Case Comment
© 2005 Donald M. Cameron,
Ogilvy Renaultcitation(s): 2004 FC 1631 , November 19, 2004 per Mosley J.
Case Comment
© 2005 Donald M. Cameron,
Ogilvy Renault
[6] The patent at issue, Canadian Patent 1,304,080 (the " '080 patent") was granted to Daiichi Pharmaceutical on June 23, 1992. The filing date of the '080 patent is June 19, 1986 and it will expire on June 23, 2009.
[7] Daiichi is also the owner of Canadian Patent 1,157,840 (the " '840 patent"), issued on May 22, 1984, which disclosed and claimed an antibiotic known as "ofloxacin". Janssen-Ortho was also licensed by Daiichi to market ofloxacin in Canada, which it did under the brand name FLOXIN . The '840 ofloxacin patent expired on May 22, 2001.
Levofloxacin and Ofloxacin
[8] Levofloxacin, the subject of the '080 patent and these proceedings, and ofloxacin, disclosed in the expired '840 patent, can both be described as broad-spectrum, synthetic antibacterial agents useful in the treatment of infections caused by certain strains of microorganisms, such as certain types of pneumonia, influenza, skin infections and urinary tract infections. Ofloxacin and levofloxacin formulas have also been marketed for eye infections under different brand names.
It was known that ofloxacin was made up of two isomers, chiral images of one another:
[9] Ofloxacin is a racemic compound, that is a substance containing equal amounts of two optical isomers...
[10] Another term for describing optical isomers is "enantiomer" . An enantiomer is one of a pair of non-superimposable mirror images; by analogy, one's hands. ...
Levofloxacin is the S(-) "levorotatory" enatiomer of ofloxacin. Levofloxacin had beneficial properties over both the racemate and the other enamtiomer:
Thus the levofloxacin had, compared to the prior art racemic ofloxacin:[11] When produced, levofloxacin was discovered to possess beneficial properties over both racemic ofloxacin and the R(+) optical isomer. The specification of the '080 patent, under the heading "Background of the Invention" at pages 1-2, discloses the beneficial properties of the S(-) enantiomer of ofloxacin (levofloxacin) in contrast to the racemic ofloxacin and the R(+) compound, as follows:
... The present inventors obtained optically active compounds of the racemic Ofloxacin and found that the S(-)-compound possesses an antimicrobial activity of about 2 times higher than that of the (")-compound and acute toxicity LD50 weaker than that of the (")-compound as determined in mice by intravenous administration. On the other hand, the present inventors found that the R(+)-compound exhibits an antimicrobial activity of only about 1/10 to 1/100 times that of the (")-compound, whereas it possess an acute toxicity substantially equal to that of the (")-compound. That is, the S(-)-form of Ofloxacin has been found to have very desirable properties, i.e., increased antimicrobial activity and reduced toxicity, and is expected to be a very useful pharmaceutical agents [sic] as compared with the (")-compound. Further, both the R(+)- and S(-)-compounds of Ofloxacin in the free form have markedly high water-solubility as compared with the (")-compound and as compared with free compounds of this type, and can be used as injectable preparations. These advantages will be apparent from the experimental data shown hereinafter.
The court appears to consider that, prior to 1984, it was known that the enantiomers of ofloxacin existed: the patent claims a process for producing them and the discovery of their beneficial properties.
[32] The existence of such enantiomers of racemic ofloxacin seems undoubtedly accepted prior to 1984 and it was the development of a process for producing the S(-) enantiomer and the discovery of the beneficial properties of this enantiomer over racemic ofloxacin or the R isomer that are claimed in the '080 patent. Whether the invention claimed was obvious or anticipated, or was improperly set out in the patent claims and is vulnerable on other grounds of invalidity, are the issues dealt with in my analysis below.
