【Volume 63】

In August 2021, the Taiwan Intellectual Property Court (IP court) ruled in its 2020 Xingzhuansuzi No. 60 Judgment that part of the claims of Gilead Sciences, Inc.’s corresponding invention patent "COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL THERAPY" of the drug for AIDS prevention, "TRUVADA® Tablets", should be revoked. ^[1]

The proportion of pharmaceutical patents being successfully invalidated by generic pharmaceutical companies is quite high in recent Taiwan pharmaceutical patents. If the active ingredient has been disclosed by prior art and the only difference lies in the parameters such as the composition ratio, inventions related to pharmaceutical composition are often considered to be obvious unless the patentee can provide methods and data of pharmaceutical test to prove that the different technical features allow the pharmaceutical composition to have unexpected effects. It is because the Taiwan Intellectual Property Office (IPO) usually believes these inventions can be easily accomplished by a person skilled in the art through simple tests of routine work. The court’s principles for judging non-obviousness of a pharmaceutical patent are introduced and analyzed as follows.

Case Facts

Gilead Sciences, Inc. is the patentee of Invention Patent “COMPOSITIONS AND METHODS FOR COMBINATION ANTIVIRAL THERAPY” (Certificate No.: I355270) (“‘270 patent”). A Taiwanese generic pharmaceutical company, Yikang Pharmaceutical Co., Ltd. filed an invalidation action against the patent and argued that ‘270 patent was obvious, which was subsequently invalidated by the IPO. Gilead lodged an administrative appeal with the IP court, which sustained the decision and dismissed the case.

Main technical features of ‘270 patent

The technical features of claim 1 of ‘270 patent:

(1A) A pharmaceutical composition for the treatment or prevention of the symptoms or effects of an HIV infection in an infected animal which comprises: (1B) tenofovir disoproxil fumarate (TDF)

(1C) emtricitabine (FTC)

(1D) wherein the TDF and the FTC are present in a weight ratio of about 1:50 to about 50:1

(1E) in the form of a tablet

Main issue of this case

Evidence 2 has disclosed the active ingredient of ‘270 patent, TDF and FTC, and suggested to use co-formulation of TDF and FTC. The main difference is that Evidence 2 does not disclose the ratio specifically (i.e., feature 1D). Is Evidence 2 then sufficient to prove that claim 1 of ‘270 patent is obvious?

Argument of Gilead

1. TDF and FTC have relatively low pKa values and tend to hydrolyze. Also, TDF has the lowest stability at pH 7~8 but FTC has the highest stability at pH 7.2. The inherent pH dependence and stability of TDF and FTC are contrary to each other. A person skilled in the art would not be motivated to compress TDF and FTC into a single tablet.

    

2. The composition of ‘270 patent has synergistic antiviral effect and the data related to the co-formulation of TDF and FTC provided by Gilead during invalidation demonstrates unexpected high synergistic antiviral activity against both HIV-1 bison and mutant strain. Therefore, the invention of ‘270 patent generates an unexpected effect.

    

The Opinion of the IP court

The IP court believed that Evidence 2 should be sufficient to prove that claim 1 of ‘270 patent is obvious and should be invalidated. The reasons are as follows:

1. Evidence 2 specifically disclosed a co-formulation of TDF and FTC for the treatment of HIV, which could result in the first combination product dosed as one pill. Furthermore, adjusting the composition ratio of a pharmaceutical composition to appropriately improve drug efficacy can be easily accomplished by a person skilled in the art through simple test (such as optimization test of composition ratio) in accordance with practical need, and the result is reasonably predictable. Evidence 2 also disclosed specifically that TDF and FTC do not have overlapping drug resistance mutation and they have high compatibility. Thus, TDF and FTC may form co-formulation. In addition, Evidence 2 taught that the only need is a CMC (chemistry, manufacturing and controls) package plus a bioequivalence study to show that co-formulated tablet gives human the same exposure to the individual components. The work involved is not that much. A bioequivalence study takes 4 weeks or so.

    

2. In response to Gilead’s first argument, merely based on the pKa level of TDF and FTC, or the optimal pH range thereof which is not vulnerable to hydrolyze do not overlap, the court considered that it is difficult to conclude that it may inevitably fail to manufacture the claimed co-formulated tablet due to stability or degradation. Furthermore, there are many factors such as compatibility of ingredients, drug resistance mutation, suitability for processing, pH value and so on affecting the stability of a pharmaceutical. That is to say, even if there are some slight conflicts between the ingredients in a drug due to a certain factor (such as pH), those skilled in the art would adjust other factors to moderately mitigate the influence of the certain factor, and then obtain a composition with reasonable stability. Stability test is one of essential items for drug registration application or marketing authorization. Therefore, to put the pharmaceutical composition into practice, a person skilled in the art will consider all the influential factors mentioned above and thus the invention of ‘270 patent can be easily accomplished through routine experiments (such as optimization tests of ingredients, composition, ratio, pH).

    

3. As for Gilead’s second argument, the court held that unexpected effects include generating new properties or significant change in quantity. In terms of the change in the level of quantified value of the effects, the evidence submitted by Gilead is not sufficient to prove the general expected level of quantified value of the effects for a person skilled in the art. It is hard to confirm that the change in the quantified value of the effects of the drug in ‘270 patent achieves a particularly good level that a person skilled in the art can expect according to the data, not to mention to believe that the change in the quantified value of the effects increased to an unexpected level. The data provided by Gilead during invalidation action comes from the test of combination of FTC and pharmaceutical substance TFV (not its prodrug, TDF). It is hard to believe that the demonstrated effects are directly generated by the technical feature of the ‘270 patent. Also, the combination of TFV and FTC is tested only at a specific concentration while the ratio of the two ingredients defined in the ‘270 patent ranges from 50:1 to 1:50. Based on the uncertainty of the correlation between the drug efficacy and ingredients concentration, it is still hard to conclude that a person skilled in the art can confirm all the concentration in the range mentioned above may generate the effects merely in accordance with the efficacy of specific concentration. Therefore, it cannot be concluded that the invention of ‘270 patent has unexpected effects.