iCeutica Pty Ltd
[2018] APO 78
•30 October 2018
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
iCeutica Pty Ltd [2018] APO 78
Patent Number: 2010239080
Title:A novel formulation of diclofenac
Patentee: iCeutica Pty Ltd
Hearing Officer: Dr S.D. Barker – Deputy Commissioner of Patents
Decision Date: 30 October 2018
Hearing Date: Written submissions filed on 3 September 2018; on 27 September 2018 the patentee advised that they did not wish to be heard in person
Catchwords: PATENTS – application for an extension of term – examiner objection – a unit dose of diclofenac acid of specified particle size and dissolution rate – pharmaceutical substance per se identified – whether the goods Zorvolex have the specified dissolution rate – dissolution rate not established on the balance of probabilities – application for extension of term refused
Representation: Patent attorney for the applicant: Wrays
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Number: 2010239080
Title:A novel formulation of diclofenac
Patentee: iCeutica Pty Ltd
Date of Decision: 30 October 2018
DECISION
I refuse the application for an extension of term.
For the purposes of section 74(4)(a) this decision constitutes notification in writing of the reasons for refusal.
For the purposes of section 224(2) this decision constitutes written notice of the making of a decision and, subject to the Administrative Appeals Tribunal Act 1975, that the patentee or a person whose interests are affected by this decision may make an application to the Administrative Appeals Tribunal for review of this decision.
REASONS FOR DECISION
The present decision relates to one of three applications for an extension of term filed by iCeutica Pty Ltd on 26 April 2017. In each case the extension is based on the goods Zorvolex.
Patent number 2010239080 in the name of iCeutica Pty Ltd (the patentee) was granted on 11 December 2014. On 26 April 2017 the patentee filed an application for an extension of term of the patent based on the goods Zorvolex. Several deficiency notices were issued, and on 2 August 2018 a Senior Examiner issued an intention to refuse the extension of term. The patentee requested a hearing, provided written submissions and asked for a decision to be issued based on those submissions.
Background
The patent relates to the substance known as diclofenac, which is used as an anti-inflammatory and an analgesic. The name diclofenac derives from its chemical name: 2-(2,6-dichloroanilino)phenylacetic acid. The structural formula of diclofenac is:
The patent commences with the following statement of the field of the invention:
"The present invention relates to methods of producing particles of diclofenac using dry milling processes as well as compositions comprising diclofenac, medicaments produced using diclofenac in particulate form and/or compositions, and to methods of treatment of an animal, including man, using a therapeutically effective amount of diclofenac administered by way of said medicaments."[1]
[1] Specification at page 1.
The specification describes a method of producing particles of a wide range of active substances. The particles are stated to be of a particle size equal to or less than 2000 nanometres. A nanometre (nm) is 10-9 metre. The specification asserts generally that small particles should be more soluble, and thus be more useful as pharmaceutical agents.
"It is known that the rate of dissolution of a particulate drug will increase with increasing surface area. One way of increasing surface area is decreasing particle size. Consequently, methods of making finely divided or sized drugs have been studied with a view to controlling the size and size range of drug particles for pharmaceutical compositions."[2]
[2] Specification at page 1.
"Diclofenac is a poorly water soluble drug so dissolution and absorbtion to the body is slow. So a method such as the present invention which provides for improved dissolution, will likely provide much faster absorption resulting in a more rapid onset of the therapeutic effect. By using a method such as the present invention, which provides faster absorption, a drug such as diclofenac, could be used more readily to treat acute pain as well as chronic pain."[3]
"In a preferred embodiment the present invention is directed to the unexpected finding that particles of diclofenac can be produced by dry milling processes at commercial scale."[4]
"The process results in the biologically active material having an improved dissolution profile. An improved dissolution profile has significant advantages including the improvement of bioavailability of the biologically active material in vivo."[5]
"The diclofenac compositions of the invention exhibit faster therapeutic effects."[6]
"The diclofenac compositions of the invention preferably exhibit increased bioavailability (AUC) and require smaller doses as compared to prior conventional compositions administered at the same dose."[7]
[3] Specification at page 3.
