Background

The Supreme Court of India (SCI) recently considered an appeal by Novartis against the rejection of their patent application by the Indian Patent Office. The patent application in question related to a salt of the known biologically active compound imatinib. Imatinib mesylate is marketed by Novartis under the trade name Glivec® for the treatment of various cancers.

Imatinib in free base form was invented by Jürg Zimmermann in the early 1990s and was patented in both the US and Europe (US 5521184 and EP 0564409) in an application covering a number of derivatives of N-phenyl-2-pyrimidineamine. Novartis subsequently developed the mesylate salt and filed a patent application covering imatinib mesylate, the beta crystalline form of imatinib mesylate, processes for the manufacture of the mesylate salt and medicinal use of the mesylate salt. This later filed application (Indian Patent Application No. 1602/MAS/1998) was the subject of the appeal to the SCI, it having previously been rejected by the Patent Office and the Intellectual Property Appellate Board under Section 3(d) of the Indian Patents Act.

The Law

As with most jurisdictions, Indian patent law requires that a chemical compound is novel and inventive if it is to be patented. However, Section 3(d) of the Indian Patents Act (the Act) also prevents patents being granted for:

the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant.”

Explanation. - For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.”[Emphasis added]

Therefore, when seeking patent protection for a new “form” of a known biologically active compound in India, an additional patentability test must be applied, namely does the new form possess improved efficacy compared to any known form(s) of the compound?

The Decision

In the present case, Novartis argued that both imatinib mesylate and the beta crystalline form of imatinib mesylate possess enhanced efficacy (relative to the alpha crystalline form) and hence both the salt and the beta crystalline form of the salt should be patentable.

The SCI considered imatinib mesylate and the beta crystalline form of imatinib mesylate to be two separate inventions. The first invention was rejected on the grounds that imatinib mesylate was a known substance at the effective filing date of Novartis’ patent application (partly because when filing a New Drug Application for imatinib mesylate in the US Novartis stated that US 5521184 covered imatinib mesylate and when applying for a patent term extension for US 5521184 Novartis again stated that the patent covered imatinib mesylate).

The second invention, relating to the beta crystalline form required careful consideration of Section 3(d) of the Act. In its judgement the SCI referred to the text of Novartis’ patent application which stated that:

It goes without saying that all the indicated inhibitory and pharmacological effects are also found with the free base, 4- (4- methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3-yl) pyrimidin-2-ylamino)phenyl] benzamide, or other salts thereof. The present invention relates especially to the b-crystal form of the methanesulfonic acid addition salt of a compound of formula I in the treatment of one of the said diseases or in the preparation of a pharmacological agent for the treatment thereto.” [Emphasis added]

The SCI considered that this disclosure showed that the pharmacological properties of the beta crystalline form of imatinib mesylate were the same as imatinib in its free base form or in the form of a salt. Therefore, the beta crystalline form of imatinib mesylate could not be said to possess enhanced therapeutic efficacy compared to imatinib mesylate.

Novartis submitted affidavits explaining that the beta crystalline form of imatinib mesylate had superior physical properties compared to the alpha crystalline form of imatinib mesylate, namely improved (i) flow properties, (ii) thermodynamic stability, and (iii) lower hygroscopicity. However, the SCI considered that, although such physical properties may be beneficial, they could not be taken into account for the purpose of Section 3(d) since they had not been demonstrated to affect therapeutic efficacy. On this basis, those claims directed to the beta crystalline form of imatinib mesylate were rejected.

Conclusions

This decision confirms that for a new form of a known pharmaceutical to be considered patentable in India, it must possess improved therapeutic efficacy relative to known forms of that compound. Properties that do not relate to therapeutic efficacy, such as improved stability, will not be taken into account when assessing whether or not a new form of a pharmaceutical meets the requirements of Section 3(d) of the Act.

In its decision, the SCI stated that Section 3(d) of the Act does not bar patent protection for all incremental inventions of chemical and pharmaceutical substances. However, this statement is difficult to reconcile against the reality that demonstrating improved therapeutic efficacy is generally far easier said than done. In practice, acquiring such data requires undertaking costly and time-consuming clinical trials, the outcome of which is seldom certain. It remains to be seen whether data derived from animal models that is asserted to be predicative of improved therapeutic efficacy in humans would be sufficient to meet the requirements of Section 3(d) of the Act. However, if the new “form” of the compound in question converts to the known form in vivo, then no improvement in efficacy is likely to be observed even though the new form might possess improved properties (unrelated to efficacy) that render that form particularly well suited to commercial development.

Applicants desirous of patent protection for new forms of known compounds in India should consider the impact of the recent SCI decision carefully. In the absence of data to support improved therapeutic efficacy for a new form of a known pharmaceutical, it is likely that the sole claims allowable in India will be restricted to novel and inventive processes of preparing that form. In the case of product claims, it would appear that being novel and inventive is simply not enough.