Case Comment

Sanofi-Aventis Canada Inc. et al v. Apotex Inc. and Ratiopharm Inc.

citation(s): 2009 FC 676, per Snider J. (June 29, 2009)

copyright 2010 Donald M. Cameron, Cameron MacKendrick LLP




[1] Sanofi-Aventis Canada (Sanofi Canada) sells a drug in Canada with the trademark of ALTACE, which is used primarily in the treatment of high blood pressure and cardiac insufficiency. The active ingredient in ALTACE is ramipril. With some exceptions, Sanofi Canada purchases ramipril from its affiliate, Sanofi-Aventis Deutschland GmbH (Sanofi Deutschland) who manufactures ramipril in Germany. Ramipril is included in Canadian Patent No. 1,341,206 (the '206 Patent), a patent that was issued March 20, 2001 and held by Schering Corporation (Schering). Each of Sanofi Canada and Sanofi Deutschland are licensees under the '206 Patent.

The Decision

[6] For the reasons expressed in these Reasons for Judgment, I have concluded that Apotex and Novopharm have infringed certain claims of the '206 Patent. However, I have also found that Claims 1, 2, 3, 6 and 12 of the '206 Patent are invalid. In very general terms, the key determination leading to this result is my finding that, on a balance of probabilities, the inventors of the '206 Patent could not soundly predict, as of October 20, 1981, that all of the eight compounds of Claim 12 of the '206 Patent would have the utility promised by the patent. Claims 1, 2, 3 and 6 include the same compounds as are covered by Claim 12. Accordingly, it follows that Claims 1, 2, 3, 6 and 12 of the '206 Patent are invalid and the claims of Schering and Sanofi will be dismissed.

[7] If I am wrong in this conclusion, and the claims were based on a sound prediction, it follows – on the particular facts of this case – that the same prior art that would form the basis of a sound prediction would render the relevant claims of the '206 Patent obvious as of the appropriate date for assessing obviousness.

[8] The Defendants have raised other grounds of invalidity. In light of my finding of invalidity on the basis of lack of utility, it is not strictly necessary for me to rule on these other grounds. However, if I were required to do so, I would conclude that:

Construction of Claim 12

[105] Insofar as Novopharm is concerned, the “shoe pinches” in the construction of Claim 12 of the '206 Patent. Claim 12 is as follows:

12. The compound 1- [N- (l-carboethoxy-3-phenylpropyl) – (S) - alanyl] octahydrocyclopenta [b] pyrrole-2 (S) -carboxylic acid and its pharmaceutically acceptable salts thereof.

[106] As written, Claim 12 specifies the stereochemistry at only two stereocentres: (S)-alanyl and 2(S)-carboxylic acid at the 2-position of the bicyclic ring structure. As noted, those are set in the S configuration; the others are not specified. Yet, as agreed by all of the experts and accepted by me, the skilled person would know that the described structure would have five stereocentres or chiral centres. Since the Claim does not exclude any possible diastereomers for the unspecified three stereocentres, Claim 12 includes eight possible compounds. Each compound would have two centres designated in the S configuration, with the other three in either an R or S configuration. When all stereocentres are in the S configuration, the compound is ramipril.

[107] With respect to the construction of Claim 12, the question that has arisen is whether it claims each of the eight individual diastereomers, as submitted by Schering and Sanofi, or only a mixture of the eight – and not to the individual diastereomers – as asserted by Novopharm. Initially, both Apotex and Novopharm claimed that Claim 12 was a claim to a mixture. In final argument, only Novopharm pursued this argument. The question is important because, if Novopharm is correct, Claim 12 cannot be construed to cover ramipril.

[110] I am not persuaded that the construction proposed by Novopharm should prevail.

