Euroceltique S.A. v Sandoz Pty Ltd
[2009] APO 21
•12 November 2009
ABSTRACTS OF DECISIONS
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Application : No. 2002300863 in the name of Euroceltique S.A.
Title: Controlled release formulation
Action: Opposition by Sandoz Pty Ltd to the grant of a patent
Decision: Issued 12 November 2009.
Abstract
The specification relates to a sustained release form of the drug tramadol. The invention is defined by reference to dissolution rates of the tramadol, which were found to be logically related to achieving sustained release for a 12 hour dosing. However, any preparation that achieves a 12 hour release would inevitably possess the dissolution profile of the specification.
The opposition succeeds on the grounds of inventive step and clarity.
Inventive step: The problem addressed by the specification is the provision of a sustained release tramadol preparation suitable for 12 hour dosing.
A person faced with the problem of producing a sustained release form of tramadol would have ascertained, understood and regarded as relevant documents that discussed the preparation of sustained release preparations, if those documents referred to tramadol as a suitable active ingredient. From that point it would have been a matter of routine to make adjustment to the preparation to alter the dissolution profile.
EP 147780 refers to tramadol as a drug suitable for incorporation in a sustained release preparation. The inclusion of tramadol in the preparation, and any necessary adjustment to achieve sustained release over 12 hours would have been a matter of routine. Claims 1, 18, 19 and 20 lack inventive step.
DE 3810343 is in German, and does not contain an English language abstract. Where a person has a reason to consider a document could likely be relevant, it is reasonable to expect that they would obtain a translation (which would make the full content of the document understandable). In the present case, a motivation to obtain a translation is not apparent from the face of the document. The declarants did not indicate that they considered the German language document relevant. It has not been established that this document could have been regarded as relevant.
Clarity: The scope of the omnibus claim (claim 17) could not be determined due to inconsistencies in the description.
PATENTS ACT 1990
DECISION OF A DELEGATE OF THE COMMISSIONER OF PATENTS
Re:Patent Application No. 2002300863 by Euroceltique S.A., and an opposition by Sandoz Pty Ltd to the grant of a patent
BACKGROUND
Patent application 2002300863 was filed by Euroceltique S.A. on 4 September 2002. The application is a divisional application, being the third generation of divisional applications derived from application 61963/94 (all of the parent cases have lapsed without gaining acceptance). The great-grandparent application claimed priority from four basic documents, the earliest being a German application filed on 10 May 1993.
The present application was advertised accepted on 14 October 2004. A notice of opposition was filed by Hexal Australia Pty Ltd, and the evidence stages were completed on 15 May 2009. Pursuant to regulation 5.3B, the opponent was changed to Sandoz Pty Ltd as a consequence of a take over of the business and interests of Hexal. The opposition was heard in Canberra on 12 August 2009. Sandoz were represented by Steven Burley SC and Andrew Fox, instructed by Ivan Rajkovic of Shelston IP. Euroceltique were represented by Christian Dimitriadis, instructed by John McCann and Gavin Adkins of Spruson & Ferguson.
Grounds of opposition
The statement of grounds and particulars filed under regulation 5.4 specifies the following grounds of opposition:
- Manner of manufacture
- Novelty
- Inventive step
- Utility
- Sufficiency of description
- Claims do not define the invention
- Lack of clarity, succinctness and fair basis
All grounds other than failure to define the invention were argued at the hearing.
DECISION
Claims 1 and 18 to 20 lack an inventive step in the light of EP 147780. Claim 17 is not clear.
I allow Euroceltique 60 days from the date of this decision to propose amendments to overcome these matters. I award costs according to Schedule 8 against Euroceltique.
STATEMENT OF REASONS
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 Biolab Inc [2000] FCA 283 at [67], 50 IPR 305 at 319; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18]).
Evidence
Evidence in support of the opposition was served by Ivan Alexander Rajkovic, James Steven Rowe (two declarations) and Philip Andrew Marshall. Evidence in answer was served by Andrew Alexander Somogyi and Colin William Pouton. Evidence in reply was served by James Steven Rowe. I will refer to the three Rowe declarations as Rowe 1, Rowe 2 and Rowe 3, with Rowe 1 being the earliest document.
The subject matter of the specification
Tramadol is a known analgesic. Pharmaceutical products containing tramadol were commercially available before the priority date of the application. The specification describes a “controlled release” form of tramadol, with a specific dissolution profile in vitro.
The terminology that describes such a delivery system is somewhat variable. Remington’s Pharmaceutical Sciences (1990), which appears in Exhibit PAM-2 of the Marshall declaration, describes controlled release, prolonged release and sustained release systems. These systems are represented in Figure 91-4 of that work, reproduced here:
The relevant definitions of controlled, prolonged and sustained release, which I will adopt in this decision, are:
Controlled release Systems that maintain a constant drug level in the blood or target tissue (ie profile A) Prolonged release Systems that produce an extended release compared to conventional delivery (ie profile B) Sustained release A system that produces either controlled release or prolonged release (ie either profile A or B)
The specification and the evidence use the terminology differently. When I refer to the specification or the evidence of the parties, I will use the terminology strictly as given by those documents.
The description
The title of the application is “Controlled release formulation”. The background and nature of the invention is presented on pages 1 and 1A of the specification. I will quote these pages in full.
“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 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 a controlled release, oral pharmaceutical preparation suitable for dosing every twelve hours containing 50 to 400 mg of tramadol or pharmaceutically acceptable salt thereof (calculated as hydrochloride) in a controlled release matrix, the preparation containing between 1 and 80% w/w of one or more hydrophilic or hydrophobic polymers and having the following dissolution rate in vitro when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1N hydrochloric acid at 37°C and using UV detection at 270 nm:
between 5 and 50% (by weight) tramadol released after 1 hour,
between 10 and 75% (by weight) tramadol released after 2 hours,
between 20 and 95% (by weight) tramadol released after 4 hours,
between 40 and 100% (by weight) tramadol released after 8 hours,
more than 50% (by weight) tramadol released after 12 hours,
more than 70% (by weight) tramadol released after 18 hours,
more than 80% (by weight) tramadol released after 24 hours.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.”
