Part I - First Victory for Generic Drug Company: Bayer’s Anti-cancer Drug Nexavar® Patent Successfully Challenged under New Patent Linkage System

Date: 16 December 2021

【Volume 60】On 30 November, 2021, the Taiwan Intellectual Property Court (IP Court) made the first dismissal decision on a patent linkage-derived infringement suit, which was filed by the brand drug company Bayer HealthCare LLC against the generic drug company Synmosa Biopharma Corporation (IP Court 2021 Minzhuansuzi No. 8 Judgment [1] ). Wisdom successfully represented and assisted the defendant, Synmosa Biopharma Corporation, in obtaining a complete victory. Wisdom Director George J. H. Huang (Attorney at Law, Patent Attorney) led the team representing Synmosa.

Bayer v Synmosa is the first case where the court found in favor of the generic drug company ever since the patent linkage system took effect in Taiwan on 20 August, 2019 (for more information, see Wisdom News Volume 33). The case has attracted keen attention as another generic drug company, Lotus Pharmaceutical Co., Ltd, also made a Paragraph IV declaration against the same Bayer’s drug Nexavar while the present case was ongoing.

I. Background

The case involves the validity of two patents. The court deemed that all the claims (26 claims in total) of Bayer’s two corresponding patents, which refer to the polymorph patent of sorafenib tosylate (Certificate No.: I382016) and pharmaceutical composition patent thereof (Certificate No.: I324928), are invalid. Bayer’s complaint was therefore dismissed. In accordance with the Taiwan Pharmaceutical Affairs Act, Synmosa is granted a 12-month period of marketing exclusivity for the generic drug of “Nexavar ® film-coated tablets” for treating advanced liver cancer.

At present, in order to maintain the market of brand drug after the expiration of active pharmaceutical ingredients (API) patents, some globally well-known pharmaceutical corporations generally tend to extend the exclusive period with patents of various polymorphs or pharmaceutical compositions. Bayer v Synmosa is one of these cases. It is quite representative as it is also Taiwan’s first court decision determining the obviousness of the crystal form of a compound.

II. Main Technical Features of Bayer’s Patents

The two patents concerned are the polymorph patent of sorafenib tosylate (Certificate No.: I382016, “‘016 patent”) and the pharmaceutical composition patent thereof (Certificate No.: I324928, “‘928 patent”).

  1. ‘016 patent:

 (1) The technical features of claim 1 of ‘016 patent include:

(1A) A compound of the formula (I) (sorafenib tosylate)

(1B) in the polymorph I form, which shows in the X-ray diffractometry peak maxima of the 2 Theta angle of 4.4, 13.2, 14.8, 16.7, 17.9, 20.1, 20.5, 20.8, 21.5 and 22.9.

 (2) Claims 2-3 of ‘016 patent contain additional limitations that the claimed polymorph I shows specific peak in the IR spectrum and Raman spectrum.

 (3) Claims 4-6 of ‘016 patent relate to the process for preparing the polymorph I of claim 1, which recite different recrystallization methods, specifically by inert solvent (claims 4-5), melt crystallization (claim 6, which defines specific heating and cooling conditions), to convert the compound of formula (I) in the polymorph II form to the polymorph I form.

 (4) Claims 7-15 of ‘016 patent are directed to the medical use and the pharmaceutical composition of the polymorph I in claim 1.

 2. ‘928 patent:

 (1) Claim 1 of ‘928 patent is directed to a pharmaceutical composition, having the following technical features:

(1A) active agent in a portion of at least 55% by weight of the composition (drug load feature);

(1B) said active agent is sorafenib tosylate (active agent feature);

(1C) at least one pharmaceutically acceptable excipient selected from the group consisting of filler, disintegrant, binder, lubricant, and surfactant (excipient feature);

(1D) the composition is a tablet (dosage form feature).

 (2) Claim 2 of ‘928 patent relates to further limitation on the feature 1A, where the active agent present in the composition is at least 75% by weight; claim 3 relates to additional limitation on feature 1B, where sorafenib tosylate exists for at least 80% in the stable polymorph I; claims 4-5 relate to additional limitation on the feature 1C, where the claimed composition comprises the excipients in specific types, and in specific amounts; claim 6 relates to further limitation on the feature 1D, where the tablet is an immediate release tablet; claims 7-8 relate to further limitation on the feature 1B, where the active agent is micronized and with a particle size from 0.5 to 10 micrometer.

 (3) Claims 9-11 of ‘928 patent further define the water content of the claimed composition, as well as the combination with other therapeutic agents and the medical use.

III. IP Court’s Opinion:

  1. Bayer did not show that the polymorph I of sorafenib tosylate (i.e. the compound of the formula (I) in polymorph I) with thermodynamic stability produces unexpected effects, and thus failed to prove the inventive steps of the polymorph I:

    The ‘016 patent has disclosed in the [Background of the invention] of the specification that the compound of the formula (I) was mentioned in WO 03/068228 (Synmosa Exhibit 1). Therefore, “the compound of formula (I)” in the ‘016 patent (sorafenib tosylate) has been disclosed by prior art. The difference lies in that Synmosa Exhibit 1 does not disclose the polymorph I form of sorafenib tosylate, characterized by a specific X-ray diffractometry pattern.

    The ‘016 patent states in its specification that the purpose of the invention is provision of a thermodynamically stable form of sorafenib tosylate, which is the polymorph I, to avoid an undesired conversion to another polymorph during preparation of a pharmaceutical agent, which may affect the solubility and bioavailability of the pharmaceutical agent. However, Synmosa Exhibits 2, 3, 29, 30 , 31 respectively teach that a person skilled in the art may select the appropriate polymorph for thermodynamic stability. Moreover, a skilled person may understand that polymorphs are a common phenomenon in active pharmaceutical ingredients.

    As a result, with reference to the respective teachings of Synmosa Exhibits 2, 3, 29, 30, 31, a skilled person would be reasonably motivated to find the thermodynamically stable form of sorafenib tosylate through routine experiments (recrystallization or automated crystallization simulation system), and thus obtain the polymorph I. The feature values of the polymorph I can be obtained by standard X-ray diffractometry.

  2. The stability to mechanical stress exhibited by the polymorph I of sorafenib tosylate (i.e. the compound of the formula (I) in polymorph I) is not an unexpected effect:

Bayer also maintained that the ‘016 patent presented stability to mechanical stress, and supplemented experimental data (Bayer Exhibits 31, 32) during litigation with affidavits from two PhD holders. Bayer also submitted expert opinions and requested the court to summon an expert witness to testify at the Taipei Representative Office in the Federal Republic of Germany via video call.

The court nonetheless held that:

 (1) During micronization of active ingredients, external mechanical stress may cause a metastable polymorph to convert to a more stable polymorph. Thus, it is reasonably expected that a thermodynamically stable polymorph has better stability to mechanical stress. The two are positively correlated and is not an unexpected effect for a skilled person.

 (2) The expert’s testimony did not explicitly describe the milling conditions (e.g. methods, time, temperature and frequency of milling). As the conditions have significant impact on whether the polymorphs will convert to amorphous forms, the expert’s testimony shall not be taken into account.

More in Part II

Apart from the reasons above, the court further opined in its 130-page decision on obviousness determination on the parametric claims (including drug loads, micronized particle size, composition and percentage of excipients, etc.), as well as judgment on beneficial effects, determination on the evidence related to commercial success and so on, which is of great value for future pharmaceutical litigation. Our analysis of the remainder of the decision and our suggestions will be introduced in Part II.

 

 

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