National Research Development Corporation

[1992] APO 22

official notice

decision of a delegate of the commissioner of patents

Application        :    No. 59784/90  in the name of NATIONAL RESEARCH DEVELOPMENT CORPORATION

Title:    Anxiolytic compositions containing Dioxopiperidine derivatives

Action:    Objection by the Commissioner during examination

Decision:    Issued            .  Description and claims found to have fundamental discrepancies so that section 40 not complied with. Claims specifying a particular quantity of a known pharmaceutical found to be not novel.

patents act 1990

decision of a delegate of the commissioner of patents

Re:Patent Application No. 59784/90 by NATIONAL RESEARCH DEVELOPMENT CORPORATION, and an objection by the Commissioner during examination.

background

Patent application 59784/90 was lodged on 24 July 1990 as a divisional application of application 602716. The earliest priority date that could be accorded the present application is that associated with 602716 - viz 8 September 1986.

The present application was lodged as a divisional application in response to certain objections raised during the examination of 602716. During the examination of the present application, those same objections were raised. The applicant requested a hearing, which was held in Melbourne on Feb 20 1992. The applicant was represented by Ms Elizabeth Eadie of Davies Collison Cave, Melbourne

specification

The specification of 59784/90 relates to the use of certain dioxopiperidines as anxiolytic drugs. It states that these dioxopiperidines have suprisingly been found to have strong anxiolytic activity. It refers to several prior art disclosures as follows:

-GB 1455687 (open for public inspection in Australia on 2 March 1977) discloses certain dioxopiperidines having use as antidepressants. The dose level is 0.1 to 100 mg/kg or 1 to 1000 mg per unit dose.

-US 4461771 (open for public inspection in Australia on 12 April 1985) discloses certain dioxopiperidines having use for treatment of migraine. The dose level is 0.01 to 10 mg/kg or 0.1 to 200 mg per unit dose.

-GB 2181346 (open for public inspection in Australia on 6 July 1987) discloses dioxopiperidine compositions which exhibit anxiolytic activity in the range of 0.1 to 20 mg/kg and hence pharmaceutical compositions containing 10 to 500 mg were proposed. GB 2181346 derives priority from GB 8621577 which is one of the basic documents of the parent application of the present case (although the present specification does not derive priority from GB 8621577).

The specification then states that "it has now suprisingly been found that the compounds are active at much lower dose levels, down to nanogram/kg amounts".

On page 10, the specification states:

"The amount of compound administered will vary and can be any anti-anxiety effective amount. Depending upon the patient and the mode of administration, the amount of compound administered may vary over a wide range to provide from about 10-7 to 10+2 mg/kg, usually 10-5 to 10+2 mg/kg, especially 10-4 to 10+2 mg/kg of body weight of the patient per unit dose. Unit doses in accordance with the invention can contain, for example, from about 10-6 mg to 10-2 mg, usually 10-4 to 10-2 mg, especially 10-3 to 10-2 mg of the compound and may be administered, for example, from 1 to 4 times daily. A unit dose form of 10-2 mg or less is convenient to reduce the risk of side effects arising from the medication".

(In the specification as lodged, the last sentence of this passage referred to "avoiding any possibility of drowsiness"; it was amended before examination commenced. There was no equivalent statement in the parent specification.)

The specification continues:

"The term "unit dosage form" is used herein to mean a single or multiple dose form containing a quantity of the active ingredient in admixture with or otherwise in association with a diluent or carrier, said quantity being such that one or at most a small number of predetermined units are normally required for a single therapeutic administration."

The specification then enumerates many of the compounds according to the formula, provides examples, and ends with 8 claims. Claim 1 is in the following terms:

A pharmaceutical preparation in unit dose form comprising, with a pharmaceutically acceptable diluent or carrier, an amount of 10-6 to 10-2 mg per unit dose of compound of the following formula:

(Thereafter the claim  specifies the formula of certain known dioxopiperidine compounds, which is not relevant to this decision.)

Claims 2 to 7 are dependent claims, directed to more specific chemical structures, while claim 8 is a dependent claim specifying a particular unit dose concentration.

(By way of comparison, claim 1 of the parent application is as follows:

A method of treating anxiety which comprises administering to a patient suffering anxiety, an effective anxiolytic amount within the range of 10-7 to 10-1 mg/kg of a compound of the following Formula 1.

