This appeal focuces on the patentability of dextrorotatory ('265) in view of its known racemate described in earlier Sanofi ( '596).
The clain at issue was claim 3. DC had identified the liitations stated in claim 3 of the '265 patent as (a) the bisulfate salt (b) dextrorotatory isomer (c) the compound MATTPCA (d) substantially separated from the levoisomer. The references Apotex relied on were '596 patent and its canadian counterpart CA'875. DC had ruled that these prior arts show clopidogrel only as a racemate and do not show the separated isomer or the bisulfate salt thereof. Apotex argued that these properties are inherent, althou the references do not teach how to separate isomers, each detail is not required because POSA will know the existing methods for separation.
FC however stated that this is not the correct view of the law of anticipation which requires specific description as well as enablement of the subject matter of issue. To anticipate a reference must not only disclose the all elements of the claim in the four corners of the prior art reference but must also disclose those elements arranged as in the claim.
A generic disclosure is not necessarily a disclosure of every species that is a member of the genus.
General statements that these compounds exists as isomers cannot be considered as an anticipating disclosure of the separated dextrotatory isomer of clopidogrel as per the DC.
While considering In re Petering and In re Schaumann, the court pointed out that in both these cases the generic disclosured identified " specific preferences" which were met by the later described species.
To distinguish the case from In re Anderson the court stated that the case dealt with obviousness and did not suggest a previously unseparated and unknown enantiomer might be deemed anticipated by the known isomer.
With respect to enablement DC had held that the asserted references are not enabling for they contan no guidance as to how to separate the enantiomers of clopidogrel. Absent such evidence undue experimentation would be required. Apotex argued that it is entitled to a presumption of enablement because the asserted references are patents , which are presumed to be enablong because they are presumed to be valid ( Amgen Inc vs Hoechst Marion Roussel Inc 314.F.3d, 1313, 1355)
DC found that the prior art patents merely state that if desired enantiomers could be separated, they contained no descriptions as to how to separate the enantiomers.
While addressing obviousness DC had assumed that Apotex had made a prima facie case of obviousness. Upon consideration of Graham factors the court held that the unpredictability and unusual properties of the dextro isomer and the therapeutic advantages provided therein weighed in the factor of nonobviousness.
Apotex asserted that Sanofi's previous of PCR4099 as a promising replacement to ticlopidine wuld have led a POSA to start with PCR4099 as a lead compound. Seoaration to isomers can be carried out by techniques well known in the art.
Expert testimonials during the trial had indicated that no know scientific principle allows prediction of the degree to which stereoisomers will exhibit different levels of therapeutic activity and toxicity.
On the basis of this trial evidence DC found that a POSA would not have reasonably have predicted that the dextrorotatory enantiomer would provide all of the antiplatelet activity and none of the adverse neurotoxicity. Clear error has not been shown in this finding and in the consluion of nonobviousness based thereon. Apotex had also argued that Sanofi had followed a know process for separation. DC observed that in 1987 , there were atleast 10 techniques that had been used to separate enantiomers and they all required experimentation to determine whether they could be successful for a particular compound, including choices of reagents, solvents, concentrations, temperature etc.,
The court observed that Pasteur's diasteriomeric salt formation technique had long been described in text books, but the textbooks also explain that the method is difficult and that there no "infallible recipe" for obtaining separation. DC found that this sepration is not a simple routine separation. Apotex had not shown any prior ats teahcing separation of analogous compounds. The court described the separation as a "paradigm of trial and error" and found that neither the chemist at Sanofi nor a person of ordinary skill in the art could have reasonable expected that the separate isomers could be otained at the time that Sanofi was contemplating wheher to investigate them and if obtained , they could not have predicted by what method and configuration. Court determined that only with hindsight knowledge that the dextro isomer has highly desirable properties, can Apotex argue it wuld have been obvious to select this particular racemate and undertake the arduous separation. The application of hindsight is inappropriate where the prior art does not suggest that this isomer could reasonably be expected to manifest the advantages and properties that were found for this Dextro isomer. Regarding bisulphate salt, the court distinguished this case from Pfizer vs Apotex in that in Pfizer case there was evidence that based on prior art a POSA would have narrowed the possible salts to only a few including the claimed besylate salt. In this case Sanofi showed that the prior art taught away from use of sulfuric acid with an enantiomer , for strong acids could encourage re-racemization.
Plavix, sold by Bristol-Myers in the U.S. under an agreement with Sanofi, last year regained its title as the world’s second- best-selling drug, behind Pfizer Inc.’s Lipitor, with $8.1 billion in global sales. The drug first gained regulatory approval in 1997.
The Apotex copies cost from $1.45 billion to $1.75 billion in lost sales, Bristol-Myers said Feb. 22 in a
regulatory filing. Under the failed agreement, Bristol-Myers and Sanofi can’t ask for compensation of more than 70 percent of net lost sales and waived their right to ask the judge to triple the damages because of willful infringement, Sanofi said in an Aug. 8, 2006, statement.
