NOVARTIS AG v. UNION OF INDIA & OTHERS

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[AFTAB ALAM, J.] Office (PTO) of the applicant's claims 13-15 for "Solid Polymers A of Olefins" under 35 USC § 102, 103, 112 (first paragraph) and 132.

150Copy pinpoint150. The application, though filed in 1971, was in continuation of the first application filed on January 27, 1953. B One of the main issues involved in the case was whether a "later state of the art" could be taken as evidence to support a rejection of the patent claim.

151Copy pinpoint151. Among the reasons given by the Board for rejecting the claim of the applicant was that the disclosure in the original , C 1953 Hogan and Banks' application was not enabling, because the disclosure was limited to making crystalline polymers. But the claims which the Board rejected included an amorphous polymer as well, which was manifestly outside the scope of the enabling teaching present in the case. The Court of Customs D and Patent Appeals reversed the decision of the Board of Patent Appeals, observing and holding as under: ·

"The PTO has not challenged appellants' assertion that their 1953 application enabled those skilled in the art in E 1953 to make and use "a solid polymer" as described in claim 13. Appellants disclosed, as the only then existing way to make such a polymer, a method of making the crystalline form. To now say that appellants should have disclosed in 1953 the amorphous form which ori this record did not exist until 1962, would be to impose an impossible burden on inventors and thus on the patent system. There cannot, in an effective patent system, be such a burden placed on the right to broad claims, To restrict appellants to the crystalline form disclosed, under such circumstances, would be a poor way to stimulate invention, and particularly to encourage its early disclosure. To demand such restriction is merely to state a policy against broad protection for pioneer inventions, a policy both shortsighted and unsound· from the standpoint of H

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A promoting progress in the useful arts, the constitutional ;,._ purpose of the patent laws."

152Copy pinpoint152. The Court seems to have taken the view that the amorphous form did not exist at the time of the patent B application and therefore, that the patentee could not have been expected to Claim the amorphous form at that time. The Court further took the view that the broad claim for a solid polymer would satisfy the enablement requirement under the state of the art, as that was known at the time of the filling of the pa~ent application, because the amorphous form was not known at that c .time. The Court observed: "Consideration of a later existing state of the art in testing for compliance with § 112, first paragraph, would not only preclude the grant of broad claims, but would wreak havoc in other ways as well. The use of a subsequently-existing improvement to show lack of enablement in an earlier-filed application on the basic invention would preclude issuance of a patent to the inventor of the thing improved, and in the case ofissued patents, would invalidate all claims (even some "picture claims") therein. Patents are and should be granted to later inventors upon unobvious improvements. Indeed, encouragement of improvements on prior inventions is a major contribution of the patent system and the vast majority of patents are issued on improvements. 1 ~ F lt is quite another thing, however, to utilize the patenting or publication of later existing improvements to "reach back" and preclude or invalidate a patent on the underlying invention." •

153Copy pinpoint153. The polypropylene case in the US gave rise to an G extraordinary legal precedent for the enablement requirement, --\_ according to which a patentee is free to claim a genus that includes unknown species that may be discovered in the future, if the specification describes and enables all the species that are known at the time of filing the patent application. The H

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[AFTAB ALAM, J.] ___, rationale on which the decision is based is described by A Professors Merges and Duffy as the "temporal paradox" 46 • The professors explain that, approached in this way, the description and enablement requirements for the genus are determined as of the date of filling the patent, and the patentee gets the benefit ·Of any addition to the genus discovered later. 8

154Copy pinpoint154. It needs to be noted here that even in the US, Hogan represents a decision given in the context of the special set of facts and circumstances of the litigation over polypropylerie. In ~ later decisions, the Federal Circuit appears to have drastically narrowed Hogan's scope as a precedent. In Plant Genetics c System, N. V. v. DeKalb Genetics Corp, 47 the effect of Hogan was considerably constricted and its effect is virtually eliminated in Chiron Corp. v. Genentech, lnc. 48 Since Chiron, the Federal Circuit has not referred to Hogan in any of its cases that involve claims to a genus where a single species was enabled. D '(

155Copy pinpoint155. Mr. Subramanium refers to the Hogan decision in order to support his contention that the Zimmermann patent is a patent covering a genus with certain known species, and many other species that were unknown at that time, but which E are equally covered by the patent, even though there is no enabling disclosure in the patent in respect thereof. But it is already found and held earlier that lmatinib Mesylate is a known -+ substance from the Zimmermann patent. The finding that lmatinib Mesylate is a known substance from the Zimmermann F • patent is not based on the conduct of the appellant alone, as objected to by Mr. Andhyarujina, but the finding has been arrived at on an objective consideration of all the material facts

46. Apart from the Hogan Decision, Mr. Subramanium also relied upon the G f- relevant passage under the heading "Enablement and the Temporal Paradox" from the book "Patent Law and Policy: Cases and Materials" (Fifth Edition) by Robert Patrick Merges and John Fitzgerald Duffy ... at pg. 298- 300

47. 315 F. 3d 1335, 1341 (Fed. Cir. 2003)

48. 363 F. 3d 1247, 1257 (Fed. Cir. 2004) H

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A and circumstances. In view of that finding, we fail to see any _,_ I

application of the Hogan decision to the facts of the case. We have also considered the two decisions relied upon by Mr. Andhyarujina. Those two decisions also have no application to the facts of the present case, for the same reason as in case B of Hogan.

156Copy pinpoint156. Ho_wever, before leaving Hogan and proceeding further, we would like to say that in this country the law of patent, after the introduction of product patent for all kinds of substances in the patent regime, is in its infancy. We certainly x )-

c do not wish the law of patent in this country to develop on lines where there may be a vast gap between the coverage and the disclosure under the patent; where the scope of the patent is determined not on the intrinsic worth of the invention but by the artful drafting of its claims by skillful lawyers, and where patents are traded as a commodity not for production and marketing of the patented products but to search for someone who may y be sued for infringement of the patent.

