Pharma Mar S.A
[2020] APO 8
•31 January 2020
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Pharma Mar S.A. [2020] APO 8
Patent:754073
Title:Pharmaceutical formulation of a didemnin compound
Patentee: Pharma Mar S.A.
Delegate: Dr S. J. Smith
Decision Date: 31 January 2020
Hearing Date: 4 November 2019, in Sydney
Catchwords: PATENTS – application for extension of term of patent – ARTG registered goods a combination of plitidepsin preparation and reconstitution solvent – combination in substance falls within the scope of the claims – combination is not a pharmaceutical substance per se – extension refused
Representation: Counsel for the patentee: Ben Mee
Solicitor for the patentee: Tim Francis of Wrays
Patent attorneys for the patentee: Steven Gurney of Marks & Clerk and Craig Humphris of Wrays
IP AUSTRALIA
AUSTRALIAN PATENT OFFICE
Patent:754073
Title:Pharmaceutical formulation of a didemnin compound
Patentee: Pharma Mar S.A.
Date of Decision: 31 January 2020
DECISION
I refuse the application for an extension of term.
For the purposes of section 74(4) this decision constitutes notification in writing of the reasons for refusal of the application.
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 adversely affected by this decision may make an application to the Administrative Appeals Tribunal for review of this decision.
REASONS FOR DECISION
Background
This matter concerns a request for an extension of the term of patent number 754073 in the name of Pharma Mar S.A. (the patentee). The date of the patent is 18 February 1999 and accordingly the normal term of the patent expired on 18 February 2019. An application for extension of the term of the patent under section 70 of the Patents Act 1990 (the Act) was filed on 5 February 2019.
The basis for the request for an extension of term is the inclusion in the Australian Register of Therapeutic Goods (ARTG) of APLIDIN, which has an ARTG start date of 12 December 2018. It follows from the formula set out in section 77 of the Act that if an extension of term is granted the patent would expire on 18 February 2024. Pursuant to section 79, when, as in this case, the term of the patent expires prior to the grant of an extension of term, the patentee has, if the extension is granted, the same rights to start proceedings in respect of an act done between the expiration and the grant of the extension as if the extension had been granted when that act was done.
A delegate of the Commissioner issued three deficiency notices explaining that he considered that the application did not meet the requirements of the Act, followed by a final deficiency notice indicating that the matter would be passed to a hearing officer, and providing the patentee with an opportunity to request to be heard. The patentee requested to be heard on 29 July 2019 and the hearing was held in Sydney on 4 November 2019.
Specification
The specification relates to a pharmaceutical formulation of a didemnin compound. Didemnins are cyclic depsipeptide compounds.
The specification indicates that cytotoxic and antiviral activity of didemnin compounds is known, referring to US 5,294,603.[1] The problem addressed by the specification is then identified:
“In practice, there are some difficulties in preparing pharmaceutical compositions of didemnin compounds suited for administration to patients, and there is especially a need for a stable parent[er]al pharmaceutical dosage form. More specifically, didemnin compounds such as dehydrodidemnin B, also known as aplidine, require mixing with bulking agents, such as mannitol, for optimal, stable preparation of pharmaceutical dosage forms, in particular lyophilised preparations.
Certain bulking agents for this purpose, such as mannitol, require water for solubilisation, while drugs such as aplidine are poorly soluble in water. However, drug delivery to patients requires resuspending of the lyophilised materials before use.”[2]
[1] Page 1.
[2] Pages 1-2.
The specification goes on to identify the invention:
“The present invention solves the problem by providing a pharmaceutical composition of a didemnin compound, comprising firstly a lyophilised didemnin preparation including water-soluble materials and secondly a reconstitution solution of mixed solvents. The mixed solvents comprise an aqueous solvent, with the water serving to dissolve the water soluble material and the other solvent serving to dissolve the didemnin compound.
According to another embodiment of this invention there is provided a method of preparing a pharmaceutical composition of a didemnin compound, which comprises freeze drying a didemnin/water-soluble additive/alkanol/water mix to provide a lyophilised first component, and separately providing an alkanol/water mix as reconstitution solvent.”[3]
[3] Page 2.
