Grunenthal GmbH v Mundipharma Medical GmbH

[2006] APO 39

ABSTRACTS OF DECISIONS

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application  :          No. 735113 in the name of Mundipharma Medical GmbH

Title:          Opioid Formulations for Treating Pain

Action:          Opposition to the grant of a patent by Grunenthal GmbH

Decision:          Issued  18 December 2006.

Abstract

The present invention provides a method of treating pain comprising the once-daily administration of sustained release morphine formulations. The compositions provide a time to maximum plasma concentration (Tmax) of about 2 to 8 hours and a peak-to-trough ratio (Cmax/C24) of between 2.6 and 3.4.  The grounds of opposition were manner of manufacture, novelty, inventive step and section 40.

The opponent submitted that the claims lacked fair basis as there was no real and reasonable disclosure of the Cmax/C24 ratio.  However the invention as defined in the claims has been found to be consistent with the invention as described.

The opponent argued that the claims lacked novelty in view of AU 617573 (“Faulding”), but this citation and evidence is not sufficient to establish that there are clear and unmistakable directions to a formulation providing a therapeutic effect of 24 hours.  The opponent submitted that the claims lacked inventive step in view of Faulding as there was no suggestion that the Tmax and Cmax/C24 parameters were in any way significant and inventive and that the present claims lacked inventive step in view of Faulding combined with the common general knowledge relating to the commercial product Kapanol.  These submissions have been unsuccessful, and the claims are considered to meet the threshold test for inventiveness.

As the opposition has been unsuccessful on all grounds, costs are awarded against the opponent.

PATENTS ACT 1990

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Re:Patent Application No. 735113 in the name of Mundipharma Medical GmbH, and an opposition under section 59 to the grant of a patent by Grunenthal GmbH.

BACKGROUND

1. Patent application number 735113 in the name of Mundipharma Medical GmbH (“the applicant”), was filed on 25 September 1998.  The application was a divisional of 693134, which was withdrawn by the applicant on 1 December 2000.  Application 693134 was itself a divisional of application 66105/95, which claims priority from US basic application 08/156468 23 November 1993.  Application 66105/95 lapsed prior to gaining acceptance.

2. The present application was advertised accepted on 28 June 2001, and a notice of opposition was filed by Grunenthal GmbH (“the opponent”) on 28 September 2001.  A statement of grounds and particulars was filed on 2 January 2002.  Evidence in support was completed on 29 June 2003, evidence in answer on 3 June 2005, and evidence in reply on 10 February 2006.

3. The opposition was heard in Sydney on 30 August 2006.  The applicant was represented by Mr Phillip Kerr, Solicitor, assisted by Ms Claudia Wallman and Ms Carolyn Morely of Allens Arthur Robinson, Sydney.  The opponent was represented by Ms Katrina Howard of Counsel, instructed by Dr Jacinta Flattery-O'Brien, patent attorney of Shelston IP, Sydney.

GROUNDS OF OPPOSITION

4. The grounds of opposition were manner of manufacture, novelty, inventive step and section 40.  The opponent made submissions at hearing in relation to all of these grounds.

THE EVIDENCE

5. Evidence in support consisted of a declaration by Professor Stephan A Schug, Department of Pharmacology, University of Western Australia, dated 23 June 2003 and comprising Exhibits SAS1 to SAS7.

6. Evidence in answer consisted of declarations by:

• Dr Kenneth Frederick Brown, self employed consultant, dated 1 June 2005, and comprising Exhibit KFB1.

• Dr Andrew Alexander Somogyi, Department of Clinical and Experimental Pharmacology, University of Adelaide, dated 8 November 2004, and comprising Exhibit AAS-1.

7. Evidence in reply consisted of declarations by:

·Professor Schug dated 5 December 2005 and comprising Exhibit SAS8.

·Dr James Steven Rowe, Technical Consultancy Services Pty. Ltd., dated 9 February 2006 and comprising Exhibits JSR1 and JSR2.

8. Further evidence consisted of a declaration by Dr Jacinta Flattery-O’Brien dated 8 September 2006 and comprising Exhibit JFO-1.

9. Evidence in response consisted of a declaration by Mr Phillip John Kerr dated 27 September 2006 and comprising exhibits PJK-1 and PJK-2.