157Copy pinpoint157. In light of the discussions made above, we firmly reject the appellant's case that lmatinib Mesylate is a new product and the outcome of an invention beyond the Zimmermann patent. We hold and find that lmatinib Mesylate is a known substance from the Zimmermann patent itself. Not only is lmatinib Mesylate known as a substance in the t-- F Zimmermann patent, but its pharmacological properties are also known in the Zimmermann patent and in the article published in the Cancer Research journal referred to above. The consequential finding, therefore, is that lmatinib Mesylate does not qualify the test of "invention" as laid down in section 2(1 ){j) and section 2(1 )(ja) of the Patents Act, 1970. G 158.This leaves us with the beta crystal form of lmatinib Mesylate, which, for the sake of argument, may be accepted to be new, in the sense that it is not known from the Zimmermann patent. (Whether or not it involves an "inventive H

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[AFTAB ALAM, J.] ~4 step" is another matter, and there is no need to go into that A aspect of the matter now). Now, the beta crystalline form of lmatinib Mesylate being a pharmaceutical substance and mo'reover a polymorph of lmatinib Mesylate, it directly runs into section 3(d) of the Act with the explanation appended to the provision. Mr. Subramanium, however, contended that section B 3(d) has no application in this case. The main ground on which he denied the applicability of section 3(d) to decide the question .... of grant of patent to the beta crystalline form of the lmatinib Mesylate is earlier held to be untenable. He, however, questioned the applicability of section 3(d) on another ground. c Mr. Subramanium submitted that in order to attract section 3(d), a the subject product must be a new form of known substance having known efficacy. The learned counsel laid some stress on the expression "known" that equally qualifies the substance of which the subject product may be another form, and the .)" D efficacy of that substance. The learned counsel submitted that a "conceivable" substance is not a "known substance" within the meaning of the provision. He contended that the word "known" here connotes proven and well-established; "known efficacy" implies efficacy established empirically and proven beyond doubt. He further contended that neither lmatinib nor E lmatinib Mesylate had any known efficacy and that, therefore, there was no question of showing that the beta crystalline form ..... of lmatinib Mesylate had any enhanced efficacy over lmatinib or lmatinib Mesylate. F

159Copy pinpoint159. There is no sanction to construe the expression "known" in section 3(d) in the manner suggested by Mr. Subramanium, and the submission is unacceptable both in law and on facts. It may be noted here that clauses (e) and (f) of J.- section 64(1) of the Act, which contain two of the grounds for G revocation of patents, also use the expression "publicly known". The expression "publicly known" may normally be construed more widely than "known", and in that sense it is closer to the submission made by Mr. Subramanium. But even the expression "publicly known" received quite the opposite H

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_,. - A interpretation by this Court in Monsanto Company v. Coramandal lndag Products (P) Ltd. 49 In paragraph 6 of the judgment, Justice Chinnappa Reddy, speaking for the Court, held and observed as under:

" ... To satisfy the requirement of being publicly known as B used in clauses (e) and (f) of Section 64(1 ), it is not necessary that it should be widely used to the knowledge of the consumer public. It is sufficient if it is known to the persons who are engaged in the pursuit of knowledge of the patented product or process either as men of science c or men of commerce or consumers. The section of the public, who, as men of science or men of commerce, were interested in knowing about Herbicides which would destroy weeds but notrice, must have been aware of the discovery of Butachlor. There was no secret about the D ·active agent Butachlor as claimed by the plaintiffs sinc_e there was no patent for Butachlor, as admitted by the plaintiffs. Emulsification was the well-known and common process by which any herbicide could be used. Neither Butachlor nor the process of emulsification was capable E of being claimed by the plaintiff as their exclusive property. The solvent and the emulsifier were not secrets and they were admittedly not secrets and they were ordinary market products. From the beginning to the end, there was no secret and there was no invention by the plaintiffs. The F ingredients, the active ingredients the solvent and the emulsifier, were known; the process was known, the product was known and the use was known. The plaintiffs were merely camouflaging a substance whose discovery was known through out the world and trying to enfold it in G their specification relating to Patent Number 125381. The patent is, therefore, liable to be revoked ... ."

160Copy pinpoint160. On facts also we are unable to accept that lmatinib Mesylate or even lmatinib was not a known substance with

H 49. (1986) 1 sec 642.

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[AFTAB ALAM, J.]

~,,} known efficacy. It is seen above that lmatinib Mesylate was a A known substance from the Zimmermann patent. In the NOA submitted by the appellant before the US FDA, it was clearly stated that the drug had undergone extensive preclinical, technical and clinical research. The clinical studies included one multiple dose tolerability/dose-finding study (Phase I) and three B large open, uncontrolled efficacy and safety studies (Phase II); and a total of 1,234 patients with CML and other Ph+ .leukemias were enrolled iri the studies. The efficacy of lmatinib was equally .,,,._ known, as is evident from the Zimmermann patent itself, besides the two articles referred to above. c

161Copy pinpoint161. The subject product, that is, beta crystalline form of lmatinib Mesylate, is thus clearly a new form of a known substance, i.e., lmatinib Mesylate, of which the efficacy was well known. It, therefore, fully attracts section 3(d) and must be shown to satisfy the substantive provision and the explanation appended to it. 'f' 162. We now proceed to examine how far the beta crystalline form of lmatinib Mesylate stands up to the test of section 3(d) of the Act. It is noted, in the earlier part of judgment, that the patent application submitted by the appellant contains a clear and unambiguous averment that all the therapeutic qualities of beta crystalline form of lmatinib Mesylate are also possessed by lmatinib in free base. The relevant extract ...... I from the patent application is once again reproduced here: "It goes without saying that all the indicated inhibitory and pharmacological effects are also found with the free base, 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3- (4-pyridin-3-yl) pyrimidin-2-ylamino)phenyl] benzamide, or other cells thereof. The present invention relates especially to the b-crystal form of the methanes~lfonic acid G j- addition salt of a compound of formula I in the· treatment of one of the said diseases or in the preparation of a pharmacotoi;iical agent for the treatment thereto." (emphasis added) H

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163Copy pinpoint163. Now, when all the pharmacological properties of beta crystalline form of lmatinib Mesylate are equally possessed by lmatinib in free base form or its salt, where is the question of the subject product having any enhanced efficacy over the known substance of which it is a new form?