Six Months’ Supply
When the agreement was rejected by U.S. regulators and state attorneys general, Apotex began selling a generic version until it was ordered to stop by U.S. District Judge
Sidney Stein in New York. During a three-week period, the company shipped about six months’ worth of the medicine.
In an August 2006 interview, Apotex’s Sherman said he expected the agreement to be rejected by regulators, and signed the agreement in order to wring concessions, including the limit on damages.
Bristol-Myers rose $1.06, or 4.9 percent, to $22.51 at 4:15 p.m. in New York Stock Exchange composite trading. Sanofi American depositary receipts, two of which represent one ordinary share, rose 87 cents to $29.78.
The case is Sanofi-Synthelabo v. Apotex Inc., 2007-1438, U.S. Court of Appeals for the Federal Circuit (Washington). The lower case is Sanofi-Synthelabo v. Apotex Inc., 02cv2255, U.S. District Court, Southern District of New York (Manhattan).
For quick reference the cases in Australia and Canada are provided below:
In a recent decision by the Federal Court of Australia, Justice Gyles found that certain claims of Sanofi-Aventis’ (Sanofi) Australian Patent AU 597784 (AU 784) relating to the dextro-rotatory isomer of methyl alpha-5 (4,5,6,7 - tetrahydro (3,2-c) thioeno pyridyl) (2-chlorophenyl)-acetate (clopidogrel) were invalid for lack of novelty and lack of inventive step. Despite this finding however, claims relating to specific salts of the isomer were found to be novel and not obvious and consequently, were found valid.
Background
Prior to filing AU 784 in Australia in 1988, Sanofi had filed a French patent application for racemic methyl alpha-5 (4,5,6,7 - tetrahydro (3,2-c) thioeno pyridyl) (2-chlorophenyl)-acetate, a chiral molecule (the French Patent).
Chiral molecules comprise two distinct forms of non-super imposable mirror images, known as enantiomers. Synthesis of chiral compounds ordinarily results in a mixture of equal amounts of the two enantiomers, called a “racemic mixture” or a “racemate”. One enantiomer, the levo or (-) enantiomer, rotates plane polarised light to the left, and the other, the dextro or (+) enantiomer, rotates plane polarised light to the right. This property can, however, only be identified when the enantiomer is separated from the racemic mixture. Enantiomers commonly have different biological activities because of their different interactions with other enantiomeric molecules in the body.
In Australia, Sanofi markets Plavix, a platelet aggregation inhibiting agent used to reduce thrombotic events such as heart attacks and strokes. The active ingredient in Plavix is clopidogrel bisulfate (hydrogen sulfate), which is a salt of the enantiomer covered by the claims of AU 784.
The patents
AU 784 claimed the dextro (+) enantiomer, a process for its preparation, the pharmaceutical composition containing it and specified salts (hydrochloride, hydrogen sulphate, hydrobromide and taurochlorate) thereof. Reportedly, the (+) enantiomer had more activity and lower toxicity than the levo (-) enantiomer. The French Patent specifically described each enantiomer of the racemic mixture as well as the racemic mixture itself. Significantly, AU 784 also claimed pharmaceutically acceptable salts of the (+) enantiomer.
The proceedings
Apotex (formerly GenRx Pty Ltd) commenced proceedings against Sanofi in 2007 seeking revocation of AU 784 on several grounds, including that the claims of AU 784 were not novel and were obvious in light of the French Patent. Apotex also claimed that the patent was invalid on the grounds of false suggestion or misrepresentation, inutility, and that the claimed invention was not a manner of manufacture.
Lack of novelty
Sanofi argued that AU 784 was not invalid for want of novelty because the French Patent prior art relied on by Apotex was not an enabling disclosure of the (+) enantiomer. Justice Gyles accepted that, in relation to process claims, an alleged anticipation must contain “clear instructions to do or make something” that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent. However, in relation to a product claim, there must only be a “clear description of something” that would infringe the patentee’s claim if carried out after the grant of the patentee’s claim.
Here, it was found that the earlier French Patent gave Sanofi a monopoly in relation to the making and using of the disclosed racemate and each of its enantiomers, either together or separately. Similarly, Justice Gyles found that the existence and the advantages of each of the enantiomers, as well as those of the racemic mixture, were clearly disclosed in the French Patent. Importantly, Justice Gyles stated that “no doubt, if only the racemate were claimed, there would be a large risk that this would not protect against competition from a drug with one of the enantiomers as the active ingredient”.
