iCeutica Pty Ltd
[2018] APO 77
•30 October 2018
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
iCeutica Pty Ltd [2018] APO 77
Patent Number: 2013273795
Title:Method for the Preparation of Biologically Active Compounds in Nanoparticle Form
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 – nanoparticles of diclofenac – pharmaceutical substance per se identified – contained in the goods Zorvolex – nanoparticles of fenofibrate contained in the goods Lipidil – Lipidil is an earlier first inclusion in the ARTG – application not made within 6 months of the date of first inclusion of Lipidil – application for extension of term refused
Representation: Patent attorney for the applicant: Wrays
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent Number: 2013273795
Title:Method for the Preparation of Biologically Active Compounds in Nanoparticle Form
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 2013273795 in the name of iCeutica Pty Ltd was granted on 8 September 2016. On 26 April 2017 the patentee filed an application for an extension of term of the patent based on the goods Zorvolex diclofenac. 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 for the preparation of biologically active compounds in nanoparticulate form. The invention also relates to biologically active compounds in nanoparticulate form produced by said methods, to compositions comprising such compounds, to medicaments produced using said biologically active compounds in nanoparticulate form and/or compositions, and to methods of treatment of an animal, including man, using a therapeutically effective amount of said biologically active compounds administered by way of said medicaments."[1]
[1] Specification at page 1.
In general terms, the patent relates to a pharmaceutical composition of diclofenac in which the diclofenac is in the form of small particles. The composition is formed by dry milling an active compound (which can be diclofenac), a surface stabiliser (which can be sodium lauryl sulfate – abbreviated to SLS) and a grinding compound (which can be lactose).
The specification relates to a method of producing nanoparticles of a wide range of active substances. A nanoparticle is a very small particle. The specification indicates that nanoparticles have an average size of less than 1000 nanometres.[2] A nanometre (nm) is 10-9 metre. The specification asserts generally that nanoparticles 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."[3]
"Many drugs are amenable to the methods of the invention, including but not limited to diclofenac, olanzapine, sildenafil, raloxifene, and others."[4]
"biologically active compounds that are poorly water soluble at physiological pH will particularly benefit from being prepared in nanoparticulate form"[5]
"In addition, some biologically active compounds may have the benefit of absorption through the skin if presented in nanoparticle formulation. Such biologically active compounds include, but are not limited to, Voltaren (diclofenac)"[6]
[2] Specification at page 11.
[3] Specification at page 1.
[4] Specification at page 11.
[5] Specification at page 28.
[6] Specification at page 29-30.
The specification generically discusses forming nanoparticle by dry milling a biologically active compound with a surface stabiliser and a millable grinding compound:
"In another aspect of the invention, provided herein is a nanoparticle composition comprising nanoparticles of a biologically active compound, wherein the nanoparticle composition is formed by the process of dry milling a biologically active compound, a surface stabiliser and a millable grinding compound in a mill for a sufficient time period to produce a solid dispersion comprising nanoparticles of the biologically active compound dispersed in at least partially milled grinding compound."[7]
[7] Specification at page 21.
The specification exemplifies grinding of diclofenac acid with sodium chloride.[8] The specification reports that nanoparticles are formed. The sodium chloride is removed by washing. The properties of the nanoparticles are not reported, and no compositions of the nanoparticles with other components are exemplified.
[8] Specification at page 68.
The examples focus on raloxifene, and show that nanoparticles of raloxifene have improved pharmacokinetics:
"Administration of the particulate raloxifene HCl resulted in an approximate 59% increase in maximum plasma concentration (Cmax) and 56% increase in area under the concentration vs. time curve (AUC0-t) compared with those following administration of the commercial API … In addition, the median time to maximum concentration (Tmax) was shorter (1.00 vs. 1.50 hours, respectively) following the administration of the particulate raloxifene HCl compared with that following administration of the commercial API."[9]
[9] Specification at page 84.
This leads to the conclusion that
"the formulations of the present invention have the potential to influence the plasma pharmacokinetics of raloxifene in a manner which will result in higher plasma concentrations being achieved both initially and throughout the treatment period."[10]
[10] Specification at page 84.
The invention, in so far as it is claimed, is defined as a nanoparticle composition. I will return to the exact wording of the claims later in this decision.