164Copy pinpoint164. It may also be stated here that while going through the Zimmermann patent one cannot but feel that it relates to some very serious, important and valuable researches. The subject patent application, on the other hand, appears to be a loosely assembled, cut-and-paste job, drawing heavily upon the C Zimmermann patent. As a matter of fact, Mr. Kuhad, learned Additional Solicitor General, submitted before us a tabular chart showing over a dozen statements and averments made in the subject application that are either lifted from the Zimmermann patent or are very similar to corresponding statements in the D Zimmermann patent. The aforesaid chart is appended at the end of the judgment as Appendix II.

165Copy pinpoint165. It further needs to be noted that, on the issue of section 3(d), there appears to be a major weakness in the case of the appellant. There is no clarity at all as to what is the substance immediately preceding the subject product, the beta crystalline form of lmatinib Mesylate. In course of the hearing, the counsel appearing for the appellant greatly stressed that, in terms of invention, the beta crystalline form of lmatinib Mesylate is two stages removed from lmatinib in free base form. The same is said in the written notes of submissions filed on behalf of the appellant. But this position is not reflected in the subject application, in which all the references are only to lmatinib in free base form (or to the alpha crystalline form of lmatinib Mesylate in respect of flow properties, thermodynamic stability and lower hygroscopicity). On going through the subject application, the impression one gets is that the beta crystalline form of lmatinib Mesylate is derived directly from lmatinib free base. This may, perhaps, be because once the beta crystalline form of the methanesulfonic acid salt of lmatinib came into H

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/ [AFTAB ALAM, J.] . _,,/ being, the lmatinib free base got seeded with the nuclei of A lmatinib Mesylate beta crystalline form and, as a result, starting from lmatinib one would inevitably arrive directly at the beta crystalline form of lmatinib Mesylate. But all this is nowhere said in the subject application. B

166Copy pinpoint166. Apart from the subject application, the appellant filed four affidavits before the Controller. Two of the affidavits are meant to explain and refute the results of the experiments --,;... conducted by the llCT at the instance of one of the objectors, NATCO Pharma Ltd. But the other two, one by Paul William Manley, dated July 22, 2005, and the other by Giorgio Pietro c Massimini, dated _September 2005, were filed to meet the requirements of section 3(d), which was amended while the application lay in the "mailbox".

167Copy pinpoint167. Massimini, in paragraph 8 of the affidavit, explained that it was being filed to meet the conditions under section 3(d) 1 of the Act. He stated that the proviso to section 3(d) was unique to India and there was no analogous provision in any other country of the world. The appellant was, therefore, never called upon to satisfy the tests laid down in section 3(d) of the Act to establish the patentability of the patent subject. He further stated that since no occasion to do so had arisen earlier, no study relating to the efficacy of the free base was carried out in the ~ past. Upon coming to know the requirement of section 3(d), the deponent, asked by the appellant, immediately commenced such a study, ensuring that accuracy and universally accepted scientific and ethical guidelines were not sacrificed. I

168.Manley, in paragraph 8 of his affidavit, stated:

"The physical properties of the Free Base and imatinib mesylate differ in that the Free Base is only very slightly soluble in water (0.001 g/100 ml) while imatinib mesylate is very soluble in water (beta crystalline form: 130 g/100 ml). Other physical characteristics of the subject compound are described at pages 2 - 3 of the specification. The H

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A attendant advantages because of these properties are ...,. - '

also simultaneously described therein. These characteristics and hence the attendant pJoperties/ advantages are not shared by the Free Base. Furthermore, the Beta form significantly differs from the alpha form: B Physical attributes:

(a) The beta crystal form has substantially more beneficial flow properties and thus results in better processability than the alpha crystal form. c (b) The beta-crystal form of the methanesulfonic acid addition salt is the thermodynamically more stable form at room temperature. Greater stability is thus to be expected. D (c) The beta-crystal form is less hygroscopic than the alpha-crystal form of the methanesulfonic acid addition salt of a compound of formula I.

(d) The lower hygroscopicity is a further advantage for E processing and storing the acid addition salt in the beta-crystal form."

(emphasis added)

169Copy pinpoint169. Massimini, in paragraph 9 of his affidavit stated: F "A study conducted in rats provided statistical evidence for a difference in the relative bioavailability of the Free Base and lmatinib mesylate in the beta crystalline form. In such study, a mean AUC (0-48h) value of 264.000 h*ng/ml was G found for the Free Base compared with a mean AUC (0- 48h) value of 344000 h*ng/ml for lmatinib mesylate having the beta crystal form. In other words, an about 30% improvement in bioavailability was observed for the beta crystalline for of lmatinib mesylate compared to the Free H Base. The test results are attached herewith as Annexure

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[AFTAB ALAM, J.] "A"." A

170Copy pinpoint170. It is to be noted that the higher solubility of the beta crystalline form of lmatinib Mesylate is being ·compared not to lmatinib Mesylate but, once again, to lmatinib in free base form. The whole case of the appellant, as made out in the subject 8 application and the affidavits, is that the subject product, the beta crystalline form of lmatinib Mesylate, is derived from lmatinib, and that the substance immediately preceding the beta crystalline form is not lmatinib Mesylate but lmatinib in free base form. This position is sought to be canvassed in the subject application and the affidavits on the premise that the C Zimmermann patent ended at lmatinib in free base and did not go beyond to lmatinib Mesylate. Not only is this premise unfounded as shown earlier, but the appellant itself appears to take a somewhat different stand, as before this Court it was ·contended that the subject product, in terms of invention, is two D stages removed from lmatinib in free base, and the substance immediately preceding the subject product is lmatinib Mesylate (non"crystalline).

171Copy pinpoint171. That being the position, the appellant was obliged to E · show the enhanced efficacy of the beta crystalline form of lmatinib Mesylate over lmatinib Mesylate (non-crystalline). Jllere is, however, no material in the subject application qr, in the supporting affidavits to make any comparison of efficacy, or _ . even solubility, between_the beta crystalline form of Tmatinlb F Mesylate and lmatinib Mesylate (non-crystalline).

