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Aventis Pharma Inc. v. Apotex Inc.
Aventis Pharma Inc., applicant, and
Apotex Inc. and the Minister of Health, respondents, and
Schering Corporation, respondent/patentee
2005 FC 1283
2005 CF 1283
Mactavish J.
Heard: June 23, 24, 27, 28 and 29, 2005.
Intellectual property law -- Patents -- Criteria for patentability -- Inventive ingenuity --Infringement actions -- Defences -- Ambiguity -- Prior knowledge or use -- Nature of patent --Description -- Elements -- Notice of compliance. Application by Aventis Pharma Inc. for an order prohibiting the Minister of Health from issuing a Notice of Compliance to Apotex until after the expiration of Aventis' patent. In October 1981,Schering Corp. filed an application for a Canadian patent for a group of compounds which weresaid to be useful as angiotensin converting enzymes. As a result of protracted conflict proceedings,the 206 patent did not issue until March 2001. In accordance with the Regulations, Aventis listedthe 206 patent on the Patent Register maintained by the Minister of Health, in relation to ramipriloral capsules in a variety of strengths. Under the terms of a license between Aventis and Schering,Aventis was entitled to manufacture and sell ramipril in Canada. Apotex sought to manufacture andsell ramipril in Canada. Aventis argued that the manufacture and sale of ramipril by Apotex wouldinfringe the 206 patent. Apotex asserted that the 206 patent was not valid for a number of reasons.
HELD: Application dismissed. The claims in issue were not invalid for anticipation. A subsequentpatent, filed in November 1981, did not claim the class of compounds that was claimed in the 206patent. However, the court was satisfied on a balance of probabilities that, given the limited state ofthe knowledge in October of 1981 with respect to the structure of the compounds coming within acertain claim of the 206 patent, the skilled person would not have been able to isolate orcharacterize individual stereoisomers falling within the claim, including ramipril, without usinginventive ingenuity. Accordingly, disclosure of the 206 patent was deficient in that regard.
Statutes, Regulations and Rules Cited:
Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, ss. 5, 6 Counsel:
Gunars Gaikis, Sheldon Hamilton, David Morrow and Kavita Ramamoorthy, for the applicant.
Harry Radomski, Andrew Brodkin, Rick Tuzi and Sorelle Simmons, for the respondent, Apotex Inc.
Anthony Creber, for the respondent/patentee - Schering Corporation.
Are the Claims in Issue in the '206 Patent Are the Claims in Issue Invalid By Reason Are the Claims in Issue in the '206 Patent Invalid by Reason of Section 61(2) of the Are the Claims in Issue in the '206 Patent Angiotensin I is a peptide occurring naturally in the human body. As a result of the action of an enzyme known as angiotensin converting enzyme or "ACE", angiotensin I is converted by the bodyinto a second peptide known as Angiotensin II. Angiotensin II is a vasoconstrictor or pressor. Thatis, it causes the muscles surrounding blood vessels to contract, thereby narrowing the blood vessels,causing blood pressure to rise.
It has long been posited that if one could affect the synthesis of angiotensin II through the inhibition of ACE, blood pressure in humans could be lowered. By the late 1970's, a number ofpharmaceutical companies were actively involved in research in this area.
On October 20, 1981, Schering Corporation filed an application for a Canadian patent for a group of compounds which were said to be useful as ACE inhibitors and anti-hypertensive agents.
As a result of protracted conflict proceedings, patent 1,341,206 (the '206 patent) did not issue untilMarch 20, 2001.
Under a licence granted by Schering, Aventis Pharma Inc. manufactures a drug containing a medicine called ramipril, which is one of the compounds covered by the '206 patent. It is commonground that ramipril is an extremely effective ACE inhibitor.
In accordance with Section 5 of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133, on June 20, 2003, Apotex Inc. served a Notice of Allegation on Aventis in relation toramipril. In its Notice, Apotex asserts that the '206 patent is invalid on a number of bases. Apotexcontends that Schering did not have a valid basis for soundly predicting that the compounds inthe'206 patent, and, in particular, in Claim 12 of the patent, would, if made, be useful for their statedpurpose. Apotex further says that the '206 patent is invalid as the claims are broader than theinvention and lack utility. Apotex also challenges the validity of the '206 patent on the grounds ofinsufficiency, anticipation and double patenting.
In addition, Apotex relies on section 61(2) of the pre-1989 Patent Act, R.S.C. 1970, c. P-4 (the "old Patent Act") to say that the '206 patent should not have issued in light of the fact that otherpatents had been granted to Aventis' predecessor, Hoechst Aktiengesellschaft (patent No. 1,187,087or the "'087 patent" and patent No. 1,246,457 or the "'457 patent". The '087 patent covers some ofthe compounds within the '206 patent, including ramipril, whereas the '457 patent covers the use ofcompounds, including ramipril, for the treatment of cardiac insufficiency.
Finally, Apotex asserts that a conflict should have been declared between the '206 patent and In this application, Aventis seeks an order declaring that the Notice of Allegation is not a valid Notice of Allegation as contemplated by the PM(NOC) Regulations. In the alternative, Aventisseeks an order prohibiting the Minister of Health from issuing a Notice of Compliance to Apotexfor ramipril until after the expiration of the '206 patent. Because of its interest in these proceedings,as owner of the '206 patent, Schering has been named as a respondent in this case, although it isallied in interest with Aventis.
The Minister of Health did not participate in the hearing of this matter.
For the reasons that follow, I am dismissing Aventis' application.
Aventis' application is brought under the PM(NOC) Regulations. The legislative history and purpose of these Regulations has been described in detail in a number of decisions, and need not be repeated here. (See, for example, Bristol-Myers Squibb Co. v. Canada (Attorney General), [2005]S.C.J. No. 26; Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare),[1994] F.C.J. No. 662, 55 C.P.R. (3d) 302 (F.C.A.); AB Hassle v. Canada (Minister of NationalHealth and Welfare), [2000] F.C.J. No. 855, 7 C.P.R. (4th) 272 ; and Novartis AG et al. v. AbbottLaboratories Ltd. et al., [2000] F.C.J. No. 941, 7 C.P.R. (4th) 264 (F.C.A.)).
For the purpose of this proceeding, it is, however, helpful to have some understanding of the regulatory scheme as it relates to disputes of this nature.
The Supreme Court of Canada has accepted the view that the PM(NOC) Regulations were enacted to thwart the possible appropriation by generic drug companies of the research anddevelopment initiatives of innovator companies: Bristol-Myers Squibb Co., supra, at para. 45.
Under the terms of the licence between Aventis and Schering, Aventis is entitled to manufacture and sell ramipril in Canada. In accordance with the Regulations, Aventis has listed the'206 patent on the Patent Register maintained by the Minister of Health, in relation to ramipril oralcapsules in a variety of strengths.
Apotex would like to be able to manufacture and sell ramipril in Canada, but cannot do so without first being issued a Notice of Compliance (NOC) by the Minister.
In this proceeding, Aventis seeks to prohibit the Minister from issuing a NOC to Apotex, on the basis that the manufacture and sale of ramipril by Apotex would infringe the '206 patent. Asnoted earlier, Apotex asserts that, for a number of different reasons, the '206 patent is not valid.
There is no issue of infringement in this case.
The issues of patent validity between Aventis and Schering, on the one hand, and Apotex on the other, originate with the service of Apotex's Notice of Allegation (NOA) on Aventis. Pursuantto sub-section 5(3) of the PM(NOC) Regulations, Apotex is required to include a detailed statementof the legal and factual basis for its allegations in its NOA.
In accordance with section 6 of the Regulations, Aventis has applied for an order prohibiting the Minister of Health from issuing a Notice of Compliance to Apotex until after the '206 patent hasexpired.
Proceedings under section 6 of the PM(NOC) Regulations are not to be equated with actions for the determination of patent validity or infringement. Rather, they are judicial reviewproceedings, whose aim is to determine whether the Minister is free to issue the requested NOC toApotex.
The scope of such proceedings is limited to administrative purposes - that is, whether or not a NOC should issue to Apotex: Apotex Inc. v. Canada (Minister of National Health and Welfare),[1997] F.C.J. No. 1251, 76 C.P.R. (3d) 1 (F.C.A.). My decision must turn on whether the allegations made by Apotex are justified so as to support the conclusion, for administrativepurposes, that the '206 patent would not be infringed if Apotex's product were put on the market:Pharmacia Inc. v. Canada (Minister of National Health and Welfare), [1995] 1 F.C. 588, 58 C.P.R.
(3d) 209 (F.C.A.).
Under the regulatory scheme, by commencing this proceeding, Aventis obtains what is tantamount to an interlocutory injunction, without having first satisfied any of the usual criteria forthe obtaining of such relief: Merck Frosst Canada Inc. v. Canada (Minister of National Health andWelfare), [1998] 2 S.C.R. 193. As the Supreme Court of Canada noted in the Bristol-Myers SquibbCo. decision previously cited, in such circumstances, applications for NOC's such as that filed byApotex simply go into the 'deep freeze' until the statutory procedures play themselves out (assumingthat this occurs within the 24 month period provided for in the Regulations).
It is the existence of this statutory freeze that has caused the Supreme Court of Canada to describe this process as 'draconian': Merck Frosst, supra.
The PM(NOC) Regulations allow the Court to determine summarily, on the basis of the evidence adduced, whether Apotex's allegations are justified. Section 6 proceedings cannot betreated as res judicata: AB Hassle v. Genpharm Inc., [2003] F.C.J. No. 1910, 2003 FC 1443, para.
11.
These proceedings do not serve to deprive either Aventis or Schering of any rights that they might otherwise have with respect to the '206 patent. If a full trial of the validity issues is required,this can be obtained in the usual way by commencing an action: Pfizer Canada Inc. v. Apotex Inc.
(2001), 11 C.P.R. (4th) 245 (F.C.A.), para. 25; Novartis A.G. v. Apotex Inc. (2002), 298 N.R. 348(F.C.A.), 2002 FCA 440, para. 9.
Before turning to the facts of this case, it is first necessary to have an understanding of certain chemical structures and conventions, in order to understand the nature of the invention claimed inthe '206 patent.
"Stereochemistry" is concerned with the three dimensional spatial orientation of compounds made up of atoms. Molecules having exactly the same chemical composition and the same sequenceof covalent bonds may differ in their arrangement in three dimensions. Such compounds arereferred to as "stereoisomers".
