WRITTEN SUBMISSIONS ON BEHALF OF THE INTERVENOR
I FACTS OF THE CASE 3
A History of Glivec 3
B The Patents at Issue 5
C Key Issues in the Dispute 7
II THE SECTION 3(D) STANDARD 8
A Meaning of “Efficacy” 9
1 Drawing from the Orphan Drugs Act (ODA) 11
B Proving Efficacy 15
C When can proof of efficacy be submitted? 16
D Does Increased Bio-Availability Amount to Significantly Enhanced Efficacy? 17
E What is the “known substance” for the purpose of section 3(d)? 18
III NOVELTY AND INVENTIVE STEP 25
IV PATENTS, PUBLIC ORDER AND EXCESSIVE PRICING 27
IN THE SUPREME COURT OF INDIA
CIVIL APPELLATE JURISDICTION
I. A. NO. _____ OF 2011
IN
S.L.P. (C) NO. 20549/2009
IN THE MATTER OF:
NOVARTIS AG … PETITIONER
VERSUS
UNION OF INDIA & ORS. … RESPONDENTS
AND
SHAMNAD BASHEER … INTERVENOR
WRITTEN SUBMISSIONS ON BEHALF OF THE INTERVENOR
I FACTS OF THE CASE
A History of Glivec
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 genetic 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 at the University of Chicago determined that the chromosomal abnormality produced a cancer-causing kinase enzyme.
With this enzyme as the target, Novartis researchers (led by Drs. Zimmermann and Buchdunger) in close collaboration with a prominent scientist, Dr. Brian Druker created and tested 400 molecules to find one that would inhibit this enzyme, without disrupting 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 by converting it to a particular salt form, namely imatinib mesylate. Novartis found that the most stable version of this salt 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 [Known as Gleevec in US]. 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 various steps in the discovery and development of Glivec can be broken down as below:
1. Discovery of the Philadelphia Chromosome (a genetic mutation found in patients with Chronic Myeloid Leukemia): 1960
2. Discovery that the genetic abnormality results in a cancer causing kinase enzyme: 1980s (this enzyme is effectively the “target” that any drug must inhibit).
3. More than 400 compounds screened to assess for potential in inhibiting the enzyme (target): late 1980s
4. Scientists identify STI571 (Imatinib free base) as most promising “lead” that would inhibit the enzyme, without affecting other cells: 1992 [1]
5. Novartis files a patent claiming imatinib (free base) and all pharmaceutically acceptable salts: 1993[2]
6. Novartis files a patent claiming the beta crystalline version of imatinib mesylate, the active ingredient underlying the drug, Glivec: 1997 (Switzerland) and 1998 (India).[3] The Indian application claims priority from the Swiss application date: 18 July, 1997[4]
7. Glivec is granted FDA approval : 2001[5]
B The Patents at Issue
The patent dispute that is now before this Hon’ble Court centres around the beta crystalline form of imatinib mesylate claimed in the 1998 patent application referred to above.
Novartis claims that about 40 patents covering this polymorphic beta crystalline form have been granted to it in various countries. However, owing to the unavailability of drug patents in India until 1 January 2005, Novartis claimed this new crystalline form in a “mailbox” application, which had been filed on 17 July, 1998.[6]
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 and Designs 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 writ 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 the TRIPS Agreement.
Pursuant to a Government notification, the Hon’ble High Court transferred the first writ 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 for the second writ petition, it held that section 3(d) was constitutionally valid and that the TRIPS challenge was not maintainable; it could only be agitated before the WTO dispute settlement panel.
The IPAB effectively upheld the Controller's finding that the petitioners’ application was not patentable. In particular, it held that although the invention was novel and inventive, it could not be granted a patent since it (i) contravened section 3(d) and; (ii) violated public order under section 3(b).
(i) Absence of significant enhancement of efficacy under section 3(d)
The IPAB refused to accept that a 30% increase in bio-availability demonstrated in favour of the beta crystalline form would lead to ‘significantly enhanced efficacy’ under section 3(d). Relying on the medical dictionary meaning of ‘efficacy’ as endorsed by the Madras High Court, the tribunal held that it is “the ability of a drug to produce a desired therapeutic effect”. The tribunal concluded that efficacy and bioavailability are not equivalent to each other. It further refused to read in ‘advantageous properties’ under the ambit of enhanced efficacy, reasoning that better storability, flow properties or shelf life, were concerned more with the formulation or presentability of a pharmaceutical substance, and had no relationship with the curing effect of the pharmaceutical substance. In the words of the IPAB,
“Common sense tells that efficacy is a property which is related to curing effect of a drug, whereas better shelf life, better storability and better flow properties are something which is related to formulation or presentability of a drug/pharmaceutical substance which has no relationship with the curing effect. Hon’ble Madras High Court with the help of a dictionary on pharmacology has given a meaning of efficacy as therapeutic effect in healing a disease or having a good effect on the body.”(supra). We also are respectfully in full agreement with this meaning.”
(ii) Violation of Public Order due to excessive pricing of the claimed drug under section 3(b).
The IPAB also held that the claimed invention was not eligible for a patent, under section 3(b), since the drug corresponding to the patent was marketed at an excessive and unaffordable price to patients in India. This, according to the IPAB, would be against ‘public order’ under section 3(b) of the Patent Act.
