In a two part posting in June 2013, we examined the genesis of Section 3(d) of the Indian Patents Act, 1970 (hereinafter referred to as the “Act”) (Part I), and provided patent drafting strategies to reduce the risk of receiving a Section 3(d) objection as well as overcoming an objection received during prosecution and/or an opposition proceeding (Part II).

In this post, we examine 4 decisions/orders passed by the Controller of Patents & Designs (Controller) and the Intellectual Property Appellate Board(IPAB) within the last two months entailing Section 3(d). These cases are:

1. Takeda GmBH v. Controller of Patents and Designs (Controller);

2. Monsanto Technology LLC. v. The Controller of Patents and Designs and The Deputy Controller of Patents and Designs (IPAB);

3. Fresenius Kabi Oncology Limited v. Glaxo Group Limited and The Controller of Patents (IPAB); and

4. Fresenius Kabi Oncology Limited v. Glaxo Group Limited and The Controller of Patents (IPAB).

The Takeda and Fresenius cases are directed to small molecules while the Monsanto case is directed to a method of producing transgenic plants. In the Takeda case and the first Fresenius case, experimental evidence demonstrating that the claimed compounds exhibited enhanced or improved metabolic stability, intrinsic clearance values, thermodynamic stability and moisture absorption properties was not deemed sufficient to establish enhanced therapeutic efficacy under Section 3(d). In the Monsantocase, evidence of surprising results was also not helpful in overcoming the Section 3(d) objection where the claimed invention involved a new use of a known substance. In the second Fresenius case, the Board held that the burden of proof falls on the party bringing a revocation action to demonstrate that the claimed invention:

1. Does not comply with the requirements of Section 3(d); and

2. Has the same therapeutic efficacy as a known (prior art) substance.

Section 3(d)

By way of a refresher, Section 3(d) of the Act currently reads as follows:

“Section 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.”

Takeda GmBH v. Controller of Patents and Designs

On June 24, 2013, the Controller refused Indian patent application 293/MUMNP/2008 entitled “Isotopically Substituted Pantoprazole” owned by Takeda GmBH (Takeda) for falling under the purview of Section 3(d) of the Act.

Takeda’s application discloses and claims isotopically substituted (deuterated) pantoprazole and enantiomers thereof that can be used to inhibit acid secretion in subjects suffering from a gastrointestinal disorder. According to the specification, the claimed deuterated compounds exhibit a decreased metabolization rate compared to the corresponding non-deuterated compounds and thus have an improved (longer) half-life. The specification also contained data demonstrating that 5 deuterated compounds exhibited higher metabolic stability and intrinsic clearance values compared to their equivalent non-deuterated (pantoprazole) compounds. Takeda argued that this data demonstrated that the claimed compounds exhibited higher efficacy than pantoprazole.

The closest prior art was European Patent Application 0 005 129 (D1) which disclosed non-deuterated pantoprazole derivatives for the same use and U.S. Patent 6,818,200 (D2) which taught that deuterated compounds have enhanced efficiency and thus are less susceptible to the typical metabolic pathways, thereby resulting in an increase in half-life. In view of this prior art, the Examiner rejected the claims as being obvious and for failing to qualify as an invention under Section 3(d).

In affirming the Examiner, the Controller noted that when examining whether or not a claimed invention violates Section 3(d), the following analysis must be performed:

1. Compare the claimed invention with the closest compound known in the prior art (in this case the closest prior art compound was pantoprazole); and

2. Determine whether Applicant has provided sufficient evidence (such as through arguments and experimental evidence) to demonstrate that the claimed compounds demonstrate significantly improved therapeutic efficacy when compared to the closest prior art compound.

The Controller found that the only experimental evidence provided related to metabolic stability and intrinsic clearance values. According to the Controller, this data demonstrated how the system (human body) acted on the claimed compounds. However, evidence of therapeutic efficacy requires demonstrating how the drug acts upon the system (human body). Because such evidence was missing, the Controller affirmed the Examiner’s rejection under Section 3(d) (while reversing the Examiner’s objection based on obviousness).