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),[11] Bennett J said that the definition of pharmaceutical substance focused "on the ingredient for therapeutic use that involves the relevant type of interaction".
[11] [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).[12] 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[13](Boehringer). The Full Court said that the pharmaceutical substance must be "included amongst the things claimed".[14] I will return to these matters later in this decision.
[12] [2005] FCA 137, 64 IPR 547.
[13] [2001] FCA 647, 52 IPR 529.
[14] 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:[15]
"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."
[15] 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 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."[16]
[16] G.D.Searle LLC [2008] APO 31, 80 IPR 210 (Searle) 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 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 objection under section 70(3) also noted that as a consequence of that objection it was likely that there would also be an objection under section 71. The intention to refuse summarised the outstanding issues (including confirming that an objection under section 71 applied) 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.795 diclofenac acid mixture (i.e. a composition comprising a surface stabiliser and submicron diclofenac acid dispersed in a millable grinding composition – lactose).
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
·the application for extension of time was not made within 6 months of the first inclusion in the ARTG due to the goods Lipidil.
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 may reflect the responses provided by the patentee at each stage. I do not consider this to represent a denial of natural justice.
CONSIDERATION
This matter can be decided on the basis of whether Zorvolex is the first inclusion in the ARTG of relevant goods. For reasons that will be explained, Zorvolex is not the first inclusion, so the application for extension of time does not comply with the timing requirement of section 71(2)(b). It follows that it is not necessary to consider whether the application would comply with subsections 70(2) and 70(3). However, for completeness I will briefly consider these matters.
Is a pharmaceutical substance per se in substance within the scope of the claims (section 70(2)(b))?
As already noted, a pharmaceutical substance is "the ingredient for therapeutic use that involves the relevant type of interaction".[17] 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.[18] 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."[19]
[17] Lundbeck at [238].
[18] 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
[19] 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 chemical or physico-chemical interaction with the human physiological system.[20]
[20] 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[21] I said that a specific polymorph of lenalidomide was a pharmaceutical substance. On appeal,[22] 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.
[21] [2011] APO 37, 93 IPR 309 at [17].
[22] 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".[23] 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. [24] A method of treatment of a disorder by administering a pharmaceutical substance is not a claim to a pharmaceutical substance per se. [25] The same conclusion applies when the claim is directed to a pharmaceutical composition when used for treating a particular disorder.[26]
[23] Boehringer at [42].
[24] Spirit Pharmaceuticals Pty Ltd v Mundipharma Pty Ltd [2013] FCA 658, 102 IPR 55 (Spirit) at [42].
[25] Prejay Holdings Ltd v Commissioner of Patents [2003] FCAFC 77, 57 IPR 424 at [24].
[26] 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[27] 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."
[27] [2006] FCA 305, 69 IPR 1 at [100].
Similarly in Zentaris Aktiengesellschaft[28] 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."
[28] [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."[29]
[29] 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 nanoparticle composition comprising nanoparticles of a biologically active compound, wherein the nanoparticle composition is formed by the process of dry milling a biologically active compound, a surface stabiliser and a millable grinding compound in a mill for a sufficient time period to produce a solid dispersion comprising nanoparticles of the biologically active compound dispersed in at least partially milled grinding compound."
The claim is directed to a composition containing nanoparticles of an active compound. The active compound is not specified, but what is specified is that the nanoparticles are formed by dry milling with a surface stabiliser and a millable grinding compound. To the extent that this claim incorporates process elements – the nanoparticles are produced by dry milling – there could be a difficulty as to whether this is a pharmaceutical substance per se. However, it is not necessary to consider this point in detail because there is also claim 16 which reads:
"A nanoparticle composition comprising a surface stabiliser and nanoparticles of a solid biologically active compound selected from the group consisting of: diclofenac, olanzapine, raloxifene and fenofibrate; dispersed in a millable grinding compound selected from the group consisting of: NaCl and lactose."
The composition of this claim is characterised by the components of the composition: a surface stabiliser, nanoparticles of an active compound and a grinding compound that is either sodium chloride or lactose. This would appear to be the more relevant claim. A composition where the nanoparticles are diclofenac is the subject of the appended claim 27, and with a view to the goods asserted by the patentee, it is the relevant composition.