SPECIFICATION

10. The present application relates to sustained-release opioid formulations that are intended for once-daily administration for the treatment of pain.  Such formulations have the advantage that less drug may be used compared with normal dosage regimes over the same time period.  This is particularly important in opioid analgesic formulations since the level of opioid in the blood must be maintained at an appropriate level in order to achieve effective pain relief.

11. The specification sets out several objectives of the invention.  These include:

·    To provide a method for treating patients in moderate pain with an orally administered opioid analgesic dosage form that is suitable for once-a-day administration.

·    To provide a method for treating patients with a once-a-day analgesic formulation which provides greater analgesic efficacy than that which is obtainable with 12-hourly analgesic therapies.

·    To provide an opioid analgesic dosage form which provides sustained-release of the opioid and is also suitable for use in titrating a patient receiving opioid analgesic therapy.

12. The invention is related in part to the discovery that in order to provide a 24 hour dosage form it is “critical” for the formulation to provide an initially rapid opioid release so that the minimum effective analgesic concentration can be approached.  The present invention is also predicated on the discovery that quicker and greater analgesic efficacy is achieved by 24 hour oral opioid formulations “which do not exhibit a substantially flat serum concentration curve.”  The state-of-the-art approach to controlled release opioid therapy has been to seek formulations that exhibit zero order pharmacokinetics (a generally flat serum concentration curve over time) and have minimal “peak to trough” fluctuation in opioid levels with repeated dosages.  The “peak to trough” ratio is calculated from the Cmax and Cmin (the plasma concentration at the end of the dosage period), and therefore corresponds to the Cmax/C24 ratio.  Dr Somogyi provided calculations to show that the examples provide a Cmax/C24 ratio within the range defined by the present claims (2.6, 3.0 and 3.4). 

13. The specification ends with 11 claims.  The claims define a method of effectively treating pain in humans, wherein an oral sustained release opioid formulation is administered on a “once-a-day” basis.  I interpret this to mean that the formulation provides effective analgesia for a 24 hour period.  The claim further defines several physical features of the invention.  In particular, the composition comprises a plurality of inert pharmaceutical beads that are coated with an opioid analgesic, and overcoated with certain hydrophobic polymers.  The parties were in general agreement as to the essential features of the claims and at hearing focussed on the invention as defined by Claim 1:

“A method of effectively treating pain in humans, comprising orally administering to a human patient on a once-a-day basis an oral sustained release opioid pharmaceutical composition comprising a plurality of inert pharmaceutical beads coated with an analgesically effective amount of an opioid analgesic, said opioid coated beads overcoated with an effective amount of at least one hydrophobic polymer selected from the group consisting of a pharmaceutically acceptable acrylic polymer, a hydrophobic cellulosic material, and combinations thereof, said pharmaceutical composition providing a time to maximum plasma concentration T(max) from about 2 to 8 hours and a maximum plasma concentration C(max) which is from about 2.6 to 3.4 times the plasma level of said opioid in said patient at 24 hours after single administration of the dosage form.”

14. The claim does not specifically define the actual amount of the opioid used in the method, or indeed the specific composition of the sustained-release coatings.  Rather, the claim includes two features defined in terms of a result to be obtained: namely that the formulation provides a Tmax of 2 to 8 hours and a Cmax/C24 ratio of 2.6 to 3.4.  As an aside, I also note that the Cmax and C24 values are not specifically quantified in the claim, but I have interpreted the claims to define that effective analgesia is provided for a period of about 24 hours.  It follows that the C24 value will be at least equal to the minimum effective plasma concentration of the opioid, and the Cmax will be at least 2.6 to 3.4 times that amount.

DECISION

Section 40: Fair Basis

15. The opponent’s submissions on fair basis were primarily in regard to the Cmax/C24 parameter, which they claimed was not mentioned in the specification.  In particular, they submitted that it is impossible to divine from the specification that the Cmax/C24 ratio is of any significance, let alone an important feature of the invention.  As such they argued that the claims lack fair basis since there is no “real and reasonable disclosure” of the matter claimed.  The applicant also disputed the priority date of the present claims based on these submissions, so the consideration of internal fair basis will be equally applicable to fair basis in relation to priority.