172Copy pinpoint172. As regards the averments made in the two affidavits, for all one knows the higher solubility that is attributed to the beta crystalline form of lmatinib Mesylate may actually be a property of lmatinib Mesylate itself. One does not have to be G an expert in chemistry to know that salts normally have much better solubility than CO!!J_pounds in free base form. If that be so, the additional properties that may be attributed to the beta crystalline form of lmatinib Mesylate would be limited to the following: H

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A i. More beneficial flow properties,

ii. Better thermodynamic stability, and

iii. Lower hygroscopicity

s 173. The aforesaid properties, ("physical attributes" according to Manley), would give the subject product improved processability and better and longer storability but, as we shall see presently, on the basis of those properties alone, the beta crystalline form of lmatinib Mesylate certainly cannot be said x c to possess enhanced efficacy over lmatinib Mesylate, the known substance immediately preceding it, within the meaning of section 3(d) of the Act.

174Copy pinpoint174. We have so far considered the issue of enhanced efficacy of the subject product in light of the finding recorded D earlier in this Judgment that lmatinib Mesylate (non-crystalline) is a known substance from the Zimmermann patent and is also the substance immediately preceding the patent product, that is, lmatinib Mesylate in beta crystalline form.

175Copy pinpoint175. Let us now consider the case of the appellant as made . out 'iii the subject application and the supporting affidavits, and examine the issue of enhanced efficacy of the beta crystalline form of lmatinib Mesylate vis-a-vis lmatinib in free base form. It is seen above that all the pharmacological effects of lmatinib F Mesylate in beta crystalline form are equally possessed by lmatinib in free base form. The position is not only admitted but . '

repeatedly reiterated in the patent application. Mr. Subramanium, with his usual fairness and candour, explained the position by stating that lmatinib free base is actually the G active therapeutic ingredient, but in free base form lmatinib has very little or no solubility. It is, therefore, not capable of being administered as a drug to human beings. In the words of Mr. Subramanium, if given in solid dosage form, lmatinib free base would sit in the stomach like a brick and would pass out with

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[AFTAB ALAM, J.] no therapeutic effect. The invention of methanesulfonic acid addition salt of lmatinib makes the therapeutic ingredient (that continues to be the same) highly soluble, and therefore very suitable for being administered as a drug to humans. The further invention of the beta crystalline form of lmatinib Mesylate adds to its properties and makes it an even better drug than lmatinib Mesylate. The subject product, that is, the beta crystalline form of lmatinib Mesylate, thus demonstrates a definite and tangible enhancement of efficacy over lmatinib in free base form.

176Copy pinpoint176. The way in which the c·ase is presented by Mr. c Subramanium is an entirely new case made before this Court for the first time. Nevertheless, let us consider the case of the appellant as presented by Mr. Subramanium. '

177Copy pinpoint177. The portion added in section 3(d) by the 2005 D amendment reads as under:

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 ... [is not inventions within the meaning. of the Act].

178Copy pinpoint178. The Explanation to section 3(d) also added by the 2005 amendment provides as under:

"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." G

179Copy pinpoint179. It may be seen that the word "efficacy" is used both in the text added to the substantive provision as .also in the explanation added to the provision.

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180Copy pinpoint180. What is "efficacy"? Efficacy means 50 "the ability to \ r-- produce a desired or intended result". Hence, the test of efficacy in the context of section 3(d} would be different, depending upon the result the product under consideration is desired or intended to produce. In other words, the test of B efficacy would depend upon the function, utility or the purpose of the product under consideration. Therefore, in the case of a medicine that claims to cure a disease, the test of efficacy can only be "therapeutic efficacy". The question then arises, what would be the parameter of therapeutic efficacy and what are c the advantages and benefits that may be taken into account for determining the enhancement of therapeutic efficacy? With regard to the genesis of section 3(d), and more particularly the circumstances in which section 3(d) was amended to make it even more constrictive than before, we have no doubt that the "therapeutic efficacy" of a medicine must be judged strictly and 0 narrowly. Our inference that the test of enhanced efficacy in case of chemical substances, especially medicine, should receive a narrow and strict interpretation is based not only on external factors but there are sufficient internal evidence that leads to the same view. It may be noted that the text added to section 3(d) by the 2005 amendment lays down the condition of "enhancement of the known efficacy". Further, the explanation requires the derivative to "differ significantly in properties ,with regard to 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.

181Copy pinpoint181. While dealing with the explanation it must also be kept in mind that each of the different forms mentioned in the explanation have some properties inherent to that form, e. g., solubility to a salt and hygroscopicity to a polymorph. These forms, unless they differ significantly in property with regard to efficacy, are expressly excluded from the definition of "invention". Hence, the mere change of form with properties

H 50. The New Oxford Dictionary of English, Edition 1998.

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[AFTAB ALAM, J.] - ..( inherent to that form would not qualify as "enhancement of efficacy;' of a known substance, In other words, the explanation · is meant to indicate what is not to be considered as therapeutic efficacy. · 182. We have just noted that the test of enhanced therapeutic efficacy must be applied strictly, but the question needs to be considered with greater precision. In this connection, we take note of two slightly diverging points of view -~ urged before this Court.

183Copy pinpoint183. Mr. Anand Grover, learned counsel appearing for one of the Objectors, Cancer Patients Aid Association, took a c somewhat rigid position. The learned counsel submitted that in the pharmaceutical field, drug action is explained by "pharmacokinetics" (effect of the body on the drug) and "pharmacodynamics" (effect of the drug on the body). He further submitted that efficacy is a pharmacodynamic property, and contended that, in the field of pharmaceuticals, efficacy has a well-known meaning. Efficacy is the capacity of a drug to produce an effect. The IUPAC describes efficacy as "the property that enables drugs to produce responses". It is that property of a drug which produces stimulus. When comparing the efficacy of two substances, efficacy describes "the relative intensity with which agonists vary in the response they produce even when they occupy the same nurriber of receptors". [IUPAC . _J.- Glossary of Terms used in Medicinal Chemistry; 1998 in CPAA volume 9, at page 7]. In the words of Goodman and Gilman, F "the generation of response from the drug receptor complex is governed by a property described as efficacy". They further clarify that "efficacy is that property intrinsic to a particular drug that determines how good an agonist the drug is" [Goodman - }--- and Gilman in CPAA compilation, volume 9, at page 22, LHC]. G Another source describes efficacy as "the ability of the drug to produce the desired therapeutic effect" [Dorland's Medical dictionary in Novartis' volume P, at page 19].