It is explained that the lyophilised didemnin preparation is preferably prepared by freeze drying a mixture of didemnin, alkanol (particularly t-butanol) and water, and a bulking agent such as mannitol can also be included. The reconstitution solution is said to preferably comprise a mix of surfactant (especially a nonionic surfactant), alkanol (especially ethanol) and water.[4]
[4] Pages 3-4.
The example describes freeze-drying of a 1.0 mg/mL solution of aplidine in 40% v/v t-butanol in water for injection containing 25 mg/mL mannitol, and it is indicated that 1.0 mg aplidine and 25 mg mannitol per vial is the optimal formulation in terms of solubility, length of freeze-drying cycle and dosage requirements. A solution comprising 15/15/70% (v/v/v) Cremophor EL/absolute ethanol/water for injection is identified as the optimal reconstitution solution.[5] It is then stated:
“Thus, the preferred aplidine product of this invention is a dual-package containing:
an injection vial containing aplidine 1 mg/vial lyophilized product, and an injection vial containing 2 ml of 15/15/70% (v/v/v) Cremophor EL/absolute ethanol/water as reconstruction [sic] solution.”[6]
[5] Page 4.
[6] Page 5.
The specification ends with 14 claims and the entire claim set is reproduced at Annex A. Some claims of particular relevance are reproduced below:
1. A pharmaceutical composition of a didemnin compound, comprising firstly a lyophilised didemnin preparation including water-soluble material and secondly a reconstitution solution of mixed solvents.
2. A didemnin composition according to claims 1, intended for reconstitution for administration to patients as an antitumor treatment.
8. A didemnin composition according to any one of the preceding claims, which comprises a vial of lyophilised didemnin preparation including a water-soluble bulking agent, and a separate vial of a premix of non-ionic surfactant/ethanol/water.
12. A pharmaceutical composition as defined in claim 1 and substantially as herein described with references to the Examples.
The statutory framework
Part 3 of Chapter 6 of the Act provides a statutory framework for the extension of the term of standard patents relating to pharmaceutical substances. Section 70 relevantly provides:
“(1)The patentee of a standard patent may apply to the Commissioner for an extension of the term of the patent if the requirements set out in subsections (2), (3) and (4) are satisfied.
(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;
(b) one or more pharmaceutical substances when produced by a process that involves the use of recombinant DNA technology, 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.
(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.”
The expression “pharmaceutical substance” is defined in Schedule 1 of the Act, and is:
“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 vitro testing.”
The expression “therapeutic use” is also defined in Schedule 1. It means:
“use for the purpose of:
(a) preventing, diagnosing, curing or alleviating a disease, ailment, defect or injury in persons; or
(b) influencing, inhibiting or modifying a physiological process in person; or
(c) testing the susceptibility of persons to a disease or ailment.”
If an extension of term is granted section 77 provides for the term of the extension:
“(1)If the Commissioner grants an extension of the term of a standard patent, the term of the extension is equal to:
(a) the period beginning on the date of the patent and ending on the earliest first regulatory approval date (as defined by section 70) in relation to any of the pharmaceutical substances referred to in subsection 70(2);
reduced (but not below zero) by:
(b) 5 years.
Note: Section 65 sets out the date of a patent.
(2)However, the term of the extension cannot be longer than 5 years.”
The deficiency notices
Each of the deficiency notices indicated that the requirements of section 70(2)(a) were not satisfied. The delegate stated that plitidepsin (the didemnin contained in APLIDIN), which the patentee asserted as the relevant pharmaceutical substance, does not fall within the scope of the claims (that is, a didemnin is an integer of the claim, but does not in itself fall within the scope of the claimed monopoly) and therefore cannot ground an extension of term. He further stated that in his view the claims are directed to a kit or combination of separate parts, and, consistent with a previous decision of the Commissioner,[7] combinations of separate integers are not considered to be pharmaceutical substances per se.
[7] The Children’s Medical Center Corporation [2011] APO 80.
In response to a deficiency raised in relation to section 70(3) the patentee provided the Product Information for APLIDIN.