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. Specifically, the invention is directed to an improved tramadol preparation suitable for 12 hour dosing.
It is also apparent from the Figures of the patent specification (reproduced in the Annex to this decision) that the present invention fits the definition of a prolonged release system rather than a controlled release system. However, nothing of importance hangs on this distinction.
What preparations of tramadol are described?
The specification begins by describing the preparations in a broad consistory statement already quoted above. Five Tables are provided, giving preferred dissolution rates. Several of these Tables disclose dissolution profiles that are inconsistent with the consistory statement. The specification ends with eight examples, which demonstrate the preparation of tablets, and data on dissolution rates in vitro. Two Figures are provided showing serum levels and plasma profile resulting from administration of tablets. These Figures are reproduced in the Annex to this decision. Several of the examples have dissolution profiles in vitro that fall outside that in the consistory statement, particularly tablets 2 and 3 of example 6, and the tablet of example 8.
The specification reflects a change in emphasis during prosecution. The specification as accepted claims a 12 hourly dosage, whereas initially it extended to a 24 hourly dosage. The description has not been amended to remove all reference to the 24 hourly aspect. Overall, the failure to bring the description into perfect alignment with the claims does not cause unworkable difficulties in understanding.
It is clear that the specification discloses a specific preparation of relevance. The consistory statement is clear in its statement of the broadest form of the invention that is now advanced. From the information provided, Dr Rowe considers it would not be a difficult matter to produce preparations having a dissolution profile within the range of the consistory statement; see Rowe 2 at [30]:
“the release rate will depend on various factors such as water solubility of the drug, the drug loading, tablet compression pressure, viscosity of the polymer matrix and particle size of the drug to name a few. The formulation scientist will simply prepare various formulations with known matrix excipients and determine in vitro release rates. This is standard pharmaceutical development work.”
Two questions follow. First, does the specification disclose therapeutic activity for the preparations? Second, does the specification disclose a reason for the selection of the ranges?
Does the specification disclose therapeutic activity?
The specification does not draw a clear link between the in vitro dissolution profile and in vivo therapeutic effect. There is no evidence that the blood concentration in Figure 1 is in the therapeutic range for tramadol. I have been unable to locate any statements by the declarants that they consider that the plasma concentration demonstrated in the Figures would, or would not, be therapeutically effective. It is the inevitable conclusion that the specification provides no demonstration that a concentration in the therapeutic range would be achieved using ANY preparation according to the invention, and there is no logical basis for inferring such a result. Consequently, I have considered whether the art provides information that would lead to a conclusion that the preparations of the invention would be likely to be therapeutically effective.
I have considered the document “Bioavailability of enteral tramadol formulations” by W. Lintz, H. Barth, G. Osterloh and E. Schmidt-Böthelt in Arzneim.-Forsch./Drug Res. 36 (1986) at page 1278. This document appears as an exhibit to the declaration of Dr Marshall. The article discusses studies into the bioavailability of tramadol after oral administration of tablets or intravenous injection of solution. The value of 100 ng/ml was the assumed threshold value for analgesic efficacy. This concentration is demonstrated in Figure 1 of the present application. Having regard to the Lintz article and Figure 1 of the patent application, it is apparent that the preparation of Figure 1 at least would be expected to be therapeutically effective.
Does the specification disclose a basis for the ranges?
The specification uses the dissolution profile to describe the invention. Sandoz questioned whether the limits of the dissolution profile are selected on the basis of a technical significance, or whether they are an arbitrary choice. I note that it is not necessary to prove that the benefits of the invention are unique to the claimed ranges. Consistent with Pfizer Inc v Commissioner of Patents [2005] FCA 137 at [65], 64 IPR 547 at 556 it is legitimate to select limits on the basis of a sound prediction. Dr Rowe states that the ranges are wide and meaningless (Rowe 2 at [10]). The fact that a range is wide does not logically compel a conclusion that it is without technical significance.
Looking at the specification, Example 2 has a dissolution profile falling within the terms of claim 1. The values are:
Time (hours) Claim 1 (%) Example 2 (%) 1 5 to 50 35 2 10 to 75 47 4 20 to 95 62 8 40 to 100 78 12 More than 50 86 18 More than 70 24 More than 80
Example 2 falls somewhere towards the middle of the ranges. Also, the specification exemplifies preparations falling outside the scope of claim 1. Figure 2 provides data for one such preparation, and it is apparent that there is a much slower release to the blood plasma. It is evident to me that this is unlikely to be useful as a 12 hour dosage preparation.
The specification offers no explanation for why the limits of the dissolution profile were selected. There is no suggestion of a special advantage achieved, or a disadvantage avoided, by these particular values. However, it appears to be a reasonable inference that these are expected to be the ranges over which the invention will work. It is to be expected that a specification will pay more attention to Examples at the heart of the invention rather than those at the periphery.
Dr Rowe has asserted that there would be preparations within the scope of the claims that are not therapeutically effective. However, this opinion is not substantiated by either tests or calculations. I am satisfied that I should treat the limits of the dissolution profile as based on technical significance rather than arbitrary choice. While I cannot say that every value in the dissolution profile has been selected with precision, I do not think that is the test. The dissolution rates are logically related to achieving sustained release for a 12 hour dosing, and at least one preparation outside the range appears to be unsuited to 12 hour dosing. There is no evidence, other than unsupported opinion, to the contrary.
Of course the converse of what I have said is that any preparation that achieves a 12 hour sustained release inevitably possesses the dissolution profile of the specification. While this might seem a sweeping generalisation, it is the only logical conclusion open to me. The specification provides no other technical basis for the selection of the dissolution profile.
