Mundipharma Pty Limited v Alza Corporation
[2015] APO 30
•24 June 2015
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Mundipharma Pty Limited v Alza Corporation [2015] APO 30
Patent Application: 2006308718
Title:Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms
Patent Applicant: Alza Corporation
Opponent: Mundipharma Pty Limited
Delegate: Dr M-A. Fam
Decision Date: 24 June 2015
Hearing Date: 20 May 2015, in Canberra
Catchwords: PATENTS – section 59 – opposition to the grant of a patent – grounds of novelty, utility, fair basis and clarity considered – dosage forms defined in terms of structural (hydrophobic component) and functional (in vitro alcohol dissolution test) requirements – in vitro test provides a means for determining dosage forms that reduce the adverse effects of alcohol-induced dose dumping – lack of novelty not established – lack of utility not established – claims fairly based and clear – opposition fails
Representation: Patent applicant: Katrina Crooks and Jacinta Flattery-O’Brien of Shelston IP
Opponent:Philip Kerr, Linda Govenlock and James Gonczi of Allens Patent and Trade Mark Attorneys
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Application: 2006308718
Title:Methods of reducing alcohol-induced dose dumping for opioid sustained release oral dosage forms
Patent Applicant: Alza Corporation
Date of Decision: 24 June 2015
DECISION
The opposition fails on all grounds. Subject to appeal, I direct the application proceed to grant. Costs according to Schedule 8 are awarded against Mundipharma Pty Limited.
REASONS FOR DECISION
Background
The present application was filed by Alza Corporation (Alza) on 31 October 2006. The application was examined and advertised accepted on 10 January 2013.
A notice of opposition was served by Mundipharma Pty Limited (Mundipharma) on 12 April 2013. The hearing was held in Canberra on 20 May 2015. Alza was represented by Katrina Crooks and Jacinta Flattery-O’Brien of Shelston IP. Mundipharma was represented by Philip Kerr, Linda Govenlock and James Gonczi of Allens Patent and Trade Mark Attorneys.
It is noted that the request for examination in relation to the application was filed on 30 June 2010. Consequently, substantive amendments of the Patents Act 1990 brought about by the Intellectual Property Laws Amendment (Raising the Bar) Act 2012 do not apply to the present application. This includes the amendment to subsection 60 (3A) that allows the Commissioner to refuse a patent application if satisfied on the balance of probabilities that a ground of opposition exists. It is further noted that any subsequent references to sections of the Patents Act relate to the Patents Act 1990 prior to amendment by the Raising the Bar Act.
Proposed amendments to the specification
Alza filed section 104 amendments on 16 April 2015. On 20 April 2015, a letter was issued by a Delegate of the Commissioner proposing that the hearing proceed on the basis of the specification as proposed to be amended.
At the hearing, Mundipharma indicated that its submissions were based on the claims as accepted rather than the claims as proposed to be amended. However, Mundipharma stated that comment on the amended claims would be provided where appropriate. Alza indicated that its submissions were directed to the claims as proposed to be amended, in accordance with the proposal outlined in the Delegate’s letter. However, where separate arguments arise in respect of the claims as accepted, these would be addressed.
The following decision is based on the claims as accepted, however comment on the claims as proposed to be amended is provided where appropriate. I note that the proposed amendments are still under consideration by a Delegate of the Commissioner and that Mundipharma filed comments on the amendments on 11 May 2015.
Supplementary submissions
Both parties filed their submissions on time. On 18 May 2015, Mundipharma filed supplementary submissions in response to issues raised by Alza in its submissions. At the hearing Alza requested the opportunity to file further submissions in response to the supplementary submissions. Alza was provided with a period of 7 days from the date of the hearing in which to file submissions and Mundipharma did not object to this. Alza’s submissions were subsequently filed on 27 May 2015.
Grounds of opposition
The statement of grounds and particulars was filed on 10 July 2013 and specifies the following grounds of opposition:
- novelty
- inventive step
- utility
- section 40 issues of lack of full description, lack of fair basis and lack of clarity.
At the hearing the opposition was limited to the grounds of novelty (with respect to WO 2006/079550), utility, fair basis and clarity.
Standard of proof
The onus of proof in this opposition proceeding rests with the opponent, who must demonstrate 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 [67]; 50 IPR 305; Commissioner of Patents v Sherman [2008] FCAFC 182 at [18]; 79 IPR 426).
Evidence
The evidence filed is summarised in the table below.
Evidence Declarant Exhibits Date Reference In Support Angelo Mario Morella AMM-1 to AMM-7 7 March 2014 Morella-1 Phillip Reece PR-1 and PR-2 3 June 2014 Reece Geoffrey K. Gourlay GG-1 and GG-2 6 June 2014 Gourlay Benjamin J. Boyd BB-1 and BB-2 6 June 2014 Boyd Ian Pitman IP-1 and IP-2 6 June 2014 Pitman In Answer Desmond B. Williams DW-1 and DW-2 6 June 2014 Williams-1 Michael McNamara MM-1 and MM-2 23 June 2014 McNamara Jacinta Flattery‑O’Brien JFO-1 29 July 2014 Flattery-O’Brien Nadia Pece-Barbara NPB-1 to NPB-13 31 July 2014 Pece-Barbara Desmond B. Williams DW-3 to DW-11 31 July 2014 Williams-2 In Reply Angelo Mario Morella AMM-8 to AMM-20 30 October 2014 Morella-2 Cornelia Hentzsch CH-1 and CH-2 30 October 2014 Hentzsch Further Desmond Williams DW-3 to DW-11 14 August 2014 Williams-3 The subject matter of the specification
Background of the invention
The specification relates to methods for reducing alcohol-induced dose dumping of opioid sustained release oral dosage forms. Such dosage forms are designed to release the opioid over an extended period, thereby providing prolonged pain relief. There is a high demand for once‑per‑day and twice-per-day dosage forms that provide a patient with pain relief for an entire day (page 1, lines 19 – 23).
