Smithkline Beecham Plc and Smithkline Beecham Corporation v Lek Pharmaceutical and Chemical Company D.d

OFFICIAL NOTICE
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Application : No. 712269 in the name of Smithkline Beecham plc and Smithkline Beecham Corporation

Title: Composition Comprising Amoxycillin and Clavulanic Acid

Action: Opposition under Section 59 of the Patents Act 1990 by Lek Pharmaceutical and Chemical Company d.d.

Decision: Issued.
Abstract

The invention relates to antibiotic compositions comprising a combination of the antibiotic amoxycillin and the beta-lactamase inhibitor potassium clavulanate for administration to children where the amoxycillin/clavulanic acid weight ratio is within the range 6:1 to 8:1. This ratio allows for twice daily administration and has the unexpected benefit of reducing the acknowledged problem of gastric irritancy.
The opposition was found to be successful on the ground of novelty and inventive step only in regard to certain composition claims 10, 12 and 15 where the ratio was construed in the broader range of between 5.74:1 to 8.58:1. Claims 10, 11, 12 and 15 are not fairly based on the matter described in the specification.
All other claims were found to be both novel and inventive. Clarity issues and the ground of manner of manufacture were not made out. An award of costs against SKB was made up to the date on which the amendments were allowed but the parties were ordered to bear their own costs after that time.
PATENTS ACT 1990
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Re: Patent Application No. 712269 in the name of Smithkline Beecham plc and Smithkline Beecham Corporation and opposition under Section 59 of the Patents Act 1990 by Lek Pharmaceutical and Chemical Company d.d.
BACKGROUND

Patent application number 712269 in the name of Smithkline Beecham plc and Smithkline Beecham Corporation (SKB) was filed on 2 May 1996 as PCT/EP96/01881, based on applications GB 9508989.2 (earliest priority date 3 May 1995) and GB 9523655.0 (earliest priority date 18 November 1995). The application was advertised accepted on 4 November 1999. A notice of opposition was filed on 3 February 2000 by Lek Pharmaceutical and Chemical Company d.d. (Lek) and a statement of grounds and particulars served on 3 May 2000. This statement was revised by amendment filed on 30 August 2002. The evidence stages were completed on 12 September 2003. A further notice of opposition in the name of DSM N.V. was filed on 4 February 2002 but this was subsequently withdrawn.
The matter was heard in Canberra on 11 and 12 February 2004. SKB was represented by Mr Bruce Caine of counsel instructed by Mr Michael Caine and Mr John Carroll, both patent attorneys of Davies Collison Cave, Melbourne. Lek was represented by Ms Katrina Howard of counsel, instructed by Mr Stephen Sharp, patent attorney of Griffith Hack, Sydney. Also present was Mr Chris Connell from SKB.
GROUNDS OF OPPOSITION
The grounds of opposition pursued at the hearing were those relating to:
·    Manner of manufacture
·    Novelty
·    Inventive step
·    Section 40 matters
EVIDENCE
Evidence in support comprises the following:
·    Statutory Declaration of James S Rowe dated 2 March 2001 (Rowe 1) together with Exhibits JSR-1 to JSR-32
·    Statutory Declaration of Alison Margaret Kesson dated 28 February 2001 (Kesson 1)together with Exhibits AMK-1 to AMK-29
·    Statutory Declaration of Moreno Giovannoni dated 19 February 2001 together with Exhibits MG-1 to MG-2
·    Statutory Declaration of Tuong Tran dated 28 December 2000 together with Exhibits TT-1 to TT-2
·    Statutory Declaration of Tuong Tran dated 28 December 2000 together with Exhibits TT-3 to TT-4
·    Statutory Declaration of Ngaire Pettit-Young dated 1 March 2001
The evidence in answer comprises the following:
·    Statutory Declaration of John Douglas Turnidge dated 27 November 2002 together with Exhibits JDT-1 to JDT-3
·    Statutory Declaration of Desmond B Williams dated 27 November 2002 together with Exhibits DBW-1 to DBW-4
·    Statutory Declaration of Justin J Beilby dated 27 November 2002 together with Exhibits JJB-1 to JJB-3
·    Statutory Declaration of Patrick John Crowley dated 4 December 2002 together with Exhibits PJC-1 to PJC-13
·    Statutory Declaration of Rienk Pypstra dated 10 December 2002 together with Exhibits RP-1 to RP-11
The evidence in reply comprises the following:
·    Statutory Declaration of Alison Margaret Kesson dated 27 August 2003 (Kesson 2) together with Exhibits AMK-30 to AMK-34
·    Statutory Declaration of James S Rowe dated 10 September 2003 (Rowe 2) together with Exhibit JSR-32
·    Statutory Declaration of Stephen Dean Sharp dated 10 September 2003 together with Exhibit SDS-1
SPECIFICATION
The specification is that as amended with the request to amend filed on 9 August 2001. It describes compositions comprising a combination of the antibiotic amoxycillin and the beta-lactamase inhibitor potassium clavulanate, these compositions being used to treat bacterial infections in children under the age of 12.
The combination of amoxycillin (as amoxycillin trihydrate) and potassium clavulanate is acknowledged in the specification to be a well known and widely used oral medicament for bacterial infections and marketed in many countries by SKB under the trade name Augmentin. Regulatory approval appears to have been given for different dosages and ratios of the two components depending on the country and/or severity of the infection to be treated.
It is said that for children it is preferable to provide the combination as a powder for reconstitution, prior to use, as a liquid aqueous suspension. The specification also acknowledges that it is more convenient to administer a twice daily (bid) dosing schedule for children that three times daily (tid) in order to avoid having to give the medicine during the day when the child may be at school. However, not all drug substances have pharmocokinetics that are compatible with such a regimen. Additionally, the specification mentions that gastric intolerance, manifested in
symptoms such as loose stools, is perceived in some countries to be a side effect associated with the use of amoxycillin/potassium clavulanate in the present three times daily (tid) dosage schedule.
Page 2B of the specification indicates that the compositions of the invention are "distinguishable over previously available compositions on account of the different ratio of amoxycillin trihydrate:potassium clavulanate used and the differing amounts of amoxycillin trihydrate and potassium clavulanate per unit dose, to achieve the higher daily dosage regime. These compositions comprise amoxycillin and clavulanic acid in the weight ratio of between 6:1 and 8:1, with a 7:1 ratio being preferred.
The specification ends with 15 claims, which define the invention. Claims 1, 6, 10, 11, 13 and 15 are independent claims and these are reproduced as follows:
1.A method for treating bacterial infections in paediatric patients which comprises the twice daily oral administration of a liquid aqueous suspension comprising amoxycillin trihydrate and potassium clavulanate in combination, in a weight ratio of from 6.5:1 to 7.5:1 (the weights being expressed as the free parent acids amoxycillin and clavulanic acid) to provide a dosage of from 20 to 70mg/kg/day of amoxycillin and pro rata amounts of clavulanic acid.
6.A pharmaceutical composition for the treatment of bacterial infections in paediatric patients provided as dry powder or granule formulation which is reconstituted into a multiple oral dosage aqueous suspension, comprising amoxycillin trihydrate and potassium clavulanate in combination, in a weight ratio of from 6.5:1 to 7.5:1 (the weights being expressed as the free parent acids amoxycillin and clavulanic acid), such that amoxycillin and clavulanic acid are present in concentrations corresponding to an amoxycillin:clavulanic acid ratio of 200±10%:28.5±10%, or 400±10%:57±10% mg/5ml.
10.A pharmaceutical composition provided for the treatment of bacterial infections in paediatric patients, which is adapted for reconstitution as a liquid aqueous suspension for oral twice daily administration, comprising amoxycillin trihydrate and potassium clavulanate and which, when reconstituted, comprises amoxycillin in an amount 200±10% and clavulanic acid in an amount 28.5±10%, or amoxycillin in an amount 400±10% and clavulanic acid in an amount 57±10% mg/5ml of liquid aqueous suspension.
11.A composition of formula A or formula B listed below, expressed as mg/5ml dose of reconstituted aqueous suspension, where the amount of each ingredient is within ±10% of the amount specified below, and where the amounts of amoxycillin trihydrate and potassium clavulanate are expressed as free acid equivalents:

A B

Ingredient mg/5ml mg/5ml

amoxycillin trihydrate 408.0 204.0

potassium clavulanate 61.56 30.78

xanthan gum 12.5 12.5

colloidal silica 25.0 25.0

succinic acid 0.84 0.84

orange flavour 26.25 26.25

golden syrup flavour 23.75 23.75

aspartame 12.5 12.5

hydroxypropylmethylcellulose 79.65 79.65

silicon dioxide to 885.5 to 537.5

13.The use of amoxycillin trihydrate and potassium clavulanate in combination, in a weight ratio of from 6.5:1 to 7.5:1 (the weights being expressed as the free parent acids amoxycillin and clavulanic acid), in the manufacture of a liquid aqueous suspension formulation for treating bacterial infections in paediatric patients which medicament is administered orally twice daily (bid), at a dosage of between 20 and 70mg/kg/day of amoxycillin and pro rata amounts of clavulanic acid.

15.A pharmaceutical composition provided for the treatment of bacterial infections in paediatric patients, in the form of a liquid aqueous suspension for oral administration, comprising amoxycillin in an amount 200±10% and clavulanic acid in an amount 28.5±10%, or amoxycillin in an amount 400±10% and clavulanic acid in an amount 57±10% mg/5ml of liquid aqueous suspension.