[4] Specification at page 4.
[5] Specification at page 28.
[6] Specification at page 45.
[7] Specification at page 46.
The specification exemplifies milling of diclofenac acid with additives such as anhydrous lactose, lactose monohydrate, mannitol and sodium dodecyl sulphate.[8] The specification reports that small particles are formed. The dissolution rates and bioavailability of the particles are also reported.
[8] Specification at page 57 and following, and Figures.
The information in the specification presents a clear case that the enhanced solubility and activity is associated with the use of milled particles of diclofenac.
The invention, in so far as it is claimed, is defined as a unit dose of a composition. A unit dose is the amount of a medication that is administered in a single dose, often in the form of a tablet or capsule. The unit dose contains either 18mg or 35 mg of diclofenac acid, along with lactose monohydrate and sodium lauryl sulfate (SLS). The median particle size of the diclofenac acid is less than 1000 nm and greater than 25 nm. A dissolution rate of the unit dose is specified.
The law
Extensions of term of patents are dealt with in Part 3 of Chapter 6 of the Patents Act (the Act). Extensions under these provisions are limited to standard patents relating to pharmaceutical substances. Pharmaceutical substance is defined in Schedule 1 of the Act:
"pharmaceutical substance means a substance (including a mixture or compound of substances) for therapeutic use whose application (or one of whose applications) involves:
(a) a chemical interaction, or physico-chemical interaction, with a human physiological system; or
(b) action on an infectious agent, or on a toxin or other poison, in a human body;
but does not include a substance that is solely for use in in vitro diagnosis or in in vitro testing."
In H Lundbeck A/S v Alphapharm Pty Ltd (Lundbeck),[9] Bennett J said that the definition of pharmaceutical substance focused "on the ingredient for therapeutic use that involves the relevant type of interaction".
[9] [2009] FCAFC 70, 81 IPR 228 at [238].
The relationship between the pharmaceutical substance and the patent is specified in section 70(2):
"(2) Either or both of the following conditions must be satisfied:
(a) one or more pharmaceutical substances per se must in substance be disclosed in the complete specification of the patent and in substance fall within the scope of the claim or claims of that specification; …"
Thus, the pharmaceutical substance must "in substance" be both described and fall within the scope of the claims of the specification. The meaning of "in substance be disclosed" was considered by Bennett J in Pfizer Inc v Commissioner of Patents (Pfizer).[10] The meaning of "in substance fall within the scope of the claim or claims" was considered by the Federal Court in Boehringer Ingelheim International GmbH v Commissioner of Patents[11](Boehringer). The Full Court said that the pharmaceutical substance must be "included amongst the things claimed".[12] I will return to these matters later in this decision.
[10] [2005] FCA 137, 64 IPR 547.
[11] [2001] FCA 647, 52 IPR 529.
[12] at [42].
The relationship between the pharmaceutical substance and the Australian Register of Therapeutic Goods (ARTG) is specified in section 70(3):
"(3) Both of the following conditions must be satisfied in relation to at least one of those pharmaceutical substances:
(a) goods containing, or consisting of, the substance must be included in the Australian Register of Therapeutic Goods;
(b) the period beginning on the date of the patent and ending on the first regulatory approval date for the substance must be at least 5 years."
This is a simple requirement, going no further than asking whether the pharmaceutical substance is contained in the goods in the ARTG. In Lundbeck Bennett J said:[13]
"There is no requirement in s 70(3) to compare or contrast the effectiveness of the pharmaceutical substance with the goods with ARTG approval, nor to consider the purity of the pharmaceutical substances. There is no suggestion from the words of s 70(3) that the relevant 'goods' could or must include no more than one pharmaceutical substance. What is required is an analysis of whether there are goods containing or consisting of [the pharmaceutical substance] and, if so, which of those goods had the first regulatory approval date."