The patentee’s submissions
The patentee presented five alternative ways in which the pharmaceutical substance could be envisaged. They are:
a.plitidepsin
b.a mixture (or a compound) of: plitidepsin; Cremaphor EL (PEG-35 castor oil); ethanol; and water (in a reconstituted solution)
c.a mixture (or a compound) of: a first component comprising plitidepsin and a second component comprising Cremaphor EL, ethanol and water
d.a mixture (or a compound) of: a first component comprising plitidepsin and mannitol; and a second component comprising Cremaphor EL, ethanol and water (in a reconstituted solution)
e.a mixture (or a compound) of: a first component comprising plitidepsin and mannitol; and a second component comprising Cremaphor EL, ethanol and water
I have considered the relevant matters under section 70 with these alternatives in mind and reflected the patentee’s more specific submissions as they arise below. In the present case I have considered the nature of the goods listed on the ARTG first, in order to focus the consideration.
The goods listed on the ARTG
The Public Summary for the ARTG entry identifies the product as “APLIDIN plitidepsin 2 mg powder for solution for infusion; vial (2 mg powder) and ampoule (4 mL solution)” and the product type as “Composite Pack”. The Product Information for APLIDIN indicates that it “must be reconstituted and further diluted prior to administration” and states:
“Each vial contains 2 mg of plitidepsin.
After reconstitution, each mL of reconstituted solution contains: 0.5 mg of plitidepsin, 158 mg of PEG-35 castor oil, and ethanol 0.15 mL/mL.”The Product Information further indicates that the excipient in the powder (i.e. the plitidepsin for reconstitution) is mannitol, and the solvent comprises PEG-35 castor oil, ethanol and water for injection. The patentee submitted that the plitidepsin powder is lyophilised plitidepsin and I accept that submission.
It is clear from the foregoing that the two-part mixture of a vial of plitidepsin powder and reconstitution solvent ampoule is included on the ARTG. The Product Information indicates that the unopened vial and ampoule have a shelf life of 4 years when stored at 2-8°C (compared with the reconstituted solution which, depending on storage conditions, must be used within 24 hours or less). The patentee submitted that the reconstituted formulation is also listed on the ARTG, referring in particular to the reference in the Product Information to the route of administration being intravenous infusion – clearly the dry powder in a vial is not administered via intravenous infusion, and I note that there are multiple references in the Product Information to the properties of the reconstituted solution.
While there has been no consideration of a situation directly analogous to the present facts, the nature of goods registered on the ARTG has been considered on a number of previous occasions. In Celgene Corporation[8] the delegate considered the provisions of the Therapeutic Goods Act 1989 (TG Act) and the distinction therein between therapeutic goods and their indication (section 3 of the TG Act provides the following definition: “indications, in relation to therapeutic goods, means the specific therapeutic uses of the goods”), concluding that:
“… in identifying the goods that are included in the ARTG I should not import elements of the indications of the goods. The ‘goods’ for the purposes of the Patents Act is equivalent to the product that appears in the ARTG certificate, and does not extend to the indications.”[9]
[8] [2011] APO 37, 93 IPR 309.
[9] Ibid at [23].
He went on to identify the goods as the product the patentee has approval to supply.[10] This accords with the observation of Bennett J in H Lundbeck A/S v Alphapharm Pty Ltd:[11]
“The level of enquiry required by s 70(3) does not look to the therapeutic effect of the pharmaceutical substance. Rather, it is a simple comparison of the pharmaceutical substance with the ‘ingredients’ of the goods on the ARTG.”
[10] Ibid at [24].
[11] [2009] FCAFC 70, 81 IPR 228 at [239].
In Children’s Medical Center the delegate followed the approach taken in Celgene,[12] and similarly in The Regents of the University of California & Regeneron, Inc. the delegate rejected a submission that “the product-specific indications for a pharmaceutical substance registered in the ARTG, or similar information in other documents relevant to the registration process, identify goods included in the ARTG for the purposes of paragraph 70(3)(a).”[13] I note that the decisions in Celgene and Children’s Medical Center were affirmed by the AAT.[14]
[12] Children’s Medical Center at [15].
[13] [2016] APO 33 at [22].