The claims
The specification ends with 21 claims. Claims 1 and 17 are independent claims. Claim 1 reads:
A controlled release, oral pharmaceutical preparation suitable for dosing every twelve hours containing 50 to 400 mg of tramadol or pharmaceutically acceptable salt thereof (calculated as hydrochloride) in a controlled release matrix, the preparation containing between 1 and 80% w/w of one or more hydrophilic or hydrophobic polymers and having the following dissolution rate in vitro when measured using the Ph. Eur. Paddle Method at 100 rpm in 900 ml 0.1N hydrochloric acid at 37°C and using UV detection at 270 nm:
between 5 and 50% (by weight) tramadol released after 1 hour,
between 10 and 75% (by weight) tramadol released after 2 hours,
between 20 and 95% (by weight) tramadol released after 4 hours,
between 40 and 100% (by weight) tramadol released after 8 hours,
more than 50% (by weight) tramadol released after 12 hours,
more than 70% (by weight) tramadol released after 18 hours,more than 80% (by weight) tramadol released after 24 hours.
Claim 17 is an omnibus claim:
A controlled release, oral pharmaceutical preparation, substantially as hereinbefore described with reference to any one of the examples.
Claim 1
Sandoz’s written submissions state that claim 1 “is not a claim to a formulation, as all of the components except for the polymer content are left to the skilled worker” (paragraph [36]). I must disagree. The claim says that it is directed to a “pharmaceutical preparation”, and I can see no language in the claim that would lead away from such a conclusion. The components of the preparation are identified, albeit in broad terms, as tramadol and a polymer.
Broadly, the features of the preparation as claimed in claim 1 are:
(i) A controlled release, oral preparation
(ii) Suitable for 12 hourly dosing
(iii) Containing 50 to 400 mg of tramadol or a salt in a controlled release matrix, and 1 to 80% w/w of hydrophilic or hydrophobic polymers
(iv) Having a dissolution profile specifiedI will consider each of these features in turn.
(i) “controlled release, oral pharmaceutical preparation”
An oral preparation means that the preparation can be orally administered, such as a tablet.
The term “controlled release” has a meaning that is recognised in Remington’s as maintaining a constant drug level in the blood. Other documents in evidence, such as “Pharmaceutical Dosage Forms” by Lieberman, Lachman and Schwartz (reproduced in PAM-2) make it clear that for tablets this is an ideal, and that in reality the aim is to achieve a prolonged release that approximates (as nearly as possible) a controlled release. Dr Rowe supports this view (at Rowe 1 at [19]) when he says that in practice controlled release means “release of a drug from a dosage form which occurs in a sustained way over a period of time”. I believe that the claim should be understood against this background, and thus construed as a prolonged release preparation.
(ii) “dosing every twelve hours”
The 12 hour dosing was raised as an issue, because the claim states that it is allowable for some of the tramadol to remain undissolved after 24 hours. On the face of it, this could be seen as inconsistent with a 12 hour dosage. I am not convinced that this is automatically correct. The dissolution profile relates to in vitro dissolution, whereas the dosing is clearly in vivo.
However, it is intuitive that there is a relationship between the in vitro test results and in vivo results. This is supported by the Figures in the specification. Where one tablet is not fully dissolved before the next tablet is administered, the in vivo concentration will be the sum of the dissolution profiles of the two tablets, with the individual profiles offset by 12 hours. This might be expected to smooth the total blood concentration over time.
(iii) Tramadol “in a controlled release matrix”
The amount of tramadol and polymer is defined in broad terms, but the limits on these components are clear. The claim specifies that the tramadol is “in a controlled release matrix”. I note that it is possible to achieve sustained release by the use of a polymer matrix, or by coating a standard matrix. Both arrangements can legitimately be regarded as use of a controlled release matrix, but in the second arrangement the active compound is enveloped by the controlled release membrane rather than intimately mixed with it, so is the active compound “in” the controlled release matrix? In order to resolve this ambiguity, I will follow the approach of the High Court in Interlego AG v Toltoys Pty Ltd (1973) 130 CLR 461 at 479:
“If the expression is not clear it is then permissible to resort to the body of the specification to define or clarify the meaning of words used in the claim without infringing the rule that clear and unambiguous words in the claim cannot be varied or qualified by reference to the body of the specification”
At page 6, the specification states:
“The active ingredient in the preparation according to the invention may suitably be incorporated in a matrix. This may be any matrix that affords controlled release tramadol over at least a twelve hour period and preferably that affords in-vitro dissolution rates and in vivo absorption rates of tramadol within the ranges specified above. Preferably the matrix is a controlled release matrix. Alternatively, normal release matrices having a coating which provides for controlled release of the active ingredient may be used.”
[lines 9 – 15]The controlled release matrix is any matrix that affords sustained release, including a normal release matrix with a coating. I will adopt this construction of the claim.
(iv) “dissolution rate in vitro”
The final feature is the dissolution profile. The test method is clearly identified as that in the European Pharmacopoeia. The paddle method is used (as against other methods, such as the basket method). The conditions for carrying out the test are precisely identified as “at 100 rpm in 900 ml 0.1N hydrochloric acid at 37°C and using UV detection at 270 nm”. The interpretation of the elements of the profile warrants some explanation. I will discuss the first element as an example of the whole.
The dissolution is “between 5 and 50% (by weight) tramadol released after 1 hour”. Euroceltique submitted that the range “between 5 and 50%” should be interpreted precisely. While it would not be surprising to adopt a purposive construction of such terminology, I see no reason to depart from the literal meaning of these terms. I will interpret these terms precisely. While it is true that this is a broad range, it cannot be said that it is unclear.
In relation to “after 1 hour”, it was suggested that this could mean at any time after 1 hour (i.e. 12 hours or more after the test has started). Read in context, I do not think this is a fair interpretation. I believe that the dissolution is determined 1 hour after the test has started.
