Sandoz Pty Ltd v Euro-Celtique S.A
[2013] APO 54
•27 September 2013
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Sandoz Pty Ltd v Euro-Celtique S.A. [2013] APO 54
Patent Application: 2004229058
Title:Controlled Release Formulation
Patent Applicant: EURO-CELTIQUE S.A.
Opponent: Sandoz Pty. Ltd
Delegate: Dr B. Akhurst
Decision Date: 27 September 2013
Hearing Date: 12 June 2013, in Canberra
Catchwords: PATENTS - section 59 – opposition to grant of a patent – novelty – whether therapeutic effect disclosed – inventive step – whether the starting point can include matters outside the common general knowledge – manner of manufacture – whether a new pharmaceutical preparation is a manner of manufacture if prepared using known formulation principles – utility – whether a pharmaceutical preparation defined by its therapeutic effectiveness can lack utility –– clarity – inconsistency between elements of a dependent claim requirement for therapeutic effectiveness argued –best method – no better method identified – opposition fails on all grounds
Representation: Patent applicant: Katrina Howard of Counsel, instructed by Dr Richard Grant and Shahnaz Irani of Spruson & Ferguson, Sydney
Opponent:Andrew Fox of Counsel, instructed by Rebekah Gay of Shelston IP, Sydney
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2004229058
Title:Controlled Release Formulation
Patent Applicant: EURO-CELTIQUE S.A.
Date of Decision: 27 September 2013
DECISION
The opposition fails on all grounds. Costs according to Schedule 8 awarded against Sandoz Pty. Ltd.
REASONS FOR DECISION
Background
Patent application 2004229058 by EURO-CELTIQUE S.A. (Euroceltique) is the last of a series of divisional applications, claiming an earliest priority date of 10 May 1993. The original application 61963/94 and two serial divisionals, 39957/97 and 65526/99, lapsed without gaining acceptance. The subsequent divisional application 2002300863 was filed on 4 September 2002 and accepted on 24 September 2004. An opposition to grant of a patent was filed by Hexal Australia Pty Ltd, later amended to Sandoz Pty Ltd (Sandoz). That opposition was heard on 12 August 2008.
Application 2004229058, the subject of this opposition, was filed as a divisional of 2002300863 on 11 November 2004. After examination, it was advertised as accepted on 1 March 2007. Sandoz filed a notice of opposition on 1 June 2007 and served the statement of grounds and particulars on 31 August 2007. A request to amend the statement was allowed unopposed on 16 March 2013.
After extensions were granted for each evidentiary stage, service of evidence in support was completed on 27 November 2008, evidence in answer on 29 August 2011 and evidence in reply on 20 December 2012. Sandoz’s evidence in support consisted of declarations by:
·Ivan Alexander Rajkovic dated 30 November 2007 (IAR)
- Phillip Andrew Marshall dated 17 May 2006 (PAM)
- James Steven Rowe dated 21 October 2005 (JSR#1)
- James Steven Rowe dated 13 April 2006 (JSR#2)
- James Steven Rowe dated 27 November 2007 (JSR#3)
·James Steven Rowe dated 26 November 2008 (JSR#4)
Exhibited to JSR#3 in this opposition, the JSR#1 and JSR#2 declarations were originally filed as evidence in the opposition to grant of patent application 2002300863.
Euroceltique’s evidence in answer consisted of declarations by:
- Andrew Alexander Somogyi dated 19 April 2011 (AAS)
- Colin William Pouton dated 20 June 2011 (CWP)
- Louisa King dated 26 August 2011 (LK)
- Gavin James Adkins dated 31 August 2009 (GJA)
·Kevin John Smith 25 May 2011
The GJA declaration was also filed in the opposition to grant of patent application 2002300863.
The evidence in reply consisted of declarations by:
- James Steven Rowe dated 9 November 2011 (JSR#5)
- James Steven Rowe dated 19 December 2012 (JSR#6)
- Laurence Edward Mather dated 22 November 2012 (LEM)
Exhibited to JSR#6, JSR#5 was originally filed as evidence in the opposition to an amendment request under section 104 for the related patent application 2002300863.
It is clear from most declarations in evidence that the experts provided their opinion with the priority date of 10 May 1993 in mind. However, in his first declaration Dr Rowe comments on the state of knowledge in Australia in the relevant field, but his instructions (at [13]) and his evidence do not identify the date to which his evidence applies. Nevertheless, since the majority of the textbooks and journal articles he cites pre-date the 10 May 1993 priority date of the application, I accept Dr Rowe’s first declaration as evidence of the state of knowledge in Australia before this date.
Much of the evidence in support and answer in this opposition was before the delegate in the opposition to grant of patent application 2002300863 (the parent application) from which application 2004229058 is divided. The delegate’s decision in the earlier opposition was issued as Euroceltique S.A. v Sandoz Pty Ltd [2009] APO 21 (the parent decision).
Grounds of opposition
Sandoz opposed the grant of a patent for application 2004229058 on the grounds of manner of manufacture, novelty, inventive step, usefulness and the section 40 issues of lack of clarity and failure to define the best method.
Standard of proof
The onus of proof in opposition proceedings lies with the opponent, who must establish that it is clear that a valid patent cannot be granted (F.Hoffman-La Roche AG v New England Biolabs Inc [2000] FCA 283 at [29], [67]; 50 IPR 305; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18], [22]; 79 IPR 426).
The primary facts are to be established on the balance of probabilities, but the ultimate facts - the facts leading directly to a conclusion of a lack of novelty or a conclusion of obviousness - must be proved to the level of practical certainty (Justice Besanko in Aspirating IP Ltd v Vision Systems Ltd [2010] FCA 1061 at [35]; 88 IPR 52).
The subject matter of the specification
The title of the specification is “Controlled release formulation”. Tramadol is an analgesic that in conventional release form had been commercially available outside of Australia for many years before the priority date of the application. The specification describes controlled release forms of tramadol, and methods for their preparation. I note that although the scope of the terms is not identical, in practice, the experts use the terms “controlled release” and “sustained release” interchangeably (JSR#1 at [19]; PAM at [12], [41]; CWP at [18]).
The description of the invention
The background and nature of the invention are summarised on pages 1 and 1A of the description, as follows:
“The present invention relates to a controlled release preparation for oral administration, to processes for its preparation and to its medical use. In particular, the invention relates to a controlled release preparation comprising tramadol or a pharmaceutically acceptable salt thereof.
Tramadol, which has the chemical name (±)-trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl) cyclohexanol, is an orally active opioid analgesic. Conventional release preparations in the form of capsules, drops and suppositories containing tramadol, or more particularly its hydrochloride salt, have been commercially available for many years for use in the treatment of moderate to severe pain; such preparations, however, do not provide a controlled release of the tramadol. Moreover, despite tramadol's long-standing use, controlled release preparations for oral administration containing tramadol as active ingredient have not even previously been described in the literature.
It is an object of the present invention to provide an oral controlled release tramadol preparation suitable for at least twelve-hourly (e.g. up to twenty-four hourly) administration for the treatment of pain.
The present invention therefore provides an oral controlled release preparation of tramadol or a pharmaceutically acceptable salt thereof, effective for the treatment of moderate to severe pain for 12 hours or more, wherein:
(A) the oral controlled release preparation comprises the tramadol or a salt thereof incorporated in a controlled release matrix which includes one or more materials selected from (a) digestible Ca-C50 substituted or unsubstituted hydrocarbons such as; fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral or vegetable oils or waxes and (b) polyalkylene glycols; or
(B) the oral controlled release preparation comprises the tramadol or salt thereof in a controlled release matrix and in the form of multiparticulates, the matrix including a hydrophobic fusible carrier or diluent having a melting point of 35 to 140°C or a tablet obtained by compressing said multiparticulates; or
(C) the oral controlled release preparation comprises the tramadol or salt thereof incorporated in a normal release matrix which is a spheroid comprising the tramadol or a pharmaceutically acceptable salt thereof and a spheronising agent, the spheroid having a controlled release coating chosen from water insoluble waxes, water insoluble polymethacrylates and water insoluble celluloses.
