Date: 20040121
Docket: T-2282-01
Citation: 2003 FC 1428
OTTAWA, ONTARIO, WEDNESDAY, THIS 21ST DAY OF JANUARY, 2004
PRESENT: THE HONOURABLE MADAM JUSTICE SNIDER
BETWEEN:
PFIZER CANADA INC.
and PFIZER INC.
Applicants
- and -
APOTEX INC. and
THE MINISTER OF HEALTH
Respondents
Restriction on publication:
"These are the public version of sealed reasons, dated December 9, 2003, pursuant to the Protective Order dated June 6, 2002."
REASONS FOR ORDER
SNIDER J.
[1] Pfizer Canada Inc. ("Pfizer") produces Zithromax, an antibiotic that contains crystalline azithromycin dihydrate ("dihydrate"), a form of azithromycin. The dihydrate is specifically claimed in Canadian Letters 1,314,876 (the '876 patent) that is included in the patent register maintained by the Minister of Health (the "Minister") pursuant to section 3(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR93-133 (the "Regulations").
[2] In this application, Pfizer seeks an Order prohibiting the Minister from granting to Apotex Inc. ("Apotex") a Notice of Compliance ("NOC") for tablets of azithromycin until after the expiration of the '876 patent.
[3] This proceeding arises as a result of a submission by Apotex to the Minister for a NOC and for approval to sell tablets of azithromycin isopropanolate monohydrate clathrate ("IPA monohydrate"). In accordance with s. 5(1)(b)(iv) of the Regulations, on November 12, 2001, Apotex sent a Notice of Allegation ("NOA") to Pfizer wherein it alleged that "making, constructing, using or selling by us of tablets containing the medicine azithromycin in strength of 250 mg for oral administration" would not infringe Pfizer's '876 patent. The NOA stated that the Apotex's tablets contain azithromycin but not the dihydrate.
[4] Starting with a letter to Apotex on December 3, 2001, Pfizer has been requesting samples of the bulk and tableted material produced by Apotex in its clinical trials. In response to this first request, Apotex, in a letter dated December 4, 2001, stated that the tablets would contain IPA monohydrate and provided one document taken from its abbreviated new drug submission ("ANDS") made to the Minister. Apotex refused then and has continued to refuse, in spite of repeated requests and an unsuccessful motion before this Court (discussed below at paragraph 25), to provide the requested samples.
[5] In response to the NOA and the subsequent details provided on December 4, 2001, Pfizer commenced this prohibition proceeding, claiming that the NOC is not justified.
ISSUES
[6] The sole issue in this proceeding is whether the allegation of non-infringement contained in the NOA is justified. In examining this overarching issue, the following questions must be addressed:
· Once Pfizer has raised the concern that the requested samples are necessary to its case, does the burden of proof shift to Apotex to show that its product will not infringe the '876 patent?
· Did Apotex's failure to provide the requested samples give rise to a common law presumption that its product would infringe the '876 patent?
· Based on existing jurisprudence, is it necessary for Apotex to produce samples?
· Was the NOA of Apotex deficient or its detailed statement of December 4, 2001 inadequate?
· Does the evidence satisfy this Court that the allegation of non-infringement is justified?
ANALYSIS
Issue #1: Did the burden of proof shift to Apotex?
[7] It is important to remember the purpose of this proceeding. This is not a proceeding where the Court is asked to make a declaration of invalidity or non-infringement. This is a summary application for judicial review. Even if the order of prohibition is denied and the second person obtains a NOC, the first person can still sue for patent infringement if, after the issuance of the NOC and the subsequent marketing of the generic drug in Canada, the first person discovers that the second person has infringed its patent (Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 at 319-20 (F.C.A.), approved of in S.C.C. Eli Lilly and Co. v. Novopharm Ltd. (1998), 80 C.P.R. (3d) 321 at 361-62, 161 D.L.R. (4th) 1)).
[8] There are two burdens of proof in legal proceedings (Eli Lilly and Co. v. Nu-Pharm Inc. (1996), 69 C.P.R. (3d) 1 at 14-15 (F.C.A.):
The first is commonly referred to as the "persuasive burden" or the "legal burden". In a civil case, it is the burden of establishing a case to the civil standard of proof. The other is commonly referred to as the "evidential burden". It is the burden of putting an issue in play and means that a party has the responsibility to ensure that there is sufficient evidence of the existence or non-existence of a fact or an issue on the record to pass the threshold for that particular fact or issue. (See J. Sopinka, S.N. Lederman, A.W. Bryant, The Law of Evidence in Canada (Toronto: Butterworths, 1992) at pages 56-57.)
[9] It is well established that, in a proceeding under subsection 6(2) of the Regulations, the party who has carriage of the litigation, has the burden of proving on a balance of probabilities that a NOA is not justified (Merck Frosst, supra at 319; AB Hassle v. Canada (Minister of National Health and Welfare), [2002] F.C.J. No. 1533 at 35 (C.A.) (QL), 2002 FCA 421; Pfizer Canada Inc. v. Nu-Pharm Inc., supra at 3; Hoffman-La Roche Ltd. v. (Minister of National Health and Welfare) (1996), 70 C.P.R. (3d) 206 (F.C.A.)). Further, the facts contained in the NOA and detailed statement are presumed to be true (Merck Frosst, supra at 319; Eli Lilly and Co., supra at 20).
For these reasons, it is clear that Pfizer bears the legal burden in these proceedings and "cannot expect to be able to make his case out of the mouth of the Respondent" (Merck Frosst, supra at 320 per Hugessen J.). Pfizer, however, argues that it can succeed in these proceedings if it can demonstrate that Apotex's failure to put forward the requested samples is a failure of Apotex to meet its evidential burden.