Claim 17
Claim 17 is more problematic. Claim 17 is an omnibus claim. The claim specifies that the features of the preparation are “substantially as hereinbefore described”. As the claim is not appended to claim 1, the features are to be found in the description. Those features are limited by reference to the examples. The only question is what are the features of the preparation as described? The description contains a consistory statement consistent with claim 1. However, the description also contains text that relates to a broader form of the invention, for instance at pages 2 to 4. This broader form of the invention was present in the specification as filed, but the claims were narrowed by amendment during examination (with a matching consistory statement inserted). The references to the broader form of the invention were not excised during examination. The examples of the invention include preparations that relate only to this broader form of the invention. The specification clearly describes two quite different preparations - the narrow and the broad forms. I am unable to resolve the conflict as to what is the invention as described. This makes it impossible for me to determine the features of the claim.
For the purposes of my consideration of novelty and inventive step I will proceed on the basis that claim 17 is intended to be restricted to the invention defined by claim 1, but this construction is not apparent from the specification.
Novelty
It is well established that the general test for lack of novelty 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) 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 the essential features of the invention as claimed (see Nicaro Holdings Pty Ltd v Martin Engineering Co (1990) 91 ALR 513 at 517). It is well established that to meet this requirement, the prior art must “contain clear and unmistakeable 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). A citation is part of the prior art base for the purposes of novelty if it was published before the priority date of the claim (see definition of "prior art base" in Schedule 1 of the Act).
There are four documents that are relevant to the novelty of the application. I will deal with each in turn.
EP 147780
This document was published on 10 July 1985, well before the earliest priority date of the present application. The broad thrust of the document is disclosed in the first lines of the specification:
“The invention relates to a novel method and compositions for release of drugs through a rate limiting barrier by coating a formulation with polyvinyl alcohol, which serves as a membrane for said drugs or acts as a barrier film which will selectively permit passage of the desired species.”
A wide range of active agents are stated to be suitable for use by this method. Tramadol is included in a list that runs over three pages. The active agent is prepared in a conventional tablet, which is then coated with polyvinyl alcohol. The function of the polyvinyl alcohol coating is to control the release of the active ingredient. Rowe 2 states at [34]:
“EU 0147780 describes compositions in which the release of drugs are controlled through a rate limiting membrane by coating the formulation with polyvinyl alcohol (PVA).”
This is consistent with the passage of the citation quoted above. Dr Rowe goes on in the same paragraph to conclude that EP 147780
“describes both matrix controlled release formulations of Tramadol and normal release matrices having a coating for the controlled release of Tramadol”
I have been unable to find a disclosure in the citation of a matrix sustained release preparation, so I cannot agree with Dr Rowe on this point. Dr Rowe’s conclusion follows directly after a quote from the specification under opposition relating to both forms of sustained release. This leads me to conclude that he may have been confused when he referred to the content of the citation. Dr Marshall states that this citation discloses preparations with a film coating (paragraphs [58] to [59]), which is clearly correct.
I conclude that the citation discloses preparations in which the sustained release of the active agent is achieved by a film coating of polyvinyl alcohol. There is no disclosure of an active agent embedded in the controlled release matrix. The claims include normal release tablets with a controlled release coating. The key question is whether the preparation of the citation would have a dissolution profile according to the present claims. No dissolution profile is given. I have already stated at paragraph 26 that a 12 hour dosing would inevitably have a dissolution profile falling within the ranges of the present application. The citation refers to “dispensing a composition of matter at a controlled rate for a prolonged period of time” (page 2). However, I can find no reference to the period of release. I am not satisfied that there is a clear and unmistakable disclosure that the preparations are intended for 12 hour dosing. Consequently I cannot infer that the preparations would have a dissolution profile according to the present claims.
DE 3810343
This document was published on 5 October 1989 (identified by INID code 43 on the document). A translation of this document was provided in the evidence. The specification commences with the following statement:
“The invention is concerned with a procedure for the production of solid pharmaceutical depot-formulations with a hydrophilic polymer binding agent, whereby the mixture of all components is shaped at temperatures above the glass transition temperature (Tg) of the polymer binding agent and below the decomposition temperature of the active substance. Hereby the type and quantity of the binding agent are chosen in such a way as to enable the controlled release of the active ingredient.”
Suitable binding agents are identified, and the list includes:
“polyethylene-glycol, polyvinyl alcohol, polyvinyl acetate, which is de-acetylised to a minimum of 70%, methyl-cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyacrylic acid and alginates”
Suitable active substances include tramadol, although it does not appear in any of the worked examples of the invention.
Clearly the citation discloses a preparation containing the same ingredients as the present application. The citation also discloses a rudimentary dissolution profile for the preparations that are exemplified. While the profiles were determined under conditions different to the present application, they are broadly consistent with the present application. More significantly, the citation asserts that the preparations enable controlled release of the active substance in the gastrointestinal tract, “delayed” over 3 to 24 hours. It is clear that this does not mean that dissolution starts after 3 to 24 hours, as the examples in the citation clearly demonstrate. What is disclosed clearly includes a 12 hour dosing. As a 12 hour dosing would inevitably have a dissolution profile falling within the ranges of the present application (see paragraph 26 above), I am satisfied that the preparations of the citation would have the same dissolution profile as claim 1.
However, I must consider whether the citation discloses a preparation with the same dose of tramadol and amount of polymer. The citation describes the preparations by reference to the number of parts of each component. For instance, Example 23 has 45 parts of a polymer mixture, 2.5 parts of stearin acid, 2.5 parts of palmitin acid and 50 parts of theophylline. While this is sufficient disclosure in relation to the amount of polymer used, it is not sufficient in relation to the amount of active agent. There is no disclosure of selecting a quantity of the preparation that would contain 50 to 400 mg of the active agent as required by claim 1. While it is clearly possible to select such a quantity, this is not sufficient to establish clear and unmistakable directions to do so. Consequently, lack of novelty has not been established.