The amount of opioid contained in sustained release oral dosage forms, particularly once-per-day forms, is significantly greater than that present in immediate release opioid dosage forms. Consequently, anything that causes dose dumping, i.e. immediate release, of the opioid can result in a drug overdose, leading to respiratory depression and possibly death (page 1, lines 24 – 28).
The specification indicates that the inventors have recognised that enhanced release can occur when opioid sustained release dosage forms are co-administered with aqueous alcohol and in particular aqueous ethanol. Thus, various alcohols increase the rate of release and in certain circumstances this may approach dose dumping or immediate release. This can present serious problems for patients taking such dosage forms (page 1, line 29 to page 2, line 3).
Aim of the invention
The specification states (page 2, lines 4 – 8):
“Accordingly, it would be desirable to develop opioid sustained release oral dosage forms, and related methods, that do not have the problems of the prior art relating to alcohol-induced dose dumping, especially ethanol-induced dose dumping. It would be even more desirable if those opioid sustained release oral dosage forms and related methods were once-per-day or twice-per-day opioid sustained release oral dosage forms and related methods.”
Nature of the invention
The specification indicates that it is possible to reduce the adverse effects associated with alcohol–induced dose dumping in patients who are orally receiving a sustained release opioid through the administration of certain opioid dosage forms. In particular, the dosage form is such that when tested in an in vitro test method that employs a test medium that comprises aqueous alcohol at a concentration of about 20% volume/volume, it releases less than or equal to about 50 weight percent of the opioid in a period of 2 hours following initiation of the test (page 16, lines 12 – 23).
The specification further states that it is possible to reduce or prevent aqueous alcohol-induced dose dumping through the use of particular coatings or hydrophobic components in the dosage form. Thus, coatings may modify the time of release (enteric coatings), or may be resistant to swelling or dissolution in alcohol (semi-permeable membranes) (page 19, lines 4 – 11). Similarly, hydrophobic components may be either polymeric or non-polymeric and are selected such that they are relatively insoluble in water and minimally swell in aqueous alcohol. In particular, components that exhibit equal or lesser swelling and/or solubility in aqueous alcohol than in water are preferred (page 19, lines 12 – 26).
One technique for determining useful coatings and hydrophobic components is to cast films of the relevant material and then test these for swelling in the presence of aqueous alcohol. Mass screening techniques can be employed to test a range of materials and similar methods employed to evaluate the solubility of such materials (page 19, line 27 to page 20, line 1).
The examples
The examples describe various dosage forms, including those containing a semi-permeable membrane (Example 1), or hydrophobic components such as stearyl alcohol (Example 7). In vitro release studies for certain dosage forms are also described, wherein the rate of release is determined in various aqueous ethanol solutions. A further example relates to an in vivo study to evaluate the effect of alcohol on the pharmacokinetics of the opioid hydromorphone (Example 5).
The claims of the specification
The claims as accepted consist of independent claim 1 and dependent claims 2 – 11. The proposed amendments filed on 16 April 2015 result in minor changes to accepted claims 1, 3 and 11, and introduce several new dependent claims. Thus, the claims as proposed to be amended consist of independent claim 1 and dependent claims 2 – 16.
Claim 1 is reproduced below, with the proposed amendments underlined in parentheses:
“1. A method for reducing adverse effects associated with alcohol-induced dose dumping comprising orally administering an opioid sustained release dosage form to a subject (patient) in need thereof, wherein:
the dosage form, when tested using an in vitro test method that employs a test medium that comprises aqueous alcohol (ethanol) at a concentration of 20% volume/volume, releases less than or equal to 50 weight percent of the dose of the opioid in a period of 2 hours following initiation of the in vitro test method; and wherein:
(a) the dosage form comprises a semi-permeable membrane; and/or
(b) the dosage form comprises at least one hydrophobic component that is relatively insoluble in water and minimally swells in aqueous alcohol (ethanol), wherein:
(i)when the hydrophobic component comprises a hydrophobic polymer, the polymer exhibits equal or lesser swelling and/or solubility in aqueous alcohol (ethanol) than in water, and
(ii)when the hydrophobic component is non-polymeric, the component exhibits less solubility/swelling in aqueous alcohol (ethanol) than in water.”
Dependent claims 2 – 10 define additional features of the dosage form and dependent claim 11 is an omnibus claim.
Claims construction
The approach to claims construction was considered by Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70 at [118]-[120]; 81 IPR 228:
“the end point is that the words in a claim should be read through the eyes of the skilled addressee in the context in which they appear. … While the claims define the monopoly claimed in the words of the patentee’s choosing, the specification should be read as a whole … It is not permissible to read into a claim an additional integer or limitation to vary or qualify the claim by reference to the body of the specification … However, terms in the claim which are unclear may be defined or clarified by reference to the body of the specification …”
Claim 1
“A method for reducing adverse effects associated with alcohol-induced dose dumping”
Mundipharma submitted that it is not clear whether the claimed method prevents or reduces dose dumping (and as a consequence reduces the adverse effects that would otherwise have resulted), or whether the method allows dose dumping to occur, but the adverse effects are nevertheless reduced (Morella-1 at [80] and [112]).
Alza stated that it is clear from the plain wording of the claim that the method is for reducing adverse effects associated with dose dumping. It further submitted that the skilled addressee would understand that if dose dumping itself is reduced, the adverse effects of dose dumping would also be reduced and that Dr Williams interpreted the words as such (Williams-3 at [81]). Reference was also made to Example 5 in the specification, which demonstrates not only a reduction in the occurrence of dose dumping, but also its adverse effects (page 20, lines 3 – 25).
It seems appropriate to adopt the plain meaning of the words. Claim 1 is therefore considered to define a method wherein the adverse effects associated with alcohol-induced dose dumping are reduced.