Monsanto Technology LLC. v. The Controller of Patents and Designs and The Deputy Controller of Patents and Designs

On July 5, 2013, the Intellectual Property Appellate Board (Board) refused Indian Patent Application no. 2407/DELNP/2006 entitled “Methods for Enhancing Stress Tolerance in Plants and Methods thereof” (which was later amended to “A Method of Producing a Transgenic Plant with Increased Heat Tolerance, Salt Tolerance, or Drug Tolerance”) owned by Monsanto Technology LLC (Monsanto) for obviousness and for failing to qualify as patentable subject matter under Section 3(d) of the Act.

The claims pending before the Board were directed to a method of producing a transgenic plant comprising the steps of inserting into the genome of plant cells a recombinant DNA molecule.  Specifically, claim 1 read as follows:

1. A method of producing a transgenic plant comprising the steps of:
(a) inserting into the genome of plant cells a recombinant DNA molecule comprising a DNA encoding a cold shock protein, wherein said DNA encoding said cold shock protein is operably linked to a promoter and operably linked to a 3’ transcription termination DNA polynucleotide;
(b) obtaining transformed plant cell [sic] containing said recombinant DNA;
(c) regenerating plants from said plant cells; and
(d) selecting a plant for increased heat tolerance, salt tolerance, or drought tolerance.

The cold shock proteins defined in the specification were referred to as “Csp(s)” or “CSP(s)” proteins that had greater than 40% identity toEscherichia coli CspA protein (SEQ ID NO:1) or Bacillus subtilis Csp B protein (SEQ ID NO:2).

During the proceeding, Monsanto admitted that as of the priority date of its application that a number of eukaryotic, including plant, stress related genes were known and had been identified in the art. However, Monsanto argued that a person skilled in the art would have used eukaryotic genes to produce stress tolerant plants rather than bacterial genes because the expression of bacterial genes in plants is unpredictable. Thus, at the time of the priority date of the application, the prior art taught away from methods of producing stress tolerant plants by incorporating bacterial genes (whose function, even in the bacterial system, was unclear). Therefore, according to Monsanto, there was no reason for one skilled in the art to resort to a bacterial system for such genes.

The closest prior art, WO 90/09447 (D2), disclosed expressing proteins obtained from the cold shock domain (such as CspA and CspB) in E. coli, yeast cells, vertebrate cells, human cells (Hela) and rat cells (BLAB/C 3T3, NIH 3T3 and embryo fibroblasts). D2 taught that “it is understood [that] other competent microorganism hosts (eukaryotic and prokaryotic) can be transformed genetically in accordance with the invention (such as yeast cloning and plant cells).” However, D2 did not specifically teach the expression of cold shock proteins in plants.

Monsanto argued that its invention did not fall under the purview of Section 3(d) of the Act because the claimed method did not constitute a “new use” of a known process but instead involved a “new product” (a transgenic plant) transformed with a prokaryotic cold stress gene that exhibited heat, salt or drought tolerance. In addition, Monsanto further argued that it had submitted sufficient data demonstrating the superiority of the new plants when compared to wildtype plants exposed to the same conditions of heat, salt or drought tolerance.

However, the Board held that the claims fell under the purview of Section 3(d) of the Act. Even though D2 taught the expression of proteins obtained from the cold shock domain (such as CspA and CspB) in E. coli, yeast cells, vertebrate cells, human cells and rat cells but not in plant cells, the Board found that the “specific selection of specific proteins from the ‘cold shock domain’ to achieve better results in plants was nothing more than a new use of such a substance.”  Specifically, the Board stated that the “[M]ere use of [an] admittedly known substance is not permitted under Section 3(d).” The Board also held that Monsanto’s evidence of “surprising” results did not change the result because the invention would “still be a new use of [a] known [substance] even if it produces better results.” In fact, the Board agreed with the Examiner who argued that “Thus [the] invention is related to [the] application of [a] cold shock protein in product of plant which are heat, salt and drought tolerant, while [the] cold tolerant property of cold shock protein are already known in the prior art, which is [a] new use/application of [an] admittedly known substance and not allowed under section 3(d) of The Patents Act, 1970”.

