For those of you not familiar with the Novartis patent litigation (given the 100 odd posts that we've done so far on this big ticket patent litigation in India, its highly unlikely that our readers may not have come across this till now), here is a brief gist, from a recent paper of ours that was published a few days back in Script-ed, a publication from the Univ of Edinburgh. (A copy of this paper, as published, is available on SSRN: once you access the link, click on "chose download location", a tab which appears right on top of the webpage and then click button titled "SSRN (New York, USA)").
“Like all drug sagas, the story of Gleevec begins with two outstanding scientists, who rarely figure in the “patent” narratives that are doing the rounds today.
In 1960, Peter C Nowell, then a junior faculty member at the University of Pennsylvania School of Medicine, together with a graduate student, David Hungerford, discovered a genetic mutation in patients with chronic myelogenous leukemia (CML), a debilitating form of cancer. The discovery of this abnormality, designated the Philadelphia chromosome after the city in which it was discovered, broke fresh ground and spurred the search for a potential cure for CML. In the 1980’s, researchers determined that the chromosomal abnormality produced a cancer-causing kinase enzyme.
With this enzyme as a target, Novartis researchers (led by Drs. Zimmermann and Buchdunger) in close collaboration with a prominent scientist, Brian Drucker created and tested 400 molecules to find one that would target this enzyme, without disrupting any of the hundreds of other similar enzymes in a healthy cell. Pioneering the concept of rational drug discovery, they closed in on a promising candidate, “Imatinib,” a free base. In 1993, Novartis filed a patent covering this free base and all pharmaceutically acceptable salts.
Imatinib was then further researched upon and improved – first, by converting it to a particular salt form, namely imatinib mesylate. From this salt, Novartis found that the most stable version was a particular polymorphic form, namely the beta crystalline form. Novartis then formulated the beta crystalline form of imatinib mesylate into a pharmaceutically useful drug, Glivec. After its approval by the FDA in 2001, Glivec has proven effective for innumerable patients and has been hailed as nothing short of a wonder drug.
The Novartis (Glivec Patent Dispute)
The patent dispute centres around the beta crystalline form of imatinib mesylate referred to above. To date, 40 patents covering this polymorph have been granted to Novartis in various countries. However, owing to the unavailability of drug patents in India until 1 January 2005, Novartis claimed this polymorph in a “mailbox” application.
Pursuant to the 2005 amendment to India’s patent regime, which introduced product patents for pharmaceuticals, the mailbox application by Novartis, as above mentioned, was opened and examined. The grant of a patent was opposed by several generic drug companies (and an NGO, the Cancer Patients Aid Association (CPAA)) on several grounds including:
i) lack of novelty/anticipation;
ii) lack of significantly enhanced “efficacy” under section 3(d);
iii) obviousness, and;
iv) wrongful priority.
Agreeing with the above arguments, the Assistant Controller of Patents rejected the patent application.
Aggrieved by this rejection, Novartis AG, along with its Indian subsidiary, Novartis India, filed two writ petitions in the Madras High Court. These petitions not only sought a reversal of the Assistant Controller’s order, but also a declaration that Section 3(d) was unconstitutional and in violation of India’s obligations under TRIPS. The Madras High Court ruled against Novartis on both counts.
Pursuant to a government notification, the High Court transferred the first petition to the Intellectual Property Appellate Board (IPAB) – a specialist tribunal set up to deal with appeals from the various intellectual property offices across the country. As of today, the matter is still pending before the IPAB.
Section 3 of the Indian Patents Act is the key section on “patent eligibility” and lists out what are not “inventions” under the Indian Patents Act. Section 3 (d) lists out one such non-eligible patentable subject matter:
d) the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such process results in a new product or employs at least one new reactant.
Explanation: For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significantly in properties with regard to efficacy.
In essence, section 3(d) aims to prevent a phenomenon commonly referred to as “ever-greening” by providing that only those pharmaceutical derivatives that demonstrate significantly enhanced “efficacy” are patentable.”
The Patent Office Manual and Section 3(d):
Now, coming to the patent office manual, in relation to section 3(d), para 4.5.3 of the Manual states: “The examiner makes comparison with regard to properties or enhancement of efficacy between the known substance and the new form of known substance. In case the new form is further converted into another new form, the comparison is made between the already existing form and another new form but not between the base compound and another new form.”
This appears a clear attempt to prejudge the Novartis case. The various steps in the alleged inventive process that went into the making of Glivec are as below (again, I’ve reproduced this verbatim from our paper):
i) Synthesizing imatinib as its free base, a compound that was patented in the US, EU and several other countries. However, this could not be patented in India, owing to the fact that in 1993, India did not provide product patents for pharmaceutical substances.
ii) Converting the free base to a particular salt form, imatinib mesylate, by adding methanesulfonic acid.
iii) Crystallising the imatinib mesylate to obtain the beta crystalline form, which is allegedly the most stable polymorphic form of the salt. A patent application was filed for this and it is this application that is the subject matter of dispute.
iv) Formulating the beta crystalline form of imatinib mesylate into a pharmaceutically useful drug, Glivec.
