Euro-Celtique S.A. v Grunenthal GmbH

[2006] APO 38

ABSTRACTS OF DECISIONS

DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS

Application  :          No. 716793 in the name of Euro-Celtique S. A.

Title  :          Opioid Formulations Having Extended Controlled Release

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

Decision  :          Issued            .

Abstract

The opposed invention relates to an opioid-containing solid controlled-release oral dosage form providing an extended duration of therapeutic effect of about 24 hours after administration.  The opponent pursued the grounds of novelty, inventive step and manner of manufacture at hearing. 

Submissions were made that certain features of the present invention were a mechanical equivalent of the prior art, and that certain parameters were an inherent feature of prior art formulations.  The evidence did not support such submissions, and the claims are novel.  Furthermore, the evidence did not establish that a skilled person would have been directly led to the invention in view of the prior art, and the claims 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. 716793 in the name of Euro-Celtique S. A., and an opposition under section 59 to the grant of a patent by Grunenthal GmbH.    

BACKGROUND

1. Patent application number 716793 in the name of Euro-Celtique S. A. (“the applicant”), was filed on 6 February 1998.  The application was advertised accepted on 9 March 2000, and a notice of opposition was filed by Grunenthal GmbH (“the opponent”) on 9 June 2000.  A statement of grounds and particulars was filed on 8 September 2000.  Evidence in support was completed on 25 February 2002, evidence in answer on 18 March 2004, and evidence in reply on 22 June 2005. 

2. The applicant filed further evidence on 10 November 2005.  Evidence in response to the further evidence was completed on 20 March 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 of Shelston IP, Sydney.  In addition to providing written submissions at hearing, both parties provided further submissions following the hearing.

GROUNDS OF OPPOSITION

4. The grounds of opposition were manner of manufacture, novelty, inventive step and section 40, but only novelty, inventive step and manner of manufacture were the subject of submissions at hearing. 

THE EVIDENCE

5. Evidence in support consisted of declarations by:

·Stephan A. Schug, Department of Pharmacology, University of Western Australia, dated 19 February 2002 and comprising Exhibits SAS1 to SAS9.

·James Steven Rowe, Technical Consultancy Services Pty. Ltd., dated 6 February 2002 and comprising Exhibits JSR1 to JSR21.

·Denis Eng Tuffery, Shelston IP Sydney, dated 8 February 2002.  This declaration merely confirmed the publication dates of a number of patents referred to in Dr Rowe’s evidence.

6. Evidence in answer consisted of declarations by:

·Kenneth Frederick Brown, self employed consultant, dated 12 March 2004, and comprising Exhibit KFB1.

·Martin Peter O’Sullivan, Wray & Associates Perth, and dated 19 November 2003.  This declaration merely entered Australian application 29207/02 into evidence.

·Andrew Alexander Somogyi, Department of Clinical and Experimental Pharmacology, University of Adelaide, dated 18 November 2003, and comprising Exhibit AAS-1.

7. Evidence in reply consisted of declarations by:

·Professor Schug dated 17 June 2005.

·Dr Rowe (2) dated 21 December 2004 and 21 March 2005.

8. Further evidence consisted of a declaration by Joachim Fritz, Borden Ladner Gervais LLP Canada, dated 9 November 2005 and comprising Exhibits JF-1 to JF-3.

9. Evidence in response to the further evidence comprised declarations by:

·Santosh Chari, Blake Cassels and Graydon LLP Canada, dated 16 February 2006.

·Dr Rowe, dated 20 March 2006.

THE SPECIFICATION

10. Controlled-release formulations avoid peaks and troughs in drug concentration and provide a smoother plateau in the drug plasma concentration profile compared with conventional immediate-release formulations.  This may reduce the severity and incidence of side effects.  Controlled-release formulations also have the advantage that less active ingredient may be required compared with normal dosage regimes over the same time period.

11. The present invention relates to an opioid-containing solid controlled-release oral dosage form for use in the treatment of pain.  The controlled-release formulations of the invention are said to provide an extended duration of therapeutic effect and a peak plasma level from about 2 to 8 hours, thereby providing pain relief “well beyond 12 hours, and preferably, for about 24 hours after administration.”  This provides for once-daily administration.  The specification describes various suitable overcoat materials, including alkylcelluloses and acrylic polymers.  The formulation releases the opioid at a rate that is independent of pH, thereby avoiding “dose dumping” of the active ingredient upon oral administration. 