16. Furthermore, the opponent expressed some concerns that “contrary to the usual practice” the applicant had not provided an explanation of the invention other than to recite the features of the claims, and submitted that such an explanation would have been particularly useful in this case as none of the inventors had provided evidence.  Notwithstanding that such an explanation would have been particularly beneficial for a consideration of fair basis, the specification is addressed to a person skilled in the art and is construed in the light of the common general knowledge in the relevant art at the priority date of the application (see for example Décor Corp v Dart Industries 13 IPR 385). Evidence was provided by four independent experts, and while the opponent’s experts commented on matters such as the breadth of the claims, all of the experts were prima facie able to determine the invention as described.  Where necessary I will rely on this evidence to clarify any issues that arise in relation to fair basis (Vidal Dyes v Levinstein 29 RPC 245).

17. As noted above, the present invention lies in the provision of opioid formulations “which do not exhibit a substantially flat serum concentration curve.”  In evidence, Dr Somogyi stated that a fluctuation in this ratio in the order of 2.6 to 3.4 would have been considered undesirable since the plasma concentrations would be too high and would have an increased incidence of side effects.  A Cmax/C24 ratio of 2.6 to 3.4 is therefore consistent with the broad disclosure of substantially non-zero order pharmacokinetics.  Moreover, the specification provides examples that include Cmax/C24 values that span the defined range.  Thus, while the description does not specifically refer to the specific Cmax/C24 range defined by the claims, I consider that there is fair basis for such a range.

Novelty

18. The opponents questioned the priority date of the present claims based on their arguments in relation to fair basis and the disclosure of the Cmax/C24 ratio.  As noted above I consider that there is fair basis for the Cmax/C24 ratio as presently defined.  As the present description and examples are the substantially the same as the priority document, it follows that the present claims are fairly based on, and entitled to the priority date of the parent application (23 November 1993, based on US basic application 08/156468).  This is therefore the relevant date for determining novelty.

19. Although the opponent had provided an extensive list of documents in their statement of grounds and particulars, they focussed their submissions at hearing to just one document: Australian Patent 617573 (Faulding).  This citation describes methods of treating pain using sustained release formulations comprising a “core element” that includes morphine and a core coating that is partially soluble at highly acidic pH.  The slow release coating may include cellulosic materials and acrylic polymers.

20. The Faulding formulations are purported to provide peak-to-trough variations in the steady state of 60-100% (page 12, line 38 to page 13, line 2), and my understanding is that this corresponds to a Cmax/C24 range of 1.6 to 2.0.  This is a relatively flatter serum concentration curve than defined by the present claims.  However, Professor Schug provided an analysis of the plasma concentration versus time profile shown in Figure 7 of the citation which suggests that this formulation has a Tmax of about 2 to 8 hours and a Cmax/C24 ratio of about 2.9.  The opponent asserted that this amounted to a disclosure of each and every feature of the claims, and it was enough that these values fell within the ranges defined in the present claims to deprive the claims of novelty (Williams Advanced Materials Inc v Target Technology Co LLC (2004) 63 IPR 645 at [47] to [48], Cadbury Schweppes PLC v Effem Foods Pty Ltd [2002] APO 38 at [52] to [53]). The opponents noted that the Faulding formulations are intended to provide release of the active ingredient over an extended period of time of “10 to 24 hours or greater,” and that following the teaching provided by Faulding would inevitably produce something having the parameters defined in Claim 1. However, the applicants submitted that Faulding did not state in “certain terms” that the formulation would be suitable for once-daily dosing and referred to passages of the citation stating that the dosage form can be administered on a two, three or four times daily dosage regimen.

