Glivec and Selection Patent


IPAB (Intellectual Property Appellate Board) has begun hearing the Glivec case. Please read Prashant’s post here. One of the arguments, by the Novartis’s counsel, makes reference to an article on selection patents with respect to section 3(d), which is interesting and relevant also.
In practice only a few chemicals compounds from a class, comprising several related chemical compounds, are tested for their use as an active ingredient in a commercial product. Grant of a patent for the whole class may result in a broad monopoly but at the same time restricting the patent claims to the few tested chemical compounds would allow the competitors to reverse engineer and use the nearest alternative from the nearest class of chemical compounds. Hence to resolve this problem selection patents came into picture wherein patent protection was granted to the new forms discovered for other members of a class of chemical compounds.
Selection patent is therefore founded on the discovery of new discovered forms. It can also be viewed as a forerunner of the method of treating the variation in the use of the newly discovered form as an integral technical feature of the invention, provided it can be clothed in a product claim, where novelty is derived from the use of the newly discovered form. A selection patent will be tested for novelty and inventive step in the normal way but these may be found in the use.
At this juncture, a recent decision by the Supreme Court of Canada in the case, Apotex Inc. vs. Sanofi-Synthelabo Canada Inc., 2008 SCC 61, seems very relevant.
Case outline –
In 2003, Apotex served a Notice of Allegation, under the Patented Medicines (Notice of Compliance) Regulations (NOC Regulations), on Sanofi to obtain a Notice of Compliance from the Minister of Health for a generic version of Plavix. Apotex, in its Notice of Allegation, contented the invalidity of Sanofi’s ‘777 patent for Plavix on account of anticipation, obviousness and double patenting. As a counter, Sanofi initiated proceedings seeking an order prohibiting the Minister of Health from issuing a Notice of Compliance to Apotex on the grounds that its generic version of Plavix would infringe the ‘777 patent. The Federal Court granted an order of prohibition to Sanofi. Apotex appealed in the Federal Court of Appeal which was dismissed. Thereafter Apotex appealed in Supreme Court.
Sanofi (respondent) is the holder of patent ‘875 which discloses a genus or a class of compounds. These are useful in inhibiting platelet aggregation activity in blood which in turn is important in treating coronary artery, peripheral vascular and cerebral vascular diseases. This genus patent discloses over 250,000 possible different compounds useful for this purpose and one of the compounds is a “racemate”.
A racemate is a substance containing equal amounts of two structurally different compounds, called enantiomers or optical isomers. The two isomers, the dextro-rotatory isomer and the levo-rotatory isomer, are mirror images of each other and rotate plane-polarized light in opposite directions.
Sanofi is also the holder of subsequent patent ‘777, which is the patent in suit. It discloses and claims clopidogrel bisulfate, marketed under the trade name Plavix (an anti-coagulant that inhibits platelet aggregation activity in blood).
Clopidogrel is the dextro-rotatory isomer of the “racemate” and clopidogrel bisulfate is a salt of Clopidogrel.
To test whether ‘777 patent is anticipated by ‘875 patent, the Supreme Court of Canada took up two questions to be answered. They are –
1. what constitutes disclosure at the first stage of the test for anticipation; and
2. how much trial and error or experimentation is permitted at the enablement stage?
The Court, while exploring ‘Disclosure’ for the purposes of anticipation, took into account the ‘875 genus patent covering over 250,000 possible different compounds (based on sound prediction, the reason being that every compound was not made or tested). Any disclosure of the specific beneficial properties associated with the dextro-rotatory isomer of the “racemate” or any disclosure of any advantages flowing from using the bisulfate salt in combination with the dextro-rotatory isomer was not found.
As regards the ‘enablement stage’ there was an absence of any evidence suggesting that the person skilled in the art, from reading the ‘875 patent, would know that the dextro-rotatory isomer would be less toxic than the racemate or levo-rotatory isomer or any of the other compounds made and tested. Thus the Court opined that since the ‘875 patent did not disclose the special advantages of the dextro-rotatory isomer and of its bisulfate salt, as compared to the levo-rotatory isomer or the racemate and their salts referred to in the ‘875 patent, the invention of the ‘777 patent cannot be said to have been disclosed and therefore it cannot be said to have been anticipated.
Obviousness was tested by applying the four steps of Windsurfing/Pozzoli. As well known, the four-step approach to the obviousness inquiry was first outlined in Windsurfing International Inc. v. Tabur Marine (Great Britain) Ltd., [1985] R.P.C. 59 (C.A.). The Windsurfing approach was updated in Pozzoli SPA v. BDMO SA, [2007] F.S.R. 37, [2007] EWCA Civ 588.
A trained pharmachemist was identified as the notional person skilled in the art. On evidence, the relevant common general knowledge of this person was settled on to five well known methods to separate the “racemate” into its isomers. However, these methods were not found encompassing the method which made known the relative advantage of the dextro-rotatory isomer.
Moving further, the inventive concept of the claims in ‘777 patent was identified as a compound useful in inhibiting platelet aggregation having greater therapeutic effect and less toxicity than the other compounds of the ‘875 patent. Measuring this up against any existing difference between the ‘875 patent and the ‘777 patent, the Court found that ‘875 patent did not differentiate between the properties of the racemate, its dextro-rotatory isomer and levo-rotatory isomer. On the other hand, the ‘777 patent claims the dextro‑rotatory isomer of the racemate i.e. clopidogrel, and its bisulfate salt disclosing their beneficial properties over the levo‑rotatory isomer and the racemate and expressly describes how to separate the “racemate” into its isomers.