Justice Gyles distinguished this case from the situation in Alphapharm Pty Ltd v H LunbeckA/S [2008] FCA 559 (a decision which has been appealed to the Full Court) where there was no express reference to, or claim to, the enantiomers of the racemate in the prior art. In that case Justice Lindgren found that a skilled addressee would understand that the (+) enantiomer of citalopram exists when it is contained in the disclosed racemate, however, for an alleged anticipation to be an “enabling disclosure”, it must point unmistakeably to the enantiomer as distinct from the racemate, as a desirable drug to obtain. In Lindgren J’s opinion the prior art patent claiming the racemic mixture of citalopram did not refer to, or disclose, by implication or otherwise, the existence of the two enantiomers.
Here, Justice Gyles found that the French Patent expressly disclosed the existence of the two enantiomers as having the claimed advantage. Consequently, the French Patent was found to anticipate AU 784 , unless AU 784 could be viewed as a selection patent.
Justice Gyles indicated that selection patent principles set out in Re IG Farbenindustrie AG’s Patent (1930) 47 RPC 289 apply to a patent where a compound claimed is specifically identified in an earlier specification as a member of a larger class, not merely where there is express identification for the first time, of a particular member of a larger class with the special characteristic. Justice Gyles stated that a patent application will overcome a prior publication as a selection patent if:
there is some substantial advantage to be secured by use of the selected members of a class,
the whole of the selected members possess the advantage,
the selection is in respect of a quality of a special character, which can fairly be said to be peculiar to the group, and
the advantage possessed by the selected members is clearly disclosed in the specification.
Here, it was found that there was substantial advantage to be secured by the use of the (+) enantiomer when compared to the use of either the racemic mixture or the (-) enantiomer and the whole of the (+) enantiomer class of compounds possessed the advantage. Similarly, the advantage was clearly disclosed. However, His Honour did not accept that the advantage gained was the inventor’s own discovery, but was rather a verification of previous predictions in the French Patent that the enantiomers would not have equal qualities. Consequently, claims of AU 784 relating to the (+) enantiomer per se were not capable of being a valid selection from the compounds described in the French Patent.
Despite finding the (+) enantiomer was anticipated by the French Patent, Justice Gyles found that, significantly, the salts of the (+) enantiomer claimed in AU 784 were not clearly described in the French Patent. Consequently, claims 2, 3, 4 and 5 relating to the salts of the (+) enantiomer were not found to have been anticipated.
Lack of inventive step
Justice Gyles acknowledged that an inventive step does not have to be a “flash of genius” but that there must be a step from one thing to another. In deciding whether AU 784 disclosed an inventive step, His Honour applied the test of whether a hypothetical addressee, when faced with the same problem, would have taken as a matter of routine, whatever steps led from the prior art to the invention.
Although generally the starting point for analysis of inventive step is what was in the common general knowledge at the relevant time, because the enantiomer had been previously disclosed in the prior art, the Court looked at the inventive step described in the specification of the patent in suit.
Sanofi argued that the claimed invention was ascertaining that only the (+) enantiomer exhibited platelet aggregation inhibiting activity and that the (-) enantiomer was inactive and less tolerated and that this was not obvious. However, Gyles J held that it was common general knowledge in Australia at the priority date that one of the two enantiomers might contain all of the activity and “the discovery of that characteristic in this case was not so unexpected as to amount to an inventive step”.
Justice Gyles next turned to assessing the inventiveness of the salts of the claimed enantiomer. His Honour said that if the starting point for assessing inventiveness is the single (+) enantiomer, then the salt of the enantiomer would be obvious. However, the inventive step claimed in relation to the salts was not the method of obtaining the salts, but rather the identification of the properties of the salts obtained. Consequently, the claims to specific salts were found to involve an inventive step when compared with the common general knowledge in Australia at the relevant time (which did not include clopidogrel). Unlike the enantiomer claims, the salts were novel compounds without any consideration as selection patents and therefore inventiveness was to be viewed from the starting point of what was common general knowledge.
As a result, while claims of the patent relating to the (+) enantiomer were found to lack novelty and inventive step, claims to specified salts of the (+) enantiomer, including the active ingredient in Sanofi’s product Plavix, the hydrogen sulphate salt, were found to be valid. The Court also rejected Apotex’s arguments that these claims were invalid on the grounds of false suggestion or misrepresentation, inutility, and that the claimed invention was not a manner of manufacture.
Claims to the process of resolving the enantiomers from the racemic mixture were found to be invalid on the ground of obviousness, as the process claimed was routine.
Comment
This case raises the difficult issue of when an Australian patent can be treated as a selection patent. If it is to be treated as a selection patent, does a different obviousness test apply? The question identified by Justice Gyles at para [80], of whether a valid selection patent can exist if the compound claimed was specifically identified in the first patent as a member of a larger class, remains to be definitively resolved.