(Thereafter the claim  specifies the same formula of certain known dioxopiperidine compounds.)

Claims 2 to 9 are dependent claims.)

The description refers to both doses, and unit doses. As a pharmaceutical the alleged advantages arise when (and only when) the pharmaceutical is administered within a certain dose range (ie. mg per kg of body weight). However much of the description, and all the claims, refer to a "unit dose" - that is, an entity containing a specified quantity of the pharmaceutical, as defined in the description (see above).

The difference of meaning of these terms is important to the present application - specifically:

-the performance of the invention requires the administration of a certain dose (ie. mg/kg). To specify that dose requires a reference to weight of the body to which the dose is administered. Prima facie, this requires method-type claims. (I note that the present application has no claims of this form, whilst the claims of the parent application are method claims of this form.)

-the claims define a unit dose - that is, an entity that can be fully defined in isolation from the body to which it is administered. (I note however that the unit dose might only embody the advantages of the invention if it is administered to give a certain dose - that is, restricted to its application as in a method-type claim.)

examiner's objections, and applicant's submissions

The examiner has maintained only one objection to the claims, viz. that the claims are not novel in the light of the admitted prior art, including US 4461771. This citation, OPI in Australia on 12 April 1985, discloses the use of compounds of the formula of claim 1 at dose levels of 0.01 to 10 mg/kg, and doses of 0.1 to 200 mg.

At the hearing Ms Eadie made substantial submissions regarding manner of manufacture; I am satisfied that this is not an issue in the present case.

Ms Eadie's submissions were otherwise directed to the issues of prior publication and novelty, and to selection. She placed particular emphasis on the range specified in the claims (10-6 to 10-2 mg) being an essential feature of the claims; she referred to EMI v Lissen 56 RPC 32 to support her submission that it is not open to read down the language of the claims and interpret that range as inessential - and therefore the claims were distinguished from and novel over the prior art.

Ms Eadie agreed that compounds of the chemical formula of claim 1 were known at the relevant priority date, as also were unit doses containing the compounds. I agree with her that at the priority date, there is no explicit disclosure in the citation of unit doses having the quantity of pharmaceutical claimed in the present application. As a result, the issue I have to determine is simply whether novelty can reside in a particular quantity of a known pharmaceutical in a carrier.

During the course of the hearing, I noted that the specification seemed to be incomplete. Although the examples in specification made reference to drawings, no drawings had apparently been filed. An amendment to include the missing drawings was filed on 25 February, together with further submissions.

decision

US 4461771 discloses pharmaceutical compounds falling within the formula of the present claims. It discloses use of these compounds in a dose of 0.01 to 10 mg/kg of body weight, and unit doses containing 0.1 mg to 200 mg.

I note that in the specification filed the upper range of the concentration was specified as 10-1 mg per unit dose. In response to an examiner's objection, the applicant has proposed amendments to the description and claims to specify an upper limit of 10-2 mg. This was said to be done "in order to clearly distinguish over the prior art".

The sole examiner's objection is that the invention claimed is not novel having regard to US4461771. The examiner referred to the decisions of:

Application No. 15931/70 by Boehringer Ingelheim GmbH, (1979) AOJP 4299, and

Application No. 42369/78 by Fisons Limited, unpublished decision of 30 October 1981.

Both of these decisions dealt with a pharmaceutical composition containing a known compound having a known pharmaceutical activity, the alleged novelty residing in the concentration of the compound.

I also note the decision of Application No. 54718/73 by F.Hoffman La-Roche & Co. Aktiengesellschaft, (1977) AOJP 2995, in which the hearing officer stated:

"Clearly, novelty for the composition cannot flow from the nature of a known pharmaceutical carrier or base or from the fact that the known active compound has been incorporated in a known pharmaceutical carrier or base... .  Thus all that is claimed by the composition claims is an oral or parenteral composition comprising a known pharmaceutical carrier or base and a specified amount of known active compound, and perhaps being restricted to a known physical form"

and

"if the composition is known, there can be no novelty in forming it into a number of tablets each having a particular weight of active compound..."

These decisions are particularly pertinent to the present application. If I follow these precedents I must find the invention claimed not novel.

Ms Eadie submitted that these decisions were not approriate to the present case because of the wide disparity in the quantity of compound present in the unit doses; and that the present claims defined a selection.