[10] In Pharmacia Inc. v. Canada (Minister of National Health and Welfare), (1995) 60 C.P.R. (3d) 328 (F.C.T.D.), aff'd 64 C.P.R. (3d) 328 (F.C.A.), Justice Strayer held that the generic Respondent or second person does have an evidential burden in NOC proceedings. Justice Strayer described this burden as follows:
The generic is required, by virtue of s. 5(1), to make an allegation. The allegation made by the generic must be supported by a detailed statement of the legal and factual basis for that allegation. This allows the patentee to determine if an order for prohibition should be sought, either because the facts as set out in the detailed statement are deficient, or because the legal conclusion as to non-infringement is unsupported by the facts. At this stage, since a further and better statement cannot be compelled, concerns with the detailed statement should be highlighted. Moreover, the grounds that the patentee has for challenging the generic's notice of allegation should be advanced in the originating notice of motion filed pursuant to s. 6(1) of the Regulations. This approach flows from the dual requirements of the Federal Court Rules, Part V.1, and the legal burden on the applicants. The patentee should also present evidence to support its grounds whether such grounds are based on fact, law, mixed fact and law or opinion evidence. The generic may then be informed as to what vexes the patentee and why a prohibition order barring entry should be issued. Initially, i.e., before the Minister, the generic has raised the issue of non-infringement. At this stage, before the court, the generic now has the opportunity to file evidence supporting its detailed statement. In essence, this is the evidential burden on a respondent [emphasis added].
It is clear that Apotex has an evidential burden to 'put into play' the issue of non-infringement by issuing a NOA and detailed statement to Pfizer and the Minister. Whether these documents contain a sufficient amount of detail is considered later. What needs to be made clear at this point, however, is that these documents, if determined to be adequate, will satisfy the evidential burden on a Respondent. Apotex has the opportunity, but not the obligation, of filing further evidence in support of its detailed statement. Thus, if it is determined that the NOA and detailed statement are not deficient, it can be said that Apotex has discharged its evidential burden. This is logical, given that a detailed statement by its nature is intended to substantiate the allegations put into play in the NOA. Conversely, if an Applicant fails to provide sufficient information, it does so at its own peril, as the Applicant could discharge its legal burden by proving that the NOA is defective. (Bayer AG v. Canada (Minister of National Health and Welfare) (1995), 60 C.P.R. (3d) 129 at 134; Procter & Gamble Pharmaceuticals Canada, Inc. v. Canada (Minister of Health) (2001), 15 C.P.R. (4th) 496 at 504 (F.C.T.D.), aff'd (2000) 20 C.P.R. (4th) 1 at 10 (F.C.A.)).
[11] Pfizer seems to be arguing that, once it put Apotex on notice that it was vexed by Apotex's failure to disclose actual bulk and tableted samples of its azithromycin, Apotex's evidential burden became weightier, meaning it had to disclose the requested samples or else this burden would not be discharged. I do not agree. I read Justice Strayer's decision to mean that the Notice of Application is intended to inform the Respondent of the issues that the Applicant will raise and the reasons for which it believes that an order of prohibition should issue. I do not read Justice Strayer's comments as permitting an applicant to expand the evidential burden on the Respondent at its whim. Further, it would be nonsensical to allow one party to state what vexes it, thereby putting an issue into play, and then determine that the other party has the burden of providing evidence in support of such vexation. If Pfizer believes that the samples are necessary for it to discharge its legal burden, it must convince this court of this, as it has put this very issue into play.
[12] In conclusion on this point, the legal burden rests with Pfizer as does the evidential burden with respect to the samples requested. I will now consider the necessity of these samples and the common law presumption that Pfizer seeks to rely upon.
Issue #2: Does the common law presumption apply?
Common Law Presumption
[13] Pfizer submits that the common law presumption applies to this case. This presumption provides: "where a party fails to lead evidence of fact that it is in a better position to establish, the Court will infer that the facts are adverse to that party's interest." (Eli Lilly and Co. v. Nu-Pharm Inc. (1996), 69 C.P.R. (3d) 1 at 18 (F.C.A.), citing from 54 C.P.R. (3d) 145 at 152-153 (F.C.T.D.); Pleet v. Canadian Northern Quebec R. Co., [1923] 4 D.L.R. 1112 (S.C.C.), aff'g 64 D.L.R. 316 (Ont. S.C. App. Div.); Hoffmann-La Roche Ltd. v. Apotex Inc. (1984), 1 C.P.R. (3d) 507 (Ont. C.A.), aff'g 71 C.P.R. (2d) 20 (Ont. H.C.J.), leave to appeal to S.C.C. refused 2 C.P.R. (3d) 431. As applied to the facts of this case, Pfizer submits that the failure of Apotex to provide samples should lead me to presume that the samples contain the infringing dihydrate.
[14] The maxim that Pfizer seeks to rely upon was first articulated by Lord Mansfield in Blatch v. Archer (1774), 1, Cowp. 63 at page 65, 98 E.R. 969 at page 970 (K.B.):
"It is certainly a maxim that all evidence is to be weighed according to the proof which it was in the power of one side to have produced, and in the power of the other to have contradicted."
[15] It is true that, if information is "manifestly beyond the power of" a party to "discover and prove in evidence" (Eli Lilly and Co., supra at 19 citing Hoffmann- La Roche Ltd., supra, and it pleads, in its originating notice of motion, the nature of the information which is within the exclusive knowledge of the generic (Eli Lilly and Co., supra at 19 citing Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1995), 60 C.P.R. (3d) 328 (F.C.T.D.)), it may be able to rely on the common law presumption. However, it must additionally demonstrate that the information required is not in its possession and that it is peculiarly within the knowledge of the other party (Eli Lilly and Co., supra at 19). Thus Pfizer must also show that the information was not adduced in evidence by Apotex and that Pfizer had no other means of accessing it (Eli Lilly and Co., supra at 20).