Dependent claims 2 to 5, 7 and 14 further define particular weight ratios and dosages to be administered. Claim 8 defines the weight percentage of amoxycillin and clavulanic acid in the formulation while claim 9 defines a composition substantially free of mannitol. Claim 12 is the process for manufacturing the composition by mixing the dry ingredients.
DECISION
What are the essential features of the claims?
There seemed to be no dispute that the invention is concerned with a revised dosage form of an amoxycillin/clavulanic acid composition. The formulations are those suitable for paediatric use, namely in the form of a liquid oral suspension or as a dry powder or granule formulation for reconstitution into a liquid aqueous suspension. This dosage form is for the twice daily (bid) treatment of bacterial infections in children, so the bid administration is an essential feature of the method type claims. However, I do not believe that this feature places any real limitation on a composition claim. In addition, the dosage of the two components to be administered appears to be an essential feature of the method of the treatment.
There were however, three issues that were debated at the hearing and require further consideration. These are as follows:
(a) amoxycillin:clavulanic acid ratio
The specification discloses that the ratio of amoxycillin to clavulanic acid is important to the invention. The specification describes a weight ratio between 6:1 and 8:1, with a preferred range being 6.5:1 to7.5:1. The most preferred ratio is 7:1 and this is the ratio described in connection with the clinical trials. I note that SKB amended their claims during the opposition process from a ratio range of 6:1 to 8:1 to the narrower range of 6.5:1 to 7.5:1.
Lek argued at the hearing that the ratio was not an essential feature of the invention and that altering this ratio was merely a variation of an arbitrary parameter in order to avoid the prior art.
The specification indicates that one of the problems of the prior art tid formulations that SKB sought to overcome was that of gastric intolerance. This appears from the evidence to be a widely accepted and long-standing problem. The examples show the results of two clinical trials. These clinical trials compared the results of administration to children of a bid dosage of a 7:1 ratio product according to the invention with tid administration of the known 4:1 ratio product. In each trial it was said that the bid regimen was shown to be as safe as the tid regimen with similar clinical success rates for the two administration regimes. In clinical trial A, the incidence of diarrhoea was significantly lower for the bid regimen but the bid formulation did not contain mannitol, while the tid dosage did.
Mannitol is acknowledged in the specification to have a diuretic effect and that avoiding its use may be associated with reduced gastric irritancy. Clinical trial B compared formulations without mannitol and the overall incidence of diarrhoea was found to be low, with a lower incidence in the bid group, although this was not thought to be statistically significant. However, compliance was higher with the bid group.
It is not entirely clear from the described clinical trials if the presently claimed formulations with particular weight ratios of components actually achieved a lowering of gastric symptoms. Professor Beilby for SKB gives evidence from his own experience of prescribing the new product that this did result in significantly fewer complaints of diarrhoea and other gastric problems. Lek argued that any improvement in gastric problems shown in the clinical trials was due to the absence of mannitol rather than as a result of the 7:1 ratio used. However, their evidence did not establish conclusively that the amount of mannitol used in the formulations was sufficient to cause diarrhoea nor did they prove that the particular ratio range of 6:1 to 8:1 had no effect on reducing gastric intolerance.
On balance, I must conclude that the compositions of the invention do show a lowering of gastric intolerance when used to treat paediatric patients and that this effect is due to the ratio of the two components. Given this, I find the ratio of 6:1 to 8:1 to be an essential feature of the invention.
(b) amoxycillin:clavulanic acid concentration
In some of the composition claims the concentration of the two components is given per 5ml of liquid aqueous suspension. This limitation of the concentration on the composition claims is not as clear as with the ratio of the two components. Page 3 lines 17 to 35 describe the concentration range. A unit dose is said to lie within the range of 50 to 800mg amoxycillin and a convenient volume of suspension to be within the range of 2 to 10ml. At lines 23 to 26 on page 3 it is said that "the appropriate unit dosage will be at the discretion of the physician and will depend inter alia upon the age and weight of the patient and the nature and severity of the infection to be treated."
It seems to me that the concentration of the two substances is not an essential feature of the composition claims. Provided that the weight ratio of the two substances is maintained as discussed above and an appropriate amount of each is administered to the patient, the actual concentration does not appear to be essential to the working of the invention. The concentrations given in certain composition claims necessarily define the ratio of amoxycillin to clavulanic acid but otherwise appear to be arbitrary limitations on the amount of drug per volume of solution. Thus, I will interpret the concentration ratios as if they were weight ratios.
Claim 10 for example defines the concentration as "amoxycillin in an amount 200±10% and clavulanic acid in an amount 28.5±10%, or amoxycillin in an amount 400±10% and clavulanic acid in an amount 57±10% mg/5ml of liquid aqueous suspension". This corresponds to a weight
ratio of amoxycillin:clavulanic acid of between 5.74:1 to 8.58:1 as given in Rowe 1 at paragraph 81. SKB submitted that the ±10% amount is to account for "overage" which is necessary with an unstable product to take into account its degradation over time.
Claims 10 and 15 are thus construed as comprising an amoxycillin:clavulanic acid ratio of between 5.74:1 to 8.58:1. Claim 6 and dependent claims 7 to 9 and 12 define both the weight ratio of 6.5:1 to 7.5:1 and the concentration of amoxycillin and clavulanic acid, so effectively defining two different weight ratios in the same claim. However, the way claim 6 is drafted leads to the construction that the concentration is a further limitation on the weight ratio and is necessarily within the scope of the weight ratio of 6.5:1 to 7.5:1. These claims are therefore construed as having the narrower ratio of 6.5:1 to 7.5:1 for the purposes of novelty and inventive step.
(c) for the treatment of bacterial infections
Independent claims 6, 10 and 15 define pharmaceutical compositions provided "for the treatment of bacterial infections in paediatric patients". It was not in dispute that such words of purpose are merely indicative of the environment in which the composition is to be used. That is, these types of claims define compositions that must be suitable for the stated purpose but are otherwise construed as claims to compositions per se.
However, Ms Howard for Lek submitted that this same construction should also apply to method and "Swiss-style" claims. Claim 1 defines "a method for treating bacterial infections in paediatric patients" and claim 13 is the corresponding "Swiss-style" claim. It is common practice that a method claim using words of purpose is construed as being restricted to that purpose. This practice is outlined in the Australian Patent Office Manual of Practice and Procedure, Volume 2 at Part 10.8.2.1. A situation where the word "for" was not considered to restrict the claim to the purpose stated occurred in CSL Limited v Pharmacia & Upjohn AB [2000] APO 38. Ms Howard put forward the view that this is the correct construction.
Nevertheless, if a method claim is not construed as being limited by the words of purpose, I do not see how it can be properly construed. In my view, the details of the administration, the dosage etc describe the method steps but the method of claim 1 is necessarily limited to being a method of treating bacterial infections in paediatric patients. How else could a method claim be worded?
Ms Howard also made submissions on the meaning of 'Swiss-style" claims. In Europe, methods for the treatment of the human body by therapy are not patentable and "Swiss-style" claims are drafted in the way they are to overcome the exclusion. According to Ms Howard, the novelty of a "Swiss-style"claim is found in the second or subsequent therapeutic use and the claim is said to have novelty yet not considered to be for a method of treatment. A similar approach has been adopted in the UK and in New Zealand. As stated in Pharmaceutical Management Agency Limited v The Commissioner of Patents & Ors [1999] NZCA 330 (17 December 1999) in relation to "Swiss-style" claims:
"It is not a product claim because a combination of the active compound and the carrier not made for the purpose of producing a cancer treatment medicine would not infringe. Nor would sale of the combination for other purposes. It is akin to a method claim - a method by which the newly discovered properties of the active compound can be exploited."
Ms Howard argued that there has been no determination in Australia of the meaning of "Swiss-style" claims and that European decisions are irrelevant to Australia since methods of treatment are patentable in Australia. However, despite the fact that method claims are patentable in Australia, I see no reason for "Swiss-style" claims to be construed any differently in Australia than they are elsewhere. The same rules of construction apply here as elsewhere but an applicant has a choice about how they may claim their invention. For a new use of a known substance, an applicant may choose to claim their invention in the form of a method claim, a "Swiss-style" claim or both.