The term "chiral centres", as it appears in stereochemistry, is used in connection with carbon atoms. A carbon atom with four different functional groups attached to it is referred to as a "chiralcentre". A chiral centre may have two possible arrangements, such that one arrangement may not besuperimposable on the other by rotating in space. In such cases, the carbon atom is referred to asstereogenic, and the compound is termed 'chiral'.
In order to describe the stereochemistry of molecules having chiral centres, chemists have devised a number of conventions. Where the direction from the highest to lowest priority atom orgroup attached to the chiral carbon, determined by atomic number, is clockwise, the chiral centre isdescribed as being in the "R" position, whereas a counter-clockwise arrangement is referred to as"S".
Because chiral centres exist in three dimensions, it is necessary to have a convention for indicating the atoms' position in space, when molecules are represented on paper. To distinguishisomers based on the arrangement of the atoms attached to the chiral centre in space, chemists showa bond that projects up from the plane of the paper, towards the viewer, with a solid wedge shape. Achemical bond that projects away from the viewer is indicated by a hatched wedge shape.
Where two groups are attached to separate carbon atoms, chemists use the term "cis" to describe situations where both groups are on the same side of the plane. The term "trans" is usedwhere the two groups are on opposite sides of the plane.
Pairs of mirror image molecules that cannot be superimposed on each other are referred to as enantiomers. In this regard, an analogy is often drawn to left and right hands. Diasteromers arestereoisomers that are different in stereochemistry and which are not mirror images. Enantiomershave identical physical properties, whereas diasteromers differ in their physical properties. That is,diasteromers will have different melting and boiling points, solubility, reactivity, affinity towardsadsorbents and partition coefficients. These differences are important, as they can be used by aperson skilled in the art to separate diasteromers.
Stereochemistry played a very important role in the development of ACE inhibitors, as ACE is a chiral molecule. To be effective as an ACE inhibitor, the compound in question must be able tointeract with the chiral ACE. ACE will exhibit a preference for certain chiral configurations - just asa left hand will prefer a left glove. The closer the fit of the chiral ACE molecule to the ACEinhibitor - the more effective will be the inhibitory effect.
The development of ACE inhibitors in the late 1970's and early 1980's was complicated by the fact that the precise configuration of ACE was not known, and, indeed, has only recently beenunderstood.
With this understanding of some of the basic concepts of stereochemistry, I turn now to review the events leading up to the development of Schering's ACE inhibitors.
The development of ACE inhibitors originated with the discovery that a series of peptides isolated from the venom of the Brazilian Pit Viper could be effective in inhibiting ACE, in vitro. Acompound known as teprotide was subsequently synthesized, which proved to be an effectiveanti-hypertensive agent in humans. However, teprotide was only effective through intravenous The transformation of an intravenously active peptide into an orally effective ACE inhibitor occurred as a result of work done by a group working for Squibb, headed by Dr. Miguel Ondetti.
Although the precise structure of ACE was not known at the time, the Squibb scientists were able toconstruct a model for ACE, relying upon what was known about another enzyme known ascarboxypeptidase A.
Based upon this analogy, in 1977, the Squibb group developed a compound known as captopril. Captopril was the first small molecule, orally effective ACE inhibitor. The molecularstructure of captopril is: [Editor's note: The illustration could not be reproduced online. Please contact Quicklaw Customer Service at 1-800-387-0899 or service@quicklaw.com to request the It should be noted that there are two chiral centres in captopril, both of which are in the "S" configuration. The five-membered ring structure on the right side of the molecule is a naturallyoccurring amino acid known as proline.
Although captopril functioned as an ACE inhibitor, it did produce a number of side-effects, such as loss of taste, the excretion of protein in urine and skin rashes. Nevertheless, its successprompted a number of other pharmaceutical companies to try to develop new and patentableanalogs.
In particular, Merck, Sharp and Dohme focussed on removing the thiol group (the structure on the left side of the captopril molecule), replacing it with a carboxmethyl function. On June 18, 1980,at a medicinal chemistry conference in Troy, New York, Merck disclosed that it had developed acompound known as enalapril, which had demonstrated activity as an ACE inhibitor.
[Editor's note: The illustration could not be reproduced online. Please contact Quicklaw Customer Service at 1-800-387-0899 or service@quicklaw.com to request the As can be seen from this diagram, enalapril has three chiral centres, all in the "S" configuration. It can also be observed that while enalapril lacks the sulphur moiety present incaptopril, what remained consistent from captopril to enalapril was the presence of the proline unitor five-membered ring structure on the right side of the compound.
Although more will be said further on in this decision about the development work done by Schering during the late 1970's and early 1980's, it is helpful at this point to have an overview of thenature of the research work that was being done by Schering leading up to the application for whatwould become the '206 patent.
Prior to the Merck announcement at the Troy conference in June of 1980, scientists at Schering, including Dr. Elizabeth Smith, were trying to develop an anti-hypertensive compound thatwould be more effective than captopril. While Merck's work involved the removal of the thiolgroup, Schering's work focussed on a different aspect of the captopril molecule - that is the prolineunit.
By late 1979 or early 1980, Dr. Smith and her colleagues had found that the replacement of the proline in captopril with certain fused ring or spirocyclic moieties resulted in efficaciouscompounds.
As a result of the Merck disclosure at the Troy conference, the Schering scientists decided to try to create compounds based, in part, upon the Merck work on the thiol end of the molecule, butalso using the fused ring moieties that Schering had already been working on in relation to theproline end of the molecule. That is, Schering's scientists decided to try using various bicyclic ringstructures in place of the proline on an enalapril-type molecule.
This proposed work was documented in an invention disclosure report dated June 20, 1980.
According to Dr. Smith, this report shows the conception of the generalized structure of thecompounds in what ultimately became the '206 patent.
On August 5, 1980, Dr. Smith made the first compound within the scope of the '206 patent, which became known as SCH 31335. Over the next few months, Dr. Smith and the other scientistsat Schering made several of these compounds using different bicyclic ring structures. Initial testingof these compounds indicated that they demonstrated ACE inhibition activity.
On October 23, 1980, Schering applied for a patent in the United States in relation to this work. A second American patent was applied for on April 28, 1981.
Throughout this time, Dr. Smith and her colleagues continued to create and test additional compounds using the bicyclic ring structure coupled with Merck's enalapril-type "backbone". Oneof the compounds created during this period was SCH 31925, which contained molecules having a5,5 ring structure at the proline end. Preliminary pharmacological testing revealed that SCH 31925was a potent ACE inhibitor.
Dr. Smith says that SCH 31925 is within the scope of Claim 12 of the '206 patent, which, the parties are agreed, is the primary claim in issue in this case.
On Oct. 20, 1981, Schering applied for patent protection in Canada for its work in this area.
Schering's application claimed priority dates of October 23, 1980, and April 28, 1981, based uponthe American patent application dates. The Canadian application ultimately resulted in the issuanceof the '206 patent in March of 2001.
The '206 patent is entitled "Carboxyalkyl Dipeptides, Processes for Their Production and Pharmaceutical Compositions Containing Them". The patent states at page one that it relates tocompounds (carboxyalkyldipeptides) which are useful as inhibitors of angiotensin-convertingenzyme and as anti-hypertensive agents.
The '206 patent covers within its claims three currently commercial compounds - ramipril, spirapril and trandolapril. This makes it an extremely valuable patent. Its value is enhanced by thefact that the patent only issued in 2001, and thus has some 13 years left to run.
The claims of the '206 patent are broad and cover a genus of compounds that include ramipril.
It should be noted, however, that nowhere in the '206 patent is there specific disclosure of eitherramipril or ramiprilat, nor any claim or claims directed to those compounds alone. Ramiprilat is themetabolite formed in the body of those who take ramipril.
The breadth of the scope of the '206 patent is confirmed by the evidence of Dr. Garland Marshall, whose affidavit was filed by Apotex. Dr. Marshall is a Professor of Biochemistry andMolecular Biophysics and of Biomedical Computing at the Washington University School ofMedicine at Washington University.
Claim 1 of the '206 patent claims a genus of carboxyalkyldipeptides of a general formula consisting of three main units: (a) bicyclic rings in a variety of configurations; (b) a central alanylunit; and (c) the end chain unit, and is not limited to a specific stereochemistry. Dr. Marshallestimates that there are in excess of 24,000,000 compounds included within Claim 1.
Claim 2 also covers compounds with a specified general formula and is not limited to specific stereoisomers. Dr. Marshall estimates that the number of compounds encompassed by this claim tobe in excess of 200,000,000.
The claims in issue in this case are Claims 1, 2, 3, 6, 12 and 13. Dr. Marshall estimates the number of compounds encompassed by Claims 3, 6, 12 and 13 to range from 150,000, in the case ofClaim 3, to 8 in the case of each of Claims 12 and 13.
Ramipril is one of the compounds that comes within Claims 1, 2, 3, 6, and 12 of the '206 patent. Claim 13 covers a number of compounds, including ramiprilat.
Before addressing the issues relating to the validity of the '206 patent, it is necessary to construe the patent. The construction of a patent is a matter of law: Canamould Extrusions Ltd. v.
Driangle Inc., [2004] F.C.J. No. 266, 30 C.P.R. (4th) 129 para. 3 (F.C.A.).
The jurisprudence relating to the construction of patents was recently succinctly summarized by Justice Mosley in Merck & Co. v. Apotex Inc., [2005] F.C.J. No. 937, 2005 FC 755, para. 26, A patent is notionally addressed to a person skilled in the art or science of thesubject matter and is to be read as such a person would have read it when it firstbecame public. Claims are to be read in an informed and purposive way to permitfairness and predictability and to define the limits of the monopoly. It is onlysuch novel features that the inventor claims to be essential that constitute the"pith and marrow" of the claim. "The key to purposive construction is thereforethe identification by the Court with the assistance of the skilled reader, of theparticular words or phrases in the claims that describe what the inventorconsidered to be the "essential" elements of his invention" (Whirlpool, supra atparagraph 45).
The patent is not addressed to an ordinary member of the public, but to a worker skilled in the a hypothetical person possessing the ordinary skill and knowledge of theparticular art to which the invention relates, and a mind willing to understand aspecification that is addressed to him. This hypothetical person has sometimesbeen equated with the "reasonable man" used as a standard in negligence cases.
He is assumed to be a man who is going to try to achieve success and not onewho is looking for difficulties or seeking failure." (H.G. Fox, in The Canadian Law and Practice Relating to Letters Patent for Inventions, 4th Ed.