Suitable pharmaceutically acceptable salts of tramadol for use according to the present invention are those conventionally known in the art such as pharmaceutically acceptable acid addition salts. The hydrochloride salt is particularly preferred.
A controlled release, oral pharmaceutical preparation according to the present invention is one that achieves slow release of a drug over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery. Preferably such a preparation maintains a drug concentration in the blood within the therapeutic range for 12 hours or more.
Apart from the consistory statements, the text in the description of the opposed application and its parent are the same. Having reviewed the specifications, I agree with the following statement by the delegate at [13] of the parent decision, in respect of the parent specification, which I consider to apply equally to the 2004229058 specification:
“While the title and the first sentence of the description take a broad view of the invention, the specification is focussed on tramadol, rather than analgesics generally. There are no comparative examples of analgesics other than tramadol, and there is no discussion of any other analgesic. There is no recognition of a problem with known analgesics. The thrust of the specification is towards an improved tramadol preparation.”
In this case, the invention is directed to an improved tramadol preparation that is effective for the treatment of moderate to severe pain for 12 hours or more.
The description of the invention
The consistory statement on page 1 of the specification describes the invention in broad terms. To allow for controlled release of tramadol in preparations administered once or twice daily, on pages 2-5 the specification provides seven preferred in vitro release rates, which are measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm.
In vivo, the preferred absorption rate for tramadol following administration of a controlled release preparation for oral administration twice daily is 70-95% (by weight) after 8 hours, 77-97% after 10 hours and between 80-100% after 12 hours. The formulation suitable for twice-daily dosing may have a Tmax of 1.5-8 hours (preferably 2-7 hours) and a W50 value in the range 7-16 hours. The once-daily formulations may have a Tmax in the range 3-6 hours, preferably 4-5 hours, and a W50 value in the range 10-33 hours. The Tmax parameter represents the time taken after administration of the drug for the plasma tramadol concentration to reach its peak (JSR#2 at [57]). W50 defines the length of time that the plasma tramadol concentration is equal or greater than 50% of the peak plasma tramadol concentration on a plot of plasma tramadol against time.
On page 6 of the specification, the preferred controlled release preparation is described as containing an analgesically effective amount of tramadol, or a pharmaceutically effective salt thereof, in the range 50-800 mg per unit dosage calculated as tramadol hydrochloride, especially 100, 200, 300, 400 to 600 mg. The preparation may be presented as granules, spheroids, pellets, multiparticulates, capsules, tablets, sachets, controlled release suspensions or in any other suitable dosage form incorporating such granules, spheroids, pellets or multiparticulates.
The active ingredient in the preparation may be incorporated into any matrix that affords controlled release of tramadol over at least a 12 hour period. In a preferred embodiment, the matrix provides in vitro dissolution rates and in vivo absorption rates within the ranges specified in the description. In a preferred embodiment, the matrix is a controlled release matrix. Alternatively, a normal release matrix may have a coating which provides for controlled release. Suitable materials for inclusion in a controlled release matrix are listed on pages 6-8 and include those as presently claimed.
Processes for making the controlled release tramadol preparations, and tabletting processes are broadly described on pages 8-14. On page 13:
“We have found that by suitable selection of the materials used in forming the particles and in the tabletting and the proportions in which they are used, enables a significant degree of control in the ultimate dissolution and release rates of the tramadol or salt thereof from the compressed tablets.”
Examples 1-8 describe controlled release tramadol preparations falling within opposed claim 1 paragraphs (A)(a)-(b) and (B). Two Figures are provided. Figure 1 is said to illustrate the serum levels of tramadol in 12 healthy volunteers following administration of one tablet according to Example 2. Figure 2 compares the plasma profile resulting from single dose administration of the 200 mg controlled release tramadol tablet of Example 8 with administration of a commercial preparation of 100 mg immediate release Tramal® drops. The serum and plasma blood fractions are volumetrically very similar and for the present purposes I believe the serum and plasma tramadol concentrations may be directly compared.
The claims of the specification
The specification was accepted with 21 claims. Claim 1 is the only independent claim and is as follows:
1. An oral controlled release preparation of tramadol or a pharmaceutically acceptable salt thereof, effective for the treatment of moderate to severe pain for 12 hours or more, wherein:
(A) the oral controlled release preparation comprises the tramadol or a salt thereof incorporated in a controlled release matrix which includes one or more materials selected from
(a) digestible C8-C50 substituted or unsubstituted hydrocarbons such as; fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral or vegetable oils or waxes and
(b) polyalkylene glycols; or
(B) the oral controlled release preparation comprises the tramadol or salt thereof in a controlled release matrix and in the form of multiparticulates, the matrix including a hydrophobic fusible carrier or diluent having a melting point of 35 to 140°C or a tablet obtained by compressing said multiparticulates; or
(C) the oral controlled release preparation comprises the tramadol or salt thereof incorporated in a normal release matrix which is a spheroid comprising the tramadol or a pharmaceutically acceptable salt thereof and a spheronising agent, the spheroid having a controlled release coating chosen from water insoluble waxes, water insoluble polymethacrylates and water insoluble celluloses.
Claims 2-21 are all ultimately dependent on claim 1. Claim 2 specifies the pharmaceutically acceptable salt as the hydrochloride salt of tramadol. Claim 3 specifies the tramadol dose as between 50 to 400 mg (calculated as tramadol hydrochloride).
Claims 4-8 further specify the composition of preparation (A) in claims 1-3.
4. A preparation according to claim 1, 2 or 3, wherein in (A) the preparation contains up to 60% by weight of the component (a).
5. A preparation according to claim 4, wherein the component (a) includes a fatty alcohol present in an amount of 5 to 30% by weight of the preparation.
6. A preparation according to claim 5, wherein the fatty alcohol is chosen from lauryl alcohol, myristyl alcohol, stearyl alcohol, cetyl alcohol and cetostearyl alcohol.
7. A preparation according to claim 6, wherein the fatty alcohol is cetyl alcohol.
8. A preparation according to any preceding claim, wherein in (A) the matrix includes one or more alkyl celluloses and one or more C12 to C36 aliphatic alcohols.
Claims 9-11 further define the composition of preparation (B) in claim 1.
9. A preparation according to claim 1, wherein in (B) the hydrophobic fusible carrier or diluent is a natural or synthetic wax or oil.
10. A preparation according to claim 9, wherein the hydrophobic fusible carrier or diluent is hydrogenated vegetable oil, hydrogenated castor oil, microcrystalline wax, beeswax, carnauba wax or glycerol monostearate.
11. A preparation according to any one of claims 9 or 10, wherein the matrix further includes a release control component comprising a water fusible soluble material or a particulate soluble or insoluble organic or inorganic material.
Claims 12-16 further define a composition of preparation (C) in claims 1-3.
12. A preparation according to claim 1, 2 or 3 wherein in (C) the spheroids contain other pharmaceutically acceptable ingredients such as a binder, a bulking agent and/or a colourant.
13. A preparation according to claim 12, wherein the binder is a water-soluble polymer, a water-soluble hydroxyalkylcellulose or a water-insoluble polymer.
14. A preparation according to claim 13, wherein the binder which is a water insoluble polymer also contributes controlled release properties.
15. A preparation according to claim 13, wherein the water soluble hydroxyalkylcellulose is hydroxypropylcellulose.
16. A preparation according to any one of claims 12 to 15, wherein said bulking agent is lactose.
Claims 17-20 define the oral controlled release preparation according to any preceding claim in terms of a specified in vitro release rate.