Thus, I find that method claims 1 to 5 and 14 are limited to their use in treating bacterial infections in paediatric patients. "Swiss-style" claim 13 is similarly limited. In view of this, I find that the use in treatment of bacterial infections in children is an essential feature of claims 1 to 5, 13 and 14.
The essential features
Thus, it seems that the following features are essential features of the invention:
(a)The methods of the invention are for treating bacterial infections in paediatric patients and the compositions are for paediatric use.
(b)The formulations are either in the form of a liquid oral suspension or as a dry powder or granule formulation for reconstitution into a liquid aqueous suspension.
(c)The compositions comprise a combination of amoxycillin and clavulanic acid at a ratio of between 6:1 to 8:1.
(d)The dosage to be administered is from 20 to 70 mg/kg/day of amoxycillin and pro rata amounts of clavulanic acid.
(e)The methods of the invention are directed to administration of the formulations twice daily (bid).
Fair basis
A claim will be found not fairly based if it omits one of these features found above to be essential. Claims 10, 12 and 15 all include the concentration range that I have determined to be equivalent to a weight ratio of amoxycillin/clavulanic acid of between 5.74:1 to 8.58:1. This weight ratio is not fairly based on the matter described in the specification as it travels beyond the invention as disclosed. The only weight ratio supported by the description is between 6:1 to 8:1. Claim 11 suffers from a similar problem in that the amount of each ingredient is given as ±10% of the amount specified. As a result, claims 10, 11, 12 and 15 are not fairly based and they will be considered to define that broad ratio range for the purposes of novelty and inventive step considerations.
Novelty
Astruc, J, "Efficacite et tolerance d'une nouvelle formulation d'amoxicilline 100mg- acide clavulanique 12,5 mg dans les otites aigues du nourrisson", Annales de Pediatre, 1992, vol 39, no 2, 142-148 (Astruc)
Astruc describes a study of the efficacy and tolerance of a new paediatric formulation of Augmentin comprising a liquid formulation containing 100mg amoxycillin and 12.5mg clavulanic acid per ml with a dosage of 80mg/kg/day divided over 3 or 4 doses. Table II also suggests that twice-daily treatment may have been used in some patients. However, Astruc is directed to treating infants with a sufficient dosage of amoxycillin to prevent bacteremic or meningeal complications while maintaining a sufficient dose of clavulanic acid. It does not recognise that this dosage ratio gives any benefit in terms of reduction in gastric irritancy and does not teach to vary the ratio. There is only a disclosure of an 8:1 ratio.
A specific ratio of 8:1 amoxycillin/clavulanic acid falls outside the range claimed by method type claims 1 to 5, 13 and 14 and composition claims 6 to 9. These claims are thus considered novel in light of Astruc. However, a ratio of 8:1 falls within the broader ratio defined in claims 10, 12 and 15, when construed as discussed above and so these claims lack novelty. The additional features defined in claim 11 cannot be found in the document and so this claim is considered novel.
Vidal 1994, Pages 132-134 (Vidal)
This document was described by the parties as the French MIMS equivalent. (The MIMS Annual, Australian Edition is described by Dr Kesson as “a standard reference text, which is regularly referred to by medical practitioners in Australia concerning pharmaceutical formulations available in Australia”). I will refer to the English translation of the relevant passages of Vidal. This describes oral formulations of Augmentin in the form adult tablets and powders for making up into liquid suspensions for administration to children. One of the examples refers to a drinkable suspension for nursing infants comprising 100mg amoxycillin and 12.5mg clavulanic acid per ml (8:1 ratio) to be taken tid at a dosage of 80mg/kg/day. The described formulations do not appear to contain mannitol. There is no teaching that the ratio could be varied and no recognition of the benefit of reduction in gastric irritancy by using this ratio.
Again, this specific value of an 8:1 ratio falls within the scope of the wider ratio defined by claims 10, 12 and 15. Thus, these claims lack novelty but all other claims are considered novel in light of Vidal.
WO 93/00898 (SmithKline Beecham PLC)
This patent specification discloses a dry powder or granule formulation of amoxycillin/clavulanic acid for reconstitution to a liquid suspension where the weight ratio is within the broad range of 1:1 to 12:1, preferably 1.5:1 to 8:1. Exemplified formulations include example 2, which appears to show an amoxycillin/clavulanate suspension in the form of paediatric drops at a 7.6:1 ratio. Interestingly, the applicant asserts that the ratio is actually 8:1 although this was not debated at the hearing.
The focus of WO 93/00898 appears to be to improve the stability of the formulations by including in the formulation a dicarboxylic acid salt, such as succinic acid. There is no discussion about the problems of gastric intolerance or any motivation to select any particular ratio from the wide range of 1:1 to 12:1. There is no exemplification of compositions within the narrower ratio range as claimed of between 6.5:1 and 7.5:1. The document does not give any indication of the daily dosage rate or that administration should be twice daily. I do not believe that this document gives clear and unmistakable directions to select a composition within the range of 6:1 to 8:1 rather than any other ratio. As noted above, this specific ratio range is an essential feature of the invention. As a result, I find that none of the claims lack novelty in light of this document.
Repertorio Farmaceutico Italiano, third edition, 1989, pages A-106 to A-108 (Repertorio)
This document was described by the parties as the Italian version of MIMS and I will refer to the English translation of the relevant extract. It describes the Augmentin product that is prescribed in Italy. Augmentin tablets for adults have a composition of amoxycillin:clavulanic acid at a 7:1 ratio and are administered bid, but depending on the type and seriousness of the infection, this can be increased to tid administration. The paediatric Augmentin suspension also can be administered bid but the only ratio of amoxycillin:clavulanic acid disclosed for administration to children is 4:1.
