Wednesday, July 24, 2013

Genus Anticipates Species

Hoffman-La Roche Ltd v Apotex Inc / valganciclovir (NOC) 2013 FC 718, Kane J
            2,154,721 VALCYTE

Roche’s ‘721 patent claims the compound valganciclovir in various forms. Valganciclovir is the mono-L-valine ester of ganciclovir [32]. It is a pro-drug of ganciclovir, and has better bioavailability than ganciclovir when orally administered. Ganciclovir was known in the prior art as the leading drug for the treatment of certain herpes viruses, particularly cytomegalovirus [4]. The main issues were whether the ‘721 patent was invalid for anticipation and obviousness. Kane J held that they were.

Kane J’s anticipation analysis is, in my view, very problematic. The issue was whether the ‘721 patent was anticipated by EP0375329. EP 329 disclosed and claimed the amino acid esters of ganciclovir. It was not disputed that mono-L-valine ester was encompassed with the approximately 500,000 compounds described by EP 329, and the question was whether the disclosure was sufficiently specific to anticipate. It was not disputed that valganciclovir was not disclosed in any of the examples of EP 329 [231]. Kane J did not expressly identify the anticipatory reference, and the only reference to valine and mono-esters that I have been able to find in EP 329 is the following (p 3):

The amino acid acyl residue of the above compounds [the general formula of the disclosed compounds] according to the invention may be derived for example from naturally ocurring [sic] amino acids, preferably neutral amino acids i.e. amino acids with one amino group and one carboxyl group. Examples of preferred amino acids include aliphatic acids, e.g., containing up to 6 carbon atoms such as glycine, alanine, valine and isoleucine. The amino acid esters according to the invention includes the mono- and di-esters of the compound of formula (I). The amino acids may be D-, L-and DL amino acids, with the L-amino acids being most preferred.

Examples of preferred compounds of formula (I) above include those of Examples 1 to 6.

The above-mentioned physiologically acceptable salts are preferably acid addition salts derived from an appropriate acid, e.g ., hydrochloric. sulphuric. phosphoric. maleic, fumaric, citric, tartaric, lactic or acetic acid. The above-defined amino acid esters of formula (I) and their salts which are hereinafter referred to as the compounds according to the invention. . .

The mono-L-valine ester is never singled out, and the mono-esters and valine are independently enumerated as part of separate lists. There was no disclosure of any special advantages that the mono-L-valine ester might have over the other amino acid esters that were disclosed.

Compare this with Sanofi 2008 SCC 61, aff’g 2006 FCA 421, in which the question was whether clopidogrel bisulfate, claimed in 1,336,777, was novel over the disclosure of 1,194,875. The ‘875 patent disclosed over 250,000 racemic compounds, of which only 21 individual compounds were specifically identified [FCA 9]. Clopidogrel bisulfate is the dextro-rotatory isomer of one of the specifically identified racemates, namely derivative 1, which was disclosed as Example 1 of the ‘875 patent [SCC 3, 6], [FCA 9]. Not only did the ‘875 specifically disclose the racemate, it also expressly stated at p 1 that it encompassed the enantiomers:

Ces composés comportant un carbone assumétrique peuvent exister sous la forme de 2 énantiomères. L’invention concerne aussi bien chacun des énantiomères que leur mélange.

In Sanofi, of course, the SCC held that clopidogrel bisulfate was not anticipated by the ‘875 disclosure. With respect, I find it impossible to distinguish Sanofi from this case.

Kane J held that:

[234] EP 329 discloses both the mono- and bis-ester, although it prefers and exemplified only the bis-esters. On a balance of probabilities, the POSITA would read EP 329 and understand that it was teaching both mono- and bis-esters with both promising improved bioavailability over ganciclovir.