17. An oral controlled release preparation according to any preceding claim, wherein the in vitro release rate of tramadol when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm, is:
time (h) % release 1 1-50 2 0-75 4 3-95 8 10-100 12 20-100 16 30-100 24 50-100 36 >80
18. An oral controlled release preparation according to any preceding claim, wherein the in vitro release rate of tramadol when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm, is:
time (h) % release 1 5-50 2 10-75 4 20-95 8 40-100 12 >50 18 >70 24 >80
19. An oral controlled release preparation according to any preceding claim, wherein the in vitro release rate of tramadol when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm, is:
time (h) % release 1 20-50 2 40-75 4 60-95 8 80-100 12 90-100
20. An oral controlled release preparation according to any preceding claim, wherein the in vitro release rate of tramadol when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1 N hydrochloric acid at 37°C and using UV detection at 270 nm, is:
time (h) % release 1 10-30 2 17-37 4 27-47 8 40-60 12 49-69 16 57-77
Claim 21 is an omnibus claim:
21. An oral controlled release preparation of tramadol or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-20, substantially as herein described with reference to any one of the examples.
Claims construction
The general principles of construction were summarised by Hely J in Flexible Steel Lacing Company v Beltreco Ltd [2000] FCA 890 at [74]-[75]; 49 IPR 331 at 347-350. Briefly and most relevantly, the claims are construed in the context of the specification as a whole. It is not legitimate to vary the boundaries of monopoly as fixed by the words of the claim, by adding words or glosses drawn from other parts of the specification. However reference may be made to the rest of the specification to ascertain the meaning of technical terms and to resolve ambiguities in the construction of the claims.
Claim 1 defines an oral controlled release preparation of tramadol, or a pharmaceutically acceptable salt thereof, in terms of its therapeutic efficacy and composition.
Therapeutic efficacy
Claim 1 requires that the preparation be “effective for the treatment of moderate to severe pain”.
Pain is a subjective condition (AAS at [34]; CWP at [29]; JSR#6 at [6], [40]; LEM at [88]). An adequate analgesic dose will depend on the pain source and pain level (AAS at [34]; JSR#6 at [40]; LEM at [84]), the source of stimulus and any underlying pathology, as well as any relevant social associations (LEM at [84]). The response of an individual may vary and significantly different doses may be therapeutically effective in different patients (AAS at [34]; JSR#6 at [40]; LEM at [88]). On the basis of this evidence, I construe the requirement in claim 1 that the preparation be therapeutically “effective”, as that it must significantly reduce moderate to severe pain for 12 hours or more (as compared to placebo), in some, but not necessary all individuals experiencing such pain.
Composition
The preparation comprises the active ingredient in a matrix composition specified in parts (A), (B) and (C) of claim 1. The matrix compositions defined in parts (A) and (B) are not mutually exclusive.
The embodiment of claim 1(A) places the active ingredient in a controlled release matrix which includes one or more materials selected from those listed in (a) and (b). The opponent submitted that the word “and” between (a) and (b) is to be read as “or” consistent with passages in the description. However, the words of the claim are clear. The controlled release oral preparation of claim 1(A) comprises a matrix composed of one or more materials selected from the group consisting of the materials specified in (a) and (b), i.e. one or more materials selected from digestible C8-C50 substituted or unsubstituted hydrocarbons and polyalkylene glycols.
Claim 1(B) specifies the active ingredient in a controlled release matrix, either in multiparticulate form or with the multiparticulates compressed into a tablet, where the matrix includes a hydrophobic fusible carrier or diluent broadly specified in terms of its melting point.
Claim 1(C) defines the active ingredient in a normal release spheroid matrix with a controlled release coating chosen from water insoluble waxes, water insoluble polymethacrylates and water insoluble celluloses.
The experts’ understanding of the claim is consistent with my construction of claim 1 (JSR#4 at [7]-[8]; AAS at [27]; LEM at [67]). Although the claim defines a combination of features, it does so in terms of three broad classes of matrix formulation (LEM at [68]; JSR#6 at [49]).
Claim 20, as dependent on claims 17-19
Claim 20 is dependent on any preceding claim and defines the preparation of the earlier claims in terms of an in vitro release rate of tramadol measured using a specified method. The release rate in claim 20 is not wholly consistent with the in vitro release rates provided in claims 18 or 19 to which it is appended. For completeness, I will address the construction of claim 20 as dependent on claims 17-19, which all contain release rate tables.
Where a range for “% release” in claim 20 at any given time point is narrower but wholly within the equivalent range of an earlier claim to which it is appended, as is usual the range in claim 20 applies. Where the ranges in claim 20 and the earlier claim overlap, I construe claim 20 to define the overlapping portion. Comparing the ranges in claims 19 and 20, there is no overlap at all between the ranges provided under “% released” at 2, 4, 8 and 12 hours. However, the drafter has defined the in vitro release rate with more precision in claim 20, which I take to indicate that where there is no concordance the values in claim 20 should prevail. The 16 hour values, which appear only in claim 20, apply for this claim. Accordingly, claim 20 as dependent on claim 19 defines the following release rate:
time (h) % release 1 20-30 2 17-37 4 27-47 8 40-60 12 49-69 16 57-77
Novelty
It is well established that the general test for anticipation is the reverse infringement test. The classic formulation of this test is that given by Aickin J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19 at [20]; 137 CLR 228 at 235:
“The basic test for anticipation or want of novelty is the same as that for infringement and generally one can properly ask oneself whether the alleged anticipation would, if the patent were valid, constitute an infringement.”
This test is satisfied if the alleged anticipation discloses all of the essential features of the invention as claimed (Nicaro Holdings Pty Ltd v Martin Engineering Co [1990] FCA 40 at [19]; 16 IPR 545 at 549). To meet this requirement, the prior art must contain “clear and unmistakable directions to do what the patentee claims to have invented” (The General Tire & Rubber Company v The Firestone Tyre and Rubber Company Limited [1972] RPC 457 at 486; 1A IPR 121 at 138).
Sandoz submitted that the invention of claims 1, 4-6, 9 and 11-16 is not novel in the light of:
DE 3810343 A1 (BASF AG) 5 October 1989
The applicant’s priority claim of 10 May 1993 is not in dispute. DE 3810343 forms part of the prior art base for novelty purposes pursuant to Schedule 1 of the Act. Sandoz adduced in evidence a translation into English of the DE 3810343 specification, which is not is dispute. The translated document is titled “Procedure for the manufacture of solid pharmaceutical depot-formulations”. It discloses a procedure for the manufacture of oral, solid pharmaceutical formulations containing polymer-binding agents, including polymers listed in the opposed application such as several cellulose derivatives, acrylic acid co-polymers, polyvinyl alcohol (JSR#2 at [36]-[37]; PAM at [60]; AAS at [60]). Tramadol is included in a list of more than 170 candidate drugs said to be suitable for processing in accordance with the invention, but no exemplified formulations contain tramadol (AAS at [64]).
Euroceltique contended that DE 3810343 does not provide clear and unmistakable directions that the controlled release preparation will be effective for the treatment of moderate to severe pain for 12 hours or more.
To establish disclosure of the required therapeutic effect, Sandoz relied on a statement in the translated document that the preparations:
“release the active substance in the gastrointestinal tract not immediately, but rather with a delayed action (usually over a period of at least 3 (to 24 hours) [in a specified in vitro test]”.
The experts placed different interpretations on the word “delayed” in that statement (JSR#2 at [36]; PAM at [60]; AAS at [63]; JSR#6 at [64]-[67]). However, it is not necessary that I determine that point. Euroceltique’s experts state that DE 3810343 provides no disclosure of the preparation being effective for the treatment of moderate to severe pain for 12 hours or more as required by claim 1 (AAS at [65]; CWP at [37]). Dr Rowe for Sandoz confirms this in his last declaration at [71].
Sandoz has not established that the claims lack novelty in light of DE 3810343.
Inventive step
Sandoz opposed all claims under this ground, submitting that the claimed invention was obvious on the basis of the common general knowledge alone, and the common general knowledge in combination with either one of the following prior art documents:
GB 2196848 (Euroceltique S.A.) 11 May 1988
EP 0249347 (Euroceltique S.A.) 16 December 1987
Under the provisions of subsections 7(2) and 7(3) of the Patents Act 1990, an invention is taken to involve an inventive step when compared with the prior art base unless it would have been obvious to a person skilled in the art. The invention must be obvious in the light of the common general knowledge as it existed in the patent area before the priority date, either on its own, or together with information in a document or a combination of documents that the person skilled in the art could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood and regarded as relevant and where necessary combined.