The last and the crucial question, in this chain, testing obviousness of the ‘777 patent, is about the difference between the ‘875 and ‘777 patent. The difference supposed to constitute steps, which would have been obvious to the person skilled in the art or required a degree of inventiveness. This is viewed with a pre condition that there is no knowledge of the ‘777 patent.
The dextro-rotary isomer and its bisulfate salt were discovered after experimenting interrelated variables, therefore to appreciate the evidence on discovering beneficial properties of it, the Court broke this question into a series of questions centric to “obvious to try” test.
[1] Is it More or Less Self-evident that What is Being Tried Ought to Work?
The Court observed that the evidence must prove that the known methods of separating a “racemate” into its isomers are more or less self-evident to try them. The Court ruled out the ‘possibility’ of finding the invention as not enough. The invention must be self-evident from the prior art and common general knowledge in order to satisfy the “obvious to try” test which did not appear as evidence in this case.
[2] What is the Extent, Nature and Amount of Effort Required to Achieve the Invention?
In considering whether it was “obvious to try” to find the invention, potentially five different methods to separate the racemate would have had to have been tried and tested before determining the properties of the dextro-rotatory isomer.
[3]Is There a Motive from the Prior Art to Find the Solution that the ‘777 Patent Addresses?
The demand for an effective and non-toxic product to inhibit platelet aggregation might be assumed to exist. However, nothing in the ‘875 patent or common general knowledge provided a specific motivation for the skilled person to pursue the ‘777 invention. The prior patent was a genus patent, and selection might be expected. However, the prior patent did not differentiate between the efficacy and the toxicity of any of the compounds it covered. This suggests that what to select or omit was not self-evident to the person skilled in the art.
[4] What is the Course of Conduct which was Followed which Culminated in the Making of the Invention?
According to Sanofi’s affidavit, the discovery that the dextro-rotatory isomer was active and non-toxic and that the levo-rotatory isomer was non-active and toxic, it decided to develop the dextro-rotatory isomer and abandon its work on the racemate. However, this was after Sanofi had invested “spent millions of dollars and several years developing [the racemate] up to the point of preliminary human clinic trials” without trying to see if the dextro‑rotatory isomer had advantageous properties to those of the racemate.
[5] Was the Invention of the ‘777 Patent “Obvious to Try”?
It was not self-evident from the ‘875 patent or common general knowledge what the properties of the dextro-rotatory isomer of this racemate would be or what the bisulfate salt’s beneficial properties would be and therefore that what was being tried ought to work. The course of conduct and the time involved throughout demonstrate that the advantage of the dextro-rotatory isomer was not quickly or easily predictable. The prior art and common general knowledge of persons skilled in the art at the relevant time were not sufficient for it to be more or less self-evident to try to find the dextro-rotatory isomer.
Concluding on Obviousness, the Court said that there was a significant difference between the ‘875 genus patent and the ‘777 selection patent. The difference was not obvious.
Appeal was dismissed on the findings which rendered ‘777 patent neither anticipated nor obvious.
The above case, particularly the Court’s Analysis in testing anticipation and obviousness, in my opinion, may throw some light on the probable course of hearing of the Novartis’s appeal in IPAB filed on rejection of its drug Gleevec.
M/s. Novartis AG on July 17, 1998 had filed a patent application for an invention titled “Crystal Modification of A N – Phenyl – 2 Pyrimidineamine derivative, processes for its manufacture and its use” claiming Switzerland priority date of July18, 1997. The patent application in effect claimed beta crystal of methanesulphonic acid salt of 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[4-pyridine-3-yl) pyrimidine-2-ylamino) phenyl]-benzamide commercially called as imatinib mesylate. Representation by way of opposition were filed under section 25(1) of the Patents Act, 1970 as amended by Patents (Amendment) Act, 2005 and rule 55 of the Patents Rules, 2003 as amended by Patents (Amendment) Rules, 2005.
The arguments of the Applicant and the Opponents were on the following three issues.
[1] Not an Invention, [2] Section 3(d) of the Patents Act and [3] Priority
The first issue had a two pronged approach – Anticipation by Prior publication & Obviousness.
This issue in the light of the Apotex vs. Sanofi (above mentioned) decision, may give a platform to apply the questions – 1) what constitutes disclosure at the first stage of the test for anticipation, and (2) how much trial and error or experimentation is permitted at the enablement stage – and the approach taken by the Canadian Supreme Court in the Novartis Case.
The opponents, in the pre-grant opposition, contented that imatinib mesylate is anticipated from prior publications viz. Nature Medicine (May 5, 1996), Cancer Research (Vol.56, Issue I, 1996) and Blood (Nov.1 1997) besides also known from the US Patent no. 5521184. The opponents further contented that beta crystalline form is the most stable form of imatinib mesylate salt, hence obvious for a person skilled in the art to prepare corresponding pharmaceutically acceptable salts once the freebase is known by the disclosure of the US Patent. The applicants, on the other hand, argued that the disclosure made in the US Patent is of the free base, ‘imatinib’ and not its salt, imatinib mesylate, therefore the present invention involves two-fold improvement over the prior art – [1] The imatinib free base is chemically changed into a salt form and [2] The beta crystal form of the salt is made through human ingenuity. Further that the US Patent does not give any example for the preparation of imatinib mesylate nor are there any claims made for it, however the US Patent may embrace imatinib mesylate.
The applicant’s arguments, maybe, substantiated with the evidence that the person skilled in the art would not know from reading the prior art the special advantages of the beta crystalline form and also investigating ‘obviousness’ through application of the four steps of Windsurfing/Pozzoli, may turn the tide in favour of Novartis.