[14] Celgene Corporation and Commissioner of Patents and Children’s Medical Center Corporation (Joined Party) [2013] AATA 55.
It is apparent that the product associated with the relevant ARTG registration is the two-part mixture of powder and reconstitution solvent. This is the product that is supplied. Reference to intravenous infusion (requiring use of the reconstituted mixture) in the Public Summary document is under the headings “Dosage Form” and “Route of Administration”. References to reconstitution are, as noted above, also present in the Product Information. Section 3 of the TG Act identifies “appropriate doses of the goods” and “the method of administration or use of the goods” as “directions for use, in relation to therapeutic goods”. Accordingly, there seems to be, analogous to the circumstances previously considered in relation to indications, a distinction between the therapeutic goods (the product listed on the ARTG) and their use. I consider the reasoning of the delegate in Celgene apposite to the present situation and persuasive.
It follows that I do not consider that the goods included in the ARTG extend beyond the (two-part) product associated with the ARTG registration to include the reconstituted solution – in my view preparation of this solution is part of the directions for use.
What in substance falls within the scope of the claims?
The key claims are reproduced above and claim 1, the broadest claim, defines a pharmaceutical composition comprising firstly a lyophilised didemnin preparation, and secondly a reconstitution solvent. While a “composition” is often understood as an admixture of components, in this case it seems clear, in particular having regard to appended claims 2 (specifying that the composition is intended for reconstitution) and 8 (defining two separate vials), that claim 1 encompasses a two-part mixture: first the lyophilised didemnin preparation, and second the reconstitution solution. The patentee agreed with this, but submitted that claim 1 includes the components “in separate vials, in mixture immediately prior to reconstitution, after reconstitution, or otherwise.”[15]
[15] Patentee’s written submissions at [12].
Given that section 70(3) requires that the conditions of section 70(2) must be satisfied in relation to a good included on the ARTG containing or consisting of the pharmaceutical substance, it is unnecessary to decide whether the claim includes mixtures immediately prior to or after reconstitution. The relevant goods listed on the ARTG is, as indicated above, in the form of a two-part mixture. Such a mixture does not contain or consist of the reconstituted composition.
The patentee submitted that the conditions created by sections 70(2) and 70(3) do not require focus on the state of any embodiment within a claim at a fixed point in time (that is, whether before or after reconstitution). However, section 70(3) focusses attention on a point defined by the goods listed on the ARTG, and while the goods may contain both the relevant pharmaceutical substance per se and other integers,[16] the form of the goods places a limitation on the nature of the pharmaceutical substance for the purpose of section 70(2)(a) to the extent that it must be contained therein.
[16] See, e.g., Lundbeck at [240]-[242].
The patentee submitted that “‘in substance’ falling within a claim means something less than actually falling within a claim” and that plitidepsin itself (per se) in substance falls within the scope of the claims.[17] In support of this proposition the patentee referred to Bennett J’s reference in Pfizer Inc v Commissioner of Patents,[18] when considering “in substance” disclosure, to AMP Inc v Commissioner of Patents,[19] a decision relating to the allowability of an amendment which would not be allowable if, as a result of the amendment, a claim of the specification would not in substance fall within the scope of the claims before the amendment. A longer portion of the passage quoted by Bennett J provides further context:
“…it is not necessary before an amendment is allowed to find that the amended claim would actually fall within the scope of one or all of the other claims. It need only fall in substance within that scope. Here, again, a good test is whether or not an alleged infringement, different though it may be in particulars, falls within the scope of the claims. It would be of little avail to an alleged infringer to say that his article did not infringe one claim if it infringed another even though he may not in the infringement have incorporated all the features of that other claim.”[20]
[17] Patentee’s written submissions at [25], [27].
[18] [2005] FCA 137, 64 IPR 547 at [76].
[19] (1974) 48 ALJR 278.
[20] Ibid at 282.