12. The specification ends with 30 claims.  At hearing the parties focussed on the invention as defined by Claim 1:  

“A solid controlled release oral dosage form, the dosage form consisting of a plurality of inert pharmaceutical beads coated with an analgesically effective amount of an opioid analgesic or a mixture of opioid analgesics or a salt thereof, said inert pharmaceutical beads overcoated with a controlled release coating, wherein the dissolution rate in vitro of the dosage form, when measured by the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100rpm at 900ml aqueous buffer at 1.6 and 7.2 pH and 36ºC is from about 16.8% to about 42.5% (by wt) opioid released after 1 hour, from about 25% to about 65% (by wt) opioid released after 2 hours, from about 45% to about 85% (by wt) opioid released after 4 hours and greater than about 60% (by wt) opioid released after 8 hours, the in vitro release rate being substantially independent of pH in that a difference at any given time between an amount of opioid released at one pH and an amount released at any other pH,  when measured by the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at 100rpm at 900ml aqueous buffer, is no greater than 10%, the in vitro release rate being chosen such that the peak plasma level of said opioid obtained in vivo occurs from about 2 hours to about 8 hours after administration of the dosage form, said dosage form providing an extended duration of therapeutic effect of about 24 hours.”

13. The claims essentially define a formulation comprising three layers: an inert core, an opioid-containing layer and a slow release layer.  The various dissolution parameters and the time to peak plasma concentration level (Tmax) may be determined using known techniques.  In the case of hydromorphine, the plasma concentration level that provides a “therapeutic effect” may be determined by reference to the trough plasma level concentration of a known formulation (Dilaudid).  At hearing the parties were in substantial agreement that a hydromorphone plasma concentration of 300 pg/ml was indicative of a therapeutic effect for this drug.

14. I note that in addition to the opioid-coated beads defined in Claim 1, the specification describes controlled release formulations that comprise opioid-containing beads.  In particular, pages 19 to 22 describe alternative embodiments wherein the opioid is dispersed within a slow-release matrix or spheronising agent and optionally coated with a controlled-release coating.  Furthermore, while the specification provides 13 examples of different controlled-release formulations, only Examples 1, 5, 9, 10, 11 appear to possess the in vitro and in vivo dissolution properties defined in the claims.  It was suggested in the opponent’s evidence that this caused some confusion as to what new feature the present application disclosed over the prior art.  However, I do not consider this a significant problem as it is not unusual for a specification to disclose several different inventions but claim only certain embodiments. 

DECISION

Novelty

15. The test for novelty has been discussed recently in the Full Federal Court decisions of Pfizer Overseas Pharmaceuticals v Eli Lilly and Company [2005] FCAFC 224 (see paragraphs 311 et seq) and Bristol-Myers Squibb Company v FH Faulding & Co Limited (2000) 97 FCR 524. As noted in both decisions, the basic test for novelty is the “reverse infringement test” as set out in Meyers Taylor Pty Ltd v Vicarr Industries (1977) 137 CLR 228 at page 235 where Aickin J stated:

“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 invention would if the patent were valid, constitute an infringement.”

16. Infringement is said to occur where “each and every one of the essential features of that claim have been taken” (Rodi and Wienenberger AG v. Henry Showell Ltd (1969) RPC 367). However, as Pfizer noted it is not sufficient for a citation to contain all the essential features of the claim, there must be "clear and unmistakable" directions to the claimed invention. In addition, the citation has to “enable” the skilled worker to produce the invention from the written disclosure. The basic principle is explained in Hill v Evans (1862) 4 De G F & J 288; 45 ER 1195be where the court noted:

“the antecedent statement must be such that a person of ordinary knowledge in the subject would at once perceive, understand, and be practically able to apply the discovery without the necessity of making further experiments and gaining further information before the invention can be made useful.  If something remains to be ascertained which is necessary for the useful application of the discovery that affords sufficient room for another valid patent.”

17. 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 three patent documents: US 4990341 and US 4844909 (“Goldie”), and EP 548448 (“Euroceltique”).  The two Goldie patents disclose essentially the same material, and the opponent made submissions only in relation to EP 548448 and US 4990341.  I will deal with each of these in turn.

EP 548448 (Euroceltique)

18. Euroceltique discloses controlled-release formulations having a similar three-layered structure to the present invention.  The controlled-release layer provides in vitro dissolution properties that are almost identical to the present compositions.  Indeed, Euroceltique describes specific formulations that are identical to the present formulations with the exception of the quantity of opioid used.  Euroceltique does not disclose any of the in vivo characteristics defined in the present claims (particularly the Tmax and 24-hour duration of therapeutic effect), but the opponent argued that these would be inherent properties of the prior art formulations.  They particularly noted the similarity of the in vitro dissolution rates, and submitted that formulations having such similar in vitro dissolution rates would be expected to provide similar plasma levels after 24 hours

19. However even if the in vitro dissolution properties could be used in this manner to predict the in vivo characteristics of a formulation, I am not satisfied that the formulations described in Euroceltique would provide a 24-hour duration of therapeutic effect.  Of greatest relevance is Example 2 of the present application, which as noted above has essentially the same composition but comprises twice the drug loading of the Euroceltique formulations.  My understanding of the clinical studies suggests that the plasma concentration provided by this example falls below the level that is capable of providing a therapeutic effect (300 pg/ml) well before 24 hours.  Given this result, I consider it unlikely that similar dosage form containing half as much drug would provide a therapeutic effect for 24 hours. 