[16] Pfizer alleges that it requires samples of Apotex's bulk material and tablets of azithromycin. While this material is in the possession of Apotex, I question whether the information that Pfizer seeks to obtain by testing these samples is peculiarly within the knowledge of Apotex. By Order of this Court dated May 3, 2002 (see paragraph 25 below) Apotex was compelled by Court order to disclose portions of its ANDS so that Pfizer could follow the procedures therein, obtain the product and test it. For this reason, the information sought by Pfizer - that being whether Apotex's product will contain the dihydrate - was not peculiarly within the knowledge of Apotex.
[17] What Pfizer really seems to be saying is that it requires the samples to prove conclusively whether they contain the dihydrate. This is not the information that is required in this proceeding. The purpose of this proceeding is not to determine conclusively whether Apotex's clinical trial product infringes Pfizer's '876 patent. Rather, the purpose of this proceeding is to determine whether Apotex is justified, on a balance of probabilities, in alleging that its product will not infringe the '876 patent. This is not an infringement action. Because of the purpose of this proceeding and the applicable standard of proof, the samples do not, on the facts of this case, fall within the meaning of "required information". Given the disclosure of the ANDS, it is not manifestly beyond the power of Pfizer to determine on a balance of probabilities whether Apotex's product will contain the dihydrate. For these reasons, the common law presumption is not available to Pfizer.
Issue #3: Is production of the materials necessary?
a) Decision in AB Hassle
[18] Pfizer relies heavily on the decision of Justice Kelen in AB Hassle v. Apotex Inc. (2002), 21 C.P.R. (4th) 173 at 189 (F.C.T.D.). In that case, experts on both sides were left to speculate about whether Apotex's product would infringe AB Hassle's patent. Since the best evidence would have been actual samples of Apotex's product, Justice Kelen concluded that, if Apotex's product was in fact non-infringing, it would have analyzed it and submitted the results instead of forcing the expert witnesses to "shadow-box" with one another. Justice Kelen granted the Application for Prohibition on the basis that Apotex's NOA was deficient and non-compliant with the Regulations.
[19] In this case, Pfizer submits that, as in AB Hassle, supra, there are insufficient facts provided in the Respondent's NOA to justify its allegation of non-infringement of the '876 patent. Part of the information required was samples of Apotex's actual product, which are central to the question of infringement.
[20] I do not agree with Pfizer that this case is analogous to AB Hassle, supra. In AB Hassle, supra, the experts were forced to speculate about whether the subcoating on the tablets of the generic's drug would infringe AB Hassle's patent. None of the experts had produced the tablet and samples of the tablet were not made available by Apotex. For these reasons, the experts were left to speculate as to whether the subcoating would infringe the Applicant's patent.
[21] In these proceedings, however, the experts have not been forced to "shadow-box" with one another. This is because, although Apotex did not provide Pfizer with samples of its azithromycin, it did disclose a significant portion of its ANDS to Pfizer
pursuant to the order of Justice O'Keefe. Both Drs. Stahly and Tam conducted experiments to follow the ANDS procedure to obtain azithromycin. These samples were then tested to determine whether they contain the infringing substance, dihydrate. Nearly 4000 pages of expert evidence are now before this Court as a result of these experiments and tests. This cannot reasonably lead to a situation as was described in AB Hassle, supra. Thus, the case before me can be distinguished from that considered by Justice Kelen.
[22] Since the hearing of this case, the decision of Justice Kelen has been upheld on appeal (AB Hassle v. Apotex Inc., [2003] F.C.J. No. 1604 (QL)). Each of Pfizer and Apotex were invited to make written submissions on the effect of the Federal Court of Appeal decision. I have considered those submissions.
[23] The Court of Appeal decided the appeal on the basis of the patent construction. With respect to the adequacy of the NOA, Justice Rothstein, on behalf of the Court, stated as follows:
[25] In finding the Notice of Allegation inadequate in this case, the motions judge relied on the decision of this Court in Genpharm Inc. v. The Minister of Health and Procter & Gamble Pharmaceuticals (Canada) Inc., supra. In Genpharm, the Notice of Allegation failed to address relevant patent claims. In this case, the Notice of Allegation does address the relevant patent claim.
[26] The point to be made is that the adequacy of the Notice of Allegation must be decided on the facts of each case, and in particular, the wording of the Notice of Allegation. Although I entertain some doubt that the Notice of Allegation in this case was inadequate, it will not be necessary to decide that issue because of my determination with respect to the construction of claim 1 in the 693 Patent.
[24] These comments of Justice Rothstein, while obiter, weaken substantially the arguments of Pfizer on this point.
b) Order of Justice O'Keefe
[25] Before commencing this proceeding, Pfizer sought, by way of an interlocutory motion, production of "samples of bulk azithromycin used in Apotex's azithromycin tablets, together with samples of such tablets". Having heard this motion, by Order dated May 3, 2002, O'Keefe J. ordered Apotex to produce the requested samples only if Apotex provided such samples to the Minister in its NOC submissions. Apotex had not, however, provided the Minister with such samples. Consequently and in compliance with Order, Apotex did not provide samples to Pfizer. In the reasons for his Order, Justice O'Keefe commented as follows:
"Production of requested material is clearly relevant to the issues in this proceeding as it will enable the applicants to examine whether the tablets do include the dihydrate and would infringe the '876 patent. The production of samples is required to enable the applicants to analyse the tablets so that this Court will have access to relevant information in determining whether the NOA is justified . . .
In the exercise of my discretion, on the evidence before me, I am satisfied on the balance of probabilities that the production of the requested information and samples are necessary to provide the evidentiary foundation for this Court to assess the allegations of non-infringement."
[26] Pfizer submits that I should rely on the Order of Justice O'Keefe as support for its position that the Apotex samples are necessary to provide the evidentiary foundation for the Court to determine whether the NOA is justified.