(Toronto: Carswell Co. Ltd., 1969) at p. 184, cited in Free World Trust v. Électro Santé Inc., [2000]2 S.C.R. 1024, 2000 SCC 66, para. 44).
In the case of patents of a highly technical and scientific nature, the person skilled in the art would be someone "possessing a high degree of expert scientific knowledge and skill in theparticular branch of the science to which the patent related": Consolboard Inc. v. MacMillanBloedel (Saskatchewan) Ltd., [1981] 1 S.C.R. 504.
There is no question that a patent filed under the old Patent Act is to be construed as of the date of issue: Free World Trust, supra, para. 54. The '206 patent was issued on March 20, 2001.
The parties agree that Claim 12 is the narrowest claim in the '206 patent, and that Apotex's case will stand or fall on whether it succeeds in relation to this claim. It is therefore unnecessary toconstrue any of the other claims.
The compound 1-[N-(1-carboethoxy-3-phenylpropyl-(S)-alanyl]octahydrocyclopenta[b]pyrrole-2(S)-carboxylic acid and its pharmaceutically acceptable salts The parties also agree that Claim 12 can properly be depicted as: [Editor's note: The illustration could not be reproduced online. Please contact Quicklaw Customer Service at 1-800-387-0899 or service@quicklaw.com to request the The proper construction of Claim 12 is not in dispute in this case. The parties are in agreement that properly construed, Claim 12 is directed to a compound, and describes a genus of eightstereoisomers, one of which is ramipril.
The general structure of Claim 12 depicted above describes a group of molecules with a 5,5 bicyclic ring structure in lieu of the proline ring in the class of compounds disclosed and claimed byMerck in the enalapril patent.
The molecular structure of Claim 12 has five chiral centres, each of which is indicated with an asterisk in the above diagram. The claim restricts the stereochemistry of two of the chiral centres tothe "S" position. The two chiral centres contain the carbons to which the carboxylic acid (-COOH)and the methyl (-COOC2H5) are attached. The stereochemistry of the three remaining chiral centresis not specified, meaning that they can have either an "R" or an "S" configuration.
Given that the three unspecified chiral centres can be in either the "R" or "S" configuration, the formula of Claim 12 describes 2x2x2 (23 or 8) stereoisomers.
In the case of ramipril, all five chiral centres are in the "S" position.
The central issue to be determined in this case is the validity of the '206 patent in light of Apotex's allegations. Apotex's Notice of Allegation raises the following issues in relation to thevalidity of the '206 patent: Did Schering have a sound basis for predicting that the compoundscovered by the claims in issue would be useful as ACE inhibitors and inthe treatment of hypertension in humans? Are the claims in issue in the '206 patent invalid for failure to comply withthe requirements of section 34 of the old Patent Act ("insufficiency")? Are the claims in issue broader than the invention or do they lack utility? Are the claims in issue invalid by reason of anticipation? Are the claims in issue in the '206 patent invalid by reason of section 61(2)of the old Patent Act? and Are the claims in issue in the '206 patent invalid by reason of doublepatenting? In its Notice of Application for Judicial Review, Aventis asserts that Apotex's NOA is a nullity. At the hearing of this application, both Aventis and Schering identified several areas inwhich they say that Apotex either failed to provide a sufficient factual and legal basis to support itsarguments, or was trying to rely on evidence or arguments that were not identified in the NOA.
Each of the arguments as to the alleged deficiencies in Apotex's NOA will be addressed in thecontext in which they arise in the course of this decision.
Before turning to consider each of the attacks on the validity of the '206 patent mounted by Apotex, threshold questions arise as to the burden and standard of proof in proceedings such as this.
Each of the parties made extensive submissions at the hearing as to their respective perspectives onthese questions.
It is not necessary to review the various authorities cited by each of the parties to support their arguments on these issues, as it appears from the recent jurisprudence emanating from the FederalCourt of Appeal that the matter is now well settled: see Proctor and Gamble PharmaceuticalsCanada Inc. v. Canada (Minister of Health), [2004] F.C.J. No. 1973, 2004 FCA 393, para. 12-24.
As the Applicant in these proceedings, Aventis has the overall burden of establishing that none of Apotex's allegations are justified. In this case, all of the issues raised by Apotex in its NOArelate to the validity of the '206 patent. In the absence of evidence to the contrary, there is astatutory presumption that a patent is valid: section 45 of the old Patent Act, subsection 43(2) of thepost-1989 Patent Act, R.S.C. 1985, c.P-4.
Relying upon the presumption of validity, Aventis can thus meet its initial burden merely by proving the existence of the patent.
Once this is done, the burden shifts to Apotex to establish that the patent is invalid. The standard of proof that Apotex is required to satisfy is that of a balance of probabilities: Bayer v.
Canada (Minister of National Health and Welfare), [2000] F.C.J. No. 464, 6 C.P.R. (4th) 285(F.C.A.), para. 9.
With this understanding of the burden and standard of proof, I turn now to consider the various grounds of attack on the validity of the '206 patent raised by Apotex in its Notice ofApplication.
Much of the time in this hearing was devoted to the question of whether Schering had a sound basis for predicting that the compounds covered by the claims in issue, and, in particular, by Claim12 of the '206 patent, would be useful as ACE inhibitors, and in the treatment of hypertension inhumans.
To be patentable, an invention must be useful. Where the compound is a new one, its utility need not be stated in the claims, but utility must be set out in the disclosure.
In the case of a pharmaceutical invention, utility may be demonstrated through testing. It is not, however, essential that complete testing have been carried out: the doctrine of sound predictioncan be relied upon by an inventor to justify patent claims whose utility has not been actuallydemonstrated, but can be soundly predicted based upon the information and expertise available:Apotex Inc. v. Wellcome Foundation Ltd., [2002] 4 S.C.R. 153, 2002 SCC 77.
In Wellcome, the Supreme Court of Canada noted that the doctrine of sound prediction balances the public interest in the early disclosure of new and useful inventions - even before theirutility has been fully verified by tests - with the public interest in avoiding the granting of monopolyrights in exchange for speculation, misinformation or lucky guesses: supra, para. 66 and 69.
The soundness or otherwise of the prediction is a question of fact.
In the Wellcome case, 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 purported inventor. Thethree elements of the test are: There must be a factual basis for the prediction; The inventor must have an articulable line of reasoning from which the desiredresult can be inferred from the factual basis; and There must be proper disclosure, although it is not necessary to provide a theoryas to why the invention works.
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 prove to be devoid of utility.
The Proper Date for Assessing the Soundness of Schering's Prediction There was much debate between the parties at the hearing as to the proper date to be used to assess the soundness of the prediction made by the '206 patent. Apotex says the soundness ofSchering's prediction should be determined as of the earliest of the priority dates claimed in theCanadian patent application - that is, October 23, 1980, whereas Aventis and Schering both submitthat the date that should be used is the Canadian filing date of October 20, 1981.
This issue is important, as the soundness of a prediction is to be assessed based upon the information and expertise available at the relevant time. The determination of whether the October23, 1980 priority date is to be used versus the October 20, 1981 Canadian filing date affectswhether, in assessing the soundness of the prediction, regard may be had to the work that Dr. Smithand her colleagues at Schering did between October of 1980 and October of 1981 in formulatingand testing compounds within the '206 patent.
The parties all rely on the Supreme Court's decision in the Wellcome case to support their respective positions regarding the relevant date.
A review of the Wellcome decision discloses that there was no debate between the parties as to the appropriate date for assessing the soundness of the prediction in issue, and, perhaps as a resultof this, the phrases "application date" and "priority date" are used virtually interchangeably in thedecision. By way of example, at paragraphs 3, 56, 71 and 72, Justice Binnie refers to the prioritydate as being the date to be used in evaluating the soundness of the inventor's prediction, whereas inparagraphs 46, 55 and 97 reference is made to the date of the Canadian application as being therelevant date.
However, it is in paragraph 70 of the decision that the Court sets out the tripartite test for sound prediction, explicitly stating that "[T]he inventor must have at the date of the patentapplication an articulable and 'sound' line of reasoning from which the desired result can be inferredfrom the factual basis".
Thus, while the issue is not free from doubt, it appears that the Wellcome test contemplates that the Canadian filing date be used for the purposes of assessing the soundness of the prediction.
This makes a certain amount of sense, from a policy perspective, as it is only when the application for patent protection is filed in Canada that the inventor is required to commit him- orherself to the precise details of the patent claims and specification for the purposes of obtaining amonopoly in Canada.
The date of filing for patent protection in another country may be of some assistance in ascertaining the date of the invention for patents governed by the old Patent Act (the new Patent Actcontemplates a 'first to file' priority system as opposed to the 'first to invent' regime under theformer legislation). Nevertheless, as happened here, inventors are free to continue to carry outadditional research and testing, and to add additional information to the patent claims andspecification, prior to filing for a patent in Canada.
As a consequence, I intend to assess the soundness of Schering's prediction based upon the information and expertise available as at October 20, 1981. However, for the reasons that follow, itis not necessary to finally resolve this issue in this case, as I am satisfied that even using the laterCanadian application date, as submitted by Aventis and Schering, Schering did not have a soundbasis for predicting that the compounds coming within the '206 patent would be useful as ACEinhibitors and anti-hypertensive agents.
In applying the three-part Wellcome test, the parties generally dealt with the first two issues together, and I intend to do so here.
Was There a Factual Basis for the Prediction? and Did the Inventors Havean Articulable Line of Reasoning from Which the Desired Result Could Be The first issue that has to be addressed is the sufficiency of Apotex's NOA as it relates to the first two parts of the Wellcome test.
We also allege that each of the Claims in Issue of the '206 Patent is invalid on thebasis that the claims are broader than the invention (if any) made. By the relevantdate, which we allege in every case to be the earliest priority filing date of the'206 Patent (October 23, 1980), the purported inventors of the '206 Patent did notmake, isolate, characterize or test all of the compounds covered by the Claims inIssue. [at page 5] Apotex then goes on to identify, at some length, the compounds that were not made, isolated, characterized or tested prior to the earliest of the priority dates.
Further on in the NOA, Apotex goes on to say, specifically in relation to the issue of sound Furthermore, the specification does not provide test data with respect to any ofthe compounds covered by the Claims in Issue, including Ramipril andRamiprilat, which would evidence that these compounds possessed the requisitelevel of activity and the requisite pharmacological and toxicological profilewhich would allow for their use as an ACE inhibitor which is suitable for oral orparenteral administration to provide compositions useful in the treatment ofcardiovascular disorders and particularly mammalian, including human,hypertension.
