India: Novartis Denied Patent for Gleevec

Patents are available only for inventions that are novel, non-obvious as well as useful. Therefore, where novelty is a bedrock concept of all patent systems, nonobviousness is the ultimate condition of patentability but first of all an invention i.e. a product of investigation and experiment must qualify as an invention. Section 3 of the Patents Act 1970 as amended by Patents (Amendment) Act 2005, in a very succinct way provides for what are not inventions. Clause (d) disqualifies a new form of a known substance which does not result in the enhancement of the known efficacy, as an invention. The Explanation further elaborates that salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of the known substances are to be considered the same unless they differ significantly in properties with regard to efficacy.

In the light of this amendment made to usher India into an era of product patent regime, a new era in the Indian Pharmaceutical industry, based on innovation and new drug development, has been heralded. The instant provision of the Patents Act together with the opposition provision serves as a legal tool for both generic and pioneer pharmaceutical companies to challenge the validity of a claimed invention. The recent denial of the patent application for an anti cancer drug beta crystals of Imatinib mesylate filed by the Swiss pharma major Novartis AG and opposed by a cache of Indian pharma generic producers including Cipla and Ranbaxy, is the first major decision on patent application after India complied with the TRIPS regime in 2005 and is widely seen as a scenario of the Indian pharmaceutical industry in the product patent regime wherein opposition is an important tool to thwart off frivolous claims and also to obtain commercial benefits.

An application for patent was filed by M/s. Novartis AG on July 17, 1998 for an invention titled "Crystal Modification of A N – Phenyl – 2 Pyrimidineamine derivative, processes for its manufacture and its use" claiming Switzerland priority date of July18, 1997. The patent application in effect claimed beta crystal of methanesulphonic acid salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[4-pyridine-3-yl)pyrimidine-2-ylamino)phenyl]-benzamide commercially called as imatinib mesylate.

Cipla Ltd along with other generic producers filed their representation by way of opposition under section 25(1) of the Patents Act, 1970 as amended by Patents (Amendment) Act, 2005 and rule 55 of the Patents Rules, 2003 as amended by Patents (Amendment) Rules, 2005.

The arguments of the Applicant and the Opponents were on the following issues.

[1] Not an Invention

Anticipation by Prior publication

Obviousness

[2] Section 3(d) of the Patents Act

[3] Priority

As regards the First Issue the opponent contention was that imatinib mesylate is known from prior publications viz. Nature Medicine (May 5, 1996), Cancer Research (Vol.56, Issue I, 1996) and Blood (Nov.1 1997) besides already known from the US Patent no. 5521184 hence the subject matter of the application is anticipated the opponents tried to prove that there is no ingenuity or human intervention or novelty and inventive step in the preparation of beta crystal salt of imatinib mesylate as that is only a new form of a known substance and not an invention under the amended Patents Act.

The opponents further argued that the beta crystalline form is the most stable form of imatinib mesylate salt, which is also evident from the affidavit submitted by the applicant, which states that the beta form of the salt is thermodynamically more stable. The affidavit was based on the studies done by two reputed government institutions namely Indian Institute of Chemical Technology, Hyderabad and Indian Institute of Technology, Delhi. From their repeated studies and experiments the salt was found to steadily exist in the beta crystalline form. Also that, it is obvious for a person skilled in the art to prepare corresponding pharmaceutically acceptable salts once the freebase is known by the disclosure of the US Patent.

The applicants argued that the disclosure made in the US Patent is of the free base, ‘imatinib’ and not its salt, imatinib mesylate, therefore the present invention involves two-fold improvement over the prior art - [1] The imatinib free base is chemically changed into a salt form and [2] A particular crystal form, beta crystal form, of the salt is made through human intervention. Further that the US Patent does not give any example for the preparation of imatinib mesylate nor are there any claims made for it, however the US Patent may embrace imatinib mesylate.

It was held that the US Patent discloses methanesulphonic acid as one of the salt forming groups and the patent specification clearly states that the required acid addition salts are obtained in a customary manner. The claims 6 to 23 of the US Patent claim a pharmaceutically acceptable salt of the base compound and the patent term extension certificate, specifically mentions imatinib mesylate as the product. Thus imatinib mesylate is already known from prior publications. Also that imatinib mesylate normally exist in the beta crystals form which is thermodynamically most stable product.

Thus the opponents succeeded in proving that the invention of Novartis is obvious and anticipated by prior publication hence not an invention.

Under the Second Issue the opponents reiterated the submissions made under the first issue and further argued that the application claims only a Polymorphic form of imatinib mesylate and as regards efficacy the Patent application itself states that wherever beta crystals are used the imatinib freebase or other salts can be used equally in the treatment of diseases or in the preparation of pharmacological agents. To further corroborate the arguments, studies were conducted by technical experts to compare the relative bioavailability of the freebase with that of the beta crystal form of imatinib mesylate. A difference of 30% was found which, it was said, could be due to difference in their solubility in water. Therefore, it was argued that, the present Patent Specification does not bring out any improvement in the efficacy of the beta crystals over the known substance.

The applicant countering the argument said that section 3 (d) couldn’t be used against the subject application as the aspect of this section, that a discovery graduating into a patentable invention solely on the basis of efficiency defies logic and therefore unable to stand legal scrutiny. Further submitted that this aspect of section 3 (d) is against the tenets of the Patents Act as well as the established principals of jurisprudence and that the beta crystal form of imatinib mesylate is an invention, a new substance and not a mere discovery.

It was concluded on the basis of the above argument by the learned judge that as rightly argued by the opponents the subject matter of this application is not patentable under section 3 (d) of the Patents Act, 1970 as amended by the Patents (Amendment) Act, 2005.

The opponent’s contention under the Third Issue was that the patent application was filed on July 17, 1998 as a convention application claiming convention priority from an earlier Swiss application whereas Switzerland was not a convention country on that date, therefore the application deserves to be rejected on the ground of legal and technical disqualification.

The applicant responded by saying that the priority claim is discretion of the applicant and only a facility to avoid anticipation by prior publication of the invention between the priority date and filing date in India.

It was held that the patent application wrongly claims priority, hence legally and technically disqualified

In view of the above findings and all the circumstances of the case the learned judge in the instant case, Asst. Controller of Patents & Designs Mr.V.Rengaswamy, refused to proceed with the application for Patent

It was widely speculated that the product patent regime would destroy almost 15% of the existing Indian pharma market as the generic producer will have to withdraw the product when the patents controller accords patent to any of the mailbox applications. However domestic pharma companies were confident that many of these applications would not be patentable, as mailbox facility was designed to facilitate patent filings for drugs discovered between 1995 and 2005 only and that the number of new chemical entities discovered during that period is around 135 only, therefore a huge majority of the pending mail box applications would either be frivolous or those for salts, isomers, metabolites, polymers, solvents or such modification of an already patented entity.

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