[27] This motion was heard in January 2002, prior to the production of the vast majority of the evidence now before me in this proceeding. In the hearing of the motion, only limited evidence was before the motions judge. For example, at that time, the results of the experiments of Dr. Tam were not before the motions judge. Nor was the motions judge aware that samples from Dr. Tam's experiments were provided to Pfizer. On that basis, I am disinclined to rely on the interlocutory decision of the motions judge or to give weight to his reasons; with different evidence before him, Justice O'Keefe may well have expressed a different view on the relevance of the samples to the allegations of non-infringement. It would be inappropriate for me to be bound by the reasons of his Order or even to give it more than passing reference.
c) Samples as the "Best Evidence"
[28] In any event, the mere fact that the sample materials are relevant is, in my view, insufficient to order their production or to form the basis of a successful application by Pfizer.
[29] Pfizer points out that it was acknowledged by Dr. Threlfall that "the most representative material of the Apotex process would be samples of what Apotex itself had made". In my view, there is no need to deal with whether the samples would be or would not be the "best evidence". Pfizer's positions seems to be that, if the samples are the best evidence, I should conclude that they must be the only evidence possible. On the evidence before me, that is simply not the case. There are other avenues open to the first party (here Pfizer) to assess the NOA in a meaningful way. Neither the Regulations nor the jurisprudence require the production of the materials as a matter of course.
[30] What is necessary is to examine what was provided to Pfizer and to ascertain whether this sophisticated pharmaceutical company was provided with sufficient information to carry out that assessment. The question of the sufficiency of the NOA and the detailed statement is dealt with in the following issue.
Issue #4: Were the NOA and detailed statement adequate?
[31] The NOA and the detailed statement of December 4, 2001 are likely the two most important documents in the NOC process. Generally speaking, the NOA is intended to inform the Minister and the patent holder that the patent will not be infringed if a NOC is issued. The detailed statement is intended to place the patent holder in a position where it is able to decide whether to fight the allegations or stand aside (SmithKline Beecham Inc. v. Apotex Inc. (2001), 10 C.P.R. (4th) 338 at 346 (F.C.A.)). Whether a detailed statement is adequate depends on the facts and law relied upon in the detailed statement itself (SmithKline Beecham Inc., supra at 346). The ultimate adequacy of the allegation and evidence must be adjudicated by the judge hearing the application for prohibition on its merits (Pharmacia Inc. v. Canada (Minister of National Health and Welfare) (1994), 58 C.P.R. (3d) 209 at 218 (F.C.A.)). As well, it must be kept in mind that this proceeding in no way deprives Pfizer of legal recourse in the event that its patent is infringed after a NOC is issued (Merck Frosst, supra).
[32] In assessing the adequacy of the NOA, the following guidance can be taken from a number of decisions of the Federal Court of Appeal, including Bayer AG v. Canada (Minister of National Health and Welfare) (1993), 51 C.P.R. (3d) 329 (F.C.A.); Glaxo Group Ltd. v. Canada (Minister of National Health and Welfare) (2000), 6 C.P.R. (4th) 73 at 81 (F.C.T.D.), aff'd (2001) 11 C.P.R. (4th) 417 (F.C.A.);
· A bald assertion of non-infringement is insufficient.
· It is permissible for the second person to withhold certain information regarding its formulation until subsequent to a confidentiality order being in place.
· The NOA will be adequate if further disclosure elaborates on the basis for which the allegation of non-infringement was made such that there is sufficient evidence upon which to evaluate the allegation.
[33] In this case, we do not have a "bald assertion". The NOA, while brief, is clear that there is no intention to produce dihydrate and, thus, infringe on the '876 patent. It is further expanded on in the letter of December 4, 2001 where the statement is made that the product to be produced is IPA monohydrate. In addition, attached to that letter was an extract from the ANDS which sets out, in summary chart form, the "Specification and Certificate of Analysis - Raw Material". This document named the tests, specifications and results for the "material" that is the subject of the ANDS and of the NOA. As noted above, prior to a confidentiality order, it was not necessary for Apotex to provide all of the information. On June 5, 2002, Justice Layden-Stevenson issued a protective Order, subsequent to which, Apotex disclosed portions of its ANDS that are relevant to these proceedings.
[34] Pfizer relies on the case of & Gamble Pharmaceuticals Canada, Inc. v. Canada (Minister of Health) (2001), 15 C.P.R. (4th) 496 at 504 (F.C.T.D.), aff'd (2000) 20 C.P.R. (4th) 1 at 10 (F.C.A.) as authority for its position that the NOA of Apotex was fatally flawed.
[35] However, & Gamble Pharmaceuticals Canada, Inc., supra, can be distinguished from the present case. In that case, the NOA was held to be fatally flawed because the Respondent failed to allege that its use of the drug would not infringe the first person's use claims in its patent. Thus, the NOA was defective and not in compliance with s. 5(1)(b)(iv) of the Regulations. Here, Apotex clearly stated that "making, constructing, using or selling by us of tablets containing the medicine azithromycin in strengths of 250 mg for oral administration" will not infringe the Applicant's '876 patent.
[36] Aside from its concern that it did not have access to the clinical trial samples, Pfizer's only other assertions of deficiencies in the NOA or the detailed statement were minor or without merit. For example, although the NOA did not state what form of azithromycin would be used, that information is contained in the December 4 letter.
[37] In my view, there was sufficient information contained in the NOA and the detailed statement upon which Pfizer could (and did) evaluate the allegation. Based solely on this information, Pfizer prepared its Notice of Application to commence this proceeding. That Notice contained a detailed listing of concerns and grounds for Pfizer's conclusion that the NOA was not justified.
[38] As discussed above, the Federal Court decision relied on extensively by Pfizer - A.B. Hassle, supra - is readily distinguishable and does not assist Pfizer in this case.
[39] I conclude that the NOA and the detailed statement were not fatally flawed.
Issue #4: Is the NOA justified?
[40] Before considering the issue of infringement, this Court has a duty to construe the patent at issue by identifying the claims that the inventor considered essential (Whirlpool Inc. v. Camco Inc., [2000] 2 S.C.R. 1067 at para. 43). The parties agree that the only claim at issue in this proceeding is claim 1 ofthe '876 patent and that its essential element is "crystalline azithromycin dihydrate". I agree.