20. I note that the role of an opposition is only to refuse a patent application if it is clearly invalid (F. Hoffmann-La Roche AG v New England Biolabs, Inc. (2000) 99 FCR 56). The onus in this case is on the opponent to prove that in addition to possessing the in vitro dissolution properties, the prior art formulations also possess the in vivo properties defined in the claims.  However, rather than providing experimental evidence to demonstrate that the prior art formulation possessed these properties, the opponent relied on the similarity of the in vitro tests to support their argument of inherency.  I am not satisfied on the evidence before me that such a conclusion may be made.

21. Therefore, I consider that the present claims are novel in view of Euroceltique as there are no clear and unmistakeable directions in this citation to a dosage form that provides a therapeutic effect of about 24 hours.

US 4990341 (Goldie)

22. Goldie describes controlled-release formulations that provide in vivo and in vitro dissolution rates and peak plasma levels that are similar to those defined for the present invention.  Goldie specifically describes two types of formulations that provide the desired dissolution rates.  The first type comprises a controlled release matrix, which is essentially a single-layer structure.  The second type of formulation comprises a “normal release matrix” which comprises film coated spheroids.  This formulation essentially comprises a two-layer structure, wherein the inner layer consists of a matrix in which the opioid is dispersed.  Neither of these formulations comprises the three-layer structure defined by the present claims.

23. I also note that the citation does not specifically disclose a duration of therapeutic effect of 24 hours.  The opponent argued that Goldie disclosed a therapeutic effect of at least 12 hours, which they asserted encompasses 24 hours. I do not find this argument persuasive as Goldie states that the dosage forms “afford therapeutic levels of hydromorphone in vivo over at least a 12 hour period, and may therefore be used on a twice daily basis.”  Such a dosage regime is inconsistent with a dosage form that provides a therapeutic level of activity of about 24 hours.

24. The opponent further argued that even if a three-layer formulation was not disclosed by Goldie, the person skilled in the art would understand that the present system was a mechanical equivalent that could be substituted for the two-layer formulations described in Goldie (Nicaro Holdings Pty Ltd v Martin Engineering (1990) 91 ALR 513 at 527-8). I do not consider this argument persuasive.

25. In the first instance all features of a claim are taken to be essential (Catnic Components Ltd v Hill and Smith (1982) RPC 183), and for the doctrine of mechanical equivalents to apply the evidence must show that the difference represents no more than the substitution of an inessential feature with an obvious equivalent (R. D. Werner & Co Inc v Bailey Aluminium Products Pty Ltd, (1989) 13 IPR 513). Further guidance in this regard is provided by the recent Federal Court decision in PhotoCure ASA v Queen’s University at Kingston [2005] FCA 344 wherein the issue of infringement in substance was determined by applying the questions set out by Hoffmann J in Improver Corporation v Remington Consumer Products Ltd [1990] FSR 181.

26. I acknowledge that the present specification does describe alternative embodiments, including one in which the claimed opioid-coated beads are substituted by a matrix comprising the opioid.  This suggests that the two systems provide a similar function, but it does not lead to a conclusion that the discrete coating is a mechanical equivalent of the matrix in which the active ingredient is incorporated.  Prima facie there would be significant differences in the dissolution characteristics of a formulation in which the active ingredient is entirely adjacent the controlled release layer, as opposed to a matrix in which the opioid was distributed throughout a matrix which is surrounded by a controlled release layer.  The key consideration is whether or not the evidence shows that the opioid coating has a material effect upon the way the invention works (PhotoCure ASA v Queen’s University at Kingston [supra]).  No evidence was provided that addressed this issue.  As a consequence the evidence does not support the assertion that the opioid-coated beads defined by the present claims are a mechanical equivalent of the matrix disclosed in Goldie.

27. Therefore I am not satisfied that Goldie discloses either the opioid-coated bead overcoated by particular slow release coatings or the defined in vivo and in vitro properties defined in the present claims.  Accordingly, I do not consider that the Goldie patent deprives the present claims of novelty.

Inventive Step

28. The opponent made submissions only in relation to both Euroceltique and Goldie under Subsection 7(3) of the Patents Act 1990, which they submitted allows a document that does not form part of the common general knowledge to be considered for obviousness purposes. In particular, this section sets out that a claimed invention will lack an inventive step if it is obvious to a person skilled in the relevant art in the light of common general knowledge considered together with information publicly available in a single document or through doing a single act, provided that the document or act could reasonably be expected to have been ascertained, understood and regarded as relevant to work in the relevant art in the patent area by the person skilled in the art.

