Solid-form characterization and research are important for improving the understanding of and modification of the physical properties of APIs to ensure therapeutic benefit, optimize product development,and protect intellectual property. Although the primary goal early in drug development is to find a stable form of the drug, the potential patentability of other solid forms offers opportunities in maintaining product exclusivity or for product-life extension. Solid-state chemistry is of growing importance not only for pharmaceutical companies, but also for contract manufacturers and specialists serving the pharmaceutical industry.
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Recent intellectual property cases
In an era of increased generic-drug competition and growth in emerging markets where intellectual property laws may differ from developed markets, strategies in solid-state chemistry are ever-more important. This issue was brought into prominence with the recent ruling against Novartis by India's Supreme Court in the company's appeal to be granted a patent for the company's anticancer drug, Glivec/Gleevec (imatinib mesylate) in India. Although the ruling, which was issued on Apr. 1, 2013, has broader implications for intellectual property protection and the role of innovator drugs in India's market, it also serves as a useful example on how solid-state chemistry can play a role in building a patent estate.
At issue in the case was whether Glivec was considered an innovative product and, therefore, afforded protection under Indian patent law. Novartis had argued that the beta-crystal form of imatinib mesylate was novel and that it should be given patent protection under India law. India, which is part of the World Trade Organization, had amended its patent law in 2005 to assert that pharmaceutical companies had to prove enhanced clinical efficacy of their drugs over already patented compounds (1). In its ruling against Novartis, the Indian Supreme Court cited a 1996 patent (US Patent No. 5,521,184), which included several derivatives of N-phenyl-2-pyrimidine-amine, including imatinib, in a free-base form (2). Novartis asserted that it had first developed the methanesulfonic acid addition salt, imatinib mesylate, and later the beta-crystalline form of the salt, which had improved properties, such as flow, thermodynamic stability, and lower hygroscopicity compared with the alpha-crystal form. The India Supreme Court, however, ruled that the beta-crystalline form of imatinib failed to meet the tests of "invention" and "patentability" under Indian law (1).
Patricia Van Arnum
Novartis had filed a Special Leave Petition with the Indian Supreme Court in 2009 challenging the denial of the Glivec beta-crystal form patent on two grounds based on Sections 3(d) and 3(b) of the Indian patent law. In addition to seeking a patent for Glivec, the company filed the case to help clarify these aspects of the patent law.
"Novartis has never been granted an original patent for Glivec in India," said Ranjit Shahani, vice-chairman and managing director, Novartis India Limited, in an Apr. 1, 2013 company's statement. "We strongly believe that original innovation should be recognized in patents to encourage investment in medical innovation especially for unmet medical needs. We brought this case because we strongly believe patents safeguard innovation and encourage medical progress, particularly for unmet medical needs. This ruling is a setback for patients that will hinder medical progress for diseases without effective treatment options."
The recent ruling against Novartis followed another court ruling in India against a large pharmaceutical company as it related to a solid form. In September 2012, Roche lost a case in the High Court of Delhi, where it had argued that the Indian drug producer Cipla was infringing on its patents by selling a generic version of the anticancer drug Tarceva (erlotinib). In its ruling, the court sided with Cipla's contention that Tarceva is based on a different polymorph of the active ingredient erlotinib than the one Roche patented in India. Roche had attempted to patent the different polymorph, but the India court had rejected it as too similar to the patented one (3, 4).
Other cases outside of India are of interest as well. For example, in March 2013, the US Patent and Trademark Office (USPT0) rejected an appeal by Boehringer Ingelheim against its refusal to patent the mesylate salt form of the thrombin inhibitor Pradaxa (dabigatran). In its decision, the USPTO asserted that a salt form of the drug was an obvious choice given that the drug molecule had poor solubility and an ionizable center (5).