[13] at [240].
It is also a requirement of section 70(4) that there has not been a previous extension of the term:
"(4) The term of the patent must not have been previously extended under this Part."
The manner in which an application for an extension of term is made is found in section 71(1):
"(1) An application for an extension of the term of a standard patent must:
(a) be in the approved form; and
(b) be accompanied by such documents (if any) as are ascertained in accordance with the regulations; and
(c) be accompanied by such information (if any) as is ascertained in accordance with the regulations."Finally, the time for making an application for extension of term is found in section 71(2). Relevantly for the present case, pursuant to paragraph (b) of that subsection, the period is 6 months from:
"the date of commencement of the first inclusion in the Australian Register of Therapeutic Goods of goods that contain, or consist of, any of the pharmaceutical substance referred to in subsection 70(3)"
The date of first inclusion relates to the first goods that are covered by the claims:
"Based on the structure of the Act, I conclude that the intention of the Act is that an application for extension of term is to be made within 6 months of the earliest first inclusion in the ARTG. Consistent with this intention, when subsection 71(2) refers to the date of first inclusion of any pharmaceutical substance, it must be construed as a reference to the earliest first inclusion date."[14]
[14] G.D.Searle LLC [2008] APO 31, 80 IPR 210 at [18].
The relevant regulations on the information to accompany the application are found in regulation 6.8:
"(2) For paragraph 71(1)(c) of the Act, the application must be accompanied by information showing that goods containing, or consisting of, the substance are currently included in the Australian Register of Therapeutic Goods.
(3) The application must also be accompanied by information identifying the substance, as it occurs in those goods, in the same way (as far as possible) as the substance is identified in the complete specification of the patent."The grounds for the intention to refuse
The first notice of deficiency raised section 70(2), and this ground was maintained in the second notice of deficiency maintained this ground and added section 70(3). The second notice added extra information to better explain the objection. The intention to refuse summarised the outstanding issues so that the issues for the hearing were clear.
The intention to refuse sets out five different ways to envisage the pharmaceutical substance, and explains why each leads to a conclusion that an extension of term is not possible. The five different options are:
a.diclofenac acid;
b.diclofenac acid mixture (i.e. diclofenac acid, SLS and lactose monohydrate);
c.submicron diclofenac acid;
d.submicron diclofenac acid mixture (i.e. submicron diclofenac acid, SLS and lactose monohydrate; and
e.080 diclofenac acid mixture (i.e. unit dose of submicron diclofenac acid mixture, SLS and lactose monohydrate having the release profile defined in claim 1 or claim 6).
I consider that it was helpful to set out the full range of options. The intention to refuse sets out the following grounds:
·the pharmaceutical substance per se does not in substance fall within the scope of the claims, and
·the goods Zorvolex have not been shown to have the necessary dissolution.
The patentee has raised a concern that the grounds raised during the examination of the application for extension of term have shifted. This is reflected in the following comments:
"Each notice of deficiency was issued by a different examiner, which has apparently resulted in different examiners' views on the same issues resulting in different outcomes for the patentee, denying procedural fairness to the patentee, and needlessly costing the patentee thousands of dollars in unnecessary expense. …
the Patents Office has raised new grounds of alleged deficiency in each subsequent notice of deficiency. At each turn, the patentee has answered these grounds, and then new grounds have been raised."
It is clear that the emphasis of the objections has been adjusted during examination. This may in part reflect the fact that different examiners were involved in each notice, but also probably reflects the responses provided by the patentee at each stage. I do not consider this to represent a denial of natural justice.
CONSIDERATION
This case raises several questions in relation to the way in which section 70(2) applies. First, the claims are directed to a specific amount of diclofenac. Second, the claims are directed to a specific particle size. Third, the claims are directed to a specific dissolution rate. Finally, there is also a question of whether section 70(3) is satisfied in relation to whether the goods Zorvolex contain the pharmaceutical substance.
