Date: 18 February 2025

【Volume 149】

In the previous part, the clarity requirements for the crystalline forms of compounds were introduced, highlighting that crystal structures are often defined by numerical values such as XRPD. The court emphasized that these values must clearly differentiate between different crystalline forms to meet the clarity requirement. This article further explores the assessment of the inventive step of hydrates and crystalline forms of compounds. The court overturned the conclusions of the TIPO and the MOEA, ruling that the crystalline form A of Nilotinib hydrochloride salt dihydrate lacks an inventive step. The detailed reasoning is as follows.

1、The combination of Lotus Exhibits 11 to 13 fails to render ‘661 patent obvious:

Lotus Exhibits 11-13 demonstrate that Nilotinib hydrochloride salt belongs to prior art, with the difference from the ‘661 patent lying only in the absence of disclosure regarding the “crystalline form A of dihydrate” of Nilotinib hydrochloride salt. A person ordinarily skilled in the art would recognize the structural distinction between the anhydrous and dihydrate forms.:

Moreover, Lotus Exhibits 11 to 13 do not disclose whether Nilotinib hydrochloride salt can be identified or reasonably expected to exist in a “hydrate” form, nor do they explore the possibility of hydrate formation during the pharmaceutical development process. Furthermore, these Exhibits do not consider the potential impacts of a hydrate on the drug’s solubility, dissolution rate, bioavailability, and the chemical and physical stability of the formulation. Therefore, Lotus Exhibits 11 to 13 fail to provide a reasonable motivation for a person ordinarily skilled in the art to complete the dihydrate form of Nilotinib hydrochloride salt through routine experimentation. Let alone evaluating the effects of the various crystalline forms of this dihydrate on drug development and manufacturing processes to ultimately achieve its crystalline form A.

2、The combinations of Lotus Exhibits 11 to 14 and 17, Lotus Exhibits 11 to 14, 17, and 19, as well as Lotus Exhibits 11 to 14, 17, and 20, all fail to render ‘661 patent obvious:

Lotus presented new evidence, namely Lotus Exhibits 14, 17, and 19-21, during the administrative litigation. However, the court determined that Lotus Exhibit 14 only provides a general statement that salts of the compound represented by formula (I) (the broader concept of Nilotinib) could exist as hydrates, without offering any specific example demonstrating the preparation of hydrates of compounds under formula (I). Thus, it cannot be confirmed or predicted that the hydrochloride salt of the compound in Example 92 (i.e., Nilotinib) could form hydrates. Similarly, a person ordinarily skilled in the art would not be able to confirm or predict the existence of hydrates for Nilotinib hydrochloride salt based on the disclosure of Lotus Exhibits 17, 19, or 20.

3、The combination of Lotus Exhibits 11 to 14, 17, and 21 renders ‘661 patent obvious:

(1) A person ordinarily skilled in the art, by referring to Lotus Exhibit 21, would recognize the hydrate form of “Nilotinib hydrochloride salt” by routine works.

Lotus Exhibits 11 to 13 prove Nilotinib hydrochloride salt to be prior art. Lotus Exhibit 21 presents a strategic approach to drug registration regulations and guidelines from the Food and Drug Administration which, emphasizing the importance of controlling the crystal forms of drugs and the need for suitable analytical methods to measure polymorphs, hydrates, or amorphous forms of pharmaceutical compounds. Figure 6 of Exhibit 21 outlines the drug development process (tailored to meet the requirements reviewed for drug registration), suggesting that researchers should assess whether the pharmaceutical compound exists in hydrated or solvated forms. This involves testing with various recrystallization solvents and parameters, such as temperature, concentration, and pH value, followed by characterization through X-ray powder diffraction (XRPD). Additionally, the physical and chemical properties of any hydrates, including their stability and solubility, should be evaluated. Such procedures represent the standard practice in drug development.

Therefore, a person ordinarily skilled in the art, with reference to Lotus Exhibit 21, would easily recognize the hydrate form of “Nilotinib hydrochloride salt” through routine works, followed by a series of analyses to ascertain the physical and chemical properties of its various hydrates (e.g., stability). Ultimately, identifying the most suitable form to optimize these properties. Through these routine experiments, “Nilotinib hydrochloride salt dihydrate” could be easily achieved by a person ordinarily skilled in the art, based on the disclosure of Lotus Exhibits 11 and 21, with reasonable motivation.

(2) A person ordinarily skilled in the art, using “Nilotinib hydrochloride salt dihydrate” as a starting point for research, would have a reasonable motivation to accomplish crystalline form A through routine experiments.

According to “5.3.1.3 Inventive Step of Polymorphs of Compounds” of Chapter 13 Pharmaceutical-Related Inventions, Part II of Patent Examination Guidelines, it is described that: “if the claimed invention pertains to a polymorph of a known compound that differs only in crystalline form and the polymorph can generally be obtained through ‘routine experimental methods’, it is typically deemed that the polymorph of the known compound lacks an inventive step unless the polymorph demonstrates an unexpected effect compared to the known compounds.”

Lotus Exhibit 21 has disclosed the drug development process, indicating that researchers should evaluate whether the studied pharmaceutical compound exhibits polymorphism and examine the physicochemical properties of such polymorphs. Therefore, it is reasonable to be motivated to identify a suitable crystalline form during drug development. Although “Nilotinib hydrochloride salt dihydrate” has not been explicitly disclosed in prior art and does not fall under the definition of “a known compound” as stipulated in Section 5.3.1.3 of the Pharmaceutical-Related Inventions in Patent Examination Guidelines regarding the inventive step of polymorphs, it can still be obtained through routine experimental methods, as previously stated, and is therefore considered obvious. Based on the aforementioned guidelines, two or more polymorphs of the same structure that can be produced through routine experimental methods should be deemed non-inventive. Using “Nilotinib hydrochloride salt dihydrate” as a starting point, there exists a reasonable motivation to achieve a pure and stable crystalline form A through routine experimental methods. The crystalline form A can then be defined using X-ray powder diffraction values.

(3) Novartis failed to demonstrate the crystalline form A of Nilotinib hydrochloride salt dihydrate possessing an unexpected effect.

The court pointed out that Novartis, in its response submitted during the patent examination phase, stated that the “hydrochloride salt monohydrate” exhibited a bioavailability more than 13 times higher than that of the “free base”. However, “Nilotinib hydrochloride salt” belongs to prior art, and the invention in '661 patent concerns “Nilotinib hydrochloride salt dihydrate, crystalline form A”. In comparison with prior art, the data provided by Novartis does not demonstrate that “Nilotinib hydrochloride salt dihydrate, crystalline form A” has an unexpected effect when compared to “Nilotinib hydrochloride salt”.