[36] In determining whether a patent claim is obvious, the Court must avoid using the benefit of hindsight. The question to ask is whether the solution taught by the patent would be "plain as day" to the skilled technician who was searching for something novel, without having to do experimentation or research. Suggestions or signposts in the prior art are not sufficient to make a patent invalid for obviousness: Apotex Inc. v. Wellcome Foundation Ltd. (1998), 79 C.P.R. (3d) 193 (F.C.T.D.), varied but not on the issue of obviousness, [2001] 1 F.C. 495 (C.A.), aff'd [2002] 4 S.C.R. 153, Bayer Aktiengesellschaft v. Apotex Inc. (1995), 60 C.P.R. (3d) 58 (Ont. Gen. Div.), varied on other grounds (1998), 82 C.P.R. (3d) 526 (O.C.A.), leave to appeal to the Supreme Court of Canada denied [1998] S.C.C.A. No. 563(QL) and Fabwerke Hoechst v. Halocarbon (Ont) Ltd., [1979] 2 S.C.R. 929. ... [emphasis added]
[37] With obviousness, the invention need not be disclosed in one single patent or piece of prior art, as is the case for anticipation. The Court is entitled to look at all the patents and other publications that a skilled technician would discover in a "reasonable and diligent search" to determine whether the resulting "mosaic" leads directly to the invention: Illinois Toolworks Inc. v. Cobra Fixations Cie. (2002), 221 F.T.R. 161, aff'd on this point, varied only with respect to costs: (2003), 312 N.R. 184 (F.C.A.).
[43] With respect to the remainder of the references cited by Novopharm, Janssen maintains that they do not disclose the beneficial properties of the S(-) optical isomer, since these were only ascertainable through separating the isomer from the racemate and performing multiple experiments with the S(-) and R(+) enantiomers and racemic ofloxacin. The applicant submits that it was only after the S(-) optical isomer was "made" and then experimentation performed, that the invention, that is levofloxacin as a separate compound having certain benefits, was discovered. This discovery has enough inventive ingenuity to demonstrate that the patent claims are not obvious.
[44] The applicant refers to an article written by Novopharm's expert, Dr. Caldwell, entitled "Putting Chirality to Work: The Strategy of Chiral Switches", wherein he recognized that in pairs of enantiomers in racemic mixtures it is uncertain which enantiomer is the "antagonist" or "active" one. Janssen stresses, relying on Bayer Aktiengesellschaft, supra, that the test for obviousness does not involve testing or experimentation, but rather the mythical, skilled technician is expected to "instantly and spontaneously" know the answer which the patent teaches from the state of knowledge in the art at the date of invention.
[45] The respondent, also relying on Bayer Aktiengesellschaft, supra, submits that the applicants' interpretation of the test for obviousness is incorrect since the case law establishes that the notional person skilled in the art is entitled to carry out routine investigations including chemical analyses directed to merely determining characteristics of a known compound. Novopharm describes the tests done to determine the relative pharmacological characteristics of known enantiomers of racemic compounds as in the nature of "mere verification" of inherent, already known attributes of the compound, rather than in the nature of "searching for something novel". This "searching for something novel" must form part of the inventive process, as per Bayer Aktiengesellschaft, supra, and such inventiveness is lacking in the '080 patent.
Novopharm's characterization of the law was wrong:
On the other hand, the term "verification" suggests that you already know the attributes of the enantiomer. Finding nothing new is not inventive (due to lack if novelty).
[46] Novopharm refers to the Federal Court of Appeal decision of SmithKline Beecham Pharma Inc. v. Apotex Inc. (2002), 21 C.P.R. (4th) 129 (F.C.A.) where the prior art disclosed that the drug could be formulated by conventional methods, and that "mechanical skill" rather than inventive genius was required in order to arrive at the claims in the impugned patent; the "improvements" noted in the patent's disclosure merely verified the properties of a known substance formulated using common techniques.
The SmithKline Beecham case was different: it set out every way of making the compound [**add more later]
Mosley then dealt with "selection patents" per se:
[47] The '080 patent can be described as a "selection patent" in that levofloxacin was selected out of its class of substances - the racemate and the two enantiomers - because of its beneficial properties. The following passage from H.G. Fox in The Canadian Law and Practice Relating to Letters Patent for Inventions, 4th Ed., (Toronto: Carswell Company Ltd., 1969), pp.89-90, describes inventiveness in the context of selection patents:
Invention may be exercised by selecting one out of a number of substances for a particular purpose even though others of that class have been used before for the same purpose, provided there is a special advantage to be derived from the use of the selected substance and its selection constitutes a definite advance upon existing knowledge. While one who merely picks out a number of items from an already disclosed group or series has not invented anything, yet it may be otherwise if his researches have led him to the discovery that certain items in the group or series possess qualities or characteristics peculiar to themselves and hitherto unknown. [Emphasis added]
[48] Novopharm relies on the following passage from Fox, supra at page 90:
Selection patents are more usually met with in the chemical, than in the other arts. If for practical purposes it is not obvious to skilled chemists in the state of chemical knowledge existing at the date of a selection patent that the selected components possess a special property, there is then, or at least there may be, a sufficient inventive step to support the patent. But mere verification is not invention. Where the method of manufacture is laid down in the originating patent, the selection patent must not be an exact reproduction of the same process coupled with a statement of the properties possessed by the selected bodies. No man can have a patent merely for ascertaining the properties of a known substance. [Emphasis added]
[49] Novopharm submits that the '080 patent does not meet the requirements for a selection patent. Adopting Professor Fox's words, it argues that mere verification is not invention and that a selection patent must not reproduce the same process with a statement of the properties possessed by the selected bodies. Unlike the patent at issue in the case of Re E.I. DuPont Nemours & Co. Application, [1982] F.S.R. 303 (H.L.), the respondent asserts that the '080 patent does not make a discovery of a selected entity that has different valuable properties in a different field.