[118] In sum, I prefer the evidence of Dr. Bartlett and the other experts for Sanofi, Schering and Apotex over that of Dr. Ehlers and Dr. Moody. As taught by Whirlpool, above, at paragraph 49, claims “must be read with a mind willing to understand”. In my view, a skilled reader would not embark on a dry, linguistic interpretation of this patent but would read the claims in the context of the specification and having regard to the inventor's purpose. Reading Claim 12 as proposed by Novopharm is not a reading by a mind willing to understand but by a mind seeking to distort the logical meaning that flows from a reading of the claims in their context. I find that a person skilled in the art would construe Claim 12 as a claim to eight individual compounds. One of those compounds is ramipril.

The “Promise” of the '206 Patent

[119] A serious disagreement exists between the experts for the Defendants and the Plaintiffs on the question of whether claims should be construed to include an inherent promise that the compounds are useful as both ACE inhibitors and as antihypertensive agents. The experts for Apotex and Novopharm construe the patent such that the compounds claimed would have utility in both ACE inhibition and reduction of high blood pressure. In contrast, the experts for Schering and Sanofi are of the view that the claims do not include a promise of antihypertensive reduction.

[120] The place to begin is the '206 Patent specification. What meaning can be drawn from the words used by the inventors to describe their invention?

[121] As noted, the '206 Patent opens with a simple declaration that:

The present invention relates to carboxyalkyl dipeptides which are useful as inhibitors of angiotensin-converting enzyme and as antihypertensive agents. [Emphasis added]

[122] A key statement is made on p. 24 of the patent specification, where the inventors state that

The compounds of this invention have useful pharmacological properties. They are useful in the treatment of high blood pressure. The compounds of the present invention can be combined with pharmaceutical carriers and administered in a variety of well known pharmaceutical forms suitable for oral or parental administration to provide compositions useful in the treatment of cardiovascular disorders and particularly mammalian hypertension. [Emphasis added]

[123] There is absolutely no language on p. 23-25 of the patent description that places any limitation on the usefulness of any of the compounds. There is nothing in the words that can be read to indicate that only some of the compounds will be useful or that only some of them will work as either ACE inhibitors or antihypertensive agents.

[124] When these provisions at pages 23-25 of the patent are read in light of the assertion that the compounds “are useful in the treatment of high blood pressure”, I believe that the skilled reader would assume that the inventors were alleging that all of the compounds covered by Formula I would be useful in treating hypertension. Of course, the compounds claimed in the patent are subsets of those included in Formula I. Thus, if the patent is interpreted such that it asserts that all of the compounds will be useful in the treatment of hypertension, it follows that the inventors are also asserting that all of the claimed compounds of Claim 12 (and the other claims) would have such use.

132] On this question, I prefer the opinion of Dr. Thorsett and Dr. Ehlers, each of whom concluded that the '206 Patent promises that all of the compounds will have utility as both ACE inhibitors and antihypertensives.

[133] My conclusion of a dual promise is consistent with existing jurisprudence on the promised utility of this and other ACE inhibition patents.

[134] Although the decision of Justice Mactavish in Ramipril II (FC), above, may not be binding, I observe that Justice Mactavish was faced with the same question of the promise of the '206 Patent. Her conclusion was that the '206 Patent had a two-fold promise: “that is, the patent promises that the compounds claimed by the patent will have utility as both ACE inhibitors and as anti-hypertensive agents” (Ramipril II (FC), above, at para. 280). Similarly, Justice Harrington in Ramipril IV (FC), above, at paragraph 45, stated that “The promise was simply that the compounds claimed by the patent would have utility as both ACE inhibitors and anti-hypertensive agents”.

Sound Prediction

[146] The doctrine of sound prediction can be relied upon by an inventor to justify patent claims whose utility has not actually been demonstrated, but can be soundly predicted based upon the information and expertise available (Wellcome AZT (SCC), above, at para. 56). At paragraph 70 of Wellcome AZT (SCC), above, the Supreme Court of Canada articulated a three-part test that must be satisfied in order to establish that a sound prediction has been made by the an inventor. The three elements of the test are:

1. There must be a factual basis for the prediction;

2. The inventor must have an articulable and “sound” line of reasoning from which the desired result can be inferred from the factual basis; and

3. There must be proper disclosure.

[147] To be sound, a prediction does not need to amount to a certainty, as it does not exclude the risk that some compounds within the area claimed may, at some later time, prove to be devoid of utility. With these principles in mind, I turn to the '206 Patent and the evidence before me.

