Friday, 12 April 2013

The Glivec Decision

“…A statute is best interpreted when we know why it was enacted. … If a statute is looked at, in the context of its enactment, with the glasses of the statute-maker, provided by such context, its scheme, the sections, clauses, phrases and words may take color and appear different than when the statute is looked at without the glasses provided by the context…” - Justice Chinnappa Reddy in Reserve Bank of India v. Peerless General Finance and Investment Co. Ltd. and others

The recent compulsory licensing judgments have done their bit in bringing concepts such as “Public Interest” and “Public Morality” in to the limelight in the Intellectual Property arena. An increasing number of people are now talking about “Role of Patents in Facilitating Affordable Drugs” and mechanisms through which one can maintain the balance between “Patent Rights” and “Public Rights”. 

Thus, it was, but expected that the recent decision by Supreme Court of India in the Glivec patent case would trigger another round of heated discussions on India’s stance on drug patents. The Glivec decision has left the multinationals apprehensive and unsure about their strategies in India. Industry pundits are speculating that the Glivec decision will drive the pharmaceutical multinationals away from India to regions which they believe would provide more fertile grounds for their R&D as well as generate better returns on their IP. 

There are also sections in the Industry who believe that India has stuck the right chord and the Glivec decision will ensure that essential drugs can now be made available more easily to those in need as well as the judgment can act as precedent to similar patent cases all over the world, especially in the developing countries. 


Following is a snapshot of some of the key points as well as summarization of circumstances surrounding the Glivec decision. 

CGP 571481 in free base form (International Nonproprietary Name ‘Imatinib’), was one of the derivatives of N-phenyl-2- pyrimidineamine (formula I) invented by Jürg Zimmermann. The free base form and other derivatives displayed valuable anti-tumoral properties. These properties allow them to be used in anti-tumoral drugs and in drugs for treating atherosclerosis. 

A patent application was filed on April 28, 1994 by Novartis in the United States for the N-phenyl-2-pyrimidine-amine derivatives, including Imatinib and the application was granted as US Patent No. 5,521,184 on May 28, 1996.

In their submission, Novartis stated that starting from Imatinib free base one could reach to the beta crystal form of Imatinib Mesylate in two ways. The two ways are specified below:
1.      By digesting another crystal form (Alpha crystal form) or an amorphous starting material of the methane sulfonic acid addition salt of compound of formula I. In this process, one would first arrive at Imatinib Mesylate in amorphous form, as the intermediate stage, and thereafter, following further processes, reach the beta crystal form of Imatinib Mesylate.
2.      By dissolving another crystal form (Alpha crystal form) or an amorphous starting material of the methane sulfonic acid addition salt of compound of formula I. In this process one would reach the beta crystal form of Imatinib Mesylate directly thereby skipping the intermediate stage of the amorphous form.
In their submission, Novartis also stated that the best way to produce the beta form is by directly proceeding from the free base form to the beta form by introducing a specified amount of the beta crystals at a specified step during the processing.
The beta crystal form of Imatinib Mesylate, according to Novartis, had the following benefits over the alpha crystal form of Imatinib Mesylate:
·         Better flow properties
·         Better thermodynamic stability
·         Lower hygroscopicity

Based on the above benefits, a patent application was filed in India claiming the beta crystal form as a “new” and “superior” invention. However, an important point to be noted is that no claim of superiority of the beta crystal form of Imatinib Mesylate in regard to the beneficial properties over the starting material Imatinib, or even over Imatinib Mesylate in amorphous form or any form other than the alpha crystal form was made.

The patent application was filed on July 17, 1998 at the Chennai Patent Office bearing application number 1602/MAS/1998. The priority date for the application was July 18, 1997, the date on which the patent application was filed in Switzerland. An important thing to point here is that Switzerland was not a convention country as defined under section 2 (1)(d) read with section 133 of the Act and it was notified as a convention country only on November 30, 1998.

Stage 1: Patent Office
As India’s patent laws on product (Drugs) patent were still evolving in 1990s, the Indian patent application was kept in the “mailbox” and was taken out of the “mailbox” only after January 1, 2005 when India started recognizing product patents (facilitated by deletion of Section 5 of the Act). 

However, before the application was taken out of the mailbox, some interesting events had already happened. Novartis had received a grant of exclusive marketing rights (EMR) on the subject matter of the patent application on March 27, 2002. Also, the patent application had received five pre-grant oppositions.

The Assistant Controller at the Indian Patent Office heard all the parties of pre-grant opposition on December 15, 2005 and rejected the Indian patent application (1602/MAS/1998). The main reasons for the rejection were:

1.      The Indian patent application was anticipated by US Patent 5,521,184 (Novartis own patent on N-phenyl-2-pyrimidine-amine derivatives, including Imatinib).