Therefore, the purported inventors of the '206 Patent did not have a sound basisfor predicting that all of the compounds covered by the scope of the Claims inIssue (including Ramipril and Ramiprilat) could be used as an ACE inhibitorwhich would be suitable for oral or parenteral administration to providecompositions useful in the treatment of cardiovascular disorders and particularlymammalian, including human, hypertension. Therefore, each of the Claims inIssue is broader than the purported invention (if any) made.
Aventis asserts that Apotex's NOA is deficient as it relates to the issue of sound prediction.
Aventis says that the sum total of Apotex's argument that Schering did not have a sound basis for itsprediction as contained in its NOA was its assertion that Schering failed to provide test data.
According to Aventis, subsequent to serving the NOA, Apotex amplified its argument to argue thatSchering should have demonstrated utility by testing in order to establish matters such as potency, toxicity, bioavailability, selectivity and so on.
In Novopharm Limited v. Pfizer Canada Inc. Pfizer Inc. and the Minister of Health, [2005] F.C.J. No. 1318, 2005 FCA 270, the Federal Court of Appeal recently restated the test to be appliedin assessing the adequacy of Notices of Allegation. While the decision in Novopharm relates toissues of infringement, the same principles can readily be applied to questions of patent invalidity.
[4] In its more recent jurisprudence, this Court has repeatedly stated that the testof the adequacy of a NOA is whether the detailed statement was sufficient tomake the patentee (Pfizer) fully aware of the grounds on which the generic(Novopharm) claimed that the relevant patent would not be infringed if a NOCwas issued by the Minister (see AB Hassle v. Canada (Minister of NationalHealth and Welfare) (2000), 7 C.P.R. (4th) 272 (F.C.A.) at paragraph 17, perStone J.A. (AB Hassle 1); SmithKline Beecham Inc. v. Apotex Inc. (2001), 10C.P.R. (4th) 338 (F.C.A.) at paragraph 26, per Noël J.A.; and also Pfizer CanadaInc. v. Apotex Inc. (2004), 38 C.P.R. (4th) 400 (F.C.A.) at paragraph 24, perEvans J.A.).
A review of Apotex's NOA reveals that Apotex put Aventis on notice that it would be arguing that Schering failed to conduct the tests necessary to establish that the compounds coveredby the '206 patent possessed the requisite level of activity and the requisite pharmacological andtoxicological profile. What do these terms mean? Clearly the 'level of activity' relates to the potencyof the compounds in question. The use of the phrase 'toxicological profile' clearly puts Aventis onnotice that the issue of toxicity was in issue. Finally, the 'requisite pharmacological profile' can bereasonably understood to relate to issues such as bioavailability and selectivity.
Moreover, a review of Aventis' Notice of Application reveals that it understood Apotex's position in relation to these issues, as it responds to it.
Finally, it should be noted that no affidavit was filed on behalf of Aventis asserting that it was not in a position to decide whether to challenge Apotex's NOA in relation to this issue becauseof the statement's lack of specificity: see Astrazeneca AB and Astrazeneca Canada Inc. v. ApotexInc. and the Minister of Health, [2005] F.C.J. No. 842, 2005 F.C.A. 183, para. 13.
In these circumstances, I am therefore satisfied that Aventis was sufficiently aware of the basis on which Apotex was claiming that the '206 patent was invalid as it related to the first twoelements of the test for sound prediction.
Turning now to the merits of the issue, the question is whether as of the date of the Canadian filing, Schering and its scientists had a factual basis for their prediction, and whether the inventorshad an articulable line of reasoning from which the desired result could have been inferred from the What precisely was Schering's prediction? Schering states that it predicted that by putting bicyclic rings on the proline end of an enalapril molecule, one would have compounds that wouldbe useful as ACE inhibitors and anti-hypertensive agents. In light of what was publicly knownabout ACE inhibitors at the time, and the work that was done at Schering by Dr. Smith and hercolleagues, Schering says its had a factual basis for its prediction, and an articulable line ofreasoning to support it. While the prediction continues to be verified, Schering asserts that it hasstill not been shown to be unsound.
Before turning to consider the parties' submissions in relation to the first two aspects of the Wellcome test for sound prediction, it is necessary to return to consider, in greater detail, the stateof the public knowledge regarding ACE inhibitors, as well as the nature and extent of the workbeing done by Dr. Smith and the other scientists at Schering at the relevant time.
As mentioned earlier in this decision, prior to June of 1980, it was known that captopril was an orally effective ACE inhibitor. As of June 18, 1980, it was also publically known that removingthe thiol group of the left side of the captopril molecule and replacing it with a carboxymethylfunction resulted in ACE inhibition. This was enalapril. It will be recalled that enalapiril had threechiral centres, each of which was specified to be in the "S" position.
On November 20, 1980, an article entitled "A new class of Angiotensin-converting enzyme inhibitors" was published in the journal "Nature". The authors of the article were a group ofscientists at Merck, Sharp and Dohme. This article discloses a compound known as "Merck No. 6",which was an effective ACE inhibitor. Merck No. 6 can be depicted as: [Editor's note: The illustration could not be reproduced online. Please contact Quicklaw Customer Service at 1-800-387-0899 or service@quicklaw.com to request the As can be seen from the above depiction, like enalapril, Merck No. 6 contains three chiral centres, but unlike enalapril, only two of the chiral centres are specified as being in the "S"configuration. The third chiral centre was left unspecified, allowing for variability in the chirality atthis point.
There is some debate between the parties as to whether the Merck No. 6 compound was actually disclosed several months earlier, at the Troy conference. Given that I am considering theissue of sound prediction as of the Canadian filing date, it is not necessary to resolve this questionas it is common ground that, in any event, Merck No. 6 was publically known by November of1980.
Schering's work in this area focussed on the proline end of the enalapril molecule.
Specifically, Dr. Smith and her colleagues altered the proline to add a second ring system. Whatwas known about the ability to make changes at that location prior to October of 1981? In Januaryof 1980, an article was published in the Journal of Biological Chemistry entitled "Binding of Peptide Substrates and Inhibitors of Angiotensin-converting Enzyme" (the "Cheung article"). TheCheung article indicated that there was substantial molecular tolerance at the proline binding site.
That is, the site was relatively promiscuous, and could accommodate a variety of variations on thecyclic proline1.
In other words, as of January, 1980, it was known that a variety of structures could be used, each of which would interact with Angiotensin I, so as to generate an inhibiting effect.
By this time it was also known that there was molecular space available at the proline end of the molecule so as to be able to accommodate bicyclic rings, with one ring being five-memberedand the other six-membered (a "6,5 ring"), and that such a compound would exhibit ACE inhibition.
The Cheung authors tested a number of ACE inhibitors, including a compound known astryptophan, which contained a 6,5 ring. Tryptophan demonstrated the best ACE inhibiting effect ofthe compounds tested.
With this understanding of the prior art, I turn now to the work being done at Schering by Dr.
Smith and her colleagues. As noted earlier, by late 1979 or early 1980, the Schering scientists hadfound that the replacement of the proline in captopril with certain fused ring or spirocyclic moietiesresulted in efficacious compounds.
A number of compounds had been made by Dr. Smith and her colleagues before the Troy conference in mid-June of 1980. By late 1979, Dr. Smith had created a compound known as SCH30178, which replaced the proline in a captopril molecule with a 6,5 ring.
In December of 1979, SCH 30178 demonstrated what Dr. Smith recorded as "very good activity" in in vitro testing, although no specific level of activity was recorded. It should also benoted that as SCH 30178 was based on the captopril model, this compound is not within the scopeof the '206 patent.
A second compound made by the Schering scientists was SCH 30928. This compound was created by replacing the five-member cyclic proline in captopril with a 6,5 bicyclic ring. SCH30928 was tested in vitro on May 8, 1980 and in vivo starting on June 12, 1980. This compound isalso not within the scope of the '206 patent.
Although SCH 30928 also demonstrated good activity, Dr. Richard Silverman, who was one of Schering's principle witnesses on the issue of sound prediction, conceded that Dr. Smith did notrecord any information as to the stereochemistry of this compound. As a consequence, it is notpossible to know which stereoisomer had good activity.
After the Merck disclosure at the Troy conference, the Schering scientists decided to try using various bicyclic ring structures in place of the proline on an enalapril-type molecule.
On August 5, 1980, Dr. Smith made the first compound within the scope of the '206 patent, which became known as SCH 31335. According to Schering, this was the date of its invention.
Schering submits that all of the work that was done between that date and the date of the Canadianfiling was merely verification.
SCH 31335 had a 6,5 ring structure at the proline end of an enalapril molecule, and can be [Editor's note: The illustration could not be reproduced online. Please contact Quicklaw Customer Service at 1-800-387-0899 or service@quicklaw.com to request the Given that the absolute configuration of this molecule was not depicted, it can reasonably beinferred that it was not known.
The next compound to be formulated by the Schering scientists was SCH 31336. This was a stereoisomer of SCH 31335, and once again, the absolute configuration of this compound was notknown.
While initial testing of these compounds indicated that they demonstrated ACE inhibiting activity, it should be noted that, as neither of these compounds had a 5,5 ring structure, neither camewithin Claim 12 of the '206 patent.
The next compound to be formulated by Schering was SCH 31924. It is not clear from Dr.
Smith's affidavit whether this compound falls within Claim 12 of the '206 patent. SCH 31924 wastested in an in vivo ACE assay in rats, and was found to be inactive up to 300 micrograms perkilogram, which was the upper limit that Schering had adopted as a practical limit for screeningACE inhibitors in 1980. In other words, the compound was inactive, as that term was being used bySchering.
The only compound clearly claimed by Dr. Smith to come within Claim 12 of the '206 patent that was actually created prior to the Canadian filing date was SCH 31925. SCH 31925. was astereoisomer of SCH 31924, and according to Dr. Smith's affidavit, was a 'very potent' compound.
Although there was some suggestion that this compound may have been a mixture which containedramipril, it cannot be said with certainty that this compound in fact comes within Claim 12, as at thetime that Dr. Smith was testing the compound, its chirality was not completely known. Specifically,Dr. Smith's lab notes indicate the chiral centre within the bicyclic ring with a question mark. Tocome within Claim 12, this chiral centre had to be in the "S" configuration.
