Date: 24 January 2025

【Volume 148】

Pharmaceutical crystalline patents are commonly characterized by X-ray powder diffraction (XRPD) patterns. However, how many 2θ degrees are required to define a crystalline structure with clarity is not explicitly stipulated under Taiwan Patent Examination Guidelines. In an invalidation case concerning the crystalline patent of Novartis' drug Tasigna® (Nilotinib), both Intellectual Property and Commercial Court (IP Court) and the Supreme Administrative Court in Taiwan specifically presented the judgment criteria. The courts held that even a single XRPD value can satisfy the clarity requirement if it effectively distinguishes the crystalline form from other polymorphs. Conversely, if the values used to define lead to overlapping features or fail to distinguish between polymorphs, they may violate clarity requirements.

Additionally, this case involves the judgement of inventive step for pharmaceutical compounds in hydrate and polymorph forms. The current Patent Examination Guidelines¹ only address the criteria for evaluating obviousness in situations involving known compounds. However, in NOVARTIS AG v. Lotus Pharmaceutical Co. Ltd., it does not pertain to such known compounds as specified in the guidelines. Accordingly, the courts adopted a step-by-step reasoning process based on the evidence provided by Lotus. First, the court determined whether the existence of the pharmaceutical compound in a hydrate form is predictable or confirmable. Then, the court considered whether the evidence provides a motivation to seek crystalline forms with favorable characteristics (e.g., stability, solubility).

The following provides a detailed analysis of the specific reasoning by the IP Court and the Supreme Administrative Court:

Case Fact

Taiwan Invention Patent No. I406661 (hereinafter referred to as ‘661 patent), held by Novartis, pertains to the crystalline patent associated with Tasigna®. The ‘661 patent covers crystalline form A (claims 2 and 3) and crystalline form B (claims 11 and 12) of Nilotinib, as well as pharmaceutical compositions thereof (claims 37 and 38). Lotus filed an invalidation action against the '661 patent, alleging violations of the enablement, clarity, and support requirements, along with lack of an inventive step. However, the Taiwan Intellectual Property Office (TIPO) dismissed the invalidation action, affirming the validity of claims 2-3, 11-12, and 37-38 of the ‘661 patent.

Lotus appealed to the Ministry of Economic Affairs (MOEA) which partially overturned the TIPO's decision by revoking the TIPO’s ruling of “findings that claims 11-12 and 37-38 were valid”. Both Novartis and Lotus subsequently filed administrative lawsuits over unfavorable parts of the MOEA’s decision. The IP Court sided with the MOEA’s opinion on the invalidity of claims 11-12 and 37-38 of the ‘661 patent, finding violations of the enablement, clarity, and support requirements in these claims². However, the IP Court differed from the opinions of both the TIPO and MOEA on claims 2-3, judging that claims 2-3 of the ‘661 patent failed to meet the requirements for enablement, clarity and support, and were also deemed obvious³.

Although Novartis appealed to the Supreme Administrative Court, the court dismissed the appeal, and the judgment became final and binding⁴⁵.

Major Technical Features of '661 patent

1. Crystalline Form A of Nilotinib Hydrochloride Salt as a “Dihydrate”
   1. Claim 1 has been deleted after post-grant amendment, and the interpretation of Claim 2 still includes all the technical features of Claim 1. Its scope can be interpreted as:
      A substantially pure crystalline form A of Nilotinib hydrochloride salt “dihydrate”, characterized by an XRPD pattern having “at least one” maxima selected from 8.5°, 11.0°, 11.5°, 17.2°, 18.8°, 19.2°, 20.8°, 22.1°, and 26.0° (2θ degrees); wherein “substantially pure” means that more than 50% of crystalline Nilotinib hydrochloride salt dihydrate is present in said crystalline form.
   2. Claim 3, dependent on Claim 2, can be interpreted as follows:
      A substantially pure crystalline form A of Nilotinib hydrochloride salt “dihydrate”, characterized by an XRPD pattern having “at least four” maxima selected from 8.5°, 11.0°, 11.5°, 17.2°, 18.8°, 19.2°, 20.8°, 22.1°, and 26.0° (2θ degrees).