Having "different valuable properties in a different field" has never been the test of selection patents. What Novopharm appears to be referring to here is that the "special advantage", "definite advance upon existing knowledge" or "special property" must be an advantage due to a new characteristic or new property that was not recognized in the rest of the class or, as characterized by Novopharm, the properties must be in a "different field".
For example, the old larger class of paint thinners, may have a subset that is found to be water soluble (making it easier to clean up afterwards).
This suggested criterion, that it have different valuable properties in a different field is new, and not supported by other case law.
[50] Janssen's position is that section 32 of the Patent Act permits a patent based on improvements to any patented invention and there was such an inventive step in ascertaining that levofloxacin possesses special properties in comparison to the racemate, ofloxacin.
[51] What Fox and the jurisprudence suggest, in my view, when dealing with selection patents, is that in order to demonstrate sufficient inventive ingenuity, there must be discovered some special advantage or quality, previously unknown, or an advantage discovered for a new use, which constitutes a definite advance upon the knowledge already existing with regard to the original group or series. In Pfizer Canada Inc. v. Apotex Inc. (1997), 77 C.P.R. (3d) 547 (F.C.T.D.), Richard J. (as he then was), found a selection patent valid that claimed the pharmaceutical preparation of fluconazole, the originating patent having claimed "an enormous class of compounds".
This appears to be merely a recitation of the previous case law.
[52] In that case, the compound described in the subsequent patent was not described in the original patent, and neither were "its superior and previously unknown efficacy" previously known. The Court there relied upon expert evidence that described the surprising features of fluconazole, and the discovery that it was soluble in water as compared to the earlier disclosed compound that was virtually insoluble. Justice Richard concluded that since fluconazole had "unexpected and valuable properties which are not possessed by the structurally closest compounds disclosed" in the original, prior patent, it was not invalid on the grounds of either obviousness or anticipation.
[53] In my view, in the case at hand, such reasoning is applicable, but to bring about the opposite result. The beneficial properties discovered and set out in the '080 patent were not unknown. They were the same beneficial properties found in ofloxacin, only to a greater degree of effectiveness. Further, I find that knowledge of the existence of and the possibility of separating the two enantiomers of ofloxacin was common to the ordinary chemist, and the determination of which enantiomer possessed a greater amount of the same benefits of the previously known racemic antibiotic was not surprising or inventive. This determination was made from one of three possibilities, not a great number of possibilities; that is, either the S (-) enantiomer, R (+) enantiomer or the racemate would exhibit better qualities, in comparison to each other, relating to the properties of antimicrobial activity, toxicity or solubility. [emphasis added]
Here, Mosley either got the facts wrong, or the law wrong:
This can be gleaned from Mosley's comments in this paragraph that two things had to be done:
Mosley must have therefore been wrong when he said "The beneficial properties discovered and set out in the '080 patent were not unknown". Perhaps what Mosley was trying to say was that:
[54] With regard to Janssen's contention that if experimentation or testing is required in order to determine the invention, the resulting invention cannot be said to be obvious, I am persuaded by Novopharm's submission that the test for obviousness does not exclude routine testing to determine characteristics of known compounds, not undertaken for the purpose of "searching for something novel", but rather for the purpose of verifying the actual attributes of already known compounds, where the results indicate no new uses or surprising results, or properties that are clearly superior to the already known parent compound. Concerning the issue of determining whether there has been an inventive step or "undue experimentation" in the obviousness inquiry, see the reasoning of Justice Dawson of this Court in Pfizer Canada Inc. v. Apotex Inc. (2002), 22 C.P.R. (4th) 466 (F.C.T.D.) at paras 103-114.
