Merck Sharp & Dohme v. TSH Biopharm:
an alternative new drug for treating a hypercholesterolemia disease found not infringing

Merck Sharp & Dohme (“MSD”) is the owner of Taiwanese patent I337076 entitled “The use of substituted Azetidinone compounds for the treatment of sitosterolemia.” Sitosterolemia is a lipid metabolism disorder where the patient absorbs excessive amounts of plant sterols from vegetables or nuts. As plant sterols accumulate in the serum and are deposited in tissues, some patients may suffer blockages in blood vessels, elevating the risks of coronary heart disease or, in critical situations, stroke or cardiac arrest. Shering Corporation (“Shering”) developed ezetimibe under the trade name Ezetrol (and others) as a cholesterol absorption inhibitor for curing certain hypercholesterolemia diseases including sitosterolemia. Shering applied for a patent for ezetimibe compound in Taiwan in 2002; the patent was granted in 2011 and is estimated to end in January 2022. Merck acquired Shering in November 2009 to become Merck Sharp & Dohme. MSD is, therefore, currently the patentee in title for I337076. After the pharmaceutical-patent linkage system was instituted into the laws, MSD listed the ‘076 patent to declare it associated with Ezetrol 10mg tablets.

TSH Biopharm (“TSH”), established in 2010, is a Taiwanese local pharmaceutical company with an R&D program focusing on products related to cardiovascular, gastrointestinal and autoimmune disorders. TSH developed Cretrol tablets, a medication that contains ezetimibe and rosuvastatin calcium as active ingredients for curing primary hypercholesterolemia. In October 2020, TSH completed its duty in applying for regulatory approval and declared that Cretrol does not infringe the ‘076 patent pursuant to the Pharmaceutical Act and relevant regulations.

In response to TSH’s declaration, MSD filed an infringement suit aiming to prevent the manufacture, use, sale, offer for sale, or import activities relating to Cretrol. MSD asserted that Cretrol also treats sitosterolemia as a result of treating primary hypercholesterolemia. TSH Biopharm retains Tsai, Lee & Chen to defend itself.

The court addressed several main issues arising from both parties’ complaints and defensive responses.

The first question is whether Article 96(1) of the Patent Act constitutes sufficient grounds for raising an infringement suit in this case. TSH tried to argue that it had only filed for an application for regulatory approval for its alternative to ezetimibe and said that its activity was exempted by the patent right according to the Patent Act. TSH’s application for drug approval did not mature to be of any threat to the patented invention since there was no exploitation of the patent at issue.

The court ruled that Article 96(1) is not only to stop an ongoing infringing activity but also to prevent the likelihood of patent infringement. In order to protect public health and interests, the patent linkage system was designed to resolve any patent disputes at any stage, even as early as the application for regulatory approval. The purpose of an infringement suit in the linkage system is not to determine whether the generic applicant practices the patented invention but—more importantly—to ascertain whether the generic drug application embodies a product that would potentially infringe the patent at issue, and thus preemptively resolve a potential dispute before a generic drug is launched into the marketplace. Article 96(1) was the rightful grounds for the linkage system.

On a separate note, there is a drafted bill pending codification to the Patent Act (to become Article 60-1) which will serve as the specific grounds for action dedicated to linkage-related lawsuits. It reads that where the applicant for the generic’s market approval submits a P4 challenge, within 45 days from receiving the P4 challenge, the patentee may sue to stop or prevent potential infringement. In fact, the institution of Article 60-1 was designed to benefit both parties. In addition to providing a means for the patentee to challenge, it also affords the generic applicant an opportunity to clear hindrances by seeking declaratory judgement of non-infringement as long as the patentee does not sue within said 45 days.

For the second question, of whether the ‘076 patent’s Claims 1-6, 8-9, 11, 14 and 31 read on TSH’s Cretrol tablet, the court’s answer is no.

All the claims in dispute were “product-by-use” claims. Based on the patent examination guidelines prior to 2013, the features of use were limitations to the scope as claimed. Claim 1 directs to a pharmaceutical composition for the treatment of sitosterolemia comprising an effective amount of a sterol absorption inhibitor (this being the compound of ezetimibe), or a pharmaceutically acceptable salt or solvate of the sterol absorption inhibitor, or a mixture thereof, in a pharmaceutically acceptable carrier. The “treatment of sitosterolemia” was a limiting feature, while “treatment” suggested the therapeutic effect arising from “an effective amount of a sterol absorption inhibitor…” as claimed.

“Primary hypercholesterolemia” (excluding the heterozygous familial type) and “homozygous sitosterolemia” are two distinguishable disorders. Ezetimibe was confirmed to have beneficial effects for treatment of both “primary hypercholesterolemia” and “sitosterolemia.” However, as the court found particularly noteworthy, the packaged inserts for Cretrol did not contain clinical data supporting the treatment of sitosterolemia, neither did it name sitosterolemia as one of the indications for treatment. While the pharmaceutical composition recited in Claim 1 of the ‘076 patent was limited to treatment only for “sitosterolemia,” the Cretrol—composed of ezetimibe and rosuvastatin calcium for treating “primary hypercholesterolemia”—did not fall within the literal scope of said Claim 1.

Claims 2-6 and 8-9 directly or indirectly depended from Claim 1. While Claim 1 did not read on Cretrol, neither did the subsequent claims read on Cretrol.

Claim 11 is a pharmaceutical composition—as Claim 1—which comprises an effective amount of a bile acid sequestrant or other lipid-lowering agent, and Claim 14 is a pharmaceutical composition—as Claim 1—which comprises an effective amount of sterol biosynthesis inhibitor. However, the indication treatable by Cretrol is primary hypercholesterolemia rather than sitosterolemia, meaning that Cretrol does not have all elements found in either Claim 11 or Claim 14.

Lastly, regarding Claim 31, it has “treatment of sitosterolemia” as an essential element. The court’s investigation particularly focused on the prosecution history of the case and its attention was drawn to one of MSD’s responses to an Office action; the agent for MSD stressed that this invention for which a patent was requested was a new use for a known compound. Hence, such a new use—that of specifically treating sitosterolemia—surely amounted to a higher weight of significance in constructing the scope of the claim. Yet for the same reasoning that sitosterolemia was different from primary hypercholesterolemia wherein Cretrol does not include the former as an indication, the court found that Cretrol did not have all elements in Claim 31.

To conclude, although MSD was entitled to raise an infringement action under Article 96(1) of the Patent Act in view of the policy of the patent linkage institution, none of the Claims 1-6, 8-9, 11, 14 or 31 were found to read on TSH Biopharm’s Cretrol tablet. Finally, the court made the judgement (IPC-110-CivPatTrial-No.4) that Cretrol did not infringe and dismissed all of MSD’s requests in the suit. According to TSH Biopharma, Cretrol was originally projected to be launched in mid-2022.

The judgement remains appealable until the end of November.

On a different but similar note, earlier this year there was another P4 patent linkage-related lawsuit concerning a generic version of the same Ezetrol tablet of MSD. The outcome of the case was a defeat for the P4 challenger. (MSD v. CCPC; IPC-109-CivPatTrial-No.46; January 2021)

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