2. Crystalline Form B of Nilotinib Hydrochloride Salt as a “Monohydrate”

1. Claim 10 has been deleted after post-grant amendment, and the interpretation of Claim 11 still includes all the technical features of Claim 10. Its scope can be interpreted as:
   A substantially pure crystalline form B of Nilotinib hydrochloride salt “monohydrate”, characterized by an XRPD pattern having “at least one” maxima selected from 7.2°, 9.2°, 11.4°, 12.0°, 12.3°, 14.6°, 14.8°, 15.7°, 17.6°, 19.2°, 19.5°, 20.5°, 22.0°, 23.4°, 23.9°, 25.0°, 25.5°, 25.9°, and 27.0° (2θ degrees); wherein “substantially pure” means that more than 50% of crystalline Nilotinib hydrochloride salt monohydrate is present in said crystalline form.
2. Claim 12, dependent on Claim 11, can be interpreted as follows:
   A substantially pure crystalline form B of Nilotinib hydrochloride salt “monohydrate”, characterized by an XRPD pattern having “at least four” maxima selected from 7.2°, 9.2°, 11.4°, 12.0°, 12.3°, 14.6°, 14.8°, 15.7°, 17.6°, 19.2°, 19.5°, 20.5°, 22.0°, 23.4°, 23.9°, 25.0°, 25.5°, 25.9°, and 27.0° (2θ degrees).

Main Disputed Issue

1. Does defining the crystal structure by "at least one" or "at least four" XRPD maxima lack clarity and violate the enablement and support requirements?
2. Can the combination of the evidences prove crystalline form A of Nilotinib hydrochloride dihydrate obvious?

IP Court and Taiwan Supreme Administrative Court’s Opinions

1. Crystalline form A and B fail to meet the clarity requirement:

Lotus argued that according to the Chinese Pharmacopoeia, European Pharmacopoeia, and United States Pharmacopeia, identifying crystalline types using XRPD typically requires the inclusion of 10 (2θ degrees) peak values to sufficiently characterize the XRPD pattern. This level of detail allows those ordinarily skilled in the art to determine the crystalline form accurately.

However, the court pointed out that, from the perspective of pharmaceutical ingredient development, it is essential to disclose and fully understand the characteristics of the substance as comprehensively as possible. Therefore, if multiple peak values are detected, they should ideally all be disclosed. Nevertheless, the clarity requirement under Paragraph 2, Article 26 of the Taiwan Patent Act differs in nature from the spirit of pharmaceutical ingredient development. According to the relevant provisions in the current Taiwan Patent Examination Guidelines regarding the crystallization of compounds⁶, the critical point is to establish a distinction from prior art. The guidelines do not explicitly stipulate the number of XRPD peaks required to clearly define the crystalline characteristics of a compound. Therefore, as long as the XRPD peaks used to define sufficiently distinguish the crystalline form from prior art or adequately describe the necessary technical features, the definition is considered satisfactory. However, based on the reasons outlined below, the court found that crystalline form A and B of Nilotinib in the ‘661 patent, characterized by "at least one" or "at least four" 2θ degrees maxima in the XRPD pattern, presented an issue of unclear definition.