As I understand this passage and the discussion that follows, Jacobs J was referring to the consideration of essential and inessential integers of the claims as understood in the context of infringement. I discussed this understanding at the hearing, and while the patentee agreed that this was an example of what might “in substance” but not actually fall within the scope of the claims, the patentee submitted that the reconstitution solvent features are not inessential but that the latitude afforded by the “in substance” language is not so narrow. I understood the patentee’s submission to be that where additional elements of the claim could also fall within the concept of a pharmaceutical substance (such as formulation integers), the presence of those elements did not preclude an active agent being considered to in substance fall within the scope of the claim.[21] More specifically, the patentee submitted that in this case, where the patent application was filed in 1999 and allowed a drug product containing plitidepsin to come to market for the first time in 2018, with the formulation described in this patent, there is a reason to provide some latitude within the boundaries of normal statutory construction.
[21] Patentee’s written submissions at [24].
If the consequence of such latitude is to conclude that plitidepsin per se in substance falls within the scope of the claims I do not believe that this can be correct. The Full Court has said that “in the context of s 70(2)(a), we think that falling with the scope of a claim in a patent specification means included among the things claimed” and where a substance together with a container was defined in a claim, the substance was “not a thing claimed in the patent sense.”[22] I understand the “patent sense” to be the claim anticipation and infringement sense, which aligns with previous decisions of the Court and the Commissioner.[23] It follows that I am not persuaded that plitidepsin per se in substance falls within the scope of the claims.
[22] Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647, 52 IPR 529 at [42].
[23] See, e.g. Spirit Pharmaceuticals Pty Ltd v Mundipharma Pty Ltd [2013] FCA 658, 102 IPR 55; Wyeth LLC [2019] APO 1, 144 IPR 146, iCeutica Pty Ltd [2018] APO 76.
The patentee also advanced an argument that there need not be exact correspondence between the pharmaceutical substance per se relied on and the subject matter of the claim, referring to Bennett J’s statement in Lundbeck:[24]
“In my view, s 70 recognises that the pharmaceutical substance per se may not equate with the subject matter of the claim of the patent in terms. For example, a chemical compound claimed in a patent may not have the necessary therapeutic use or enable the required physico-chemical interaction unless formulated.”
[24] Lundbeck at [242].
However, viewed in context I do not think that Bennett J can reasonably be understood to be suggesting that the pharmaceutical substance per se need not fall within the scope of the claimed monopoly. Her Honour’s reference is to a situation in which a claim defines a chemical compound, but the compound must be formulated to exhibit the required physico-chemical interaction. This is consistent with the fact situation in Lundbeck, and I do not think it is a fair corollary of this to say, for example, that if a claim defines a tablet by reference to both an active and excipients, the active alone is the relevant pharmaceutical substance per se.[25]
[25] In this regard, I note that in both Pharmacia Italia SpA v Mayne Pharma Pty Ltd [2006] FCA 305, 69 IPR 1 and Spirit the pharmaceutical substance per se was considered to include the excipients required by the relevant claims.
Such a view is reinforced by consideration of the provision of section 78 that a person exploiting, during the extended term of a patent, a pharmaceutical substance per se that in substance falls within the scope of the claim or claims for a purpose other than therapeutic use does not infringe the rights of the patentee. The effect of this was described in the Explanatory Memorandum as: “the exclusive rights of the patentee are limited to exploiting the invention as defined in claims to a pharmaceutical substance per se … for therapeutic use.”[26] The patentee submitted, and I agree, that section 78 simply limits what can be considered an infringement, but does not positively create an infringement. However, it is consistent with the operation of the extension of term provisions as a cohesive whole that the patentee has exclusive rights to exploit the pharmaceutical substance per se that in substance falls within the scope of the claim or claims prior to the end of the normal term of the patent, and that such rights are limited during the term of the extension. In my view, if the pharmaceutical substance were considered to be plitidepsin per se, the facts here with respect to the “in substance” consideration would be, notwithstanding the nature of the additional integers in the claim, analogous to those considered in Boehringer, where the Full Court said:
“It is apparent from s 78(i)(b)(ii) that only exploitation of the pharmaceutical substance itself by a third party is an infringement during the extended term. No other embodiment of the invention is protected. In the present case, however, exploitation of the substance itself is not an infringement of any claim which might be extended.”[27]
[26] Explanatory Memorandum, Intellectual Property Laws Amendment Bill 1997 at page 19.
[27] Boehringer at [41].