GB 2196848
This citation relates to a controlled release preparation of hydromorphone. There is no suggestion in the citation that it also relates to tramadol.
EP 249347
This citation relates to a controlled release preparation of dihydrocodeine. There is no suggestion in the citation that it also relates to tramadol.
Conclusion on novelty
It has not been established that there is a lack of novelty.
Inventive step
An invention is taken to involve an inventive step unless the invention would have been obvious to the person skilled in the art (section 7(2)). 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.”
[Wellcome Foundation Ltd v V.R. Laboratories (Aust.) Pty Ltd (1981) 148 CLR 262 at 286]The High Court in Aktiebolaget Hassle v Alphapharm Pty Ltd [2002] HCA 59, 212 CLR 411 approved this approach.
What is the problem?
The most important question in this opposition is whether the problem lies in provision of an alternative pain relief preparation, or the provision of a sustained release preparation of tramadol. These different points of view are best seen in the evidence of the Euroceltique’s own declarants. The first view is advanced by Professor Pouton at [26]:
“In my opinion, a significant aspect of the invention in the Opposed Application is that the inventors have selected a drug having opioid agonist activity, namely tramadol, as a drug to be delivered in a controlled release formulation for oral administration in May 1993.”
Professor Somogyi presents the second view at [21]:
“On review of the Opposed Application, it is my understanding that the broader ‘problem’ addressed by the invention described in the Opposed Application is to provide tramadol for pain relief, in a preparation (formulation) suited for administration once or twice a day.”
In my discussion of the description, I came to the conclusion that the specification only provides support for viewing the invention as directed to a sustained release tramadol preparation. I will adopt this as the problem unless there is a compelling reason to do otherwise.
Professor Pouton’s views appear to have been shaped by his understanding of the state of the art in 1993. He was aware that non-steroidal anti-inflammatory drugs and some weakly acting opioids were generally used to treat chronic pain (paragraphs 26 and 28). At [26] he states that there was “a general reluctance prior to 10 May 1993 to consider developing new controlled release formulations of opioid drugs”. Professor Pouton does not state that he was aware of any dissatisfaction with the existing treatments, or any desire to develop alternative treatments. However, it is fair to infer such a view from the following passage at paragraph [30] of his declaration:
“In my view, a significant step taken and demonstrated in the Opposed Application is the realisation that the above factors combine to provide an opportunity for the development of effective controlled release tramadol products for the prolonged treatment of chronic pain in osteoarthritis and other conditions.”
Supporting evidence for a recognised problem with the existing opioid analgesics is hard to find. Rowe 3 appears to address the point at [9] by commenting that tramadol would have been a natural choice if there were a problem with opioid analgesics:
“Tramadol’s opioid like activity would have been well known to physicians who regularly prescribe opioid analgesics, and physicians generally, before May 1993. In my view it would have been a natural choice to use Tramadol as an alternative to conventional opioid analgesics.”
I am not satisfied that the evidence establishes that there was a perceived need to develop alternative analgesics. I conclude that the only reasonable way to interpret the problem is the way that the specification itself speaks. The problem is the provision of a sustained release tramadol preparation suitable for 12 hour dosing.
Could patent documents have been ascertained?
A significant issue in the present opposition is whether the key patent documents could have been ascertained for the purposes of inventive step. Dr Rowe says that he would have consulted patent documents. In Rowe 1 at [17] he states:
“if there was a specific problem associated with formulating a given drug candidate I would do a literature search which would include patent literature”
In Rowe 2 at [33] he further states:
“I would not normally consult patent specifications to provide assistance but if I did find the need for further information, I would undertake an online search, which would and normally did include patent specifications.”
Dr Marshall at [7] appears to support this view:
“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)”
The evidence on behalf of Sandoz indicates that workers in the art had access to means to search the patent literature, but this was not a routine source of information. Professor Somogyi declares that he did not consult the patent literature prior to 1993. At [26] he states:
“As a preliminary matter, I have been asked to comment on whether, in my role as a research scientist in the field of pharmacology, I would have searched the patent literature if asked to develop a new formulation for an active pharmaceutical prior to 10 May 1993, for the purpose of ascertaining technical information that might assist me in that task. I do not believe that I would have done so. I did not search the patent literature for research purposes in my work prior to 10 May 1993. In particular, I did not have regard to patent specifications as a source of information for the purpose of developing new formulations.”
I accept that some people never consulted the patent literature, while others consulted the patent literature when they needed further information. Since some people did consult the patent literature when needed, it is reasonable to conclude that an average skilled person could reasonably have been expected to consult the patent literature, at least when they needed further information.
Euroceltique referred me to the decision of Branson J in E.I. du Pont de Nemours & Co v Imperial Chemical Industries PLC [2002] FCA 230 at [108], 54 IPR 304 at 333. Her Honour stated that although the particular patent document could be found by using appropriate search terms in relevant databases, the necessary search strategy was likely to be influenced by knowledge of the result sought to be achieved. In that case the patent application and the citation related to refrigeration gases. The application claimed a mixture of at least two gases selected from a list of three, i.e. it was restricted to a small group of gases. The citation discussed the gas as at least one fluorine containing hydrocarbon containing one or two carbon atoms, i.e. it covered a very large range of gases, albeit that it was sufficient to deprive the application of novelty. It is easy to see how locating that citation might be seen to require knowledge of the solution.
In the present case, the problem is to develop a sustained release form of tramadol suitable for 12 hour dosing. I found above that a person could be reasonably expected to have regard to the patent literature as a part of considering the problem. The key question is which specific documents could be reasonably expected to be ascertained. Branson J has highlighted that searches undertaken with the benefit of hindsight should not be regarded as reasonable. In the present case, the problem relates to the development of a sustained release form of tramadol, so documents that relate to tramadol and sustained release are clearly directly relevant to the problem (rather than the solution), and it is prima facie reasonable to expect that they could have been ascertained. However, suitable evidence to the contrary might displace this view. In the present case I have no such evidence. Documents that relate only to sustained release might be ascertained if that is how a person skilled in the art would investigate the problem. I have not been given clear evidence on this point. In the light of the du Pont case and the standard of clear invalidity that applies to oppositions, I am not satisfied that a person skilled in the art could have ascertained such documents. I will return to this matter when I consider each citation in detail.