“In vitro test” and opioid release requirements
The parties agreed that the in vitro test does not form part of the method of claim 1, i.e. the test specifies a parameter that the dosage form must meet, however there is no requirement that the test actually be performed as a separate step in the method. Both parties submitted that the claimed method is one of administration. Mundipharma further stated that it would be impractical to administer a dosage form to a patient whilst conducting an in vitro test.
It is considered that the dosage form of claim 1 must satisfy the release requirements of the in vitro test, however the test is not performed as a step in the claimed method.
Mundipharma further submitted that the requirement that the dosage form “releases less than or equal to 50 weight percent of the dose of the opioid in a period of 2 hours following initiation of the in vitro test method” simply indicates that the dosage form is one that does not dose dump, i.e. the claim merely defines a dosage form that does not dose dump and which comprises the features specified in parts (a) and/or (b). In support of this construction reference was made to the specification, which equates dose dumping with immediate release (page 1, lines 29 – 30), wherein an “immediate-release dosage form” is one that releases greater than or equal to about 75% of the drug in less than or equal to about 45 minutes following administration of the dosage form to a patient (page 25, lines 1 – 3). Thus, a dosage form that releases less than or equal to 50% of the opioid in a period of 2 hours implicitly cannot dose dump.
Alza submitted that the “immediate-release dosage form” is defined with reference to an in vivo process, whereas the test of claim 1 is an in vitro one. Thus, the dissolution test of claim 1 does not measure dose dumping per se. Rather, a dosage form that satisfies the test (and having the other technical features of claim 1) will reduce the adverse effects of alcohol-induced dose dumping.
I agree with Alza’s point of view. Claim 1 is therefore considered to define a dosage form that releases less than or equal to 50 weight percent of the opioid dose in the 2 hour period following initiation of the in vitro test and wherein the dosage form comprises the features as indicated in parts (a) and/or (b).
“Aqueous alcohol”
During the hearing there was some discussion of the term “aqueous alcohol”. Mundipharma submitted that the term is broad and further that there is no indication of the nature or concentration of the alcohol used to determine the solubility and swelling properties of the hydrophobic component specified in part (b) of the claim, and that such properties will vary depending on the alcohol (Morella-1 at [37] and [131]).
Alza submitted that in the context of part (b) of the claim, “aqueous alcohol” would mean aqueous alcohol having the same percentage water and alcohol as the aqueous alcohol of the test medium used for the 2 hour in vitro test, i.e. 20% volume/volume (Williams-3 at [83]).
The specification defines “alcohol” as an organic compound having from 1 to about 5 carbon atoms, in which a hydroxyl group is bound to a carbon atom. Preferably the alcohol is ethanol (page 22, lines 1 – 3). “Aqueous alcohol” means a combination comprising water and alcohol (page 22, lines 7 – 15).
Notwithstanding this definition, the claim must be read through the eyes of the skilled addressee and in the context of the specification as a whole (H Lundbeck A/S v Alphapharm Pty Ltd supra). Although the skilled addressee was not specifically discussed at the hearing, Mundipharma submitted that the skilled person would comprise a team of people, including a pharmaceutical formulator, a pharmacist or pharmaceutical scientist and/or pharmacologist, as well as a physician (submissions dated 6 May 2015 at [42]). Alza submitted that it is not necessary to determine whether the skilled team would include all such persons, but did not accept that the specification would be addressed to a pharmacist or physician (submissions dated 13 May 2015 at Footnote 30).
I note that the skilled addressee does not include an organic chemist, who would be most likely to interpret “alcohol” according to the definition given in the specification, and that this definition encompasses toxic alcohols that would not be consumed, for example methanol. In contrast, I consider that a pharmaceutical formulator or pharmacologist would give the term its plain meaning, i.e. ethyl alcohol (Macquarie Dictionary). This is consistent with reducing the adverse effects associated with alcohol-induced dose dumping arising from co-ingestion or co‑administration of the opioid with an alcoholic beverage (Morella-1 at [49]; Williams-3 at [81]).
The specification refers to ethanol-induced dose dumping (page 1, lines 17 – 18; page 18, line 24 to page 19, line 2) and problems that arise when opioids are co-administered with alcoholic beverages (page 24, lines 5 – 12). Similarly, the hydrophobic components are described in terms of their solubility or swelling properties in ethanol (pages 59 – 60) and the in vitro and in vivo release studies are conducted in the presence of ethanol.
Dr Morella also concluded that, to the extent he could attribute a meaning to the terms used in claim 1 when read in the light of the specification as a whole, that the hydrophobic component swells minimally in aqueous ethanol (Morella-1 at [133]). More specifically, the properties of the hydrophobic component are as determined in 20% aqueous ethanol (Morella-1 at [133]).
“Aqueous alcohol” is therefore considered to mean “aqueous ethanol”. With regard to part (b) of the claim, “aqueous alcohol” in this context is taken to mean aqueous ethanol at a concentration of 20% volume/volume.
I note that as a consequence, the proposed amendment to claim 1 (and also to claim 3) to replace “alcohol” with “ethanol” merely makes an implicit meaning explicit.
“Hydrophobic component that is relatively insoluble in water and minimally swells in aqueous alcohol”
The nature of the hydrophobic component was considered in detail at the hearing, and is also relevant to the grounds of fair basis and utility as discussed below. Mundipharma submitted that the solubility and swellability of the hydrophobic component would vary depending on the alcohol and its concentration and that such properties do not provide a means for identifying or distinguishing such a component (Morella-1 at [41] – [42]). It was further stated that the terms “relatively insoluble” and “minimally swells” are vague and do not enable suitable substances to be identified (Morella-1 at [132] and [151]). Such terms are not considered to be commonly used, whereas “practically insoluble” or “slightly soluble” are recognised in the literature (Morella-1 at [35] – [36]; Morella-2 at [110] – [111]).
Alza submitted that “relatively insoluble in water” and “minimally swellable” in the context of the specification would be understood by those working in the field (Williams-3 at [82] and [84]).