7 comments.

  1. AvatarAnonymous

    Hi,

    I back Varun on the fact that the question of argument of selection patent working in case of polymorphs is very unlikely.

    Moreover, selection patent principles support surprising or unexpected advantage of the selection over the genus of compounds from which it was chosen. Novartis is claiming increased efficacy of its salt over the same property, i.e. bioavailability over its prior form.

    In order to get some of the basic concepts regarding selection patents cleared, please see http://www.langmichener.ca/index.cfm?fuseaction=content.contentDetail&id=10150&lid=0 in which the author Dr. Irene M. Waller comments upon landmark cases such as Eli Lilly Canada Inc. v. Apotex Inc., 2007 FC 455, 58 C.P.R. (4th) 353, Aventis Pharma Inc. v. Apotex, 2006 FCA 64, Aventis Pharma Inc. v. Apotex, 2006 FCA 64 .
    Please lay emphasis upon the author’s observations including:
    “In a pharmaceutical selection patent, the invention is the discovery of a surprising or unexpected advantage of the selection over the genus of compounds from which it was chosen. The utility of such a selection is not found in the fact that it works to successfully treat some human condition or ailment but rather that it works surprisingly better than the compounds monopolized by the genus patent. That is the inventive promise made and the inventive promise that must be established.”
    “However, the Applications Judge noted that in order to establish that a compound has a particular advantage over the genus from which it was chosen requires that the advantage not be found or be predicted to be found in a large number of members of the genus. The selected species must have an advantage over the class as a whole.” See Aventis Pharma Inc. v. Apotex, 2006 FCA 64
    The corollary that the author of this post has attempted to draw between the US case and Novartis matter do not appear to be well founded at all. This is perhaps a common fallacy for authors who are not technically sufficiently qualified attempt their hand at writing patent related articles.

    Anonymous 1

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  2. AvatarChhonkar; Varun

    Indeed it was a good attempt but still it lacks technical rationale. Hindsight what you tried to provide not only lacks fundamental understanding of selection patents but also immaturity in dealing with polymorphism patent issues.

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  3. AvatarDr. K. G. Rajendran

    Kamakhya, Is “Selection patent” a concept present in Indian Patent Act? Should we copy the US and Canadian patent concepts blindly?

    The framers of the Indian Patents Act (amended in 2005) meant to prevent evergreening patents in India. So any ambiguity in the wordings of the Act should be interpreted by using the yardstick of what the framers of the Act had in mind. Shifting interpretations of the Act based on changing political climate should not be allowed.

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  4. Avatarkamakhya

    Sir, Your sentiments with respect to the sanctity of legislative intent is not disputable at all. My only attempt was to bring into focus the approach taken by Canadian Supreme Court in deciding anticipation and obviousness.
    Regards.

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  5. AvatarChhonkar; Varun

    Selection patent is an integral concept of patent law and Indian patent law is no exception. Selection patent theory finds strong presence in pharmaceutical compounds in fact the jurisprudence of selection patent has particularly evolved around pharmaceutical compounds. It is well known phenomenon that identifying lead compound from thousands, sometimes even millions of structural variations from a genus (base) structure is tremendously tedious and highly innovative task.

    Though I am not much in agreement with Kamakhya’s argument of selection patent in Novartis case but I sincerely appreciate his efforts of providing analytical approach of looking into the case. As a patent practitioner, I personally believe that there should be a positive and analytical approach by patent practitioners to deal with pharmaceutical patents, hindsight of which is only possible in light of leading US and European case laws.

    I completely agree with Dr. Rajendran that we should not copy the US and Canadian patent jurisprudence blindly but it is important that we must use them as a background reference to construct our own reasoning about selection patent. Yes interpretation should likely be made in accordance with legislature intent but what if legislature themselves do not know nitty-gritty of selection patent?


    VC | Patent Circle

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