[41] Having determined the foregoing issues, the remaining task for me is to examine the claims of each of the parties and to determine, on a balance of probabilities, whether the allegation of non-infringement is justified. Since I have rejected the arguments of Pfizer related to the burden of proof and common law presumption, the experiments of Dr. Stahly and the testimony of Pfizer's experts are of critical importance. If this evidence does not withstand scrutiny, this application should not succeed, as Pfizer has failed to satisfy the burden it carries to show, on a balance of probabilities, that the allegation is unjustified.
[42] Azithromycin is a polymorph. This means that, as a solid, it can exist in different crystal forms. Each crystal form has a unique structure and distinct properties. Pfizer specifically claimed the dihydrate form of azithromycin in its '876 patent. The dihydrate crystal contains two moles of water and is distinct because it is non-hygroscopic, meaning it does not absorb water from the atmosphere. In contrast, crystalline IPA monohydrate, the compound that Apotex intends to market:
· Contains only one mole of water.
· Is a clathrate, meaning small molecules of one compound are trapped in the crystal lattice of another substance.
· Is hygroscopic, meaning it absorbs water from the atmosphere.
Apotex alleges that, it will not produce the dihydrate form when it makes its azithromycin. Pfizer seeks an order of prohibition on the grounds that Apotex will produce the dihydrate either as a byproduct or as its final product and that, even if its final product is free of dihydrate, it will nevertheless convert into the dihydrate upon storage and scaling up of production. Each of these claims will be considered.
a) Manufacturing
I) Dr. Stahly's Experiments
[43] Pfizer enlisted the services of Drs. Stephen Byrn, David Bugay and Patrick Stahly from SSCI Inc., a problem-solving and analytical contract research laboratory in West Lafayette, Indiana. Dr. Byrn founded and consults for SSCI Inc., and is the Charles B. Jordan professor of medicinal chemistry at Purdue University in Indiana. He is an expert in crystal chemistry and pharmaceutical chemistry and processes. Dr. Bugay is Vice-President of Analytical Chemistry at SSCI Inc. and an expert in microscopy, x-ray powder diffraction ("XRPD") and spectroscopy, including Raman spectroscopy. Dr. Stahly is the Chief Operating Officer for SSCI Inc. and has experience in the areas of organic synthesis and the development of crystallization methods.
[44] Dr. Stahly was given relevant portions of Apotex's ANDS, so that he could follow the process contained therein, obtain Apotex's azithromycin and ascertain whether it contains the dihydrate. According to Dr. Stahly, there are four key steps in Apotex's ANDS process where azithromycin is crystallized and, therefore, where the dihydrate can be obtained:
[subject to the protective order dated June 6, 2002]
[1] Samples obtained from all four steps were given to Dr. Bugay. He tested Dr. Stahly's samples using techniques known as XRPD, Raman spectroscopy, and solid-state NMR. He determined that the product obtained following the [subject to the protective order dated June 6, 2002] contained 24% dihydrate. As for the other samples, he could only conclude that they may contain small amounts of dihydrate. Dr. Bugay took the sample containing the dihydrate, and stored it under ambient conditions and at other temperatures. He tested the stored materials after 1, 2, 3 and 4 weeks using the same techniques mentioned earlier and found that in all cases, the amount of dihydrate in them increased.
[2] At his initial cross-examination, Dr. Stahly produced laboratory notebooks, which contained the details of the experiments supervised by Dr. Stahly. Apotex's experts examined these notebooks and rendered a unanimous opinion on Dr. Stahly's experiment. In the words of Dr. McClelland, expert for Apotex, Dr. Stahly's experiments went "horribly wrong". Put simply, according to Apotex's experts, Dr. Stahly took liberties that a person skilled in the art would not have, gravely and without justification deviated from the ANDS process and even added an extra step that is mentioned nowhere in the ANDS. Dr. Stahly's major errors can be summarized as follows:
[subject to the protective order dated June 6, 2002]
· He did not properly dry his final product.
[45] It is worth briefly reviewing what Apotex's experts had to say about Dr. Stahly's experiments upon reviewing the lab's notebooks and Apotex's ANDS process.
[46] Dr. Robert McClelland is a professor of chemistry at the University of Toronto and an international expert on the mechanisms of organic and bio-organic reactions. Dr. McClelland criticized Dr. Stahly's extra step and his failure to filter the hot solution to remove tiny undissolved crystals. Someone skilled in the art would have done this. He further criticized Dr. Stahly for deliberately using dihydrate in his experiment. Both of these liberties taken by Dr. Stahly could have introduced seed crystals in the solution that would promote the formation of dihydrate. Dr. McClelland also stated that Dr. Stahly's drying methods could very well promote conversion to dihydrate. Dr. Stahly deviated from standard practices by leaving his final product on a bench for 9 hours before commencing the drying process and leaving the material to stand mid-drying when it still contained 140.8 grams of water.
[47] Dr. McClelland also criticized Dr. Stahly for not using any of the conventional methods for dissolving azythromycin in acetone-water, such as the Vogel method, described in Vogel's Textbook of Practical Organic Chemistry, 5th edition, B.S. Furniss, A.J. Hannaford, P.W.G. Smith, A.R. Tatchell, Longman Scientific and Technical, 1989. Dr. McClelland stated that an experienced scientist, upon discovering that he did not properly dissolve the azithromycin in [subject to the protective order dated June 6, 2002], would have repeated his experiments and replicated the conditions for his [subject to the protective order dated June 6, 2002], where the azithromycin dissolved and crystallized without dihydrate. Dr. McClelland concluded that Dr. Stahly's experiments deviated so significantly from the ANDS that his samples cannot be trusted.