Alza further stated that the use of the term “relatively insoluble” is commonplace in granted patent specifications in Australia (Exhibits NPB-1 to NPB-13) and that the equivalent granted European patent contains the same terminology (Flattery-O’Brien and Exhibit JFO-1). However, the terminology used in other granted patent specifications, either here or in other jurisdictions, is not considered relevant to the present application.
I have already determined that “aqueous alcohol” means “aqueous ethanol at a concentration of 20% volume/volume”. The hydrophobic component is therefore one that minimally swells in such a solution and is relatively insoluble in water.
The terms “relatively insoluble” and “minimally swells” are qualitative rather than quantitative descriptors. As stated in Leonardis v Sartas No 1 Pty Ltd and Another (1996) 35 IPR 23 at 32:
“It is not inadmissible to use in a claim an imprecise word, in an appropriate context, where it conveys the necessary meaning”.
The specification discusses suitable hydrophobic components and makes reference to the solubility and swelling properties of these substances in water and aqueous ethanol (see, for example, pages 59 – 62).
It is considered that, in the context of claim 1, the hydrophobic component will not swell to any significant extent in 20% aqueous ethanol and similarly not dissolve to any significant extent in water, wherein the levels of swelling and solubility would be comparable to the hydrophobic components discussed in the specification.
Novelty
Under subsection 7(1), an invention is taken to be novel unless it is not novel in the light of the prior art base. Information in a document forms part of the prior art base for the purposes of novelty if it was published before the priority date of a claim, or the information was contained in a specification published after the priority date of the claim under consideration and, if that information is, or were to be, the subject of a claim of the specification, that claim has, or would have, a priority date earlier than that of the claim under consideration (referred to as “whole of contents” 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 Aicken J in Meyers Taylor Pty Ltd v Vicarr Industries Ltd [1977] HCA 19 at [20]; 137 CLR 228:
“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 claimed (Nicaro Holdings Pty Limited v Martin Engineering Company [1990] FCA 40 at [19]; 16 IPR 545). In order 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).
In addition, in order to raise a “whole of contents” objection, it must be possible to draft a notional claim (assuming there is not an actual claim to the relevant subject matter) that is fairly based on the disclosure of the prior specification relied upon (Danisco A/S v Novozymes A/S (No 2) [2011] FCA 282; (2011) 91 IPR 209 at [178]).
Mundipharma submitted that claims 1, 3, 5 and 7 lack novelty (“whole of contents”) based on the disclosure of WO 2006/079550 (D1). In order to establish whether the claims lack novelty, it is necessary to determine:
(i) the priority date of the claims of the specification;
(ii)whether there is relevant information in D1 that would deprive the claims of novelty; and
(iii) where there is relevant information, the “priority date” of that information, i.e. if that information is, or if it were to be, the subject of a claim of D1, whether that claim has, or would have, a priority date earlier than that of the claims of the specification.
Priority date – general considerations
Under regulation 3.12, where a claim is fairly based on matter disclosed in 1 or more priority documents, the priority date of the claim is the date of filing of the priority document in which the matter was first disclosed. The parties were in agreement that the fair basis test for determining the priority date of a claim is the same as that for determining whether a claim is fairly based in accordance with subsection 40(3).
Subsection 40(3) requires that the claims must be fairly based on the matter described in the specification. The test for fair basis was stated by the High Court in Lockwood Security v Doric Products [2004] HCA 58 at [69]; 217 CLR 274 as:
“Rather, 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.”
The relevant dates for the present specification and D1 are set out in chronological order in the table below.
Date Present Specification D1 28 January 2005 Filing date of 1st priority document (D1-P1) 11 February 2005 Filing date of 2nd priority document (D1-P2) 12 April 2005 Filing date of 3rd priority document (D1-P3) 26 October 2005 Filing date of 4th priority document (D1-P4) 31 October 2005 Filing date of 1st priority document (P1) 27 January 2006 Filing date 18 May 2006 Filing date of 2nd priority document (P2) 3 August 2006 Publication date 11 August 2006 Filing date of 3rd priority document (P3) 31 October 2006 Filing date
The specification (page 1, lines 7 – 8) and D1 (page 3, lines 8 – 9) both incorporate the contents of their respective priority documents in their entirety.
Priority date of claims of specification
Mundipharma submitted that claim 1, in so far as it relates to the embodiment pertaining to the hydrophobic component, is not entitled the earliest priority date of 31 October 2005. It was argued that the bulk of the description and all of the examples of the earliest priority document (P1) relate to osmotic dosage forms, i.e. forms comprising a semi-permeable membrane. Consequently, there is “no real and reasonably clear disclosure” of dosage forms comprising a hydrophobic component that meet the in vitro test requirements and do not dose dump. It was submitted that the only dosage forms containing hydrophobic components that are discussed in P1 are prior art forms known to dose dump (P1 at [0005] and [00036]).
Alza submitted that P1 describes the hydrophobic component at [000170], [000172] and [000174] and that claims 25 and 28 define the use of sustained release dosage forms that meet the in vitro test requirements. It was argued that this combined disclosure provides the basis for dosage forms comprising a hydrophobic component that do not dose dump.
As indicated in Lockwood Security v Doric Products supra at [69] and [77], the words “real and reasonably clear disclosure” do not limit disclosures to preferred embodiments. Thus, although there are no specific examples in P1 that relate to dosage forms containing hydrophobic components, this document is nevertheless considered to provide a “real and reasonably clear disclosure” of this subject matter when read as a whole. In particular, the parts of P1 referred to above by Alza, namely [000170], [000172] and [000174] when read in conjunction with claims 25 and 28, provide a basis for such dosage forms.
Mundipharma further submitted that claim 1 is not fairly based as it “travels beyond” the subject matter of P1. In order to be fairly based, the desired functional result, i.e. a reduction in the adverse effects associated with alcohol-induced dose dumping and less than or equal to 50% opioid release after 2 hours in 20% volume/volume aqueous ethanol, must be achieved by every hydrophobic component satisfying the solubility/swellability criteria specified in claim 1. Otherwise, the claim will have been drafted too broadly and travel beyond what Alza has identified as its “invention”.