I consider that what relevantly falls in substance within the claims is a two-part combination of first, a didemnin preparation (comprising a lyophilised didemnin and water soluble material, such as mannitol) and second, a reconstitution solution as defined (corresponding to the fifth alternative pharmaceutical substance presented by the patentee). While it does not fall for determination in the context of the present application, I note that a combination of separate known components is prima facie in the nature of a kit and generally not considered patentable subject matter.
It is apparent, having regard to the ARTG Public Summary and Product Information provided by the patentee, that the goods listed on the ARTG reflect the claimed mixture of separate parts and I am satisfied that that mixture is in substance disclosed in the specification as filed and in substance falls within the scope of the claims. All that remains is to determine whether this is a pharmaceutical substance per se – that is, whether the requirements of section 70(2)(a) are satisfied.
Are the requirements of section 70(2)(a) satisfied?
The meaning of the expression “pharmaceutical substance per se” in section 70(2)(a) has been considered by the Federal Court on a number of occasions. The Full Court in Boehringer[28] approved the trial judge’s conclusions in relation to the scope of section 70(2)(a), including the following statement:
“Broadly speaking, a claim in relation to a pharmaceutical substance can be made in three ways
(i) a new and inventive product alone;
(ii) an old or known product prepared by a new and inventive process;
(iii) an old or known product that is used in a new and inventive mode of treatment.What is clear in s 70 is that only the first type of claim to a pharmaceutical product is to be subject to extension rights.
……the relevance of the expression ‘per se’ becomes clear. Section 70(2)(a) is only to make extension rights available when the claim is for a pharmaceutical substance as such, as opposed to a substance forming part of a method or process.”[28] Ibid at [17].
In response to the appellant’s submissions in Boehringer, including that the pharmaceutical substance must simply be a claimed feature of the invention, even if as one element in a combination of elements, the Full Court stated:
“There are serious difficulties about the appellant’s argument. One is that it effectively reads out of s 70(2)(a) the words ‘per se’. On the appellant’s argument, it is enough that the complete specification disclose one or more pharmaceutical substances, whether as the sole element in an invention or in combination with other elements. If that had been the legislative intention, the paragraph could have read: ‘one or more pharmaceutical substances must in substance be disclosed’. There would have been no need for ‘per se’.”[29]
[29] Ibid at [38].
The delegate in Children’s Medical Center considered a combination of two drugs presented as separate dosage forms and concluded that such a combination was not a pharmaceutical substance per se:
“the definition of ‘pharmaceutical substance’ is qualified in Section 70(2) by the words ‘per se’. The meaning of ‘pharmaceutical substance per se’ has been considered by the Federal Court in a number of decisions (H. Lundbeck A/S v Alphapharm Pty Ltd [2009] FCAFC 70, Boehringer Ingelheim International GmbH v Commissioner of Patents [2001] FCA 647, Prejay Holdings Ltd v Commissioner of Patents [2003] FCAFC 77 and Pharmacia Italia SpA v Mayne Pharma Pty Ltd [2006] FCA 305).
It is clear from these decisions that the term ‘pharmaceutical substance per se’ is intended to be a pharmaceutical that is presented as a single entity, and not in the form of a kit or as separate dosage forms. As noted in Boehringer, the per se qualification was introduced by the 1998 amendments to the Patents Act, in order to limit the operation of this section to patents disclosing and claiming a pharmaceutical substance ‘by or in itself, intrinsically, essentially’ or ‘taken alone; essentially; without reference to anything else’ (Boehringer at 34).”[30]
[30] Children’s Medical Center at [23]-[24].
The patentee submitted that this must be understood in the context of its facts: a claim to a combination of two known active agents, rather than a new formulation of an active agent. In this regard, the patentee submitted that the problematic nature of the kit in Children’s Medical Center was affected by the nature of the claims – what was claimed was a kit of two separate, known, dosage forms to be administered separately, in contrast with the present claims directed to a new and inventive product which is, as a practical matter, stored in two parts, but is reconstituted prior to administration. The patentee also noted that what was determinative of the extension application in Children’s Medical Center was section 70(3): the goods relied on by the patentee contained only one of the active agents. If Children’s Medical Center is properly understood to support a proposition that a medicine that requires reconstitution of one component in another prior to administration cannot support a patent term extension, the patentee submitted that that is wrong in law.