With respect, it is not correct to say that EP 329 “discloses” the mono-ester, at least if that word is used in the sense of the two-part test for anticipation set out in Sanofi, which requires disclosure and enablement. It is entirely true that EP 329 taught that both the mono- and bis-esters of the amino acid esters would have improved bioavailability over ganciclovir, but it taught this in respect of the entire class. The question is whether EP 329 taught that the mono-L-valine ester specifically has particularly good bioavailability, and the answer is that it does not. That ester is not singled out in any way from the other amino acid esters disclosed in EP 329.

It is also true is that EP 329 describes the mono-ester, and that its disclosure encompasses the mono-ester, just as it was true that in Sanofi the ‘875 patent described and encompassed the enantiomers. But one the major holdings in Sanofi is that a species is not anticipated by a genus simply because the genus encompasses the species. While Sanofi set out a two-part test for anticipation, on the facts, the ‘777 patent was held to be novel on the first part, disclosure:

[41] 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, or the other compounds made and tested or otherwise 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.

It was not even suggested by any of the experts for Apotex in this case that EP 329 disclosed any special advantages of the mono-L-valine ester as compared with the other esters disclosed by that document.

Kane J’s analysis appears to go astray on two points. She understood Sanofi as “rejecting the stringent test which required that the exact invention had already been made and disclosed” [202], and similarly, she relied on Hughes J’s summary of the law of anticipation in 2008 FC 1359 [75] that “The disclosure does not have to be an ‘exact description’ of the claimed invention. The disclosure must be sufficient so that when read by a person skilled in the art willing to understand what is being said, it can be understood without trial and error” [209]. It is true that in Sanofi the SCC said that “in light of recent jurisprudence, I am of the respectful opinion that the applications judge overstated the stringency of the test for anticipation that the ‘exact invention’ has already been made and publicly disclosed” [23]. However, the SCC did not reject the law as set out in Beloit and General Tire, which it described as having been accepted in Canada “without reservation” [22]. What was new in Sanofi was to explicitly separate disclosure and enablement. The SCC described this as “is a refinement of the approach set out in Beloit.” The test for disclosure remains stringent: “No trial and error is permitted” [32]. It is in the test for enablement – which, as the SCC pointed out, was not at issue in Beloit [28] – that the stringency is relaxed. Some trial and error is permitted, though “the skilled person must still be able to perform or make the invention of the second patent without undue burden” [33].

The second point emphasized by Kane J is that the civil burden of proof applies rather than the criminal burden [211], [209.6], [207]. This is no doubt true, but Kane J seems to have understood this, combined with the purportedly relaxed standard for anticiaption set out in Sanofi, to mean that the claimed invention is anticipated if a skilled person following the prior art might produce the claimed invention. This is not what the civil standard implies. The point that the civil standard applies arose ultimately from Actavis UK Ltd v Janssen Pharmaceutica NV [2008] EWHC 1422 (Pat) [cited by Hughes J in 2008 FC 1359 [69]]. In Actavis the claimed invention was the use of RSSS isomers of specified blood pressure drugs to potentiate other, non-RSSS, blood pressure drugs [53]. The anticipation point arose because the prior art compound asserted to anticipate contained the RSSS isomer, as well as the SRRR isomer and the other stereoisomeric pair of RSRR and SRSS [82]. It was established that when a medicine is made from only RSSS and SRRR the former will potentiate the latter, but there was some question on the facts as to whether RSSS would potentiate SRRR when it was combined with the other stereoisomeric pair as well [83]. It was on that point that Floyd J held that the civil standard of proof was to be applied. This was not a case where the prior art disclosed a variety of compounds, and the question was whether one picked at random would fall within the claims. Rather, there was one compound, which either did or did not have the claimed property, and it is that question which is to be decided on the balance of probabilities.

I cannot draw a straight line from these two points to Kane J’s conclusion in respect of anticipation, but between the two she seems to have understood the test for disclosure as being relatively relaxed. Qualitative descriptions of a test as being “relaxed” or “stringent” are not always a reliable guide, and however we characterize the test for anticipation, Sanofi and Roche/ valganciclovir (NOC) are very similar in their facts, and cannot be reconciled on this point.

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