Fresenius Kabi Oncology Limited v. Glaxo Group Limited and The Controller of Patents

On July 27, 2013, the Board revoked Indian Patent No. 221171 entitled “Quinazoline Ditosylate Salt Compounds” owned by Glaxo Group Limited (Glaxo) for obviousness and for failing to qualify as an invention under Section 3(d) of the Indian Patents Act. Specifically, Fresenius Kabi Oncology Limited (Fresenius) filed a revocation action against Glaxo’s patent arguing that the patent should be revoked for obviousness, insufficiency of description, failing to comply with the requirements of Section 8 and falling under the purview of Section 3(d) of the Act.

The quinazoline ditosylate salt compounds that were the subject of Glaxo’s patent are protein tyrosine kinase inhibitors (PTKs) belonging to the ErbB family. Inappropriate or uncontrolled or aberrant PTK activity results in uncontrolled cell growth which has been implicated in a variety of disorders, including as psoriasis and cancer. It is believed that inhibition of PTKs would provide a treatment for disorders characterized by aberrant erbB activity.

The closest prior art was Glaxo’s own prior patent application, PCT/EP99/00048 (Indian Patent 221017 (which is the subject of the last case discussed in this post)) (D1). D1 disclosed a number of bicyclic compounds such as N-[3-chloro-4-[(3-flurobenzyl)oxy]penyl}-6-5({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4quinazolinamine; (4-(3-fluoro-benzyloxy)-3-chlorphenyl)-(6-(2-((2-methanesulphonyl-ethylamino)methyl)-thiazol-4-yl)quinazoline-4-yl)-amine; and (4-(3-fluro-benzyloxy)-3-bomophenyl)-(6-(5-((2-methanesulphonyl-ethylamino)-methyl)-furan-2-yl)quinazolin-4-yl)-amine and hydrochloride salts thereof (these compounds are collectively referred to as “di-HCl salts”). One problem with the di-HCl salts was that they absorbed large amounts of water which caused stability issues when these salts were incorporated into a formulation.

According to its specification, Glaxo identified new ditosylate salts of 4-quinazolineamines that were members of the ErbB family of PTK inhibitors. The crystal form of these 4-quinazolineamines were found to exhibit enhanced thermodynamic stability and moisture absorption properties (namely, these crystal forms exhibited less hygroscopicity) when compared to the prior art di-HCl salts.

Glaxo argued that the primary purpose of Section 3(d) of the Act was to prevent evergreening while also encouraging incremental inventions. Glaxo also argued that the use of the phrase “new form of a known substance” in Section 3(d) presupposed that there existed as of the priority date of the application a “known substance” (namely, a substance which was publicly known) having proven efficacy as opposed to a substance which was just known to the inventor or applicant. According to Glaxo, the use of the words “enhancement” and “differ significantly” in Section 3(d) meant that efficacy was to be measured empirically. Therefore, because the claimed compounds were thermodynamically more stable and exhibited less hygroscopicity, the claimed invention did not fall under the purview of Section 3(d) of the Act.

The Board disagreed with the submissions and revoked Glaxo’s patent for falling under the purview of Section 3(d) of the Act. Specifically, the Board found that Glaxo failed to prove that the claimed ditosylate salts exhibited enhanced therapeutic efficacy. According to the Board, the improvement in thermodynamically stability and moisture absorption properties of the claimed compounds did not constitute sufficient evidence to demonstrate that the claimed compounds exhibited greater therapeutic efficacy. In this context, the Board cited the Madras High Court decision in Novartis Ag. v. Union of India (2007 4 MLJ 1153). Some of the key portions of the High Court’s decision specifically mentioned by the Board are quoted below:

“The position therefore is, if the discovery of a new form of a known substance must be treated as an invention, then the Patent applicant should show that the substance so discovered has a better therapeutic effect.

…Going by the meaning for the word ‘efficacy’ and ‘therapeutic’ extracted above, what the patent applicant is expected to show is, how effective the new discovery made would be in healing a disease/having a good effect on the body?  In other words, the patent applicant is definitely aware as to what is the ‘therapeutic effect’ of the drug for which he had already got a patent and what is the difference between the therapeutic effect of the patented drug and the drug in respect of which patent is asked for. Therefore it is a simple exercise of, though, preceded by research, – we state – for any patent applicant to place on record what is the therapeutic effect/efficacy of a known substance and what is the enhancement in that known efficacy. The word ‘therapeutic’ is linked with healing of disease which means healing of that disease.