184Copy pinpoint184. Mr. Grover further submitted that in pharmacology, efficacy is distinct from affinity, potency and bioavailability. H

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A Affinity, a pharmacodynamics property, "is the tendency of a molecule to associate with another''. The affinity of a drug is its ability to bind to its biological target (receptor, enzyme, transport system, etc.). Potency is "the dose of drug required to produce a specific effect of given intensity as compared to a standard reference". Bioavailability, on the other hand, is a 8 pharmacokinetic property. It "is the term used to indicate the • fraction extent to which a dose of drug reaches its site of action I

or a biological fluid from which the drug has access to its site of action" [Goodman and Gilman in CPAA compilation, C volume .. ., internal page 4]; or "the degree to which a drug or other substance becomes available to the target tissue after administration" [Dorland's Medical Dictionary in Novartis' volume B, at page 65). A demonstration of increase in bioavailability is not a demonstration of enhanced efficacy.

0 185. Prof. Basheer, who appeared before this Court purely in academic interest as an intervenor-cum-amicus, agreed that not all advantageous properties of a new form (such as improved processability or flow characteristics, stQrage potential, etc.) ought to qualify under section 3(d), but only those E properties that have some bearing on efficacy. However, taking a less rigid position than Mr. Grover, Prof. Basheer argued that safety or significantly reduced toxicity should also be taken into consideration to judge enhanced therapeutic efficacy of a pharmaceutical product in terms of section 3(d). 51

F 51. Prof. Basheer traced the origins of the amended part of section 3(d) in Article 10(2)(b) of European Drug Regulatory Directive, 2004 which defines a "generic medicinal product" as: "a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product, and whose. bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and/or efficacy. In such cases, additional information providing proof of the safety and/or efficacy of the various salts, esters or derivatives of a authorized active substance must be supplied by the applicant."

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[AFTAB ALAM, J.]

186Copy pinpoint186. We have taken note of the submissions made by Mr. A Grover and Prof. Basheer in deference to the importance of the issue and the commitment of the counsel to the cause. However, we do not propose to make any pronouncement on the issues raised by them, as this case can be finally and ... effectively decided without adverting to the different points of B view noted above.

187Copy pinpoint187. In whatever way therapeutic efficacy may be interpreted, this much is absolutely clear: that the physico- chemical properties of beta crystalline form of lmatinib Mesylate, namely (i) more beneficial flow properties, (ii) better c thermodynamic stability, and (iii) lower hygroscopicity, may be otherwise beneficial but these properties cannot even be taken into account for the purpose of the test of section 3(d) of the Act, since these properties have nothing to do with therapeutic efficacy. D

188Copy pinpoint188. This leaves us to consider the issue of increased bioavailability. It is the case of the appellant that the beta crystalline form of lmatinib Mesylate has 30 per cent increased bioavailability as compared to lmatinib in free base form. If the submission of Mr. Grover is to be accepted, then bioavailability also falls outside the area of efficacy in case of a medicine. Leaving aside the submission of Mr. Grover on the issue, however, the question is, can a bald assertion in regard to increased bioavailability lead to an inference of enhanced therapeutic efficacy? Prof. Basheer quoted from a commentator52 on the issue of bioavailability as under:

He pointed out that the expressions used in a different context in the European Drug Regulatory Directive were incorporated in the Patents Act G for an altogether different purpose and raised some important and interesting points for interpretation of section 3( d) but in this case we see no reason to go into those aspects of the matter.

52. 42 FR 1640 (1977). Cf. Moffitt, Jane, Appropriateness of Bioavailability and Bioequivalency as Pre-Market Clearance Considerations, 34 Food Drug Cosm. L.J. 640 (1979) H

274 SUPREME COURT REPORTS. [2013] 13 S.C.R

A "It is not the intent of a bio-availability study to demonstrate ",.- effectiveness, but to determine the rate and extent of absorption. If a drug product is not bio-available, it cannot be regarded as effective. However a determination that a drug product is bio-available is not in itself a B determination of effectiveness." ,.., -~

(emphasis added)

189Copy pinpoint189. Thus, even if Mr. Grover's submission is not taken into consideration on the question of bioavailability, the position that k c emerges is 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. In this case, there is absolutely nothing on this score apart from the adroit submissions of the counsel. No material has been offered to indicate that the beta crystalline form of lmatinib Mesylate will produce an enhanced or superior efficacy (therapeutic) on molecular basis than what could be achieved with lmatin.ib free base in vivo animal model.

190Copy pinpoint190. Thus, in whichever way section 3(d) may be viewed, whether as setting up the standards of "patentability" or as an extension of the definition of "invention", it must be held that on the basis of the materials brought before this Court, the subject +- F product, that is, the beta crystalline form of lmatinib Mesylate, fails the test of section 3(d), too, of the Act

191Copy pinpoint191. We have held that the subject product, the beta crystalline form of lmatinib Mesylate, does not qualify the test G of Section 3(d) of the Act but that is not to say that Section 3(d) ~· bars patent protection for all incremental inventions of chemical and pharmaceutical substances. It will be a grave mistake to read this judgment to mean that section 3(d) was amended with the intent to undo the fundamental change brought in the patent H

NOVARTIS AG v. UNION OF 1NDIA 275 [AFTAB ALAM, J.]

regime by deletion of section 5 from the Parent Act. That is not said in this judgment.

192Copy pinpoint192. Section 2(1)0) defines "invention" to mean, "a new product or ... ", but the new product in chemicals and especially pharmaceuticals may not necessarily mean something altogether new or completely unfamiliar or strange or not existing before. It may mean something "different from a recent previous" or "one regarded as better than what went before" ""'- or "in addition to another or others of the same kind" 53 . However, in case of chemicals and especially pharmaceuticals if the c product for which patent protection is claimed is a new form of a known substance with known efficacy, then the subject product must pass, in addition to clauses 0) and Oa) of section 2(1), the test of enhanced efficacy as provided in section 3(d) read with its explanation. D ~

193Copy pinpoint193. Coming back to the case of the appellant, there is yet another angle to the matter. It is seen above that in the US the drug Gleevec came to the market in 2001. It is beyond doubt that what was marketed then was lmatinib Mesylate and not the E subject product, lmatinib Mesylate in beta crystal form. It is also seen above that even while the appellant's application for grant --..+ of patent lay in the "mailbox" awaiting amendments in the law of patent in India, the appellant was granted Exclusive Marketing Rights on November 10, 2003, following which F ~ Gleevec was marketed in India as well. On its package, the drug was described as "lmatinib Mesylate Tablets 100 mg" and it was further stated that "each film coated tablet contains: 100 _,)- mg lmatinib (as Mesylate)". On the package there is no reference at all to lmatinib Mesylate in beta crystalline form. G

53. The New Oxford Dictionary of English Edition 1998

54. A copy of the package is enclosed at the end of the judgment as appendix Ill. H

p. 276 Copy page pinpoint

A What appears, therefore, is that what was sold as Gleevec was lmatinib Mesylate and not the subject product, the beta crystalline form of lmatinib Mesylate.