[148] As of the Canadian filing date – that is, October 20, 1981 – Schering had not made and tested all of the compounds that are included in the claims in dispute. While Schering had carried out some testing and obtained some positive results, it is evident that the efficacy of most of the compounds of the '206 Patent was based on a prediction. In other words, Schering – supported by Sanofi – asserts that the prediction of utility of all compounds included in the claims of the '206 Patent was sound.

[149] The Defendants are not asserting that there is evidence of lack of utility. Rather, they submit that the prediction at the date of application was not sound.

[150] I will focus first on the eight compounds of Claim 12. If the defendants are successful in their arguments with respect to any one of the compounds of Claim 12, they have met their burden. Since Claims 1, 2, 3 and 6 all encompass Claim 12, they will also fail if Claim 12 fails.

[152] ... The Plaintiffs submit that their sound prediction rests on a combination of Schering’s research program into ACE inhibitors and the publicly-available literature and other information, from which they could infer utility of those compounds not yet tested. In other words, they argue that the actual research work of the Schering scientists, together with knowledge in the public domain, would have given Schering a factual basis and an articulable line of reasoning to soundly predict, as of October 20, 1981, that all of the compounds of Claim 12 of the '206 Patent would have utility.

[155] The opinions of the experts were of assistance, particularly in the understanding of the literature and knowledge in the field. However, in assessing the factual basis, the task facing me was to comprehend the nature and extent of the work of the Schering scientists. Fortunately, I had the benefit of hearing from Dr. Smith and Dr. Neustadt, two of the named inventors of the '206 Patent. These two witnesses spoke candidly and honestly about the research program of Schering and about their understanding of the knowledge in the field at the relevant time of October 20, 1981.

[180] Two other compounds synthesized were SCH 32494, a compound with a trans 6,5-bicyclic ring configuration and SCH 31846, a cis-endo 6,5 bicyclic configuration. SCH 32494 was inactive and SCH 31846 was active at the levels tested. In short, Schering was unable to show that any 6,5 bicyclic enalapril analogue with a trans configuration at the bridgehead exhibited ACE inhibition. The testing results of these two compounds demonstrate that Schering could not predict, based on the results from cis-endo compounds, that compounds with a trans- 6,5 bicyclic configuration would have activity.

(d) Summary of Schering work

[184] In summary, the Schering scientists’ synthesis and testing program was limited. With respect to compounds that included a 5,5 bicyclic ring within Claim 12, only one compound – a mixture – has been made and tested by the Canadian filing date. Of particular interest, the scientists:

• Had not synthesized a single stereoisomer within Claims 6 and 12;

• Had not synthesized compounds with 5,5 bicyclic moieties in the cis-exo and trans configurations;

• Had synthesized two mixtures of compounds with 5,5 cis-endo bicyclic moieties and found one to be active and the other to be inactive in vivo.

[185] Given that Schering tried unsuccessfully to synthesize the cis-exo form of the 6,5 bicyclic ring compound and had never even attempted such syntheses for the 5,5 cis-exo configuration, it is difficult to accept that, based on their experimental work, the Schering scientists had a factual basis to predict that these configurations, which are included in Claim 12, would be active either in vitro or in vivo. For the stereoisomers in the cis-exo and trans configurations, this conclusion would apply even if the promise of the patent is for ACE inhibition only.

[186] I digress for a moment to discuss an argument made by the Plaintiffs in respect of the “inactive” testing results reported by Schering. The Plaintiffs submit that the “inactive” results should be read in the context of the limits of the testing. Schering had evidently set an internal testing threshold to provide them with guidance on which compound warranted further testing. At a higher dosage, they assert, it is entirely conceivable that the compounds would show activity. Thus, the Plaintiffs argue, I should not conclude that a compound is devoid of ACE inhibition or antihypertensive effect on the basis of an “inactive” finding by the Schering scientists.