I note that in these decisions, the concentrations of the pharmaceutical in the unit dose were of similar order of magnitude. Although I generally concur with the conclusions in each of those decisions, I do not believe that they fully address the situation where the respective concentration of the substances in a carrier differ by many orders of magnitude.

However, before dealing with these issues, I believe that there are section 40 issues which must be addressed.

Section 40

To put the present claims into their proper perspective, I will assume that the preparation is being used in humans. (Although human use is clearly implied as the main use of the present invention, I note that this is not a limitation on the claims - indeed, the examples illustrate that the invention could be used on animals. The citation likewise is primarily for human use.)

Teenage and adult humans weigh in the range of approximately 50 to 100kg - for the purpose of this argument I will assume an average weight of 70kg. The specification states that the compound should be administered over the range of 10-7 to 10+2 mg/kg - that is, a unit dose of the order of 7.10-6 to 7.10+3 mg. The specification gives a most preferred dosage of 10-4 to 10+2 mg/kg - that is, a unit dose of the order of 0.007 to 7000 mg.

To achieve the most preferred dose (10-4 to 10+2 mg/kg) in an average (70kg) patient, using the maximum concentration unit dosage provided by the claims (10-2 mg), would require the administration of between [10-4 x 7.10+1 /10-2] to [10+2 x 7.10+1 /10-2] unit doses - that is, between 0.7 and 700,000 unit doses.

The most preferred range of unit doses described is 10-3 to 10-2 mg/kg. At the lower limit of this range, 10 times as many unit doses would be required than in the above example - that is, 7 to 7,000,000 unit doses would be required to administer the most preferred dose.

These examples illustrate that generally, for the performance of the preferred form of the invention many unit doses are required. This is clearly contrary to the stated definition of a unit dose - ie `such that one or at most a small number of predetermined units are normally required for a single therapeutic administration'.

In this context, the restriction of the unit dose in claim 1 to less than 10-2 mg is clearly arbitrary, is not based upon the stated doses in the specification, and excludes the best method of performing the invention.

This is reinforced by the examples, said to illustrate the invention. Examples 1 to 5 illustrate tablets, suppositories and capsules. The quantity of pharmaceutical in these examples are (in mg) 1, 10, 10, 10, and 2.5 respectively - all well above the range claimed.

Furthermore, while many of the figures illustrate the use of doses down to 10-6 mg/kg, figs 4, 5, 9, 12, 13 and 15 (all of which are said to be illustrative of the invention) relate to doses of 0.1 to 100 mg/kg. In the context of humans, the corresponding unit doses are clearly much greater than that claimed. Even in the context of a mouse (said to weigh 25 to 30 g), 100 mg/kg leads to a unit dose of the order of 3 mg, which is greater than the claimed range.

Ms Eadie submitted that the claims were distinguished from the prior art on the basis that (because of the low unit dosage) too many unit doses of the present invention would be required to perform the prior art. However, as illustrated above, it seems to me that the invention as claimed is subject to exactly the same criticism when performing its preferred embodiment.

I am thus of the opinion that there are fundamental discrepancies between the invention described and as claimed; as a result the requirements of section 40 have not been complied with.

Novelty

There are a number of tests for novelty. One is that of Griffin v Isaacs (1942) 12 AOJP 739, (1938) 12 ALJ 169:

"Where variations from a device previously published consist in matters which make no substantial contribution to the working of the thing or involve no ingenuity or inventive step and the merit of the two things considered as inventions is the same, it is, I think, impossible to treat the differences as giving novelty".

Applying this test, I note that the difference from US4461771 (in the dose concentration) has not come about as a feature essential for the performance of the invention; rather it is an arbitrary limitation in the present claims, provided to avoid anticipation. Furthermore, the merit of the two things considered as inventions would seem to be the same. The preferred dosage of the citation is 0.01 to 10 mg/kg - which is fully encompassed in the preferred dosage of the present invention, of 10-7 to 10+2 mg/kg. I therefore conclude that the invention claimed, albeit restricted to unit doses containing 10-6 to 10-2 mg, is not novel.

Ms Eadie submitted that the invention is novel on the basis of the reverse infringement test of Meyers Taylor Pty Ltd v Viccar Industries (1977) 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.' (my underlining).

