The China National Intellectual Property Administration (CNIPA) has issued landmark decisions upholding the validity of a crystal form patent for the antidepressant drug Vortioxetine, establishing significant precedents for pharmaceutical intellectual property in China.
The decisions (No. 48337 and No. 48339) specifically addressed both clarity and inventiveness requirements for crystal form patents, which have become increasingly important in China's pharmaceutical patent landscape.
Crystal Form Patents Gain Strategic Importance in China
Crystal form patents for pharmaceuticals have seen a sharp increase in China recently, yet they remain outside the country's patent linkage system. This creates a complex situation where generic manufacturers who successfully challenge a compound patent may still be unable to market their products due to existing crystal form patents.
This regulatory gap has elevated the strategic importance of crystal form patent invalidation requests, as they can become critical barriers to market entry even after successful compound patent challenges.
The Vortioxetine Patent Case
The disputed patent (ZL 200780022338.5) covers the β-type crystal form of Vortioxetine hydrobromide, the active ingredient in the antidepressant medication Brintellix®. Since 2018, both the compound patent (ZL02819025.4) and this crystal form patent have survived multiple invalidation challenges in China.
The patent claims the specific β-type crystal form characterized by its X-ray powder diffraction (XRPD) pattern, along with compositions containing this form and its use in treating neurological diseases.
CNIPA's Ruling on Clarity Requirements
Invalidation requesters had argued that Claim 1 lacked clarity because the XRPD pattern referenced in the claim contained over 30 characteristic peaks, while the specification only described four main peaks without specifying all peak values.
The CNIPA examiner rejected this argument, noting that it is standard practice in the field to define crystal forms using selected main characteristic peaks rather than exhaustively listing all diffraction peaks. The specification had adequately disclosed the main characteristic peaks at 6.89, 9.73, 13.78, and 14.62(°2θ), providing sufficient information for a skilled person to understand and distinguish the claimed β-type crystal form.
Landmark Decision on Inventiveness
More significantly, the CNIPA established important criteria for evaluating the inventiveness of crystal form patents. The examiner emphasized that unexpected technical effects must consider not only differences between various salt forms but also between different crystal forms of the same salt.
The patent specification provided comprehensive data on the melting point, hygroscopicity, and solubility of multiple crystal forms, demonstrating that the β-type crystal form of Vortioxetine hydrobromide achieved a unique balance of properties:
- Higher melting point (indicating greater stability)
- Lower hygroscopicity (beneficial for storage and handling)
- Appropriate solubility (advantageous for oral tablet formulations)
The examiner noted that achieving this optimal balance of properties represented an unexpected technical effect not suggested by prior art. While forming salts typically increases solubility and crystallization often reduces it, the β-type crystal form successfully maintained appropriate solubility while gaining the stability and low hygroscopicity benefits of crystallization.
Implications for Pharmaceutical Patents in China
This decision establishes important precedents for evaluating crystal form patents in China:
- Crystal forms can be adequately defined by referencing XRPD patterns and main characteristic peaks without exhaustively listing all peaks
- Inventiveness can be established through a balanced combination of beneficial properties, even when individual properties might be expected
- The "balance" of multiple favorable properties can constitute an unexpected technical effect sufficient to demonstrate inventiveness
For pharmaceutical companies, this ruling underscores the strategic value of developing and patenting specific crystal forms with optimized property profiles, particularly in the Chinese market where such patents can provide extended market exclusivity beyond compound patents.
Industry Impact
For generic manufacturers in China, this decision highlights the importance of comprehensive patent landscape analysis beyond just compound patents. The exclusion of crystal form patents from China's patent linkage system creates a potential trap where successful compound patent challenges may still not enable market entry.
For innovator companies, the ruling reinforces the value of robust crystal form patent portfolios as part of a comprehensive IP strategy in China, potentially extending market exclusivity beyond primary compound patents.
The case also demonstrates China's evolving approach to pharmaceutical patent evaluation, with increasing sophistication in assessing technical effects and unexpected advantages of crystal forms—a trend likely to influence future patent strategies for both innovator and generic companies in this important market.
