Introduction:
In the pharmaceutical industry, crystalline forms such as polymorphs, salts, and cocrystals have long been the subject of IP protection. These solid forms can have different physical properties which impact the efficacy of drugs or the procedures for their preparation. For decades, companies have patented these forms to extend their market exclusivity. However, in recent years, patent litigation around these forms has become increasingly challenging, with courts and regulatory bodies raising the bar for patenting them.
Case Study: Paroxetine and Its Ripple Effect
Paroxetine is an antidepressant that was initially patented by SmithKline Beecham (now GSK) and marketed as a hydrochloride salt, under the brand name Seroxat. To extend their exclusivity beyond the original compound patent’s expiration, SmithKline Beecham patented a new anhydrous, crystalline form of paroxetine hydrochloride, which differed from the original hemihydrate form.
However, in the early 2000s, Apotex, a Canadian generic manufacturer, challenged the patent on the anhydrous crystalline form in multiple jurisdictions. Apotex argued that the discovery of the anhydrate form was obvious, as it was a routine modification of the already known hemihydrate form, lacking the novelty and inventive step required for patent protection. The case reached the UK Court of Appeal in 2004, where the key question was whether the anhydrate form of paroxetine was truly inventive.
SmithKline Beecham argued that the anhydrate form had distinct advantages over the hemihydrate form, such as better stability and manufacturability. They claimed that these properties justified the patent, while Apotex proposed that the discovery of the anhydrate form was predictable and the differences between the two forms were minimal. They presented the argument that any skilled person in the field would expect to find multiple crystalline forms (polymorphs) of a compound, and that the discovery of the anhydrate was a natural progression of the development process.
Perhaps more importantly, Apotex also argued that, once ingested, the anhydrate form of paroxetine converted back to the hemihydrate form in the body (in vivo), suggesting that the therapeutic effect of the anhydrate form would be indistinguishable from that of the hemihydrate. If the new crystalline form reverted to the previous one inside the body, it would not provide any additional therapeutic benefit.
To support this argument, Apotex conducted experiments showing that the anhydrate form, when exposed to moisture in biological environments, would naturally convert into the hemihydrate. To do this, Apotex prepared a tablet of paroxetine anhydrate and tied it to a thread. The patient, then, would swallow the tablet while one end of the string was held outside their mouth. The tablet would then enter the GI tract, specifically the stomach, where it would be exposed to gastric fluids. After some time, the tablet was pulled out using the string and analyzed by XRPD, demonstrating that the starting anhydrate form had now turned into the previously known hemi-hydrate form.
The string method provided critical empirical evidence during the litigation. It showed that the anhydrate form reverted to the hemihydrate once exposed to gastric conditions, weakening SmithKline Beecham’s patent claims. This experiment, alongside other evidence, supported Apotex’ claim that the anhydrate form was obvious and, therefore, not inventive.
The story of the string method is a well-known anecdote in patent and pharmaceutical law circles, though it is rarely described in formal legal judgments or scientific literature.
The UK Court of Appeal ruled in favor of Apotex, finding that the discovery of the anhydrate form was obvious. The court noted that polymorphs are well known in pharmaceutical chemistry and that discovering a new crystalline form through routine experimentation does not constitute an inventive step. Additionally, the in vivo transformation argument played a role in the court’s reasoning. Although not the primary basis for the ruling, the fact that the anhydrate form reverted to the hemihydrate in the body diminished the claim that the anhydrate form had unique therapeutic properties.
The ruling invalidated the patent on paroxetine anhydrate in the UK, allowing Apotex and other generic manufacturers to introduce their versions of the drug into the market. This not only had significant financial consequences for SmithKline Beecham but also set a critical precedent in the pharmaceutical industry.
The decision highlighted the growing judicial skepticism toward patents on solid state forms that did not exhibit clear, unexpected benefits over previously known forms. The in vivo transformation argument further stressed that for a new solid form to be patentable, it must demonstrate a meaningful distinction in therapeutic effect, not just in physical or manufacturing properties.
SmithKline Beecham attempted to defend its patent in other jurisdictions, including the US, where the Federal Circuit also ruled in favor of Apotex. The in vivo transformation argument played a more prominent role in the US litigation, where the court agreed that the transformation rendered the anhydrate form essentially indistinguishable from the hemihydrate in practical terms.
Conclusions:
In recent years, the standards for patenting new crystalline solid forms have become increasingly stringent. For once, patent examiners and courts now demand more evidence that a new solid form provides a significant, unexpected benefit. Minimal changes in solubility or stability may not be enough to secure patent protection. This is pushing companies to focus on obtaining broader protection through formulation or process patents rather than relying solely on solid form patents. Also, although it is important to take into consideration that different regions apply different standards, there’s been a global movement toward harmonizing stricter criteria for solid form patents, with courts around the world becoming more reluctant to grant patents unless strong evidence of innovation is shown.
Although the identification of new polymorphs and crystalline forms should always be pursued and never become neglected, given that the performance of the drug is closely linked to the physical properties of its crystalline form, pharmaceutical companies must continue ensuring the protection of their assets, and must continue innovating beyond traditional polymorphs. Demonstrating utility to reenforce the non-obviousness of a new solid form should be the driver, and not simply its novelty. As standards for patentability tighten, companies must adapt by pursuing deeper innovations and more comprehensive IP strategies.
References:
1. Smithkline Beecham Corp. v. Apotex Corp., 403 F.3d 1331 (Fed. Cir. 2005)
2. Smithkline Beecham plc v. Apotex Europe Ltd [2004] EWCA Civ 1703