It bears noting that although both SCH 31924 and SCH 31925 were prepared prior to the Canadian filing date for the '206 patent, the stereochemistry at the C-2 carbon of theoctahydrocyclopental[b] pyrrole ring was not specified in the '206 patent, since this was left blankin the characterization of the compounds at pages 95 and 96 of the '206 patent.
Aventis and Schering submit that based upon the above-described work, at the date of the Canadian filing in October of 1981, the Schering scientists were able to soundly predict thatcompounds coming within Claim 12 would have utility as ACE inhibitors and anti-hypertensiveagents.
In support of this contention, Aventis and Schering rely on the evidence of Dr. David Triggle and Dr. Richard Silverman. Dr. Triggle is a Distinguished Professor at the School of Pharmacy andPharmaceutical Sciences at the State University of New York, holds a PhD in Chemistry, and is an expert in the fields of medicinal chemistry and pharmacology. Dr. Silverman is a Professor ofChemistry and Biochemistry, Molecular Biology and Cell Biology at Northwestern University. Heholds a PhD in chemistry from Harvard and has carried out post-doctoral research on enzymeinactivation. Dr. Silverman is an expert in the field of medicinal chemistry.
Both Dr. Triggle and Dr. Silverman have impressive publication records.
In contrast, Apotex says that what Schering did was to say that since some compounds with a 6,5 head group on captopril- and enalapril-type tails with unknown stereochemistry demonstrateactivity, it was sound to predict that every stereochemical configuration of a 5,5 enalapril tail wouldbe useful as an ACE inhibitor and as an anti-hypertensive. According to Apotex, there is a'disconnect' between what was done and what was claimed, and there was simply neither asufficient factual basis nor an articulable line of reasoning to support such a prediction as ofOctober, 1981.
Apotex's argument is supported by the evidence of Dr. Garland Marshall, who, as noted earlier in this decision is a Professor of Biochemistry and Molecular Biophysics and of BiomedicalComputing at the Washington University School of Medicine at Washington University. Dr.
Marshall has a PhD from Rockefeller University, where his thesis dealt with the synthesis ofAngiotensin II. Dr. Marshall is an expert in the field of ACE inhibitors.
According to Dr. Marshall, while the work done by the Schering scientists, coupled with what was publically known may have been sufficient to lead them to conduct further research, theydid not have, and could not have had, a sound basis, as of October, 1981, for predicting that thecompounds in Claim 12 would have activity as ACE inhibitors and anti-hypertensive agents.
Dr. Marshall states that the knowledge gained from the work done by Schering by adding 6,5 bicyclic rings to an enalapril molecule is not transferrable to a 5,5 bicyclic ring. (It should also berecalled that one of the 6,5 molecules tested by Schering did not work at all.) The only compoundscontaining 5,5 bicyclic ring molecules that were created by Schering prior to the Canadian filingdate, which allegedly come within Claim 12, were SCH 31924 and SCH 31925. SCH 31924 did notexhibit any activity as an ACE inhibitor, and its complete chirality was unknown.
Dr. Marshall states, and indeed, both Drs. Triggle and Silverman agree, that even small changes in a molecule can have unpredictable pharmacological effects. In cross-examination, Dr.
Triggle acknowledged that if one were to introduce a new chiral centre into a compound, it was notpossible to predict the effect that this would have, stating: . Am I correct that one of the implications of the fact that stereoisomers havedifferent chemical and physical properties is that they also have differentactivities in terms of if we are talking about ACE inhibitors? Yes. Stereoselectivity of action, yes.
I just want to ask you, would you agree with this statement, "It is not possible topredict qualitatively or quantitatively biological activity as between different From a de novo consideration, that is true.
As in the absence of any preceding information.
That is if you introduce a new chiral centre into a molecule where it has not beenbefore, it becomes very difficult to predict what that activity will be, whetherthere will be stereoactivity and, if there is, which direction and of whatmagnitude. [Aventis' Record, at pp. 14648-9] Dr. Marshall confirms that a slight change in chirality can render an active compound inactive with respect to ACE inhibition. The importance of chirality in relation to ramipril-likecompounds is illustrated by the differences in the test results between SCH 31924 and SCH 31925.
In this regard, it will be recalled that Dr. Smith's testing found SCH 31925 to be a 'very potent'compound, whereas SCH 31924 was inactive up to 300 micrograms per kilogram.
Specifically in reference to Claim 12 of the '206 patent, Dr. Marshall stated that as of October, 1981, only compounds with the "SSS" configuration on the enalapril backbone could havebeen expected by a person skilled in the art to be possibly effective as an ACE inhibitor oranti-hypertensive agent. Dr. Marshall's evidence was clear: one could not predict the impact ofchirality in the bridgehead carbons of the bicyclic ring system.
In this light, and given the limited knowledge available to Dr. Smith and her colleagues at Schering at the relevant time, Dr. Marshall concluded that as of October of 1981, Schering did nothave a factual basis for its prediction, nor did it have an articulable line of reasoning from which thedesired result could have been inferred from the factual basis.
I have examined the evidence of each of the experts dealing with the issue of the soundness of Schering's prediction as of October of 1981. After careful consideration, I have concluded thatthe evidence of Dr. Marshall is to be preferred over that of Drs. Triggle and Silverman. I haveseveral reasons for coming to this conclusion.
Firstly, and perhaps most importantly, a review of the curriculum vitae of each of the experts discloses that while all three are undoubtedly scholars of great repute, it is Dr. Marshall who hasdevoted his entire academic career specifically to the study of ACE inhibitors. In the nearly 40 yearsthat he has worked in the field, Dr. Marshall has published dozens of papers dealing withAngiotensin II and ACE inhibition. Dr. Marshall has won many awards from around the world forhis work in the field of ACE inhibition. Indeed, Apotex's description of Dr. Marshall as a "worldclass expert" in the field does not appear to be an overstatement.
In contrast, Dr. Triggle notes that his research interests include the chemical pharmacology of molecules that interact with autonomic receptors, and particularly drugs that interact with ionchannels. He indicates that he has worked for many years in the area of calcium channel blockers, which are used in the treatment of hypertension. While Dr. Triggle has done some work in relationto ACE inhibitors, they are clearly not the primary focus of his academic career, nor does hisresumé indicate any active involvement with ACE inhibitors during the period in question.
Dr. Silverman's area of expertise is also more general than that of Dr. Marshall. In Dr.
Silverman's curriculum vitae, he describes his research interests as including "Medicinal andbio-organic chemistry; mechanism of drug action; design of medicinal agents; specific enzymeinactivation; enzyme mechanisms; enzyme models".
A second reason for preferring the evidence of Dr. Marshall to that of either Dr. Triggle or Dr. Silverman is that his affidavit offers a far more detailed and complete analysis of the issue thanis offered in the affidavit of either of the other two experts.
There is a third reason for preferring the evidence of Dr. Marshall over that contained in the affidavit filed by Dr. Triggle in this proceeding. Dr. Triggle's affidavit in this case is very similar toone that he swore on behalf of Aventis in connection with a different proceeding involving the '206patent (Aventis Pharma Inc. v. Pharmascience Inc., [2005] F.C.J. No. 511, 2005 FC 340). There is,however, one material difference between the two. That is, there were three paragraphs in Dr.
Triggle's affidavit in the Pharmascience matter that did not find their way into his affidavit in thiscase. These paragraphs are significant as they go some considerable way towards corroborating Dr.
Marshall's opinion that it is not possible to predict qualitatively or quantitatively biological activityas between different isomers, in part because the actual three dimensional structure of the receptoror enzyme is frequently not known. As was mentioned earlier in this decision, in the case of ACE,the three dimensional structure of the enzyme was not known until 2003.
Apotex points to the decision in Biovail Pharmaceuticals Inc. et al. v. Canada (Minister of National Health and Welfare) (2005), 37 C.P.R. (4th) 487, 2005 FC 9, as authority for theproposition that expert evidence should be "the independent product of the expert, uninfluenced asto form or content by the exigencies of litigation" (para. 16). The removal of the three paragraphs inquestion from the affidavit filed by Dr. Triggle in this proceeding, Apotex says, shows that Dr.
Triggle's opinion had clearly been influenced by the exigencies of this litigation.
Although Apotex cross-examined Dr. Triggle at some considerable length, this proposition was never put to him, and I do not intend to speculate as to the reasons why the three paragraphs inquestion were removed from the affidavit before it was filed with the Court in this proceeding. Thefact is that when the paragraphs in his Pharmascience affidavit were put to Dr. Triggle incross-examination, he agreed with them.
I have also considered Aventis and Schering's submission that Dr. Marshall set the bar too high in relation to the test for sound prediction - that he was looking for a certainty. In this regard, Inote that Dr. Marshall's affidavit recites the tripartite Wellcome test for sound prediction. Thus it isclear that he was aware that certainty was not required in order to make a sound prediction.
Moreover, I am satisfied from reviewing Dr. Marshall's evidence, in its entirety, that he properly understood the test in issue in this regard.
Finally, I have carefully considered Aventis and Schering's argument that in stressing the need to test for things such as toxicity, bioavailability and potency, Dr. Marshall was really lookingto see whether it could be soundly predicted that the compounds coming within Claim 12 of the'206 patent had commercial utility, as opposed to utility in the sense that it is used in the patentcontext.
I agree that it does appear that in some places in his evidence, Dr. Marshall was examining the issue of utility from the perspective of whether the compounds created by the Schering scientistshad potential use as ACE inhibitors and anti-hypertensive agents in the commercial sense of theword. As the Supreme Court of Canada noted in Wellcome, it is not necessary to have carried outclinical trials in humans to establish toxicity, metabolic features, bioavailabiltity and other suchfactors in order to be able to make a sound prediction. The issue is not safety and effectiveness, butrather utility in the context of inventiveness: Wellcome, supra, para. 77.
More will be said about this argument in the context of my analysis in relation to the issue of utility. Suffice it to say at this juncture that while I do have some concerns with respect to Dr.
Marshall's evidence regarding the need to test for things such as toxicity in order to be able to makea sound prediction, I do not view that as otherwise undermining the weight to be attributed to hisevidence. The nature of the utility required in the patent context is a legal question, which is anissue outside of Dr. Marshall's area of expertise. In this regard, Dr. Marshall was obviously relianton the nature of the instructions that he received from counsel.
