In China, besides a composition, a patent for a new drug combination invention may claim a combination, or medical use thereof, as the subject matter. Due to the rarity of judicial precedents, the rules on how to interpret the claimed scope of a ‘combination’ have been murky in infringement cases. However, a decision rendered by China’s Supreme People’s Court (SPC) in a drug patent linkage case involving Actemra sheds some light on this issue.
Background to the Actemra case
Tocilizumab (also known as MRA) is an anti-interleukin 6 receptor monoclonal antibody jointly developed by Roche and Chugai. Actemra, the originator drug of tocilizumab, was approved in China in 2013 for the treatment of rheumatoid arthritis (RA), specifically indicated for the “treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to disease-modifying anti-rheumatic drugs (DMARDs). Tocilizumab is used in combination with methotrexate (MTX) or other DMARDs.”
Roche, in its capacity as the marketing authorisation holder of Actemra, registered medical use claims of a patent, ZL201511004468.9 (CN468), which is owned by Chugai, on the China Platform for Registration of Patent Information of Marketed Drugs in October 2021.
In December 2021, a biosimilar applicant, Livzon, made a Category 4.1 statement against CN468, asserting that the patent should be declared invalid. In response to the allegation, Chugai filed a patent linkage lawsuit with the Beijing Intellectual Property Court (BIPC), requesting the court to confirm that the biosimilar falls within the protection scope of CN468. On November 24 2022, the BIPC ruled in favour of Chugai, finding that the accused biosimilar falls within the patented scope.
Livzon appealed before the Intellectual Property Court of the SPC, which, on July 28 2023, dismissed the lawsuit, based on the finding that CN468 was not an eligible registered patent as it does not even cover the originator drug, Actemra.
On March 4 2022, Livzon initiated an invalidation action against CN468 before the CNIPA, which, on April 6 2023, upheld the validity of the patent at issue based on the amended claims.
Court findings
The amended independent claim 1 of CN468 claims use of MRA and MTX for manufacture of a combination of MRA and MTX for the treatment of RA, wherein MRA is administered by intravenous injection once per four weeks at a dosage of 8 mg/kg, and MTX is administered orally once a week at a dosage of 10-25 mg per patient.
A hotly debated issue in the case is how to construe the combination in claim 1.
In the patent linkage suit, Livzon questioned the eligibility of the registered patent, arguing that CN468 failed to cover the originator drug Actemra, and thus was not even a “relevant patent” as prescribed in Article 76 of the Patent Law. Specifically, Livzon contended that claim 1 relates to use for manufacture of a medicament, which restricts the manufacturing behaviour of a manufacturer, and the claimed scope should be limited to the manufacturing process. Consequently, Livzon argued that claim 1 can only be interpreted as “making separate preparations of MRA and MTX but packing them together as a single product”. Actemra, however, comprises only MRA.
Livzon’s arguments did not convince the BIPC.
The interpretation of the Beijing Intellectual Property Court
The BIPC found that the claimed use is related to combined use of MRA and MTX and the defined dosages. Even if a claim for use of manufacture of a medicament restricts the manufacturing behaviour, in the event that MRA and MTX are made into separate preparations, whether to pack them into a single product shall have no bearing on their combined use and dosages, let alone on the use defined in the claim.
The court therefore affirmed that claim 1 should be interpreted as protecting the combination use of MRA and MTX, with each administered separately at the defined dosage, for treating RA. Based on such finding, the court concluded that Actemra falls within the claimed scope.
The interpretation of the Supreme People’s Court
Apparently, the SPC disagreed. The court of appeal opined that the combination, which is the object of manufacture, should be construed as a combined product in kind. As to the combination formed by two active substances, there are two possible interpretations, namely, it could be:
A pharmaceutical composition in the form of a compound preparation as prepared by two active substances; or
A product formed by combining the two active substances through a certain way of packaging.
In the present case, MRA and MTX cannot be made into a single compound preparation (due to their different ways of administration), and thus the combination in claim 1 cannot be interpreted as a pharmaceutical composition. However, it would be reasonable to interpret it as a combination product formed by a certain way of packaging.
The SPC also found the BIPC’s reasoning to be flawed. Specifically, the BIPC’s interpretation did not take into account that the combination is an object of manufacture, and it would be erroneous to incorporate an unpatentable technical solution into the claimed scope during reasonable interpretation of the claim. The Patent Law explicitly bans patenting methods for the diagnosis or treatment of diseases, but medicines and methods of preparing medicines are patentable. Claim 1 is granted as it constitutes use of manufacture of a medicament. If the combination of MRA and MTX is to be construed as a combination use, it would constitute a method of treating a disease, which is unpatentable under the law.
The SPC’s interpretation of the claim aligns with that of the CNIPA elaborated in the invalidation decision. In examining the validity of CN468, the CNIPA reiterated its stance that the features embodied only in the administration of medicine have no limiting effect on use of manufacture of a medicament. The CNIPA reasoned that the varied route and method of administration corroborates that it would be unfeasible to make MRA and MTX into a compound preparation. The CNIPA thus defined claim 1 as claiming use of MRA and MTX for manufacture of a packaged pharmaceutical product for treating RA, rather than a treatment regimen using MRA and MTX in combination.
Likewise, based on the aforesaid claim construction, the SPC found that claim 1 does not encompass Actemra, as Actemra merely contains a single substance of MRA, and its combination with MTX is only indicated in the drug label, which does not constitute a combination product. As a result, the SPC ruled that CN468 is not an eligible patent for filing the linkage suit and dismissed the case.
Final comments on the patent scope of drug combination inventions
The invention of a drug combination is often based on the discovery that two drugs used in combination have superior efficacy to either drug being used alone. The combination is not intended to be limited to the form of a single formulation comprising the two active ingredients. It is also common practice that a drug product, containing a single ingredient, indicates the inventive combination on the label.
However, a combination in the form of packaging two pharmaceutical formulations, as mentioned by the SPC and CNIPA, is much less common in practice. Two formulations with different administration routes are not even allowed to be provided in one package in China. Under such circumstances, it would be difficult to protect an invention over the combination of two drugs, which could not be viably made into a single formulation.
It would be more advisable to draft the claim at issue as “use of MRA in the manufacture of a medicament in combination with MTX for treating RA” to ensure the covering of the originator drug in the claim. However, it remains controversial as to whether the adoption of “in combination with MTX” has any limiting effect on the claimed use of manufacture and has any material impact in the patentability assessment. Under the current practice, the patentee would struggle to assert such combination invention, at least for the time being.