Matters of routine
In the present case the problem is the provision of a sustained release preparation of tramadol, and the solution claimed is a preparation that has a defined in vitro dissolution profile. However, for the purposes of obviousness, what must be considered is whether a preparation falling within the dissolution profile of the claim would have been obvious, not whether the dissolution profile would have been obvious.
The evidence suggests to me that a person seeking to solve this problem would not have started with a target in vitro dissolution profile in mind. The general approach is described by Dr Rowe in Rowe 2 at [30] as follows:
“The formulation scientist will simply prepare various formulations with known matrix excipients and determine the in vitro release rates. This is standard pharmaceutical work. Once the parameters affecting in vitro dissolution rates have been established, biostudies will be performed in an effort to determine a correlation between in vitro dissolution rates and in vivo bioavailability”
This is inherently reasonable, and I accept it as a representation of the general approach. This leads to two questions:
i)would it have been a matter of routine to prepare a sustained release form of tramadol; and
ii)if yes, would such a preparation fall within the scope of the claims
The evidence of Dr Rowe provides a strong basis for concluding that it would have been a matter of routine to prepare a sustained release form of tramadol. In Rowe 2 at [33] he states:
“If I had been asked before 10 May 1993 to provide a controlled release coating formulation of for example Tramadol my methodology would be to first refer to the standard reference books including those that I have identified in my previous declaration. I would usually expect to be able to produce an acceptable formulation to meet the required criteria of the project. I would not normally consult patent specifications to provide assistance but if I did find the need for further information, I would undertake an online search, which would and normally did include patent specifications.”
Dr Rowe discusses the substitution of tramadol in a known preparation in Rowe 2 at [30]:
“I do not see the drug, Tramadol or a pharmaceutically acceptable salt thereof as being anything special or behaving in any way different to any other drug when used in these matrix formulations. As I have stated, the release rate will depend on various factors such as water solubility of the drug, the drug loading, tablet compression pressure, viscosity of the polymer matrix and particle size of the drug to name a few. The formulation scientist will simply prepare various formulations with known matrix excipients and determine the in vitro release rates. This is standard pharmaceutical development work.”
On the other hand, Professor Somogyi indicates that the outcome could not be predicted with certainty. At [65] he states:
“the association demonstrated for the formulation of a particular active compound does not automatically apply for a different active compound with different properties when formulated in the same matrix. In my opinion, in May 1993, the in vivo release rate into blood of an active compound would have to have been experimentally determined for that particular compound. Similarly, a predictive association between in vitro release data and in vivo blood plasma levels would have to have been experimentally determined for a particular active compound.”
and at [88] he succinctly states:
“it would not have been possible simply to substitute tramadol into these known formulations and achieve the desired release characteristics”
Professor Pouton at [19] agrees that it would be necessary to adjust the preparation to achieve the desired outcome:
“A formulation scientist would not expect all formulation approaches to be suitable for a given drug, and would be aware that the pharmacokinetic properties of the drug are key considerations in formulation design.”
I accept that it would probably be necessary to carry out an adjustment of the preparation in order to ensure a 12 hour dosing. The question is whether adjusting the preparation is a routine step. Professor Somogyi states at [57] that it is a difficult process:
“it is usually quite difficult to adjust the several factors of a formulation, including drug loading and the nature of the polymer, in order to achieve a desired release rate”
whereas Dr Rowe states in Rowe 3 at [23] that it is easy:
“the release rate of the drug could be easily controlled by variation of factors such as drug loading and the nature of the polymer”
The question that I need to consider is whether it is routine. Dr Rowe’s evidence in Rowe 2 at [30] seems to imply that it would be routine:
“The formulation scientist will simply prepare various formulations with known matrix excipients and determine the in vitro release rates. This is standard pharmaceutical development work.”
While this relates to in vitro studies, it is clear that adjusting a preparation to alter the dissolution rate is routine. I am satisfied that adjustment would have been a difficult but routine process.
I am satisfied that a person faced with the problem of producing a sustained release form of tramadol could have ascertained, understood and regarded as relevant documents that discussed the preparation of sustained release preparations, if those documents referred to tramadol as a suitable active ingredient. From that point it would have been a matter of routine to make adjustment to the preparation to alter the dissolution profile. Earlier in this decision I stated that any preparation that achieves a 12 hour sustained release would be expected to possess the dissolution profile of the specification.
I also note Professor Pouton’s opinion at [31]:
“In my opinion, the fact that tramadol had been known for several years before 10 May 1993, but had only been available in formulations for immediate release, despite the fact that controlled release technologies were widely used and developing during that period and were being used in relation to many different drugs, is significant and emphasises the significance of the step taken by development of the controlled release formulations of tramadol provided in the Opposed Application.”
Essentially, I understand Professor Pouton’s point to be that a sustained release preparation of tramadol is unlikely to have been a matter of routine since it was not developed until many years after tramadol was first released. The failure to produce the preparation earlier is an indication of inventiveness IF workers in the art were attempting to solve the problem. However, the logic does not follow if workers were not attempting to solve the problem.
The common general knowledge alone
Above I reached the conclusion that a person faced with the problem of producing a sustained release form of tramadol would have readily made any adjustment to known preparations to alter the dissolution profile. For present purposes, the key question is whether sustained release preparations were common general knowledge. Dr Rowe states repeatedly throughout Rowe 2 that sustained release preparations were known. I think it is a fair reading of his declaration that he is asserting they were common general knowledge. However, it appears from Rowe 2 that the common general knowledge was restricted to the principle of sustained release, rather than details of specific sustained release preparations. A person wishing to do work on sustained release would need to carry out a literature investigation of known preparations; see Rowe 1 at [18]:
“In the case where a sustained or controlled release of the drug is required, I and other experienced formulation chemists would follow essentially the same approach as discussed above, ie the starting point would be a known or familiar formulations.”
