 to 188.
I conclude that while the problem-solution approach may not be the only approach to inventive step, this approach is applicable if a problem can reasonably be inferred on the basis of the specification as a whole and surrounding facts. In the present case I believe that such a problem can be formulated, so the problem-solution approach remains appropriate and I can see no reason for departing from this approach.
I will now apply the problem-solution approach to the present case. The problem-solution approach was explained in the American Home Products decision as having four parts:
". what is the problem confronted by the application;
.can the information in the document be considered for inventive step purposes
- is it part of the prior art base
-is it reasonable to expect it to have been ascertained, understood and regarded as relevant to work in the art;
.what does the citation disclose; and
.is the solution obvious to the person skilled in the art in the light of the disclosure of the citation."
I consider that this is the approach that I should apply in the present case.
What is the problem?
The specification commences with the statement:
"In French Patent FR 72/00,505, published under the number 2,166,314, a description was given, in particular, of 6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine, also known by the name of zopiclone, which is a noteworthy hypnotic product.
As a result of the presence of an asymmetric carbon atom at the 5-position of the 5H-pyrrolo[3,4-b]-pyrazine ring-system, zopiclone must be considered, in racemic form, to consist of a strictly equimolecular mixture of the laevorotatory and dextrorotatory forms.
It has now been found, and this forms the subject of the present invention, that the dextrorotatory isomer of zopiclone possesses properties which are not obvious in the light of those of racemic zopiclone.
The subject of the present invention is hence the dextrorotatory isomer of zopiclone, its preparation and pharmaceutical compositions containing it."
The specification then describes the advantageous properties of the dextrorotatory isomer:
"In the case of zopiclone, it was found, surprisingly and unexpectedly, that the dextrorotatory isomer is not only approximately twice as active as the racemate while having a lower toxicity than that of the racemate, and that the laevorotatory isomer is both almost inactive and more toxic than the racemate."
These passages from the specification suggest that the problem was to find a compound having the properties of improved sedative effects and reduced toxicity relative to zopiclone. This formulation of the problem is echoed in the comments of the patent attorney for the applicant in the response to the first and third adverse reports.
In material filed with the applicant's response to the second adverse report, another possible formulation of the problem is suggested:
"Thus the pharmacological profile of the d-isomer of zopiclone differs from that expected in the light of the properties of the racemate. It involves a hypnotic effect, progressing to an anaesthetic effect with increasing dose, whereas no anaesthetic effect is observed with the racemate or the l-isomer. The spectrum of activity of the d-isomer is therefore totally unexpected in the light of the properties of the racemic mixture.
Thus the d-isomer of zopiclone shows a superior activity to the racemic mixture with a lower toxicity and a different spectrum of activity."
Here the implied problem includes finding a compound with a particular spectrum of activity. The information about the spectrum of activity of the dextrorotatory isomer does not appear in the specification of the application, so I do not believe that I can use it for the formulation of the problem.
I consider that the reasonable formulation of the problem solved by claim 1 is "to find a compound having the properties of improved sedative effects and reduced toxicity relative to zopiclone".
In the case of claim 2, a different form of the problem is needed: "to find a method of preparing a compound having the properties of improved sedative effects and reduced toxicity relative to zopiclone". For claim 3, I consider that the problem is "to find a pharmaceutical composition having the properties of improved sedative effects and reduced toxicity relative to zopiclone". In the case of claim 4, the problem could reasonably be formulated as "to find a method for improving sleep quality and time relative to that achieved using zopiclone".
The two properties that are sought - increased sedative activity and reduced toxicity - relate to known properties of the racemic zopiclone.
These problems lie in the art of pharmaceutical chemistry.
Can the information in the document be considered?
The relevant document in the present case is any of the documents that disclose zopiclone and its use. The specification admits that the French patent FR 2,166,314 discloses zopiclone. In addition, the Merck Index lists zopiclone, and refers to several patents and journal articles. For the purposes of this decision I will rely only on the disclosure of the Australian equivalent of FR 2,166,314, i.e. application number 50754/73. This document was published in Australia on 4 July 1974, which is before the priority date of the present application. Consequently, the document is part of the prior art base.
I consider that this document could have been ascertained (through a search using the IPC), would have been understood (it is a clear and intelligible document), and is relevant to work in the art of pharmaceutical chemistry (as it deals with pharmaceutically useful compounds). I do not believe that it is necessary to demonstrate that the citation is more relevant than any other document in the prior art base.
What does the citation disclose?
The citation discloses novel pyrrolo[3,4-b]pyrazine derivatives that are active as tranquillisers and anti-convulsant agents. The citation specifically discloses the compound now known as zopiclone.