Repertorio does not disclose a paediatric suspension within the range 5.74:1 to 8.58:1. I do not consider that it is reasonable to construe a tablet as a form suitable for reconstitution into a liquid aqueous suspension. As a result, I find all claims novel in light of Repertorio
Todd PA and Benfield P, "Amoxicillin/Clavulanic Acid- An Update of its Antibacterial Activity, Pharmacokinetic Properties and Therapeutic Use", Drugs, 1990, vol39, no 2, 264-307 (Todd and Benfield)
Todd and Benfield is a review article on the use of the combination of amoxycillin/clavulanic acid and does not present any original information. It describes that numerous formulations are available worldwide. The usual dosage for oral use in adult infections is said to be 250/125mg (2:1) or 500/125mg (4:1) tid but acknowledges that in Italy, the dosage is 875/125mg (7:1) bid or tid. Suspensions and syrups are said to be available for paediatric use with bodyweight adjusted dosages being administered to children to give a recommended daily dose of amoxycillin of 20 to 40 mg/kg. However, the article does not mention what the weight ratio is for the paediatric suspensions.
In my mind, this article does not give clear and unmistakable directions to formulate a suspension with a ratio of amoxycillin/clavulanic acid falling within the range defined in the claims of the opposed application. As a result, all claims are considered novel in light of this document.
GB2005538 (Beecham Group Limited)
Here the disclosed ratio of amoxycillin:clavulanic acid is from 1:1 to 6:1. Tablets or capsules are the preferred dosage form although powders and granules for reconstitution are mentioned. Example 4 shows a single-dose sachet containing a dry powder for reconstitution with water although the exemplified weight ratio is 1.9:1. Other exemplified products are limited to tablets with weight ratios between approximately 2:1 and 5:1. I do not believe that there is a clear disclosure in this document to anticipate any of the claims of the opposed application.
WO91/15197 (Beecham Group PLC)
This patent specification discloses an effervescent formulation of amoxycillin, which may also contain clavulanic acid. Example 2 shows an amoxycillin/clavulanic acid formulation at a 7:1 ratio. However, it was argued by SKB that this specification is directed to the formation of a solution rather than a suspension. Page 1 of the specification describes how solutions are favoured over suspensions since drugs in solution are more readily absorbed. I note that all the claims of the opposed application are directed to liquid suspensions and, as such, are novel over WO91/15197.
Jacobsson, S. et al, "Evaluation of Amoxycillin Clavulanate Twice Daily Versus Thrice Daily in the Treatment of Otitis Media in Children", Eur. J. Clin. Microbiol. Infect. Dis., 1993, vol 12, no 5, 319-324 (Jacobsson)
Jacobsson compares the clinical efficacy and safety of twice daily versus three times daily administration of amoxycillin/clavulanate to treat otitis media in children. The study showed that while there was a higher incidence of adverse reactions such as diarrhoea in the bid group, overall bid administration was found to be as efficacious as the tid. The dosage administered was at the 4:1 ratio. This ratio is outside the range claimed in any of the claims and so this document does not render any of the claims not novel.
Fraschini, F. et al, "Pharmacokinetics and Tissue Distribution of Amoxicillin plus Clavulanic Acid after Oral Administration in Man", Journal of Chemotherapy, 1990, vol 2, no 3, 171-177 (Fraschini)
This describes administration of tablets comprising a 7:1 ratio of amoxycillin/clavulanate to adults. There is no disclosure of paediatric oral suspensions and all claims are novel in light of this document.
US 4537887 (Rooke et al)
This document describes and claims tablets of amoxycillin/clavulanate in the weight ratio range of from 1:1 to 12:1, 2:1, 4:1 and 8:1 being preferred ratios. There is no disclosure of liquid oral suspensions for administration to children and so does not anticipate any of the claims.
Inventive step
The test for inventive step is as given by Aicken J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd (1981) 148 CLR 262 (at page 286)
"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."
This test was recently affirmed by the High Court in Aktiebolaget Hassle v Alphapharm Pty Limited [2002] HCA 59 (12 December 2002).
What is the problem to be solved?
From reading the specification, it seems that the problems with the administration of the known Augmentin product were that tid administration for children is inconvenient and that gastric intolerance, in the form of loose stools, was a side effect of the product. The specification also states that it was recognised that a bid dosing schedule would be more convenient although not all drugs have pharmacokinetics which are compatible with such a regime.
To me, this is an indication that the bid dosing schedule is part of the problem rather than a solution. It would seem that the problem to be solved is that of providing a revised dosage regimen of Augmentin for children which would allow for bid administration while, at the same time, alleviating the side effects of gastric intolerance. This problem was solved by the bid administration of an aqueous liquid formulation of amoxycillin/clavulanic acid at a ratio of 6:1 to 8:1 as discussed above.
Who is the person skilled in the art?
The person skilled in the art is a person, or team of people, who is a skilled but non-inventive worker in the relevant field of technology in Australia. According to Ms Howard, the team in this case would include:
· the notional medical practitioner working in Australia before 3 May 1995 in the treatment of infectious diseases, and
· a pharmaceutical formulator working in Australia before 3 May 1995
Dr Pypstra also suggests that the team would include a pharmacologist. There appeared to be no argument on the issue of the person skilled in the art.
The evidence from expert declarants can be useful in determining what is the common general knowledge and what the person skilled in the art would have done in light of that common general knowledge. In this case, there was some argument at the hearing about the relevance of the expert opinions. Lek criticised the SKB experts Mr Crowley and Dr Pypstra since they are both employed by GlaxoSmithKline (GSK) so not considered independent witnesses. In addition, both of them are based overseas (USA) so Lek submitted that their evidence is of questionable relevance and should be given little weight.
