Beyond the active ingredient: Patentability of salt forms, stereoisomers and polymorphs in Australia

Bringing a new pharmaceutical product to market is a costly, lengthy, and high-risk endeavour.

This is hardly news to anyone in the pharmaceutical industry.

Drug candidates take a long, often convoluted, and expensive journey to regulatory approval – and there’s a high attrition rate along the way. The discovery of a new API is only the beginning of a development pathway involving pre-clinical testing, clinical trials, regulatory review and approval, and ultimately commercial launch. By the time the product reaches market, that pathway may have consumed a substantial portion of the standard 20-year patent term, meaning patents often expire before the product has generated meaningful commercial revenue.

Accordingly, the commercial value of a pharmaceutical product is closely tied to the period of market exclusivity that remains after regulatory approval is obtained. It is therefore unsurprising that pharmaceutical companies seek to build layered patent portfolios around successful APIs.

One common strategy is to pursue follow-on patents covering alternative forms of a known API, such as salt forms, stereoisomeric forms, and crystal forms. Although these inventions differ in important respects, they often face a common patentability challenge: whether they deliver unexpected technical benefits beyond those that would ordinarily be obvious and arrived at through routine pharmaceutical development.

Salt forms

Salt forms are ionic derivatives of APIs formed by reaction with a pharmaceutically acceptable acid or base. Although the underlying API remains unchanged, different salts forms can exhibit distinct physicochemical properties, including solubility, stability, and manufacturability. Consequently, salt selection is an important aspect of pharmaceutical development.

From a patentability perspective, salt screening is generally regarded as a matter of routine optimisation. However, because different salts of the same API may exhibit significantly different and sometimes unpredictable properties, a claim directed to a salt form may involve an inventive step where it provides unexpected advantages over other salt or free forms. Patent protection may therefore be sought at different levels, ranging from claims directed broadly to pharmaceutically acceptable salts of an API to claims directed to specific salt forms exhibiting advantageous properties.

Stereoisomers

Stereoisomers are compounds that share the same molecular formula and atomic connectivity, but differ in the three-dimensional arrangements of their atoms. These spatial arrangements can significantly influence biological activity, affecting a compound’s selectivity, safety, and pharmacokinetic profile.

Stereoisomer inventions often sit at the intersection of routine pharmaceutical optimisation and genuine technical innovation. Where a racemic mixture is known, separating and characterising individual stereoisomers may appear to be an obvious step in drug development. However, as recognised by the Federal Court in Alphapharm v Lundbeck¹,the properties of individual enantiomers are often unpredictable from a known racemate. Specifically, one stereoisomer may be responsible for the desired therapeutic effect, while the other may offer little benefit or even contribute to adverse effects. Furthermore, isolating the desired stereoisomer may involve overcoming significant synthetic or processing challenges.

Australian and overseas decisions further illustrate how these factors may influence the assessment of inventive step.

In Apotex v Sanofi-Aventis², claims to the clopidogrel enantiomer were held obvious because resolution of the known racemate using established techniques was considered routine.

By contrast, in Ranbaxy v AstraZeneca³, claims to optically pure (-)-omeprazole were upheld because resolving the enantiomers and achieving the claimed level of optical purity was not considered routine at the priority date.

Notably, the corresponding foreign decisions reached different outcomes, with the US Patent Office upholding the clopidogrel patent based on unexpected therapeutic advantages⁴, while the European Patent Office revoked the omeprazole patent for lack of inventive step⁵.

Together, these decisions highlight that patentability is more likely to arise where (i) a single stereoisomer exhibits unexpected properties or (ii) its isolation involves more than routine experimentation.

Crystal forms

Crystal forms are different solid-state forms of a compound that may share the same chemical composition but differ in the molecular arrangement or association. These forms, including polymorphs, amorphous forms, co-crystals, and solvates or hydrates, can significantly influence pharmaceutical properties, such as stability, bioavailability, and processability.

Much like a salt screen, polymorph screening is typically regarded as routine experimentation because it is common practice to investigate crystallisation behaviour across a range of solvents and temperatures. Nevertheless, the solid-state arrangement of molecules remains inherently unpredictable, meaning that the existence and characteristics of a particular polymorph cannot be reliably predicted. Accordingly, an isolated crystal form determined to demonstrate unexpected technical advantages may involve an inventive step despite the routine nature of the initial screening process.

Demonstrating the importance of a crystal form is often just as critical as establishing its novelty. Improved properties, supported by comparative data, will strengthen patentability, while detailed characterisation using techniques such as XRPD, DSC, and TGA will help define and distinguish the claimed crystal form. This is particularly important where the claimed form may already be obtainable using known processes. Consistent with this, a recent Australian opposition decision found that a claimed bixlozone polymorph lacked novelty and an inventive step because the same crystal form was inherently produced by a prior-art process⁶.

Careful claim drafting is also essential. Too few defining features may fail to distinguish a crystal form adequately⁷, while too many may unduly restrict claim scope⁸. This balance is particularly important for XRPD-defined polymorph claims. Although the Australian Patent Office has objected to claims characterised by fewer than ten XRPD peaks, the understood position is that no fixed minimum applies. Rather, the key question is whether the claimed crystal form can be reliably identified and distinguished from other solid-state forms.

Claim scope matters

Careful claim drafting serves not only to distinguish a crystal form from the prior art, but also to ensure that the resulting patent provides meaningful protection.

The Full Court’s decision in Novartis AG v Pharmacor Pty Limited⁹ highlights the importance of claim construction in pharmaceutical patents. The Court held that a valsartan-sacubitril salt complex fell outside claims directed to the individual active ingredients and their salts, demonstrating that later-developed variants may not be captured by claims directed to a parent API or its conventional forms. The decision reinforces the need to draft claims that expressly cover commercially important embodiments.

Practical takeaways

• Unexpected advantages matter: Comparative data showing improved properties will significantly strengthen patentability.
• Think beyond the API: Later-developed pharmaceutical variants may fall outside existing claims, while claiming every conceivable variant upfront may limit opportunities for subsequent protection. Portfolio strategy therefore requires a balance between present and future patent.

Seeking protection for pharmaceutical variants, as they relate to commercial aspects of the product, will provide valuable additional exclusivity. But their effectiveness depends on thoughtful planning and execution. Regular review of patent strategies with experienced patent attorneys will help ensure those strategies remains aligned with evolving legal and commercial considerations.