In short, the base compound (“Imatinib Free Base”) is converted to a salt (Imatinib Mesylate) which is then further crystallized to another new form” (Beta Crystal form of Imatinib Mesylate). One might also contend that prior to the discovery of the beta crystalline form, there existed an alpha crystalline form of Imatinib Mesylate.
Unfortunately, the patent office decision rejecting the application for Glivec is quite sketchy on this point. It is "non speaking" to the extent that it does not answer a critical question: What is the “earlier known substance” against which the beta crystalline form was compared for "increased efficacy" under section 3(d)?
The “known” substance for the purposes of section 3(d) could either be the salt (Imatinib Mesylate) or the polymorphic form (alpha crystalline form). However, such substances can be taken to be "known" substances, only if they were, in fact, "known" as on the date of filing the patent application covering Glivec (the beta crystal form). If the salt (imatinib mesylate) or the polymorphic form (alpha) is not “known” (i.e still novel) as on the date of filing the patent application for beta crystalline version, then such substances cannot be used as the basis for comparison under section 3(d).
In short, as to whether a substance is "known" or not is an issue that has to be determined on a case by case basis and one cannot assume that in every case, a new salt or a new form emerging during the course of an alleged invention will always be a “known” substance. Unfortunately, from a reading of the patent office manual, this is the kind of "prejudged" result that one gets.
Does Novartis' earlier application anticipate Imatinib Mesylate?
Having said all of the above, we wish to draw your attention to one of our earlier posts ,where we opine that, from the available evidence, the earlier 1993 application covering the imatinib free base "in fact" appears to anticipate "imatinb mesylate". However, it does not anticipate the "alpha cystal" form or the beta crystal form. I noted in that post as follows:
"Novartis claims that Glivec (beta crystalline form of imatinib mesylate) is more effective than the Imatinib free base, since it displays better bio-availability properties i.e. it is absorbed more easily into the blood.
Novartis claims all acceptable pharmaceutical salt forms in its main 1993 patent (step (i) above). This would ordinarily include Imatinib Mesylate as well. The question however is: does the 1993 patent "enable" the making of imatinib mesylate? I personally think it does--but am happy to be corrected. If it does not, then imatinib mesylate cannot form part of the claims. It also cannot taken to be a "known" substance. Section 3(d) requires that the new form demonstrate increased efficacy over the "known" substance. If Imatinib Mesylate is not a "known" substance, then the comparison under section 3(d) cannot be with Imatinib Mesylate. And to this extent, the case against Novartis on section 3(d) becomes a weak one.
However, as I said earlier, I personally think the patent enables the making of Imatinib Mesylate and the case on section 3(d) therefore still remains a strong one."
I’ve now found an international (PCT) prelim examination report which buttresses our point by clearly stating that the application for the beta crystal form of imatinib mesylate (Glivec) was "novel", as on the date of filing. However, the salt (imatinib mesylate) itself was anticipated by the first application filed in 1993 covering the imatinib free base. We quote this PCT examination report finding in our paper as below:
“Methanesulfonic acid addition salts of the present compound….are disclosed in D1(D1: US Patent Application)….However, no mention is made of a particular crystalline form of the monomethanesulfonic acid addition salt of said compound. The novelty of the present claim can therefore be acknowledged.” (edited)”
This point also seems to be endorsed by an EPO ruling, which Tahir Amin drew my attention to in a comment to our post:
"when the EPO was examining the B-crystalline patent, the examination report held that the '184 patent disclosed the methanesulfonic acid additional salts for formula (I) - but the application was considered novel because the '184 patent did not disclose the b-crystalline form. "
Given that the patent office will hold another 2 hearings or so on the patent office manual, we hope that some of our readers who attend these hearings will raise this issue (if they are convinced, of course, that a manual ought not to blatantly prejudge a case, but decide the "known substance" issue on a case by case basis).
Patent Office Does Not Have Force of Law: So Why Worry?
Lastly, it bears reiteration that the patent manual does not have the force of law And indeed, the manual itself acnowledges this by stating so in the preface. However, as many of you who practice before the patent office are aware, the manual pretty mush assumes a sacrosanct /biblical position with patent examiners. Therefore, any proposition included in the manual is likely to be religiously adhered to--unless challenged and struck down by a court of law. And therein lies the danger. (interestingly, the patent office has had a history of "secret internal circulars" that were religiously adhered to as well. Such circulars were famously used for rejecting biotech applications containing living subject matter and documented in this paper).
We'd be very interesting in hearing what our readers think of the draft manual in general. Better than the last one? Good bed time reading? More of a paper tiger--and in the language of the bard: "full of sound and fury, signifying nothing" (paper tiger has such a nice homely ring to it, given that we're speaking of India…doesn't it?)