1. Regarding the crystalline form A of Nilotinib, with reference to the XRPD patterns of other crystalline forms described in the '661 patent, the court considered that a person ordinarily skilled in the art would understand that one or two XRPD maxima of the crystalline forms A”, B, B’, SB, SB’, C, and SE, such as 11.5°, 19.2°, 20.8°, 22.1°, and 26.0°, overlap with those of crystalline form A.
   If the crystalline form A is defined by one XRPD maxima value, such as 11.5°, to determine its crystal structure, it could potentially overlap with one of the XRPD maxima value of crystalline form A", crystalline form B', or crystalline form SB (11.5°). This would lead to confusion for those ordinarily skilled in the art, making it unclear whether it refers to "substantially pure crystalline form A", "substantially pure crystalline form A"", "substantially pure crystalline form B'", or "substantially pure crystalline form SB". This results in the omission of necessary technical features and thus an unclear description.
   Moreover, if the crystalline form A of Nilotinib hydrochloride salt “dihydrate” and crystalline form B' (anhydrous form) of Nilotinib hydrochloride salt are both defined by one XRPD maxima value of "11.5°", this would result in different "molecular structures" but identical crystal structures. This clearly contradicts established pharmaceutical scientific principles, further confirming that the claims of the '661 patent omit necessary technical features and contain unclear descriptions.
2. In the case where crystalline form A is defined by "at least four" XRPD maxima values, there are no more than four identical 2θ degrees shared with the XRPD maxima values of other crystalline forms (A, A', A", B, B', SB, SB', C, C', SC, and SE) disclosed in the specification of the '661 patent.
   However, the '661 patent specification states, "The XRPD pattern for form A' (monohydrate) of the hydrochloride salt shows at least one, more preferably at least two, still more preferably at least four, and most preferably all, maxima selected from ‘about’ 4.3°, 8.6°, 11.6°, 12.1°, 17.1°, 20.6°, 24.5°, 25.3°, 25.8°, 27.3°, and 31.6°." Further, the '661 patent specification describes, “the term ‘about’ with regard to XRPD maxima values (in °) generally means within 0.3°, more preferably within 0.2°, and most preferably within 0.1° of the given value. Alternatively, the term ‘about’ means (in this and all contexts) within an accepted standard of error of the mean, when considered by a person ordinarily skilled in the art.” Therefore, considering the error ranges of "±0.2" and "±0.3," the XRPD maxima values of crystalline forms A', A", B, SB, C, and SC, with "at least four values," have error ranges that overlap with the XRPD maxima values of crystalline form A. Similarly, this would cause the claimed crystalline form A to be indistinguishable from the other crystal forms disclosed in the specification of the '661 patent, resulting in the omission of necessary technical features and an unclear description.

2. Violation of the Enablement Requirement:

As mentioned above, if crystalline form A is defined by “any one” or even “any two” of XRPD maxima values selected from 11.5°, 19.2°, 20.8°, 22.1°, and 26.0°, it could indicate that the crystalline form may contain other crystal forms with one or two XRPD maxima values identical to those of crystalline form A, implying a mixture of crystal forms. For example, if crystalline form A is defined by a single XRPD maxima value of 19.2°, the XRPD maxima value of crystalline form B also corresponds to 19.2°, which could result in the possibility of crystalline form A being mixed with crystalline form B. (Since the claims define "substantially pure" crystalline form A as comprising more than 50% crystalline form A, with other components including impurities, this definition does not rule out the possibility of the presence of other crystal forms.) However, when defined by only one or two identical XRPD maxima values, the specification of the '661 patent fails to disclose the technical means necessary to determine whether the content of crystalline form A exceeds 50% (relative to crystalline form A", B, B', SB, SB', C, and SE). This results in the corresponding specification content not being clearly and sufficiently disclosed, thus violating the requirements for enablement.

3. Lacking Written Description Support:

As mentioned above, defining crystalline form A or crystalline form B by "at least one" or "at least four" XRPD maxima values to characterize their crystal structures makes it impossible to distinguish them from other crystal forms disclosed in the '661 patent specification. Furthermore, such definitions may indicate the presence of mixed crystalline forms. The '661 patent specification does not disclose, under the “single crystalline form” embodiment, how to identify the defined crystalline form as crystalline form A, rather than other crystalline forms such as crystalline form A". Nor does it provide the means to determine the content of crystalline form A being more than 50% in the “mixed crystal form” embodiment. Therefore, the claimed invention cannot be supported by the specification.