Mundipharma further made reference to stearyl alcohol, which it argued is not expressly disclosed in P1, but is identified in the specification as a preferred hydrophobic component. Palladone contains stearyl alcohol (Morella-1 at [99]), however it is known to dose dump (P1 at Example 3). Mundipharma submitted that claim 1 therefore travels beyond the matter disclosed in P1, as it omits the technical features of the dosage form required to achieve the desired functional result.
Alza stated that there is no “technical feature” missing from claim 1, as the 2 hour in vitro test defines the requirements that the dosage form must meet to ensure that it does not dose dump.
The in vitro test method defined in claim 1 is considered to provide the means for determining whether a particular dosage form is suitable. Thus, although Palladone contains a hydrophobic component that meets the necessary solubility/swelling requirements, it does not meet the requirements of the in vitro test, i.e. Palladone does not meet both the structural and functional requirements as defined by the claim. Consequently, claim 1 does not omit the “technical features” necessary to achieve the result of reducing adverse effects associated with alcohol‑induced dose dumping.
Although the priority date of dependent claims 3, 5 and 7 was not specifically discussed at the hearing, I note that there is a real and reasonably clear disclosure in P1 for the features defined by these claims. These features are at least disclosed as follows:
·Claim 3, alcohol concentration in test medium is 40% volume/volume – P1 at [00066].
·Claim 5, dosage form comprises an opioid antagonist – P1 at [00052].
·Claim 7, dosage form is a twice-per-day dosage form – P1 at [0006].
Conclusion on priority date of claims of specification
Claims 1, 3, 5 and 7 are entitled to the earliest priority date of 31 October 2005 as they are fairly based on P1.
Disclosure of WO 2006/079550 (D1)
As indicated above, the priority date of claims 1, 3, 5 and 7 is 31 October 2005. Therefore, the relevant information in WO 2006/079550 (D1) (that is the subject of a notional claim) must derive priority from at least one of the four priority documents, in order for D1 to meet the requirements of a “whole of contents” citation.
D1 relates to controlled release dosage forms comprising an opioid which are resistant to alcohol extraction. The most relevant information disclosed in D1 is that relating to Examples 2.1, 2.2 and 6 – 9. I will firstly consider Examples 2.1 and 2.2 and then Examples 6 – 9.
Examples 2.1 and 2.2 of WO 2006/079550 (D1)
Example 2.1 describes a sustained release dosage form comprising the opioid hydromorphone and the hydrophobic components ethylcellulose (Morella-1 at [169]) and glyceryl palmitostearate (present specification at page 60, lines 29 – 32). Example 2.2 indicates that the dosage form of Example 2.1 releases 19 weight percent of the opioid in 20% volume/volume ethanol in simulated gastric fluid (SGF, which is an aqueous test medium; Morella-1 at [164] and [170]) in a period of 1 hour.
Mundipharma submitted that the 1 hour in vitro data relating to Example 2.1 as presented in Example 2.2 can be extrapolated to provide an estimation of the dissolution data at a 2 hour time point. It was further submitted that the measurement of the amount of drug released at any time point is merely the confirmation of an inherent property of the dosage form.
Dr Morella stated (Morella-1 at [172] – [174]):
“If one has data for the percentage of drug released at the 1 hour time point, it is possible to estimate the percentage of drug release at 2 hours in a dissolution medium comprising SGF with the same concentration of alcohol if one has data on the dissolution profile of the same or similar compositions in aqueous dissolution media, dose form and/or the composition and dose form of the example in question.
Figure 1 discloses dissolution results over a 24 hour period for matrix pellet compositions A to F of Example 5, which are similar to Example 2.1, and contain hydromorphone hydrochloride. Figure 1 shows that the drug release is not a linear function of time, rather there is an initial burst of release, then the rate of drug release decreases after the 1 hour time point. At 2 hours drug release is less than double that released at 1 hour (ie, the dose form does not show linear/zero order release). (I estimate the drug released at 2 hours is less than 50% more than that at 1 hour). Such non-linear release kinetics are in my opinion commonly found with matrix drug compositions.
If I assume that Example 2.1 releases hydromorphone by a matrix mediated mechanism and shows drug release kinetics similar to the formulations of Example 5 in ethanol/SGF, then drug release at 2 hours would be less than twice that released at 1 hour, possibly less than 50% greater than that released at 1 hour as shown in Table AMM 4 below.”
He concludes (Morella-1 at [175] – [176]):
“If these assumptions hold true, I would expect a composition according to Example 2.1 to release less than 50% when tested in ethanol/SGF for 2 hours with concentrations of less than 35% alcohol if the formulation releases in a non-linear fashion.
If I assume that in a ‘worst case scenario’ Example 2.1 releases hydromorphone in a zero order fashion, then drug release at 2 hours would be twice that released at 1 hour and would release less than 50% when tested in ethanol/SGF with concentrations of alcohol up to 20%.”
Alza submitted that Dr Morella’s approach is based on a series of assumptions, in particular that the dosage form of Example 2.1 would exhibit very similar dissolution characteristics to the different formulations of Example 5, and that Example 2.1 releases hydromorphone by a matrix mediated mechanism.
Dr Williams stated, with respect to Example 2.2 (Williams-3 at [14]):
“The table does not provide any insights as to the percentage of opioid released after shorter or longer dissolution. It is my view that, from the results shown, it cannot be confidently predicted what percentage of opioid would be released at a later time point. Without knowledge of the duration of the lag time …. , i.e. the time it would take for dissolution to start, it would be difficult to predict the rate of release and therefore the slope of any graph depicting the release over time.”