21. I acknowledge that the various features defined by the present claims are broadly disclosed by Faulding.  However, a further key consideration is whether or not Faulding provides clear and unmistakable directions to a once-daily dosage regime (Pfizer Overseas Pharmaceuticals v Eli Lilly and Company [2005] FCAFC 224), and whether the citation provides sufficient information to enable the person skilled in the art to be practically able to apply the invention without further experiments or information (Hill v Evans (1862) 4 De G F & J 288; 45 ER 1195be). In this regard, I do not consider that the formulation referred to by the opponents provides a therapeutic effect for a period of 24 hours as the plasma level concentration falls below the required level for a therapeutic effect. The specific example therefore does not in itself provide sufficient information for the skilled person to prepare a formulation that is capable of providing a therapeutic effect for about 24 hours. Moreover, there is insufficient information provided by Faulding in the way of dosage levels, type of formulation and the like to achieve the combination of parameters defined by the present claim. Indeed, the Faulding formulations are intended to provide a flatter serum concentration curve that required by the present claims, and accordingly I consider the teaching of Faulding to be away from the present invention. The evidence before me does not adequately establish that Faulding provides clear and unmistakable directions to the invention defined by the present claims, and specifically the therapeutic effect of 24 hours. I therefore consider that the claims are novel in view of Faulding.

Inventive Step

22. An appropriate test for inventive step is that given in Olin Mathieson v Biorex (1970) RPC 157, and approved by the High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59:

“Would the notional research group at the relevant date in all the circumstances ... directly be led as a matter of course to try the invention claimed in the expectation that it might well produce a useful desired result.”

23. Where an invention relates to a specific combination of integers or features further guidance is provided in Minnesota Mining & Manufacturing Co v Beiersdorf (Australia) Ltd (1979-80) 144 CLR 253 at page 293:

“In the case of a combination patent the invention will lie in the selection of integers, a process which will necessarily involve rejection of other possible integers. The prior existence of publications revealing those integers, as separate items, and other possible integers does not of itself make an alleged invention obvious. It is the selection of the integers out of, perhaps many possibilities, which must be shown to be obvious.”

24. The opponent provided submissions in relation to the Faulding patent under section 7(3) of the Patent Act.  The opponent also made submissions in relation to the common general knowledge surrounding the commercially available slow-release product, Kapanol, which the opponent submitted was described in Faulding.  They argued that the information provided by Faulding would be read in light of the common general knowledge of Kapanol being used on a once daily basis.  I will deal with each of these submissions in turn.

Faulding

25. The opponent argued that Faulding would have been ascertained, understood and regarded as relevant by the person skilled in the art.  This was disputed by the applicant, who claimed that the opponent had failed to adduce any evidence to show that patents would be consulted in this art or that Faulding would have been ascertained by the skilled person.  Indeed, a perusal of the evidence suggests that the applicant is correct as neither of the opponent’s experts addressed this matter in evidence.  I further note that the opponent’s submissions at hearing referred to the evidence of Dr Rowe but the cited evidence was in fact in relation to whether Dr Rowe would have been able to ascertain the formulation of Kapanol from its disclosure at a conference.  Nevertheless, I consider it reasonable to assume that a person working in the area of slow release formulations would have regard to patent documents, and as it concerns opioid formulations they would ascertain the Faulding document.

26. The opponent further submitted that even if Faulding patent did not teach the present Tmax and Cmax/C24 parameters, there was no invention in selecting the ranges defined.  In particular they submitted that the specification mentioned the Tmax value, but it was merely referred to as a characteristic of the formulations and there was no suggestion that it was in any way significant.  Similarly, the Cmax/C24 parameter was not mentioned in the specification, and there was otherwise nothing to explain the relevance of the parameter in Claim 1.  They considered this was analogous to Williams v Target [supra] at [47] to [48].

27. However, the specification indicates that the Tmax and Cmax/C24 parameters have been selected for a purpose (Austal Ships Pty Ltd v Stena Rederi Aktiebolag [2005] FCA 805 at [108]). The Cmax/C24 value indicates a substantially non-zero order pharmacokinetic profile which is in contrast to the intention of the Faulding formulations to provide relatively flatter serum concentration profiles. Similarly the Tmax value has been selected in order to provide an initially rapid rise in the plasma concentration such that pain relief is achieved in a relatively short time. Such a rapid rise in plasma concentration is a feature of the Faulding formulations, but the present combination and the purported advantages conferred by all the various features are not otherwise taught or suggested. Moreover the teaching of Faulding is towards a relatively flat serum concentration curve and away from the relatively large fluctuations in plasma concentration levels defined by the present claims. Hence, there is nothing in the evidence before me to establish that the person skilled in art would be directly led to pursue formulations having substantially non-zero order pharmacokinetics in order to develop a formulation that could be used once-daily. Accordingly, I do not consider that the opponent has established that the claims lack inventive step in view of Faulding.

