Package inserts prove crucial in patent linkage litigation in Taiwan

Since the patent linkage system’s implementation on 20 August 2019, there have been more than 30 paragraph-four (P4) cases filed by generics against NDAs, alleging patent invalidity or non-infringement under Article 48-9(3)(4) of the Pharmaceutical Affairs Act. Among them, several IP court rulings on P4 applications have focused on the connection between the indications of generic drugs’ package inserts and claims of patent infringement. Now that there is a significant body of case law in this area, in-depth analysis can provide valuable insights for Taiwan’s pharmaceutical industry, particularly for generic drug companies.

For example, TSH Biopharm submitted a P4 application for a generic drug Crestor, which was intended for the treatment of hypercholesterolemia (no 110-Min Zhuan Su Zi-9). It had also attached a declaration of non-infringement of patent rights and a portion of the draft package insert. The patent linked to this disputed drug was numbered I 238720 and titled “Pharmaceutical Compositions for the Treatment of Heterozygous Familial Hypercholesterolemia” ('720 patent).

This patent had two sets of independent claims. One was “a pharmaceutical composition for the treatment of patients with heterozygous familial hypercholesterolemia” and the other was for “a pharmaceutical composition for lowering LDL-C, increasing HDL-C, lowering Apo B, and increasing Apo A-I in patients with heterozygous familial hypercholesterolemia, all of which include an effective amount of active ingredients and a pharmaceutically acceptable carrier”. The plaintiff, AstraZeneca, claimed that the drug potentially infringed the ‘720 patent and initiated a P4 infringement lawsuit. The first-instance judgment found that the disputed drug fell within the scope of the ‘720 patent claims and constituted infringement, resulting in a victory for the plaintiff.

Amendments to the package insert

AstraZeneca contended that the active ingredients in the disputed drug were rosuvastatin calcium and ezetimibe, but according to the defendant's original package insert, the indication was primary hypercholesterolemia. The second paragraph in the indications section stated:

Used as adjunctive therapy to diet for patients with primary hypercholesterolemia (excluding heterozygous familial hypercholesterolemia) or mixed hyperlipidemia to reduce elevated total cholesterol, low-density lipoprotein, apolipoprotein B, non-high-density lipoprotein cholesterol and triglycerides, as well as to increase high-density lipoprotein cholesterol.

During the course of the litigation, following the recommendation of the Center for Drug Evaluation, the defendant modified the indications on the package insert to “Patients with primary hypercholesterolemia (excluding heterozygous familial hypercholesterolemia)” and removed the entire second paragraph.

In this case, the plaintiff contended that the comparison basis for determining infringement should be the indications as listed on the original package insert prior to the amendment. The defendant countered by arguing that the basis for comparison should be the indications as amended on the package insert.

The court had to determine whether the disputed drug fell within the scope of Claim 1 of the ‘720 patent and should be determined based on the therapeutic efficacy of the disputed drug itself as derived from the human clinical trial results cited in the complete package insert, and not solely on “the revised package insert of the disputed drug”.

While package inserts serve as essential guidance for healthcare or pharmaceutical professionals, they also carry significant reference value in patent linkage litigation. However, even if the original package insert of the disputed drug is modified, the consideration of its continued reference value should depend on whether the drug’s therapeutic efficacy can be supported by clinical trial results cited in the package insert and whether the insert is medically rational.

However, the court in this case determined that the indications listed in the revised package insert of the disputed drug could not be supported by the human clinical trial results that were cited. The indications, as presented in the revised package insert, appeared to be a deliberate attempt by the defendant to circumvent the literal scope of the ‘720 patent. Additionally, the clinical trial reports submitted for registration by the defendant were identical to those submitted in other countries. In these other jurisdictions, the disputed drugs had also been granted indications for “heterozygous familial hypercholesterolemia”. Therefore, the disputed drug itself indeed has therapeutic efficacy. The court thus determined that whether the disputed drug fell within the scope of the ‘720 patent should be based on “the therapeutic effects of the disputed drug itself as derived from the clinical trial results cited in the complete package insert” and not solely on “the revised package insert of the generic drug”. The court concluded that the disputed drug fell within the literal scope of the ‘720 patent and constituted a literal infringement.

In patent linkage litigation, when it comes to determining whether the indications of the disputed drug fall within the scope of the disputed patent claims, the complete package insert is essential comparative data. As is evident from the example case, courts in Taiwan take into consideration the indications listed in the package insert when determining whether the generic drug falls within the patent’s scope.

However, the package insert content is not the sole consideration, and if the indications in this have been modified, courts will consider the reasons for any modifications and the substantive technical significance, especially in terms of therapeutic efficacy, which is demonstrated in the generic drug’s clinical trials. Each case is subject to specific judgments. Therefore, generic drug companies must be cautious when adopting a design-around strategy to avoid the indications of the disputed patent claims, ensuring that it aligns with clinical trial results and adheres to clinical treatment practices.