Is the solution obvious in the light of the disclosure of the citation?
It is necessary to establish some common general knowledge before proceeding further. The examiner stated in the first adverse report that
"where a particular racemic mixture of a compound possesses certain pharmaceutical properties, normally it would not be unexpected that a specific enantiomer shows enhanced activity compared with one of the other enantiomers in the mixture. Therefore, it is "common general knowledge" that one particular enantiomer would almost certainly show greater activity than the mixture (see, for example, "Comprehensive Heterocyclic Chemistry", volume 1, published 1986, pages 146-149). As acknowledged by the applicant in present application, the compound per se, as claimed in the present invention is known as a racemic mixture."
The applicant's response to that report included a statement of remarks, which included the following:
"As acknowledged in the paragraph bridging pages 1 and 2 of the present application, it is known that in racemic product, one of the two enantiomers is often more active than the other enantiomer. Under certain circumstances, therefore, it may be obvious to resolve a racemic mixture in order to ascertain which of the two enantiomers is the more active, in order to solve the technical problem of providing a more active substance. The present invention, however, not only provides a form of zopiclone which is more active than the racemic product but also provides a form which has much lower toxicity than that of the racemic product. ... Although in a racemic product one of the two enantiomers is often more active than the other, the increased activity is often linked to an increased toxicity."
[emphasis in original]
I consider that it is reasonable to accept that it is common general knowledge that one isomer is often more active than the other, but this is not to say that it is always the case. [I note, although it is not a precedent, that this view was accepted as scientifically correct by the European Patent Office in the decision T296/87 HOECHST/Enantiomers [1990] EPOR 337 at 348.]
To determine whether the claimed solution is obvious, the test laid down in Wellcome Foundation Ltd v V.R. Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 at 286 should be followed:
"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."
It is not necessary for success to be guaranteed, so long as there is a reasonable basis for expecting success.
Referring now to claim 1 specifically, this matter hinges on the following question:
Would it have been a matter of routine for a person wishing to find a compound that was both more active as a sedative and less toxic than zopiclone to separate the isomers?
In answering this question, I do not believe that it is necessary to realise before hand whether the dextrorotatory or the laevorotatory isomer might be the solution. Additionally, it would only be a matter of routine to try separating the isomers of zopiclone if there was a basis for believing one isomer could be more active and less toxic than the racemic mixture. The common general knowledge that one isomer often has a greater activity than the other isomer or the racemic mixture provides a basis for this belief. The applicant suggested that it would not have been expected that one isomer would embody both desirable properties, and that increased activity can be associated with increased toxicity. I consider that there is no evidence that toxicity should not be regarded as a property like any other, with the expectation that one isomer is often less toxic than the other, although it cannot be predicted which isomer will be less toxic. I think it would have been considered worthwhile to separate the isomers to determine whether one isomer embodied the two desirable properties. In addition, I accept the uncontested view that it is a matter of routine how to separate isomers and to determine the activity of an isomer once it has been separated. I conclude that separation of the isomers would have been worth trying, although success was not guaranteed. There is no evidence that any difficulty was involved in separating the isomers. Significant in my conclusion is the fact that the separation only involves two isomers, and that the problem relates to two known properties of the racemic mixture.
The invention defined by claim 1 is lacking in inventive step.
Turning now to claim 2, the claimed process is fairly involved. The key question is:
Would it have been a matter of routine for a person wishing to find a method of preparing a compound having the properties of improved sedative effects and reduced toxicity relative to zopiclone to use the method in claim 2?
I have no evidence that the process lacks inventive step. In particular, the use of D(+)-O,O'-dibenzoyltartaric acid has not been shown to be a matter of routine.
In the case of claim 3, the key question is:
Would it have been a matter of routine for a person wishing to find a pharmaceutical composition having the properties of being both more active as a sedative and less toxic than zopiclone to separate the isomers of zopiclone?
I do not believe that there is any significant difference between this question and that formulated for claim 1. It follows that claim 3 also lacks an inventive step.
Finally, for claim 4, the key question is:
Would it have been a matter of routine for a person wishing to find a method for improving sleep quality and time relative to that achieved using zopiclone to separate the isomers of zopiclone?
In the light of what I have said above, the answer must be yes. Claim 4 is also lacking in inventive step.
CONCLUSION
I have found that the invention claimed by claims 1 to 4 does not define the invention. If the claims are amended to overcome this problem, then claims 1, 3 and 4 will still be lacking in inventive step.
I allow the applicant the time remaining for acceptance to propose amendments to overcome these objections.
S.D.BARKER
Delegate of the Commissioner of Patents
Patent attorneys for the applicant : Davies Collison Cave, Melbourne
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