Inventive step in light of Kapanol

28. The opponent submitted that the disclosure of Kapanol at the 7^th World Congress on Pain, Paris, August 1993 and of various clinical trials prompted discussions that it could be used on a once-daily basis.  The opponent argued that this congress was attended by 3000 to 4000 delegates, and that given the importance of the conference and the number of attendees this information could be considered common general knowledge.  The opponent argued that Faulding disclosed Kapanol, and that the common general knowledge of once-daily administration of Kapanol would be combined with the formulation provided by Faulding to provide the invention defined by present Claim 1.

29. The Paris conference abstracts describe various clinical studies using Kapanol, but there is no disclosure of the composition of the formulation or any reference to the Faulding patent or any other document that provides that information.  Dr Rowe provided evidence that had he wished to ascertain the formulation of Kapanol he would considered the authors and their employer(s) as listed on the abstract, and undertaken a search of patents by Faulding.  This would have provided the Faulding patent, and the information provided in the patent of a sustained release formulation would prompt him to consider the patent as covering Kapanol.  This appears a reasonable means of obtaining information on the formulation used in Kapanol, and there was otherwise no apparent dispute as to this formulation being disclosed by Faulding.

30. The Tmax parameter is also disclosed in the abstracts, but there is no disclosure of the C24 value.  This precludes calculation of the Cmax/C24 value.  Moreover, the only reference to a dosage regimen is 12-hourly administration.  In order to address this point and provide evidence that Kapanol is a once-daily dosage form, the opponent filed further evidence comprising an extract of the 1997 MIMS Annual on Kapanol.  This detailed the once- or twice-daily administration of Kapanol.  In response the applicant provided extracts of the 1995 and 1996 MIMS annuals which both only describe a twice-daily dosage schedule.  They argued that this showed that Kapanol was not known to be suitable for once-daily dosage until about 1996.

31. On balance I am not satisfied that the use of Kapanol as a once-daily sustained release dosage form was common general knowledge as of the priority date of the present claims (23 November 1993).  The product per se certainly became public knowledge as a result of the Paris conference, and the inclusion in MIMS is a very strong indication of its general acceptance in the art by 1995.  However, even if the abstracts of the Paris conference are taken as being indicative of the nature of the common general knowledge in relation to Kapanol, they only teach 12-hourly administration.  Mere conjecture during a conference as to the potential of a drug does not provide sufficient basis for the use of Kapanol on a once-daily regimen being regarded as common general knowledge.  Accordingly, the use of Kapanol on a once-daily basis has not been established as common general knowledge, and the present claims are considered inventive in view of Faulding combined with the common general knowledge relating to Kapanol.

Manner of Manufacture

32. The opponent submitted that the present claims do not define a manner of manufacture as there is no invention on the face of the specification (Advanced Building Systems Pty Ltd v Ramset Fasteners (Aust) Pty Ltd (1998) 152 ALR 604 at 614). In particular, they argued that the features of the invention were known, and there was no invention in the selection of the various parameters defined by the present claims.

33. However, I have found that the claims are both novel and inventive in view of Faulding (either alone or in view of Kapanol).  On that basis I consider that the present claims meet the threshold test for inventiveness and this argument cannot be sustained.

CONCLUSION

34. The opposition has been unsuccessful on all grounds.

35. Under Rule 58 of the Federal Court Rules, the opponent has 21 days from the date of this decision to file a notice of appeal with the court.  I therefore direct that the application be sealed after seven (7) days from the date set out under Rule 58.  If the Commissioner of Patents is served with a notice of appeal from this decision before that time, I direct that sealing not occur until the appeal has been decided or discontinued.

COSTS

36. The power of the Commissioner to award costs is based on section 210 and regulation 22.8.  The opposition has been unsuccessful on all grounds and I therefore award costs against the opponent Grunenthal GmbH.

L. F. McCaffery
Delegate of the Commissioner of Patents

18 December 2006

Patent attorneys for the applicant  :  Allens Arthur Robinson, Sydney

Patent attorneys for the opponent  :  Shelston IP, Sydney