In the pharmaceutical industry, a drug manufacturer, in addition to seeking patent protection for novel compounds, would typically file other related patent applications to meet the needs of the subsequent development of said compounds, including new crystalline forms, new derivatives, new formulations/dosage forms, new preparation methods and/or new medical uses. In this manner, the protection period of the relevant drugs could also be extended.
Using new crystalline form as an example: Since small molecule compounds usually exhibit polymorphism, by controlling different solvents or crystallization conditions, the atoms of the compound molecules can have different three-dimensional arrangements in the crystal lattice, presenting different solid crystalline forms (crystalline forms). Each crystalline form may produce different physical and chemical properties, such as solubility, stability, hygroscopicity, bioavailability, processability, etc., which can, in turn, affect the clinical efficacy and safety of the drug.
With the evolution of pharmaceutical technology and the needs of the pharmaceutical industry, it is generally considered that those skilled in the relevant art should have a reasonable motivation to attempt to screen and prepare a specific crystalline form with superior properties using routine experimental methods. Therefore, the difficulty in obtaining patent rights for crystalline form inventions is increasing from time to time. Even if a crystalline form patent is considered to have inventive step over prior art during the examination stage (such as having unpredictable effects), the validity of the crystalline form patents might still be challenged in infringement litigation. Moreover, it is not of rare occurrence for generic drug manufacturers to choose different crystalline form to produce drugs so as to stay away from others’ patents.
The particular challenges in enforcing crystalline form patents are crystal clear by a review of two Judgments rendered by the Intellectual Property and Commercial Court (hereinafter referred to as the IPC Court). The two judgments are:
IPC Court's Civil Patent Litigation No. 8 of 2021 (rendered on November 30, 2021); and
IPC Court's Civil Patent Litigation No. 51 of 2023 (rendered on April 10, 2023).
The two lawsuits are both revolved around pharmaceutical patent linkage infringement. The Plaintiff in both cases is Bayer HealthCare LLC (hereinafter referred to as Bayer). The Defendants are “Synmosa Biopharma Co.” and “Lotus Pharmaceutical Co., Ltd.”, respectively, both of which are Taiwanese generic pharmaceutical manufacturers.
In these two lawsuits, Bayer’s based-upon patents are not limited to one, but that which is related to crystalline form is only Taiwan Patent No. I382016 entitled “Thermodynamically Stable Form of a Tosylate Salt.” (hereinafter referred to as the patent in question)
IPC Court's Civil Patent Litigation No. 8
The patent in question mainly provides a thermodynamically stable polymorph of a specific structure compound of formula (I). This polymorph can prevent unwanted polymorphic conversion of another polymorph, and thus, impact the solubility and bioavailability of the formula (I) compound preparation during pharmaceutical manufacturing. The specification of the patent in question also states that, compared to two other polymorphs and ethanol and methanol solvate compounds of the same compound, the protected specific polymorph is thermodynamically stable at room temperature and even remains stable in storage after suspension processing, making it particularly suitable for use in pharmaceutical formulation. As the Defendant did not present any argument to the effect that their generic drugs do not fall into the patent scope of the patent in question, the IPC Court focused primarily on whether the patent in question should be revoked.
After examining the relevant evidence, the IPC Court found that while the prior art failed to disclose the specific polymorph of the patent in question defined by values obtained from spectral analysis including X-ray diffraction, IR, Raman and NMR, and thermal analysis including TGA and DSC, it did teach or suggest that different polymorphs of one and the same active drug ingredient could have different physical and chemical properties. To avoid impacting the quality, safety, efficacy, and manufacturability of the final drug product, it is necessary to identify a stable polymorph from them. As a result, those of ordinary skill in the art would have a reasonable motivation to choose an appropriate and stable crystalline form to prepare drug preparations, and could easily arrive at the patented invention through routine experiments (such as recrystallization experiments or simulated crystallization systems).
The Plaintiff argued that, in addition to being thermodynamically stable, the specific crystalline form of the patented invention demonstrates “mechanical stress stability”, as it does not change form after being ground in a mortar for 30 seconds, which is an unpredictable effect compared to other crystalline forms.
Moreover, the commercial success of the patented drug allegedly proved the inventive step achieved by the patented invention.
The IPC Court held that, according to the relevant evidence, stable polymorphs, when compared to metastable polymorphs, need to absorb higher activation energy to convert into an amorphous state with higher free energy. This can be understood to mean that stable polymorphs have a higher resistance to the activation energy applied during the grinding process, and therefore would not lead to a crystalline form conversion. Hence, thermodynamic stability and mechanical stress stability essentially match up in quality and are positively related. Those of ordinary skill in the relevant art would reasonably expect that stable polymorphs have higher mechanical stress stability.
Regarding the alleged commercial success, the IPC Court assumed that Nexavar® film-coated tablets still exclusively dominate Taiwan pharmaceutical market due to the fact that the patent term of the patent in question has not expired. Further, as the commercial success is not solely or directly attributable to the technical features of the patented invention, the Plaintiff's argument is not convincing.
IPC Court's Civil Patent Litigation No. 51
Since the Defendant’s generic drug had not been marketed at the time the lawsuit was filed, Bayer argued that it should be the Defendant’s burden to prove non-infringement and provide the generic drug in question for identification and analysis. However, the IPC Court did not accept Bayer's argument. It believed that the data submitted by the Defendant during inspection and registration process of the generic drug in question could adequately represent the generic drug itself in the adjudication of the patent infringement dispute.
Regarding the dispute over infringement, the IPC Court found that, a generic drug is defined as a “preparation with the same ingredients, same dosage form, same dosage, and same efficacy” as an approved, patented drug in Taiwan according to the provisions of Regulations for Registration of Medicinal Products. On this score, the generic drug in question should have the same active ingredient as the approved patented drug (i.e., sorafenib tosylate), but this fact, by itself, is not sufficient to conclude that they share the same polymorphic form. According to the inspection and registration data of the generic drug in question, the crystalline form of said generic drug is different from that presented by the patented drug and therefore does not fall within the scope of the patent in question.
Furthermore, according to the IPC Court, even if the Plaintiff claimed that during the tablet manufacturing process, through grinding, spray granulation, drying, and tabletting, the crystalline form of the active ingredient of the generic drug in question “might” undergo a crystal conversion to become the most stable polymorph claimed by the patented invention. However, this crystal conversion is not a “necessary” occurrence, and there is currently no evidence to confirm this. It is thus difficult to rule on infringement based on the Plaintiff’s claim.
Suggestions
Crystalline form patents can provide a second-tier protection for drugs besides compound patents. However, in tandem with the rapid growing of the technology in the pharmaceutical industry, the threshold for judgment of the inventive step of crystalline inventions has been elevated. Thus, when there is a need to seek patent protection for crystalline form(s) of a drug, one should spend careful attention in mapping out a sophisticated patent strategy. For instance, the following practices can be taken into account in the layout of a patent specification:
- Demonstrate in multiple ways that the specific crystalline form has improved or unpredictable physical and chemical properties.
- Submit comparative experimental data versas other unwanted crystalline forms.
- Enhance the credibility of experimental data. It is more recommended to carry out actual experiments under objective test conditions that are customary in the pharmaceutical sector or are internationally recognized.