In my view, the evidence from both Mr Crowley and Dr Pypstra appears highly relevant and I am not convinced that the common general knowledge in this particular art is much different in Australia than in the USA. A further criticism levelled by Lek was that SKB had not obtained evidence from the inventors and that such evidence would have been helpful in determining obviousness. However, it seems to me that inventors are rarely sought to give evidence since their evidence would be criticised as being not objective, a criticism that has been made in these proceedings against other employees of the applicant, Mr Crowley and Dr Pypstra.
In any event, I do not believe that anything hangs on me according different weight to the evidence from any of the declarants in this case and I will consider all the evidence and refer to it where necessary in my decision.
What is the common general knowledge?
In its submissions, SKB acknowledge that “the combination of amoxycillin in the trihydrate form and potassium clavulanate was, at the priority date, a well known and widely used oral medicament for bacterial infections. The combination was marketed in many countries, including Australia, under the name Augmentin.” According to both Dr Rowe and Dr Kesson, some bacteria have developed a resistance to amoxycillin and other b-lactam antibiotics by producing enzymes known as β-lactamases which destroy the antibiotics. Clavulanic acid is a β-lactamase inhibitor so, when administered in combination with amoxycillin, extends its antimicrobial spectrum to include protection against organisms usually resistant to amoxycillin due to β-lactamase production.
Augmentin was known to be effective for the treatment of bacterial infections in both adults and children and its pharmacokinetics in children appear to be similar to that in adults. It was also not a point of contention that it is well known that it is preferable to administer the product to children in the form of a liquid suspension since children are reluctant to take tablets. Augmentin is unstable in the presence of moisture so paediatric formulations are usually presented in the form of a dry powder or granules for reconstitution just prior to use.
SKB set out in their submissions the known dosage regimens around the world for the administration of the amoxycillin/clavulanic acid combination and these were not disputed by Lek. This is also discussed on page 1 of the specification. In Australia, the recommended dosing schedule of amoxycillin/clavulanic acid for adults at the priority date of the application was tid with a daily dose of 750/375mg for normal infections (2:1) or 1500/375mg for severe infections (4:1). This is the same as the recommended dosage regimens in the USA and UK. In Italy and Spain however, the recommended adult dosages were at a ratio of 7:1 with a bid schedule (1750/250mg/day) for normal infections and tid (2625/375mg/day) for severe infections.
The recommended dosage regimen for children in Australia, USA and UK was at a 4:1 ratio of amoxycillin/clavulanic acid administered tid with a daily dosage of 20/5mg/kg/day for normal
infections and 40/10mg/kg/day for severe infections. In Continental Europe, the only difference from this was a higher daily dosage of 30/7.5mg/kg/day for normal infections and 60/15mg/kg/day for severe infections. In Italy, the recommended ratio for administration to children was still 4:1, although the dosage schedule was bid for normal infections (30/7.5mg/kg/day) but still tid for severe infections (45/11.25mg/kg/day). Only in France did the ratio for paediatric formulations vary to 8:1, with tid administration at a 80/10mg/kg/day dosage.
Thus it seems that the following features are considered to be common general knowledge:
·    Pharmaceutical compositions comprising amoxycillin (as the trihydrate) and clavulanic acid (as the potassium salt) are widely used around the world for the treatment of bacterial infections in both adults and children.
·    For children, it is preferable to administer the formulation as a liquid oral suspension- this can be in the form of a dry powder or granule formulation for reconstitution prior to use.
·    Amoxycillin/clavulanic acid is more usually administered around the world at a 2:1 or 4:1 ratio, whether for children or adults.
·    The ratio of the two components could be varied over a wide range.
·    Amoxycillin/clavulanic acid in particular could be administered tid and that drugs such as antibiotics could also be administered with a bid regimen.
Does the opposed application relate to optimisation of known properties or a mere workshop improvement?
Lek argued that there was no invention, merely optimisation of the known features to achieve a dosage suitable for bid administration and one that avoided the known prior art formulations. However, as I concluded above, the invention appears to lie in the formulation of the dosage ratio of from 6:1 to 8:1. In this dosage range there appears to be a selective advantage, namely the reduction of gastric side effects. I must conclude that this dosage ratio is not a mere workshop variation of known parameters and do not find this ground of opposition has been made out.
Is there lack of inventive step in light of common general knowledge alone?
I need to decide if the person skilled in the art, armed with the common general knowledge would have been directly led to formulate amoxycillin/clavulanic acid for administration to children in a weight ratio of 6:1 to 8:1.
It was known that the product was normally administered at a 2:1 or 4:1 ratio but that the ratio could be varied. There appears to be no strong teaching in the common general knowledge to any other particular weight range. From all the evidence before me, it appears that it is well known that there is a problem with gastric intolerance with the administration of Augmentin both to adults and children, although these adverse effects may be more common in children. However, it is not clear what causes this effect. There is no teaching that varying the ratio to between 6:1 to 8:1 could reduce these adverse side effects. I am not convinced that there is anything in the common general knowledge to teach the PSA away from using the commercially known formulations of Augmentin let alone to replace those formulations with one comprising a ratio in
the claimed range. I find the claims are inventive in light of the common general knowledge alone.
Would the person skilled in the art have ascertained, understood and regarded the documents as relevant?