“Obvious” means “very plain” and a “scintilla of inventiveness” is all that is required (Lockwood Security Products Pty Ltd v Doric Products Pty Ltd(No 2) [2007] HCA 21 at [51]-[52]; 72 IPR 447 (Lockwood (No 2)). It is the combination of integers that make up the claimed invention that must be obvious (Aktiebolaget Hässle v Alphapharm Pty Ltd [2002] HCA 59 at [72]; 212 CLR 411 (Alphapharm)).
The test for obviousness is whether it would have been a matter of routine to proceed to the claimed invention.
“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.” (Aicken J in Wellcome Foundation Ltd v VR Laboratories (Aust) Pty Ltd [1981] HCA 12 at [45]; 148 CLR 262 at 286)
More recently, in Alphapharm at [53] the High Court approved the approach taken in Olin Mathieson Chemical Corporation v Biorex Laboratories Ltd [1970] RPC 157 at 187 in which Graham J had posed the reformulated Cripp’s question:
“Would the notional research group at the relevant date, in all the circumstances, … directly be led as a matter of course to try [the claimed combination of integers] in the expectation that it might well produce a [useful or desired result]?” (Emphasis in original)
Sandoz submitted that the claimed invention is obvious “in the sense that … it is simply the consequence of the routine application of ordinary skills and techniques of the person skilled in the art at the priority date when devising a slow release formulation for a drug”. Sandoz contended that the claims define “no more that the identification of three well-known categories of controlled release formulations to produce a controlled release formulation of tramadol that is effective for the treatment of moderate to severe pain for 12 hours or more”.
Euroceltique submitted that the claims are for a combination of integers and that combination is not obvious. Euroceltique submitted that the “combination” claims considered in Alphapharm are analogous to the opposed claims and it pressed for the Cripps question to be applied in this case, in preference to the Wellcome Test. I understand the reformulated Cripps question to be supplementing the Wellcome test and in some circumstances it may provide additional clarity when considering inventive step. However, the considerations are not dissimilar (Dynamite Games Pty Ltd v Aruze Gaming Australia Pty Limited [2013] FCAFC 96 at [24], [26]). Since both approaches are equally applicable in the circumstances of this case, I will apply the reformulated Cripps question as requested.
The reference in the reformulated Cripps question to “expectation” means a reasonable expectation of achieving the desired result (Alphapharm Pty Ltd v H Lundbeck A/S [2008] FCA 559 at [180]; 76 IPR 618). In a summary of the test for obviousness handed up at the hearing, Euroceltique drew my attention to the High Court’s approval in Alphapharm of statements by US Judge Rich in Re O’Farrell (1988) 853 F. 2d 894, 903. For the avoidance of doubt, I will quote the full passage from Re O’Farrell (but absent citations):
“Obviousness does not require absolute predictability of success. Indeed, for many inventions that seem quite obvious, there is no absolute predictability of success until the invention is reduced to practice. There is always at least a possibility of unexpected results, that would then provide an objective basis for showing that the invention, although apparently obvious, was in law nonobvious. For obviousness under [the US patent legislation], all that is required is a reasonable expectation of success.”
The words “might well” in the reformulated Cripps question confirms that, consistent with the US approach, in Australia the reasonable expectation does not require the person skilled in the art to know before they try that a step, or series of steps, will in fact produce a useful result.
The usual approach to obviousness is the problem-solution approach. Once the problem has been formulated, and the common general knowledge or prior art base have been determined, the question of whether the claimed solution is obvious must be addressed.
The problem
The parties disagreed as to the “starting point” (or problem) for considering inventive step in this opposition. Sandoz submitted that the starting point is that found by the delegate in the parent decision - the provision of a sustained release tramadol preparation suitable for 12 hour dosing. In contrast, Euroceltique argued that the starting point is the provision of alternative preparations for pain relief, with tramadol being part of the solution.
Euroceltique contended that the starting point cannot involve tramadol in circumstances where it has not been proven that the drug is common general knowledge in the art. Euroceltique acknowledged that this position is inconsistent with the judgement of Justice Jagot in Apotex Pty Ltd v AstraZeneca AB (No 4) [2013] FCA 162; 100 IPR 285 (Apotex) in which the starting point involved a compound that was not part of the common general knowledge. However, Euroceltique argued that Apotex had been appealed on this point, and the approach taken by Justice Middleton in Ranbaxy Laboratories Ltd v AstraZeneca AB [2013] FCA 368; 101 IPR 11 (Ranbaxy) should be preferred.
I do not consider Ranbaxy to support Euroceltique’s proposition that the starting point cannot include matter that is not common general knowledge in the art. At [230], Justice Middleton says that information in the specification may be relevant to the starting point question if it assists in understanding, among other things, the starting point and context of the invention. He does not mandate that the starting point or problem necessarily excludes anything that is not common general knowledge. To the contrary, at [232], the starting point can include such matters:
“… while the “starting point” may include information that was not within the common general knowledge, this will only be for the purpose of defining the “problem” for the skilled addressee …”
Where the problem-solution approach is appropriate, admissions in the specification of a patent may assist in determining the starting point. However, they must be weighed against the other evidence. The authority on this point is the High Court in Lockwood (No 2) at [105]:
“While not every invention constitutes a solution to a problem, it is commonplace so to describe an invention where it is appropriate to do so. Admissions in a specification about any problem said to be overcome by an invention are made from the vantage point of knowing the solution. When used as evidence, they would always need to be weighed with evidence, if it exists, from persons skilled in the relevant art of their perception of any problem at the time before the priority date, before their exposure to any solution contained in the invention.” (Citations omitted)
In this opposition, no evidence of any perceived problem was given by the experts before their exposure to the opposed specification (or to the substantially similar content of the parent specification). I have borne this in mind when considering the evidence on this point.
The delegate in the parent decision considered many of the same statements in support and answer as are in evidence in this opposition and similar submissions by the parties. He found at [59] that the specification only provides support for viewing the invention as directed to a sustained release (i.e. controlled or prolonged release) tramadol preparation. He was not satisfied that the evidence established that there was a perceived need in the art to develop alternative analgesics such that it would outweigh the admissions in the specification.
I have considered the delegate’s reasons at paragraphs [58]-[62] of the parent decision. I agree with what the delegate said, and I consider that, based on the evidence before him, his conclusion that “the only way to interpret the problem is the way the specification itself speaks” is equally applicable in the present opposition. The additional evidence in this opposition does not alter my conclusion, for the reasons that follow.
Consistent with his evidence in the opposition to the parent application, Professor Somogyi initially identifies the broader problem addressed by the invention as the provision of tramadol in a preparation suited for oral administration once or twice daily (AAS at [22]). However, on being asked for the purposes of this opposition to comment on whether there was a need for the provision of alternative pain relief preparations before 10 May 1993, Professor Somogyi at [23] says there was. His evidence is as follows:
“In my view, there was a need for the provision of alternative pain relief preparations generally before 10 May 1993. In any population of patients, there is a need for a range of treatment options. This is particularly so in the area of pain relief. Morphine was widely used for the treatment of chronic pain before 10 May 1993, particularly in Australia, and was available in both immediate release and controlled release preparations (the latter as MS Contin tablets (modified release). However preparations containing morphine had problems associated with perceived physical dependence and side effects such as nausea, vomiting and respiratory depression. The same applied to preparations containing other opioids, such as codeine. Similarly, preparations of other kinds of analgesic drugs such as the non-steroidal anti-inflammatory drugs … had other kinds of disadvantages.”