As stated by Jessup J in Novozymes A/S and Another v Danisco A/S and Another [2013] FCAFC 6; (2013) 99 IPR 417 at [177]:
“If the information [i.e. D1] contains directions which, if carried out, would constitute an infringement of the patent in suit, the invention under the latter is not novel.” (emphasis in original)
The evidence does not demonstrate that the amount of drug released can be predicted with certainty. Furthermore, although the amount of drug released at 2 hours may be an inherent property of the dosage form, there is insufficient evidence that the property is inherent in this case.
Consequently, Examples 2.1 and 2.2 do not provide clear and unmistakeable directions to use a dosage form that releases less than or equal to 50 weight percent of the opioid in 2 hours for reducing the adverse effects associated with alcohol-induced dose dumping.
As the information contained in Examples 2.1 and 2.2 is not relevant for novelty purposes, it is not necessary to determine the priority date of a notional claim based on that information.
Examples 6 – 9 of WO 2006/079550 (D1)
Examples 6 – 8 describe sustained release dosage forms containing the opioid oxycodone hydrochloride and the opioid antagonist naloxone hydrochloride. The dosage forms also contain hydrophobic components, including ethyl cellulose, stearyl alcohol and magnesium stearate (Morella-1 at [160] – [161]; Williams-3 at [126]). Example 9 shows the in vitro dissolution data for Examples 6 – 8 in 20% and 40% volume/volume aqueous ethanol. In each case the dosage forms release less than 50 weight percent of oxycodone in the 2 hour period following initiation of the test. This information is clearly relevant to the novelty of claims 1, 3, 5 and 7.
Mundipharma submitted that the information contained in Examples 6 – 9 could be the subject of a notional claim that is fairly based on D1. It was further stated that the notional claim is fairly based on the 4th priority document (D1-P4) and is therefore entitled to a priority date of 26 October 2005.
Of the 4 priority documents, D1-P3 and D1-P4 are the most relevant. However, neither document contains examples that correspond to Examples 6 – 9. Although other in vitro dissolution tests for sustained release dosage forms comprising a hydrophobic component in 20% volume/volume and 40% volume/volume aqueous ethanol are described, the dissolution data are obtained at 1 hour and not 2 hours.
As I have found above, it is not possible to predict the 2 hour data based on an extrapolation of the 1 hour data. Furthermore, reading the priority documents as a whole, the emphasis is clearly on a 1 hour in vitro dissolution test. The only reference to dissolution data at time periods greater than 1 hour is in Figure 1 of D1-P4. However, these results are obtained in simulated gastric fluid, i.e. 0% aqueous ethanol (Morella‑1 at [71]; although this comment is made with respect to Figure 1 in D1, the two figures are the same) and do not relate to the compositions of Examples 6 – 9. I do not consider that the priority documents provide a “real and reasonably clear disclosure” of a 2 hour in vitro test method conducted in 20% volume/volume aqueous ethanol. The whole focus of the priority documents is on a 1 hour test.
Consequently, I do not consider that the information contained in Examples 6 – 9 is fairly based on D1‑P4 (or any of the earlier priority documents for D1). Therefore, the “priority date” of the information contained in Examples 6 – 9 is the filing date of D1, namely 27 January 2006. This is after the priority date of claims 1, 3, 5 and 7 (31 October 2005). Thus, the information contained in Examples 6 – 9 is not part of the prior art base and cannot be used for novelty purposes.
I note that both parties made submissions on the time point of the in vitro test, i.e. 1 hour versus 2 hours, and in particular the purpose and advantages of such tests. However, as I have found that D1 does not disclose a 2 hour test as defined by claim 1, it is not necessary to consider this issue further. Certain aspects of the submissions also appear more relevant to the ground of inventive step, which was not pressed at the hearing, and not applicable to D1, being a “whole of contents” citation.
WO 2006/079550 (D1) as part of prior art base
Alza submitted that D1 does not form part of the prior art base for the assessment of novelty as it was not filed before the earliest priority date of the present specification. Whilst this issue was discussed at the hearing, it does not require further consideration given that D1 does not deprive the claims of novelty for the reasons outlined above.
Conclusion on novelty
It has not been demonstrated that there is a lack of novelty in the light of WO 2006/079550.
Fair basis
The test for fair basis was previously considered in the context of determining priority dates. Mundipharma submitted that claim 1 is not fairly based, as it does not define the technical features of the dosage form that are required to achieve the result of reducing adverse effects associated with alcohol-induced dose dumping. For similar reasons, claim 1 “travels beyond” the alleged invention as described in the body of the specification and is not fairly based. Mundipharma also stated that dependent claims 2 – 7 and 9 – 11 lack fair basis.
In support of this argument, Mundipharma made particular reference to the prior art dosage forms Palladone and OxyContin. Both of these forms contain stearyl alcohol, however Palladone dose dumps (page 18, lines 27 – 30; Example 3) whereas OxyContin does not (page 21, lines 8 – 13; Example 12). It was submitted that as the same hydrophobic component produces different results, claim 1 is missing the technical feature required to make the dosage form work. Thus, the claim is too broad as it extends beyond dosage forms that work and there is an inconsistency between the hydrophobic components as described and claimed.
In regard to the submission that claim 1 omits the technical features necessary to achieve the result of reducing adverse effects associated with alcohol-induced dose dumping, I have previously found that the in vitro test method defined in the claim provides the means for determining whether a particular dosage form is suitable. Thus, although Palladone and OxyContin both contain stearyl alcohol, which meets the necessary solubility/swelling requirements, only OxyContin meets the requirements of the in vitro test. The fact that the features of the dosage form of claim 1 are defined in terms of both structural (hydrophobic component) and functional (in vitro test) requirements does not lead to a lack of fair basis. Similar reasoning applies to dependent claims 2 – 7 and 9 – 11.
Mundipharma made further submissions in relation to the hydrophobic component magnesium stearate. Figure 12 of the specification shows the amount of oxycodone hydrochloride released from dosage forms containing magnesium stearate, either with or without stearyl alcohol. For those dosage forms that contain only magnesium stearate, the rate of release is linear and all of the opioid has essentially been released by 2 hours. Mundipharma contended that this demonstrates that magnesium stearate is not capable in all circumstances of producing a dosage form as claimed.