In wonderful, double negative fashion, Mosley is saying, in effect, it is obvious to do routine testing so long you are looking for, and find, nothing new or surprising. If you've found nothing new, you have no invention. As discussed above, it seems not to bear any connection to the facts of this case where the efficacy values of the enantiomer were unknown.
In the following paragraphs, Mosley found:
Mosley repeated his concept, discussed above, that in order to be inventive, the enantiomer must show different functionality (physical characteristics) than the racemic compound:
[68] ... The improvements contemplated on the already discovered racemic compound must demonstrate "sufficiently different" characteristics from what was already known in order for the patent not to be declared invalid for obviousness. This is just a different way of articulating the "special property" concept described by Fox, above, that a selection patent must possess in order to qualify for a new patent on the selection and description of an item from an already known group or series.
[69] Verification of certain attributes of an already disclosed compound does not meet the threshold of inventiveness required for patent protection. In SmithKline Beecham, supra, the Federal Court of Appeal found that only "mechanical skill", rather than inventive genius, was needed to apply the prior art to arrive at the invention contained in the challenged patent. As stated by the Court at page 138-39, "The only 'improvement' referenced in the disclosure merely verifies properties of a known substance formulated using common techniques." In my opinion, the present case is similar, given that the inventors of the '080 patent were merely verifying properties of the known racemic ofloxacin by determining which of its enantiomers displayed better results with respect to antimicrobial activity, solubility and toxicity.
Mosley has the facts mixed up here: you are not "verifying" the activity, solubility and toxicity properties of the racemic by measuring those same properties of its two enantiomers. Instead, you are determining the characteristics of each of the enantiomers and thus learning what you did not know before: you are researching and discovering: hallmarks of an invention according to the Supreme Court in Hoescht quoting Pope: "... After all, what is invention? It is finding out something which has not been found out by other people."
In paragraph 70, Mosley quotes from Sharp & Dohme at p. 191-192:
"In my opinion, the ascertainment of the valuable properties of a chemical substance (important as it may be from the point of view of utility, where it is desired to obtain a patent for an entirely new substance) is not of itself, especially when such substance is one which anybody is entitled to make, a patentable invention, but at most a discovery. The Plaintiffs, when they obtained their four alkyl bodies by [published art] method, no doubt put them through the usual well-known tests to establish their identity and their respective therapeutic value."
[**explain why this is out of context or on the wrong point]
[71] I prefer Dr. Caldwell's evidence that the purportedly superior qualities of the S(-) enantiomer of ofloxacin with respect to antimicrobial activity set out in the '080 patent are not actually different, or of a special and unexpected nature, from the properties set out in the prior art, including in the '840 patent detailing the nature of ofloxacin. From Repta et al., the above-mentioned U.S. patents, and the two Gerster references, I am satisfied on a balance of probabilities that it would have been obvious to the skilled chemist that one of the enantiomers of racemic ofloxacin could exhibit higher beneficial properties and that all that would be needed to confirm this was to conduct routine, simple testing. Determining and noting which enantiomer possessed higher antimicrobial activity, a quality already existing in the racemate, did not require inventive ingenuity.
This paragraph appears to be Mosley's conclusion of his "Different characteristic" requirement discussed above with reference to paragraphs ** and **.
If "all that would be needed" was testing then it cannot be said to meet Fox's test, endorsed by Lederman in Bayer v. Apotex and followed by those who followed the Bayer case:
"In order that a thing shall be 'obvious', it must be something that would directly occur to someone who was searching for something novel, a new manufacture, or whatever it might be, without the necessity of his having to do any experimenting or serious thought, or research, whether the research be in the laboratory or amongst literature." [emphasis added]
It is also contrary to the Supreme Court of Canada’s endorsement of the Pope Appliance v. Spanish River concept endorsed in Hoescht (discussed above) that an invention is:
“… finding out something which has not been found out by other people.”
[72] Moreover, I accept the evidence that, not only would it be expected from the prior art that the antimicrobial activity would be attributable to one of the two known enantiomers of ofloxacin, but based on another similar compound, a pharmaceutical chemist of ordinary skill in the art would have expected that the (-) enantiomer would be the one to exhibit higher antimicrobial activity. The Gerster flumequine references addressed this subject.
This holds that a person in the art would have predicted that the levo-enantiomer would have higher microbial activity than the racemate.