[48] Dr. James Hendrickson is an internationally recognized expert in chemical synthesis and works at Brandeis University in Massachusetts. He reiterated the importance of ensuring that no seed crystals of dihydrate are present at any stage of the ANDS process and stated that Dr. Stahly skipped crucial purification steps in the ANDS. [subject to the protective order dated June 6, 2002] . This step is critical to get rid of excess water, thereby discouraging the production of dihydrate. As well, Dr. Stahly's failure to filter and purify materials at various steps means that seed crystals of dihydrate would ensure the production of dihydrate. Filtration is a standard procedure widely accepted in the art. Dr. Hendrickson feels that Dr. Stahly's extra crystallization step, which was not mentioned in the ANDS, was an effort to induce some dihydrate to the process.
[49] Dr. Edward Lee-Ruff is a professor of chemistry at York University and an expert in synthetic and mechanistic organic chemistry. Dr. Lee-Ruff stated that, by not performing all of the steps in the ANDS, Dr. Stahly allowed for possible contamination and production of dihydrate. [subject to the protective order dated June 6, 2002] and at no point did the azithromycin completely dissolve. Dr. Stahly extracted the sample from this extra step, scraped off solids remaining in the pot that had been standing for a day, mixed this with the sample and [subject to the protective order dated June 6, 2002]. Dr. Lee-Ruff criticized Dr. Stahly for not filtering the mixtures in either [subject to the protective order dated June 6, 2002], even though there were good reasons to do so, such as the presence of a black speck [subject to the protective order dated June 6, 2002] that was visible to the naked eye. Dr. Lee-Ruff also stated that Dr. Stahly's use of pure dihydrate was not consistent with the ANDS and this would be clear to any person skilled in the art. Finally, Dr. Lee-Ruff disapproved of Dr. Stahly's methods for drying his samples.
[50] Dr. George Olah is a pre-eminent organic chemist, Nobel laureate and a distinguished professor at the University of Southern California. Dr. Olah held the same opinion as Apotex's other experts. He stated that Dr. Stahly did not follow the full procedure set out in the ANDS and, therefore, his purported reproduction of Apotex's process is not accurate, reliable or relevant. He stated that there is no justification for omitting the steps that Dr. Stahly did and, further, such omissions could certainly have affected his results. Dr. Olah drew a useful analogy between the ANDS and a cooking recipe. One cannot deviate from the recipe, obtain a bad dish and then complain that the recipe is wrong or useless. Further, even with the best of efforts, a first attempt to follow a process frequently fails. It is usually necessary to try again. As well, when every detail is not set out, some work is required to define the appropriate conditions for obtaining the desired product. Someone skilled in the art would not have filled in the details of the ANDS as Dr. Stahly had. Dr. Olah stated that Dr. Stahly did not act in good faith and deliberately used conditions favouring the formation of the dihydrate. He stated that it is easy to obtain the dihydrate if one so desires and even if Dr. Stahly did not intend it, he de facto used conditions to do just that.
[51] Dr. Terrence Threlfall is an expert in Raman spectroscopy and XRPD. He is a honorary research fellow at the Department of Chemistry in Southhampton, United Kingdom. Dr. Threlfall criticized Dr. Stahly's experiments for much the same reasons as Apotex's other experts.
[52] Dr. Michael Cima is an expert in crystallography, Raman spectroscopy and XRPD. He is a professor of materials science and engineering at the Massachusetts Institute of Technology. Dr. Cima also criticized Dr. Stahly for not taking sufficient care to control important conditions, such as temperature and water so that he would obtain IPA monohydrate and not the dihydrate. Dr. Cima concluded that Dr. Stahly did not follow Apotex's process as described in the ANDS.
[53] Dr. Peter Griffiths is an expert in spectroscopy and a professor of chemistry at the University of Idaho. He stated that Dr. Stahly skipped important steps when attempting to reproduce the ANDS process without knowledge of the consequences. This, in his view, seriously affected the resulting product.
[54] Dr. Stahly vehemently denied suggestions that he deliberately induced the dihydrate in his experiments. He claimed that he carried out his mandate, which was to follow the ANDS process. The ANDS state in one sentence that the azithromycin must be [subject to the protective order dated June 6, 2002] and Dr. Stahly claimed that he did just that. Since the ANDS were silent on how this was to be done, a person skilled in the art was left to determine the conditions under which this instruction should be carried out.
[55] Dr. Stahly stated that [subject to the protective order dated June 6, 2002], the ANDS should contain details about how these crystallizations should be executed. Since they did not, one is not in a position to criticize Dr. Stahly's methods on the basis that
they deviated from the ANDS. Dr. Stahly stated that Apotex's experts mischaracterized his so-called "extra step". He claimed that he was merely trying to carry out the instruction in the ANDS, [subject to the protective order dated June 6, 2002]. He claimed that the azithromycin did dissolve completely and that it does not matter if this sample was combined with other azithromycin [subject to the protective order dated June 6, 2002]. This is because once the material dissolves [subject to the protective order dated June 6, 2002], all memory of that material is lost, meaning the crystallized product is not influenced in any way by the content of the starting material.
[56] Although I appreciate that the ANDS did not provide Dr. Stahly with details [subject to the protective order dated June 6, 2002], this is an inadequate answer to the charges waged by Apotex's experts about his failure to filter and purify his mixtures throughout his experiments. [subject to the protective order dated June 6, 2002]. In my view, a person skilled in the art would not have carried out the ANDS process under the conditions that Dr. Stahly chose.
[57] I have carefully reviewed the submissions of both parties. Although Dr. Stahly and Dr. Byrn tried to defend SSCI Inc.'s experiments, the fact remains that Dr. Stahly took liberties that someone skilled in the art would not have and deviated significantly from the ANDS process. Dr. Stahly himself admitted on cross-examination, "I did not do [subject to the protective order dated June 6, 2002] and many of the other things as well that were provided in [the ANDS]". Given the sound criticism of Dr. Stahly's experiments by a number of respected experts, I agree with Dr. McClelland's conclusion that Dr. Stahly's experiments went "horribly wrong".
