The development of prodrug formulations may present challenges to patent owners seeking to enforce patent claims to the active metabolite.
What are the key issues that arise in relation to enforcement of metabolite claims where a prodrug is subsequently developed?
What is a prodrug?
A prodrug is a substance with limited or no pharmacological activity which is converted into a pharmacologically active metabolite within the body (in vivo) after administration. Prodrug formulations may have increased stability over their active metabolite and can be used to optimise the pharmacokinetic and targeting properties of drugs, for instance by improving the bioavailability of drugs which are poorly absorbed in the gastrointestinal tract or by mediating site-selective drug delivery which can reduce adverse side effects. These benefits make prodrugs an attractive option for drug design and prodrugs represent a significant share of all newly designed drugs.
Despite their prominence as commercial therapeutic options in Australia, there has been limited judicial consideration of whether use of a prodrug would infringe an existing patent claim to its active metabolite.
Infringement by conversion in vivo
Australian courts have not directly considered whether use of a prodrug would infringe a claim to its active metabolite, however non-binding judicial comments suggest that at a minimum, therapeutic use of a prodrug which results in conversion of the prodrug to the metabolite in vivo, may constitute infringement.
In Merck v Arrow Pharmaceuticals (2003) 59 IPR 226;  FCA 1344, the applicant Merck & Co., Inc (Merck) appealed a decision by the Patent Office to refuse grant of a patent term extension for its Australian Patent No. 535944, which claimed the metabolite lovastatin beta-hydroxy acid (LHA). LHA has potent cholesterol-lowering activity, and is the active metabolite of the prodrug lovastatin. The extension of term was based on the ARTG registration of the prodrug held in the name of a third party.
Among other things, for an extension of term to be granted the Commissioner must be satisfied that one or more pharmaceutical substances per se (i.e. the prodrug) 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.
In support of its extension of patent term application, Merck’s counsel argued that pharmaceutical use of the prodrug lovastatin would necessarily involve infringement of Merck’s claim to the LHA metabolite. Although the Patent Office accepted that human pharmaceutical use of the prodrug lovastatin generates the patented metabolite in vivo and such use would infringe the claims to LHA, the Patent Office was not prepared to find that prodrug lovastatin in substance falls within the scope of the LHA metabolite claims for the purposes of the pharmaceutical substance per se requirement.
On appeal to the Federal Court, Justice Wilcox granted the extension on an alternative argument, however, in obiter he suggested that Merck’s argument that use of the prodrug would necessarily infringe their metabolite claim should be rejected expressing approval for the delegate’s reasoning that:
While Merck have argued that the only reasonable use of Lovastatin is a human pharmaceutical use, the fact remains that use of Lovastatin in any other manner, or possession for a purpose other than such use, would not constitute an infringement of the claims to the metabolite.
The Court also noted that in the circumstances where a prodrug is discovered and patented before its active metabolite, accepting infringement by in vivo conversion could result in the “extraordinary situation” that a party holding a patent for the prodrug could be held to infringe a metabolite claim during the currency of its patent, even though the prodrug patent had an earlier priority date.
Infringement by non-therapeutic use
The Patent Office and the Court in Merck v Arrow accepted that the prodrug could be used in a manner that would not infringe a claim to its metabolite. This accords with the authorities in relation to new uses of a known substance, which allows claims taking advantage of unknown properties of known substances, provided they meet the requirements for inventive step. For example, if subsequent to a metabolite being patented, it was discovered that the prodrug could be used as a herbicide (and this fact was not disclosed in the metabolite patent) a subsequent patent claiming the prodrug for use as a herbicide may be granted.
A finding that non-therapeutic use of the prodrug as a herbicide would infringe the metabolite patent would effectively extend the metabolite claim outside the monopoly justified by its disclosures.
Application of contributory infringement provisions
The development of prodrugs for patented metabolites also raises questions in relation to the application of contributory infringement provisions. For example, if the prodrug is supplied along with instructions for therapeutic use or advertisements which contain inducements to use the product as a therapeutic, then supply of the prodrug would likely constitute infringement.
The popularity and continued development of prodrug formulations raises interesting questions for the enforceability of existing metabolite claims. Therapeutic use of a prodrug may constitute infringement of a claim to its active metabolite, either by conversion in vivo or through breach of contributory infringement provisions, but this has not been directly tested in Australian courts and may depend on whether other legitimate non-therapeutic uses exist.
 From 2008 to 2018, the US Food and Drug Administration approved at least 30 prodrugs, representing more than 12% of all approved small-molecule new entities, see Rautio et. al., Nature Reviews Drug Discovery 17, 559-587 (2018), see Rautio et. al., Nature Reviews Drug Discovery 17, 559-587 (2018)
 Merck & Co., Inc v Arrow Pharmaceuticals Limited  APO 13, , .
 On the basis that LHA was the relevant “pharmaceutical substance” which fell within the scope of Merck’s patent, Wilcox J found that trace amounts of LHA contained in the Merck’s lovastatin product before ingestion were sufficient to satisfy the requirement that the substance be “included in the ARTG” for the purpose of s 70(3)(a) of the Patents Act 1990 (Cth).
 Merck v Arrow Pharmaceuticals (2003) 59 IPR 226;  FCA 1344,  (Wilcox J) citing Merck & Co., Inc v Arrow Pharmaceuticals Limited  APO 13, .
 Ibid, . This was a hypothetical situation raised in the Merck v Arrow proceedings as the prodrug Lovastatin was the subject of an earlier patent held by a third party Sankyo Co Pty Ltd.
 See e.g., National Research Development Corp v Commissioner of Patents (1959) 102 CLR 252.
 Patents Act 1990 (Cth) ss 117(1) and 117(2)(c).
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