Rebutting Novratis

As mentioned in Case Study II of the previous article on pharmaceutical patenting, Novartis obtained US patent 6894051 on 17 May 2005 for a new crystalline form of its blockbuster blood cancer drug Gleevec/Glivec. This crystal modification was termed the b-crystalline form of imatinib mesylate. Novartis applied for an Indian patent for this polymorph but the application was rejected by the IPO (Indian Patent Office) under Section 3(d) in January 2006 after an appeal by Indian generic manufacturer Natco.

The Swiss pharmaceutical major has now filed a case in the Chennai High Court protesting the Indian patent law. Novartis is challenging the validity of Section 3(d), claiming that this section discriminates against the pharmaceutical industry and is not in line with TRIPS (Trade-related aspects of intellectual property rights). To comply with TRIPS, India must allow patents for all inventions irrespective of the technological field, provided they are new, involve an inventive step and are capable of industrial application. According to the Indian Patent Act, an inventive step would feature a technical advance over existing knowledge or have economic significance or both, and would make the invention non-obvious to a person skilled in the art (1).

Section 3(d) was framed in 1970 as a safeguard to prevent the evergreening tactics (practice of prolonging IP rights) of pharmaceutical firms on existing drugs. This section prohibits the patenting of new forms (including polymorphs), new uses or minor modifications of existing drugs unless an appreciable difference in drug efficacy is indicated. Salts and other derivatives of known substances will be considered as the same substance unless there is a significant increase in efficacy. However this section is only with regard to the pharmaceutical industry. Novartis claims this violates Article 14 of the Indian Constitution, which promotes equality before law. The Indian generic drug industry represented by the Indian Pharmaceutical Alliance (IPA) is contesting the case (2).

Novartis states that the patent protection in India would be only for the paying market and that it will make Gleevec available to any Indian person diagnosed with cancer who cannot afford the cost of treatment (3). Treatment with Gleevec costs Rs 1,20,000 per month for a patient compared to the generic price of Rs 8,000 (4).

US6894051 claims a crystalline form of the monomethanesulfonic acid addition salt of a compound of formula I, which is non-hygroscopic in a glass climatic chamber at 25°C and relative humidities up to and including 93%.

Compound of formula I
N-phenyl,-2-pyrimidine amine derivative
Where N-H represents amine groups and cyclic N=N the pyrimidine structure

Due to its non-hygroscopic nature, the polymorphic b-crystalline form with non-needle shaped crystals is stated to possess better flow characteristics and to be better suited to storage than the previously known needle shaped a-crystals that readily absorb moisture. The preferred process for the preparation of the b-crystalline form includes:

(i) Digesting another crystal form or amorphous starting material of the methanesulfonic acid addition salt of a compound of formula I in a suitable polar solvent at a temperature between 20° and 50°C.

(ii) Dissolving another crystal form or amorphous starting material of the methanesulfonic acid addition salt of a compound of formula I in a polar solvent at a suitable temperature of 25°C up to the reflux temperature of the reaction mixture, and then initiating crystallization by adding a small amount of the d-crystal form as seed crystal at a temperature between 20° and 70°C.

The preference for the b-crystalline form appears to be based on its better storage characteristics and the fact that it does not liquefy easily when compared to the a-crystal form, which turns amorphous to some extent at relative humidities of 93% or greater. However the more readily biosoluble form of a chemical compound is often preferred by manufacturers, as the body will better absorb it. An analysis of the US patent in question does not reveal any other reason for the polymorph to be preferred over the previously existing salt. All therapeutic uses claimed for the polymorph especially have also been claimed for the methanesulfonic acid addition salt of a compound of formula I and there is no extension of its therapeutic properties.

Article 35 under Section 101 of US patent law states that whoever invents or discovers any new and useful process, machine, manufactures, or composition of matter, or any new and useful improvement thereof, may obtain a patent thereof (5). The U.S. Patent and Trademark Office (USPTO) requires an invention to be non-obvious and to possess an inventive step. The USPTO may reject a drug terming it obvious on the basis of its structural similarity to existing chemical compositions. The applicant can overturn the rejection by demonstrating the improved results of the drug (6).

In India, the inventions not patentable under The Patents Act, 1970 include any process for the medicinal, surgical, curative, prophylactic (diagnostic/therapeutic) or other treatment of human beings. This is in the interest of keeping those inventions that most closely impact upon life and living beings accessible to all within the public domain. The argument against patenting derivative versions of existing pharmaceutical products may be extended with reference to this provision. For a curative or prophylactic treatment to be readily available in a country like India, generic drug manufacturers must play a leading role. The production of a generic drug requires that the brand name drug be off patent. Attempts by non-generic pharma companies to perpetuate their patent rights by patenting derivatives with minor differences in efficacy will only delay generic production and inhibit public access in India and the rest of the developing world.

REFERENCES

1. Drug efficacy may be open to interpretation- Article in The Hindu Business Line; 25 Feb 2007
2. Novartis case raises fresh controversy- Article in India Business (The Times of India); 21 Feb 2007
3. Novartis rejects Glivec link to S.Africa AIDS row- Interview, Reuters India; 21 Feb 2007
4. Health organizations urge Novartis to drop patent case- Article in The Hindu Business Line; 30 Jan 2007
5. Report of the Technical Expert Group on Patent Law Issues- Indian Drug Manufacturers Association; Dec 2006
6. Taking TRIPS to India- Novartis, Patent Law and Access to Medicines- Article, Commonwealth Secretariat; 8 Feb 2007

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