The patentee submitted that Boehringer and Prejay Holdings Ltd v Commissioner of Patents[31] establish that the function of “per se” is to distinguish claims that are to substances that form part of a process, are made by a particular process, or involve a mode of delivery, as distinct from claims that are to a new substances, including mixtures and compounds. In both cases, the integers that fell outside what could be considered to be a pharmaceutical substance were not mere formulation integers. In Boehringer the additional integer could be viewed as a container or a mode of administration (noting that later decisions have referred to Boehringer as a case that involved elements of process[32]) and in Prejay the claims were to methods of treatment. The patentee submitted that there is no aspect of process in the presently relied on claims. I agree. However, in both Boehringer and Prejay reference is made separately to claims to a combination of a pharmaceutical substance with other products, and claims to a pharmaceutical substance in a method or process, neither of which is considered a claim to a pharmaceutical substance per se.[33]
[31] [2003] FCAFC 77, 57 IPR 424.
[32] See, e.g. Spirit at [38], Pharmacia at [92], [96]. I note that the claim set considered in Boehringer included both claims to the substance in a container and method of treatment claims.
[33] Prejay at [22], Boehringer at [38]-[40].
Here, what is claimed is not an integrated dosage form, but a plitidepsin preparation together with a separate solvent mixture which the specification indicates has been optimised for reconstitution. To adopt the words of the Full Court in Boehringer what is defined is, prima facie, a plitidepsin preparation “in combination with other elements”.
The patentee submitted that a patentee should not be disadvantaged because of the nature of the problem they seek to solve (for example, sodium content in a tablet/caplet core was reduced in the patent considered in Wyeth,[34] where an extension of term was granted, as opposed to stability/solubility addressed in this case):
“It would be entirely perverse if a claim to a new formulation of a known stable and soluble drug that does not require reconstitution prior to administration (eg Pharmacia, Spirit, Wyeth) could form the basis of a term extension, but not a claim to a new formulation of a drug that has stability and/or solubility issues and which formulation overcomes difficulties arising from those issues. In circumstances where the extension of term regime addresses the lengthy delays that can occur in developing and bringing a new drug or formulation to market, this would be a surprising outcome that runs contrary to the clear legislative purpose. Patents for novel and inventive formulations overcoming known formulation difficulties affecting important therapeutic substances would not enjoy the same ‘effective patent life’ as patents for other formulations like those in Pharmacia, Spirit and Wyeth.”[35]
[34] [2019] APO 1, 144 IPR 146.
[35] Patentee’s written submissions at [37].
I am not unsympathetic to this submission. However, the consideration with respect to section 70(2) is not one of the merits of the invention, or what difficulties the patentee has overcome in arriving at a formulation, but simply whether a pharmaceutical substance per se in substance falls within the scope of the claims. In this case, whether a combination of, separately, a plitidepsin preparation and a reconstitution solvent, is a pharmaceutical substance per se.
The patentee submitted that “[t]here is no basis in law to exclude an unreconstituted composition from the term extension regime”[36] and that to do so would be “entirely to elevate form over substance.”[37]
[36] Patentee’s written submissions at [50].
[37] Patentee’s written submissions at [8].
I am mindful of the sentiment of Deputy Commissioner Spann in N.V. Organon[38] echoed recently by Deputy Commissioner Barker in iCeutica: [39]
“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.’”
[38] [2009] APO 8, [2009] AIPC 92-345 at [21].
[39] [2018] APO 76 at [26].
Deputy Commissioner Spann went on to say:
“It may be that, beyond the clear cases, it is difficult to determine whether a particular feature of a product is correctly considered part of a ‘substance’ rather than a separate physical integer. However this difficulty can be addressed, as in this case, by asking whether the characteristics of what is claimed more predominantly lies with it being a substance rather than a substance in combination with a separate integer.”[40]
[40] Organon at [23].
