The Glivec saga in India is finally over

As it has been widely covered by media in and outside India, it is no new news to the pharmaceutical and patent fraternity that Novartis has lost about the 7-year long legal battle to secure patent protection for its invention on the beta crystalline form of imatinib mesylate in India.

A 112 page long Supreme Court judgment delivered by a Supreme Court (SC) bench comprising Justice Aftab Alam and Justice Ranjana Prakash Desai details a complete account of all events leading to appeal to the Supreme Court and a historical account of India’s patent regime including policy decisions leading to the amendment of section 3d in 2005, in addition to providing detailed discussion on entire facts of the case.

The whole pharmaceutical community around the world were eagerly waiting for the decision and particularly to know how the Supreme Court construes a controversial section 3d. We would discuss herein SC’s discussion and decision, especially in section 3d.

Events leading to appeal to the Supreme Court

1. Novartis filed a patent application 1602/MAS/1998 at the Indian Patent Office.
2. Five pre-grant oppositions were filed by various Indian generic companies and the Cancer Patient Aid Association (CPAA).
3. The Application was rejected by the Controller in 2006 after hearing 5 pre-grant oppositions.
4. Novartis filed an appeal to Madras High Court. The appeal was eventually transferred to the Intellectual Property Appellate Board (IPAB) after its formation. Novartis also filed writ petitions challenging section 3d of the Indian Patent Act which were dismissed by the High Court after which no further action was taken by Novartis.
5. IPAB upheld the Controller’s decision in 2009.
6. Novartis filed an appeal to the Supreme Court later in 2009.

What is Section 3d?

This case mainly revolves around whether the beta crystalline form of imatinib mesylate is hit by section 3d and thus unpatentable in India. There was a detailed discussion in the judgement on how to section 3d is introduced and amended and how to section 3d is a part of patentability criteria.

So, let us first see what section does section 3d mean: Section 3d bars patent protection to new forms (including salts, esters, polymorphs, crystalline forms, derivatives etc.) of known substances unless the new forms result in an enhancement of the known efficacy.

Supreme Court held that in this case, “known substance” is imatinib mesylate and not imatinib in free base

SC held that that the prior art patent US Patent No. 5,521,184 (Zimmermann patent) claiming imatinib, also discloses imatinib mesylate and the known substance with which the beta crystalline form must be compared to show enhanced efficacy thus should be imatinib mesylate and not imatinib in free base form.

Novartis in its arguments had compared the beta crystalline form of imatinib mesylate with imatinib in free base form to prove enhanced efficacy (Novartis showed 30% enhanced bioavailability in beta crystalline form over imatinib in free base plus other physicochemical properties as discussed hereinafter).

Evidence that proved that imatinib mesylate is disclosed in the Zimmermann patent :

Zimmermann patent discloses imatinib in free base form and further discloses a broad coverage of pharmaceutically acceptable salts (including acid addition salts) generally where explicit disclosure of mesylate salt is not there. The patent is granted in 1998.

Novartis filed a new US patent on a beta crystalline form of imatinib mesylate. The patent is granted in 2005.

NDA (New Drug Application) for Glivec or Gleevec was filed in 2001, where the active ingredient of the drug was started as Imatinib mesylate. The active ingredient, composition and method of use were also declared by Novartis to be covered by the Zimmermann patent.

Further, when Novartis sent a legal notice in 2004 to Natco, the company selling a generic version of Glivec in the UK, Novartis stated in the notice that the Zimmermann patent (EP equivalent) claims imatinib and its acid addition salts such as the mesylate salt.

The judges concluded based on the above evidence that imatinib mesylate is disclosed in Zimmermann patent and thus is a known substance with which beta crystalline form must be compared to show enhanced efficacy over the known substance.

Supreme Court held that “efficacy” in case of chemical substances, especially medicine, is “therapeutic efficacy”

Madras High Court earlier, in this case, held efficacy to mean therapeutic efficacy.

SC re-clarifies the meaning by saying,

“Efficacy means“the ability to produce a desired or intended result”….. Therefore, in the case of a medicine that claims to cure a disease, the test of efficacy can only be “therapeutic efficacy”……..What is evident, therefore, is that not all advantageous or beneficial properties are relevant, but only such properties that directly relate to efficacy, which in case of medicine, as seen above, is its therapeutic efficacy.” (emphasis added)

Novartis tried to prove enhanced efficacy by showing better physicochemical properties (such as better flow properties, better thermodynamic stability, lower hygroscopicity etc.) over imatinib in free base form. However, SC held that these properties can give better processability, storability, stability etc. but cannot be said to possess enhanced efficacy (that is therapeutic efficacy) over Imatinib Mesylate under section 3d.

Whether a 30% increase in bioavailability is an enhancement in therapeutic efficacy in this case?

SC clarifies that

“…just increased bioavailability alone may not necessarily lead to an enhancement of therapeutic efficacy. Whether or not an increase in bioavailability leads to an enhancement of therapeutic efficacy in any given case must be specifically claimed and established by research data.”

It was held that no evidence was provided by Novartis to prove that the beta crystalline form of Imatinib Mesylate shows an enhanced therapeutic efficacy (on the molecular basis) over Imatinib free base in vivo animal model.

SC thus finally concluded and held that the beta crystalline form of Imatinib Mesylate fails the test of section 3(d) and thus is unpatentable.

Conclusion:

1. Efficacy in section 3d would be construed as the “therapeutic efficacy”, especially in the case of inventions pertaining to chemical compounds in medicine.

2. How much “enhancement” in efficacy makes the new form to overcome 3d, is still an open-an ended question?

3. Whether an increase in bioavailability is an increase in therapeutic efficacy would depend on a case to case basis. If a fact that an increase in bioavailability increases a therapeutic efficacy, is claimed and is established by research data (preferably in vivo), then section 3d could be overcome.

4. The judgement sets a legal precedent to all pending and forthcoming patent cases involving section 3d in India. However, it is being discussed and speculated that judgement will act as only limited precedent because the judgement is very fact-specific.

5. (An obvious point) Generic companies, health activist groups and patients in India are very happy with the decision, whereas MNCs and innovator companies around the world condemned the decision.

About the Author: Ms Meenakshi Khurana, Patent Attorney at Khurana & Khurana and can be reached at [email protected]

Follow us on Twitter: @KnKIPLaw