194Copy pinpoint194. If that be so, then the case of the appellant appears 8 in rather poor light and the claim for patent for beta crystalline form of lmatinib Mesylate would only appear as an attempt to obtain patent for lmatinib Mesylate, which would otherwise not be permissible in this country.

195Copy pinpoint195. In view of the findings that the patent product, the beta crystalline form of lmatinib Mesylate, fails in both the tests of invention and patentability as provided under clauses 0), Oa) of section 2(1) and section 3(d) respectively, the appeals filed by Novartis AG fail and are dismissed with cost. The other two o appeals are allowed.

196Copy pinpoint196. Before putting down the records of this case, we would like to express our deep appreciation for the way the hearing of the case took place before the Court. Every counsel E presented the issues under consideration from a different angle and every counsel who addressed the Court had something important and valuable to contribute to the debate. It was also acknowledged that the illuminating addresses of the counsel were the result of the hard work and painstaking research by +- F the respective teams of young advocates working for each senior advocate. The presence of those bright young ladies and gentlemen in the court rocm added vibrancy to the proceedings and was a source of constant delight to us.

K.K.T. Appeals disposed of.

p. 277 Copy page pinpoint

[AFTAB ALAM, J.] APPENDIX I A

Table (1)

Comparative Table of Applications for Patents in India during the periods (a) 1930-38: (b) 1949-58 . . B 1930-1938 1949-58

Year Total . By By Year . Total By By number Indians other number Indians other r of than of than application Indian application Indian c 1930 1,099 114 985 1949 1,725 345 1,380

p. 278 Copy page pinpoint

-...,,_ A Table (2) Patents Granted From 1950-57- analysed according to the subject of the inventions Food B Year Indian Foreign Total

No. Percentage No. Percentage

1950 22 16.5 111 83.5 133 c 1951 35 28.6 87 71.4 122 1952 18 18.9. 77 81.1 95 1953 30 18.8 129 81.2 159 D 1954 31 8.3 341 91.7 372 1955 48 10.0 430 90.0 478 1956 30 7.0 402 93.0 432 1957 8 13.5 51 86.5 59 E Total 222 1628 1850 Chemical 1950 13 4.5 271 95.4 284 1951 33 8.7 378 91.3 411 F 1952 36 8.0 414 92.0 450 1953 27 7.1 351 92.9 378 1954 44 9.7 409 90.3 453 G 1955 56 12.5 448 87.5 504 1956 34 6.6 479 93.4 513 1957 68 9.3 656 90.7 727 Total 311 3406 3717 H

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[AFTAB ALAM, J.] Table (3) A Applications for Patents relating to Drugs and Pharmaceuticals Pharmaceuticals

Year Indian Foreign Total B No. Percentage No. Percentage

1947 12 7.7 (sic 143 72.3 155 17.7) c 1948 7 5.5 121 94.5 128 1949 5 3.5 139 96.5 144 1950 8 5.0 151 95.0 159 D 1951 17 7.7 203 92.3 220 1952 18 6.2 224 93.8 242 1953 18 6.3 267 a3.7 285 1954 13 4.1 300 95.9 312 E

1955 7 2.1 325 97.9 332 1956 13 2.6 476 97.4 489 1957 25 5.3 543 94.7 568 F Total 143 2892 3035 Table (5) Number of Patents in force on the 1st January, 1958 G Total Number 13,774 Owned by Indians 1,157 Owned by Indians and Foreigners jointly 21 Owned by Foreigners 12,596 H

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A APP~NDl~'I! '1- . Comparative Chart of Zimmermann Patent & Application for Beta-Crystalline form of lmatinib Mesylate in India B Zimmermann Patent Beta-crystal Application (Vol. C-4) in India (Vol. C-4)

1. Column 4: Page No. 60:

c The compounds of formula The methanesulfonic acid I have val.uable addition salt of a compound pharmacological of formula I, which is properties and can be preferably used in the B- used, for example, as anti- crystal form ... possesses tu m ora I drugs and as valuable pharmacological D drags (sic drugs) against properties and may, for atherosclerosis. example, be used as an anti- tumour agent, as an agent to treat atherosclerosis.

2. Column 5: Page No. 60: E " ... and anti-bacterial " ... preventing the invasion of active ingredients .. " warmblooded animal cells by certain bacteria, such as Porphyromonas gingivalis."

F 3. Column 4: Page No. 60: +- The phosphorylation of The phosphorylation of proteins has long been proteins has long been known as an important step known as an essential step in in the differentiation and the differentiation and division G protein kinases which are of proliferation of cells. The divided into serine/ cells. Phosphorylation is threonine kinases and catalysed by protein kinases tyrosine kinases. The subdivided into serine/ serine/threonine kinases threonine and tyrosine include protein kinase C kinases. The tyrosine H

p. 281 Copy page pinpoint

[AFTAB ALAM, J.)

and the tyrosine kinases kinases include PDGF A the PDGF (platelet- (Platelet-derived Growth derived growth factor)- Factor) receptor tyrosine receptor tyrosine Kinase. kinase. ~

4. Column 7: Page No. 60 B PDGF (platelet-derived PDGF (Platelet-derived growth factor) is a very Growth Factor) is a very frequently occurring commonly occurring growth growth factor which plays factor, which plays an an important role both ill important role both in normal normal growth and in growth · and also in . pathological cell prolifera- pathological cell proliferation, tion, such as in carcinoge- such as is seen in nesis and disorders of the carcinogenesis and in smooth muscle cells of diseases of the smooth- blood vessels, for example muscle cells of blood in atherosclerosis and vessels, for example in thrombosis. atheros- atherosclerosis and clerosis and thrombosis. thrombosis.