2.      The patent was not allowed under section 3(d) of the Indian Patent Act; and

3.      The priority date (July 18, 1997) was wrongly claimed as the priority date for the Indian patent application and was thus also anticipated by the patent application filed in Switzerland.

In response, Novartis filed five writ petitions challenging the orders of the Assistant Controller as well as two writ petitions challenging the constitutionality of Section 3(d) in the Madras High Court. While the five writ petitions were transferred to the IPAB as appeals, the Madras High Court dismissed the two writ petitions on Section 3(d).

Stage 2: IPAB
The IPAB heard the five appeals challenging the decision of the Assistant Controller and pronounced its judgment on June 26, 2009.  In the decision, the IPAB reversed the findings of the Assistant Controller on the issues of anticipation and obviousness and said that the Indian patent application fulfilled the tests of novelty and non-obviousness. The IPAB also accorded the priority date of July 18, 1997 to the Indian patent application based on the amended Section 133. 

However, the IPAB rejected the application based on Section 3(d) stating that India’s laws on drug patents demanded higher level of inventiveness so that the act was successful in preventing evergreening of patents. The IPAB also weighed in the pricing of Glivec (Rs 1, 20,000 per month) under Section 3(b) and concluded that while a process patent could be given for preparation of Imatinib Mesylate in beta crystal form, a product patent on Glivec would be disastrous to public order and morality and thus Novartis could not be granted a product patent.

Stage 3: Supreme Court
“…Patent systems are not created in the interest of the inventor but in the interest of national economy. The rules and regulations of the patent systems are not governed by civil or common law but by political economy…” - Michel on Principal National Patent Systems

Before dwelling into the merits of the case, the Supreme Court took a look into the history of patent laws in India, specifically; they cited the Justice Ayyangar’s work and recommendations on revamping the patent system of India. The Supreme Court observed that historically, barring USA, the rest of the world did not allow product patents in the field of food, medicines and chemistry. 

In addition to Justice Ayyangar’s report, the Supreme Court also cited works of Sudip Chaudhuri in his book “The WTO and India’s Pharmaceuticals Industry” to understand the performance of Indian Pharmaceutical Industry and how it has been impacted time and again with changes in Patent Laws. The Supreme Court also cited letters from various organizations such as HIV/AIDS Director of the WHO, and Director of Advocacy, Communication and Leadership for UNAIDS to the Indian Government expressing their concern on availability of affordable drugs to poor nation and role of Indian pharmaceutical industry in ensuring the continued availability of such drugs.
Coming to Section 3(d), the Supreme Court observed that the section was specifically amended to deal with chemical substances and more particularly to pharmaceutical products. Thus, the Supreme Court viewed Section 3(d) as a second tier of qualifying standards to identify genuine inventions in chemical and pharmaceutical domains and thereby put a check on evergreening of patents

In an interesting turn of events, the Supreme Court took time to discuss the differences between the concepts of “inventions” and “patentability” during the proceedings. The Supreme Court acknowledged the fact that Section 3(d) represents the concept of “patentability”. However, the Supreme Court also stressed on the fact that when Section 3(d) is isolated from rest of Section 3 and when the legislative history behind the incorporation of Chapter II in the Patents act, 1970 is disregarded, one can observe that it is possible to see Section 3(d) as an extension of the definition of “invention”. Thus, the Supreme Court concluded that the Act sets different standards for qualifying as “inventions” things belonging to different classes.

During the hearing, the following arguments were made by Novartis:
1.      The Genesis of beta crystalline form of Imatinib Mesylate (derivative of N-phenyl-2- pyrimidine-amine) was disclosed in example 21 of the US patent number 5,521,184.
2.      The beta crystalline form was brought to being by not one but two inventions. The first invention was to select example 21 and the second invention was to choose methane sulfonic acid to produce the methane sulfonic acid addition salt of the free base Imatinib, called Imatinib Mesylate. Novartis claimed that 5,521,184 patent did not teach or suggest to a person skilled in the art to select example 21 in preference to other compounds. Moreover, US patent 5,521,184 did not teach a person to select one particular salt even when example 21 was selected. Thus, Novartis argued that creating Imatinib Mesylate from Imatinib in free base was the result of an invention that involved technical advance as compared to the existing knowledge. Further, Novartis argued that once the salt form of Imatinib was arrived at, further research was required to ensure that that particular salt form of Imatinib is suitable for administration in a solid oral dosage form. As the relevant crystalline form of the salt that was synthesized needed to be invented, Novartis said that arriving at the beta-crystalline comprised two inventions.
The Supreme Court observed the following in response to arguments made by Novartis:
1.      The US patent 5,521,184, granted on May 28, 1996 expressly stated that the compounds of N-phenyl-2-pyrimidine-amine derivatives included their respective salts.