Is a pharmaceutical substance per se in substance within the scope of the claims (section 70(2)(a))?
As already noted, a pharmaceutical substance is "the ingredient for therapeutic use that involves the relevant type of interaction".[15] Normally this will be the active compound, or a mixture containing the active compound. There are numerous decisions of the Commissioner in which the pharmaceutical substance has been found to be a composition having specific or relative amounts of components, or specific pharmacokinetic parameters.[16] As Deputy Commissioner Spann noted, the concept of a pharmaceutical substance should be understood with common sense in a way that does not draw artificial distinctions:
"It also appears that I should be cautious in interpreting 'substance' in a way that would unnecessarily exclude innovations in the pharmaceutical sector for which the extension of term scheme appears to be intended."[17]
[15] Lundbeck at [238].
[16] For instance, Southern Cross Pharma Ltd v Euro-Celtique S.A. [2016] APO 1; Sanofi-Aventis [2007] APO 35; N.V. Organon [2009] APO 8, [2009] AIPC 92-345
[17] N.V. Organon [2009] APO 8, [2009] AIPC 92-345 at [21].
What is clear is that the pharmaceutical substance should not include any separate physical integers that are unnecessary for the physico-chemical interaction with the human physiological system.[18]
[18] Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647, 52 IPR 529; Sanofi-Aventis [2007] APO 35.
Different physical forms of an active compound have seldom arisen in the context of section 70. In Celgene Corporation[19] I said that a specific polymorph of lenalidomide was a pharmaceutical substance. On appeal,[20] the Administrative Appeals Tribunal (AAT) made no reference to the polymorph aspect and proceeded on the basis that the pharmaceutical substance was lenalidomide. There was no suggestion that the chemical or physico-chemical interaction with the human physiological system was a consequence of the specific polymorph as distinct from the chemical structure of lenalidomide. It is implicit in the AAT decision that in that case the pharmaceutical substance was lenalidomide rather than the specific polymorph. It follows that caution should be exercised when treating physical aspects of a compound as aspects of the pharmaceutical substance.
[19] [2011] APO 37, 93 IPR 309 at [17].
[20] Celgene Corporation and Commissioner of Patents and Children's Medical Center Corporation (Joined Party) [2013] AATA 55.
The meaning of "in substance fall within the scope of the claim or claims" is that the pharmaceutical substance must be "included amongst the things claimed".[21] Normally this means that the pharmaceutical substance will be the same as the subject matter of the claim, although that is not always the case. [22] A method of treatment of a disorder by administering a pharmaceutical substance is not a claim to a pharmaceutical substance per se. [23] The same conclusion applies when the claim is directed to a pharmaceutical composition when used for treating a particular disorder.[24]
[21] Boehringer at [42].
[22] Spirit Pharmaceuticals Pty Ltd v Mundipharma Pty Ltd [2013] FCA 658, 102 IPR 55 (Spirit) at [42].
[23] Prejay Holdings Ltd v Commissioner of Patents [2003] FCAFC 77, 57 IPR 424 at [24].
[24] Celgene Corporation and Commissioner of Patents and Children's Medical Center Corporation (Joined Party) [2013] AATA 55.
However, a claim can include elements of a process if that is part of defining the substance. In Pharmacia Italia SpA v Mayne Pharma Pty Ltd[25] Weinberg J held that a claim must be read as a whole, and in that case the process elements:
"simply mark out the basis upon which the new and inventive substance can be distinguished from other prior art, and enable the scope of the protection to be more accurately understood."
[25] [2006] FCA 305, 69 IPR 1 at [100].
Similarly in Zentaris Aktiengesellschaft[26] the Deputy Commissioner held that "the only way to properly characterise the particular morphological form at the time of filing the application would be by reference to the method steps required to prepare it."
[26] [2002] APO 41 at [17].