29. The parties differed in relation to whether the documents could reasonably have been ascertained and considered relevant by the person skilled in the art.  Dr Rowe stated that he did not normally consult patent specifications, but if he did find the need for such information he would undertake an online search that generally included patent specifications.  He also stated that he would normally have patent searches carried out by a specialist information department who would carry out the search in consultation with him using various parameters such as key words.

30. However, the applicant argued that the opponent had failed to meet the requirements of subsection 7(3) in that no evidence had been provided as to how either of the documents would have been found in a search (Commissioner of Patents v Emperor Sports Pty Ltd (2006) 667 IPR 488 at 495). In particular, the applicant noted that Dr Rowe did not specify the search parameters that would have captured the cited documents, and given that he did not routinely consult patent literature unless there was a need for further information, there was no evidence as to why he would have conducted an online search of the patent literature in this case. The applicant also referred to the evidence of Dr Somogyi to the extent that even if a search of patent literature had been performed, the person skilled in the art would not have regarded the information in these documents useful for preparing a 24 hour preparation.

31. On balance I am satisfied that the person skilled in the art would have regard to the patent literature.  The evidence of Dr Rowe indicates that searches of this type were routine in the art of formulation chemistry.  Furthermore, while the evidence does not provide any search terms that would be used, I consider it reasonable to conclude that the skilled person would ascertain and consider relevant documents relating to controlled release formulations regardless of whether or not they were for a once-daily administration.  Accordingly, I consider that the Goldie and Euroceltique documents are relevant for determining inventive step.

32. 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.”

33. 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.”

34. Euroceltique does not specify any specific dosage regime, but as noted above I consider it unlikely that the specific dosage forms described would provide a 24 hour duration of therapeutic effect.  Similarly, the Goldie formulations are clearly intended for twice daily administration.    However, the opponent argued that it would be obvious to the person skilled in the art to increase the drug loading in order to obtain a prolonged period of therapeutic effect.  This particular issue overarches both citations and in my opinion is key in determining the inventiveness of the present formulations. 

35. Dr Rowe expressed doubts in evidence as to the ability of the present formulations to provide a 24 hour duration of therapeutic effect when greater than 60% of the active ingredient is released in a period of 8 hours.  I note in this regard that the Goldie and Euroceltique formulations both release between 55 and 85% of the active ingredient after 6 hours, so presumably Dr Rowe would have similar doubts in regard to these formulations. 

36. Notwithstanding his submissions in this regard, Dr Rowe also argued that therapeutic levels of a drug could be achieved after 24 hours if the initial loading dose was sufficiently high.  However, he noted that simply increasing the dosage may lead to other problems, including an increased risk of side effects.  This point was also made by Dr Schug who stated that a drug which is designed for 12 hour administration could not simply be changed over to once-daily use by doubling the dose, and that in some products this would on the one hand result in excessive peak concentrations a few hours after administration and on the other hand too low a trough concentration for major parts of the dosage period.

37. In view of the evidence from both parties, I am not satisfied that the opponent has established that the present claims are obvious in view of Goldie or Euroceltique.  The evidence clearly shows that a skilled person would not be directly led to further pursue a formulation of the type described by these citations, particularly since the evidence suggests that the dissolution profiles of Euroceltique and Goldie would not immediately lend themselves to providing a duration of therapeutic effect of about 24 hours.  Furthermore, there appears to be no predictability in increasing the dosage of the opioid in order to extend the duration of effect, and increasing the drug loading may also risk undesirable side effects associated with the increase in the peak plasma levels.  My view is therefore that the opponent has failed to establish that the claims lack inventive step.

Manner of Manufacture

38. 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 noted that the specification states that “it has been known in the art that controlled-release compositions of opioids or salts thereof could be prepared in a suitable matrix,” and further acknowledges that formulations having the in vitro dissolution properties of the present formulations are known.  The specification further states that it was a desired goal in the art to obtain formulations suitable for once-daily administration.  The opponent asserted that the claims are merely to a known dosage, and at most were to an analogous use of what was described in Goldie (Merck & Co Inc. v Arrow Pharmaceuticals Ltd [2006] FCAFC 91 at [75]).

39. I have found that the claims are both novel and inventive in view of Goldie and Euroceltique.  On that basis I consider that the present claims meet the threshold test for inventiveness and this argument cannot be sustained.

CONCLUSION

40. The opposition has been unsuccessful on all grounds.

41. Under the rules of the Federal Court, the opponent will have 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 twenty-eight (28) days from the date of this decision.  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

42. 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

Patent attorneys for the applicant  :  Allens Arthur Robinson, Sydney

Patent attorneys for the opponent   :  Shelston IP, Sydney