This test is said to be generally applicable. In my view, one instance of its inapplicability is where a claim includes a limitation of an essential feature which is not related to the performance of the invention. An arbitrary restriction might result in a finding of no infringement, but in my view such an arbitrary restriction cannot give rise to novelty.

In the present circumstances, I do not accept that the limiting values of 10-2 mg is an essential feature of the invention claimed. The specification as lodged claimed up to 10-1 mg. No particlar reason is evident for specifying 10-2 rather than 10-1 - other than to avoid a prior publication. Furthermore the specification refers to using doses of up to 10+2 mg/kg - that is, unit doses of over 1000 mg. In these circumstances I do not think that the reverse infringement test can sensibly be applied on the basis of a maximum value of 10-2mg per unit dose.

Selection

Ms Eadie argued that the invention resided in the discovery that there was surprising efficiacy at low doses; that is, the invention is a `selection'.

The matter of "selection" patents was fully considered in the case of I.G. Farbenindustrie A.G.'s Patents, 47 RPC 289. The following criteria for a valid "selection" patent were laid down at pages 322-323:

(a)the selection must be based on some substantial advantage gained or some substantial disadvantage avoided;

(b)the whole of the selected members must possess the advantage in question;

(c)the selection must be in respect of a quality of a special character which may fairly be said to be peculiar to the selected group.

In the present case, the specification illustrates efficacy of the pharamceutical at low doses; it suggests that efficacy is greater than would be otherwise expected. However, the applicant's specification clearly states that dioxopiperidines can effectively treat anxiety in amounts from 10-7 to 10+2 mg/kg. The examples also illustrate that these compounds are effective over such a large range. Their efficacy at low doses might be greater than expected, but there is nothing which shows that the low doses are more efficacious than higher doses - indeed, the contrary is shown. Therefore, Maugham J.'s third rule for selection patents is not satisfied - the compounds are clearly effective for treating anxiety over a large range outside the range claimed.

Another possible basis for a selection is the alleged advantage of reduced side effects at low doses. However I note that the specification is essentially silent on this issue. The specification provides a single sentence (quoted above) relating to this issue, but there is nothing to suggest that this advantage comes especially from particular low concentrations. Rather it is an assertion which, in the specification as lodged, is associated with unit doses of less than 10-1 mg. Therefore I do not consider that the third element of the selection criteria is satisfied on this issue.

However, overriding these considerations is a fundamental problem with applying the selection criteria to the present case. The beneficial properties likely to be relied upon to characterise the selection are all associated with a low administered dose (ie mg/kg), and not a low unit dosage (ie mg per unit dose). It seems to me that unless the claim is somehow restricted to a particular range of bodies or body weights (such as by showing that the compound can only have application within certain body weights or on certain animals), the selection criteria cannot possibly be satisfied. In making this observation, I am not suggesting that such a restriction is in fact possible in the present circumstances - indeed, such restrictions are likely only possible in method-type claims.

Position in other countries

Ms Eadie submitted that claims corresponding to the present claims had been allowed before both the European Patent Office and the United Kingdom Patent Office.

I note Article 52(4) of the EPC, which provides:

Methods for treatment of the human or animal body by surgery or therapy and diagnostic methods practised on the human or animal body shall not be regarded as inventions which are susceptible of industrial application.... This provision shall not apply to products, in particular substances or compositions, for use in any of these methods.

There is a similar prohibition in the United Kingdom.

In Australia, since the decision of the High Court in Bernhard Joos v. Commissioner of Patents 126 CLR 611, patents are granted for subject matter which is excluded before the EPO by Art. 52(4) of the EPC.

The present invention relates primarily to the treatment of a human or animal body. The difference between the EPC (and any other country that has a similar prohibition) and Australian law indicates to me that the fate of the corresponding application before the European Patent Office is of low persuasion.

Conclusion

I consider the present claims are not novel. Also, there are fundamental discrepancies between the description and claims, so that the requirements of section 40 have not been complied with.

Although I consider it unlikely, it may be possible to amend the present description and claims so that the selection criteria are properly satisfied, and the inconsistencies between the description and claims removed. Consequently, I will not refuse the application at this time, but allow the applicant to propose further amendments within the time allowed for acceptance of the application.

D. HERALD

Assistant Commissioner of Patents

Patent attorneys for the applicant  :  Davies Collison Cave, Melbourne