“Salt-forming groups in a compound of formula I are groups or radicals having
basic or acidic properties. Compounds having at least one basic group or at
least one basic radical, for example a free amino group, a pyrazinyl radical or a
pyridyl radical, may form acid addition salts, for example with inorganic
acids, such as hydrochloric acid, sulfuric acid or a phosphoric acid, or with
suitable organic carboxylic or sulfonic acids…”

“….any reference to the free compounds should be understood as including the corresponding salts, where appropriate and expedient.”

2.      The application also stated that “Acid addition salts can be convened into the free compounds in customary manner, for example by treatment with a suitable basic agent.”

3.      The application for beta crystalline form of Imatinib Mesylate was filed in the US on January 18, 2000 and was granted on May 17, 2005 following the order of US Appellate Court dated November 23, 2003.

4.      The Drug, Glivec, was however launched much earlier in the market based on US patent 5,521,184 itself.

5.      The patent information filed along with the New Drug Application (NDA) filed on February 27, 2001 showed that the active ingredient as Imatinib Mesylate.

6.      The description on package of GLEEVEC (Imatinib Mesylate capsules), launched on July 3, 2001stated that the capsules contained Imatinib Mesylate equivalent to 100 mg of Imatinib free base.

Based on the above facts, the Supreme Court concluded that Imatinib Mesylate, marketed under the name Gleevec, was covered by US patent 5,521,184. Moreover, the court also stressed on the fact that how Novartis had used the European counterpart of the US patent 5,521,184 for preventing Natco Pharma to market its drug, VEENAT 100 in UK in order to support its conclusion. The Court also cited the findings of US Board of Patent Appeals in its judgment granting patent for beta crystalline form of Imatinib Mesylate. The court brought to notice that even the US Board of Patent Appeals mentioned in their judgment that though the beta crystal form might not have been covered by US patent 5,521,184, it did have the teaching for the making of Imatinib Mesylate from Imatinib, and for its use in a pharmacological compositions for treating tumours or in a method of treating warm blooded animals suffering from a tumoral disease.

Thus, the Supreme Court held that Imatinib Mesylate as a substance and its pharmacological properties were well known in the art. Having concluded on Imatinib Mesylate, the Supreme Court then focused on beta crystalline form of Imatinib Mesylate. As the beta crystalline form of Imatinib Mesylate is a pharmaceutical substance and moreover a polymorph of Imatinib Mesylate, it is governed by Section 3(d) of the Act.
The counsel for Novartis argued that in order to attract section 3(d), the subject product must be a new form of a known substance having known efficacy. The counsel also stated that a “conceivable” substance is not a “known substance” within the meaning of the provision. He contended that the word “known” connotes proven and well-established and thus “known efficacy” would imply efficacy established empirically and proven beyond doubt. As neither Imatinib nor Imatinib Mesylate had any known efficacy, he contended that there was no question of showing that the beta crystalline form of Imatinib Mesylate had any enhanced efficacy over Imatinib or Imatinib Mesylate.

However, the Supreme Court rejected the counsel’s arguments as unacceptable both in law and on facts. Consequently, the court concluded that beta crystalline form of Imatinib Mesylate would correspond to a new form of a known substance, i.e., Imatinib Mesylate, of which the efficacy was well known as described in the NDA filed with the US FDA. The court also went on to defined efficacy as “the ability to produce a desired or intended result”. An interesting point over here is that Supreme Court also brought to attention how the patent application for beta form was based on US patent 5,521,184, and how most of sections were directly lifted from the US patent 5,521,184.
In another interesting aspect, the court observed that while the application for grant of patent lay in the “mailbox”, Novartis was granted Exclusive Marketing Rights on November 10, 2003, following which Gleevec was marketed in India as well. The package described the drug as “Imatinib Mesylate Tablets 100 mg” and it was further stated that “each film coated tablet contains: 100 mg Imatinib (as Mesylate)”. However, nowhere on the package is a reference to Imatinib Mesylate in beta crystalline form.  This indicates that what were sold as Gleevec were Imatinib Mesylate and not the subject product, the beta crystalline form of Imatinib Mesylate. This leads one to believe that the claim for patent for beta crystalline form of Imatinib Mesylate is nothing but an attempt to obtain patent for Imatinib Mesylate, which would otherwise not be permissible.
Thus, the Supreme Court held that the beta crystalline form of Imatinib Mesylate, does not qualify the test of Section 3(d) of the Act. 

This decision has forced the pharmaceutical multinationals to come up with new strategies as well as create a checklist for launching new patented drugs in India. Companies are going to be more apprehensive than ever before to do business in India. Partnerships with local companies may emerge as one of the short term solution but questions are being already raised on its implications in the long run. Till then, it will be interesting to see whether India continues to be the “pharmacy of the world”.