Dr Rowe and Professors Pouten and Mather agree that prior to 10 May 1993 there was need in the art for alternative pain relieving drugs (JSR#6 at [5]-[7], [11]; CWP at [29]; LEM at [48]). Dr Rowe (JSR#6 at [5]) and Professor Mather at [48], understand Professor Somogyi’s reference to a need for a range of treatment options to encompass two propositions:
(i) the need to provide a choice of different pain relieving drugs, and
(ii)the need for alternative delivery systems for the various drug options, including controlled release preparations as an alternative to immediate release formulations.
The need for alternatives had driven drug development for pain therapy because it addressed the disadvantages associated with the use of pain relieving drugs (LEM at [48]; JSR#6 at [8], [11]). By May 1993 there were a number of different formulations of opioid drugs available in Australia, offering a choice of route of administration and duration of action, including four controlled release preparations containing hydromorphone or morphine (LEM at [51]; JSR#6 at [24]).
I accept that prior to 10 May 1993, there was a perceived need in the art for alternative analgesics and alternative formulations for existing analgesics. Prima facie, this evidence would support either party’s statement of the problem equally, which leads me to conclude that it is not sufficient to displace the problem disclosed in the specification.
Claim 1 of the opposed application defines the tramadol preparation as “effective for the treatment of moderate to severe pain for 12 hours or more”. This therapeutic effect is consistent with the references on page 1 of the specification to (i) preparations that are suitable for at least 12 hourly dosing, and (ii) the longstanding use of tramadol to treat moderate to severe pain. I find that in this opposition, the problem and starting point for inventive step purposes is that described and claimed in the opposed specification - the problem of providing a sustained release preparation of tramadol that is effective for the treatment of moderate to severe pain for 12 hours or more.
The person skilled in the art
There was no dispute that the person skilled in the art in this opposition is a pharmaceutical scientist or team of such scientists with experience in drug delivery systems.
Drs Rowe and Marshall are pharmaceutical scientists with experience in pharmaceutical formulation (JSR#1 at [1]-[10], [11] and exhibit JSR-1; PAM [2]-[6] and exhibit PAM-1). Professor Pouten is an academic pharmaceutical scientist with experience in drug formulation through his own research and collaboration with industry, and his consultancy work (CWP at [3]-[5], [12]-[15] and exhibit CWP-1). Professor Somogyi is an academic pharmacologist, with a research interest and experience in the clinical pharmacology of opioid drugs for pain control (AAS at [2]-[14] and exhibit AAS-1). Professor Mather is a pharmaceutical scientist with experience in drug development and formulation through his work in industry and as an academic researcher into the application of opioid analgesics to pain medicine (LEM at [1]-[10], [12], [23]-[24] and exhibit LEM-1). All of these experts are relevant persons skilled in the art.
Dr Louisa King has given evidence regarding electronic literature searching. She is a professional patent searcher with a doctorate in organic chemistry. There is no evidence that she has, and she does not claim to have, any relevant experience in the art of drug delivery systems. Dr King is not a relevant person skilled in the art for the purposes of this opposition.
The common general knowledge in the art
A definition of common general knowledge was provided by Aitken J in Minnesota Mining and Manufacturing Company and Another v Beiersdorf (Australia) Limited [1980] HCA 9; 144 CLR 253 at 292:
“The notion of common general knowledge itself involves the use of that which is known or used by those in the relevant trade. It forms the background knowledge and experience which is available to all in the trade in considering the making of new products, or the making of improvements in old, and it must be treated as being used by an individual as a general body of knowledge.”
Information cannot be treated as part of the common general knowledge unless there is “evidence of its general acceptance and assimilation” by persons skilled in the art (Alphapharm at [31]).
Sandoz alleged that a number of matters were part of the common general knowledge. Most relevantly, that the principles involved in formulating controlled release preparations were common general knowledge.
In his second declaration, Dr Rowe describes various aspects of formulation practice for controlled release preparations as “known” (JSR#2 at [5], [8], [13], [14], [17]-[20], [29]-[30], [62]). I agree with the delegate at [79] in the parent decision, that on a fair reading Dr Rowe is asserting that the principles involved in formulating a pharmaceutical agent for controlled release were common general knowledge in the art before the priority date.
While Professor Somogyi disputes elements of Dr Rowe’s evidence, he does not dispute that the various formulation approaches of the opposed claims were known. On a fair reading of his evidence at [109], he appears to acknowledge that these principles are common general knowledge:
“I do not propose to respond in detail to all of Dr Rowe’s comments. However, by way of general response, in my view it is not possible to say that particular known techniques or known types of formulations or preparations will necessarily be applicable to the making of a new controlled release preparation of a drug such as tramadol. The fact that individual features or aspects of the claims of the Opposed Application were previously known or disclosed in the prior art does not, to my mind, mean that the preparation that is claimed was not new or innovative. Dr Rowe tends to deal with the various features of the preparation in a piecemeal fashion rather than focusing on the preparation as a whole and all of its characteristics.” (Emphasis added)
Professor Mather at [65] says that before the priority date a great deal was known about the general principles founding the science of controlled release preparations. Professor Pouten confirms this at [36]:
“It is true that the general types of formulation approaches used in the Opposed Application were not new, and that many of the particular excipients used were previously known.”
I am satisfied that, broadly speaking, the principles involved in formulating a controlled release pharmaceutical substance for the treatment of humans were within the conscious awareness of the person skilled in the art before the priority date.
Euroceltique submitted that the delegate’s finding in the parent opposition was correct, that the details of specific sustained release preparations were not common general knowledge. It was not argued in this opposition that a sustained or controlled release preparation of any particular drug was common general knowledge in the art, and I have made no finding on this point.
Tramadol
The parties disagreed as to whether tramadol formed part of the common general knowledge in Australia at the priority date of 10 May 1993. However, since I have already determined that the problem in this case involves formulating tramadol, the question is moot whether tramadol was common general knowledge at the priority date of the application.
I agree with Sandoz’s submission that the starting point involving tramadol confers on the hypothetical person skilled in the art possession and knowledge of the characteristics of tramadol.
Obviousness in the light of the common general knowledge
The problem in this case is the provision of a controlled release preparation of tramadol that is effective for the treatment of moderate to severe pain for 12 hours or more. The solution claimed is the matrix formulations specified by claim 1. Applying the reformulated Cripps question, the question to be answered is:
Would the person skilled in the art seeking to provide a sustained release preparation of tramadol that is effective for the treatment of moderate to severe pain for 12 hours or more before 10 May 1993, directly be led as a matter of course to try a preparation falling within the claims of the opposed application in the expectation that it might well produce the desired result?
Dosage form
Sustained and controlled release products are designed to release their pharmaceutical agent in a controlled manner, at a pre-determined rate, duration and location to achieve and maintain optimum therapeutic blood levels of the drug (PAM at [13]). These products were common in the pharmaceutical industry before 10 May 1993 (CWP at [18]; JSR#6 at [23]-[24]; LEM at [56]). They improved patient compliance by providing a more convenient dosage regimen (CWP at [19]; LEM at [61(b)]; JSR#6 at [8]), typically once or twice daily (CWP at [19]).
Historically, an oral route of administration has been used most, to maximise ease of use, patient acceptance and compliance (PAM at [10]). The specification refers to conventional release preparations in the form of capsules, drops and suppositories. However, the experts’ evidence is directed to oral dosage forms, with little or no mention of other routes of administration. I am satisfied that the person skilled in the art would directly be led as a matter of course to formulate controlled release tramadol in an oral dosage form.