C Key Issues in the Dispute
The key issues now before this Hon’ble Court are:
1. Whether or not the petitioners’ patent covering the beta crystalline version complies with section 3(d)?
2. Whether or not the said version is novel and inventive?
3. Whether or not it violates public order?
The intervenor seeks to assist the court with the above issues, and in particular to help it evolve guidelines for future pharmaceutical patent disputes. The interest of the intervenor lies in the robust development of sound patent jurisprudence for India that appropriately balances the competing interests of drug originators against that of generic companies and patients.
II THE SECTION 3(D) STANDARD
Section 3(d) currently reads as under:
“3. What are not inventions: The following are not inventions within the meaning of this Act….
(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 known 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) stipulates that a new form of a known substance would be patentable only when the said new form demonstrates significantly enhanced efficacy when compared with the known substance.[7] The key issues in interpreting the scope and ambit of section 3(d) are:
1. the meaning of the term efficacy
2. whether increased bioavailability qualifies as efficacy?
3. the standard of proof required to establish efficacy
4. the point in time at which proof of efficacy must be adduced
5. what is the known substance under section 3(d)?
A Meaning of “Efficacy”
The central issue in section 3(d) revolves around the meaning of the term “efficacy”. More specifically, the issue is whether or not efficacy ought to be interpreted narrowly to mean only “therapeutic” efficacy or whether it ought to be broadened out to include any kind of advantageous property attributable to the new form in question.
The Madras High Court held that “efficacy” meant only “therapeutic” efficacy and not every advantageous property claimed for the new drug derivative in question.[8] The IPAB endorsed this interpretation.
The intervenor submits that, based on the history of the section 3(d) and its current structure, this appears to be a correct reading of section 3(d). However, one important caveat needs to be borne in mind; section 3(d) is not limited to pharmaceutical technology alone. Rather, it applies also to chemicals (such as paints) and agro-chemicals (such as pesticides), for which therapeutic efficacy cannot be an appropriate standard.[9]
A nuanced interpretation of efficacy would therefore suggest that it be defined in a technologically specific way i.e. while it would mean therapeutic efficacy in the pharmaceutical context, it would translate to an ability to destroy pests in a pesticide context. Such an interpretation is in conformity with prevailing patent jurisprudence in countries such as the US and EU which have been known to interpret facially neutral patent standards in a technologically specific way.[10]
The structure of section 3(d) as also its legislative history supports a narrow reading of the term “efficacy”.
Illustratively, the Explanation to section 3(d) clearly states that all pharmaceutical derivatives would be considered the same “substance”, unless “they differ significantly in properties with regard to efficacy.”
The above clause refers to only those “properties” that have some bearing on “efficacy” and not all properties. Therefore, not all advantageous properties of a new form ought to qualify under section 3(d), but only those properties that have some bearing on efficacy. Although this precise line of argument pointing to the phrase “properties with regard to efficacy” does not appear to have been explicitly made by either the Madras High Court or the IPAB to support their conclusion, it is one that compellingly supports a restrictive interpretation of the term “efficacy”.
This interpretation is further buttressed by the objectives of the Act, which suggest that section 3(d) was introduced to prevent ever-greening.[11] The Madras High Court states in this regard:[12]
“…We have borne in mind the object which the Amending Act wanted to achieve namely, to prevent ever-greening; to provide easy access to the citizens of this country to life saving drugs and to discharge their Constitutional obligation of providing good health care to it's citizens…”
Although the term ever-greening does not have a scientific definition as yet, it is widely understood to mean an inappropriate extension in patent monopoly which does not convert to a significant benefit for the patient.[13]
Put another way, it is a patenting strategy “consisting of acquiring patents on minor, often trivial, modifications of existing pharmaceutical products or processes in order to indirectly extend the period of patent protection over previously patented compounds.”[14]
1 Drawing from the Orphan Drugs Act (ODA)
Based on all of the above, the intervenor submits that the term efficacy under section 3(d) ought to be interpreted to mean any “therapeutic advantage”. The Orphan Drugs Act is illustrative in this regard and could be used to delineate the contours of “therapeutic advantage”.
The ODA was enacted by the US Congress to help incentivise the creation of what are known as “orphan drugs” i.e. any drug used to treat a rare disease or condition that affects fewer than 200,000 patients in the US or for which there is no reasonable expectation that the cost of developing the drug for a disease will be recovered from sales.[15]
Given that pharmaceutical companies generally shy away from research on orphan drugs, owing to the lack of large markets for such drugs, the ODA was brought into existence to grant additional incentives for creating such drugs to benefit minority patient populations. The incentive is in the form of a seven year marketing exclusivity to drug originators, so that they are able to recover their R&D costs and also make a healthy profit during this period of exclusive protection.[16] Contrast this with regular data exclusivity regimes, which grant drug originators a period of exclusivity lasting only 5 years from the date of their approval. Further, such exclusivity is limited to preventing the use of and reliance upon “data” submitted by the drug originator to regulatory authorities, such that no follow-on drug manufacturer’s drug can be approved using this very same data during the time of protection. However, follow-on manufacturers are free to conduct their own clinical trials and procure drug marketing approval during this time period.[17]
Contrast this with the ODA which offers complete and absolute “market” exclusivity, independent of the clinical trial data that is submitted. In other words, the protection is against all follow-on drug manufacturers, who cannot enter the market, even if they repeat the clinical trials and are able to submit independently generated data.[18]