The documents considered to be the most relevant for inventive step are the documents, Repertorio, Todd and Benfield, Fraschini, Vidal, Astruc and Jacobsson referred to above in the novelty considerations. Repertorio is described by various declarants as the Italian equivalent of MIMS and Vidal the French equivalent. Todd and Benfield, Astruc, Fraschini and Jacobsson are articles from scientific journals.
Dr Kesson and Dr Rowe both state that when investigating new pharmaceutical formulations, they would routinely conduct literature searches to identify relevant literature concerned with alternative treatment regimes. These searches would have included standard reference texts, patent specifications, scientific journal articles and commercial databases. Dr Rowe further indicated that the fact that certain documents were not in English would not have deterred him from considering them. As they were clearly of interest, he would have arranged for a translation to be prepared.
On the other hand, Mr Crowley and Dr Pypstra both indicate that they would not normally research amongst patent publications and non-English language sources such as country specific drug compendiums for example, Repertorio and Vidal.
However, in my view the notional PSA team would have conducted extensive literature searches and that these would have included patent literature and journal articles. I would have expected that the PSA would have been keeping up to date with the published literature concerning the treatment of bacterial infections with amoxycillin/clavulanic acid in both adults and children. Documents such as Todd and Benfield, Jacobsson, Astruc and Fraschini all are clearly related to the use of amoxycillin/clavulanate even from their titles. I would have also expected that the PSA would have considered what was prescribed elsewhere in the world as a starting point for further development. I must conclude that the PSA team would have found the documents Todd and Benfield, Fraschini, Astruc, Repertorio, Vidal and Jacobsson and, having done so, would have clearly regarded them as relevant to the problem at hand.
Is there lack of inventive step in light of the common general knowledge and one document?
a) Extrapolation from adults to children
Repertorio, Todd and Benfield and Fraschini are all documents that refer to the Italian dosage regimen, namely the administration to adults of a 7:1 formulation of amoxycillin/clavulanate in tablet form. Lek argued that it would be obvious to adjust the known adult dosage amount for administration to children based on the body weight of the child. Their declarants maintain that there is nothing inventive in preparing a liquid oral suspension for children based on the same ratio of the two components as in the adult tablet form and that the preparation of such a formulation would be a routine matter. Lek's declarant Dr Rowe states at a number of places that it would have been immediately apparent to him that the 7:1 ratio of amoxycillin/ clavulanic acid could have been used for the twice daily treatment of bacterial infections in children.
Mr Crowley for SKB on the other hand stated in his declaration that the "formulation of amoxicillin-clavulanate oral liquid products is no mean feat" and that it is inappropriate to extrapolate from an adult formulation when there is an approved paediatric formulation available.
However, while the skilled reader may have been able to prepare the paediatric formulation, the question is whether they would have been directly led to do so in view of the prior art. The fact is that in Italy, the recommended dosage for the treatment of children is bid at a ratio of 4:1 despite the fact that the recommended adult dosage is at the 7:1 ratio. The documents do not teach that side effects such as diarrhoea are alleviated in adults by the use of the 7:1 ratio, although Todd and Benfield refers to one document that links the frequency of gastrointestinal adverse effects to the dosage of clavulanic acid administered. Nevertheless, the conclusion reached in Todd and Benfield was that these side effects may limit the usefulness of amoxycillin/clavulanic acid and that this "needs to be addressed in special studies."
The adult and paediatric formulations are in use concurrently and I do not believe that there is any teaching in either document to depart from the known paediatric dosage form to mirror the adult dosage ratio. I believe that Lek is viewing the documents with the benefit of hindsight. As a result, all claims are considered inventive in light of these documents.
b) Extrapolation from other weight ratios for children
Astruc and Vidal disclose a paediatric liquid oral suspension of amoxycillin/clavulanic acid for tid where the amoxycillin:clavulanic acid ratio is 8:1, which is the ratio recommended for administration in France. Jacobsson discloses bid administration of the 4:1 ratio product. The question to be asked is whether, in the light of either of these documents and the common general knowledge, the person skilled in the art would have been directly led to reformulate the known paediatric suspensions in the particular ratio range claimed.
According to Dr Kesson, "it would have been very plain to me that one could make a minor variation to the weight ratio" as given in documents Vidal, Astruc and Jacobsson, to prepare a composition falling within the scope of the present claims. Dr Rowe's evidence is given in very similar terms. However, the documents do not teach that the weight ratio for children may be varied. Neither do they teach that the incidence of diarrhoea may be reduced by the administration of a dosage ratio of 6:1 to 8:1. Jacobsson only teaches that bid administration of the 4:1 product had a higher incidence of adverse effects that tid administration. Astruc teaches that its new 8:1 formulation enables a higher dosage of amoxycillin to be used to prevent bacteremic or meningeal complication whilst not exceeding the recommended daily dose of clavulanic acid.
I am not convinced that the person skilled in the art reading either Astruc, Vidal or Jacobsson would have been directly led to depart from the known dosage ratios for administration to children, let alone to replace those with the precise claimed ratios. As suggested by Mr Crowley, no motivation to vary the dose has been provided by Lek and their analysis seems to have been done with the benefit of hindsight. Astruc and Vidal were found above in novelty considerations to anticipate claims 10, 12 and 15 since the specific weight ratio of 8:1 is encompassed within those claims. I believe that, in light of the problem to be solved for inventive step purposes, these claims also lack inventive step in light of Astruc and Vidal. All other claims are found to be inventive in light of Astruc, Vidal and Jacobsson.