Formulation of the drug
Only Dr Rowe provides direct evidence of how he would approach the task of formulating a controlled release preparation of tramadol. In his first declaration at [18], referring to his earlier statements at [15]-[17], Dr Rowe says he would do so in the following manner:
“15. It is usual practice by formulation chemists to initially select the excipients (binder, disintegrant, lubricant etc), in part, based upon the physiochemical properties and the chemical structure of a drug. …”
“16.However, an experienced formulation chemist would have a number of “favourite” formulations that they are most familiar with which could be used as a starting point. These formulations would cover most situations that would be encountered in practice. I would expect that the formulation chemist would incorporate the new drug into one of these formulations, especially if the physiochemical properties of the active ingredient are similar to a previously formulated drug. Should one of these formulations be unsuitable for any reason I would expect a formulation chemist to consult one or more of the standard textbooks and handbooks on pharmaceutical formulation. [Dr Rowe at [18] identifies two books relevant to sustained and controlled release drug delivery systems]
17. Although the standard texts, manufacturers literature and the like cover the vast majority of formulation situations, and in practice I would mostly refer to such literature, if there was a specific problem associated with formulating a given drug candidate I would do a literature search which would include patent literature. If a particularly relevant patent specification was brought to light which contained information on a particularly useful combination of excipients, I would use such knowledge to formulate a drug having similar properties.” (JSR#1 at [18])
In the context of prior patent specifications, in his second declaration at [33], Dr Rowe states that had he been asked to formulate tramadol before 10 May 1993, he would first refer to the information in standard reference books (JSR#2 at [33]). I do not understand Dr Rowe to be contradicting his earlier evidence that he would start with favourite formulations. Rather, I understand him to be confirming his earlier evidence that he would consider the information provided by textbooks before he conducted a literature search.
In summary Dr Rowe’s evidence establishes that he would first try favourite formulations. If these were unsuitable, he would consult standard textbooks, handbooks and the manufacturer’s literature on pharmaceutical formulation, and if there were specific problem he would resort to the scientific literature. I will consider these options in turn.
Favourite formulations
Dr Rowe’s evidence is that he would first try favourite known and familiar formulations (JSR#1 at [16], [18]; JSR#6 at [50]). Professor Mather confirms at [56] that most formulators have their favourite tools (such as stock formulations and platform technologies) for drug delivery that they would routinely try with new drugs.
I accept that faced with the problem of formulating a controlled release preparation of a drug, the hypothetical person skilled in the art would directly be led as a matter of course to first try a favourite and familiar formulation. However, it does not appear that any particular formulation approach would constitute a favourite of all or even a majority of formulation chemists. The choice of formulation appears to depend entirely on the skilled worker’s personal experience or, in respect of proprietary formulations or platform technologies, their place of employment (LEM at [56]; JSR#6 at [50]).
The evidence does not support a conclusion that the hypothetical person skilled in the art applying favourite and familiar formulations approaches would directly be led as a matter of course to try the approach that would lead to the claimed invention. It follows that the claims are not obvious on this basis.
Other Formulations
If the known and familiar formulations were not achieving the desired result, Dr Rowe would consult standard textbooks on pharmaceutical formulation and the excipient supplier’s literature (JSR#1 at [15]-[18]; JSR#2 at [33]).
Prior to 10 May 1993, the excipient suppliers provided “extensive details on what excipients are most appropriate for the intended application of the pharmaceutical” to guide the chemist in their use, including in controlled release preparations (JSR#1 at [15]; JSR#6 at [110]). Dr Rowe does not suggest that the information provided by the excipient manufacturers would have been common general knowledge in the art, and there is no suggestion to this effect in the balance of the evidence.
The evidence establishes that the person skilled in the art seeking to formulate a controlled release preparation of any particular drug would look beyond the common general knowledge in the art if a favourite formulation did not work. Sandoz has not discharged the onus of establishing that the claimed invention is obvious in the light of the common general knowledge alone.
GB 2196848 & EP 0249347
As a preliminary matter, the document adduced in evidence for the EP 0249347 specification was the B1 specification published on 26 June 1994, after the priority date of the specification. The content of the A2 specification published on 16 December 1987 is essentially the same as that of the B1 specification. On 26 August 2013 pursuant to reg 5.11, I advised the parties of the situation and that I proposed to refer to the A2 specification in deciding the opposition and would apply the parties’ submissions to that document. The parties were invited to make representations or give evidence in respect of the document. Sandoz advised they were content with the proposed course of action, while Euroceltique made no comment. Consequently, the document considered in this decision is the A2 publication.
Section 7(3) provides that a document is prior art for the purposes of inventive step if the person skilled in the art could, before the priority date of the relevant claim, be reasonably expected to have ascertained, understood, and regarded the document as relevant. “Ascertained” means found or discovered (Commissioner of Patents v Emperor Sports Pty Ltd [2006] FCAFC 26 at [29]-[30]; (2006) 67 IPR 488).
Ascertained
Professors Pouten and Mather provide no evidence on whether GB 2196848 and EP 0249347 would have been ascertained. Dr Rowe initially provided evidence that he would not normally consult the patent literature but if there was a specific problem with formulating a drug or if he needed further information he would do a literature search that would include the patent literature (JSR#1 at [17]; JSR#2 at [33]). In his reply evidence for this opposition, Dr Rowe unequivocally states at [86]:
“If I had been tasked with preparing a controlled release formulation of tramadol, prior to May 1993, I would have conducted a search for publications such as this which disclose formulations for another opioid analgesic drug.”
Dr Marshall does not comment on when and how he would search for information, but he confirms that the relevant person skilled in the art had access to patent literature:
“In my experience prior to May 1993, persons working in the area of pharmaceutical formulation had ready access to a wide variety of information sources, such as computer-assisted literature searches (including the patent literature) …” (PAM at [7])
Professor Somogyi at [43] states that he did not search the patent literature for research purposes in his work prior to 10 May 1993 and that he did not have regard to patent specifications as a source of information for the purpose of developing new formulations. When he did search the literature, he did not search the Chemical Abstracts database, instead using PubMed, Current Contents and Index Medicus which do not list patents.
Drs Rowe and Marshall are primarily pharmaceutical formulation chemists, whereas Professor Somogyi’s research is primarily into the clinical pharmacology of drugs. I consider the databases on which they search reflect their primary field of interest. The problem in this case is that of formulating a drug, and on that basis I prefer the evidence of Dr Rowe, which is supported by that of Dr Marshall. I conclude that the hypothetical person skilled in the art in this opposition could reasonably be expected to conduct a search that would identify patent literature, at least when they needed more information. In view of Dr Rowe’s evidence, I accept that the person skilled in the art would search for documents which disclose controlled release formulations for an opioid analgesic (JSR#6 at [86]).
Dr King’s evidence seeks to clarify whether the cited documents would have been ascertained by the person skilled in the art at the priority date, by determining whether the documents were incorporated into searchable databases prior to 10 May 1993, and whether they would have been retrieved using particular search strategies. Although I have found above that Dr King is not a relevant person skilled in the art, the factual evidence she provides is of assistance.
GB 2196848 and EP 0249347 were both present in the Chemical Abstracts database and EP 0249347 in the PATDPA database prior to 10 May 1993 (LK at [10]). I have no evidence that the online searches undertaken by formulation chemists would include information from PATDPA. However, I am confident it would include Chemical Abstracts, described by Dr King at [8] as “the most authoritative and comprehensive source of chemical information”. Both documents would have been identified in a total of 1670 records on Chemical Abstracts before the priority date, using the broad search terms “controlled release” or “controlled release formulation” or any of “tramadol”, “opioid analgesic”, “pain relief”, “oral controlled release dosage form” or the Chemical Abstracts registry number for tramadol (LK at [16]-[18] and LK-8).
GB 2196848 is titled “Controlled release hydromorphine composition” and EP 0249347 “Controlled release dihydrocodeine composition”. I am satisfied that GB 2196848 and EP 0249347 would have been ascertained by the person skilled in the art searching for controlled release pharmaceutical compositions of opioids.
Understood
GB 2196848 and EP 0249347 are both in the English language. Prima facie the documents would have been understood.
Regarded as relevant
The test for whether a particular document is relevant was given in Beecham Groups Limited’s (Amoxycillin) Application (1980) RPC 261 at 282:
“The test in my judgement is whether it can be expected that the skilled man will be likely to recognize the document in question as being particularly pertinent to, though it may not specifically solve the problem before him.”
GB 2196848 describes a controlled release preparation of the opiate hydromorphone, and EP 0249347 a similar controlled release preparation of the opiate dihydrocodiene.