Canada case:On November 6, 2008, in Apotex Inc. v. Sanofi-Synthelabo Canada Inc.,1 the Supreme
Court of Canada unanimously confirmed that a selection patent (described as a patent
whose subject matter is a fraction of a larger known class of compounds that was the
subject matter of a prior patent) is permissible under the Canadian Patent Act. Indeed,
the Court confirmed that a selection patent “does not in its nature differ from any
other patent,” and its validity should be evaluated by the usual statutory criteria, such
as novelty and inventiveness. The Court also refined the tests for these important
prerequisites to patentability.
Facts
The selection in this Sanofi case was clopidogrel bisulfate, marketed as Plavix. The
invention was the selection of clopidogrel and its bisulfate salt. A prior patent disclosed
a class of compounds that included clopidogrel, but not its beneficial properties, which
include enhanced inhibition of platelet aggregation (clotting) and a superior toxicity
and tolerability profile. The prior patent also did not disclose the benefit of the
bisulfate salt, which was found to have superior properties over other salts.
Earlier Decisions and the Selection Patents Controversy
Apotex argued that the patent for clopidogrel bisulfate was invalid for lack of novelty,
obviousness and double patenting, because it had been disclosed generically in the
prior patent. The lower courts disagreed, finding that it was a valid selection from the
previous class. Apotex appealed to the Supreme Court, asking it to abolish selection
patents altogether. The Court refused, holding that an inventor who makes and
discovers the special advantages of a member of a class should be entitled to a patent
for that member. The Court then considered the validity of the clopidogrel bisulfate
patent in light of Apotex’s validity attacks: anticipation, obviousness and double
patenting. In doing so, the Court refined the law for each of these requirements.
Anticipation
The Court noted two requirements for the test for anticipation: prior disclosure and enablement. The test is not simply whether “the exact invention has already been made and publicly disclosed.”
“Prior disclosure” means that the prior patent must disclose subject matter that, if performed, would necessarily result in infringement of that patent. At this first stage, the skilled reader must find a disclosure: the skilled person cannot say that there would be a disclosure with some trial and error or experimentation. The skilled person is simply reading the prior patent to understand and try to find the disclosure of the invention – and not as a precursor. Most importantly in the context of selection patents, if the genus patent does not disclose the special advantages of the invention covered by the selection patent, the disclosure requirement is not met and the selection patent is therefore not anticipated by the genus patent.
“Enablement” means that the person skilled in the art would have been able to perform the subject matter of the prior art constituting the asserted anticipation. For purposes of enablement, the question is not what the skilled person would think the disclosure of the prior patent meant, but whether he or she would be able to work the subject matter. The Court asked itself, how much trial and error and experiment is permitted at the enablement stage? The answer: the prior patent must provide enough information to allow the subsequently claimed invention to be performed without “undue burden.” Routine trials are acceptable, but inventive steps are not permitted. If inventive steps are required, the prior art will not be considered enabling.
The Court concluded that since the genus patent in this case did not disclose the special advantages of the dextro-rotatory isomer and of its bisulfate salt, the invention of the selection patent was not disclosed and therefore was not anticipated.
Obviousness
The Court began its obviousness analysis with the well-known test in Beloit: whether the skilled person, in light of the state of the art and common general knowledge, would have come directly and without difficulty to the solution taught by the patent. Since Beloit, lower courts had explicitly rejected an “obvious to try” approach. Because both the United States and United Kingdom have accepted a (stringent) version of an “obvious to try” test, the Court examined the question whether it might be appropriate, in certain circumstances, to use a similar standard in Canada.
Noting that “obvious to try” is not a mandatory test in the United States and United Kingdom, the Court stated that it must be approached cautiously. The Court concluded that in Canada, it is not sufficient if an invention was simply “obvious to try;” rather, an invention would be obvious when it is “more or less selfevident that what is being tested ought to work.” The mere possibility that something might turn up is
simply not enough. Moreover, the Court was clear that the “obvious to try” inquiry is but one factor to assist in the obviousness inquiry, which becomes relevant only in narrow circumstances. The invention must still be self-evident from the prior art and common general knowledge to satisfy the obviousness test.
On the facts of this case, the Court held that Apotex had not established obviousness.
Double Patenting
Apotex argued that a genus patent and selection patent covering the same compound necessarily
amounted to double patenting. The Court rejected this argument, stating that a generalized concern about evergreening does not justify an attack on the doctrine of selection patents. The reasons are two-fold: first,a selection patent may be sought by a party other than the inventor or owner of the original genus patent.
Second, selection patents encourage improvements by selection. The Court agreed that the focus in a double-patenting challenge is on the claims of the two patents rather than on the disclosure. Because theclaims of the genus patent are broader than those of the selection patent, there cannot be “same-type”double patenting. Furthermore, where a selection patent claims a compound that is patentably distinctfrom the genus patent (i.e., not obvious), it will not be invalid for obviousness double patenting.
On the facts of this case, the Court found that there was no double patenting.
