Pharmaceutical extensions of term – whether indication for use of therapeutic goods in combination with another substance constitutes an inclusion of the combination on the register – whether a combination of separate known dosage forms is a ‘pharmaceutical substance per se’
The drug thalidomide is an anti-angiogenic agent – it suppresses the formation of new blood vessels in tissues and organs, something which occurs in only limited circumstances in healthy individuals, but which can occur in an uncontrolled manner in certain disease states, such as cancers.
Australian patent no. 2005202596 (‘patent’), in the name of The Children’s Medical Center Corporation (‘patentee’), relates to combinations comprising anti-angiogenic compounds – particularly thalidomide – with anti-inflammatory compounds (including steroids). The patent is the grandchild of an application originally filed on 4 November 1997, so its maximum 20-year term will expire on 4 November 2017.
The patentee sought an extension of the term of the patent of five years, until 4 November 2022, based upon registration of thalidomide on the Australian Register of Therapeutic Goods (ARTG). This registration includes indications for the use of thalidomide in combination with various steroids for treatment of multiple myeloma.
In this decision of Delegate Dr L. F. McCaffery, the Australian Patent Office has refused to extend the term of the patent on two grounds:
- thalidomide in combination with a steroid does not constitute goods included on the ARTG, where there is an indication for the combination in an entry for thalidomide; and
- a combination of separate known dosage forms does not constitute a ‘mixture’ within the meaning of the term ‘pharmaceutical substance per se’.
LEGAL BASIS FOR EXTENSION OF PATENT TERMPatent term extensions are intended to compensate patent owners for delays incurred in obtaining marketing approval for pharmaceutical products. This process generally involves multiple-stage trials to ensure safety and efficacy of a drug, and can consume may years of a patent’s normal 20 year term.
Section 70(2)(a) of the Patents Act 1990 provides that an extension of the term of a patent may be granted on the condition that:
…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.
A further condition for the grant of an extension of term is that (section 70(3)(a)):
…goods containing, or consisting of, the substance must be included in the Australian Register of Therapeutic Goods.
Further requirements regarding timing of the application for extension of term were not at issue in this case (see our earlier article Extension of Time Granted to Correct Extension of Term Error for further details in a case concerning the time limits).
THE CLAIMED SUBSTANCE AND THE ARTG ENTRYClaim 1 of the patent is sufficiently representative for our purpose, and defines the invention as a combination of drugs in the following terms:
1. An anti-cancer combination comprising a therapeutically effective amount of thalidomide and a therapeutically effective amount of a steroid.
The patentee relied upon four entries on the ARTG to support its request for an extension of term, each of which identifies the relevant goods as ‘THALOMID, thalidomide X mg hard capsule blister pack’ (where X is respectively 50, 100, 150 and 200 for each of the four entries). Each entry also includes the following ‘product specific indication’:
MULTIPLE MYELOMA – Thalomid in combination with mephalan and prednisone is indicated for the treatment of patients with untreated multiple myeloma aged 65 years or over or ineligible for high dose chemotherapy. Thalomid in combination with dexamethasone is indicated for induction therapy prior to high dose chemotherapy with autologous stem cell rescue, for the treatment of patients with untreated multiple myeloma. Thalomid, as monotherapy, is indicated for the treatment of multiple myeloma after the failure of standard therapies. ERYTHEMA NODOSUM LEPROSUM (ENL). Thalomid is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Thalomid is not indicated as monotherapy for such ENL treatment in the presence of moderate to severe neuritis. Thalomid is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
The questions to be resolved in the present case were whether or not the claimed combination constitutes a ‘pharmaceutical substance per se’, as required by section 70(2)(a), and whether the product specific indication for treatment of multiple myeloma with the combination satisfies the requirement for inclusion in the ARTG under section 70(3)(a).
GOODS INCLUDED IN THE ARTGThe patentee identified the relevant pharmaceutical substance as a combination of thalidomide and at least one steroid, presented as separate oral dosage forms of the individual drugs in order to enable the clinician to control the side effects of the drug combination.
However, the registered product THALOMID consists only of thalidomide. The patentee’s argument was essentially that the entire ARTG entry should be taken into account when determining the goods included in the ARTG including, in this case, the reference in the Product Specific Indications to Thalomid being used in combination with various steroids.
The Delegate referred (at ) to the recent decision in Celgene Corporation  APO 37 (see Celgene Denied Term Extension on REVLIMID Patent), in which it was stated that:
The goods that are included in the ARTG are limited to therapeutic goods …, which are goods intended for therapeutic use …. Goods included in the ARTG have an indication, which is defined as the therapeutic use of the goods …. The Therapeutic Goods Act draws a clear distinction between the goods and their indications. This distinction is evident in H Lundbeck A/S v Alphapharm Pty Ltd  FCAFC 70 at  … where Bennett J stated: ‘The level of the inquiry … 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.’
Accordingly, the Delegate found that ‘there are no goods containing or consisting of [the claimed] combination included in the ARTG’, and therefore that the requirements of section 70(2)(a) were not satisfied (at ).
PHARMACEUTICAL SUBSTANCE PER SESchedule 1 of the Patents Act 1990 includes the following definition of the term ‘pharmaceutical substance’:
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”.
A ‘substance’ can therefore be a mixture or a compound, but can it be a ‘combination’ such as that encompassed by the patent claims in this case?
In order to resolve this question, the Delegate found it necessary to construe the term ‘combination’ as it was used in the patent specification and claims. Although there was no explicit definition of the term, the Delegate found that it encompasses both an admixture (i.e. precombined single unit dosage form) and administration of the individual drugs as separate unit dosage forms (at ).
Referring to the authorities (H. Lundbeck A/S v Alphapharm Pty Ltd  FCAFC 70, Boehringer Ingelheim International GmbH v Commissioner of Patents  FCA 647, Prejay Holdings Ltd v Commissioner of Patents  FCAFC 77 and Pharmacia Italia SpA v Mayne Pharma Pty Ltd  FCA 305), the Delegate concluded that ‘it is clear … 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’ (at ). The requirements of section 70(2)(a) were therefore also not satisfied.
CONCLUSIONAccording to this decision, a patent relating to a ‘combination’ therapy cannot be extended based upon the inclusion of one component of the combination in the ARTG, even if the complete combination is identified in a product specific indication.
Furthermore, unless the combination is provided as a precombined single unit dosage form, then it does not constitute a pharmaceutical substance per se, which is again a barrier to obtaining an extension of the patent term.
Presumably a different outcome would result if the combination were produced, marketed and registered on the ARTG as a single unit dosage. However, based on the patentee’s submissions it appears that this would not have been practical in the present case, due to the desirability of the clinician controlling the individual dosages.