In Spirit a different situation was considered. The pharmaceutical substance was oxycodone, and the claim was directed to a dosage of oxycodone within the range of 10 to 160 mg with excipients to achieve a controlled release. The reasons why this was a claim to a pharmaceutical substance per se are instructive.
"The specification or (as Spirit characterised it) the nominated result in the pharmacokinetic parameters, simply had the function of defining the necessary characteristics of whatever excipients were selected as part of the mixture to embody the formulation that would achieve the controlled release of the particular dosage of oxycodone. However, the mixtures formulated with the relevant dosages and excipients to achieve the pharmacokinetic parameters for the controlled release, as specified in claims 3 and 4, were all embodiments of the pharmaceutical substance per se, OxyContin, that met the criteria in s 70(2)(a). The same applies for formulations made in accordance with claims 5 to 12."[27]
[27] at [73].
The parameters were the pharmacokinetic parameters necessary for achieving the chemical or physico-chemical interaction in the human body. The parameters were not a matter of choice or convenience, but were the essence of the invention.
Having set out the legal principles I now turn to the claims of the present patent. Claim 1 of the specification reads:
"A unit dose of a pharmaceutical composition containing 18 mg or 35 mg of diclofenac acid and comprising lactose monohydrate and sodium lauryl sulfate wherein the particles of diclofenac acid have a median particle size on a volume average basis of equal to or less than 1000 nm and greater than 25 nm, wherein the unit dose when tested in vitro by USP Apparatus I (Basket) method of U.S. Pharmacopoeia at 100 rpm at 37.degree. C. in 900 ml of 0.05% sodium lauryl sulfate in citric acid solution buffered to pH 5.75 has a dissolution rate of diclofenac acid such that at least 91 %, by weight, is released by 45 minutes."
In the present case the chemical or physico-chemical interaction is caused by the diclofenac. The particle size of the diclofenac contributes to the activity of the composition. The SLS and lactose monohydrate do not clearly contribute to the interaction with the human physiological system, but as apparently inert ingredients in conjunction with the active ingredient they are reasonably considered part of the mixture that is the pharmaceutical substance in this case.
The quantity of the diclofenac is limited to either 18 mg or 35 mg. Such a limitation is only a feature of a pharmaceutical substance per se if it is selected so as to achieve the chemical or physico-chemical interaction with the human physiological system. In the present case the goods that are listed in the ARTG are a unit dose containing 18 mg of diclofenac. It seems a reasonable inference that 18 mg represents an amount selected to achieve the chemical or physico-chemical interaction, and is not merely a convenient selection.
The dissolution rate is logically a consequence of the way in which the unit dose is constructed and the median particle size of the diclofenac. The rate of dissolution is relevant to releasing the diclofenac into the human physiological system, and thus the rate at which the chemical or physico-chemical interaction takes place. I consider that the dissolution rate has been selected to achieve the chemical or physico-chemical interaction.
In the present case the chemical or physico-chemical interaction with the human physiological system is caused by the unit dose of the mixture of 18 mg of diclofenac acid particles, SLS and lactose monohydrate having the release profile set out in claim 1.
Is the pharmaceutical substance per se in substance disclosed in the complete specification (section 70(2)(a))?
The meaning of "in substance be disclosed" was considered by Bennett J in Pfizer:[28]
"There is, in my view, much to be said for the proposition that 'in substance disclosure' imports a 'real and reasonably clear disclosure'. If there is a difference, to my mind the requirement for 'in substance' disclosure is a lesser requirement than for a 'real and reasonably clear disclosure' or description. Section 70(2)(a) does not require express disclosure. If it did, there would be no need for the words 'in substance'. It seems to me that the additional words cannot import a higher test than 'real and reasonably clear disclosure'."
[28] at [75].
SLS and lactose are mentioned as a suitable material to use in the grinding matrix,[29] and are also mentioned as preferred materials.[30] There are no examples of the use of SLS and lactose with diclofenac. While this combination is only listed as part of a long list of options, I am satisfied that it can be regarded as an in substance disclosure of the pharmaceutical substance.