This has an affinity with the words of Weinberg J in Pharmacia:
“The matter must largely be one of impression, and degree. Reasonable minds may differ as to whether the legitimate boundaries of a ‘pharmaceutical substance per se’ have been crossed.”[41]
[41] [2006] FCA 305, 69 IPR 1 at [98].
While the language of section 70(2) is such that new formulations of known actives in the form of tablets or solutions have been considered pharmaceutical substances per se and provided a basis for a patent term extension,[42] this cannot be determinative of the present matter. In the decided cases there are, on the one hand, substances together with other integers which have been found not to be pharmaceutical substances per se,[43] and on the other, integrated formulations of multiple actives or actives and excipients that have been found to be pharmaceutical substances per se.[44] In this case, what is relevantly claimed, a two-part combination, is, to my mind, more in the nature of a substance in combination with a separate (excipient) integer, than a “substance” as such or taken alone – I am not persuaded that a pharmaceutical substance per se can be understood to encompass a “deconstructed” formulation intended for later reconstitution. While I appreciate that there is a subtlety in the distinction between a two-part mixture (or kit) for reconstitution and the reconstituted mixture, I do not think that either the words of the Act or the decided cases provide support for extending the term of a patent on the basis of a claim to a kit of parts. What is relevantly defined in the claim and included on the ARTG is the antecedent to the pharmaceutical substance which is to be applied to the human physiological system but is not itself a pharmaceutical substance per se within the meaning of section 70(2)(a).[45]
[42] See, e.g., Spirit, Pharmacia, Wyeth, iCeutica.
[43] Boehringer, Children’s Medical Center.
[44] See, e.g. The Regents of the University of California & Regeneron, Inc. [2016] APO 33, Southern Cross Pharma Ltd v Euro-Celtique S.A. [2016] APO 61, Pharmacia, Spirit, Organon.
[45] To the extent that the claims may encompass a reconstituted solution of plitidepsin together with the solvent, that substance is not contained in the goods listed on the ARTG, and therefore the requirements of section 70(3) would not be satisfied with respect to that substance.
Conclusion
Pursuant to section 74(3), the Commissioner must refuse to accept an application for extension of term if the requirements of section 70 are not satisfied. I have found that the present application does not satisfy those requirements and so I must refuse the application for an extension of term.
Dr S. J. Smith
Delegate of the Commissioner of PatentsAnnex A
1. A pharmaceutical composition of a didemnin compound, comprising firstly a lyophilised didemnin preparation including water-soluble material and secondly a reconstitution solution of mixed solvents.
2. A didemnin composition according to claim 1, intended for reconstitution for administration to patients as an antitumor treatment.
3. A didemnin composition according to claim 1 or 2, wherein the didemnin is chosen from didemnins, dehydrodidemnins, nordidemnins, didemnin congeners and didemnin analogs.
4. A didemnin composition according to claim 3, wherein the didemnin compound is aplidine.
5.A didemnin composition according to any one of the preceding claims, wherein the reconstitution solution comprises an alkanol/water mix.
6. A didemnin composition according to claim 5, wherein the reconstitution solution includes a nonionic surfactant.
7. A didemnin composition according to claim 6, wherein the nonionic surfactant is 10 to 25% v/v of the solution; the alkanol is ethanol and is 10 to 25% v/v of the solution; and the water is 50 to 80% v/v of the solution.
8. A didemnin composition according to any one of the preceding claims, which comprises a vial of lyophilised didemnin preparation including a water-soluble bulking agent, and a separate vial of a premix of non-ionic surfactant/ethanol/water.
9. A method of preparing a pharmaceutical composition of a didemnin compound, which comprises freeze drying a didemnin/water-soluble additive/alkanol/water mix to provide a lyophilised first component, and separately providing an alkanol/water mix as reconstitution solution.
10. A method according to claim 9 wherein the alkanol in the mix is t-butanol.
11. A method according to claim 9 or 10 wherein the amount of alkanol in the alkanol/water mix is 25 to 60% v/v.
12. A pharmaceutical composition as defined in claim 1 and substantially as herein described with reference to the Examples.
13. A method as defined in claim 9 and substantially as herein described with reference to the Examples.
14. A pharmaceutical composition made by the methods of any one of claims 9-11 or 13.
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