Part II - First Victory for Generic Drug Company: Bayer’s Anti-cancer Drug Nexavar® Patent Successfully Challenged under New Patent Linkage System
Date: 28 January 2022
【Volume 71】Previously, we covered the background, technical features and some court opinions regarding two Bayer’s cancer drug patents, the polymorph patent of sorafenib tosylate (Certificate No.: I382016, “‘016 patent”) and the pharmaceutical composition patent thereof (Certificate No.: I382016, “‘928 patent”), that were successfully challenged by Synmosa under Paragraph IV declaration, marking the first victory for Taiwan generic drug manufacturers. In this article, we analyze the remainder of the court decision and offer our suggestions.
IP Court’s Opinion (Continued)
3. The process for preparing polymorph I (“melt crystallization”, “recrystallization in inert solvent”, “crystal seeding”) recited in dependent claims 4-6 of ‘016 patent are all well-known technical means:
Bayer did not provide any examples and comparative examples in the specification proving that the claimed technical method produces unexpected effects compared to methods of other polymorphs. In addition, although Bayer has set parametric ranges for the melting point, cooling temperature, heating rate and cooling rate for melt crystallization in claim 6, the step “melt crystallization” has already been disclosed by prior art. Though the prior art did not disclose actual values, ‘016 patent also did not provide any documentation (e.g. examples and comparative examples) to reasonably prove the features in the dependent claims may produce unexpected effects compared to the prior art. Despite the slight difference in values, it may still be achieved by a person skilled in the art through simple tests on the basis of prior art, and the effects may be reasonably expected. Bayer was thus unable to prove the inventive step of claims 4-6 of the ‘016 patent.
4. A skilled person is motivated to increase the purity of polymorph I of sorafenib tosylate in a pharmaceutical composition:
Claim 9 of ‘016 patent further defines the purity of polymorph I of sorafenib tosylate in a pharmaceutical composition as exceeding 90%. However, in order to enhance drug stability, increasing the proportion of stable polymorph in a compound and thereby maintaining the quality of the active ingredients and ensuring effective treatment is common general knowledge in the pharmaceutical field. Accordingly, “the purity of polymorph I of sorafenib tosylate present at over 90% in a pharmaceutical composition” can be easily accomplished by a skilled person through simple test.
5. Bayer failed to prove the unexpected effects of the high drug load feature in ‘928 patent:
Claim 1 of ‘928 patent is directed to a pharmaceutical composition in tablet form, which comprises sorafenib tosylate as an active agent in a portion of at least 55% by weight of the composition (high drug load), and at least one pharmaceutically acceptable excipient. In view of prior art, the sole distinguishing feature of claim 1 is the specific drug load (55%) of sorafenib tosylate in a tablet, and the other features are disclosed by the prior art and are also general knowledge in the pharmaceutical field.
Bayer argued that since many technical problems, such as compaction properties, process stabilities, etc., should be considered when preparing high drug load tablets, blindly increasing the concentration of sorafenib tosylate in a tablet and neglecting stability, hardness, releasing time and other properties of a drug cannot result in the successful production of high drug load tablets.
However, the court considered that based on the high administration dosage of sorafenib tosylate disclosed by prior art, a skilled person would be motivated to increase the concentration of sorafenib tosylate in a single tablet to facilitate patient compliance. In addition, no examples or comparative examples are described in the specification of ‘928 patent to prove the unexpected effects of the tablets of sorafenib tosylate at a specific drug load (55%). Also, for improving the efficacy of a pharmaceutical composition, said specific value (55%) would be obviously achieved through routine experiments and simple changes by a skilled person.
6. The desirable dosage forms, micronized particle sizes, and composition or percentage of excipients can all be easily accomplished through routine experiments and simple selection by a skilled person:
Claim 6 of ‘928 patent contains an additional limitation on the dosage form, which is an immediate release tablet. Claims 7, 8 relate to micronized active agent and its particle size. Claims 4, 5 define specific types of excipients and specific ranges thereof. Claim 9 relates to a certain water content of the claimed pharmaceutical composition.