The fact that Dr. Marshall may have looked to commercial utility at some points in his evidence in no way takes away from the validity of Dr. Marshall's conclusion that there was simplynot enough known about the chirality or stereochemistry of the compounds tested by Schering in theperiod leading up to the Canadian filing in October of 1981 so as to be able to predict whether thecompounds coming within Claim 12 of the '206 patent would exhibit any activity. This conclusionis one entirely within Dr. Marshall's field of expertise, and for the reasons articulated above, I preferDr. Marshall's evidence in this regard to that of Drs. Triggle and Silverman.
Conclusion on the First Two Elements of the Wellcome Test The law is clear that a patentee is not to be limited to specific compounds that he or she has actually made and tested prior to filing for patent protection. A patentee is able to claim morebroadly, so as to cover a class of compounds, as long as the claim is based upon a sound prediction.
There is no question that the '206 patent turned out to be a very useful invention. However, this sort of "after the fact validation" was specifically rejected by the Supreme Court of Canada inWellcome. Thus, the fact that three compounds within the '206 patent later turned out to havecommercial value is of no assistance in determining the soundness of the prediction at the time inquestion: see Wellcome, supra, para. 78-85.
To be sound, there must have been 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 beeninferred from the factual basis. I appreciate that the jurisprudence teaches that I should approachthese issues with an anxiety to support a really useful invention: Wellcome, supra, para. 92.
However, for the reasons given, I am satisfied, on a balance of probabilities, that as of October,1981, the prediction made by Schering that the eight compounds within Claim 12 would be usefulas ACE inhibitors and as anti-hypertensive agents was not sound, and that, as a result, Apotex'sallegations in this regard were justified.
The third element of the tripartite test articulated by the Supreme Court of Canada in the Wellcome decision is the requirement that the inventor make proper disclosure.
Disclosure has been described as part of the quid pro quo that the applicant offers in exchange for the patent monopoly: see Wellcome, supra, para. 70.
Normally, it is sufficient if the specification provides a full, clear and exact description of the nature of the invention and the manner in which it can be practised: Wellcome, supra, para. 70.
xiting Fox in The Canadian Law and Practice Relating to Letters Patent for Inventions, at p.167.
The Supreme Court went on in Wellcome to observe that what readers want to know is that theinvention does in fact work, and how to work it. Because the precise requirements for disclosure didnot arise on the facts of the case in Wellcome, the Supreme Court declined to say more about them.
Before turning to consider the sufficiency of the disclosure in this case, it is once again necessary to address the appropriate date for the determination of this question.
I will return to this question in relation to my analysis of the sufficiency issue under subsection 34(1) of the old Patent Act. However, for the purposes of addressing the third element ofthe Wellcome test for sound prediction it is clear that the date to be used is either the priority date orthe Canadian filing date. There is nothing in the Wellcome decision that would suggest that the dateof issue should be used.
As noted earlier, Wellcome is less clear as to whether it is the priority date or the Canadian filing date that is to be used in relation to the test for sound prediction. However, as for the reasonscited above, I have concluded that it is the date of the Canadian filing that should be used. It doesnot make any sense that the first two elements of the test for sound prediction be determined as ofone date, and the third element as of another date - that is, the date of issue - nor is there anysuggestion in Wellcome that this should be the case. Accordingly, I intend to assess the sufficiencyof the disclosure in the '206 patent as of October 20, 1981.
At the end of the day, however, the choice of date would not have affected the result of my analysis, as I would have come to the same conclusion whether I used the October 23, 1980 priority Apotex asserts that the disclosure was deficient in several respects. Each of these will be In its NOA, Apotex asserts that the first step in Example 20A is not operable to produce the compounds of Claim 12. Apotex asserts that the title compound of Example 20A: .could not be synthesized by virtue of the inoperability of the method ofExample 18A . since the mercuric acetate oxidation ofoctahydracyclopenta[b]pyrrole, as described in Example 18A, is inoperative toproduce the corresponding imine needed for synthesis of a series of subsequentintermediates required for the production of the title compound of Example 20.
Additionally the specification does not teach one skilled in the art how to preparethose compounds covered by the Claims in Issue, including claims 12 and 13,wherein the chiral centers [are in the trans configuration].
Example 20A may be understood by reference to the following diagram: [Editor's note: The illustration could not be reproduced online. Please contact Quicklaw Customer Service at 1-800-387-0899 or service@quicklaw.com to request the Aventis asserts that while Apotex asserts that a specific oxidation process (mercuric acetate) is not operable, Apotex failed to assert that a skilled person could not practice the invention by theexercise of routine workshop experimentation. Moreover, Aventis says that Example 20 is operableand that, in any event, there are a variety of methods available to synthesize compounds of Example20A.
Schering notes that Apotex does not allege that any of the other steps of Example 20A do not work, only that one particular reaction in one example in a very long patent does not work.
According to Schering, this allegation is not justified as the NOA itself is deficient, in that it doesnot allege that a skilled person could not make the product of Example 20A having regard to thewhole of the specification, and based on common general knowledge at the relevant time.
Moreover, Schering says that Example 20A does work.
In addressing this issue, I am mindful that disclosure is directed to a person skilled in the art, with a mind willing to understand, not desirous of misunderstanding. The person skilled in the art ispermitted to employ his background knowledge and other public information. Such constructionshould be done purposively, not literally. Moreover, a patent ought not be struck out on technicalgrounds: Burton Parsons Chemicals Inc. v. Hewlett-Packard (Canada) Ltd. [1976] 1 S.C.R. 555, 17C.P.R. (2d) 97 at 104 (S.C.C.); Airseal Controls Inc. v. M & I Heat Transfer Products, [1993] F.C.J.
No. 1417, para. 40, 53 C.P.R. (3d) 259 at 274 (F.C.T.D.); Sandoz Patents Ltd. v. Gilcross Ltd.
[1974] S.C.R. 1336, 8 C.P.R. (2d) 210 at 217-218(S.C.C.); and Johnson Controls Inc. v. VartaBatteries Ltd., [1984] F.C.J. No. 239, 80 C.P.R. (2d) 1 at 41(F.C.A.).
In order that the invention be complete as of the date of the patent application, it is necessary that no additional inventive ingenuity be required in order to make the patent work. It is, however,sufficient if all that remains to be done involves "ordinary workshop effort": Merck & Co. Inc. v.
Apotex Inc., [1995] 2 F.C. 723 para. 68, 60 C.P.R. (3d) 356, at p. 385.
Thus, there are three questions to be addressed. The first is the sufficiency of Apotex's NOA as it relates to the issue of the sufficiency of the disclosure in the '206 patent. Secondly, it must bedetermined whether Example 20A does in fact work. Finally, if I conclude that Example 20A doesnot work as it is presently drafted, the question then arises as to whether the title compound ofExample 20A could be made to work through routine, non-inventive experimental laboratory work.
Aventis and Schering assert that Apotex's NOA is insufficient as it does not assert that a skilled person could not make the product of Example 20A having regard to the whole of thespecification and common general knowledge.
As was noted earlier in this decision, the question is whether the detailed statement was sufficient to make Aventis fully aware of the grounds on which Apotex was claiming that therelevant patent would not be infringed if a NOC was issued by the Minister: Novopharm Limited,previously cited.
Apotex's NOA specifically contemplates that the invention will be practised by a skilled person. Implicit in this is that the skilled person will be one who possesses the relevant commongeneral knowledge. Moreover, it is clear from the voluminous evidence adduced by Aventis andSchering in relation to the sufficiency argument in relation to Example 20A that both Aventis andSchering fully appreciated the nature of the attack that was being mounted by Apotex.
As a consequence, I am satisfied that Apotex's NOA was sufficient in relation to this issue.
In support of its contention that the first stage in the sequence of reactions set out in Example 20A is inoperable, Apotex relies on the evidence of Dr. Edward Lee-Ruff, who deposes that he triedand failed to practice Example 20A to synthesize the title compound of Example 20A.
Apotex also cites the evidence of Dr. Robert McClelland in support of its assertion that the first reaction in Example 20A was inoperable. Dr. McClelland failed in an attempt to use Example20 to synthesize trans stereoisomers.
Finally, Apotex relies on experimental work conducted by Dr. Edward Taylor, Sir Harold Barton and Dr. Volker Teetz, described in declarations filed by Aventis' predecessor, Hoechst, inpatent proceedings in Europe and the United States. Taylor and Barton each report having failed inattempts to practice Example 20A, while Teetz allegedly obtained a small yield of the desiredintermediate.
Aventis and Schering say that given that Apotex chose not to file affidavits from any of the declarants, thereby depriving Aventis and Schering of the right of cross-examination, the Taylor,Barton and Teetz declarations are all inadmissible hearsay, and should thus be disregarded.
Aventis relies on the evidence of Dr. James Wuest in support of its assertion that Example 20A does indeed teach an operable method to be used in the formulation of the compounds withinClaim 12 of the '206 patent. Dr. Wuest deposes that a skilled organic chemist would be able toprepare the 5,5 trans compound through routine laboratory work, including limited reading of theavailable chemical literature.
In this regard, Dr. Wuest points to a 1959 article disclosing the synthesis of an analogous 5,5 trans ring, which he describes as "a potential precursor" for synthesizing substituted derivatives.
According to Dr. Wuest, based upon this, the skilled person could have prepared the 5,5 trans rings,and could then have used the procedures taught by Example 20A to synthesize the final compoundwith trans stereochemistry.
Aventis also relies on the evidence of Dr. William Pirkle. Dr. Pirkle is a Professor Emeritus at the University of Illinois, where he taught and carried out research in relation to analyticalchemistry, in particular, the separation of chiral compounds.
In cross-examination, Dr. Pirkle asserted that the reactions in question were "standard reactions", which have been known for many years. In Dr. Pirkle's view, the tools were at hand soas to allow a competent chemist to have prepared the material in issue.
Schering relies on the evidence of Dr. Braden Roach, who states that he and his associate, Professor Meinwald, successfully practiced Example 20A in the late 1980's. Professor Meinwaldwas accepted by Apotex's expert, Dr. McClelland, as an internationally recognized organic chemist.
Dr. Roach deposes that in one repetition, his yield was approximately 32-35% of the desired [delta]1 intermediate in the cis configuration.