[58] For these reasons, I will give little weight to Dr. Stahly's experiments or the samples obtained therefrom. Further, since Dr. Stahly's samples were used for the conversion studies carried out by SSCI Inc. and Dr. Bugay's tests, they too are tainted by Dr. Stahly's errors and are, therefore, equally unreliable for the purposes of this proceeding.
(b) Dr. Tam's experiments
[59] Given the heavy burden on Pfizer, the concern I have with Dr. Stahly's experiments and the reliant testimony of Drs. Byrn and Bugay is likely sufficient for me to dismiss this application. As noted above in paragraph 10, it is not necessary for Apotex to present any evidence. Nevertheless, Apotex had an employee of one of its affiliates, Dr. Tim Tam, attempt to follow the ANDS process himself and obtain the IPA monohydrate free of dihydrate. As discussed below, these experiments, in my view, provide significant support for Apotex's NOA and are preferable to those of Dr. Stahly.
[60] Dr. Tam conducted a number of experiments and obtained samples from different stages of the process, including the final product. Dr. Srebri Petrov works at the University of Toronto and has thirty years of experience in crystallography. He tested eight samples given to him by Dr. Tam using XRPD. It was Dr. Petrov's conclusion that the four samples that were produced by Dr. Tam were composed of IPA monohydrate and contained no dihydrate. Dr. Cima also examined the XPRD patterns from Dr. Tam's samples and concluded that Dr. Tam produced IPA monohydrate free of dihydrate. Dr. Griffiths reviewed Dr. Cima's report and agreed with his methodology, analysis, interpretations and conclusions. Dr. Threlfall reviewed Dr. Petrov and Dr. Cima's reports and agreed with their findings and methodology.
[61] Dr. Lee-Ruff endorsed Dr. Tam's reproduction experiments as being consistent with the ANDS and stated that the slight changes that Dr. Tam made when carrying out his experiments do not alter the outcome of the process. According to Dr. Lee-Ruff, Dr. Tam has demonstrated that it is possible to follow the ANDS and avoid forming the dihydrate. Dr. Olah also stated that Dr. Tam's experiments substantiate Apotex's claim that, when the ANDS process is followed, the result is IPA monohydrate. Dr. McClelland also endorsed Dr. Tam's experiments. Dr. Hendrickson reviewed in detail all of the quantities used by Dr. Tam in his one-tenth-bench scale reproduction of the ANDS process and found that they were exactly the same as what is prescribed in the ANDS. Although Dr. Tam deviated from the ANDS process, his deviations make no difference according to Dr. Hendrickson, as the nature and quality of the crystals was not affected. In fact, since Dr. Stahly criticized these slight deviations, Dr. Tam repeated his experiments to more closely approximate the ANDS process and still obtained IPA monohydrate free of dihydrate. In sum, four experts confirmed that Dr. Tam followed the ANDS process and another four experts confirmed that he obtained IPA monohydrate and no dihydrate. Finally, it is significant that, after being given Dr. Tam's samples and, therefore, having the opportunity to test them, none of Pfizer's experts disagreed that Dr. Tam did in fact obtain azithromycin free of dihydrate.
[62] Pfizer argues that Dr. Tim Tam's experiments should not be relied upon by this Court because he is an employee of an affiliate of Apotex. This Court has dealt with the independence of experts in other prohibition proceedings. However, all of the cases that Pfizer relies upon are readily distinguishable from the facts before this Court.
[63] In Norvartis AG v. Apotex Inc. (2000), 6 C.P.R. (4th) 129 (F.C.T.D.), the Court assigned little weight to the testimony of two experts. One expert was a long-time employee of the Applicant and actually named as an inventor in the patent at issue. The other expert consulted with the Applicant for many years, was given research money by the Applicant, and was professionally inactive for a number of years. In fact, his affidavit was drafted without him ever having read the relevant patent. Dr. Tam is not similarly situated to either of these experts. He is not a named inventor of IPA monohydrate. Further, no reasons, considered cumulatively, cast doubt on Dr. Tam's independence or abilities. In AB Hassle v. Canada (Minister of National Health and Welfare) (1998), 78 C.P.R. (3d) 489 at 503-504 (F.C.T.D.), an expert's testimony was discredited for not being independent because he was the inventor of the process that was challenged, and, therefore, he was essentially opining about whether he had successfully bypassed the Applicant's patent. In this case, Dr. Tam has repeatedly stated that he was never involved in the manufacturing of Apotex's azithromycin. In SmithKline Beecham Pharma Inc. v. Apotex Inc. (2001), 14 C.P.R. (4th) 76 at 92-93 (F.C.T.D.), the Court followed AB Hassle, supra, because the expert was an employee of the Applicant; he supervised a group that was responsible for trying to solve a problem associated with the invention; a member of the group he supervised was an inventor of the formulation procedure; and finding a solution to the problem was in his self-interest, as this was important to his employer. Here, Dr. Tam neither invented nor assisted in remedying problems associated with Apotex's azithromycin. In Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1998), 84 C.P.R. (3d) 492 at 499 (F.C.T.D.), one of the experts was the Head of Medicinal Chemistry with Apotex and fundamentally involved in developing the process at issue. Again, Dr. Tam does not stand in a position that is analogous to an inventor or any other person that is fundamentally involved in the development of an invention.
[64] Most importantly, unlike in the cases relied upon by Pfizer, I am not being asked to rely upon Dr. Tam's opinions. The samples obtained from Dr. Tam's experiments were tested by Dr. Petrov, who is not an employee of Apotex or its affiliates. Further, Dr. Cima, who is also not employed by Apotex or its affiliates, examined the XRPD patterns from Dr. Tam's samples to identify their content. They, not Dr. Tam, concluded that his experiments yielded the IPA monohydrate free of dihydrate. Further, other Apotex experts reviewed Dr. Tam's laboratory notes and concluded that his experiments adhered to the ANDS process. For these reasons, whether Dr. Tam is independent is not relevant to the issues under consideration by this Court. In any event, even if I had not found Dr. Tam's evidence to be compelling, more important to this analysis is the failure of Pfizer, through the evidence of its experts, to discharge its burden.
