Written by：Tina Tai，Jie Wei (Intellectual Property)
Legal Key Points
1. Determination of the Disclosure Sufficiency of the Salt Form of Pharmaceutical Compounds
2. Determination of the Inventiveness of the Salt Form of Pharmaceutical Compounds
Section I The Patent-in-Suit
This case involves an international non-patent drug named “eltrombopag”. Eltrombopag is a TPO receptor agonist used to promote platelet production and treat chronic immune thrombocytopenia (shown as abnormal low platelet count, abbreviated as ITP). Eltrombopag was originally invented and developed by GSK and NOVARTIS has obtained all rights and interests thereof including the present patent. Being approved by the National Medical Products Administration (NMPA) of China in December 2017, Eltrombopag was launched in China under the trade name Revolade® for the treatment of ITP. Revolade® entered the National Medical Insurance Catalogue in August 2019. Said drug’s global sales in 2020 exceeded 1.7 billion U.S. dollars with an increase of more than 20%.
The patent-in-suit is directed to a bis(monoethanolamine) salt of eltrombopag. The description discloses that the bis(monoethanolamine) salt of eltrombopag has a 14,200 fold increase in water solubility compared with the free acid of eltrombopag, thereby turning the insoluble free acid of eltrombopag into a slightly water-soluble salt form.
Invalidity Petitioner believed that the present patent does not meet the requirement for sufficient disclosure, and the reasons include the following.
(1) The bis(monoethanolamine) salt of eltrombopag may cover a variety of solid forms, including salt, co-crystal, or other clathrate or complex forms. The present patent does not provide any data to prove what form the obtained compound is. Because solubility depends on the specific form, those skilled in the art cannot confirm whether any specific form can solve the technical problem of improving the water solubility of the free acid of eltrombopag.
(2) The solubility of the bis(monoethanolamine) salt of eltrombopag in 0.1 M HCl is not improved, and no solubility data of eltrombopag or a salt thereof in a liquid environment with a pH value equal to that of gastric juice or blood are provided.
(3) The present patent discloses increase in bioavailability, but does not disclose any bioavailability data.
Invalidity Petitioner also believed that the present patent does not meet the requirement for inventiveness, and the reasons include the following:
(1) WO01/89457 discloses a compound of eltrombopag and a pharmaceutically acceptable salt thereof. The closest prior art should be determined as a pharmaceutically acceptable salt of eltrombopag, so the present invention should be a selection invention of said prior art, and therefore should require unexpected technical effects compared with other salts.
(2) Based on nearly 30 pieces of prior art exhibits submitted, Petitioner claims that salt formation will increase solubility, and that monoethanolamine is a known organic base and can be used to form salts with acidic drugs. There are 2 acidic groups in eltrombopag, so it is obvious that a 1:2 di-salt can be formed. The effect of the present patent in improving water solubility can also be expected by those skilled in the art.
Section II The Content of the Final Judgement/Decision
The China National Intellectual Property Administration (CNIPA) determined as follows.
1. Regarding disclosure sufficiency
The description of the present patent has disclosed the chemical name, structural formula, and preparation method of eltrombopag bis(monoethanolamine). The nomenclature of the chemical name complies with the general nomenclature for acid-base salts. The description also provides NMR and IR spectral data, further confirming that the obtained compound is in salt form. Example 5 discloses data proving that eltrombopag bis(monoethanolamine) achieves the technical effect of improving water solubility.
For the present patent, there is no exhibit showing that said compound is not a salt. Regarding the problem of no increase in solubility in 0.1 M HCl, the requirement for sufficient disclosure is satisfied as long as the solubility in water is improved compared with the free acid form. Generally speaking, the increase in the solubility of the compound helps increase the bioavailability.
Thus, the present patent satisfies the requirement for sufficient disclosure in the description.
2. Regarding inventiveness
For the closest prior art, the collegial panel believed that the general formula compound pointed out by Petitioner is not directed to a specific compound; while in the prior art, the examples thereof only disclose the free acid of eltrombopag, and do not disclose any specific salt form. Therefore, free acid is more suitable as the closest prior art, which is also consistent with the starting point for the invention of the present patent.
For technical effects, the collegial panel believed that the present patent explicitly discloses that the water solubility of the bis(monoethanolamine) salt of eltrombopag obtains a 14,200 fold increase compared with the free acid of eltrombopag. Although the prior art provides many teachings that salt formation can improve solubility, there are also many examples showing that salt formation cannot improve solubility or even reduces solubility, indicating that the effects of salt formation on solubility cannot be expected. Furthermore, in a large number of prior art, salt formation with organic bases can increase the solubility by only a few hundred folds, and salt formation with inorganic bases can only increase the solubility to about three thousand folds. Therefore, it is unexpected that the present invention achieves a 14,200 fold increase in water solubility.
For technical suggestion, the collegial panel believed that though the prior art discloses that some other specific compounds can form salts with monoethanolamine, these compounds are not similar in structure to eltrombopag, and the prior art does not disclose anything that can form a 1:2 disalt with monoethanolamine. One cannot predict whether or what kind of salt can be formed. Therefore, the eltrombopag bis(monoethanolamine) salt of the present invention is nonobvious.
In conclusion, the collegial panel determined that the patent-in-suit possesses inventiveness, and therefore upheld the validity of the patent-in-suit in its entirety.
Section III Discussion
It is worth noting that said decision is the only decision of the CNIPA in the past ten years supporting the inventiveness of the salt based on the technical effects of improved water solubility alone. In the past examination practice, it was generally believed that salt formation would improve water solubility, so regardless of the extent of the technical effects in improving solubility, it was not considered unexpected. But in this case, the salt-forming agent monoethanolamine is not a commonly used substance in the pharmaceutical field, and its water solubility is 14,200 folds higher than that of the free acid form, which is far beyond what can be expected in the prior art, therefore proving the inventiveness of the present patent.
In this case, the King & Wood Mallesons team had in-depth communication with Patentee, conducted thorough technical research and discussion on the substance of the invention, made sufficient preparation in terms of the substance spectra, relevant data, prior art exhibits and theoretical verification disclosed in the description of the patent, and anticipated the potential objections and exhibits Petitioner might put forward. In this case, Petitioner submitted more than 30 pieces of exhibits to prove that said patent should be invalidated. Agents from King & Wood Mallesons successfully maintained the validity of the patent by analyzing the contradictions of the comparative documents and discovering the non-obviousness of said special salt.
The maintenance of the validity in this case fully safeguards the commercial interests of the client. Given the expiration of the eltrombopag compound patent in May 2021, the maintenance of validity of said salt patent will enable the client to maintain the patent rights of said drug until 2023.