5. Column 7: Page No. 60: E The inhibition of PDGF- The inhibition of PDGF- stimulated receptor stimulated receptor tyrosine · tyrosine kinase activity in kinase activity in vitro is vitro is measured in measured in PDGF receptor --+ PDGF receptor immuno- vitro is measured in PDGF complexes of BALB/c 3T3 receptor immune complexes F cells, analogously to the of BALB/c 3T3 cells, as method described by E. described by E. Andrejauskas-Buchdunger Andrejauskas-Buchdunger and U. Regenass in and U. Regenass in Cancer Cancer Research 52, Research 52, 5353-5358 G 5353-5358 (1992). The (1992). A compound of compounds of formula I formula I described in more described in detail above detail hereinbefore, such as inhibit PDGF-dependent especially its B-crystal form, cell-free receptor phos- inhibits PDGF-dependent H

p. 282 Copy page pinpoint

A phorylation at acellular receptor phosphorylation. concentrations of from 0.005 to 5 µmoll liter, especially from 0.01 to 1.0, more B especially from 0.01 to 0.1 µmol/liter. The inhibition of PDGF- receptor tyrosine kinase in the intact cell is detected by c means of Western Blot Analysis, likewise analogously to the method described by E. D Andrejauskas- Buchdunger and U. Regenass in Cancer Research 52, 5353- 5358 (1992). In that test the inhibition of ligand-stimulated PDGF-receptor autophosphorylation in BALB/c mouse cells is measured with the aid of anti- phosphotyrosine with the aid of anti- ph osp hotyros i ne antibodies. The G compounds of formula I described in detail above inhibit the tyrosine kinase activity of the PDGF H receptor at L..J~~~~~~~--1-~~~~~~~~~~--'

p. 283 Copy page pinpoint

[AFTAB ALAM, J.] concentrations or trom A 0.005 to 5 µmol/liter, especially from 0.01 to 1.0 and more especially from 0.01 to 0.1 µmol/liter. At concentrations below 1.0 B µmol/liter, those compounds also inhibit the cell growth of a PDGF- depe ndent cell line, namely BALB/c 3T3 mouse fibroblasts. c

6. Column 8: Page No. 61: The compounds of this " ... the corresponding invention inhibit enzyme methanesulfonate salt activity by 50% (IC50) inhibit the tyrosine kinase D typically in a concentra- activity of the PDGF tion of 0.1to10 µm. receptor at an IC50 (concentration at which activity is inhibited by 50% compared with the control) of about 120 µM and about E 100 µM, respectively."

7. Column 7: Page No. 61: Owing to the properties On the basis of the described, compounds of described properties, the formula I can be used not methanesulfonic acid only as tumour-inhibiting addition salt of a compound active ingredients but of formula I, such as also as drugs against especially the Bcrystal form non-malignant thereof, may be used not G proliferative diseases, only as a tumour-inhibiting e.g. atherosclerosis, substance, for example in thrombosis, psoriasis, small cell lung cancer, but sclerodermitis and also as an agent to treat fibrosis. non-malignant proliferative disorders. such as H

p. 284 Copy page pinpoint

A They are also suitable for · atherosclerosis, thrombosis, the further applications psoriasis, scleroderma, and mentioned above for fibrosis ... protein kinase C- modulators and can be It may especially be used used especially in the for the treatment of B treatment of diseases diseases which respond to that respond to the an inhibition of the PDGF inhibition of PDGF- receptor kinase. receptor kinase. c 8. Column 9: Page No. 62: In addition, the In addition, the methan- compounds of·formula I esulfonic acid addition salt prevent the development of a compound of formula I,· of resistance (multi-drug such as especially its D resistance) in cancer P..crystal form C, prevents the treatment with other development of multidrug chemotherapeutic drugs resistance in cancer therapy or remove existing with other chemotherapeutic resistance to other agents or other chemo- E chemotherapeutic drugs. therapeutic agents.

9. Column 6: Page No. 62: Some of the compounds Also abl kinase, especially of formula I wherein R4 v-abl kinase, is inhibited by and RS are hydrogen 4-(4methylpiperazin-1- F inhibit not only protein ylmethyl) -N-(4methyl-3-(4- kinase C but, at a p y rid in-3-yl)pyrimid in2- concentration IC50 as ylamino) phenyl) benzamide low as approximately and its methanesulfonate from 0.01 to 5 µmol/liter, salt. G especially approximately from 0.05 to 1 µmol/liter, also certain tyrosine kinases, such as especially PDGF- receptor kinase or abl- H

p. 285 Copy page pinpoint

[AFTAB ALAM, J.]

kinase, for example v-abl A kinase.

10. Column 7: Page No. 62: The above-mentioned The inhibition of v-abl inhibition of v-abl-tyrosine tyrosine kinase is 8 kinase is determined in determined by the accordance with the methods of N. Lydon et at. methods of N. Lydon et at., Oncogene Research 5, Oncogene Research 5, 161 - 173 (1990) and J.F. 161 - 173 (1990) and J.F. Geissler et al., Cancer · Geissler et al., Cancer Research 52, 4492-8 C · Research 52, 4492-4498 (1992). In those methods (1992). In those methods [Val5]-angiotensinll and [y- [Val5]-angiotensin II and [Y- 32P]-ATP are used as 32 P]~TP are used as substrates. substrates. D .~~ 11. Column 20: Page No.68: The invention relates also The invention relates also to a method of treating to a process for the ~~um-blooded animals treatment of warmblooded suffering from a tumoral animals suffering from E disease, which comprises said diseases, especially administering to warm- a tumour disease, .... is blooded animals requiring administered to warm- · such treatment an effective, blooded animals in need of tumour-inhibiting amount of such treatment. F a compound of formula I or of a pharma-ceutically acceptable salt thereof.

12. Column 20: Page No.68: G The invention relates further The invention relates to the use of a compound moreover to the use of the of formula I or of a B-crystal form of the pharmaceutically methanesulfonic acid acceptable salt thereof for addition salt of a compound H

p. 286 Copy page pinpoint

A inhibiting PDGF-receptor of formula I for the inhibition kinase or to the use of a of the above-mentioned compound of formula I tyrosine kinases, especially wherein R4, and RS are PDGF receptor kinase, v- each hydrogen, or of a abl kinase, and/or c-kit 8 pharmaceutically receptor kinase, or for the acceptable salt thereof, for preparation of pharma- inhibiting protein kinase C ceutical compositions for in warm-blooded animals use in treating the human or or for preparing pharma- animal body. ceutical compositions for c use in the or animal body.

