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1 April 2013AsiaRahul Vartak

Slow but positive change? The evolution of section 3d

The Indian pharmaceutical scene has been plagued by Section 3d of the Indian Patents Act for almost a decade. Section 3d has been wielded skilfully by various companies for challenging pharmaceutical patents. Various tactics have been used by innovators for overcoming the challenges posed by Section 3d, including a challenge to TRIPS compliance and constitutional validity. However, Section 3d has been able to withstand all challenges.

The significance of Section 3d

Section 3d was amended by the Patents (Amendment) Act, 2005. The intention was to prohibit so-called ‘evergreening’ by providing that only those pharmaceutical derivatives that demonstrate significantly enhanced ‘efficacy’ would be patentable. However, Section 3d has also been criticised for being overly restrictive and preventing patenting of good inventions. Section 3d has been frustrating to the extent that innovator companies had announced that they would freeze all investments in India and divert to more patent-friendly territories.

Interpretation of efficacy

The decision of the Madras High Court in the case of Novartis AG v Union of India is significant since the court had stated that “efficacy means therapeutic efficacy”. In the Novartis matter, an attempt was made to establish efficacy by stating that the beta-crystalline form of imatinib (Glivec) demonstrates a 30 percent increase in bioavailability as compared with the imatinib free base. However, the court felt that this by itself does not demonstrate any therapeutic advantage in relation to the patient.

Similarly in the post-grant opposition to the Valcyte (antiviral valganciclovir hydrochloride) patent in India, the Controller mentioned that Roche’s claim of an increase in bioavailability does not necessarily equate to an increase in ‘efficacy’.

However, there had been no guidance provided on what could be considered as therapeutic efficacy, or on the data required for efficacy, or on the quantum of enhancement to overcome the objection of Section 3d.

Winds of change

The interpretation of Section 3d seems to have changed over the years. The Controller’s decision of December 2012 for application no. 106/ DELNP/2008 regarding polymorphic forms is likely to change the manner in which Section 3d has been interpreted in India in the past.

The Controller felt that the enhancement in efficacy lay in the fact that the polymorph for which the patent application was filed showed an in vivo absorption level which was about 100 times lower than the original form. This resulted in reduction of the toxicity by 100 times due to reduced absorption. The Controller was of the opinion that a 100-fold reduction in toxicity while maintaining the efficacy was appropriate for overcoming a Section 3d objection.

However the Controller had already defined what is meant by efficacy in a pre-grant opposition matter decided in 2007 wherein application no. 841/DEL/1996 of Astra Zeneca was opposed by GM Pharmaceuticals.

The applicant had claimed enhanced potency for invented compounds as compared to the compounds of the prior art by a comparison of ED50 value (the minimum effective dose for 50 percent of the population) with IC50 value (the minimum inhibitory concentration of the compound required to inhibit 50 percent of the test target).

The Controller was of the view that the IC50 value is not a correct parameter to test the efficacy of the compound, as it may be possible that the highly active compound may also be highly toxic. A more reliable parameter for testing efficacy of a compound is therapeutic index (the lethal dose of a drug for 50 percent of the population [LD50] divided by ED50). The lower the therapeutic index the better its efficacy. The applicant had provided only ED50 values, whereas the proper parameter to judge the efficacy of a molecule is therapeutic index.

This interpretation of efficacy seems to have changed in another recent case decided by the Patent Office in January 2013 for application no. 5185/CHENP/2007 of Aventis Pharma. Here, the Controller’s decision mentioned objections relating to inventive step and Section 3d, wherein the applicant had submitted in vitro minimum inhibitory concentration data and in vivo animal data.

These exhibited that the claimed compounds had higher antibacterial activity when compared to known compounds. The Controller found that the submissions were sufficient to overcome the objections raised by the Patent Office and in order for a grant.

The Supreme Court decision of April 1, 2013 in the Glivec matter now provides guidance on the term ‘efficacy’ mentioned in Section 3d. The court clarified that the test of efficacy can only be ‘therapeutic efficacy’. The court also clarified that physico-chemical properties such as beneficial flow properties, better thermodynamic stability or lower hygroscopicity, cannot qualify the efficacy standard.

Further the court clarified that increased bioavailability alone may not necessarily lead to an enhancement of therapeutic efficacy. So the court also provided guidance on what cannot be considered as efficacy, but did not clarify on the parameters for ‘therapeutic efficacy’.

However, the court has not entirely refused the applicability of increased bioavailability to enhancement in efficacy. The decision also states that whether an increase in bioavailability leads to an enhancement of therapeutic efficacy in any given case must be specifically claimed and established by research data.

An analysis of decisions seem to give an impression that the rigid stance of the Patent Office concerning the interpretation of efficacy in Section 3d is changing. Although the quantum of efficacy required to overcome Section 3d objections is not clear, the minimum inhibitory concentration data which was previously not a correct parameter to test the efficacy seems now to be acceptable at the Patent Office.

Further, the same therapeutic value with reduced toxicity of the claimed compound also seems acceptable to overcome Section 3d objections at the Patent Office.

The Supreme Court judgment in the Glivec matter also seems to suggest that translation of increased bioavailability into enhanced efficacy supported by research data and specific claims may be a solution to overcome Section 3d objections in future.

Rahul Vartak is a patent attorney and a partner with Krishna & Saurastri Associates. He can be contacted at: rahul@krishnaandsaurastri.com