However, the selection of dosage forms, micronized particle sizes, and composition or percentage of excipients are all general practice for preparing pharmaceuticals. Further, only a single example regarding the dosage form of immediate release tablet is described in the specification without comparative examples relating to other dosage forms of the pharmaceutical composition, which fails to prove the superior effects of the claimed composition as immediate release tablets. Also, no comparative example is provided to prove the differences in the efficacy of the claimed tablets which are prepared based on different particle sizes, different types or ratio of excipients. Accordingly, the selection of dosage forms, micronized particle sizes, and composition or percentage of excipients are all common issues which need to be considered to improve the efficacy of a pharmaceutical composition, and can be accomplished with common knowledge by a person having ordinary skill in the art.
7. When determining the inventive step of the claimed invention with the secondary considerations of commercial success, such success must be brought directly by the technical features of the invention:
Bayer argued that the patented drug “Nexavar® film-coated tablets”, ranking seventh in the 2015’s best-selling domestic pharmaceuticals, achieved commercial success due to the inventions of ‘016 patent and ‘928 patent, which proved the inventive steps of the claimed inventions. However, the court held that whether a claimed invention achieves commercial success is a secondary consideration in affirming inventive step depends on if such success is brought directly by the technical features of the invention, rather than other factors such as sales technique or advertisement. There are at least three factors that affect how well a patented drug sells, namely existence of obstructive patents, sufficiency of capital cost and marketing of the pharmaceuticals. Also, pharmaceutical corporations with abundant funds are more likely to successfully market a patented drug for clinical treatment. Accordingly, Bayer’s argument was rejected.
Wisdom Analysis and Suggested Strategies
Our client Synmosa became the first entity ever to successfully challenge a new drug patent under Paragraph IV declaration since the patent linkage system took effect. This judgment is a great encouragement for generic drug manufacturers. For litigation derived from patent linkage, the first-instance verdict must be issued within one year after the suit is filed by the plaintiff, and trials are held on a more intensive and swifter schedule. Accordingly, before filing an Abbreviated New Drug Application (ANDA) under Paragraph IV declaration, generic drug manufacturers shall formulate defensive strategies and be well prepared for potential litigation in the future. In addition, according to adjudication procedure of patent infringement litigation in Taiwan, the judge usually requires the plaintiff and the defendant to determine the issues in question on the date of the first oral argument. If the generic drug company claims that the patent shall be revoked, then it must provide all evidence and determine the combination of the evidence on the date of the second oral argument. No new evidence or new combination of the evidence may be introduced after that. Consequently, before making a Paragraph IV declaration, the generic drug company is recommended to conduct detailed prior art search and invalidation analysis to establish the evidence for invalidation and its combination well in advance.
On the other hand, the critical reason for Bayer’s failure in this case is that no examples and comparative examples are provided in the specification of the patents to prove the claimed technical features, including the claimed polymorph, process for preparing the polymorph, selection of the dosage form, micronized particle size, types and amounts of the excipients and so on, showing unexpected effects compared to prior art. The Taiwan IP Court holds stricter standards on patent validity than the Intellectual Property Office. Therefore, in many pharmaceutical patent lawsuits, the patentee lost because they all failed to evidence the inventive steps due to insufficient disclosure of examples and comparative examples in the specification.
In addition, this case relates to a crystalline form patent. The compound of a crystalline form patent is usually disclosed by prior art, and the technical effects given by a specific crystalline form of a drug, such as stability, purity, well bioavailability, solubility, storage durability and so on, are well known in the art. Hence, the crystalline form of a known compound lacks inventive steps unless the claimed crystalline form produces a significant enhancement of efficacy (i.e., a quantitative change) or a new performance (i.e., a qualitive change) as compared with prior art. The proof of above-mentioned technical effects largely relies on experimental data, so the requirements for experimental data in crystalline form patent may be higher. Accordingly, when filing a patent application relating to the crystalline form of a drug, pharmaceutical companies shall provide detailed description of the technical effects of the claimed crystalline form, and these technical effects must be supported by sufficient experimental data to ensure the validity of such patent.