13. Column 20: Page No. 68: Effective doses, for Depending on species, example daily doses of age, individual condition, D approxi1T1ately from 1 to mode of administration, 1000 mg, especially from and the clinical picture in 50 to 500 mg, are question, effective doses, administered to a for example daily doses of warmblooded animal of about 12500 mg, preferably approximately 70 kg body 1-1000 mg, especially 5- E weight according to 500 mg, are administered species, age, individual to warm-blooded animals condition, mode of of about 70 kg bodyweight. administration and the individual syndrome. F

14. Column 20: Page No. 68: The invention relates also The invention relates also to to pharmaceutical com- pharmaceutical pre- positions comprising an parations which contain an G effective amount, effective amount, especially especially an amount an effective amount for effective in the prevention prevention or treatment of or therapy of one of the one of the said diseases, of above-mentioned the methanesulfonic acid diseases, of the active in- addition salt of a compound H

NOVARTIS AG v. UNION OF INDIA 267

[AFTAB ALAM, J.] grea1em togeu1er w1m of formula I in the -crystal pharmaceutically (sic Bcrystal) form, together acceptable carriers that with pharmaceutically are suitable for topical, acceptable carriers which enteral, for example oral are suitable for topical, or rectal, or parenteral enteral for example oral or administration, and may rectal, or parenteral be inorganic or organic, administration and may be solid or liquid. For oral inorganic or organic and administration there are solid or liquid. Especially used especially tablets or tablets or gelatin capsules gelatin capsules containing the active c comprising the active substance together with ingredient together with diluents, for example diluents, for example lactose, dextrose, sucrose, lactose, dextrose, mannitol, sorbitol, cellulose sucrose, mannitol, and/or glycerin, and/or sorbitol, cellulose and/or lubricants, for example glycerol, and/or silicic, talc, stearic acid, or lubricants, for example salts thereof, typically .silicic acid, talc, stearic magnesium or calcium acid or salts thereof, such stearate, and/or as magnesium or polyethylene glycol, are calcium stearate, and/or used for oral administration. polyethylene glycol. Tablets may likewise Tablets may also contain binders, for comprise binders, for example magnesium example magnesium aluminium silicate, aluminium silicate, starches, typically corn, starches, such as corn, wheat or rice starch, gelatin, wheat or rice starch, methylcellulose, sodium gelatin, methylcellulose, carboxymethylcdlulose sodium carboxymethyl- and/or polyvinylpyrrolidone, cellulose and/or polyvinyl- and, if so desired, pyrro lid one, and, if disintegrants, for example desired, disintegrators, starches, agar, alginic acid for example starches, or a salt thereof, typically agar, alginic acid or a salt sodium alginate, and/or H

p. 288 Copy page pinpoint

A thereof, such as sodium effervescent mixtures, or alginate, and/or adsorbents, colouring effervescent mixtures, or agents, flavours, and absorbents, dyes, sweetening agents. The flavourings and pharmacologically active B sweeteners. The compounds of the present pharmacologically active invention may further be ·compounds of the used in the form of present invention can preparations for parenteral also be used in the form administration or infusion of parenterafly solutions. Such solutions are G administrable preferably isotonic aqueous compositions or in the solutions or suspensions, form of infusion these possibly being solutions. Such solutions prepared before use, for are preferably isotonic example in the case of D aqueous solutions or lyophilised preparations suspensions, which, for containing the active example in the case of substance either alone or lyophilised compositions together with a carrier, for that comprise the active example mannitol. The E ingredient alone or pharmaceutical substances together with a carder, for may be sterilised and/or example mannitol, can may comprise excipients, be prepared before use. for example preserVatives, The pharmaceutical stabilisers, wetting agents '1--- ' compositions may be and/or emulsifiers, solubilisers, salts for sterilised and/or may comprise excipients, for regulation of the osmotic examplepreservatives, pressure, and/or buffers. stabilisers, wetting The present pharmac- agents and/or eutical preparations which, emulsifiers, solubilisers, if so desired, may contain salts for regulating the further pharmacologically osmotic pressure and/or active substances, such as buffers. The present ph- antibiotics, are prepared in armaceutical composi- a manner known per se, for H

p. 289 Copy page pinpoint

[AFTAB ALAM, J.] t1ons which, if desired, may example oy means ot A comprise further conventional mixing, pharmacologically active granulating, coating, substances, such as dissolving or lyophilising antibiotics, are prepared in processes, and contain a manner known per se, for from about 1% to 100%, B example by means of especially from about 1% conventional mixing, to about 20%, of the granulating, confectioning, substance or substances. dissolving or lyophilising processes, and comprise approximately from 1% to c 100%, especially from approximately 1 % to approximately 20%, active ingredient(s). D

15. Column 21: Page No. 69: The following Examples The following Examples illustrate the invention but illustrate the invention do not limit the invention in without limiting the scope any way. The Rf values are thereof. R1 - values are determined on silica gel determined on TLC plates thin-layer plates (Merck, coated with silica gel Darmstadt, Germany). The (Merck, Darmstadt, ratio to one another of the C!ermany). The ratio of the eluants in the eluant solvents to one another in mixtures used is given in the solvent systems used proportions by volume (v/v), is indicated by volume (v/ and temperatures are given v), and temperatures are in degrees Celsius. given in degrees Celsius (OC). G

N CD 0

(/) c -0 {f) N 0 y A RT 1 S Each film coated tablet contains : Mfg. Uc. No. : KD-2069-A ::u m 100 mo lmatinib (as mesylate). Stickered by! s:: fmatinib Mesyfate Doiage : As directed by the physician. Novartis· India Umlted m Do not 'tore above 30" C. Arihant Compound, ()

Tablets 100 ml1 $tore la orialnal Jlackage. Purna Village, > 0 c · '·j~ keep out of teacb an.d sight of Bhlwandi-421 302, Thane. ""1 ""1 ::u Glivec®100 mg cra.lldrea. At : M -f

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