[187] The critical flaw in this argument is that, in respect of some of the compounds covered by Claim 12, the Schering scientists have no results that could lead to a prediction of activity at any level. Inactive test results do not provide any insight as to how the Schering scientists could predict activity at a higher dose. A prediction of activity at a higher does would be pure speculation.

[188] Having concluded that no factual basis for a sound prediction can be founded on the Schering work alone, it is necessary to turn to the knowledge that was available to Schering as of the relevant date. Upon consideration of all of the testimony and arguments by the parties, I believe that there are two determinative areas. The first of these relates to the stereochemistry at the carboethoxy position. The second area is the overall “space” theory, which relates to the notion of the three-dimensional shape of the active site of ACE.

[212] To be sound, there must be a factual basis for Schering’s prediction, and the inventors must have had an articulable line of reasoning from which the desired result could have been inferred from the factual basis. I appreciate that the jurisprudence teaches that I should approach these issues “with a judicial anxiety to support a really useful invention” (Wellcome AZT (SCC), above, at para. 92). However, for the reasons given, I am satisfied, on a balance of probabilities, that as of October 20, 1981, the prediction made by Schering that the eight compounds within Claim 12 (with the exception of ramipril) would be useful as ACE inhibitors and as antihypertensive agents was not sound.

C. Sound Prediction: Disclosure

[213] In the event that I am in error and there was, as of October 20, 1981, a factual basis and an articulable line of reasoning upon which inventors could soundly predict the utility of the compounds of Claim 12, I turn to the final criterion of sound prediction. Specifically, the test for sound prediction obliges the patentee to disclose the facts and reasoning for soundly predicting the utility of his invention.

[214] The Federal Court of Appeal recently provided the following guidance on the disclosure requirement in Eli Lilly Canada Inc. v. Apotex Inc., 2009 FCA 97 at paras. 13-15 [Raloxifene (FCA)]:

13. The importance of the disclosure obligation in applying for a patent has been emphasized by the Supreme Court of Canada on a number of occasions in recent years (Pioneer Hi Bred Ltd. v. Canada (Commissioner of Patents), [1989] 1 S.C.R. 1623 at paragraph 23; Cadbury Schweppes Inc. v. FBI Foods Ltd., [1999] 1 S.C.R. 142 at paragraph 46; Free World Trust v. Électro Santé Inc. 2000 SCC 66, [2000] 2 S.C.R. 1024 at paragraph 13; Apotex Inc. v. Wellcome Foundation Ltd., 2002 SCC 77, [2002] 4 S.C.R. 153 at paragraph 37 (commonly referred to as AZT and hereinafter referred to as such)).

14. The decision of the Supreme Court in AZT is particularly significant to the disposition of this appeal. According to AZT, the requirements of sound prediction are three-fold: there must be a factual basis for the prediction; the inventor must have at the date of the patent application an articulable and sound line of reasoning from which the derived result can be inferred from the factual basis; and third, there must be proper disclosure (AZT, supra, at paragraph 70). As was said in that case (para. 70): "the sound prediction is to some extent the quid pro quo the applicant offers in exchange for the patent monopoly". In sound prediction cases there is a heightened obligation to disclose the underlying facts and the line of reasoning for inventions that comprise the prediction. [Emphasis added]

15. In my respectful view, the Federal Court Judge proceeded on proper principle when he held, relying on AZT, that when a patent is based on a sound prediction, the disclosure must include the prediction.

[215] In Raloxifene (FCA), a particular study (the Hong Kong study) was necessary to turn the prediction on which the patent was predicated into a sound one. The result of failure to disclose the Hong Study in the patent was that “the underlying factual basis for the prediction and the sound line of reasoning that grounded the inventors’ prediction were not disclosed” (Raloxifene (FCA), above, at para. 12).