Conclusion on inventive step
The ground of inventive step has only been made out in regard to claims 10, 12 and 15 by the specific disclosure of an 8:1 ratio in Astruc and Vidal. All other claims are inventive whether considered in the light of common general knowledge alone or common general knowledge and one of the cited documents. The specification does not relate to a mere workshop improvement or optimisation of known properties.
Manner of Manufacture
Lek submitted that the claims do not pass the threshold requirement of patentability and that there is no invention on the face of the specification, merely a compilation of features known from the prior art. Furthermore, that the claims merely define a new use of a known compound- that is the application to children of a known treatment for adults.
Page 1 of the specification discusses the various formulations of amoxycillin/clavulanic acid used in various countries around the world. There is no disclosure in the specification that it was known to administer to children a liquid oral suspension of a 6:1 to 8:1 ratio of amoxycillin/clavulanic acid. I have found above that the skilled reader would not be directly led from the prior art to such a ratio of the two components and that the claims do not lack inventive step. I similarly find that there is no lack of invention on the face of the specification itself.
Furthermore, I have also found that there is an inventive step in going from the bid treatment of adults with a 7:1 ratio of amoxycillin/clavulanic acid in tablet form to the treatment of children at that dosage regimen. Accordingly, I find no lack of invention on the face of the specification in relation to this aspect either.
Section 40 issues
(a) nominally 7:1
Claims 2 and 7 define the weight ratio of amoxycillin trihydrate to potassium clavulanate as "nominally 7:1". Lek submitted that this term lacks clarity and is ambiguous. I agree with Mr Crowley that the term has to be taken as a further limitation on the ratio of the ratio 6.5:1 to 7.5:1 defined in claims 1 and 6 to which these claims are appended. He then goes on to say that this "implies that the intention is to provide a ratio of 7:1 but that manufacturing tolerances may mean that, in practice, this ideal ratio is not achieved precisely." Dr Pypstra has a similar view.
Dr Rowe and Dr Kesson both point out that the term is not used elsewhere in the specification and that it is not clear how much variation from 7:1 would be included. However, in my view, nothing turns on the exact determination of the phrase. I believe it is not a precise ratio but that it necessarily is a narrower range than the broader range of 6.5:1 to 7.5:1. Thus, a meaning can be placed on the term and I am of the view that there is no lack of clarity.
(b) multiple oral dosage aqueous suspension
Lek submitted that the term "multiple oral dosage aqueous suspension" in claim 6 is unclear and uncertain as it depends on to whom it is to be administered and the intended dose. Dr Kesson states that any aqueous suspension may be used to provide either multiple doses to a single patient or single doses to a number of different patients. She also made the point that the claim does not require the suspension to be stable for any particular time period.
It appears to be well known to formulate paediatric formulations as dry powder or granules which are reconstituted into an aqueous suspension, usually by the dispensing pharmacist, shortly before administration. It would be usual for the suspension to remain stable for the duration of the course of treatment and I believe that the person skilled in the art reading the specification would appreciate this and make up the formulation accordingly. I can find no lack of clarity in this phrase.
(c) substantially free
According to Lek, the meaning of the words " substantially free" in claim 9 is not clear. Dr Rowe suggests that the term means that there may be some mannitol present. Mr Crowley appears to understand "substantially free' to indicate that there is no more than a minimal amount of mannitol. Thus it seems to me that experts for both parties have been able to place a meaning on the term and there is agreement between them on what the term means. As a result, I find there is no lack of clarity.
CONCLUSION
I have found that the opposition was successful on the ground of novelty and inventive step only in regard to certain composition claims where the ratio was construed in the broader range of between 5.74:1 to 8.58:1. Thus, claims 10, 12 and 15 lack novelty and inventive step. Claims 10, 11, 12 and 15 are also not fairly based on the matter described in the specification.
All other claims were found to be both novel and inventive. Clarity issues and the ground of manner of manufacture were not made out.
I believe it is possible for the applicant to amend the claims to overcome the novelty, fair basis and clarity issues noted above. Accordingly, I allow the applicant 60 days from the date of this decision in which to propose suitable amendments.
COSTS
Costs normally follow the event. In the present case, there were no submissions from either party for other than the normal award of costs. The opposition was successful on some of the grounds only. However, these include the ground of novelty, which is major ground of opposition. Nevertheless, this ground was made out only in regard to a ratio of 8:1, which is claimed in certain claims as a result of how these claims are construed. I also note that the claims were amended during the opposition process and that this resulted in a narrowing of the claims, presumably to avoid some of the prior art raised by Lek. I believe that it is appropriate to make an award of costs against SKB up to the date on which the amendments were allowed but for the parties to bear their own costs after that time.
Dr Gillian Jenkins
Delegate of the Commissioner of Patents
Patent attorneys for the applicant : Davies Collison Cave, Melbourne
Patent attorneys for the opponent : Griffith Hack, Sydney

A	B
Ingredient	mg/5ml	mg/5ml
amoxycillin trihydrate	408.0	204.0
potassium clavulanate	61.56	30.78
xanthan gum	12.5	12.5
colloidal silica	25.0	25.0
succinic acid	0.84	0.84
orange flavour	26.25	26.25
golden syrup flavour	23.75	23.75
aspartame	12.5	12.5
hydroxypropylmethylcellulose	79.65	79.65
silicon dioxide	to 885.5	to 537.5

[2004] APO 10

14 May 2004