…Efficacy means ‘the ability to 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 efficacy would depend on the function, utility or the purpose of the product under consideration. Therefore, in the case of medicine that claims to cure a disease, the test of efficacy can only be ‘therapeutic efficacy’”.

Further, the Board also cited the following from the recent Supreme Court judgment in Novartis v. Union of India:

“…With regard to the genesis of section 3(d), and more particularly the circumstances in which section 3(d) was amended to make it more constrictive than before, we have no doubt that the ‘therapeutic efficacy’ of a medicine must be judged strictly and narrowly.

…From this it is seen that only those properties that are directly related to efficacy are relevant for S. 3(d) and not all advantageous or beneficial properties.  More importantly, considering the genesis of S. 3(d) the words ‘therapeutic efficacy’ must receive a narrow and strict interpretation.  The net cannot be widened to bring in other non therapeutic advantages” (emphasis added).

The Board held that while the improved properties of the claimed invention might provide certain advantages over the prior art di-HCl compounds, these advantages did not result in greater therapeutic efficacy. Therefore, the patent was revoked for failing to comply with the requirements of Section 3(d) (as well as for obviousness).

Fresenius Kabi Oncology Limited v. Glaxo Group Limited and The Controller of Patents

In a second decision issued on July 27, 2013, the Board dismissed a revocation action brought against Indian Patent No. 221017 entitled “Bicyclic Heteroaromatic Compounds” that is also owned by Glaxo.  Specifically, Fresenius filed a revocation action against Glaxo’s patent arguing that the patent should be revoked for obviousness, insufficiency of description, for failing to comply with the requirements of Section 8 and falling under the purview of Section 3(d) of the Act.

Glaxo’s application disclosed and claimed Lapatinib, a synthetic, orally-active quinazoline compound having antineoplastic activity. Lapatinib blocks phosphorylation of the growth factor receptors EGFR and ErbBs which have been implicated in the growth of various types of tumors. Because Lapatinib is an inhibitor of PTKs of the ErbB family, it is useful in the treatment of disorders mediated by aberrant activity of such kinases. Glaxo markets Lapatinib (in the form of ditosylate monohydrate) under the names TYKERB® (in the U.S. and in certain international markets such as India) and TYVERB® (in the European Union and in other European countries).

Fresenius argued that Glaxo’s claimed compound was a derivative of the prior art compounds disclosed in two PCT applications, WO 97/13771 and WO 97/30034, and there was no data in Glaxo’s application to show that the claimed compound differed significantly with respect to efficacy in view of the prior art compounds. In addition, based on this prior art, Fresenius argued that Lapatinib was nothing more than “mere” discovery of a known form of a substance.

In response, Glaxo argued that Lapatinib was a new chemical entity (NCE) and not a derivative of a known substance and that the burden of proof fell on Fresenius to demonstrate that:

1. Section 3(d) barred the patentability of a NCE; and

2. Lapatinib was the “mere” discovery of a new form of a known substance.

The Board held that Fresenius failed to prove that Lapatinib fell under the purview of Section 3(d) of the Act. The Board noted that the burden of proof falls on the party bringing a revocation action to demonstrate that the claimed invention:

1. Does not comply with the requirements of Section 3(d); and

2. Has the same therapeutic efficacy as a known (prior art) substance.

Once such proof is provided, the burden shifts to the patentee to prove that:

1. Its claimed invention is not a derivative of a known substance (namely, it is a NCE); or

2. Even if its invention is a claimed derivative of a known substance, the claimed invention exhibits enhanced therapeutic efficacy.

The Board found that Fresenius’ pleadings were vague because it merely consisted of citing two prior art publications and alleging that Glaxo’s claimed compound was a new form of these compounds. The Board specifically stated, “It is only when the pleadings show how the invention is one kind of a derivative of [a] known substance [that] the patentee will have to explain how the grant of [a] patent is justified because of the enhancement of therapeutic efficacy.”

Therefore, since Fresenius also failed to prove that the claimed invention was obvious, lacked a sufficient description and failed to comply with the requirements of Section 8, the revocation action was dismissed.

This post was written by Lisa Mueller and the attorneys at Chadha & Chadha.