[216] Raloxifene (FCA) arose from an application under the NOC Regulations. The underlying patent was for the use of certain chemical compounds for the treatment of osteoporosis. Nevertheless, I can see no reason why the legal principles applied by the Court of Appeal in that NOC proceeding on the question of sound prediction should not apply in the case before me. Nor can I accept the Plaintiffs’ apparent argument that this “heightened obligation” for disclosure only applies when we are dealing with a use patent, as was the case in Wellcome AZT (SCC) and Raloxifene (FCA). Indeed, the Federal Court of Appeal has stated unequivocally that the doctrine of sound prediction applies to a claim for a new compound (Pfizer Canada Inc. v. Apotex Inc., 2007 FCA 195, 60 C.P.R. (4th) 177 at para. 3).

[217] The case before me stands in contrast to Wellcome AZT (SCC) where the court held that the disclosure requirements had been met given that both the underlying facts (the test data) and the sound line of reasoning (the chain terminator effect) were in fact disclosed. The facts of the case before me are closer to those in Raloxifene (FCA) than to those in Wellcome AZT (SCC).

[218] The disclosure provided by Schering in its ‘206 Patent is insufficient for several reasons. First, there is no test data included in the specification of the patent. Test data may provide the public with enough information from which to make significant inferences. The '206 Patent provides no in vitro or in vivo data for any of the compounds disclosed in the claims. It does not describe how the allegedly useful properties of ACE inhibition and antihypertensive activity were established. It also does not give any indication as to how potent or selective any of the compounds are.

[219] Second, nowhere in the patent is there any discussion that the active site of the ACE inhibitor has sufficient volume to fit all stereoisomers of the bicyclic rings disclosed in the '206 Patent. Further, there is no explanation that this belief is based on certain spiro and 6,5 bicyclic rings fused to the enalapril or captopril backbone or how activity for all the clamed compounds can be inferred from the limited information the inventors had with respect to these compounds.

[220] Third, the '206 Patent also makes no reference to the Troy conference or any publications. There is also no evidence that the inventors relied on those disclosures to predict that all of the various permutations of the side chain claimed in the '206 Patent would have utility. Likewise, the '206 Patent makes no reference to any Squibb disclosures about captopril.

[221] Fourth, no reference to any of the work Schering did on captopril analogues, including the analogues where the proline ring was substituted with one or more substituents, is set out.

[222] Finally, I turn to the argument of the Plaintiffs that the promise of the '206 Patent is a differentiated promise that all of the compounds will have ACE inhibition with a potential or possibility of reducing hypertension in mammals. As discussed in the section of these reasons dealing with the construction of the patent, certain of the Plaintiffs' experts argue for a stepwise or quasi-bifurcated promise of utility in which all of the claimed compounds are promised to be ACE inhibitors while only certain compounds are promised to exhibit antihypertensive effect. If this is a correct interpretation of the promise of the '206 Patent (which I do not accept), then I have further difficulty with the lack of disclosure in the Patent.

[223] The failure to provide information as to which claimed compounds have the promised utility of a patent was specifically addressed by the English Court of Appeal in American Home Products Corp, v. Novartis Pharmaceuticals, [2001] R.P.C. 8 (Eng. C.A.). In American Home Products, Lord Justice Aldous held that a sufficient specification requires that there be an enabling disclosure across the breadth of the claimed invention.

The invention as described was the discovery that rapamycin had those advantages. Some derivative would be expected to have similar advantages, but the skilled person would not be able to predict which ones would have that actuality and, even if the right one was selected, it would take prolonged tests to find out whether it had the appropriate qualities. It follows that, as Lord Hoffmann pointed out in Biogen, the patent, to be sufficient, must provide an enabling disclosure across the breadth of the claim. [Emphasis added]

. . .