According to Dr. Roach, Drs. Taylor and Barton's failure to practice Example 20A resulted from their use of inappropriate procedures. Dr. Taylor was unable to detect the desired compoundbecause of an inappropriate work-up procedure and inappropriate analytical procedures for thedetection of small quantities of imine. Dr. Roach says that Sir Harold Barton was unable to detectthe presence of the desired imine due to loss during distillation and binding to mercury precipitategenerated during the reaction which was discarded. Such binding can be avoided by addition ofsulfide before removal of the precipitate, an operation reported in the prior art. Hence, Dr. Roach says, Sir Harold essentially discarded the product.
As a consequence, Dr. Roach concluded that the discrepancy between his yield and that of Drs. Barton and Taylor was in the procedures that they used to isolate the imine, not in theoxidation step itself.
Dr. Roach also identified a number of what he says were flaws in the work done by Drs.
Lee-Ruff and McClelland. Specifically, Dr. Roach says that after a couple of failed attempts atcarrying out the oxidation process, he realized that the compound was very volatile, and that it wasnecessary to add a sulfide to the mix to effect the desired reaction. According to Dr. Roach, thissolution would have been evident from a search of the relevant literature.
Dr. Roach also faulted Drs. McClelland and Lee-Ruff for failing to carry out a mass balance.
Further, he says, Dr. Lee-Ruff failed to shield the mercuric acetate from light, failed to check theprecipitate for the desired intermediate, and failed to take the necessary steps to avoid atrimerization reaction.
Schering also points to the evidence of Edward Mazer, a patent attorney employed by Schering. Mr. Mazer reviewed the history of the '206 patent, pointing out that Hoechst's earlierallegations of inoperability were either rejected or had been abandoned.
Before turning to analyze the evidence of the various experts in relation to the issue of the operability of Example 20A, a threshold issue arises with respect to the admissibility of the Barton,Teetz and Taylor declarations.
Should the Barton, Teetz and Taylor Declarations be Admitted as Evidence? While conceding that there is no evidence that any of the three declarants were not available to prepare affidavits in this proceeding, Apotex argues that their evidence from the Americanproceedings should nonetheless be admitted in this case. According to Apotex, any concern as to thereliability of the evidence evaporates, given that it was Hoechst, now Aventis itself, who tenderedthe affidavits in the foreign proceedings.
Further, Apotex submits that as the declarations were referred to in the affidavit of Dr.
Roach, this has "legitimized the evidence".
I do not accept Apotex's submissions in this regard.
The rule against hearsay may be stated as: Written or oral statements, or communicative conduct made by persons otherwisethan in testimony at the proceeding in which it is offered, are inadmissible, ifsuch statements or conduct are tendered either as proof of their truth or as proofof assertions implicit therein.
(See: J. Sopinka, S. N. Lederman and A. W. Bryant, The Law of Evidence in Canada (2nd ed.
1999), at p. 173.) The evidence in question is clearly hearsay, and should not be admitted, unless it falls within one of the exceptions to the hearsay rule: see Merck & Co. v. Apotex Inc. [1998] 3 F.C. 400, para.
7, 79 C.P.R. (3d) 501.
There is clearly no issue of necessity in this case, counsel for Apotex having candidly acknowledged that there is no evidence before the Court to suggest that any of the three declarantswas not available to provide affidavits in this proceeding.
Moreover, there is no indication that any of Drs. Barton, Teetz or Taylor were ever subject to cross-examination in the United States or Europe in relation to the declarations that they provided.
Thus there has been no opportunity to test the reliability of their evidence. Indeed, as I understandit, Schering was not a party to the U.S. proceeding, whereas Apotex was not involved in either theAmerican or European cases.
The fact that the declarations were put forward by Hoechst/Aventis does not, in my view, by itself, provide a sufficient justification for their admission in this proceeding. As was noted bySopinka, Lederman and Bryant, this type of reasoning should be rejected as it relies on the premisethat, in tendering a witness, a party vouchsafes his or her credibility: The Law of Evidence inCanada, supra, para. 6.291.
In a related vein, I have also considered whether the evidence should be admitted as an admission against interest. The theory underlying this exception to the hearsay rule is that humannature being what it is, one would not normally expect a party to lie when it was against theirinterests to do so. As a result, an admission against one's interest may be deemed to be sufficientlyreliable as to justify excepting it from the usual rule against the admission of hearsay.
In my view, there are three reasons why this exception to the hearsay rule does not assist Apotex in this case. Firstly, it should be noted that, the statements in issue were not made byHoechst/Aventis itself, but by individuals, two of whom (Barton and Taylor) were completelyindependent of the company.
Secondly, while the evidence was indeed proffered by Hoechst/Aventis, at the time that the evidence was tendered, the statements were not against the company's interest, but rather weresupportive of Hoechst/Aventis' efforts to oppose the grant of a patent to Schering in relation to theinvention allegedly covered by the '206 patent in the case of Europe, or to obtain a patent for itselfin the American case.
Finally, the fact that Dr. Roach makes reference to the three declarations in his affidavit goes no distance, in my view, towards establishing the truth of the declarations, nor does it address thefairness issues referred to in the preceding paragraphs.
For these reasons, the Barton, Teetz and Taylor declarations are excluded.
Analysis With Respect to the Operability of Example 20A It is clear that a specification is sufficient if a skilled worker can practice the invention, even if routine trials and experiments not amounting to invention might be necessary to arrive at thedesired result: Mobil Oil Corp. v. Hercules Canada Inc. [1995] F.C.J. No. 1243 para. 29, 63 C.P.R.
(3d) 473 at 484-486 (F.C.A.): Merck & Co. v. Apotex Inc. (1995), supra, para. 67.
In this case, Schering concedes that it took some trial and error to make Example 20A work, but both Aventis and Schering submit that this effort was no more than the sort of routine trials andexperiments permissible under the jurisprudence.
I have carefully considered the evidence of the various experts on this point. While it is clear that each of the chemistry process experts (thus excluding Mr. Mazer) were highly qualified expertsin their fields, I have concluded that the evidence of Aventis and Schering's experts is to bepreferred over that of Dr. McClelland and Dr. Lee-Ruff. As a result, I am satisfied, on a balance ofprobabilities, that the process described in the mercuric acetate oxidation step in Example 20A wasoperable as of October, 1981.
The principle reason for coming to this conclusion is that, at the end of the day, neither Dr.
Lee-Ruff, nor Dr. McClelland could state with any degree of assurance that they had not in factactually created the desired compound using the process described in Example 20A.
In cross-examination, neither Dr. Lee-Ruff nor Dr. McClelland could account for all of their material despite the fact that the concept of a mass balance (accounting for all of the material in asystem) was a well known concept for a chemist. Dr. McClelland could not account for all of hisstarting material. Most significantly, Dr. McClelland also could not exclude the possibility that hehad actually made the [delta]1 imine in a small amount using the process described in Example20A. In this regard, he stated the following in cross-examination: Am I correct that you can't exclude that the peak at 109 in the mass spec that weare looking at is the desired imine? It could be the other imine. If it is an imine, we don't [know] whether it is thedelta-1 imine or the delta-1 6A. I would have said, if it was going to be any imineat [all], it would be the delta-1 6A imine, because that is much more stable thanthe delta-1 imine.
My question was, you can't exclude that it could be the delta-1 imine? If it is a delta-1 imine, it is present in less than one per cent yield, and I don't seeit in the NMR. I would see a signal that would correspond to that.
You can't exclude that it is the delta-1 imine; you have an expectation, but youcan't tell me conclusively that it is not the delta-1imine.
If it is the delta-1 imine, then I am unable to extract that, and prove it, and I tried, from this experiment. I am expecting to get the delta-1 6 imine from thisreaction, as I said in my report. But I saw, when I did the first experiment, when Ihad to isolate the delta-1 6 imine and the story would be over.
It went the wrong way. The reaction didn't work at all; it producedanything other than starting material, and possibly some decompositionproducts.
If that is an imine, and I have no evidence other than the suggestion thatthere is a 109-peak, then I can't exclude that it is a delta-1 imine. But myexpectation is that it is a delta-1 6 imine. But there isn't enough of itpresent for me to analyse it. [Aventis Record, at pp. 13300-1] Insofar as Dr. Lee-Ruff is concerned, he admitted in cross-examination that he failed to check the precipitate for the desired intermediate, despite the fact that a reaction had occurred. Dr.
Lee-Ruff stated: Where is the precipitate now that you refer to in your affidavit that was removedfrom the reaction scheme as described by you? It is probably sitting in my laboratory somewhere.
Was that precipitate examined in any way to determine its identity? Dr. Lee-Ruff later admitted that the target molecule may have adhered to this precipitate.
Morover, he also agreed that he may have been successful in making a small amount of the desiredimine using the process taught in Example 20A: Looking at the third try which is labelled "Page 21", there is still a very smallpeak at about 7.2, 7.4, 7.6 and 7.8. There are actually four small peaks there. Doyou see that? Since this was not run in chloroform or CECL3, that can't be a chloroform peak,is it? It could be a small amount of the desired imine? In other words, while neither Dr. Lee-Ruff nor Dr. McClelland were able to isolate or identify the desired compound in question after using the mercuric acetate oxidation processdescribed in Example 20A, neither could either of them rule out the possibility that the process hadsucceeded in creating the desired compound.
Once again, the burden is on Apotex to establish, on a balance of probabilities, that the disclosure in Example 20A was insufficient. In the circumstances, they have failed to discharge thatburden.
Moreover, in the event that I am mistaken in my conclusion in this regard, I am satisfied that, as of October, 1981, there were other, non-inventive methods available to a skilled person toachieve the desired result. This issue will be addressed next.
Were There Other, Non-Inventive Ways to Do It? Aventis and Schering say that even if the first step in Example 20A does not work, there were other oxidation systems, apart from that described in Example 20A, that were known at therelevant time, which could have been used to create the desired compound.
By way of example, Dr. Wuest points to literature from 1959 teaching how to make a 5,5 trans ring by using an intra molecular nucleophilic substitution reaction involving an amino groupand a bromoethyl group located in a 1,2 trans orientation as substituents on a five-membered ring.
Both Dr. Lee-Ruff and Dr. McClelland only address the methodology set out in Example However, in cross-examination, a specific series of reactions were put to Dr. McClelland as a possible alternate route for the preparation of the desired intermediate.2 Dr. McClellandacknowledged that the starting materials in this sequence were known in 1980. He was thencarefully walked through each stage of what is a multi-step process. In most instances, Dr.
McClelland expressly acknowledged that the reaction in issue in each step was something that askilled person would have known how to carry out in 1980.