Since it would be necessary to look beyond the common general knowledge, the invention is not obvious in the light of the common general knowledge alone. This takes me to the alleged citations, and a consideration of section 7(3).
EP 147780
This document refers to tramadol as a drug suitable for incorporation in a sustained release preparation. This document is clearly relevant to the problem. The active agent is prepared in a conventional tablet, which is then coated with polyvinyl alcohol. The reference to controlled release of tramadol means this document could have been ascertained, and it is clearly relevant to the problem.
The inclusion of tramadol in the preparation, and any necessary adjustment to achieve sustained release over 12 hours would have been a matter of routine. A sustained release preparation would inevitably fall within the scope of claim 1. The only remaining questions relate to the amount of tramadol and polymer in the preparation.
Claim 1 specifies the amount of polymer as 1 to 80% w/w. The citation states that the amount of polymer generally ranges from 1 to 15% by weight, and the examples lie within this range. There is no doubt that the citation teaches a range well within that of claim 1. Claim 1 also specifies 50 to 400 mg of tramadol or pharmaceutically acceptable salt (calculated as hydrochloride). The citation states that the amount of active agent would be regulated by the known therapeutically effective unit dose. I note that the known tramadol drops are administered as 100 mg (page 23 of the application). Consequently, the invention covered by claim 1 lacks an inventive step in the light of this document.
Turning to the claims appended to claim 1, I note that claims 2 to 16 either specify the polymer that is used, or specify further ingredients, but in no case is the polymer polyvinyl alcohol. Claims 17 and 21 are omnibus claims, and none of the examples involve a polyvinyl alcohol layer. These claims cannot be considered to lack an inventive step. Claims 18 to 20 are directed to use of the preparation. To the extent that these claims relate to claim 1, they lack an inventive step as it is a matter of routine to use a preparation for its intended use.
DE 3810343
This document is written in German, and does not contain an English language abstract. While I have been provided with an English translation, it is not suggested that the translation was a part of the prior art base. The key issue with this document is whether it could have been understood and regarded as relevant. Euroceltique have stated that there is no evidence that a person skilled in the art has proficiency in German, or that they would have routinely obtained translations.
Where a person has a reason to consider a document could likely be relevant, it is reasonable to expect that they would obtain a translation (which would make the full content of the document understandable). In the present case, a motivation to obtain a translation is not apparent from the face of the document. The declarants do not indicate that they considered the German language document relevant. It has not been established that this document could have been regarded as relevant.
GB 2196848
This citation relates to a sustained release preparation of hydromorphone, and there is no suggestion that it also relates to tramadol. Consequently it has not been established that this document could have been ascertained.
EP 249347
This citation relates to a sustained release preparation of dihydrocodeine, and there is no suggestion that it also relates to tramadol. Consequently it has not been established that this document could have been ascertained.
Conclusion on inventive step
Claims 1 and 18 to 20 lack an inventive step in the light of EP 147780.
Fair basis
The High Court in Lockwood Security Products Pty Ltd v Doric Products Pty Ltd [2004] HCA 58 at [69], 217 CLR 274 at 300 approved the words of Gummow J in Rehm Pty Ltd v Websters Security Systems (International) Pty Ltd (1988) 81 ALR 79 at 95:
“the question is whether there is a real and reasonably clear disclosure in the body of the specification of what is then claimed, so that the alleged invention as claimed is broadly, that is to say in a general sense, described in the body of the specification”
Sandoz based its submissions on
i)the concentration of matrix components (being 1 to 80% w/w) is very broad and beyond the disclosure of 24 to 49%;
ii)there is no information on therapeutic efficacy
The body of the specification has a consistory statement in the same terms as claim 1, i.e. 1 to 80%. The examples of the invention relate to preparations where the concentration of matrix components ranges from 23.7% to 47.5%. In this situation I cannot agree that specification does not provide a disclosure of 1 to 80%, at least in a general sense. Turning now to the therapeutic efficacy of the preparation, I have found above that the preparation of Figure 1 at least would be expected to be therapeutically effective. Consequently, there is a disclosure of therapeutic efficacy.
I am not satisfied that the opposition on the ground of lack of fair basis has been made out.
Sufficiency of description
The High Court in Kimberly-Clark Australia Pty Ltd v Arico Trading International Pty Ltd [2001] HCA 8 at [25], 207 CLR 1 at 17 explained the requirement of sufficiency of disclosure as:
“The question is, will the disclosure enable the addressee of the specification to produce something within each claim without new inventions or additions or prolonged study of matters presenting initial difficulty?”
Sandoz submitted that the specification does not provide sufficient information to enable a person to produce a sustained release preparation as there is no disclosure of a correlation between the in vitro dissolution, and therapeutic activity.
I have found previously that it is apparent that the preparation of Figure 1 at least would be expected to be therapeutically effective. Consequently, the specification does enable the addressee to produce a suitable sustained release preparation (i.e. the preparation of Figure 1) without the need for prolonged study. That is all that is required.
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, 183 CLR 655).
Sandoz argued that the specification does not reveal an invention, as tramadol is admitted to be known, sustained release preparations are known, use of hydrophilic and/or hydrophobic polymers was known, and the need to establish dissolution rates for a candidate drug was known. Thus the present invention is no more than an analogous use. In this regard, Sandoz referred to Morgan & Co v Windover & Co (1890) 7 RPC 131 at 134, where the House of Lords held that there was no subject matter in an invention that was “simply the application well-known and well-understood things to an analogous use”.