Regarding the relevance of the documents, Dr King’s evidence is directed to the method by which a professional searcher would have processed the patent documents identified to determine their relevance. The cost and time involved in downloading the titles, abstracts and specifications featured prominently in her decision-making. As I indicated at the hearing, I do not find this part of Dr King’s evidence helpful. I do not believe it appropriate to place cost and time constraints as the primary concerns when modelling the actions of the hypothetical skilled person seeking relevant information in order to solve the problem posed by the application.
Dr Rowe states the relevance of these documents as follows:
GB 2196848:
“… this publication, which was published in 1987, relates to a controlled release, oral dosage formulation of hydromorphone (or pharmaceutically acceptable salts thereof), for use in the treatment of moderate to severe pain. I consider this publication to be very relevant since it demonstrates that a controlled release preparation of an opioid analgesic drug was known at least 6 years before the date of the Opposed Application.” (JSR#6 at [86])
“This publication is also very relevant since the description of possible excipients identified at page 2 line 16 to page 2 line 22 are the same as those identified in Option A of claim 1 of the Opposed Application. Substituting tramadol into the controlled release matrix formulation described at page 2 line 16 to line 22 of this publication would therefore result in a preparation of the kind described in Option A of claim 1 of the Opposed Application.” (JSR#6 at [87])
At [88]-[89], Dr Rowe makes further observations that substituting tramadol into the formulation taught by this document would result in a preparation falling within the opposed claims.
EP 0249347:
“… this publication relates to a controlled release oral dosage formulation of dihydrocodeine. As with [GB 2196848], I consider this publication to be very relevant since it relates to controlled release formulations of an opioid analgesic drug. For the same reasons discussed in relation to that publication, I do not consider the differences in the properties of dihydrocodeine to be of any significance from a formulating perspective.” (JSR#6 at 102)
“This publication is also very relevant since the description of possible excipients identified at page 3 line 17 to line 23 and at page 3 line 31 to 33 of this publication are the same as those identified in Option A of claim 1 of the Opposed Application. Substituting tramadol into the controlled release matrix formulation described at page 3 line 17 to line 23 and at page 3 line 31 to 33 of this publication would therefore result in preparation of the kind described in Option A of claim 1 of the Opposed Application.” (JSR#6 at 103)
Dr Rowe describes the relevance of the documents in terms of how they each disclose formulations containing the excipients in the claims of the opposed application. However, at the priority date of the application, Dr Rowe would not have been aware of the claims of the opposed application and he could not have identified the documents as relevant on this basis. Nevertheless, Dr Rowe also considers the documents relevant because they each disclosed a controlled release formulation of an opioid analgesic.
GB 2196848 and EP 0249347 each deal with significantly different drugs compared to tramadol with distinctly different properties (AAS at [80], [92]). Although it may have opioid activity, tramadol is not structurally related to the opioids (CWP at [28]; AAS at [82], [115]).
Dr Rowe considers a similar water solubility critical when considering substituting a drug into an existing formulation:
“In my opinion, it is possible and entirely practical to substitute a new drug into an existing formulation, so long as the drugs have similar physiochemical properties, particularly water solubility and stability. Of course, the other components of the formulation will have to be adjusted having regard to the above mentioned considerations and the loading of the drug, based on the required plasma levels for optimal activity. However, these sorts of considerations are standard in the formulation chemistry field.
In my opinion the most critical consideration in formulating a new drug is its water solubility. If two drugs have very similar water solubility I would expect that the release characteristics would be largely similar for a given formulation. Apart from water solubility, in formulating a new drug I would consider all the physico-chemical characteristics of that drug.” (JSR#1 at [26]-[27])
Hydromorphone hydrochloride and dihydrocodeine are both less water soluble than tramadol (AAS at [80], [92]). Since the physicochemical properties and in particular the water solubility of hydromorphone hydrochloride and dihydrocodeine do not appear similar to those of tramadol, at the priority date of the opposed application, I am unsure on what basis Dr Rowe would have identified GB 2196848 and EP 0249347 as relevant. His evidence does not establish that on or before 10 May 1993, without prior knowledge of the opposed application, Dr Rowe would have considered GB 2196848 or EP 0249347 pertinent to the problem of formulating tramadol for controlled release.
Professor Pouten does not appear to consider the documents relevant. In a brief comment on the prior art documents he states at [36]:
“It will not always be possible to make a controlled release formulation of a particular drug that will work. Nor is it possible simply to substitute one drug for another in an existing controlled release formulation and expect that it will work, even if [as suggested by Dr Rowe] the two drugs have similar properties such as solubility. In my view, such an approach is not supported by either science or experience.”
Professor Somogyi does not consider GB 2196848 or EP 0249347 as pertinent to the problem. He does not expect that substituting tramadol into the formulation of GB 2196848 or EP 0249347 would be successful in achieving a controlled release tramadol preparation with the therapeutic effect as claimed (AAS at [81] and [85], [94] referring to [46]-[47]). Dr Marshall and Professor Mather do not address the relevance of the documents.
I am not satisfied that at the priority date, the person skilled in the art would have considered GB 2196848 or EP 0249347 relevant to solving the problem of providing a controlled release preparation of tramadol effective for the treatment of moderate to severe pain for 12 hours or more. It follows that the opposed claims are not obvious in light of either one of prior art documents GB 2196848 or EP 0249347.
In summary, Sandoz has not discharged the onus of establishing that the claimed invention lacks an inventive step.
Manner of Manufacture
Section 18(1)(a) requires that an invention must be a manner of manufacture within the meaning of section 6 of the Statute of Monopolies. Manner of manufacture is assessed by asking whether the claimed invention lacks the necessary quality of inventiveness on the face of the specification (NV Philips Gloeilampenfabrieken v Mirabella International Pty Ltd [1995] HCA 15 at [9]; (1995) 183 CLR 655).
Sandoz argued that the invention is not a manner of manufacture since the opposed application applies known principles of drug formulation to a known candidate drug suitable for the purposes of extended release formulation. Euroceltique submitted that the combination of features in the tramadol preparation of claim 1 were not generally known to be suitable to provide an effective treatment for moderate to severe pain for 12 hours or more.
In the parent decision, the delegate rejected a similar argument by Sandoz on the basis that it was not apparent on the face of the specification that claimed substance was known. I have considered the delegate’s reasons at paras [99] to [102] of that decision and I agree with what he said. At [101]-[102], the delegate considered the Federal Court decision in Merck & Co Inc v Arrow Pharmaceuticals Ltd [2006] FCAFC 91; 68 IPR 511 and distinguished the claims of parent application 2002300863, finding that they defined a new substance, as follows:
“In the present case there is no new active substance, no new characteristics of that substance, and the therapeutic use of the substance is the same, i.e. as an analgesic. However, there is a new preparation in the form of a preparation containing 50 to 400 mg of the active substance and 1 to 80% w/w of polymer. On the face of the specification, it is not apparent that this is a known substance. It is not sufficient to say that sustained release preparations and the use of hydrophilic and/or hydrophobic polymers were known, as this is not the invention that is the subject of the claims. The present case [is] distinguished from the Merck case.”
For the present application, Sandoz argued that at least claims 1-16 of 2004229058 can be distinguished from the claims of the parent for manner of manufacture purposes because they “involve no more than the identification of three well-known methods of controlled release formulations to produce a controlled release formulation of tramadol that is effective for the treatment of moderate to severe pain”. I do not agree. While they may involve such matter, the claims of application 2004229058 define a new controlled release preparation of the active substance tramadol effective for the treatment of moderate to severe pain for 12 hours or more. On the face of the specification it is not apparent that this is a known substance. It follows that Sandoz has not established that the claims do not define a manner of manufacture.
