Intellectual Property Battles in Solid-State Chemistry

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.

Patricia Van Arnum

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).

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).

Technical considerations

Although intellectual property concerns play a role in the development of pharmaceutical solid forms, the rationale to use a particular solid form (e.g., salt, polymorph, or cocrystal) of an API is dictated by the target product profile and encompasses various factors, such as bioavailability, physical and chemical stability, desired dissolution properties, the impurity profile of the API, drug-substance hygroscopicity, morphology, size distribution, compaction properties, and the ability to formulate the drug (6).

In the case of polymorphs, for example, screening for and identifying polymorphs when developing and manufacturing APIs is an ongoing challenge for pharmaceutical manufacturers. Polymorphism is the ability of a compound to exist in more than one crystalline structure. Polymorphs or other solid forms are identified using a polymorph study or screen (6). Different solid forms can possess different properties, including solubility, which, in turn, can affect the bioavailability of the drug.

One of the more well-chronicled examples of polymorphism occurred in ritonavir, the API in Norvir, a protease inhibitor developed by Abbott Laboratories (now AbbVie), The drug was approved in 1996, and in mid-1998, Abbott encountered manufacturing difficulties with the capsule formulation (5). Ritonavir exhibited conformational polymorphism of two unique crystal lattices that had significantly different solubility properties (6, 7). The formation of the polymorph caused Abbott to pull the drug from the market and reformulate.

Polymorph stability is evaluated experimentally by monitoring the phase transition of the different polymorphs in different crystallization media and at different temperatures by using in-situ monitoring probes and analytical solid-state methods (6). These data are used to manufacture the desired polymorph and to control it through the various manufacturing steps. Polymorphs can undergo phase transitions when exposed to a range of manufacturing processes, such as drying, milling, micronization, wet granulation, spray drying and compaction. Exposure to environmental conditions, such as humidity and temperature, also can induce polymorph transition. The extent of transition depends on the relative stability of the polymorphs, kinetic barriers to phase transition, and applied stress (6). Moreover, the physical stability of polymorphs may be monotropic or enantiotropic, where the relative thermodynamic stability between the two forms can be inverted with temperature (6). Additional considerations are made when the physical form of the drug-substance may be modified in the formulation process, such as in hot-melt, lyophilization, solubilization or suspension in a semisolid matrix. Drug substance–excipient interactions also are considered when stabilizing particular physical and other process parameters that may affect the performance or quality of the product.

References

1. Indian Supreme Court, Civil Appeal No. 2728 Novartis AG vs. Union of India and Others (Mumbai, 2013).

2. J. Zimmerman, "Pyrimidine Derivatives and Processes for the Preparation Thereof (US Patent No,521,184), 28, May, 1996.

3. R. Ahmed, "India Revokes Roche Patent," Wall Street Journal, Nov. 3, 2012.

4. J.F. Tremblay, C&E News, 90 (38), 9 (2012).

5. S. Houlton, "India Rejects Novartis Patent Appeal," Chemistry World Apr. 8, 2013.

6. P. Van Arnum, Pharm. Technol. 35 (7), 44-48 (2011).

7. SEC, Abbott 10-K Annual Report (Washington, DC, 1998).

Patricia Van Arnum is a executive editor of Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com.