There is a difference between on the one hand a specification which requires the skilled person to use his skill and application to perform the invention and, on the other, a specification which requires the skilled person to go to the expense and labour of trying to ascertain whether some product has the required properties. When carrying out the former the skilled person is trying to perform the invention, whereas the latter requires him to go further and to carry out research to ascertain how the invention is to be performed. If the latter is required the specification would appear to be insufficient. [Emphasis added]

(American Home Products, at paras. 37, 40)

[224] Although Lord Aldous wrote these comments under the heading "Insufficiency", they are, on any plain reading, directed to more than the simple question of whether the specification discloses a method of preparation. As I read these reasonable and comprehensive remarks of Lord Aldous, the principles contained therein are directly applicable to the situation before me. This interpretation of the disclosure obligation is also fully consistent with the broader principles of disclosure set out by the Supreme Court of Canada in cases such as Free World Trust v. Électro Santé Inc., 2000 SCC 66, [2000] 2 S.C.R. 1024 [Free World Trust], Consolboard, Wellcome AZT (SCC) and others.

[225] Assuming that the patent promises that some but not all of the claimed compounds are potential antihypertensive agents, the '206 Patent does not specify which of the compounds within the scope of the patent would have a potential for in vivo antihypertensive activity. As acknowledged by Dr. Horovitz, the '206 Patent provides no criteria by which the skilled reader would be able to ascertain which compounds would be antihypertensive agents. Furthermore, as mentioned above, there is no in vitro or in vivo activity data contained within the '206 Patent. Thus, a skilled reader of the patent could not determine which compounds are promised to have antihypertensive activity without going to “the expense and labour of trying to ascertain whether some product has the required properties” (American Home Products, above, at para. 40).

[226] The Plaintiffs rely quite heavily on a concept called ADME to support their argument that the ‘206 Patent contains a bifurcated promise of utility. ADME refers to the following pharmacological considerations: oral absorption of the compound (A); distribution of the compound (D); metabolism (M); and excretion of the compound and/or its metabolites (E). According to the Plaintiffs, the promise of the patent is that the compounds disclosed are useful as ACE inhibitors and, subject to ADME, as antihypertensive agents. Thus, the concept of ADME assists in determining whether any given ACE inhibitor would have the potential to lower blood pressure in mammals. Yet, this principle is not disclosed anywhere in the specification of the '206 Patent. The absence of information on ADME in the specification could possibly have been overcome by the inclusion of test results. Had the inventors provided test results in the specification, it is possible that the skilled person reading the patent could draw reasonable inferences from that information. Yet, no test results are included.

[227] In light of the foregoing, the lack of information in the '206 Patent makes it very hard, if not impossible, for a person skilled in the art to make a decision about exactly which of the compounds disclosed are active, and which are not active. As a result, if the invention of the '206 includes a promise that some of the compounds will be active as antihypertensives, the patent fails to teach what is the invention and how it works; there is no enabling disclosure across the breadth of the claimed invention.

[228] In conclusion, on the question of disclosure, I find that there is inadequate disclosure in the '206 Patent. The '206 Patent discloses neither the underlying facts (their test data) nor a sound line of reasoning (for example, ADME considerations and space theory). The underlying factual basis and line of reasoning that grounded the inventors’ alleged prediction were not disclosed. D. Conclusion on Sound Prediction

[229] I return to the words of Justice Binnie in Wellcome AZT (SCC), above, at paragraph. 56, where he stated: If a patent sought to be supported on the basis of sound prediction is subsequently challenged, the challenge will succeed if, per Pigeon J. in Monsanto Co. v. Commissioner of Patents, [1979] 2 S.C.R. 1108, at p. 1117, the prediction at the date of application was not sound, or, irrespective of the soundness of the prediction, "[t]here is evidence of lack of utility in respect of some of the area covered".

[230] In this case, the Defendants’ challenge of the Plaintiffs’ claim of sound prediction succeeds; they have persuaded me that, on a balance of probabilities, Schering’s prediction at the date of application (October 20, 1981) was not sound. The Plaintiffs have failed on all three requirements making up the test for sound prediction – factual basis, articulable line of reasoning and disclosure. On this basis, Claims 1, 2, 3, 6 and 12 are found to be invalid for lack of sound prediction.

[231] Given this conclusion, there is no need to consider the other grounds of invalidity advanced by the Defendants. Nevertheless, I will express my views of the balance of the arguments advanced by the Defendants, in the hope that they will be of assistance.




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