[29] Specification at page 6.
[30] Specification at page 7.
Do the goods Zorvolex contain or consist of the pharmaceutical substance (section 70(3))?
The ARTG entry states that Zorvolex contains diclofenac as the active ingredient. The article "Advances in NSAID Development: Evolution of Diclofenac Products Using Pharmaceutical Technology"[31] refers to Zorvolex as approved in the USA. The article suggests that the drug particles are 200-800 nm in diameter.[32] In the intention to refuse, the Senior Examiner accepted that the goods Zorvolex have a median particle size that satisfies the requirement in the claims of the patent. I agree with that conclusion.
[31] Drugs (2015) 75:859-877.
[32] at page 871.
The intention to refuse drew attention to the dissolution profile aspect of the pharmaceutical substance:
"However, in relation to the dissolution profile, which is clearly an essential feature of the claims, the response of 15 February 2018 merely states: 'We are instructed that the 080 Diclofenac Acid Mixture is contained or comprised in ZORVOLEX.' Reg 6.8(2) requires that an application for an extension of term must be accompanied by information showing that goods containing, or consisting of, the substance are currently included in the ARTG. A mere assertion by the patentee is not sufficient to satisfy the requirements of s 70(3)."
The question that I must answer is whether I can be satisfied on the balance of probabilities that the goods Zorvolex, when tested in vitro by USP Apparatus I (Basket) method of U.S. Pharmacopoeia at 100 rpm at 37 degree C in 900 ml of 0.05% sodium lauryl sulfate in citric acid solution buffered to pH 5.75, would have a dissolution rate of diclofenac acid such that at least 91%, by weight, would be released by 45 minutes?
The patentee's final response does not address this point, despite the opportunity provided. In the end, the patentee's case relies on the hearsay statement, which was not provided in declaratory form, that "We are instructed that the 080 Diclofenac Acid Mixture is contained or comprised in ZORVOLEX." I interpret this statement as meaning that the patent attorney prosecuting the extension of term application has been instructed by the patentee that the goods Zorvolex contain a unit dose of submicron diclofenac acid mixture, SLS and lactose monohydrate having the release profile defined in claim 1 or claim 6. I infer that the patent attorney has not personally inspected any evidence that shows that Zorvolex has the requisite dissolution profile. Is this sufficient to satisfy me on the balance of probabilities?
It is well established that the balance of probabilities means simply "more probable than not".[33] However, this requires a tribunal, such as the Commissioner in this matter, to feel an actual persuasion of the relevant facts:
"when the law requires the proof of any fact, the tribunal must feel an actual persuasion of its occurrence or existence before it can be found. It cannot be found as a result of a mere mechanical comparison of probabilities independently of any belief in its reality."[34]
[33] Miller v Minister for Pensions [1947] 2 All ER 372
[34] Briginshaw v Briginshaw (1938) 60 CLR 336 at 361.
The patentee has, for whatever reason, withheld the information it has as to the dissolution rate of the goods Zorvolex. In this case the patentee can only succeed by a mechanical consideration of the probabilities. I do not feel an actual persuasion that the goods Zorvolex would have the requisite dissolution rate of diclofenac acid. I am not satisfied on the balance of probabilities that section 70(3) is satisfied.
Conclusion
Pursuant to section 74(3), the Commissioner must refuse to accept an application for extension of term if she is not satisfied that the requirements of section 70 and 71 have been met:
"(3) The Commissioner must refuse to accept the application if the Commissioner is not satisfied, on the balance of probabilities, that the requirements of sections 70 and 71 are satisfied in relation to the application."
I am not satisfied that sections 70 and 71 are satisfied. I must refuse the application for extension of term.
Pursuant to section 74(4)(a) I must notify the applicant in writing of the reasons for the refusal. This decision constitutes notification of those reasons. A notice of refusal will be published in the Official Journal.
Dr S.D. Barker
Deputy Commissioner of Patents
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