[65] In summary on this point, Pfizer has failed to show that, on a balance of probabilities, Apotex would infringe its patent by producing the dihydrate either as a byproduct or final product.
b) Storage and Scaling Up
[66] A major thrust of Pfizer's submission is that, upon storage and scaling up, the conversion of the IPA monohydrate will occur, thus infringing the '876 patent.
[67] Dr. Byrn explained that the laws of thermodynamics dictate that a compound in a less stable form will convert into a more stable form. As well, compounds at a higher energy state tend to convert to a lower energy state. Dr. Byrn explained that the dihydrate form of azithromycin is thermodynamically more stable than the IPA monohydrate and, therefore, the latter will tend to convert into the former under certain conditions. Dr. Byrn believes that, during storage, Apotex's product could convert to the dihydrate.
[68] However, in reaching his conclusions, Dr. Byrn relies upon the conversion studies that were undertaken using Dr. Stahly's samples, which were improperly obtained by the failure to follow the ANDS process. Further, Drs. Olah, Griffiths, McClelland, Cima and Threlfall criticized Dr. Byrn for offering nothing more than unscientific speculations. Significantly, Dr. Byrn admitted upon cross-examination that, if Apotex is exceedingly cautious and properly stores its product, it can ensure that its product will not be exposed to moisture and, therefore, not convert to the dihydrate.
[69] Absent evidence that Apotex intends to use an inferior form of packaging for its product, it cannot be said that Pfizer has proven on a balance of probabilities that conversion will occur upon storage of Apotex's azithromycin. In this regard, I note that Apotex, in its detailed statement of December 4, 2001, stated that its product should be stored in "tight containers". Assertions by Pfizer that storage would be inadequate are not substantiated.
[70] The same conclusion can be reached in respect of Dr. Byrn's claim that Apotex's product could convert to dihydrate once it scales up its production of azithromycin. Upon reviewing Apotex's manufacturing process, Dr. Byrn concluded that it will be much more difficult to control for moisture absorption at a large scale than at a small scale. Dr. Byrn stated that upon tableting azithromycin, Apotex's IPA monohydrate could convert to the dihydrate because of the pressure and humidity involved in this process. Excipients, non-active ingredients, are added to the product at this stage and would, according to Dr. Byrn, accelerate conversion. One such excipient is microcrystalline cellulose, which can have a water content of 7%. The water in this excipient could create sufficient moisture for some conversion. Dr. Byrn conceded that Pfizer could have tableted Dr. Tam's sample in an effort to substantiate its conversion theory. Pfizer, however, claimed that this process was much too difficult and so chose not to tablet Apotex's product.
[71] The submissions of Pfizer in this case are similar to those considered by Justice McGillis in SmithKline Beecham Inc. v. Apotex Inc. (1999), 1 C.P.R. (4th) 99 (F.C.T.D.), where she commented as follows:
[39] Apotex has alleged in its notice of allegation that its tablets will not infringe the '060 patent. That allegation is presumed to be true, "... except to the extent that the contrary has been shown ..." by SmithKline. (See Merck Frosst Canada Inc. v. Canada (Minister of National Health and Welfare) (1994), 55 C.P.R. (3d) 302 (F.C.A.) at 319.) In my opinion, the evidence adduced by SmithKline, including the two experiments, raises no more than a possibility of infringement by Apotex, and does not establish, on a balance of probabilities, that Apotex's allegation of non-infringement is not justified.
[40] I have therefore concluded that Apotex should not be prevented from taking its anhydrate tablets to market on the basis of a potential conversion to hemihydrate at some undisclosed and imprecise time in the future. In the event that Apotex's anhydrate tablets do convert to hemihydrate, in whole or in part, it will face "very grave" consequences at that point in time. (See Hoffmann-La Roche Ltd. v.Canada (Minister of National Health and Welfare) (1996), 70 C.P.R. (3d) 206 (F.C.A.) at 213; Zeneca Pharma Inc. v. Canada (Minister of National Health and Welfare) (1996), 69 C.P.R. (3d) 451 (F.C.A.) at 452). [emphasis added]
[72] I adopt her comments as my own in the case before me.
[73] Again, absent evidence beyond Dr. Byrn's conjectures about what might occur in the future, Pfizer has failed to prove that conversion upon scaling up of production will occur on a balance of probabilities.
CONCLUSION
[74] In summary, the evidence before me fails to establish, on a balance of probabilities, that Apotex's allegation of non-infringement is not justified. The application will be dismissed.
"Judith A. Snider"
____________________________
Judge
FEDERAL COURT
Names of Counsel and Solicitors of Record
DOCKET: T-2282-01
STYLE OF CAUSE: PFIZER CANADA INC. ET AL v. APOTEX INC. ET AL
PLACE OF HEARING: TORONTO, ONTARIO
DATE OF HEARING: OCTOBER 27, 28 AND 30, 2003
REASONS FOR ORDER
AND ORDER: THE HONOURABLE MADAM JUSTICE SNIDER
DATED: WEDNESDAY, JANUARY 21, 2004
APPEARANCES BY:
MR. ANTHONY CREBER FOR APPLICANT
MS. CRISTIN WAGNER
MR. HARRY RADOMSKI FOR RESPONDENT APOTEX
MR. ANDREW BRODKIN
MR. IVOR HUGHES
SOLICITORS OF RECORD:
GOWLING LAFLEUR HENDERSON LLP FOR APPLICANT
OTTAWA, ONTARIO
GOODMANS LLP FOR RESPONDENT APOTEX
TORONTO, ONTARIO
DEPARTMENT OF JUSTICE FOR RESPONDENT MINISTER
CIVIL LITIGATION SECTION
OTTAWA, ONTARIO