Alza stated that the opioid release data in Figure 12 is normalised to 100%, as indicated by the abbreviation “%MB” and the definition of this term given in the specification (page 75, lines 15 ‑ 17). Consequently, the percentage release of the opioid at 2 hours is not 100% in the case of formulations without stearyl alcohol and the absolute percentage dissolution of the opioid at this time point cannot be ascertained from the figure. Thus, for example, the actual amount released at 2 hours could have been 25%, with no further release after this time. Alza further submitted that the purpose of the example was to investigate stearyl alcohol as a hydrophobic component and that the data indicates alcohol-induced dose dumping is reduced in the presence of stearyl alcohol, and not that formulations containing magnesium stearate are susceptible to dose dumping.
I agree with Alza’s submissions and do not consider that claim 1 lacks fair basis with respect to the use of magnesium stearate as a hydrophobic component. For similar reasons, dependent claims 2 – 7 and 9 – 11 do not lack fair basis.
Amended claims 13 and 14
Claims 13 and 14, as proposed to be amended, are as follows:
“13. The method of claim 1 wherein the dosage form is a once-per-day, osmotic sustained‑release hydromorphone dosage form,
and wherein, should the patient co-ingest the dosage form with an alcoholic beverage having an ethanol content of 20% or more, the individual single dose maximum plasma hydromorphone concentration is limited to less than about 2 times the individual single dose maximum plasma hydromorphone concentration achieved when the dosage is co-ingested with water.
14. The method of claim 13 wherein the individual single dose maximum plasma hydromorphone concentration is limited to less than about 1.6 times the individual single dose maximum plasma hydromorphone concentration achieved when the dosage is co-ingested with water.”
The claims refer to “individual single dose maximum plasma concentration” rather than “individual patient single dose maximum plasma concentration”, which is defined in the specification (page 23, lines 14 – 17). Mundipharma submitted that if something else is intended by the expression “individual single dose maximum plasma concentration” (as distinct from “individual patient single dose maximum plasma concentration”), then claims 13 and 14 are not fairly based on the matter disclosed in the specification.
Claim 13 refers to the patient co-ingesting the dosage form with an alcoholic beverage and then specifies that the individual single dose maximum plasma hydromorphone concentration is a particular value compared with that achieved when the dosage is co-ingested with water. Given that the patient is the individual that has ingested the dosage form (either with alcohol or water), it is reasonable to expect that the single dose maximum plasma concentrations that are then determined are those of the same individual patient. Therefore, the reference in claim 13 to “individual single dose maximum plasma concentration” is taken to implicitly mean “individual patient single dose maximum plasma concentration”. Similar reasoning applies to claim 14.
Mundipharma further submitted that the specification does not disclose an “individual single dose maximum plasma concentration” of “less than about 2 times” or “less than about 1.6 times” the individual single dose maximum plasma hydromorphone concentration when the dosage form is co-ingested with water.
I have addressed the issue of “individual single dose maximum plasma concentration” as discussed above. The specification indicates that the ratio of an individual test subject’s single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of an aqueous solution having an alcohol concentration of about 20% volume/volume, to the same test subject’s single dose maximum plasma hydromorphone concentration as a result of co-ingestion within about 30 minutes of the dosage form and about 240 milliliters of the aqueous solution with water substituted for the alcohol, is most preferably equal to or less than about 2.5:1 (page 8, line 12 to page 9, line 13). “Test subject” is defined as a subset of “patient” (page 26, lines 8 – 14).
Example 6 determines individual test subjects’ single dose maximum plasma hydromorphone concentrations and the results are depicted in Figures 10 and 11. The relevant ratios are those shown for “20% Alcohol” and include values that are “less than about 2” and “less than about 1.6”. I note, however, that the results shown in Figures 10 and 11 were obtained when the dosage form was co-ingested with orange juice (page 74, lines 9 – 10), whereas claims 13 and 14 indicate that the dosage is co-ingested with water. Although there is a difference in the solution that the dosage form is co-ingested with, the results obtained in orange juice are not inconsistent with the general range of “less than about 2.5” described in the specification with respect to co-ingestion with water.
It has not been demonstrated that claims 13 and 14 as proposed to be amended lack fair basis.
Conclusion on fair basis
I am not satisfied that the opposition on the ground of lack of fair basis has been made out.
Utility
The requirements for utility were considered by the Full Court of the Federal Court in H Lundbeck A/S v Alphapharm Pty Ltd supra at [81]; 81 IPR 228:
“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”.
Mundipharma submitted that the in vitro test defined in claim 1 is not an appropriate parameter to distinguish utility. In this regard reference was made to Palladone and OxyContin. As discussed previously, both contain the hydrophobic component stearyl alcohol, yet Palladone dose dumps whereas OxyContin does not. Mundipharma submitted that it is not appropriate for the claim to encompass OxyContin which works and exclude Palladone which does not, i.e. the claim arbitrarily chooses to encompass dosages forms that have utility and omit those that do not. Consequently claims 1 – 11 lack utility.
Alza submitted that the in vitro test is the feature that separates dosage forms comprising hydrophobic components which fall within the scope of the claim and those that do not. Thus, if a dosage form is capable of satisfying the in vitro test, then it will achieve the result claimed, i.e. a method of reducing the adverse effects of alcohol-induced dose dumping. In the case of Palladone, the dosage form simply falls outside the scope of the claim altogether.
As I have previously indicated, I consider that the features of the dosage form of claim 1 are defined in terms of both structural (hydrophobic component) and functional (in vitro test) requirements. If the dosage form satisfies the requirements of the in vitro test, it will produce the desired result when used in the method as claimed.
Mundipharma also made submissions regarding the use of the hydrophobic component magnesium stearate as exemplified in the specification. However as discussed previously, the examples do not demonstrate that dosage forms containing magnesium stearate are susceptible to dose dumping.