In one instance, Dr. McClelland could not confirm that a particular reaction in question would work; nor, however, did he deny that it would work. Similarly, in relation to a different stepin the process, Dr. McClelland did not specifically address whether the step in question was knownto a skilled person at the material time.
At end of the day, the burden is on Apotex to show that the compounds necessary to make the compounds described in Claim 12 of the '206 patent could not have been created by a skilled person at the relevant time, without inventive activity. In the circumstances, Apotex has failed topersuade me, on a balance of probabilities, that, as of October, 1981, a skilled person could not havecreated the desired imine based upon what was generally known in the field.
Sufficiency in Relation to the Issues of Separation and Characterization Apotex also asserts that the disclosure in the '206 patent is insufficient in that it fails to teach how to either separate or characterize stereoisomers, including the stereoisomers of ramipril.
Additionally, the '206 Patent specification does not teach one skilled in the arthow to isolate or characterize the various 32 stereoisomers of the compoundslisted below, wherein R2 can be hydrogen or ethyl. Included among thestereoisomers which the specification does not teach how to isolate orcharacterize are the compounds which have an (S), (S), (S), (S), (S) configurationat the chiral centres identified by an *. These are compounds Ramipril andRamprilat. [structure omitted] In carrying out the synthetic process used to make the ramipril molecule, it is likely that, at different stages, various diastereomic mixtures will be created. As a consequence, in designing asynthetic process, it will be necessary to carry out separations along the way, so as not to potentiallyend up with a mixture of 32 different stereoisomers.3 It is also necessary to determine the structure and stereochemistry of the compound created, in order to be able to determine whether the sought-after result has been achieved.
Apotex submits that the disclosure in the '206 patent is deficient, in that it does not teach how to separate the various 5,5 bicyclic stereoisomers from one another, nor does it teach how thecompounds should be characterized.
Aventis relies on the evidence of Dr. Pirkle and Dr. Wuest in support of its contention that, as of 1980, a skilled person would have been able to isolate and characterize the stereoisomers inissue.
The '206 patent notes that the diasteromers in the examples may be separated by column chromatography or by fractional crystallization techniques. In the examples that follow, the '206patent sets out details of the separations to be carried out in the course of the synthesis.
In his evidence, Dr. Pirkle discusses both chromatographic and fractional crystallization techniques, opining that both would have been readily available to a skilled person seeking toseparate disasteromic mixtures in 1980. Dr. Pirkle also asserts that two other separation methods,namely simple distillation and ligand-exchange chromatography were available in 1980.
As was noted earlier, diasteromers have different physical properties, which can be used to assist in the separation process. This is not so in the case of enantiomeric mixtures, as enantiomershave identical physical properties. Dr. Pirkle described techniques whereby racemic mixtures ofenantiomers could be separated by reacting the racemic mixture with a reagent, so as to give amixture of diasteromers. This mixture can then be separated by chromatography or crystallization,and, if necessary, can then be converted back to the original enantiomers. According to Dr. Pirkle,this technique was known in the 1970's.
Finally, Dr. Pirkle describes a variety of techniques that were commonly known and available at the relevant time to 'characterize', or determine the structure and stereochemistry of thecompounds created. These include x-ray crystallography, chiroptic measurements, chemicaldegradation, nuclear magnetic resonance spectroscopy and reactions conducted using a singleenantiomer of either a catalyst or reactant.
According to Dr. Pirkle, the '206 patent contains sufficient information so as to allow a skilled person to isolate and characterize any of the 32 stereoisomers of ramipril. Further, he is ofthe view that even if the patent was silent on the issue of separation, a skilled person could haveconducted the separation and characterization necessary to make the individual stereoisomers.
Dr. Wuest also addressed the issues of separation and characterization in his evidence.
According to Dr. Wuest, it would not be necessary to have to try to segregate out a single isomerfrom a mixture of 32 different isomers, as a skilled person would be expected to minimize oreliminate the formation of undesired stereoisomers by choosing the route of synthesis, as well as bychoosing the stereochemistry of the reactants used to build the target molecule.
Like Dr. Pirkle, Dr. Wuest also points to the fact that the '206 patent discloses well-known separation techniques. Finally, Dr. Wuest asserts that, as of 1980, a skilled person could havereadily separated and characterized the stereoisomers.
Apotex relies on the evidence of Dr. Lee-Ruff and Dr. McClelland with respect to the issues In his evidence, Dr. Lee-Ruff reviews, in considerable detail, his various attempts to separate mixtures of various stereoisomers of ramipril in order to determine whether a skilled person,without using inventive ingenuity could have isolated ramipril. Based upon his lack of success inthis regard, Dr. Lee-Ruff concluded that, without the benefit of hindsight, the skilled personfollowing the teachings of the '206 patent could not have isolated ramipril without using inventiveingenuity.
Dr. McClelland also addressed the separation issue in his evidence. He agrees with Dr.
Wuest that the general methods for separating and characterizing stereoisomers identified by Dr.
Wuest were available as of 1980. However, Dr. McClelland disagrees with Drs. Wuest and Pirkle inrelation to whether, given the information available with respect to the compounds in Claim 12 of the '206 patent, these methods could be used successfully.
Dr. McClelland notes that separation methods often involve a great deal of trial and error. In this context, he observes that the '206 patent does not provide any teachings as to the preparation ofeither ramipril or ramiprilat, or the separation of any of the eight diastereomers referred to in Claim12 out of a mixture containing other stereoisomers. As a consequence, Dr. McClelland says even ifExample 20A worked, it would be very difficult to separate out any of the individual diastereomersas the '206 patent provides no physical data to characterize the individual stereoisomers. Thus, Dr.
McClelland says, the skilled person would have no guidance as to whether the separations wereproducing a specific stereoisomer.
Dr. McClelland observes that it would be especially difficult to separate out ramipril without guidance as to its physical characteristics. He opines that an unimaginative skilled person "wouldcertainly not have been led directly and without difficulty to the separation of ramipril".
(McClelland affidavit, para. 158) With respect to the characterization issue, Dr. McClelland notes that several of the methods suggested by Dr. Pirkle require prior knowledge of the physical data for the compounds in question,which, as noted above, was not available at the relevant time. Dr. McClelland points to the blanksleft in the description of the compounds set out at pages 95 and 96 of the '206 patent, which, it isasserted by Aventis and Schering, are compounds falling within Claim 12 of the '206 patent.
According to Dr. McClelland, if the separation and characterization of the stereoisomers were asroutine as Dr. Pirkle and Dr. Wuest suggest, these compounds would have been separated intosingle stereoisomers, and the absolute configuration at each centre would have been identified.
Instead, Dr. Smith's lab notes disclose that she had not been able to characterize the compoundsobtained as single stereoisomers, nor was she able to identify the stereochemistry of the compoundsin question.
Finally, Dr. McClelland notes that Dr. Smith prepared the two compounds in question (SCH 31924 and SCH 31925) in February of 1981, some nine months prior to the Canadian filing date.
Nevertheless, despite the fact that Schering had nine months in which to separate and characterizethe compounds into individual stereoisomers and to characterize their structures, this was not done,as the same gaps in the characterization of the compounds appear in the '206 patent.
Assuming that the skilled person was able to successfully create the desired product referred to in Example 20A of the '206 patent, the question thus arises as to whether, as of October, 1981,that same skilled person would have been able to prepare or isolate individual stereoisomers fallingwithin Claim 12, including ramipril.
Having carefully considered the evidence of the experts in relation to this point, I am satisfied that the evidence of Dr. McClelland and Dr. Lee-Ruff is to be preferred to that of the experts tendered by Aventis and Schering on this point. Further, I am satisfied that while theseparation and characterization techniques may have been known by October of 1981, withoutsufficient information as to the physical characteristics of the compounds in question, the separationand characterization process could not be successfully carried out.
As a consequence, I find that as of October, 1981, the disclosure of the '206 patent was insufficient, as it fails to teach how to either separate or characterize stereoisomers, including thestereoisomers of ramipril.
In coming to this conclusion, I note that while Drs. Pirkle and Wuest were speaking from a theoretical perspective, it was Dr. Lee-Ruff and his students who actually tried to carry out theseparation and characterization steps, and were unable to do so.
While Dr. Wuest asserted that the number of methods for separating diasteromers is so large that he failed to see how a skilled person would fail to effect some degree of separation ofdiasteromers within Claim 12 through routine experimentation, he was unable to identify specificconditions under which this could be carried out.
Similarly, Dr. Pirkle asserted that he was of the view that "some method" could be found. He was not able, however, to specifically identify what that method would have been.
The weight to be attributed to the theoretical evidence provided by Drs. Pirkle and Wuest also has to be considered in light of Dr. Pirkle's concession that, in dealing with the separation ofunknown compounds, theory does not always translate into practice.
Moreover, Dr. Pirkle acknowledged that he himself had encountered situations where he had been unable to separate enantiomers. Similarly, he acknowledged that he was also aware of caseswhere large pharmaceutical companies had not been able to separate enantiomers.
Finally, Dr. Pirkle conceded that, as of October, 1980 - just a year before the Canadian filing date - the separation of enantiomers was not well understood. There is no indication in the evidencethat there were any significant advances in the state of the public knowledge with respect to theseparation of enantiomers in the months leading up to the Canadian filing in October of 1981.
In these circumstances, I am satisfied that the evidence of the witness who had actually tried to carry out the separation and characterization processes is to be preferred over that of thosespeaking in purely theoretical terms.
Conclusion with Respect to the Third Element of the Wellcome Test While it is undisputed that since October of 1981, ramipril has been both separated and characterized, for the reasons cited, I am satisfied, on a balance of probabilities, that given thelimited state of the knowledge in October of 1981 with respect to the structure of the compounds coming within Claim 12 of the'206 patent, the skilled person would not have been able to isolate orcharacterize individual stereoisomers falling within Claim 12, including ramipril, without usinginventive ingenuity.
As a consequence, Apotex has satisfied me, on a balance of probabilities, that the disclosure of the '206 patent was deficient in this regard.
Conclusion with Respect to Sound Prediction Apotex has persuaded me that Schering had not satisfied any of the three elements of the tripartite Wellcome test for sound prediction in relation to the compounds coming within Claim 12of the '206 patent as of the date on which it filed for patent protection in Canada in October of 1981.
Given that each of the compounds included in Claim 12 is also included in each of Claims 1,

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