In the present case the chemical or physico-chemical interaction is caused by the diclofenac. The nanoparticle form of the diclofenac contributes to the activity of the composition. A surface stabiliser and a millable grinding compound do not clearly contribute to the interaction with the human physiological system, but they are reasonably considered part of the mixture that is the pharmaceutical substance.
I am satisfied that the mixture of a surface stabiliser, nanoparticles of diclofenac and a millable grinding compound of claim 16 (and also claim 27) is a pharmaceutical substance per se.
Is the pharmaceutical substance per se in substance disclosed (section 70(2)(a))?
The meaning of "in substance be disclosed" was considered by Bennett J in Pfizer:[30]
"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'."
[30] at [75].
The substance diclofenac in nanoparticle form is specifically mentioned in the specification. The specification generally discusses nanoparticle compositions formed by dry milling a biologically active compound, a surface stabiliser and a millable grinding compound.[31] I am satisfied this can be regarded as in substance a disclosure of the pharmaceutical substance.
[31] Specification at page 21.
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"[32] refers to Zorvolex as approved in the USA. The article suggests that the drug particles are 200-800 nm in diameter.[33] In the intention to refuse, the Senior Examiner accepted that the goods Zorvolex contain the pharmaceutical substance. I agree with that conclusion.
[32] Drugs (2015) 75:859-877.
[33] at page 871.
Is Zorvolex the first goods that contain or consist of a pharmaceutical substance (section 71)?
Based on what I said in Searle, it is necessary to consider whether Zorvolex is the earliest first inclusion in the ARTG. Claim 16 is directed to compositions that can contain an active compound selected from diclofenac, olanzapine, raloxifene or fenofibrate. The other components are a surface stabiliser and either sodium chloride or lactose. The intention to refuse drew attention to the goods Lipidil, which contains fenofibrate in nanoparticle form as the active compound. Lipidil also contains additives including sodium lauryl sulfate and lactose monohydrate. It is clear to me that the goods Lipidil contain a pharmaceutical substance that is a mixture of a surface stabiliser, nanoparticles of fenofibrate and a millable grinding compound. Lipidil is a composition that is essentially equivalent to Zorvolex, except having fenofibrate nanoparticles in place of diclofenac nanoparticles. The pharmaceutical substance contained in Lipidil is in substance disclosed and in substance falls within the claims of the patent.
The patentee's submissions addressed this issue by indicating that it could make the extension of term application in relation to a different claim:
"In any event, this is answered by making the Application in respect of a claim that does not include fenofibrate, such as claim 27, which is set out below:
'27. The nanoparticle composition according to any one of claims 16 to 26 wherein the biologically active compound is diclofenac.'
Accordingly, the Lipidil fenofibrate identified in the 795 Notice is not a relevant product included on the ARTG containing the pharmaceutical substance per se for the purposes of s70 in respect of claim 27, and the Application was filed within the relevant time limit – as set out in our response, dated 5 October 2017, to the First Notice."
If this is correct, then a patentee can register numerous goods in the ARTG, and obtain an extension of term based on the last registration. This is not consistent with the nature of the extension of term scheme:
"An extension of up to five years will be available for a standard patent relating to a pharmaceutical substance that is the subject of first inclusion on the Australian Register of Therapeutic Goods."[34]
[34] Second reading speech for the Intellectual Property Laws Amendment Bill 1997: Commonwealth, Parliamentary Debates, House of Representatives, 26 November 1997, 11275 (Warren Truss).
A consideration of the words of the Act does not support the patentee's submission. The Act does not allow a patentee to select a claim in the way suggested by the patentee. The approved form for an application does not include a facility to select a claim. Section 70(2) makes it clear that there can be more than one pharmaceutical substance in relation to any patent. Section 71 states that the extension is based on the first inclusion of goods that contain any of the pharmaceutical substances. Section 77 then confirms that the term of the extension is based on the "earliest first regulatory approval date … in relation to any of the pharmaceutical substances".
I consider that the goods Lipidil are an earlier first inclusion in the ARTG of goods that contain a pharmaceutical substance that is disclosed in the specification and in substance falls within the scope of the claims of the specification. Lipidil was first included in the ARTG on 16 May 2006. This is a period of ten years prior to the inclusion of Zorvolex. It follows that the application has not been made within 6 months of the date of first inclusion of Lipidil, and the application for extension of term does not comply with section 71(2).
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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