It is instructive to consider the facts of the Windover case. The patent related to the use of a certain type of spring on the front of a carriage, as well as at the rear where it had previously been used. Lord Watson explained the issue in the following terms at 136:
“the springs described in the Specification differ in no respect from carriage springs then in common use. The purpose to which they are applied is not only analogous to, but might fairly be described as identical with, the purpose which they previously served, viz.: that of giving support to the body of a carriage. … No mechanical contrivance or adjustment is specified or required in order to make the substituted springs fit into their new position, or to render them efficient when they are placed there.”
100. It is apparent that the present case differs significantly from Windover. It is not suggested that a controlled release preparation of tramadol was known, and is now being used in an analogous way. Rather, it is the elements of the preparation that are known, and are being put together in a way analogous to the prior art. The Windover case is of little assistance.
101. Of more interest is the Federal Court decision in Merck & Co Inc v Arrow Pharmaceuticals Ltd [2006] FCAFC 91, 68 IPR 511. In that case the invention related to a method of treating a particular disease using an amount of a known drug already known to treat that disease, with the qualification that the drug is taken weekly. The Full Court held (at 532 [75]) that there was no manner of new manufacture as the dosage regimen was known (in the treatment of a different disorder), and the advantage of reduced GI side effects was known in that context:
“The patent specification discloses no new substance, no new characteristic of a known substance, no new use and no new method. There is, therefore, no manner of new manufacture.”
102. 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 can also be distinguished from the Merck case.
103. It has not been established that the present invention is not a manner of manufacture.
Utility
104. The argument in relation to utility is that the specification does not establish that the preparations would deliver a therapeutically effective level of tramadol. In this regard, Sandoz has asserted that dissolution of only 5% after 1 hour would not be effective. Additionally, it was suggested that a preparation containing only 1% of polymer could not provide a sustained release preparation.
105. The issue of utility was recently considered by the Full Court of the Federal Court in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70, 81 IPR 228. Emmett J at 247 [81] stated:
“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”
106. Lack of utility is established when a claim includes subject matter that “will not” produce the desired result. In the present case, I have been provide with speculation that the some parts of the claimed invention would not work. I have not been provided with evidence that any preparation within the scope of the claims would fail to achieve a therapeutic effect, or alternatively a detailed explanation of why the invention could not work. Sandoz has not discharged the onus of showing that the claimed invention would clearly be invalid on this basis.
Clarity
107. I found that I could not determine the scope of claim 17. Although this matter was not raised by Sandoz, I conclude that claim 17 is not clear.
Parameteritis
108. At the hearing it was suggested that the style of claiming by reference to the degree of dissolution of tramadol at various points in time was an example of “parameteritis”, or “parametritis”. In the end, this point has not been decisive. However, it is worth stating how the concept applies to the present case.
109. Parameteritis was discussed by Laddie J in Raychem Corp’s Patents [1998] RPC 31. At page 37, he defines the concept:
“This is the practice of seeking to repatent the prior art by limiting claims by reference to a series of parameters which were not mentioned in the prior art. Sometimes it includes reference to parameters measured on test equipment which did not exist at the time of the prior art. The attraction of this to a patentee is that it may be impossible to prove now that the prior art inevitably exhibited the parameters and therefore it is impossible for an opponent to prove anticipation. Even if that is what has happened here, it does not alter the task of the court. It must decide whether the opponent has proved anticipation or some other statutory ground of invalidity. Parametritis may make the court’s task more difficult, but at the end of the day the test of invalidity must be the same, whatever the form of the claims.”
At page 46, he refers to the parameter (the S/D volume ratio) that is used in the claims as:
“essentially arbitrary and has little technical significance. The selection of a group of compositions by reference to such a parameter does not involve any inventive step. Although it may not be obvious, in the common use of that word, to limit a claim by reference to this particular meaningless and arbitrary parameter, that has nothing to do with patentability. Patents are not given for skill in inventing technically meaningless parameters.”
110. It is clear that parameteritis is not objectionable per se. However, it may give rise to grounds of opposition, depending on the merits of the case. In Australia there have been several cases where the issue has arisen, and they provide useful understanding. In Williams Advanced Materials Inc v Target Technology Co LLC [2004] FCA 1405 at [48], 63 IPR 645 at 654, Bennett J considered claims to an optical storage medium having a reflective layer including a silver – palladium alloy. Her Honour noted that the parameters were selected without a purpose:
“there is nothing in the specification that suggests that the proportions or the ranges of the metals in the alloys are in any way part of the invention, other than the mere reference to them. It is a case of ‘parameteritis’.”
Her Honour then found that certain of the claims were not novel.
111. In Austal Ships Pty Ltd v Stena Rederi Aktiebolag [2005] FCA 805 at [108], 66 IPR 420 at 437, Bennett J referred to the Williams case, and distinguished it because:
“there is reference in the patent specification and evidence which supports the fact that the parameters have been carefully chosen, are part of the invention and are related to a claimed advantage as part of the combination of the design”
112. The critical question in the present case is whether the parameters used to define the dissolution of tramadol preparations have been chosen to achieve a technical effect, or whether they are an arbitrary convenience. I found that the dissolution profile does have a technical effect, so this is not a case of parameteritis.
Conclusion
113. Claims 1 and 18 to 20 lack an inventive step in the light of EP 147780. I have also found that claim 17 is not clear. As claim 2 has an inventive step, it is clearly possible to overcome these matters by amendment. It is appropriate to allow Euroceltique 60 days to propose amendments.
Costs
114. Sandoz have succeeded in the opposition on the ground of inventive step. I see no reason to depart from the normal approach that costs before the Commissioner follow the event. I award costs according to Schedule 8 against Euroceltique.
Dr S.D.Barker
Delegate of the Commissioner of Patents12 November 2009
Patent attorneys for the applicant : Spruson & Ferguson
Patent attorneys for the opponent : Shelston IP
ANNEX
Figures of patent application 2002300863
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