After reviewing the evidence concerning the Gerstner prior art reference upon which he based his decision, Mosley reiterated:
[77] Even if I were to find that the Gerster references dealing with flumequine are not valid prior art references, this would not affect my conclusion that the general state of knowledge for chemists in the field of stereoisomers in 1984 would have included the common understanding that one of the enantiomers of ofloxacin would likely exhibit higher antimicrobial activity. Therefore, verifying which enantiomer possessed this quality - and to what degree in comparison to the racemate and the other optical isomer - did not involve the exercise of any inventive step. [emphasis added]
Mosley does not discuss the degree of likelihood. The test of obviousness is "would", not "would likely" (Hoescht). Mosley's last statement would be better expressed by him (incorrectly in law) as "the experimentation would be non-inventive" whereas he should have asked, to ask the correct legal question, "because you would have to experiment, it is not obvious".
Mosley repeats the finding that the characteristics could not have been predicted with certainty without testing:
[82] Dr. Caldwell's evidence is that the tests to establish the beneficial properties of the S(-) enantiomer were entirely routine, uncomplicated, generally accepted well prior to 1985, and did not amount to any inventive step. While the exact antimicrobial, solubility and toxicity characteristics of levofloxacin could not have been predicted with absolute certainty without verification through testing, such characteristics would have been easily predictable or obvious to the skilled chemist with knowledge of enantiomers and stereochemistry, and could have been verified by using the routine analytical tests available to pharmaceutical chemists in 1984.
This paragraph best summarizes Mosley's confusion: the exact characteristics were not known without experiment - hence they were not obvious without experimentation.
[83] While not prior art, a section of the English text by Philip W. Grubb, Patents in Chemistry and Biotechnology (Clarendon Press: Oxford, U.K.,) published in 1986, illustrates the common knowledge at that time among chemists respecting the nature of optical isomers claimed as new compounds in patents. As stated at page 134:
Perhaps the closest that a new compound can be to the prior art is the situation when the new compound is an optically active enantiomer of a compound previously known only in racemic form. This may be regarded as an extreme form of a selection invention, and it has been argued that the optically active form cannot be regarded as novel if the racemate is known, since the racemate could be considered as an equimolar mixture of the d- and l- forms. However, in cases both in the UK and the USA it has been decided that optical isomers of known racemates may be considered as novel per se.
Usually, however, the problem is regarded as one of obviousness rather than lack of novelty. It is obvious from the presence of an asymmetric centre in the molecule that optically active forms can exist, and it is usually obvious that they can be isolated by one or other of the standard methods of resolution. The only way in which an optical isomer can be patentable is if it has surprisingly superior properties as compared with the racemate, or if it has a use that the racemate did not have. [Emphasis added]
[84] As mentioned, I accept Dr. Caldwell's evidence that the properties described in the '080 patent concerning the levorotatory isomer of ofloxacin were not unexpected or surprisingly superior to what had already been disclosed with respect to ofloxacin. Based on the prior art of Repta et al., the Gerster references, the '840 patent disclosing ofloxacin as racemic with particular beneficial properties, and the U.S. patents cited dealing with other racemic compounds similar in structure to ofloxacin[3], such "discovery" would have been obvious to the ordinary skilled chemist, knowing the state of the art of stereoisomers in 1985.
[85] I am satisfied that Novopharm has established on a balance of probabilities that a technician skilled in the art would have come directly and without difficulty to the solution taught by the '080 patent by simply conducting known, routine experiments with racemic ofloxacin. I conclude that the claims set out in the '080 patent are obvious; what is claimed as the "discovery" or "invention" in the '080 patent does not suggest the scintilla of inventive ingenuity to qualify for the patent monopoly, but rather was the result of "mere verification" of the attributes of already known components of a compound.
[86] Furthermore, based on the state of knowledge in 1985, I am satisfied that an average chemist would have been led directly to the conclusion, prior to such testing, that one enantiomer was likely to have more beneficial characteristics than the racemate, or the other optical isomer, in relation to the same beneficial qualities that had already been discovered, namely antimicrobial activity, solubility and toxicity. Therefore, in undertaking experimentation to verify which enantiomer possessed comparatively better qualities in these areas, no inventive step was involved.
[87] I find that the '080 patent is invalid for obviousness. Overall, Janssen has not demonstrated on a balance of probabilities that Novopharm's allegation of invalidity on this ground is not justified.
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