Conclusion on utility
It has not been established that there is a lack of utility.
Clarity
Subsection 40(3) requires that the claims must be clear. A claim will lack clarity if a third party could not ascertain whether a proposed action would fall within the ambit of the claim (Monsanto Co v Commissioner of Patents (1974) 48 ALJR 59).
Mundipharma submitted that claims 1 – 11 lack clarity as the language and scope of the claims is not clear. Particular reference was made to terms and phrases used in the claims as indicated below.
“A method for reducing adverse effects associated with alcohol-induced dose dumping”
Mundipharma submitted that it is unclear whether the claimed method prevents or reduces dose dumping (and as a consequence reduces the adverse effects that would otherwise have resulted), or whether the method allows dose dumping to occur, but the adverse effects are nevertheless reduced.
I have previously found that based on a plain meaning of the words, the claims define a method wherein the adverse effects associated with alcohol-induced dose dumping are reduced, and therefore the claims are clear in this regard.
Mundipharma further stated that dependent claim 5, which recites that the dosage form includes an opioid antagonist, lacks clarity. In particular, it is unclear as to which adverse opioid side effects are mitigated by the opioid antagonist and which are mitigated by the presence of the hydrophobic component (Morella-1 at [114]).
Alza submitted that there must simply be some reduction in the adverse effects associated with alcohol-induced dose dumping, relative to a dosage form without the characteristics of claim 1.
I agree that the claims do not require that the reduction in adverse effects be attributed to a particular component of the dosage form. Claim 5 is therefore considered to be clear.
“Hydrophobic component”
Mundipharma submitted that the hydrophobic component is defined only in terms of relative solubility and/or swellability in 20% volume/volume of an unspecified alcohol solution. It was further stated that this lack of clarity is compounded by the fact that hydrophobic components that the specification indicates as being suitable for use in the invention, for example stearyl alcohol and magnesium stearate, do not give rise to dosage forms that meet the in vitro test requirements. In this regard reference was made to Examples 3 and 7 – 11.
I have already determined that “aqueous alcohol” means “aqueous ethanol at a concentration of 20% volume/volume”. As previously noted, the specification discusses suitable hydrophobic components and makes reference to their solubility and swelling properties in water and aqueous ethanol (see, for example, pages 59 – 62). Means for determining these properties are also described (page 19, lines 27 – 31).
Example 3 describes in vitro test results for Palladone, which does not fall within the scope of the claims for reasons previously outlined. Examples 7 – 11 describe dosage forms in which certain hydrophobic components, including magnesium stearate and stearyl alcohol, are either present or absent. The in vitro test release results for these forms are depicted in Figures 12 – 16, wherein the opioid release data are normalised to 100% (page 75, lines 14 – 17).
As indicated by Alza, the fact that the release results are normalised to 100% means that the absolute percentage dissolution of the opioid at 2 hours cannot be ascertained from these figures. Alza additionally stated that the figures relate to dissolution in 40% volume/volume ethanol and not 20% volume/volume as required by the claims. Further, as previously discussed, the examples indicate that alcohol-induced dose dumping is reduced in the presence of stearyl alcohol, and not that formulations containing magnesium stearate are susceptible to dose dumping.
The meaning of the term “hydrophobic component” is therefore considered to be clear.
“Relatively insoluble”
Mundipharma submitted that the meaning of the term “relatively insoluble” is unclear. I have previously found that the use of imprecise words in a claim is permissible in an appropriate context. As discussed above, the specification describes hydrophobic components that are suitable in terms of their solubility properties. It is considered that the skilled addressee, reading the specification as a whole, would be able to determine the meaning conveyed by the term “relatively insoluble”.
“Aqueous alcohol”
Mundipharma submitted that the term “aqueous alcohol” lacks clarity due to the broad nature of the term. In particular, there is no indication of the nature or concentration of the alcohol used to determine the solubility and swelling properties of the hydrophobic component specified in part (b) of claim 1. Mundipharma further stated that Alza has apparently conceded the inherent lack of clarity arising from the term “aqueous alcohol”, as the proposed amendments filed on 16 April 2015 replace references in the claims to “aqueous alcohol” with “aqueous ethanol”.
I considered the term “aqueous alcohol” in detail above and concluded that it means “aqueous ethanol”. With regard to part (b) of claim 1, “aqueous alcohol” means aqueous ethanol at a concentration of 20% volume/volume. As stated previously, the proposed amendment to claim 1 (and also to claim 3) to replace “alcohol” with “ethanol” merely makes an implicit meaning explicit.
Conclusion on clarity
It has not been established that the claims lack clarity.
Conclusion
The opposition fails on all grounds.
Costs
Mundipharma submitted that costs should follow the event. Alza submitted that the late filing of the supplementary submissions by Mundipharma should be taken into account in relation to costs. Alza stated that it is appropriate to award indemnity costs, or costs in accordance with scale.
The award of costs on an indemnity basis has been considered by the courts. In Colgate‑Palmolive Company and Another v Cussons Pty Limited [1993] FCA 536; 28 IPR 561 at 569 Sheppard J stated:
“In consequence of the settled practice which exists, the court ought not usually make an order for the payment of costs on some basis other than the party and party basis. The circumstances of the case must be such as to warrant the court in departing from the usual course.”
At 570 Sheppard J noted circumstances that would warrant the award of costs on an indemnity basis. These include the making of allegations of fraud knowing them to be false and the making of irrelevant allegations of fraud, evidence of particular misconduct that causes loss of time to the court and to other parties, the fact that the proceedings were commenced or continued for some ulterior motive or in wilful disregard of known facts or clearly established law, and the making of allegations which ought never to have been made or the undue prolongation of a case by groundless contentions.
I do not consider that the present circumstances warrant an award of costs on an indemnity basis.
I award costs in accordance with Schedule 8 against Mundipharma.
Dr M-A. Fam
Delegate of the Commissioner of Patents
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