Useful
The requirements for utility in a claimed invention under section 18(1)(c) were provided by the Full Court of the Federal Court as follows:
“If the claimed invention does what it is intended by the patentee to do and the end result obtained is itself useful, the invention is useful within the meaning of s 18(1)(c) … As to the first aspect, the invention as claimed must attain the result promised by the patentee” (Ranbaxy Australia Pty Ltd v Warner-Lambert Co LLC [2008] FCAFC 82 at [141]; 77 IPR 449)
“A claim is bad if it covers means that will not produce the desired result, even if a skilled person would know which means to avoid. That is to say, everything that is within the scope of a claim must be useful, otherwise the claim will fail for inutility.” (H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [81], [217]; 81 IPR 228)
Relying on the evidence of Dr Rowe and Professor Mather, Sandoz pressed this ground in respect of claims 17-20 and dependent claim 21, claiming that the in vitro release rates of tramadol set out in claims 17-20 encompass pharmaceutical preparations that would not provide effective relief of moderate to severe pain for 12 hours or more. Euroceltique submitted that the claims are expressly limited to therapeutically effective compositions, and that in any event inutility must be established with evidence, not by mere speculation that the invention will not work.
I have construed the claims to define a therapeutically effective preparation of tramadol. It follows that the claimed invention is necessarily useful.
Section 40 issues
Clarity
A claim is lacking in clarity if a third party could not ascertain whether an act would fall within the scope of the claim (Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59 at 60). However, a claim does not lack clarity because it uses inexact language or is difficult to construe, as long as it provides a “workable standard” suitable to the intended use (Minnesota Mining & Manufacturing Co v Beiersdorf (Aust) Ltd [1980] HCA 9 at [46]; (1980) 144 CLR 253 at 274).
Sandoz’s submissions for this ground mirrored those for lack of utility. Specifically, that claims 17-20 and dependent claim 21 are not clear due to the inconsistency between the dissolution rates disclosed in the claims and the requirement for the formulation to be effective for the treatment of moderate to severe pain.
Dr Rowe and Professor Mather both describe the dissolution rates as “meaningless”. However, it is clear from their evidence that they can each give a meaning to the terms in the claims, but that they consider the claims to be unduly broad (JSR#2 at [7], [10], [11]; JSR#4 at [22]; JSR#6 at [33], [76]; LEM at [67]-[68], [76]-[77], [84], [88], [95]). Professors Somogyi and Pouten find the dissolution rates understandable (AAS at [106]; CWP at [36]).
Dr Rowe states that an in vitro dissolution profile may be used to specify the necessary characteristics of a pharmaceutical preparation for quality control of the manufacturing process (JSR#1 at [25]; JSR#2 at [30]). Euroceltique have chosen to use the in vitro dissolution profile in claims 17-20 to further define the preparation of the earlier claims. The evidence does not establish that this renders the claims unclear.
Sandoz has not established that the claims lack clarity.
Best Method
Section 40(2)(a) requires that a complete specification must describe the invention fully, including the best method known to the applicant of performing the invention. The “invention” in section 40 is “the embodiment which is described, and around which the claims are drawn” Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at [19], [21]; (2001) 207 CLR 1.
In order to demonstrate invalidity for failure to provide the best method it is necessary to show that at the time of filing of the complete specification, the patentee was aware of a specific “best method” of performing the invention that was not included in the specification at its filing date (Re Rescare Ltd v Anaesthetic Supplies Pty Ltd [1992] FCA 537 at [61]-[63]; (1992) 111 ALR 205 at 220-222).
Relying primarily on Professor Mather’s evidence at [77]-[85] that no conclusions can be drawn regarding the analgesic effect of the exemplified tramadol formulations and that the specification lacked information regarding a therapeutically effective dose, Sandoz’s submissions under this ground can be summarised as that the specification does not disclose a controlled release formulation of tramadol which is demonstrated as a matter of fact to be effective in the treatment of moderate to severe pain. In particular, Sandoz considered the specification deficient in that it lacked the following information:
(a) details of the in vitro release rates and the corresponding in vivo absorption rates of tramadol which would result in a controlled release preparation which is effective for the treatment of moderate to severe pain for 12 hours or more;
(b) the threshold or minimum blood/serum concentration of tramadol required to treat moderate to severe pain for 12 hours or more;
(c) details of the therapeutic range of blood/serum/plasma concentration of tramadol required to treat moderate to severe pain for 12 hours or more; or
(d) details of the amount of tramadol or a pharmaceutically acceptable salt thereof which would need to be administered and the dosage regimen required to produce the in vitro release rates and the corresponding in vivo absorption rates of tramadol referred to in (a) and (b).
Professor Mather at [79] and Dr Rowe at [41] state that at the priority date of the application there was no consensus as to the threshold or minimum serum concentration of tramadol required to achieve analgesia; one study reporting 100 ng/mL and another that more than 300 ng/mL was required (Lintz, W. et al. (1986) Drug Research 36(II): 1278-1283 and Lehmann, K. A. et al. (1990) The Clinical Journal of Pain 6: 212-220, respectively).
Lintz et al. and Lehmann et al. are in evidence as LEM-18 and LEM-19. I do not find these reports to be inconsistent regarding the threshold or minimum effective blood concentration of tramadol for pain relief. The Lintz paper investigates the bioavailability of tramadol. Lintz et al. did not investigate the threshold concentration of tramadol required for analgesic effect, but relied on a 100 ng/mL threshold (minimum) concentration in serum derived from two earlier studies (see page 1279 section 2.5.3)(JSR#6 at [41]; [43]; LEM at [75]). Lehmann et al. investigated the analgesic efficacy of tramadol in post-operative patients by measuring the serum concentration of tramadol at the time when analgesia begins to subside. They report the minimum effective concentration of serum tramadol during patient controlled analgesia as between 20-986 ng/mL (mean ± SD) with a median of 288 ng/mL (Abstract and page 218). On page 218, Lehmann et al. compare their findings with a report of a minimum effective serum concentration of 272-1900 ng/mL, median 916 ng/mL by Hackl et al. in (1986) Anaesthetist 35: 665-671. The minimum effective concentrations for tramadol identified in Lehmann et al. encompasses and is not inconsistent with the 100 ng/mL single value reported by Lintz et al.
The wide variation in the individual minimum effective dosages reported by Lehmann et al. and Hackl et al. to which it refers, confirm the subjective nature of pain agreed by all the experts (AAS at [34]; CWP at [29]; JSR#6 at [6], [40]; LEM at [88]).
In context, particularly in view of the words “to get into”, the following statement in Lehmann et al. regarding the 300 ng/mL concentration is an extrapolation from the data to what might be required in the initial loading dose for any individual in the population presenting for patient controlled analgesia after surgery:
“Our findings suggest that “analgesic” threshold concentrations vary considerably after surgery. To get into the therapeutic window for analgesia, serum tramadol concentrations of more than 300 ng/ml seem necessary”
The Lehmann study demonstrates that serum tramadol concentrations as low as 20 ng/mL are analgesically effective in some patients. In healthy volunteers administered the 100 mg controlled release tramadol preparation of Example 2 of the specification, serum tramadol remained at or above approximately 50 ng/mL over a 12 hour period (Figure 1). Also in healthy volunteers, the 200 mg tramadol preparation of Example 8 of the specification maintained plasma tramadol above 100 ng/mL for more than 12 hours (Figure 2).
The opposed specification does not prove that the exemplified controlled preparations will in fact be effective in the treatment of moderate to severe pain for 12 hours or more. However, on the basis of the minimum effective concentrations reported in Lehmann et al. prima facie, the controlled release tramadol preparations of Examples 2 and 8 achieve blood concentrations that can reasonably be expected to provide effective analgesia over a 12 hour period in at least a proportion of individuals with moderate to severe pain.
The method disclosed in the specification achieves the desired result. Sandoz has not identified any method that is a better method of performing the invention than that disclosed in the specification, nor that any such method was known to the applicant at the filing date of the opposed application. It follows that Sandoz’s opposition under this ground fails.
CONCLUSION
The opposition fails on all grounds.
COSTS
Both parties submitted that costs should follow the event. I award costs in accordance with Schedule 8 against Sandoz Pty Ltd.
Dr B. Akhurst
Delegate of the Commissioner of Patents
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