China: Defending Patent Validity on Inventiveness
by Honghui Hu (WAN HUI DA Law Firm & Intellectual Property Agency – China)
Bayer successfully defended its patent relating to the world’s leading oral contraceptive, Yasmin in Beijing Higher Court. Although the patent was invalidated by Patent Reexamination Board on the ground of lacking inventiveness, its Decision was reversed by the court.
The patent claims a pharmaceutical composition comprising 0.01-0.05 mg ethinylestradiol (“EE”) and 2-4 mg drospirenone (“DRSP”), wherein DRSP is in micronized form.
The Patent Reexamination Board (PRB) cited three references, i.e., WO9804269A, Krause I, and Krause III, wherein WO9804269A disclosed a closest contraceptive composition comprising EE and DRSP, but did not teach micronized DRSP. DRSP is known to isomerize and lose activity under acidic condition. It is also known to be insoluble in water. The Krause references concern pharmacokinetics studies of spirorenone (“SP”) as a diuretic in experimental conditions and found SP isomerized in vitro, but no isomerized product was detected after oral administration. Krause references suggested that attempts should be given to micronize SP as well as taught that DRSP is one of metabolites of SP.
The PRB concluded in its Decision that Bayer’s patent is not inventive because the feature of micronization of DRSP is obvious. It held that micronization of DRSP could lead to two opposite results, one is increased dissolution and bioavailability, and the other is increased isomerization and thus reduced bioavailability. Whether bioavailability can be increased depends on the drug’s solubility, digestion, absorption, etc. in the gastrointestinal tract. According to Krause references SP is sensitive to acid but without isomerization after oral administration in vivo. SP is closely related to DRSP in structure and properties, thus a person skilled in the art could predict the following: they have similar metabolism and absorption, DRSP does not isomerize in vivo either, and should be micronized to increase bioavailability.
Bayer appealed against the Decision before the First Intermediate Court of Beijing in 2012. The dispute lies in whether the oral contraceptive containing the micronized DRSP is obvious over the combination of the said references and common knowledge in the art, whether DRSP’s metabolism is similar to SP, and whether the prior art suggests micronizing DRSP in the closest contraceptive composition.
The court of first instance ruled in favour of Bayer. The court held: Firstly, it could not be reasonably concluded from Krause references’ tests that SP does not isomerize in vivo because SP was not micronized in Krause’s tests. Secondly, the evidence has made it clear that SP and DRSP have many differences in physicochemical and metabolic characteristics. It cannot be inferred from only their relatedness in structure and acid liability that they have similar metabolism and absorption process in vivo. Thirdly, it’s only a conception that as taught in Krause references, a high dose of SP could be micronized. This was not verified by tests. Normal tablet and micronization formulation will result in a big difference in medicine’s dissolved amount.
The PRB and the third party appealed the case to Beijing Higher Court in 2014. The Court upheld the judgment of the first instance and added the following:
Teaching away from the prior art is an important factor for determination of obviousness. The opposite teaching of the cited prior art “micronization of DRSP would decrease the bioavailability under acidic condition” cannot lead the direction of the invention toward using micronization. Although Krause references found no isomerized product of SP detected in blood, this cannot explicitly exclude “teaching away” from micronizing DRSP as indicated in the prior art.